Archivio Italiano di Urologia e Andrologia - Vol. 93 - n. 2 - 2021

ISSN 1124-3562

Vol. 93; n. 2, June 2021

ORIGINAL PAPERS 127

Diagnostic efficacy and safety of transperineal prostate targeted and systematic biopsy: The preliminary experience of first 100 cases Shahbaz Mehmood, Khalid Ibraheem Alothman, Abdulaziz Alwuhaibi, Samia Mohamed Alhashim

132

Diagnostic accuracy of the Novel 29 MHz micro-ultrasound “ExactVuTM” for the detection of clinically significant prostate cancer: A prospective single institutional study. A step forward in the diagnosis of prostate cancer Francesco Chessa, Riccardo Schiavina, Ercolino Amelio, Caterina Gaudiano, Davide Giusti, Lorenzo Bianchi, Cristian Pultrone, Emanuela Marcelli, Concetta Distefano, Luca Lodigiani, Eugenio Brunocilla

139

mpMRI PI-RADS score 3 lesions diagnosed by reference vs affiliated radiological centers: Our experience in 950 cases Pietro Pepe, Giuseppe Candiano, Ludovica Pepe, Michele Pennisi, Filippo Fraggetta

143

Endothelin-1 indicates unfavorable prognosis in primary high-grade non-muscle-invasive urothelial bladder cancer Lampros Mitrakas, Stavros Gravas, Foteini Karasavvidou, Ioannis Zachos, Anastasios Karatzas, Athanasios Oeconomou, Georgios Koukoulis, Vasilios Tzortzis, Christos Papandreou

148

Gas6 expression and Tyrosine kinase Axl Sky receptors: Their relation with tumor stage and grade in patients with bladder cancer Murat Akgül, Özgür Baykan, Zeynep C¸ağman, Mustafa Özyürek, İlker Tinay, Cem Akbal, Fikriye Uras, Levent Türkeri

153

Specialist management of testicular cancer: Report of the last 10 years at a Portuguese tertiary referral academic centre André Marques-Pinto, Ana Inês Gomes, Joana Febra, Eugénia Rosendo, Manuel Castanheira de Oliveira, Avelino Fraga, José LaFuente de Carvalho, Nuno Louro

158

Early morning kidney transplantation: Perioperative complications Mário Pereira Lourenço, Miguel Eliseu, Duarte Vieira Brito, João Carvalho, Edgar Tavares-Silva, Lorenzo Marconi, Pedro Moreira, Pedro Nunes, Belmiro Parada, Carlos Bastos, Arnaldo Figueiredo

162

The Matryoshka technique in percutaneous nephrolithotomy Stefano Paolo Zanetti, Matteo Fontana, Elena Lievore, Matteo Turetti, Fabrizio Longo, Elisa De Lorenzis, Giancarlo Albo, Emanuele Montanari

167

Mini percutaneous nephrolithotomy versus retrograde flexible ureterorenoscopy in the treatment of renal calculi in anomalous kidneys Hussein M. Abdeldaeim, Omar El Gebaly, Mostafa Said, Abdel Rahman Zahran, Tamer Abouyoussif

173

Minimal invasive percutaneous nephrolithotomy (Mini-PCNL) in children: Ultrasound versus fluoroscopic guidance Ali Eslahi, Faisal Ahmed, Mohammad Mehdi Hosseini, Mohammed Reza Rezaeimehr, Nazanin Fathi, Hossein-Ali Nikbakht, Mohammad Reza Askarpour, Seyed Hossein Hosseini, Khalil Al-Naggar

178

Time dependant functional and morphological recovery of the kidney after relief of obstruction in patients with impacted ureteral stones Hüseyin Kocatürk, Fevzi Bedir, Ömer Turangezli, Engin Şebin, Mehmet Sefa Altay, Banu Bedir, Kemal Sarica

184

Phyllanthus niruri and Chrysanthellum americanum in association with potassium and magnesium citrates are able to prevent symptomatic episode in patients affected by recurrent urinary stones: A prospective study Tommaso Cai, Daniele Tiscione, Marco Puglisi, Gianni Malossini, Lorenzo Ruggera, Paolo Verze, Davide Arcaniolo, Alessandro Palmieri

189

Obesity rates in renal stone formers from various countries Elenko Popov, Murtadha Almusafer, Arben Belba, Jibril O. Bello, Kamran Hassan Bhatti, Luca Boeri, Kaloyan Davidoff, BM Zeeshan Hameed, Adam Haliński, Ita Pfeferman Heilberg, Hongyi Hui, Kremena Petkova, Bapir Rawa, Fernanda Guedes Rodrigues, Iliya Saltirov, Francisco R. Spivacow, Alberto Trinchieri, Noor Buchholz

195

The new patterns of nephrolithiasis: What has been changing in the last millennium?

Elisa Cicerello, Matteo Ciaccia, Gian D. Cova, Mario S. Mangano continued on page III

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ASSOCIATE EDITORS Emanuele Montanari, Department of Urology, IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Italy – Gianpaolo Perletti, Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy; Department of Human Structure and Repair, Ghent University, Ghent, Belgium - Angelo Porreca, Robotic Urology and Mini Invasive Urologic Surgery Unit, Abano Terme Hospital, Abano Terme, Italy EXECUTIVE EDITORIAL BOARD Alessandro Antonelli, Department of Urology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), Verona, Italy - Antonio Celia, Department of Urology, San Bassiano Hospital, Bassano del Grappa, Italy - Luca Cindolo, Department of Urology, Villa Stuart Hospital, Rome, Italy - Andrea Minervini, Department of Urology, University of Florence, Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy - Bernardo Rocco, Department of Urology, University of Modena and Reggio Emilia, Modena, Italy - Riccardo Schiavina, Department of Urology, University of Bologna, Bologna, Italy ADVISORY EDITORIAL BOARD Pier Francesco Bassi, Urology Unit, A. Gemelli Hospital, Catholic University of Rome, Italy – Francesca Boccafoschi, Health Sciences Department, University of Piemonte Orientale in Novara, Italy – Alberto Bossi, Department of Radiotherapy, Gustave Roussy Institute, Villejuif, France –Tommaso Cai, S. Chiara Hospital, Trento, Italy – Paolo Caione, Department of Nephrology-Urology, Bambino Gesù Pediatric Hospital, Rome, Italy – Luca Carmignani, Urology Unit, San Donato Hospital, Milan, Italy – Liang Cheng, Department of Urology, Indiana University School of Medicine, Indianapolis, IN; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN – Giovanni Colpi, Retired Andrologist, Milan, Italy – Giovanni Corona, Department of Urology, University of Florence, Careggi Hospital, Florence, Italy – Antonella Giannantoni, Department of Surgical and Biomedical Sciences, University of Perugia, Italy – Paolo Gontero, Department of Surgical Sciences, Molinette Hospital, Turin, Italy – Steven Joniau, Organ Systems, Department of Development and Regeneration, KU Leuven, Belgium – Frank Keeley, Bristol Urological Institute, Southmead Hospital, Bristol UK – Laurence Klotz, Division of Urology, Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada – Börje Ljungberg, Urology and Andrology Unit, Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden – Nicola Mondaini, Uro-Andrology Unit, Santa Maria Annunziata Hospital, Florence, Italy – Gordon Muir, Department of Urology, King's College Hospital, London, UK – Giovanni Muto, Urology Unit, Bio-Medical Campus University, Turin, Italy – Anup Patel, Department of Urology, St. Mary's Hospital, Imperial Healthcare NHS Trust, London, UK – Glenn Preminger, Division of Urologic Surgery, Duke University Medical Center, Durham, NC, USA – David Ralph, St. Peter's Andrology Centre and Institute of Urology, London, UK – Allen Rodgers, Department of Chemistry, University of Cape Town, Cape Town, South Africa – Francisco Sampaio, Urogenital Research Unit, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil – Kemal Sarica, Department of Urology, Kafkas University Medical School, Kars, Turkey – Luigi Schips, Department of Urology, San Pio da Pietrelcina Hospital, Vasto, Italy – Hartwig Schwaibold, Bristol Urological Institute, Southmead Hospital, Bristol, UK – Alchiede Simonato, Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy – Carlo Terrone, Department of Urology, IRCCS S. Martino University Hospital, Genova, Italy – Anthony Timoney, Bristol Urological Institute, Southmead Hospital, Bristol, UK – Andrea Tubaro, Urology Unit, Sant’Andrea Hospital, “La Sapienza” University, Rome, Italy – Richard Zigeuner, Department of Urology, Medical University of Graz, Graz, Austria BOARD OF REVIEWERS Maida Bada, Department of Urology, S. Pio da Pietrelcina Hospital, ASL 2 Abruzzo, Vasto, Italy - Lorenzo Bianchi, Department of Urology, University of Bologna, Bologna, Italy - Mariangela Cerruto, Department of Urology, Azienda Ospedaliera Universitaria

Integrata (A.O.U.I.), Verona, Italy - Francesco Chessa, Department of Urology, University of Bologna, Bologna, Italy - Daniele D’Agostino, Robotic Urology and Mini Invasive Urologic Surgery Unit, Abano Terme Hospital, Abano Terme, Italy - Fabrizio Di Maida, Department of Urology, University of Florence, Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy - Antonio Galfano, Urology Unit, Niguarda Hospital, Milan, Italy - Michele Marchioni, Department of Medical, Oral and Biotechnological Sciences, "G. d'Annunzio" University of Chieti, Laboratory of Biostatistics, Chieti, Italy - Andrea Mari, Department of Urology, University of Florence, Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy - Antonio Porcaro, Department of Urology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), Verona, Italy - Stefano Puliatti, Department of Urology, University of Modena and Reggio Emilia, Modena, Italy - Daniele Romagnoli, Robotic Urology and Mini Invasive Urologic Surgery Unit, Abano Terme Hospital, Abano Terme, Italy - Chiara Sighinolfi, Department of Urology, University of Modena and Reggio Emilia, Modena, Italy - Tommaso Silvestri, Urology Clinic, Department of Medical, Surgical and Health Science, University of Trieste, Trieste, Italy - Petros Sountoulides, Aristotle University of Thessaloniki, Department of Urology, Thessaloniki, Greece SIEUN EDITOR Pasquale Martino, Department of Emergency and Organ Transplantation-Urology I, University Aldo Moro, Bari, Italy SIEUN EDITORIAL BOARD Emanuele Belgrano, Department of Urology, Trieste University Hospital, Trieste, Italy Francesco Micali, Department of Urology, Tor Vergata University Hospital, Rome, Italy Massimo Porena, Urology Unit, Perugia Hospital, Perugia, Italy – Francesco Paolo Selvaggi, Department of Urology, University of Bari, Italy – Carlo Trombetta, Urology Clinic, Cattinara Hospital, Trieste, Italy – Giuseppe Vespasiani, Department of Urology, Tor Vergata University Hospital, Rome, Italy – Guido Virgili, Department of Urology, Tor Vergata University Hospital, Rome, Italy UrOP EDITOR Carmelo Boccafoschi, Department of Urology, Città di Alessandria Clinic, Alessandria, Italy UrOP EDITORIAL BOARD Renzo Colombo, Department of Urology, San Raffaele Hospital, Milan, Italy – Roberto Giulianelli, Department of Urology, New Villa Claudia, Rome, Italy – Massimo Lazzeri, Department of Urology, Humanitas Research Hospital, Rozzano (Milano), Italy – Angelo Porreca, Department of Urology, Polyclinic Abano Terme, Abano Terme (Padova), Italy – Marcello Scarcia, Department of Urology, "Francesco Miulli" Regional General Hospital, Acquaviva delle Fonti (Bari), Italy – Nazareno Suardi, Department of Urology, San Raffaele Turro, Milano, Italy.

GUN EDITOR Arrigo Francesco Giuseppe Cicero, Medical and Surgical Sciences Department, Sant’Orsola-Malpighi University Hospital, Bologna, Italy GUN EDITORIAL BOARD Gianmaria Busetto, Department of Urology, Sapienza University of Rome, Italy – Tommaso Cai, Department of Urology, Santa Chiara Regional Hospital, Trento, Italy – Elisabetta Costantini, Andrology and Urogynecological Clinic, Santa Maria Hospital of Terni, University of Perugia, Terni, Italy – Angelo Antonio Izzo, Department of Pharmacy, University of Naples, Italy – Vittorio Magri, ASST Nord Milano, Milano, Italy – Salvatore Micali, Department of Urology, University of Modena and Reggio Emilia, Modena, Italy – Gianni Paulis, Andrology Center, Villa Benedetta Clinic, Rome, Italy – Francesco Saverio Robustelli della Cuna, University of Pavia, Italy – Giorgio Ivan Russo, Urology Department, University of Catania, Italy – Konstantinos Stamatiou, Urology Department, Tzaneio Hospital, Piraeus, Greece – Annabella Vitalone, Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

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ORIGINAL PAPERS 200

Efficacy and safety of intravesical fibrin glue instillation for management of patients with refractory hemorrhagic cystitis: 12-months results. A promising therapy for hemorrhagic cystitis Alessandra Cassani, Michele Marchioni, Francesco Silletta, Carlo D’Orta, Giulia Primiceri, Ambra Rizzoli, Patrizia Di Gregorio, Sandra Verna, Annalisa Natale, Stella Santarone, Francesco Berardinelli, Luigi Schips

206

Prevalence of urinary tract infection in children in the kingdom of Saudi Arabia Mariam Alrasheedy, Hoda Jehad Abousada, Mutaz Mansour Abdulhaq, Raghad Abdulelah Alsayed, Khalid Abdullah Alghamdi, Fayez Dhyefallah Alghamdi, Abdullah Faisal Al Muaibid, Refal Ghassan Ajjaj, Seham Salem Almohammadi, Sarah Salem Almohammadi, Wajd Adnan Alfitni, Abdulrahman Mohamed Homsi, Meqbel Majed Alshelawi, Hassan Ali Alshamrani, Abdulrauf Abdulatif Tashkandi, Sara Mohammed Mannan, Salihah Attiah Alsamiri

211

The role of the multi-disciplinary team and multi-disciplinary therapeutic protocol in the management of the chronic pelvic pain: There is strenght in numbers!

Antonella Centemero, Lorenzo Rigatti, Donatella Giraudo, Guglielmo Mantica, Davide De Marchi, Elisabetta Francesca Chiarulli, Franco Gaboardi

215

Sexual dysfunction in dialytic patients. A prospective cross-sectional observational study in two hemodialysis centers Carlo Pavone, Antonio Simone Di Fede, Piero Mannone, Gabriele Tulone, Arjan Bishqemi, Alberto Abrate, Vincenzo La Milia, Vincenzo Serretta, Alchiede Simonato

221

A new original nutraceutical formulation ameliorates the effect of Tadalafil on clinical score and cGMP accumulation Vincenzo Mirone, Luigi Napolitano, Roberta D’Emmanuele di Villa Bianca, Emma Mitidieri, Raffaella Sorrentino, Arianna Vanelli, Domenico Vanacore, Carlotta Turnaturi, Roberto La Rocca, Giuseppe Celentano, Davide Arcaniolo, Giuseppe Cirino

227

Contribution of pre-varicocelectomy color Doppler ultrasonography finding to surgery and its correlation with semen parameters Caner Ediz, Muhammed Cihan Temel, Suna S¸ahin Ediz, Serkan Akan, Serkan Yenigürbüz, Mehmet Pehlivanoğlu, Ömer Yılmaz

233

Feasibility of local anaesthesia for varicocele correction in one-day-surgery setting. A single center experience Giovannni Saredi, Fabrizio I. Scroppo, Paolo Capogrosso, Giacomo Maria Pirola, Lorenzo Capone, Andrea Pacchetti, Giuseppe Gianesini, Paolo Maggio, Giulio Carcano, Federico Dehò

237

Does two-piece PPI provide improvement in patient-partner quality of life?

Engin Özbay, Remzi Salar, Halil Ferat Öncel

241

Pulsed fluoroscopy in retrograde urethrograms Hazem Elmansy, Waleed Shabana, Radu Rozenberg, Abdulrahman Ahmad, Ahmed Kotb, Amer Al Aref, Walid Shahrour

244

Optimal clamping time in meatotomy procedure for children with meatal stenosis: Experience with 120 cases Mehdi Shirazi, Umayir Chowdhury, Faisal Ahmed, Mohammad-Bagher Rajabalian, Hossein-Ali Nikbakht, Khalil Al-Naggar, Ebrahim Al-Shami

CASE REPORT 248

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GENERAL INFORMATION AIMS AND SCOPE “Archivio Italiano di Urologia e Andrologia” publishes papers dealing with the urological, nephrological and andrological sciences.

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Archivio Italiano di Urologia e Andrologia 2021, 93, 2

III

DOI: 10.4081/aiua.2021.2.127

ORIGINAL PAPER

Diagnostic efficacy and safety of transperineal prostate targeted and systematic biopsy: The preliminary experience of first 100 cases Shahbaz Mehmood, Khalid Ibraheem Alothman, Abdulaziz Alwuhaibi, Samia Mohamed Alhashim King Faisal Specialist Hospital & Research Center, Riyadh, KSA.

Summary

Background: Post-biopsy urosepsis is a major concern for patient morbidity and cost.

Trasperineal biopsy is reported to have less complications and higher detection rate of clinically significant prostate cancer (csPCa).

Objectives: To determine the diagnostic efficacy and safety of transperineal prostate biopsy in patients with elevated prostatic specific antigen (PSA).

Material and methods: A prospective study included men with elevated PSA > 3 ng/ml and previous negative biopsy from January 2018 to April 2019. All patients had multiparametric magnetic resonance imaging (mpMRI) and suspicious lesions reported as Prostate Imaging Reporting and Data System (PIRADS) score version 2. Average twelve systematic and two targeted cores were biopsied under general anaesthesia. Patients received single dose of antibiotic prebiopsy.

Results: 100 Consecutive patients having median age 64.0 years and median PSA of 6.1ng/ml were included for mpMRI-US fusion transperineal biopsies. Cancer detection rate was 45% (targeted 38% and systematic 22%) and csPCa were detected in 75.55% (targeted 86.84% and systematic 59.09%). MRI-US fusion targeted biopsies detected 63.88% csPCa in PIRADS 5, 33.33% in PIRADS 4 and 5.88% in PIRADS 3 lesions. PSA > 10 (p = 0.012), PSA density > 0.15 (p = 0.0002), and PIRADS 5 (0.0001) were significantly associated with PCa. Factors like Age (0.0001), initial PSA (0.022) and PSA density (0.006) were significant on univariate analysis while age (0.0001) was significant on multivariate analysis. There was no case of urinary tract infection.

Conclusions: Transperineal prostate biopsy is safe and effective in diagnosing csPCa. There is no risk of sepsis and major complications.

KEY WORDS: Multiparametric MRI; Transperineal; Urosepsis; Targeted biopsy; Systematic biopsy.

Submitted 19 October 2020; Accepted 28 December 2020

INTRODUCTION

Prostate cancer (PCa) is the most common solid cancer in men and third leading cause of death in developed world (1). Traditionally, PCa is diagnosed with transrectal ultrasound guided biopsy (TRUSBx) in a patient with high Prostatic Specific Antigen (PSA) and or abnormal digital rectal examination. However, most studies (2, 3) and

American Urological Association (AUA) white paper (4) determined that transrectal ultrasound guided biopsy (TRUSBx) is associated with 5 to 7% of risk of infection and 2 to 4% of hospital admission despite giving prophylactic antibiotics.

For the last decade, transperineal TRUS guided prostate biopsy (TTPB) is gaining popularity in the diagnosis of prostate cancer (5). As there is no intrusion of gastrointestinal or urogenital tract, TTPB is relatively considered a clean procedure. There is an ample published evidence that TTPB carried a very low risk of infection and hospital re-admission rate as compared to TRUSBx (6-8). TTPB is mostly performed under general anaesthesia but some centres have even reported under local anaesthesia (9).

Similarly, there is an increasing evidence that multiparametric magnetic resonance imaging (mpMRI) of prostate can helps diagnosing high risk prostate cancer and decreases number of unnecessary biopsies (30). In order to increase cancer detection rate, concept of mpMRI detected suspicious areas were targeted with transrectal ultrasound guidance biopsy (10). Transperineal mpMRIUS fusion biopsy has advantage of detecting more cancers in anterior prostate as compare to transrectal mpMRI-US fusion biopsy (11). As for as targeted or systematic biopsy is concerned, although mpMRI has highest detection rate of clinically significant prostate cancer, combination of targeted and systematic mpMRI-US fusion transperineal biopsy are still required (12, 13).

In spite of highest detection rate, mpMRI may still miss 8-24% of clinically significant prostate cancer (csPCa) if we compare total foci detected on prostatectomy specimen with mpMRI detected lesions (14, 15).

In this prospective study we will report our experience of first hundred patients with mpMRI-US fusion transperineal prostate biopsy under general anaesthesia.

Primary aim of this study is to detect infectious complications and cancer detection rate. The ultimate goal is to reduce infectious complications, increase detection rate of csPCa and reduce unnecessary biopsies.

MATERIALS

AND METHODS

This prospective study was approved by office of research assistant (ORA) an institutional review board of king

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 2

127

S. Mehmood, K. Ibraheem Alothman, A. Alwuhaibi, S. Mohamed Alhashim

Faisal Specialist Hospital & Research Centre Riyadh.

Informed written consent was taken from every patient before MRI-US fusion transperineal biopsy. From January 2018, we converted to transperineal MRI-US fusion prostate biopsy from TRUSBx in all patient with elevated PSA and suspicious mpMRI. Between January 2018 and July 2019, an hundred consecutive patients were recruited prospectively for transperineal prostate biopsy. All patients who had high PSA > 3.0 ng/ml with reference to age and previous negative conventional biopsy were included and subjected to pre biopsy multiparametric MRI (mpMRI) by our dedicated uro-radiologist. Patients in whom MRI was contraindicated or refused by patients either for mpMRI or for transperineal biopsy were excluded from study. Patient in whom normal mpMRI [< Prostate imaging reporting and data system (PIRADS) Score 3] and high PSA were also included for systematic biopsy. mpMRI and biopsy protocol All patients underwent pre biopsy mpMRI of prostate.

MRI images were reviewed by our dedicated Uro-radiologist and reported with PIRADS version 2 (16). These mpMRI images were stored in hospital computer ICIS network and imported for fusion with real-time TRUS via localized network system. MRI/US fusion-guided biopsy was performed with the BioJet fusion system and software (D&K Technologies, Barum, Germany). A minimum of one and preferably 2-4 cores were taken from each target lesion. A systematic 12 core transperineal biopsies were performed in every patient after targeted biopsy.

All patients received only single one-gram Cephazolin intravenously at the time of induction of general anaesthesia and procedure was performed under dorsal lithotomy position. Patients were only given analgesics in the form paracetamol and no oral postbiopsy antibiotics. Biopsies were done by a single urologist who had an experience in transperineal mpMRI-US fusion prostate biopsy.

Outcome We investigated the clinical safety in term of complications like urinary tract infection, sepsis, hospital admission rate, urinary retention, pain and perineal hematoma. Moreover, overall cancer detection and clinically significant prostate cancer detection rate in targeted and systemic biopsies were analysed. A clinically significant prostate cancer was defined as Gleason score of ≥ 7, Gleason score ≥ 2 positive cores, and bilateral cancer on prostate biopsy (17).

Statistical analysis Analysis of patient demographics along with clinical and pathologic variables using descriptive statistics was performed. Fisher’s exact test and chi-square test were used for statistical analysis for categorical variables and student’s t-test for continuous variable and are specified as percentage. Statistical analysis was done using the SAS software package, version 9.4 (Statistical Analysis System, SAS Institute Inc., Cary, NC, USA). Univariate logistic regression analysis was used to determine the association between baseline patient characteristics like age, body mass index (BMI), PSA, PSA density and detection of PCa.

128

Archivio Italiano di Urologia e Andrologia 2021; 93, 2

Multivariable regression analysis was used to investigate the association between PCa detection and variables which were significant in univariate regression model.

A p-value of < 0.05 was considered statistically significant.

RESULTS

Between January 2018 and June 2019, 100 consecutive patients with clinically and biochemically suspected for PCa were recruited for transperineal mpMRI-US fusion prostate biopsy. Median age of patients was 64.0 (60.072.0) and median initial PSA and PSA density were 6.1 (4.8-11.5) ng/ml and 0.12 (0.10-0.27) ng/ml2 respectively. Mean time from mpMRI to transperineal targeted biopsy was 4.1 ± 3.6 months. Average two targeted and 12 systematic biopsies were taken in every patient.

A total of 45 patients (45.0%) were diagnosed as prostate cancer. Among these, 22 patients were diagnosed as cancer on systematic biopsy while 38 patients were found to have cancer on targeted biopsy. Similarly, detection rates of csPCa were 13/22 patients (59.09%) in systematic biopsy while 33/38 patients (86.84%) were in targeted arm and 34/45 patients (75.55%) in combination. Systematic biopsy detected more (10%) insignificant prostate cancer than targeted biopsy (5%). Among 45 patients, 16 patients had a prostate cancer diagnosed on both systematic and targeted biopsy and 3 of them had discordant Gleason score between systematic and targeted biopsies and these patients were upgraded to targeted biopsy cores because of Gleason score. Similarly, 22 (22%) patients were exclusively diagnosed on targeted biopsy while systematic biopsy diagnosed exclusively 7 (7.0%) patients.

Prostate cancer detection and mpMRI PIRADS score Among mpMRI and its reporting on the basis of PIRADS version 2, 20 patients (20.0%) without suspicious lesion on mpMRI (PIRADS < 3) and high PSA, systematic biopsies revealed none of the patient with prostate cancer; 17 (17.0%) patients had PIRADS 3, targeted biopsies detected only 2 patients of whom one cancer of clinically significant and one with insignificant PCa while systematic biopsies confirmed 3 cancer patients, of whom only one patient was having csPCa; 27 patients (27.0%) had PIRADS 4 lesions, targeted biopsies diagnosed 11 cancer patients (40.74%), of whom 3 had GS 6, 6 GS 3+4, and 2 GS 4+3 while systematic biopsies detected 6 patients (18.51%), of whom 4 had GS 6 and 2 GS 3+4; lastly 36 patients (36.0%) were reported as PI-RADS 5, targeted biopsies detected 25 patients (69.44%) cancer, of whom 2 patients had GS 6, 6 GS 3+4, 3 GS 4+3, 3 GS 8, 9 GS 9, and 2 GS 10 while systematic biopsies diagnosed cancer in 14 patients (38.88%), of whom 4 patients had GS 6, 3 GS 3+4, one GS 4+3, 2 GS 8, 2 GS 9, and 2 with GS 10. A total of 8 patients had prior negative prostate biopsy with conventional TRUSBx, three (37.5%) were diagnosed as cancer on transperineal mpMRI-US fusion biopsy. All 3 patients were having csPCa, found in anterior prostate and none had cancer diagnosed on systematic biopsy as shown in Table 1.

We categorised PSA into < 4, 4-10 and > 10 ng/ml and found that higher the PSA, more patients with PCa were diagnosed (p = 0.0127). Similarly, PSA density > 0.15

Transperineal mpMRI-US fusion prostate biopsy

Table 1.

PI-RADS Score and PCa detection rate.

Variables

Total Systematic biopsy Benign cisPCa csPCa PIRADS < 3 20 20 0 0 PIRADS 3 17 14 02 01 PIRADS 4 27 22 03 02 PIRADS 5 36 22 04 10 Prior negative biopsy 08 08 0 0

p-value

Targeted biopsy p-value Benign cisPCa csPCa 20 0 0 0.0214 15 01 01 < 0.0001 16 02 09 11 02 23 05 0 03

prostate. Almost all patient had mild temporary hematuria which settled down in 48-72 hours while complaint of hematospermia remained for 2-3-month post biopsy. Temporary skin bruising was noted in almost all patients. All patients received single intravenous dose of antibiotics at induction of anaesthesia. None of patient received postoperative oral antibiotics. Most importantly, there was not a single case of urosepsis who needed hospital admission.

PI-RADS: Prostate imaging reporting and data system; PCa: Prostate cancer, cisPCa: Clinical insignificant prostate cancer; csPCa: Clinically significant prostate cancery.

DISCUSSION

Table 2.

PSA, PSA density and overall malignancy rate.

Variables PSA <4 4-10 > 10 PSA density <= 0.15 > 0.15

Total

Benign

Malignant

p- value

11 60 29

9 36 10

2 24 19

0.0127

66 34

45 10

21 24

0.0002

PSA: Prostate specific antigen.

Table 3.

Univariate and multivariate analysis of variables for overall detection of prostate cancer.

Variables Age BMI Initial PSA Prostate vol.

PSA density

Univariate analysis OR 95%CI p value 1.181 1.097-1.272 < 0.0001 1.018 0.921-1.124 0.7318 1.071 1.010-1.136 0.0228 0.996 0.979-1.014 0.6934 109.41 3.761->999.99 0.0063

Multivariate analysis OR 95% CI p value 1.193 1.098-1.295 0.0001 0.947

0.868 -1.033 0.5127

500.29 0.695–>999.99 0.0641

PSA: Prostate specific antigen; OD: Odd ratio; BMI: Body mass index; Vol.: Volume; CI: Confidence interval.

was significantly associated with PCa as in Table 2.

In order to identify factors associated with prostate cancer, univariate logistic regression analysis was done.

Factors like age, initial PSA and PSA density were significant associated with prostate cancer. When these significant factors were analysed by multivariate regression analysis, only age was the significant factor for PCa as in Table 3.

Transperineal biopsy and complications In our series of 100 cases of mpMRI-US fusion TPBx, few minor and no major complication was reported following TPBx. Five patients (5.0%) presented with urinary retention in emergency room; 3 of them were already having lower urinary tract symptoms pre biopsy and taking alpha blocker. These patients had significantly greater mean prostatic volume (70.2 cm3) than patient who did not develop (49.8 cm3) (p = 0.024). Similarly, more systematic biopsy cores (15.5) than patients who did not develop retention (12.0) (p = 0.012). Urine cultures were negative in these patients. All had temporary catheterization, of whom 4 had successful trial without catheter and one ended up transurethral resection of

Traditionally, PSA has been used for prostate cancer screening and TRUS guided 10-12 cores systematic biopsy was considered a diagnostic method for prostate cancer for more than two decades. However, this diagnostic method no doubt detects prostate cancer but also detect insignificant prostate cancer which leads to over diagnosis. Therefore, systematic biopsies have low sensitivity and tend to diagnose more insignificant PCa (18).

In order to improve detection of clinically significant PCa and reduce rate of negative biopsies, mpMRI targeted biopsies has been reported a high sensitivity and specificity in many studies (19, 20). PIRADS version 2 categories were assigned prospectively to all lesions in our series. This system was established in 2012 and updated in 2014 as PIRADS version 2. PIRADS v2 dictates that scores 3-5 lesions should be subjected to MRI image guided targeted biopsies and found to have excellent detection rate for PCa and csPCa (21, 22). In our study, we found highest overall PCa (40.74% & 69.44%) and csPCa (33.33% & 63.88%) detection rate for PIRADS 4 & 5 respectively. Twenty patients with PIRADS score < 3 with high PSA > 4 underwent systematic biopsies, all turned out to be negative.

Similarly, in our series with relatively low rate of PCa detection, mpMRI-US fusion biopsies diagnosed cancer in 45.0% of the patients; 75.55% of these cancers were clinically significant, and targeted biopsies alone detected 33/80 (41.25%) of csPCa. Moreover, MRI-US fusion targeted biopsies missed seven cases, including two having csPCa which were diagnosed on systematic biopsies.

This stresses the essentiality of systematic cores during prostate biopsy.

There are inconsistent results in detection rates of targeted and systematic biopsies. One of the prospective study of MRI/US fusion targeted versus concurrent systematic transperinel biopsy showed that detection rate of csPCa was higher in systematic biopsy arm compared to targeted biopsy 57.1% vs 48.0%, p = 0.088 (23).

In contrast Valerio et al. performed a systemic review on 15 studies and found a consistent results that MRI-US fusion targeted biopsies diagnosed more csPCa (median: 33.3% vs 23.6%) compared to conventional random biopsy technique and even MRI-US fusion targeted biopsies detect csPCa (median: 9.1%; range: 5-16.2%) that would have been missed by conventional biopsy (24).

In our series, we had only eight cases with high PSA and prior negative conventional TRUS guided biopsies.

Of whom 3 cases diagnosed with csPCa on MRI-US fusion targeted biopsy and all were anteriorly located suggesting the necessity of MRI-US fusion targeted transperineal Archivio Italiano di Urologia e Andrologia 2021; 93, 2

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approach for prostate biopsy in these anterior located lesions. Similarly, D'Agostino et al. (25) found that MRI-US fusion targeted biopsy is safe and highly accurate for diagnosing csPCa especially in patients with prior negative TRUS guided prostate biopsy in their 155 patients.

The primary objective of this study was to determine diagnostic efficacy and safety of transperineal mpMRI-US fusion prostate biopsy. From safety perspective, we have not found a single case of urosepsis in our series. Five patients developed urinary retention, received temporary catheterization and one of them ended up TURP as he was on alpha blocker and having preoperative lower urinary tract symptoms. Similarly, Vyas et al. (26) found a similar result in relatively large series. There was not a single case of urosepsis and 1.7% of cases developed temporary urinary retention post transperineal biopsies. It is well recognised that infectious complications and after TRUSBx is steadily increasing worldwide. Multidrug resistant organisms are also increasing due to repeated use of antibiotics (27, 28) Lack of infectious complications makes transperineal prostate biopsy alternative to transrectal biopsy.

Transperineal biopsy should be considered a clean procedure as neither gastrointestinal nor urinary tract is traversed. Similarly, Pepe et al. (31) presented the morbidity and clinical complications of transperinal biopsy in 3000 patients and found that complications are directly related with number of biopsy cores taken Our study is strengthened because of its prospective nature, single institution and single surgeon performed the biopsy. There are also limitations of our study.

First, there was no control arm like patients with systematic TRUS guided non fusion biopsies. Although mpMRI reporting were done by our dedicated uro-radiology team but mpMRI reporting and practical use of MRI for prostate biopsies obviously needs a learning curve (29). Moreover, this study is limited due to nonvalidation of biopsy results with histopathological finding of whole gland prostatectomy specimen. Although we have got csPCa and index lesions correspond to targeted biopsy results, it cannot be said with certainty that all csPCa has been detected without histological analysis of whole gland specimens.

Next, the number of patients in our study was relatively low to accurately determine the cancer detection rate. In addition, transperineal prostate biopsy is safer than transrectal biopsy with regards to lower risk of sepsis and hospital re admission. Although some centres have published transperieal biopsy under local anaesthesia successfully but this is a disadvantage in our series by using general anaesthesia.

CONCLUSIONS

Transperineal mpMRI-US fusion prostate biopsy is highly accurate and safe in diagnosing clinically significant prostate cancer. There is no risk sepsis or major complications.

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8. Pepdjonovic L, Tan GH, Huang S, et al. Zero hospital admissions for infection after 577 transperineal prostate biopsies using singledose cephazolin prophylaxis. World J Urol. 2017; 35:1199.

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15. Le JD, Tan N, Shkolyar E, et al. Multifocality and prostate cancer detection by multiparametric magnetic resonance imaging: correlation with whole-mount histopathology. Eur Urol. 2015; 67:56976.

16. Seo JW, Shin SJ, Taik Oh Y, et al. PI-RADS version 2: detection of clinically significant cancer in patients with biopsy gleason score 6 prostate cancer. AJR Am J Roentgenol. 2017; 209:W1-9.

17. Matoso A, Epstein JI. Defining clinically significant prostate cancer on the basis of pathological findings. Histopathology. 2019; 74:135-145.

18. Heidenreich A, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. Eur Urol. 2011; 59:61-71.

19. Thompson JE, Moses D, Shnier R, et al. Multiparametric magnetic resonance imaging guided diagnostic biopsy detects significant prostate cancer and could reduce unnecessary biopsies and over detection: a prospective study. J Urol. 2014; 192:67-74.

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21. Zhao C, Gao G, Fang D, et al. The efficiency of multiparametric magnetic resonance imaging (mpMRI) using PI-RADS version 2 in the diagnosis of clinically significant prostate cancer. Clin Imaging. 2016; 40:885-8.

22. Rosenkrantz AB, Verma S, Choyke P, et al. Prostate magnetic resonance imaging and magnetic resonance imaging targeted biopsy in patients with a prior negative biopsy: a consensus statement by AUA and SAR. J Urol. 2016; 196:1613-8.

23. Hakozaki Y, Matsushima H, Kumagai J, et al. A prospective study of magnetic resonance imaging and ultrasonography (MRI/US) fusion targeted biopsy and concurrent systematic transperineal biopsy with the average of 18-cores to detect clinically significant prostate cancer. BMC Urology. 2017; 17:117.

24. Valerio M, Donaldson I, Emberton M, et al. Detection of clinically significant prostate cancer using magnetic resonance imagingultrasound fusion targeted biopsy: a systematic review. Eur Urol.

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25. D'Agostino D, Mineo Bianchi F, Romagnoli D, et al. MRI/TRUS FUSION guided biopsy as first approach in ambulatory setting:

Feasibility and performance of a new fusion device. Arch Ital Urol Androl. 2020; 91:211-217.

26. Vyas L, Acher P, Kinsella J, et al. Indications, results and safety profile of transperineal sector biopsies (TPSB) of the prostate: a single centre experience of 634 cases. BJU Int. 2014; 114:32-37.

27. Loeb S, van den Heuvel S, Zhu X, et al. Infectious complications and hospital admissions after prostate biopsy in a European randomized trial. Eur Urol. 2012; 61:1110-4.

28. Chang DT, Challacombe B, Lawrentschuk N. Transperineal biopsy of the prostate-is this the future? Nat Rev Urol. 2013; 10:690-702.

29. Gaziev G, Wadhwa K, Barrett T, et al. Defining the learning curve for multiparametric magnetic resonance imaging (MRI) of the prostate using MRI-transrectal ultrasonography (TRUS) fusionguided transperineal prostate biopsies as a validation tool. BJU Int. 2016; 117:80-6.

30. Donato P, Morton A, Yaxley J, et al. Improved detection and reduced biopsies: the effect of a multiparametric magnetic resonance imaging-based triage prostate cancer pathway in a public teaching hospital. World J Urol. 2020; 38:371-379.

31. Pepe P, Aragona F. Morbidity after transperineal prostate biopsy in 3000 patients undergoing 12 vs 18 vs more than 24 needle cores. Urology. 2013; 81:1142-1146.

Correspondence Shahbaz Mehmood, MD Assistant Consultant Urologist shahbazmalik49@gmail.com Khalid Ibraheem Alothman, MD (Corresponding Author) Consultant Urologist kialothman@gmail.com Abdulaziz Alwuhaibi, MD Senior Resident Urology abdulaziz.a.w@hotmail.com Samia Mohamed Alhashim, MD Biostatistician samia@kfshrc.edu.sa King Faisal Specialist Hospital & Research Center Riyadh (KSA)

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DOI: 10.4081/aiua.2021.2.132

ORIGINAL PAPER

Diagnostic accuracy of the Novel 29 MHz micro-ultrasound “ExactVuTM” for the detection of clinically significant prostate cancer: A prospective single institutional study.

A step forward in the diagnosis of prostate cancer Francesco Chessa 1, 2, Riccardo Schiavina 1, 2, Ercolino Amelio 1, Caterina Gaudiano 3, Davide Giusti 3, Lorenzo Bianchi 1, 2, Cristian Pultrone 1, 2, Emanuela Marcelli 4, Concetta Distefano 1, Luca Lodigiani 5, Eugenio Brunocilla 1, 2 1 Division

of Urology, IRCCS Azienda Ospedaliero Universitaria di Bologna; of Urology, University of Bologna, S. Orsola-Malpighi University Hospital, Bologna, Italy; Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Cardio-Nephro-Thoracic Sciences Doctorate, University of Bologna, Bologna, Italy; 3 Division of Radiology, IRCCS Azienda Ospedaliero Universitaria di Bologna; 4 Laboratory of Bioengineering, Department of Experimental Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy; 5 Product Manager AB Medica, Italy.

2 Department

Summary

Introduction and Objective: ExactVuTM is a real-time micro-ultrasound system which provides, according to the Prostate Risk Identification Using MicroUltrasound protocol (PRI-MUS), a 300% higher resolution compared to conventional transrectal ultrasound. To evaluate the performance of ExactVuTM in the detection of Clinically significant Prostate Cancer (CsPCa).

Materials and methods: Patients with Prostate Cancer diagnosed at fusion biopsy were imaged with ExactVuTM. CsPCa was defined as any Gleason Score ≥ 3+4. ExactVuTM examination was considered as positive when PRI-MUS score was ≥ 3.

PRI-MUS scoring system was considered as correct when the fusion biopsy was positive for CsPCa. A transrectal fusion biopsy-proven CsPCa was considered as a gold standard. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under the receiver operator characteristic (ROC) curve (AUC) were calculated.

Results: 57 patients out of 68 (84%) had a csPCa. PRI-MUS score was correctly assessed in 68% of cases. Regarding the detection of CsPCa, ExactVuTM ’s sensitivity, specificity, PPV, and NPV was 68%, 73%, 93%, and 31%, respectively and the AUC was 0.7 (95% CI 0.5-0-8). For detecting CsPCa in the transition/anterior zone the sensitivity, specificity, PPV, and NPV was 45%, 66%, 83% and 25% respectively ant the AUC was 0.5 (95% CI 0.2-0.9). Accounting only the CsPCa located in the peripheral zone, sensitivity, specificity, PPV, and NPV raised up to 74%, 75%, 94%, 33%, respectively with AUC 0.75 (95% CI 0.5-0-9).

Conclusions: ExactVuTM provides high resolution of the prostatic peripheral zone and could represent a step forward in the detection of CsPCa as a triage tool. Further studies are needed to confirm these promising results.

KEY WORDS: Prostate Cancer; Imaging; Detection rate; Microultrasound; PRI-MUS score.

Submitted 7 February 2020; Accepted 8 February 2021

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INTRODUCTION

Prostate cancer (PCa) is the second most common cancer among men and represents the fifth cause of cancer death worldwide (1). The diagnosis of PCa represents a challenge for urologist as too many indolent tumors are still diagnosed after random or systematic prostate biopsy (2, 3). Thus, in the era of active survelliance, it is crucial to identify patients with clinically significant PCa (CsPCa) (4). Historically, standard ultrasound (US) has been utilized for the diagnosis of PCa with very low accuracy (5, 6). Advances in multiparametric Magnetic Resonance Imaging (mpMRI) techniques have improved the diagnostic accuracy of PCa and nowadays mpMRI represents the mainstay of PCa diagnosis (7). Recently, PRECISION study demonstrated that mpMRI-targeted biopsies increased diagnostic yield compared with systematic biopsies, particularly for CsPCa, and reduces overdetection of clinically insignificant PCa (8).

However, to date, high quality prostate MRI is not always available in all the centers and mpMRI still remain an expensive and time-consuming test: therefore, we are far to consider it as a triage test in the detection of CsPCa (9).

Over time, several enhanced ultrasound techniques such as the colour/power Doppler, and contrast-enhanced transrectal ultrasound (TRUS) have been used in an attempt to improve the accuracy of ultrasonography.

However, these techniques have showed modest improvements over conventional TRUS, and their clinical use is limited (10, 11).

Recently, a novel US technology based on 29 MHz, ExactVuTM micro-ultrasound devices, has been proposed for the evaluation of prostatic gland for the diagnosis and staging of PCa and for the execution of fusion biopsy (12).

ExactVuTM is a new imaging modality that operates at high frequency (29 MHz). Throughout the Prostate Risk No conflict of interest declared.

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Diagnostic accuracy of the Novel 29 MHz micro-ultrasound “ExactVuTM” for the detection of clinically significant prostate cancer

Identification Using Micro-Ultrasound (PRI-MUS) protocol, suspicious regions can be characterized, stratified, and targeted, similar to the Prostate Imaging-Reporting and Data System (PI-RADS) protocol for mpMRI (12, 13).

The aim of our study was to evaluate the diagnostic accuracy of ExactVuTM ultrasound in the detection of CsPCa in a cohort of patients with PCa previously diagnosed with targeted mpMRI/Toshiba Aplio 500TM fusion biopsy.

MATERIALS

AND METHODS

Study population After internal review board approval, between June 2018 and September 2018, 83 consecutive patients with biopsy proven PCa made by targeted mpMRI/TRUS fusion biopsy were registered into a prospective database and evaluated with ExactVuTM ultrasound. In the absence of a validated learning curve, the first fifteen patients were excluded in order to reduce operator bias. Fusion biopsy was performed by one experienced urologist using the Toshiba Aplio 500TM system. Inclusion criteria were: 1) presence of one single index lesion on mpMRI according to the Prostate Imaging Reporting and Data system version 2 (PIRADS-v2) (14), 2) mpMRI/ultrasound fusion biopsy performed at our Department 3) diagnosis of PCa. Each patient included had complete demographic, clinical and pathologic parameters.

Study design This prospectively recorded study included male patients referred to our tertiary center with diagnosis of PCa. First, patients underwent mpMRI which led to the identification of an index lesion defined as PIRADS-v2 score ≥ 3. Thereafter a fusion biopsy was carried out.

All patients with biopsy proven PCa at the level of the Index lesion were imaged with 29MHz ExactVuTM transrectal micro-ultrasound.

Imaging All the mpMRI examinations were performed before the biopsy, with a 1.5-T whole body scanner (Signa HDxt; GE Healthcare, Milwaukee, WI, USA) and a standard 8channel pelvic phased-array surface coil combined with a disposable endorectal coil (MedRad, Indianola, PA).

Parameters of mpMRI sequences and study acquisition were performed as previously reported in detail (15).

All MRI images were analysed by one expert uroradiologist, according to the 2012 European Society of Urogenital Radiology guidelines (16). The presence of PCa on mpMRI was defined as equivocal, likely or highly likely according to the PIRADS-v2 score.

mitter adjacent to the patient, as well as an electromagnetic sensors attached to the US transducer. After local anaesthesia with 10 mL of Lidocaine, a side by side images of US and MRI was obtained. Once that the index lesion was identified and marked, 3-5 cores were taken according to the size of the index lesion. Further random biopsy was taken in biopsy-naïve patients.

Histopathologic analysis Histopathologic biopsy analysis was performed by a single experienced uro-pathologist according to International Society of Urological Pathology standards (17, 18).

Clinically significant prostate cancer was defined as any Gleason score ≥ 7.

ExactVuTM micro-ultrasound Imaging All patients underwent 29MHz ExactVuTM transrectal micro-ultrasound at least 3 weeks after the fusion biopsy.

One uro-radiologist and one urologist with extensive expertise in prostate imaging but naïve to micro-ultrasound, were trained by an experienced mentor to use the ExactVuTM probes. Investigators and mentor were blinded to the mpMRI and to the pathologic report. Prostate risk identification using micro-ultrasound (PRIMUS) is an evidence-based scale for ExactVuTM, developed to characterize tissue and stratify suspicious regions, as with PI-RADS for mpMRI (12). As previously described by Ghai, the echoic characteristics of the prostate gland were analysed and dichotomized in a 5 point-risk scale (Table 1) (12).

Table 1.

Echoic findings and corresponding PRIMUS risk assessment.

PRIMUS risk score ExactVu microultrasound findings PRIMUS 1 Small regular ducts, “Swiss cheese” with nother heterogeneity or bright echoes PRIMUS 2 Some hyperechoic with or without ductal patches (possible ectatic glands or cysts) PRIMUS 3 Mild heterogeneity or bright echoes in hyperechoic tissue PRIMUS 4 Hetereogeneous cauliflower/smudgy/mottled appearance or bright echoes (possible comedonecrosis) PRIMUS 5 Irregular shadowing (originating in prostate, not prostate border) or mixed echo lesions, or irregular prostate and/or peripheral zone border

Figure 1.

Parasagittal micro-ultrasound of the right lateral edge of the prostate. The ExactVuTM shows mottled tissue consistent with PRI-MUS grade 4 on the base of the prostate (red line underlines the lesion).

Biopsy protocol All men underwent transrectal fusion biopsy with the Toshiba AplioTM 500 scanner (Canon Medical Systems Corporation) equipped with an end-fire 8-5.5 MHz transducer. After uploading the MRI images into the archive of the ultrasound machine (US), the registration between MRI and US images was done in the axial plane.

The fusion technique used an electromagnetic field tracking system, composed of an electromagnetic transArchivio Italiano di Urologia e Andrologia 2021; 93, 2

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According to PRI-MUS protocol, ExactVuTM imaging consisted of a five steps procedure: 1) identifying the prostate border; 2) identifying the peripheral zone; 3) identifying the transition/anterior zone; 4) identifying any suspicious features in the peripheral (Figure 1), transition (Figure 2) Figure 2.

The ExactVuTM shows bright Echoes and “Cauliflower” area (arrow) consistent with PRI-MUS grade 4 on the transition zone of the prostate.

Figure 3.

“Smudgy/Mottled” tissue consistent with PRI-MUS 4 in the anterior part of the prostate (red line underlines the lesion).

and anterior zone (Figure 3) and their nearness to the prostatic capsule (Figure 4); 5) assign a PRI-MUS risk score based on previously reported features 12. ExactVuTM imaging was considered positive when the PRI-MUS score was ≥ 3.

Statistical analysis Patient’s demographic and detection performance of ExactVuTM were analysed descriptively. For generating metrics of accuracy, the risk strata from the biopsy report was dichotomized to a non-clinically significant PCa and a Clinically Significant PCa. The presence of a “fusion biopsy proven CsPCa” was set as the gold standard and then the ExactVuTM detection rate was evaluated. PRIMUS scoring system was considered as correct when the ExacVu findings matched with the location of the CsPCa at fusion biopsy. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under the receiver operator characteristic curve (AUC) were calculated. Chi square test was used to evaluate the correlation between PRI-MUS score and CsPCa. Statistical analysis were performed using SPSS Statistics 20 (IBM Corp, Armonk, NY, USA).

RESULTS

The demographic and clinical characteristics of the 68 patients available for the final analysis are shown in Table 2. Mean age at diagnosis was 63 years (± 8.6) and mean PSA value was 9.6 ng/mL (± 2.8). Digital-rectal examination was suspicious for PCa in 17 men (25%).

Table 2.

Clinical characteristics of 68 patients in the study group.

Figure 4.

Lateral micro-ultrasound of the left lobe of the prostate.

The ExactVuTM shows mottled tissue consistent with PRI-MUS grade 4 causing irregular prostate border (arrow).

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Parameters Age Mean ± SD Median (IQR) PSA ng/mL Mean ± SD Median (IQR) DRE, n (%) Positive Prostate volume, mL Mean ± SD Median (IQR) Prior negative biopsy, n (%) MpMRI score, n (%) PI-RADS 3 PI-RADS 4 PI-RADS 5 Transition/Anterior Lesions, n (%) Targeted mpMRI/ultrasound fusion biopsy cores per patient Mean ± SD Median (IQR) Total positive cores Mean ± SD Median (IQR) PRI-MUS score, n (%) PRI-MUS 1 PRI-MUS 2 PRI-MUS 3 PRI-MUS 4 PRI-MUS 5

Value 63.4 ± 8.6 67.5 (56-71) 9.6 ± 2.8 9.0 (7-12) 17 (25) 42 ± 16.4 37 (31-52) 23 (34) 28 (41.2) 36 (52.9) 4 (5.9) 14 (20.6) 4 ± 0.6 4 (4-4) 3 ± 1.1 3 (2-4) 10 (14.7) 16 (23.5) 18 (26.5) 17 (25.0) 7 (10.3)

Diagnostic accuracy of the Novel 29 MHz micro-ultrasound “ExactVuTM” for the detection of clinically significant prostate cancer

Table 3.

Pathological characteristics of 68 patients in the study group.

Parameters Biopsy Gleason score, n (%) 6 7 (3+4) 7 (4+3) 8 or Greater

Value

Figure 6.

Receiver operating characteristic curve of ExactVuTM in the detection of clinically significant prostate cancer located in the peripheral zone.

11 (16.2) 44 (64.7) 6 (8.8) 7 (10.3)

Table 4.

Performance characteristic of ExactVuTM ultrasound in the detection of prostate cancer in the overall population.

Detection rate Positive predictive value

72% 94%

Twenty-three patients (34%) had a previous negative random biopsy. Mean prostate volume was 42 mL (± 16.4).

Mean number of cores taken in the index lesion were 4 (± 0.6), mean number of positive cores was 3 (± 1.1), 20% of the index lesions were in the transition/anterior zone and PRI-MUS score ≥ 3 was found in 42 (62%) patients.

Table 3 depicts in detail the pathological features of the targeted mpMRI/ultrasound fusion biopsy: 57 patients out of 68 (84%) had a csPCa. Gleason score 3+3 was found in 11 patients (16.2%), Gleason score 3+4 was found in 44 patients (64.7%), Gleason score 4+3 was found in 6 patients (8.8%) and Gleason score ≥ 8 was found in 7 patients (10.3%).

Figure 5.

Receiver operating characteristic curve of ExactVuTM in the detection of clinically significant prostate cancer.

Figure 7.

Receiver operating characteristic curve of ExactVuTM in the detection of clinically significant prostate cancer located in the anterior/transition zone.

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Figure 8.

Detailed report of the PRI-MUS score assignment in a cohort of 68 patients.

Diagnostic accuracy of the ExactVuTM e micro-ultrasound Table 4 shows the pooled detection rate (DR) and PPV of ExactVuTM e imaging for the diagnosis of PCa. Overall, ExactVuTM micro ultrasound had DR and PPV of 72% and 94%, respectively. Considering exclusively the CsPCa (Figure 5), sensitivity, specificity, PPV, and NPV in the detection of CsPCa was 68%, 73%, 93%, and 31%, respectively and the AUC was 0.706 (95% CI 0.5-0-8). Accounting the anatomic distribution of the index lesions using the PIRADs-v2 scheme, the sensitivity, specificity, PPV, and NPV were 45%, 66%, 83%, 25% with AUC 0.540 (95% CI 0.2-09) for the detection of CsPCa in the transition/anterior zone, while for the CsPCa located in the peripheral zone the sensitivity, specificity, PPV, and NPV raised up to 74%, 75%, 94%, 33%, with AUC 0.754 (95% CI 0.5-0-9) (Figures 6, 7). Figure 8 shows the correlation between PRI-MUS score and presence of PCa: there were no cases of PRI-MUS 1-2 in Gs 3+3 PCa. In Gleason score 3+4 PCa patients, PRIMUS was false negative in 18 (40%; p = 0.05) cases (PRI-MUS grade 1-2).

However, for Gleason score 4+3 or higher, ExactVuTM was always (100%; p = 0.05) reported as positive (PRIMUS ≥ 3). Figure 9 depicts graphically the correlations between PRI-MUS score and presence of CsPCa: among the 57 CsPCa, in 39 (68%) cases ExactVuTM was considered as positive (PRIMUS ≥ 3; p = 0.01).

DISCUSSION

The biggest issue linked to PCa workup is represented by the need to avoid overdiagnosis of low-grade tumours and the prominence of csPCa detection. Trans-rectal ultrasound (TRUS) has been widely used for the diagnosis and staging of PCa, showing poor sensitivity in identifying neoplastic lesion, often indistinguishable from normal tissue. Traditionally, men with a clinical suspicion of PCa underwent a random transrectal ultrasonography-guided biopsy, which has a rough overall detecFigure 9.

Correlation between PRI-MUS score and clinically significant Prostate cancer in 68 patients. Table shows the chi square analysis.

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Diagnostic accuracy of the Novel 29 MHz micro-ultrasound “ExactVuTM” for the detection of clinically significant prostate cancer

tion rate of 30-50% (19-21). Nowadays, mpMRI seems to be the best imaging technique for the prostate, with a negative predictive value of 90% and an accuracy of 98% in diagnosing significant cancers (22, 23). Indeed mpMRI is increasingly performed before prostate biopsy, leading to fewer men who underwent biopsy, higher detection rate of csPCa and reducing the overdetection of clinically insignificant cancer (8). However, to date, mpMRI is burdened by some contraindications such as claustrophobia and pacemakers ant its widespread diffusion is limited by high costs, steep learning curve reporting the MRI findings and it is also a time consuming test.

Since conventional TRUS have shown an overall detection rate of 30-50%, in the last two decades, a multitude of enhanced ultrasound devices have been proposed with the aim to improve the accuracy of ultrasonography (19-21). Contrast-enhanced TRUS (CE-TRUS) was first described in 1968, it’s based on air bubbles that remains inside the blood vessels showing the increased tumour vascularity (23). CE-TRUS have shown a detection rate of 30-60% and nowadays is mainly used in other medical specialities such as detection of liver malignancies (24). Colour Doppler is another tool that have been proposed to improve the ultrasound performance, showing an overall detection rate of 20% (25).

Recently, the ExactVuTM system has been introduced in the market as a real-time micro-ultrasound system capable of providing 300% higher resolution (down to 70 μm) compared to conventional TRUS (26). Ghai et al., in a recent publication, developed the PRI-MUS protocol, based on the ExactVuTM findings, demonstrating promising levels of accuracy for the detection of CsPCa (12).

Some results of our study are noteworthy: first, to our knowledge this represents one of the few prospective series of patients investigating the accuracy of ExactVuTM imaging in the detection of CsPCa. Second, our study demonstrated that the improved visualization of prostatic parenchyma lead to an improved detection of CsPCa. ExactVuTM ultrasound shows an overall sensitivity and specificity of 68% and 73%, respectively with an AUC of 0.7. These results are consistent with those previously described by Ghai et al. who have showed an AUC of 74% for csPCa. Similarly, Pavolvich et al. using a different high frequency probe (21MHz) found improved accuracy in the detection of high grade PCa compared to conventional TRUS (84% vs 60%) (10). Third, since PRIMUS protocol was developed for peripheral zone lesions, we found differences in the ExactVuTM ’s accuracy basing on their location. Indeed, as expected, we found some false-negative and false-positive results, particularly when the index lesions were in the transition/anterior zone. It is well known that TRUS has lower detection rate for the anterior zone, and TRUSguided biopsy miss the 80% of anterior PCa (27). In our series, the sensitivity for transition/anterior lesions was 45%, but it raises up to 74% for the peripheral lesions.

Similarly, to PIRADS score, PRI-MUS score has been developed to ease the characterization of prostatic lesions, to standardize the imaging methodology and to provide a scoring system to differentiate the risk of carcinoma in each zone of the prostate. As PIRADS, PRIMUS score evaluation requires experience and can be

burdened by interobserver discrepancy. In our series, PRI-MUS was correctly assessed in 68% of cases.

As expected, the widest rates of misinterpretations were for low-intermediate (PCa Gleason Score ≤ 3+4), in higher Gleason Score no misinterpretations were observed.

Despite our limited experience, we gained surprisingly high sensitivity and specificity. These promising results, suggests a potential use of ExactVuTM both as a triage tool, discerning the best patients candidates to underwent mpMRI and as well as an alternative to mpMRI in centers where this technology is not yet available. The low value of NPV can be explained by our limited practice with this new technology and by the small sample size.

Further studies with larger cohorts are needed to clarify the true potential of micro-ultrasound devices.

Unfortunately, the lack of similar studies using ExactVuTM probe, made comparison more challenging.

Our study has some limitations: first all the investigators were naïve to micro-ultrasound devices and to PRI-MUS protocol. Second, even though investigators were blinded to the previous clinicopathological findings, all patients underwent a previous fusion biopsy, which scars can be detected by ExactVuTM ultrasound, affecting the index lesion detection rate. Third, the number of the patient’s cohort is quite limited, but it inevitably depends on the novelty of this diagnostic tool and the prospective design of the study. Fourth, we used the mpMRI-targeted fusion biopsy as a reference standard, even if the ideal gold standard for assessing the true diagnostic performance of an imaging tool actually remains the final pathology in radical prostatectomy specimens. Moreover, our study shows the accuracy of ExactVu in the detection of CsPCa, since all patients included in analysis already had a previous diagnosis of PCa. In Conclusion, ExactVuTM showed a promising and quite high accuracy in the detection of CsPCa as assessed by targeted mpMRI/fusion biopsy. ExactVuTM provides high resolution of the prostatic peripheral zone and represents a step forward in the detection of CsPCa. These results encourage the use of ExactVuTM as a triage test and can help clinicians in the selection of borderline patients candidate to mpMRI. Further studies with larger cohort taking in account as reference the pathologic specimen of radical prostatectomy are needed to confirm these promising results.

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2. Ahmed HU, El-Shater Bosaily A, Brown LC, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet.

2017; 389:815-822.

3. D'Agostino D, Mineo Bianchi F, Romagnoli D, et al. MRI/TRUS FUSION guided biopsy as first approach in ambulatory setting: Feasibility and performance of a new fusion device. Arch Ital Urol Androl. 2020; 91:211-217.

4. Schiavina R, Borghesi M, Brunocilla E, et al. The biopsy Gleason score 3+4 in a single core does not necessarily reflect an Archivio Italiano di Urologia e Andrologia 2021; 93, 2

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5. D'Agostino D, Mineo Bianchi F, Romagnoli D, et al. Comparison between "In-bore" MRI guided prostate biopsy and standard ultrasound guided biopsy in the patient with suspicious prostate cancer: Preliminary results. Arch Ital Urol Androl. 2019; 91:87-92.

6. Schiavina R, Vagnoni V, D'Agostino D, et al. "In-bore" MRI-guided prostate biopsy using an endorectal nonmagnetic device: a prospective study of 70 consecutive patients. Clin Genitourin Cancer. 2017; 15:417-427.

7. Hamoen EHJ, de Rooij M, Witjes JA, et al. Use of the Prostate Imaging Reporting and Data System (PI-RADS) for prostate cancer detection with multiparametric Magnetic Resonance Imaging: a diagnostic meta-analysis. Eur Urol. 2015; 67:1112-1121.

8. Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-targeted or standard biopsy for prostate-cancer diagnosis. N Engl J Med. 2018; 378:1767-77.

9. Schiavina R, Chessa F, Borghesi M, et al. State-of-the-art imaging techniques in the management of preoperative staging and restaging of prostate cancer. Int J Urol. 2019; 26:18-30.

10. Pavlovich CP, Cornish TC; Mullins JK, et al. High-resolution transrectal ultrasound: pilot study of a novel technique for imaging clinically localized prostate cancer Urol Oncol. 2014; 32:34.e27-32.

11. Halpern EJ, Frauscher F, Strup SE, et al. Prostate: high-frequency Doppler US imaging for cancer detection Radiology. 2002; 225:71-77.

12. Ghai S, Eure G, Fradet V. Assessing cancer risk on novel 29 MHz micro-ultrasound images of the prostate: creation of the Micro-Ultrasound Protocol for Prostate Risk Identification. J Urol.

2016; 196:562-9.

13. Lughezzani G, Saita A, Lazzeri M, et al. Comparison of the diagnostic accuracy of micro-ultrasound and magnetic resonance imaging/ultrasound fusion targeted biopsies for the diagnosis of clinically significant prostate cancer. Eur Urol Oncol. 2019; 2:329-332.

14. Weinreb JC, Barentsz JO, Choyke PL, et al. PI-RADS prostate imaging—reporting and data system: 2015, version 2. Eur Urol.

2016; 69:16-40.

15. Schiavina R, Bianchi L, Borghesi M, et al. MRI displays the prostatic cancer anatomy and improves the bundles management before robot-assisted radical prostatectomy. J Endourol. 2018; 32:315-321.

16. Antunes HP, Parada B, Carvalho J, et al. Prognostic value of subclassification (pT2 stage) of pathologically organ-confined prostate cancer: Confirmation of the changes introduced in the 8th edition of the American Joint Committee on Cancer (AJCC) staging system. Arch Ital Urol Androl. 2018; 90:191-194.

17. Barentsz JC, Richenberg J, Clements R, et al. ESUR prostate MR guidelines 2012 Eur Radiol. 2012; 22:746-757.

18. Epstein JI, Egevad L, Amin MB, et al. The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol.

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19. Durkan GC, Sheikh N, Johnson P, et al. Improving prostate cancer detection with an extended-core transrectal ultrasonographyguided prostate biopsy protocol. BJU International. 2002; 89:33-39.

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24. Kuru TH, Fütterer JJ, Schiffmann J, et al. Transrectal ultrasound (US), contrast-enhanced US, real-time elastography, histoscanning, magnetic resonance imaging (MRI), and MRI-US fusion biopsy in the diagnosis of prostate cancer. Eur Urol Focus. 2015; 1:117-126.

25. Taverna G, Morandi G, Seveso M, et al. Colour Doppler and microbubble contrast agent ultrasonography do not improve cancer detection rate in transrectal systematic prostate biopsy sampling.

BJU Int. 2011; 108:1723-7 26. Ghai S, Van der Kwast T. Suspicious findings on micro-ultrasound imaging and early detection of prostate cancer. Urol Case Rep. 2017; 16:98-100.

27. Schouten MG, van der Leest M, Pokorny M. Why and where do we miss significant prostate cancer with multi-parametric magnetic resonance imaging followed by magnetic resonance-guided and transrectal ultrasound-guided biopsy in biopsy-naïve men? Eur Urol. 2017; 71:896-903.

Correspondence Francesco Chessa, MD (Corresponding Author) francesco.chessa@live.it francesco.chessa3@unibo.it Riccardo Schiavina, MD rschiavina@yahoo.it Ercolino Amelio, MD amelio.ercolino@studio.unibo.it Lorenzo Bianchi, MD lorenzo.bianchi13@unibo.it Cristian Vincenzo Pultrone, MD cristian.pultrone@gmail.com Concetta Distefano, MD concetta.distefano@aosp.bo.it Eugenio Brunocilla, MD eugenio.brunocilla@unibo.it Department of Urology, University of Bologna, S. Orsola-Malpighi University Hospital, via Pelagio Palagi 9 40130, Bologna (Italy) Caterina Gaudiano, MD caterina.gaudiano@aosp.bo.it Davide Giusti, MD davide.giusti@studio.unibo.it Division of Radiology, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna (Italy) Emanuela Marcelli, MD emanuela.marcelli@unibo.it Laboratory of Bioengineering, Department of Experimental Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna (Italy) Luca Lodigiani, MD lodigiani.luca@abmedica.it Product Manager AB Medica (Italy)

DOI: 10.4081/aiua.2021.2.139

ORIGINAL PAPER

mpMRI PI-RADS score 3 lesions diagnosed by reference vs affiliated radiological centers: Our experience in 950 cases Pietro Pepe 1, Giuseppe Candiano 1, Ludovica Pepe 1, Michele Pennisi 1, Filippo Fraggetta 2 1 Urology

Unit, Cannizzaro Hospital, Catania, Italy; Unit, Cannizzaro Hospital, Catania, Italy.

2 Pathology

Summary

Introduction: The detection rate for clinically significant prostate cancer (csPCa) in men with mpMRI PI-RADS score 3 diagnosed by affiliated radiology centers vs radiological reference center was evaluated.

Materials and methods: From January 2017 to December 2020, 950 men (median age 64 years) underwent mpMRI for abnormal PSA values (median 6.3 ng/ml). Among the 950 patients who underwent mpMRI 500 were evaluated by a reference center and 450 by outpatient radiological affiliated centers. All the mpMRI index lesions characterized by a PI-RADS 3 underwent targeted cores combined with extended prostate biopsy. Two radiologists of the radiological reference center revised all the mpMRI lesions 3.

Results: Overall, 361/950 (38%) patients had a mpMRI lesion PI-RADS score 3: 120/500 cases (24%) vs 241/450 cases (53.5%) were diagnosed by reference vs affiliated radiological centers. The detection rate for cT1c csPCa was equal to 26.7% (35/120 cases) vs 16.6% (40/241 cases) in men with PI-RADS 3 lesions diagnosed in the reference vs the affiliated radiological centers (p < 0.05). Among the 241 PI-RADS score 3 lesions diagnosed by affiliated radiological centers 86/241 (35.7%) and 36/241 (15%) were downgraded (PI-RADS scores < 3) and upgraded (PI-RADS score 4) by the dedicated radiologists of the reference center.

Conclusions: In our series, about 35% and 15% of PI-RADS score 3 lesions diagnosed by affiliated radiological centers were downgraded and upgraded when revised by experencied radiologists, therefore a second opinion is mandatory especially in men enrolled in active surveillance protocols in whom mpMRI is recommended to reduce the number of scheduled repeated prostate biopsies.

KEY WORDS: Prostate cancer; MRI and prostate cancer; PI-RADS score 3; Transperineal targeted biopsy.

