Renal & Urology News - July-August 2020 Issue

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VOL UME 19, IS SUE NUMBE R 4

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Hypokalemia Common With COVID-19 Investigators implicate renal loss of potassium as a result of disordered renin-angiotensin-system activity COVID-19 AND HYPOKALEMIA More than half of 175 patients hospitalized with COVID-19 in Wenzhou, China, had hypokalemia, according to investigators.*

Normokalemia (K+ above 3.5 mmol/L)

37% 46% 18%

Hypokalemia (K+ 3-3.5 mmol/L) Severe hypokalemia (K+ below 3 mmol/L) *Total percentage exceeds 100% due to rounding.

Source: Chen D, et al. Assessment of hypokalemia and clinical characteristics in patients with coronavirus disease 2019 in Wenzhou, China. JAMA Netw Open. 2020;3(6):e2011122.

BY JODY A. CHARNOW HYPOKALEMIA is highly prevalent among patients with coronavirus disease 2019 (COVID-19), according to investigators.

In a study of 175 patients with COVID-19 receiving care at hospitals in Wenzhou, Zhejiang Province, China, 64 (37%) had hypokalemia, 31 (18%) had severe hypokalemia, and 80 (46%) had normokalemia, Dong Chen, MD, of The Ding Li Clinical College of Wenzhou Medical University, and colleagues reported in JAMA Network Open.

The novel coronavirus that causes COVID-19 — severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) — binds to angiotensin-converting enzyme 2 (ACE2). The investigators

Hemodialysis Ups RCC Death Risk Belimumab May PATIENTS WITH renal cell carci- prognostic factor for cancer-specific Improve Renal noma (RCC) have a higher risk of dying survival among patients with RCC. from the cancer if they are on hemodiThe 5-year cancer-specific survival Outcomes in LN alysis (HD), according to a new study. rate was 82.8% among the HD patients Among 388 patients who underwent partial or radical nephrectomy for RCC at a Japanese hospital from 2005 to 2013, the 66 patients on HD had a significant 5.1-fold increased risk for cancer-specific mortality compared with the 322 patients not on dialysis, after adjusting for tumor stage and size, Fuhrman nuclear grade, and other factors, Noriko Hayami, MD, of Toranomon Hospital in Kanagawa, Japan, and colleagues reported in Seminars in Dialysis. The investigators said their report is the first to document HD as being an independent

compared with 93.5% for the patients not on dialysis.

The study also found that the incidental diagnosis of RCC was less frequent in the HD group than in the patients not on dialysis (65% vs 78%).

Compared with the nondialysis group, the HD group had a higher proportion of patients with multicentric tumors (41% vs 1.2%), bilateral disease (14% vs 0.6%), and papillary histology (18 vs 7%). In addition, tumors in the HD group were smaller and of lower stage compared with tumors in the continued on page 10

ADDING BELIMUMAB to standard therapy for lupus nephritis (LN) is associated with better renal outcomes compared with standard therapy alone, according to data presented at the European Renal Association-European Dialysis and Transplant Association 2020 virtual congress.

The data are from the 2-year BLISSLN study, a randomized, double-blind, placebo-controlled trial that included 448 adult patients with active LN. Patients who received belimumab, a recombinant human monoclonal antibody approved for use in patients older than 5 years with active systemic lupus erythematosus, in addition to standard therapy were significantly more likely than those who received placebo plus standard therapy to have a primary efficacy renal response (PERR, 43% vs 32%) and a complete renal response (CRR, 30% vs 19.7%) at 2 years.

Investigators Brad H. Rovin, MD, Director of the Division of Nephrology continued on page 10

concluded that the high prevalence of hypokalemia among patients with COVID-19 suggests the presence of disordered renin-angiotensin-system (RAS) activity, which increases as a result of decreased counteractivity of ACE2.

Patients with severe hypokalemia (plasma potassium levels below 3 mmol/L) were treated with potassium chloride supplements at a dosage of 3 g/d, for a total mean of 34 g of potassium chloride during their hospital stay. Three severely ill patients with hypokalemia required potassium supplements for 10 to 14 days to have steady normokalemia, whereas 3 mildly ill patients with hypokalemia achieved continued on page 10

IN THIS ISSUE 8

Higher muscle-to-fat ratio is associated with lower CKD risk

10

AKI is linked to a decreased likelihood of kidney stones

13

Odds of prostate cancer higher among metformin users

18

Diet is a factor in urologic and renal diseases

21

Acute myocardial infarction risk higher in HD than PD patients

22

Kidney stones are associated with elevated glucose in men

22

Bariatric surgery may prolong survival in patients with ESKD Nutrition impacts urologic and renal diseases.

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New Guideline Issued for Managing Advanced PCa

BY JODY A. CHARNOW THREE MAJOR MEDICAL organizations have released a new clinical guideline to help physicians manage advanced prostate cancer (PCa).

The guideline, a joint effort of the American Urological Association (AUA), American Society for Radiation

Oncology (ASTRO), and Society of Urologic Oncology (SUO), provides recommendations for early evaluation and counseling as well as diagnostic workups and treatments.

The guideline, which was developed by a panel of experts, provides recommendations for men with biochemical

recurrence without metastatic disease after exhaustion of local treatment options; nonmetastatic hormone-sensitive prostate cancer (nmHSPC); nonmetastatic castration-resistant prostate cancer (nmCRPC); metastatic castrationresistant prostate cancer (mCRPC); and bone health.

In an AUA news release, William Lowrance, MD, MPH, who chaired the guideline panel, noted that PCa care has been evolving rapidly in the past several years because of changes in PSA screening standards and the approval of new classes of treatment options for use in various prostate cancer

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disease states. The new guideline comprises clinical recommendations based on this new evidence “and aims to further support the medical community and patients as they navigate through the various stages of this disease,” Dr Lowrance said.

The guideline panel strongly recommends that continued androgen deprivation therapy (ADT) in combination with either androgen pathway directed

therapy or docetaxel chemotherapy be offered to patients with mHSPC. Androgen pathway directed therapy includes abiraterone plus prednisone, apalutamide, and enzalutamide. The panel also strongly recommends that these patients not be offered first-generation antiandrogens (such as bicalutamide or flutamide) in combination with luteinizing hormone releasing hormone (LHRH) agonists, except

to block testosterone flare. Both of these recommendations are based on what the guideline panel considers grade A evidence, defined as coming from well-conducted and highlygeneralizable randomized controlled trials (RCTs) or exceptionally strong observational studies with consistent findings.

To establish prognoses for men with ­ oderate mHSPC, the panel makes a m

Renal & Urology News 3

recommendation, based on grade B ­evidence (defined as data from RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings), that clinicians should assess if a patient with newly diagnosed mHSPC “is experiencing symptoms from metastatic disease at the time of presentation to guide discussions of prognosis and further

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PCa guidelines continued from page 3

­ isease m d ­ anagement.” By way of clinical principles, according to the panel, clinicians should assess the extent of metastatic disease using conventional imaging in men with newly diagnosed mHSPC and obtain a baseline PSA measurement and serial PSA measurements at 3- to 6-month intervals

after starting ADT and consider periodic conventional imaging. The panel ­defined a clinical principle “as a statement about a component of clinical care widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature.”

In addition, the panel recommends, based on expert opinion, that men with mHSPC be offered genetic c­ ounseling

and germline testing, regardless of age and family history.

For men with nmCRPC, clinicians should obtain serial PSA measurements every 3 to 6 months and calculate a PSA doubling time (PSADT) starting from onset of castration resistance, a recommendation based on clinical principle.

Clinicians also should assess patients for development of metastatic disease using c­ onventional imaging at intervals

of 6 to 12 months, a recommendation based on expert opinion.

Regarding treatment, the guideline panel strongly recommends, based on grade A evidence, that clinicians offer patients apalutamide, darolutamide, or enzalutamide with continued ADT to those at high risk of progressing to metastatic disease, defined as patients with a PSADT of 10 months or less.

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Clinicians should assess men with mCRPC for extent of metastatic disease using conventional imaging at least annually or at intervals determined by lack of response to therapy. They should also offer patients germline testing and somatic tumor genetic testing “to identify DNA repair deficiency mutations and microsatellite instability status that may inform prognosis and counseling regarding family risk as well as potential

targeted therapies.” Both of these recommendations are based on expert opinion.

The guideline strongly recommends that patients with newly diagnosed mCRPC be offered continued ADT with abiraterone plus prednisone or enzalutamide (grade A evidence) or docetaxel (grade B evidence).

The panel strongly recommends, based on grade B evidence, that clinicians offer radium-223 treatment to

patients who have symptomatic bony metastases from mCRPC and without known visceral metastases.

Noting that optimal sequencing of agents in mCRPC remains an understudied area of research, the guideline panel gives a moderate recommendation, based on grade B evidence, to “consider prior treatment and consider recommending therapy with an alternative mechanism of action.”

Renal & Urology News 5

The panel strongly recommends, based on grade B evidence, that men with mCRPC who received prior docetaxel chemotherapy and abiraterone plus prednisone or enzalutamide be offered cabazitaxel instead of an alternative androgen pathway directed therapy.

Bone Health The also offered clinical principles with respect to bone health in men with advanced PCa. Clinicians should discuss the risk of osteoporosis associated with ADT and assess the risk of fragility fracture. They also should recommend preventive treatment for fractures and skeletal-related events (SREs), including supplemental calcium, vitamin D, smoking cessation, and weight-bearing exercise. For patients with a high fracture risk due to bone loss, clinicians should recommend preventive treatments with bisphosphates or denosumab.

In a moderate recommendation based on grade B evidence, the guideline advises clinicians to prescribe a boneprotective agent such as denosumab or zoledronic acid for men with bony metastases to prevent SREs.

Clinicians should discuss with patients the ADT-associated risk of osteoporosis.

“The treatment landscape of advanced prostate cancer has expanded rapidly over the past decade driven by our better understanding of the molecular underpinning of prostate cancer,” said Keyan Salari, MD, PhD, a urologic oncologist and surgeon at Massachusetts General Hospital in Boston. “The new guideline provides an important, unified resource for the medical community to help navigate this complex landscape.”

Notably, Dr Salari told Renal & Urology News, the guideline recommends germline genetic testing for all patients with metastatic hormonesensitive or castration-resistant PCa as well as somatic tumor genetic testing in patients with mCRPC to identify DNA repair deficiency mutations and microsatellite instability status. “This new guideline reflects our growing appreciation of how the genetic makeup of a patient’s tumor can inform prognosis and treatment decisions and ultimately help us realize the potential of precision cancer medicine,” he said. ■

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FROM THE EDITOR EDITORIAL ADVISORY BOARD

The Rise of Prostate Cancer Genetic Testing

G

enetic testing is increasingly being integrated into the management of men with prostate cancer (PCa) as part of a larger move to personalized medicine.

Clinicians routinely use commercially available genetic assays to identify inherited (germline) mutations that may place men at higher risk for PCa death. Regarding diagnostic risks, genetic assays can help clinicians distinguish men predisposed to aggressive disease from those who likely will have an indolent course so they can adjust screening accordingly. When therapy is needed, results of genetic tests also help guide the use of targeted therapies for men with advanced PCa. For example, identifying certain DNA-repair gene alterations is a prerequisite to the use of PARP inhibitors in men with metastatic castration-resistant prostate cancer (mCRPC).

Recognition of the importance of genetic testing in PCa risk assessment and management has been underscored by the release of 2 new guidelines. One guideline emerged from the 2019 Philadelphia Prostate Cancer Consensus Conference hosted by the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia (see article on page 21). The guideline strongly recommends that the BRCA2 gene be included in all testing scenarios to inform precision therapy in metastatic prostate cancer and to inform active surveillance discussions in early-stage disease and PCa early detection strategies. For men with non-metastatic PCa, the guideline recommends that germline testing be considered for men with Ashkenazi Jewish ancestry, advanced disease (T3a or higher), intraductal or ductal pathology, or Grade Group 4 disease (Gleason sum 8) or higher. Germline testing is recommended for men with 1 brother or father or 2 or more male relatives diagnosed with PCa when they were younger than 60 years, died from PCa, or had metastatic PCa. The other guideline, which was developed jointly by the American Urological Association, American Society for Radiation Oncology, and Society of Urologic Oncology, contains recommendations for managing advanced PCa that include the use of genetic testing (see article on page 2). The guideline recommends that all men with metastatic PCa be offered genetic counseling and germline testing regardless of age and family history. For men with mCRPC, clinicians should offer germline testing and somatic tumor genetic testing “to identify DNA repair deficiency mutations and microsatellite instability status that may inform prognosis and counseling regarding family risk as well as potential targeted therapies.”

Use of PCa genetic testing to stratify risk and guide screening and management continues to gain momentum. Its inclusion into guidelines with specific recommendations could accelerate its integration into PCa care, offering the promise of more nuanced management and better outcomes.

Jody A. Charnow Editor

Medical Director, Urology

Medical Director, Nephrology

Robert G. Uzzo, MD, MBA, FACS G. Willing “Wing” Pepper Chair in Cancer Research Professor and Chairman Department of Surgery Fox Chase Cancer Center Temple University School of Medicine Philadelphia

Kamyar Kalantar-Zadeh, MD, PhD, MPH Professor & Chief, Division of Nephrology, Hypertension & Kidney Transplantation UC Irvine School of Medicine Orange, CA

Nephrologists Anthony J. Bleyer, MD, MS Professor of Internal Medicine/Nephrology Wake Forest University School of Medicine Winston-Salem, NC

Urologists Christopher S. Cooper, MD Director, Pediatric Urology Children’s Hospital of Iowa Iowa City

David S. Goldfarb, MD Professor, Department of Medicine Clinical Chief New York University Langone Medical Center Chief of Nephrology NY Harbor VA Medical Center

R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto

Csaba P. Kovesdy, MD Chief of Nephrology Memphis VA Medical Center Fred Hatch Professor of Medicine University of Tennessee Health Science Center Memphis

Stanton Honig, MD Department of Urology Yale University School of Medicine New Haven, CT J. Stephen Jones, MD Chief Executive Officer Inova Health System Falls Church, VA Professor and Horvitz/Miller Distinguished Chair in Urologic Oncology (ret.)

