Renal & Urology News - Mar/Apr 2017

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Treatment of Advanced RCC Improving Real-world survival times after initiation of first-line targeted therapy have gotten longer, researchers report FIRST-LINE TARGETED THERAPIES COMPARED In a study showing that survival times associated with first-line targeted therapy for advanced renal cell carcinoma are increasing, researchers found that pazopanib was associated with significantly longer survival than sunitinib and sorafenib. Shown here are the median survival times in months

19.6

17.3

17.2

Pazopanib

Sunitinib

Sorafenib

MONTHS

MONTHS

MONTHS

Source: Pal SK et al. Real-world survival outcomes and prognostic factors among patients receiving first targeted therapy for advanced renal cell carcinoma: A SEER-Medicare database analysis. Clin Genitourin Cancer.

2017; published online ahead of print.

NLR Predicts Post-RC Survival PREOPERATIVE NEUTROPHILto-lymphocyte ratio (NLR) predicts survival outcomes among patients undergoing radical cystectomy (RC) for bladder cancer, researchers reported at the 2017 Genitourinary Cancers Symposium in Orlando, Florida. NLR is predictive regardless of whether patients have had neoadjuvant chemotherapy.

In a retrospective cohort study, Janet B. Kukreja, MD, and colleagues at the University of Texas MD Cancer Center in Houston obtained NLR data from 1435 patients within 30 days prior to undergoing RC. The median follow-up among survivors was 5.9 years. The median overall survival (OS) was 5.2 years. continued on page 8

HOW BUNDLING CHANGED DIALYSIS CARE DELIVERY

Peritoneal dialysis is on the rise and ESA use has decreased.

PAGE 10

BY JODY A. CHARNOW REAL-WORLD survival has improved over time among patients with advanced renal cell carcinoma (aRCC) receiving first-line targeted therapy, according to a study.

Using the Surveillance, Epidemiology and End Results (SEER)-Medicare database, Sumanta K. Pal, MD, of the City of Hope Comprehensive Cancer Center in Duarte, California, and colleagues identified 1245 adult RCC patients who received first-line targeted therapy.

Researchers grouped the patients into an early cohort (2006–2009, 604 patients) and a late cohort (2010–2012, 641 patients) based on the year of first-line targeted therapy initiation. Patients had a mean age of 68 years. Overall survival

Kidney Stones, Asthma Linked in Children

BY JODY A. CHARNOW KIDNEY STONES are more common among children with asthma compared with the general pediatric population, new findings suggest.

“To our knowledge, this is the first report of an association between asthma and kidney stone formation,” Ganesh K. Kartha, MD, and colleagues at Cleveland Clinic in Ohio wrote.

In a study conducted at their institution, the investigators found that, compared with the general pediatric population, the prevalence of kidney stones was 4-fold greater among pediatric patients with asthma, and children with kidney stones have a 4-fold greater prevalence of asthma, according to a paper published online in PLoS One. “This correlation may suggest a mechanistic link between asthma and nephrolithiasis,” the researchers concluded.

The researchers ruled out body mass index (BMI) as a factor because BMI continued on page 8

(OS) was significantly longer in the late compared with the early cohort (23.4 vs 16.7 months), Dr. Pal’s group reported online in Clinical Genitourinary Cancer.

Targeted therapies included sorafenib, sunitinib, and pazopanib, which are vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs); axitinib, a selective VEGFR inhibitor; everolimus and temsirolimus, which are mammalian target of rapamycin (mTOR) inhibitors; and bevacizumab, a humanized anti-VEGF monoclonal antibody.

The study also identified prognostic factors. These included higher tumor grades, lung, bone, and liver metastasis, previous nephrectomy, and use of continued on page 8

IN THIS ISSUE 5

Obesity is associated with an increased risk of kidney cancer

6

Escalating sunitinib doses may benefit mRCC patients

14

Novel MRI protocol enhances PCa risk stratification

17

Testosterone replacement therapy improves anemia

23

Emergent lithotripsy may be better for some ureteral stones

24

Metabolic profiles shown to predict renal pathology

24

Adding bicalutamide to PCa salvage radiotherapy ups survival

Point-of-care ultrasound can improve CKD management.

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www.renalandurologynews.com MARCH/APRIL 2017

Renal & Urology News 3

FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD Medical Director, Urology

Medical Director, Nephrology

Robert G. Uzzo, MD, 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, MPH, PhD Professor & Chief Division of Nephrology & Hypertension University of California, Irvine School of Medicine Orange, Calif.

Urologists

Nephrologists

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

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

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

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

Stanton Honig, MD Department of Urology Yale University School of Medicine New Haven, CT J. Stephen Jones, MD, FACS President, Cleveland Clinic Regional Hospitals & Family Health Centers Professor & Horvitz/Miller Distinguished Chair in Urological Oncology Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology University of California Irvine

Csaba P. Kovesdy, MD Chief of Nephrology Memphis VA Medical Center Fred Hatch Professor of Medicine University of Tennessee Health Science Center, Memphis Edgar V. Lerma, MD, FACP, FASN, FAHA 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.

James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City

Rulan Parekh, MD, MS Associate Professor of Pediatrics and Medicine University of Toronto

Kenneth Pace, MD, MSc, FRCSC Assistant Professor Division of Urology St. Michael’s Hospital University of Toronto

Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center Detroit

Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada

Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J.

Renal & Urology News Staff Editor

Jody A. Charnow

Web editor

Natasha Persaud

Production editor Group art director, Haymarket Medical Production manager Production director Circulation manager National accounts manager Group publisher Editorial director

Kim Daigneau Jennifer Dvoretz Brian Wask Kathleen Millea Grinder Paul Silver William Canning Chad Holloway Kathleen Walsh Tulley

Senior VP, medical journals & digital products

Jim Burke, RPh

CEO, Haymarket Media Inc.

Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 16, Number 2. Published bimonthly by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. Periodicals postage paid at New York, NY, and an additional mailing office. The subscription rates for one year are, in the U.S., $75.00; in Canada, $85.00; all other foreign countries, $110.00. Single issues, $20.00. www.renalandurologynews.com. Postmaster: Send address changes to Renal & Urology News, c/o DMD Data Inc., 2340 River Road, Des Plaines, IL 60018. Copyright: All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without the prior written permission of Haymarket Media, Inc. Copyright © 2017.

MRIs for Patients With Pacemakers

M

RI is an essential imaging modality for patients with genitourinary pathologies. In patients with CKD stage 3 or worse, it provides excellent renal anatomic detail without the risk of iodinated contrast. Additionally, in men screened for, or who have, prostate cancer, multiparametric MRI can assist in the performance of targeted biopsies as well as in cancer staging and management.

Nearly 2 million people in the United States have non–MRI-compatible pacemakers or implantable cardioverter defibrillator devices (ICD). At least half will have a clinical indication for MRI after device implantation.1 The current standard of care makes patients with pacemakers/ICDs ineligible for MRIs due to safety concerns, including cardiac lead heating, myocardial thermal injury, and adverse changes in pacing properties.

Results of the recently published prospective, multicenter MagnaSafe Registry study, however, suggest that MRIs for patients with pacemakers/ICDs can be performed safely. The study evaluated 1500 patients with non-MRI-compatible pacemakers/ICDs undergoing clinically indicated non-thoracic MRIs (1.5T). A multidisciplinary process was employed whereby physicians or extenders with cardiac device expertise and advanced training were in attendance for monitoring. They noted no deaths, no lead failures, no losses of capture, and no ventricular arrhythmias in 1500 MRIs. There were 6 cases of self-terminating atrial fibrillation/flutter and/or partial electrical reset. The authors concluded that device or lead failure did not occur in any patient with non–MRI “compatible” pacemakers/ICDs who underwent non-thoracic MRIs.1 Pacemakers were developed in the 1950s and MRI machines in the 1970s. For the last 35 years, clinicians have not used one in the presence of the other. The reasons for this are multifactorial, but may include the availability of imaging substitutes, limited knowledge, and a lack of multidisciplinary coordination and processes. The question now is: How long will it take to change culture and practice whereby patients with pacemakers/ICDs can safely undergo MRI at most hospitals?

As a profession, we excel at disseminating new knowledge, but are far less effective at implementing it. Implementation science is an emerging discipline within medical hierarchies to study the methods that increase integration of evidence-based interventions into practice settings.

Translating research into practice is more complex that it may initially seem.

Sustaining those changes requires a new level of cooperation, collective will, incentives, disincentives, and clinical champions. Physicians should lead these efforts. The data from MagnaSafe offer an easy place to start.

Robert G. Uzzo, MD, 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

1. Russo RJ et al: Assessing the Risks Associated with MRI in Patients with a Pacemaker or Defibrillator N Engl J Med. 2017;376:755-764.

4 Renal & Urology News

MARCH/ APRIL 2017

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Contents

MARCH/ APRIL 2017 ■ VOLUME 16, ISSUE NUMBER 2

Urology 6

ONLINE

17

this month at renalandurologynews.com Clinical Quiz

24

Test your knowledge by taking our latest quiz at renalandurologynews.com/ ClinicalQuiz 24

HIPAA Information breaches can lead to imposition of corrective action plans as well as fines.

Drug Information

PCa Salvage Radiotherapy Plus Androgen Blockade Ups Survival The combined treatment reduced the risk of death by 23% compared with salvage radiotherapy alone.

Metabolic profiles May Predict Renal Pathology Serum and urine analyses could help distinguish benign and malignant renal masses.

13

High-Volume Hospitals Recover More Usable Organs Hospitals with the highest volume of deceased donors were 52% more likely than the hospitals with the lowest volume to procure 4 or more organs per donor.

15

Timing of Renal Replacement Therapy Initiation in AKI Sean M. Bagshaw, MD, MSc, and Ron Wald, MDCM, MPH, review the evidence for early versus delayed RRT.

22

ESRD Risk Elevated in Blacks with Sickle Cell Trait The risk of end-stage renal disease is twice as high among carriers of the trait compared with non-carriers.

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

News Coverage Visit our website for daily coverage of the American Urological Association annual meeting in Boston, May 12–16.

Testosterone Replacement Therapy Improves Anemia Among older hypogonadal men, TRT for 12 months increased the likelihood of a 1.0 g/dL or greater increase in hemoglobin versus placebo.

Nephrology

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

Job Board

Sunitinib Dose Escalation May Benefit mRCC Patients A Canadian study demonstrated improved progression-free survival, a delay in the change of systemic therapy, and acceptable toxicity.

25

Vitamin D Status, Fat Mass Linked in Older Women Findings suggest that adipose tissue is a factor to be considered when evaluating vitamin D supplementation, according to researchers.

Emergent lithotripsy, either ureteroscopic or

extracorporeal, can be offered as an effective and safe treatment for patients with symptomatic ureteral stone.

See our story on page 23

CALENDAR American Urological Association Annual Meeting Boston May 12–16 American Society of Clinical Oncology Annual Meeting Chicago June 2–6 European Renal Association-European Dialysis and Transplant Association 54th Congress Madrid June 3–6 Canadian Urological Association Annual Meeting Toronto June 24–27 International Continence Society Annual Meeting Florence, Italy September 12–15 American Society for Radiation Oncology Annual Meeting San Diego September 24–27 American Society of Nephrology Kidney Week 2017 New Orleans October 31–November 5

26

Departments 3

From the Medical Director MRI scans for patients with pacemakers

5

News in Brief Obesity increases the risk of kidney cancer

26

Practice Management Physician time-wasting can be a source of inefficiency

www.renalandurologynews.com MARCH/APRIL 2017

Renal & Urology News 5

News in Brief

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

Short Takes Anemia Indication Sought For a Phosphate Binder

men only, the percentage of motile

The FDA is reviewing a supplemental

progressive motility, and rapid progres-

New Drug Application (sNDA) for ferric

sive motility were increased after PDE5

citrate (Auryxia) that seeks to expand

inhibitor treatment. The percentage of

the indication for the drug to include

morphologically normal spermatozoa

treatment of iron deficiency anemia in

also increased in infertile men.

spermatozoa, the percentage of total

patients with non-dialysis-dependent Ferric citrate, which is made by

AKI Predictors in Pulmonary Embolism Patients Identified

Boston-based Keryx Biopharmaceuti-

Pre-existing chronic kidney disease

cals, is currently approved for control

(CKD) and anemia are among the

of serum phosphorus in patients with

independent risk factors for acute

end-stage renal disease on dialysis.

kidney injury (AKI) in patients hospital-

chronic kidney disease (NDD-CKD).

ized for pulmonary embolism (PE),

Oral Erectile Dysfunction Drugs Benefit Infertile Men

investigators reported in Medicine (2017;96:9:e5822).

Oral phosphodiesterase type 5 (PDE5)

Chih-Hsiang Chang, MD, of Chang

inhibitors, which are used to treat erec-

Gung Memorial Hospital Taoyuan City,

tile dysfunction, can improve sperm

Taiwan, and colleagues studied 7588

parameters in infertile men, according

patients hospitalized for PE and admin-

to a new systematic review and meta-

istered anticoagulation or thrombolytic

analysis published online ahead of print

agents. AKI was diagnosed in 372 pa-

in Urology.

tients (4.9%). On multivariable analysis,

In an investigation that included 11

AKI patients had nearly 6-, 3-, 2-, and

studies and a total of 1317 men, Ping

3-fold higher odds of have pre-existing

Tan, MD, and colleagues at Sichuan

CKD, anemia, sepsis, and massive PE,

University, Chengdu, Sichuan, China,

respectively, than non-AKI patients. AKI

found that PDE5 inhibitors had no effect

patients also had 29% and 34% higher

on semen volume and sperm concen-

odds of having diabetes mellitus and

tration overall, but, among infertile

hypertension, respectively.