Submitted 21 February 2021; Accepted 14 March 2021

INTRODUCTION

Multiparametric magnetic resonance imaging (mpMRI) is strongly recommended before biopsy for the diagnosis of clinically significant prostate cancer (csPCa) (1) in order to reduce the risk of overdiagnosis and to improve the costeffectiveness of prostate biopsy (2). Recently, the European Association of Urology guidelines (3) suggested

the evalution of mpMRI combined with clinical parameters (i.e., PSA density, digital rectal examination) instead scheduled prostate biopsies in the reevaluation of men enrolled in Active Surveillance protocols (4-7); therefore, mpMRI quality and radiologist expertice represent a central topic in the decision making for prostate biopsy. The detection rate of csPCa is directly related with the PI-RADS score (8, 9) and the results depend on clinical parameters, the number of previous negative biopsies and the quality of targeted mpMRI/TRUS fusion biopsy procedures; the gray zone of mpMRI evaluation is still today represented by the diagnosis of a PI-RADS 3 lesion that could harbour the presence of a clinically significant prostate cancer (csPCa) in about 20-25% of the cases (1012). At the same time, the number of PI-RADS score 3 diagnosed by radiologists should be limited to a low percentage among all the mpMRI procedures similarly as reported by pathologists for the diagnosis of Atypical Small Cell Acinar Proliferation.

In this study, we report the detection rate for csPCa in men with PIRADS score 3 diagnosed by reference vs affiliated radiological centers.

PATIENTS

AND METHODS

From January 2017 to December 2020, 950 men (median age 64 years; range: 47-75 years) with negative digital rectal examination underwent mpMRI for abnormal PSA values (median 6.3 ng/ml; range 2.9-102 ng/ml); 680 and 270 underwent initial and repeated prostate biopsy. In 500 men mpMRI was performed at our Hospistal Imaging Department considered aa a reference center; on the contrary, 450 patients were submitted to mpMRI by outpatient radiological affiliated centers.

All mpMRI examinations were previously performed using a 1.5 Tesla scanner equipped with surface 16 channels phased-array coil placed around the pelvic area with the patient in the supine position; multi-planar turbo spin-echo T2-weighted, and axial diffusion weighted imaging, and axial dynamic contrast (ADC) enhanced MRI were performed for each patient (4).

All the mpMRI index lesions characterized by a PI-RADS (version 2) > 3 underwent targeted cores (TPBx: four cores) combined with extended systematic prostate

No conflict of interest declared.

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biopsy (at least 12 cores); the procedure was performed transperineally using a tru-cut 18 gauge needle (Bard; Covington, GA, USA) under sedation and antibiotic prophylaxis (5). The TPBx was done using an Hitachi 70 Arietta ecograph, Chiba, Japan) supplied by a bi-planar trans-rectal probe (13). The data have been collected following the START criteria (14).

Two radiologists of the radiological reference center with 11 years of experience blinded to pre-imaging clinical parameters evaluated the mpMRI data separately and independently. The detection rate for csPCa in men with PIRADS score 3 diagnosed by affiliated vs radiological reference center was evaluated; in addition, all PI-RADS 3 lesions diagnosed in the affiliated radiological centers were revised by the dedicated radiologists and compared with biopsy histology results. For statistical analysis a p value < 0.05 was considered statistically significant.

RESULTS

Overall, 361/950 (38%) patients had a mpMRI lesion PIRADS score 3: 120/500 cases (24%) vs 241/450 cases (53.5%) were diagnosed by reference vs affiliated radiology centers, respectively.

The PI-RADS 3 lesions were located in the peripheric and anterior zone of the gland in 190 and 171 cases; moreover, 151 (41.8%) vs 210 (58.2%) men underwent cognitive vs fusion targeted biopsy procedure, respectively. The detection rate for T1c csPCa was equal to 26.7% (35/120 cases) vs 16.6% (40/241 cases) in men with PI-RADS 3 lesions diagnosed in the reference vs the affiliated radiological centers (p < 0.05) (Table 1): in detail, 24 and 11 vs 25 and 15 of the csPCa were located in the peripheric and anterior zone of the prostate, respectively. None had significant complications (Clavien-Dindo grade I) (15) from prostate biopsy that needed hospital admission.

Table 1.

Quantitative biopsy histology, clinical parameters and ADC values in men with PI-RADS (prostate imaging-reporting and data system) score 3 lesions and clinically significant prostate cancer (csPCa).

Radiological Radiological P value reference center affiliated centers Overall number of patients with csPCa: 75/361 35/120 40/241 < 0.05 (26.7%) (16.6%) csPCa csPCa Median PSA values (ng/ml) 8.7 9.1 > 0.05 Grade group (ADC value) 35 pts 40 pts 1 (0.750 ± 0.162) 2 < 0.05 2 (0.635 ± 0.117) 28 19 < 0.05 3 (0.489 ± 0.093) 17 19 > 0.05 Median number of positive TPBx cores 1.5 1.0 > 0.05 Median number of systematic positive cores 4 (1-9) 5 (1-12) > 0.05 Median GPC (range) 50% 50% > 0.05 Median prostate weight (grams) 50 46 > 0.05 Median mpMRI lesion index diameter (mm) 10 9 > 0.05 PSA: Prostate specific antigen; TPBx: Targeted transperineal fusion biopsy; GPC: Greatest percentage of cancer for single core; ADC: Apparent diffusion coefficient; mpMRI: Multiparametric magnetic resonance imaging; pts: Patients.

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The clinical parameters (i.e., PSA, weight, PSA density) and the biopsy quantitative histology (i.e., number of positive cores, greatest percentage of cancer and Grade Group) is reported in Table 1; a normal parenchyma was diagnosed in the remaining 286/361 (79.2%) men.

The median diameter of PI-RADS 3 index lesions was 10 mm. vs 9 mm. in men with csPCa vs normal parenchyma, respectively. Among the 241 PI-RADS score 3 lesions diagnosed by affiliated radiological centers 86/241 (35.7%) and 36/241 (15%) were respectively downgraded (PI-RADS scores < 3) and upgraded (PI-RADS score 4) by dedicated radiologist of the reference center. The presence of csPCa was significantly correlated with the ADC value (Table 1).

DISCUSSION

The improvement of diagnostic imaging by mpMRI has allowed targeted biopsies of the suspicious area, increasing the diagnosis of csPCa and reducing the number of unnecessary systematic biopsy.

Although mpMRI is strongly recommended in men candidate for prostate biopsy (3) or in men enrolled in active surveillance protocols (7), still today, systematic biopsy should be always combined with mpMRI/TRUS fusion biopsy because the increased false negative rate (5, 14) of mpMRI (about 20% of the cases) (6) and the variable diagnostic accuracy of the different mpMRI/TRUS fusion biopsy platforms (17). While the risk of clinically significant in case of PIRADS 4-5 is well established, PIRADS 3 lesions are presented as equivocal and at low risk of aggressive disease with the identification of csPCa is not neglegible (6, 8-11-12).

The PI-RADS 3 lesions identified on mpMRI are considered to be “a gray area” in the diagnosis protocol of PCa (18, 19). The main objectives regarding PIRADS 3 score are to accurately diagnose csPCa and avoiding unnecessary biopsies that could have undesirable side effects on patients and thus, avoiding overdiagnosis and overtreatment.

In a recent review, Maggi et al. (20) demonstrated the superiority of combined target and systematic biopsy in detecting csPCa in patients with PIRADS 3 lesions; moreover, they also found that combining PIRADS 3 score with a PSAD > 0.15 ng/ml/ml could improve the detection rate of csPCa on prostate biopsy (21).

In addition, to identify the PI-RADS score at high risk for csPCa irrespective of clinical findings many parameters have been reported: index lesion diameter, shape and location of the lesion and the ADC values (6, 9, 11). Wu et al. (22) showed that higher ADC values (0.830×10-3 mm2/sec) were significantly associated with low-risk prostate cancer; on the contrary, Kim et al. (23) reported a mean ADC value for csPCa equal to (0.741 ± 0.164) ×10-3 mm2/sec.

In our series, the detection rate for T1c csPCa was equal to 26.7% (35/120 cases) vs 16.6% (40/241 cases) in men with PI-RADS 3 lesions diagnosed in the reference vs the affiliated radiological centers; in detail, among the 241 PI-RADS score 3 lesions diagnosed by affiliated radiological centers 35.7% (86/241) and 15% (36/241) were downgraded (PI-RADS scores < 3) and upgraded (PI-

mpMRI PI-RADS score 3 lesions diagnosed by reference vs affiliated radiological centers:

RADS score 4) by dedicated radiologist of the reference center. In addition, PSA density and ADC value of 0.747×10-3 mm2/sec, threshold obtained from ROC curve analysis improved the diagnosis for csPCa in the presence of PI-RADS 3 lesions.

Regarding our results some considerations should be made. Firstly, the results were evaluated on biopsy specimens and not on the entire prostate gland or by performing a template mapping biopsy; secondly, although our study represent the real life clinical practice a quality control of the affiliated radiological centers was unknown.

Finally, a greater number of patients and a centralized evaluation of mpMRI results should be performed; moreover, among the 361 men with PI-RADS score 3 only 210 (58.2%) underwent fusion targeted prostate biopsy.

In conclusion, PI-RADS 3 lesions exhibited aggressive features in a not negligible proportion of cases but a quality control of mpMRI by experienced radiologists improve the accuracy of the procedure; a second opinion is mandatory especially in men enrolled in AS protocols in whom clinical parameters (5, 24, 25) and mpMRI (2628) are recommended to reduce the number of scheduled repeated prostate biopsies.

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Correspondence Pietro Pepe, MD (Corresponding Author) piepepe@hotmail.com Urology Unit, Cannizzaro Hospital, Via Messina 829, Catania (Italy) Giuseppe Candiano, MD urocandia@gmail.com Ludovica Pepe, MD ludopepe97@gmail.com Michele Pennisi, MD michepennisi2@virgilio.it Filippo Fraggetta, MD filippofra@hotmail.com Pathology Unit, Cannizzaro Hospital, Via Messina 829, Catania (Italy)

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27. Lourenço M, Pissarra P, Vieira D, et al. Lesion location agreement between prostatic multiparametric magnetic resonance, cognitive fusion biopsy and radical prostatectomy piece. Arch Ital Urol Androl. 2020; 91:218-223.

28. Stanzione A, Creta M, Imbriaco M, et al. Attitudes and perceptions towards multiparametric magnetic resonance imaging of the prostate: A national survey among Italian urologists. Arch Ital Urol Androl. 2020; 92:291-296.

DOI: 10.4081/aiua.2021.2.143

ORIGINAL PAPER

Endothelin-1 indicates unfavorable prognosis in primary high-grade non-muscle-invasive urothelial bladder cancer Lampros Mitrakas 1, Stavros Gravas 1, Foteini Karasavvidou 2, Ioannis Zachos 1, Anastasios Karatzas 1, Athanasios Oeconomou 1, Georgios Koukoulis 2, Vasilios Tzortzis 1, Christos Papandreou 3 1 Department

of Urology, Faculty of Medicine-School of Health Sciences-University of Thessaly, University Hospital of Larissa, Greece; 2 Department of Pathology and Cytology, Faculty of Medicine-School of Health Sciences-University of Thessaly, University Hospital of Larissa, Greece; 3 Department of Oncology, School of Medicine, Aristotle University of Thessaloniki, “N.Papageorgiou” Hospital of Thessaloniki, Ring Road of Thessaloniki, Greece.

Objective: To conduct a prospective study of the potential prognostic role of endothelin-1 (ET-1) in a cohort of primary high-grade non-muscle-invasive urothelial bladder cancer patients, who were treated with adjuvant intravesical Bacillus Calmette-Guérin (BCG).

Material and methods: Patients with primary high-grade nonmuscle-invasive urothelial bladder cancer, who received postoperatively induction and maintenance BCG therapy, were prospectively included. Recurrence and progression were histologically proven. Immunohistochemical staining for ET-1 was assessed. Epidemiological, pathological and clinical parameters as well as the expression of ET-1 in tumor specimens were statistically analyzed for recurrence, progression, recurrence-free survival (RFS) and progression-free survival (PFS).

Results: ET-1 associates significantly with recurrence (p = 0.000), progression (p = 0.000), RFS (p = 0.000) and PFS (p = 0.000).

The patient’s age is also significant for recurrence (p = 0.003, OR = 1.273 95% CI: 1.086-1.492) and RFS (p = 0.013).

Conclusions: ET-1 seems to deteriorate prognosis in patients suffering from primary high-grade non-muscle-invasive urothelial bladder cancer, who are treated with adjuvant BCG instillations.

Furthermore, the patient’s age associates with an increased likelihood for recurrence.

tification of the patients who will not respond to BCG, in order to implement an aggressive therapy, aiming to maximize the clinical benefit, is clinically important (4).

Endothelin-1 (ET-1) is a multifunctional peptide. ET-1 and its receptors A/ETAR and B/ETBR consist the endothelin-axis (ET axis), which plays a role in cancer biology. ET-1 stimulates tumor cell proliferation, facilitates tumor invasion and metastasis and has antiapoptotic and neoangiogenic effects (5). ETAR associates with tumor-cell proliferation and tumor progression, inhibition of apoptosis, effects on bone matrix, production of vascular endothelial growth factor (VEGF) leading to endothelial cell proliferation and vascular permeability, by increasing the levels of hypoxia-inducible factor1a/HIF-1a (5). ETBR inducts proliferation of endothelial cells and migration (5).

Our purpose is to conduct a prospective study of the potential prognostic significance of ET-1 in a cohort of primary HGNMIUBC patients who were treated postoperatively with BCG (induction as well as maintenance).

KEY WORDS: ET-1; High-grade; Non-muscle-invasive bladder cancer; Prognosis.

We prospectively included patients with transurethrally (TUR) resected, primary (single or multiple), non-muscle-invasive, high-grade, urothelial carcinoma of the urinary bladder. The follow-up period started on the day of the first postoperative follow-up cystoscopy (at 3 months after the original endoscopic surgery). Exclusion criteria were: present or previous upper urinary tract carcinoma and muscle-invasive disease.

The patients received a single immediate postoperative intravesical instillation of chemotherapy (Epirubicin 50 mg), if there was no contraindication. Random biopsies of the bladder were performed, if there was a suspicion of carcinoma in situ (Tis). Whenever necessary (cases of incomplete resection or biopsy material without muscle fibers), a TUR was repeated within 6 weeks. All patients received an induction (6 weekly intravesical BCG instillations) as well as a 3-year maintenance BCG therapy (6). The follow-up was based on the Guidelines for “Non-muscle-invasive bladder cancer” by the European

Summary

Submitted 17 November 2020; Accepted 25 January 2021

INTRODUCTION

In urothelial bladder cancer about 75% of new patients are diagnosed with a non-muscle-invasive tumor.

The most effective adjuvant treatment for high-grade nonmuscle-invasive urothelial bladder cancer (HGNMIUBC) is the use of intravesical instillations of Bacillus CalmetteGuérin (BCG) (1). Unfortunately, recurrence and progression are documented in about 30% and 12% (0-35%) of these patients (2). Furthermore, pT1G3 patients have a 5-year disease progression rate of 19.8% and a 5-year disease-specific death rate of 11.3%, which proves a poor prognosis (3). Radical cystectomy is the chosen treatment in cases of failure of BCG therapy. Therefore, the early iden-

MATERIAL

AND METHODS

No conflict of interest declared.

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L. Mitrakas, S. Gravas, F. Karasavvidou, I. Zachos, A. Karatzas, A. Oeconomou, G. Koukoulis, V. Tzortzis, C. Papandreou

Figure 1.

High-grade nonmuscle invasive urothelial carcinoma, stage pT1. Strong cytoplasmic immunostaining for ET-1 (x400). Positive marker the vascular endothelium (arrows).

Association of Urology/EAU (GEAU) (7). Histologically proven urothelial carcinoma after transurethral resection of any cystoscopic lesion found during the follow-up period was set as “disease recurrence”. Any change from pTa to at least pT1 and from pT1 to at least pT2 stage was set as “disease progression”. Our further treatment decisions concerning recurrence and progression were based on the recommendations made by the GEAU (7).

Group A consists of 40 consecutive patients with disease recurrence ± progression. A patient was allocated in Group A as soon as recurrence was initially documented in the follow-up period. Apparently, there can be no progression without the event of recurrence, but it is not for sure that every patient with recurrence will end up in having progression. Group B includes 20 consecutive patients who had neither recurrence nor progression.

Taking into account the predefined size of Group A, this size of Group B is the minimum numerical value allowing a reliable statistical analysis within a prospective framework. All included patients provided their consent.

The pathology staging was done according to the 2009 TNM classification approved by the Union International Contre le Cancer (UICC) which was updated in 2017 (8th Edition) and grading was estimated according to the 2004 WHO grading system. A central pathology review was applied for the grading of the immunohistochemical

= 2, strong = 3) in a manner consistent with previous investigations (5).

Epidemiological (age, gender, smoking), pathological (stage T, concomitant carcinoma in situ/Tis) and clinical parameters (number of tumors, tumor size, patient group), and ET-1 expression were statistically analyzed.

Univariate analysis for recurrence (REC) and progression (PR) was performed using Chi-Square or Fisher’s Exact test and multivariate analysis using multiple logistic regression. Univariate analysis for recurrence-free survival (RFS) and progression-free survival (PFS) was performed using Log-rank test for categorical variables and Cox regression for scale variables. Multivariate analysis for RFS and PFS was assessed using Cox regression analysis after checking the proportional hazards assumption.

The level of statistical significance was set as p ≤ 0.05.

All analyses were performed with the use of IBM SPSS Statistics version 21 software.

The study was approved by the Ethics CommitteeScientific Board of the University Hospital of Larissa and it conforms to the provisions of the Declaration of Helsinki (as revised in Tokyo 2008).

RESULTS

We totally included 60 patients, 40 patients in Group A and 20 patients in Group B. Median follow-up was 63.2 months for Group A (n = 40) and 87.8 months for Group B (n = 20). Baseline characteristics for the total number of patients as well as for the patients of Groups A and B are shown in Table 1. The results of the IHC for both Groups are summarized in Table 2 and the detailed results of the IHC regarding REC and PR for Group A are presented in Table 3.

In Group A, 27 patients had recurrence (27/40, 67.5%) and the median RFS was 11.3 months. Moreover, 13 patients had recurrence and progression (13/40, 32.5%) and the median PFS was 38.9 months. The patients of

Table 1.

Baseline characteristics of patients in Group A and B. Patients’ baseline characteristics Median age (years) Gender (♂/♀) Smoker (Yes/No/Ex) Number of tumors (Single/Multiple) Tumor size (> 3 cm/< 3 cm) Concomitant carcinoma in situ (Yes/No) Tumor stage T (Ta/T1)

TOTAL (n = 60) 67.3 ± 8.4 (38-87) 50/10 (83.3%/16.7%) 30/9/21 (50%/15%/35%) 31/29 (51.7%/48.3%) 30/30 (50%/50%) 12/48 (20%/80%) 15/45 (25%/75%)

GROUP A (n = 40) 68.7 ± 7.4 (58-87) 34/6 (85%/15%) 20/5/15 (50%/12.5%/37.5%) 20/20 (50%/50%) 21/19 (52.5%/47.5%) 8/32 (20%/80%) 11/29 (27.5%/72.5%)

GROUP B (n = 20) 64.3 ± 9.1 (38-77) 16/4 (80%/20%) 10/4/6 (50%/20%/30%) 11/9 (55%/45%) 9/11 (45%/55%) 4/16 (20%/80%) 4/16 (20%/80%)

p value 0.749 (*) 0.356 (^) 0.112 (^) 0.471 (^) 0.355 (^) 0.642 (^) 0.490 (^)

(^): Pearson Chi-Square test; (*) : T-test, statistical significance was set as p ≤ 0.05.

staining (IHC). Representative samples of good morphology and antigenicity of the primary tumors were obtained for staining. Staining was performed in a single run and by applying mouse monoclonal antibody for ET-1 (clone TR.ET.48.5, dilution 1:250, NOVUS Biologicals, Littleton, Colorado, USA). Staining intensity (SI) of ET-1 on a highpower field (Figure 1) was classified according to an arbitrary four-tiered scale (no staining = 0, mild = 1, moderate

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Table 2.

Summarized results of the immunohistochemical staining (IHCS) for Groups A and B. IHCS ET-1

0 1 (2.5%)

Grading of IHCS 1 (mild) 2 (moderate) 3 (strong) 18 (45%) 15 (37.5%) 6 (15%)

ET-1

5 (25%)

12 (60%)

2 (10%)

1 (5%)

Patients’ group A (n = 40) B (n = 20)

ET-1 worsens prognosis in bladder cancer

Table 3.

Detailed results of the immunohistochemical (IHC) staining for Group A regarding recurrence and progression.

IHC ET-1 ET-1

0 1/1 (100%) 0/1 (0%)

Grading of IHC 1 (mild) 2 (moderate) 6/18 (33.3%) 14/15 (93.3%) 2/18 (11.1%) 7/15 (46.7%)

Group A 3 (strong) 6/6 (100%) 4/6 (66.7%)

Recurrence n = 27/40 (67.5%) Recurrence & Progression n = 13/40 (32.5%)

REC 0.000 *

p value RFS 0.000 ^

PR

PFS

0.000 *

0.000 ^

*: Chi Square-Fisher’s Exact test; ^: Log rank test, statistical significance was set as p ≤ 0.05; REC: Recurrence; PR: Progression; RFS: Recurrence-free survival; PFS: progression-free survival.

Figure 2.

The expression of ET-1 in primary high-grade non-muscle-invasive urothelial bladder cancer (HGNMIUBC) significantly associates with recurrence-free survival/RFS (IHC: immunohistochemical staining).

Figure 3.

The expression of ET-1 in primary high-grade non-muscle-invasive urothelial bladder cancer (HGNMIUBC) significantly associates with progression-free survival/PFS (IHC: immunohistochemical staining).

Group B had neither recurrence nor progression. Median RFS and median PFS were 87.8 months.

Recurrence: In univariate analysis, ET-1 (p = 0.000) and age (p = 0.001, T-test) were statistically significant.

Specifically, among the patients of Group A who had recurrence (n = 27/40), 26 of them (26/27, 96.3%) showed ET-1 expression in the IHC. The multivariate analysis showed significance only for the patient’s age (p = 0.003, OR = 1.273, 95% CI: 1.086-1.492).

Progression: In univariate analysis, ET-1 (p = 0.000) was significant. Notably, among the patients of Group A who had progression (n = 13/40), 13 of them (13/13, 100%) showed ET-1 expression in the IHC. No parameter showed significance in multivariate analysis.

Recurrence-free survival (RFS): In univariate model, ET-1 was importantly associated with RFS (p = 0.000), which is illustrated in the Kaplan-Meier curves (Figure 2). Age is significant too (p = 0.013, Cox regression). The multivariate model provided no significant finding.

Progression-free survival (PFS): As it is shown by Kaplan-Meier curves (Figure 3), the univariate analysis revealed the significance of ET-1 (p = 0.000). No parameter proved to be significant in multivariate analysis.

DISCUSSION

The two major events in the natural history of HGNMIUBC are recurrence and progression to muscle-invasiveness, despite the initial high response-rate to postoperative intravesical BCG treatment (8). From a clinical point of view it is difficult and of value to identify on time and correctly those patients who will experience a failure of BCG-therapy and consequently recurrence and/or progression. Of course, the heterogeneity of the tumor does not facilitate a safe prognosis.

Risk tables for predicting recurrence and progression, based on the six most significant clinical and pathological factors, were developed by the European Organization for Archivio Italiano di Urologia e Andrologia 2021; 93, 2

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Research and Treatment of Cancer (EORTC) and represent a means whose prognostic value was confirmed by data from other studies (7, 9). The EORTC scoring system has not achieved a universal and unanimous acceptance though. One of the main reasons for this fact is that none of the included patients received maintenance therapy with BCG, which is currently recommended for all the high-risk patients (3). Another prognostic model was proposed from the Club Urológico Español de Tratamiento Oncológico (CUETO). In this study, patients were stratified according to the risk of recurrence and progression, which also stratified a patient’s risk of recurrence after BCG plus interferon-a therapy (3). The maintenance scheme lasted for 5-6 months, which is considerably shorter than the actually recommended one by the EAU (3). Except for these two widespread prognostic tools, there are numerous studies, which propose different prognostic factors, including molecular ones, for categorizing patients in terms of clinical course and outcome (4). For example, Cambier et al. studied a total of 1812 Ta-T1 patients from EORTC studies 30962 and 30911 (3). Patients were allocated either to 3 years of maintenance BCG or 1 year of maintenance. The prior recurrence rate and the number of tumors were identified by multivariable analyses as statistically significant prognostic factors for recurrence (3). Tumor stage and grade were found to be important for progression and death caused by bladder cancer (3). This study had also limitations (no patients with Tis were included, routine repeat TUR resection was not performed in high-risk patients, there was no central pathology review, upper urinary tract was not investigated upon recurrence or progression, no use of biomarker). Furthermore, Palou et al. documented that female gender and carcinoma in situ in the prostatic urethra are negative prognostic factors for recurrence (p = 0.0003, HR:2.53), progression (p = 0.001, HR: 359) and disease specific mortality (p = 0.004, HR: 3.53) in pT1G3 bladder cancer patients treated with BCG (10).

Another interesting study from Gontero et al., showed that pT1G3 patients ≥ 70 years old with tumors ≥ 3 cm and concomitant carcinoma in situ should be handled aggressively because of the high risk of progression (11).

Recently, Sahan et al. found in a retrospective cohort of pT1 bladder urothelial carcinoma patients treated postoperatively with intravesical BCG, for at least 1 year, that the tumor invasion to the muscularis mucosaevascular plexus significantly associates with recurrence (12). In closing, no molecule is turned to be a marker until today.

The available data regarding the expression of ET axis in bladder cancer does not give a clear end result. Eltze et al. examined retrospectively the expression of the endothelin axis in 154 patients with primary bladder cancer (pTa-pT2). They ascertain that both lack of ET-1 and ETAR have a negative prognostic impact (13). Moreover, an IHC study of 157 radical cystectomy samples demonstrated an overexpression of the entire ET axis. A survival benefit (disease-free survival, overall survival) was established only for ETBR (+) tumors (14). Two experimental studies, in which KU-19-19 bladder cancer cells were implanted in mice, showed that the administration of atrasentan, a selective ETAR antagonist, lead to a diminished tumor-growth rate with an increased necrosis in

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the tumor tissue, no significant cytoreduction and increased ETAR expression, implying an escape mechanism to overcome the antiproliferative effect caused by targeting ETAR (15, 16). In another IHC retrospective study, ET-1 and the microvessel density (MVD) seemed to be “good prognostic factors”, cause the ET-1 overexpression was importantly associated with increased MVD and organ-confined disease (17).

Coming to an end, a prospective study of 2015, based on IHC, recorded that the overexpression of ET-1 was remarkably correlated with an increased hazard ratio of progression and death (5). In this case, the included patients suffered from non-metastatic muscle-invasive bladder cancer.

We found that the expression of ET-1 indicates a higher risk for disease recurrence and progression. Regarding the relative survival estimations (RFS, PFS), this higher risk remains documented. ET-1 could make us alert, in order to recognize the patients with primary HGNMIUBC who are at risk for a bad clinical outcome, taking into consideration that we can accurately identify patients who will not progress or die due to bladder cancer (pTaG1), but we cannot reliably identify the ones who do progress and die of their disease (3). Within this context, we could offer these patients a radical treatment early in the natural course of the disease, aiming to maximize the clinical benefit. Finally, only the patient’s age, among all the rest studied parameters, correlates significantly with recurrence and RFS. So, the implementation of a strict follow up for the elderly patients with primary HGNMIUBC is a reasonable decision.

The prospective nature of our work is an important advantage. Another quality which worths to be mentioned is that our patients are the most homogenous group compared to the included patients of the abovementioned researches (different stages, different types of carcinoma). They all are primary HGNMIUBC patients treated postoperatively with intravesical BCG instillations (induction and 3-year maintenance). Likewise, we study ET-1 using IHC staining, which is the most common methodology in current literature. In our opinion, it is also positive the fact that we applied a central pathology review. On the other hand, it remains as a disadvantage the limited sample. Regarding this point, we need to mention that there is no other similar study addressing the same issues, meaning a prospective study of a rather homogenous cohort.

The standard of care in HGNMIUBC does not achieve an ideal clinical result. The prognosis also remains problematic. Taking into account, that a molecular marker could be helpful in this field, our study gives an evidence for the usefulness of ET-1 in HGNMIUBC as an alert marker for disease recurrence as well as progression.

CONCLUSIONS

ET-1 seems to deteriorate prognosis in patients suffering from primary high-grade non-muscle-invasive urothelial bladder cancer, who are treated with adjuvant BCG instillations. Furthermore, the patient’s age associates with an increased likelihood for recurrence. Further studies are needed in order to clarify the potential role of

ET-1 worsens prognosis in bladder cancer

ET-1 in the active molecular mechanism in bladder cancer and confirm or not our promising finding.

to clinicopathologic and molecular prognostic parameters. Eur Urol.

2009; 56:837-847.

ACKNOWLEDGEMENTS

14. Wülfing C, Eltze E, Yamini J, et al. Expression of the endothelin axis in bladder cancer: Relationship to clinicopathologic parameters and long-term survival. Eur Urol. 2005; 47:593-600.

The corresponding author has been awarded a supporting funding from the Hellenic Urological Association (HUA).

REFERENCES

1. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC Genito-Urinary Group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guérin, and bacillus Calmette-Guérin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010; 57:766-773.

2. Soloway M, Khoury S. Bladder Cancer. 2nd Edition: ICUD-EAU 2012; 254-261.

15. Wülfing C, Tiemann A, Persigehl T, et al. In vivo activity of ABT627, a selective endothelin-A-receptor antagonist, in bladder cancer xenograft tumors. Proc Am Soc Cancer Res. 2005; 46:abstract 3039.

16. Herrmann E, Tiemann A, Eltze E, et al. Endothelin-A-receptor antagonism with atrasentan exhibits limited activity on the KU-1919 bladder cancer cell line in a mouse model. J Cancer Res Clin Oncol. 2009; 135:1455-1462.

17. Herrmann E, Bögemann M, Bierer S, et al. The role of the endothelin axis and microvessel density in bladder cancer - correlation with tumor angiogenesis and clinical prognosis. Oncol Rep. 2007; 18:133-138.

3. Cambier S, Sylvester RJ, Collette L, et al. EORTC nomograms and risk groups for predicting recurrence, progression, and diseasespecific and overall survival in non-muscle-invasive stage Ta-T1 urothelial bladder cancer patients treated with 1-3 years of maintenance Bacillus Calmette-Guérin. Eur Urol. 2016; 69:60-9.

4. Mitrakas L, Gravas S, Papandreou C, et al. Primary high-grade non-muscle-invasive bladder cancer: high NF-B expression in tumor specimens distinguishes patients who are at risk for disease progression. Pathol Oncol Res. 2019; 25:225-231.

5. Mitrakas L, Gravas S, Karasavvidou F, et al. Endothelin-1 overexpression: a potential biomarker of unfavorable prognosis in nonmetastatic muscle-invasive bladder cancer. Tumour Biol. 2015; 36:4699-705. Erratum in: Tumour Biol. 2015; 36:3127 6. Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guérin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000; 163:1124-1129.

7. Babjuk M, Böhle A, Burger M, et al. EAU Guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol. 2017; 71:447-461.

8. Zachos I, Tzortzis V, Mitrakas L, et al. Tumor size and T stage correlate independently with recurrence and progression in high-risk non-muscle-invasive bladder cancer patients treated with adjuvant BCG. Tumour Biol. 2014; 35:4185-4189.

9. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006; 49:466-5.

10. Palou J, Sylvester RJ, Faba OR, et al. Female gender and carcinoma in situ in the prostatic urethra are prognostic factors for recurrence, progression, and disease-specific mortality in T1G3 bladder cancer patients treated with bacillus Calmette-Guérin. Eur Urol.

2012; 62:118-25.

11. Gontero P, Sylvester R, Pisano F, et al. Prognostic factors and risk groups in T1G3 non-muscle-invasive bladder cancer patients initially treated with Bacillus Calmette-Guérin: results of a retrospective multicenter study of 2451 patients. Eur Urol. 2015; 67:74-82.

12. Sahan A, Gerin F, Garayev A, et al. The impact of tumor invasion to muscularis mucosaevascular plexus on patient outcome in pT1 bladder urothelial carcinoma. Arch Ital Urol Androl. 2020; 92:239-243.

13. Eltze E, Wild PJ, Wülfing C, et al. Expression of the endothelin axis in noninvasive and superficially invasive bladder cancer. Relation

Correspondence Lampros Mitrakas, MD, PhD (Corresponding Author) lamprosmit@gmail.com Roosevelt 61, 41222 Larissa (Greece) Stavros Gravas, MD, PhD sgravas2002@yahoo.com Ioannis Zachos, MD, PhD johnbzac@yahoo.gr Anastasios Karatzas, MD, PhD adkaratzas@yahoo.gr Athanasios Oeconomou, MD thaoik@hotmail.com Vasilios Tzortzis, MD, PhD tzorvas@otenet.gr Department of Urology, University Hospital of Larissa, 41110 Larissa (Greece) Foteini Karasavvidou, MD, PhD fotkarasa@yahoo.gr Georgios Koukoulis, MD, PhD kougeo@med.uth.gr Department of Pathology and Cytology, University Hospital of Larissa, 41110 Larissa (Greece) Christos Papandreou, MD, PhD cpapandreou@auth.gr Department of Oncology, N.Papageorgiou Hospital of Thessaloniki Ring Road of Thessaloniki, 56 403 Thessaloniki (Greece)

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DOI: 10.4081/aiua.2021.2.148

ORIGINAL PAPER

Gas6 expression and Tyrosine kinase Axl Sky receptors: Their relation with tumor stage and grade in patients with bladder cancer Murat Akgül 1, Özgür Baykan 2, Zeynep Çağman 3, Mustafa Özyürek 4, !lker Tinay 5, Cem Akbal 6, Fikriye Uras 7, Levent Türkeri 6 1 Department

of Urology, Tekirdag Namık Kemal University Medical School, Tekirdag˘, Turkey; of Biochemistry, Balıkesir University Medical School, Balıkesir, Turkey; 3 Department of Biochemistry, Bezmialem University, School of Pharmacy, Istanbul, Turkey; 4 Department of Physiology, Marmara University, School of Medicine, Istanbul, Turkey; 5 Anadolu Medical Center, Gebze, Kocaeli,Turkey; 6 Department of Urology, Acıbadem University, School of Medicine, Istanbul, Turkey; 7 Department of Biochemistry, Marmara University, School of Pharmacy, Istanbul, Turkey.

2 Department

Summary

Objectives: It has been shown that the dysregulation of tyrosine kinase Axl receptor and its ligand growth arrest-specific gene (Gas6) are associated with poor prognosis in various types of tumors but there is not enough study about their importance in bladder cancer (BC).

We evaluated the relation of Gas6 gene expression and tyrosine-kinase Axl and Sky (Tyro 3) receptors with tumor stage and grade in patients with BC. Material and Methods: The study group consists of 55 patients whose transurethral resection of bladder (TUR-B) has been performed due to BC and the control group consists of 12 patients with normal bladder mucosa. In tissues mRNAs of Gas6, Axl, and Sky receptors were examined by quantitative (Real-Time) PCR (qPCR). Protein expression was measured by immunohistochemistry. Plasma Gas6 protein levels were compared with control group by ELISA method.

Results: Patients with BC were grouped as Ta low (n=17), Ta high (n=5), T1 low (n=9), T1 high (n=8) and T2 (n=16) according to their TUR-B pathologies. The qPCR analysis showed that the expression of Gas6 gene and Axl receptor is higher in the tumor-positive group and the immune-histochemical showed that the bladder samples of the tumor-positive group stained significantly positive. When the patients are grouped according to the TUR-B pathologies, a statistical significant difference was observed among groups in the qPCR analysis ratios of Gas6 gene and Axl receptor by (p < 0.05) but no significance was found for Sky receptor (p > 0.05). When Gas6 protein levels in plasma samples were compared by ELISA method, a statistical significance was determined among groups (p = 0.001).

Conclusions: Our findings indicate that mRNAs of Gas6 and Axl receptor are closely related to tumor stage and grade in patients with BC. Further studies are needed for understanding the role of Gas6 and its receptors on the neoplastic transformation in terms of novel biomarkers and potential therapeutic targets.

KEY WORDS: Bladder cancer; Gas6; Axl; Sky; Tyro3.

Submitted 31 March 2021; Accepted 17 May 2021

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INTRODUCTION

According to the GLOBOCAN data, bladder cancer (BC) is the 7th most commonly diagnosed cancer in men and it declines to 11th worldwide, when both sexes are considered (1). Worldwide age-standardized mortality rate has been reported as 3.2 for men vs. 0.9 for women per 100.000 persons, however incidence and mortality rates vary depending on the healthcare systems, management protocols and development level of the countries.

The most common subtype of BC is urothelial carcinoma (UC) and the molecular mechanism of UC is not completely understood as in other cancers (2).

Receptor tyrosine kinases (RTKs) play key roles in cellular signal transduction and they are one of the most common types of molecules investigated for this purpose. In humans, 20 distinct subfamilies of RTKs exist that are categorized according to their aminoacid sequence identities and structural similarities in their extracellular regions (3). One of these is the subfamily of TAM receptors comprising Sky (Tyro3), Axl, and Mer. They participate in a signaling axis where growth arrest-specific 6 (Gas6) protein is a ligand (4). The oncogenic nature of Axl, Sky and Mer is demonstrated through activation of signaling pathways involved in proliferation, migration, invasion, angiogenesis, inhibition of apoptosis, and therapeutic resistance (5). It has been shown that overexpression of Axl, Sky, Mer RTKs, and their ligand Gas6 is associated with poor prognosis in various types of tumors (6). The close relationship with the pathogenesis of many cancers suggests that Gas6 and its TAM receptors could be potential biomarkers and targets for treatment (7).

The molecular biology of BC is complex and not fully understood. There is a very limited number of studies investigating the relationship between BC and Gas6/TAM receptors. Yeh et al. investigated the role of Axl in the pathogenesis of locally advanced and metastatic BC patients (8). They indicated that c-Met and its crosstalk with Axl could contribute to the progression of No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 2

Gas6 and Axl Sky receptors’ relation with bladder cancer

human BC. Rui et al. investigated the relationship between long noncoding RNA and BC (9). They showed that GAS6-AS2, a long noncoding RNA, was significantly up-regulated in BC tissues and positively correlated with tumour stages and poor prognosis. Identification of new prognostic markers and therapeutic targets for BC is urgently required. In the present study, we aimed to elucidate the relation between Axl/Sky/Mer RTKs and its ligand Gas6 in patients with UC of bladder.

MATERIALS

Figure 1.

The cytoplasmic staining of immune expression for Gas6 protein and Axl, Sky receptors proteins positivity in BC tissue.

According to the intensity of staining, it was scored as 1A: 0, 1B: +1, 1C: +2, 1D: +3.

AND METHODS

The sample size was calculated based on the formula according to the previously published studies (6, 8). Our study group includes 55 patients with transurethral resection of bladder tumor, where the histopathological diagnosis of the tumors was UC. The control group consists of the 12 patients whom bladder mucosa has been biopsied during radical prostatectomy operation. Tissues from bladder tumor or mucosa were stored at -80 °C. In this study, mRNA expression of Axl, Sky, and Gas6 in the tissues was analyzed by quantitative (real-time) polymerase chain reaction (qPCR). Protein expression of Gas6, Axl, and Sky was analyzed by immunohistochemistry.

Plasma and urine samples of patients were collected before transurethral resection and Enzyme linked Immunosorbent Assay (ELISA) was used to measure Gas6 protein level. Plasma and urine samples of a control group, who are older than 40 years of age and without any history of malignancy, has been used for comparison. The urine and venous plasma aliquots were stored at -80°C before analysis after centrifugation at 2300 g for 15 min at room temperature.

The study has been approved by the local institutional ethics committee (Approval number: 09.2012.0087) and conducted in conformity with the Declaration of Helsinki in 1995. Written informed consent were obtained from all patients included in the study.

Real-time PCR (qPCR) Total RNA was isolated using TriPure isolation reagent solution (Roche, Mannheim, Germany) according to the manufacturer's instructions. The mRNA expression of the Gas6, Axl and Sky were determined using specific primer sequences.

Specific primer sequences used for the Gas6 gene: • 5’-TGCTGTCATGAAAATCGCGG-3’ (gas6-5’; 13281347) • 5’ CATGTAGTCCAGGCTGTAGA-3’ (gas6-3’; 15941613) Specific primer sequences used for the Axl receptor gene: • 5’-GGTGGCTGTGAAGACGATGA-3’ (Axl-5’; 18201839) • 5’ CTCAGATACTCCATGCCACT-3’ (Axl-3’; 21032122) Specific primer sequences used for the Sky receptor gene: • 5’-CACTGAGCTGGCTGACTAAGCCCC-3’(Sky-5’; 2719-2742) • 5’-AATGCATGCACTTAAGCAGCAGGG-3’(Sky-3’; 3039-3062)

The qPCR analysis was performed using SYBR Green dye (Light Cycler-RNA Amplification Kit SYBR Green I; Roche, Mannheim, Germany). Target gene expression was determined by comparing the amount of threshold loop with the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene.

Immunohistochemical analysis Streptavidin biotin peroxidase immunohistochemical staining method was applied to show the immune expression of Gas6 protein and Axl, Sky receptors proteins in paraffin-embedded tissues. The immune expression positivity in BC tissue was observed as cytoplasmic staining.

According to the intensity of staining, it was scored as 0 (Figure 1A), +1 (Figure 1b), +2 (Figure 1c), +3 (Figure 1d). Immunohistochemistry expression index was obtained by multiplying the cytoplasmic staining density and the ratio of stained cells. Two authors, who were blinded to the clinical course of the patients, independently evaluated immunoreactivity, and the average counted by these two authors was used for statistical analyses.

ELISA method The human GAS6 sandwich ELISA development kit (R&D Systems, Inc., Minneapolis, MN, USA) and a Substrate Reagent Pack (Color reagent A&B) (R&D Systems, Inc.) were used to measure plasma GAS6 levels.

Our group has been optimized the development kit to measure human plasma GAS6 levels and established reference intervals (10). Briefly, the following parameters were tested for optimization: type of antibody; capture antibody concentration; dilution solution; dilution ratio of samples and calibrators; blocking agent (BSA or nonfat dry milk), and incubation time and temperature.

Dilution solution for samples and calibrators was PBST containing 1 mM EDTA and 1% BSA. Dilution ratio of samples and calibrators was 1/40. Incubation time during antigen antibody interaction (both capture and detection antibodies) was 1h at 37°C. After analytical validation studies of the method, samples were analyzed.

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Statistical analysis In descriptive statistics of the data, frequency, ratio, mean and standard deviation values were used.

The distribution of data was tested with KolmogorovSmirnov. Student t test and ANOVA were used to analyze the parametric section data. Mann-Whitney U and Kruskal-Wallis tests were used for the analysis of nonparametric data. SPSS 15.0 software (SPSS, USA) was used in the analysis.

Table 2.

Immunohistochemical expression index of Gas6 protein, Axl, Sky receptors for BC and control group. n

Gas6 Axl Sky

6 6 6

Control group Median Min. Max.

5 15 50

0 0 0

90 70 200

Tumor-positive patient group n Median Min. Max.

32 28 32

85 60 180

0 10 0

300 200 300

p

0.006 0.037 0.261

Figure 3.

Gas6 protein levels in plasma samples according to the stage and the grade of the BC patients with ELISA analysis.

RESULTS Patient demographics The BC patients were grouped according to their pathological degrees and stages: Ta low grade (n=16), Ta high grade (n=5), T1 low grade (n=10), T1 high grade (n=10), T2 high grade (n=14) and normal bladder mucosa control group (n=12). Mean ages of the patients with BC and the control group were 62.8 ±10.7 and 57.3 ± 7.0 years, respectively (p > 0.05). Patients with BC, were male in 81.8% and female in 18.2%, while the control group consisted of male patients.

Tissue analyses The qPCR results showed that the mRNA expression of Gas6 and Axl receptor were higher in the tumor-positive patient group, where Sky receptor gene were higher in control group, these differences were not significant (p > 0.05) (Table 1). When the patients are grouped according to the grade and stage, significant differences were observed for Gas6 and Axl receptor genes (p < 0.05). But no significant difference was found for Sky receptor (p > 0.05) by qPCR (Figure 2).

Table 1.

Gas6, Axl, Sky receptor gene expression copy level assessed by the qPCR method.

Gas6 Axl Sky

n

Control group Median Min. Max.

Tumor-positive patient group n Median Min. Max.

11 12 11

60.6 7 294 288.7 145 578 10000 2888 15497

50 55 54

73.1 421.5 8048

10 87 1591

1810 1997 31333

p

0.223* 0.288* 0.588*

The immunohistochemical expression index for the Gas6 and Axl receptor were statistically higher compared to the control group (p < 0.05). The immunohistochemical expression index of Gas6 protein, Axl, Sky receptors for BC and control group is shown in Table 2.

Plasma and urine analyses The mean plasma Gas6 protein levels for the control group and the BC patient group were 6.5 ± 2.6 ng/mL and 9.9 ± 2.4 ng/mL, respectively (p < 0.001). The distribution according to the stage and the grade of the patients are shown in Figure 3. Gas6 protein was not detected in urine samples by ELISA.

* Mann Whitney U test.

DISCUSSION

Figure 2.

Expression of Gas6 and Axl receptor mRNAs in BC against tumor stage and grade by qPCR.

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In the present study, an association between BC and expression of Gas6, Axl and Sky was identified using three different methods: qPCR and immunohistochemistry in tissues and Gas6 levels in plasma by ELISA. The qPCR analysis showed that mRNA expression of Gas6 and Axl are higher in the BC group than the control group but not significantly (p > 0.05). mRNAs of Gas6 and Axl was higher in Ta high grade and T1 low grade significantly, but gradually decreasing in T1 high grade and T2 stages. Using the immunohistochemical examination, the BC group showed significantly higher (p < 0.05) Gas6 and Axl receptor expression compared to the control group. ELISA analysis showed higher Gas6 protein levels in plasma of the BC group compared to the control group (p=0.001), where highest levels are detected in patients with T2 tumors.

Gas6 and Axl Sky receptors’ relation with bladder cancer

The definitive diagnosis of BC ultimately depends on cystoscopic examination of the bladder, which is an invasive method. There are continuous efforts for the development of non-invasive reliable tumor markers to facilitate the diagnosis. However, none of these markers have been accepted for the diagnosis or follow-up in routine practice (11). By the help of further studies, the Gas6/Axl axis may represent an attractive diagnostic tool for BC. Relationship between various physiological events and Gas6, and/or its receptors has been demonstrated, however, its exact mechanism has not been elucidated yet (12, 13). The relationship between Gas6 and/or its receptors with tumor suppressor genes such as Inositol polyphosphate-4-phosphatase (INPP4B) remains uncertain (14). The Gas6 gene and particularly the Axl receptor are highly overexpressed in many diseases. Numerous biological dysfunctions, inflammatory diseases and autoimmune disorders are related to the overexpression of Gas6 and its receptors (6).

They also participate in the development, progression and metastatization of a range of malignancies (15). Prostate cancer, breast cancer, lung cancer, leukaemia and cancers of gastrointestinal tract including colon are the most studied malignancies (5, 6, 16). Recent studies have also demonstrated an important role of AXL signaling in tumor proliferation, survival, stem cell phenotype, prognosis, metastasis, and resistance to cancer therapy (16).

However, there is an opposite situation in renal cell carcinoma, which is a urogenital tumor where the Gas6 and Axl-Sky receptors are associated with good prognosis (17).

When we look at the stage and grade of BC, it seems that mRNAs of Gas6 and Axl receptor are very close to each other in the control and Ta low grade group.

The malignant potential of low-grade BC, that was formerly regarded as 'low malignant potential papillary urothelial neoplasia', may be related to different molecular pathological and histopathological features. In this respect, it is similar to the new WHO-ISUP classification (18). In the present study, the expression of Gas6 was higher at Ta high grade and T1 low grade, but differentiation was gradually decreasing at T1 high grade and T2 stages. Similarly, in the study of Sun et al., the gene expression of Gas6 and Axl receptor was found to be higher in G1 endometrial cancer, however, it was gradually decreasing in G2 and G3 endometrial cancers where the differentiation is poor (19).

Using the immunohistochemical examination, Gas6 and Axl receptor were found to have a significantly higher protein expression at BC compared to the control group.

However, similarly to Sky receptor qPCR results, there was no statistically significant difference between the BC and the control group. Using immunohistochemistry examination, Hattori et al. investigated the relationship between increased expression of the Axl/Gas6 signal cascade and prognosis of patients with upper tract urothelial carcinoma. They concluded that the protein expression of Axl and its ligand Gas6 is related to worse clinical outcome in upper tract urothelial tumors (20).

The plasma levels of Gas6 protein measured by ELISA were significantly higher in the BC group compared to the control group. In addition, mean levels of Gas6 protein in plasma were significantly higher in T2 patients compared to other groups. This may be important for the separation

of the muscle invasive BC from non-muscle invasive BC. Therapeutic potential of AXL inhibition has been explored for cancer therapy (21). A variety of AXL inhibitors have been developed and are efficacious in preclinical studies. These agents offer new opportunities for therapeutic intervention in the prevention and treatment of advanced disease. For the treatment of the breast cancers, BGB324 (R428) and SGI7079, which are the highly selective Axl tyrosine kinase inhibitors, entered in clinical studies (22, 23). Mao et al. showed that GAS6 was overexpressed in BC cells. They also found that high levels of GAS6 expression were related to tumor stage, grade, and poor overall survival (24). Unfortunately, there are no enough clinical studies on anti-Axl/Gas6 therapy focusing on BC. However, in light of the future studies, this pathway could be a candidate as novel biomarker and as an approach for treatment for BC. Limitations of the study This hypothesis-generating study and our results have some limitations such as small sample size. The control group consists of the normal bladder tissues of the prostate cancer patients is another limitation of the study. Normal bladder tissue is excised as a standard surgical procedure during radical prostatectomy operations.

We preferred to use this normal bladder tissue as a control group without an ethical restriction. We could not excise the normal bladder tissue from healthy individuals as a control group because of the ethical problems.

Gas6 and its ligands might represent an attractive diagnostic tool in the future. However, expression of these proteins was studied in tissues requiring an invasive biopsy to be obtained. On the other hand, plasma Gas6 ELISA results were also promising for BC diagnosis and could be used as non-invasive diagnostic test. Of course, future studies with larger sample size will provide more reliable information for implementation of plasma Gas6 test as a biomarker. ELISA method was used to detect the urine Gas6 protein levels but Gas6 protein was not detected in urine samples. The sensitivity of this method may not be appropriate for determining the level of Gas6 protein in urine samples. Gas6 protein could make a complex with soluble form of Axl (25). Further studies for optimization of plasma Gas6 ELISA method for measurement of Gas6 in urine samples are necessary.

CONCLUSIONS

We evaluated the relationship between Gas6/RTKs and BC with three different methods by performing qPCR analysis, immunohistochemistry and ELISA analysis.

Our findings indicate that mRNAs of Gas6 and Axl receptor are closely related to tumor stage and grade in patients with BC. Further studies are needed for understanding the role of Gas6 and its TAM receptors on the neoplastic transformation in terms of novel biomarkers and potential therapeutic targets.

ACKNOWLEDGMENTS

This study was supported by Marmara University Scientific Research Projects Committee (Grant number: SAG-C-TUP130612-0208).

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21. Wu X, Liu X, Koul S, et al. AXL kinase as a novel target for cancer therapy. Oncotarget. 2014; 5:9546.

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25. Ekman C, Stenhoff J, Dahlback B. Gas6 is complexed to the soluble tyrosine kinase receptor Axl in human blood. J Thromb Haemost. 2010; 8:838.

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18. Sauter G, Algaba F, Amin M, et al. Tumors of the urinary system: non-invasive urothelial neoplasias. In: Eble JN, Sauter G, Epstein Jl, Sesterhenn I, eds. WHO classification of classification of tumors of the urinary system and male genital organs. Lyon: IARCC Press 2004; 29.

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Correspondence Murat Akgül MD (Corresponding Author) drmuratakgul@gmail.com - Assistant Professor Tekirdag Namık Kemal University, Medical School, Urology Department, Süleymanpas¸a, Tekirdağ, Turkey, 59030 Özgür Baykan, MD ozgurbaykan@gmail.com - Associated Professor Balıkesir University, Biochemistry Laboratory Balıkesir, Turkey, 10020 Zeynep Çağman, PhD zeynep794@gmail.com - Assistant Professor Bezmialem University Pharmacy School, Biochemistry Department, Istanbul,Turkey, 34734 Mustafa Özyürek, PhD mustafaozyurek1@gmail.com - Research Assistant Marmara University, Medical School, Physiology Department, Maltepe, Istanbul, Turkey, 34854

! lker Tinay, MD itinay@yahoo.com - Associated Professor Anadolu Medical Center, Gebze, Kocaeli, Turkey, 41400 Cem Akbal, MD cakbal@gmail.com - Professor Acıbadem University, Urology Department, Altunizade-Üsküdar, Istanbul, Turkey, 34660 Fikriye Uras, PhD furas@marmara.edu.tr - Professor Marmara University Pharmacy School, Biochemistry Department, KadıköyIstanbul,Turkey, 34734 Levent Türkeri, MD levent.turkeri@acibadem.com - Professor Acıbadem University, Urology Department, Altunizade-Üsküdar, Istanbul, Turkey, 34660

DOI: 10.4081/aiua.2021.2.153

ORIGINAL PAPER

Specialist management of testicular cancer: Report of the last 10 years at a Portuguese tertiary referral academic centre André Marques-Pinto 1, Ana Inês Gomes 2, Joana Febra 3, Eugénia Rosendo 3, Manuel Castanheira de Oliveira 1, Avelino Fraga 1, 2, José LaFuente de Carvalho 1, 2, Nuno Louro 1, 2 1 Urology

Department, Centro Hospitalar Universitário do Porto, Porto, Portugal; de Ciências Biomédicas Abel Salazar, Porto, Portugal; 3 Medical Oncology Department, Centro Hospitalar Universitário do Porto, Porto, Portugal.

2 Instituto

Summary

Objectives: To describe our experience on testicular cancer (TC) management, underlining the clinical/pathological scope, administered treatments, outcomes, and challenges. TC incidence is rising globally.

The predominant histology is germ cell tumour (GCT). In most patients, orchiectomy is curative. Still, a significant proportion of patients will need further tailored treatment. Specialist Reference Centres have proven themselves successful in this setting.

Published data regarding TC in Northern Portugal is lacking.

Methods: Retrospective review of consecutive TC patients at a specialist tertiary referral academic centre between January 2010 and December 2020. Statistical analysis was performed using the STATA® version 13.1 software. Multivariate logistic and survival analyses were performed.

Results: 125 patients met the inclusion criteria. The median age is 35 (28-40) years; 19% of patients had risk factors for TC – infertility being the most common (11%); 50% of patients wanted sperm cryopreservation prior to treatment; 68% of patients had stage I GCT, 16% stage II, and 17% stage III. Compared to seminoma, non-seminomatous GCT were associated with younger age (p < .001) and higher stages at diagnosis (p = .02); 24% of stage IA/B GCT underwent adjuvant chemotherapy; 47% of patients with metastatic GCT at presentation had refractory disease, requiring tailored treatment. The median follow-up time is 33 (13-65) months. There was no late relapse. The 5-year OS rate is 98.0%. The 5-year survival of metastatic disease is 95.8%.

Conclusions: Despite contemporary excellent cure rates, the challenges of testicular cancer management still endure, especially in advanced stages. Therefore, public awareness is recommended, in order to avoid late presentations - special attention should be given to those who have known risk factors. The existence of Reference Centres is of paramount importance in order to achieve the best outcomes possible.

KEY WORDS: Testicular cancer; Germ cell tumour; Reference centre; Metastatic disease; Relapse; Risk-adapted treatment.

Submitted 9 February 2021; Accepted 5 March 2021

INTRODUCTION

Testicular cancer (TC) accounts for approximately 1% of all male cancers worldwide (1). Over recent decades, its

incidence has steadily increased, predominantly in more developed countries, up to 1/10.000 person-years (2).

In many patients, TC is associated with high psychological and physiological burden (3).

Risk factors for developing TC are the presence of the other components of the testicular dysgenesis syndrome (TDS) – cryptorchidism, hypospadias, and sub-/infertility (4); familial history of TC in first-grade relatives (5); and personal history of a contralateral TC (6). The predominant histology is germ cell tumour (GCT) in over 90% of cases (7). The most common CGT are derived from germ cell neoplasia in situ (GCNIS), comprising seminoma and non-seminomatous (NS)GCT – embryonal carcinoma, teratocarcinoma, post-pubertal teratoma, post-pubertal yolk sac tumour, choriocarcinoma, and mixed GCT; GCNIS-unrelated GCT include pre-pubertal GCT and spermatocytic tumours; there is also a minority of non-GCT that includes sex cord/stromal tumours (derived from Leydig cells, Sertoli cells or granulosa cells) and secondary cancers (8). TC typically presents as a painless testicular mass or as an incidental ultrasound (US) finding, albeit a significant minority of patients refer pain, either scrotal or in the flank (9).

The diagnostic evaluation of TC, with few exceptions, includes physical examination, imaging [testicular US and computerised tomography (CT) of the thorax, abdomen, and pelvis], serum tumour markers (alphafetoprotein, beta subunit of human chorionic gonadotropin, and lactate dehydrogenase), and radical orchiectomy (1).

The anatomical extent of the disease should be documented in appropriate staging and classification systems (1, 10), in order to initiate adequate early treatment thus improving patients’ outcome.

In most patients, orchiectomy is curative, therefore the prognosis is good. Those with metastatic TC may benefit from cisplatin-based chemotherapy regimens [specifically a combination of bleomycin, etoposide, and cisplatin (BEP)], due to generally high GCT chemosensitivity – this results in excellent cure rates, overall (11).

Still, there is a significant minority of patients that need further tailored treatment, such as retroperitoneal lymph node dissection (RPLND)/residual mass excision or sal-

No conflict of interest declared.

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vage chemotherapy; in rare cases, high-dose chemotherapy with autologous stem cell support may be needed (12). Thus, there is a worldwide trend towards establishing Reference Centres, which have proven themselves successful by their multidisciplinary approach, meticulous follow-up, and suitable salvage therapies (13). Since 2016, the Centro Hospitalar Universitário do Porto is an official Reference Centre in TC management, in collaboration with the Instituto Português de Oncologia do Porto, on a national level (Despacho n.° 3653/2016).

This study aims to describe our experience on TC management, underlining the clinical and pathological scope, administered treatments, outcomes, and challenges.

METHODS

A retrospective review was performed, comprising consecutive adult patients who had pathologically confirmed TC at a specialist tertiary referral academic centre, Centro Hospitalar Universitário do Porto, between January 2010 and December 2020, after institutional review board approval. All cases were discussed in a multidisciplinary tumour board. Exclusion criteria comprised primary extragonadal GCT, and incomplete data in any of the key variables. Relevant information was collected from medical records regarding age, clinical presentation/referral, risk factors, staging [according to the 2016 Tumour, Node, Metastasis classification of the International Union Against Cancer, respective prognostic groups, and the International Germ Cell Cancer Collaborative Classification for metastatic testicular cancer (1, 10)], pathology, systemic treatment, follow-up, special management problems and outcome.

Statistical analysis Statistical analysis was performed using the STATA® version 13.1 software. Results for continuous variables were expressed as mean ± standard deviation or as median (interquartile range) according to its distribution.

The chi-square test was applied to compare categorical variables. Independent sample Student t-test and oneway ANOVA were used to compare continuous variables. Univariate and multivariate linear and logistic regression analyses were performed according to the variables and expressed as a coefficient or odds ratio (OR) and respective 95% confidence interval (95%CI).

A survival analysis was performed in order to calculate the overall survival (OS) rate. A p value < .05 was considered statistically significant.

RESULTS

The initial study cohort consisted of 129 patients.

Those with primary extragonadal GCT (n = 1) and incomplete data (n = 3) were excluded to give the final cohort for analysis of 125 patients who met the inclusion criteria. There was a 60% increase in the number of patients with newly diagnosed TC since 2016 (20102015 n = 48 versus 2016-2020 n = 77).

The median patient age is 35 (28-40) years. All patients are European Caucasians. Overall, 24 patients (19%) had a confirmed risk factor for TC – cryptorchidism (n = 5,

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4.0%), infertility (n = 14, 11%), family history of TC (n = 2, 1.6%), and personal history of contralateral TC (n = 3, 2.4%). The majority of patients presented with a testicular mass (n = 73, 60%) and/or testicular pain (n = 42, 35%). A significant proportion of patients presented with an incidental US finding (n = 30, 25%), some of them in the workup of a retroperitoneal mass (n = 10, 8.0%) or gynecomastia (n = 5, 4.0%).

Altogether, there was no difference between the number of patients that presented with left sided TC (n = 63, 50%), versus right sided TC (n = 62, 50%). One patient presented with synchronous bilateral TC. After thorough anamnesis and physical examination, a scrotal US was performed on the same day, if not previously done. A minority of patients (n = 15, 12%) had a scrotal US on the following days. A staging CT was performed upfront preferably, though it did not delay radical orchiectomy, which was performed as quickly as possible, within the reference interval – 7 days after the first contact. The majority (n = 75, 66%) desired for a testicular prosthesis to be implanted in the same procedure, irrespective of age (OR = .96, p = .10 95%CI [.92-1.00]).

All men were offered sperm cryopreservation prior to starting treatment (with a few exceptions of life-threatening disseminated disease), and a significant proportion chose to do so (n = 59, 50%) – that decision was inversely related to age (OR = .90, p < .001 95%CI [.86-.95]).

Pathological exam reported GCT in 87% of patients (Table 1) – of those, the most frequent was pure seminoma, followed by NSGCT, and mixed seminoma-NSGCT. Almost half the NSGCT consisted of embryonal carcinoma (n = 22, 48%), either pure or as the major component of mixed GCT. The median tumour size was 30 (17-50) millimetres. Notably, there was a histological scar and no evidence of primary tumour in a significant minority (n = 6, 4.8%) – five patients that were diagnosed with burned-out testis tumour and one patient that underwent chemotherapy before orchiectomy – all these patients had histological confirmation of metastatic GCT. Two thirds of patients had stage I GCT, while roughly one third presented with advanced disease (Table 1).

Compared to seminoma, NSGCT were associated with younger age (28.7 ± 5.3 vs. 36.1 ± 7.8, p < .001) and higher stages at diagnosis (22 vs. 13, p = .02).

A significant proportion of stage IA/B GCT underwent adjuvant chemotherapy (Table 2), according to risk factors for metastatic relapse – either carboplatin in seminoma or BEP in NSGCT. No patient underwent adjuvant radiotherapy. There were a few stage IA/B GCT that relapsed (Table 2), requiring systemic salvage treatment followed, whenever appropriate, by RPLND – seminoma was found in one case, and fibrosis in another. None of them had had adjuvant chemotherapy.

Regarding metastatic GCT at presentation (that is, stage IS and higher), all patients (n = 43) underwent primary BEP chemotherapy, according to prognostic based groups – in good prognosis (n = 32, 74%), BEPx3 (one patient had cisplatin plus etoposide x4 due to previous pulmonary disease), and in intermediate/poor prognosis (n = 11, 26%), BEPx4. Chemotherapy started as soon as possible after multidisciplinary discussion. Most patients had tumour marker decline and regressive TC radiologi-

Testicular cancer management: 10-year report

Table 1.

Characteristics of participants at diagnosis by histological type.

Patients, n (%) Age, years* Stage, n (%) I II III

Seminoma NSGCT Mixed S-NSGCT SCST ** 63 (50%) 34 (27%) 12 (9.6%) 14 (11%) 36.1 ± 7.8 28.7 ± 5.3 36.2 ± 7.2 41.7 ± 12.2 50 (79%) 7 (11%) 6 (10%)

17 (50%) 9 (26%) 8 (24%)

7 (58%) 1 (8.3%) 4 (33%)

Total *** 125 35.1 ± 9.3

-

75 (68%) 17 (16%) 18 (17%)

GCT: Germ cell tumour; NSGCT: Non seminomatous GCT; S NSGCT: Seminoma NSGCT; SCST: Sex cord/stromal tumours; SD: Standard deviation. Estimates were given as mean ± SD* or frequency (percentage). **: All SCST were Leydig cell tumours; ***Includes one case of spermatocytic tumour and one case of testicular lymphoma.

Table 2.

Disease management of GCT by histological type.

Stage IA/B GCT Adjuvant chemotherapy Salvage chemotherapy RPLND Viable GCT Teratoma Fibrosis Persistent/relapsing metastatic GCT Salvage chemotherapy RPLND Viable GCT Teratoma Fibrosis

Seminoma NSGCT Mixed S-NSGCT 50 (77%) 9 (14%) 6 (9%) 11 (22%) 3 (33%) 2 (33%) 1 (2.0%) 1 (11%) 1 (17%) 0 1 (11%) 1 (17%) 1 (100%) 1 (100%) 4 (20%) 11 (55%) 5 (25%) 2 (50%) 2 (18%) 1 (20%) 2 (50%) 11 (100%) 4 (80%) 3 (27%) 4 (36%) 2 (50%) 2 (100%) 4 (36%) 2 (50%)

Total 65 16 (25%) 3 (4.6%) 2 (3.1%) 1 (50%) 1 (50%) 20 5 (25%) 17 (85%) 3 (18%) 6 (35%) 7 (41%)

GCT: Germ cell tumour; NSGCT: Non seminomatous GCT; RPLND: Retroperitoneal lymph node dissection; S NSGCT: Seminoma NSGCT. Estimates were given as frequency (percentage).

Table 3.

Multivariate logistic regression to predict refractory GCT. Variable Age (years) Histological group Seminoma NSGCT Mixed S-NSGCT Stage I II III

OR 1.1

95%CI .99-1.2

p value .09

Reference 12.3 16.3

– 1.9-78.5 2.1-125.2

< .01 < .01

Reference 4.6 28.9

– 1.0-21.9 6.2-134.1

.05 < .001

GCT: Germ cell tumour; NSGCT: Non seminomatous GCT; S NSGCT: Seminoma NSGCT: 95%CI: 95% confidence interval; OR: Odds Ratio.

cal features at repeated evaluations. Of note, no patient with stage IIA/B seminoma underwent primary radiotherapy.

Almost half the patients with metastatic GCT (n = 20, 47%) presented refractory disease (Table 2), requiring systemic salvage treatment and/or RPLND. The chosen salvage chemotherapy regimen consisted of cisplatin, ifosfamide, and either paclitaxel (n = 3) or vinblastine (n = 2). There was one cisplatin-refractory NSGCT that remitted after second salvage combination of gemcitabine and oxaliplatin. Regarding RPLND (Table 2), viable GCT was found in a significant minority of these

patients, while the majority had either teratoma or fibrosis. Regarding persistent disease/relapse, a logistic model adjusting for age, histological type and stage was found [chi2 (5) = 46.45, p < .001]: when compared to seminoma, NSGCT and mixed seminoma-NSGCT were associated with higher chances of disease persistence/relapse (Table 3); furthermore, higher stages were associated to higher chances of persistent disease/relapse when comparing with stage I GCT. The median follow-up time is 33 (13-65) months (n = 125). There was no record of late relapses. The 5-year OS rate is 98.0% – there were two patients that died: one with stage IIIC NSGCT, and other with malignant Leydig cell tumour; the remaining patients are in remission.

Stratifying by histological type, 5-year OS is lower for NSGCT (96.8%) than for seminoma (100%). Regarding stage, the 5-year survival of metastatic disease is 95.8%.

A minority of GCT patients was lost to follow-up within the 5-year period after diagnosis (n = 7, 5.6%).

DISCUSSION

In this cohort, the majority of patients was in the third/fourth decade of life, which is in concordance with the available literature (2). Since the encompassed population for reference centres in Northern Portugal is not strictly demarcated, and some patients are treated in private practice, no conclusions can be made regarding regional trends in TC incidence. However, our institution has noticed a much higher referral numbers over the last years, since we became an official Reference Centre for TC management.