Cleveland Clinic Lerner College of Medicine Cleveland Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology UC Irvine School of Medicine Orange, CA James M. McKiernan, MD John K. Lattimer Professor of Urology Chair, Department of Urology Director, Urologic Oncology Columbia University College of Physicians and Surgeons New York Kenneth Pace, MD, MSc Assistant Professor, Division of Urology St. Michael’s Hospital University of Toronto Vancouver, Canada

Edgar V. Lerma, MD Clinical Associate Professor of Medicine Section of Nephrology Department of Medicine University of Illinois at Chicago College of Medicine Chicago Allen Nissenson, MD Emeritus Professor of Medicine The David Geffen School of Medicine at UCLA Chief Medical Officer, DaVita Inc. Denver Rulan Parekh, MD, MS Associate Professor of Pediatrics and Medicine University of Toronto Robert Provenzano, MD Associate Professor of Medicine Wayne State University School of Medicine Detroit Vice President of Medical Affairs, DaVita Healthcare Denver Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital Teaneck, NJ

Renal & Urology News Staff Editor Jody A. Charnow Web editor Natasha Persaud Production editor Kim Daigneau Group creative director Jennifer Dvoretz Production manager Brian Wask Vice president, sales operations and production Director of audience insights National accounts manager Editorial director, Haymarket Oncology

Louise Morrin Boyle Paul Silver William Canning Lauren Burke

Vice president, content, medical communications Kathleen Walsh Tulley General manager, medical communications President, medical communications Chairman & CEO, Haymarket Media Inc.

James Burke, RPh Michael Graziani Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 19, Number 4. Published bimonthly by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales & Editorial, call (646) 638-6000 (M–F, 9am–5pm, ET). For reprints/ licensing, email Kerry Niessing at kerry.niessing@haymarketmedia.com, or call (646) 638-6026. Postmaster: Send address changes to Renal & Urology News, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018. All rights reserved.

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Contents

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J U LY / A U G U S T 2 0 2 0

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Nephrology 10

ONLINE

this month at renalandurologynews.com

21

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Clinical Quiz Test your knowledge by taking our latest quiz at renalandurologynews.com/ run-quiz

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HIPAA Compliance Read timely articles on various issues related to keeping protected health information secure.

Drug Information Search a comprehensive drug database for prescribing and other information on more than 4000 drugs.

News Coverage Visit our website for daily reports on the latest developments in clinical research.

AMI Is More Likely in HD vs PD Patients Compared with patients on peritoneal dialysis, those on hemodialysis have a significant 30% higher risk for acute myocardial infarction.

Bariatric Surgery Ups Survival in ESKD Obese patients with kidney failure who had bariatric surgery experienced a significant 31% decreased risk of death compared with those who received usual care.

PD Infection Rates Vary By Country Peritonitis rates, in episodes per patient-year, ranged from 0.26 in the United States to 0.40 in Thailand, according to findings from the Peritoneal Dialysis Outcomes and Practice Patterns Study.

VOLUME 19, ISSUE NUMBER 4

CALENDAR Editor’s note: With the cancellation of medical conferences thus far in 2020 in response to the COVID-19 pandemic and the status of other meetings unclear, we are providing listings of medical conferences scheduled for 2021.

Genitourinary Cancer Symposium San Francisco January 21 to 23, 2021 American Urological Association Annual Meeting Las Vegas May 13–14, 2021 ERA-EDTA Annual Congress Berlin, Germany June 5–8, 2021 Canadian Urological Association Annual Meeting Niagara Falls, Ontario, Canada June 26–29, 2021 International Continence Society Annual Meeting Melbourne, Australia October 12–15, 2021

Urology 11

Management of Low-Grade UTUC: Evolving Strategies Therapeutic goals for patients with low-grade upper tract urothelial cancer should include balancing oncologic and renal functional risks.

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Higher Risk of Prostate Cancer Observed in Metformin Users Use of the diabetes drug was significantly associated with 76% increased odds of highgrade PCa, a study found.

Job Board Be sure to check our latest listings for professional openings across the United States.

AKI Linked to Reduced Stone Risk A history of acute kidney injury is significantly associated with a 58% decreased risk for kidney stones, investigators reported.

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PCa Genetic Testing Guideline Issued Genetic testing is recommended for all men with metastatic prostate cancer.

Kidney Stones Are Associated with Higher Glucose in Men Men with glucose levels of 126 mg/dL or higher had a 27% increased risk for kidney stones compared with those who had levels below 90 mg/dL.

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Departments 6

From the Editor New guidelines elevate role of genetic testing in prostate cancer

8

News in Brief Re-treatment in stone cases is more likely with shock wave lithotripsy

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Ethical Issues in Medicine Choose words carefully when explaining treatment risks to patients

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Practice Management Improving the bottom line during the COVID-19 pandemic

The new guideline provides an important,

unified resource for the medical community to help navigate this complex landscape.

See our story on page 2

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News in Brief

Please visit us at www.renalandurologynews.com for the latest news updates from the fields of urology and nephrology

Short Takes Avelumab Cleared for UC Maintenance Treatment

found that 47% of them did not see

Avelumab has received FDA approval

a rheumatologist over 1 year of follow-

for the maintenance treatment of

up, Laura Bartels-Peculis, PharmD, of

patients with locally advanced or

Mallinckrodt Pharmaceuticals, Inc., of

metastatic urothelial carcinoma (UC)

Bedminster, New Jersey, and col-

that has not progressed with first-line

leagues reported.

a nephrologist and 36% did not see

Guideline-recommended preventive

platinum-containing chemotherapy.

therapy with hydroxychloroquine was

The agency based the approval on data from the multicenter, parallel-arm

prescribed for 54% of patients, the

phase 3 JAVELIN Bladder 100 study,

researchers noted.

which compared avelumab plus best Overall survival was 21.4 months in

Radical Cystectomy Costs More for Obese Patients

the avelumab arm compared with

Radical cystectomy (RC) costs signifi-

14.3 months for BSC alone. The

cantly more for obese and morbidly

avelumab-treated patients had a sig­nif­

obese patients than for those who

icant 31% decreased risk of death.

are overweight, new data published in

supportive care (BSC) with BSC alone.

Urologic Oncology suggest.

Health Resource Underuse

By LN Patients Reported

cost of the RC index hospitalization

Patients with lupus nephritis (LN)

for overweight patients was $24,596,

insured by a large commercial health

Melissa J. Huynh, MD, of Brigham

plan in the United States appeared

and Women’s Hospital in Boston, and

to underuse outpatient specialist

colleagues reported. For obese and

services and guideline-recommended

morbidly obese patients, however, the

hydroxychloroquine therapy, according

costs were $2158 and $5308 higher,

to findings published in Open Access

respectively. Increased operative

Rheumatology: Research and Reviews.

times and longer hospital stays were

In a study of 1242 patients, the

The study of 1039 patients with LN

the main contributors to the higher costs, according to the investigators.

(median age 47 years; 83% female)

Sex Differences Among Gout Patients A new study confirms sex differences in clinical characteristics and comorbidities among patients with newly diagnosed gout. Compared with men, women on average were older and had higher serum uric acid levels, and they were more often obese. Women also were more likely to have the comorbidities shown here.

78%

80 64%

56%

Percentage

60 40

39%

31%

17%

20 0

■ Women ■ Men

Reduced renal function

Hypertension

Type 2 diabetes

23% 12% Heart failure

Source: Kampe KT, et al. Sex differences in the clinical profile among patients with gout: Cross-sectional analyses of an observational study.

J Rheumatol. 2020; published online ahead of print. doi: 10.3899/jrheum.200113

PUL Outcomes Favorable, Durable for Up to 24 Months P

rostatic urethral lift (PUL), a minimally invasive treatment for benign prostatic hyperplasia, is well tolerated and provides favorable and durable functional outcomes for up to 24 months, according to a new systematic review and metaanalysis published in International Urology and Nephrology (2020;52:999-1008).

The review, by Karthik Tanneru, MD, of the University of Florida in Jacksonville, and colleagues included 5 studies, both randomized and nonrandomized, enrolling a total of 322 patients who underwent PUL (Urolift) and were available for follow-up at 24 months. The investigators categorized patients in the randomized studies as group A and those in nonrandomized studies as group B. At 24 months, the mean reduction in International Prostate Symptom Score from baseline was 9.1 and 10.4 in groups A and B, respectively. The mean improvement in peak flow rate was 3.7 and 3.0 mL/s in groups A and B, respectively. Both groups experienced improvement in quality of life.

Higher Muscle-to-Fat Ratio Linked to Lower CKD Risk H

igher muscle mass relative to fat mass may decrease the risk of chronic kidney disease (CKD) among individuals with normal renal function, investigators concluded in the Journal of Cachexia, Sarcopenia and Muscle (2020;11:726-734).

In an analysis of data from 7682 participants in the prospective communitybased Korean Genome and Epidemiology Study, Jong Hyun Jhee, MD, of Yonsei University College of Medicine, Seoul, Korea, and colleagues found that each 1-point increase in muscle-to-fat (MF) ratio was significantly associated with a 14% decreased risk of CKD in adjusted analyses. CKD, defined as an estimated glomerular filtration rate below 60 mL/min/1.73 m2, developed in 633 individuals (8.2%) during a median follow-up of 140 months.

Re-Treatment Is More Likely With Shock Wave Lithotripsy R

e-treatment for kidney and ureteral stones is more likely with shock wave lithotripsy (SWL) than ureteroscopy (URS), investigators reported in the Journal of Urology (2020;203:1156-1162).

Diana K. Bowen, MD, of The Children’s Hospital of Pennsylvania in Philadelphia, and collaborators studied a retrospective cohort using all-payer claims data for patients who underwent SWL or URS from 1997 to 2016 at 74 hospitals in South Carolina. The primary outcome measure was subsequent SWL or URS within 6 months of initial surgery.

Overall, 136,152 SWL and URS procedures were performed in 95,227 unique patients, with re-treatment representing 9% of all surgeries, according to the researchers. SWL was significantly associated with 20% increased odds of retreatment compared with URS. Patients with initial SWL were more likely to have SWL for re-treatment (84.6%) than those patients who had initial URS were to have re-treatment with URS (29.3%), the investigators reported.

“These results have implications for shared decision making and value based surgical treatment of nephrolithiasis,” the authors concluded.

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AKI Linked to Reduced Stone Risk ACUTE KIDNEY injury is associated with a lower risk of subsequent kidney stone formation, according to data presented at the European Renal Association-European Dialysis and Transplant Association 2020 virtual congress.

Hicham Cheikh Hassan, MB BCh, of Wollongong Hospital in New South Wales, Australia, and colleagues studied 180,927 hospitalized adult patients, of whom 12,338 (6.8%) were diagnosed with AKI and 4495 (2.5%) with kidney stones.

Patients with AKI were more likely

Hypokalemia continued from page 1

normokalemia after receiving potassium supplements for 5 to 8 days.

“Because of the possible effects on cardiovascular functions, neurohormonal activation, and other vital organs by hypokalemia, clinicians should pay attention to hypokalemia and the patients’ response to [potassium] supplements,” the authors advised.

Hypokalemia correction is challenging because of continuous renal loss of potassium resulting from the degradation of ACE2 by the binding of SARSCoV-2, according to the investigators.

The cessation of potassium loss may be a reliable, timely, and sensitive biomarker that reflects the end of disruption of the RAS by the coronavirus, they stated.

The present study also found that the degree of hypokalemia was a­ ssociated

with some clinical features that reflected the severity of the disease, including underlying conditions, high body temperature, and, notably, elevated laboratory indices reflecting myocardial injuries.

Although both gastrointestinal (GI) and urinary loss of potassium could cause hypokalemia, the study’s

Continuous renal loss of potassium makes hypokalemia correction challenging. f­indings suggest that GI loss might not contribute much to hypokalemia, the investigators said. Only a small proportion of patients with hypokalemia had GI symptoms, they noted.

In addition, among patients with

hypokalemia, there were no differences between those with and without diarrhea, and most patients had mild diarrhea. “Therefore, hypokalemia might primarily result from increased urine loss.”

The new report adds to growing evidence of COVID-19’s adverse effects on the kidneys. For example, investigators at the Feinstein Institutes for Medical Research in Manhasset, New York, found that acute kidney injury (AKI) developed in 1993 (36.6%) of 5449 patients hospitalized with COVID-19 at 13 Northwell Health hospitals in the New York metropolitan area from March 1 to April 5, 2020. According to the report, which was published in Kidney International, AKI was mainly observed in patients with respiratory failure, with AKI developing in 89.7% of patients on mechanical ventilation compared with 21.7% of patients not requiring ventilation. ■

to be older (75 vs 50 years) and have more comorbidities such as diabetes (21.5% vs 9.4%), hyperten-

Belimumab for LN

sion (31.8% vs 12.7%), coronary

continued from page 1

artery disease (14.6% vs 7%), and

at Ohio State University Wexner Medical Center in Columbus, and his collaborators defined PERR as a urine protein creatinine ratio (UPCR) of 0.7 or less, estimated glomerular filtration rate (eGFR) not exceeding 20% below pre-flare value or 60 mL/min/1.73 m2 or higher, and no treatment failure. They defined CRR as a UPCR below 0.5, an eGFR not more than 10% below preflare value or 90 mL/min/1.73 m2 or higher, and no treatment failure.