How You Rate Obamacare President Donald Trump has called the Affordable Care Act (“Obamacare”) a “disaster.” As the president and the Republican-controlled Congress continue to grapple with the repeal and replacement of Obamacare, we asked readers in an online a poll, “Do you think Obamacare Do you think Obamacare has been disaster? has been a disaster?” Here are the results based on 169 responses.

40.2%

No: 54.4% Yes: 40.2%

54.4%

Do Not Know: 5.3% 5.3%

FDA Approves Nivolumab For Urothelial Carcinoma N

ivolumab (Opdivo) injection has received FDA approval for treating patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or after platinum-containing chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with ­platinum-containing chemotherapy.

In the CheckMate-275 phase 2 open-label trial, 53 (19.6%) of 270 of patients responded to treatment with nivolumab: 7 patients (2.6%) had a complete response and 46 patients (17%) had a partial response, according to a press release from Bristol-Myers Squibb Company, the maker of nivolumab. Among responders, the median time to response was 1.9 months and the median duration of response was 10.3 months.

Obesity Increases Kidney Cancer Risk, Review Finds O

besity is associated with an increased risk of kidney cancer and 10 other cancers, according to a recent umbrella review of systematic reviews and meta-analyses.

For every 5 kg/m2 increase in body mass index, the risks for kidney cancer rose by 30%, Maria Kyrgiou, MD, of Imperial College London, and colleagues reported online in BMJ. The risk increase for the other 10 cancers ranged from 9% for rectal cancer in men to 56% for biliary tract system cancer. The risk for postmenopausal breast cancer not due to hormone replacement therapy rose by 11% for each 5 kg women gained in adulthood, and the risk for endometrial cancer rose by 21% for each 0.1 increase in waist-to-hip ratio. The team considered the possible influences of sex, menopause, smoking, and hormone replacement therapy. They did not evaluate the quality of individual studies included in the original meta-analyses, which was a limitation.

Mirabegron for OAB Shows Superior Patient Adherence P

atients with overactive bladder (OAB) prescribed mirabegron remain on treatment longer than those prescribed traditional antimuscarinics, British researchers reported in a paper published online ahead of print in European Urology.

In a retrospective, longitudinal, observational study looking at persistence and adherence to OAB pharmacotherapy among 21,996 eligible patients, Christopher R. Chapple, MD, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, Sheffield, UK, and colleagues compared mirabegron with tolterodine ER, solifenacin, darifenacin, fesoterodine and other antimuscarinics over a 12-month period. In an unmatched analysis, the median time-to-discontinuation—the study’s primary endpoint—was significantly longer for mirabegron than tolterodine ER (169 vs 56 days) and other antimuscarinics (range 30–78 days). Compared with mirabegron use, tolterodine ER use was associated with a 1.55 times higher risk of treatment discontinuation in adjusted analyses. Use of other antimuscarinics was associated with 1.24 to 2.26 times increased risk.

6 Renal & Urology News

■ GUCS 2017, Orlando

MARCH/APRIL 2017

www.renalandurologynews.com

2017 Genitourinary Cancers Symposium, Orlando, Florida.

Drug Strategies for mCRPC Compared Improved survival seen with docetaxel followed by cabazitaxel and then abiraterone or enzalutamide

BY JODY A. CHARNOW NEW STUDIES MAY provide insight into which sequences of medications provide optimal treatment for men with metastatic castration-resistant prostate cancer (mCRPC). In one study, docetaxel followed by cabazitaxel and then an androgen-receptor targeted agent (ART), either abiraterone or enzalutamide, offered the longest survival. In another study, clinical or radiologic progression was less likely with abiraterone plus prednisone than cabazitaxel following first-line docetaxel therapy.

In a retrospective study of 574 mCRPC patients, Nicolas Delanoy, MD, of Georges Pompidou European Hospital in Paris, and colleagues evaluated the impact of 3 different drug sequences: docetaxel followed by cabazitaxel (267 patients, group 1), docetaxel followed by ART and then cabazitaxel (183 patients, group 2), and docetaxel followed by cabazitaxel and then ART (124 patients,

No Upswing in RCC Brain Metastases

BY JODY A. CHARNOW BRAIN METASTASES at the diagnosis of renal cell carcinoma (RCC) are associated with a higher risk of death.

Their incidence does not appear to be increasing, however, and researchers have developed a model for predicting which patients are more likely to harbor brain metastases.

The findings are based on a study examining the contemporary incidence and epidemiologic trends of RCCassociated brain metastases. For the study, investigators Maxine Sun, PhD, MPH, and colleagues at Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School in Boston, used 2010–2013 data from the Surveillance, Epidemiology, and End Results (SEER) database and 2010–2012 data from the National Cancer Data Base (NCDB). Dr Sun’s group found an overall incidence proportion of brain metastases at RCC diagnosis of 1.5%, a proportion

Drug-Sequence-Related Survival Characterized In a retrospective study of metastatic castration-resistant prostate cancer patients, median overall survival times in months (shown below) varied among 3 drug sequences examined.

DOC

CAB

30.1

DOC

ART

CAB

37.1

DOC

CAB

ART

40.1

DOC=docetaxel ART=androgentargeted receptor agent therapy (either enzalutamide or abiraterone) CAB=cabazitaxel

Source: Delanoy N, et al. Sequencing in metastatic castration-resistant prostate cancer (mCRPC): Updated results of the FLAC International Database. Data presented in poster format at the 2017 Genitourinary Cancers Symposium in Orlando, Florida. Poster Session B Board #D7. Abstract 267.

group 3). The median overall survival from the first docetaxel cycle in groups 1, 2, and 3 was 30.1, 37.1, and 40.1 months, respectively, reported in a poster presentation. Compared with group 1 patients, group 2 and 3 patients had a significant 12% and 40% decreased risk of death.

that remained stable during the short study period. Results also showed that the presence of brain metastases, compared with their absence, was associated with an 85% higher risk of death.

Dr. Sun’s team also identified variables significantly associated with brain metastases, such as lymph node involvement, clear cell (vs. papillary/chromophobe) histology, tumor size 7 cm or larger (vs. less than 7 cm), white race (vs. black race).

They used these variables to develop a model for brain metastases at RCC diagnosis. The model assigns point values to these variables. The higher the score, the greater the likelihood of brain metastases. The incidence of brain metastases was 0.2%, 1.1%, and 6.5% in patients with scores of 0–3 (low risk), 4–6 (intermediate risk), and 7 or more (high risk), respectively, the investigators reported.

Compared with patients in the low-risk category, those in the intermediate- and high-risk categories have 7.3 and 46 times higher odds of brain metastases. The model was developed using the SEER database and validated in the NCDB. “This type of model may be useful to consider as justification for baseline imaging in asymptomatic but highrisk patients,” Dr. Sun told Renal & Urology News. ■

Results also showed that higher baseline PSA level, shorter response to first androgen deprivation therapy (ADT), and clinical progression are major prognostic factors for overall survival at docetaxel initiation, according to the investigators.

In the other study, Arancha Gonzalez del Alba, MD, of the Hospital Son Dureta, Palma de Mallorca, Spain, and colleagues, recruited 150 mCRPC patients as part of the prospective, multinational, observational CAPRO study.

At a median follow-up of 7.8 months, 100 (67%) patients received abiraterone plus prednisone, 44 (29%) received cabazitaxel, and 6 (4%) received other treatments as second-line therapy.

The median clinical or radiologic progression-free survival (PFS) was significantly longer in the abiraterone than cabazitaxel group (8.7 vs. 6.4 months).

Compared with cabazitaxel recipients, abiraterone-treated patients had a significant 44% lower risk of clinical or radiologic progression. The median biochemical PFS was similar for the abiraterone and cabazitaxel groups (9.2 and 9.9 months, respectively), as was the proportion of patients who had a greater than 50% PSA response (47.3% and 32.3%). ■

Sunitinib Dose Escalation May Benefit mRCC Patients Dose escalation of sunitinib after

sive disease as the best response on

progression of metastatic renal cell

50 mg doses achieved either partial

carcinoma (mRCC) may be beneficial,

response (1 patient) or stable disease (2

with added progression-free survival,

patients) after dose escalation.

a delay in the change of systemic therapy, and an acceptable toxicity.

Jacques Raphael, MD, and colleagues

The overall survival for the 25 patients was 63.6 months. The patients had a median progression-free survival of

at Sunnybrook Health Sciences Centre

6.1 months on the 50 mg dose and

in Toronto studied 25 mRCC patients who

6.7 months when on dose-escalated

experienced disease progression while

sunitinib, according to the investigators.

on the standard 50 mg dose of sunitinib.

Patients experienced grade 1–2

At progression, physicians escalated the

toxicities, most commonly fatigue and

dose to 62.5 and 75 mg on an individual

diarrhea.

schedule if toxicity permitted.

At the 50 mg dose, 60% and 16% of

The cohort had a mean age of 54 years, and 22 patients (88%) were

patients had a partial response and sta-

male. The median follow-up period was

ble disease, respectively, as per RECIST

40.3 months. Eighteen patients had

1.1 criteria, for a median duration of 11.4

clear cell RCC, 6 had papillary RCC, and

months, Dr. Raphael’s group reported.

1 had other RCC histology.

After progression, 36% and 28% had

The rationale behind the study is

a partial response and stable disease,

supported by preclinical data suggest-

respectively, for a median duration of 7.8

ing that dose escalation may overcome

months. Three patients who had progres-

resistance to standard doses. ■

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Renal & Urology News 7

Calcium-Based Binders Up Elemental Calcium Intake PATIENTS WITH end-stage renal disease (ESRD) who take calcium-based phosphate binders may take in high levels of elemental calcium that could lead to complications related to calcium balance, according to a new report.

Previous studies have demonstrated an association between use of calciumbased binders and hypercalcemia, vascular calcification, and adynamic bone disease. To examine the effects of calcium loading associated with calcium-based binders in ESRD patients, Rosamund J. Wilson, PhD, of Spica Consultants in Marlborough, UK, and J. Brian Copley, MD, of Shire Pharmaceuticals in Lexington, Massachusetts, conducted a post hoc analysis of data from a phase IV study of 752 ESRD patients who switched to lanthanum carbonate monotherapy for 16 weeks after having been on monotherapy with calcium acetate (551 patients) or calcium carbonate (201 patients).

Vascular calcification and adynamic bone disease could result, researchers say.

Kidney Disease Outcomes Quality Initiative (KDOQI) 2003 guidelines recommend a maximum daily elemental calcium intake of 1.5 g/day and maximum total intake of calcium from all sources of 2 g/day, the investigators noted. The guidelines also suggest that calcium-based binders should be avoided in dialysis patients who have vascular calcification, hypercalcemia, or plasma parathyroid hormone (PTH) levels below 150 pg/mL. Of the 551 patients who were on calcium acetate prior to switching to lanthanum carbonate, 271 (49.3%) had an elemental calcium intake of at least 1.5 g/day at baseline, and 142 (25.8%) had an intake of at least 2.0 g/day, the maximum daily intake for all sources recommended by the KDOQI guidelines, the researchers reported in Drugs in Context (2017;6:212302). Mean serum phosphate levels were 6.1 mg/dL at baseline and 6.2 mg/dL after 16 weeks of lanthanum carbonate therapy. Their mean corrected serum calcium levels were 9.3 mg/dL and 9.2 mg/dL, respectively. Mean PTH levels were high at both time points (511.0 and 582.7 pg/mL, respectively.

Of the 221 patients on calcium carbonate therapy before switching to

lanthanum carbonate, 117 (58.2%) had an elemental calcium intake at baseline of at least 1.5 g/day, and 76 (37.8%) had an intake of at least 2.0 g/day, according to the investigators. Mean serum phosphate levels were 5.8 mg/ dL at baseline and 5.8 mg/dL at 16 weeks. Their mean corrected ­calcium

levels were comparable at baseline and 16 weeks (9.7 and 9.2 mg/dL, respectively), as were mean PTH levels (286.5 and 294 pg/mL, respectively), the researchers reported.

“This post hoc analysis of real-world clinical data shows that a large proportion of patients with ESRD tak-

ing ­calcium acetate/calcium carbonate monotherapy to treat hyperphosphatemia ingest elemental calcium at levels above the KDOQI-recommended daily limits,” Dr. Wilson and Dr. Copley concluded. “These patients may be at risk of developing vascular calcification and adynamic bone disease.” n

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Real-world survival continued from page 1

pazopanib (compared with sorafenib and sunitinib) as first-line therapy.

Compared with patients who had grade 1 or 2 tumors, those with grade 3 or 4 tumors had a significant 61% increased risk of death. Lung, bone, and liver metastases were associated with a significant 27%, 37%, and 42% higher risk of death, respectively. Previous nephrectomy was associated with a significant 45% lower risk of death.

Patients who received first-line therapy with sorafenib and sunitinib had a significant 77% and 55% increased risk of death, respectively, compared with those who started with pazopanib.

“Our data contribute valuable information regarding OS associated with first-line targeted therapy used for aRCC,

NLR predicts survival continued from page 1

The cutoff point of presurgery NLR with the strongest association with OS was 3.09. Median OS and disease-specific survival (DSS) were 5.87 and 15.64 years, respectively, among patients with an NLR below 3.09, compared with 4.18 and 7.47 years among those with an NLR of 3.09 or higher, investigators reported. The 5-year DSS rates were 74% for patients with an NLR below 3.09 and 56% for those with an NLR of 3.09 and above. In multivariate analysis, increasing NLR was associated with significantly higher risks of death from any cause and disease-specific death.