The main predictor of TC development appears to be the presence of any component of the TDS, which may share genetic and/or environmental triggers (4). In fact, a significant proportion of patients in this cohort consists of patients with TDS whose TC might have gone unnoticed for a longer period had they not undergone testicular imaging. A large proportion of TC (up to 25%) seem to be genetically linked (14). However, in this cohort, only a negligible proportion of patients reported familial history of TC in first grade relatives.

Early detection and referral of TC leads to improved overall survival rates. Actually, routine scrotal US in patients with TDS, specifically those presenting with a personal history cryptorchidism and sub-/infertility, may detect TC in its earlier stages, for which orchiectomy is curative. On the other hand, while testicular pain may lead to earlier presentation, we did not find any difference in TC stages when stratifying by pain. Despite the increasing awareness for TC among young men and their partners, roughly one third of patients presented with metastatic disease. This may arise from ignorance, carelessness, shame, fear, denial, rurality, and reliance in alternative medicine. The definitive reasons cannot be assessed in this cohort.

In this cohort, as reported in literature (1), the majority of GCT consisted of seminoma, whereas NSGCT presented earlier and behaved more aggressively. Overall, GCT accounted for 87% of cases, which is slightly below what is commonly reported (7). This may be due to a higher proportion of sex cord/stromal tumours, namely Archivio Italiano di Urologia e Andrologia 2021; 93, 2

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A. Marques-Pinto, A.I. Gomes, J. Febra, E. Rosendo, M. Castanheira de Oliveira, A. Fraga, J. LaFuente de Carvalho, N. Louro

Leydig cell tumours, which accounted for 11% of cases, which is roughly 5-fold the proportion historically mentioned in literature (15). We could not establish the reasons for this pathological difference.

The pivotal step of TC treatment is radical orchiectomy, which is a procedure associated with fairly low morbidity as it allows early control of testicular lymphovascular supply, as well as en bloc removal of the specimen (1).

Usually, with proper counselling, patients are not reluctant to undergo surgery as the possibilities of sperm cryopreservation and prosthesis implantation are reassuring for both fertility and aesthetics, whenever patients may find those issues relevant. Remarkably, the proportion of patients that presented with advanced disease with no histological evidence of a primary TC other than a scar is similar to that of recent reports (16).

After orchiectomy, further treatment depends on both clinical staging and the pathology report. In this cohort, the majority of patients underwent chemotherapy at any point (adjuvant, primary or salvage) with good compliance and tolerance, overall. In this cohort, no patient underwent adjuvant/primary radiotherapy. The scrupulous follow-up plan might have led to timely identification of relapses and quick tailored treatment, which could explain the low mortality in this cohort. In fact, the multidisciplinary approach that exists in our centre, among other factors, seems to lead to a 5-year OS rate of 98.0% and, in metastatic disease, to a 5-year survival of 95.8%, which is higher than what has been recently reported (7, 17).

In this cohort, there seems to exist a stronger association between mixed seminoma-NSGCT and disease persistence/relapse than in other histological types, which is in concordance with recent reports that show a seminoma component in mixed GCT might be associated with more aggressive disease (18). Yet, we could not determine whether it is a true association or not, as it may be confounded by the relative proportion of other NSGCT components.

The major limitation of this study is its retrospective nature, which may have led to some bias, specifically in what concerns risk factors other than those mentioned.

Furthermore, the follow-up median is still below 5 years.

In addition, genetic studies are not routinely undertaken at our centre, therefore no specific genetic counselling could be offered.

Overall, according to data, our centre offers state-of-theart treatment for TC. In the future, we hope to help to develop a national database, in order to uniformise medical records and standardise clinical procedures.

CONCLUSIONS

Despite contemporary excellent cure rates, the challenges of testicular cancer management still endure, especially in what concerns advanced stages. Late presentation, regardless of the underlying causes, may correlate to higher stages, and represents a major shortcoming even in more developed countries, such as Portugal.

Therefore, increasing public awareness and education in schools, primary care, and media is recommended – special attention should be given to those who have known

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Archivio Italiano di Urologia e Andrologia 2021; 93, 2

risk factors for testicular cancer. Furthermore, the inclusion of testicular self examination in school curricula might be considered, seeking to detect testicular cancers at a lower stage. The existence of Reference Centres is of paramount importance in order to achieve the best outcomes possible.

ACKNOWLEDGMENTS

We thank the homologous team of Instituto Português de Oncologia do Porto for their cooperation in order to achieve the best results possible for the patients being treated in either institution of our Reference Centre over the years.

ETHICS

APPROVAL

This retrospective chart review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

The Institutional Human Investigation Committee (IRB) approved this study.

REFERENCES

1. Albers P, Albrecht W, Algaba F, et al. Guidelines on Testicular Cancer: 2015 Update. Eur Urol. 2015; 68:1054-68.

2. Gurney JK, Florio AA, Znaor A, et al. International trends in the incidence of testicular cancer: lessons from 35 years and 41 countries. Eur Urol. 2019; 76:615-23.

3. Kreiberg M, Bandak M, Lauritsen J, et al. Psychological stress in long-term testicular cancer survivors: a Danish nationwide cohort study. J Cancer Surviv. 2020; 14:72-9.

4. Skakkebaek NE. Testicular dysgenesis syndrome. Horm Res. 2003; 60 Suppl 3:49.

5. Kharazmi E, Hemminki K, Pukkala E, et al. Cancer risk in relatives of testicular cancer patients by histology type and age at diagnosis: a joint study from five nordic countries. Eur Urol. 2015; 68:283-9.

6. Schaapveld M, van den Belt-Dusebout AW, Gietema JA, et al.

Risk and prognostic significance of metachronous contralateral testicular germ cell tumours. Br J Cancer. 2012; 107:1637-43.

7. Park JS, Kim J, Elghiaty A, Ham WS. Recent global trends in testicular cancer incidence and mortality. Medicine (Baltimore). 2018; 97:e12390.

8. Williamson SR, Delahunt B, Magi-Galluzzi C, et al. The World Health Organization 2016 classification of testicular germ cell tumours: a review and update from the International Society of Urological Pathology Testis Consultation Panel. Histopathology.

2017; 70:335-46.

9. Moul JW. Timely diagnosis of testicular cancer. Urol Clin North Am. 2007; 34:109-17; abstract vii.

10. Mead GM, Stenning SP. The International Germ Cell Consensus Classification: a new prognostic factor-based staging classification for metastatic germ cell tumours. Clin Oncol (R Coll Radiol). 1997; 9:207-9.

11. Hoffmann R, Plug I, McKee M, et al. Innovations in health care

Testicular cancer management: 10-year report

and mortality trends from five cancers in seven European countries between 1970 and 2005. Int J Public Health. 2014; 59:341-50.

12. Oechsle K, Lorch A, Honecker F, et al. Patterns of relapse after chemotherapy in patients with high-risk non-seminomatous germ cell tumor. Oncology. 2010; 78:47-53.

13. Collette L, Sylvester RJ, Stenning SP, et al. Impact of the treating institution on survival of patients with "poor-prognosis" metastatic nonseminoma. European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Collaborative Group and the Medical Research Council Testicular Cancer Working Party. J Natl Cancer Inst. 1999; 91:839-46.

14. De Toni L, Sabovic I, Cosci I, et al. Testicular Cancer: Genes, Environment, Hormones. Front Endocrinol (Lausanne). 2019; 10:408.

15. Kim I, Young RH, Scully RE. Leydig cell tumors of the testis. A clinicopathological analysis of 40 cases and review of the literature.

Am J Surg Pathol. 1985; 9:177-92.

16. Astigueta JC, Abad-Licham MA, Agreda FM, et al. Spontaneous testicular tumor regression: case report and historical review.

Ecancermedicalscience. 2018; 12:888.

17. Miller KD, Nogueira L, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 2019; 69:363-85.

18. Akan S, Ediz C, Tavukcu HH, et al. The Clinical Significance of Seminoma Component in Testicular Mixed Germ Cell Tumour.

Urol Int. 2020; 104:489-96.

Correspondence André Marques-Pinto, MD (Corresponding Author) andre.fmpinto@gmail.com Manuel Castanheira de Oliveira, MD manuelantonielo@gmail.com Avelino Fraga, MD avfraga@gmail.com José LaFuente de Carvalho, MD lafuentecarvalho@gmail.com Nuno Louro, MD nunorlouro@gmail.com Urology Department, Centro Hospitalar Universitário do Porto, Porto (Portugal) Ana Inês Gomes, MD anainesmg@gmail.com Instituto de Ciências Biomédicas Abel Salazar, Porto (Portugal) Joana Febra, MD joana.febra@gmail.com Eugénia Rosendo, MD eugenia.rosendo@gmail.com Medical Oncology Department, Centro Hospitalar Universitário do Porto, Porto (Portugal) Archivio Italiano di Urologia e Andrologia 2021; 93, 2

157

ORIGINAL PAPER

DOI: 10.4081/aiua.2021.2.158

Early morning kidney transplantation: Perioperative complications Mário Pereira Lourenço, Miguel Eliseu, Duarte Vieira Brito, João Carvalho, Edgar Tavares-Silva, Lorenzo Marconi, Pedro Moreira, Pedro Nunes, Belmiro Parada, Carlos Bastos, Arnaldo Figueiredo Urology and Renal Transplantation Department, Coimbra University Hospital Centre, Coimbra, Portugal.

vation can have serious consequences on the surgeon, affecting his ability to maintain his mental and motor abilities. Studies show that sleep deprivation can have the same effect as alcohol intoxication on the surgeon’s abilities (3-6). It has been reported that there is an increase in the number of surgical complications and mortality when surgeries are performed after the professionals normal working hours (4-6).

Kidney transplant (KT), although not being an urgent procedure, is most of the times executed at late hours, even ate dawn. The reasons for such are several and include: the complex organization needed to distribute renal grafts, elective surgery that occupies surgical theatre and the need to prepare the receptor for surgery (7).

The main reason for such high number of late procedures is the need to reduce cold ischemia time (CIT) as much as possible in KT, as larger CIT relates to worst graft function, smaller survival time of graft and higher patient mortality (8). Although, studies show that with an 18 hours window of CIT there isn´t a significant difference in outcomes (9, 10). On the other hand, it has been described that surgical factors and the existence of complications influence the outcome of KT (11, 12). As such, it is pertinent to address what can be more favourable, having the lowest CIT possible or having a “fresh” surgical team with hypothetically smaller number of complications. For reason external to the surgical team, CIT was longer in specific cases up to the point where it was relevant to decide between performing surKEY WORDS: Early morning transplantation; Kidney transplanta- gery at night or in the morning. If waiting until morning tion; Kidney transplant complications; Immediate diuresis; Surgery could cause CIT to be considered unsafe, procedures starting hour. were conducted at later hours, being the group with the largest CIT the one that could not wait any more Submitted 9 January 2021; Accepted 23 February 2021 time. To our knowledge, there are only five large scale studies that studied this problem concerning Kidney Transplantation, with conflicting results and comparing INTRODUCTION different hours from the ones in this work (7, 13-16).

Medical error and its influence on the health of patients is an important and current subject in modern medicine.

In 1999, the Institute of Medicine of the United States of MATERIALS AND METHODS America reported that medical errors where responsible for one hundred thousand annual deaths and had a globStudy design al cost of 29 billion dollars (1). Sleep deprivation increasRetrospective analyses of all KT occurring in the Urology es the risk of medical error, so far as being called the and Kidney Transplant Service of the “Centro Hospitalar e Achilles heel of the medical profession (2). Sleep depriUniversitário de Coimbra”, Portugal, between June 1980

Summary

Introduction: To reduce cold ischemia time (CIT), many kidney transplants are performed in the early morning. Conducting complex surgeries in the early morning may influence the surgeon's technical capacity and rate of surgical complications (SC). Aim: Evaluate the influence of surgery start hour (SSH) regarding duration of surgery (DS), immediate diuresis (ID), SC and acute rejection (AR); evaluate the influence of CIT regarding SC, ID, and AR. Methods: 2855 cadaveric transplants performed between June 1980 and March 2018 were retrospectively evaluated. Regarding SSH, two groups were created: Group M (00: 00h-05.59h, n = 253) and Group D (06: 00h - 23: 59h, n = 2602). Analyzing the impact of SSH on DS, ID, SC and AR. Evaluate the relationship between CIT (< 18h, 18-30h and > 30h) on ID, SC and AR utilizing univariate and multivariate statistical analysis with SPSS. Results and Conclusion: Groups M and D were comparable in all evaluated demographic variables (p > 0.05), except cold ischemia time (Group M with higher CIT, p < 0.001).

Regarding univariate analysis, Surgery start hour did not influence DS (p = 0.344), and SC (p = 0.264), but related with higher ID (p = 0.028) and AR (p = 0.018). CIT related with immediate diuresis (p = 0.020) and acute rejection (p < 0.001) but did not relate with complications (p = 0.734). Regarding multivariate analysis, SSH only influenced immediate diuresis (p = 0.026) and did not influenced acute rejection (p = 0.055). CIT influenced immediate diuresis (p = 0.019) and acute rejection (p < 0.001). Surgery start hour influences Immediate diuresis.

With this study, we conclude that the priority must be a short cold ischemia time.

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No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 2

Early morning kidney transplantation

and July 2018. Patients with combined transplant (pancreas, lung, heart and liver) and from living donor where excluded, being selected 2855 consecutive transplants.

The resulting population was divided into two groups based on the surgery start hour (SSH): Group M (00:00h05:59h) and Group D (06:00h-23:59h). Four outcomes where defined and measured based of SSH: duration of surgery (DS), the number of surgical complication (SC), immediate diuresis (ID) measured on the operating table and acute rejection (AR) of the graft.

The population was equally studied on the CIT and its influence in the ID, AR and DS. Surgical team composition was not gathered in this study, but in the institution where the analysis was performed the presence of residents is not dependant of the hour of transplant. Being most teams composed of a senior surgeon and a resident.

Data collected was inserted in multiple labour laws, surgeons on the transplantation department are exclusively allocated to the task after normal working hours, having the right to rest after night procedures.

Table 1.

Demographic characteristic of the population.

Definitions Marginal donor was defined as having at least one of the following characteristics: over 60 years old, over 50 years and arterial hypertension, death by cerebral vascular accident or serum creatine level of over 1.5 mg/dl (17, 18).

Acute rejection was defined as worsening of graft function on the first year, having been admitted a clinical diagnosis (increase in creatine blood level, imagological alteration, need for corticoid treatment) or histologic (kidney biopsy). Immediate diuresis was defined by the observation of urinary output in patients with no need for dialysis on the first week after kidney transplant.

Surgical complications were divided in: urologic (urinary fistula, ureteric stenosis, ureteric necrosis), vascular (arterial or venous thrombosis, arterial stenosis, vascular anastomosis dehiscence), lymphocele, haemorrhage (need of surgical revision or transfusion), wound dehiscence, incisional hernia and others.

Table 2.

Mean surgery duration time in relation to surgical starting time.

Statistical analysis Baseline and demographic characteristics of group M and D were compared using the chi-squared test for categorical variables and the student’s T test for continuous variables. Univariate analysis of the effects of SSH and CIT in outcomes were described using the chi-squared test.

Multivariate analysis was conducted by applying the logistic regression method.

RESULTS Demographic characteristics Between 00:00 hours and 05:59 hours there were 253 cadaveric transplants in contrast to 2602 in the other time period. Demographic characteristic of Group M and Group D are summarized in Table 1. In comparison, more patients from the group M presented CIT superior to 30 hours (p < 0.001). All other characteristics were similar.

Mean surgical time for group (group D is further divided) is summarized in Table 2.

Populational demographic characteristic Group M 253 Number of patients Marginal donor (%/n) 50.6% (128) Age of receptor (y) 46.6 ± 13.9 Sex of receptor Male 69.2% (175) Right side implant 79.8% (202) Number of transplants (%/n) 1 94.5% (239) >1 94.4% (2457) Number of arteries of the graft 1 78.3% (198) >1 78.7% (2047) Cold ischemia time (%/n) < 18h 38.3% (97) 10-30h 53.9% (134) > 30h 8.7% (22)

Surgery start hour Grupo M 00:00-05:59 Grupo D 06:00-11:59 12:00-17:59 18.00-23:59 Total

Group D 2602 50.2% (1307) 45.6 ± 13.7 66.9% (1740) 2131 (81.9%)

p value 0.932 0.291 0.458 0.828 0.608

5.5% (14) 14.6% (155) 0.953 22.7% (55) 21.3% (553) < 0.001 38.7% (1004) 58.6% (1521) 2.8% (72)

% (n)

Mean duration of surgery (min)

8.8% (253)

157.2(45-330)

12.9% (366) 40.3% (1151) 38.0% (1085) 2855

165.9 (55-555) 149.1 (45-615) 152.1 (45-390) 153.5 (45-615)

Univariate analysis The effects of surgical star hour in the outcomes defined (DS > 3 hours, ID, SC e AR) are summarized in Table 3.

The effects of CIT on the same outcomes (except duration of surgery) are summarized in Table 4.

Multivariate analysis The effects of SSH and CIT when analysed together (multivariate analysis) are summarized in Table 5.

Table 3.

Effect of surgery starting hour in outcomes of renal transplant.

Surgery duration > 3 hours Immediate diuresis Surgery complications Vascular Urologic Lymphocele Bleeding Wound dehiscence Abscess Hernia Other Acute rejection

Group M 20.6% (52) 71.1% (180) 20.9% (53) 5.9% (15) 5.5% (14) 2.0% (5) 6.3% (16) 1.2% (3) 25.3%

Group D 18.1% (472) 79.0% (2055) 18.1% (471) 4.1% (107) 6.5% (168) 1.4% (37) 3.3% (85) 1.6% (42) 0.4% (11) 0.4% (11) 0.4% (10) 18.9%

p value 0.344 0.028 0.264

0.018

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M. Pereira Lourenço, M. Eliseu, D. Vieira Brito, J. Carvalho, E.Tavares-Silva, L. Marconi, P. Moreira, P. Nunes, B. Parada, C. Bastos, A. Figueiredo

Table 4.

Effects of cold ischemia time in the outcomes of kidney transplant.

Cold ischemia time Immediate diuresis Surgery complications Acute rejection

< 18h 81.4% (900) 18.4% (203) 14.4% (159)

18-30h 77.2% (1277) 18.1% (299) 22.0% (364)

> 30h 66.0% (62) 21.3% (20) 41.5% (39)

p 0.020 0.734 < 0.001

Table 5.

Multivariate analysis of the effect of surgery starting hour and cold ischemia time in the outcomes of kidney transplant.

Outcome Immediate diuresis Surgery complications Acute rejection

Variable SSH CIT SSH CIT SSH CIT

DISCUSSION

p 0.026 0.019 0.282 0.796 0.055 < 0.001

This work presents the highest number of patients analysed in relation to surgery start hour and its possible effects in kidney transplantation. Defined SSH was different when compared with other articles. In two different studies Kienz-Wagner et al. and Fechner et al. divided patients in groups of 08:00h-19:59h and 20:00h-07:59h (7,14). Seow et al. divided SSH in 07:30h-17:59h; 18:00h-23:59h; 00:00h-07:29h (13), while Shaw et al. and Emmanouilidis divided the groups into periods of 3h (15, 16). We chose to divide SSH in two blocks of 00:00h-05:59h and 06:00-23:59h such as to reinforce the effects of physical tiredness and sleep deprivation at dawn. Although, group M clearly presented a smaller number of patients, the high number of patients allows for reliable comparisons. Other distinct aspects are the outcomes studied, as most studies analyse the perioperative complications and renal graft survival. In this article we found favourable to try and relate fatigue of the surgeon and short-term outcomes, such as surgery duration, immediate diuresis and surgical complications. As short to median term outcome we evaluated the rate of AR. The M and D groups are comparable in relation to all variables studied, except in CIT of the graft (Table 1), it being superior in group M. These results are logical, as they represent grafts that where implanted “at any hour” as a way to prevent achieving critical CIT time that could possibly stop the realization of the transplant.

Utilizing univariate analysis, SSH influenced significantly the ID and AR, not having influenced the DS or the number of SC (Table 3). In a similar significant analysis, CIT influenced the same outcomes (Table 4). As group M and D where distinct in relation to CIT, multivariate analysis was conducted (Table 5) showing that SSH influenced the ID but did not alter the rate of AR. Kienzl-Wagner and Seow also did not find a relationship between SSH and the number of surgical complications while Fechner et al. demonstrated a larger number of vascular complications in KT conducted during the night

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period (7, 13, 14). Shaw et al. in their analysis evidenced a larger number of urologic complications during 03:0005:59h and a higher number of any complications between 00:00-02:59h (15). Emmanouilidis et al. also demonstrated higher likelihood for the need of reoperation during the 03:00-05:59h interval (16).

Duration of surgery was not influenced by the SSH, although there isn´t sufficient data from literature regarding this specific outcome. One Danish study, analysing the effects of sleep deprivation on the cognitive and technical abilities of surgeons, evidenced that surgeons can compensate for changes to their circadian rhythm, what may explain the results obtained in our study (19).

On this study, SSH significantly influenced ID. In the work by Kenzl-Wagner there was also a lower rate of ID in the nocturnal group (63.4% vs. 69.9%), although, without statistical significance. In that review, the author justified that tendency by the existence of a larger number of surgeries with marginal donor in the nocturnal group, what was not observed with our study. One simple justification could be that group M has a higher CIT, but changes to this outcome, ID, are maintain even after multivariate analysis. Notwithstanding the absence of a clear answer for this relation, it is known that a delay of graft function is associated with poorer outcomes and higher risk of graft loss, as show in a previous study done by our transplant centre (20).

The rate of AR in the M and D groups where 25.9% and 18.9%, respectively. On multivariate analysis a distinct association between SSH and AR was not found, consistent with the results from Kienzl-Meyer et al. (14).

The key factor that influenced graft function was CIT. As it is showed by our work, CIT has a significant influence in ID and AR (8, 10, 21, 22). Although, studies suggest similar outcomes in the CIT time frame of less than 18h, one study conducted by Debout et al. demonstrated that with every hour of CIT the probability of graft failure increases (hazard ratio: 1.013) and that the time frame of 18 hours can be suboptimal (9, 10). The same work stated the existence of a relation between CIT and graft failure (8).

Nevertheless, the recent study by Emmanouilidis et al., demonstrated that in the time frame of less than 23.5 hours of CTI, it is unfavourable to perform KT with the SSH in the 03:00-05:59h period (16).

The effects of sleep deprivation and of SSH has been studied in other specialities and surgeries. Regarding hepatic transplantation, Lonze et al. stated that surgery conducted in the nocturnal period was not associated with a higher number of complications but related with longer SD and risk of short term mortality (23).

Analysing thoracic organ transplant, George et al. did not identify differences between outcomes in patients whose surgery was conducted at night (24). Other works in pancreatic surgery, heart, trauma surgery did not find worst outcome with late SSH (25-28).

There were some limitations to this study, starting with the retrospective analysis of collected data, the definition of early morning surgery (00:00-05:59) is arbitrary and may not relate precisely with the fatigue state of the surgical team. Regarding AR its characterization was expanded to include clinic and histologic diagnoses. It was decided not to assess the relation between SSH and graft survival

Early morning kidney transplantation

as we considered there were no negative outcomes in the short term, and any data extrapolation would be too complex to explain.

CONCLUSIONS

Conducting KT at dawn showed no association with SD, SC or AR. However, it is connected with lower ID. The CIT strongly influences ID and AR. In summary, data collected in this study support that SSH should prioritize CIT, making sure CIT is the lowest possible. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

ACKNOWLEDGMENT

The authors of this article would like to give special reference to Doctors António Roseiro, Vítor Dias and Francisco Rolo whom without their continuous and valuable work in the area of Kidney transplant this work would not be possible.

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15. Shaw TM, Lonze BE, Feyssa EL, et al. Operative start times and complications after kidney transplantation. Clin Transplant. 2012; 26:E177-83.

16. Emmanouilidis N, Boeckler J, Ringe BP, et al. Risk balancing of cold ischemic time against night shift surgery possibly reduces rates of reoperation and perioperative graft loss. J Transplant. 2017; 2017:5362704.

17. Gopalakrishnan G, Gourabathini SP. Marginal kidney donor.

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18. Chapman JR. Marginal kidneys for transplantation. BMJ 2015; 351:h3856.

19. Amirian I. The impact of sleep deprivation on surgeons' performance during night shifts. Dan Med J. 2014; 61:B4912.

20. Moreira P, Sá H, Figueiredo A, Mota A. Delayed renal graft function: risk factors and impact on the outcome of transplantation.

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21. Salahudeen AK, Haider N, May W. Cold ischemia and the reduced long-term survival of cadaveric renal allografts. Kidney Int. 2004; 65:713-8.

22. Hernández D, Estupiñán S, Pérez G, et al. Impact of cold ischemia time on renal allograft outcome using kidneys from young donors. Transpl Int. 2008; 21:955-62 23. Lonze BE, Parsikia A, Feyssa EL, et al. Operative start times and complications after liver transplantation. Am J Transplant.

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4. Chen CL, Chen Y Sen, Liu PP, et al. Living related donor liver transplantation. J Gastroenterol Hepatol. 1997; 12: S342-345.

24. George TJ, Arnaoutakis GJ, Merlo CA, et al. Association of operative time of day with outcomes after thoracic organ transplant.

JAMA. 2011; 305:2193-9.

5. Rothschild JM, Keohane CA, Rogers S, et al. Risks of complications by attending physicians after performing nighttime procedures.

JAMA. 2009; 302:1565-72.

25. Araujo RL, Karkar AM, Allen PJ, et al. Timing of elective surgery as a perioperative outcome variable: analysis of pancreaticoduodenectomy. HPB (Oxford). 2014; 16:250-62.

6. Gray A. United Kingdom national confidential enquiry into perioperative deaths. Minerva Anestesiol. 2000; 66:288-92.

26. Heller JA, Kothari R, Lin HM, et al. Surgery start time does not impact outcome in elective cardiac surgery. J Cardiothorac Vasc Anesth. 2017; 31:32-36.

7. Fechner G, Pezold C, Hauser S, et al. Kidney's nightshift, kidney's nightmare? Comparison of daylight and nighttime kidney transplantation: impact on complications and graft survival. Transplant Proc.

2008; 40:1341-4.

27. Zafar SN, Libuit L, Hashmi ZG, et al. The sleepy surgeon: does night-time surgery for trauma affect mortality outcomes? Am J Surg.

2015; 209:633-9.

8. Debout A, Foucher Y, Trébern-Launay K, et al. Each additional hour of cold ischemia time significantly increases the risk of graft failure and mortality following renal transplantation. Kidney Int. 2015; 87:343-9.

28. Dalton MK, McDonald E, Bhatia P, et al. Outcomes of acute care surgical cases performed at night. Am J Surg. 2016; 212:831-836.

9. van Roijen JH, Kirkels WJ, Zietse R, et al. Long-term graft survival after urological complications of 695 kidney transplantations.

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Mário Pereira Lourenço, MD (Corresponding Author) mariolourenco88@gmail.com Miguel Eliseu - mgl.nobre@gmail.com Duarte Vieira Brito - duartevbrito@hotmail.com João Carvalho - joao.andre.mendes.carvalho@gmail.com Edgar Tavares-Silva - edsilva.elv@gmail.com Lorenzo Marconi - lorenzooliveiramarconi@gmail.com Pedro Moreira - pedronetomoreira@gmail.com Pedro Nunes - ptnunes@gmail.com Belmiro Parada - parada.belmiro@gmail.com Carlos Bastos - cabastos@netcabo.pt Arnaldo Figueiredo - ajcfigueiredo@gmail.com Urology and Renal Transplantation Department. Coimbra University Hospital Centre Rua Maria Bourbon Bobone, nº57, RE/esq, 3030-481, Coimbra (Portugal)

10. Opelz G, Döhler B. Multicenter analysis of kidney preservation.

Transplantation. 2007; 83:247-53.

11. Król R, Ziaja J, Chudek J, Heitzman M, et al. Surgical treatment of urological complications after kidney transplantation. Transplant Proc. 2006;38:127-30.

12. Agüera Fernandez LG, Robles JE, Rosell D, et al. Análisis multivariado del impacto de las complicaciones quirúrgicas en el trasplante renal (Multivariate analysis of the impact of surgical complications in renal transplant). Arch Esp Urol. 1994; 47:999-1006.

13. Seow YY, Alkari B, Dyer P, Riad H. Cold ischemia time, sur-

Correspondence

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DOI: 10.4081/aiua.2021.2.162

ORIGINAL PAPER

The Matryoshka technique in percutaneous nephrolithotomy Stefano Paolo Zanetti 1, Matteo Fontana 1, Elena Lievore 1, Matteo Turetti 1, Fabrizio Longo 1, Elisa De Lorenzis 1, 2, Giancarlo Albo 1, 2, Emanuele Montanari 1, 2 1 Fondazione

2 Department

IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Department of Urology, Milan, Italy; of Clinical Sciences and Community Health, University of Milan, Department of Urology, Milan, Italy.

Summary

Objective: Miniaturized percutaneous nephrolithotomy (PCNL) reduces the risk of haemorrhagic complications, but the limited field of work represents a drawback. To obtain the best outcomes, the percutaneous access size should be intraoperatively tailored. Our purpose is to describe the indications and the procedural steps of the Matryoshka technique and to report its clinical outcomes.

Materials and methods: We performed a retrospective analysis of the data from consecutive Matryoshka PCNL procedures from October 2016 to January 2018. Collected data included patients’ history, stone characteristics, intra- and post-operative items, stone clearance and need for retreatment. The main indication to the Matryoshka technique is the inability to securely position a guidewire due to an obstruction or narrowness in the pyelocalyceal system. This technique begins by puncturing the calyx hosting the stone and advancing a hydrophilic guidewire through the needle. If the guidewire cannot proceed beyond the stone, the Matryoshka technique is employed for tract stabilization. The tract is carefully dilated with small-bore instruments and a cautious lithotripsy is performed to create enough space to introduce the guidewire beyond the stone under visual control. Once the access has been stabilized the surgeon can upsize the tract to the optimum to complete the procedure. Additionally, the technique can be employed when an intraoperative reassessment induces the surgeon to further dilate the tract to quicken the procedure.

Results: Sixteen patients were included, with a median stone volume of 3.49 cm3. Median operative time was 112 minutes.

Three Clavien I-II (postoperative fever) and one Clavien IIIB (colon perforation) complications were reported. No blood transfusions were recorded. Three patients underwent scheduled retreatment as part of a multistep procedure. Out of the remaining 13 patients, 10 (76.9%) obtained a complete stone clearance.

Conclusions: The Matryoshka technique helps the urologist to obtain a secure percutaneous access and makes PCNL flexible and progressive, potentially minimizing the risk of access-related complications.

providing satisfactory stone-free rates (SFR) even in case of remarkable stone burden. Despite its effectiveness, the main drawbacks of this technique are its invasiveness and the significant risk of haemorrhagic complications, requiring a blood transfusion in around 7% (range 0-20%) of the cases (2). The site of the percutaneous renal puncture and the technique employed for the dilation of the access route are the most crucial steps to perform an effective and safe procedure (3-4). In the last decades, the introduction of small calibre instruments contributed to reduce the complications rate (5), making PCNL safer. However, miniaturized techniques added a few limitations, including reduced visibility, scarce instrument choice for lithotripsy and lapaxy, longer operative times and elevated renal pelvic pressures, restricting the applicability of these techniques to smallto-medium sized stones (6). In order to obtain the best outcomes, the percutaneous access size should be tailored to the distinctive characteristics of both the stone and the patient. This principle allows the urologist to minimize the morbidity of the treatment, enhancing at the same time its effectiveness. The minimally invasive PCNL (MIP) set, devised by Nagele (7), includes various progressive size nephroscopes and access sheaths in a single system. This modular set can be employed to intraoperatively adjust the tract size to the characteristics of the stones and to the anatomy of the collecting system, and to overcome potentially dangerous accessrelated issues. This allows to combine the advantages of miniaturized and standard PCNL: we defined this concept as the “Matryoshka technique” (8).

The aim of this study is to describe the indications and the procedural steps of the “Matryoshka technique” in PCNL and to report the clinical outcomes from our experience with this approach.

KEY WORDS: Kidney stones; Percutaneous nephrolithotomy; Minimally invasive surgical procedures; Percutaneous nephrostomy.

MATERIALS

Submitted 9 December 2020; Accepted 16 January 2021

INTRODUCTION

Percutaneous nephrolithotomy (PCNL) is the gold standard for the treatment of kidney stones larger than 20 mm (1),

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METHODS

Study design The PCNL database of our tertiary referral stone centre was retrospectively reviewed, and all consecutive patients who underwent a Matryoshka PCNL from October 2016 to January 2018 were included in this study. All procedures were carried out by a single expert urologist (more than 1000 PCNLs performed) in the No conflict of interest declared.

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same centre. Collected data included patients’ anthropometrics and medical and surgical history, stone characteristics, intra- and post-operative items, complications, stone clearance and need for retreatment.

Comorbidities were graded according to the Charlson Comorbidity Index. All patients underwent a preoperative contrast-enhanced CT scan to evaluate the stone characteristics (laterality, stone number and location, total volume and mean density expressed in Hounsfield Units) and to plan the surgical approach. The stone volume was measured by means of the ellipsoid formula (a x b x c x π/6) and in case of multiple stones, total stone volume was calculated as the sum of the volumes of the single stones. Intraoperative data included the number of percutaneous tracts employed, the successful placement of a safety guidewire, the access sheath size, lithotripsy modality, intraoperative complications, exit strategy and operative time, defined as the time from the kidney puncture to the exit strategy. The Matryoshka technique was evaluated both in terms of indication and tract size upscaling. Postoperative items included haemoglobin drop, need for blood transfusions, estimated glomerular filtration rate (eGFR) change and length of hospital stay.

Postoperative complications were graded according to the PCNL-adjusted Clavien Score (9). Stone clearance was assessed through follow-up imaging (CT scan or ultrasound) performed 3-6 months after surgery and was defined as the total absence of residual fragments.

All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all patients or from the legal guardians for patients having age less than 18. This study was approved by the local Ethics Committee (Comitato Etico Milano Area 2). Data were collected and analysed using the statistical software SPSS 25.0 (IBM Cor., Armonk, NY, USA).

Indications The main indication to the Matryoshka technique in PCNL is the inability to safely pass a guidewire into the renal collecting system without risking disrupting the calyx, due to the presence of a stone occupying the punctured calyx (calyceal staghorn) or its infundibulum (stone-engaged infundibulum), possibly causing the calyx to retain urine (stone-engaged hydrocalyx). In each one of these cases, the lack of a securely positioned guidewire could render the access ineffective and could cause several access-related complications. To minimize these risks, a less disruptive, smaller size tract should be initially employed until the setting is carefully evaluated and a safety guidewire is positioned under visual control, so that the access can be stabilized and upsized.

The indication to the Matryoshka technique may be posed preoperatively if the urographic phase of the CT scan shows a narrow calyceal infundibulum hosting the stone or a calyceal staghorn stone, but more often it becomes clear during the procedure, when, after puncturing the target calyx, the guidewire cannot proceed beyond the stone in the renal pelvis and down the ureter.

Furthermore, the Matryoshka technique can be employed in those situations in which the guidewire has properly passed, but the surgeon prefers to assess the local anatomy and the actual stone load before dilating the tract.

Armamentarium The armamentarium to perform a Matryoshka PCNL doesn’t differ from that of a classic PCNL. What is essential, though, is the availability of two or more different size nephroscopes and access sheaths to perform a progressive access. At least the first scope and sheath should be miniaturized, in order to start the procedure in the least invasive possible way. The availability of different size instruments allows the surgeon to shift from a smaller to a larger access when the local conditions demand and allow it. In our series we used the MIP set (Karl Storz SE, Tuttlingen, Germany). The complete MIP set is composed of three nephroscopes (7.5 Ch., 12 Ch., 19.5 Ch.), and by a series of compatible dilators and metallic percutaneous sheaths, categorized in the extra-small (XS, 9,5 Ch.), small (S, 12 Ch.), medium (M, 16-22 Ch.) and large (L, 24-26 Ch.) subsets (8).

Technique As the traditional PCNL, the Matryoshka procedure starts by placing a ureteral catheter up to the renal pelvis and by performing a retrograde pyelogram. If the preoperative urographic CT scan or the pyelogram show a staghorn or an infundibular stone, possibly obstructing the calyceal neck, the setting for the Matryoshka technique is defined.

Subsequently, after placing the patient in the supine Valdivia position, the calyx hosting the stone is punctured under fluoroscopic and/or ultrasonographic control and an hydrophilic guidewire is advanced through the needle.

If the calyceal neck is narrow or obstructed and the guidewire cannot proceed beyond the stone (Figure 1A), the Matryoshka technique can be employed for tract stabilization. The tract is carefully dilated with small-bore dilators and sheaths (MIP XS, S or M subsets), and a compatible nephroscope is introduced. Once the stone has Figure 1.

Representation of the Matryoshka technique.

(A) Stone obstructing the calyceal neck, preventing the guidewire from being inserted; (B) Cautious lithotripsy through a small access until creating enough space for the guidewire(s) to pass; (C) Tract dilation to the needed or allowed size according to the anatomical relation between the calyx and the stone; (D) Further tract dilation in order to speed up the procedure in case of very large stones with favourable anatomy.

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been visualized, cautious Holmium:YAG laser lithotripsy is started, creating enough space for the guidewire to pass, under visual control, beyond the stone into the renal pelvis and possibly down the ureter (Figure 1B). Since it is always possible to accidentally displace or kink the working guidewire during further manoeuvres and progressive tract dilations, the use of a safety guidewire is recommended as it minimizes the risk of losing the tract. When the access has been stabilized and the anatomical relation between the calyx and the stone is assessed, the surgeon can choose the dilation size needed or allowed, taking care not to dilate the tract beside the stone and not to force the calyx to a diameter exceeding its anatomy (Figure 1C).

This is the key concept of the Matryoshka technique. This technique can also be employed in case of a narrow or partially obstructed calyceal neck irrespective of the secure placement of a working guidewire, or when a miniaturized access is initially chosen to limit PCNL morbidity but nephroscopic evaluation after partial lithotripsy reveals enough space to further dilate the tract. In this situation, it is possible to upsize the tract to the largest calibre that is respectful of the pyelocalyceal anatomy to speed up the procedure. After the secondary dilation is performed, lithotripsy can be continued. An upsized tract offers a wider choice of lithotripsy probes, better irrigation, clearer vision and lower intrapyelic pressures. In case of very large stones, the tract diameter can be further upscaled according to intraoperative needs (Figure 1D). After lithotripsy, fragments are evacuated through the vacuum cleaner effect, a nitinol basket or endoscopic graspers. At the end of the procedure, a nephrostomy tube is placed, when needed, over the safety guidewire.

RESULTS

The Matryoshka technique was applied in 16 out of 74 procedures (21.6%) performed at our institution in the study period. Patients’ and stones’ characteristics are described in Table 1. In the 75% of the cases, multiple stones were treated. Median total stone volume was 3.49 cm3 (IQR 1.81-5.02). Intraoperative items and postoperative outcomes are reported in Table 2. Median operative time was 112 minutes (IQR 91-130). The indication to the Matryoshka technique was access stabilization in 14 cases (87.5%), due to the inability to advance the guidewire beyond the stone because of a calyceal staghorn stone (six cases), a stone-engaged calyceal infundibulum (four cases) or a stone-engaged hydrocalyx (four cases). In the remaining two cases (12.5%), intraoperative reassessment induced the surgeon to upsize the access to speed up and complete the procedure. In all the cases, through the Matryoshka technique, we managed to position a safety guidewire and obtain a secure access to the collecting system. Three patients reported postoperative fever (Clavien I-II) and one experienced a colonic puncture that was managed by temporary loop colostomy (Clavien IIIB).

Median hemoglobin drop was -1.6 g/dL (IQR -1.3 - -2.2), and none of the patients experienced a hemorrhagic complication or received a blood transfusion. We registered no complications regarding urinary leakage or drainage.

Concerning stone clearance, the overall stone free rate was 62.5% (10 out of 16 patients). Four patients needed a

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Table 1.

Patients' and stones' characteristics.

Sex n (%) Male Female Age (years) mean (± SD) BMI (kg/m2) mean (± SD) Charlson Comorbidity Index n (%) 0-1 ≥2 History of ipsilateral stone treatment n (%) SWL URS PCNL Pyelolithotomy Any treatment None Laterality n (%) Right Left Stone number n (%) Single Multiple Stone volume (cm3) median (IQR) Stone mean HU value (HU) median (IQR)

11 (68.7%) 5 (31.3%) 51.4 (13.7) 26.0 (3.4) 12 (75%) 4 (25%) 4 (25%) 2 (12.5%) 3 (18.8%) 2 (12.5%) 6 (37.5%) 10 (62.5%) 8 (50%) 8 (50%) 4 (25%) 12 (75%) 3.49 (1.81-5.02) 907 (834-1003)

BMI: Body Mass Index; SD: Standard deviation; SWL: Shockwave lithotripsy; URS: Ureteroscopy; PCNL: Percutaneous nephrolithotomy; IQR: Interquartile range; HU: Hounsfield Units.

Table 2.

Intraoperative items and postoperative outcomes.

Operative time (min) median (IQR) Percutaneous tract number n (%) Single Double Matryoshka technique - indication n (%) Access stabilization Calyceal staghorn Stone-engaged infundibulum Stone-engaged hydrocalyx Intraoperative reassessment Matryoshka technique - size n (%) XS → M S→M M→L S→M→L Exit strategy n (%) Nephrostomy Nephrostomy + Double J stent Nephrostomy + Ureteral splint Tubeless/Totally tubeless Hb change (g/dL) median (IQR) eGFR change (mL/min) median (IQR) Post-operative complications n (%) None Clavien I-II Clavien III Length of stay (days) median (IQR) Stone clearance n (%) Yes No Need for retreatment n (%) No Yes (planned) Yes (unplanned)

112 (91-130) 12 (75%) 4 (25%) 14 (87.5%) 6 (37.5%) 4 (25%) 4 (25%) 2 (12.5%) 2 (12.5%) 8 (50%) 3 (18.8%) 3 (18.8%) 10 (62.5%) 2 (12.5%) 2 (12.5%) 2 (12.5%) -1.6 (-1.3 – -2.2) 0.7 (-2.3-6.6) 12 (75%) 3 (18.8%) 1 (6.3%) 5 (4-6) 10 (62.5%) 6 (37.5%) 12 (75%) 3 (18.8%) 1 (6.3%)

IQR: Interquartile range; eGFR: estimated glomerular filtration rate; XS: Extra-small = 9,5 Ch.; S: Small = 12 Ch.; M: Medium = 16-22 Ch.; L: Large = 24-26 Ch.

Matryoshka technique in PCNL

Table 3.

Matryoshka procedures.

Patient N.S., ♀, 35 yrs.

R.P., ♂, 45 yrs.

B.R., ♂, 62 yrs.

U.L., ♂, 38 yrs.

O.P., ♀, 54 yrs.

C.C., ♂, 54 yrs.

S.P., ♂, 52 yrs.

I.A., ♀, 72 yrs.

T.I., ♀, 62 yrs.

S.T., ♂, 56 yrs.

B.S., ♂, 56 yrs.

P.M., ♂, 14 yrs.

C.L., ♀, 56 yrs.

C.C., ♂, 53 yrs.

C.S., ♂, 65 yrs.

M.E., ♂, 49 yrs.

Stone load 18.9 cm3; HU max 1278; HU mean 681 staghorn (pelvis, middle calyx, lower calyx) 0.74 cm3; HU max 835; HU mean 593 multiple (middle calyx, lower calyx) 1.79 cm3; HU max 1193; HU mean 904 multiple (middle calyx, lower calyx) 3.80 cm3; HU max 592; HU mean 458 multiple (pelvis, lower calyx) 3.18 cm3; HU max 1415; HU mean 775 single (upper calyx) 1.44 cm3; HU max 1659; HU mean 997 multiple (middle calyx, lower calyx) 0.82 cm3; HU max 1646; HU mean 962 multiple (middle calyx) 3.53 cm3; HU max 1145; HU mean 900 staghorn (pelvis, lower calyx) 3.45 cm3; HU max 1256; HU mean 906 staghorn (pelvis, lower calyx) 6.83 cm3; HU max 1045 ; HU mean 950 staghorn (pelvis, lower calyx) 2.99 cm3; HU max 1380; HU mean 1150 staghorn (pelvis, lower calyx) 10.42 cm3; HU max 1049; HU mean 853 staghorn (pelvis, middle calyx, lower calyx) 1.82 cm3; HU max 1859; HU mean 1300 multiple (pelvis, middle calyx, lower calyx) 4.42 cm3; HU max ; HU mean staghorn (pelvis, middle calyx, lower calyx) 24.02 cm3; HU max 1619; HU mean 1200 staghorn (complete) 3.61 cm3; HU max 1285; HU mean 908 staghorn (pelvis, lower calyx)

retreatment, which was already scheduled as part of a planned multistep procedure for three of them. Ten out of the 13 patients scheduled for a single step procedure (76.9%) obtained a complete stone clearance.

The single procedures are presented in Table 3, with details regarding the stone load, the Matryoshka technique indication and the access tracts size.

DISCUSSION

The authors of a recent review on miniaturized PCNL stated that the surgical treatment that each patient should be offered ought to be tailored to the distinctive characteristics of both the patient and the stone (10).

The Matryoshka technique is the extremization of this concept: the opportunity to intraoperatively individualize the tract diameter to the anatomy of the pyelocalyceal system enables the surgeon to take advantage of the benefits of the different sized scopes and sheaths in every single procedural step. To the best of our knowledge, this is the first report of a series of patients treated with the Matryoshka technique. The main benefit of this technique is to provide a more secure percutaneous approach to the pyelocalyceal system in case of several access-related issues that could potentially undermine both the safety and proficiency of the tract creation.

In order to safely dilate the access and to position a percutaneous sheath, a guidewire should be firmly set inside the urinary tract: this manoeuvre is crucial to minimize the risk of kinking or slipping of the guidewire itself, that would render the access difficult or ineffective, and to reduce the mobility of the punctured kidney. When the guidewire cannot be securely held in the pyelocalyceal system, it is prudent to establish the smallest possible tract, which can be created with less strain on the guidewire and the kidney, and it is less harmful than a larger one. After the initial nephroscopy and the subsequent individuation of the issue underlying the suboptimal placement of the guidewire, the route for its

Percutaneous tract 2 tracts (lower calyx) 2 tracts (lower calyx) 1 tract (lower calyx) 2 tracts (lower calyx) 1 tract (upper calyx) 1 tract (lower calyx) 1 tract (middle calyx) 1 tract (lower calyx) 1 tract (lower calyx) 1 tract (lower calyx) 2 tracts (lower and middle calyx) 1 tract (lower calyx) 1 tract (lower calyx) 1 tract (middle calyx) 1 tract (lower calyx) 1 tract (lower calyx)

Matryoshka Indication Calyceal staghorn Stone-engaged infundibulum Stone-engaged hydrocalyx Stone-engaged infundibulum Stone-engaged hydrocalyx Stone-engaged hydrocalyx Stone-engaged hydrocalyx Intraoperative reassessment Intraoperative reassessment Stone-engaged infundibulum Calyceal staghorn Calyceal staghorn Stone-engaged infundibulum Calyceal staghorn Calyceal staghorn Calyceal staghorn

Matryoshka size 17.5 Ch. → 22 Ch. 12 Ch. → 16 Ch. 9.5 Ch. → 16 Ch. 9.5 Ch. → 17.5 Ch. 12 Ch. → 16 Ch. 12 Ch. → 16 Ch. 12 Ch. → 16 Ch. 12 Ch. → 16 Ch. 12 Ch. → 16 Ch. 17.5 Ch. → 24 Ch. 12 Ch. → 16 Ch. 12 Ch. → 17.5 Ch. → 24 Ch. 12 Ch. → 17.5 Ch. 12 Ch. → 17.5 Ch. → 24 Ch. 16 Ch. → 24 Ch. 12 Ch. → 17.5 Ch. → 24 Ch..

advancement can be created by means of a prudent lithotripsy. Once the guidewires are firmly positioned, the tract can be dilated to the desired calibre.

In addition, the initial assessment of the urinary tract through a miniaturized nephroscope allows a precise recognition of anatomical variations, enabling the surgeon to preserve the integrity of the pyelocalyceal system: for instance, the identification of a narrow calyceal infundibulum could compel the urologist to complete the PCNL with small bore instruments, possibly preventing inadvertent disruptions of the urinary tract.

Flexibility and scalability are two more strengths of this technique, which allows the reassessment of the local conditions during the procedure and the modification of the surgical approach in case of need. With this concept in mind, the chosen instruments can be readjusted on the basis of the characteristics of both the stone and the patient, and a truly tailored approach can be achieved.

The results from our initial experience seem to support these concepts. Although we treated complex cases, with significant stone loads and a high prevalence of multiple, staghorn stones, none of the patients experienced an haemorrhagic complication or required a blood transfusion; moreover, no cases of postoperative urine extravasation were recorded. Additionally, with the employment of the Matryoshka technique, all of the gained accesses have been successfully stabilized and exploited, and none was rendered ineffective because of guidewire slipping or kinking. Although we registered a colonic perforation, we do not believe that this complication is related to the Matryoshka technique in itself, as it generally occurs during the primary tract creation and not during secondary dilations, that are performed on an already established tract. Specifically, the perforation we reported occurred during the initial access despite ultrasonographic control, in a paraplegic patient that suffered from severe bowel disfunction and enlargement.

Regarding our stone free rate, we believe it can be deemed satisfactory considering that the Matryoshka technique is Archivio Italiano di Urologia e Andrologia 2021; 93, 2

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especially useful in complex and challenging cases, usually characterized by less favourable results.

Our work is not devoid of limitations. First of all, our sample is quite meagre: this is due to the particular indications of the Matryoshka technique, that was applied in a limited number of patients in the considered period of time. Secondly, even if the results are encouraging, our work lacks a control group, that we believe would be hard to identify because of the unusual characteristics of the cases treated. Additionally, randomizing patients would be extremely difficult, as the indication to our technique is frequently defined intraoperatively.

CONCLUSIONS

The Matryoshka technique appears to be a safe and effective approach to obtain a secure percutaneous access to the kidney in challenging situations. It makes the PCNL procedure flexible and progressive, allowing the surgeon to intraoperatively adjust the tract size according to the local anatomy and stone characteristics. In this way, the less invasive achievable tract is stabilized, tailored to the patient and the stone, potentially minimizing the chances of calyceal tear and the related risk of complications.

REFERENCES

1. Türk C, Skolarikos A, Neisius A, et al. EAU Guidelines on Urolithiasis. 2019.

Correspondence Stefano Paolo Zanetti, MD (Corresponding Author) stefano.p.zanetti@gmail.com Matteo Fontana, MD teo.fontana@yahoo.it Elena Lievore, MD elena.lievore01@gmail.com Matteo Turetti, MD matteo.turetti@gmail.com Fabrizio Longo, MD longomd@gmail.com Elisa De Lorenzis, MD elisa.delorenzis@gmail.com Giancarlo Albo, MD albo.giancarlo@gmail.com Emanuele Montanari, MD emanuele.montanari@unimi.it Via Della Commenda 15, 20122, Milano, Italy

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2. Seitz C, Desai M, Häcker A, et al. Incidence, Prevention, and Management of Complications Following Percutaneous Nephrolitholapaxy. Eur Urol. 2012; 61:146-158.

3. Tahra A, Sobay R, Bindayi A, et al. Papillary vs non-papillary access during percutaneous nephrolithotomy: Retrospective, matchpaired case-control study. Arch Ital Urol Androl. 2020; 92:50-52.

4. Sahin A, Uruc F. The comparative analysis of the three dilatation techniques in percutaneous nephrolithotomy: Which one is safer?

Arch Ital Urol Androl. 2019; 91:171-173.

5. Ruhayel Y, Tepeler A, Dabestani S, et al. Tract sizes in miniaturized percutaneous nephrolithotomy: a systematic review from the European Association of Urology Urolithiasis Guidelines Panel. Eur Urol. 2017; 72:220-235.

6. Heinze A, Gozen AS, Rassweiler J. Tract sizes in percutaneous nephrolithotomy: does miniaturization improve outcome? Curr Opin Urol. 2019; 29:118-123.

7. Nagele U, Schilling D, Anastasiadis AG, et al. Minimally invasive percutaneous nephrolitholapaxy (MIP). Urol - Ausgabe A. 2008; 47:1066-1073.

8. Zanetti SP, Boeri L, Gallioli A, et al. Minimally invasive PCNL MIP. Arch Esp Urol. 2017; 70:226-234.

9. De La Rosette JJMCH, Opondo D, Daels FPJ, et al. Categorisation of complications and validation of the Clavien score for percutaneous nephrolithotomy. Eur Urol. 2012; 62:246-255.

10. Proietti S, Giusti G, Desai M, Ganpule AP. A Critical Review of Miniaturised Percutaneous Nephrolithotomy: Is Smaller Better? Eur Urol Focus. 2017; 3:56-61.

DOI: 10.4081/aiua.2021.2.167

ORIGINAL PAPER

Mini percutaneous nephrolithotomy versus retrograde flexible ureterorenoscopy in the treatment of renal calculi in anomalous kidneys Hussein M. Abdeldaeim, Omar El Gebaly, Mostafa Said, Abdel Rahman Zahran, Tamer Abouyoussif Department of Urology, Alexandria University, Alexandria, Egypt.

Summary

Objectives: To report our single center experience in comparing mini-percutaneous nephrolithotomy versus flexible ureterorenoscopy for management of renal stones up to 2 cm in anomalous kidneys.

Materials and methods: Records of the last 30 patients with stones less than 2 cm in anomalous kidney treated by mini-percutaneous nephrolithotomy were reviewed and compared to last 30 patients treated by flexible ureterorenoscopy.

Results: Mean stone size was significantly higher in the minipercutaneous nephrolithotomy group (17.90 mm) than in flexible ureterorenoscopy group (14.97mm) (p < 0.001). Mean operative time (80.33 min vs 56.43 min) and fluoroscopy exposure time (4.49 min vs 0.84 min) were significantly higher in the mini-percutaneous nephrolithotomy group than in the flexible ureterorenoscopy group (p < 0.001). The mean post-operative drop in hemoglobin concentration was significantly higher in the mini-percutaneous nephrolithotomy group (0.47 gm versus 0.2 gm) (p < 0.001). Stone free rate after 12 weeks follow up was not statistically significant between the 2 groups (90% in minipercutaneous nephrolithotomy vs 80% in flexible ureterorenoscopy) (FEp = 0.472).

Conclusions: Both modalities were found to be safe and effective for treatment of stones less than 2 cm in anomalous kidneys.

KEY WORDS: Mini percutaneous nephrolithotomy; Flexible ureterorenoscopy; Anomalous kidneys.

Submitted 22 February 2021; Accepted 21 April 2021

INTRODUCTION

Congenital anomalies of the kidney including anomalies of lie, rotation and fusion are caused by impaired migration of the ureteric bud and metanephric blastema upwards from pelvis to upper abdomen. The renal calyces are normally rotated 30-50 degrees behind the coronal axis so that the calyces point laterally, and the pelvis points antero-medially, when this axis is disturbed, the condition is known as renal malrotation (1).

The incidence of urolithiasis in anomalous kidneys is higher than in normal kidney, as these conditions lead to impaired urine drainage and urinary stasis as well as an increased incidence of upper urinary tract infection.

The anatomy and location of these kidneys makes the management of urolithiasis challenging (2). The majority of those patients have been historically treated with open surgery. However nowadays various minimally

invasive modalities for stone treatment are used in those patients, such as, percutaneous nephrolithotomy (PNL), mini-perc, ultramini-perc, micro-perc, extracorporeal shockwave lithotripsy (SWL) and flexible ureterorenoscopy (F-URS) with reported variable stone free rates. Other possible available treatment options are laparoscopicassisted PNL and laparoscopic pyelolithotomy (LP) (3).

In the present study, we report our single center experience in comparing mini-perc versus F-URS for management of renal stones up to 2 cm in patients with anomalous kidneys.

MATERIALS

AND METHODS

We retrospectively reviewed the records of patients with stones in anomalous kidneys treated by miniperc between January 2016 to June 2020 and we compared them to the records of patients with same stone criteria treated by flexible ureterorenoscopy. We excluded patients below 18 years, stones more than 2 cm in maximum diameter or patients with multiple stones and patients with ectopic pelvic kidneys. Preoperative radiological investigations included plain X-ray of abdomen and pelvis and non-contrast CT. Stone size was calculated by measuring the maximum stone diameter.

All procedures were performed by the same surgeon at our institute.

Mini-perc group All procedures were performed under general anesthesia. Insertion of a 6 Fr open tip ureteric catheter was performed in the lithotomy position, then the patient was turned prone. All pressure points were padded.

The optimal calyx of entry was determined by using both biplanar C-arm fluoroscopy after retrograde injection of the half-diluted contrast and ultrasonography (Figure 1). If bowel and/or viscera were found across the chosen access, then it was displaced away by pressure of US probe as was described by Desai et al. (4). A tract was gradually dilated with fascial dilators (Cook Urological, USA) and 16.5/17.5 operating sheath was inserted.

A 34-cm long semirigid ureteroscope (9.5 Fr) (Karl Storz; Tuttlingen, Germany) was used with Auriga XL 50W Holmium Laser machine (Boston scientific; USA) and 600 µ laser fiber. After inspection of the pelvicalyceal system, the

No conflict of interest declared.

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Figure 1.

(A). Plain KUB showing right hypochondrial radiopaque shadow (B). Axial CT cut showing 1.2 cm stone in right laterally malrotated kidney (C).

Fluoroscopic image after retrograde pyelogram showing complete lateral renal pelvis malrotation with stone inside (blue arrow).

A.

B.

stone was dusted using holmium-Yag laser with energy of 0.5-0.8 J and frequency of 12-16 Hz. Most of the small fragments were cleared spontaneously with irrigation fluid coming out around the ureteroscope. Larger fragments were retrieved by a 5 Fr forceps (Karl Storz, Tuttlingen, Germany). If the pelvicalyceal system, under fluoroscopic and nephroscopic inspection, was found to be clear, a 6 Fr double-J stent (DJ) was placed if needed with or without insertion of 14 Fr nephrostomy tube (PCN).

F-URS group All procedures were performed under general anesthesia with the patient in the lithotomy position, using a 9.5-Fr semi-rigid ureteroscope (Karl Storz; Germany); the ureter was cannulated with a 0.038-inch hydrophilic tip guidewire. The lower ureter was dilated by the semi-rigid ureteroscope (Karl Storz, Germany) over the guidewire.

Retrograde pyelogram through the ureteroscope was done for better understanding of the pelvi-calyceal anatomy. After dilating the ureteral orifice and lower ureter a second hydrophilic tip guidewire was inserted into the pelvicalyceal system. Under fluoroscopic guidance a 7.5 Fr F-URS (Flex-X2; STORZ, Tuttlingen, Germany) was back loaded on one of the guidewires into the kidney (Figure 2). A pressurized manual irrigation pump was used to have clear vision. After inspection of the pelvis and calyces and identification of the stone, Auriga XL 50W Holmium YAG Laser machine (Boston scientific; USA) and 200/312 µ laser fiber, with settings of 0.5-0.8 J/12-16 Hz was used for dusting the stone. In some patient when in situ stone dusting was difficult, the stones were relocated into the upper calyx using a zero tipped nitinol basket (Boston scientific, USA) basket. A JJ stent was placed in all patients after the completion of the procedure under fluoroscopy. Intraoperative variables A.

B.

C.

were recorded including operative time, fluoroscopy time, need for blood transfusion, complications, etc.

Postoperative assessment included hemoglobin level, serum creatinine level, need for auxiliary procedures, complications according to Clavian Dindo classification, and pain assessment using visual analogue scale (VAS) (5). Plain X-ray abdomen and pelvis was done on the first postoperative day and at 3 months. Non contrast CT was also performed. Stone free status (SFR) was defined as the absence of any residual fragments ≥ 3 mm at 3 months in CT. Statistical analysis was carried out using SPSS statistics software version 20. Categorical variables were described using frequencies and percentages. Chi-square test was used for testing associations between categorical variables.

When the assumptions of chi-square test were not met, Fisher’s exact p value was selected for 2:2 tables and Monte Carlo p value was reported for more than 2:2 tables.

Continuous variables were described using mean and standard deviation. In such case, independent sample ttest was used for comparing two independent groups and paired sample t- test was used for comparing two dependent groups. Statistical significance was accepted as p < .05.

All applied statistical tests of significance were two-tailed.

RESULTS

Both groups were comparable regarding age, sex, body mass index and mean stone density.

Mean stone size was significantly higher in the mini-perc group than in F-URS group (p < 0.001). Patients’ demographic data and stone criteria are listed in Table 1.

Overall, the most common presenting symptom was pain (66.7% of patients in mini-perc group vs 40% in FURS group) and the most common stone location was the renal pelvis in both groups.

C. Figure 2.

(A). Axial CT cut showing 1.5 cm stone in the lower calyx of left kidney in patient having horseshoe kidney (B).

Intraoperative fluoroscopic image showing the f-URS inside the left kidney and the stone (black arrow) (C). Fluoroscopic image after retrograde contrast injection into the pelvicalyceal system through the f-URS and showing the stone in the lower calyx (black arrow).

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Mini-Perc vs flexible ureteroscopy in anomalous kidneys

Table 1.

Comparison between the two studied groups according to demographic data and stone criteria.

Mini perc (n = 30) No. % Sex Male Female Age (years) Mean ± SD BMI Mean ± SD Nature of the renal anomaly Medial malrotation Ventral malrotation Lateral malrotation Horseshoe kidney Renal duplication Crossed ectopic kidney Stone side Right Left Stone site Renal pelvis Lower calyx Upper calyx Middle calyx Stone size (mm) Mean ± SD Stone density (HU) Mean ± SD

RIRS (n = 30) No. %

p 0.519

25 5

83.3 16.7

23 7

76.7 23.3 0.594

42.53 ± 10.47 41.07 ± 10.71 0.553 29.30 ± 2.78 28.80 ± 3.64 6 10 1 10 3 0

20.0 33.3 3.3 33.3 10 0.0

4 13 2 10 0 1

13.3 43.3 6.7 33.3 0.0 3.3

12 18

40.0 60.0

18 12

60.0 40.0

25 4 0 1

83.3 13.3 0.0 3.3

17 9 1 3

56.7 30.0 3.3 10.0

MCp = 0.451

DISCUSSION

0.121 MCp = 0.136

< 0.001* 17.90 ± 2.43

14.97 ± 3.50

1148.7 ± 279.6

1087.9 ± 225.3

for residual fragments and one patient was considered for follow up. In F-URS group, 2 patients required a second session of F-URS for residual fragments, 1 patient underwent SWL and 3 patients were considered for follow up. In terms of complications, 4 patients in miniperc group suffered moderate postoperative pain (Clavien grade I) despite receiving sodium diclofenac and 2 patients developed fever. In F-URS group, three patients suffered moderate colic pain postoperatively (Clavien grade I) and fever developed in 6 patients (20%). Mild postoperative hematuria was observed in 15 patients (50%) in each group.

0.358

From January 2016 till June 2020. 103 patients with stones in anomalous kidneys were treated in our institution; 25 patients were excluded from the current study as they were not meeting the inclusion criteria; 37 patients were treated with mini-perc and 35 patients were treated with f-URS. After excluding 7 patients in the mini-perc group who were lost to follow up and 5 patients in f-URS group, we evaluated 30 patients in the mini-perc group and 30 in the F-URS group (Figure 3).

Operative time (80.33 min vs 56.43 min) and fluoroscopy exposure time (4.49 min vs 0.84 min) were significantly higher in the mini-perc group than in the F-URS group respectively. Also, the post-operative drop in hemoglobin concentration was significantly higher in the mini-perc group than f-URS group (0.47 gm versus 0.2 gm respectively) (p < 0.001). No statistically significant difference between the 2 groups was found regarding hospital stay.

Blood transfusion was required in only 1 patient in the mini-perc group (Clavien grade II). Clinical and operative outcomes are summarized in Table 2.

Middle calyceal puncture was done in 15 patients, upper calyceal puncture in 10 patients, lower calyceal puncture in 4 patients and non-papillary puncture in 1 patient.

Stone free rate on day 1 postoperative was 76.7% (23/30) in mini-perc group and 40% (12/30) in F-URS group; the difference was statistically significant (p = 0.004). After 3 months there was no statistically significant difference in the SFR between both groups. The clinical and operative outcomes are summarized in Table 2.

In the mini-perc group, two patients underwent SWL

Stones within the normal pelvicalyceal system are accessed and endoscopically treated based on specific and well-known stone factors such as size and location.

Guidelines and indications of endoscopic management of stones are well known in orthotopic and orthomorphic renal units. However, in the anomalous renal units, deviation from the standard anatomical structure makes stone access and manipulation more challenging.

In this study, we observed our previously managed patients with stones in anomalous kidneys. The purpose of this research wss to compare the outcome of mini-perc and flexible URS in treating stones less than 2 cm in diamTable 2.

Comparison between the 2 groups regarding clinical and operative outcomes.

Mini perc (n = 30) No. % Intraoperative complications Yes (red out) No Blood transfusion Yes No Operative time (minutes) Mean ± SD Radiation exposure time (minutes) Mean ± SD SFR (3 months) Stone free Significant residual Hospital stay (day) Mean ± SD Hb drop Mean ± SD Auxiliary procedure Yes No Fever Yes No Hematuria Yes (mild) No (VAS) Pain No pain Mild Moderate

RIRS (n = 30) No. %

3 27

10 90

0 30

0 100

1 29

3.3 96.7

0 30

0 100.0

p FEp =

0.237 FEp = 1.000

< 0.001* 80.33 ± 15.42

56.43 ± 18.6

4.49 ± 0.80

0.84 ± 0.41

< 0.001* 27 3

90 10

24 6

80 20

FEp = 0.472

0.704 1.27 ± 0.64

1.33 ± 0.71

0.47 ± 0.34

0.20 ± 0.14

< 0.001* 2 28

6.7 93.3

3 27

10 90

2 28

6.7 93.3

6 24

20 80

15 15

50 50

15 15

50 50

1 25 4

3.3 83.3 13.3

3 24 3

10 80 10

FEp = 1.000 FEp =

0.254 FEp = 1.000 MCp = 0.214

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Figure 3.

Flow chart like diagram of inclusion and exclusion criteria showing number of patients excluded, number of patients enrolled, and number of patients subjected to analysis in each group.

eter in patients with anomalous kidneys. Several variables were studied and correlated to stone free rate and incidence of complications. Patients of the two groups were matched in terms of preoperative factors except for stone size, which reflected the surgeon's preference for the miniperc in large stones over f-URS. To our knowledge, there is not much data in the literature comparing mini-perc with f-URS for treatment of small and medium sized stone in anomalous kidneys. Although the SFR in the mini-perc group (90%) is higher than the f-URS group the difference is not statistically significant and it is associated with a lower complication rate in the f-URS group. Post-operative Hb drop was significantly higher in the mini-perc group than the f-URS group.

PNL is considered an acceptable intervention for stones in anomalous kidneys with reported high SFR (> 90%) (6, 7). Unfortunately, in anomalous kidneys, PNL is

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challenging and potentially associated with risks of access failure and vascular injuries (7).

There are several studies that reported the SFR after PNL in patients having different renal anomalies (6-9).

Mosavi-Bahar et al. (8), initially reported 81% success rate after a first session which increased to 100% after second-look PNL and/or SWL in 16 patients with anomalous kidneys. Similar data with comparable outcome were reported by Gupta et al. (6) and Rana et al. (9).

In a larger series, Osther et al. (7), reported standard-PNL in 202 anomalous-kidneys with SFR of 76.6%.

Furthermore, mini-perc in anomalous kidneys was prospectively evaluated by Sanjay-Khadgi et al. (10) who reported a SFR of 89.8% after a single session, which was improved to 93.2% after a 2nd mini-perc session and to 98.3% after auxiliary SWL. Similarly, in our cohort, despite the retrospective nature and the smaller size, we

Mini-Perc vs flexible ureteroscopy in anomalous kidneys

reported 90% initial SFR. In the current study, significantly longer operative time was reported in the miniperc group that can be a consequence of a selection bias as larger stones were more frequently treated by miniperc while small stones by flexible URS. Operative time in the current study in mini-perc group (45.0-110 min) is comparable to what was previously reported with standard PNL (69-100 min) (6-9) and in other mini-perc studies (25-105 min). (10) Mean operative time in FURS group in the current study was 56.43 ± 18.6 min compared with other series, which showed an operative time of 106 min by Weizer et al. (2), 126 min by Molimard B et al. (11) and 74 min by Gajednra et al. (12).