In the study, 118 patients received cyclophosphamide (CYC)-based induc­tion therapy followed by azathioprine maintenance of remission and 328 patients received mycophenolate mofetil (MMF) for both induction and maintenance of remission therapy.

Overall, 224 patients received belimumab and 224 received placebo.

peripheral vascular disease (5.4% vs 1.8%), the investigators reported.

The proportion of patients with kidney stones was significantly lower in those with a history of AKI than in those who never had AKI (1.1% vs 2.5%). A history of AKI was significantly associated with a 58% decreased risk of kidney stones compared with no AKI history.

When the investigators compared the 12,338 AKI patients with a propensity score–matched cohort of 12,338 patients with no AKI, they found that AKI was significantly associated with a 43% decreased risk of kidney stones.

“Our findings suggest that patients with AKI appear to be at

Overall, 28.3% of placebo recipients experienced a renal-related event or death compared with 15.7% of belimumab-treated patients. Belimumabtreated patients had a significant 49% lower risk of a renal-related event or death at any time point during the study compared with placebo recipients.

Belimumab found to lower the risk of a renal-related event or death vs placebo.

“MMF is already used in many patients. It has been shown to be equivalent to cyclophosphamide in the induction therapy of LN, and superior to azathioprine in the maintenance phase.

Adding belimumab can f­ urther improve

the treatment results,” Dr Rovin said in an ERA-EDTA press statement.

Among patients who received CYC induction, 33.9% of belimumabtreated patients achieved PERR at 104 weeks compared with 27.1% of placebo recipients. Among patients who received MMF induction, 46.3% of belimumab-treated patients achieved PERR at 104 weeks compared with 34.1% of placebo recipients.

Among patients who received CYC induction, both belimumab-treated patients and placebo recipients achieved a CRR of 18.6% at week 104, whereas among those who received MMF induction, a significantly higher proportion of belimumab-treated patients than placebo recipients had a CRR (34.1% vs 20.1%).

The safety profile for belimumab plus standard therapy was similar to that of standard therapy alone, according to Dr Rovin. ■

significantly lower risk of developing subsequent kidney stone formation when compared to patients with no previous AKI episodes,” Dr Hassan’s team concluded in a poster presentation.

The investigators explained that AKI may result in long-term renal damage and fibrosis. A potential effect is impairment in urine concentration that would limit kidney stone formation, they noted. No prior study has examined this potential association. ■

RCC death risk continued from page 1

­ ondialysis group. The HD group had n a higher proportion of patients with Fuhrman nuclear grade 3 (13% vs 4%) and 4 (18% vs 8%) disease.

In addition, the study found that tumor stage and Fuhrman nuclear grade independently predicted ­cancerspecific survival. On multivariate analysis, tumor stages II, III, and IV were significantly associated with 7.5-, 38.2-, and 125-fold increased risk for RCC mortality, respectively,

c­ ompared with stage I. Compared with Fuhrman nuclear grade 1, grade 4 was significantly associated with a 26-fold increased risk for RCC mortality.

Patients in both the HD and nondialysis groups had a median age of 61 years. The median follow-up period was shorter for the HD group (42.5 vs 54.5 months).

The incidence of RCC is high among patients with end-stage kidney disease, Dr Hayami’s team noted. Factors possibly associated with this higher incidence include depressed immunity, oxidative stress, impairment of DNA

HD patients had a 5.1-fold higher risk of RCC death than nondialysis patients. repair, and excessive production of free radicals related to inflammation.

In addition to its retrospective nature, the study was limited by the small number of HD patients, a consequence of having been conducted at a single center, according to the i­ nvestigators. ■

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COVID-19 Infection Risk Lower in ADT Recipients MEN RECEIVING androgen deprivation therapy (ADT) for prostate cancer (PCa) appear to be at lower risk for infection by the coronavirus that causes COVID-19, according to a new report.

In a study of men with PCa in Veneto, an Italian region especially hard hit by COVID-19, only 4 of the 5273 patients receiving ADT became infected with the SARS-CoV-2 coronavirus compared with 114 of the 37,161 who were not receiving ADT. Compared with ADT recipients, the no-ADT group had significant 4-fold increased odds of testing positive for SARS-CoV-2, a team led by Andrea Alimonti, MD, of the Università della Svizzera Italiana in Bellinzona, Switzerland, reported in Annals of Oncology.

Study findings showed that cancer patients have an increased risk of SARS-CoV-2 infection compared with noncancer patients. For example, of Veneto’s total male population of 2.4 million, 0.2% of patients with cancer tested positive for SARS-CoV-2 compared with 0.3% of those without cancer, Dr Alimonti and his colleagues reported.

The authors speculated that the apparent protective effect of ADT may involve inhibition of TMPRSS2, a serine protease involved in multiple physiologic and pathologic processes, including cancer and viral infection. Previous studies have implicated TEMPRSS2 as a critical host cell factor for the spread of several clinically relevant viruses, including SARS-CoV and MERS-CoV

PSA screening benefit continued from page 1

may not provide a “sufficient time horizon” to examine the mortality benefit from screening because men often begin screening in their 50s and the median age at death from PCa is 80 years. Based on their analysis, they estimated that 385 men would have to be screened and 11 additional cases of PCa would need to be diagnosed to prevent 1 PCa death over a 25-year time span.

In an interview, Dr Shoag called these projections extremely conservative and pointed out that PSA screening has benefits beyond lowering PCa death risk, such as prevention of metastatic disease

Prostate MRI continued from page 1

time between prostate biopsies was 16.5 months. The overall negative predictive value (NPV) of a negative mpMRI scan was 79.5%. The NPV ranged from 74.4% at the confirmatory (second) biopsy to 84.6% for all subsequent biopsies up to the fourth surveillance biopsy.

Further, among men with a PSA density (PSAD) of 0.15 ng/mL/cm3 or

RCC death risk continued from page 1

­ ondialysis group. The HD group had n a higher proportion of patients with Fuhrman nuclear grade 3 (13% vs 4%) and 4 (18% vs 8%) disease.

In addition, the study found that tumor stage and Fuhrman nuclear grade

coronaviruses. TEMPRSS2 is highly expressed in localized and metastatic PCa, and its transcription is regulated by androgen receptors (ARs). ARs have been shown to regulate TMPRSS2 expression in nonprostatic tissue,

including the lung. “The androgendependent regulation of TMPRSS2 expression in the lung may explain the increased susceptibility of men to

develop SARS-CoV-2 severe infections when compared with women.”

They also observed, “Given that TMPRSS2 levels are under the control of androgens not only in the prostate but also in the lung, we put forward the hypothesis that androgen deprivation therapies (ADTs) may protect patients affected by prostate cancer from SARSCoV-2 infections,” the authors explained.

Dr Alimonti and his colleagues noted that cancer patients infected with SARS-CoV-2 are more often hospitalized than noncancer patients, so they may have been tested for the coronavirus at a higher rate. “This may explain the higher prevalence of infected individuals in the cancer patient population,” the investigators wrote. ■

and the impaired quality of life associated with its treatment.Regarding the PSA test, he observed, “It’s been in use for 3 decades, and we’re turning our backs on it based on misguided assumptions.”

Data suggest that the incidence of metastatic PCa at diagnosis is rising after many years in decline, and this apparent trend is part of the reason for conducting the new analysis, said senior investigator Jim C. Hu, MD, MPH, also of Weill Cornell Medicine. A plausible explanation for this trend is a decline in screening following release of 2012 guidelines from the US Preventive Services Task Force that discouraged screening.

Dr Hu said information on PSA screening disseminated by the task

force is misleading and based on obselete data. In particular, he has issues with a chart aimed at patients titled “Is Prostate Cancer Screening Right for You,” in which the task force recommends that for men aged 55 to 69 years, the decision to receive PSA screening should be an individual one. The chart informs patients about the sequence of events set in motion by PSA screening, starting with 1000 men offered screening. According to the chart, 240 will get a positive result showing an elevated PSA level, and of these, 100 will be found to have PCa on a prostate biopsy.

The chart also informs patients about the potential side effects of prostate biopsies (pain, bleeding, and infection)

and complications of treatment, namely erectile dysfunction and urinary incontinence. Dr Hu said the information provided in the chart is outdated, fails to capture recent trends in PCa detection and management, and does not represent the current standard of care. One trend is the use of prebiopsy magnetic resonance imaging scans of patients with an elevated PSA to identify suspicious lesions. If none are found, patients need not undergo biopsy. Dr Hu noted that approximately one third of men with an elevated PSA do not have to undergo biopsy. Another trend is the use of active surveillance to manage most men with low-risk PCa, thus addressing a concern about overtreatment. ■

higher, the overall NPV of mpMRI was 65.5% and ranged from 57.1% to 73.3% across serial mpMRI scans. In contrast, among patients with a PSAD less than 0.15 ng/mL/cm3 and a prior confirmatory biopsy, a negative mpMRI scan “appears to be reliably reassuring.”

“This is the first study reporting the NPV of mpMRI at multiple time points during AS,” the investigators wrote. “It supports previous findings that a percentage of clinical significant

prostate cancers remain undetectable by mpMRI.” The authors concluded that mpMRI alone is insufficient to rule out grade reclassification among men on AS, especially among those with a PSA density of 0.15 ng/mL/cm3 or higher, and, in particular, mpMRI should not replace confirmatory biopsy.

At diagnosis, 120 (35%) men were younger than age 60 years at diagnosis, 187 (54%) were aged 60 to 69 years, and

37 (11%) were aged 70 years or older.

White men made up 77% of the study cohort. Of the 344 patients, 158 had a PSAD of 0.15 ng/mL/cm3 or higher and 245 had a PSAD below that, the investigators reported.

With regard to study limitations, the authors noted that their findings “reflect an experience at an academic tertiary care center, which may limit the generalizability to other clinical practice settings.” ■

independently predicted cancer-specific survival. On multivariate analysis, tumor stages II, III, and IV were significantly associated with 7.5-, 38.2-, and 125-fold increased risk for RCC mortality, respectively, compared with stage I. Compared with Fuhrman nuclear grade 1, grade 4 was significantly associated with a 26-fold increased risk for RCC mortality.

Patients in both the HD and nondialysis groups had a median age of 61 years. The median follow-up period was shorter for the HD group (42.5 vs 54.5 months).

The incidence of RCC is high among patients with end-stage kidney disease, Dr Hayami’s team noted. Factors possibly associated with this higher inci-

dence include depressed immunity, oxidative stress, impairment of DNA repair, and excessive production of free radicals related to inflammation.

In addition to its retrospective nature, the study was limited by the small number of HD patients, a consequence of having been conducted at a single center, according to the investigators. ■

PCa patients not receiving ADT had 4-fold increased odds of testing positive.

www.renalandurologynews.com JULY/AUGUST 2020

Renal & Urology News 11

n REVIEW

Management of Low-Grade UTUC: Evolving Strategies Therapeutic goals should include balancing oncologic and renal functional risks

BY MARSHALL C. STROTHER, MD, AND ROBERT G. UZZO, MD, MBA

U

pper tract urothelial cancer (UTUC) represents approximately 5%-10% of all urothelial cancers, although the incidence is increasing. Modifiable risk factors include exposure to toxins such as tobacco smoke, industrial toxins (including aromatic hydrocarbons, coal, coke, chlorinated solvents, and tars), arsenic, the analgesic phenacetin, and aristolochic acid. Produced by plants of the genus Aristolochia, aristolochic acid can contaminate grain and is found in some traditional Chinese medicine. Nonmodifiable risks including gender (2:1 male: female) and genetics (eg, microsatellite instability and Lynch syndrome).1 Despite improvements in urinary markers, pathology, imaging, and endoscopy, the diagnosis and management of UTUC is complex. Unlike with bladder cancer, diagnosis and management is hindered by lack of early symptoms; limitations of radiographic diagnostic tests for small luminal tumors; complexities and variations in upper tract anatomy; need for multiple forms of evaluation to confirm the diagnosis; poor predictive value of biopsy to assess grade and stage; need to map the extent of the disease within a single or both kidneys; absence of comprehensive treatment strategies and guidelines focused on matching treatment to UTUC biology while simultaneously sparing nephrons and preserving renal function. As such, many patients are subjected to repeated laboratory, urine, imaging, and endoscopic evaluations, often under anesthesia. In the case of low-grade UTUC, current treatment options include endoscopic attempts using thermal ablation (eg, laser or cautery) with repetitive surveillance or overtreatment via nephroureterectomy with resultant loss of global kidney function.

factors w ­ arrant a renewed look at diagnostic and therapeutic options for lowgrade UTUC.

Guidelines and risk stratification

Marshall C. Strother, MD

Robert G. Uzzo, MD, MBA

While it has been estimated that bladder cancer is among the most expensive tumors to manage on a per-patient basis, due in large part to surgical, imaging, and surveillance intensity,2 UTUC may in fact be costlier given the complexities of ongoing and episodic management expenses, surgical risks, long-term complications of progressive chronic kidney disease (CKD), and/or the need for renal replacement therapy. These

Algorithms and guidelines for management of UTUC are limited and often bundled with those of bladder cancer due to the lower incidence and prevalence of UTUC, its concurrence in patients with bladder cancer, a lack of recognition of UTUC as a distinct biological entity, and lack of randomized data addressing UTUC, particularly for low-grade, low-stage disease.