“There has been a surge of interested in predictive markers, especially when it pertains to response to immunotherapy with PD-L1 assays,” co-investigator Ashish Kamat, MD, told Renal & Urology News. “While these are definitely worth pursuing, we should not

Stones, asthma link continued from page 1

was similar among stone patients with and without asthma.

The investigators reported that the prevalence of kidney stones was 0.08% in the general pediatric population, but 0.31% in the pediatric asthmatic population and 0.53% among the patients aged 13 to 18 years. The prevalence of asthma in the pediatric population was 6.8% compared with 26.7% among the pediatric patients with kidney stones and 35% in the pediatric stone patients younger than 12 years.

provide real-world validation of several prognostic factors noted in clinical settings, and could assist clinicians in choosing the optimal therapy for patients with aRCC according to their individual prognostic factors,” the investigators wrote.

clinical trial, according to Dr. Pal and colleagues. “Also, patient outcomes could differ in real-world practice compared with the outcomes in clinical trials,” they noted. “For the physicians captured in the present data set, pazopanib might indeed offer a survival advantage owing to its more predictable and manageable toxicity profile.”

Aly-Khan A. Lalani, MD, a genitourinary oncology fellow at the DanaFarber Cancer Institute’s Lank Center for GU Oncology in Boston, who was not involved in the study, commented that real-world studies that reflect contemporary experience with trends, practices, and outcomes in advanced RCC are important for both physicians and patients, particularly to harmonize the observations seen in clinical trial settings.

“Dr. Pal and colleagues should be commended on their analysis, using the

SEER-Medicare database, of patients with advanced RCC,” Dr. Lalani told Renal & Urology News. “The results confirm what we intuitively expect in clinic to be adverse prognostic factors, namely Fuhrman grade and presence of visceral metastasis. Their study also highlights the learning curve associated with the introduction of VEGF-TKIs, evidenced by the improved outcomes in their later era cohort.”

Given the limited treatment sample sizes and follow up, Dr. Lalani pointed out, the results do not inform on the optimal first-line VEGF-TKI therapy.

“Future real-world studies that capture the practice of individualized dosing schedules on VEGF-TKIs, which have been increasingly incorporated into the clinic, may be more informative of the current targeted therapy era,” he said. n

lose sight of readily available ­markers of immunologic activity such as the neutrophil to lymphocyte ratio.”

During the study, 917 patients (64%) died and 518 (36%) were alive at last follow-up; 472 patients (33%) died from bladder cancer and 963 (67%) died from other causes or were alive at last followup. Of the 1435 patients, 887 had an NLR below 3.09, and 339 (38.2%) of these patients received neoadjuvant chemotherapy. The remaining 548 patients had an NLR of 3.09 or above, and 247 (45.1%) of them had received neoadjuvant chemotherapy.

David J. McConkey, PhD, Director, Johns Hopkins Greenberg Bladder Cancer Institute in Baltimore, noted that the study by Dr. Kukreja and colleagues “definitely represents a significant contribution to the field.” As the investigators pointed out, prior studies had suggested the presence of an association between NLR and post-RC survival, but inclusion and ­exclusion

criteria were limitations of those studies, he said. “This study not only confirms the previous hypothesis [of an association], it expands the findings to include all patients regardless of whether or not they received chemotherapy,” Dr. McConkey said. “The

DSS and OS results remain highly significant in multivariable analysis, and the measures used to generate the NLR are routine and robust. However, as is true for all retrospective studies, I would want to see the observations validated in a prospective study prior to making any recommendations for clinical practice.”

In a previous study published online recently in the Journal of Surgical Oncology, David D’Andrea, MD, of the Medical University of Vienna, Vienna, Austria, and colleagues found that NLR and lymphocyte-to-monocyte ratio independently improve preoperative prediction of recurrence-free, cancer-specific, and overall survival among patients undergoing RC for bladder cancer.

In a study involving 1551 patients undergoing transurethral resection of bladder tumor for non-muscle-invasive bladder cancer, Minyong Kang, MD, and colleagues at Seoul National University Hospital in Seoul, Korea, found that patients with an NLR of 2.0 or higher had a significantly 52% higher risk of death compared with those who had an NLR below 2.0 in multivariable analysis, according to findings published online in Oncotarget. Each 1-unit increase in NLR was associated with a significant 12% increased likelihood of cancer-specific death. n

Dr. Kartha’s group found no difference in 24-hour urine profiles between stone patients with asthma and patients with stones but not asthma.

The study included 865 patients diagnosed with nephrolithiasis at age 6 months to 18 years. Of these, 142 also had a diagnosis of asthma.

Asthma prevalence has been on the rise for the past 20 years, and although kidney stones are rare in the pediatric population, the kidney stone rate is increasing, Dr. Kartha’s team wrote.

“While obesity is thought to predispose children to kidney stones, the association between asthma and kidney stones

in this study was not related to BMI,” study co-investigator Manoj Monga, MD, Director of the Stevan B. Streem Center for Endourology and Stone Disease at Cleveland Clinic’s Glickman Urological & Kidney Institute, said in a press release. “To date, theories regarding kidney stone formation have centered around abnormalities in urinary chemistries. As no differences were identified in this study, alternative links between the two diseases, perhaps involving inflammatory pathways or epithelial dysfunction, will need to be explored.”

As for what could explain the link between asthma and kidney stones, the

investigators noted that stone formation in children has been linked to metabolic and genetic abnormalities, including cystic fibrosis (CF). The prevalence of kidney stone formation among adolescent CF patients is 4% to 6%, which is significantly higher than in the general adolescent population and in their population of children with asthma, according to the researchers.

“The greater prevalence of kidney stones in CF and asthma supports a link between airway inflammatory disease and renal tubular handling of electrolytes and stone formation,” the investigators wrote. n

Higher-grade tumors were associated with an increased death risk, new study finds.

Regarding the survival advantage associated with pazopanib versus sunitinib, the equivalent OS found in the COMPARZ trial (N Engl J Med. 2013;369:722-731) for pazopanib and sunitinib might not extend to physicians who did not participant in the

The presurgery NLR cutoff point with the strongest association with OS was 3.09.

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n FEATURE

How ‘Bundling’ Changed Dialysis Care in the US Imposition of flat-rate reimbursement was followed by reduced reliance on erythropoiesisstimulating agents, a drop in mean hemoglobin levels, and an uptick in peritoneal dialysis

I

ntroduction of the federal government’s prospective payment system for dialysis care (“bundling”) on January 1, 2011 has brought about a new frugality and costconsciousness in the use of medications and other resources in the management of patients with end-stage renal disease (ESRD). Dialysis providers were now being challenged to control costs — especially those associated with medications — while providing quality care.

“As a result of the bundle, medicines suddenly became a cost center versus a profit center,” said John Burkart, MD, Chief Medical Office for Health Systems Management at Wake Forest University Medical Center in Winston-Salem, North Carolina, who oversees the university’s outpatient dialysis facilities.

Faced with fixed payments for services, dialysis providers starting taking a hard look at whether one medicine really is more beneficial than another, or whether prescribing medications to achieve the highest possible value of a laboratory metric makes a meaningful clinical difference.

“The pharmaceutical industry adjusted to that and changed the way things were packaged, changed the way things were marketed, changed what was available for a dialysis unit, whereas before maybe it wasn’t available for a dialysis unit.”

Rob Chioini, Chief Executive Officer for Rockwell Medical, Inc., a maker of dialysis products, noted, “As a pharma company, we started looking for products or ways that could demonstrate cost savings to providers while still improving patient outcomes.”

accountable for clinical outcomes and for resource stewardship,” said Allen R. Nissenson, MD, Chief Medical Officer of Kidney Care for DaVita HealthCare Partners, Inc. The introduction of bundling has encouraged dialysis providers to focus on how they can achieve the best patient outcomes while restraining costs, he said.

“The challenges around a bundled system’s payment constraints are balanced by the move toward valuebased care models,” said Franklin W. Maddux, MD, Executive Vice President of Clinical & Scientific Affairs and Chief Medical Officer for Fresenius Medical Care North America. “These new models afford the ability to add innovation investments that address the greater risk and responsibility providers assume in managing the total cost of care for our patients.”

The bundled payment includes all renal dialysis services provide for outpatient

maintenance dialysis, including drugs and biologics (except oral-only medications until 2025) and other renal dialysis items and services that used to be payable separately. On its website, the Centers for Medicare & Medicaid Services (CMS), which oversees reimbursement for dialysis care, said it expects to pay about $9 billion to approximately 6000 dialysis facilities in 2017 for costs associated with the provision of dialysis care. The bundle base rate for 2016 was $230.39; the proposed base rate for 2017 is $231.04. The bundled payment is case-mix adjusted for various factors relating to patient characteristics. CMS also makes facility-level adjustments for dialysis facilities that have a low patient volume or rural locality.

Shift in medication use In the 6 years since bundling debuted, changes have occurred in the pharmacologic treatment of ESRD c­ omplications,

Accountability “I think bundling gave us the first look at what happens when you’re held

The proportion of end-stage renal disease patients starting renal-replacement therapy on peritoneal dialysis rather than hemodialysis inched upward after the debut of bundling.

especially anemia. Use of erythropoiesisstimulating agents (ESAs) has decreased substantially.

“The price of ESAs didn’t change, but the amount used was cut in half,” Chioini said.

“ESAs are the most costly of the injectable drugs. Its use has definitely gone down across the industry,” Dr Nissenson said. Innovation in anemia management has driven this with no evidence of changes in clinical outcomes, he added.

Researchers who have studied the impact of bundling on dialysis care cite the flat-rate reimbursement as a contributing factor to a decline in ESA use, along with FDA revisions to ESA labeling that encouraged more conservative use of these drugs. Concomitant with the decline in ESA use was a decrease in mean hemoglobin levels among dialysis patients.

“In terms of anemia management, the biggest trend by far is a substantial drop in mean hemoglobin levels since the advent of the bundle,” said James Wetmore, MD, MS, Medical Director for Nephrology Research for the Chronic Disease Research Group at Hennepin County Medical Center in Minneapolis. The bundle itself is not solely responsible for this, he stated. Key studies in pre-dialysis chronic kidney disease patients suggested that enthusiasm for high Hb levels probably was misguided, and thought leaders began to embrace lower levels. The FDA label change for ESAs also likely contributed to decreased enthusiasm for ESAs. As a result, ESA use is down and dialysis patients have lower hemoglobin levels and are receiving more transfusions compared with before the bundle,” Dr. Wetmore said.

© SPL / SCIENCE SOURCE

BY JODY A. CHARNOW

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More hospital transfusions Indeed, in a recent study examining the effect of bundling on anemia management in dialysis patients, Dr. Wetmore and colleagues found that the number of blood transfusions administered in hospital emergency departments or during inpatient stays increased 13.9% and 26.4%, respectively, from 2009 to 2011, according to a report in BMC Nephrology (2016;17:53). The finding provides “some evidence for a partial shift in the cost and site of care for anemia management from dialysis facilities to hospitals,” the investigators concluded.

Shifts in the pharmacologic treatment of secondary hyperparathyroidism also have occurred since bundling went into effect. These include a trend towards increasing use of oral 1,25 vitamin D compounds, such as rocaltrol, as a replacement for IV-administered 1,25 vitamin D compounds, Dr Wetmore said. “This may be because oral vitamin D compounds are less expensive and … traditional IV 1,25 D compounds are contained in the bundle.”

New medicines introduced Since the debut of bundling, new medications have been approved for managing end-stage renal disease complications.

These include ferric pyrophosphate citrate (Triferic), which FDA approved in January 2015 to maintain hemoglobin levels in dialysis patients. The drug became commercially available in late 2015. The drug’s maker, Rockwell Medical, developed the drug to deliver iron safely and improve patient outcomes while also providing a more cost-effective way for providers to deliver iron (via dialysate), Chioni said. Clinical data have shown the drug can replace IV iron as a maintenance therapy and maintain hemoglobin concentration while significantly decreasing the need for ESAs and the dialysis center staff time required to give IV iron injections, he said. In the PRIME study, published in Kidney International (2015;88:11871194), Triferic use demonstrated a 35% reduction in prescribed ESA dose compared to placebo. The CRUISE studies showed that patients on Triferic were able to maintain their hemoglobin without receiving IV iron and without a change in ESA dose.

Cost savings According to Rockwell, a 2% reduction in ESA dose would result in an approximately $156 savings per patient annually, and cutting down on IV iron injections could trim approximately 3 million ­registered

nurse hours in the United States, an estimated cost of $200 million.

All patients lose iron at every dialysis treatment, Chioini said, and Triferic is needed to replace that iron loss real-time (similar to how magnesium, calcium and potassium are replaced at every treatment). Therefore, all patients should receive the drug as an iron maintenance therapy to maintain hemoglobin. If a patient has bacteremia, fungemia, or sepsis and the doctor wants to exclude iron for the patient, Chioini stated, then the bicarbonate line to the dialysis machine is simply is turned off and a jug of standard liquid bicarbonate is used.

“Triferic uptake will be interesting to observe,” Dr. Wetmore said. “This drug has promising clinical effects, but the tradeoff providers make is whether the cost of the medication will offset the savings induced by ease-of-use and the concomitant reduction in time required by staff. The drug must be priced sufficiently aggressive before providers will actually realize the savings conferred by ease of use.”

Another drug to become available since bundling debuted is ferric citrate (Auryxia), an oral drug approved for use in 2014 as a phosphate binder in dialysis patients. The drug also increases iron stores, suggesting it could be useful in treating iron-deficiency anemia.

In February, FDA approved etelcalcetide (Parsabiv), a novel calcimimetic indicated for the treatment of SHPT in dialysis patients. It is administered intravenously after each dialysis session.