In the current series the targeted calyces were selected according to the site of the stone inside the kidney, although in horseshoe kidney upper calyceal puncture was selected in all patients to facilitate access to renal pelvis and lower calyx and avoid bowel injury. The lower calyceal stones which represented 30.0% of the total stone site in f-URS group were approached by the scope deflection in order to take them by tipless nitinol Dormia baskets and to reposition in a more favorable site (upper calyces or renal pelvis) for laser lithotripsy (5 patients) or to dust them in situ (4 patients) which took a longer operative time than stones in the other sites, so explaining the wide variation in operative time in f-URS group.

The mean hospital stay in the present series is shorter (1.27 days) than reported in previously mentioned standard PNL studies (3-3.2 days) (6-9) and in a mini-perc study (2.75 days) (10).

Intraoperative blood loss and consequent blood transfusion was the most alarming adverse event in our miniperc series. This group reported significantly greater hemoglobin drop 0.47 g/dl than in flexible URS group and required blood transfusion in one patient (3.3%).

Blood loss was comparable to what reported by similar studies, due to the presence of abnormal vasculature (6, 13, 14). However, none of our patients in the mini-perc group required angio-embolization, that was reported in some studies using standard PNL (15).

In the current study, no pleura related complications occurred in either group.

Correspondingly, Shokeir et al. (15), and Viola et al. (16), did not report pleural injuries after upper pole puncture in patients with horseshoe-kidney. On the other hand, Mosavi-Bahar et al. reported mild pleural complication in two patients (8). Gupta et al. (6), and Ozden et al. (17), reported pleural injury which was managed by intercostal tube insertion in one patient. Raj et al. reported pneumothorax in 6 % of patients with horseshoe kidneys undergoing PNL (18).

Acute deflection capability (up to 270°) and clear vision of new generation flexible ureteroscope together with progressively thinning of laser fibers and introduction of nitinol stone baskets have facilitated management of calculi located in lower calyces or difficult accessed calyces, therefore f-URS has the potential ability to overcome the anatomical and technical challenges of stone treatment in renal anomalies, leading to SFR (70 to 88.2%) in up to 1.5 sessions for stones < 3 cm (2, 11). In the current series the SFR after 3 months was 80% after a single session of f-URS and 86.6% after the second session. Molimard et al. (11)

reported SFR of 53% after the first session, and 88.2 % after the second one. Gajendra et al. (12) reported 72% SFR after the first procedure and 88% after the second session. Haddad et al. reported stone-free rate of 75% for stones with average diameter of 12.22 mm (19).

In the current study we reported the SFR of miniperc and f-URS in patients with horseshoe kidneys; 80% (8 patients) who underwent miniperc were stone free after a single session, while in the f-URS group the SFR was 60% (6 patients) after a single session and 70% after the second session which is comparable to the SFR in study conducted by Eryildirim et al. (84.2% with conventional PNL and 82.0% with f-URS) (20). The higher SFR in the miniperc group can be attributed to better fragments drainage during the procedure. The retrospective nature of the study allowed us to witness surgeons’ preference in these cases. It was clear the preference of mini-perc over the flexible URS for large stones.

The SFR in the current series might have been increased and the need for second look mini-perc or SWL might have been lowered if flexible nephroscope was used in combination with mini-perc. However, the outcome of mini-perc in the current series is comparable to other standard PNL and mini-perc studies, taking into consideration that the smaller size of mini-perc allows maneuverability and the access to more calices which might not be reached by standard PNL. Being an observational and retrospective study, we acknowledge limitations such as mismatch between study groups, the non-blinding of the surgeons, small sample size, and the lack of cost analysis.

Consequently, larger prospective randomized studies are needed to accurately compare f-URS and mini-perc in the management of stone in anomalous kidneys and to acknowledge the specific indications of each modality.

CONCLUSIONS

Mini-perc and f-URS are both feasible, with considerable safety, in the management of stones in anomalous kidneys. The choice between the available endourological procedures requires wisdom in the decision, good evaluation and planning.

REFERENCES

1. Yosypiv IV. Congenital anomalies of the kidney and urinary tract: a genetic disorder? Int J Nephrol. 2012; 2012:909083.

2. Weizer AZ, Springhart WP, Ekeruo WO, et al. Ureteroscopic management of renal calculi in anomalous kidneys. Urology 2005; 65:265-9.

3. Gupta M, Lee MW. Treatment of stones associated with complex or anomalous renal anatomy. Urol Clin North Am 2007; 34:431-41.

4. Desai M. Ultrasonography-guided punctures-with and without puncture guide. J Endourol 2009; 23:1641-3.

5. Graham B. Generic health instruments, visual analog scale, and the measurement of clinical phenomena. J Rheumatol 1999; 26:22-3.

6. Gupta NP, Mishra S, Seth A, et al. Percutaneous nephrolithotomy in abnormal kidneys: single-center experience. Urology 2009; 73:710-4.

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7. Osther PJ, Razvi H, Liatsikos E, et al. Percutaneous nephrolithotomy among patients with renal anomalies: patient characteristics and outcomes; a subgroup analysis of the clinical research office of the endourological society global percutaneous nephrolithotomy study. J Endourol 2011; 25:1627-32.

8. Mosavi-Bahar SH, Amirzargar MA, Rahnavardi M, et al.

Percutaneous nephrolithotomy in patients with kidney malformations. J Endourol 2007; 21:520-4.

14. Binbay M, Istanbulluoglu O, Sofikerim M, et al. Effect of simple malrotation on percutaneous nephrolithotomy: a matched pair multicenter analysis. J Urol 2011; 185:1737-41.

15. Shokeir AA, El-Nahas AR, Shoma AM, et al. Percutaneous nephrolithotomy in treatment of large stones within horseshoe kidneys. Urology 2004; 64:426-9.

9. Rana AM, Bhojwani JP. Percutaneous nephrolithotomy in renal anomalies of fusion, ectopia, rotation, hypoplasia, and pelvicalyceal aberration: uniformity in heterogeneity. J Endourol 2009; 23:609-14.

16. Viola D, Anagnostou T, Thompson TJ, et al. Sixteen years of experience with stone management in horseshoe kidneys Urol Int 2007; 78:214-8.

10. Khadgi S, Shretha B, Ibrahim H, et al. Mini-percutaneous nephrolithotomy for stones in anomalies-kidneys: a prospective study. Urolithiasis 2017; 45:407-14.

17. Ozden E, Bilen CY, Mercimek MN, et al. Horseshoe kidney does it really have any negative impact on surgical outcomes of percutaneous nephrolithotomy? Urology 2010; 75:1049-52.

11. Molimard B, Al-Qahtani S, Lakmichi A, et al. Flexible ureterorenoscopy with holmium laser in horseshoe kidneys. Urology 2010; 76:1334-7.

18. Raj GV, Auge BK, Weizer AZ, et al. Percutaneous management of calculi within horse-shoe kidneys. J Urol 2003; 170:48-51.

12. Gajednra A, Singh J, Sabnis R, et al. Role of flexible uretrorenoscopy in management of renal calculi in anomalies kidneys: single-center experience. World J Urol 2017; 35:319-24.

13. Di Mauro D, La Rosa VL, Cimino S, Di Grazia E. Clinical and psychological outcomes of patients undergoing Retrograde Intrarenal Surgery and Miniaturised Percutaneous Nephrolithotomy for kidney

Correspondence Hussein M Abdeldaeim, MD h_abdeldaeim@hotmail.com Omar El Gebaly, MD omarelgebaly@hotmail.com Mostafa Said, MD (Corresponding Author) mstmst2007@yahoo.com Abdel Rahman Zahran, MD abdelrahmanzahran@gmail.com Tamer Abouyoussif, MD tamer.abouyoussif@alexmed.edu.eg Urology Department, Faculty of Medicine, Sultan Hussein street, Alexandria (Egypt)

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19. Haddad R, Freschi G, Figueiredo F, et al. Flexible ureterorenoscopy in position or fusion anomaly: is it feasible? Rev Assoc MED BRAS 2017; 63:685-8.

20. Eryildirim B, Kucuk EV, Atis G, et al. Safety and efficacy of PNL vs RIRS in the management of stones located in horseshoe kidneys: A critical comparative evaluation. Arch Ital Urol Androl. 2018; 90:149-154.

DOI: 10.4081/aiua.2021.2.173

ORIGINAL PAPER

Minimal invasive percutaneous nephrolithotomy (Mini-PCNL) in children: Ultrasound versus fluoroscopic guidance Ali Eslahi 1, 2, Faisal Ahmed 3, Mohammad Mehdi Hosseini 4, Mohammed Reza Rezaeimehr 5, Nazanin Fathi 5, Hossein-Ali Nikbakht 6, Mohammad Reza Askarpour 1, Seyed Hossein Hosseini 1, Khalil Al-Naggar 3 1 Department

of Urology, School of medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Geriatric Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 3 Urology research center, Al-Thora General Hospital, Department of Urology, Ibb University of Medical Since, Ibb, Yemen; 4 Shiraz Nephrology-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 5 Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; 6 Social Determinates of Health Research Center, Department of Biostatics and Epidemiology, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.

2 Shiraz

Summary

Background: Miniaturization of endoscopic instruments in percutaneous nephrolithotomy (PCNL) allowed less invasive procedures with low complication rates, especially in children. This study was conducted to evaluate the safety and efficacy of ultrasonography-guided (USG) versus fluoroscopy-guided (FG) mini-PCNL in children.

Materials and methods: This is a retrospective comparative study conducted from June 2015 to June 2020. The sample included 70 children (35 pateints underwent USG mini-PCNL and 35 pateints underwent FG mini-PCNL). They were compared mainly by the patients’ demographic characteristics, procedural information, and post-treatment outcomes. In the USG mini-PCNL group, puncturing was performed using a 3.5 MHz US probe, whereas fluoroscopy was utilized in the FG miniPCNL group.

Results: Both groups were comparable in terms of gender, previous history of failed ESWL, and hydronephrosis grade.

The mean stone burden was 15.94 ± 3.69 mm and 19.20 ± 7.41 mm in USG and FG groups, respectively (p = 0.024). The stonefree rate (SFR) was 97.1% in the USG group and 94.3% in the FG group, which was not statistically significant (p = 0.16).

Mean operative time in the USG group and FG group was 69.00 ± 13.33 minutes and 63.48 ± 16.90 minutes, respectively.

Four (11.4%) patients in the FG group required blood transfusions to restore the hemodynamic state (p = 0.039). Fever was detected in 4 (11.4%) patients in the USG group and 15 (31.4%) patients in the FG group (p = 0.041).

Conclusions: In children, mini PCNL under USG is safe and as effective as fluoroscopy.

KEY WORDS: Fluoroscopy; Minimal invasive; Nephrolithotomy; Percutaneous; Ultrasonography.

Submitted 28 January 2021; Accepted 13 March 2021

INTRODUCTION

Epidemiologic studies have confirmed the continually growing rate of urinary stone disease in the pediatric population over the past years. Due to stone sizes and higher recurrence rate, while being less common than adults, pediatric urinary tract stones require much more difficult

management (1). For the treatment of the upper tract urinary stones in the pediatric population, extracorporeal shock wave lithotripsy (ESWL) is still the first-line management option. However, the unpredictable outcome and lower stone-free rates (SFR) are the main disadvantages of this approach (2). On the other hand, using a retrograde intrarenal surgery (RIRS) in children might cause vesicoureteral reflux and ureteral strictures and require a longer general anesthesia duration (2). Several studies demonstrated acceptable SFR using mini-PCNL in the pediatric population (2, 3). Short hospitalization and decreased incidence of bleeding are the main advantages of the mini-PCNL procedure. In contrast, there are some downsides, including prolonged operation time and the need for miniature-sized instruments. An ideal miniPCNL tract size in children is the smallest tract possible, as long as it provides enough space for removing the stone fragments. This decrease in the tract size results in a decreased risk of bleeding (3). When performing access to the pyelocaliceal system (PCS) system, for guidance, the surgeon might choose fluoroscopy or ultrasonography (US), based on his/her experience with these devices, their availability in the operation room, and the patient's calyceal anatomy. Advantages of using the US as guidance is decreased exposure to radiation and overall cost, decreased rate of visceral injury due to better visualization of adjacent organs, safety in pregnancy, real-time visualization of the PCS and renal parenchyma, better differentiation of the anterior and posterior calyx, detection of radiolucent stones, and the potential to avoid vascular injury by adding Doppler flow imaging (3, 4).

Critical appraisal of mini-PCNL techniques and evaluation of their outcomes in children remain under-reported. Therefore, we evaluated the safety and efficacy of USG versus FG mini-PCNL in children in our center.

MATERIALS

AND METHODS

This study was approved by the ethics committees of Shiraz University of Medical Sciences (Approval code#

No conflict of interest declared.

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A. Eslahi, F. Ahmed, M.M. Hosseini, M. Reza Rezaeimehr, N. Fathi, H.-Ali Nikbakht, M. Reza Askarpour, S. Hossein Hosseini, K. Al-Naggar

IR.sums.med.rec.1399.638). All pediatric patients who had undergone Ultrasound and Fluoroscopy-guided mini-PCNL in our referral centers (Namazi Teaching Hospital and Ali-Asghar Teaching Hospital, Shiraz, southern Iran) from June 2015 to June 2020 were enrolled in our study. We gathered the patients' preoperative data, including age and gender, US finding, previous history of ESWL failure, stone characteristics such as radiopacity, location, and size. We also gathered perioperative clinical lab data, including complete blood count (CBC), renal function test [blood urea nitrogen (BUN) and creatinine], and urine culture. Positive cultures were treated with proper antibiotics and admitted with sterile urine for operation.

Operation and post-operation data including the length of operation, SFR, and hospitalization period were also gathered. Using the Modified Clavien grading system (5), we classified the post-operative complications into five grades. This grading system describes fever as grade I; blood transfusion need, urine leakage, and urinary tract infection as grade II; double-J placement for urine leakage, ureteroscopy, and need to an axillary procedure as grade III; urosepsis and neighboring organ injury as grade IV; and death as grade V. The inclusion criteria were age under 18 years, normal renal function, renal stones more than 10 mm, and/or history of previous ESWL failure.

The exclusion criteria were all cases with active urinary tract infection (UTI), uncorrected coagulopathy, congenital abnormalities, and those patients who had undergone transplant or urinary diversion.

Surgical procedure All patients were admitted 6 hours before the operation and received parenteral hydration and a single prophylactic antibiotic dose. The procedure was done under general anesthesia. In supine position with abducted thigh position, a ureteral catheter 3 Fr or 4 Fr was inserted into the kidney and taped to a fixed urethral Foley catheter (8-12 Fr depending on the patients’ age and size). Then, the patient was switched into the prone position. After proper padding of the chest, abdomen, knee, and ankle, the patient was draped with sterile coverage. Considering the children's increased risk of hypothermia, the patients were kept warm throughout the procedure.

In ultrasound guidance group By performing Color-Doppler US guidance with a 3.5MHz probe (BK Medical), the PCS was visualized. Based on the child’s age and degree of hydronephrosis, the optimal tract length was chosen. Using a one-shot dilatation technique, we passed an 18-gauge access needle into the target calyx using a curved US probe. Afterward, its stylet was removed, and 0.035-inch J- tipped guidewire was introduced into the targeted calyx. The skin was incised, and an 8 Fr polyurethane dilator first dilated the nephrostomy tract and was then removed. Alken was then inserted to guide 18 Fr Amplatz dilator into the PCS. Using the length of the measured tract and Amplatz shadow for precise placement, we passed the Amplatz sheath into the PCS. After confirmation of the Amplatz sheet optimal position, both Amplatz dilator and Alken were removed, leaving the Amplatz sheath and guidewire in place. Using a 15 Fr rigid nephroscope, we

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performed the nephroscopy to pinpoint the stones' site and then crush them with a pneumatic lithoclast. All stone particles were removed by forceps. All steps, including SFR status, were monitored under the guidance of the US without using FG. In fluoroscopic guidance group For better visualization of the PCS, the contrast was injected through the ureteral catheter. Then, under the FG, an 18-gauge needle was passed into the system.

Next, a safety guidewire was introduced into the PCS. The rest of the procedure was the same as described in the USG group; yet, it was carried out under FG. The tubeless procedure was only performed in those patients with single tract access, minimal bleeding, no significant perforation injuries or residual stones, and no secondary procedure requirement.

Post-surgery, after 12 to 24 hours, urethral Foley and ureteral stent catheter were removed. Nephrostomy tubes were removed on the second day after the operation. A plain abdominal film (KUB x-ray) and the US was done on the day after the operation, and residual stones, if presented, were followed at least eight weeks for spontaneous passage of fragments less than 4-5 mm.

Statistical analysis The mean ± SD, median, and Inter-Quartile Range (IQR) described the quantitative variables, and for qualitative variables, frequency (percent) was used. Nonparametric test was used if data distribution was not standard.

Chi-square test was used to assess the potential statistically significant difference. ANOVA was applied to compare the difference of the means between more than two different levels. A P-value of less than 0.05 was considered statistically significant. All data were analyzed using SPSS version 20 software.

RESULTS

Demographic characteristics of the patients and the stone of the two groups are shown in Table 1. The total number of patients in each group was 35 patients. In the USG group, the mean age was 5.68 ± 3.05 years, and in the FG group, it was 7.47 ± 3.75 years (p = 0.032).

The mean stone size was 15.94 ± 3.69 mm (range15-40 mm) and 19.20 ± 7.41 mm (range15-40 mm) in the USG and FG groups, respectively (p = 0.024). Successful access to the target calyx and collecting system was 100% in both groups. The mean length of the tract was 3.17 ± 0.35 mm in the USG group and 3.19 ± 0.37 mm in the FG group. The mean access time to the PCS in the USG group was 1.60 ± 0.70 minutes, while it was 1.56 ± 0.56 minutes in the FG group. Mean operative time in the USG group was 69.00 ± 13.33 minutes, and in the FG group, it was 63.48 ± 16.90 minutes. The initial stone-free rate was 94.3% in the USG group and 94.3% in the FG group. However, the final stone-free rate was 97.1% in the USG group and 94.3% in the FG group.

The hospital stay was 45.94 ± 4.58 hours and 46.40 ± 5.15 hours in the USG and FG groups. Post-operative nephrostomy insertion was performed in 5 (14.3%) patients in the USG group and 11 (31.4%) patients in the

Mini PCNL using ultrasound versus fluoroscopy

Table 1.

Demographic and clinical characteristics of the patients.

Variable Age (years) a Gender b Male Female Size of stone (mm) a History of failed ESWL b Previous PCNL b Single kidney b History of UTI b Stone opacity b Radiopaque Radiolucent Hydronephrosis Grade b Mild Moderate Sever Laterality b Right Left

Fluoroscopic group (35) 7.47 ± 3.75

Ultrasonographic group (35) 5.68 ± 3.05

p value

23 (65.7%) 12 (34.3%) 19.20 ± 7.41 8 (22.9%) 10 (28.6%) 8 (22.9%) 11 (31.4%)

25 (71.4%) 10 (28.6%) 15.94 ± 3.69 11 (31.4%) 9 (25.7%) 0 (0.0%) 5 (14.3%)

0.607

26 (74.3%) 9 (25.7%)

35 (100.0%) 0 (0.0%)

0.001

18 (51.4%) 13 (37.1%) 4 (11.4%)

20 (57.1%) 12 (34.3%) 3 (8.6%)

0.855

8 (22.9%) 27 (77.1%)

22 (62.9%) 13 (37.1%)

0.001

0.032

0.024 0.420 0.788 0.003 0.088

P-values of < 0.05 were considered significant. a Data was presented as Mean ± SD; b Data was presented as n (%).

ESWL = Extracorporeal shock wave lithotripsy; PCNL = Percutaneous nephrolithotomy; UTI = Urinary tract infection.

FG group (p = 0.088). According to modified Clavien classification, Grade 1 complications [Fever (axillary temperature more than 38° C)] was 31.4% in the FG group versus 11.4% in the USG group (p = 0.041).

All patients were treated with suitable antipyretics and antibiotics. Regarding Grade 2 complications, 4 (11.4%) patients in the FG group experienced intraoperative bleeding, which required transfusions to restore the hemodynamic state (p = 0.039), while the rate of Grade 3 complications (need for additional surgery, ESWL) was 5.7% in the FG group versus 2.9% in the USG group.

The rate of Grade 4 complications (Urosepsis) was 2.9% in the FG group. Other significant complications were not detected (Table 2).

Table 2.

Intraoperative and postoperative data.

Variable Fluoroscopy screening time (minutes) a Length of tract (mm) a Access time (minutes) a Hemoglobin drop (mg/dL) a Residual stone > 5 mm b Hospital stays (hours) a Operation time (minutes) a Post op nephrostomy b Initial success rate b Final success rate b *Complications Grade 1 Fever b Complications Grade 2 Blood transfusion b Complications Grade 3 2nd-look ESWL b

Fluoroscopic group (35) 0.60 ± -0.46 3.19 ± 0.37 1.56 ± 0.56 2.21 ± 2.59 2 (5.7%) 46.40 ± 5.15 63.48 ± 16.90 11 (31.4%) 33 (94.3%) 33 (94.3%) 15 (31.4%) 4 (11.4%) 2 (5.7%)

Ultrasonographic group (35) 3.17 ± 0.35 1.60 ± 0.70 0.74 ± 0.29 1 (2.9%) 45.94 ± 4.58 69.00 ± 13.33 5 (14.3%) 33 (94.3%) 34 (97.1%) 4 (11.4%) 0 (0.00%) 1 (2.9%)

p value 0.0001 0.845 0.780 0.002 1.00 0.696 0.134 0.088 1.000 0.574 0.041 0.039 0.931

P-values of < 0.05 were considered significant. a Data was presented as Mean ± SD; b Data was presented as n (%).

*Complication rate according to Clavien–Dindo score and types. ESWL = Extracorporeal shock wave lithotripsy.

DISCUSSION

We have suggested US-guided mini-PCNL as a harmless choice for managing pediatric renal calculi with excellent outcomes and little complications in the present study.

Abnormalities in the urinary tract anatomy, metabolic disorders, and infections are the most common causes of urinary tract stone formation, especially in pediatric cases (3). In the upper tract calculi, ESWL, PCNL, and RIRS are standard treatment options in children. We preferred to treat the stones with the least invasive options since the stone recurrence rate is high. Thus, ESWL is the preferred option for stones less than 20 mm in diameter. However, ESWL lower stone free rate, the possibility of increasing hypertension and diabetes mellitus in the long-term and the possible need for multiple treatment sessions are main limitations of this procedure since complete stone removal is the target (6, 7).

The technology of miniaturization of the access sheath has progressed recently, and the miniaturized PCNL has recently been categorized into mini-PCNL (≤ 22Fr), Chinese mini-PCNL (14-20Fr), super-mini-PCNL (1014 Fr), ultra-mini-PCNL (11-13Fr), micro-PCNL (4.8Fr), and mini-micro-PCNL (8 Fr) (8).

Several studies have investigated the outcome and safety of mini-PCNL and reported that mini-PCNL was associated with less bleeding and postoperative pain, similar SFR, and lower complication rates than the standard PCNL (9-11).

USG mini-PCNL has many advantages, such as an ongoing monitoring of the surrounding tissues and vessels during the procedure, increased accuracy in access to the stone, less staff exposure to radiation, and no need for contrast injection (12). Since the tract to the collecting system is shorter in the pediatric population than adults, the US makes it easier for safer tract dilation and precise placement of the needle to the collecting system (13).

It was recommended that when used by experienced hands, USG could be a safe and effective alternative to fluoroscopy as guidance (4, 6). Despite all the mentioned benefits of using the US in mini-PCNL, it has one major limitation. As an operator-dependent modality, the experience of a surgeon with the US is a major key factor. An additional limiting factor is the low echogenicity of Amplatz dilatator and Amplatz sheath (14).

With a decent residency training program, we can improve the speed of the learning curve. It is suggested that this method should be initially performed in adult patients with simple calculi and it should be performed in younger children with larger complex stones only when the surgeon is fully experienced (13).

Tian et al. studied the feasibility and safety of ambulatory mini-PCNL on the upper urinary tract calculi; based on the results, the age and stone size showed no effect on the surgery outcome (15). Like our study, the mean age and stone size were not statistically equal between the groups. In our study, the average stone size was 15.9 mm in the USG group and 19.2 mm in the FG group.

Since managing larger stones requires a well-experienced surgeon in order to avoid the need for a second-lookPCNl, this may explain the tendency in surgeons to choose the standard PCNL technique in patients with larger stones. Resorlu et al. studied the effect of previous Archivio Italiano di Urologia e Andrologia 2021; 93, 2

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open renal surgery and failed ESWL on the outcomes of PCNL and reported no significant increase in the risk of PCNL complication (16). Likewise, in our study, a history of failed ESWL, previous renal surgery, or PCNL, the grade of hydronephrosis and stone location were not statistically significant between the FG and USG groups.

For an ideal PCNL outcome, optimal percutaneous access to the PCS is a must. This is achieved under fluoroscopy, US, or CT guidance with a success rate between 86.7-100% (4, 17). In our study, we have a 100% access success rate in both groups. Whether using FG or USG, the success rate was the same for accessing the PCS. In the present study, all stones were opaque in the USG group. At the same time, 74% of the FG group patients had opaque stone (p = 0.001). In previous studies, it has been suggested that the incidence of non-opaque stones is accompanied by longer operative times and increased complications, which was noticed in our article (18).

Zhu et al. reported SFR according to different stone sizes and complexities. In this study, PCNL SFR of US guidance was similar to PCNL with fluoroscopy guidance when treating simple kidney stones (STONE scores of 56), but PCNL with fluoroscopy guidance was more effective when stone complexity was higher (STONE scores of 7-8). The final SFR was 69.8% for PCNL with US guidance vs. 89.4% for PCNL with fluoroscopy guidance (19). In a systematic review including 14 studies, miniPCNL, and Ultra mini-PCNL, the SFR was 80%-100% (3). Similar to the others, our study showed a stone-free rate of 94.3% vs. 97.1% in the FG and USG groups, respectively, without any statistically significant difference (p = 0.57).

Our study showed no significant differences in the operative time (63.48 vs. 69.00) in minutes between US-guided and fluoroscopy-guided groups.

In another study, the mean operation time in the USG and FG groups was reported to be 88.92 and 79.28 minutes, respectively (20).

In our studies, gaining access to the PCS under US guidance was similar to the fluoroscopic-guided access.

The mean access time was 1.56 ± 0.56 minutes in the USG group vs. 1.60 ± 0.70 minutes in the FG group. In another study by Falahatkar et al., the duration of access to the target calyx was 14.36 ± 14.84 seconds in the USG group vs.14.78 ± 25.54 seconds in the FG group (14).

The mean access time to PCS and mean operative time is similar to other studies with no statistically significant difference (12, 21, 22). Additionally, the USG had zero radiation exposure.

In a systemic review, less than 1% of the patients had a nephrostomy tube placed (3). In our study, nephrostomy drainage time was higher in the FG group, which defies the result of the previously published article (14).

This might be due to better visualization of PCS in the USG group and larger stone size in the FG group.

The hospital stay was 45.94 ± 4.58 hours in the USG and 46.40 ± 5.15 hours in the FG group (range 2-4 days) in our study, while other studies reported 2.7 to 4.1 days (4, 23). Therefore, there was no significant difference in the hospital stay, similar to previous studies.

Using the Clavien-Dindo grading system, we found that the overall operative complication rates were not similar.

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We noticed a relatively higher postoperative fever rate in the FG group [11.4% versus 31.4%, (p = 0.041)].

A higher positive preoperative urine culture in the FG group, an essential prognostic factor for postoperative infectious complications, more nonopaque stones in the FG groups, and shorter time in USG to access the collecting system could explain this higher rate in the FG groups (19). In the present study, four patients in the FG group experienced intraoperative bleeding, which required blood transfusions with patients' successful recovery.

This finding is in the same line with Andonian et al.’s findings (24). However, a systematic review revealed no significant difference between USG and FG regarding bleeding (22). Our explanation was better visualization of the vital organ in the US group and US ability to provide information on the surrounding viscera and the depth of needle penetration and to provide distinguishing images to identify the posterior and anterior calyces (25).

Two patients needed an axillary procedure (ESWL) in the FG group, while one patient needed it in the USG group.

Additionally, one patient developed urosepsis in the FG group, which was treated with proper antibiotics. In the study by Guven et al., which included 107 children aged less than14 years, ureteroscopy was needed in two patients and second-look PCNL in nine patients (26). In another multicentric study on 1205 children, there was one death case due to septic shock (27). No significant complications such as pneumothorax or hydrothorax, colon damage, or any adjacent injuries occurred in both groups, almost similar to previous articles (3). The retrospective nature of this study and the small sample size was our significant limitations. Randomization was not done in our study, and we detected the heterogenicity of the stone size and age between our groups. We performed all mini-PCNLs in the prone position, and postprocedure imaging was almost limited to plain XR or US. The prone positioning was performed in all of the patients during the procedures. Stone composition analysis data were also unavailable. No specific information was available about the operators' experience or the number of surgeons operating on children. Therefore, further investigations of the long-term effects in a large sample size with one endourologist are recommended.

CONCLUSIONS

Our study supports the results of previous studies, suggesting US-guided mini-PCNL as a harmless choice for managing pediatric renal calculi with excellent outcomes and little complications.

ACKNOWLEDGMENTS

The authors would like to thank Shiraz University of Medical Sciences, Shiraz, Iran and, also the Center for Development of Clinical Research of Nemazee Hospital and Dr. Nasrin Shokrpour for editorial assistance.

REFERENCES

1. Ward JB, Feinstein L, Pierce C, et al. Pediatric Urinary Stone Disease in the United States: The Urologic Diseases in America Project. Urology. 2019; 129:180.

Mini PCNL using ultrasound versus fluoroscopy

2. Srisubat A, Potisat S, Lojanapiwat B, et al. Extracorporeal shock wave lithotripsy (ESWL) versus percutaneous nephrolithotomy (PCNL) or retrograde intrarenal surgery (RIRS) for kidney stones.Cochrane Database Syst Rev. 2014:Cd007044.

3. Jones P, Bennett G, Aboumarzouk OM, et al. Role of Minimally Invasive Percutaneous Nephrolithotomy Techniques-Micro and Ultra-Mini PCNL (<15F) in the Pediatric Population: A Systematic Review. J Endourol. 2017; 31:816.

4. Basiri A, Ziaee SA, Nasseh H, et al. Totally ultrasonographyguided percutaneous nephrolithotomy in the flank position. J Endourol. 2008; 22:1453.

5. Tefekli A, Karadag MA, Tepeler K, et al. Classification of percutaneous nephrolithotomy complications using the modified clavien grading system: looking for a standard. Eur Urol. 2008; 53:184.

6. Hong Y, Ye H, Yang B, et al. Ultrasound-guided minimally invasive percutaneous nephrolithotomy is effective in the management of pediatric upper ureteral and renal stones. J Invest Surg. 2020:1.

7. Ahmed F, Askarpour M-R, Eslahi A, et al. The role of ultrasonography in detecting urinary tract calculi compared to CT scan.

Res Rep Urol. 2018; 10:199.

8. Zeng G, Zhu W, Lam W. Miniaturised percutaneous nephrolithotomy: its role in the treatment of urolithiasis and our experience.

Asian J Urol. 2018; 5:295.

9. Haghighi R, Zeraati H, Ghorban Zade M. Ultra-mini-percutaneous nephrolithotomy (PCNL) versus standard PCNL: A randomised clinical trial. Arab J Urol. 2017; 15:294.

20. Osman M, Wendt-Nordahl G, Heger K, et al. Percutaneous nephrolithotomy with ultrasonography-guided renal access: experience from over 300 cases. BJU Int. 2005; 96:875.

21. Abed SM, Alhamdani N. Ultrasonographic guidance versus fluoroscopic guidance for renal access in percutaneous nephrolithotomy (PCNL): a comparative study.Iraqi J Med Sci. 2019; 18:335.

22. Corrales M, Doizi S, Barghouthy Y, et al. Ultrasound or fluoroscopy for percutaneous nephrolithotomy access, is there really a difference? A review of literature. J Endourol. 2021; 35:241-248.

23. Karami H, Rezaei A, Mohammadhosseini M, et al.

Ultrasonography-guided percutaneous nephrolithotomy in the flank position versus fluoroscopy-guided percutaneous nephrolithotomy in the prone position: a comparative study. J Endourol. 2010; 24:1357.

24. Andonian S, Scoffone CM, Louie MK, et al. Does imaging modality used for percutaneous renal access make a difference? A matched case analysis. J Endourol. 2013; 27:24.

25. Lojanapiwat B. The ideal puncture approach for PCNL: Fluoroscopy, ultrasound or endoscopy?. Indian J Urol. 2013; 29:208.

26. Guven S, Frattini A, Onal B, et al. Percutaneous nephrolithotomy in children in different age groups: data from the Clinical Research Office of the Endourological Society (CROES) Percutaneous Nephrolithotomy Global Study. BJU Int. 2013; 111:148.

27. Onal B, Dogan HS, Satar N, et al. Factors affecting complication rates of percutaneous nephrolithotomy in children: results of a multi-institutional retrospective analysis by the Turkish pediatric urology society. J Urol. 2014; 191:777.

10. ElSheemy MS, Elmarakbi AA, Hytham M, et al. Mini vs standard percutaneous nephrolithotomy for renal stones: a comparative study. Urolithiasis. 2019; 47:207.

11. Izol V, Satar N, Bayazit Y, et al. Which factors affect the success of pediatric PCNL? Single center experience over 20 years. Arch Ital Urol Androl. 2020; 92:345-9.

12. Agarwal M, Agrawal MS, Jaiswal A, et al. Safety and efficacy of ultrasonography as an adjunct to fluoroscopy for renal access in percutaneous nephrolithotomy (PCNL). BJU Int. 2011; 108:1346.

13. Desai M. Ultrasonography-guided punctures-with and without puncture guide. J Endourol. 2009; 23:1641.

14. Falahatkar S, Allahkhah A, Kazemzadeh M, et al. Complete supine PCNL: ultrasound vs. fluoroscopic guided: a randomized clinical trial. Int Braz J Urol. 2016; 42:710.

15. Tian Y, Yang X, Luo G, et al. Initial prospective study of ambulatory mPCNL on upper urinary tract calculi. Urol J. 2020; 17:14.

16. Resorlu B, Kara C, Senocak C, et al. Effect of previous open renal surgery and failed extracorporeal shockwave lithotripsy on the performance and outcomes of percutaneous nephrolithotomy. J Endourol. 2010; 24:13.

17. Basiri A, Ziaee AM, Kianian HR, et al. Ultrasonographic versus fluoroscopic access for percutaneous nephrolithotomy: a randomized clinical trial. J Endourol. 2008; 22:281.

Correspondence Ali Eslahi, MD alieslahi@yahoo.com Mohammad Mehdi Hosseini, MD mmhosseini66@gmail.com Mohammed Reza Rezaeimehr, MD maareza2000@gmail.com Nazanin Fathi, MD nazaninfathi1997@gmail.com Mohammad Reza Askarpour, MD askarvip2@gmail.com Seyed Hossein Hosseini, MD shhosseini_6687@yahoo.com Urology Office, Faghihi Hospital, Zand Blvd., Shiraz (Iran)

18. Maghsoudi R, Etemadian M, Kashi AH, Ranjbaran A. The association of stone opacity in plain radiography with percutaneous nephrolithotomy outcomes and complications. Urol J. 2016; 13:2899.

Faisal Ahmed, MD (Corresponding Author) fmaaa2006@yahoo.com Khalil Al-Naggar, MD alnajjarkh1234@gmail.com Urology Office, Althora General Hospital, Alodine street, Ibb (Yemen)

19. Zhu W, Li J, Yuan J, et al. A prospective and randomised trial comparing fluoroscopic, total ultrasonographic, and combined guidance for renal access in mini-percutaneous nephrolithotomy. BJU Int. 2017; 119:612.

Hossein-Ali Nikbakht, MD ep.nikbakht@gmail.com Social Determinates of Health Research Center, Babol University of Medical Sciences, Babol, (Iran)

Archivio Italiano di Urologia e Andrologia 2021; 93, 2

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DOI: 10.4081/aiua.2021.2.178

ORIGINAL PAPER

Time dependant functional and morphological recovery of the kidney after relief of obstruction in patients with impacted ureteral stones Hüseyin Kocatürk 1, Fevzi Bedir 1, Ömer Turangezli 1, Engin S¸ebin 2, Mehmet Sefa Altay 1, Banu Bedir 3, Kemal Sarica 4 1 Department

of Urology Health Sciences University, Erzurum Regional Training and Research Hospital, Erzurum, Turkey; of Biochemistry Health Sciences University, Erzurum Regional Training and Research Hospital, Erzurum, Turkey; 3 Aziziye District Health Directorate, Erzurum, Turkey; 4 Biruni University, Faculty of Medicine, Department of Urology, Istanbul, Turkey.

2 Department

Summary

Objectives: To assess the course of functional and morphological recovery of the kidney following the relief of obstruction with ureteral JJ stent in cases with unilateral impacted stones.

Materials and methods: A total of 42 adult patients who were admitted to our clinic with unilateral obstructing impacted ureteral stones requiring JJ stent placement were included in the study.

The course of functional recovery was assessed by evaluating the serum creatinine levels, renal resistive index (RRI) values and urinary levels of kidney injury molecule-1, neutrophil gelatinaseassociated lipocalin as well as microalbumin before at 1 day, 1 week and 4 weeks after JJ stent placement. Course of morphologic recovery was evaluated by evaluating the degree of hydronephrosis, kidney size, perirenal straining and ureteral diameter.

Results: Our results showed that all relevant parameters began to decrease after 24 hours and continue to normalize during 1 week evaluation; majority of these variables indicating the functional and morphological recovery were in normal range after 4 weeks. Decompression of the obstructed kidneys with JJ stent placement in patients with impacted ureteral stones was found to be effective enough with recovery of normal renal functional and morphological status after a minimum time period of 4 weeks.

Morphological recovery of affected kidneys following JJ stenting was obtained with a significant difference between baseline and 1-month evaluation findings (p = 0.001, p < 001, p < 001, respectively). KIM-1 excretion began to decline to normal levels after 4 weeks (3.52 ± 0.99 ng/ml versus 2.84 ± 0.66 ng/ml, p < 0.001). The same findings were observed for the urinary excretion levels of NGAL, which normalized at the 1-month evaluation (604.55 ± 140.28 ng/ml versus 596.87 ± 80.17 ng/ml p = 0.895). Urinary microalbumin excretion levels however remained high even until 1-month follow-up with a statistically significant difference when compared with the normal excretion values (p < 0.001). There was a statistically significant difference in RRI values between baseline and 1-month follow-up findings in obstructed kidney (p < 0.001).

Conclusions: Elective management of the obstructing impacted ureteral stone(s) will be safer with limited risk of infective complications after functional and morphological normalization in such kidneys following 4 weeks of JJ stent placement.

KEY WORDS: Impacted ureteral stones; Renal function; Morphology; JJ stent; Obstruction.

Submitted 21 April 2021; Accepted 2 May 2021

178

INTRODUCTION

Urolithiasis is a very common disease that can affect all age groups and is seen in 1-13% of the general population depending on regional differences (1, 2).

Obstructing impacted ureteric stones require removal on time to decompress the upper urinary tract and to avoid possible renal functional, morphological alterations which may be irreversible in some cases (3, 4).

Depending on the departmental principles and surgeons preference, drainage of renal collecting system obstructed by such stones could be performed by placement of either a percutaneous nephrostomy tube or an indwelling ureteric stent. Both approaches are being accepted as equally effective by the EAU guidelines (5). Although randomized controlled studies could not demonstrate any significant difference between these two techniques, most urologists tend to insert a stent with this aim (6-8).

Ureteral stenting is a commonly performed procedure to drain the collecting system particularly in cases with impacted stones in whom the spontaneous stone passage is less likely and the conservative medical management is ineffective. Additionally this approach is mandatory when evident hydronephrosis and infective symptoms are present (9-13). However, highly limited data is available regarding the course of renal functional and morphological recovery after stenting on a time dependant manner.

Additionally no commonly accepted or established consensus is available regarding the optimal indwelling time of a ureteral stent in these cases. To our knowledge our study is the first evaluating the course of functional and morphological recovery following JJ stenting on a time dependant manner in cases with obstructive impacted ureteral calculi.

Among the markers of renal damage, as a type-1 transmembrane protein, urinary kidney injury molecule-1 (KIM1) is not normally present in urine and its excretion has been found to increase as a valuable indicator of kidney injury along with histopathological changes in the proximal tubule in response to many pathophysiological states including obstruction. Again neutrophil gelatinase-associated lipocalin (NGAL), an iron-transporting protein was found to accumulate in urine rapidly after nephrotoxic and ischemic insults. It was used as an early, sensitive biomarker for No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 2

Recovery course of the obstructed kidney

acute kidney injury (14-16). Lastly, by providing information about the changes in microvascular blood flow, renal parenchymal doppler sonographic evaluation of the vascular impedance renal resistivity index (RRI) may be helpful in the asssessment of the functional or structural changes caused by acute and chronic obstructive renal diseases (1719). We aimed to evaluate the time dependant functional and morphological recovery of obstructed kidneys after JJ stenting in cases with impacted ureteral stones. Optimal time period for stenting to achieve a complete renal recovery following obstruction relief was also evaluated.

MATERIALS

AND METHODS

Study design and participants This prospective study was conducted in line with the ethical standards specified by the Declaration of Helsinki and following receipt of local ethical committee approval (2019/14-132). Informed consent was obtained from all individual participants included in the study. The data derived from 42 adult patients with a single impacted unilateral obstructing ureteral stone requiring JJ stent placement were evaluated in a prospective manner. Patients with bilateral, multiple stones, previous stone-related procedures, pregnancy, active urinary infection, renal tumour, congenital anomalies, solitary kidneys and a treatment of nephrotoxic drugs were excluded. Following the management of colic pain, in 42 cases with impacted ureteric stones obstruction has been decompressed by indwelling ureteral stenting. In addition to a non-contrast computed tomography (NCCT), plain X-ray of the kidney and urinary ultrasonography were also done to assess the degree of hydroneprosis and follow-up of the cases. Degree of hydronephrosis was graded as mild, moderate and severe.

Kidney dimensions and the density (HU), size, side, localization of the stone and the diameter of the ureter above the stone were recorded. Patients with impacted obstructing ureteric stones with evident hydronephrosis were treated with a double J stent placement for an effective decompression and to evluate the functional as well as morphological changes on a time based manner. Following the stenting, the degree of hydronephrosis, perirenal staining and upper ureteral diameter were outlined on CT images and urinary ultrasonography to evaluate the course of morphologic recovery; the value of RRI assessed on Doppler sonography, urinary KIM-1, NGAL and urinary microalbumin levels were measured for functional recovery before, 1 day, 1 week and 4 weeks after JJ stent placement.

Collection of urine specimens Midflow urine samples of the patients were obtained before, 1 day, 1 week and 1 month after the procedure.

Urine (10 mL) was collected in plastic tubes, without any specific preservative. The urine samples obtained from all cases were centrifuged at 2000-3000 rpm for 20 min at + 4°C. The supernatant urine samples were transferred to Eppendorf tubes. The samples were kept in a deep freezer system at -80°C until analysis.

Measurement of NGAL and KIM-1 in the urine The urinary NGAL and KIM-1 levels were measured with

enzyme-linked immunosorbent assay (ELISA) method by using the human NGAL ELISA kit (Sunred Biological Technology Co., Ltd, Shanghai, China, Cat. No: 201-12-1720) and the human KIM-1 ELISA kit (Sunred Biological Technology Co., Ltd, Shanghai, China, Cat. No: 201-12-1100) in accordance with the manufacturer’s instructions. The analysis was performed with a ChemWell® Automated EIA and Chemistry Analyzer device (Awareness Technology, Inc.; Miami, USA). Each sample was measured in duplicate and the obtained values were expressed as ng/ml.

Measurement of blood urea nitrogen (BUN), creatinine and urinary microalbumin BUN, creatinine and urinary microalbumin were measured using Abbott kits on Architectc16000 (Abbott Diagnostics, Illinois, USA) device.

Statistical analysis Recruitment and evaluation of the research data in this study was done by using Statistical Package fort the Social Science (SPSS) v24 for Windows program. Categorical variables were expressed with numbers and percentages; values, numerical variables were expressed with mean and standard deviation values. The consistency of the numerical variables to the analysis was searched by using Kolmogorov Smirnov Test. Mann-Whitney U and Chisquare tests were used in the evaluation of the obtained data, Friedman test was used in the comparison of the repeatedly assessed parameters without normal distribution, and lastly Wilcoxon Signed Rank test and Bonferoni correction were used for the comparison of the parameters within the group. Statistically significance value has been accepted to be p < 0.05.

RESULTS

In the group of 42 adult patients (> 18 years, M/F 3.6), mean age was 41.86 ± 13.61 (23-67) years, mean stone size was 10.16 ± 1.99 (7-14) mm. The overall mean body mass index (BMI) of these cases was 25.35 ± 2.74 (19.229.4) kg/m2. Majority of the stones (40.5%) was located in the upper ureter. Patient demographics along with stone related parameters are given in Table 1.

Table 1.

Patients' demographic features and stone characteristics.

Age Gender Male Female BMI ( kg/m2) Stone side Right Left Stone size (mm) Stone localization Lower Mid Upper Stone density (HU)

Mean ± SD/n (%) 41.86 ± 13.61

Median (min-max) 41 (23-67)

33 (78.6) 9 (21.4) 25.35 ± 2.74

25.60 (19.20-29.40)

22 (52.4) 20 (47.6) 10.16 ± 1.99

9.95 (7-14)

16 (38.1) 9 (21.4) 17 (40.5) 649.60 ± 207.66

626.50 (336-1016)

BMI = Body Mass Index, HU = Hounsfield Units.

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Table 2.

Kidney morphological parameters and Resistivity Index values.

Mean ± SD (min-max)

Pre-op

Mean ± SD (min-max)

Post-op (first day)

Post-op (first week)

Post-op (first month)

p

0.58 ± 0.03 (0.52-0.67) 0.74 ± 0.04 (0.66-0.83)

0.58 ± 0.03 (0.54-0.67) 0.62 ± 0.02 (0.54-0.73)

0.58 ± 0.02 (0.53-0.64) 0.59 ± 0.02 (0.53-0.64)

0.57 ± 0.01 (0.54-0.62) 0.58 ± 0.02 (0.55-0.63)

p = 0.407*

108.92 ± 8.15 90-128 52.66 ± 4.64 44-62 25.95 ± 3.61 19-32

-

-

-

-

-

-

-

-

-

111.69 ± 9.51 92-133

110.73 ± 8.59 93-130

110.54 ± 8.15 92-127

109.92 ± 7.94 93-126

Transverse diamater

62.0 ± 6.27 48-72

58.71 ± 5.71 46-69

56.69 ± 5.31 45-68

54.78 ± 4.77 45-65

Parenchymal thickness

31.57 ± 5.57 21-43

28.85 ± 4.43 20-39

28.33 ± 5.07 20-48

27.26 ± 4.99 20-46

18.35 ± 2.95 (12.90-24.10)

-

-

5.92 ± 1.14 (3.90-8.20)

Normal contralateral kidney RI Obstructive kidney RI Normal contralateral kidney size (mm) Long diameter Transverse diamater Parenchymal thickness Obstructive kidney size (mm) Long diameter

Ureter diameter (mm)

Mean ± SD (min-max)

Mean ± SD (min-max)

p < 0.001*

p = 0.002a p = 0.001b p = 0.009c p < 0.001a p < 0.001b p < 0.001c p < 0.001a p < 0.001b p = 0.002c p < 0.001

RI = Resistivity Index, p = Level of significance, SD = Standard deviation, * = Statistical difference between each other in the pre and post-operative periods,

a = It shows the statistical difference between the averages of preop and postoperative day 1 of obstructive kidney size, b = It shows the statistical difference between the averages of preop

and postoperative day 7 of obstructive kidney size, c = It shows the statistical difference between obstructive kidney size on postop 7 day and averages of postop 1 month kidney size.

Morphologic recovery of the affected kidneys ance of perirenal staining (moderate to severe changes) following JJ stent insertion required 4-weeks in obstructed kidneys. Morphological Comparative evaluation of the baseline renal diameters changes and related values in the obstructed kidneys are of the affected kidneys with normal values revealed a stagiven on a time dependant manner in Tables 2, 3. tistically significant difference before and during early phase of the follow-up period (p = 0.002, p < 0.001, Evaluation of the functional recovery in obstructed kidp < 0.001, respectively). Evaluation of values in the ney after JJ stent insertion obstructed kidneys showed that while there was an Serum creatinine levels decreased significantly following JJ insignificant difference between 1 day and 1 week evalstent insertion after 7 days (p < 0.001) and came down to uation (p = 0.637), a significant difference was noted normal levels at 1-month follow up (0.85 ± 0.15 mg/dL vs between baseline and 1-month evaluation findings 0.83 ± 0.12 respectively). (p = 0.001, p < 001, p < 001, respectively).

Additionally as demonstrated in Table 4, baseline urinary These findings emphasized the necessity of keeping JJ KIM-1 excretion continued to increase until the end of the stent in place for at least a period of 4 weeks particularfirst week after JJ stent insertion, and it returned to normal ly in severely obstructed kidneys to catch the values of normal kidneys (108.92 ± 8.15 mm vs 109.92 ± 7.94 mm) (p = 0.566).

Table 3.

Evaluation of the mean ureteral diameter above Evaluation of the presence and degree of hydronephrosis the impacted stone site showed a significant and perirenal staining in study group cases. decrease (p < 0.001) which came down to the No % (n) Mild % (n) Moderate % (n) Advenced % (n) normal size of a ureter after 4 weeks.

Hydronephrosis Assessment of the hydronephrosis level in our Pre-op 31.0% (13) 69.0% (29) cases revealed that while majority of the kidPost-op (first day) 2.4% (1) 59.5% (25) 38.1% (16) neys had a moderate or severe hydronephrosis Post-op (first week) 9.5% (4) 88.1% (37) 2.4% (1) (31% and 69%) prior to stenting; there was no Post-op (first month) 57.1% (24) 42.9% (18) or mild hydronehrosis detected during 1month follow-up evaluation. Detection of Perirenal staining moderate hydronephrosis in a certain percent Pre-op 9.6% (4) 19.0% (8) 23.8% (10) 47.6% (20) of these cases still during both 1 day (38.1%) Post-op (first day) 11.9% (5) 21.4% (9) 28.6% (12) 38.1% (16) and 7 day (2.4%) follow-up again showed the Post-op (first week) 16.7% (7) 54.7% (23) 26.2% (11) 2.4% (1) importance of keeping the stent in place for at Post-op (first month) 81.0% (34) 19.0% (8) least a month period. Similarly, the disappear-

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Recovery course of the obstructed kidney

Table 4.

Evaluation of the urinary KIM-1, NGAL, microalbumin and serum BUN, creatinine levels.

KIM-1

Pre-op Mean ± SD (min-max) Post-op (first day) Mean ± SD (min-max) Post-op (first week) Mean ± SD (min-max) Post-op (first month) Mean ± SD (min-max) P1 P2

Levels ng/ml

Levels ng/ml

NGAL

Urinary micro-albumin Levels ng/ml

Levels

BUN

Creatinine

2.50 ± 0.57 (1.22-3.51) 3.52 ± 0.99 (2.11-6.15) 3.34 ± 0.81 (1.94-5.69) 2.84 ± 0.66 (1.56-4.46) p < 0.001 p < 0.001

596.88 ± 92.31 (362.90-781.56) 761.16 ± 137.85 (483.80-1164.78) 686.54 ± 106.10 (426.87-877.73) 604.55 ± 140.28 (333.29-959.15) p < 0.001 p < 0.001

83.59 ± 89.10 (5.0-407.0) 435.54 ± 94.30 (167.0-500.0) 316.19 ± 142.33 (62.0-500.0) 159.66 ± 112.66 (23.0-452.0) p < 0.001 p < 0.001

33.47 ± 14.43 (9.20-67.70) 24.33 ± 8.11 (13.0-47.20) 20.66 ± 6.97 (11.0-36.0) 20.91 ± 8.11 (10.0-38.0) p < 0.001 p = 0.979

1.08 ± 0.29 (0.57-1.89) 0.92 ± 0.21 (0.60-1.70) 0.85 ± 0.15 (0.59-1.38) 0.83 ± 0.12 (0.61-1.08) p < 0.001 p = 0.769

Levelsl

KIM-1 = Kidney Injury Molecule-1, NGAL = Neutrophil Gelatinase Associated Lipocalin, SD = standard deviation, p = Level of significance.

1Difference with before treatment; 2Difference between 7 days and 1 month after the operation.

levels after 4 weeks (3.52 ± 0.99 ng/ml vs 2.84 ± 0.66 ng/ml, p < 0.001).

The same findings were observed for the urinary excretion levels of NGAL which normalized at 1-month evaluation (604.55 ± 140.28 ng/ml vs 596.87 ± 80.17 ng/ml, p = 0.895) following a significant initial elevation.

Evaluation of these two parameters demonstrated that the functional normalization of the obstructed kidney occurs after at least 4 weeks later following stenting.

Urinary microalbumin excretion levels however remained high even until 1-month follow-up with respect to normal excretion values (Table 4).

Lastly, while the assessment of RRI values of in normal contralateral kidneys didn’t show any significant difference during follow-up (p = 0.407), there was a statistically significant difference between baseline and 1month follow-up findings in obstructive kidney (p < 0.001) which came down to the levels of normal levels after 4 weeks (Table 2).

DISCUSSION

Unilateral ureteral obstruction due to an impacted calculi is a common emergency status requiring a quick drainage of the upper urinary tract to avoid possible detrimental alterations in the kidney. Renal interstitial fibrosis is the characteristic pathological manifestation in such kidneys which is directly related to the level of obstruction and renal functional impairment (15, 20).

Rational approach in such cases is the quick relief of obstruction by insertion of either a nephrostomy tube or an indwelling double J ureteral stent before making an elective treatment plan. Although placement of a nephrostomy tube directly into the dilated collecting system is considered to be a more effective and rapid drainage method, this approach is more invasive and not indicated particularly in cases under anticoagulant medication.

Thus, majority of the urologists conisder placing a double J stent as a safe and efficient way of decompression (21, 22). However, although limited, randomized comparative studies demonstrated that the efficacy of both approaches is equally acceptable (6, 7, 21-24).

Effective decompression of the obstructed kidney by

stenting will result in morphological and functional normalization prior to a planned stone removal procedure which will certainly increase the success rates and limit the possible infectious complications. Despite the effectiveness of the use of JJ stents with this aim is accepted, the optimal time duration of stenting for an adequate drainage has not been clearly outlined. No evidence based and commonly accepted time period has been reported for keeping the stents in place to obtain the complete normalized status of the kidneys. Most urologists tend remove stents after 1-2 weeks simply by checking the degree of dilatation of the upper urinary tract (25-27).

Current EAU and AUA guidelines contain no definite information for the optimal duration of stenting in such cases and practice patterns vary dramatically from 1 week to 3 months depending on the personal experience and also departmental principles (5, 9). Moreover, no particular clinical trial had been performed so far to outline the course of clinical recovery in these kidneys after stent placement where the urologists tend to remove the stents without having any idea about the functional and morphological status of the kidneys.

Shigemura et al. evaluated the infection related morbidity induced by JJ stents concluding that stents staying up to 2 weeks period have less risk of relevant problems (13). In another study evaluating the calcification risk on stent surface, Kawahara et al. found that stents kept in place for more than 3 months are associated with higher risk of calcification. Similar studies emphasized the relationship between time of stenting and encrustation risk of the stents (28, 29).

Among functional biomarkers of kidney, KIM-1 is a transmembrane protein that is undetectable in urine of the healthy cases, but its increased expression was found to be correlated with ischemic and nephrotoxic kidney injury. Additionally, its levels has been found to increase as a result of parenchymal damage induced by urinary obstruction (14-16). On the other hand, another reliable biomarker is NGAL, a 25-kDa protein that is secreted by proximal tubular cells. Published data demonstrated that NGAL could also be used as one of the most reliable markers in the assessment of kidney injury after ischemic or nephrotoxic states among which urinary obstruction Archivio Italiano di Urologia e Andrologia 2021; 93, 2

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H. Kocatürk, F. Bedir, Ö. Turangezli, E. Şebin, M. Sefa Altay, B. Bedir, K. Sarica

is the most common (16). Lastly, Doppler sonographic evaluation of the vascular impedance in the renal parenchyma was used be to evaluate the functional or structural changes induced by acute and chronic obstructive renal diseases (17-19).

In our study, JJ stent placement provided an effective decompression of the upper urinary tract in obstructed kidneys with adequate functional and morphological recovery after 4-weeks. Although most of the parameters began to decrease after 24 hours and continue to decrease at 1 week evaluation, the majority of these variables returned to normal range after 4 weeks period.

In other words, keeping the stent in place for a minimum duration of 4 weeks (if there is no other indication for removal) seems to be important for the functional and anatomical recovery of the affected kidneys. Our findings constitute reliable and objective data regarding the optimal duration of stenting in cases with obstruction induced by impacted ureteral calculi. Early removal of the stent without complete elimination of the obstructive alterations will leave the kidney with residual functional deterioration and dilatation. This condition may compromise the outcomes of a planned elective surgery performed for the removal of obstructing ureteral stone(s).

Additionally as such approaches, namely shock wave lithotripy and ureteroscopy, have possible detrimental effects on the kidneys due to either direct tissue damaging effects or to the elevated intrarenal pressures, residual dilation and functional deterioration in such kidneys will make them more prone to infective complications which will be a main problem during postoperative follow-up period.

CONCLUSIONS

Impacted ureteral stones will cause obstruction associated changes in functioning kidneys and quick drainage by stenting is highly effective to limit the chance of such detrimental alterations. Our results indicated that decompression of the obstructed system will let these kidneys to obtain normal functional and morphological status after a mimimum time period of 4 weeks limiting the risk of infective complications after elective treatment. However, we believe that further studies including large case series are certainly needed.

ACKNOWLEDGMENT

Special thanks to Radiology Expert Dr. Muammer Altınkaynak for his helps on the radiological evaluation.

6. Pearle MS, Pierce HL, Miller GL, et al. Optimal method of urgent decompression of the collecting system for obstruction and infection due to ureteral calculi. J Urol. 1998; 160:1260-4.

7. Mokhmalji H, Braun PM, Martinez Portillo FJ, et al.

Percutaneous nephrostomy versus ureteral stents for diversion of hydronephrosis caused by stones: a prospective, randomized clinical trial. J Urol. 2001; 165:1088-92.

8. Sammon JD, Ghani KR, Karakiewicz PI, et al. Temporal trends, practice patterns, and treatment outcomes for infected upper urinary tract stones in the United States. Eur Urol. 2013; 64:85-92.

9. Preminger GM, Tiselius HG, Assimos DG, et al. EAU/AUA: nephrolithiasis Guideline panel. 2007 guideline for the management of ureteral calculi. J Urol. 2007; 178:2418-2434.

10. Christoph F, Weikert S, Müller M, et al. How septic is urosepsis? Clinical course of infected hydronephrosis and therapeutic strategies. World J Urol. 2005; 23:243-7.

11. Zheng J, Wang Y, Chen B, et al. Risk factors for ureteroscopic lithotripsy: a case-control study and analysis of 385 cases of holmium laser ureterolithotripsy. Wideochir Inne Tech Maloinwazyjne.

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13. Shigemura K, Yasufuku T, Yamanaka K, et al. How long should double J stent be kept in after ureteroscopic lithotripsy? Urol Res. 2012; 40:373-6.

14. Wasilewska A, Taranta-Janusz K, Debek W, et al. KIM-1 and NGAL: new markers of obstructive nephropathy. Pediatr Nephrol.

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15. Xie Y, Xue W, Shao X, et al. Analysis of a urinary biomarker panel for obstructive nephropathy and clinical outcomes. PLoS One. 2014; 9:e112865.

16. Devarajan P. Biomarkers for the early detection of acute kidney injury. Curr Opin Pediatr. 2011; 23:194-200.

17. Eryildirim B, Sahan A, Türkog˘lu Ö, et al. Non-invasive evaluation of obstruction after ureteroscopic stone removal: Role of renal resistive index assessment. Arch Ital Urol Androl. 2020; 92:244247.

18. Darmon M, Schortgen F, Vargas F, et al. Diagnostic accuracy of Doppler renal resistive index for reversibility of acute kidney injury in critically ill patients. Intensive Care Med. 2011; 37:68-76.

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2. Tiselius HG. Epidemiology and medical management of stone disease. BJU Int. 2003; 91:758-767.

20. Zul Khairul Azwadi I, Norhayati MN, Abdullah MS. Percutaneous nephrostomy versus retrograde ureteral stenting for acute upper obstructive uropathy: a systematic review and metaanalysis. Sci Rep. 2021; 23:6613.

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3. Wood K, Keys T, Mufarrij P, Assimos DG. Impact of stone removal on renal function: a review. Rev Urol. 2011; 13:73-89.

4. Moe OW. Kidney stones. Pathophysiology and medical management. Lancet. 2006; 367:333-344.

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21. Ramsey S, Robertson A, Ablett MJ, et al. Evidence-based drainage of infected hydronephrosis secondary to ureteric calculi. J Endourol. 2010; 24:185-9.

22. Lynch MF, Anson KM, Patel U. Percutaneous nephrostomy and

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ureteric stent insertion for acute renal deobstruction. Consensus based guidelines. Br J Med Surg Urol. 2008; 1:120-125.

23. Guercio S, Ambu A, Mangione F, et al. Randomized prospective trial comparing immediate versus delayed ureteroscopy for patients with ureteral calculi and normal renal function who present to the emergency department. J Endourol. 2011; 25:1137-41.

26. Dauw CA, Simeon L, Alruwaily AF, et al. Contemporary practice patterns of flexible ureteroscopy for treating renal stones: results of a Worldwide Survey. J Endourol. 2015; 29:1221-1230.

27. Torricelli FC, De S, Hinck B, Noble M, Monga M. Flexible ureteroscopy with a ureteral access sheath: when to stent? Urology.

2014; 83:278-281.

24. Chen Y, Feng J, Yue Y, et al. Externalized ureteral catheter versus double-J stent in tubeless percutaneous nephrolithotomy for upper urinary stones: a systematic review and meta-analysis. J Endourol. 2018; 32:581-588.

28. Kawahara T, Ito H, Terao H, et al. Ureteral stent encrustation, incrustation, and coloring: morbidity related to indwelling times. J Endourol. 2012; 26:178-82.

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Correspondence Hüseyin Kocatürk, MD (Corresponding Author) kocaturk78@hotmail.com Fevzi Bedir, MD fevzibedir84@gmail.com Ömer Turangezli, MD omerturangezli@gmail.com Mehmet Sefa Altay, MD memsefaaltay@gmail.com Department of Urology, Health Sciences University Erzurum Regional Training and Research Hospital, 25070 Palandöken/Erzurum (Turkey) Engin S¸ebin, MD sebinengin@gmail.com Department of Biochemistry, Health Sciences University Erzurum Regional Training and Research Hospital, 25070 Palandöken/Erzurum (Turkey) Banu Bedir, MD banubedir89@gmail.com Aziziye District Health Directorate, Erzurum (Turkey) Kemal Sarica, MD saricakemal@gmail.com Biruni University, Faculty of Medicine, Department of Urology, Istanbul (Turkey)

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DOI: 10.4081/aiua.2021.2.184

ORIGINAL PAPER

Phyllanthus niruri and Chrysanthellum americanum in association with potassium and magnesium citrates are able to prevent symptomatic episode in patients affected by recurrent urinary stones: A prospective study Tommaso Cai 1, Daniele Tiscione 1, Marco Puglisi 1, Gianni Malossini 1, Lorenzo Ruggera 2, Paolo Verze 3, Davide Arcaniolo 4, Alessandro Palmieri 5 1 Department

of Urology, Santa Chiara Regional Hospital, Trento, Italy; of Urology, University of Padua, Padua, Italy; 3 Department of Medicine, Surgery, Dentistry "Scuola Medica Salernitana" - University of Salerno, Baronissi, Italy; 4 Department of Urology, University Vanvitelli, Naples, Italy.

5 Department of Urology, University of Naples, Federico II, Naples, Italy.

2 Department

Objective: The aim of this study is to evaluate the efficacy of a food supplement containing Phyllanthus niruri and Chrysanthellum americanum in association with potassium and magnesium citrates in the treatment and prophylaxis of urinary stones.

Materials and methods: Eighty-two patients (mean age 49.7 ± 11.2) with history of urinary stones received this food supplement, one capsule a day for 6 months. Each administration contained a combination of the following ingredients: 244 mg Potassium citrate, 735 mg Magnesium citrate, Phyllanthus (Phyllantus niruri) herb d.e. 15% mg Tannins 220 mg, Chrysanthellum (Chrysanthellum americanum Vatke) plant d.e. ¼ 55 mg. After 6 months, all patients underwent urologic visit, urinalysis, imaging and quality of life (QoL) questionnaires evaluation. Each patient was also evaluated by computed tomography (CT) scan at baseline and at 6 months.

Result: From January 2018 to March 2019, 82 patients (mean age 49.7 ± 11.2) completed the follow-up period and were analyzed. Fifty patients showed lower stone dimensions (60.9%).

The average stone size was 0.9 mm, with a significant reduction in comparison with the baseline (-6.7 mm ± 3 mm) (p < 0.001).

Forty-nine patients (59.7%) did not show any symptomatic episode with an improving in QoL (+0.4 ± 0.1) (p < 0.001) in comparison with the baseline. At the end of the follow-up period, 27 patients out of 82 were stone-free (32.9%). Moreover, we report a significant reduction of patients with asymptomatic bacteriuria (ABU) between the baseline and the end of the follow-up evaluation (p < 0.001).

Conclusions: In conclusion, this food supplement is able to improve quality of life in patients with urinary stones, reducing symptomatic episodes and the prevalence of ABU.

Summary

KEY WORDS: Stones; Phyllanthus niruri; Chrysanthellum americanum; Potassium; Magnesium; Asymptomatic bacteriuria.

Submitted 16 April 2021; Accepted 26 April 2021

INTRODUCTION Urinary tract stones are one of the most common cause of urological visits, with a prevalence among urological patients of 1-15% (1, 2). The impact on everyday clini-

184

cal practice is high, due to the high number of recurrences and due to the impact of symptoms on patients’ quality of life (2, 3).

The recurrence rate of urinary calculi is 50% within 10 years of the first episode (3, 4). Symptomatic recurrence episodes are associated with high direct and indirect costs (admission to emergency departments, imaging, drugs and working day lost). For these reasons, the prevention of symptomatic episodes due to urinary stones should be the first aim in the management of this kind of patients. Several authors recommended some diet interventions for reducing the risk of urinary stone formation and its recurrence but there is no conclusive consensus in the literature regarding the effectiveness of dietary interventions and recommendations about specific diets for patients with urinary calculi (5). On the other hand, the use of medicinal plants and nutraceuticals have long been used worldwide for the management of recurrence in patients affected by urinary stones (6).

Ettinger et al., published in 1997 one of the first clinical trial on the use of potassium-magnesium citrate in preventing recurrent calcium oxalate kidney calculi, demonstrating that potassium-magnesium citrate effectively prevents recurrent calcium oxalate stones (7).

Focusing on the plant extracts, Phyllanthus niruri, commonly known as “stone-breaker”, is able to increases urinary excretion of magnesium and potassium and to cause a significant decrease in urinary oxalate and uric acid in patients with hyperoxaluria and hyperuricosuria, contributing to the elimination of urinary calculi (4).

Moreover, Chrysanthellum americanum seems to be effective in the reduction of stone formation, probably due to the effect of chrysantellin, a saponin, on the stone aggregation (8).

Starting from these evidences, we aim to evaluate the efficacy of a medical device containing Phyllanthus niruri and Chrysanthellum americanum in association with potassium and magnesium citrates in the treatment and prophylaxis of symptomatic episode in patients affected by recurrent uncomplicated urinary stones.