The American Urological Association (AUA), the American Society of Clinical Oncology, and the European Society for Medical Oncology do not offer guidelines for managing UTUC. The National Comprehensive Cancer Network (NCCN) relegates their UTUC guidelines to the subtext of those on management of bladder cancer.3 Among major urologic and/or oncologic professional societies, only the European Association of Urology has developed specific UTUC guidelines.4 As with urothelial cancers (UC) of the bladder, UTUC risk stratification is largely based on stage and grade.

Unfortunately, unlike with bladder cancer, clinical staging is notoriously poor, while endoscopic staging and grading are far more difficult given the limitations of upper-tract radiography; endoscopic visibility and mapping; endoscopic tissue sampling given small luminal size; and adequacy of endoscopic instrumentation limiting resection particularly given the thin-walled upper tract anatomy.

While the AUA has established risk stratification criteria for non-muscle invasive bladder cancer (NMIBC) as

low, intermediate, and high risk,5 no such system exists for UTUC. Instead, World Health Organization criteria have been adopted. These criteria divide tumors into low and high risk based on tumor size, location, focality, cytology, grade on biopsy, signs of invasion on imaging,6 and architecture.4,7 Additionally, while nomograms attempting to better risk-stratify UTUC using similar clinical criteria exist,7 physicians also assess risk using cytology, biopsy, and imaging features that have not been routinely incorporated into overall risk models.

Characteristics of low-risk UTUC include low volume/low focality, small size (<2 cm), low-grade cytology confirmed by biopsy, and no evidence of invasion on imaging.4 Although insufficient data exist to subclassify low risk UTUC, smaller, lower volume, unifocal papillary lesions likely represent the lowest biological risk; however, even in cases such as this, tumor location and intrarenal anatomy may affect therapeutic options and increase the risk of nephroureterectomy.

Managing low-risk UTUC Given the complexities of endoscopic diagnosis and the management of lowrisk UTUC, many clinicians resort to radical nephroureterectomy (RNU) early in patients deemed at low risk for immediate need of renal replacement.

Unfortunately, among patients in the age demographic at risk for UTUC, up to 50% already demonstrate CKD stage 3 or higher.8 Despite this, 80% of those with low-risk UTUC undergo RNU as primary treatment.9 While this practice addresses the common risk of understaging seen in UTUC, it unfortunately underestimates the long-term

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consequences of CKD and the surgical risks in elderly patients with cancer.

As many as 1 in 3 patients ­undergoing RNU suffer a complication,8 which has also been associated with a 25%-30% decline in eGFR.10 This decline may be even greater in those with preexisting CKD stage 3 or higher. Importantly, current guidelines do not support the use of radical surgery (cystectomy) in untreated low-risk NMIBC, although more endoscopic and intravesical options exist for lower-tract UTUC.

Evolving management paradigms As mentioned, there is perceived uncertainty in assuming UTUC to be low risk given the endoscopic, pathologic, and radiographic limitations of current techniques. Based on this uncertainty, patients with adequate renal reserve are often defaulted to RNU unless they and their managing clinician deem that adequate endoscopic management of low-volume, low-grade papillary tumors is especially safe and feasible. The result may be loss of nephron mass for disease that did not require it. Given that 38%-50% of patients in this age demographic,11 and up to 57% of those with UTUC,12 already have CKD stage 3 with both kidneys in place, this additional loss in renal function renders most individuals ineligible for future cisplatin-based therapy should their disease progress elsewhere, as well as adding to their co-morbidity burden.

Of greater clinical concern are patients whose renal function is already markedly compromised and in whom radical nephrectomy poses a more substantial risk of dialysis that may exceed the oncologic risks of their low-grade UTUC. In these patients, repeated endoscopic management with intracavitary therapies via

a retrograde or antegrade approach have been used, but no clear guidelines exist.

Administration of bacillus CalmetteGuérin (BCG) into the upper tract has been performed by slow gravity antegrade drip or retrograde via a cystoscopically placed ureteral catheter. A far less reliable method used has been via reflux from the bladder into the upper tract via an indwelling stent. Each of these methods is inadequate due to lack of dwell time; uneven topical distribution in the renal calyces, pelvis, and ureter; higher risks for infection and systemic absorption compared with lower-tract administration; and constant urine production, making adequate dosing difficult. Although administration of upper-tract BCG, or less commonly liquid chemotherapy, have been described with modest efficacy based on retrospective data, patient selection and physician experience are exceptionally heterogeneous. Current administration options are suboptimal, and standards are lacking, making upper-tract management with topical therapies for UTUC the exception rather than the rule.13 The recent development, testing, and approval of reverse-thermal hydrogelbased delivery for mitomycin C (Jelmyto, UroGen Pharma) into the upper urinary tracts for low-risk UTUC offers the possibility of improved urothelial coverage, dwell, delivery, and chemoablation. In a recently published single-arm phase 3 open-label trial (OLYMPUS), 42 of 71 patients with low grade UTUC in the intent-to-treat population achieved a complete response, including 59% who were considered endoscopically unresectable.14 The most common adverse events seen included ureteric stenosis, urinary tract infection, hematuria, flank pain, and nausea. These data have led to

a recent FDA approval and incorporation in the updated NCCN bladder cancer guidelines for UTUC.3 In patients with positive cytologies, high-grade disease and/or high endoscopic or radiographic suspicion for high-risk UTUC, neoadjuvant chemotherapy is increasingly considered the standard of care, given that at least 45% of patients will be cisplatin-ineligible following RNU.12,15 While no data from randomized controlled trials exist directly supporting neoadjuvant therapy for high-risk UTUC, and the experience is largely extrapolated from phase 3 data in bladder cancer, there are level 1 data to support the use of adjuvant chemotherapy in UTUC. In the phase 3 POUT trial, adjuvant gemcitabine and cisplatin for patients with resected pT2-4N0-3M0 and adequate renal function resulted in improved progression-free survival compared with surveillance.16

Unmet needs and future directions There is growing recognition that UTUC is a biologically and clinically distinct entity requiring unique guidelines, algorithms, and expertise. Goals of therapy should include balancing oncologic and renal functional risks. As new treatment options emerge, a refocus on nephron preservation for well-selected patients should be included in treatment paradigms for UTUC. n Marshall C. Strother, MD, and R ­ obert G. Uzzo, MD, MBA are affiliated with the Fox Chase Cancer Center in Philadelphia. Dr Strother is a first-year urologic oncology fellow. Dr Uzzo is the G. Willing “Wing” Pepper Chair in Cancer Research, Chairman of the Department of Surgery, and Professor of Surgery at

Temple University School of Medicine in Philadelphia. He also is medical director, urology, for Renal & Urology News.

REFERENCES 1. Soria F, Shariat SF, Lerner SP, et al. Epidemiology, diagnosis, preoperative evaluation and prognostic assessment of upper-tract urothelial carcinoma (UTUC). World J Urol. 2017;35:379-387.

2. Mossanen M, Gore JL. The burden of bladder cancer care. Curr Opin Urol. 2014;24:487-491.

3. Flaig T, Spiess P, Agarwal N, et al. NCCN clinical practice guidelines in oncology: Bladder cancer. Version 5.2020. https://www.nccn.org/professionals/physician_gls/ pdf/bladder.pdf (accessed May 16, 2020).

4. Rouprêt M, Babjuk M, Burger M, et al. EAU guidelines on upper tract urothelial carcinoma. EAU Guidel. 2020, Arnhem, The Netherlands: EAU Guidelines Office; 2020.

5. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. J Urol. 2016;196:1021-1029.

6. Rouprêt M, Colin P, Yates DR. A new proposal to risk stratify urothelial carcinomas of the upper urinary tract (UTUCs) in a predefinitive treatment setting: Low-risk versus high-risk UTUCs. Eur Urol. 2014;66:181-183.

7. Krabbe LM, Eminaga O, Shariat SF, et al. Postoperative nomogram for relapse-free survival in patients with high grade upper tract urothelial carcinoma.

J Urol. 2017;197:580-589.

8. Raman JD, Lin YK, Shariat SF, et al. Preoperative nomogram to predict the likelihood of complications after radical nephroureterectomy. BJU Int. 2017; 119:268-275.

9. Upfill-Brown A, Lenis AT, Faiena I, et al. Treatment utilization and overall survival in patients receiving radical nephroureterectomy versus endoscopic management for upper tract urothelial carcinoma: evaluation of updated treatment guidelines. World J Urol. 2019;37:1157-1164.

10. Campbell S, Uzzo RG, Allaf ME, et al. Renal mass and localized renal cancer: AUA guideline. J Urol.

2017;198:520-529.

11 Centers for Disease Control and Prevention. Chronic Kidney Disease Surveillance System—United States.

Crude Prevalance of CKD Stages 1-4 By Age 20152016 from National Health and Nutrition Examination Survey 2016.

12. Singla N, Gayed BA, Bagrodia A, et al. Multi-institutional analysis of renal function outcomes following radical nephroureterectomy and partial ureterectomy for upper tract urothelial carcinoma. Urol Oncol Semin Orig Investig. 2015;33:268.e1-268.e7.

13. Rastinehad AR, Smith AD. Bacillus Calmette-Guérin for upper tract urothelial cancer: Is there a role?

J Endourol. 2009;23:563-568.

14. Kleinmann N, Matin SF, Pierorazio PM, et al. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, singlearm, phase 3 trial. Lancet Oncol. 2020;21:776-785.

15, Margulis V, Puligandla M, Trabulsi EJ, et al. Phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery in patients with high grade upper tract urothelial carcinoma. J Urol.

2020;203:690-698.

16. Birtle A, Johnson M, Chester J, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet. 2020;395:1268-1277.

Avelumab Prolongs Survival in Advanced Urothelial Carcinoma ADDING THE checkpoint inhibitor avelumab to best supportive care (BSC) following chemotherapy for advanced urothelial carcinoma significantly improves overall survival (OS) compared with BSC alone, according to study findings presented as part of the American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program.

In the randomized phase 3 JAVELIN Bladder 100 trial, the median overall survival was 21.4 months for patients treated with avelumab plus BSC compared with 14.3 months among those who received BSC alone, a team led by Thomas Powles, MD, PhD, Director of

Barts Cancer Centre in London, reported. Compared with BSC alone, avelumab combined with BSC was significantly associated with a 31% decreased risk of death. Avelumab plus BSC also significantly improved OS compared with BSC alone among patients with PD-L1+ tumors, significantly decreasing the risk of death by 44%. Median OS was 17.1 months in the BSC-only group and was not reached in the avelumab-BSC arm.

Compared with BSC alone, avelumab plus BSC was significantly associated with a 38% decreased risk of disease progression for all randomized patients and 44% among patients with PD-L1+ tumors.

“Overall, avelumab first-line maintenance therapy in patients whose disease has not progressed with platinum-based induction chemotherapy is a new firstline standard of care for advanced urothelial carcinoma,” Dr Powles said during a virtual press briefing.

The trial included 700 patients with unresectable locally advanced or metastatic urothelial carcinoma and who had no disease progression following chemotherapy, which was gemcitabine with either cisplatin or carboplatin.

Investigators randomly assigned 350 patients to receive BSC alone and 350 to receive avelumab plus BSC. The groups

had a median follow-up period of 19.2 and 19.6 months, respectively. Of the 700 patients, 358 (51%) had PD-L1+ tumors.

Although avelumab has been shown to be effective for metastatic urothelial carcinoma, the JAVELIN 100 trial provides the first data demonstrating the efficacy of avelumab as first-line treatment in the maintenance setting.

Grade 3 or higher adverse events (AEs) occurred in 47.4% of patients who received avelumab plus BSC compared with 25.2% of those who had BSC alone.

The most common grade 3 or higher AEs were urinary tract infection, anemia, hematuria, fatigue, and back pain. n

www.renalandurologynews.com JULY/AUGUST 2020

Renal & Urology News 13

Higher Risk of Prostate Cancer Observed in Metformin Users

Hydrogel Spacer May Lower Risk of RT Toxicities

New study casts doubt on the use of the drug for chemoprevention

PERIRECTAL HYDROGEL spacer placement prior to radiation therapy (RT) for prostate cancer may be a prudent preventive strategy to reduce radiation-induced rectal toxic effects, investigators concluded based on a systematic review and meta-analysis.

Larry E. Miller, PhD, of Miller Scientific of Johnson City, Tennessee, and colleagues reviewed 7 studies involving 1011 men undergoing RT, of whom 486 received a hydrogel spacer and 525 served as controls. The spacer is injected between the Denonvilliers fascia and anterior rectal wall prior to treatment. It provides perirectal separation through a typical 3-month course of RT and is completely metabolized after 6 months, according to the investigators.

The studies included 1 randomized clinical trial and 6 cohort studies.

The median duration of follow-up was 26 months. The main outcomes and measures included procedural results, the percentage volume of rectum receiving at least 70 Gy radiation (v70), early (3 months or less) and late (more than 3 months) rectal toxic effects, and early and late changes in bowel-related quality of life on the Expanded Prostate Cancer Index Composite.

was significantly associated with 76% and 77% increased odds of high-grade PCa and overall PCa, respectively, the investigators reported in Prostate Cancer and Prostatic Diseases.

The investigation showed that none of the 27 candidate SNPs in metformin metabolic pathways had significant interaction with the metformin-cancer ­association. One SNP (rs149137006)

© STEVE GSCHMEISSNER / SCIENCE PHOTO LIBRARY / GETTY IMAGES

BY JOHN SCHIESZER CONTRARY TO previous research, a new study examining how genetic variations impact the effect of metformin suggests that this drug may not be an effective agent for the chemoprevention of prostate cancer (PCa).