In studies, etelcalcetide reduced parathyroid hormone and corrected calcium and phosphate levels. “Its uptake will depend on its real-world effectiveness beyond clinical trials as well as how long it remains outside the bundle,” Dr. Wetmore said.

Home dialysis Bundling also may have set in motion a trend toward greater use of home dialysis.

Following the introduction of bundling, Dr. Burkart said he observed a slight uptick in the number of patients starting renal-replacement therapy on home dialysis — especially peritoneal dialysis (PD) — rather than in-center hemodialysis (HD). Prior to bundling, he said, dialysis providers had the potential to make more money with HD patients because of greater use of intravenous (IV) medications compared with PD. When these IV medications became part of the bundled payment, “providers recognized more of a balance between payment for services and modality choice, which when combined with emerging clinical data, and the transfer of some of the

Renal & Urology News 11

No Increase in Adverse Cardiovascular Events, Death Found After Bundling Two studies published in 2016 showed that the risks of adverse cardiovascular events and death among dialysis patients did not increase after the January 1, 2011 debut of the federal government’s prospective payment system for dialysis care (“bundling”) and, about 6 months later, revision of FDA drug labeling for erythropoiesis-stimulating agents (ESAs).

The modified drug labels for epoetin alfa and darbepoetin alfa advised against the use of ESAs in patients with end-stage renal disease and hemoglobin levels of 11 g/dL or higher.

In a study of 69,718 incident hemodialysis (HD) patients aged 66 years or older, Cunlin Wang, MD, PhD, of the FDA’s Center for Drug Evaluation and Research in Silver Spring, Maryland, and colleagues found that, compared with patients who started HD before bundling, those who started HD after bundling had similar risks for major adverse cardiovascular events (MACE), death, venous thromboembolism (VTE), and hospitalization for congestive heart failure and a significant 23% lower risk of stroke. Results also showed that the use of ESAs decreased and the risk of blood transfusion increased by 9%. Black patients in the post-bundling period had a significant 18% decreased risk of MACE and 18% decreased risk of death from any cause. The researchers published their findings in JAMA Internal Medicine (2016;176:1818-1825).

For the other study, Glenn M. Chertow, MD, of Stanford University in Palo Alto, California, and colleagues examined data from annual cohorts of dialysis patients from 2005 to 2012. Observed rates of all-cause mortality, cardiovascular mortality, and myocardial infarction in 2011 and 2012 were consistent with expected rates, Dr. Chertow’s group reported in the Journal of the American Society of Nephrology (2016;27:3129-3131). In addition, during 2012, observed rates of stroke, VTE, and heart failure were lower than expected.

“This initial evidence suggests that action taken to mitigate risks associated with ESA use and changes in payment policy did not result in a relative increase in death or major cardiovascular events and may reflect improvements in stroke, VTE, and heart failure,” Dr. Chertow and his colleagues concluded.

financial risk to the providers, favored the use of home dialysis,” Dr. Burkart said. “All of a sudden there was a desire by many providers to do more home [dialysis] than was done previously.”

National statistics do show an increase since bundling debuted. In 2010, a year prior to bundling, 92.2% of incident ESRD patients started RRT with HD and 6.7% started on PD, according to the U.S. Renal Data System. The proportions were 87.9% and 9.3%, respectively, in 2014.

In the Wake Forest system, the proportion of patients starting on PD rose from 16.5% before bundling to 18.4% currently, Dr. Burkart said.

He pointed out that clinical data suggest home dialysis would be a more appropriate therapy than in-center HD for a much larger percentage of the ESRD population than it is currently.

He also observed that “physicians and providers are now embracing these data and trying to optimize clinical outcomes and patient quality of life while on dialysis. This often favors use of home dialysis.”

Dr. Wetmore said he observed an increase in PD use right after bundle implementation, but this has slowed.

“There are some suggestions that the recent apparent shortage of PD fluid and associated changes in PD fluid pricing may have impacted this trend. Of course, no one knows what the ‘right’ percentage of patients on PD should be.”

Fresenius’ Dr. Maddux stated: “Home therapies for dialysis patients continue to rise and have the opportunity to grow further. That includes developing more patient-friendly and connected health options for helping home dialysis patients maintain that modality for longer times.”

Dr. Maddux noted that that home dialysis is associated with high attrition rates and that Fresenius is “determined to help alleviate the churn that can exist between some modalities for renal-replacement therapy.”

Dr. Nissenson, of DaVita, said his company has had steady growth in the use of home dialysis, even before bundling.

“We’ve always believed that home therapy is a good choice for the right patients.” n

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Alternative SHPT Surgery Found Safe for the Elderly TOTAL parathyroidectomy without autotransplantation is safe and effective for elderly patients with secondary hyperparathyroidism (SHPT) and a good alternative to total parathyroidectomy with autotransplantation, researchers reported online in Aging Clinical and Experimental Research.

To determine the optimal surgical approach in elderly SHPT patients, Andrea Polistena, MD, of the University of Perugia in Terni, Italy, and colleagues studied a retrospective series of 253 SHPT patients who underwent parathyroidectomy. The cohort included 218 patients aged less than 65 years (group A) and 35 patients older than 65 years (group B) at a single institution. In all cases, surgeons ­monitored ­intraoperative

Survival Not Worse After PC for MIBC PARTIAL CYSTECTOMY (PC) performed on carefully selected patients with

parathyroid hormone (PTH) levels.

Surgeons performed subtotal parathyroidectomy in 122 patients in group A and 7 patients in group B and total parathyroidectomy with autotransplantation in 15 patients in group A and none of the patients in group B. Surgeons performed total parathyroid-

ectomy alone in 88 patients in group A and 28 patients in group B. The investigators observed no significant difference in surgical complications between the 2 groups. Reoperation for persistent or recurrent SHPT was required for 19 patients in group A and none of the patients in the group B. Post-

operative PTH and calcium/phosphorus values returned to normal or acceptable values in 92.4% of patients at 1 month. Nearly 90% of patients achieved adequate post-operative symptom control, with no significant differences among the surgical procedures, Dr. Polistena and her colleagues reported. n

B:14.5” T:14” S:13.5”

F p

A A

muscle-invasive bladder cancer

C

(MIBC) does not appear to com-

•

promise overall survival compared with radical cystectomy (RC), data presented at the Society of Urologic Oncology 17th annual meeting in San Antonio, Texas, suggest.

•

•

David G. Alonzo, MD, and colleagues at the University of Miami Miller School of Medicine, identified 410 patients who underwent PC and 4240 who underwent RC for clinical T2 o T3, N0, M0 urothelial bladder cancer. The median age for the PC and RC groups was 67 and 75 years, respectively. A higher proportion of the PC group than RC group had pT3 disease (22% vs 15%). The 5-year overall survival rates for the PC and RC patients were 41.7% and 46.4%, a non-significant difference.

On multivariable analysis, significant predictors of worse overall survival were age older than 75 years, a non-academic treatment setting, Charlson score above 1, and clinical stage greater than pT2.

The proportion of patients who received adjuvant chemotherapy or radiation was 33% in both groups. n

R 1 N [ 2 K (

a a t e

P n

A w c G c

Renal & Urology News 13

High-Volume Hospitals Recover More Usable Organs B:14.5” T:14” S:13.5”

BY NATASHA PERSAUD HOSPITALS that handle higher volumes of deceased donors recover a greater number of transplantable organs, according to a study.

Hospitals with the highest volume of deceased donors were 52% more likely than hospitals with the lowest volume

to procure 4 or more organs per donor, Darren J. Malinoski, MD, of Portland Veterans Affairs Medical Center in Portland, Oregon, and his team reported online ahead of print in the Journal of the American College of Surgeons.

The national average is 3 transplantable organs per deceased donor, with a

goal of 3.75 established by the Donation and Transplantation Community of Practice in 2013, they noted. High donor volume remained a predictor of superior outcome after adjustment for age, ethnicity, donor type, blood type, body mass index, creatinine, and geographic region.

“Our findings suggest we can improve the organ shortage and maximize the gift that patients and their families want to make through organ donation by understanding the aspects of high-volume donor hospitals that contribute to improved outcomes,” Dr. Malinoski stated in a news release. He also suggested the creation of centralized organ recovery centers to manage deceased donors instead of hospitals.

The investigators examined all deceased donor cases from February 2012 to June 2015 managed by 10 organ procurement organizations (OPOs) across 3 organ sharing regions (covering California, Oregon, Nevada, New Mexico, Texas, and Utah). A total of 4427 deceased donor cases were handled at 384 hospitals. For analysis, the researchers grouped the hospitals into quartiles based on their case volume.

Hospitals in the top quartile of donor volume harvested 3.3 organs per donor.

B:10.25”

S:9.25”

Hospitals in the top quartile managed a mean 9 donors annually and recovered 3.3 organs per donor. Hospitals in the bottom quartile managed a mean 0.5 donors annually and recovered 2.9 organs per donor. Each quartile managed similar proportions of standard criteria donors, expanded criteria donors, and donations after circulatory determination of death.

The investigators noted that a number of reasons may explain the increase in OTPD observed in centers with higher volume and the variability in organ utilization across OPOs. “Specifically, in lower volume centers, which are not as accustomed to donor management, there may be difficulty in obtaining requested investigations for organ workup leading to both suboptimal donor management and decreased utilization by transplant centers,” the investigators stated.

In addition, with inherently more contact between high-volume donor hospitals and their respective OPO, they wrote, “these centers may also be more likely to have processes in place for early OPO referral, implementation of catastrophic brain injury guidelines, and more timely determination of neurologic death, possibly allowing for more optimal donor management after authorization for donation occurs.” n T:9.75”

al s

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MRI Protocol May Enhance PCa Risk Stratification TARGETED PROSTATE biopsy based on the findings of a novel biparametric magnetic resonance imaging (bpMRI) protocol may improve risk stratification among men with a clinical suspicion of prostate cancer (PCa).

Ivan Jambor, MD, and colleagues at the University of Turku in Turku,

Finland, enrolled 175 men with a clinical suspicion of PCa (2 repeated PSA values in 2.5 to 20 ng/mL range and/ or abnormal digital rectal examination) to compare PCa detection rates for bpMRI-targeted transrectal ultraB:7.25” sound (TRUS) biopsy T:7” (TB) and systematic 12-core biopsyS:7” (SB).

European Association of Urology guidelines recommend the use of multiparametric MRI followed by TRUS and MRI-targeted prostate biopsy if suspicion of PCa persists despite a prior a negative systematic biopsy, Dr. Jambor’s team noted. Routine multiparametric prostate MRI, they pointed

out, has long acquisition times, requires the use of intravenous contrast media, and is expensive. “A more rapid and less expensive MRI protocol with shorter imaging times, no endorectal coil, and no intravenous contrast might encourage greater use of prebiopsy MRI in men with clinical suspicion of PCa,” they stated. “Targeting suspicious areas, some of which may be outside the normal biopsy template, could also improve the diagnostic sensitivity.”

Dr. Jambor and colleagues developed a novel biparametric MRI protocol that included T2-weighted imaging and 3 separate diffusion-weighted imaging acquisitions.

The investigators reported their findings in the Journal of Magnetic Resonance Imaging (2017; published online ahead of print).

Biparametric vs. multiparametric MRI is quicker and less expensive.

B:10.25”

S:10”

T:10”

Of the 161 men who completed the trial (clinicaltrial.gov registration number: NCT01864135), 72 (45%) had PCa detected by TB and 63 (39%) had PCa detected by SB, a non-significant difference. Twenty-five men (16%) were upgraded to an intermediate- or high-risk category based on TB, whereas only 12 men (8%) were upgraded based on SB, a significant difference in upgrading rate.

Clinically significant PCa (SPCa)— defined as Gleason score 3 + 4 or higher—was diagnosed in 18 patients (11%) in TB cores only and 9 patients (6%) based on SB, a significant difference in detection rate.

“This newly developed biparametric MRI imaging protocol enabled a significant improvement in the selection of men with SPCa for biopsy, and in combination with targeted biopsy was also significantly more accurate than SB of the prostate,” the investigators concluded.

If biopsy was restricted to men with equivocal to highly suspicious bpMRI findings, 38 men (24%) would have avoided undergoing biopsy, according to the researchers. SPCa would have been missed in only 4 patients (2%).

This is the first prospective registered clinical prostate MRI trial that provides free public access to all anonymized datasets, including bpMRI reports and follow up information. n

www.renalandurologynews.com MARCH/APRIL 2017

■ NKF 2017, Orlando

Renal & Urology News 15

National Kidney Foundation 2017 Spring Clinical Meetings Preview

Timing of Renal Replacement Therapy Initiation in AKI Evidence to date provides no clear answer as to whether early or delayed RRT is the best approach Editor’s note: The authors of this article are scheduled to participate in a session titled “Controversies in Renal Replacement Therapy for Acute Kidney Injury” at the National Kidney Foundation’s 2017 Spring Clinical Meetings in Orlando, Florida, April 20, 2:00 to 3:30 p.m.

hospital or ICU admission, and time relative to the development of complications attributable to AKI. However, the terms “early” and “delayed” are generally relative. As such, “early” RRT in one clinical context may be “delayed” in another. Many studies have also failed to include outcome comparisons among patients who received early RRT with those who did not receive RRT, recognizing that selected patients will survive and recover kidney function without the need for RRT.4,5 Such heterogeneity in definitions for timing and strategies for comparing groups, in particular from observational data (often with variable designs and methodological quality), has generated challenges to provide clear guidance for health care professionals on this issue.