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 2

Nutraceuticals and recurrent urinary stones

MATERIALS

AND METHODS

Study schedule and population From January 2018 to March 2019, all patients attending two referral institutions with history of recurrent uncomplicated urinary stones were enrolled in this prospective phase IV, post-marketing clinical trial. All enrolled patients underwent a urological visit for inclusion and exclusion criteria assessment with quality of life (QoL) questionnaires, serum chemistry, urinalysis and non-contrast-enhanced CT scanner. All patients were encouraged to make lifestyle changes and received a food supplement containing Phyllanthus niruri and Chrysanthellum americanum in association with potassium and magnesium citrates, one capsule a day for 6 months. After 3 months, all patients were contacted by phone by the trialists in order to check the adherence to the treatment. After 6 months, all patients underwent urologic visit, urinalysis, imaging (CT scan) and QoL questionnaires evaluation. Figure 1 shows the study schedule.

logical demonstration of urinary tract infection, noncontrolled diabetes, chronic liver disease and all the other serious comorbidities. Moreover, all patients with the evidence of ureterohydronephrosis or renal colic were excluded. Pregnant women were excluded, too.

Outcome measures The main outcome measures were the reduction of symptomatic episodes and improvement in questionnaire result from baseline at the end of the follow-up period. Stone dimension reduction and stone-free status at 6 months follow-up CT scan were also considered as secondary outcome measures.

Patients’ clinical, laboratory and instrumental assessment At the baseline, all patients underwent urological visit with QoL questionnaires, serum chemistry and blood analysis, urinalysis and non-contrast-enhanced CT scan.

The identified calculi were classified according to their number, location (superior, middle, inferior calyx) and size. Clinical data comprised systolic and diastolic blood pressure and anthropometric evaluation (weight, height, body mass index (BMI). Serum chemistry and blood analysis comprised blood count, assessment of urea, creatinine, sodium, potassium, glucose, uric acid, total and ionized calcium, total cholesterol and fractions, triglycerides, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, amylase and bilirubin levels. Urinalysis with urinary pH measurement and a urine culture were performed using spontaneous voided urine. Moreover, before enrolment all patients received a screening evaluation which includes a medical and dietary history by an experienced nephrologist.

The enrolment has been done on the basis of the baseline metabolic profile, as suggested by the international guidelines (5).

Inclusion and exclusion criteria We considered for the inclusion, all patients with CT demonstration of one or multiple renal stones up to 15 mm. All patients with the following characteristics were excluded: serum creatinine level > 1.6 mg/dL, microbio-

Questionnaires The impact of symptomatic episodes of renal stones on patients’ QoL has been evaluated by using an Italian version of the Quality of Well-Being, a validated, multiattribute health scale (9). This scale was selected because

Figure 1.

T0 Clinical, instrumental laboratory evaluation, Qol and ENROLMENT

Food supplement 1 tablet every 24 hours (Phyllanthus niruri, Chrysanhellum americanum, K+ and Mg+ citrates)

Treatment: 6 months

V1 (3 months)

V2 (6 months)

Contact phone for evaluating adherence to the treatment

Clinical, instrumental laboratory evaluation, Qol

Screening (up to 3 months) CONSORT FLOW DIAGRAM

Assessed for elegibility

Allocated to intervention

Follow.up

Analysed

(n = 96)

(n = 82)

(n = 82)

(n = 82)

Excluded (n = 14) • Not meeting inclusion criteria (n = 10) • Declined to partecipate (n = 4)

Lost to follow-up (n = 0)

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it has been successfully applied to acute illnesses, whereas other quality of life scales, including the Short Form36 (SF-36) Health Survey, are more suitable in chronic cases. Higher scores on the QoL scale reflect a higher quality of life (10).

Follow-up and efficacy assessment After treatment, all patients were reassessed by urologic visit with questionnaire, serum chemistry, urine analysis and imaging, in order to evaluate the changes in number, location and size of the calculi at 3 and 6 months. At 3 months all patients underwent urinary tract sonography and at 6 months non-contrast-enhanced CT scanner.

At 3 months the stone evaluation was < performed by using urinary tract sonography in order to reduce the patients’ exposition to X-ray. However, the stone freerate has been calculated between the baseline and the 6 months follow-up CT scan.

Compounds characteristics All patients were treated in line with the manufacturer’s instructions (Erbozeta S.p.A., RSM - https://www.erbozeta.com). Each administration contained a combination of the following ingredients: 244 mg potassium citrate (93 mg potassium and 150 mg citrate), 735 mg magnesium citrate (30 mg magnesium and 160 mg citrate), Phyllanthus (Phyllantus niruri) herb d.e. 15% mg Tannins 220 mg, Chrysanthellum (Chrysanthellum americanum Vatke) plant d.e. ¼ 55 mg.

Statistical analysis As null hypothesis, we consider that there is no difference in terms of number of symptomatic episodes and QoL between baseline and the end of the follow-up evaluation.

In order to obtain significant results to analyze, sample size calculation was based on the following assumptions: difference in terms of QoL between baseline and followup visit: + 0.3 ± 0.06; a error level, 0.05 two-sided; statistical power, 80%; anticipated effect size, Cohen’s d = 0.5. The calculation yielded 72 individuals. Considering a drop-out rate of 10%, the final sample size was set to 79 patients. The statistical analysis was performed as follows: continuous variables are presented as median and InterQuartile Range (IQR) and categorical variables are presented as absolute (n) and relative (%) frequency distributions. t-test were used to compare average performance between enrolment and the follow-up evaluation, and between the periods before and after enrolment.

The statistical analysis was performed using SPSS. Ethical considerations Due to the fact that this food supplement is already present in Italian pharmacopeia and that Phyllantus niruri has been approved for the management of patients affected by urinary stones in Italy, the study did not require approval by the local ethics committee (IRB).

Nevertheless, our study was conducted in line with Good Clinical Practice guidelines and the ethical principles laid down in the latest version of the Declaration of Helsinki. Before inclusion, all participants signed the written informed consent about personal data collection and storage, in accordance with national bylaws.

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All anamnestic, clinical and laboratory data containing sensitive information about patients were de-identified in order to ensure analysis of anonymous data only.

The de-identification process was performed by nonmedical staff by means of dedicated software. A placebo run-in period was considered unnecessary.

RESULTS From January 2018 to March 2019, 82 patients (mean age 49.7 ± 11.2) completed the follow-up period and were analyzed.

Baseline At the baseline, the average stone size was 7.8 mm and 23 patients showed (ABU). The most common isolated strain was Enterococcus faecalis (18/23; 78.2%).

The median number of symptomatic episodes at baseline was 3 per year. The median number of calculi was 1 (range: 1-4). In 38 patients (46.3%) the calculi were located in the right kidney, 36 (43.9%) had left kidney lithiasis, while 8 patients had bilateral kidney lithiasis (9.8%). The mean stone diameter was 7.8 ± 1.1 mm.

The mean Hounsfield units was 637.1 ± 264.8, in all enrolled patients. No difference, from the normal values, has been reported in terms of urine analysis parameters among the enrolled patients. The Table 1 shows all demographic and baseline clinical and instrumental characteristics of enrolled patients.

Table 1.

Patient clinical, instrumental and laboratory characteristics at the baseline.

No. of enrolled patients Median age (± SD) Sex Male Female Body Mass Index (BMI) (± SD) Charlson Comorbidities Index 0 1 2 Start of urinary lithiasis (years) (range) Number of symptomatic episodes per year (± SD) History of any endourological treatment (in the last 6 months) Yes No Median number of stones (range) Mean stone size (± SD) (mm) Stones side Right kidney Left kidney Bilateral Mean Hounsfield Units (± SD) Stones location (calyx) Superior Middle Inferior Presence of asymptomatic bacteriuria Yes No Isolated strains Enterococcus faecalis Escherichia coli Klebsiella spp.

82 49.7 ± 11.2 49 (59.7) 33 (40.3) 25.8 ± 6.3 75 (11.5) 7 (8.5) 2.3 ± 0.9 3 ± 1.2 12 (14.6) 70 (85.4) 1 (1-4) 7.8 ± 1.1 38 (46.3) 36 (43.9) 8 (9.8) 637.1 ± 264.8 30 (36.5) 38 (46.4) 14 (17.1) 23 (28.1) 59 (71.9) 18 (78.1) 3 (13.3) 2 (8.6)

Nutraceuticals and recurrent urinary stones

6 months follow-up Adherence to the life-style changes and treatment At the 3 months follow up by telephone call, 50 patients reported a high adherence to the life-style changes and to the treatment. At the end of the follow-up period, the adherence to the life-style changes and to the treatment was total in 60 patients (73.1%), while in twenty-two patients (26.8%) some minimal missing doses have been registered. A significant improvement has been reported between the 3- and 6-months evaluations in terms of adherence to the treatment and the life-style changes.

Clinical and instrumental outcomes and QoL Twenty-seven patients out of 82 had no evidence of stone at the non-contrast-enhanced CT scanner (32.9%) at the end of the follow-up evaluation, reporting stone expulsion, while 50 patients showed lower stones dimension (60.9%).

The average stones size at the end of the follow-up was 0.9 mm (± 0.1 mm), with a significant reduction in comparison with the baseline (-6.7 mm ± 3 mm) (p < 0.001).

Forty-nine patients (59.7%) did not show any symptomatic episode with an improving in QoL (+0.4 ± 0.1) (p < 0.001) in comparison to the baseline. No difference, from the normal values, has been reported in terms of urine analysis parameters among the enrolled patients.

The Table 2 shows all clinical and instrumental findings at the end of the follow-up.

Asymptomatic bacteriuria At the end of follow-up evaluation, 3 patients reported ABU. A significant reduction of patients with ABU between the baseline and the end of the follow-up evaluation (23 vs 3; p < 0.001) has been reported.

A significant correlation between ABU reduction and stones number and dimension reduction has been reported (r = 0.83; p < 0.001).

Adverse effects No mild or severe clinically significant adverse effects have been reported.

Table 2.

Clinical, instrumental and laboratory findings at each follow-up visit (3 and 6 months after treatment).

Adherence to life-style changes recommendations Patients with a high Grade of adherence Clinical improvement Recurrence-free patients QoL QoL improvement Difference from baseline Stone-free status Stone size (mm) Stone size (mm) Stone size reduction Difference from baseline Asymptomatic bacteriuria Patients with asymptomatic Bacteriuria Difference from baseline

Baseline

3 months

6 months

-

50 (60.9)

60 (73.1)

0 (0%) 97.1 -

38 (46.3) 97.7 +0.3 ± 0.2 p < 0.001 19 (23.1)

49 (59.7) 97.9 +0.4 ± 0.1 p < 0.001 23 (32.9)

7.8 ± 1.1

3.1 ± 0.5 -4.2 ± 2 p < 0.001

1.1 ± 0.5 -6.7 ± 3 p < 0.001

23

9 (10.9) p < 0.001

3 (3.6) p < 0.001

0 (0%)

DISCUSSION We demonstrated that a food supplement containing Phyllanthus niruri and Chrysanthellum americanum in association with potassium and magnesium citrates is able to improve QoL in patients with urinary stones, reducing symptomatic episodes, stones number and dimension and the prevalence of asymptomatic bacteriuria. Two important points should be discussed: The role of phytotherapy in the management of urinary stones and its mechanism of action and the relationship between urinary stones and ABU. Role of phytotherapy in the management of urinary stones and mechanism of action Phytotherapy is one of the first choices regarding pharmaceutical treatment of patients affected by urinary stones (2) due to the demonstrated efficacy (4, 11) and due to the patient’s preference for phytotherapeutic compounds. Micali and Pucci, in two clinical trials, demonstrated that Phyllanthus niruri is able to reduce the stone size and improve the stone free status rate (4, 11).

In line with these trials, we found a significant reduction in terms of stones size in comparison with the baseline (-6.7 mm ± 3 mm) (p < 0.001) and a high percentage of stone free patients after treatment.

These interesting findings are probably due to Phyllanthus niruri and Chrysanthellum americanum combination in association with potassium and magnesium citrates.

The efficacy of Phyllanthus niruri is probably augmented by the presence of Chrysanthellum americanum.

The role of Chrysanthellum americanum in the management of urinary stones is due to its interference, through the chrysantellin, a saponin, with some stages of crystallization in urine, such as a reduction in the nucleation, growth and aggregation of calcium oxalate crystals (8).

Moreover, the synergistic effect of Phyllanthus niruri and Chrysanthellum americanum is probably due to its diuretic effects (12, 13). Furthermore, this food supplement contains potassium and magnesium citrates, although previous studies did not favor potassium citrate therapy.

However, potassium can moderate the concentration of sodium in urine and promote the elevation of citrate, which acts to correct urinary pH and acidity, possibly contributing to an increase in calcium solubility and, then, interfere with some stages of crystallization in urine (14-17). This food supplement is, then, able to act into two different pathways: diuresis increasing and inhibition of nucleation, growth and aggregation of calcium oxalate crystals. Moving to the role of life-style changes, we found a significant improvement between the 3- and 6-months evaluations in terms of adherence to the treatment and life-style changes. The clinical reported efficacy in terms of reduction of symptomatic episodes, due to the treatment, drives the adherence to the life-style changes. In this sense, this food supplement should be considered, also, as an interesting tool for driving the adherence to the life-style changes and for obtaining a long-term efficacy on the stone recurrence. The high adherence to the treatment is due to the absence of reported adverse effects, too.

Relationship between urinary stones and asymptomatic bacteriuria This was the first study that analyzed the efficacy of a Archivio Italiano di Urologia e Andrologia 2021; 93, 2

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food supplement in reducing ABU in patients affected by urinary stones. ABU is a common clinical condition among recurrent stones patients, which does not generally require any treatment. However, the role of ABU in patients with recurrent urinary stones is not completely understood. Here, we demonstrated that this food supplement is able to statistically significantly reduce the prevalence of ABU among recurrent stone patients.

The efficacy on ABU is probably due to the increase of total daily diuresis and to the inhibition of nucleation, growth and aggregation of bacterial biofilm on the surface of calcium oxalate crystals. This mechanism is probably due to the Phyllanthus niruri and Chrysanthellum americanum action.

Finally, the role of bacteria biofilm on the urinary stone aggregation is another important field to deeply explore.

Future studies are, however, needed to confirm these hypotheses.

CONCLUSIONS In conclusion, this food supplement containing Phyllanthus niruri and Chrysanthellum americanum in association with potassium and magnesium citrates is able to reduce symptomatic episodes, improving QoL in patients with urinary stones and reduce the prevalence of ABU.

9. Kaplan RM, Bush JW, Berry CC. Health status: types of validity and the index of wellbeing. Health Serv. Res. 1976; 11:478-507.

10. Apolone G, Mosconi P. The Italian SF-36 Health Survey: translation, validation and norming. J Clin. Epidemiol. 1998; 51:1025-36.

11. Micali S, Sighinolfi MC, Celia A, et al. Can Phyllanthus niruri affect the efficacy of extracorporeal shock wave lithotripsy for renal stones? A randomized, prospective, long-term study. J Urol. 2006; 176:1020-1022.

12. Nishiura JL, Campos AH, Boim MA, et al. Phyllanthus niruri normalizes elevated urinary calcium levels in calcium stone forming (CSF) patients. Urol Res. 2004; 32:362-6.

13. Udupa AL, Sanjeeva, Benegal A, et al. Diuretic activity of Phyllanthus niruri (Linn) in rats. J Health. 2010; 2:511-2.

14. Lojanapiwat B, Tanthanuch M, Pripathanont C, et al. Alkaline citrate reduces stone recurrence and regrowth after shockwave lithotripsy and percutaneous nephrolithotomy. Int Braz J Urol.

2011; 37:611-616.

15. Soygüur T, Akbay A, Küupeli S. Effect of potassium citrate therapy on stone recurrence and residual fragments after shockwave lithotripsy in lower caliceal calcium oxalate urolithiasis: a randomized controlled trial. J Endourol. 2002; 16:149-152.

16. Cicerello E, Ciaccia M, Cova G, Mangano M. The impact of potassium citrate therapy in the natural course of Medullary Sponge Kidney with associated nephrolithiasis. Arch Ital Urol Androl. 2019; 91:.

17. Monti E, Trinchieri A, Magri V, et al. Herbal medicines for urinary stone treatment. A systematic review. Arch Ital Urol Androl.

2016; 88:38-46.

ACKNOWLEDGEMENTS The authors thank all Medical and Nursing staff at the Department of Urology, Santa Chiara Regional Hospital for clinical assistance and support of this study.

REFERENCES 1. Khan SR, Pearle MS, Robertson WG, et al. Kidney stones. Nat Rev Dis Primers. 2016; 2:16008.

2. Cealan A, Coman RT, Simon V, et al. Evaluation of the efficacy of Phyllanthus niruri standardized extract combined with magnesium and vitamin B6 for the treatment of patients with uncomplicated nephrolithiasis. Med Pharm Rep. 2019; 92:153-157.

3. Curhan GC, Willett WC, Knight EL, Stampfer MJ. Dietary factors and the risk of incident kidney stones in younger women: Nurses’ Health Study II. Arch Intern Med. 2004; 164:885-91.

4. Pucci ND, Marchini GS, Mazzucchi E, et al. Effect of phyllanthus niruri on metabolic parameters of patients with kidney stone: a perspective for disease prevention. Int Braz J Urol. 2018; 44:758-764.

5. Prezioso D1, Strazzullo P, Lotti T, et al. Dietary treatment of urinary risk factors for renal stone formation. A review of CLU Working Group. Arch Ital Urol Androl. 2015; 87:105-20.

6. Cruces IL, Patelli THC, Tashima CM, Mello-Peixoto ECT. Plantas medicinais no controle da urolitíase. Rev Bras Pl Med. 2013; 15(4 Supl 1):780-8.

7. Ettinger B, Pak CY, Citron JT, et al. Potassium-magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis. J Urol. 1997; 158:2069-73.

8. Becchi M, Bruneteau M, Trouilloud M, et al. Structure of a new saponin: chrysantellin A from Chrysanthellum procumbens Rich.

Eur J Biochem. 1979; 102:11-20.

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Correspondence Tommaso Cai, MD (Corresponding Author) ktommy@libero.it Daniele Tiscione, MD Marco Puglisi, MD Gianni Malossini, MD Department of Urology, Santa Chiara Hospital, Trento Largo Medaglie d'Oro 9, Trento (Italy) Lorenzo Ruggera, MD Department of Urology, University of Padua, Padua, Italy.

Paolo Verze, MD Department of Medicine, Surgery, Dentistry "Scuola Medica Salernitana" University of Salerno, Baronissi, Italy Alessandro Palmieri, MD Department of Urology, University of Naples, Federico II, Naples (Italy) Davide Arcaniolo, MD Department of Urology, University Vanvitelli, Naples (Italy)

DOI: 10.4081/aiua.2021.2.189

ORIGINAL PAPER

Obesity rates in renal stone formers from various countries Elenko Popov 1, 2, Murtadha Almusafer 1, 3, Arben Belba 1, 4, Jibril O. Bello 1, 5, Kamran Hassan Bhatti 1, 6, Luca Boeri 1, 7, Kaloyan Davidoff 1, 2, BM Zeeshan Hameed 1, 8, Adam Haliński 1, 9, Ita Pfeferman Heilberg 1, 10, Hongyi Hui 1, 11, Kremena Petkova 1, 12, Bapir Rawa 1, 13, Fernanda Guedes Rodrigues 10, Iliya Saltirov 1, 12, Francisco R. Spivacow 1, 14, Alberto Trinchieri 1, Noor Buchholz 1 1 U-merge

Ltd.* (Urology for emerging countries), London, UK; City Clinic Tokuda Hospital, Sofia, Bulgaria; 3 College of Medicine, University of Basrah, Basrah, Iraq; 4 Ospedale Santo Stefano, Prato & Casa di Cura Villa Donatello, Sesto Fiorentino, Italy; 5 Department of Surgery, Urology Unit, University of Ilorin Teaching Hospital, Nigeria; 6 Urology Department, Hamad Medical Corporation, Doha, Qatar; 7 Department of Urology, IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy; 8 Department of Urology, Kasturba Medical College, Manipal, Karnataka, India; 9 Private Medical Center "Klinika Wisniowa" Zielona Gora, Poland; 10 Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil; 11 Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; 12 Department of Urology and Nephrology, Military Medical Academy, Sofia, Bulgaria; 13 Smart Health Tower, Sulaymaniyah, Kurdistan region, Iraq; 14 Instituto de Investigaciones Metabólicas (IDIM), Buenos Aires, Argentina. * U-merge Ltd. (Urology in Emerging Countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. U-merge Ltd. is registered with the Companies House in London/ UK. www.u-merge.com 2 Acibadem

Summary

Objective: To collect evidence on the rate of obesity in renal stone formers (RSFs) living in different climatic areas and consuming different diets.

Materials and methods: Data of adult renal stone formers were retrospectively collected by members of U-merge from 13 participant centers in Argentina, Brazil, Bulgaria (2), China, India, Iraq (2), Italy (2), Nigeria, Pakistan and Poland.

The following data were collected: age, gender, weight, height, stone analysis and procedure of stone removal.

Results: In total, 1689 renal stone formers (1032 males, 657 females) from 10 countries were considered. Average age was 48 (±14) years, male to female ratio was 1.57 (M/F 1032/657), the average body mass index (BMI) was 26.5 (±4.8) kg/m2. The obesity rates of RSFs in different countries were significantly different from each other. The highest rates were observed in Pakistan (50%), Iraq (32%), and Brazil (32%), while the lowest rates were observed in China (2%), Nigeria (3%) and Italy (10%). Intermediate rates were observed in Argentina (17%), Bulgaria (17%), India (15%) and Poland (22%). The age-adjusted obesity rate of RSFs was higher than the age-adjusted obesity rate in the general population in Brazil, India, and Pakistan, whereas it was lower in Argentina, Bulgaria, China, Italy, and Nigeria, and similar in Iraq and Poland.

Conclusions: The age-adjusted obesity rate of RSFs was not higher than the age-adjusted obesity rate of the general population in most countries. The relationship between obesity and the risk of kidney stone formation should be reconsidered by further studies carried out in different populations.

KEY WORDS: Urinary calculi; Obesity; Diet, Body mass index.

Submitted 1 April 2021; Accepted 25 May 2021

INTRODUCTION

Obesity is considered a risk factor for urinary stone formation. A recent meta-analysis based on 7 large cohorts in the United States, China and Japan computed a relative risk for kidney stone formation of 1.21 per 5 units of increment in body mass index (BMI) (1). This scientific evidence is robust although it is mainly dependent on observations collected from cohorts in the United States.

For this reason, one might question the extension of these findings to other countries. In fact, the population of the United States is characterized by a dietary pattern that contains important risk factors for stone formation (a high animal protein load, a significant acid load due to lack of fruit and vegetable consumption).

Furthermore, morbid obesity (BMI ≥ 40) is much more prevalent in the population of the United States than in any other country excluding Pacific Islands (2). In fact, the prevalence of morbid obesity in the United States is high and is constantly increasing. From 2000 to 2010 the prevalence rate of a BMI > 40 increased by 70% (from 3.9% to 6.6%) and the prevalence of BMI > 50 has increased even more (from 0.27 to 0.55%) (3). Morbid obesity levels are also increasing in other countries but with much lower rates (< 2%) (4-6). Morbid obesity or type III obesity has a different impact on health than moderate obesity by increasing the risk and severity of many cardiovascular and non-cardiovascular comorbidities.

Particularly, it was observed that 98% of subjects with morbid obesity have at least one lithogenic risk factor identified on 24-hour urine collection (7). The obese population of the United States is therefore a different popula-

No conflict of interest declared.

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tion from obese populations observed in other countries in that it includes a higher percentage of morbid obese subjects. On the other hand, rates of overweight and obesity in a population consuming a Mediterranean diet were not different in renal stone formers with respect to a control population matched by age and gender (8) suggesting a prevalent role of the dietary pattern for the risk of stone formation (9).

The aim of the present study was to collect more evidence on the rate of obesity in renal stone formers living in different climatic areas and consuming different diets.

Age and sex adjusted rates of obesity in stone formers from different countries were compared with already known obesity rates for each corresponding country.

MATERIALS

AND METHODS

Data were collected by 13 participating centers in Argentina, Brazil, Bulgaria (n = 2), China, India, Iraq (n = 2), Italy (n = 2), Nigeria, Pakistan and Poland under the umbrella of U-merge. Each participating center collected retrospectively data of consecutively observed adult (> 18 years) renal stone former patients (RSFs) by reviewing charts of patients who passed spontaneously a stone or had extracorporeal or endourological treatment for stone removal. For each patient, the following information was collected: age, gender, weight, height, stone analysis (optional), procedure of removal (spontaneous passage, SWL, PNL, URS, open surgery). Any method of stone analysis was accepted, but the methodology had to be known and registered. Excel files containing anonymised data from each patient and numbered consecutively were mailed to the coordinating center (Umerge scientific office). Each center retained the list of the corresponding names of the participants in their own original files at their institution. BMI was computed from weight and height of each subject. Obesity was defined as a body mass index (BMI) ≥ 30 kg/m2. Tables reporting the number of subjects with obesity for each age and sex group were built. The obesity rates of RSFs in different countries were adjusted by the age distribution in the general population of each country, in order to compare them with age adjusted obesity rates in the general population of the corresponding country obtained from estimated worldwide trends in obesity by NCD Risk Factor Collaboration (NCD-RisC) (2). Briefly, RSFs of each country were grouped by sex and class age. Age and sex specific rate of obesity of RSFs of each subgroup was multiplied by the corresponding age and sex specific weight of

that country. The weights used in the age-adjustment of obesity data are the proportion of the population of each country within each age and sex group according to the estimates prepared by the Population Division of the Department of Economic and Social Affairs (DESA) of the United Nations Secretariat (10). The weighted rates are then summed across the age and sex groups to give the age and sex adjusted rate of obesity for RSFs of each country (Table 1). Age adjusted obesity rates of male and female RSFs from each country were compared with age adjusted obesity rate of male and female general population obtained from estimated worldwide trends in obesity by NCD-RisC (2). Finally, obesity rates in RSFs with stones of different chemical composition were calculated.

Statistical analysis was carried out using the Statistical Package for the Social Sciences (SPSS). Chi square analysis was used to compare rates of obesity in different groups.

Mean values of age and BMI were compared by one-way ANOVA, and differences between groups were evaluated by post hoc Bonferroni analysis. A p-value < 0.05 was considered statistically significant.

RESULTS

In total, 1689 renal stone formers (1032 males, 657 females) from 10 countries (Argentina, Brazil, Bulgaria, China, India, Iraq, Italy, Nigeria, Pakistan, Poland) were considered. Most of the cases were observed in the period 2016-2019. Only the series from Argentina included patients observed over a longer period from 2005 to 2017.

Average age was 48 (±14) years, male to female ratio was 1.57 (M/F 1032/657), average BMI was 26.5 (±) 4.8 kg/m2). Average age, M/F ratio and average BMI in series from different countries are shown in Table 2. The average age values in the different series were significantly different (p = 0.000).

The highest average age was observed in patients from Table 1.

An example of computation of age-adjusted obesity rate (Italy-males).

Class age 18-39 40-59 > 60 TOTAL

Obesity rate in RSF Weight of class ages in Italy (5) 1/29 = 0.034 0.30 17/130 = 0.130 0.38 9/108 = 0.083 0.32 27/267 = 0.101 1.00 10.1%

Age adjusted 0.010 0.049 0.026 0.085 8.5%

Table 2.

Mean age, M/F ratio and mean BMI of RSFs from different countries.

N° M F Age BMI UA %

Argentina 300 179 (60%) 121 (40%) 45 +/-11 25.8 +/-4.4 11% §

Brazil 216 114 (53%) 102 (47%) 42 +/-12 28.3 +/-5.8 -

Bulgaria 183 112 (61%) 71 (39%) 50 +/-13 26.2 +/-3.8 29% *

China 90 59 (66%) 31 (34%) 51 +/-13 24.2 +/-2.9 6% *

India 33 26 (79%) 7 (21%) 48 +/-11 26.0 +/-4.2 34% *

BMI = Body Mass Index; UA% = Rate of Uric Acid containing stones; § Present series; * Other series from the same institution.

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Iraq 246 154 (63%) 92 (37%) 46 +/-14 28.3 +/-4.7 -

Italy 428 267 (62%) 161 (38%) 56 +/-14 25.1 +/-4.3 16% §

Nigeria 31 17 (55%) 14 (45%) 44 +/-14 26.2 +/-2.4 -

Pakistan 50 41 (82%) 9 (18%) 38 +/-8 30.4 +/-6.7 25% *

Poland 112 63 (56%) 49 (44%) 48 +/-14 26.7 +/- 4.6 33% *

Obesity rates in renal stone formers

Table 3.

Crude and age-adjusted obesity rates in male and female RSFs from different countries in comparison of age-adjusted obesity rates in male and female general population.

Country

Gender

Argentina

T M F T M F T M F T M F T M F T M F T M F T M F T M F T M F T M F

Brazil

Bulgaria

China

India

Iraq

Italy

Nigeria

Pakistan

Poland

TOTAL

RSFs RSFs obesity obese/total rate (crude) 51/300 (17%) 17% 32/179 (18%) 17.8% 19/121 (16%) 15.7% 70/216 (32%) 36/114 (31%) 31.5% 34/102 (33%) 33.3% 32/183 (17%) 18/112 (16%) 16.0% 14/71 (19%) 19.7% 2/90 (2%) 1/59 (2%) 1.6% 1/31 (3%) 3.2% 5/33 (15%) 3/26 (11%) 11.5% 2/7 (28%) 28.5% 78/246 (32%) 45/154 (29%) 29.2% 33/92 (36%) 35.8% 43/428 (10%) 27/267 (10%) 10.1% 16/161 (10%) 9.9% 1/31 (3%) 17 0 1/14 (7%) 7.1% 25/50 (50%) 20/41 (49%) 48.7% 5/9 (55%) 55.5% 25/112 (22%) 18/63 (28%) 28.5% 7/49 (14%) 14.2% 332/1689 (20%) 200/1032 (19%) 132/657 (20%)

RSFs obesity General population rate (adjusted) obesity rate 2016 15.9% 15%

28.2% 30.1%

32.5% 31.9%

19.2% 26.4%

15.3% 17.7%

26.3% 25.2%

1.5% 3.3%

6.1% 6.8%

11.0% 59.5%

2.8% 5.3%

22.5% 32.3%

24.3% 38.3%

8.5% 9.5%

20.9% 20.4%

0 4.5%

4.8% 13.6%

20.7% 24.1%

6.2% 11.7%

27.9% 14.6%

24.6% 23.2%

Italy, while the lowest average age was observed in patients from Pakistan.

The average age of patients from Italy was significantly higher than that of patients from Bulgaria (p = 0.000), Iraq (p = 0.000), Pakistan (p = 0.000), Nigeria (p = 0.000), Poland (p = 0.000), Argentina (p = 0.000) and Brazil (p = 0.000). The average age of patients from Pakistan was significantly lower than that of patients from Bulgaria (p = 0.000), Iraq (p = 0.003), China (p = 0.000), India (p = 0.039), Italy (p = 0.000), Poland (p = 0.000) and Argentina (p = 0.046). The average age of patients from Bulgaria and China was significantly higher than that of patients from Pakistan (p = 0.000 and p = 0.000), Argentina (p = 0.007 and p = 0.007) and Brazil (p = 0.000 and p = 0.000) and the average age of patients from Brazil was higher than that of patients from Poland (p = 0.002) and Iraq (p = 0.005).

Male to female ratio was in favor of men in all countries, with the percentage of men ranging from 53 to 63% in most countries except Pakistan and India where males accounted for 82 and 79%, respectively.

The average BMI values of patients in different countries were significantly different (p = 0.000). In particular, the average BMI was highest in patients from Pakistan, Iraq and Brazil. The average BMI of patients in Pakistan was significantly higher than that of patients in Bulgaria (p = 0.000), China (p = 0.000), India (p = 0.001), Italy (p = 0.000), Nigeria (p = 0.004), Poland (p = 0.000), Argentina (p = 0.000) and Brazil (p = 0.000). The average BMI of patients in Iraq was significantly higher than the average BMI of patients in Bulgaria (p = 0.000), China (p = 0.000), Italy (p = 0.000) and Argentina (p = 0.000). The average BMI of Brazilian patients was intermediate, being higher than that of patients in Bulgaria (p = 0.001), China (p = 0.000), Italy (p = 0.000) and Argentina (p = 0.000).

The lowest average BMI value was observed in patients from China being lower than that of Bulgaria (0.0024) and Poland (p = 0.007).

Crude and age-adjusted obesity rates in male and female RSFs from different countries in comparison of ageadjusted obesity rates in the male and female general population are shown in Table 3. In both, males and females, the age-adjusted rate of obesity in RSFs was higher than the age-adjusted rate of obesity in the general population in Brazil, India, and Pakistan, whereas it was lower in Argentina, Bulgaria, China, Italy, and Nigeria, and similar in Iraq and Poland.

The obesity rates of RSFs were significantly different from country to country. The highest rates were observed in Pakistan (50%), Iraq (32%), and Brazil (32%), while the lowest rates were observed in China (2%), Italy (10%), and Nigeria (3%). Intermediate rates were observed in Argentina (17%), Bulgaria (17%), India (15%), and Poland (22%). These differences were maintained when obesity rates were adjusted by age in reference to a pool of all series. In a sample of 666 patients (409 males and 257 females) with stone analysis, obesity rate was 13.3% (61/456) for calcium oxalate stones, 4.7% (1/21) for calcium phosphate, 8.5% (6/70) for mixed calcium phosphate/calcium oxalate, 18.8% (13/69) for uric acid, 20.8% (5/24) for mixed calcium oxalate/uric acid.

No obese patients were observed for infection (struvite) (0/21) and cystine stones (0/5).

Mean age (56±14 vs 50±14 years, p = 0.000), mean BMI (27.2±4.6 vs 25.0±4.2, p = 0.000) and obesity rates 18/86 (21%) vs 75/580 (13%) were higher in patients who formed uric acid-containing stones than in those of patients forming other type of stones.

In the present series, rate of uric acid containing stones was 16% in Italy and 11% in Argentina and, from data of other series collected in the same centers participating to the present study, 29% in Bulgaria, 6% in China, 34% in India, 25% in Iraq, 25% in Pakistan and 33%in Poland

DISCUSSION

In 2006, a prospective study of 3 large cohorts demonstrated that a BMI > 30 is associated with an increased risk of kidney stone formation for both, men and women (11).

Some authors emphasized the presence of high rates of obesity in RSFs in some countries, whilst other authors did not confirm this finding in other countries (Table 4) (8, 12-20).

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Table 4.

Obesity rates of RSFs of different countries (from the highest to the lowest).

Author, year Country Semins, 2010 United States Abu Ghazaleh and Budair, 2013 Jordan Chou, 2011 Taiwan Saenz, 2012 Spain Funes, 2016 Paraguay Negri, 2008 Argentina Siener, 2004 Germany Daudon, 2006 France Trinchieri, 2016 Italy Oda, 2014 Japan

N° Obesity rate 1935 M+1322 F 49.9%-49.0% 8346 42.3 % 907 38.8% 346 28.6% 73 23.3 799 20.3% 527 9.9% 1931 M+F 8.4%-13.5% 1698 8.3% 238 M+82 F 2.1%-0%

Overweight 34.1%-20% 25.8% 33.5% 43.6% 39.7% 40.6% 44.6% 27.1%-19.6% 31.9% 24.4%-12.2%

The assessment of the significance of the obesity rate in a given population on one hand, and the comparison of obesity rates in different populations on the other hand are complex because one must take into account the age and gender distribution of the population as well as the chemical composition of the stones.

Our study shows that obesity rates among RSFs in different countries range between 0 and 48.7% in men, and 7.1% and 55.5% in women. These differences are maintained after age adjustment according to the general population’s age distribution, with rates ranging between 0 and 32.5% in men, and 3.3% and 59.5% in women, respectively.

These wide oscillations can be explained by the different age distributions in different countries, but also by different spectra of stone composition, dietary patterns and different climatic conditions.

In general, the rate of obesity tends to increase with increasing age, so it is possible that in populations with an older age distribution there may be a higher prevalence of obesity. To the contrary, in this study, series with higher average ages, such as those observed in Italy, Bulgaria and China, had the lowest obesity rates among both, men (1.6-16%) and women (3.2-15.7%), respectively.

On the other hand, the ranking of obesity rates in different countries does not vary after the rates have been adjusted by age taking as a reference the pooled population of all the series.

Another potential determinant of obesity rate among RSFs is the type of stone. Obesity tends to be more frequent in uric acid stone formers (21). Uric acid stones have a different prevalence in different countries.

In our series obesity rates were higher in Pakistan, Iraq and Brazil. The former two have reported a higher frequency of uric acid stones (22, 23), which was also observed in some parts of Brazil (24).

In contrast, the lowest obesity rates were observed in countries where the frequency of uric acid stones is low, such as China, Nigeria and, to a lesser extent, Italy (25-27).

One of the major determinants of the epidemiology of uric acid stones is climate, as higher environmental temperatures and humidity increase skin loss of fluids resulting in a reduction in urinary volumes, a decrease of pH

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values and, consequently, an increased urinary saturation for uric acid (28, 29). In fact, in our study, the countries with the highest rates of uric acid stones are characterized by higher environmental temperatures (30).

The finding of obesity rates in RSFs equal to or even lower than those observed in the general population of most countries can be explained by the interaction of several factors specific to each population.

Obesity is the result of the imbalance between dietary energy intake and energy expenditure that is modulated by the individual genetic characteristics that affect the absorption and metabolism of nutrients.

In Table 5 the different patterns of dietary energy intake, levels of physical activity and consumption of healthy and unhealthy foods in the general population of countries involved in the present study are summarized (31-33).

In countries with the lowest dietary energy intake, such as India, Pakistan and Nigeria, the lowest obesity rates were observed, but also in China, where dietary energy intake has an intermediate value, the obesity rate is low in view of the high levels of physical activity.

In other countries with intermediate energy intake values Table 5.

Rates of obesity, estimated energy intake, levels of physical inactivity and quality of dietary pattern of the general population in countries involved in this surveycomparison of age-adjusted obesity rates in male and female general population.

Country Argentina

Brazil

Bulgaria

China

India

Iraq

Italy

Nigeria

Pakistan

Poland

Obesity (NCD-RiskCo) M-F Kcal/day 28.2-30.1 37.6% (M) 45.3% (F) 19.2-26.4 40.4% (M) 53.3% (F) 26.3-25.2 35.6% (M) 41.4% (F) 6.1-6.8 16.0% (M) 12.2% (F) 2.8-5.3 24.7% (M) 43.9% (F) 24.3-38.3 39.5% (M) 64.6% (F) 20.9-20.4 36.2% (M) 46.2% (F) 4.8-13.6 24.7% (M) 29.6% (F) 6.2-11.7 24.4% (M) 43.3% (F) 24.6-23.3 31.5% (M) 33.4% (F)

Energy intake (FAO) * 3030

Physical inactivity (WHO) 41.6% (T)

Quality of dietary pattern (NutriCoDE)

3120

47.9% (T)

Healthy foods moderate Unhealthy foods high

2760

38.6% (T)

Healthy foods moderate Unhealthy foods low/moderate

2990

14.1% (T)

Healthy foods low Unhealthy foods low

2360

34.0% (T)

Healthy foods low Unhealthy foods very low

-

52.0%(T)

Healthy foods moderate Unhealthy foods low/moderate

3650

41.4% (T)

Healthy foods low/mododrate Unhealthy foods moderate

2710

27.1% (T)

Healthy foods moderate Unhealthy foods low

2280

33.7% (T)

Healthy foods very low Unhealthy foods low

3410

32.5% (T)

Healthy foods low/moderate Unhealthy foods high/moderate

Healthy foods very low Unhealthy foods low/mod

Obesity rates in renal stone formers

but reduced levels of physical activity, such as Brazil and Argentina, high obesity rates are observed similarly to those of countries with higher energy intakes, such as Italy and Poland. Finally, the highest levels of obesity were observed in Iraq where lowest levels of physical activity were reported.

Obesity rate in RSFs was higher than in the general population in Brazil, which is, a country with a high consumption of unhealthy foods (34, 35).

The other two countries where obesity rates were increased in RSFs, namely Pakistan and India, are not characterized by a high consumption of unhealthy foods, but have a low consumption of healthy foods such as fruits, vegetables, beans and legumes, nuts and seeds, whole grains, milk, total polyunsaturated fatty acids, fish, plant omega-3s, and dietary fibers (33).

Admittedly, our study has some limitations such as the retrospective study format, the small number of subjects observed in some countries, the heterogeneous nature of data, the variability in the population pattern and nature of cohorts and the availability of the chemical examination of the stones only in some series Particularly, series observed in some areas of large countries are representative only for those specific areas, notably Shanghai (China), Lagos (Nigeria), Pakpattan (Pakistan) and Manipal (Karnataka-India) and obesity rates cannot be translated to populations of countries with several million inhabitants. In fact, the populations of these countries are made up of different ethnicities with different genetic characteristics and different culture and religion influencing eating habits and lifestyle.

In conclusion, obesity rates among patients with urinary stones are variable in different countries. Higher obesity rates were observed in countries with a high prevalence of uric acid stones. On the other hand, obesity rates observed in RSFs tend to overlap with the rates observed in the general population, with equal or lower values even after adjustment by age. Accordingly, the role of obesity on the risk of kidney stones formation should be confirmed by further studies carried out in different populations.

REFERENCES

1. Aune D, Mahamat-Saleh Y, Norat T, Riboli E. Body fatness, diabetes, physical activity and risk of kidney stones: a systematic review and meta-analysis of cohort studies. Eur J Epidemiol. 2018; 33:1033-1047.

2. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults.

Lancet. 2017; 390:2627-2642. http://www.ncdrisc.org/data-downloads-adiposity.html 3. Sturm R, Hattori A. Morbid obesity rates continue to rise rapidly in the United States. Int J Obes (Lond). 2013; 37:889-891.

6. Basterra-Gortari FJ, Bes-Rastrollo M, Ruiz-Canela M, et al.

Prevalence of obesity and diabetes in Spanish adults 1987-2012.

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7. Duffey BG, Pedro RN, Kriedberg C, et al. Lithogenic risk factors in the morbidly obese population. J Urol. 2008; 179:1401-6.

8. Trinchieri A, Croppi E, Montanari E. Obesity and urolithiasis: evidence of regional influences. Urolithiasis. 2017; 45:271-278.

9. Esperto F, Miano R, Marangella M, Trinchieri A. Impact of food quantity and quality on the biochemical risk of renal stone formation. Scand J Urol. 2018; 52:225-229.

10. 2019 Revision of World Population Prospects is the twenty-sixth round of official United Nations population estimates and projections that have been prepared by the Population Division of the Department of Economic and Social Affairs (DESA) of the United Nations Secretariat. World Population Prospects 2019. https://population.un.org/wpp/Download/Standard/Population/ 11. Taylor EN, Stampfer MJ, Curhan GC. Obesity, weight gain, and the risk of kidney stones. JAMA. 2005; 293:455-62.

12. Semins MJ, Shore AD, Makary MA, et al. The association of increasing body mass index and kidney stone disease. J Urol. 2010 Feb; 183(2):571-5.

13. Abu Ghazaleh LA, Budair Z. The relation between stone disease and obesity in Jordan. Saudi J Kidney Dis Transpl. 2013; 24:610-614.

14. Chou YH, Su CM, Li CC, et al. Difference in urinary stone components between obese and non-obese patients. Urol Res. 2011; 39:283-7.

15. Sáenz J, Páez A, Alarcón RO, et al. Obesity as risk factor for lithiasic recurrence. Actas Urol Esp. 2012; 36:228-233.

16. Funes P, Echagüe G, Ruiz I, et al. Lithogenic risk in patients from Paraguay with urolithiasis. Rev Med Chil. 2016; 144:716-22.

17. Negri AL, Spivacow FR, Del Valle EE, et al. Role of overweight and obesity on the urinary excretion of promoters and inhibitors of stone formation in stone formers. Urol Res. 2008; 36:303-307.

18. Siener R, Glatz S, Nicolay C, Hesse A. The role of overweight and obesity in calcium oxalate stone formation. Obes Res. 2004; 12:106-113.

19. Daudon M, Lacour B, Jungers P. Influence of body size on urinary stone composition in men and women. Urol Res. 2006; 34:193-199.

20. Oda E. Overweight and high-sensitivity C-reactive protein are weakly associated with kidney stone formation in Japanese men. Int J Urol. 2014; 21:1005-11.

21. Trinchieri A, Montanari E. Biochemical and dietary factors of uric acid stone formation. Urolithiasis. 2018; 46:167-172.

22. Rafique M, Bhutta RA, Rauf A, Chaudhry IA. Chemical composition of upper renal tract calculi in Multan. J Pak Med Assoc. 2000; 50:145-148.

23. Afaj AH, Sultan MA. Mineralogical composition of the urinary stones from different provinces in Iraq. Scientific World Journal.

2005; 5:24-38.

4. Malta DC, Silva AGD, Tonaco LAB, et al. Time trends in morbid obesity prevalence in the Brazilian adult population from 2006 to 2017. Cad Saude Publica 2019; 35:e00223518.

24. da Silva SF, Silva SL, Daher EF, et al. Determination of urinary stone composition based on stone morphology: a prospective study of 325 consecutive patients in an emerging country. Clin Chem Lab Med. 2009; 47:561-564.

5. Chang HC, Yang HC, Chang HY, et al. Morbid obesity in Taiwan: Prevalence, trends, associated social demographics, and lifestyle factors. PLoS One. 2017; 12:e0169577.

25. Wu W, Yang D, Tiselius HG, et al. The characteristics of the stone and urine composition in Chinese stone formers: primary report of a single-center results. Urology. 2014; 83:732-737.

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26. Meka IA, Ugonabo MC, Ebede SO, Agbo EO. Composition of uroliths in a tertiary hospital in South East Nigeria. Afr Health Sci. 2018; 18:437-445.

32. WHO Global Health Observatory data repository, viewed 25th April 2020 https://apps.who.int/gho/data/

27. Trinchieri A, Rovera F, Nespoli R, Currò A. Clinical observations on 2086 patients with upper urinary tract stone. Arch Ital Urol Androl. 1996; 68:251-262i.

33. Imamura F, Micha R, Khatibzadeh S, et al. Global Burden of Diseases Nutrition and Chronic Diseases Expert Group (NutriCoDE). Dietary quality among men and women in 187 countries in 1990 and 2010: a systematic assessment. Lancet Glob Health. 2015; 3:e132-42.

28. Stuart RO 2nd, Hill K, Poindexter J, Pak CY. Seasonal variations in urinary risk factors among patients with nephrolithiasis. J Lithotr Stone Dis. 1991; 3:18-27.

29. Baker PW, Coyle P, Bais R, Rofe AM. Influence of season, age, and sex on renal stone formation in South Australia. Med J Aust.

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30. https://it.climate-data.org/ 31. FAO Statistics Division 2010, Food Balance Sheets, Food and Agriculture Organization of the United Nations, Rome, Italy, viewed 25th April 2020, http://faostat.fao.org/

34. Ferreira APS, Szwarcwald CL, Damacena GN. Prevalence of obesity and associated factors in the Brazilian population: a study of data from the 2013 National Health Survey. Rev Bras Epidemiol.

2019; 22:e190024.

35. Pereira DL, Juvanhol LL, Silva DC, Longo GZ. Dietary patterns and metabolic phenotypes in Brazilian adults: a population-based cross-sectional study. Public Health Nutr. 2019; 22:3377-3383.

Correspondence Elenko Popov, MD shennyp@yahoo.com

Ita Pfeferman Heilberg, MD ita.heilberg@gmail.com

Kaloyan Davidoff, MD shennyp@yahoo.com Acibadem City Clinic Tokuda Hospital - Sofia, Bulgaria

Fernanda Guedes Rodrigues, MSci RD fernanda.gr91@gmail.com Nephrology Division, Universidade Federal de São Paulo (UNIFESP) São Paulo, Brazil

Murtadha Almusafer, MD dralmusafer@yahoo.com College of Medicine, University of Basrah - Basrah, Iraq Kamran Hassan Bhatti, MS Urology kamibhatti92@gmail.com Urology Department, Hamad Medical Corporation - Doha, Qatar

Kremena Petkova, MD dr_petkova@yahoo.com

Arben Belba, MD arbenbelba@gmail.com Ospedale Santo Stefano, Prato and Casa di Cura Villa Donatello, Sesto Fiorentino, Florence, Italy

Iliya Saltirov, MD saltirov@vma.bg Department of Urology and Nephrology, Military Medical Academy Sofia, Bulgaria

Jibril O. Bello, MD jabarng@yahoo.com Department of Surgery, Urology Unit, University of Ilorin Teaching Hospital - Ilorin, Nigeria

Bapir Rawa, MD dr.rawa@yahoo.com Smart Health Tower - Sulaymaniyah , Kurdistan region, Iraq

Luca Boeri, MD dr.lucaboeri@gmail.com Department of Urology, IRCCS Ca’ Granda Ospedale Maggiore Policlinico University of Milan, Milan, Italy

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Hongyi Hui, MD 1095340463@qq.com Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

Francisco R. Spivacow, MD frspivacow@gmail.com Instituto de Investigaciones Metabólicas (IDIM) - Buenos Aires, Argentina

Adam Haliński, MD adamhalinski@gmail.com Private Medical Center "Klinika Wisniowa" - Zielona Gora, Poland

Alberto Trinchieri, MD alberto.trinchieri@gmail.com U-merge Ltd. (Urology for emerging countries), Scientific Office Athens, Greece & School of Urology, University of Milan - Milan, Italy

BM Zeeshan Hameed, MD zeeshanhameedbm@gmail.com Department of Urology, Kasturba Medical College - Manipal, Karnataka, India

Noor Buchholz, MD (Corresponding Author) noor.buchholz@gmail.com U-merge Ltd. (Urology for emerging countries), Scientific Office Athens, Greece

Archivio Italiano di Urologia e Andrologia 2021; 93, 2

DOI: 10.4081/aiua.2021.2.195

ORIGINAL PAPER

The new patterns of nephrolithiasis: What has been changing in the last millennium?

Elisa Cicerello, Matteo Ciaccia, Gian D. Cova, Mario S. Mangano Unità Complessa di Urologia, Dipartimento di Chirurgia Specialistica, Ospedale Ca’ Foncello, Treviso, Italy.

Summary

Nephrolithiasis has been increasing over the last millennium. Although early epidemiologic studies have shown that kidney stones were two to three times more frequent in males than in females, recent reports have suggested that this rate is decreasing. In parallel a dramatic increase of nephrolithiasis has also been observed among children and adolescents. Furthermore, epidemiologic studies have shown a strong association between metabolic syndrome (Mets) traits and kidney stone disease. Patients with hypertension have a higher risk of stone formation and stone formers are predisposed to develop hypertension compared to the general population. An incidence of nephrolithiasis greater than 75% has been shown in overweight and obese patients compared to those of normal weight. It has also been reported that a previous diagnosis of diabetes mellitus increases the risk of future nephrolithiasis. Additionally, an association between metabolic syndrome and uric acid stone formation has been clearly recognized.

Furthermore, 24-h urinary metabolic abnormalities have been decreasing among patients with nephrolithiasis over the last decades. Finally, nephrolithiasis could cause chronic kidney disease (CKD) and end stage renal disease (ESRD), especially in women and overweight patients. According to these observations, a better understanding of these new features among stone former patients may be required. Hence, the recognition and the correction of metabolic disorders could help not only to reduce the primary disease, but also stone recurrence.

bolic laboratories commonly present in clinics. Among five established criteria, three or more are needed to diagnose Mets. These are: waist circumference > 102 and 80 cm in men and women respectively, serum triglycerides > 150 mg/dL, high density lipoprotein < 40 mg/dL and < 50 mg/dL in men and woman respectively, blood pressure (BP) > 130/85 mmHg and fasting blood sugar < 100 mg/dL (7) (Table 1). A study based on self-reported histories has shown an increasing association of nephrolithiasis and Mets traits (3.7% with no traits, 7.5% for three traits and 9.8% for five traits) (8). Furthermore, the patients with more than 4 Mets traits also showed a significant increase in the chances of recurrent or multiple stones with respect to patients with 0 traits (9). Mets may also cause cardiovascular disease, a condition frequent in patients with nephrolithiasis (10).

These new insights confirm a new pattern of patients with nephrolithiasis that should be regarded as a systemic disease representing the result of the interaction of multiple risk factors.

This article will review the possible explanations for these new features of stone disease, with the aim to better assess them and their association with nephrolithiasis and to suggest measures for prevention not only for primary systemic disease, but also for stone recurrence.

KEY WORDS: Nephrolithiasis; Metabolic syndrome (Mets); Gender; Children; Adolescents.

Mets and nephrolithiasis Obesity, the most frequent tract of Mets, is also a condition of risk for nephrolithiasis. A positive correlation between obesity and the first-time stone, recurrent stone formation and shorter interval of recurrence have been demonstrated. Taylor et al. have reported that waist circumference, body mass (BMI), weight gain, weight gain during adulthood are linked to an increase of incidental stones (11). Other studies have shown that BMI is higher in stone formers (12, 13). In a large cohort of women without history of stones the risk for incidental stones increases with BMI 1.3 fold for 25-29 kg/m2 higher, 1.62 for 30-34.9 kg/m2 and 1.81 fold for ≥ 35 kg/m2) with respect to BMI < 25 kg/m2 (14). Next, body fat can influence the risk for stone formation. Kim et al. have shown a link between uric acid and calcium oxalate stones and visceral adipose tissue measured on computed tomography (CT) (15). A link has also been reported between non-alcoholic fat liver disease and the risk of stone formation and visceral to subcutaneous fat tissue ratio (16).

Submitted 13 April 2021; Accepted 17 May 2021

INTRODUCTION

Several studies in the last decades have showed an overall increased incidence of kidney stones (1, 2). However, nephrolithiasis is increasing in women at a greater rate than in men and the common ratio 3:1 male to female is reducing (3, 4). An increased incidence of nephrolithiasis among children during the last 25 years has also been observed (5).

Moreover, other studies have shown Mets is increasing in parallel to the incidence and prevalence of nephrolithiasis (6). Various definitions have been included for defining Mets criteria. The United States National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) is the most simple since it can be used by basic metaNo conflict of interest declared.

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Table 1.

NCEP ATP III: United States National Cholesterol Education Program.

Adult treatment panel III, Rx, Pharmacologic intervention for that component Criteria Waist circumference (cm) > 102 (males), > 88 (females) Fasting glucose (mg/dL) ≧ 100 or Rx Triglycerides (mg/dL) ≧ 150 or Rx High-density lipoprotein (mg/dL) < 40 (males), < 50 (females) or Rx Blood pressure (mmHg) > 130 (systolic), > 85 (diastolic) or Rx

Additionally, obesity has been associated with impaired carbohydrate tolerance and inappropriate calcium response to glucose ingestion. Obese patients show an increased excretion of calcium, sodium, uric acid and a lower urinary pH in relation to the non-obese (17).

Defects in renal ammoniagenesis and excessive net acid excretion (NAE), which are common in patients with Mets, could cause a decreased urinary pH (18). Next, renal acidification defects lead to hypocitraturia, another important risk for stone formation (13). Furthermore, an increased excretion of oxalate correlated with BMI has been reported among diabetic and overweight patients promoting calcium oxalate stone formation. Hence, both the percentage of uric acid and calcium oxalate stones was found higher in obese than non-obese patients (34.9 vs 23.1 and 7.7 vs 2.8 respectively) (19).

Diabetes mellitus has been clearly linked to nephrolithiasis. A previous diagnosis of diabetes increases the risk for stone formation and a previous diagnosis of stone disease leads to the onset of diabetes mellitus. In a crosssectional study of 3 large cohorts on multivariate analysis, the relative risk of prevalent stone disease in patients with type 2 diabetes was 1.38 in older women, 1.67 in younger women and 1.31 in men. Additionally, the risk of incident type 2 diabetes in patients with history of stone disease was 1.33, 1.48 and 1.49 respectively (20).

Patients with type 2 diabetes have a decreased ammonium production resulting in lower urinary pH and increased risk of uric acid stone formation and an increased excretion of oxalate which promotes calcium oxalate stone formation (21). However, uric acid stones are more frequent in patients with diabetes and glucose intolerance (22). An association between the gravity of diabetes evaluated with fasting plasma insulin and glucose and hemoglobin A1c and the risk for stone formation has also been observed (23).

It is well known that elevated serum triglycerides and low high-density lipoprotein (HDL) levels increase the cardiovascular risk. Next, dyslipidemia is associated with lower urinary pH and could be considered as an independent risk factor for kidney stones (24). An association between dyslipidemia and kidney stone disease has been reported by Masterson and colleagues. This retrospective study shows an association between dyslipidemia and kidney stones with a hazard ratio of 2.2.

Then, examining individually dyslipidemia factors, it was shown that low-density lipoprotein (LDL) and triglycerides are not associated with stone formation, while low

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HDL values (< 45 mg/dL for men; < 60 mg/dL for women) had a hazard ratio of 1.4 (25). Furthermore, nephrolithiasic patients show higher levels of total serum cholesterol and triglycerides (12). The association of total cholesterol with stone formation was higher in uric acid and calcium oxalate monohydrate/dihydrate.

Besides, LDL levels were higher in calcium oxalate monohydrate/dihydrate stone formers than in calcium oxalate monohydrate group.

Several studies have shown an association between hypertension and nephrolithiasis: patients with hypertension are more at risk for nephrolithiasis (26) and patients with a history of nephrolithiasis have an increased risk for development of hypertension (27).

Furthermore, hypertensive patients had a significantly increased calcium, oxalate and uric acid excretion with respect to normotensive controls (26, 28). Another study has shown stone formers with hypertension have reduced urinary excretion of citrate and urine pH and increased titrable acid excretion when compared with normotensive stone formers (29). The link between hypertension and stone disease could be high sodium dietary intake, common in hypertensive patients, promoting increased urinary excretion of calcium.

The association between cardiovascular disease and nephrolithiasis has also been recognized. A longitudinal study of patients affected by cardiovascular disease with follow-up more than 20-years has showed a correlation between cardiovascular features and stone disease (30).

Next, a link between carotid atherosclerosis and kidney stone disease has also been observed. Another study by the Rochester Epidemiology Project spanning 10 years has found that calcium oxalate stone formers show a high risk of mortality from cardiovascular disease and higher total cholesterol, lower HDL, higher systolic blood pressure and elevated highly sensitive C reactive protein (hsCRP) (31). Calciuria and oxaluria have also been positively correlated with 10- year cardiovascular disease risk including mortality (32). Furthermore, a positive association between risk factors for coronary artery disease (smoking) was reported (33).

Finally, abdominal aortic calcification found on CT have been associated with uric acid stone formation, low urine pH and hypocitraturia (34).

Gender and nephrolithiasis A new tract of this new epidemiology is the shifting in gender of nephrolithiasis. Although nephrolithiasis is still more frequent in men than in women, the ratio male to female is reducing and the most recent NHANES data showed an overall prevalence of 10.6% in men and 7.1% in women (35). The changing role of women in the workplace has been considered. Modification of lifestyle and dietary habits in relation to working activity could contribute to the shifting in gender difference of stone formation. Dietary factors promoting stone formation such as high animal protein, high salt and low calcium diets are more usual in men than in women, although the expansion of the high protein diet or higher fructose intake and low fluid intake to females could be a further cause of changing in gender of nephrolithiasis (36, 37).

Obesity has also been associated with increased stone

New pattern of nephrolithiasis

risk among women. Taylor et al. show that overweight among females increases the risk for stone disease with respect to men with the same characteristics. In this study, body mass, weight gain during adulthood as well as waist circumferences increased the risk of stone formation among females (11). It has also been reported that uric acid stones are present in more than 50% of obese females (38). Additionally, hyperinsulinemia, that is usually found in obese patients, may be associated to urinary acidosis with the consequent risk for uric acid stone formation (39). This could be the link between gender, obesity, insulin level and kidney stones. Another risk factor for stone formation among reproductive aged women is pregnancy. Reinstaller et al. have observed women with a history of pregnancy have more than twice the chance of stone formation than those who were never pregnant. Lithogenic factors such as hypercalciuria, hyperuricosuria and increased urinary pH have been observed during pregnancy. These data suggest that an increased lifetime lithogenicity could occur among females since many of them are pregnant in working age (40). Finally, it has been reported struvite and hydroxyapatite stones are more common in women aged less than 55 years (41). As urinary infections are increasing among females, they could be a factor for stone formation as well a further cause for the shifting in the gender of nephrolithiasis.

Chronic kidney disease (CKD) and nephrolithiasis Nephrolithiasis has also been associated with CKD. Several studies have showed that, although kidney stones can cause CKD with acute or chronic damage of the urinary tract, the risk for end stage kidney disease (ESKD) or mortality from CDK are not increased (50).

Data from the Alberta Kidney Disease network confirm similar results (51). Further cross-section analysis of NAHNES 2007 to 2010 has also reported a greater prevalence of CKD and ESRD in nephrolithiasis patients with odds ratios of 1.50 and 2.37 respectively (52).

Specific conditions associated with the risk of CKD in stone formers have been analysed by Gambaro et al. (53).

The results of this study have showed that nephrolithiasic patients have twice the risk of CKD or ESRD and the risk is higher in women and overweight stone formers.

Children and nephrolithiasis Another feature of the new pattern of nephrolithiasis is a dramatic increase of nephrolithiasis among children and adolescents over the past 25 years (42). A 25-year population based study performed in Olmsted County (Minnesota) has reported that 41% of children under the age of 18 showed incidence of stones on CT with an increase of 4% of stones per year. Next, among 12-17 year olds the incidence rate was 6% (43).

Database from the Healthcare Cost and utilization Project Kids’ inpatient admission for pediatric nephrolithiasis in 2003 shows a higher frequency among girls. This difference in gender slightly changes in favour of boys within the first decade only (44). Another study in South Carolina has reported an increase to emergency department admissions for nephrolithiasis of children aged 0 to 18 years between 1996 to 2007 (5). The annual incidence of kidney stones was higher among school aged children and adolescents. In fact, the annual incidence rate among 14 to 18 years olds dramatically increased by about 50% from 1996 to 2007 (25 per 100.000 vs 54 per 100.000 respectively), while the incidence of stones for children younger than 9 years remained stable (less than 5 per 100.000). Moreover, among children and adolescents, girls had a higher incidence of kidneys stones than boys, as also reported by other studies (45). The reason for these features is not clear, probably because of the few cohort studies performed which have not allowed the analysis of the link between gender and risk factors.

Nephrolithiasis in children is idiopathic in origin in most cases, although rare genetic anomalies or a secondary cause of lithiasis such as neurological or congenital urinary anomalies of the urinary tract have also been identified. Besides, the risk of infected stones has decreased

Comment There are changing patterns of nephrolithiasis. Shifting in gender prevalence and the increase of kidney stone disease among children and adolescents have been well observed. Moreover, a strong association between Mets traits and nephrolithiasis has been reported. Hence, it has been hypothesized that different metabolic alterations may modify urinary “milieu” through a common mechanism resulting in overly acidic urine with consequent salt precipitation and stone formation.

We have previously reported about metabolic disorders among 109 nephrolithiasic patients evaluated between 2017 and 2018 (54).

In this study metabolic urinary anomalies (hypercalciuria, hyperoxaluria, hyperuricosuria and hypocitraturia) in 24h urine samples were observed only in 11 patients, while in a cohort of stone formers evaluated between 2007-2008 these figures were present in 28 of them.

Conversely, metabolic disorders (hypertension, diabetes, dislypidemia, overweight) were present in 72% and more than 2 in 38% of the cases.

The decrease of urinary metabolic abnormalities observed in the group in the last decade could suggest that a complete metabolic evaluation is not necessary in all patients with associated comorbidities, while it may be performed in cases of relapses of stone events (55, 56).

The increase of metabolic disorders in the last decade confirm among nephrolithiasic the association between Mets and nephrolithiasis and supports the hypothesis that nowadays stone disease could be considered as a systemic disorder (Table 2).

Changes in lifestyle and dietary habits could have coincided with an increase of metabolic syndrome and in parallel of stone formation (57). Patients with Mets obvious-

probably in relation to improved diagnosis and management of anatomical and neurological conditions promoting urinary infections. Conversely, environmental factors have been suggested in the pathogenesis of idiopathic nephrolithiasis. In fact, it has been reported that obesity and nephrolitihiasis among children are increasing in parallel (46). Dietary habits such as high intake of fructose (47) or salt (48) and low intake of fluid (49), which are the same risk factors for stone formation in adults, could be involved.

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Table 2.

Summary of new patterns of nephrolithiasis.

– The latest epidemiological studies have showed a change in gender distribution and an increasing prevalence among children and adolescents of nephrolithiasis.

– The incidence and prevalence of kidney stones have been increasing in parallel with Mets, whereas rates of metabolic abnormalities diagnosed in 24-h urine is decreasing.

– Nowadays, stone disease could be recognized not as a modification of urine composition or an ordinary flank pain, but as a systemic condition including Mets, cardiovascular diseases and CKD.

ly consume more food which could influence the urinary excretion of risk factors for stone formation. Preventative measures and careful patient education should be included to promote a healthy lifestyle. An increase of physical activity has been reported to prevent metabolic syndrome. Further, an increase of fluid intake to achieve a daily urinary volume of 2 litres and a diet rich in fruit and vegetable have reduced metabolic syndrome, stone formation and urinary infections (58, 59). Specific medical treatment (antidiabetics, antihypertensive, antilipemic and anticoagulant drugs) could be required to correct each component of metabolic syndrome (60).

CONCLUSIONS

10. Boyd C, Wood K, Whitaker D et al. The influence of metabolic syndrome and its components on the development of nephrolithiasis.

As J Urol. 2088; 5:215-222.

11. Taylor EN, Stampfer MJ, Curhan GC. Obesity, weight gain, and the risk of kidney stones. JAMA. 2005; 293:455-462.

12. Inci M, Demirtas A, Sarli B, et al. Association between body mass index, lipid profiles, and types of urinary stones. Ren Fail.

2012; 34:1140-1143.

13. Cupisti A, Meola M, D’Alessandro C, et al. Insulin resistance and low urinary citrate excretion in calcium stone formers. Biomed Pharmacother. 2007; 61:86-90.

The patterns of nephrolithiasis are changing.

Nephrolithiasis is still common among men, but the gender gap is narrowing as is the increase in occurrence among children and adolescents. With the parallel increase in incidence of both nephrolithiasis and systemic disorders, lifestyle changes with dietary and specific medicaments could be the most effective way to prevent primary disease and recurrent stone disease. Nephrolithiasis from ordinary flank pain could be recognized as a systemic condition and the correction of systemic disorders could not only reduce morbidity and mortality for diabetes, cardiovascular disease and development of CKD, but also minimize the risk of stone formation.

17. Trinchieri A, Croppi E, Montanari E. Obesity and urolithiasis: evidence of regional influences. Urolithiasis. 2017; 45:271-278.

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Correspondence Elisa Cicerello, MD elisa.cicerello@tin.it Matteo Ciaccia, MD Gian D. Cova, MD Mario S. Mangano, MD Unità Complessa di Urologia, Dipartimento di Chirurgia Specialistica, Ospedale Ca’ Foncello, Treviso, Italy

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DOI: 10.4081/aiua.2021.2.200

ORIGINAL PAPER

Efficacy and safety of intravesical fibrin glue instillation for management of patients with refractory hemorrhagic cystitis: 12-months results. A promising therapy for hemorrhagic cystitis Alessandra Cassani 1, Michele Marchioni 1, Francesco Silletta 1, Carlo D’Orta 1, Giulia Primiceri 1, Ambra Rizzoli 1, Patrizia Di Gregorio 2, Sandra Verna 2, Annalisa Natale 3, Stella Santarone 3, Francesco Berardinelli 1, Luigi Schips 1 1 “G.

D'Annunzio” University of Chieti, Dept. of Medical, Oral and Biotechnological Sciences, “SS. Annunziata” Hospital, Urology Unit, Chieti, Italy; ASL Abruzzo 2, Department of Urology, Chieti, Italy; 2 “SS. Annunziata” Hospital, Chieti, Italy; ASL Abruzzo 2, Servizio di Medicina Trasfusionale ed Ematologia Aziendale Ospedaliero Centro Emofilia 52, Chieti, Italy; 3 Santo Spirito Hospital, Pescara, Department of Hematology, Bone Marrow Transplant Center, Pescara, Italy.