In fact, the new study found an increased likelihood of PCa associated with metformin use.

Researchers found a higher risk for prostate cancer (PCa) overall and high-risk PCa among men who used metformin, but this could be due to other reasons, such as diabetes.

The study, by Robert Hamilton, MD, MPH, a clinician investigator at Princess Margaret Cancer Centre in Toronto, and colleagues, is the first to examine pharmacogenetic interaction and PCa chemoprevention. He and his colleagues noted that genetic variation in metformin metabolism pathways may modify metformin glycemic control and help protect against some cancers.

The investigators collected clinical data and germline DNA from a prostate biopsy database and conducted a genome-wide association study. They examined 27 single nucleotide polymorphisms (SNPs) implicated in metformin metabolism. The team analyzed the associations between metformin use and risk of high-grade disease (Grade Group 2 or higher) and overall PCa with a case-control design.

The study included 3481 men, of whom 132 (4%) were taking metformin at diagnosis. A total of 2061 men (59%) were di­ag­nosed with PCa, with 922 (45%) of them diagnosed with high-grade disease. After adjusting for ­baseline c­ haracteristics, metformin use

had a genome-wide significant interaction with metformin for high-grade PCa, and a second SNP (rs115071742) was found to have an interaction with metformin for overall PCa. “It could be possible that metformin users were at increased risk for prostate cancer for other reasons, such as diabetes, and only a randomized controlled trial could truly tease this out,” Dr Hamilton told Renal & Urology News. “The genetic factors we studied did not seem to modify the metformin prostate cancer risk, suggesting that how a patient’s body metabolizes metformin doesn’t seem to alter how metformin affects the prostate gland.”

He added, “By no means does this mean men taking metformin should stop for fear of causing prostate cancer.

Our study must be put in the context of the many other studies published on metformin and prostate cancer risk.

Some have shown metformin to be protective, others no effect, and others, like ours, suggest it may be associated with increased risk.”

The investigators said their study findings must be viewed cautiously because

there was a heterogeneous mixture of metformin duration and dose in this cohort. This could potentially dilute any genetic signal. Also, data were not available on other antidiabetic agents or concurrent medication use.

Brock O’Neil, MD, an Assistant Professor in the Division of Urology at the University of Utah School of Medicine and the Huntsman Cancer Institute in Salt Lake City, said the new study is a thoughtful attempt to understand the relationship between metformin and PCa. Still, he pointed out that the sample of men taking metformin was too small and there were too few events (99 PCa cases and 62 high-grade PCa cases) “to have enough degrees of freedom relative to the number of covariates included in the multivariable models to make meaningful conclusions about whether metformin use is associated with prostate cancer.”

Although the authors report that metformin use was associated with a higher risk of any PCa and high-risk PCa, they were unable to account for a possible selection bias, Dr O’Neil said. In addition, he noted metformin could have an impact on PSA kinetics that leads to a greater likelihood that a prostate biopsy is performed.

“Given the small size of the study, it is too early to conclude that none of the 27 candidate SNPs in the metformin pathway are not associated with prostate cancer,” he said. “Additionally, it is too early to conclude that 2 SNPs from the GWAS are indeed meaningfully related to prostate cancer development or risk.”

Amar U. Kishan, MD, Vice Chair of Clinical and Translational Research and Chief of the Genitourinary Oncology Service at the David Geffen School of Medicine at UCLA and the UCLA Jonsson Comprehensive Cancer Center, said that despite the study’s limitations, it provides new insight into how genetic factors may play a role.

“This is a well-done case-control study,” Dr Kishan said. “The dataset is well curated and their methods are robust. Limitations are well acknowledged by the authors and relate to unknowns and heterogeneity in metformin use, duration, and dose.” ■

Hydrogel spacer recipients had better bowel-related QoL in late follow-up.

Hydrogel placement was successful in 97% of cases, Dr Miller’s team reported in JAMA Network Open. The weighted mean perirectal separation distance was 11.2 mm.

The hydrogel spacer group received 66% less v70 rectal irradiation compared with controls. The risk of grade 2 or higher rectal toxic effects was comparable between the hydrogel spacer group and control arm in early followup, but was 77% lower in the spacer group in late follow-up.

In addition, changes in bowel-related QoL were comparable between the study arms at a 3-month follow-up, but were significantly better in the spacer arm in late follow-up (median 48 months), according to the investigators. ■

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n FEATURE

Nutritional Impact on Urologic and Renal Diseases: A Review By watching their diet, patients can control such common problems as overactive bladder

T

oday, physicians and patients are more aware of the relationship between nutrition and disease. Nutrition is an important part of leading a healthy lifestyle. Combined with physical activity, diet can help patients reach and maintain a healthy weight, reduce their risk of chronic diseases (like heart disease and cancer), and promote their overall health.

Unhealthy eating habits have contributed to the obesity epidemic in the United States. One-third of US adults (33.8%) are obese.1 Even for people with a healthy weight, a poor diet is associated with major health risks that can cause illness and even death. These include heart disease, hypertension, type 2 diabetes, osteoporosis, and certain types of cancer.

Also, good dietary habits and good nutrition are important in the management of various urologic and renal diseases.

As physicians, it is important for us to establish a link between good nutrition and various urologic and renal diseases. This article will emphasize the relationship between diet, nutrition, and management of several urologic and renal diseases. The article will provide evidence-based suggestions that we can provide our patients who have these common conditions.

Overactive bladder (OAB) OAB is a sudden involuntary contraction of the detrusor muscle of the bladder causing urinary urgency, an immediate need to urinate. It is one of the causes of urinary incontinence and affects over 33 million Americans.2 Men and women who suffer from OAB often feel embarrassed about their condition and may not seek medical help or bring up their urinary symptoms with their doctors.

Dietary adjustments may ease a wide range of urinary tract diseases.

OAB symptoms appear to be multifactorial in both etiology and pathophysiology. Symptoms suggest underlying detrusor overactivity, which can be neurogenic, myogenic, or idiopathic in origin. Neurogenic causes of OAB include multiple sclerosis, dementia, Parkinson disease, and diabetic neuropathy. In postmenopausal women, estrogen deficiency can result in OAB symptoms.

Estrogen deprivation therapy in younger women with breast cancer has also been associated with increased risk for OAB. The mainstay of OAB management is anticholinergic medications and beta-3 adrenoceptor agonists. Dietary considerations, however, are also helpful in ameliorating symptoms. Patients with OAB are often sensitive to caffeinated beverages, and consuming caffeine can increase OAB symptoms. One of the treatment recommendations for those who suffer from OAB is to reduce, or better yet, eliminate caffeinated beverages,

including coffee, tea and energy drinks, which have significant caffeine content, from their diet. In addition to caffeine serving as a bladder irritant, caffeine is a weak diuretic, increasing urine output and contributing to urinary frequency.3 Other dietary culprits include acidic fruit juices such as orange or grapefruit juice, which can alter the pH of urine and exacerbate OAB symptoms. The goal of dietary therapy for OAB can include alkalinizing the urine with 2-4 grams of sodium bicarbonate twice a day. In addition, reducing or eliminating acidic foods such as tomatoes and highly spiced condiments such as chilies and wasabi may also be helpful. Finally, omitting artificial sweeteners such as aspartame and saccharin can also alleviate OAB symptoms.4 Patients can consider eliminating carbonated beverages, especially those containing large quantities of caffeine.

A British study indicated a decreased risk of OAB with increased ­consumption

of raw vegetables, which increases dietary fiber content.5 A low-fiber diet is associated with constipation and the accompanying straining to defecate.

Constipation places increased pressure on the pelvic floor muscles, which are responsible for keeping the urethra closed or coapted. If these pelvic floor muscles become damaged, such as during childbirth, and there is accompanying constipation, then urinary frequency and urgency may occur.

There are a large number of estrogen receptors located in the bladder and the pelvic muscles in women. An estrogen deficiency, as occurs in menopause, results in exacerbation of OAB symptoms. When there is evidence of estrogen deficiency, relief may be achieved with hormone replacement therapy unless the use of estrogen is contraindicated (as in cases of estrogen-positive breast cancer).

Clinicians may recommend the use of topical estrogen cream, oral estrogen, or estrogen ­patches. Topical estrogen such as estradiol vaginal cream every other day or twice a week is effective as an oral hormone replacement therapy for OAB.6 In addition, vegetables such as yam and carrots contain phytoestrogens that may supplement the natural estrogens in post-menopausal women and reduce OAB symptoms.7 In a longitudinal study of 5000 women over age 40 that focused on various dietary inclusions and OAB onset, higher intake of vitamin D, protein, and potassium were associated with a decreased onset of OAB. There are vitamin D receptors on the detrusor muscle.8 Adequate vitamin D allows relaxation of the detrusor and results in a decrease in patients’ urinary urgency.9 OAB patients may experience improvement in symptoms with 600 units of vitamin D per day.10

© ISTETIANA / GETTY IMAGES

BY DAVID F. MOBLEY, MD, HEVIN PATEL, MS, AND NEIL BAUM, MD

www.renalandurologynews.com JULY/AUGUST 2020

The onset and the symptoms of OAB may be associated with smoking. The mechanism linking smoking and OAB symptoms is unclear, but it could be related to an anti-estrogenic hormonal effect on the bladder and urethra and a nicotine-induced contraction of the detrusor muscle.11 Mandhu et al. conducted a retrospective study with more than 11,000 women and found that smoking was associated with a 14% increased risk of OAB symptoms.12 Thus, in addition to dietary modifications, smoking cessation is advised for patients with OAB. Perhaps one of the least expensive yet effective treatments of OAB is fluid restriction. Callan et al demonstrated that increasing fluid by 25% to 50% could increase daytime frequency; however, the study did not show a significant effect on urgency. Increasing fluid intake is associated with worsening of OAB symptoms in observational studies.13 Mild to moderate fluid restriction, however, results in significant improvement in OAB symptoms, especially nocturia.

Nocturia is one of the most distressing symptoms of OAB that is also amenable to fluid restriction. In a study, investigators managed nocturia using fluid restriction after 6 pm. Participants who completed behavioral treatment that included fluid restriction demonstrated a reduction in mean number of voids per day from 11.3 in baseline to 9.1 after treatment. This decrease of 2.2 voids per day (18.8%) was statistically significant (P < .001).14

Interstitial Cystitis (IC) IC or chronic pelvic pain syndrome (CPPS) consists of pelvic pain and a persistent desire to urinate accompanied by urinary frequency, nocturia, and voiding small volumes of urine. The hallmark of IC is the presence of these urinary symptoms with a negative urine culture. IC affects about 700,000 to 1 million Americans, with 90% of patients being women.15 This incidence is probably underreported. Many patients may be misdiagnosed as having cystitis or prostatitis, as these conditions share similar lower urinary tract symptoms.

Possible causes of IC include defects in the lining of the urinary bladder that cause irritation, bladder trauma, pelvic floor muscle dysfunction, autoimmune disorders, neurogenic inflammation, spinal cord trauma, genetics, or allergy.

Patients with IC are advised to avoid bladder irritants such as citrus food and caffeinated beverages for the same reason that caffeine is to be avoided in patients with OAB. A study by Shorter et al identified foods and beverages that worsened the symptoms of IC. In this

study, a questionnaire was administered to 124 patients with IC. The questionnaire asked patients to indicate whether the foods and beverages listed improved, worsened, or had no effect on their symptoms. The most frequently reported foods and fluids that exacerbated their symptoms were coffee, tea, soft drinks, alcoholic beverages, hot peppers, citrus fruits and juices, and artificial sweeteners.16 Sonmez et al reported that a combination of both calcium glycerophosphate and sodium bicarbonate improved IC symptoms.17 In another study by Shorter et al, patients were asked to take 2 tablets (0.66 grams) of calcium glycerophosphate over a 4-week period.

Patients reported improvement in their symptoms, with a decrease in urgency and dysuria. In addition, these patients also reported a reduction in IC exacerbations, especially from foods such as pizza, spicy food, chocolate, and alcohol.18 It is important to mention that there is a significant placebo effect in the management of IC patients. Patients with moderate to severe IC have experienced significant improvement after receiving only advice and support from their physicians. Supportive therapy is risk free, inexpensive, and without side effects.

Consequently, proving efficacy of any of the treatments for IC with rigorous placebo-controlled trials is difficult due to a significant effect of the placebo intervention.19 Certainly, medications are available for treating IC, such as pentosan polysulfate sodium and DMSO. Diet modification, however, can supplement pharmacotherapy. Patients should be provided with a dietary list of bladder irritants. Since the list of bladder irritants is extensive, and in order to identify which dietary culprits are responsible for symptoms of IC, it is initially advisable to eliminate all possible bladder irritants for 5-7 days and then start adding potential irritants to the diet, thus enabling identification of the offending foods or fluids that might exacerbate the symptoms.

Prostatitis Prostatitis is one of the more common conditions seen in a urologic practice.

Although an extensive review of this condition is beyond the scope of this article, prostatitis, an inflammation of the prostate gland, presents as acute or chronic, bacterial or nonbacterial.

Nonbacterial, chronic prostatitis is the most common variety. Symptoms include generalized sense of discomfort in the pelvis, and with urination, along with frequency, urgency, pressure sensation, and occasionally low-grade fever.