BY SEAN M. BAGSHAW, MD, MSC, AND RON WALD, MDCM, MPH RENAL REPLACEMENT therapy (RRT) is increasingly used for organ support among hospitalized patients with severe AKI, particularly those in intensive care unit (ICU) settings.1 RRT can play an important role in achieving and maintaining fluid, electrolyte, acid-base, and uremic solute homeostasis and, in selected circumstances, and facilitate additional therapeutic interventions (e.g., nutrition, medications, transfusions). RRT can also prevent the occurrence or worsening of life-threatening complications commonly provoked by AKI, such as hyperkalemia, acidemia, and pulmonary edema. In critical illness, RRT may also represent an important platform of multi-organ support by potentially limiting worsening nonrenal organ dysfunction that may be exacerbated by AKI. A longstanding and fundamental question about the application of RRT in AKI is: When is the optimal time to start therapy?

Earlier RRT In severe AKI, particularly in ICU settings, there is a biologic rationale to support earlier initiation of RRT, even in the absence of so-called classic indications. In this context, earlier RRT will not only prevent the occurrence of overt life-threatening complications, but may translate into more rapid correction of acid-base, metabolic and fluid balance derangements.

Observational data support this concept by showing that pre-emptive start of RRT prior to the development of conventional indications in critically ill patients with AKI was associated with reduced mortality.6,7

Definition of ‘timing’ unclear One challenge for clinicians when interpreting the literature on this issue is that there has been no consensus on how best to define “timing” related to RRT initiation in AKI. Published studies have been heterogeneous in their definitions for “early” or “delayed” start to RRT.2,3 Definitions have i­ncorporated p ­ hysiologic measures (e.g., urine output), biochemical measures (e.g., creatinine, urea), time relative to AKI onset, time relative to

Conservative or delayed RRT Alternatively, earlier RRT may confer risk for RRT-related complications, increased bedside workload and health care costs.8 For example, patients will require dedicated central venous access for RRT, be exposed to an extracorporeal circuit, and may receive anticoagulation. During treatment, ultrafiltration or rapid shifts in serum osmolarity may prompt intradialytic hypotension and contribute to iatrogenic delays in kidney recovery.9,10 As such, there is also

Sean M. Bagshaw, MD, MSc

Ron Wald, MDCM, MPH

rationale to adopt a watchful waiting approach in selected patients with severe AKI, and only start RRT in response to the development of AKIrelated complications refractory to medical management.4

containing relatively few randomized trials, have had discordant conclusions about whether early compared with delayed strategies to starting RRT may improve outcomes in AKI.2,3,14 This is not unexpected given that a significant proportion of studies included in these reviews were susceptible to bias and confounding (i.e., retrospective, small sample size, variable definitions for timing, exclusion of patients with AKI not receiving RRT) or had limited generalizability (i.e., focused on selected populations, such as cardiac surgery patients).

More recently, a number of randomized trials have been reported that focused on timing strategies for initiation of RRT in critically ill patients with AKI.4,5,15-17 The ELAIN (Early Versus Late Initiation of Renal Replacement Therapy In Critically Ill Patients With Acute Kidney Injury) trial15 was a single-center trial in Germany that randomized 231 mostly post-surgical critically ill adults with AKI to 2 thresholds for starting RRT: early RRT, which involved starting RRT within 8 hours of fulfilling criteria for KDIGO (Kidney Disease: Improving Global Outcomes) stage 2 AKI, or delayed RRT, defined as starting RRT within 12 hours of developing KDIGO stage 3 AKI or the development of conventional indications. In

Guideline recommendations Several organizations have published guidelines that include statements on the timing of RRT initiation in AKI.11-13 Each of these guidelines provided relatively uncontroversial recommendations to start RRT urgently when confronted with potentially life-­threatening ­complications of AKI related to fluid overload or severe electrolyte, metabolic, or acid-base disturbances. These guidelines further provide practical recommendations for health care professionals to weigh the broad clinical context, the patient’s illness trajectory, and the presence of conditions for which RRT will be likely to modify the course when considering the initiation of RRT. In the end, however, these guidelines all generally acknowledge the limitations of the existing literature, and each recommend additional high-quality studies be performed to inform practice.

Recent randomized trials Prior systematic reviews, derived largely from observational studies and

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RRT timing in AKI continued from page 15

this trial, all participants in the early RRT arm and 91% of participants in the delayed RRT arm received RRT (median 21 hour difference in starting RRT). ELAIN found that early compared with delayed RRT reduced the 90-day mortality rate (39.3% vs 54.7%; HR 0.66, 95% CI, 0.45-0.97). Early RRT also conferred shorter durations of RRT dependence (18 fewer days), mechanical ventilation, and hospitalization (37 fewer days).

Published studies have used different definitions for early and delayed RRT. The AKIKI (Artificial Kidney Initiation in Kidney Injury) trial was a multicenter randomized trial from France that compared 2 strategies for starting RRT among 620 critically ill adults with KDIGO Stage 3 AKI.4 The early RRT strategy started participants on RRT within 6 hours of fulfilling KDIGO stage 3 AKI, while the delayed RRT strategy deferred RRT until 1 or more conventional indications developed. Notably, only about 50% of patients randomized to the delayed RRT strategy commenced RRT. Investigators found no significant difference in 60-day mortality between strategies (48.5% for early vs 49.7% for delayed, P = 0.79).

Clinical implications The ideal time to start RRT in AKI has been a longstanding evidence care gap.18 The recent publication of several similarly-themed trials focused on this issue is clearly a welcome addition. The discrepant findings across trials may sustain the clinical uncertainty and practice variation regarding when to start RRT in AKI; however, there are fundamental differences in design, populations, and interventions across trials that warrant context-specific interpretation.

The AKIKI findings should caution those health care professionals who strongly advocate an early start to RRT, certainly in the absence of any conventional indication. Some patients may never need RRT because of early kidney recovery or changes in philosophy of care or death. Large randomized trials are the best opportunity to understand the natural history of such

patients and fully describe the relative benefits and/or harms associated with RRT timing strategies and RRT use.19 One challenge for health care professionals when confronted with patients with AKI is reliably predicting who is going to worsen and ideally benefit most from starting RRT. At present, there are no clearly validated clinical or laboratory tools to clearly discriminate those who will progress to require RRT from those whose recovery is imminent. Near real-time estimates of glomerular filtration rate in the nonsteady state conditions of AKI that inform about trajectory of kidney function would present useful tools for bedside professionals considering whether RRT should be started.20,21 Similarly, a recent small single-center prospective cohort study found the implementation of a clinical-decision support algorithm for starting RRT may be associated with improved outcomes in AKI, likely driven by greater reliability of care among those with lower illness severity.22 While promising, such adjuvants to clinical decision-making require further validation.

A key question is whether the additional data offered from these recent trials provide definitive guidance for when to ideally start RRT among critically ill patients with AKI. While prevailing findings suggest that a more conservative strategy of watchful waiting to starting RRT in AKI may be acceptable in selected circumstances, AKI, particularly in the context of critical illness, remains a massively heterogeneous and complex syndrome.

As such, recent studies have greatly extended our knowledge, but have not resolved this dilemma, and practice is likely to continue to vary widely. We believe that ongoing randomized trials remain essential to shed further light on this vexing question. n

therapy in critically ill patients with acute kidney injury: a systematic review and meta-analysis. Crit Care. 2011;15:R72.

3. Wierstra BT, Kadri S, Alomar S, et al. The impact of “early” versus “late” initiation of renal replacement therapy in critical care patients with acute kidney injury: a systematic review and evidence synthesis.

Crit Care. 2016;20:122.

4. Gaudry S, Hajage D, Schortgen F, et al. Initiation strategies for renal-replacement therapy in the intensive care unit. N Engl J Med. 2016;375: 122-133.

5. Wald R, Adhikari NK, Smith OM, et al. Comparison of standard and accelerated initiation of renal

1. Wald R, McArthur E, Adhikari NK, et al. Changing incidence and outcomes following dialysis-requiring acute kidney injury among critically ill adults: a population-based cohort study. Am J Kidney Dis. 2015;65:870-877.

2. Karvellas CJ, Farhat MR, Sajjad I, et al. A comparison of early versus late initiation of renal replacement

on a low dose of cinacalcet every other day is both safe and effective for treating secondary hyperpara-

Int. 2015;88:897-904.

thyroidism (HPT), a small study from

6. Liborio AB, Leite TT, Neves FM, et al. AKI complications in critically ill patients: association with mortality rates and RRT. Clin J Am Soc Nephrol.

2015;10:21-28.

7. Vaara ST, Reinikainen M, Wald R, et al. Timing of RRT

Thailand suggests.

Over 16 weeks, similar proportions of patients in a standard-dose and

based on the presence of conventional indications.

low-dose group experienced the

Clin J Am Soc Nephrol. 2014;9:1577-1585.

study’s primary outcome of a greater

8. Clark EG, Hiremath S. Progressively earlier initiation of renal replacement therapy for acute kidney injury

than 30% drop in intact parathyroid

is unwarranted and potentially harmful. Blood Purif.

hormone level (iPTH): 38.5% vs

2016;41(1-3):159-165.

9. Augustine JJ, Sandy D, Seifert TH, Paganini EP. A

33.3%, the investigators reported.

randomized controlled trial comparing intermittent

The low-dose group included

with continuous dialysis in patients with ARF. Am J

16 patients who received 25 mg

Kidney Dis. 2004;44:1000-1007.

10. Clark EG, Bagshaw SM. Unnecessary renal replacement therapy for acute kidney injury is harmful for renal recovery. Semin Dial. 2015;28:6-11.

11. Kidney Disease Improving Global Outcome. KDIGO

cinacalcet every other day for the first 8 weeks, with a possible dose increase to 25 mg daily if targets

Clinical Practice Guideline for Acute Kidney Injury.

were not achieved. The standard-

2012. http://kdigo.org/home/guidelines/acute-

dose group included 14 patients

kidney-injury/. Accessed May 26, 2016.

12. National Institute for Health and Care Excellence (NICE). Acute kidney injury: prevention, detection and management. 2013. https://www.nice.org.uk/ guidance/cg169/.

13. Vinsonneau C, Allain-Launay E, Blayau C, et al.

Renal replacement therapy in adult and pediatric intensive care : Recommendations by an expert panel from the French Intensive Care Society (SRLF) with the French Society of Anesthesia Intensive Care (SFAR) French Group for Pediatric Intensive Care Emergencies (GFRUP) the French

who received 25 mg cinacalcet daily to start. Use of active vitamin D and its analogs or phosphate binders was permitted during the study, and the dosages of these medications did not change.

The groups also experienced similar reductions in iPTH. In the

Dialysis Society (SFD). Ann Intensive Care.

standard-dose group, mean iPTH

2015;5:58.

levels dropped by 243.4 pg/mL

14. Wang X, Jie Yuan W. Timing of initiation of renal replacement therapy in acute kidney injury: a

from 1214.1 pg/mL. In the low-dose

systematic review and meta-analysis. Ren Fail.

group, mean iPTH levels fell by 253.5

2012;34:396-402.

15. Zarbock A, Kellum JA, Schmidt C, et al. Effect of

pg/mL from 1065.9 pg/mL at base-

early vs delayed initiation of renal replacement

line, according to the researchers.

therapy on mortality in critically ill patients with

“Among patients with second-

acute kidney injury: The ELAIN randomized clinical trial. JAMA. 2016;315:2190-2199.

16. Combes A, Brechot N, Amour J, et al. Early highvolume hemofiltration versus standard care for Am J Respir Crit Care Med. 2015;192:1179-1190.

17. Jamale TE, Hase NK, Kulkarni M, et al. Earlierstart versus usual-start dialysis in patients

ary HPT, initial treatment with cinacalcet 25 mg on alternate days can decrease serum PTH levels,” Pongsathorn Gojaseni, MD, of Bhumibol Adulyadej Hospital in

with community-acquired acute kidney injury: a

Bangkok, Thailand, and colleagues

randomized controlled trial. Am J Kidney Dis.

wrote in the International Journal

2013;62:1116-1121.

18. Wald R, Gallagher M, Bagshaw SM. Shedding new light on an old dilemma: Two trials examining the timing of renal replacement therapy initiation in acute kidney injury. Am J Kidney Dis. 2017;69:14-17.

19. Liu KD, Palevsky PM. RRT in AKI: Start early or wait?

Clin J Am Soc Nephrol. 2016.

20. Mellas J. The description of a method for accurately estimating creatinine clearance in acute kidney injury.

REFERENCES

STARTING hemodialysis patients

replacement therapy in acute kidney injury. Kidney

post-cardiac surgery shock. The HEROICS Study.

Sean M. Bagshaw, MD, MSc, is in the Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Ron Wald, MDCM, MPH, is in the Division of Nephrology, St. Michael’s Hospital and University of Toronto, Toronto, Canada, and is affiliated with the Li Ka Shing Knowledge Institute of St. Michael’s Hospital.

Low-Dose Cinacalcet An Option

Math Biosci. 2016;275:107-114.

21. Seelhammer TG, Maile MD, Heung M, et al. Kinetic estimated glomerular filtration rate and acute kidney

of Nephrology and Renovascular Disease. “The role of low-dose cinacalcet in secondary HPT should be further determined in large-scale, randomized controlled trials.”

More patients in the low-dose group reported gastrointestinal (GI) side effects (43.8% vs 7.1%). One patient

injury in cardiac surgery patients. J Crit Care. 2016;

in the standard-dose group with a

31:249-254.

dose increase to 50 mg daily experi-

22. Mendu ML, Ciociolo GR, Jr., McLaughlin SR, et al. A decision-making algorithm for initiation and

enced a serious GI problem that led

discontinuation of RRT in severe AKI. Clin J Am Soc

to medication discontinuation. n

Nephrol. 2017;12:228-236.

www.renalandurologynews.com

MARCH/APRIL 2017

Testosterone Replacement Therapy Improves Anemia Increased hemoglobin, bone strength observed in older men TESTOSTERONE replacement therapy (TRT) may improve anemia and bone density among older hypogonadal men, new studies suggest.