Summary

Objectives: Fibrin glue (FG) endo-vesical application seems to be a promising therapy for hemorrhagic cystitis (HC). We aimed to evaluate efficacy and safety of FG instillation in patients with HC. Methods: Patients with HC not responsive to conventional treatments (bladder irrigation, catheterization, blood transfusions, hyperhydration and endoscopic coagulation) were treated with FG endo-vesical instillation (April 2017- December 2018).

FG was prepared from 120 mL of patient blood with the Vivostat® system. After standard cystoscopy, bladder was insufflated with carbon dioxide (CO2) according to bladder compliance and autologous FG was applied to bladder wall and bleeding sites.

Results: Ten patients included with grade 2 or higher HC secondary to bone marrow graft for hematological diseases (30%) or to actinic cystitis caused by prostate cancer radiotherapy (RT) (70%). The median HC onset time after RT was 4.8 (IQR 3.96.3) years and 35 (IQR 27.5-62.5) days after hematopoietic stem cell transplantation (HSCT). Five patients had a complete response after one treatment, three patients had clinical response (grade < 2 hematuria, amelioration of symptoms), one of them required catheterization and bladder irrigation. One patient required a second instillation of FG achieving a clinical response. No adverse events related to the procedure were recorded, however one patient died for causes not related to the procedure. Median Interstitial Cystitis Symptoms Index was 13.0 (IQR 11.0-15.0) pre-operatively and 4.0 (IQR 2.0-5.0) post-operatively.

Conclusions: Our study showed that, even in hematological patients, autologous FG instillation maybe a safe, repeatable and effective treatment modality in patients with refractory HC.

KEY WORDS: Cystitis; Radiation; Radiotherapy; Hemorrhagic cystitis; Hemorrhagic cystitis therapy; Fibrin glue therapy; Actinic cystitis; HSCT induced cystitis; Hematuria; Allogenic transplant.

Submitted 18 January 2021; Accepted 10 March 2021

200

INTRODUCTION

Hemorrhagic cystitis (HC) is a condition defined as the presence of hematuria and lower urinary tract symptoms (LUTS), irritative voiding symptoms, such as urgency, frequency, nocturia and pain or burning with urination (1).

Radiotherapy (RT) for pelvic malignancies, including prostate cancer (2, 3), could be associated with the development of HC in up to 6.5% of patients, as result of bladder wall modification and neovascularization (4).

However, HC may be a complication of hematological cancer treatment, too. Medication toxicity and immunemediated hypersensitivity may lead to LUTS and bladder mucosae bleeding in 7 to 68% of patients treated with cyclophosphamide (5). In literature there are many possible treatments for HC. First line treatments are the most conservative and include hyperhydration, blood transfusion, transurethral three-way catheterization with continuous bladder irrigation, hyaluronic acid instillation and reversal of anticoagulation. Second line treatments also include endo-vesical instillation of several compounds (e.g. aluminum compounds, silver or formalin) as well as transurethral surgery with laser or fulguration. In case of failure, third line options proposed include hyperbaric oxygen (HBO) or arterial embolization. In extreme cases a radical cystectomy with urinary derivation might be indicated (6-10). Despite the variety of treatments available there is not a consensus about the best treatment to use in these cases (11). More recently, FG endo-vesical application seems to be a promising therapy for HC (12, 13).

However, literature is limited to only two single center experiences (12, 13). Thus, we aim to report results about efficacy and safety of FG therapy in patients with HC.

MATERIALS

AND METHODS

Patients and study population We reviewed prospectively collected data from our instiNo conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 2

Efficacy and safety of intravesical fibrin glue instillation for management of patients with refractory hemorrhagic cystitis

tutional dataset about patients with HC treated with FG between April 2017 to December 2018. Our analyses included data about patients’ demographic (age, gender), condition that led to the hematuria (RT for prostate cancer, allogenic transplant for Acute lymphoblastic leukemia, Acute myeloid leukemia, Hodgkin's lymphoma), time of hematuria onset (identified as the first episode of hematuria after RT or Hematopoietic stem cell transplantation (HSCT) after systemic chemotherapy treatment with Busulfan 12.8 mg/kg, Thiotepa 10 mg/kg, Fludarabine 150 mg/m2), RT type, treatment characteristics (management of the hematuria before the FG instillation), clinical response and toxicity.

Before treatment, all patients had urine culture test, bladder ultrasound, urine analysis, blood test and cystoscopy.

All patients had HC grade 2 (8) or more no responsive to conventional therapy, namely catheterization with bladder irrigation, blood transfusions, hyperhydration and endoscopic coagulation. HC was classified in 4 stages. The subgroup of patients who developed HC after radiotherapy was also classified with the European organization for research and treatment of cancer/Radiation therapy oncology Group (RTOG/EORTC) grading of hematuria events due to radiotherapy (14). Main Classification are reported in Table 1.

The bladder capacity was evaluated during pre-operative cystoscopy identifying as maximum capacity the filling volume at which the patient felt pain. All the procedures were performed in operative room under loco-regional anesthesia. Patients with positive urine cytology, bladder neoformation identified by imaging or during cystoscopy, with a suspect upper urinary tract tumor or any suspect of urothelial carcinoma in situ were considered not-eligible for the procedure and were not included in the current study.

Surgical procedure We performed a standard cystoscopy with an Iglesias 22 ch cystoscope evaluating the bladder mucosa to rule out eventual bladder tumors and identify mucosal lesions.

Emptied bladder is then insufflated with carbon dioxide (CO2) up to obtain a good distention of bladder wall, approximately 180-240 cc occur, according to bladder compliance.

No continuous pressure flow was used, and small adjustment were possible thank to the use of a syringe filled with ambient air. Good bladder distention is necessary to allow air spray of the FG, guarantee a good vision and

prevent bleeding. Under vision, the FG applicator is introduced through the cystoscope and autologous FG is applied to the bladder wall with specific care of bleeding sites.

The FG instillation procedure usually last approximately 30 minutes. Fibrine Glue (FG) was prepared with the Vivostat® system (Vivolution A/S, Birkerod, Denmark).

Vivostat® is automated medical device for production and application of a fibrine sealant, it produces protein components of fibrine gel Sealant from patient’ own plasma with no risk of infections related to non-autologous plasma sources.

The Vivostat® system creates from 120 ml of the patient’ blood a concentrated fibrine I solution. The solution is then applied with a pH 10 neutralizing solution in a 7:1 ratio to produce fibrine sealant. The process takes 30 minutes to obtain a syringe of fibrin I solution at a PH of 4.4. The Vivostat® application system is composed by an applicator (the mechanical and electronic working part of the system) and a single-use Spraypen®. When activated fibrin I and neutralizing solution are delivered in a stream of compressed air forming a fine low-pressure spray of fibrin sealant (12, 13, 15).

Outcomes measurement Patients response was classified as: complete response (no hematuria and no LUTS); clinical response (absence or amelioration of dysuria, urgency, and frequency, no further need of analgesic medication, persistent hematuria grade < 2) and no response (no clinical response, persistent hematuria grade ≥ 2). Full blood count was performed preoperatively and on day 1 to 3. Each patient was investigated with Interstitial Cystitis Symptoms Index (ICSI) (16) pre and postoperative at follow-up.

Patients were followed by telephone at 3 and 12 months to assess ICSI and their bladder status.

Statistical analyses Descriptive analyses were employed. Qualitative variables were reported as absolute and relative frequencies (%). Quantitative variables were reported as median and interquartile range (IQR). Wilcoxon test for paired data tested the hypothesis that the median ICSI was higher before the treatment than after.

A level of statistical significance was set at p < 0.05.

Analyses were performed using the R software environment for statistical computing and graphics (version 3.6.1; http://www.rproject.org/).

Table 1.

Classification systems.

Grade I Grade II Grade III Grade IV Grade V

RTOG/EORTC HC Grading Slight epithelial atrophy minor telangiectasia (microscopic hematuria) Moderate frequency generalized telangiectasia intermittent macroscopic hematuria Severe frequency and dysuria severe generalized telangiectasia (often with petechiae) Frequent hematuria reduction in bladder capacity (< 150 cc) Necrosis/contracted bladder (capacity < 100 cc) Severe hemorrhagic cystitis Death for uncontrolled hematuria

HC Grading Microscopic hematuria Macroscopic hematuria Hematuria with clots requiring transfusion support

ICSI Score Mild symptoms 0-6 Moderate symptoms 7-14 Severe symptoms 15-20

Macroscopic hematuria with clots and impaired renal function --

---

HC: Hemorrhagic cystitis; EORTC: European organization for research and treatment of cancer/RTOG: Radiation therapy oncology Group grading of hematuria events due to radiotherapy; ICSI: Interstitial Cystitis Symptoms Index.

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Table 2.

Pre- operative and post- operative (at discharge) patients’ blood count.

Preoperatively Hemoglobin Hematocrit (g/dl) (%) 13.8 48 12.8 44 8.4 28.3 13.7 41.8 8.9 24.7 8.9 24 9.8 31.3 9.1 25.6 12.7 38.7 13.2 41 9.8 (IQR 8.9-13.2) 35 (IQR 26.3-41.6)

Red blood cells count (*106/mm3) 4.74 4.04 2.97 4.53 2.91 2.76 3.15 2.87 4.63 4.14 3.59 (IQR2.92-4.43)

1 2 3 4 5 6 7 8 9 10 MEDIAN

Platelets count (*103/mm3) 201 220 273 180 39 46 273 25 476 238 210 (IQR 79.5-264.2)

Red blood cells count(*106/mm3) 4.5 4 2.99 3.95 2.93 2.85 // 2.79 4.63 3.79 3.79 (IQR 2.96-3.975)

Postoperatively Hemoglobin Hematocrit (g/dl) (%) 13.7 43 12.4 40 8.6 27.9 11.4 35.4 8.9 25.2 8.7 24 // // 7.7 22.1 12.7 38.7 12.1 36.7 10.15 (IQR 8.675-12.25) 35.4 (IQR 25.2-38.7)

Platelets count (*103/mm3) 150 200 254 229 56 37 // 37 476 237 200 (IQR 56-237)

Table 3.

Descriptive features of included patients treated with endovesical instillation of Vivostat®.

Age

Grade of RTOG/ HC pre EORTC pre

Primary

Cause Time from of HC HC onset

1 2

58 86

2 4

3 4

PC PC

IMRT IMRT

3

75

3

4

PC

IMRT

4 5 6 7 8

85 27 45 84 46

2 3 2 3 3

3 --4 --

PC LLA LH PC LMA

IMRT HSCT HSCT IMRT HSCT

11 years 35 days 3 months 5 years 20 days

9 10

65 75

3 3

3 3

PC PC

IMRT IMRT

5 years

1 year

Prior intravesical management

Grade of hematuria (post-op)

RTOG/ EORTC post

Response

Hospital ICSI al stay days PRE

ICSI POST

Hyperhydration Bladder irrigation, Catheterism, Blood transfusions Bladder irrigation, Catheterism, Blood transfusions Catheterism Catheterism, Bladder irrigation Catheterism Catheterism, Blood transfusions Bladder irrigation, Hyperhydration Catheterism, Bladder irrigation Bladder irrigation, Catheterism

0 0

0 0

Complete Complete

2 3

9 11

5 2

3 1 after II treatment 0 1 0 -0

3 1 after II treatment 0 -----

Clinical 2 instillations Complete Clinical Complete --Clinical

26

--

--

3 1 1 12 1

UC 19 --15

UC 1 --13

0 1

0 1

Complete Clinical

4 4

UC 13

UC 4

HC: Hemorrhagic cystitis; EORTC: European organization for research and treatment of cancer/RTOG: Radiation therapy oncology Group grading of hematuria events due to radiotherapy; PC: Prostate cancer; ALL: Acute lymphoblastic leukemia; HL: Hodgkin’slymphoma; AML: Acute myeloid leukemia; IMRT: Intensity modulated radiation therapy; HSTC: Hematopoietic stem cell transplantation after chemotherapy treatment with Busulfan, Thiotepa and Fludarabine; Complete: Complete response (no hematuria or other symptoms); Clinical: Clinical response (amelioration or absence of symptoms, grade < 2 hematuria); UC: Urinary catheter in situ.

RESULTS

A total of 10 patients were treated. The 30% (n = 3) had HC secondary to bone marrow graft for hematological diseases after systemic chemotherapy treatment, the remaining 70% (n = 7) were diagnosed with actinic cystitis due to prostate cancer RT. The median age was 70 years (IQR 49.0-81.8). In the hematological patients median age was 45 years (IQR 36.0-45.5), while in the radio therapy patients group the median age was 75 years (IQR 70.0-84.5). The median onset time of hematuria was 4.8 (IQR 3.9-6.3) years after RT and 35 (IQR 27.5-62.5) days after hematological treatment. Main preoperative and post-operative laboratory findings are reported in Table 2.

Of all, 5 patients (55%) had a complete response (no hematuria or other symptoms), 3 patients (33%) had only clinical response (improvement or absence of symptoms, grade < 2 hematuria) and one of them required catheterization and bladder irrigation. Three patients required blood transfusions. One patient died immediately after

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the loco-regional anesthesia for complications not related to the procedure. Only one patient needed a second FG instillation eleven days after the first one, due to grade 3 hematuria and achieving a clinical response after the second instillation dose. Median hospital stay was 3 (IQR 1-6) days. No adverse events related to the procedure were recorded. Moreover, we recorded a reduction of the median ICSI after treatment. Indeed, the median ICSI was 13.0 (IQR 11.0-15.0) pre-operatively and 4.0 (IQR 2.05.0) postoperatively (p = 0.02). During the median follow up of 12 months, two patients died due to the progression of their hematological condition. None of the others required additional treatment for hematuria. Descriptive features and results of included patients are reported in Table 3.

DISCUSSION

Hemorrhagic cystitis is a urological condition that can meaningfully affect patients’ quality of life. Several ther-

Efficacy and safety of intravesical fibrin glue instillation for management of patients with refractory hemorrhagic cystitis

apeutic options are available for HC treatment, however neither AUA nor EAU defined specific guidelines for the treatment of HC (11, 17). The treatment paradigm includes as first line treatment a noninvasive procedure attempting to reduce hematuria while supporting patients’ general condition, such as hyperhydration, blood transfusion, transurethral three-way catheterization, and continuous bladder irrigation (6).

In our study we investigated the results that could be obtained with the use of FG in HC patients’ treatment after that first line treatments have failed. Our results showed that a good bleeding control could be achieved with FG endo-vesical instillation with no adverse events, no major complication as ureteral orifice closure and hydronephrosis were recorded in our experience. In case of injection near the ureteral orifice the use of a ureteral open-end catheter is recommended to reduce the risk of iatrogenic ureteral occlusion. Moreover, our results suggest that the use of FG endo-vesical instillation is related with a meaningful improvement in quality of life as proven by the improvement in ICSI score. Moreover, our study showed that the procedure is repeatable and that results are reliable over time as showed by our relative long follow-up of approximately 12 months.

The use of FG as a hemostatic agent have been previously studied in urological surgery and the use of the Vivostat® system have been proven to be effective and safety when applied to urological surgery, in particular to prevent bleeding in renal surgery and lymphatic leakage in lymphadenectomy (18-21). However, only few studies investigated its use for the treatment of HC. Specifically, Bove et al. have investigated the effectiveness of FG treatment in patients with actinic cystitis with hematuria refractory to standard treatment. Their experience was based on a series of 20 patients who developed HC following RT for different types of pelvic cancer: bladder cancer (30%), prostate cancer (35%) or gynecological cancer (35%) (13). They concluded that the endoscopic application of FG is a safe and effective therapeutic alternative for the treatment of HC refractory to conventional therapy because FG adheres tenaciously to the damaged mucosa, prevents the worsening of the inflammatory process from urine exposure and allows the tissue repair process. The endo-vesical application during cystoscopy allows a better view of the bleeding points and a better adhesion of the glue to the damaged mucosa due to the constant intravesical pressure (13).

Unfortunately, Bove and colleagues included only patients with actinic cystitis, conversely in the current report we also included patients with HC related to hematological conditions. This is of importance since the HC related to allogeneic hematopoietic cell transplantation negatively affects patient’s quality of life with an increased risk of death (22, 23). Currently its therapy was studied by Tirindelli et al. (12) on 35 patients who developed grade > 2 HC not responsive to conventional therapy.

Complete remission, defined as a regression of all symptoms and the absence of hematuria, was achieved in 100% of the cases at 7 days and 83 ± 7% at 50 days from the FG's instillation. The 6-month survival rates of patients with HC was 49 ± 8% overall. Instead, if we

consider only patients with complete clinical remission the 6-month survival rates were 59 ± 9%.

The results of this study suggest that the endoscopic application of FG should be considered a safe, non-invasive, easily repeatable, and inexpensive option for the management of HC in fragile and immunocompromised patients.

When considering other options, hyperbaric oxygen HBO is a widely used treatment. However, success rates are lower than ours (34-87.5% vs. 88% of our experience) with FG (6). Browne et al. in a literature review reported a successful rate without recurrences of 74% after HBO. They also reported that the main complication of this treatment was otalgia, occurred in 33% of patients (7). Intravesical instillation of various substances such as formalin, aluminum salts or hyaluronic acid is also reported. For instance, Pascoe et al. reported a success rate instillation therapy with formalin of 6090% vs. 88% of our experience. However, authors reported serious side effects related to the use of formalin, including death in 2-4% of the cases. More specifically, Browne et al. also demonstrated the danger of formalin by recording adverse events, such as bilateral hydronephrosis with anuria, vesico-vaginal fistula, and death in 30% of patients. The same study showed a success rate with hyaluronic acid instillation of 97% (7).

Conversely, we reported no adverse events directly related to treatment. The only death reported was due to the general compromitted status of the patient and not to the FG application.

Aluminum salts were also used. However, its use is considered less effective than other endo-vesical treatment, but it is also affected by side effects: 38% of patients showed bladder spasms, transient delirium, urinary tract infections. The success rate was 60% (only 54% of responders had a durable response).

Imperatore et al. described the use of hyaluronic acid and chondroitin sulfate endo-vesical instillation treatment in 20 patients with refractory Bacillus Calmette-Guerin (BCG) induced chemical cystitis. The study showed an improvement in terms of bladder pain, urinary urgency, urinary volume per void and urinary frequency.

The clinical efficacy described in 19/20 patients had a statistically significative improvement durable in time with a permanence of benefit up to one year after therapy suspension (VAS score on bladder pain and urgency significantly decrease from the baseline; mean number of voids/24 hour and mean urinary volume per void significantly improved from the baseline p < 0.05 with respect to baseline in both cases) (24).

In a recent study Masieri et al. analyzed the use of platelet-rich plasma (PRP) in patients with HC after HSCT, they showed an alternative endo-vesical autologous instillation therapy to treat HC in hematological patients. They studied 10 patients with HC post HSTC related to BK virus infection, all patients underwent PRP instillation after electrocoagulation of the bleeding areas.

No intraoperative complications were recorded, postoperative complications Clavien-Dindo Grade II occurred in 6 patients: 3 patients required additional blood transfusion, 3 patients required antibiotic therapy. One patient was readmitted for massive hematuria. 6 patients Archivio Italiano di Urologia e Andrologia 2021; 93, 2

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A. Cassani, M. Marchioni, F. Silletta, et al.

had complete response, 3 partial response and one no response. It seems to be a promising treatment option but related to a higher risk of complication compared to our technique with a similar success rate but in a highly selected group of patients (25).

In summary our study showed that the use of FG in HC patients is safe and effective with higher success rates and lower complications than other second line treatments. Despite the limited number of patients and the lack of a control group, in our study we point out that FG treatment is a promising treatment option also in the group of hematological patients with HC. The main limitation of our study is the small number of patients included and the absence of a control group. In consequence, we are not able to infer if the use of FG treatment could lead to better result than any other conservative treatment and future prospective multicenter study are warrant. However, the same limitation applies also to other studies that included only few more patients.

In addition, due to the small number of patients included we were not able to test the effect of FG treatment on HC in analyses adjusted for possible confounders, such as age or primary cause of HC. It might be possible that the effect of FG might differ based on the baseline characteristics of included patients as a consequence of the compound interaction with the host environment. It is also possible that the coagulation cascade promotion based on FG effect might differ in younger vs. older patients.

Future studies should investigate also molecular aspects of FG instillation. Furthermore, we evaluated patients’ quality of life with ICSI score. However, other more specific scores about the quality of life in patients affected by malignancy (such as the EPIC score) would be more insightful (26). In future studies it should be included and evaluated to better clarify patients’ quality of life. Finally, we investigated only the clinical presentation of HC without any molecular or laboratory tests that could shed a light on the pharmacodynamic of FG application in HC cases. Indeed, literature is poor of evidence in this field and future studies should focus also on these aspects.

Thanks to the laboratory doctors P. Di Gregorio and S. Verna that helped us with the preparation of the FG solution from patients own plasma. All authors read and approved the final version of the manuscript.

CONCLUSIONS

11. Update Series (2015) Lesson 3: Management of emergency bleeding, recalcitrant clots and hemorrhagic cystitis | AUA University. Available from: https://auau.auanet.org/node/4709.

Autologous FG may be a safe and effective noninvasive and repeatable treatment modality in patients with refractory HC. Our report showed its efficacy also in patients treated after HC related to hematological conditions treatments and was no related to any adverse event.

AUTHORS’

CONTRIBUTION

We would like to thank all the Urologists M. Marchioni, F. Silletta, C. D’Orta, G. Primiceri, A. Rizzoli, F Berardinelli, L Schips that recruited the urological patients, performed the surgical procedures and followed them during the follow-up. They also helped with the drafting of this manuscript.

Thanks to the hematologist S. Santarone and A. Natale that recruited and followed the hematological patients during the follow-up, also for the contribution with the processing of the manuscript regarding the hematological therapies and pathologies.

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REFERENCES

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2. Galla A, Maggio A, Delmastro E, et al. Salvage radiation therapy after radical prostatectomy: survival analysis. Minerva Urol Nefrol. 2019; 71:240.

3. Antonelli A, Palumbo C, Noale M, et al. and the Pros-IT CNR study group. Overview of potential determinants of radical prostatectomy versus radiation therapy in management of clinically localized prostate cancer: results from an Italian, prospective, observational study (the Pros-IT CNR study). Minerva Urol Nefrol. 2020; 72:595-604.

4. Corman JM, McClure D, Pritchett R, et al. Treatment of radiation induced hemorrhagic cystitis with hyperbaric oxygen. J. Urol.

2003; 169:2200–2202.

5. Alesawi AM, El-Hakim A, Zorn KC, et al. Radiation-induced hemorrhagic cystitis: Curr. Opin. Support. Palliat. Care. 2014; 8:235-240.

6. Pascoe C, Duncan C, Lamb BW, et al. Current management of radiation cystitis: a review and practical guide to clinical management. BJU Int. 2019; 123:585-594.

7. Browne C, Davis NF, Mac Craith E, et al. A Narrative review on the pathophysiology and management for radiation cystitis. Adv Urol. 2015; 2015:1-7.

8. Dautruche A, Delouya G. A contemporary review about the management of radiation-induced hemorrhagic cystitis: Curr Opin Support Palliat Care 2018; 12:344-350.

9. Mangano MS, De Gobbi A, Ciaccia M, et al. Actinic cystitis: causes, treatment and experience of a single centre in the last five years.

Urol J. 2018; 85:25-28.

10) Calderone CE, Lerner SP, Taylor JM. The case for salvage cystectomy after pelvic radiation. Minerva Urol Nefrol. 2016; 68:161-71.

12. Tirindelli MC, Flammia GP, Bove P, et al. Fibrin glue therapy for severe hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 2014; 20:1612-1617.

13. Bove P, Iacovelli V, Tirindelli MC, et al. Endoscopic intravesical fibrin glue application in the treatment of refractory hemorrhagic radiation cystitis: a single cohort pilot study. J Endourol. 2019; 33:93-98.

14. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995; 31:1341-1346.

15. Dodd RA, Cornwell R, Holm NE, et al. The Vivostat application system: a comparison with conventional fibrin sealant application systems. Technol Health Care. 2002; 10:401-11.

16. O’Leary MP, Sant GR, Fowler FJ, et al. The interstitial cystitis symptom index and problem index. Urology. 1997; 49:58-63.

Efficacy and safety of intravesical fibrin glue instillation for management of patients with refractory hemorrhagic cystitis

17. Engeler D, Baranowski AP, Berghmans B, et al. EAU Guidelines on Chronic Pelvic Pain 2020. In: European Association of Urology Guidelines. 2020 Edition. European Association of Urology Guidelines Office, 2020, Arnhem, The Netherlands.

18. Schips L, Dalpiaz O, Cestari A, et al. Autologous fibrin glue using the Vivostat system for hemostasis in laparoscopic partial nephrectomy. Eur Urol. 2006; 50:801-805.

(19. Gidaro S, Cindolo L, Lipsky K, et al. Efficacy and safety of the haemostasis achieved by Vivostat system during laparoscopic partial nephrectomy. Arch Ital. Urol Androl. 2009; 81:223-227.

20. Farouk A, Tawfick A, Reda M, et al. Fibrin glue as a sealant in stentless laparoscopic pyeloplasty: A randomised controlled trial.

Arab J Urol. 2019; 17:228-233.

21. Garayev A, Aytaç Ö, Tavukcu HH, et al. Effect of Autologous Fibrin Glue on Lymphatic Drainage and Lymphocele Formation in Extended Bilateral Pelvic Lymphadenectomy in Robot-Assisted Radical Prostatectomy. J. Endourol. 2019; 33:761-766.

22. Seber A, Shu X, Defor T, et al. Risk factors for severe hemor-

rhagic cystitis following BMT. Bone Marrow Transplant. 1999; 23:35-40.

23. Leung A, Mak R, Lie A, et al. Clinicopathological features and risk factors of clinically overt haemorrhagic cystitis complicating bone marrow transplantation. Bone Marrow Transplant. 2002; 29:509-513.

24. Imperatore V, Creta M, Di Meo S, et al. Intravesical administration of combined hyaluronic acid and chondroitin sulfate can improve symptoms in patients with refractory bacillus CalmetteGuerin induced chemical cystitis: Preliminary experience with oneyear follow-up. Arch Ital Urol Androl. 2018; 90:11-14.

25. Masieri L, Sessa F, Mari A, et al. Intravesical application of platelet-rich plasma in patients with persistent haemorrhagic cystitis after hematopoietic stem cell transplantation: a single-centre preliminary experience. Int Urol Nephrol. 2019; 51:1715-1720.

26. Sosnowski R, Kulpa M, Kosowicz M, et al. Basic methods for the assessment of health-related quality of life in uro-oncological patients. Minerva Urol Nefrol. 2017; 69:409-420.

Correspondence Alessandra Cassani, MD alessandra.cassani@yahoo.com Michele Marchioni, MD mic.marchioni@gmail.com Francesco Silletta francescosilletta1@gmail.com Carlo D’Orta, MD dortacarlo.8@gmail.com Giulia Primiceri giulia.primiceri@gmail.com Ambra Rizzoli ambrarizzoli@libero.it Francesco Berardinelli, MD berardinelli.francesco@gmail.com Luigi Schips, MD luigischips@hotmail.com “G. D’Annunzio” University of Chieti, Dept. of Medical, Oral and Biotechnological Sciences, “SS. Annunziata” Hospital, Urology Unit, Chieti (Italy); ASL Abruzzo 2, Dept. of Urology, Chieti (Italy) Patrizia Di Gregorio, MD patrizia.digregorio@aslabruzzo2.it Sandra Verna, MD sandra.verna@aslabruzzo2.it “SS. Annunziata” Hospital, Chieti, Italy; ASL Abruzzo 2, Servizio di medicina trasfusionale ed ematologia aziendale ospedaliero - Centro Emofilia 52, Chieti (Italy) Annalisa Natale, MD annalisa.natale@gmail.com Stella Santarone, MD stella.santarone@virgilio.it Santo Spirito Hospital, Pescara, Department of Hematology, Bone Marrow Transplant Center, Pescara (Italy)

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DOI: 10.4081/aiua.2021.2.206

ORIGINAL PAPER

Prevalence of urinary tract infection in children in the kingdom of Saudi Arabia Mariam Alrasheedy 1, Hoda Jehad Abousada 2, Mutaz Mansour Abdulhaq 3, Raghad Abdulelah Alsayed 4, Khalid Abdullah Alghamdi 5, Fayez Dhyefallah Alghamdi 5, Abdullah Faisal Al Muaibid 5, Refal Ghassan Ajjaj 6, Seham Salem Almohammadi 7, Sarah Salem Almohammadi 7, Wajd Adnan Alfitni 8, Abdulrahman Mohamed Homsi 9, Meqbel Majed Alshelawi 10, Hassan Ali Alshamrani 11, Abdulrauf Abdulatif Tashkandi 11, Sara Mohammed Mannan 12, Salihah Attiah Alsamiri 13 1 Pediatric

Nephrology, East Jeddah Hospital, KSA; & Gynecology Physician, KAMC, KSA; 3 East Jeddah Hospital, KSA; 4 Ohod Hospital, Madinah, KSA; 5 Baha University, Baha, KSA; 6 ISNC, Jeddah, KSA; 7 KFH, Jeddah, KSA; 8 Batterjee Medical College, Jeddah, KSA; 9 Uqu University, Mecca, KSA; 10 Medical University of Silesia, Katowice, Poland; 11 Taif University, Taif, KSA; 12 King Abdulaziz University, Jeddah, KSA; 13 RCSI, Dublin, Ireland.

2 Obstetrics

Summary

Introduction: Urinary tract infection (UTI) is a common disorder in childhood. Early identification and appropriate antibiotic use are essential to avoid long-term sequels. The trial objective was to identify the prevalence of URI in children, and the risk factors.

Methods: This is an analytical cross-sectional study conducted in the Saudi Arabia, from April 4th 2020 till July 30th 2020.

The sample was randomly selected from children who presented to the ministry of health tertiary hospitals. People answered a questionnaire of 10 items.

Results: 1083 people participated in the current trial.

The prevalence of UTI was 25.8%. The mean age was 4.5-5 years. UTI was commoner in females than males. Urethritis was the main presenting complaint. Western region was the commonest identified area. Those with multivitamin deficiency had the highest prevalence.

Conclusion: UTI is not a very common problem for children in Saudi Arabia. Western region had the highest prevalence and the peak age ranged from 4.5 to 5 years. Additionally, nearly a sixth of children could develop severe/complicated UTI.

KEY WORDS: Urinary tract infection; Saudi; Pyelonephritis; Cystitis; Urethritis.

Submitted 18 November 2020; Accepted 1 December 2020

INTRODUCTION

Urinary tract infection (UTI) is a common clinical problem in childhood (1, 2). Internationally, it is anticipated that 150 million UTI cases occur annually, and it costs more than 6 billion dollars, yearly. The prevalence of UTI ranges from 6% in more developed countries to

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37% in developing countries with a prevalence rate of nearly 8% in USA (3, 4).

Prior trials have assessed the incidence of UTI in other developing countries. In Nigeria, the prevalence of UTI is 11%, and it is 12% in India, 6% in Kenya and 20% in South Africa. Saudi Arabia has a different ethnic and diverse population. Apart from Saudi citizens, it has Egyptians, Syrians, Yemeni, Indians, Pakistani, Bangladeshi, and Philippians. The study of Alanazi et al. estimated the prevalence of UTI in Saudi Arabia at 24% (5-10).

Risk factors associated with UTI include child age, lack of circumcision, urinary obstructive conditions, such as, hydronephrosis, posterior urethral valve occlusion, ureteropelvic junction obstruction, neurological conditions including myelomeningocele with neurogenic bladder, bladder and bowel dysfunction, vesicoureteral reflux (VUR), renal scarring, and/or bladder catheterization. Also, the prevalence increases in children with malnutrition. Online calculators have developed to estimate the risk for UTI, such as, the calculator from the University of Pittsburgh (3, 11-14).

Escherichia coli is the commonest pathogen in paediatric UTI and it causes 70% of infections. Other pathogens include Proteus, Klebsiella, Enterococcus, Citrobacter, and Pseudomonas aeruginosa (5, 11).

UTI manifests as either pyelonephritis which tends to present with fever and loin pain. Cystitis and urethritis usually present with urine soreness and increased frequency. It is difficult to distinguish pyelonephritis from cystitis in children below the age of two (3).

Early identification and appropriate antibiotic use are essential to avoid the long-term sequels of UTI including No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 2

Urinary tract infection in children

kidney scarring, chronic renal impairment and hypertension. On the other hand, the inappropriate use of antibiotics is one of the major reasons for antimicrobial resistance which represents a serious global problem. This is because it causes significant impacts on health-care costs, and patient morbidity, and mortality (15, 16).

The current trial main objective is to identify the prevalence of UTI in children in Saudi Arabia. Also, the research aims to know the risk factors for UTI including the region with the highest prevalence, the most common types of presentation, and the risk factors for the development of UTI.

PATIENTS

AND METHODS

Study design and setting This is an analytical cross-sectional study which was carried out in the period between April 4th 2020 and July 30th 2020 in the ministry of health hospitals in the kingdom of Saudi Arabia.

Study population The sample was randomly selected, through the computer, from children who presented to both general inpatient and outpatient departments in the ministry of health tertiary hospitals between April 4th 2020 and July 30th 2020.

The authors aimed to contact 1600 families. Selection was done by the computer to ensure that the selected sample was accurately representing the population in terms of their age, gender, and residency region. For inclusion in the current study, the surveyed sample should be either citizens or residents in the country with their family. To avoid including cases with hospital acquired UTI, for inpatients, the authors included only patients up to 2 days of their admission.

People answered a survey of 10 items about their residency region (Eastern, Western, Central, Southern, or Northern); if they have a child who developed urinary tract infection; the age of that child when having UTI; the gender of the child; the type of presentation; if the child had a risk factor including hydronephrosis, diabetes mellitus, autism, congenital abnormalities, diseases of the immune system, or vitamin deficiency; if the child was hospitalised because of UTI, people’s definition for UTI; whether UTI recurred within a period of one month after the first diagnosis.

Finally, the survey asked about the person who answered the questionnaires (Father or Mother).

People who fit with the inclusion criteria of the study were included in the current trial. Additionally, the criteria included age of children between 1 and 10 years.

Collection dates were from April 4th, 2020, to June 30th.

2020.

Study measurements The prevalence of UTI was defined as the proportion of children with the target disease among all the number of children. The current study examined the link between UTI and certain predefined factors including the region of residency, age, gender, and other comorbidities.

Also, severe/complicated UTI was defined as that which

required hospitalisation, presented with pyelonephritis, or recurrent UTI within 30 days after the initial diagnosis (17).

Statistical analysis Statistical analysis was carried out by Statistical Package for the Social Sciences (SPSS) version 17. Continuous data were presented in terms of mean, median, mode and 95% Confidence interval (CI). Univariate analysis with OR using Chi-squared test and Mann-Whitney test was performed to investigate the association between UTI, severe/complicated UTI and predefined factors including their region of residency, age, gender, and comorbidities. Multivariate analysis with HR was performed using binary logistic regression. P-value was set at a significance level of < 0.05.

Ethical consideration Ethical approval was sought from the biomedical ethics research committee of the faculty of medicine, ministry of health, Kingdom of Saudi Arabia.

Prospective informed consent was taken from all participants. The authors confirmed that they did not receive any funding from agencies in the public, commercial, or not-for-profit sectors.

Table 1.

Sample characteristics.

Age: (years)

Mean 95% CI Gender: Region:

1-3 3.1-6 6.1-8 8.1-10 Unknown

Male Female Western Eastern Central Northern Southern

Number 249 401 103 217 113 4.5-5 years 1-10 years 454 629 417 343 105 36 182

Percentage % 23 37 9.5 20 10.5

P-value 0.06

41.9 58.1 38.5 31.7 9.7 3.3 16.8

0.05 0.04

Table 2.

Patient’s characteristics.

Age: (years)

Gender: Region:

1-3 3.1-6 6.1-8 8.1-10 Unknown Mean 95% CI Male Female Western Eastern Central Northern Southern Mean

Number 64 101 27 57 30 4.5-5 years 1-10 years 118 162 109 90 15 25 41 Western

Percentage % 23% 36% 9.7% 20.5% 10.8%

P-value 0.06

42 58 39 32 5.4 8.9 14.7

0.05 0.04

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M. Alrasheedy, H. Jehad Abousada, M. Mansour Abdulhaq, et al.

Figure 1.

The frequency of surveyors who responded to the question “How to define UTI”.

What do you think is the correct definition for urinary tract infection?

Frequency Percent Valid percent Cumulative percent Valid An infection of the kidney, ureter, bladder, or urethra 540 49.9 49.9 49.9 An infection of the kidney only 31 2.9 2.9 52.7 An infection of the ureter only 34 3.1 3.1 55.9 An infection of the bladder, or urethra only 478 44.1 44.1 100.0 Total 108.3 100.0 100.0

RESULTS

One thousand six- hundred people were contacted and the authors got responses from 1083 of them. 280 people stated that their child had UTI, and the prevalence of UTI in the sample was 25.8%. Tables 1 and 2 summarised the sample characteristics and patient characteristics.

One hundred and thirty-one (47%) children presented Table 3.

Univariate analysis for UTI. Factor Age 1-6 years Age 6.1-10 Regions Western, and Eastern Other regions Male Female Comorbidities

UTI 165 84 199 81 118 162 54

No UTI 485 320 561 242 336 467 31

OR (95% CI) 0.00 (0.00-2.00) 0.035 (0.02-2.2) 0.02 (0.00-2.00) 0.04 (0.02-2.1) 0.04 (0.02-2.2) 0.03 (0.02-2.0) 1.1 (1.00-2.3)

P-value 0.04 0.05 0.04 0.05 0.06 0.05 0.04

Table 4.

Univariate analysis for severe/complicated UTI. Factor Age 1-6 years Age 6.1-10 Regions Western, and Eastern Other regions Male Female Comorbidities

UTI 30 21 35 16 20 31 31

No UTI 620 383 725 307 434 598 53

OR (95% CI) 0.00 (0.00-2.00) 0.03 (0.02-2.1) 0.03 (0.02-2.00) 0.04 (0.03-2.1) 0.05 (0.03-2.1) 0.04 (0.02-2.0) 1.05 (1.0-2.8)

P-value 0.03 0.05 0.04 0.03 0.04 0.06 0.05

Table 5.

Multivariate analysis for UTI. Factor Age 1-6 years Regions Western, and Eastern Male Comorbidities

HR (95% CI) 0.5 (0.09-1.00) 0.7 (0.5-1.1) 1.3 (0.9-2.1) 1.1(0.9-2.0)

P-value 0.03 0.04 0.06 0.05

Table 6.

Multivarte analysis for Severe/complicated UTI. Factor Age 1-6 years Regions Western, and Eastern Male Comorbidities

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HR (95% CI) 0.6 (0.1-1.00) 0.6 (0.4-1.0) 1.4 (1.1-2.1) 1.1(0.8-2.0)

Archivio Italiano di Urologia e Andrologia 2021; 93, 2

P-value 0.03 0.04 0.04 0.05

with urethritis, 93 (33%) children had cystitis, 28 (10%) children had pyelonephritis, and for the remaining 28 (10%) children location of infection was unknown.

Seven (2.2%) children had hydronephrosis; 16 (5.8%) children had diabetes mellitus; one (0.4%) child had autism; three (1.1%) children had congenital abnormalities; three (1.1%) children immune disorders; 24 (8.6%) children had a vitamin deficiency; the remaining 226 (80.8%) had no comorbidities. As shown in Figure 1, 540 (49.9%) of the responders defined UTI as infection in the kidneys, ureter, urethra, or urinary bladder; 478 (44.1%) of the sample defined UTI as infection in the urethra or urinary bladder; 31 (2.9%) of people defined UTI as infection in the kidneys only; 34 (3.1%) of people defined it as infection in the urethra only.

Twenty-eight (10%) of patients required admission for their UTI, and 24 (8.5%) of patients developed recurrent UTI within 30 days of their initial UTI. Accordingly, 51 (18%) of children with UTI developed severe/complicated UTI. To note, eight patients had recurrent UTI and they did not require admission, so they did not meet the current criteria for severe/complicated UTI. Tables 3 and 4 showed univariate analysis for UTI and severe/complicated UTI, respectively. Multivariate analysis for UTI and severe/complicated are shown in Tables 5 and 6 respectively. Finally, 54.5% of questionnaires were answered by mothers and the rest was answered by fathers.

DISCUSSIONS

The current study aims to identify the prevalence of urinary tract infection (UTI) in children in the kingdom of Saudi Arabia and the risk factors for UTI. The authors believe that the health of children has always been the health of future generations. Children are more susceptible to UTI than other age groups. Perhaps this is related to their low immunity, lack of family attention to their child hygiene and malnutrition. Saudi Arabia has a diverse ethnic population, and it depends on two sources of water, which are groundwater and water from desalination plants which remove salt from seawater. Also, serum vitamin D level is low among 40% of the Saudi population. Knowing the prevalence of the disease and identifying the risk group could help physicians in selecting patients who benefit from an additional diagnostic test and prioritise patients who require an additional care (18, 19).

The current study is a cross-sectional study that was based on interviewing families of children who presented to the outpatient department and inpatient wards in the tertiary ministry of health hospitals over 3-month period. The tertiary ministry of health hospitals represents 81% of health care services in the country and represents the well-established care level for patients.

The authors decided to conduct a cross-sectional survey which evaluates the prevalence of certain diseases and their risk factors at the same point in time. Cross-sectional survey provides the best way to identify a disease and its risk factors in a predefined population (20, 21).

Previous research was conducted in the area of paediatric UTI in Saudi Arabia.

The study of Garout et al. (22) investigated the preva-

Urinary tract infection in children

lence of UTI in Riyadh, the research conducted by AlIbrahim et al. (23) studied the prevalence of UTI in a tertiary hospital in Riyadh over a 3-year period, the study of Al-Otaibi and Bukhari (24) investigated the incidence of hospital-acquired UTI in a hospital in Riyadh and Alanazi (25) evaluated the prevalence of UTI in emergency departments amongst adults, elderly and children.

However, until the time of publication, there has not been any available data stratifying UTI prevalence based on gender, age, region, or comorbidities, and to the knowledge of the authors, this was the first study that examined the prevalence of UTI on a wide scale of people across the country. The current study focused on community-acquired UTI which is a major problem worldwide. Also, it included 1083 responders who fit with its inclusion criteria (22-25).

The current study showed the prevalence of UTI of 25.8% in children aged 1 to 10 years. The study of Alanazi et al. (25) showed comparable results. Similarly, the study of Shisana et al. (10) showed the prevalence of UTI in South Africa at 20%. Other trials showed different rates about 8%. The prevalence of UTI varies widely among countries and in different regions in the same country, due to many factors including age, gender, socioeconomic status and health condition (6, 10, 23).

This trial showed that the prevalence of UTI varied widely by age, gender and regional place and comorbidities.

The mean age of UTI was 4.5-5 years. The study of Garout et al. (22) showed a mean age of incidence of 5 years. The difference could be related to the majority of cases in the latter trial coming from the central region rather than the Western area as in the current trial. Also, UTI was more common among females. The study of Garout (22) agreed with our findings. The main presenting complaint was urethritis. The study of Alanazi (25) showed a similar finding.

Those with vitamin deficiency as comorbidity had the highest prevalence. Wald (26) agreed with the current finding as the author mentioned that low vitamin levels, including low vitamin D, increased the risk for UTI. The current trial revealed that western region had the highest prevalence rate. This is probably related to the fact that the Western region had the highest number of participants in the current trial. Also, the majority of responders did not have any comorbidity. Additionally, the majority of respondents selected the correct definition for urinary tract infection. Moreover, nearly a sixth of children developed severe UTI. This is the first trial that addresses these observations, but further trials are required to confirm the current findings.

The current trial defined severe/complicated UTI as UTI which requires admission, recurrent UTI within 30 days, and UTI presenting with pyelonephritis. The study of Colgan and Mozella (27) agreed with these definitions in adult population, although there is not any clear definition for severe UTI in paediatric population. The authors believe that there should be a consensus among physicians about the definition of complicated/severe UTI in childhood.

The current study has some limitations. It was conducted amongst patients who visited the ministry of health hospi-

tals which provide the majority of health services in the country. Further research is required to cover patients who visit community services and private hospitals. Also, the current study was conducted over a 4-month period.

Further research is required with a longer duration to confirm the current study results.

CONCLUSIONS

Urinary tract infection (UTI) is not very common for children in the Kingdom of Saudi Arabia. Western region had the highest disease prevalence and the peak age for UTI ranged from 4.5 to 5 years. The most common presenting symptom was urethritis and almost a sixth of children developed severe/complicated UTI.

REFERENCES

1. Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management, Roberts KB. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months.

Paediatrics. 2011; 128:595-610.

2. National Institute for Health and Clinical Excellence. Urinary Tract Infection in Children. London (UK): NICE; 2007.

3. Shaikh N, Morone NE, Bost JE, Farrell MH. Prevalence of urinary tract infection in childhood: a meta-analysis. Pediatr Infect Dis J. 2008; 27:302-308.

4. Foxman B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin North Am. 2014; 28:1-13.

5. The total population in 2018. general authority for statistics (Saudi Arabia). Archived from the original on 2019-04-03.

6. Alanazi MQ, Al-Jeraisy MI, Salam M. Prevalence and predictors of antibiotic prescription errors in an emergency department, Central Saudi Arabia. Drug Healthc Patient Saf. 2015; 7:103-111.

7. Ghorashi Z, Ghorashi S, Soltani-Ahari H, Nezami N. Demographic features and antibiotic resistance among children hospitalized for urinary tract infection in northwest Iran. Infect Drug Resist. 2011; 4:171-176.

8. Rabasa AI, Shattima D. Urinary tract infection in severely malnourished children at the University of Maiduguri Teaching Hospital. J Trop Pediatr. 2002; 48:359-361.

9. Kala UK, Jacobs DW. Evaluation of urinary tract infection in malnourished black children. Ann Trop Paediatr. 1992; 12:75-81.

10. Shisana O, Rehle T, Simbayi LC, et al. South African National HIV Prevalence, Incidence and Behaviour Survey, 2014. Cape Town, South Africa: HSRC Press; 2014.

11. Alshamsan L, Al Harbi A, Fakeeh K. The value of renal ultrasound in children with a first episode of urinary tract infection. Ann Saudi Med. 2009; 29:46-49.

12. Shaw KN, Gorelick M, McGowan KL, et al. Prevalence of urinary tract infection in febrile young children in the emergency department. Pediatrics. 1998; 102:e16.

13. Singh-Grewal D, Macdessi J, Craig J. Circumcision for the prevention of urinary tract infection in boys: a systematic review of randomised trials and observational studies. Arch Dis Child. 2005; 90:853.

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M. Alrasheedy, H. Jehad Abousada, M. Mansour Abdulhaq, et al.

14. Wald ER. Cystitis and pyelonephritis. In: Feigin and Cherry’s Textbook of Pediatric Infectious Diseases, 8th ed, Cherry JD, Harrison G, Kaplan SL, et al. (Eds), Elsevier, Philadelphia 2018. p.395.

15. Shim YH, Lee JW, Lee SJ. The risk factors of recurrent urinary tract infection in infants with normal urinary systems. Pediatr Nephrol. 2009; 24:309.

16. Caksen H, Cesur Y, Uner A, et al. Urinary tract infection and antibiotic susceptibility in malnourished children. Int J Urol Nephrol. 2000; 32:245-247.

17. Haynes RB, Sackett DL, Guyatt GH, Tugwell P. Clinical Epidemiology: How to Do Clinical Practice Research. 3rd ed.

Philadelphia, PA: Lippincott Williams & Wilkins, 2006.

18. Abderrahman WA Water Management in ArRiyadh, International Journal of Water Resources Development 2006; 22:277-289.

21. Schmidt CO, Kohlmann, T. When to use the odds ratio or the relative risk? Int J Public Health. 2008; 53:165-7.

22. Garout WA, Kurdi HS, Shilli AH, and Kari JA. Urinary tract infection in children younger than 5 years. Saudi Med J. 2015; 36:497-501.

23. Al-Ibrahim AA, Girdharilal RD, Jalal MA, et al. Urinary tract infection and vesicoureteral reflux in Saudi children. Saudi J Kidney Dis Transpl. 2002; 13:24-28.

24. Al-Otaibi FE, Bukhari EE. Clinical and laboratory profiles of urinary tract infections caused by extended-spectrum beta-lactamase-producing Escherichia coli in a tertiary care center in central Saudi Arabia. Saudi Med J. 2013; 34:171-176.

25. Alanazi MQ. An evaluation of community-acquired urinary tract infection and appropriateness of treatment in an emergency department in Saudi Arabia. Ther Clin Risk Manag. 2018; 14:2363-2373.

19. Amer Kamel, et al., editors. The Water, Energy, and Food Security Nexus in the Arab Region. 1st ed., ser. 2017, 2367-4008, Springer International Publishing.

26. Wald ER. Cystitis and pyelonephritis. In: Feigin RD, Cherry J, Demmler-Harrison GL, Kaplan SL, editors. Feigin and Cherry's text book of infectious diseases. 6th ed. Philadelphia (PA): Elsevier Saunders; 2009, pp. 554-569.

20. Health Indicators, Ministry of Health, Department of Statistics, 2006.

27. Colgan R, Mozella WM. Diagnosis and treatment of acute pyelonephritis in women. Am Fam Physician. 2011; 84:519-526.

Correspondence Mariam Alrasheedy, MD ma-rasheedy@moh.gov.sa Consultant Pediatric nephrology, East Jeddah Hospital (KSA)

Sarah Salem Almohammadi, MD saroon.sm1@gmail.com Intern, KFH, Jeddah (KSA)

Hoda Jehad Abousada, MD (Corresponding Author) dr.huda1992@outlook.com Obstetrics & Gynecology Physician, KAMC (KSA)

Wajd Adnan Alfitni, MD wajd.alfattani@hotmail.com Intern, Batterjee Medical College, Jeddah (KSA)

Mutaz Mansour Abdulhaq, MD Pediatric Resident, East Jeddah Hospital (KSA)

Abdulrahman Mohamed Homsi, MD abdurrahman.homsi@gmail.com Intern, Uqu University, Mecca (KSA)

Raghad Abdulelah Alsayed, MD raghadalsayed148@gmail.com Resident, Ohod Hospital, Madinah (KSA) Khalid Abdullah Alghamdi, MD iikldxii@gmail.com Fayez Dhyefallah Alghamdi, MD fayezn96@gmail.com Abdullah Faisal Al Muaibid, MD almuaibid.96@gmail.com Intern, Baha University, Baha (KSA) Refal Ghassan Ajjaj, Student refal.g@outlook.com ISNC, Jeddah (KSA) Seham Salem Almohammadi, MD seham92.sm@gmail.com

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Meqbel Majed Alshelawi, MD l.10.m@hotmail.com Intern, Medical University of Silesia, Katowice (Poland) Hassan Ali Alshamrani, MD h.alshomrani1416@gmail.com Intern,Taif University, Taif (KSA) Abdulrauf Abdulatif Tashkandi, MD abdulrauf.t@hotmail.com Intern, Taif University, Taif (KSA) Sara Mohammed Mannan, Medical Student King Abdulaziz university, Jeddah (KSA) Salihah Attiah Alsamiri, Medical Student s.at.alsamiri@gmail.com RCSI, Dublin (Ireland)

DOI: 10.4081/aiua.2021.2.211

ORIGINAL PAPER

The role of the multi-disciplinary team and multi-disciplinary therapeutic protocol in the management of the chronic pelvic pain: There is strenght in numbers!

Antonella Centemero 1*, Lorenzo Rigatti 1*, Donatella Giraudo 2, Guglielmo Mantica 3, Davide De Marchi 1, Elisabetta Francesca Chiarulli 4, Franco Gaboardi 1 1 Department

of Urology, San Raffaele Hospital, Milan; of Physiotherapy, San Raffaele Turro Hospital, Milan; 3 Department of Urology, Policlinico San Martino Hospital, University of Genoa, Genoa; 4 Department of Urology, ASST Rhodense, Rho, Italy.

2 Service

* These

authors equally contributed.

Summary

Introduction: The aim of the study is to evaluate the effectiveness of a Multi-disciplinary team (MDT) and multi-disciplinary approach in the treatment of Chronic Pelvic Pain (CPP).

Methods: The data of all consecutive patients referred for a CPP from 11/2016 to 2/2019 has been prospectively collected. The sample was divided in two groups: Group A, made by patients managed after the institution of our MDT, and Group B, made of patients managed before this date. The MDT is composed by three urogynecologists, a psychologist and a physiotherapist.

All Group A patients underwent a weekly bladder instillation with dimethyl sulfoxide (DMSO), kinesiotherapy for trigger points and Percutaneous Tibial Nerve Stimulation for 10 consecutive weeks. Patients were asked to perform a self-treatment following the Stanford Protocol and to adhere to a specific diet.

All Group B patients were managed only with DMSO instillations and a strict diet.

Results: The Group A was made of 41 females and 6 males while the Group B was made of 38 females and 5 males. The Group A patients showed a statistically significant improvement in the Pelvic Pain Urgency Frequency, in the frequency times reported at the 6 months voiding diary, and a better Patient Global Impression of Improvement.

Conclusions: Our data support the efficacy of the MDT in the management of CPP. The multimodal approach might represent an effective and reproducible non-invasive option to manage successfully CPP.

KEY WORDS: Chronic pelvic pain; Bladder pain; Multi disciplinary team; Interstitial cystitis; trigger points.

Submitted 10 January 2021; Accepted 15 February 2021

INTRODUCTION

The Chronic Pelvic Pain (CPP) is a complex and debilitating syndrome that can strongly impact the quality of life, work productivity and health care utilization of both females and males patients (1). This disease is not simply characterized by localized pain but is a syndrome that leads to a systemic worsening of the patient’s health with the appearance of a not irrelevant depression and other

symptoms (2). Tricyclic antidepressants, cognitive behavior therapy, neuromodulators, and pelvic floor kinesitherapy, stem cells and low-energy shock waves are only some of the proposed managements (3-9).

However, the fact that no definite effective treatments for CPP have been identified to date further complicates the scenario and makes most of urologists are not confident with the management of this disease and its available therapies (10). It follows that many patients “jump” from a practitioner to another starting different treatments without a precise therapeutic plan.

Since CPP is a syndrome caused by many underlying causes and involving different organs, its management might be better lead by the mutual assistance of different healthcare givers. In this light, we recently created in our Center a Multi-disciplinary team (MDT) and a multi-disciplinary protocol of treatment for CPP patients and we aim to evaluate its effectiveness.

MATERIALS

AND METHODS

The data of all consecutive patients referred to our Institution for a CPP from November 2016 to February 2019 has been prospectively collected and retrospectively evaluated. According to our Institution’s regulation, a formal IRB approval is not needed for retrospective studies, since admitted patients are required to sign a consent in order to use their data for scientific purposes.

The definition for CPP was that given by the EAU Guidelines so that “Chronic pelvic pain is chronic or persistent pain perceived in structures related to the pelvis of either men or women and must have been continuous or recurrent for at least six months” (11). Naïve patients were defined as those not previously managed for these symptoms by a urologist or a gynecologist.

Only females and male patients with urological pain syndromes are managed in our center and therefore enrolled in the study. Patients with non-urological causes of CPP such as irritable bowel syndrome or endometriosis and less than 18 years were excluded. Only naïve patients

No conflict of interest declared.

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who entirely followed the therapeutic plan and follow-up were enrolled.

The initial evaluation was made of the collection of a detailed medical history and a physical evaluation, an abdominal ultrasound, routine blood samples and urinalysis with urine culture. PSA was tested in males.

The sample was divided in two different groups: Group A, made by patients managed after the institution of our Multi-disciplinary team set in October 2017, and Group B, made of patients managed before this date.

A Multi-disciplinary team core was established at our Center, consisting of three urogynecologists, a physiotherapist and a psychologist. The protocol and the modalities of patient discussion were decided by mutual agreement by the core member of the team based on the few similar experiences in the literature (12), their own personal experience (each of the core members > 10 years of experience in the treatment of CPP) and the setting of other MDTs for different pathologies. The definition of the protocol and strategy of the MDT took about 3 months before starting. The intent of the MDT is also to continuously update to improve the offer to the patient, every 3 months. EAU guidelines (11) on Chronic Pelvic Pain and ICS updates were the base for the patients’ management. Treating physicians present and discuss the cases with the MDT. The MDT is usually called once a month by the team coordinator, in the first working Thursday, and patients are re-discussed by the MDT at 6 months and then when required. The patients with symptoms of anxiety and/or depression were referred also to the psychiatrist. Similarly, a neurologist was available “on demand” when required.

All patients underwent a complete clinical evaluation with a physical exam and a treatment motivation assessment (1-10 scale). The Pelvic Pain Urgency Frequency (PUF) questionnaire was administered before the treatment and at 6 months-time. Male patients were further assessed with the International Prostatic Symptoms Score (IPSS) while all patients were asked to provide a 72hours voiding diary (VD) at the same 0-6 months timing.

The Patient Global Impression of Improvement (PGI) was assessed at the end of the treatment.

All Group A patients underwent a weekly bladder instillation with dimethyl sulfoxide (DMSO) RIMSO-50®, a weekly kinesitherapy for trigger points treatment and a weekly Percutaneous Tibial Nerve Stimulation (PTNS) for 10 consecutive weeks. All patients were asked to perform a self-treatment following the Stanford Protocol (13) and to adhere strictly to a specific diet for interstitial cystitis.

All Group B patients were managed only with DMSO instillations and the same strict diet.

A two-items non-validated questionnaire was administered to all group A patients at the end of the therapeutic management. The questionnaire was anonymous and administered so as to avoid the Hawthorne effect.

Data were entered into a Microsoft Excel (Version 14.0) database and then transferred to Sofastat TM 1.4.6 for Windows. Descriptive statistics were reported as median (first to third quartile). Continuous variables with nonparametric distribution were compared using the MannWhitney test, while the frequencies were compared using the T-test Calculator and the Chi square test of inde-

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pendence. Two-tailed tests were used for all comparisons; a p value < 0.05 was considered statistically significant.

RESULTS

According to the inclusion criteria a total number of 90 patients were enrolled in the study. The Group A was made of 41 females and 6 males while the Group B was made of 38 females and 5 males. The baseline characteristics of the two samples are summarized in Table 1.

Interstitial cystitis, bladder pain syndrome and prostatodynia were the main causes for the referral. All patients had a suprapubic and/or perineal pain accompanied by urinary irritative symptoms (frequency and urgency).

The two groups were not statistically different in terms of age, initial PUF and IPSS score, urgency/frequency times reported at the bladder voiding diary, while were different for marital status. The main results of the two different managements are summarized in the Table 2.

Group A patients showed an improvement in term of PUF, in the frequency times reported at the 6 months VD, and a better PGI. No improvement in the IPSS was showed in Group A patients. Four female patients in Group A and three in Group B were evaluated by the psychiatrist and started on medication for anxiety/ depression. Similarly, in Group A two female patients were evaluated by the neurologist and started on Pregabalin while in Group B two females and one male.

Forty-two (89.4%) of the Group A patients felt to be ade-

Table 1.

Patients’ characteristics.

Age Males Females Parities Family history of CPP History of Sexual Abuse Anxiety and Depression Stable partner Education Primary school Secondary school University BMI Smoking Prev. Perineal Surgery Self medications at home Type of pain Suprapubic Perineal Main cause for referral Interstitial cistytis Bladder pain syndrome Prostatodynia Urinary symptoms Frequency Urgency Data are expressed as median.

Group A 40 (33-46) 6 41 21 4 3 13 25

Group B 39 (31-45) 5 38 17 5 4 18 32

2 22 23 24.3 (23-25.2) 18 13 36

1 26 16 23.4 (22.1-25) 15 17 32

43 12

38 15

6 35 6

4 34 5

35 22

34 18

p 0.38 1 1 0.67 0.73 0.7 0.23 0.049 0.41

0.41 0.83 0.26 1 0.5

0.84

0.69

The role of multi-disciplinary team in CPP

Table 2.

Outcomes of the two groups.

Group A

Group B

PUF at time 29 (25-29) SS 18 BS 11 27 (25-29) SS 16 BS 11 p 0.62

PUF at 6 months PUF improvement 13 (11-17) -16 SS 8 -10 BS 5 -6 19 (13-21) -8 SS 10 -6 BS 9 -2 p < 0.05 p < 0.05

PGI 2 (2-2)

IPSS at time 0 25 (23-29)

IPSS at 6 months 17 (11-19)

IPSS improvement -8

VD at time 0 14 (12-16)

VD at 6 months 7 (7-9)

3 (2-3)

27 (22-27)

21 (15-22)

-7

14 (13-16)

10 (7-11)

p < 0.05

p=1

p = 0.27

p = 0.31

p = 0.92

p = 0.041

Data are expressed as median (1st–3rd quartile); PUF = Pelvic Pain Urgency Frequency Questionnaire; VD = Voiding Diary; PGI = Patient Global Impression of Improvement; IPSS = International Prostatic Symptoms Score; SS = Symptom Score; BS = Bother Score.

quately followed throughout the therapeutic process, against the 69.8% of the Group B (p = 0.02).

Similarly, 39 (83%) patients of the Group A and 35 (81.4%) of the Group B felt that different professional figures available has helped/would have helped her/his treatment (p = 0.84).

DISCUSSION

Pain is a normal reaction of our body to an external potentially harmful damage. However, for many people pain persists even after the elimination of this cause of damage, sometimes even for weeks and several months, causing a chronic pain syndrome (14).

CPP is one of the most debilitating syndromes, also because of the body area interested, which is intimately connected to the psycho-sexual life (15-16). Historically, the main recognized causes of "urological" CPP are prostatitis, chronic and interstitial cystitis, nerve damages and previous pelvic urological surgery (11).

The multi-disciplinary team is a new concept born a few years ago and that is slowly spreading in medical practice as a therapeutic ideal for many different diseases (17). Its introduction and diffusion are mainly linked to oncological pathologies where complex clinical cases are discussed and managed by a heterogeneous team made up of different healthcare givers (surgeons, oncologists, radiologists, pathologists, radiotherapists, etc.). Regarding the oncological field, the MDT seem to have a significant impact on patient assessment. However, their impact on clinical and oncological outcomes in cancer patients is supported by little evidence (18).

The introduction of multi-disciplinary tasks in the treatment of benign pathologies and complex syndromes is even more recent. In particular, some recent reports have evaluated the role of MDTs in the treatment of pain syndromes such as musculoskeletal pain, daily headaches and hip pain, showing how it can facilitate the treatment of refractory patients (19-21).

The effectiveness of the MDTs in the management of CPP has been evaluated and confirmed by the very few available reports (22-26). Gupta et al. (22) reported the experience of the Beaumont Health System, with the creation of a Multi-disciplinary Women's Urology Center, including not only urologists but also gynecologists, experts in pelvic floor physical therapies, colorectal surgeons, integrative medicine practitioners who provide alternative therapies such as acupuncture, and pain psychologists. This model showed to be extremely successful in managing the symp-

toms of interstitial Cystitis and Bladder Pain Syndrome, with a very high patient satisfaction. The Women's Urology Center represents an ideal MDT which might be able to manage all the different types of CPP (not only urological) providing personalized therapeutic patient-based solutions. It is obvious that, for reasons of resources and organization, not all the hospitals may be able to set up a similar team for the treatment of a benign pathology.

Our study reports the experience of one of the easiest and more simple MDTs that can be established, consisting in the addiction of the physiotherapist and the psychologist to the urological management. It is cheap and potentially affordable for every institution and allows a multi-disciplinary management of such difficult patients.

The MDT is usually called once a month.

The treating physician may present cases directly evaluated or referred in order to plan a multimodal approach targeted on each patient.

In our study, the Group A patients showed a statistically significant improvement in the PUF, in the frequency times reported at the 6 months VD, and a better PGI. On the contrary, the IPSS showed no improvement in Group A patients but this might be influenced by the very low number of the male sample on which it was evaluated.

The questionnaire submitted to the patients showed that most of them considered useful the use of more professional healthcare givers. The availability of multiple different practitioners could not only guaranteeing a more complete therapeutic approach, but also make the patient perceive a better care and less abandonment and frustration.

The main limit of the study is that is retrospective, even if data have been collected prospectively over the years.

The small size of the cohort, and in particular in the males group, further limit the analysis of the outcomes such as IPSS change. However, we believe that it succeeded in evaluating the possible benefit of an integrated approach to CPP.

CONCLUSIONS

The multimodal approach might represent an effective and reproducible non-invasive option to manage successfully CPP patients. Of fundamental importance is the definition of the various health care givers involved, their role in the diagnostic and therapeutic process, and a strong synergy of the team. Further studies on larger samples are needed in order to confirm the effectiveness of the multimodal approach and outline the best treatment protocols.

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26. Lillemon JN, Nardos R, Kaul MP, et al. Complex female pelvic pain: a case series from a multidisciplinary clinic in urogynecology and physiatry. Female Pelvic Med Reconstr Surg. 2019; 25:e34-e39.

11. Engeler D, Baranowski AP, Berghmans B, et al. EAU 2020 Guidelines on Chronic Pelvic Pain. European Association of Urology, 2020 – www.uroweb.org 12. Magri V, Boltri M, Cai T, et al. Multidiscplinary approach to prostatitis.Arch Ital Urol Androl. 2019; 90:227-248 13. Anderson RU, Wise D, Sawyer T, et al. Equal improvement in men and women in the treatment of urologic chronic pelvic pain syndrome using a multi-modal protocol with an internal myofascial trigger point wand. Appl Psychophysiol Biofeedback. 2016; 41:21524.

14. Sammarco AG, Kobernik EK, Haefner HK, et al. Lower urinary tract symptoms in a chronic pelvic pain population. Female Pelvic Med Reconstr Surg. 2019 Jan 8.

15. Guan Y, Yu G, Wang G, Bai Z. The negative effect of urologic chronic pelvic pain syndrome on female sexual function: a systematic review and meta-analysis. Int Urogynecol J. 2019; 30:18071816.

16. Berghmans B. Physiotherapy for pelvic pain and female sexual dysfunction: an untapped resource. Int Urogynecol J. 2018; 29:631638.

17. Ambrosini F, Di Stasio A, Mantica G, et al. COVID-19 pandemic and uro-oncology follow-up: A "virtual" multidisciplinary team strategy and patients' satisfaction assessment. Arch Ital Urol Androl. 2020; 92:78-79 18. Pillay B, Wootten AC, Crowe H, et al. The impact of multidisci-

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Correspondence Antonella Centemero, MD Lorenzo Rigatti, MD Davide De Marchi, MD Franco Gaboardi, MD Department of Urology, San Raffaele Hospital, Milan (Italy) Donatella Giraudo, MD Service of Physiotherapy, San Raffaele Turro Hospital, Milan (Italy) Guglielmo Mantica, MD (Corresponding Author) guglielmo.mantica@gmail.com Department of Urology, Policlinico San Martino Hospital, University of Genoa, Largo Rosanna Benzi 10, 16132, Genoa (Italy) Elisabetta Francesca Chiarulli, MD Department of Urology, ASST Rhodense, Rho (Italy)

DOI: 10.4081/aiua.2021.2.215

ORIGINAL PAPER

Sexual dysfunction in dialytic patients.

A prospective cross-sectional observational study in two hemodialysis centers Carlo Pavone 1, Antonio Simone Di Fede 1, Piero Mannone 1, Gabriele Tulone 1, Arjan Bishqemi 1, Alberto Abrate 2, Vincenzo La Milia 3, Vincenzo Serretta 1, Alchiede Simonato 1 1 Department

of Surgical, Oncological and Oral Sciences, Section of Urology, University of Palermo, Palermo, Italy; of Surgery, Urology Unit, ASST Valtellina e Alto Lario, Sondrio, Italy; 3 Nephrology and Dialysis Department, Lecco, Italy.

2 Department

Summary

Objectives: Incidence and prevalence of patients in dialytic therapy increased considerably in recent years. The onset of new issues, once overshadowed, linked to a lower quality of life like sexual dysfunction became increasingly common. The first study in this area, dating back to the 1970s, shows the high prevalence of sexual dysfunction among patients in dialytic therapy of both sexes. Later studies proved an association of sexual dysfunction with psyche disorders, anxiety, depression and lack of self-confidence. The aim of this study is to describe the incidence of male and female sexual main dysfunctions, the latter not least in literature, in patients in hemodialytic therapy. With this aim two dialytic centers have been compared, one located in northern Italy and one in southern Italy, and the different prevalence has been compared to the general population.

Methods: We conducted a prospective cross-sectional observational study in patients undergoing dialytic therapy in two hemodialysis centers, one located in Palermo and one in Lecco.