The US prevalence of prostatitis is approximately 8.2%. Prostatitis accounts for about 8% of all urologic visits.20 There is a relationship between diet and urinary symptoms associated with chronic prostatitis. Patients with chronic prostatitis may consider avoiding foods and beverages known to exacerbate urinary symptoms.

These foods may include spices, hot peppers, alcohol, wheat, and gluten.21 Men find wheat-free or gluten-free diets to be the most beneficial in managing their prostatitis symptoms.22 Furthermore, drinking ample quantities of water and consuming foods high in fiber and zinc may reduce the symptoms of chronic prostatitis. Also, herbal tea or caffeine-free tea can be beneficial for controlling chronic prostatitis.22 Goodarzi et al found that zinc supplementation helps patients with chronic prostatitis in relieving their symptoms.

They conducted a study that included 123 patients aged 18-40 years diagnosed with chronic prostatitis.23 All patients completed a chronic prostatitis symptom index questionnaire and a pain score questionnaire before entering the study.

The zinc group was given 220 mg/day of zinc sulfate while a control group was given a placebo. At the end of 12 weeks, the zinc sulfate group had a reduction in prostatitis symptom index score and pain score compared with the control arm. The effectiveness of zinc can possibly be attributed to its anti-bacterial and immunomodulatory functions.23 Zinc is a prominent chemical in seminal fluid but its precise role in the management of prostatitis remains unclear. Supplementation with oral zinc appears to be a simple, safe, and a potentially effective option for these men.

Benign Prostatic Hyperplasia Benign prostatic hyperplasia (BPH) affects approximately 19 million men in the United States, but only about 3 million seek treatment.24 Symptoms include a decrease in the force and caliber of the urine stream, frequency of urination, urgency to void, a feeling of not emptying the bladder, nocturia, and postmicturition dribbling. The incidence of BPH increases with age. Only about 10% of men in their 30s exhibit these lower urinary tract symptoms (LUTS).

The incidence increases to 60% among men in their 60s. Nearly all men over 70 will have some degree of LUTS.25 By controlling their diet, many patients with BPH can significantly improve their urinary symptoms. Benign prostate enlargement is largely driven by the conversion of testosterone to dihydrotestosterone. It is not known if any foods affect testosterone directly, but there is strong evidence that a plant-based diet consisting of beans, peas,

Renal & Urology News 19

lentils, vegetables, and sesame seeds — essentially a Mediterranean diet — can be helpful in men with LUTS and in decreasing the risk of developing LUTS. El Jalby et al, in their extensive literature review on this subject, found 1325 citations and ultimately selected 35 studies for their review. Although dietary studies have some built-in challenges, the studies essentially revealed the above findings with regards to diet and LUTS, in addition to salutary effects on erectile dysfunction.26

Nephrolithiasis Approximately 9% of the US population is affected by nephrolithiasis.27 There are 4 major types of nephrolithiasis: calcium, uric, struvite, and cystine. Dietary modifications may help prevent recurrent nephrolithiasis, and those modifications depend on the type of kidney stone. For example, uric acid stone formers should decrease intake of red meat and shellfish because these foods contain high concentration of purines, which are metabolized into uric acid.28 Increased purine intake may lead to a higher production of uric acid, which aggregate as crystals in the collecting system of the kidneys. Patients are advised to review information readily available listing foods high in purines and be cautious in their dietary intake of these foods. Patients with uric acid kidney stones should follow a diet that consists of fruits, vegetables, and whole grains, and limit their alcohol intake.

Patients with calcium oxalate stones, the most common type, should avoid foods high in oxalate such as spinach, nuts, and wheat bran.29 Oxalate is also found in certain fruits and vegetables, such as rhubarb, beet, and potatoes.

Patients with calcium stones are often advised to avoid foods high in calcium, such as dairy products.

Although excessive calcium intake is not recommended, either dietary or supplemental calcium remains important.

Calcium restriction does not inhibit the development of calcium oxalate stones, but it does have a negative effect on bone health, especially in women who are more prone to osteopenia and osteoporosis.

Patients with calcium phosphate nephrolithiasis should limit their sodium intake because excess sodium leads to greater loss of calcium in the urine. With sodium restriction, there is a relative decrease in circulating blood volume. The result is increased reabsorption of sodium, water, and calcium at the level of the proximal convoluted tubule, thereby decreasing urinary calcium excretion. Foods containing large quantities of sodium include salted or canned meat, fish, and poultry, as well as pizza and nuts, buttermilk, olives,

20 Renal & Urology News

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and pickles.30 In addition, patients with calcium phosphate stones should also limit their intake of oxalate-rich foods.

Cystine stones Patients with cystine stones should restrict consumption of meat and other animal proteins and salt intake. They also should be advised to consume more fruits and vegetables because these foods make the urine less acidic and decrease the excretion of cystine.31 The time-honored method of prevention for all kidney stones is adequate intake of fluids, especially water. All patients with nephrolithiasis should consume at least 2.5 liters of fluid per day.

Patients with cystine stones are advised to consume 4 liters of fluid per day.31

Erectile dysfunction (ED) A study of data from the National Health and Nutrition Examination Survey (NHANES) found that the US prevalence of ED in men aged over 20 years was 18.4%, or about 18 million men. Not only is ED is strongly associated with age but also in men with diabetes, hypertension, and a history of cardiovascular disease.32 Since ED is correlated with hypertension, it is important to maintain a hearthealthy diet. A study of 555 men with type 2 diabetes showed that patients who followed a Mediterranean diet, which is high in fruits, vegetables, nuts, and whole grains and low in red meat, had a decreased prevalence of ED and were more likely to be sexually active than men who did not follow the Mediterranean diet.33 Excessive salt intake can result in hypertension and atherosclerosis, which can narrow the lumen of arteries and decrease blood flow not only to the coronary arteries but also to the penis, making erection difficult or impossible. Therefore, patients with ED should be advised to restrict foods high in salt content such as bacon,

ham, smoked meat, and potato chips.

A systematic review by Gandaglia et al showed that ED often precedes cardiovascular disease (CVD). Consequently, ED can be used as an early marker to identify men who are at a higher risk for CVD events.34 It is important to note that ED may precede a diagnosis of CVD by as many as 5 years.35 The explanation of ED preceding CVD is that the diameter of the penile arterial blood supply is normally one-third the size of the coronary arteries. As a result, symptoms of ED secondary to hypertension and hypercholesterolemia may occur before symptoms of coronary disease, ie, angina or myocardial infarction.

Chronic kidney disease (CKD) CKD affects approximately 31 million Americans, and most CKD cases are undiagnosed because it may be asymptomatic in early stages.36 Type 1 and type 2 diabetes and high blood pressure are the most common causes of CKD.37 The 4 substances that patients with CKD need to restrict or avoid are sodium, phosphorus, calcium, and potassium. Excessive sodium impacts blood pressure and water balance.

CKD and excessive sodium consumption results in a worsening of hypertension.

This can be controlled by avoiding foods high in salt such as soy sauce, teriyaki sauce, canned foods, processed foods, and snacks with high sodium content.

Patients with CKD should limit their sodium to 2000 mg per day.

As kidney function decreases, phosphorus excretion by the kidneys decreases and calcium is not absorbed from gastrointestinal tract, leading to low blood levels of calcium. In response to a decrease in calcium, parathyroid hormone (PTH) production increases and results in the loss of calcium and phosphorus from bones, which can lead to osteoporosis. The increase of phosphorus and calcium in the blood

Common Dietary Bladder Irritants Alcohol beverages

Limes

Carbonated drinks

Cranberries

Coffee

Grapes

Tea

Tomato-based products

Spicy foods

Vinegar

Aged cheese

Raw onions

Chocolate

Chili peppers

Apples

Soy sauce

Bananas

Fava beans

Oranges

Lima beans

Grapefruits

Sour cream

Lemons

Yogurt

Source: Cleveland Clinic; Mayo Clinic; Brigham and Women’s Hospital

stream can cause vascular calcifications and worsening arteriosclerosis.38 Patients with CKD are advised to restrict dietary phosphorus to less than 800-1000 mg per day. Foods high in phosphorus to avoid or decrease include milk, ice cream, cheese, yogurt, chocolate, and legumes.

Patients with CKD should also avoid excessive quantities of protein, including meat, nuts, and dried beans. Accumulation of excess protein damages glomerular structure, leading to or aggravating CKD. A low-protein diet (0.6-0.8 g/kg/day) is recommended for patients with CKD.39 Patients with CKD need to be concerned about their potassium level, as hyperkalemia can result in arrhythmias.

Potassium can be regulated by reducing consumption of bananas, melons, milk, and yogurt, as well as poultry and pork.

Patients with CKD should limit potassium intake to 2000 mg per day.

Fluid restriction may be required in patients with CKD, especially those patients with end-stage kidney disease (ESKD) who are on dialysis. Dialysis patients may need to limit fluids between dialysis treatments. Because patients with ESKD have diminished urine output, excessive fluid expands the extracellular fluid space and results in peripheral edema, weight gain, hypertension, and congestive heart failure.

Bladder cancer In 2017, approximately 80,000 adults were diagnosed with bladder cancer in the United States. Worldwide, more than 400,000 cases are diagnosed yearly, making it the seventh most common form of cancer.40 Men are 4 times more likely to be diagnosed with the malignancy than women, especially White men whose incidence rates are double those of Black men. Bladder cancer mostly affects older people, with an average age at diagnosis of 73 years.41 Although tobacco use is the single biggest risk factor for bladder cancer, dietary components may alter the natural history of bladder cancer and even reduce the risk of recurrence or progression.

Increased intake of cruciferous vegetables such as broccoli sprouts, kale, and cabbage is associated with a decreased risk of bladder cancer. Cruciferous vegetables contain isothiocyanates, which are known to induce anticarcinogenic effects through phase-2 cytoprotective enzymes.42 Evidence also suggests that tea consumption may decrease the risk for bladder cancer. Drinking water contaminated with arsenic—which is an issue in some places—is a risk factor for bladder cancer.43

Conclusion Diet and supplements impact numerous urologic conditions. Although the exact pathophysiology regarding these relationships is not apparent in all cases, it is prudent for healthcare providers to be aware of the relationships and counsel patients regarding proper diet for their particular urologic problem. There clearly are benefits and risks associated with certain foods as they pertain to the urologic problems discussed in this review, but in many respects, patients who consume a prudent diet such as the Mediterranean, the MIND, or the DASH diet can decrease the risks for these diseases or help control their symptoms, in addition to enhancing their overall health. ■ David F. Mobley, MD, is Associate Professor in Clinical Urology at the Houston Methodist Academic Institute.

Hevin Patel, MS, is a second-year student at Edward Via College of Osteopathic Medicine in Auburn, Alabama. Neil Baum, MD, is Professor of Clinical Urology at Tulane University in New Orleans.

REFERENCES 1. Centers for Disease Control and Prevention. U.S. Obesity Trends. 2011. Available at: https://www. cdc.gov/obesity/data/databases.html 2. Leron E, Weintraub AY, Mastrolia SA, Schwarzman P. Overactive bladder syndrome: evaluation and management. Curr Urol. 2018;11:117-125.

3. Palma IAF, Staack A. Impact of caffeine on overactive bladder symptoms. Curr Bladder Dysfunct Rep. 2016;11:1-7.

4. Robinson D, Giarenis I, Cardozo L. You are what you eat: the impact of diet on overactive bladder and lower urinary tract symptoms. Maturitas. 2014;79:8-13.

5. Zhu J, Hu X, Dong X, Li L. Associations between risk factors and overactive bladder: A meta-analysis. Female Pelvic Med Reconstr Surg. 2019;25:238-246.

6. Robinson D, Cardozo L, Milsom I, et al. Oestrogens and overactive bladder. Neurourol Urodyn. 2014;33: 1086-1091.

7. Cardenas-Trowers O, Meyer I, Markland A, et al.

(2018). A review of phytoestrogens and their asso­ ciation with pelvic floor conditions. Female Pelvic Med Reconstr Surg. 2018;24:193-202.

8. Yoo S, Oh S, Kim HS, et al. Impact of serum 25‐OH vitamin D level on lower urinary tract symptoms in men: a step towards reducing overactive bladder.

BJU Int. 2018;122:667-672.

9. Matyjaszek-Matuszek B, Lenart-Lipińska M, Woźniakowska E. Clinical implications of vitamin D deficiency. Prz Menopauzalny. 2015;14:75-81.

10. Langham RY. Vitamins for an overactive bladder.

LIVESTRONG.COM, Leaf Group, www.livestrong.com/ article/390405-vitamins-for-an-overactive-bladder 11. Hisayama T, Shinkai M, Takayanagi I,Toyoda T. Mechanism of action of nicotine in isolated urinary bladder of guinea‐pig. Br J Pharmacol. 1988;95:465-472.

12. Madhu C, Enki D, Drake MJ, Hashim H. The functional effects of cigarette smoking in women on the lower urinary tract. Urol Int. 2015;95:478-482.

13. Callan, L, Thompson DL, Netsch, D. Does increasing or decreasing the daily intake of water/fluid by adults affect overactive bladder symptoms? J Wound Ostomy Continence Nurs. 2015;42:614-620.

14. Wyman JF, Burgio KL, Newman DK. Practical aspects of lifestyle modifications and behavioral interventions in the treatment of overactive bladder and urgency urinary incontinence. Int J Clin Pract. 2009;63:1177-1191.

15. Bosch PC, Bosch DC. Treating interstitial cystitis/ bladder pain syndrome as a chronic disease. Rev Urol. 2014;16:83-87.