Cindy N. Roy, PhD, of Johns Hopkins University in Baltimore, and colleagues conducted a double-blind study of 788 men aged 65 years and older who had

significantly greater percentage of men whose month 12 hemoglobin levels had increased by at least 1.0 g/dL compared with placebo (52% vs. 19%) and who were no longer anemic at month 12 (60% vs. 14.8%).

In adjusted analyses, TRT for 12 months among men with anemia of

TRT Raises Hemoglobin Levels In a study of anemic hypogonadal men, testosterone replacement therapy (TRT) for 12 months significantly improved hemoglobin levels compared with placebo. Shown here are percentages of men who were no longer anemic at month 12.

70 60

60%

58.3%

■ TRT ■ Placebo

50 40 30 20

22.2%

14.8%

10 0

Unexplained anemia

Anemia with known cause

Source: Roy CN et al. Association of testosterone levels with anemia in older men. JAMA Intern Med. 2017; published online ahead of print.

average testosterone levels less than 275 ng/dL. Of these, 126 had anemia (hemoglobin levels of 12.7 g/dL or less), 62 of whom had no known cause.

Investigators randomly assigned men to receive testosterone gel or placebo for 12 months. The main outcome measure was the proportion of men with unexplained anemia whose hemoglobin levels increased by at least 1.0 g/dL in response to testosterone compared with placebo.

Among men with unexplained anemia, a significantly greater percentage of those on TRT compared with placebo had a 1.0 g/dL or greater increase in hemoglobin at month 12 (54% vs. 15%) and correction of anemia at month 12 (58.3% vs. 22.2%), the investigators reported online ahead of print in JAMA Internal Medicine.

In addition, among men with anemia of known cause, TRT resulted in a

Upcoming News

unknown cause was associated with significant 31.5-fold greater odds of 1.0 g/dL or higher increase in hemoglobin and 17-fold greater odds of anemia correction compared with placebo.

TRT for 12 months among men with anemia of known cause was associated with a significant 8.2-fold greater odds of a 1.0 g/dL or higher increase in hemoglobin level.

“Among older men with low testosterone, testosterone treatment significantly increased hemoglobin levels in those with unexplained anemia and those with anemia associated with known causes,” Dr. Roy and her colleagues concluded. “These increases may be of clinical significance, as suggested by the magnitude of the increases and the correction of anemia in the majority of men. … These results also suggest that measurement of serum testosterone levels might be considered in men 65 years

or older who have unexplained anemia and symptoms of hypogonadism.”

In a separate study published online ahead of print in JAMA Internal Medicine, researchers led by Peter J. Snyder, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, found that older men on TRT for 1 year experienced increased volumetric bone mineral density (vBMD) and estimated bone strength compare with men who received placebo. The beneficial effect was greater in trabecular than peripheral bone and in the spine compared with the hip.

The study included 211 men aged 65 years and older (mean 72.3 years, 86% white) with 2 testosterone measurements averaging less than 275 ng/L. The investigators randomly assigned patients to receive testosterone gel or placebo gel for 1 year. Compared with placebo, TRT was associated with significantly greater increases in mean spine trabecular vBMD (7.5% vs. 0.8%), spine peripheral vBMD, and hip trabecular and peripheral vBMD. Testosterone treatment significantly increased estimated strength of spine trabecular bone compared with placebo (10.8% vs. 2.4%).

Study strengths included unequivocally low testosterone levels of study participants, the double-blind study design, and excellent participant retention, according to the researchers. In a discussion of study limitations, they noted that because all patients had low serum testosterone levels, the results apply only to this population.

Commenting on the study by Dr. Snyder and colleagues, Eric Orwoll, MD, of Oregon Health & Sciences University in Portland, said in an accompanying editorial, “These results provide very strong evidence that testosterone therapy in older men with low testosterone levels yields a positive skeletal effect.” ■

Renal & Urology News 17

Etelcalcetide Is Approved For SHPT ETELCALCETIDE has received FDA approval for the treatment of secondary hyperparathyroidism (SHPT) in adult patients on hemodialysis (HD).

The drug, which its maker, Amgen, of Thousand Oaks, California, is marketing as Parsabiv, is the first treatment approved for SHPT in 12 years.

Etelcalcetide is the only calcimimetic that can be administered intravenously by dialysis caregivers thrice weekly at the end of an HD session. Etelcalcetide binds to and actives the calcium-sensing receptor on parathyroid glands, resulting in a decrease in parathyroid hormone (PTH).

The FDA approved etelcalcetide largely on the basis of data from 2 randomized, placebo-controlled phase 3 studies (Study 1 and Study 2), Amgen said in a press release. The studies included a total of 1,023 patients with moderate to severe SHPT (PTH higher than 400 pg/mL) on HD. Investigators

FDA clears the first therapy for secondary hyperparathyroidism in 12 years. randomized patients to receive etelcalcetide or placebo 3 times a week at the end of their dialysis sessions in addition to standard care that could include vitamin D or phosphate binders or both.

The primary endpoint of the studies was the proportion of patients who achieved a greater than 30% reduction in PTH from baseline during the efficacy assessment phase (EAP, weeks 20 through 27).

In Study 1 and Study 2, the proportion of patients meeting the primary endpoint was 77% and 79%, respectively, in the etelcalcetide groups compared with 11% and 11%, respectively, in the placebo arms. In addition, the proportion of patients achieving PTH levels of 300 pg/mL less during the EAP (a secondary endpoint) was 52% versus 6% in Study 1 and 56% versus 5% in Study 2. ■

Renal & Urology News will be covering the 2017 American Transplant Congress in Chicago, April 29 – May 3.

Go to www.renalandurologynews.com for daily reports on noteworthy studies.

www.renalandurologynews.com MARCH/APRIL 2017

■ NKF 2017, Orlando

Renal & Urology News 21

National Kidney Foundation 2017 Spring Clinical Meetings Preview

Improving Nephrology Care with Point-of-Care Ultrasound Benefits include rapid assessment of kidney size, cortical thickness, and volume status Editor’s note: This article is a preview of a course scheduled to be given at the National Kidney Foundation’s 2017 Spring Clinical Meetings in Orlando, Florida, April 18, 7:30 a.m. to 12:30 p.m.

BY DANIEL ROSS, MD MPH, MANGALA NARASIMHAN, DO, AND KENAR D. JHAVERI, MD EACH JULY, hundreds of fellows from around the United States gather for a 3-day in-depth hands-on course in point-of-care ultrasound for the American College of Chest Physicians (“Chest”). Over the last decade, the course instructors have trained more than 1000 fellows and 3,000 attending physicians, including intensivists, hospitalists and residents. Analysis of their outcomes prove that they have a recipe for training success.1 Mangala Narasimhan, DO, and Paul Mayo, MD, teach the course, but they are not nephrologists. Rather, they are intensivists, and the fellows they train are not nephrology fellows, but pulmonary and critical care fellows. Nevertheless, their course could have a profound impact on the nephrology community.

Extension of the physical exam At North Shore University Hospital and the Long Island Jewish Medical Center, of the Northwell Health System and the Hofstra Northwell School of Medicine in New York, Drs. Narasimhan and Mayo have made whole body point-ofcare ultrasound the standard of care in the intensive care unit (ICU). Each day, they round in the ICU with their fellows and use the ultrasound probe as an extension of their physical examination, a new stethoscope for the 21st Century.

Our faculty at the Northwell Health Division of Kidney Diseases and Hypertension work closely with the ICU staff on a daily basis and became interested in what the ICU staff was doing with the ultrasound probe. We observed that physicians who used the

ultrasound probe at the point of care made a tremendous clinical impact.

They were able to answer specific questions that came up on rounds immediately. This information, along with history and traditional physical examination, helped make timely decisions regarding the critically ill. Recognizing an opportunity, nephrology fellowship program director Hitesh H. Shah, MD, and critical care nephrologist Richard Barnett, MD, approached Drs. Mayo and Narasimhan about developing a formal training course designed specifically for nephrologists.

Curriculum content In the summer of 2015, we held our first nephrology training course in point-of-care ultrasonography at Northwell. The curriculum was adapted from the Chest course given by our critical care faculty. The 3-day course was condensed into a single half-day course. In our first year, during the first half of the course, residents and fellows learned how to image the kidney and assess size, cortical thickness, and to look for hydronephrosis.

They also learned how to assess bladder volume. The second half of the course was devoted to using ultrasound to assess volume status by examining the lungs.

The course began with a standardized patient, an experienced sonographer, and a large video monitor. The instructor applied the probe to the patient’s abdomen and the image was projected on the screen. We were taught the basics of ultrasonography and how to adjust depth and gain. Once the instructor demonstrated a thorough examination of the kidneys and bladder, the learners broke up into groups. Half of the class stayed behind and practiced interpreting normal and abnormal images. The other group subdivided into smaller groups with a training ratio of 1 instructor to 3 students. These small groups practiced scanning the kidneys and bladder on a standardized patient with the assistance of an expert instructor.

Northwell Health residents using point-of-care ultrasound to assess extravascular lung water.

The groups switched, and after a short break reconvened to repeat the same schedule for lung ultrasonography.

Assessing extravascular lung water The challenge for our nephrology division was the thought shift that came from using lung ultrasonography for assessing volume status. Many in our division were unaware that lung ultrasonography could be used to assess extravascular lung water. As it turns out, when an ultrasound beam hits a thickened interlobular septum it generates reverberation artifacts that jut away from the pleural surface like a bright white rocket. These lung rockets have come to be known as “B lines.”

Evidence has shown that the quantity of B Lines directly correlates with pulmonary capillary wedge pressure and with extravascular lung water by thermodilution.2 Not surprisingly it has been shown that B Lines are predictably reduced immediately after ultrafiltration.3 In an important work out of Italy, Carmine Zoccali, MD, and colleagues showed that pulmonary congestion on lung ultrasound is a significant predictor of mortality above and beyond traditional cardiac risk factors.4 What remains unclear is whether

lung ultrasound can be used to tailor target weight prescription. This is an area of active investigation, and results of the Lung Water by Ultrasound Guided Treatment in Hemodialysis Patients (LUST) trial hopefully will provide guidance (clinicaltrials.gov: NCT02310061). Regardless, it is clear that lung ultrasound can be a very useful tool for the nephrologist. The absence of B lines effectively rules out alveolar interstitial syndrome, including pulmonary edema, invaluable information for the ultrafiltration prescription.

After our initial training course, some members of our faculty approached point-of-care ultrasound with vigor. It was almost as if we had re-entered medical school to relearn physical examination skills. To be certain, a single halfday training course is not nearly enough to learn how to do comprehensive renal ultrasonography, but it gave us a start and allowed us to have enough knowledge to then practice on our own.

Answers to practical questions In our experience, there are discrete, practical questions that can be answered immediately at the point of care with an ultrasound probe. Does continued on page 22

22 Renal & Urology News

MARCH/APRIL 2017 www.renalandurologynews.com

PPIs Up CKD Risk Even in Absence of AKI Acute kidney injury mediated less than half of incident CKD cases related to proton pump inhibitor use

BY NATASHA PERSAUD CHRONIC KIDNEY disease (CKD) is more likely to develop in people who take proton pump inhibitors (PPIs), even if they do not first experience acute kidney injury (AKI), according to a new study.

Previously, researchers had suggested that unrecovered AKI is the sole mediator of chronic renal damage among PPI users. The acid-suppressing drugs are known to increase AKI and acute interstitial nephritis. New findings published in Kidney International hint that PPIs may harm the kidneys gradually, independent of AKI. Using Veterans Affairs databases, Ziyad Al-Aly, MD, of the VA St. Louis Health Care System, and colleagues identified a national cohort of 144,032 first-time consumers of acid suppression therapy. Of these, 125,596 received a new prescription for a PPI (e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, or rabeprazole) and 18,436 received a prescription for a

histamine H2 receptor antagonist (e.g., ranitidine, cimetidine, and famotidine).

All of the veterans had normal kidney function at baseline.

To evaluate PPI use and chronic renal outcomes in the absence of AKI, the investigators created survival models and alternately censored anyone with an

Antecedent acute kidney injury is an unreliable warning sign, researchers say. episode of AKI (defined as an increase in serum creatinine above 50% or 0.3 mg/dL) within 5 years of the study or before development of CKD. Compared with patients who took an H2 blocker, PPI users had a 19% increased risk of estimated glomerular filtration rate (eGFR) falling below 60 mL/min/1.73m2 and a 26% increased

risk of CKD (defined as an eGFR below 60 on 2 separate occasions at least 90 days apart, based on the Chronic Kidney Disease Epidemiology Collaboration equation). In addition, veterans taking PPIs were 22% more likely to experience CKD progression (eGFR decline greater than 30%), and 30% more likely to experience a eGFR decline greater than 50% or end-stage renal disease (ESRD). All findings were statistically significant. The risks of chronic renal damage increased along with duration of PPI use.

The proportion of the PPI effect on renal outcomes mediated by AKI was 44.7%, 45.5%, 46.0%, and 46.7% for incident eGFR under 60 mL/min/1.73 m2, incident CKD, eGFR decline over 30%, and ESRD or over 50% decline in eGFR, respectively, the researchers reported.