Male sexual dysfunction was investigated by the International Index of Erectile Function-15 (IIEF15) questionnaire and the Premature Ejaculation Diagnotic Tool (PEDT) questionnaire, and the female dysfunction by Female Sexual Function Index (FSFI) questionnaire. Criteria for inclusion in our study were: age < 75 years and dialytic age > 3 months; exclusion criteria were: advanced cancer diseases, life expectancy < 6 months, previous urological manipulation, anti-androgenic therapy, sexual dysfunction unrelated to kidney disease, psychiatric disorders.

Data were compared with mean-standard deviation (SD) and with the variance analysis (ANOVA). A value of p < 0.05 is considered significant. Discrete data were analyzed with contingency analysis. A chi2 < 0.05 was considered significant.

Results: Data of 78 patients have been collected. Mean age and dialytic time were 54 ± 12 years and 42 ± 35 month; 33 patients were from Palermo and 24 from Lecco; 21 patients were excluded. Age and dialytic age of the two subgroups did not demonstrate statistically significant differences. Between the two centers there was a statistically significant difference (p < 0.005) in the distribution of basic nephropathy: an higher incidence of diabetic and obstructive nephropathy has been observed in the southern center compared to northern center, while glomerulonephritis and polycystic kidney disease had an higher incidence in the northern center compared to southern one. The main sexual dysfunctions in both sexes, erectile dysfunction (ED) and premature ejaculation (PE) in men and orgasm disorder and pelvic pain in women, have been investigated. ED was present in 70%

of hemodialyzed patients, which is an higher incidence compared to the general population. The severity of ED between patients of the two groups was significantly different (chi2 < 0.001) with higher incidence of moderate/severe forms in northern Italy. The score, in addition to discrete data (severe, moderate, mild, absence), of ED was significantly different (p < 0.001) between patients of the two centers (22 ± 7 Palermo vs. 9 ± 8, Lecco). The PE was absent in 20 patients (54%), present in 12 patients (32%) and probable in 5 patients (14%) (scores of 7.6 ± 4.0 and 8.9 ± 6.8, respectively in Palermo and Lecco patients). For women, orgasmic dysfunction was severe in 10 patients (50%), mild in 4 patients (20%), very mild in 5 patients (25%), while it was normal in 1 patient (5%), with a statistically significant difference (p< 0.05) between Palermo and Lecco patients (3.0 ± 1.4 vs 1.2 ± 2.0).

Sexual pain in women was severe in 11 patients (55%), moderate in 4 patients (20%) and mild in 5 patients (25%).

Sexual pain was present in all patients (p < 0.05).

Conclusions: Regardless of sex, sexual dysfunction is one of the most common side effect in patients with end stage renal disease in dialytic therapy. Our study confirms literature data.

The growing number of the dialytic population with sexual disorders needs specialist support to improve quality of life of these patients.

KEY WORDS: Dialysis; End-Stage Renal Disease; Sexual male dysfunction; Erectile disorder; Premature ejaculation; Female sexual dysfunctions; International Index of Erectile Function; Premature Ejaculation Diagnostic Tool.

Submitted 4 November 2020; Accepted 28 December 2020

INTRODUCTION

End-Stage Renal Disesase (ESRD) is a disabling disease that forces patients to a radical change of their lifestyle and habits, causing physical and important psychological disorders. Sexual male dysfunction is an extremely common condition that manifests itself with erectile disorder (ED) and premature ejaculation (EP) (1), often present at the same time. In everyday clinical practice, both pathologies require a multidisciplinary approach in the diagnostic phase and in the therapeutic management (2, 3) due to their multifactorial genesis, such as psychological factors and endothelial dysfunction. Female sexual dysfunctions

No conflict of interest declared.

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are understudied, despite the incidence being alarmingly high: in a 30 years ago study, 76% of women were living with some symptoms of sexual dysfunction (4), while more recent literature suggest that prevalence is around 43% (5). Most common symptoms in women are dyspareunia, vaginismus, and noncoital sexual pain disorder (6).

Since population undergoing hemodialysis (HD) treatment for ESRD significantly increased in the last few years, attention is focused on its sexual disease (7).

The greater longevity of these patients and the association with dialytic therapy has led to new problems that in the past were not highlighted in an incisive way and that today have been noticed to have a significant influence on the quality of life among ESRD patients.

First studies on sexual dysfunction in dialysis patients, date back to the 1970s, highlighted the high prevalence of sexual dysfunction among patients of both sexes (8).

Following studies confirmed that sexual dysfunction is very common in men and women with ESRD, associated with anxiety and depression, affecting the quality of life with impact on self-confidence, self-esteem and selfimage (9, 10). The aim of this study is to describe the incidence of male and female main sexual dysfunctions, in patients undergoing hemodialytic therapy, considering modern dialytic techniques. Two dialytic centers have been compared, one in Northern Italy and another one in Southern Italy. Different prevalence has been compared to the general population.

METHODS

A prospective cross-sectional observational study amongst two hemodialysis centers has been conducted.

The presence of sexual dysfunctions has been assessed by questionnaires administered to patients on chronic haemodialysis treatment in both examined haemodialysis centers, one in Southern Italy (Palermo) and one in Northern Italy (Lecco). Questionnaires were administered and returned anonymously. Andrological or gynecological evaluation was offered when requested by patients.

Inclusion criteria are age < 75 years and dialytic age > 3 months. Exclusion criteria are advanced neoplastic diseases, life expectancy < 6 months, radical prostatectomy, anti-androgenic therapy, sexual dysfunctions unrelated to kidney disease, any previous surgical manipulation of the urogenital system, use of drugs to improve sexual performance, psychiatric disorders, and people who refused to participate to the study.

Dialytic patients were recruited for the study regardless of the cause that led to end-stage renal failure. Data were collected from January 2018 to December 2018.

Questionnaires administered to male patients are International Index of Erectile Function 15 (IIEF) 15 (11) and Premature Ejaculation Diagnostic Tool (PEDT) (12).

The Female Sexual Function Index test (FSFI) (13) was administered to Female patients.

Data are compared with mean standard deviation (SD) and with the variance analysis (ANOVA). A value of p < 0.05 is considered significant. Discrete data are analysed with contingency analysis. A Chi2 < 0.05 value is considered significant. In our study, the sample size was not calculated and this represents a limitation for results.

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RESULTS

78 patients were recruited into the study: 5 of them were excluded for psychiatric issues, 6 refused to answer and 10 did not complete the questionnaire. Therefore, our study was carried out on 57 patients. Patients underwent chronic hemodialysis treatment, aged 54 ± 12 years, 37 males and 20 females, with dialysis age 42 ± 35 months, of which 33 patients were hemodialyzed in a dialysis center in Southern Italy (Palermo) and 24 patients in a dialysis center in Northern Italy (Lecco).

In the dialysis center of Palermo, 23 male patients were recruited. Patient ages range from a minimum of 25 to a maximum of 72 years, with an average of 54 ± 14 years.

We also analyzed the dyalisis ages of patients from a minimum of 4 to a maximum of 84 months, with an average of 37 ± 24 months. In the dialysis center of Lecco, 14 male patients were recruited. Patient ages range from a minimum of 36 to a maximum of 70 years, with an average of 55 ± 10 years. We also collected informations about the dyalisis ages of patients ranging from a minimum of 5 to a maximum of 106 months, with an average of 45 ± 33 months. Furthermore, we paid attention to the anamnesis and chronic pathologies that led patients to need dialysis treatment in the respective center (Table 1). The average age of male patients on hemodialysis treatment in Palermo is not significant different from those in Lecco (54 ± 14 years vs 55 ± 10 years, respectively) and there is not significant difference in dialysis age, either (37 ± 24 months vs 45 ± 33 months, respectively). On the other hand, there is a difference in the most common underlying disease between the two centers: diabetic nephropathy (39%) in Palermo and polycystic kidney (29%) in Lecco.

In the dialysis center of Palermo, 10 female patients were recruited. The ages of the patients range from a minimum of 39 to a maximum of 71 years, with an average of 54 ± 11 years. 60% (n. 6) of these patients were in menopause. We also collected informations about the dyalisis ages of the patients ranging from a minimum of 10 to a maximum of 72 months, with an average of 35 ± 20 months. In the center of Lecco, 10 female patients were recruited. The ages of the patients range from a minimum of 34 to a maximum of 63 years, with an average of 53 ± 10 years. 80% (n. 8) of these patients were in menopause. We also collected the dyalisis ages of the patients ranging from a minimum of 9 to a maximum of 209 months, with an average of 57 ± 62 months.

Table 1.

Cause of ESRD. Cause of ESRD Hypertensive nephropathy Diabetic nephropathy Obstructive nephropathy Glomerulonephritis Polycystic kidney Recurrent urinary tract infections Nephroangiosclerosis Tot

Male Palermo 3 (13%) 9 (39%) 3 (13%) 4 (17%) 1 (4%) 3 (13%) 0 23

Male Lecco 0 3 (21%) 1 (7%) 2 (14%) 4 (29%) 1 (7%) 3 (21%) 14

Female Palermo 1 (10%) 4 (40%) 1 (10%) 1 (10%) 1 (10%) 2 (20%) 0 10

Female Lecco 0 2 (20%) 0 3 (30%) 4 (40%) 0 1 (10%) 10

Sexual dysfunction in dialytic patients

We also paid attention to the anamnesis and chronic pathologies that led patients to need dialysis treatment in the respective center (Table 1). The average age of female patients on hemodialysis treatment in Palermo is not significant different from those in Lecco (54 ± 11 years vs 53 ± 10 years, respectively) while there is a significant difference in dialysis age, either (35 ± 20 months vs 57 ± 62 months, respectively). As in the case of male patients, there is a difference in the most common underlying disease between the two centers: diabetic nephropathy (40%) in Palermo and polycystic kidney (40%) in Lecco.

ESRD influence on sexual function is analyzed using questionnaires. For male patients following parameters are taken into account: erectile dysfunction, orgasmic dysfunction, libido reduction, dissatisfaction of sexual relations and premature ejaculation (Table 2).

Erectile dysfunction is present in 70% of patients with different severity level distributed with a significant difference (Chi2 < 0.001). Data show prevalence of severe dysfunction among patients on hemodialysis treatment at the center of Lecco, while at the hemodialysis center of Palermo this dysfunction is absent in most patients.

We documented a different score (p < 0.001) among patients of the center of Palermo compared to those of Figure 1.

Male's main sexual dysfunctions.

the center of Lecco (9 ± 2 vs 3 ± 4, respectively). The reduction in sexual desire is absent in 2 patients (5%), very slight in 5 patients (14%), mild in 19 patients (51%), moderate in 8 patients (22%) and severe in 3 patients (8%). Libido reduction is statistically different (Chi2 < 0.05) between the male patients of the two hemodialysis centers, with a clear prevalence of severe and moderate dysfunction among the patients on hemodialysis treatment at the center of Lecco, whereas it is mild in most patients in treatment at the hemodialysis center in Palermo. We documented a significantly different score (p < 0.05).

The general sexual well-being is also statistically different (Chi2 < 0.05) with a clear prevalence of severe and moderate impairment among the patients on hemodialysis treatment at the center of Lecco, while this impairment is mild or very mild in most patients in treatment at the hemodialysis center in Palermo. We documented significantly different score (p < 0.05) among patients of the center of Palermo, compared to those of the center of Lecco (7 ± 0 vs 5 ± 1, respectively).

There is a statistically significant difference (Chi2 = 0.03) regarding premature ejaculation: this alteration of sexuality is more frequent in male patients on dialysis at the center of Lecco, compared to male patients of the hemodialysis center in Palermo.

However, when considering the total score of responses on premature ejaculation, instead of considering the discrete variables (present, absent and probable), this difference is no longer significant; in particular, the total score is 7.6 ± 4.0 and 8.9 ± 6.8 in patients being treated at the hemodialysis center in Palermo and Lecco, respectively (Figure 1) (Table 2).

Table 2.

Males’ sexual dysfunctions.

Patients features

Patients (n.) 57 Males: 37 - Females: 20 Age (years) 54 ± 12 (Palermo 54 ± 14; Lecco 55 ± 10) Dialysis age (month) 42 ± 35 (Palermo 37 ± 24; Lecco 45 ± 33

Males sexual disfunctions

Severe Moderate Erectile dysfunction (%) Orgasmic dysfunction (%) Libido reduction (%) Dissatisfaction of sexual relations (%) Premature ejaculation (%)

2 (8.7%) 1 (4.3%) 0 2 (8.7%) Present 5 (21.7%)

2 (8.7%)

Palermo Mild Light

Very light

Absent

10 (43.5%) 9 (39.1%) 1 (4.3%) 2 (8.7%) 19 (82.7%) 3 (13%) 15 (65.3%) 3 (13%) 2 (8.7%) 0 12 (52.1%) 9 (39.2%) Probable Absent 5 (21.7%) 13 (56.6%)

Severe Moderate 9 (64.3%) 3 (21.5%) 9 (64.3%) 3 (21.5%) 10 (71.4%) Present 7 (50%)

Lecco Mild Light 0 0 5 (35.8%) 2 (14.2%) Probable 0

4 (28.5%) 1 (7.1%)

Very light 3 (21.5%) 2 (14.2%) 1 (7.1%)

Absent

P value

2 (14.2%) 2 (14.2%) 0

< 0.001 < 0.001 < 0.05 < 0.001

Absent 7 (50%)

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Here below female patients’ data were then analyzed.

Through the scores we investigated parameters such as reduction of sexual desire, reduction of sexual arousal, lubrication, orgasmic dysfunction, sexual disatisfaction and sexual pain (Table 3). The reduction in sexual desire is statistically significant (Chi2 < 0.05) in female patients in hemodialysis treatment in the two hemodialysis centers, with it being severe or moderate in patients in hemodialysis treatment in Lecco, while in patients in hemodialysis treatment in Palermo it presented in a milder form. However, the analysis of the score, i.e. the continuous variable, do not show a statistically significant difference between patients of Palermo and those of Lecco (2.2 ± 0.9 vs 2.8 ± 0.9).

The reduction in sexual arousal is not statistically significant in female patients in hemodialysis treatment at the two hemodialysis centers, although the reduction in sexual arousal is more severe in hemodialysis patients in Lecco than in hemodialysis patients in Palermo. The score shows a statistically significant difference (p < 0.005) between patients of Palermo and those of Lecco (3.2 ± 1.1 vs 1.3 ± 1.7) with a greater dysfunction of sexual arousal in the latter. The reduction in lubrication is statistically significant (Chi2 < 0.01) in female patients in hemodialysis treatment at the two hemodialysis centers, being severe or moderately severe among patients in hemodialysis treatment in Lecco, while in patients in hemodialysis treatment in Palermo it manifested itself in a milder form.

The analysis of the score, i.e. the continuous variable, do not show a statistically significant difference between the patients of Palermo and those of Lecco (3.2 ± 1.2 vs 1.5 ± 2.5, respectively).

Orgasmic dysfunction is not statistically significant in female patients in hemodialysis treatment at the two hemodialysis centers, although there is a greater tendency for severe dysfunction in patients in hemodialysis treatment at the center of Lecco than in patients in hemodialysis treatment in Palermo. The score shows a statistically significant difference (p < 0.05) between the patients of Palermo and those of Lecco (3.0 ± 1.4 vs 1.2 ± 2.0, respectively). Sexual dissatisfaction is statistically significant (Chi2 < 0.001) in female patients in hemodialysis treatment at the two hemodialysis centers, with a greater tendency for severe sexual dissatisfaction in patients in hemodialysis treatment at the center of Lecco, compared to patients in treatment hemodialysis in Palermo.

The analysis of the score, i.e. of the continuous variable, also shows a statistically significant difference (p < 0.001) between the patients of Palermo and those of Lecco (3.8 ± 0.4 vs 0.7 ± 0.4, respectively).

Finally, sexual pain presents a statistically significant difference (Chi2 < 0.05) in female patients in hemodialysis treatment at the two hemodialysis centers, with a greater tendency to severe sexual pain in patients in hemodialysis treatment at the center of Lecco, compared to patients in hemodialysis treatment in Palermo.

The analysis of the score, i.e. the continuous variable, also shows a statistically significant difference (p < 0.05) between the patients of Palermo and those of Lecco (2.2 ± 0.7 vs 0.8 ± 1.8, respectively) (Figure 2, Table 3).

Figure 2.

Female's main sexual dysfunctions.

DISCUSSION

Analyzing available data, the two main male and female typical sexual dysfunctions of the chronic hemodialytic patient were compared with those present in the general population, also making a comparison with data obtained throughout this study.

Table 3.

Females’ sexual dysfunctions.

Females sexual disfunctions

Reduction of sexual desire (%) Reduction in sexual arousal (%) Female lubrication reduction (%) Orgasmic dysfunction (%) Sexual dissatisfaction (%) Sexual pain (%)

218

Severe 2 (20%) 1 (10%) 1 (10%) 3 (30%) 1 (10%) 3 (30%)

Moderate 1 (10%) 2 (20%) 2 (20%) 0 4 (40%)

Palermo Mild 7 (70%) 5 (50%) 2 (20%) 3 (30%) 3 (30%) 3 (30%)

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Very mild

Absent

2 (20%) 5 (50%) 4 (40%) 6 (60%)

0 0 0 0

Severe 3 (30%) 6 (60%) 7 (70%) 7 (70%) 7 (70%) 8 (80%)

Moderate 5 (50%) 1 (10%) 0 2 (20%) 0

Lecco Mild 2 (20%) 2 (20%) 0 1 (10%) 1 (10%) 2 (20%)

P value Very mild

Absent

1 (10%) 1 (10%) 1 (10%) 0

0 2 (20%) 1 (10%) 0

< 0.005 < 0.05 < 0.001 < 0.05

Sexual dysfunction in dialytic patients

By evaluating erectile dysfunction (ED) we can show how this dysfunction has increased in the chronic hemodialytic population, compared to the general one, as we expected. According to general data, erectile dysfunction in Italy is present in about 3-5 million men, with a prevalence percentage ranging from 10% to 17%. According to an Italian study by Parazzini et al. (14), the prevalence of ED assessed by questionnaire in the general population was 12.8%, with 70% partial ED, while 30% is complete.

These epidemiological data increase in the chronic hemodialytic population, as reported in the literature.

In fact, according to a study by Savadi et al. (15), the prevalence of ED in patients with chronic renal failure was reported in the range of 22-88% and more specifically it is 87.5% in patients on hemodialysis. Analyzing our data, ED prevalence of 70% is observed, considering also the mild form, and it is more frequent in the population of Northern Italy than in that of Southern Italy. Evaluating premature ejaculation, it has been observed that in the Italian general population it is present in about 4-5 million men with a prevalence ranging from about 15 to 20%; while according to the literature, and more precisely according to Aslan, the prevalence of premature ejaculation is determined in 31.6% of patients (16). Analyzing our data, it was observed that the prevalence of premature ejaculation in our population is 46%.

Assessing the alterations of the female sexual sphere, although data from female hemodialytic patients are very limited, it has been observed that according to one of the largest study carried out worldwide, the prevalence of these disorders is around 84%, confronted with a general population prevalence of about 45% (more precisely, in the general population there is, for example, a dyspareunia ranging from 12% in women of childbearing age up to 31% in those in menopause; or vaginismus that is about 0.5-15%) (9). Data reported by our study, however, show that sexual dysfunctions in women receiving hemodialysis are around in 100% of patients, in almost all assessed items.

Furthermore, comparing data of these sexual dysfunctions between the population of Northern Italy and that of Southern Italy, in the two hemodialysis centers, it is evident that they are different, with a greater prevalence in the Northern population compared to the Southern one.

This could be due to different reasons. These differences allow us only to be able to formulate diagnostic hypotheses underlying the different results obtained by our study.

A definitely important aspect to explain these differences is basic nephropathy: our data show a significant difference between basic nephropathy in the population assessed in the North and in the South; it cannot be excluded that the underlying pathology may contribute to these differences in sexual dysfunction between the two Italian populations. Even the dialysis age, slightly higher in Lecco patients than in Palermo patients, could explain this difference between the two populations. The cultural differences between the two regions of the country could also have influenced the test results by changing the approach to the questions and altering the answers.

In addition, by assessing the prevalence of male and female sexual dysfunctions, it is evident that these are more frequent in the male than in the female sex. This dif-

ference could be due to different pathogenetic factors in the male sex compared to the female one.

Finally, psychological factors in these differences cannot be excluded.

CONCLUSIONS

Our study confirms literature data, according to which chronic renal failure is a disabling disease, also from a sexual functionality point of view, of both male and female patients, and confirms the need for specialist andrological or gynecological advice, in addition to dialysis.

The growing number of dialytic populations with sexual disorders needs specialist support to improve their quality of life.

CONFLICT

OF INTEREST STATEMENT

Authors declare that they have no competing interests.

The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000.

Informed consent was obtained from all patients for being included in the study.

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Correspondence Carlo Pavone, MD, Professor (Corresponding Author) carlo.pavone@unipa.it Antonio Simone Di Fede, MD Piero Mannone, MD Gabriele Tulone, MD Arjan Bishqemi, MD Vincenzo Serretta, MD Alchiede Simonato, MD Department of Surgical, Oncological and Oral Sciences, Section of Urology, University of Palermo, Palermo (Italy) Alberto Abrate, MD Department of Surgery, Urology Unit, ASST Valtellina e Alto Lario, Sondrio, (Italy) Vincenzo La Milia, MD Nephrology and Dialysis Department, Lecco (Italy)

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ORIGINAL PAPER

DOI: 10.4081/aiua.2021.2.221

A new original nutraceutical formulation ameliorates the effect of Tadalafil on clinical score and cGMP accumulation Vincenzo Mirone 1, Luigi Napolitano 1, Roberta D’Emmanuele di Villa Bianca 2, Emma Mitidieri 2, Raffaella Sorrentino 2, Arianna Vanelli 3, Domenico Vanacore 2, Carlotta Turnaturi 2, Roberto La Rocca 1, Giuseppe Celentano 1, Davide Arcaniolo 4, Giuseppe Cirino 2 1 Department

of Neurosciences, Sciences of Reproduction, and Odontostomatology, University of Naples Federico II, Naples, Italy; of Pharmacy, School of Medicine and Surgery, University of Naples, Federico II, Naples, Italy; 3 Responsabile Ricerca e Sviluppo Nutrilinea SRL, Varese, Italy; 4 Urology Unit, Department of Woman Child and of General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.

2 Department

Summary

Objective: To assess the efficacy of the combination of Tadalafil 5 mg and nutritional supplements composed by Panax ginseng, Moringa Oleifera and Rutin on erectile function in men with mild and moderate vasculogenic ED. Methods: we prospectively enrolled 86 patients divided into two groups A (45), B (33) in this multicenter randomized, doubleblind, placebo-controlled trial . Drop out was 8 patients (3 patients in group A and 5 in Group B). At screening visit patients underwent clinical examination, blood test (hormonal and metabolic profile) and filled out the IIEF-5 questionnaire and the SEP-2, SEP-3. Patients were randomized by a computergenerated list to receive either Tadalafil 5 mg once daily plus nutritional supplement once daily (group A) or Tadalafil 5 mg plus placebo with the same administration schedule (group B) for 3 months. Blood samples, IIEF-5, SEP-2 and SEP-3 have been collected again after 3 months. cGMP was measured in platelets of 38 patients at baseline and after one months.

Results: Mean age was 59.98 ± 6.90 (range 38-69), mean IIEF-5 score at baseline was 13.59 ± 3.90. After three months of treatment, IIEF-5 score significantly improved in both groups compared to baseline (13.18 ± 3.75 vs 20.48 ± 2.24, p < 0.0001; 14.15 ± 4.09 vs 19.06 ± 4.36, p < 0.0001, in group A and group B respectively). Patients treated with Tadalafil plus nutritional supplement showed a significantly higher increase in IIEF-5 score compared to those who received placebo (7.27 ± 2.20 and 4.9 ± 2.79, respectively; p < 0.0001;). No hormonal differences and metabolic effects were found. According cGMP result, nutritional supplements ameliorates and extends the activity of the chronic treatment.

Conclusions: IIEF-5 significant increase in group B, can be ascribed to the nutritional supplement properties and antioxidant effects of moringa oleifera, ginseng and rutin and this can enhance the endothelial NO and cGMP production.

KEY WORDS: Erectile dysfunction; PDE5; Dietary supplement; Phosphodiesterase: Natural health product.

Submitted 25 January 2021; Accepted 5 March 2021

INTRODUCTION

Erectile dysfunction (ED) has been identified as the most common sexual problem, with high prevalence and inci-

dence worldwide, that affects the quality of life (QoL) of patients and their partner’s. It is estimated that about 322 million men would suffer from ED global by the year 2025 (1). ED primarily affects men older than 40 years of age. ED prevalence ranges between 1-10% in men younger than 40 years (International Consultation Committee for Sexual Medicine). The prevalence increases with age in a range from 2% to 9% in men between the ages of 40 and 49 years, 20-40% in men aged 60-69 years and > 50% in men older than 70 years (2). To the ED onset contributes several environmental and lifestyle risk factors such as diabetes mellitus, hypertension, hyperlipidaemia, obesity, metabolic syndrome, depression, smoking and limited or absence of physical exercise (3-7).

Penile erection is a complex of events controlled by vascular, hormonal and neuronal systems (8). For what concerns the vascular component the endothelium plays a major role through the nitric oxide (NO) pathway.

Indeed, the activation of the NO pathway causes relaxation of smooth muscle in the penile corpus cavernous, leading to increased inflow of blood (9). NO is synthesized within the endothelium starting by endothelial nitric oxide synthase (eNOS) and activates the soluble guanylyl cyclase (sGC) that leads to the formation of cyclic guanosine monophosphate (cGMP). The cGMP levels are tightly controlled by phosphodiesterases (PDEs) (10).

Nowadays, medical interventions for ED management include oral drugs, intrapenile therapies (intra-urethral suppositories and intracavernous injections) and penile prosthesis implantation (11). The most widely used therapeutic approach relies on the use of phosphodiesterase type 5 (PDE5) inhibitors (12-13). The PDE5 response rate is about 70 %.and it is significantly lower in difficult-to-treat subpopulations (14). Many studies have also shown that the dropout rate with PDE5 inhibitors therapy is still more than 50% after one year (15). Emerging shreds of evidence propose an increasing role of herbal-based dietary supplements and nutraceuticals in the management of ED, for their anti-oxidant, anti-inflammatory and anti-proliferative properties.(16).

No conflict of interest declared.

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The study aims to evaluate the efficacy of the combination of Tadalafil 5 mg and nutritional supplements composed by Panax ginseng, Moringa oleifera and rutin on erectile function in men with mild and moderate vasculogenic ED. In order to address this issue, we applied two different approaches: i) the assessment of Index of Erectile Function (IIEF) and Sexual Encounter Profile (SEP) that represent primary endpoints in clinical studies on ED (17); ii) the measurement of platelet cGMP content that represents biomarker of PDE5 activity (18-19).

METHODS

The study consisted of two different phases: a clinical one and an experimental ex vivo one.

In a multicenter randomized, double-blind, placebocontrolled trial we enrolled consecutive patients with vasculogenic ED attending Urology Clinic of University of Naples “Federico II”, University of Campania “Luigi Vanvitelli” and Interdepartmental Research Center for Sexual Medicine (CIRMS), University of Naples Federico II. Inclusion criteria were: patient age between 18 and 69 years; mild to moderate ED for at least 6 months with a short form of International Index of Erectile Function score (IIEF-5) > 7 and < 22; hypertension treated with ACE inhibitors, beta-blockers or calcium antagonists and/or type 2 diabetes treated with oral hypoglycemic agents; the patient has been in a stable sexual relationship for > 3 months. Patients have had to be naïve for PDE5inhibitors treatment. Exclusion criteria were: patients who had severe ED (IIEF-5 score < 8), ED due to endocrine disorders, premature ejaculation, previous pelvic surgery, Peyronie’s disease, liver or renal failure, history of myocardial infarction, cardiovascular disease, stroke, unstable angina and heart failure within the previous 6 months, intake of nitrates, diabetes mellitus on insulin therapy, dyslipidemia under drug treatment, spinal cord injuries.

At screening visit patients underwent clinical examination, blood test (hormonal and metabolic profile) and filled out the IIEF-5 questionnaire and the SEP (SEP-2: «Were you able to insert your penis into your partner's vagina?» and SEP3 «Did your erection last long enough for you to have sexual intercourse?»). Patients who met inclusion criteria were randomized by a computer-generated list to receive either Tadalafil 5 mg once daily plus nutritional supplement once daily (group A) or Tadalafil 5 mg plus placebo with the same administration schedule (group B) for 3 months.

Blood samples, IIEF-5, SEP-2 and SEP-3 have been collected again after 3 months. All adverse events (AEs) occurred during the study period were recorded.

The study was carried out in accordance with the Declaration of Helsinki and GCP. All patients provided written informed consent. The protocol was approved by the ethical committee of Federico II University of Napoli.

Nutritional supplement composition The nutritional supplement used for the study resulted from a combination of Panax ginseng (500 mg), Moringa oleifera (200 mg) and rutin (50 mg). The three components were assembled in a three-layer tablet that allows different timing for the release of active ingredients.

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Human washed platelets Blood samples were collected from additional patients who met inclusion and exclusion criteria described above. These subjects received Tadalafil 5 mg/daily plus nutritional supplement 1 cpr/daily for one month.

The blood samples were collected before (baseline) and after treatment.

Human washed platelets were obtained by blood (20 ml) samples collected by venipuncture. Each sample was mixed with trisodium citrate (3.8% w/v 1:10 ratio) and then centrifuged at 150 x g for 10 min to obtain plateletrich plasma (PRP) as a supernatant. Washed platelets were prepared as previously described (18, 19). PRP was centrifuged at 800 × g for 12 min after the addition of 1/10 volume ACD solution (85 mM Na3-citrate, 11 mM d-glucose, 71 mM citric acid, pH 4.4). The pellet was resuspended in Ca+ 2/Mg+ 2-free HEPES-Tyrode buffer (134 mM NaCl, 12 mM NaHCO3, 2.9 mM KCl, 0.36 mM Na2HPO4, 5 mM HEPES, 5 mM glucose, 0.5% (w/v) bovine serum albumin, pH 7.4) and adjusted to 5 × 105 platelets/µl. The platelet number was determined by using a cell counter (AcT diff 2, Instrument Laboratory, Milan, Italy). cGMP measurement Human washed platelets (5 × 105 platelets/µl) were incubated at 37 °C with vehicle or diethylamine NONOate (DEA-NONOate, Alexis; Vinci Biochem, Vinci, Italy), a stable donor of NO at the concentration of 10 µM or 100 μM. The reaction was stopped after 30 minutes in liquid nitrogen. DEA-NONOate spontaneously dissociates in a pH-dependent, first-order process with a half-life of 2 min at 37 °C, pH 7.4, to liberate 1.5 mol of NO per mole of parent compound (20).

Platelet suspensions were hydrolyzed with HCl 3.3 M. The lysates were centrifuged (600 × g for 10 min) and cGMP measured in supernatants as described in the manufacture’s protocol of cGMP EIA Kit (Cayman, Vinci Biochem, Vinci, Italy) (18).

RESULTS

A total of 86 patients were enrolled in the trial. 45 patients in group A and 33 patients in group B completed the study. Mean age was 59.98 ± 6.90 (range 38-69), mean IIEF-5 score was 13.59 ± 3.90. Table 1 showed the baseline characteristics of the two groups. No differences were noticed between groups in terms of age, baseline erectile function, comorbidities, blood tests except for total cholesterol, significantly lower in group A, and liver function tests, significantly higher in group A. After three months of treatment, IIEF-5 score significantly improved in both groups compared to baseline (13.18 ± 3.75 vs 20.48 ± 2.24, p < 0,0001; 14.15 ± 4.09 vs 19.06 ± 4.36, p < 0.0001, in group A and group B respectively, Figure 1).

Patients treated with Tadalafil plus nutritional supplement showed a significantly higher increase in IIEF-5 score compared to those who received placebo (7.27 ± 2.20 and 4.9 ± 2.79, respectively; p < 0.0001; Figure 1).

A total of 28 patients (36%) completely restored their erectile function (IIEF-5 ≥ 22) and no differences were noticed between the two groups (15/45 in group A vs

A new original nutraceutical formulation ameliorates the effect of Tadalafil on clinical score and cGMP accumulation

Table 1.

Baseline characteristics of patients.

Patients. n MEAN AGE (range) IIEF-5 MEAN (range) SEP2 Yes No SEP3 Yes No Comorbidities Hypertension Yes No Diabetes Yes No Lab values Total testosterone FSH LH PRL Fasting blood glucose Total cholesterol LDL AST ALT GGT

Group A 45 59.93 ± 6.75 (38-69) 13.18 ± 3.75 (8-20) % (N) 80% (36) 20% (9)

Group B 33 60.06 ± 7.31 (43-69) 14.15 ± 4.09 (8-21) %(N) 66.7% (22) 33.3% (11)

P value

22.2% (10) 77.8% (35) % (N)

27.3% (9) 72.7% (24) % (N)

97.8% (44) 2.2% (1)

90.9% (30) 9.1% (3)

35.6% (16) 64.4% (29)

27.3% (24) 72.7% (9)

0.44

526.04 ± 128.49 6.48 ± 1.96 6.13 ± 2.72 11.43 ± 8.32 106.80 ± 29.60 186.26 ± 28.61 142.68 ± 29.69 33.35 ± 8.28 36.82 ± 9.17 47.31 ± 7.55

481.97 ± 139.11 6.16 ± 2.09 4.93 ± 2.72 12.11 ± 4.90 104.72 ± 27.00 201.60 ± 30.67 140.51 ± 25.76 27.06 ± 8.78 30.81 ± 9.22 38.03 ± 10.94

0.15 0.49 0.06 0.67 0.75 0.02 0.17 0.002 0.006 0.0001

0.93 0.28 0.18 0.60

0.17

Figure 1.

IIEF-5 score before and after three months of treatment with Tadalafil (5 mg/daily) plus nutritional supplement (1 cpr/daily), Group A, or Tadalafil (5 mg/daily) plus placebo, Group B. Both treatments significantly increased IIEF-5 score in each group compared to baseline (Group A: 13.18 ± 3.75 vs 20.48 ± 2.24, p < 0.0001; Group B: 14.15 ± 4.09 vs 19.06 ± 4.36, p < 0.0001).

The treatment with Tadalafil plus nutritional supplement (Group A) significantly increased IEEF-5 score compared to Tadalafil plus placebo (Group B) (p < 0.0001; +7.27 ± 2.2 and 4.9 ± 2.79, respectively).

Data expressed as mean ± s.d. were analyzed by one-way ANOVA followed by Bonferroni post-test.

Figure 2.

SEP-2 and SEP-3 answers before and after three months of treatment with Tadalafil (5 mg/daily) plus nutritional supplement (1 cpr/daily), Group A, or Tadalafil (5 mg/daily) plus placebo, Group B. Both treatments significantly increased SEP-2 and SEP-3 in each group compared to baseline.

Data were analyzed by one-way ANOVA followed by Bonferroni post-test.

There was no significant difference between group A and group B.

Table 2.

Hormonal levels before and after treatment.

Total testosterone FSH LH PRL

Group A (before) Group A (after) P value 526.04 ± 128.49 532.34 ± 115.73 0.82 6.48 ± 1.96 6.50 ± 1.77 0.96 6.13 ± 2.72 6.38 ± 2.62 0.68 11.43 ± 8.32 12.61 ± 4.71 0.46

Group B (before) Group B (after) P value 481.97 ± 139.11 485.57 ± 122.48 0.89 6.16 ± 2.09 6.19 ± 2.15 0.95 4.93 ± 2.72 5.01 ± 2.62 0.89 12.11 ± 4.90 12.39 ± 4.71 0.80

13/33 in group B, p = 0.58). Regarding SEP-2 and SEP-3 questions, the proportion of "yes" responses to SEP-2 and proportion of "yes" responses to SEP-3 significantly increased in both groups (p < 0.0001, Figure 2) with no differences between groups (p = 0.73 for SEP-2; p = 0.83 for SEP-3) (Figure 2).

Treatment did not affect hormonal plasma levels (Table 2). No differences were noticed in metabolic profile before and after treatment in both groups. Table 3 shows adverse events related to treatment. The rate of AEs is comparable between the two groups.

Ex vivo study The cGMP content was measured in platelets collected from 38 patients at baseline i.e. before treatment and after one month of treatment with Tadalafil 5 mg once daily plus nutritional supplement once daily.

The uneven number between before and after treatment is due to the patients that have not returned because of Covid-19 pandemic.

Following one month treatment with tadalfil plus nutritional supplement significantly (Panax ginseng, Moringa Archivio Italiano di Urologia e Andrologia 2021; 93, 2

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Table 3.

Adverse events.

Adverse event Headache Nasal congestion Back pain Dyspepsia Myalgia Cough Insomnia Flushing Dizziness Total of adverse events reported

Group A 6 1 3 0 1 0 1 6 2 20

Group B 4 3 1 1 1 1 0 5 2 18

P value

0.38

Figure 3.

Effect of Tadalafil (5 mg/daily) plus nutritional supplement (1 cpr/daily) on platelet cGMP of ED patients.

The levels of cGMP, expressed as pmoles/ml, were measured in 5×105/μl platelet following stimulation with vehicle (V) or diethylamine (DEA)-NONOate (10, and 100 μM).

The cGMP content was evaluated before (•) or after one month of treatment (o). cGMP accumulation after treatment was significantly higher in platelets stimulated with DEANONOate 100 µM compared to the same concentration of DEA-NONOate before the treatment (*p < 0.05).

Data expressed as mean ± s.e.m. were analyzed by one-way ANOVA followed by Bonferroni post-test.

oleifera and rutin) (p < 0.05) increased the cGMP content in platelets stimulated with DEA-NONOate 100 µM compared with the same concentration of DEANONOate before the treatment i.e. at baseline (Figure 3).

DISCUSSION

A variety of natural products, including isolated compounds from plants, have been tested for treatment of male sexual dysfunction (21). Although guidelines do not give any specific recommendation for their use, natural extracts are potentially useful in the management and treatment of male sexual dysfunction (16). Ginseng has been tested for its therapeutic properties, which include improving sexual function (22), physical performance (23), treating cancer (24), diabetes (25) and

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hypertension (26). Data available suggest that ginseng has some testosterone-like effects and it could contribute to smooth muscle relaxation of the corpus cavernosum via NO pathway (27).

Moringa oleifera has been long used in traditional medicine. Many studies have reported its antioxidant, hypoglycaemic, anti-dyslipidaemia activities, tissue-protective (liver, kidneys, heart, testes, and lungs), analgesic, antihypertensive and immunomodulatory actions (28-30).

Rutin is a flavonoid glycoside characterized by antioxidant, antidiabetic, anti-lipid peroxidation actions. In particular, data suggest that rutin has antioxidant activity and increases testosterone levels in diabetic condition in preclinical studies. Furthermore, it has been shown that in vitro rutin can inhibit PDE5 and arginase increasing the availability of NO and cGMP (31-33). This nutritional supplement formulation, containing a balanced content of Moringa oleifera, rutin and ginseng, has designed to act as an endothelial protector to be used as an adjuvant in the treatment of ED. The efficacy of the nutritional supplement has been tested in a clinical study by performing a combination therapy with a low dose of chronic Tadalafil regimen that has shown to improve the erectile function in vasculogenic patients. There were no significant differences between the groups in terms of baseline erectile function and presence of comorbidities.

The addition of a daily capsule of the nutritional supplement to Tadalafil 5 mg daily did not affect total testosterone, FSH, LH and PRL values. Although several animal and human studies suggested metabolic effects of Moringa oleifera and rutin, in our study,we did not found anti-dyslipidemic and hypoglycemic activity, probably because this was a chronic effects and 3 months could be a limited time to observe the effect. In addition, human studies showed that Moringa oleifera mainly determines a reduced post-prandial blood glucose levels and a long term reduction of HbA1C, rather than fasting blood glucose and we did not assess these parameters as it was not the purpose of our study (34). The clinic al evaluation indicates a statistically significant effect on sexual function. The IIEF-5 score increased in group A of 7.27 points vs 4.90 in group B with a significant difference of 2.37 points that represents a 20% increase over the placebo treatment. There was no significant difference in SEP2 and SEP3 values between Tadalafil plus nutritional supplement and Tadalafil plus placebo. Thus, the treatment with the formulation (Panax ginseng, Moringa oleifera and rutin) improves the IEEF-5 score. The second part of the study was performed to validate the data obtained by using the questionnaires. Indeed, as in this case, questionnaires are strongly biased by the placebo treatment.

We have previously shown that platelet cGMP represents a suitable and objective biomarker of PDE5-inhibitors efficacy in ED clinical studies.

This evidence relies on the fact that i) PDE5-inhibitors act by enhancing the NO/cGMP signaling ii) PDE5 is present in human platelets (35, 36) iii) treatment with PDE5inhibitors increases platelet cGMP levels (18, 37). In particular, we have demonstrated that, following chronic treatment with vardenafil 5 mg/daily of ED patients, the platelet cGMP levels were significantly increased and well correlated (significantly) with the VSS-Rigiscan measure-

A new original nutraceutical formulation ameliorates the effect of Tadalafil on clinical score and cGMP accumulation

ment (18). Thus, the measurement of platelet cGMP from blood samples of patients represents an unbiased marker of activity. The analysis of platelets harvested from patients treated with the nutritional supplement plus Tadalafil showed a significant increase in the cGMP levels when stimulated with DEA-NONOate 100 µM. This result suggests that the treatment with the nutritional supplement ameliorates and extends the activity of the chronic treatment with Tadalafil maintaining a significant more elevated levels of inhibition of PDE5. In this context, it is important to stress that there are several clinical pieces of evidence that PDE5-inhibitors effect can go beyond their half-life (18, 38). Indeed, clinical data reported that men still have facilitated erections when the levels of PDE5-inhibitors are below of the therapeutic plasmatic concentration (39-41).

13. Lewis RJ, Johnson RD, Blank CL. Quantitative determination of sildenafil (Viagra) and its metabolite (UK-103,320) in fluid and tissue specimens obtained from six aviation fatalities. J Anal Toxicol.

2006; 30:14-20.

CONCLUSIONS

17. Rosen RC, Riley A, Wagner G, et al. The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997; 49:822-30.

In conclusion, the significant increase of the IIEF-5 can be ascribed to the nutritional supplement properties.

Indeed, beyond the well-known antioxidant effects, Moringa oleifera, ginseng and rutin, it has been reported that can enhance the endothelial NO and cGMP production (41-43).

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Correspondence Vincenzo Mirone, MD Luigi Napolitano, MD (Corresponding Author) nluigi89@libero.it Roberto La Rocca, MD robertolarocca87@gmail.com Giuseppe Celentano, MD Department of Neurosciences, Sciences of Reproduction, and Odontostomatology, University of Naples Federico II Via Sergio Pansini 5, 80131 Naples (Italy) Roberta D’Emmanuele di Villa Bianca, MD Emma Mitidieri, MD Raffaella Sorrentino, MD Domenico Vanacore, MD Carlotta Turnaturi, MD Giuseppe Cirino, MD Department of Pharmacy, School of Medicine and Surgery, University of Naples, Federico II, Via D. Montesano, 49, 80131 Naples (Italy) Arianna Vanelli, MD Responsabile Ricerca e Sviluppo Nutrilinea SRL, Varese (Italy) Davide Arcaniolo, MD Urology Unit, Department of Woman Child and of General and Specialist Surgery, University of Campania "Luigi Vanvitelli", 80131 Naples (Italy)

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DOI: 10.4081/aiua.2021.2.227

ORIGINAL PAPER

Contribution of pre-varicocelectomy color Doppler ultrasonography finding to surgery and its correlation with semen parameters Caner Ediz 1, Muhammed Cihan Temel 1, Suna Şahin Ediz 2, Serkan Akan 1, Serkan Yenigürbüz 1, Mehmet Pehlivanoğlu 1, Ömer Yılmaz 1 1 Department 2 Department

of Urology, Sultan Abdulhamid Han Education and Research Hospital, Istanbul, Turkey; of Radiology, Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkey.

Summary

Background: This study aimed to determine the contribution of color Doppler ultrasonography (CDUS) performed before varicocelectomy to the success of surgical treatment and to evaluate the correlation between CDUS findings and semen parameters.

Methods: A total of 84 patients diagnosed with grade 3 left varicocele in our clinic between 2016 and 2018 were evaluated.

The patients in whom the decision for varicocelectomy was based on only physical examination (PE) findings and abnormal semen analysis (SA) were defined as Group 1, while the patients undergoing varicocelectomy based on PE, CDUS and SA findings were defined as Group 2. The patients diagnosed with varicocele based on PE and CDUS findings who were included in a followup protocol due to normal semen parameters were defined as Group 3.

Results: In Group 1, there was a total of 28 patients and the mean number of ligated internal spermatic veins was 4.53 (range, 2-10). In Group 2, there was a total of 30 patients and the number of ligated internal spermatic veins was 3.76 (range, 1-8). No statistically significant difference was found between Group 1 and 2 in terms of the number of internal spermatic veins ligated during varicocelectomy. No statistically significant correlation was found between semen parameters and the number of veins ligated during varicocelectomy in Group 1 and 2 and between semen parameters and CDUS findings group 2 and 3.

Conclusions: In patients with primary grade 3 varicocele, diagnosed by physical examination there is no need for additional imaging in primary cases.

KEY WORDS: Varicocele; Varicocelectomy; Color Doppler ultrasonography; Semen parameters; Number of vein ligated.

Submitted 25 December 2020; Accepted 3 February 2021

INTRODUCTION

Varicocele is defined as the dilatation of the veins of the pampiniform plexus. Diagnostic methods, including physical examination, Doppler stethoscope examination, thermography, color Doppler ultrasonography (CDUS), scintigraphy, and venography are used for the diagnosis of varicocele, although the current view is that physical examination is sufficient and additional imaging methods are not always required for the diagnosis of varicocele.

After the physical exam, varicocele can be confirmed by CDUS (1) and CDUS may be required in the presence of factors interfering with physical examination.

The aim of the current treatment is the ligation of internal and external spermatic vein branches while preserving all arterial structures, lymphatics and the vas deferens. In general, varicocelectomy is performed in patients with poor semen quality, providing improvement in semen parameters in 50-80% of the patients and, in addition, varicocele repair may result in improvements in natural pregnancy rates (2-6). There are studies on the optimal number of veins to be ligated, which varies upon the varicocelectomy technique, while there are not many studies on the parameters effectively predicting this number and on the correlation of surgical success with the number of ligated spermatic veins.

In our study, we aimed to evaluate the correlation of pre-varicocelectomy physical examination findings and of CDUS measurement results with the number of internal/external spermatic veins ligated during surgery and to analyze whether CDUS findings correlate with semen parameters.

MATERIALS

AND METHODS

Patient population A total of 84 patients diagnosed with grade 3 left varicocele in our clinic between November 15, 2016 and November 15, 2018 were evaluated. Patients over 18 years of age who had infertility or abnormal semen parameters or scrotal pain (resistant to medical treatment) with grade 3 left varicocele (visible and palpable spermatic veins without Valsalva maneuver at rest) were included in the study. Patients who were found to have missing data during data recording, evaluation or analysis, recurrent cases with a history of varicocelectomy, patients with endovascular treatment history for varicose veins and patients under 18 years were excluded from the study.

Study sesign The study was designed as a retrospective study. No patients underwent any additional tests or assessments

No conflict of interest declared.

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other than the evaluations performed for the diagnosis of varicocele in routine urologic practice (physical examination, semen analysis and, if required, CDUS). All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All participating patients gave written informed consent.

In all patients, presence and localization of scrotal pain, presence of scrotal swelling, presence of infertility, varicocele grade, semen parameters (total sperm volume, total sperm count, sperm count per milliliter, ratio of forward moving sperms/motile sperms without progressive movement/immotile sperms, ratio of sperms with normal morphology, mean sperm velocity, ejaculate pH, presence of pyospermia) and the number of internal/external spermatic veins ligated during varicocelectomy were recorded. Additionally, in accordance with the guideline recommendation, the width of the pampiniform venous plexus was evaluated with CDUS and the diameter of the varicose spermatic vein measured during the Valsalva maneuver was recorded in required patients. All semen analysis results were evaluated using the reference values defined by World Health Organization (WHO) in 2010.

The time interval of two semen analysis for each patient was 15 days. The average of two semen analyzes for each patient was taken.

SonoScape S40 CDUS system (Australia) was used in all patients undergoing CDUS. A 7.5 Mhz-linear probe was used during measurements. First, the testicular structure was examined using grayscale ultrasonography during normal respiration by elevating the chest and head region by 15° while the patients were in supine position.

Testicular volume was measured by using the “prolate ellipse” formula (W x H x D x 0.52). Plexus pampiniformis veins were evaluated by identifying the most dilated vein and then measuring the increase in its diameter during the Valsalva maneuver.

The presence of reflux was assessed using the color mode during normal respiration and the Valsalva maneuver.

The patients in whom the decision for varicocelectomy was based on only physical examination (PE) findings and semen analysis (SA) were defined as Group 1, while the patients undergoing varicocelectomy based on PE, CDUS and SA findings were defined as Group 2.

The patients diagnosed with varicocele based on PE and CDUS findings who were included in the follow-up protocol due to normal semen parameters were defined as Group 3. Thus, it was planned to compare the contribution of CDUS to varicocelectomy (between Group 1 and 2) and its correlation in patients with normal or abnormal semen parameters (between Group 2 and 3). There were 28, 30 and 26 patients in Group 1, 2, and 3, respectively.

The patients in Group 1 and 2 underwent left subinguinal varicocelectomy (the routine procedure in our clinic) for the diagnosis of grade 3 left varicocele. The patients undergoing varicocelectomy had at least two sperm parameter lower than the SA reference values defined by WHO or infertility. Varicocelectomy was not performed in patients with only scrotal pain and normal SA results. Subinguinal varicocelectomy was performed

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under spinal or general anesthesia. The testis was not routinely delivered from the scrotum and the visible external spermatic vein(s) and internal spermatic veins were ligated by preserving testicular arterial and lymphatic vessels.

The patients in Group 3 were enrolled into follow-up to control the changes in semen parameters at 6-month intervals.

Study aim The study had two primary objectives. Firstly, we aimed to evaluate the adequacy of physical examination by investigating whether there was a statistically significant difference between Group 1 and 2 in terms of the number of internal and external spermatic veins ligated during varicocelectomy and to assess the contribution of radiological imaging to the determination of the optimal number of spermatic veins to be ligated. In addition, we analyzed whether each of the recorded parameters of the patients were in correlation with the number of ligated external and internal spermatic veins. The second aim was to investigate the presence of a correlation between the maximum spermatic vein diameter measured using CDUS during the Valsalva maneuver and semen parameters in Group 2 and 3 patients. We thereby aimed to evaluate the correlation between semen parameters and additional radiological imaging findings in patients with Grade 3 varicocele.

Statistical analysis Statistical analyses were performed using SPSS Statistics 22.0 software (SPSS Inc., Chicago, IL, USA). The normality hypothesis was tested using the Kolmogorov-Smirnov test during data analysis. Descriptive statistics for continuous variables were presented as median and minimum-maximum values. The independent-samples t-test and Mann-Whitney U-test were used to analyze data not conforming to a normal distribution. Pearson and Spearman tests were used for correlation analyses.

Statistical significance was defined as p < 0.05.

RESULTS

The median ages of the patients were 27.5 years (range, 22-39 years) in Group 1, 24.5 years (range, 19-39 years) in Group 2 and 26 years (range, 18-35 years) in Group 3. Regarding primary presenting complaints, testicular pain and scrotal swelling were present in 39.28% (11/28) and 39.28% (11/28) of the patients in Group 1, respectively; in 53.33% (16/30) and 30% (9/30) of the patients in Group 2, respectively; and in 69.23% (18/26) and 30.77% (8/26) of the patients in Group 3, respectively. Infertility was the presenting complaint in 25% (7/28) and 16.66% (5/30) of the patients in Group 1 and 2, respectively.

In Group 1, there was a total of 28 patients and the total number of ligated internal spermatic veins was 127. The median number of ligated internal spermatic veins was 4 (range, 2-10) in Group 1. In Group 2, there were a total of 30 patients and the total number of ligated internal spermatic veins was 113. The median number of ligated internal spermatic veins was 4 (range, 1-8) in Group 2.

Varicocele and color Doppler ultrasonography

Table 1.

No statistically significant difference was found between Group 1 and 2 in the number of internal and external spermatic veins ligated during varicocelectomy (p > 0.05).

Internal spermatic vein External spermatic vein

Group 1 (n = 28) Median (min-max) 4 (2-10) 0 (0-2)

Group 2 (n = 30) Median (min-max) 4 (1-8) 0 (0-2)

p value 0.114 0.845

No statistically significant difference was found between Group 1 and 2 in the number of internal spermatic veins ligated during varicocelectomy (p = 0.114) (Table 1).

The total number of ligated external veins was 17 and the median number was 0 (range, 0-2) in Group 1. A total of 16 external spermatic veins were ligated and the median number of ligated external spermatic veins was 0 (range, 0-2) in Group 2. No statistically significant difference was found between Group 1 and 2 in terms of the number of external spermatic veins ligated during varicocelectomy (p = 0.845) (Table 1).

A statistically significant positive correlation was found between the number of internal spermatic veins and the number of external spermatic veins ligated during varicocelectomy in Group 1 and 2 (p = 0.023 and p = 0.049).

However, a correlation analysis between the numbers of ligated internal and external spermatic veins and semen parameters found no statistically significant correlation in either groups (p > 0.05) (p and r values) (Table 2).

In Group 2, a correlation analysis was conducted to examine the correlation of the maximum spermatic vein diameter measured by CDUS during the Valsalva maneu-

ver with semen parameters and the number of ligated external and internal spermatic veins. In conclusion, the maximum spermatic vein diameter measured during the Valsalva maneuver was not significantly correlated with any of the semen parameters or the numbers of ligated external and internal spermatic veins (p > 0.05) (p and r values) (Table 3).

In Group 3, there was also no statistically significant correlation between semen parameters and the maximum spermatic vein diameter measured during the Valsalva maneuver (p > 0.05).

DISCUSSION

Varicocele is the most common correctable cause of male infertility (7). Approximately 19-41% of the patients presenting with primary infertility are diagnosed with varicocele (8, 9), while this rate ranges from 45% to 81% in patients presenting with secondary infertility (9). The most likely cause of impaired spermatogenesis is testicular hyperthermia associated with varicocele, while increased reactive oxygen products and apoptosis are closely related to the pathophysiology of varicocele (7).

Varicocele is usually asymptomatic but testicular pain may be the first presenting symptom in 10% of the patients. It is usually unilateral. Surgical treatment is extremely successful and relieves pain in 90% of the patients in cases where chronic testicular pain etiologically determined to be caused by varicocele is not relieved by conservative treatment (10). CDUS may have a role in the possible differential diagnoses particularly in cases of unexplained scrotal pain. Raghavendran et al.

(11) reported that severe testicular pain in a patient diag-

Table 2.

Correlation Analysis between semen parameter results and the numbers of ligated internal and external spermatic veins in Group 1 and 2. No positive correlation was found between any of the parameters evaluated in semen analysis and the number of ligated veins (p > 0.05).

Semen analysis results

Semen volume (ml) Sperm count (106/ml) Total sperm count (x106) Forward moving (%) Motile without progressive movement (%) Immotile (%) Morphology (%)

Group 1 (n = 28) Median (min-max) 2.3 (1-5) 27.45 (0-127) 75 (0-345) 23 (0-75.4) 17.81 (0-62.3) 49.5 (0-78) 8 (0-34)

Group 2 (n = 30) Median (min-max) 3 (1-5) 13.2 (0-89.6) 46 (0-224) 23 (0-60) 21.1 (0-39) 50 (0-95) 4 (0-20)

P-values for the correlation analysis between semen analysis and the number of ligated internal and external spermatic veins in Group 1 and 2 Group 1 Group 1 Group 2 Group 2 Internal spermatic vein External spermatic vein Internal spermatic vein External spermatic vein 0.59 0.08 0.25 0.54 0.28 0.42 0.98 0.32 0.46 0.42 0.78 0.24 0.23 0.78 0.85 0.31 0.74 0.42 0.16 0.66 0.75 0.5 0.98 0.34 0.45 0.181 0.57 0.21

Table 3.

Correlation analysis between semen parameters and spermatic vein diameters measured by CDUS in Group 2 and 3. No positive correlation was found between any of the parameters evaluated in semen analysis and spermatic vein diameter (p > 0.05).

Group 2 (n = 30) Group 3 (n = 26)

Spermatic vein diameter measured by CDUS Median (mm) (min-max) 3.8 (2.8-7) 2.9 (2.3-4)

P-values for the correlation analysis between semen analysis results and spermatic vein diameters measured by CDUS in Group 2 and 3 Semen volume Sperm count Total Forward Motile without Immotile Morphology sperm count moving progressive movement 0.99 0.96 0.78 0.57 0.055 0.98 0.37 0.54 0.56 0.85 0.9 0.4 0.68 0.9

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nosed with varicocele was due to a thrombus in a varicose vein. Presenting complaints may include prominence of testicular vessels and feeling of unilateral scrotal swelling in addition to testicular pain. The dilatation of spermatic veins causes an increase in the temperature in the testicles and scrotum. This increase in temperature may cause a progressive dysfunction in the testicles and epididymis, leading to infertility (12, 13). In our clinical practice, patients with the diagnosis of varicocele without any pathology in semen parameters are offered conservative treatments (use of analgesics or palliative treatment recommendations for pain relief) and follow up at 3-6-month intervals. We perform surgery in cases without relief of testicular pain with conservative treatment.

The diagnosis of varicocele is based on physical examination without any need for additional tests. In a study

by WHO, it was demonstrated that 70% of patients were diagnosed with varicocele using venography, while in the same patients this rate was 30-40% with physical examination and physical examination had a false positive rate of 23%. However, the sensitivity and specificity of physical examination in the diagnosis of varicocele were reported to be 71% and 69%, respectively (14-16).

We aimed to eliminate this false negativity effect by including patients with Grade 3 varicocele in our study group. Urology guidelines try to minimize this margin of error by recommending the confirmation by CDUS of the diagnosis of varicocele made by physical examination.

The benefit of additional diagnostic imaging methods usually does not go beyond supporting the diagnosis, while these methods are still used in the clinical practice of urologists. Unfortunately, the contribution of these methods in the evaluation of testicular volume and determination of venous reflux in adult patients is not substantial as in pediatric patients (17). Moreover, it contributes to the determination of surgical technique in adolescent varicocelectomy but not in adult varicocelectomy (18). We use CDUS in our practice particularly in patients with pathologies interfering with varicocele evaluation (e.g., scrotal edema, cellulitis or prior scrotal surgery), patients with recurrent varicocele and morbid obese patients. However, additional imaging methods revealed no additional result other than supporting the diagnosis and/or establishing differential diagnosis. It should be kept in mind that CDUS used in the diagnosis of varicocele is affected by many factors. Poor quality of the measuring device causes false-negative diagnoses and excessive mobility of the spermatic cord vessels leads to false-positive diagnoses (19). The employed technique is another influential factor. Measurements taken in the standing position are diagnostically more successful compared to the measurements taken in the lying or backward-leaning position (20). The caput of the epididymis is the most suitable region for optimal success of ultrasonographic measurements in varicocele evaluation (21). In analyses evaluating the success of ultrasonography, the sensitivity and specificity of color Doppler ultrasonography in the diagnosis of varicocele were 97% and 94%, respectively (22). Color Doppler examination has a higher sensitivity and specificity and a lower cost compared to thermography and angiography and is a non-

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invasive evaluation method and the procedure of choice in the diagnosis of venous reflux in varicocele (23).

Physical examination remains the most valuable method (24, 25), in fact our study found no statistically significant difference between the patients who were diagnosed via physical examination and the patients whose diagnoses were supported by CDUS in terms of the numbers of internal and external spermatic veins ligated during varicocelectomy and we concluded that additional imaging had no additional predictive value compared to physical examination in the determination of the number of spermatic veins to be ligated during varicocelectomy in patients with Grade 3 varicocele. We therefore do not think that CDUS should be used as a routine method. In contrast to the failure in predicting the number of vessels ligated during varicocelectomy, there are studies in the literature reporting that there is a correlation between CDUS findings and semen parameters and/or infertility.

Mahdavi et al. reported that semen volume, sperm count and sperm motility and morphology correlated with CDUS findings in patients with varicocele (26). In our study, the maximum spermatic vein diameter measured during the Valsalva maneuver by CDUS was not significantly correlated with any of the sperm parameters or the numbers of ligated external and internal spermatic veins in Group 2. Based on the results of our study, CDUS performed in addition to physical examination for the diagnosis of varicocele has no contribution to the interpretation of sperm parameters or to the prediction of the number of spermatic veins that should be ligated during the operation.

Retroperitoneal, laparoscopic, inguinal and subinguinal methods have been described for the treatment of varicocele. In recent years, studies showed that robot-assisted microscopic varicocelectomy is as successful as the conventional methods (27). However, microscopic subinguinal varicocelectomy is the golden standard for the treatment of varicocele (28, 29). This method includes the treatment of venous system by preserving testicular arterial and lymphatic vessels. In conventional varicocelectomy performed without using a microscope or optic magnifier, the most important cause of recurrence after the treatment of varicocele is the inability to ligate the small internal spermatic vein branches due to their invisibility to the naked eye (30). In the literature, it is reported that intraoperative indocyanine green administration is one of the ways of increasing the success of this technique and minimizing testicular artery injuries (29). Another method is the use of intraoperative microvascular Doppler ultrasonography (10). In a study evaluating 65 patients undergoing microsurgical subinguinal varicocelectomy at variance analysis, only the number of ligated veins 4 mm or more in diameter was higher in grade 3 varicoceles than in grade 1 and 2 varicoceles and the increase in varicocele grade was not related to the total number of ligated veins (31). In a new study, Babai et al. was reported that the presence of testicular reflux has no effect on semen analysis parameters, but also does not predict the consequences of varicocelectomy and therefore is not a suitable prognosis factor in varicocele patients (32). Also in our study, there was no statistically significant correlation between varicocele grade on physical examination or CDUS find-

Varicocele and color Doppler ultrasonography

ings (diameter of the vein or presence of reflux) and the total number of ligated spermatic veins. Outcomes of this study are different from those of previous studies of Belani et al. (31) and Mahdavi et al. (26), but similar to the results of Babai et al. (32).

Based on statistical results, we have not found any radiological data that predict sperm parameters or the number of internal and external spermatic veins ligated during varicocelectomy. Therefore, it was demonstrated that inclusion of CDUS in the preoperative evaluation in patients with Grade 3 varicocele has no effect on surgical decision making or the number of ligated spermatic veins which determines the surgical success index.

The present study has several limitations. Our study is limited by the small number of patients due to a singlecenter trial. In our operations, we do not use microscopic magnification routinely during surgery and not all the patients were operated on by a single surgeon experienced in the field of andrology. The last limitation of our study was its retrospective evaluation limited to findings of patients with Grade 3 varicocele. Doppler ultrasound could be useful when varicocele is not visible or palpable.

For these reasons, we believe that larger case series will be more effective in the interpretation of our study findings.

CONCLUSIONS

The best diagnostic method for grade 3 varicocele is physical examination and there is no need for additional imaging in primary cases. It is obvious that every imaging study will have an additional cost and will cause time and labor loss. Imaging studies do not contribute to surgical decision making or the prediction of surgical success.

However, it should be kept in mind that physical examination is not sufficient in all cases, yet it can provide useful information particularly for the evaluation of secondary/tertiary varicocele cases and for the diagnosis of additional testicular pathologies. Despite of this, semen parameters considered in surgical decision making in patients with grade 3 varicocele do not correlate with physical examination and imaging findings, suggesting that there are more parameters that should be examined for the diagnosis and treatment of grade 3 varicocele.

ACKNOWLEDGMENTS

The authors would like to thank the entire staff of the Departments of Urology and Radiology, Sultan Abdulhamid Han Education and Research Hospital.

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Correspondence Caner Ediz, Assoc. Prof. (Corresponding Author) drcanerediz@gmail.com Muhammed Temel Cihan, MD Serkan Akan, MD Serkan Yenigürbüz, MD Mehmet Pehlivanoğlu, MD Ömer Yılmaz, MD Department of Urology, Sultan Abdulhamid Han Education and Research Hospital Tibbiye Street. Selimiye neighborhood, 34668 Uskudar/Istanbul (Turkey) Suna S¸ahin Ediz, MD Department of Radiology, Kartal Dr. Lutfi Kirdar City Hospital, Istanbul (Turkey)

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DOI: 10.4081/aiua.2021.2.233

ORIGINAL PAPER

Feasibility of local anaesthesia for varicocele correction in one-day-surgery setting. A single center experience Giovannni Saredi 1, Fabrizio I. Scroppo 1, Paolo Capogrosso 1, Giacomo Maria Pirola 2, Lorenzo Capone 2, Andrea Pacchetti 3, Giuseppe Gianesini 1, Paolo Maggio 1, Giulio Carcano 4, 5, Federico Dehò 1, 4 1 Department

of Urology and Andrology; Circolo and Fondazione Macchi Hospital,Varese Italy; of Urology, USL Toscana Sud Est, San Donato Hospital, Arezzo, Italy; 3 Department of Urology, San Martino Hospital, University of Genova, Italy; 4 University of Insubria, Varese, Italy; 5 Department of Surgery; Circolo and Fondazione Macchi Hospital,Varese Italy.

2 Department

Summary

Objective: In this study, we compared postoperative outcomes of patients submitted to varicocele correction under general or local anesthesia at a single center.

Methods: All patients underwent varicocele surgical treatment with the Colpi-modified Marmar subinguinal technique.

They were managed with either general (Group A) or local with ileo-inguinal and ileo-hypogastric nerves block (Group B) anesthesia. The two groups were compared in terms of timing of discharge and post-operative pain as assessed with the numeric rating scale (NRS) at both rest and movement (NRSm).

Results: Overall, 63 patients were included with a mean (SD) age of 25 years ± 5 yrs. The NRS mean score was significantly lower for Group B during the first 4 days after surgery at both rest and movement (all p < 0.05). Patients receiving local anesthesia showed a faster time to first urination (210 vs. 240 min; p = 0.02), although the time to discharge was comparable between the two groups (250 vs. 250 min).

Conclusions: These results suggest that local anetshesia for varicocele surgical treatment is feasible and provide better pain control and faster recovery after surgery.

KEY WORDS: Varicocele; Local anesthesia; Infertility; Recovery.

Submitted 2 July 2020; Accepted 15 October 2020

INTRODUCTION

Varicocele is defined as dilated and tortuous veins within the pampiniform plexus of the testis (1, 2). It is one of the main cause of male infertility and is commonly associated with semen impairment. The prevalence of varicocele is approximately 15-20% in the general population, 19%-41% in men with primary infertility, and 45%-81% in men with secondary infertility (3).

The pathophysiology of varicocele-associated infertility involves different factors including blood stasis, accumulation of reactive oxygen species at the level of the testis, increased scrotal temperature and reduction of intratesticular testosterone levels (4, 5).

Surgical treatment of varicocele includes percutaneous embolization or surgical correction with different techniques including open retroperitoneal high ligation, laparoscopic ligation or subinguinal microsurgical technique (6). Large-scale comparative studies evaluating the

outcomes of various varicocele treatment options are currently lacking, and confounding factors such as the experience of the operators, the age of the patients and the severity of varicocele have a significant impact on skewing the post-treatment results (7, 8). Among all treatment options, the subinguinal approach combined with anterograde intraoperative sclerosis of venous vessels (Marmar technique modified by Colpi) represents a valid surgical treatment of varicocele (9): this approach exploits the advantages of both the Marmar (10) and the Tauber (11) technique without the need for microscope or fluoroscope, making the operation more simple and less expensive.

Surgical correction of varicocele is usually performed as a one-day surgery due to the low risk of peri-operative morbidity. In this context, the ability to resume normal activities soon after surgery is an important indicator of a successful perioperative experience and may be largely associated with the type of performed anesthesia and with peri-operative pain management (12).

To the best of our knowledge, studies investigating the best type of anesthesia to be performed in patients undergoing varicocele correction are currently lacking.

The purpose of this prospective observational study was to evaluate the difference in the timing of discharge and pain control among patients undergoing surgical correction of varicocele with either local or general anesthesia at a single academic center.

MATERIAL

AND METHODS

This is a prospective, observational investigation trial.