16. Shorter B, Ackerman M, Varvara M, Moldwin RM. Statistical validation of the Shorter-Moldwin food sensitivity questionnaire for patients with interstitial cystitis/ bladder pain syndrome. J Urol. 2014;191:1793-1801.

17. Sönmez MG, Göğer YE, Ecer G, et al. Effects of urine alkalinization with sodium bicarbonate orally on lower urinary tract symptoms in female patients: a pilot study. Int Urogynecol J. 2018;29:1029-1033.

www.renalandurologynews.com JULY/AUGUST 2020

PCa Genetic Testing Guideline Issued New guideline emphasizes that BRCA2 be included in all testing scenarios

BY JODY A. CHARNOW GENETIC TESTING is recommended for all men with metastatic prostate cancer (PCa) or who have a family history indicative of hereditary PCa, according to a new consensus guideline.

In addition, the guideline emphasizes the importance of considering family history beyond PCa, such as hereditary breast and ovarian cancer and Lynch syndrome, which have cancer risk implications for men and their families.

Further, the guideline strongly recommends BRCA2 be included in all testing scenarios to inform precision therapy in metastatic disease as well as active surveillance discussions in early-stage disease and PCa early detection discussions and strategies.

The guideline was developed by attendees of the 2019 Philadelphia Prostate Cancer Consensus Conference hosted by the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia. The conference included 97 participants in the fields of urology, medical and radiation oncology, clinical genetics, genetic counseling, and others.

Demand for genetic counseling “The consensus statement is important because, with the rising volume of men in need of germline testing, there is increasing demand for genetic counseling, and healthcare providers are ordering genetic testing to impact treatment and management,” corresponding author Veda N. Giri, MD, Associate Professor, Medical Oncology, Cancer Biology, and Urology, and Director, Cancer Risk Assessment

and Clinical Cancer Genetics at Sidney Kimmel Cancer Center, told Renal & Urology News. “Importantly, there will be an expected rise in germline testing to identify men with metastatic prostate cancer for PARP inhibitor therapy given the recent FDA approvals for rucaparib and olaparib. This consensus conference addressed how to implement responsible germline testing in this era of precision medicine with focus on which men to test, delivery of informed consent for testing, which panels are more suited for various clinical scenarios, and how results impact treatment, management, and families. Thus, we hope the consensus-driven framework for implementation of germline testing will be useful for healthcare providers, genetic counselors, and patients to streamline access to germline testing for prostate cancer.”

Germline testing priorities For patients with metastatic PCa, the guideline recommends germline testing priority be given to BRCA1/BRCA2 and DNA MMR genes, and that the ATM gene be considered for testing.

The guideline also recommends that additional genes be tested based on patients’ personal or family history.

“Broad panel testing may be more applicable in the metastatic setting for identifying therapeutic options and clinical trials eligibility,” Dr Giri said. “Reflex testing may be more suitable for models of collaboration with genetic counseling where healthcare providers may be initiating genetic testing.”

For men with non-metastatic PCa, the guideline recommends that germline testing be considered for men with Ashkenazi Jewish ancestry, advanced disease (T3a or higher), intraductal or ductal pathology, or Grade Group 4 disease (Gleason sum 8) or higher.

Germline testing is recommended for men with 1 brother or father or 2 or more male relatives diagnosed with PCa when they were younger than 60 years, died from PCa, or had metastatic PCa.

Genetic evaluation The guideline also lists “key premises” for guiding genetic evaluation. “Patients’ psychosocial needs or preferences should dictate the mode of counseling,” reads one premise. In addition, the panel noted that a full family history is important to collect during the genetic evaluation process. The panel also recommends that men should engage in informed decision making for genetic testing and states that building collaborations between healthcare and genetics providers is important for optimal genetic evaluation.

“Referral to a genetic counselor is important for men with mutations identified and may be needed for men with variants of uncertain significance, strong family cancer history, patient anxiety, or patient preference,” Dr Giri said. “Furthermore, since genetic testing can have hereditary cancer implications, genetic testing of family members of men with genetic mutations (called cascade testing) should be under the care of a genetic counselor.” ■

Renal & Urology News 21

AMI Is More Likely in HD vs PD Patients ACUTE MYOCARDIAL infarction (AMI) is more likely among patients on hemodialysis than in those on peritoneal dialysis (PD), a new study found.

Among 86,215 patients initiating maintenance dialysis during 1998 to 2010 in Taiwan’s National Health Insurance Research Database, investigators identified 5513 pairs of HD and PD patients matched by age, sex, year of dialysis initiation, and 20 relevant comorbidities such as diabetes, hypertension, heart failure, and coronary artery disease.

Patients with a prior AMI, switch in dialysis modality, kidney transplant, or malignancy were excluded.

AMI incidence was significantly higher among HD than PD patients: 9.71 vs 8.35 per 1000 patient-years, respectively, Yu-Tzu Chang, MD, of National Cheng Kung University Hospital in Taiwan, and colleagues reported in Atherosclerosis. HD patients had a 30% greater risk for AMI. Furthermore, the cumulative incidence rate for AMI increased significantly and substantially after 4 years from the start of dialysis: 0.09 vs 0.05, respectively. Analyses of the entire unmatched cohort and important subgroups showed similar trends.

These results differ from some previous research showing no differences in AMI risk between HD and PD patients. But these studies often

Nutritional impact continued from page 20

18. Shorter B, Gordon B. (2017). Diet Therapy in the Context of Chronic Pelvic Pain. In Urological and Gynaecological Chronic Pelvic Pain (pp. 51-83).

Springer, Cham.

19. Bosch PC. Examination of the significant placebo effect in the treatment of interstitial cystitis/bladder pain syndrome. Urology. 2014;84:321-326 20. Wu CC, Yang SS, Chang SJ. Re: Lifestyle and risk of chronic prostatitis/chronic pelvic pain syndrome in a cohort of United States male health professionals: R. Zhang, S. Sutcliffe, E. Giovannucci, WC Willett, EA Platz, BA Rosner, JD Dimitrakoff and K. Wu J. Urol 2015;194:1295-1300. J Urol. 2016;195:1625-1626.

21. Chen X, Hu C, Peng Y, et al. Association of diet and lifestyle with chronic prostatitis/chronic pelvic pain syndrome and pain severity: a case-control study.

Prostate Cancer Prostatic Dis. 2016;19:92-99.

22. Espinosa G, Esposito R. (2017). Naturopathy. In Healing in Urology: Clinical Guidebook to Herbal and Alternative Therapies (pp. 45-90).

23. Goodarzi D, Cyrus A, Baghinia MR, et al. The efficacy of zinc for treatment of chronic prostatitis. Acta Med Indones. 2013;45:259-264.

24. Anger JT, Goldman HB, Luo X, et al. Patterns of medical management of overactive bladder (OAB) and benign prostatic hyperplasia (BPH) in the United States. Neurourol Urodyn. 2018;37:213-222.

25. Russo G, Urzi D, Cimino S. (2018). Epidemiology of LUTS and BPH. In Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia (pp1-14), Academic Press 26. ElJalby M, Thomas D, Elterman D, Chughtai B. The effect of diet on BPH, LUTS and ED. World J Urol.

2019;37:1001-1005.

27. Mitchell T, Kumar P, Reddy T, et al. Dietary oxalate and kidney stone formation. Am J Physiol Renal Physiol. 2019;316:F409-F413.

28. Trinchieri A, Montanari E. Prevalence of renal uric acid stones in the adult. Urolithiasis. 2017;45:553-562.

29. Morgan MS, Pearle MS. Medical management of renal stones. BMJ. 2016;352;i52.

30. Han H, Kent PS, Beto JA. (2019). Nutritional management of nephrolithiasis in chronic kidney disease.

In Nutritional and Medical Management of Kidney Stones (pp. 227-242). Humana, Cham.

31. Pearle MS, Goldfarb DS, Assimos DG, et al. Medical management of kidney stones: AUA guideline. J Urol.

2014;192:316-324.

32. Selvin E, Burnett AL, Platz EA. Prevalence and risk factors for erectile dysfunction in the US. Am J Med. 2007;120:151-157.

33. Di Francesco S, Tenaglia RL. Mediterranean diet and erectile dysfunction: a current perspective. Cent European J Urol. 2017;70:185-187.

34. Gandaglia G, Briganti A, Jackson G, et al. A systematic review of the association between erectile dysfunction and cardiovascular disease. Eur Urol. 2014;65:968-978.

35. Kirby M. The association between erectile dysfunction and CVD. Trends in Urology & Men's Health.

2019;10:11-15.

36. Centers for Disease Control and Prevention. Chronic Kidney Disease (CKD) Surveillance System. Aug. 2016. https://nccd.cdc.gov/CKD/AreYouAware. aspx?emailDate=August_2016; nccd.cdc.gov/ckd/ AreYouAware.aspx?emailDate=8_18_2016.

37. National Institute of Diabetes and Digestive and Kidney Diseases. Causes of Chronic Kidney Disease. 1 Oct. 2016, www.niddk.nih.gov/healthinformation/kidney-disease/chronic-kidney-diseaseckd/causes.

38. Foque D, Mitch W. Dietary approaches to kidney diseases. In: Brenner and Rector’s The Kidney. 10th ed. Elsevier; 2016:Chapter 61.

39. Ko GJ, Obi Y, Tortorici AR, Kalantar-Zadeh K. Dietary protein intake and chronic kidney disease. Curr Opin Clin Nutr Metab Care. 2017;20:77-85.

40. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 V1.0, Cancer incidence and mortality worldwide: IARC Cancer Base No 11. http://globocan. iarc.ft/Default.aspx.

41. Antoni S, Ferlay J, Soerjomataram I, et al. Bladder cancer incidence and mortality: a global overview and recent trends. Eur Urol. 2017;71:96-108.

42. Abbaoui B, Lucas L, Riedl, K, et al. Cruciferous vegetables, isothiocyanates and bladder cancer prevention. Mol Nutr Food Res. 2018;62:e1800079.

43. Larsson SC, Andersson S, Johansson J, Wolk A. Fruit and vegetable consumption and risk of bladder cancer: a prospective cohort study. Cancer Epidemiol Biomarkers Prev. 2008;17:2519-2522.

examined a composite cardiovascular end point or excluded heart failure patients, the investigators pointed out.

According to Dr Chang’s team, “chronic myocardial ischemia induced by serial changes in hemodynamic status and microvascular changes during hemodialysis might ultimately increase the risk of cardiovascular events, including AMI.” “Preventive and surveillance programs for AMI should be customized specifically for dialysis populations with different dialysis modalities, vintage, and concomitant risk factors for AMI,” they recommended. ■

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Bariatric Surgery Ups Survival in ESKD Obese patients with kidney failure had a significant 31% decreased risk of death, study finds WEIGHT LOSS SURGERY improves long-term survival and the prospect of kidney transplantation for obese patients with end-stage kidney disease (ESKD), new research suggests.

In a retrospective study of dialysis patients with a body mass index (BMI) of 35 kg/m2 or higher from the US Renal Data System registry (USRDS), the 1597 patients who underwent bariatric surgery had lower all-cause mortality at 5 years after adjustment for potential confounders compared with a matched control group of 4750 nonsurgical patients who received usual care (25.6% vs 39.8%), Kyle H. Sheetz, MD, MSc, of the University of Michigan in Ann Arbor, and colleagues reported in JAMA Surgery. Bariatric surgery was significantly associated with a 31% decreased risk of death compared with usual care. The decrease in death risk

was driven by lower mortality from cardiovascular causes at 5 years in the surgery group compared with the control arm (cumulative incidence 8.4% vs.

17.2%). Compared with usual care, bariatric surgery was significantly associated with a 49% reduced risk of cardiovascular mortality, Dr Sheetz’s team reported.

Patients also had a better chance of receiving a kidney transplant.

In addition, a significantly higher proportion of bariatric surgery patients than controls underwent kidney transplantation at 5 years (cumulative incidence 33% vs 20.4%). Bariatric surgery

Kidney Stones Are Associated With Higher Glucose in Men ELEVATED BLOOD GLUCOSE levels,

below 90 mg/dL after multivariable

even within the nondiabetic range, are

adjustment, the investigators reported

associated with an increased risk of

in the American Journal of Kidney

kidney stones in men, but not women,

Diseases. An HbA1c of 6.0% to 6.4%,

according to investigators.

and 6.5% or higher were significantly

Seolhye Kim, MD, MSc, of the Center

associated with an 18% and 20%

for Cohort Studies, Total Healthcare

increased risk of kidney stones, respec-

Center, Kangbuk Samsung Hospital,

tively, compared with an HbA1c less

Sungkyunkwan University School of

than 5.7%.

Medicine, Seoul, Korea, and colleagues

In addition, compared with men in the

studied 278,628 Korean adults without

lowest HOMA-IR quintile, those in the

nephrolithiasis who underwent a com-

highest quintile had a significant 18%

prehensive health examination from

increased risk of kidney stones.

2011 to 2017. The investigators exam-

“Although not fully understood,

ined the association of glucose level,

insulin resistance is one of several key

glycated hemoglobin level (HbA1c),

pathophysiologic features underlying

and Homeostasis Model Assessment

the association between glycemic dys-

of Insulin Resistance (HOMA-IR) with

regulation in the prediabetic stage and

kidney stone development.

nephrolithiasis,” the authors wrote.

Kidney stones developed in 6904

The study demonstrated no signifi-

participants during a median follow-up

cant association between glycemic

of 4.2 years. Among men, glucose

status and kidney stone risk among

levels of 90 to 99, 100 to 125, and

women. This finding may relate to the

126 mg/dL or higher were significantly

protective effects of estrogen, accord-

associated with a 10%, 11%, and

ing to the investigators, who noted

27% increased risk for kidney stones,

that most women in the study were

respectively, compared with levels

premenopausal. ■

vs usual care was significantly associated with a 1.8-fold increased likelihood of undergoing kidney transplantation, according to the investigators.