The results were consistent according to various AKI definitions (NHS England AKI algorithm, Kidney Disease: Improving Global Outcomes, and inpatient ICD-9 codes)

“Reliance on antecedent AKI as a warning sign to guard against the risk of the development of CKD and progression to ESRD among PPI users is not sufficient as a sole risk mitigation strategy,” Dr. Al-Aly and colleagues stated. “Exercising vigilance in PPI use, even in the absence of AKI, and careful attention to kidney function in PPI users may be a reasonable approach.”

Study strengths included the use of national large-scale data from a network of integrated health systems collected during routine medical care, which minimizes selection bias, according to the investigators.

In a discussion of study limitations, the investigators noted that their study population included mostly older white male US veterans, which could limit the generalizability of study results. In addition, they could not account for subclinical or unrecognized AKI or use of over-the-counter PPIs and had no information on daily urine output. n

ESRD Risk Elevated in Blacks with Sickle Cell Trait SICKLE CELL TRAIT (SCT) is strongly associated with an increased risk for end-stage renal disease (ESRD) among black individuals, according to a new study. The degree of risk for ESRD was similar to that conferred by APOL1 high-risk genotypes, researchers concluded.

Rakhi P. Naik, MD, of Johns Hopkins University School of Medicine in Baltimore, and colleagues evaluated 9909 self-reported blacks who were in the population-based REGARDS [Reasons for Geographic and Racial Differences in Stroke] study. The group

included 739 individuals with SCT, 243 with hemoglobin C trait, and 8927 non-carriers. ESRD developed in 40 SCT carriers (5.4%), and 6 carriers of hemoglobin C trait, and 234 non-carriers (2.6%), the researchers reported online ahead of print in the Journal of the American Society of Nephrology. The incidence rate for ESRD was 8.5 per 1000 person-years for SCT carriers versus 4.0 per 1000 person-years for noncarriers. Participants with SCT had a 2-fold higher risk for ESRD compared with those who did not have SCT. Hemoglobin C trait was not ­associated

Point-of-care ultrasound

Cysts or masses, kidney stones, and thickened bladder walls are all best left to the experienced radiologist.

At the National Kidney Foundation’s 2017 Spring Clinical Meetings, we and faculty colleagues Varun Agrawal, MD, and Mala Sachdeva, MD, will join Dr. Mayo in offering a half-day pre-course replicating the course given at our center. The course will be held on April 18, and we will have an instructor-tolearner ratio that will enable everyone to get a thorough experience with a

continued from page 21

the patient have signs of urinary retention? Does the patient have hydronephrosis? Is the Foley catheter balloon blocked against the bladder wall? How big are the kidneys? Does the patient have evidence of extravascular lung water? These are questions that are useful at the very moment of initial consultation, not hours later when an radiology department study would be performed.

Risk was 2-fold higher among SCT carriers compared with non-carriers. with prevalent chronic kidney disease or ESRD. The incidence rate for ESRD among individuals with APOL1 high-risk genotypes was 6.6 per 1000 personyears. These individuals had a nearly 1.8 times higher risk for ESRD than

hand-held ultrasound device. Our hope is that this course is a first step to bringing point-of-care ultrasonography into common clinical nephrology practice, allowing us to enhance care for our patients.

To register visit: https://www.kidney. org/spring-clinical/registration/fees. n The authors are affiliated with ­Hofstra Northwell School of Medicine in ­Hempstead, New York. Drs. Ross and Jhaveri are in the division of nephrology

those without APOL1 high-risk genotypes. The investigators noted that APOL1 high-risk genotypes, which are present in about 11%–13% of blacks, are the most widely recognized genetic contributors to ESRD risk among blacks.

“Unlike APOL1, testing for SCT is widely performed in newborn screening programs, in athletics, and in pregnancy counseling, therefore, these findings may have immediate implications for policy and treatment recommendations in SCT,” Dr. Naik and colleagues concluded. n

and Dr. Narasimhan is in the division of pulmonary/critical care.

REFERENCES 1. Greenstein Y, Littauer R, Narasimhan M, et al. Effectiveness of a critical care ultrasonography course.

Chest. 2017;151:34-40.

2. Agricola E, Bove T, Oppizzi M, et al. “Ultrasound comet-tail images”: A marker of pulmonary edema.

Chest. 2005;127:1690-1695.

3. Noble VE, Murray AF, Capp R, et al. Ultrasound assessment for extravascular lung water in patients undergoing hemodialysis. Chest. 2009;135:1433-1439.

4. Zoccali C, Torino C, Tripepi R, et al. Pulmonary congestion predicts cardiac events and mortality in ESRD. J Am Soc Nephrol. 2013;24:639-646.

www.renalandurologynews.com MARCH/APRIL 2017

Renal & Urology News 23

Lower BP Target Not Renoprotective Levels below 130/80 do not lower CKD progression risk in patients without diabetes, meta-analysis shows

BY NATASHA PERSAUD CONTROLLING BLOOD pressure (BP) to a lower target of less than 130/80 mm Hg does not prevent chronic kidney disease (CKD) progression in nondiabetic patients, according to a new systematic review and metaanalysis. An optimal blood pressure target for this population still needs to be determined.

“Targeting BP below the current standard did not provide additional benefit for renal outcomes compared with standard treatment during a follow-up of 3.3 years in patients with CKD without diabetes,” Wan-Chuan Tsai, MD, of the Far East Memorial Hospital in New Taipei City, Taiwan, and colleagues concluded in JAMA Internal Medicine. “However, nonblack patients or those with higher levels of proteinuria might benefit from the intensive BP-lowering treatments.”

Major guidelines suggest a BP target below 140/90 mm Hg for patients with nondiabetic CKD, and some suggest further reduction to less than 130/80 mm Hg for patients with proteinuria, Dr. Tsai’s group noted.

Intensive blood pressure lowering may benefit nonblack CKD patients.

The meta-analysis included 9 randomized controlled trials (RCTs) including 8127 patients with followup times of 1.6 to 7.0 years. Over a median follow-up of 3.3 years, renal outcomes were comparable for patients attaining the lower BP (below 130/80 mm Hg) compared with the standard

Emergent Lithotripsy Better for Some Ureteral Stones EARLY RATHER THAN delayed litho-

Stone-free meant the absence of a

tripsy is better for patients with symp-

stone or fragments of 3 mm or less.

tomatic, obstructing ureteral stones,

Emergent ureteroscopy typically is

according to a new study.

reserved for distal stones, they noted.

“Emergent lithotripsy, either uretero-

Emergent ESWL was associated with

scopic or extracorporeal, can be offered

more than twice the odds of achieving

as an effective and safe treatment for

stone-free status and half the odds of

patients with symptomatic ureteral

auxiliary procedures compared with

stone,” Riccardo Autorino, MD, of Second

delayed ESWL. Again, investigators

University of Naples in Naples, Italy, and

found no differences in rates of compli-

colleagues concluded in a paper pub-

cations, such as hematuria or mucosal

lished online ahead of print in Urolithiasis.

injury. “If amenable to ESWL, based on

Dr. Autorino’s group evaluated

stone and patient characteristics, an

emergent versus delayed lithotripsy in

emergent approach should be strongly

separate systematic reviews and meta-

considered,” Dr. Autorino and colleagues

analyses of ureteroscopy (URS) and extra-

stated. This meta-analysis involved 6

corporeal shock wave lithotripsy (ESWL).

studies (including 4 randomized trials)

An emergent procedure occurred

involving a total of 711 patients.

within 6 to 72 hours of presentation.

Emergent URS performed as well as

Early treatment of stones with colic is preferable because ureteral edema

delayed URS, according to a meta-

can develop within 48 hours and inter-

analysis based on 4 studies (including

fere with stone clearance, the team

1 randomized controlled trial) involving

said. Implementing emergent litho-

a total of 1513 patients. The investiga-

tripsy would depend on the availability

tors reported no significant differences

of URS and ESWL. It is possible that

in stone-free and complication rates

specific machines and technologies

and the need for auxiliary procedures.

affect results. n

target (below 140/90 mm Hg). An aggressive BP-lowering strategy demonstrated no significant difference in the annual decline in glomerular filtration rate (GFR) (mean difference, 0.07 mL/min/1.73 m2 per year), doubling of serum creatinine level, and a 50% reduction in GFR. The odds of endstage renal disease (ESRD), a composite of renal outcomes, and all-cause mortality also were similar between the groups.

Investigators found a trend toward a lower risk of progression with intensive BP control among nonblack patients and those with proteinuria levels higher than 0.5 or 1 g per day. “Previous studies have reported that the kidney protection with antihypertensive therapy is less favorable in blacks than in whites,” Dr. Tsai and the team stated.

With regard to adverse events, intensive BP treatment did not appear to increase risks, except for dizziness.

In a previous meta-analysis published in the Canadian Medical Association Journal (2013;185:949-957), Jicheng Lv, MD, PhD, of the University of Sydney in Australia, and colleagues found that intensive BP lowering decreased the risk of composite kidney failure events (either doubling of serum creatinine level and 50% decline in GFR, or ESRD) by 17% and reduced the risk of ESRD alone by 18%. Dr. Tsai and colleagues noted that this study included posttrial follow-up data from the Modification of Diet in Renal Disease trial and African American Study of Kidney Disease and Hypertension.

“Including the posttrial cohort data in the meta-analysis increased the number of events and statistical power but might also introduce biases because patients may not have adhered to assigned BP targets during the posttrial follow-up period.” n

Diets May Delay Need for Dialysis

i­nitiation by reducing uremic toxicity.

High average protein intakes of 1.03 and 0.99 g protein/kg/day have been reported for male and female patients, respectively, in the United States. Yet a previous study by Giuliano Brunori, MD, and colleagues published in the American Journal of Kidney Diseases (2007;49:569580) found that some elderly patients assigned to SVLPD for 10.7 months safely delayed dialysis initiation.

Dietary therapy also may delay thriceweekly dialysis and permit incremental or infrequent dialysis for patients with residual renal function, the authors suggested. Well-designed LPD and SVLPD possibly reduce the production and accumulation of toxic solutes in kidney failure.

“These findings strongly suggest that dietary therapy can be used to safely delay (for up to several months) the need for chronic dialysis in selected patients with pre-ESRD,” the authors wrote. “LPDs or SVLPDs may also provide patients with advanced CKD with sufficient time for placement and maturation of a permanent hemodialysis vascular access or peritoneal dialysis catheter without requiring the use of temporary catheters needed to inaugurate dialysis urgently.”

Finally, renal diets need to ensure adequate energy intake, along with sufficient calcium, trace elements (e.g., iron, zinc, selenium), and vitamins, particularly vitamin B6, folate, vitamin C, cholecalciferol, and 1,25-dihydroxycholecalciferol. n

BY NATASHA PERSAUD DIETARY THERAPY MAY benefit patients with advanced chronic kidney disease (CKD) transitioning to renal replacement therapy (RRT) or actually in need of RRT, according to the authors of a new review published online in the Clinical Journal of the American Society of Nephrology.

Tailored renal diets potentially reduce the retention of sodium, potassium, phosphorus, acids, and water that contributes to harmful states, including oxidative stress, edema, heart failure, hyperkalemia, hyperphosphatemia, metabolic acidosis, and hyperparathyroidism.

Much research has centered on delaying CKD progression with diet. Still other benefits are possible, according to investigators Norio Hanafusa, MD, Bereket Tessema Lodebo, MD, and Joel D. Kopple, MD, of Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center in Torrance, California.

Low protein diets (LPD) with a daily protein intake of 0.6-0.8 g/kg/day and ketoacid or supplemented very low protein diets (SVLPD) might delay dialysis

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PCa Salvage Radiotherapy Plus Androgen Blockade Ups Survival Longer 12-year overall and cancer-specific survival reported

No Memory Improvement With TRT MEN OLDER than 65 years who have

SALVAGE RADIATION treatment combined with daily anti-androgen therapy for men with prostate cancer (PCa) that recurs or persists following radical prostatectomy improves longterm overall survival compared with the use of salvage radiation treatment alone, according to a new study.

The dual treatment also results in a lower incidence of metastatic disease and PCa-specific death.

In a randomized, double-blind study of 760 men who underwent salvage radiation therapy for recurrent PCa after radical prostatectomy, researchers found that patients who also received 24 months of daily bicalutamide had a statistically significant 23% lower risk of death compared with patients who received daily placebo at 12 years.

The bicalutamide and placebo groups included 384 and 376 men, respectively. Bicalutamide recipients took a 150-mg tablet of the medication daily.

In both groups, 258 patients completed therapy as planned. Surviving patients had a median follow-up of 13 years. The actuarial survival rate at 12 years was 76.3% in the bicalutamide group ­versus 71.3% in the

­ lacebo arm, William U. Shipley, MD, p of Massachusetts General Hospital in Boston, and colleagues reported study findings in The New England Journal of Medicine (2017;376:417-428). The cumulative incidence of metastatic PCa at 12 years was 14.5% in the bicalutamide group versus 23.0% in the placebo arm. The 12-year incidence of cancerspecific death was 5.8% in the bicalutamide group compared with 13.4%

Bicalutamide users had a 23% lower 12-year death risk vs. placebo patients. among placebo recipients. All of these between-group differences were statistically significant.

Both groups had a similar incidence of late adverse events associated with radiation therapy.

Since the trial was designed, gonadotropin-releasing hormone (GnRH) agonists have superseded bicalutamide as the first-choice hormonal therapy

with radiation therapy, the researchers pointed out. Randomized trials involving patients with non-metastatic disease have demonstrated that high-dose bicalutamide and GnRH agonists have similar systemic anti-cancer efficacy, they stated.

“As such, our trial presents proof of principal that the addition of hormone-based therapy to salvage radiation therapy is associated with significant and clinically important lower rates of prostate-cancer metastases and death,” they wrote.