The study protocol was approved by the Local Ethics committee of the Institution “Ospedale di Circolo e Fondazione Macchi”, Varese, Italy. Afterward, the study protocol was registered on Clinical Trials.gov (ID Number NCT02401087). Inclusion criteria were: male subjects over the age of 18; with ASA I-II scores; with a clinically significant varicocele scheduled for surgical correction.

Patients with cognitive impairment or mental retardation; habitual use of opioid analgesics; alterations in the normal values of coagulation or coagulopathies; use of non-steroidal anti-inflammatory drugs in the 5 days pre-

No conflict of interest declared.

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ceding the intervention; severe liver or kidney failure; lack of informed consent, were excluded.

After obtaining the Informed Consent, 63 patients with fulfilling the inclusion criteria were recruited in a period between June 2017 and July 2018.

Patients were divided into two groups: patients included in "Group A" underwent general anesthesia (32 patients) and patients included in "Group B" underwent local blockage of the ileoinguinal-ileohypogastric nerve (31 patients). The type of anesthesiological protocol was based on the preference of the anesthesiologist.

All patients received light sedation with Midazolam 0.03 mg/kg i.v. before entering the operating room. Moreover, they received a fluid load of 10 ml/Kg/h during the surgical procedure and another 5-8 ml/Kg in the postoperative period.

The technique is performed with a 2-3 cm subinguinal incision at the level of the superficial inguinal ring. After exposition of the spermatic cord, a vein in the spermatic cord outside the peri-arterial venous plexus is identified and isolated. The proximal and distal parts of the spermatic cord are clamped and the identified vein is cannulated using a 25 G butterfly needle. Afterwards, 1.5-3 ml of 3% atoxysclerol plus 0.5 ml of air is injected; a migration of the sclerosing agent into all visible veins of the spermatic plexus is observed as the movement of the air bubbles. The cannulated vein is then ligated to avoid sclerosing agent leakage. The clamping is released about 8 minutes after the injection. The spermatic and superficial layers are then sutured. Skin is closed in a resorbable subcuticular fashion. An ice pack on the wound is always left in situ.

Anesthesiological protocol Group A: At the discretion of the anesthesiologist in the operating room, the maintenance of general anesthesia was either with the use of a halogenated agent (Sevoflurane) or in TIVA (Propofol + Remifentanil). For induction, Fentanyl was used as opioid (for general anesthesia conducted with Sevoflurane) and Fentanyl or Remifentanil for anesthesia conducted in TIVA. Ventilation was achieved with laryngeal mask. All patients received Paracetamol 1 g i.v. as intraoperative analgesia; if the patient complained about pain upon awakening, Ketorolac 30 mg i.v. was administered.

Ondansetron 4 mg i.v. was given as an antiemetic before waking up. In addition to the amount of opioid used, the need for additional antiemetics was also reported.

Group B: After identification by ultrasound of the ileoinguinal and ileo-hypogastric nerves, by means of a plane technique, the aforementioned nerves were blocked with 0.5% Chirocaine 20 ml. Afterward, each patient recieved a subcutaneous skin infiltration with 2% Carbocaine 10 ml and an endovenous administration with Paracetamol 1 g and Ketorolac 30 mg as rescue therapy.

Patients of both groups were discharged at home with the following analgesic therapy: Tramadol 37.5 mg + Paracetamol 325 mg 1 tablet per day for 3 days. If the patient complains about pain stronger than or equal to 4 point of the numeric rating scale (NRS; Figure 1), Ketorolac 1 tablet (maximum 2 times a day) was administered as a rescue dose.

Follow-up All participants were evaluated before surgery, in the first 3 post-operative hours, at 4 days, 1 month and 3 months after the intervention.

The following clinical parameters were considered: time elapsed between the induction of anesthesia and the first urination; time elapsed between the induction of anesthesia and the first walking; pain NRS, pain NRS on movement (NRSm), and any occurred complications. Patients filled a self-assessment diary to update about pain at rest and in movement twice a day for the first 3 post-operative days and once on the 4th post-operative day.

If a patient still complained of NRS pain ≥ 4, a further outpatient re-evaluation was carried out.

Surgical technique The surgical technique used in this study was the Colpimodified Marmar subinguinal varicocelectomy combined with antegrade intraoperative sclerotherapy of venous vessels (9).

Statistical analysis The main outcomes of this study was to compare the two groups in terms of the time from surgery to discharge and reported post-operative pain according to the NRS. Differences between the two groups were tested with the Student t-Test for data with normal distribution, while the Mann-Whitney test was applied for non-normal distributed data. All measured parameters are reported as mean ± standard deviation (SD). All analyses were performed with the Med-Calc software - version 12.2.1.

RESULTS

Overall, patients had a mean age of 25 years ± 5 and a mean body mass index (BMI) of 21 kg/m2 ± 2. The mean length of surgery was 38 min ± 12 (Table 1).

The mean time elapsed between the induction of anesthesia and the first urination was 240 min in group A and 210 min in group B (p = 0.02); the time elapsed until the first walking was 230 min in group A and 220 min in group B (p = 0.6). Only 5 patients were able to stand up and walk before 120 minutes in Group B vs. no one in Group A.

Figure 1.

The Numeric Rating Scale for post-operative pain reporting.

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Local vs general anesthesia for varicocele treatment

Table 1.

Baseline characteristics of both groups.

Age (years) BMI (kg/m2) Duration (min) ASA I

Group a (n = 32) 25 ± 4 22 ± 2 38 ± 14 25

Group b (n = 31) 25 ± 6 21 ± 2 39 ± 11 29

p-value 1 0.051 0.7 0.2

ASA = American Society of Anesthesiologists; BMI = body mass index.

Table 2.

Reported pain score over the first 4 post-operative days.

3 hrs post-surgery I day 8 am I day 8 pm II day 8 am II day 8 pm III day 8 am III day 8 pm IV day

NRS Group A 1 7 6 4 4 2 2 0

NRS Group B 1 3 3 2 2 0 0 0

NRSm Group A 1 12 9 9 7 4 4 2

NRSm Group B 0 8 7 5 3 2 2 1

p-value 0.1 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05

NRS = Numeric Rating Scale.

The time elapsed between the induction of anesthesia and the patient discharge was 260 min in group A and 250 min in group B (p = 0.1).

We then assessed the severity of pain in the first 3 postoperative hours at rest and after mobilization with the NRS: both groups reported a score of 1 at rest, while an NRS score of 1 at movement was reported only for the group A (NRSm) (Table 2).

The NRS scores during the first 4 days after surgery are reported in Table 2. Mean score for Group B were significantly lower at all time-points. None of the patients required rescue therapy and none experienced complications related to the prescribed therapy.

No early or late surgical complications or treatment failures were reported.

DISCUSSION

Varicocele is highly prevalent in the young male population and frequently associated with male infertility due to semen impairment. (13) For these reason, surgical correction is often required to improve the chance of conception.

As there are various approaches for surgical correction, it is evident from current literature that each technique has its strengths and limitations.

The Marmar technique modified by Colpi is a hybrid between two different surgical approaches: it provides a subinguinal access to the spermatic cord, as in the varicocelectomy according to Marmar; on the other hand, it implies the embolization of the spermatic plexus vessels through the antegrade injection of a sclerosing agent, as per Tauber technique. The original depiction of the technique is performed under general anesthesia and there are no specific trials evaluating the feasibility of a local anesthesia approach (9, 10, 14).

This local ansesthesia approach could have numerous

advantages in an outpatient surgery setting: it does not require tracheal intubation, it allows the reduction of postoperative pain and leads to a reduction in costs, given the smaller number of drugs and assistance required. Finally, postoperative drowsiness is rare after local as compared to general anesthesia, and therefore the patient is usually more oriented and relaxed (15).

When comparing the times from surgery to discharge, we did not find any significative difference between the two groups. Therefore, our data suggest the non-inferiority of a local approach compared to a general anesthesia approach for this surgery.

Regarding the pain evaluation in the first 3 post-operative hours, we noticed significantly lower NRS score for patients receiving local anesthesia. This result is correlated to the average duration of Chirocaine for nerve blocks (analgesic coverage up to 17 hours), thanks to which patients enjoy excellent analgesia with no need of additional drugs. Similarly, lower pain was reported during the first 4 postoperative days with local anesthesia as compared to general.

Our results are in line with the literature. Nordin et al., in 2003, evaluated acceptance, satisfaction, and quality of life in patients performing hernia repair, respectively under genenal, regional and local anestehsia. The authors found that, patients in the local anesthesia group first felt pain significantly later than patients in the other two groups and they also required less analgesics during the first postoperative day (16). In 2012, Kadihasanoglu et al. presented a prospective randomized trial evaluating the feasibility of local anesthesia for varicocelectomy in place of spinal anesthesia. Sixty men with varicocele were included in the study, and the evaluation of pain during and after surgery was determined using the visual analogue scale. Pain scores between the 2 groups did not differ significantly at 2, 4, 6, 8, 12, or 24 hours after surgery.

A positive correlation was found between the duration of symptoms and the visual analogue scale score at 24 hours postoperatively. The mean dosage of injected diclofenac was 46.5 ± 23.3 mg and 32 ± 28.15 mg in the spinal and local anesthesia groups, respectively. The spinal group developed more postoperative complications, such as urinary retention, postspinal backache, headache, hypotension, and delayed mobilization. In line with our findings they concluded that local anesthesia is an effective, simple, and safe approach for subinguinal varicocelectomy with lower morbidity and fast recovery (17). Likewise, Manaf et al. compared local and general anesthesia in patients who had undergone different andrological procedures including varicocelectomy.

They concluded that office-based andrological procedures using local approach could be successfully performed without compromising surgical technique and post-operative outcomes while significantly reducing the overall costs for both the patient and the healthcare system (18).

The main limitation of this study is the relatively small number of included patients , although we were able to detect a statistically significant difference between groups. Moreover, patients were non-randomized to different treatments thus introducing a potential selection bias. Further trials are needed to confirm our findings.

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CONCLUSIONS

9. Colpi GM, Carmignani L, Nerva F, et al. Surgical treatment of varicocele by a subinguinal approach combined with antegrade intraoperative sclerotherapy of venous vessels. BJU Int. 2006; 97:142-5.

Local anesthesia for varicocele repair using a subinguinal approach is feasible and safe, providing a better control of early postoperative pain as compared to general anesthesia. and a faster recovery without experiencing significant complications. Further larger studies are needed to confirm our positive findings.

10. Marmar JL, Kim Y. Subinguinal microsurgical varicocelectomy: a technical critique and statistical analysis of semen and pregnancy data. J Urol. 1994; 152:1127-32.

REFERENCES

11. Tauber R, Johnsen N. Antegrade scrotal sclerotherapy for the treatment of varicocele: technique and late results. J Urol. 1994; 151:386-90.

1. Dubin L, Amelar RD. Etiologic factors in 1294 consecutive cases of male infertility. Fertil Steril. 1971; 22:469-74.

12. Chazapis M, Walker EM, Rooms MA, et al. Measuring quality of recovery-15 after day case surgery. Br J Anaesth. 2016; 116:241-8.

2. Jarow JP. Effects of varicocele on male fertility. Hum Reprod Update. 2001; 7:59-64.

13. Jensen CFS, Østergren P, Dupree JM, et al. Varicocele and male infertility. Nat Rev Urol. 2017; 14:523-533

3. Salonia A, Bettocchi C, Carvalho J, et al. EAU Guidelines on Sexual and Reproductive Health 2020.

14. Colpi GM, Carmignani L, Bozzini G, Picozzi S. Surgical subinguinal approach to varicocele combined with antegrade intraoperative sclerosis of venous vessels. Surg Innov. 2012; 19:252-7

4. Miyaoka R, Esteves SC. A critical appraisal on the role of varicocele in male infertility. Adv Urol. 2012; 2012:597495.

5. Dabaja AA, Goldstein M. When is a varicocele repair indicated: the dilemma of hypogonadism and erectile dysfunction? Asian J Androl. 2016; 18:213-6.

6. Marmar JL. The evolution and refinements of varicocele surgery.

Asian J Androl. 2016; 18:171-8.

15. Rivat C, Bollag L, Richebé P. Mechanisms of regional anaesthesia protection against hyperalgesia and pain chronicization. Curr Opin Anaesthesiol. 2013; 26:621-5 16. Nordin P, Hernell H, Unosson M, et al. Type of anaesthesia and patient acceptance in groin hernia repair: a multicentre randomised trial. Hernia. 2004; 8:220-5.

7. Ficarra V, Crestani A, Novara G, Mirone V. Varicocele repair for infertility: what is the evidence? Curr Opin Urol. 2012; 22:489-94.

17. Kadihasanoglu M, Karaguzel E, Kacar CK, et al. Local or spinal anesthesia in subinguinal varicocelectomy: a prospective randomized trial. Urology. 2012; 80:9-14

8. Baazeem A, Belzile E, Ciampi A, et al. Varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair. Eur Urol. 2011; 60:796-808.

18. Alom M, Ziegelmann M, Savage J, et al. Office-based andrology and male infertility procedures-a cost-effective alternative. Transl Androl Urol. 2017; 6:761-772.

Correspondence Giovannni Saredi, MD giovanni.saredi@asst-settelaghi.it Fabrizio I. Scroppo, MD Paolo Capogrosso, MD Paolo Maggio, MD Giuseppe Gianesini, MD Department of Urology and Andrology; Circolo and Fondazione Macchi Hospital, Varese Italy Giacomo Maria Pirola, MD Lorenzo Capone, MD Department of Urology, USL Toscana Sud Est, San Donato Hospital, Arezzo, Italy Andrea Pacchetti, MD Department of Urology, San Martino Hospital, University of Genova, Italy Giulio Carcano, MD Federico Dehò, MD University of Insubria, Varese, Italy

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DOI: 10.4081/aiua.2021.2.237

ORIGINAL PAPER

Does two-piece PPI provide improvement in patient-partner quality of life?

Engin Özbay 1, Remzi Salar 2, Halil Ferat Öncel 2 1 SBU 2 SBU

Istanbul Kanuni Sultan Süleyman Research and Training Hospital, Department of Urology, Turkey; Sanlıurfa Mehmet Akif İnan Research and Training Hospital, Department of Urology, Turkey.

Summary

Objective: The aim of this study is to retrospectively examine patient-partner satisfaction and changes in quality of life due to two-piece penile prosthesis implantation (PPI). There is no data about partner Quality of Life (QoL) related to two-piece PPI in the literature.

Material and Methods: SF 36 scale and modified Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), which were filled before two-piece PPI and at the sixth postoperative month follow-up by male patients (n = 45) and female partners (n = 45), were evaluated.

Results: We found patient-partner satisfaction rates as 80% and 86% respectively. The changes in all mean scores of SF 36 (mean total score, mean physical health score and mean mental health score) were statistically significant (p < 0.01).

Again, the differences between all mean scores of SF 36 according to the level of patient-partner satisfaction were statistically significant (p < 0.01).

Conclusions: Two-piece PPI is an important option for ED treatment. It provides significant improvement in patient-partner QoL with high treatment satisfaction.

KEY WORDS: Two-piece penile prosthesis implantation; Patientpartner satisfaction; Quality of life.

Submitted 13 December 2020; Accepted 2 January 2021

INTRODUCTION

Erectile dysfunciton (ED) is a benign disease and it affects physical and psychosocial health condition. It has an important effect on patient’s and partner’s quality of life.

ED treatment consists of three steps. Lifestyle modification and risk factor modification should be performed either before or together with ED treatment. Oral phosphodiesterase 5 inhibitors (PDE5I), vacuum erection device, topical/intraurethralal prostadil, and shock wave therapy are used in the first-line treatment.

In the second-line treatment, intracavernosal injection of alprostadil or combination therapy is applied. For the third-line treatment, penile prosthesis implantation (PPI) is available (1). Treatment failure is seen in approximately 80% of patients due to their discontinuation with firstline and second-line treatment (2). PPI is therefore an important option for patients that do not comply with or respond to these therapies.

In the treatment of ED, PPI is a method that provides

highest patient and partner satisfaction among all treatment options (3). In the literature, the rate of patient and partner satisfaction varies between 70 and 87% (4).The high satisfaction of the couples also increases the quality of their sexual lives (5).

Short form (SF) 36 scale is used to measure patient’s quality of life (QoL). It has both easy and short applicability.

Since it is not specific to any disease group, it is recommended to be used in all physical disease groups to determine QoL, to reveal the psychosocial aspect of the disease and to determine the change in treatment. (6).

Ure et al. evaluated patients’ QoL with SF 36 scale and observed that it was significantly increased after PPI compared to the preoperative period (7). However, in studies about patient QoL who underwent PPI, partner QoL was not mentioned much (8).

In the current study, patients that did not respond to first-line and second-line treatments, and therefore underwent two-piece PPI were evaluated. The changes in QoL with satisfaction levels of patients' and partners' were retrospectively examined.

MATERIALS

AND METHODS

The data of 61 patients that underwent PPI due to organic ED between March 2016 and March 2020 were retrospectively reviewed. In total 45 patients and 45 partners agreed to voluntarily participate in the study. Inclusion criteria: male patients with placement of two-piece PPI and their female partners, having not received a psychiatric diagnosis and treatment before PPI in their anamnesis, postoperative follow-up period of at least one year.

Depending on the medical history and socioeconomic status of the patients, the type of prosthesis to be applied was decided. The patients were informed about possible intraoperative and postoperative complications. Two-piece prosthesis implantation was performed under spinal anesthesia. In the perioperative period, the penoscrotal region was mechanically cleaned using chlorhexidine alcohol for 10 min. All operations were performed with a penoscrotal incision. Dual antibiotics (ciprofloxacin and amoxicillin-clavulanic acid) were continued for two weeks after hospital discharge. The patients were trained to use the prosthesis after one month and were allowed to use the prosthesis after six weeks.

No conflict of interest declared.

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SF-36 scale was respectively administered before PPI and at the postoperative sixth month follow-up by face-toface interviews. Modified Erectile Dysfunction Inventory of Treatment Satisfaction (mEDITS) was filled at the postoperative sixth month, too.

Statistical analysis IBM SPSS Statistics 22.0 program was used for statistical analysis while evaluating the findings obtained in the study. While evaluating the study data, in addition to descriptive statistical methods (Mean, Standard deviation), Paired Samples t test was used for the pre-post comparisons of the parameters showing normal distribution. Student t test was used for comparisons between the two groups. Significance was evaluated at the p < 0.05 level.

RESULTS

The mean age of 45 male patients was 49.7 (± 12) years, and the mean age of their female partners was 42.3 (± 10) years. The mean follow-up period was 40 (± 23) months. Diabetes mellitus (%42), radical prostatectomy (%14), penile vascular disease (%38) and Peyronie disease (%6) were the etiology of ED. Since there was no patient that presented to the hospital with priapism, we did not include it in the table. The American Medical Service (AMS®) two-piece penile prosthesis was implanted in 45 patients. The mean length of hospital stay was three days. In the early postoperative period, one patient developed scrotal hematoma and one developed soft tissue infection due to negligent antibiotic use. In two patients, penoscrotal pain lasted for two months postoperatively. At the fourth postoperative month, mechanical damage was observed in the two-piece penile prosthesis of one patient. The patient-partner satisfaction rates were evaluated using mEDITS at the sixth month. According to the results, 80% of the patients (n = 36) and 86.7% of the partners (n = 39) expressed satisfaction with PPI while 20% of the patients (n = 9) and 13.4% of the partners (n = 6) were dissatisfied with the procedure. SF 36 scale can also be evaluated under two main subscales as “Physical Health” and “Mental Health”. Table 1 shows the evaluation of SF-36 scores before and after PPI. According to mean total score before PPI, the increase seen in mean total score after PPI was statistically significant (p < 0.01) in patients. And also the increases seen in mean physical health score and mean mental health score after PPI were statistically significant (p < 0.01).

Table 1.

Evaluation of SF-36 scores before and after PPI.

Male patients

Female partners

Physical health Mental health Total scores Physical health Mental health Total scores

Before PPI Mean ± SD 63.25 ± 9.35 58.35 ± 13.65 60.80 ± 10.69 62.06 ± 10.43 55.34 ± 13.92 58.69 ± 11.69

After PPI Mean ± SD 82.11 ± 16.63 81.89 ± 18.55 82.01 ± 17.45 84.52 ± 15.21 80.09 ± 19.52 82.31 ± 17.35

Paired Samples t test. **p < 0.01.

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p 0.001** 0.001** 0.001** 0.001** 0.001** 0.001**

Table 2.

Evaluation of SF-36 scores according to satisfaction status.

Male patients Female partner

Physical health Mental health Total scores Physical health Mental health Total scores

Unsatisfied Mean ± SD 52.33 ± 13.47 46.42 ± 8.23 49.37 ± 10.67 49.10 ± 10.63 35.38 ± 10.17 42.24 ± 10.39

Satisfied Mean ± SD 89.56 ± 4.61 90.77 ± 3.55 90.16 ± 3.83 89.97 ± 4.96 86.96 ± 7.96 88.47 ± 6.46

p 0.001** 0.001** 0.001** 0.001** 0.001** 0.001**

Paired Samples t test. **p < 0.01.

According to Table 1, the statistical results of the partners were similar to the statistical results of the patients (p < 0.01). Table 2 shows the evaluation of SF-36 scores according to satisfaction status. The mean total score of the satisfied group after PPI was significantly higher than the dissatisfied group (p < 0.01). Again mean mental health score and mean physical health score of the satisfied group after PPI were significantly higher than the dissatisfied group (p < 0.01). According to Table 2, the statistical results of partners showed to be similar to the statistical results of the patients (p < 0.01).

DISCUSSION

Two-piece prostheses are preferred in patients who have undergone or are scheduled to undergo organ transplantation in the pelvic region, those with a history of radical pelvic surgery or pelvic radiotherapy, and cases that pose difficulty in terms of reservoir placement in the Retzius region (9). Other reasons for the preference of two-piece prostheses include their simple application, which makes it easier for the physician to guide the patients in terms of their use and also the full cost coverage of a twopiece penile prosthesis by Turkish Social Security Institution (10). Lastly, in socioeconomically and socioculturally developed countries, three-piece prostheses are the most preferred type since they can mimic erection as close to nature as possible and have a more cosmetic appearance (11). The disadvantages of three-piece prostheses are that mechanical damage complicates cases and they are more expensive than other types of prosthesis (12). In this study, we used two-piece prostheses for their ease of use and socioeconomic reasons, as well as due to the presence of radical pelvic surgery history in the study population.

The most common cause of dissatisfaction after PPI is shortening of the penile length, which is generally 1 to 2 cm (13). In a previous study, the satisfaction rate of patients that underwent prosthesis implantation due to priapism was observed to be 60% due to the complaint of penile shortening (14). Patients with Peyronie’s disease that undergo PPI may require additional surgical procedures to maintain penile length (15). Other reasons for patient dissatisfactions include the development of postoperative infections, mechanical damage, erosion, penile pain, short prosthesis, and soft glans syndrome (13).

Presence of DM, spinal cord injury, revision surgery, steroid-dependent patients and complicated PPI procedure increase the risk of postop infection. When prosthe-

Does two-piece PPI provide improvement in patient-partner quality of life?

sis infection develops, all elements of the prosthesis are removed (16). Infection treatment is applied. If the new prosthesis is implanted 3-6 months later, the procedure becomes very difficult and the penis becomes shorter.

To prevent this complication, salvage procedure can be performed. While removing the prosthesis, mechanical cleaning is applied to the infected tissues with antibiotic solutions in the same session. New PPI is applied in the same session or postponed after 6-8 weeks (17).

In our study three patients were dissatisfied with the shortening of their penis length, two patients used oral ciprofloxacin for two months to relieve penile pain.

The penile prosthesis of one patient was replaced due to mechanical damage. Soft tissue infection was observed in one patient and was suppressed with intravenous antibiotherapy.

The unnatural appearance of the prosthesis and the unnatural sensation may also be the cause of dissatisfaction for patient and partner (18). Sexual desire disorder, sexual arousal disorders, orgasm and ejeculation problems can also be the cause of dissatisfaction with the patient and partner related to penile prosthesis implantation (19). In the current study three patients were dissatisfied due to ejaculation disorder, two patients and four partners complained of not being fully satisfied with orgasm and one couple was dissatisfied due to the unnatural appearance of the penis.

In a study conducted with two-piece prostheses, the patient-partner satisfaction rates were observed to be over 80% (20). Çayan et al. conducted a PPI study with 883 patients and reported no statistically significant difference in patient-partner satisfaction rates related to two- and three-piece prostheses, while their satisfaction rates were higher than one-piece prostheses (21). In our study, we calculated the patient and partner satisfaction rates as 80% and 86%, respectively, which is consistent with the literature.

Ozbay et al. in a study observed that patients with erectile dysfunction due to organic origin disease had sexual dysfunction together with their female partners and the sexual dysfunction of couples improved together after PPI (19).

Studies have repeatedly shown that PPI positively affects patients’ QoL, perceived quality of the couple relationship, partner satisfaction, body image, the relationship with the outside world, and the satisfaction with the implant function (22, 23). In addition, in a study where the patient follow-up period was at least 15 years, it was found that 60% of the patients still used penile prostheses, satisfaction was high, and the QoL results were sufficient (8). In this study, patient QoL was not at a healthy level before PPI. The significant increase in patients' mean total score, mean physical health score and mean mental health score after PPI indicated an improvement in patient QoL. QoL of satisfied patients was also at a high level.

Sexual dysfunction of the female patient negatively affects QoL (24). A high rate of sexual dysfunction was observed with the decrease in QoL of female patients with organic origin diseases, and it was observed that the same findings were also observed in the male partners of the patients (25-28). Successful treatment of female

patients' diseases such as hypertension, diabetes, pituitary insufficiency, hypothyroidism and breast cancer improves their sexual dysfunction and QoL (29, 30).

There are many studies in the literature that evaluate QoL of male patients with penile prostheses, but findings evaluating QoL of female partners could not be observed in these studies (8, 22, 23). In this study, partners’ QoL was not at a healthy level before PPI. The significant increase in partners' mean total score, mean physical health score and mean mental health score after PPI indicated an improvement in partner QoL. Satisfied partner QoL was also at a high level.

CONCLUSIONS High level of patient-partner satisfaction for ED therapy is achieved with the two-piece PPI. In our study, patientpartner QoL was not at a healthy level before PPI. But it was observed that patient-partner QoL increased similarly after PPI. Satisfied patient-partner QoL was also at a high level.

ETHICS

COMMITTEE APPROVAL

Harran University Faculty of Medicine Ethical Committee approved. Consent form and permission was obtained from all patients who participated in the study.

REFERENCES

1. Hatzimourotidis K, Guiliano F, Moncada I, et al. EAU guidelines on males sexual dysfunction. 2016; p: 14-22.

2. Gümüş BH, Albaz AC. Erektil disfonksiyon tedavisinde penil protez implantasyonun uzun dönem klinik sonuçları. Androl Bul. 2017; 19:117-122.

3. Efesoy O, Özbay E, Tek M, et al. Longterm outcomes and couple’s satisfaction with three-piece inflatable penile prosthesis surgery in the treatment of erectile dysfunction. Türkiye klinikleri J MedSci, 2010; 30:1965-70.

4. Levine LA, Estrada CR, Morgentaler A. Mechanical reliability andsafety of and patient satisfaction with the Ambicor inflatable penileprosthesis: results of a 2 center study. J Urol. 2001; 166: 932-7.

5. Barton GJ, Carlos EC, Lentz AC. Sexual quality of life and satisfaction with penile prosthesis. Sex Med Rev. 2019; 7:178-188.

6. Newman SP. Psychosocial measures in musculoskeletal trials. J Rheumatol. 1997; 24:979-84.

7. Ure I, Ozen A, Can C. Life quality change after inflatable penile prosthesis implantation. Aging Male. 2020; 23:362-368.

8. Chierigo F, Capogrosso P, Dehò F, et al. Long-term follow-up after penile prosthesis implantation-survival and quality of life outcomes. J Sex Med. 2019;16:1827-1833.

9. Morey AF. Re: Ambicor 2-piece inflatable penile prosthesis: who and how? J Urol. 2018; 200:691-692.

10. Ozan T, Karakeçi A, Pirinçci A, et al. Iki parçalı sisirilebilir penil protez cerrahisine ait klinik sonuçlar ve hasta memnuniyetinin degerlendirilmesi. F.Ü.Sag.Bil.Tıp.Derg. 2018; 32:27-30.

11. Usta MF. Penil protez cerrahisinde yenilikler: 2016 güncelleme.

Androloji bülteni. 2016; 18 :212-216.

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E. Özbay, R. Salar, H.F. Öncel

12. Esengen S, Nalbant I, Öztürk U, et al. Comparison of penile prosthesis methods: which is more successful? J Clin Anal Med. 2017; 8:421-4.

13. Küçük E, Bindayı A. Penil protez cerrahisi komplikasyonları ve basaçıkma yöntemleri. And Bült. 2016; 18:25-29.

14. Zacharakis E, Garaffa G, Raheem A et al. Penile prosthes insertion in patients with refractory ischaemic priapism: early vs delayed implantation. BJU Int 2014; 114:576-581.

22. Carvalheira A, Santana R, Pereira NM. Why are men satisfied or dissatisfied with penile implants? A mixed method study on satisfaction with penile prosthesis implantation. J Sex Med. 2015; 12:2474-80.

23. Caraceni E, Utizi L. Questionnaire for the evaluation of quality of life after penile prosthesis implant: Quality of Life and Sexuality with Penile Prosthesis (QoLSPP). To what extent does the implant affect the patient’s life? J Sex Med 2014; 11:1005-1012.

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Correspondence Özbay Engin, MD (Corresponding Author) nozbay63@gmail.com SBU Istanbul Kanuni Sultan Süleyman Research and Training Hospital, Department of Urology, Istanbul (Turkey) Salar Remzi, MD Öncel Halil Ferat, MD SBU Sanlıurfa Mehmet Akif !nan Research and Training Hospital, Department of Urology, Sanliurfa (Turkey)

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26. Bilgic D, Gokyildiz S, Kizilkaya Beji N, et al. Quality of life and sexual functıon in obese women with pelvic floor dysfunction.

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2007; 369(9559):350-2.

DOI: 10.4081/aiua.2021.2.241

ORIGINAL PAPER

Pulsed fluoroscopy in retrograde urethrograms Hazem Elmansy 1, Waleed Shabana 1, Radu Rozenberg 2, Abdulrahman Ahmad 1, Ahmed Kotb 1, Amer Al Aref 2, Walid Shahrour 1 1 Department

of Urology and 2 Radiology, Northern Ontario School of Medicine, Thunder Bay, ON, Canada.

Summary

Objectives: Retrograde urethrogram (RUG) is one of the corner stones for the reconstructive urologist. With hundreds of RUGs being performed yearly in busy reconstructive center, the concern for radiation exposure to the patient and the medical personnel becomes important. We propose the use of pulsed fluoroscopy to decrease the radiation exposure for patient and medical personnel.

Methods: Patients presenting to our center with urethral strictures between March 2016 and March 2019 were included in our study. The fluoroscopy machine was set for pulsed fluoroscopy at a setting of 4 pulses per second. Patient information including demographics, pre-operative diagnosis, Intra-op findings, and fluoroscopy time were recorded. RUG was performed to localize the stricture pre-operatively and post-operatively.

Results: A total of 185 RUG were performed between March 2016 and March 2019. The median age was 63 (14-81).

The remaining 154 RUG had 77 performed pre-operatively and 77 performed post-operatively. Pathology was identified in 77 patients. Intra-operative confirmation of pre-operative finding was found in 76 patients (98.7%). Median fluoroscopy time was found to be 2.43 seconds (0.5 sec- 6.5 sec).

Conclusions: Pulsed fluoroscopy reduces the radiation exposure in RUG without a reduction in the diagnostic capacity of the test.

Reduction of fluoroscopy can have beneficial cumulative effect as per the ALARA principle for patients and medical personnel.

Further studies with randomized control trials could be of great benefit.

KEY WORDS: Urethrogram; Pulsed fluoroscopy.

Submitted 19 March 2021; Accepted 21 April 2021

INTRODUCTION

Retrograde urethrography (RUG) and voiding cystourethrography (VCUG) are the modalities of choice for imaging the male urethra. First, RUG is performed to visualize the adequately distended anterior urethra, and VCUG is then performed to properly evaluate the posterior urethra.

Urethrography is a dynamic imaging modality that should be done by an expert urologist to assure the accuracy of the technique and the correct interpretation thereafter (1, 2). Reducing the fluoroscopic exposure without compromising the image quality was always the first priority for manufacturers as well as the surgeons, hence the invention and implementation of the ALARA principle "As Low As Reasonably Achievable" in 1990 (3).

The ALARA principle has 3 factors, time, distance, and

shielding. There are a variety of ways to reduce fluoroscopy time during interventional procedures; some are methodological and others involve taking advantages of technical features present in modern equipment such as intermittent fluoroscopy, removal of grid, last image hold, electric collimation, dose spreading, adjustment of beam quality, image magnification, dose level settings, and pulsed fluoroscopy (4).

The idea behind pulsed fluoroscopy is that modern gridcontrolled x-ray tubes have a grid placed between the cathode and the anode which allows pulses of fluoroscopy to leave the tube at a rate between 1 and 30 frames per second (FPS).

Thus, radiation no longer enters a patient continuously, but rather in a series of short x-rays flashes. When we use fluoroscopy at 30 FPS it is called continuous fluoroscopy; on the other hand, Aufrichtig et al. (5) defined pulsed fluoroscopy as 15 FPS or less. Each fluoroscopy unit could be manually set as pulsed fluoroscopy (PF) with refresh rates of 15, 8, or even 4 FPS. Using phantom models, PF at rates of 15, 10, 7.5, and 3.75 FPS were associated with radiation reduction by 22%, 38%, 49%, and 87%, respectively (6, 7). Although using pulsed fluoroscopy appears promising in reducing radiation, it always has a potential penalty of a decrease in image quality. On a real-time fluoroscopic image, low pulse rate makes image becomes more noisy or grainy.

Moreover, with very slow pulse rates, motion such as swallowing, peristalsis and heart beating becomes jerky (choppy). To overcome this obstacle, manufacturers increase the milliamperage settings to achieve a similar visual appearance (8, 9). During retrograde urethrography, using pulsed fluoroscopy is ideal because there is minimal patient movement and we use the real time imaging to delineate the urethra with better identification of the urethral pathology (10).

The primary objective is to identify if the use pulsed fluoroscopy mode during retrograde urethrogram to minimize radiation exposure for both the operator and the patient.

The secondary objective is to assess whether using 4 frames per seconds (FPS) in pulsed mode is sufficient without the need to increase the number of FPS. We will also assess the image quality of the study and the concordance between the image and the intraoperative finding during diagnostic cysto-urethroscopy.

No conflict of interest declared.

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H. Elmansy, W. Shabana, R. Rozenberg, A. Ahmad, A. Kotb, A. Al Aref, W. Shahrour

METHODS

Patients presenting to our center with urethral strictures between March 2016 and March 2019 were included in our study. RUGs were performed by a single urologist.

The fluoroscopy machine was set for pulsed fluoroscopy at a setting of 4 pulses per second. The same technique of RUG was used in every test. The urologist controlled the pedal for fluoroscopy. Patient information including demographics, pre-operative diagnosis, fluoroscopy time, stricture location and length, intra-op findings, and intraop cystoscopy were recorded. RUG was performed to localize the stricture pre-operatively. If there is no identification of a stricture, cystoscopy is performed to confirm the negative findings. It was also performed in select patients post-operatively with cystoscopy to confirm the findings. The data was collected retrospectively after ethics approval. Patients that had complex stricture disease requiring fluoroscopic manipulation were excluded.

RESULTS

A total of 185 RUG were performed between March 2016 and March 2019. The median age was 63 (14-81).

There were 20 RUG that did not show a stricture, and this was confirmed by cystoscopy in the same setting.

There were 11 patients that were excluded as they had complex stricture disease requiring fluoroscopic manipulation. The remaining 154 RUG had 77 performed preoperatively and 77 performed post-operatively.

Pathology was identified in 77 patients. Intra-operative confirmation of pre-operative finding was found in 76 patients (98.7%). There were no recorded complications from the RUG. Strictures locations and demographics were recorded in Table 1. Median fluoroscopy time was found to be 2.43 seconds (0.5 sec-6.5 sec).

DISCUSSION

RUG is a fundamental test for reconstructive urethral surgery. In the high-volume centers, multiple RUGs are being performed on a daily basis. As per the ALARA principle, we would always strive to decrease the amount of radiation used. This can help the medical personnel that are exposed on daily basis to radiation. In addition, Table 1.

Study population and pulsed urethrogram data.

Number of patients Total number of RGU Negative RUG (excluded) Pre and post-operative RUG Complex RUG (excluded) Median age (IQR) years Median fluoroscopy time seconds Intra-operative confirmation of structure Stricture location: Penile n (%) Bulbar n (%) Pan-urethral n (%)

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77 185 20 154 11 63 (58-71) 2.43 (0.5-6.5) 76 (98.7%) 21 (27.2%) 42 (54.5%) 14 (18.1%)

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with increased dependence on radiological assessments, we would aim at decreasing the accumulated radiation for patients over the years. In our current study, we noted that the fluoroscopy time has a median of 2.43 seconds.

According to the studies on phantom models, this might mean an 87% reduction in the amount of radiation (6, 7). We do not have previous results with continuous fluoroscopy or higher pulse rate as this was adopted from the beginning. The usual extrapolation of the data would be that the amount of fluoroscopy would be more than doubled with the higher pulse rate. The use of the fluoroscopy time is not always the best indicator for the cumulative dose compared to the use of the air kerma area product or dose area product (DAP). In our study we used the fluoroscopy time as it is a simple way to convey the result and it is one of the indicators for the reduction in the dose.

The exclusion of the complicated cases that required fluoroscopic manipulation was due to the fact that they were not representative of the usual fluoroscopy time used in regular diagnostic procedure. This was not due to the image quality being poorer rather than it would bring the average fluoroscopy time to be higher than usual expected. This should not exclude the use of low pulse fluoroscopy in those cases as it would mean lower radiation dose for patients and personnel specially when maneuvers are needed and longer fluoroscopy would be used. The only case where the RUG was not diagnostic entirely because of improper opacification of the distal urethra during the RUG and not because of reduction of the image quality. This was identified during surgery where the intra-operative finding showed the stricture to be extending all the way to the distal urethra. The comparison between the intra-operative findings and the RUG findings did not show reduction in the diagnostic capacity or the capability of pre-operative planning for the surgery.

One of the downsides of the lower pulse rate is the lower quality of the image. The image becomes grainy in appearance and it takes some time to get used to that.

This grainy appearance does not affect the image contrast or the ability to diagnose stricture as shown in our study.

Another downside is the noticeable delay between pressing the pedal and the appearance of the image on the screen. This delay can be a matter of seconds or milli seconds and it does not usually affect the outcomes.

This would be apparent when the urologist is performing manipulation under fluoroscopy. Since the RUG does not require manipulation, this delay is acceptable for the reduction of the radiation exposure.

Another method to decrease radiation exposure is by having the doctor, residents and fellows taking radiation-safety programs. Gendelberg et al. (11) has shown that radiation-safety programs decrease the radiation emission and usage after the program was taken by the residents.

While some might argue that they use just one image, it is still using the usual frames of the machine. Many machines are set on rates of 15 FPS while newer machines are set at 8 FPS which would be a lower FPS used. The regular continuous fluoroscopy is 30 FPS which would mean more than 7 times the number of frames needed for one image.

Pulsed fluoroscopy urethrograms

There are methods to decrease the fluoroscopy time and radiation exposure in general that can be used. One can bring the part to be examined (in our case, the urethra) as close as possible to the receiving end of the C-arm or the image intensifier. Using the last image option if we require more than one image can also reduce the radiation exposure.

Our study is a retrospective one with the known limitations of retrospective studies. Randomized multi-institutional trial can prove beneficial in such situation.

3. European ALARA Network Workshop, "Experience and new Developments in implementing ALARA in Occupational, Patient and Public Exposures", Prague, Czech Republic, 12-15 September 2006, proceedings available on www.eu-alara.net.

CONCLUSIONS

7. Lederman HM, Khademian ZP, Felice M, et al. Dose reduction fluoroscopy in pediatrics. Pediatr Radiol. 2002; 32:844-848.

Pulsed fluoroscopy reduces the radiation exposure in RUG without a reduction in the diagnostic capacity of the test. Reduction of fluoroscopy can have beneficial cumulative effect as per the ALARA principle for patients and medical personnel. Further studies with randomized control trials could be of great benefit.

REFERENCES

1. Pavlica P, Barozzi L, Menchi I. Imaging of male urethra. Eur Radiol 2003; 13:1583-1596.

2. Kawashima A, Sandler CM, Wasserman NF, et. al. Imaging of urethral disease: a pictorial review. RadioGraphics 2004; 24(suppl 1): S195-S216.

4. Vehmas T, et al. Hawthorne effect. Shortening of fluoroscopy times during radiation measurement studies. Br J Radiol. 1997; 70:10531055.

5. Aufrichtig R, Xue P, Thomas CW, et al. Perceptual comparison of pulsed and continuous fluoroscopy. Med Phys. 1994; 21:245-256.

6. Cohen M. Optimizing the use of pulsed fluoroscopy to reduce radiation exposure to children. Am Coll Radiol. 2008; 5:205-209.

8. Brown PH, Thomas RD, Silberberg PJ, et al. Optimization of a fluoroscopeto reduce radiation exposure in pediatric imaging.

Pediatr Radiol. 2000; 30:229-235.

9. Schueler BA, Julsrud PR, Gray JE, et al. Radiation exposure and efficacy of exposure-reduction techniques during cardiac catheterization in children. AJR Am J Roentgenol. 1994; 162:173-7.

10. Ward VL, Strauss KJ, Barnewolt CE, et al. Pediatric radiation exposure and effective dose reduction during voiding cystourethrography. Radiology, 2008; 249:1002-1009.

11. Gendelberg D, Hennrikus W, Slough J et al. A radiation safety training program results in reduced radiation exposure for orthopaedic residents using the mini C-arm. Clin Orthop Relat Res. 2016; 474:580-4.

Correspondence Hazem Elmansy, MD hazem.mansy@rocketmail.com Waleed Shabana, MD waleed.shabana@gmail.com Abdulrahman Ahmad, MD dr.aaa.186@gmail.com Ahmed Kotb, MD kotba@tbh.net Walid Shahrour, MD walid.shahrour@gmail.com Department of Urology, Northern Ontario School of Medicine, Thunder Bay, ON (Canada) Radu Rozenberg, MD rozenber@tbh.net Amer Al Aref, MD alarefa@tbh.net Department of Radiology, Northern Ontario School of Medicine, 980 Oliver Road, Thunder Bay, ON (Canada)

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ORIGINAL PAPER

Optimal clamping time in meatotomy procedure for children with meatal stenosis: Experience with 120 cases Mehdi Shirazi 1, 2, Umayir Chowdhury 3, Faisal Ahmed 4*, Mohammad-Bagher Rajabalian 1, Hossein-Ali Nikbakht 5, Khalil Al-Naggar 4, Ebrahim Al-Shami 4 1 Department

of Urology, Shiraz University of Medical Sciences, Shiraz, Iran; and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 3 School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; 4 Urology Research Center, Al-Thora General Hospital, Department of Urology, Ibb University of Medical Since, Ibb, Yemen; 5 Social Determinates of Health Research Center, Department of Biostatics and Epidemiology, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.

2 Histomorphomettery

tus to an irritating environment of the diaper (diaper dermatitis) is the common pathologic cause of this condition (3). Post circumcision meatal stenosis may also result from ischemia of the meatal mucosa secondary to damage to the frenular artery (2).

Patients with MS can present with symptoms of voiding difficulties, such as pinpoint meatus, difficulty to aim or an upward and forceful urinary stream, dysuria, urgency, frequent and prolonged urination. Therefore, untreated MS can lead to urinary tract infections and kidney problems (1). To confirm the diagnosis, detailed history and physical exam including observation of urination and examining the urethral opening are evaluated carefully (1). Regarding the methods of circumcision, it was hypothesized by Graves that MS is more common after a Plastibell circumcision (2).

Meatotomy is a simple common procedure for the treatment of MS that can be performed with minimal instrumentation and in this procedure, the ventrum of the meatus is crushed with a straight clamp and then the crushed ventral tissue is incised sharply with fine-tipped scissors (1). Side effects of meatotomy are bleeding during or after meatotomy, mild discomfort for the first day following the operation, recurrence, pain, dysuria, and dysuria induced urinary retention, infection, edema, and spraying of the urine stream as a consequence of edema for a while (2-4).

Among all the complications mentioned above, bleeding could be a matter of utmost importance in which clamping time might have played a key role. The clamping times recommended in previous literature were between 60 seconds to 3 minutes (1, 4-7).

In these circumstances, we could not find any study that KEY WORDS: Bleeding; Clamping time; Meatal stenosis; Meatotomy. shows us if there is any correlation between clamping time and bleeding during and after meatotomy proceSubmitted 10 March 2021; Accepted 2 May 2021 dure. Therefore, we conducted a study to find out the optimal clamping time in meatotomy.

Summary

Objective: During meatotomy procedure for children with meatal stenosis (MS), a straight clamp used as a hemostat on the ventrum of the meatus before incised with scissors for clamping and holding bleeding from the site of operation. The aim of this study was to evaluate the optimum clamping time for meatotomy in children with MS. Materials and methods: All the patients with MS between 2014 to 2019 were enrolled in this retrospective study. Patients with uncircumcised penis, traumatic catheterization, any kind of penile abnormality such as hypospadias or penile curvature, and active urinary tract infection (UTI) were excluded. The indication of meatotomy was a pinpoint meatus that develops with dorsal or lateral deflection of the urinary stream and high-velocity urine flow. During meatotomy procedure, clamping time was examined in different groups such as 2, 3, and 4 minutes.

The main symptoms of presentation and ultrasonography (US) findings were recorded and compared between groups. To assess the optimum time clamping, postoperative bleeding was noted carefully in all groups. The success rate was recorded at onemonth postoperative follow-up in the clinic.

Results: Of the 120 patients with MS who underwent a meatotomy procedure, there were 40 (33.3%) participants in each group.

The main symptoms were painful urination and urine stream deviation that represented in 54 (46%) patients. Bladder wall thickness was the main pre-operation finding in the US which was observed in 67 (55.8%) patients. In comparison between the groups related to clamping time, bleeding was observed and required suturing when clamping was applied for 2 minutes in 4 (3.3%) patients (p = 0.016). With a minimum follow-up of 12 months, no recurrent meatal stenosis was reported.

Conclusions: Clamping time for more than 2 minutes may prevent bleeding during and after meatotomy.

INTRODUCTION

One of the most common complications after circumcision is meatal stenosis (MS) which occurs in approximately 9%-10% of patients (1). MS is defined as narrowing of the opening of the external urethral meatus less than 2 mm (2). Prolonged exposure of the delicate mea-

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MATERIALS

AND METHODS

Study design The Ethics Committee of Shiraz University of Medical Sciences approved the protocol of the study (IR.SUMS.MED.REC. No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 2

Clamping time in meatotomy

1397.507). This is a retrospective study, which included all the patients with MS during five years from July 2014 to September 2019, which evaluated by one single pediatric urologist were enrolled in this study. Patients with uncircumcised penis, traumatic catheterization, prior penile surgery, any penile abnormality such as hypospadias or penile curvature, and active urinary tract infection (UTI) were excluded. Written informed consent was taken from the patient’s parents before the operation and the benefit and risk of this procedure were explained. The indication of meatotomy was a pinpoint meatus that develops with dorsal or lateral deflection of the urinary stream and highvelocity urine flow (8).

During meatotomy procedure, clamping time was checked in different groups such as 2, 3, and 4 minutes.

The demographic characteristics such as skin eruption around meatus, age, history of allergy, age of circumcision, US finding, main symptoms, and Quality of voiding after operation were recorded and compared between groups. to assess the optimum time clamping, postoperative bleeding was noted carefully in all groups.

The success rate was recorded at one-month postoperative follow-up in the clinic.

When data were non-normally distributed, the non-parametric test was used. The Chi-square test was used to assess a probable statistically significant difference between qualitative variables for limitations on the observed frequency of Fisher's exact test. ANOVA was applied to compare the difference of means between more than two different levels or the non-parametric Krusal Wallis test was applied.

The collected data were analyzed by SPSS version 20.

A P-value less than 0.05 was considered statistically significant.

RESULT

The patient's characteristics were summarized in Table 1.

Of the 120 patients diagnosed with MS were enrolled in this study. The mean patient age was 50.88 ± 29.73 months. The time between circumcisions to meatotomy procedure was 49.5 ± 30.84 months. Skin eruption around meatus was found in 6 (5.0%) patients. All coagulation tests (PT, PTT, INR, and Platelet) were normal in all patients. Related to symptoms of MS, the main symptoms were painful urination and urine stream deviation which represented in 54 (46%) patients. Other symptoms were summarized in Table 2. Bladder wall thickness was the main pre-operation finding in US which represented in 67 (55.8%) patients. US finding were summarized in Table 2.

Voiding quality at one month after operation excellent in 79 (65.8%) patients, improved in 38 (31.7%) patients, and partially improved in 3 (2.5%) of patients and at long term (12 months) follow-up remained without symptoms.

In comparison between the groups related to clamping

Surgical procedure All procedures were done under general anesthesia in the supine position. Minimal skin prep and drape of the genitalia were done with Iodopovidone. Then one jaw of a well-lubricated mosquito hemostat was introduced into the ventral aspect of the urethral meatus to a depth of approximately 2-3 mm, depending on the severity of stenosis and patient age. Then, by closing the hemostat, the ventral tissue was crushed. Clamping time was checked in different groups such as 2, 3, and 4 minutes. Then crushed tissue was divided gen- Table 1. tly with a fine-tipped scissor. A small amount Main characteristics of patients. of antibiotic was placed over the raw edges (8).

P value 4 min clamping 3 min clamping 2 min clamping The meatotomy site was shown to the partime (40) time (40) time (40) ents and the surgeon demonstrated how to 0.031 60.07 ± 33.74 49.85 ± 30.76 42.73 ± 21.39 open the meatus two times daily to apply 1.000 2 (33.3) 2 (33.3) 2 (33.3) Dexpanthenol-Chlorhexidine cream for 2 0.265 2 (14.2) 6 (42.9) 6 (42.9) weeks (9).

0.19 2.47 ± 2.35 3.51 ± 5.87 3.39 ± 3.78 Surgical outcome During the procedure bleeding of the surgical site was recorded by a pediatric urologist and if occurred, firstly pressure on the edges performed and if not stopped then it would be sutured with 6/0 Polyglactin suture material.

Quality of voiding and symptoms were asked from the patient’s family and meatal opening using visual inspection was recorded in the outpatient clinic one month after the operation.

Statistical analysis The mean ± SD and median, Inter-Quartile Range (IQR), described the quantitative variables, and frequency (percent) was used for qualitative variables. We assessed the normality as the assumption of the variables in the study by the Kolmogorov-Smirnov test.

0.016

0 (0)

0 (0)

4 (100)

Total number 120 50.88 ± 29.73 6 (5.0) 14 (11.7) 3.12 ± 4.24 4 (3.3)

Variables Age (months) a Skin eruption around meatus b History of allergy b Age at circumcision (months) c Bleeding b

P-values of < 0.05 were considered significant. a: Data was presented as Mean ± SD; b: Data was presented as n (%); c: Median (IQR).

Table 2.

US finding and symptoms of patients.

P value 4 min clamping 3 min clamping 2 min clamping Total 120 Variables Main symptoms b 0.010 18 (33.3) 18 (33.3) 18 (33.3) 54 (46) Painful urination and urine stream deviation 9 (37.5) 4 (16.7) 11 (45.8) 24 (20) Stream narrowing and infrequent voiding 10 (62.5) 5 (31.3) 1 (6.3) 16 (13.3) Urge incontinence and retention 2 (16.7) 5 (41.7) 5 (41.7) 12 (10) No symptoms 0 (0.0) 8 (61.5) 5 (38.5) 13 (10.7) Prolonged time of micturition US finding before operation b 0.877 23 (34.3) 21 (31.3) 23 (34.3) 67 (55.8) Bladder wall thickness 5 (31.3) 6 (37.5) 5 (31.3) 16 (13.4) Unilateral mild hydronephrosis 2 (50) 2 (50) 0 (0) 4 (3.3) Bilateral mild hydronephrosis 10 (30.3) 11 (33.3) 12 (36.4) 33 (27.5) Normal US finding US, Ultrasonography. P-values of < 0.05 were considered significant. b Data was presented as n (%).

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Table 3.

Summary of published studies with clamping time, type of anesthesia and complications.

The clamping times recommended in previous literature were between 60 seconds to 3 minutes Table 3 shows the earlier published study with clamping time and complications Study Patients Type of Clamping time Complication (1, 3-9, 11-13). number anesthesia (minutes) David Ben-Meir et al. noted that bleeding Neheman (9) 25 General 2 Mild meatal stenosis in 3 patients occurred in two patients who received sedaFronczak (8) 55 Topical Repeated meatotomy in 3 patients tion and general anesthesia and one patient Wang (1) General 1 No complication who received penile block and general anesPriyadarshi (12) 48 Local 2-3 Penile numbness in 2 patients for 1 day thesia. Clamping time in all patients was one Ben-Meir (3) 76 General/Local 1 Bleeding in 3 patients, Laryngospasm in 2 patients minute. However, children who had bleeding Lane (5) 3 No complication had various degrees of skin reaction (edema Cubillos (11) 85 General 1 No complication and blanching) and they concluded that Roth (7) 100 Local 5 No complication blanching may have increased the risk of bleeding due to fragility of tissue or the diffiElkhafifi (13) 86 General 1–2 No complication culty in cutting precisely through the crush line made by the hemostat (3). time, there was no statistically significant difference James et al. recommended that clamping for three minamong the groups in terms of skin eruption around meautes reduces bleeding and facilitates placement of tus, history of allergy, circumcision method, US finding, sutures (5). Our result was similar to the previous studvoiding quality after one month of operation, and meatal ies and showed significant bleeding was observed and width. However, the mean age in 2 minutes group was required suturing when the clamping time was for 2 younger than another group (p = 0.031). minutes.

Significant bleeding was observed and required suturing Parisa and associates evaluated 87 children with MS and when clamping time was for 2 minutes in 4 (3.3%) they concluded that decreased urine stream is a common patients (p = 0.016). Painful urination and urine stream symptom which was seen among 54% of patients with deviation was the main symptoms in all groups MS. Besides, increased bladder wall thickness was the (p = 0.010). Besides, with a minimum follow-up of 12 most common finding in Ultrasonography (US) which months, no recurrent MS was reported. was revealed in 82% of the patients (14). Our result was similar to the previous study.

David et al. assessed the quality of void at 24 hours and DISCUSSION 1 month after meatotomy (3). In agreement with this The main cause of MS is circumcision. It is usually comstudy, we also evaluated the quality of voiding one mon in Jews and Muslims and this problem is highly month after surgery, and in our opinion; this time was detected in Israel, where most boys are ritually circumenough for the meatus to heal. cised in early infancy (3).

Local anesthesia was highly recommended in recent studDifferent methods are approved to perform neonatal ciries. However, it is important to mention that restlessness cumcision but three techniques are used regularly: the and anxiety, especially in the patient less than 4 years, is Mogen clamp, the Gomco clamp, and the Plastibell the main limitation for local anesthesia in meatotomy proDevice. Previously published articles revealed that cedure. Besides, meatoplasty under general anesthesia had neonatal circumcision using Plastibell Device with intact a lower recurrence rate compared to meatotomy under frenulum technique decreases the rate of delayed MS local anesthesia (0.2% vs 3.5%) (3, 6, 8).

(10), whatever in our study frequency of MS between the Although in some parts of the world like our country Sleeve and the Plastibell methods was not statically sig(Iran) the cost of a meatotomy under GA and meatotomy nificant between groups. under local anesthesia might be roughly the same (8).

Sever MS is a late complication that is mainly noticed 1Mahmoudi et al. mentioned that US might not be neces2 years after circumcision which is simply treated by sary for every patient with MS after meatotomy. meatotomy.

However, it is recommended to perform the radiologic Meatotomy is a simple common procedure for the treatstudy in cases of specific symptom continuation. We ment of MS that can be performed with minimal instruagree with him and we also did not perform any US after mentation and in this procedure, the ventrum of the meatotomy procedure unless specific symptom was meatus is crushed with a straight clamp and then the found in post-surgical follow-up (15). crushed ventral tissue is incised sharply with fine-tipped The current study had some limitations. Firstly, the scissors (1). Side effects of meatotomy are bleeding dursmall size number of patients. Secondly, the lack of longing or after the procedure, mild discomfort for the first term follow-up. day following the operation, recurrence, pain, dysuria, Thirdly, the surgeon's propensity to operate could be dysuria induced urinary retention, infection, edema, biased by their propensity to diagnosis MS and this and spraying of the urine stream as a consequence of could affect the rates cited. edema for a while (2-4). Among all the complications Fourthly, it is hard to assess the quantity of bleeding by mentioned above, bleeding could be a matter of utmost laboratory investigation and the amount of bleeding and importance in which clamping time might have played the need for suturing was assessed by pediatric urologist. a key role.

Finally, it was a retrospective analysis.

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Archivio Italiano di Urologia e Andrologia 2021; 93, 2

Clamping time in meatotomy

CONCLUSIONS

The main symptoms of MS are painful urination and urine stream deviation. Additionally, clamping time for more than 2 minutes may prevent bleeding during and after meatotomy.

However, this observation needs to be validated in a large number cohort study with long-term post-procedural follow-up.

ACKNOWLEDGMENTS

The authors would like to thank Shiraz University of Medical Sciences, Shiraz, Iran and, also the Center for Development of Clinical Research of Nemazee Hospital and Dr. Nasrin Shokrpour for editorial assistance.

REFERENCES

1. Wang M-H. Surgical management of meatal stenosis with meatoplasty. J Vis Exp. 2010.

2. Van Howe RS. Incidence of meatal stenosis following neonatal circumcision in a primary care setting.Clin Pediatr. 2006; 45:49-54.

3. Ben-Meir D, Livne PM, Feigin E, et al. Meatotomy using local anesthesia and sedation or general anesthesia with or without penile block in children: a prospective randomized study. J Urol. 2011; 185:654-7.

4. Ajemian EP, Lichtwardt JR, Gonzalez J, et al. Technique for avoiding stricture following urethral meatotomy. J Urol. 1961; 86:340-2.

5. Lane JW. Modified technique of urethral meatotomy in males.

Urology. 1986; 27:170.

6. Cartwright PC, Snow BW, McNees DC. Urethral meatotomy in the office using topical EMLA cream for anesthesia. J Urol. 1996; 156:857-9.

7. Roth RB. Office Urology. J Postgrad Med. 1971; 49:109-13.

8. Fronczak C, Villanueva C. Clinic meatotomy under topical anesthesia.J Pediatr Urol. 2017; 13:499. e1-. e3.

9. Neheman A, Rappaport YH, Darawsha AE, et al. Uroflowmetry before and after meatotomy in boys with symptomatic meatal stenosis following neonatal circumcision-A long-term prospective study.

Urology. 2019; 125:191-5.

10. Karami H, Abedinzadeh M, Moslemi MK. Assessment of meatal stenosis in neonates undergoing circumcision using Plastibell Device with two different techniques. Res Rep Urol. 2018; 10:113.

11. Cubillos J, George A, Gitlin J, et al. Tailored sutureless meatoplasty: A new technique for correcting meatal stenosis. J Pediatr Urol. 2012; 8:92-6.

12. Priyadarshi V, Puri A, Singh JP, et al. Meatotomy using topical anesthesia: a painless option. Urol Ann. 2015; 7:67.

13. Elkhafifi MH. Presentation and management of postcircumcision meatal stenosis at Hawari Center, Benghazi, Libya: A clinical review of 86 cases. Libyan Int Med Univ J. 2019; 4:69.

14. Saeedi P, Ahmadnia H, Akhavan Rezayat A. Evaluation of the Effect of Meatal Stenosis on the Urinary Tract by using Ultrasonography. Urol J. 2017; 14:3071-4.

15. Mahmoudi H. Evaluation of meatal stenosis following neonatal circumcision. Urol J. 2005; 2:86-8.

Correspondence Mehdi Shirazi, MD shirazim@sums.ac.ir Umayir Chowdhury, MD umayir09@gmail.com Mohammad-Bagher Rajabalian, MD mj.rajabalian@yahoo.com Urology Office, Faghihi Hospital, Zand Blvd., Shiraz (Iran) Faisal Ahmed, MD (Corresponding Author) fmaaa2006@yahoo.com Urology Office, Al-Thora General Hospital, Alodine street, Ibb (Yemen) Hossein-Ali Nikbakht, MD ep.nikbakht@gmail.com Social Determinates of Health Research Center, Babol University of Medical Sciences, Babol (Iran) Khalil Al-Naggar, MD alnajjarkh1234@gmail.com Ebrahim Al-Shami, MD alshami_ebrahim@yahoo.com Urology Office, Althora General Hospital, Alodine street, Ibb (Yemen)

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DOI: 10.4081/aiua.2021.2.248

CASE REPORT

Endoscopic treatment of intraluminal ureteral suture with holmium laser Jorge Panach-Navarrete, María Negueroles-García, José María Martínez-Jabaloyas Department of Urology, University Clinic Hospital of Valencia, Facultat de Medicina i Odontologia, Universitat de València, Valencia, Spain.

Summary

Although reconstructive surgery is the most accepted treatment for ureteral injury, there are reports of cases where endourologic treatment led to correct resolution of the problem. We present the case of a female patient aged 72-year-old who was previously underwent sacralcolpopexy because of anterior vaginal compartment prolapse.

The patient underwent surgery to remove the mesh, due to the pain she had had since it was placed. A mid-line laparotomy was performed removing completely the mesh. At 48 hours after intervention, the patient started feeling an intense pain in the left renal fossa that was not relieved with anti-inflammatories and morphic drugs. In the diagnostic ureteroscopy, it was found iatrogenic suture of the ureter. Due to the availability of holmium laser, an endoureterotomy was performed in the 12h central position on the tip, with laser parameters of 1J-10Hz. A 6F ureteral stent was maintained for one month. During follow-up, the patient remained asymptomatic and without dilation of the left system on imaging tests. Although we accept that open reconstruction is the gold standard treatment for ureteral trauma, we describe holmium laser endoureterotomy as a promising technique to consider in the event of ureteral intraluminal ligation.

KEY WORDS: Ureteral trauma; Endourology; Holmium laser.

Submitted 2 February 2021; Accepted 5 February 2021

INTRODUCTION

Ureteral injury represents only 1-2,5% of urologic trauma. The main cause of ureteral injury is in 75% of the cases iatrogenic by urologic, gynaecologic, or colorectal surgery. Ureteral injury diagnosis must be suspected since there are no specific signs to identify it. Patient symptoms will depend on the degree of the wound, location, or the type of damage (perforation, ligation, transection). Computed tomography urography (CTU) and anterograde or retrograde pyelography presents high sensibility for ureteral trauma diagnosis (1).

Although reconstructive surgery is the most accepted treatment for ureteral injury, there are reports of cases where endourologic treatment led to correct resolution of the problem. Various procedures have been described from resolution of urinary leak by means of ureteral stent to ureteral realignment in case of complete transection (1). In this study, we present a case of an iatrogenic ureteral ligation with an intraluminal suture resolved by laser endoureterotomy. Here we describe the key points of the surgery as well as review similar cases reported in literature.

248

CASE

REPORT

We present the case of a female patient aged 72-year-old who previously underwent sacral-colpopexy because of anterior vaginal compartment prolapse. The patient underwent surgery to remove the mesh, due to the pain she had had since it was placed. A mid-line laparotomy was performed removing completely the mesh.

At 48 hours after intervention, the patient started feeling an intense pain in the left renal fossa that was not relieved with anti-inflammatories and morphic drugs, as well as nausea and vomiting. CT scan showed left uretero-hydronephrosis with complete ureteral dilation from a few centimetres above the bladder. Moreover, it was observed free perirenal fluid. Based on these findings, it was decided emergency surgery performing retrograde pyelography.

During pyelography (Figure 1), it was checked stop in retrograde pass contrast about 4 cm from the bladder.

With the increase of the instillation pressure of contrast in the ureter, a filiform passage of contrast was observed through the stop area. At that time, a ureteroscopy was decided, introducing a 9.5 F semi-rigid instrument to the problem area (Figure 2). Under direct vision, concentric closure of the ureter lumen could be observed, suspecting iatrogenic suture of the ureter. A guide pass was achieved through the central area of the stenotic area, verifying its correct location with intraoperative fluoroscopy. Due to the availability of holmium laser, an endoureterotomy was performed in the 12h central position on the tip, with laser parameters of 1J-10Hz. Almost instantaneously, the stenotic area was opened, showing the polyglactin suture that entered from the outside of the ureter to the inside and leaving the ureter tract with a good caliber without resistance to the passage of the ureteroscope. In the rest of the ureter no injuries were evidenced.

A 6 F ureteral stent was maintained for one month.

During follow-up, the patient remained asymptomatic and without dilation of the left system on imaging tests.

DISCUSSION

The use of holmium laser for the endoscopic treatment of intraluminal ureteral sutures has been previously described, with correct resolution in all cases.

The summary of the published literature is summarized in Table 1 (2-5).

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 2

Treatment of intraluminal ureteral suture

Figure 1.

Retrograde pyelography where a retrograde stop in the contrast passage was found about 4 cm from the bladder.

By increasing the instillation pressure of contrast in the ureter, a filiform passage (white arrow) of contrast was observed through the stop area.

Figure 2.

Image of ureteroscopy.

(A) Guide passage through the stenotic area.

(B) Endoureterotomy with holmium laser in position 12h on the guide.

(C) Image of the injured area once the stenosis has been incised.

The white arrow indicates the polyglactin suture, with the gray arrow the area of the ureter wall incised with laser.

As can be seen in the review, endoscopic ureterotomy is a successful surgery which can prevent the patient from a more aggressive surgery.

As shown in Table 1, the use of the balloon dilatation catheter or the weeks of permanence of the stent are not clearly defined.

In our experience, the clinical course of the patient was optimal without the use of a balloon and with maintenance of the stent for 4 weeks. From our point of view, it is a simple endourological procedure if you are used to ureteroscopy.

The main limiting factor could be the availability of laser in case of emergency surgery, so the possibility of its use must be foreseen. Although we accept that open reconstruction is the gold standard treatment for ureteral trauma, we describe a promising technique to consider in the context of ureteral intraluminal ligation.

REFERENCES

1. Bryk DJ, Zhao LC. Guideline of guidelines: a review of urological trauma guidelines. BJU Int. 2016; 117:226-34.

2. Hao Z, Zhang L, Zhou J, et al. Minimally Invasive Management of Iatrogenic Ureteral Injuries with Ureteroscope Facilitated by Holmium YttriumAluminum-Garnet Laser. Int Sch Res Notices. 2014; 2014:307963.

Table 1.

Endoscopic treatment of intraluminal sutures, summary of published cases.

Author Hao, Z. (2) Bagley, D.H. (3) Lawrentschuk (4) Klett, D.E. (5)

Number of cases 12 1 1 1

Balloon dilatation catheter Yes No No No

Weeks of stent 12 weeks 6 weeks 2 weeks 8 weeks

Success 100% 100% 100% 100%

Postoperative complication No No No No

3. Bagley DH, Schultz E, Conlin MJ. Laser division of intraluminal sutures. J Endourol. 1998; 12:355-7.

4. Lawrentschuk N, Rogerson J, Bolton DM. Use of holmium laser for removal of an intraluminal ureteric suture. Int J Urol. 2004; 11:916-8.

5. Klett DE, Mazzone A, Summers SJ. Endoscopic Management of Iatrogenic Ureteral Injury: A Case Report and Review of the Literature. J Endourol Case Reports. 2019; 142-144.

Correspondence Jorge Panach-Navarrete, MD (Corresponding Author) jorge.panach@uv.es María Negueroles-García, MD maria.negueroles@gmail.com José María Martínez-Jabaloyas, MD, PhD marjabaloyas@gmail.com Department of Urology, University Clinic Hospital of Valencia, Facultat de Medicina i Odontologia, Universitat de València, Valencia, Spain Av Blasco Ibáñez, 17, CP 46010 Valencia, Spain

Archivio Italiano di Urologia e Andrologia 2021; 93, 2

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