At 1 year, however, bariatric surgery was significantly associated with a higher cumulative incidence of death from any cause compared with usual care (8.6% vs 7.7%). Compared with usual care, bariatric surgery was significantly associated with a 1.4-fold increased risk of all-cause mortality at 1 year.

“These findings suggest that bariatric surgery may warrant further consideration in the longitudinal management of patients with obesity and end-stage kidney disease,” according to the investigators.

“Bariatric surgeons need to look beyond the short-term increased risk of surgery in this patient population and consider the vast survival benefits for patients

made eligible for kidney transplant,” Melina R. Kibbe, MD, and David A. Gerber, MD, of the University of North Carolina at Chapel Hill, commented in an accompanying editorial. “Taking this further, we believe that bariatric surgeons should be incentivized to operate on this patient population instead of being penalized through public reporting because of the risks of higher morbidity.”

As for why more obese patients with ESKD are not receiving bariatric surgery given the new findings and the potential for greatly increased survival, they observed: “In large part, it is likely because of the higher risk of perioperative complications and early mortality for patients receiving dialysis who undergo bariatric surgery. However, recent studies have demonstrated that the risk of bariatric surgery for patients receiving dialysis is not as high as originally thought.” ■

PD Infection Rates Vary

By Country

­ eritonitis risk, with the risk decreasing p by 5% with each 10 percentage point increase in the proportion of patients using this modality, after adjusting for patient factors. Facilities that used antibiotics at catheter insertion, compared with those that did not, had a significant 17% decreased risk of peritonitis.

Facilities with PD training duration of 6 or more days compared with shorter periods had a significant 19% decreased risk of peritonitis. The risk of peritonitis was significantly associated with facility size only in Japan, with the risk rising 7% for each 10 patients receiving PD at a facility.

In addition, the investigators reported that the microbiology of peritonitis was similar across countries, except for Thailand, where Gram-negative peritonitis rates exceeded Gram-positive rates. Dr Perl and his collaborators said this finding likely reflects underrecognition of Gram-positive episodes that is driven by a disproportionately high rate of culture-negative peritonitis (0.11 episodes per year) in that country, a rate nearly twice that in the United States, United Kingdom, and Canada.

“We have identified important regional differences in the risk for peritonitis and potentially modifiable practices that may reduce these risks,” Dr Perl’s team reported. “Improvement in culture-­ negative peritonitis rates should be a priority of all participating countries.” ■

PERITONITIS RISK among patients on peritoneal dialysis (PD) differ internationally, according to a new study of 7051 adult PD patients from 209 facilities in 7 countries.

The countries, which are participants in the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS), included the United States, Canada, United Kingdom, Japan, Thailand, and Australia/New Zealand.

Facility peritonitis rates were variable within each country and exceeded 0.50 episodes per patient-year in 10% of facilities, Jeffrey Perl, MD, of Arbor Research Collaborative for Health in Ann Arbor, Michigan, and St. Michael’s Hospital in Toronto, and colleagues reported in the American Journal of Kidney Diseases. Overall peritonitis rates, in episodes per patientyear, were 0.40 in Thailand, 0.38 in the United Kingdom, 0.35 in Australia/ New Zealand, 0.29 in Canada, 0.27 in Japan, and 0.26 in the United States, the investigators reported.

Greater use of automated PD was sig­n i­ficantly associated with lower

www.renalandurologynews.com JULY/AUGUST 2020

Renal & Urology News 23

Ethical Issues in Medicine Physicians should choose words that promote clarity and accuracy when explaining treatments to patients BY DAVID J. ALFANDRE, MD, MSPH

Promote clarity and accuracy Professionally, our most frequent interaction with risk involves the conversations we have with patients about treatments and procedures for their medical care.

Those conversations about risk are mediated by the informed consent discussion and physicians’ disclosure and by the patients’ understanding of the harms and benefits of various treatment options. The

nature of ‘benefits.’ Presenting treatment decisions as a comparison of risks vs benefits creates an inherent imbalance in which benefits simply exist, whereas harms are uncertain.”1

Probability and magnitude Physicians may understand the risks of a treatment, but how should the risks be communicated so that patients understand? First, risk can be broken down into probability and magnitude: the likelihood of an event occurring and how large or small that outcome is.

The probability of death from a treatment might be extremely low, but most would consider death a risk of large magnitude. Conversely, a drug’s side effect might be extremely common but hardly noticeable.

There are also barriers that interfere with risk perception, such as when risks are withheld or misrepresented through overly emotive language or cognitive biases. Physicians may downplay risks by not mentioning them, as when they avoid disclosing cancer diagnoses and poor prognoses to patients.

Using technical language or emotive descriptions may overly influence or confuse patients and impair communication. A “negative test result” or a treatment that is “very high risk”

Patients are more likely to understand and appreciate a probability of “5 out of 100” rather than “5% of all patients.” words physicians choose when discussing risk should promote clarity and accuracy of information exchange. Specifically, physicians should frame treatment options by their “harms and benefits,” not by their “risks and benefits.” As Daniel J. Morgan, MD, and colleagues describe in a recent article, “Referring to harms as ‘risks’ emphasizes that the unfavorable outcome may or may not happen, whereas there is no parallel language that highlights the equally probabilistic

without reference to specific numbers or context may mean different things to patients. Framing, a type of cognitive bias in which physicians describe risk in one form exclusively, can lead to inaccurate risk assessment by patients. A risk of 5% mortality rather than 95% survival is clinically equivalent even if patients interpret the latter more favorably.2 Another potential issue is availability bias, which is an overemphasis of a risk because of a recent association with it.

© TBRADFORD / GETTY IMAGES

L

eaving work the other day in New York City, I spotted a motorcyclist zooming down the street wearing a mask but no helmet. During the COVID19 pandemic, masking is required for all state residents when unable to socially distance (motorcycle helmets are always required). I found this scene intriguing because it seemed to be an overt display of how members of the public can interpret risk. I do not know what went through his head as he got on his motorcycle that afternoon, but he appeared to have decided that the risk of COVID-19 transmission was greater than the risk of a head injury from a motorcycle crash.

Was dying from COVID-19 worse than dying from a motorcycle-induced head injury? However he chose, there are some lessons for how physicians communicate risk to patients so that we can help promote their health.

Physicians need to consider how people evaluate risks when counseling them about treatment.

Factor in literacy and numeracy Patients may also have limited literacy or numeracy, making written materials sometimes unhelpful. However, even patients with high literacy and numeracy can have difficulty in appreciating differences in risk. Evidencebased practices for communicating probabilistic information is available3 and should be used to improve the quality of information exchange. This includes the use of frequencies over percentages in describing probability.

Patients are more likely to understand and appreciate a probability of “5 out of 100” rather than “5% of all patients.”

In addition, patients understand absolute risk reduction better than relative risk reduction, although use of the latter can lead to higher treatment uptake rates.4 Rather than describe risks verbally, physicians may be more successful in conveying risks by graphically illustrating them using an icon array, which visually displays proportions of different outcomes. Some websites (eg, ­www.­iconarray.com) allow users to develop their own icon arrays to educate patients by entering the relevant data.

In spite of these considerations, all the information in the world may not be enough when patients are beset with hard choices. Even the most capable

physician using evidence-based risk communication tools, working with the most numerate, literate, and wellinformed patient, may still struggle with the uncertainty of risk. Although physicians cannot eliminate risk, they can serve as an interpreter who guides patients to articulate their values, preferences, and concerns, and make it easier for patients to make better decisions. ■ David J. Alfandre MD, MSPH, is a health care ethicist for the National Center for Ethics in Health Care (NCEHC) at the Department of Veterans Affairs (VA) and an Associate Professor in the Department of Medicine and the Department of Population Health at the NYU School of Medicine in New York. The views expressed in this article are those of the author and do not necessarily reflect the position or policy of the NCEHC or the VA. REFERENCES 1. Morgan DJ, Scherer LD, Korenstein D. Improving physician communication about treatment decisions: Reconsideration of “risks vs benefits” [published online March 9, 2020]. JAMA. doi: 10.1001/jama.2020.0354 2. Freeman, Alexandra LJ. How to communicate evidence to patients. Drug Ther Bull. 2019;57:119-124. doi: 10.1136/dtb.2019.000008 3. Zipkin DA, Umscheid CA, Keating NL, et al. Evidencebased risk communication: a systematic review.

Ann Intern Med. 2014;161:270-280. doi: 10.7326/ M14-0295 4. Schrager SB. Five ways to communicate risks so that patients understand. Fam Pract Manag. 2018;25:2831. https://www.aafp.org/fpm/2018/1100/p28.pdf

24 Renal & Urology News

JULY/AUGUST 2020 www.renalandurologynews.com

Practice Management C

hris Carson, a Managing Director in the Health Solutions practice at FTI Consulting Inc. in Atlanta, relates that he, his spouse, and friends recently dined at a restaurant for the first time in months. Upon entering, they were stunned by the sight of workers wearing masks and gloves. Tables had no tablecloths. Moreover, while waiting for a table, he and his spouse had to move twice at the bar to adhere to social distancing. Then, when seated, they noted they had nearly an entire section of the restaurant to themselves.

When the restaurant owner came by to check on them, he was wearing a hockey-like face mask. The owner said they were only serving at 50% capacity, but the place was busy and doing well.

Restaurants suddenly have something in common with medical practices. Both have been hit hard by the COVID-19 pandemic and need to continue providing services while taking precautions to prevent COVID-19 transmission. In the case of medical practices, a major challenge will be to maintain patient volume while ensuring the safety of caregivers and patients.

said Chris Zaenger, the Principle of Z Management Group, Ltd., based in Elgin, Illinois. “They really ought to focus on both ends of the ledger — what they can generate and save,” he said.

Zaenger suggests looking at all areas of spending to identify places to cut costs, such as medical and office supplies.

Providers may be able to work with other practices to get volume discounts on medical supplies or seek out places to get office supplies at lower prices.

“It’s okay to go to Target,” he said.

Debra Phairas, President of Practice & Liability Consultants LLC in Napa, California, suggests holding staff contests that challenge employees to find the best way to save money each quarter, with a reward given to the winner.

She also recommends that practices, as they ramp up after reopening, make anticipatory 6-month budget forecasts of expenses, taking into account changes in patient volume.

Rent and payroll usually are an organization’s biggest expenses, so practices should look at those first, Phairas said.

If a practice is not billing as much as before the pandemic, they may want

Working with other providers to get volume discounts on medical supplies is among the tactics practices can use to lower expenses.

“It’s going to take experimentation, flexibility, a positive attitude, and thinking through all parts of the business,” Carson said.

Many of his medical practice clients have expanded their office hours to get more patients in the door, he said, adding that some health systems are open for patient visits in the evening and on weekends to compensate for social distancing requirements during the weekdays.

Cutting costs Surgical practices net about 37% of every dollar they bill to an insurer, but “every dollar saved is a dollar kept,”

to consider such cost-cutting measures as reducing hours worked by medical assistants, whose workload is tied closely with that of doctors, she said.

Consider downsizing Groups also can consider whether they should downsize their practice space.

Practices should look at morning and afternoon shifts to determine how rooms are used each day, Phairas said.

“They can’t afford to have empty rooms while doctors are in surgery or doing procedures,” she said.

An obvious way to increase a group’s income is to see more patients. But as

© PINSTOCK / GETTY IMAGES

Increasing patient volume and cutting costs during the pandemic can improve practices’ bottom lines BY TAMMY WORTH

Telehealth offers a way for practices to maintain and boost revenue.

practices reopen, some patients may have gone to other physicians or opted to forgo nonemergent services. All offices have an inventory of charts from patients who have not been seen at the practice recently, Zaenger said. Staff should follow up with these patients to make appointments or at least to stay connected.

“How many orthopedic doctors call parents of kids who had a fractured forearm to see how they are doing?” he asked. “This is a great time to build goodwill and add to physician presence.”

In addition, practices should review referral networks and touch base with physicians who had been a regular source of referrals. Many electronic medical record systems track who is sending patients to a practice. Practices that find out providers who used to give referrals are not doing so any longer should call those providers to let them know they are still taking new patients, Zaenger said.

Administrative staff can also play a role in increasing income. It is imperative to send out insurance claims with clean billing and coding to get reimbursed as quickly as possible, Carson said. More than 500 new CPT codes are being released next year, he said.

Practices can start reviewing how these new codes might impact their billing.

Lab bills are another area frequently overlooked when money is tight,

Zaenger said, adding that these bills are frequently wrong. Differences in coding between third-party payers and laboratories can result in practices paying more for lab services and potentially losing money. Staff should review lab bills monthly to ensure that third-party reimbursements match the amounts billed.

Telehealth Telehealth offers another way to maintain and potential boost revenue. Many practices are already performing visits this way. Carson said one of his clients went from no telehealth visits to 5,000 such visits a week. Assuming regulations on telemedicine visits remain favorable, this modality could be a great way to increase caseload and income, especially for practices that serve large numbers of older, less mobile patients and those in rural areas, Zaenger said.

Expanded use of telehealth can help providers better manage patient visits, increase the number of patients seen, and potentially reduce the need for some office space and staff.

“What the pandemic did was give telemedicine an adrenaline shot; it catalyzed it as a new way to look at the practice,” Zaenger said. ■ Tammy Worth is a freelance medical journalist based in Blue Springs, MO.