Given the lower rate of death and the lack of evidence of higher other-cause mortality in the bicalutamide recipients versus the placebo group, Dr. Shipley and his colleagues calculated that 20 patients would need to be treated with bicalutamide to avoid 1 death over a 12-year period.

To be eligible for study, patients were required to have a detectable PSA level of 0.2 to 4.0 ng/mL at least 8 weeks after surgery and a Karnofsky performance-status score of 80 or higher. Patients also could not have previously received chemotherapy or radiation therapy for PCa. In all patients, abdominal and pelvic computed tomographic and bone scans showed no evidence of metastatic disease. n

age-related memory impairment and testosterone deficiency do not experience improvement in cognitive performance with a year of testosterone replacement therapy (TRT), a new study finds.

“In spite of previously reported associations between testosterone and verbal memory, the results of this Cognitive Function Trial offer no support for a benefit to memory and little or no support for a benefit to other cognitive functions in older hypogonadal men, Susan M. Resnick, PhD, and colleagues wrote in the Journal of the American Medical Association.

Cognitive functions as well as testosterone levels typically decline with aging. Previous studies have suggested that TRT might improve some functions, including verbal and visual memory, executive function, and spatial perception. The investigators evaluated these specific outcomes in 493 men (mean age 72.3 years) with age-associated memory impairment, half of whom were randomly assigned to 1 year

Metabolic Profiles May Predict Renal Pathology

of TRT (testosterone gel 1%) and the

METABOLIC PROFILES determined by serum and urine analyses may distinguish benign renal masses and renal cell carcinoma (RCC), according to a pilot study. They also may differentiate pT1 from pT3 RCC. Investigators used 1H nuclear magnetic resonance (NMR) spectroscopy and gas chromatography mass spectrometry (GCMS) to conduct metabolomic analyses of preoperative fasting serum and urine samples from 53 patients undergoing surgery for small renal masses.

The group of metabolites in serum that differentiated benign masses and RCC varied considerably from those detected in urine, Oluyemi S. Falegan, a PhD candidate at the University of Calgary in Canada, and colleagues reported in Metabolites (2017;7[1]). Still, glycolytic and tricarboxylic acid cycle intermediates and amino acids and their derivatives were the most significant metabolites identified as potentially useful variables, according

low testosterone levels (mean tes-

to the investigators. In serum and urine specimens, pyruvate and lactate differentially increased in RCC versus benign cases, whereas levels of succinate and citrate were reduced. Glutamate levels increased in patients with RCC compared with those who had benign masses in both serum and urine, whereas glutamine was reduced in serum. Falegan’s group observed depleted threonine and taurine levels and increased trigonelline, tryptophan, and isoleucine levels in the RCC patients compared with controls.

In addition, urinary levels of glycine, creatinine, and phenylalanine decreased in response to cancer development.

These differences in metabolite levels also discriminated between pT1 and pT3 RCC. The serum and urine GCMS models had area under the curve (AUC) values of 0.93 and 0.98, respectively; the AUC values for the NMR models were 0.83 to 0.98, respectively. “This indicates

excellent predictive ability of these metabolomics platforms and shows that they can reliably distinguish between benign and malignant renal masses and identify different stages of RCC.” The increased glutamine levels in RCC found in the current study corroborates findings in similar studies “and further strengthens the proposition that increased glutamate levels may indicate increased glutaminolysis for biosynthetic purposes in RCC,” the investigators stated. Taken together, this sequence of biological events underscores the role and importance of metabolic remodeling in RCC tumorigenesis, according to the researchers. Thus, therapeutic alternatives that exploit these “biological loopholes” may improve clinical outcomes of patients with RCC. “These tools can be potentially employed clinically to identify renal neoplastic transformation in asymptomatic individuals,” the researchers concluded. n

other half to placebo. All of the men had hypogonadism symptoms and tosterone at baseline, 234 ng/dL).

The investigators defined age-related memory impairment as subjective memory complaints along with subpar performance on objective tests of verbal and visual memory.

Results showed no significant change in the ability to recall a spoken paragraph after a time lapse. Average scores for delayed paragraph recall were 14.0, 16.0, and 16.2 at baseline, 6 months, and 12 months, respectively, for the TRT group compared with 14.4, 16.0, and 16.5 for the placebo group at the same time points. Men who received TRT also had no significant improvement in visual memory, executive function, or spatial ability, based on a battery of well-chosen tests. n

www.renalandurologynews.com MARCH/APRIL 2017

Renal & Urology News 25

TRT May Lower Cardiovascular Risks Large study of androgen-deficient men demonstrates reduced rates of cardiac and stroke events TESTOSTERONE replacement therapy (TRT) is associated with a lower risk of adverse cardiovascular (CV) events among men with testosterone deficiency, according to a new study.

Researchers led by T. Craig Cheetham, PharmD, MS, of the Southern California Permanente Medical Group, identified a retrospective cohort of 44,335 men aged 40 years and older with evidence of testosterone deficiency. The cohort included 8808 men who had ever been dispensed testosterone (ever-TRT group) and 35,527 men never dispensed testosterone (never-TRT group). The primary outcome was a composite of cardiovascular endpoints that included acute myocardial infarction (AMI), coronary revascularization, unstable angina, stroke, transient ischemic attack (TIA), and sudden cardiac death (SCD).

After a median follow-up of 3.2 years in the never-TRT group and 4.2 years in the ever-TRT group, the rates of the composite endpoint were significantly higher in the never-TRT than ever-TRT group (23.9 vs 16.9 per 1000 person-years), Dr. Cheetham and colleagues reported online ahead of print in JAMA Internal Medicine. After adjusting for potential confounders, the ever-TRT group had a significant 33% lower risk of the primary outcome compared with the never-TRT

Cardiovascular Benefits from TRT In a study of men with androgen deficiency, those who had ever been on testosterone replacement therapy (TRT) experienced the following risk reductions compared with those who never used TRT:

40

33%

34%

Composite CV outcome

Cardiac outcomes

28%

30 20 10 0

Stroke outcomes

Source: Cheetham TC et al. Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency. JAMA Intern Med 2017;published online ahead of print.

group. The investigators found similar results when looking separately at combined cardiac events (AMI, SCD, unstable angina, coronary revascularization) and combined stroke events (stroke and TIA). The ever-TRT group had a significant 34% and 28% lower risk of cardiac events and stroke events, respectively, compared with the never-TRT group.

“While these findings differ from those of recently published observational studies of TRT, they are consistent with other evidence of CV risk and the benefits of TRT in androgendeficient men,” the investigators wrote.

Previous studies have found an association between low serum testosterone levels in aging men and an increased risk of coronary artery disease as well as an inverse relationship between serum testosterone and carotid intima thickness, Dr. Cheetham’s team pointed out.

The never-TRT and ever TRT groups had a mean age of 59.8 and 58.4 years, respectively. In the never-TRT group, 13,824 men (38.9%) were aged 40 to 55 years, 10,902 (30.7%) were aged 56 to 65 years, and 10,801 (30.4%) were older than 65 years. In the ever-TRT group, 3746 men (42.5%) were aged

40 to 55, 2899 (32.9%) were aged 56 to 65 years, and 2163 (24.6%) were older than 65 years.

The researchers defined testosterone deficiency as a coded diagnosis and/or a morning serum total testosterone level below 300 ng/dL. With regard to study limitations, the investigators noted that their criterion for identifying men with testosterone deficiency (a diagnosis or at least 1 morning testosterone measurement) does not meet the strict criteria established by the Endocrine Society. “Therefore some individuals in the study could be misclassified as being androgen-deficient.” In addition, as the study was observational in design, “unmeasured confounding may have had an influence on the results; unmeasured confounders could possibly influence clinicians to selectively use testosterone in healthier patients.”

In an accompanying editorial, Eric Orwoll, MD, of Oregon Health & Sciences University in Portland, commented that while the study by Dr Cheetham’s group “provides reassuring data concerning the effects of testosterone on cardiovascular health, convincing answers about this question—and other safety issues like prostate health— remain elusive and will require large, prospective randomized trials.” n

Vitamin D Status, Fat Mass Linked in Older Women OLDER WOMEN tend to have low serum 25 hydroxyvitamin D [25(OH)D] levels, low bone mineral density, and high parathyroid hormone (PTH) levels, all harbingers of frailty. Based on new findings, Italian investigators suggest that clinicians should consider fat mass when addressing the bone health of these women.

In a study of 218 fit and healthy women older than 65 (mean age 71 years), fat mass significantly related with serum vitamin D status in agreement with previous research, Caterina Trevisan, MD, of the University of Padova in Italy, and colleagues reported in the Journal of Nutrition, Health and Aging. Higher fat mass correlated with lower 25(OH)D levels, yet higher bone mineral density (BMD), including in the lumbar, femoral neck, and total hip regions. Women with higher adiposity had 58% lower ­ yperparathyroidism risks of secondary h

(SHPT), binary logistic analysis revealed.

The average body mass index was 27.1 kg/m2. By contrast, consumption of vitamin D from foods, without dietary supplementation, showed no relationship with 25(OH)D levels, BMD, or SHPT, also in line with p ­ revious s­ tudies. None

Fat mass, more than vitamin D intake, may influence serum 25(OH)D levels. of the older women achieved the recommended dietary allowance for vitamin D of 800 IU/day.

“This study demonstrates that fat mass, more than vitamin D intake, may significantly influence serum 25(OH) D levels in fit and healthy older women

at or slightly above normal weight,” Dr. Trevisan told Renal & Urology News. “These findings confirm that adipose tissue is a factor to be considered when evaluating vitamin D supplementation, since it may influence the achievement of normal values of serum 25(OH)D. At the same time, the protective effect of adipose tissue on bone mineral density suggests that excessive weight loss in such women could be unhealthy for bone mass.”

Fat can store vitamin D and thereby reduce its bioavailability, the investigators noted.

“The fact that bone health parameters did not deteriorate despite the low serum 25(OH)D levels might be due to gravitational loading and to fatmediated endocrine mechanisms likely preserving bone mass,” they wrote.

Physiologic or pathologic changes in fat mass or fat-free mass can ­significantly

influence bone metabolism, Dr. Trevisan added. In clinical practice, she recommended using validated methods to assess the body composition of older patients.

For the study, participants completed a 3-day food diary and food frequency questionnaire. They underwent laboratory testing for 25(OH)D and intact PTH. BMD and body composition were estimated using dual-energy X-ray absorptiometry with fan-beam technology. The investigators defined vitamin D insufficiency as 25(OH) D levels below 50 mmol/L. SHPT was indicated by PTH above 60 pg/ mL. Nearly 62% of participants had vitamin D insufficiency and 21% had elevated PTH levels.

Osteoporosis and osteopenia developed in 29.8% and 53.7% of patients, respectively. None of the participants had pre-existing kidney disease. n

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Practice Management I

f physicians took a hard look at theirpractice, would they see annoyed patients sitting for too long in the waiting room? Phone lines going unanswered? If so, they may be looking at a practice suffering from inefficiencies.

What follows are some suggestions for addressing them.

The most expensive labor in a medical practice is the physician. If a urologist, for instance, makes $350,000 annually and staffing expenses are $150,000, physician costs are more than double that of everyone else.

“Because of this, 2 to 3 times as much focus should be put on their own behavior,” said Keith Borglum, a member of the National Society of Certified Healthcare Business Consultants, and owner of Professional Management & Marketing based in Santa Rosa, California. “That needs to be where a majority of the inspection of efficiency occurs.”

So where do physicians start in their process of self-evaluation? They should ask their staff to offer feedback and make sure they feel comfortable doing so. If they think they will “get in trouble” for speaking their mind, they may not honest about where physicians may be holding things up.

For instance, Borglum often sees physicians prone to deviating from the

behind their patients. This allows them to check the time — without being too obvious — so they can track how long they are taking. Another option is having staff knock on the door using codes. For instance, one of Borglum’s clients who was perpetually long-winded chose the name of a deceased close friend as a trigger. The emotional impact of the name would get his attention. The staff would say, “Dr. Green is on the phone for you,” and knock a single time for each 10 minutes he was behind schedule.

Another challenge for both doctors and staff is being prepared for the first appointments in the morning and after lunch. Physicians should make sure they and their staff members are in the office well before the first patients arrive so their appointments can start right on time, if not earlier.

Buck-a-minute game Borglum recommends offices play the buck-a-minute game with physicians who are frequently tardy. Whenever a staffer catches a doctor being late for those first patients, the doctor pays $1 per minute on the spot. The money can be held by someone to pay for an office holiday party or staff bonuses. One of his clients put so much money in the jar he used it to take the staff to Hawaii

Doctors who chitchat with patients about matters unrelated to the medical encounter can hold things up. purpose of the visit during a patient examination. “Doctors start talking about their kids, grandkids, travel and things like that, and it puts them behind,” he said. “It helps make the day more tolerable and is a distraction … but would you pay a medical assistant to jawbone with patients about their grandchildren?”

One way physicians can address this habit is to put a clock on the wall

for Christmas. A painful lesson, but it helped him change his ways.

“The activity of paying money out brings a physicality to the behavior that usually fixes it … or the doctor gets mad and cancels the game,” he said.

A team huddle Another good practice to perform before the morning and afternoon work periods is a team huddle. It does

© THINKSTOCK

Physician time-wasting behavior can contribute to inefficiencies in a medical practice BY TAMMY WORTH

Patients sitting for a long time in a waiting room could be a sign of practice inefficiency.

not have to be a major affair, but a 1-minute standup meeting with your receptionist and medical assistant can make your work go more smoothly.

Physicians should look at the upcoming patients and review their goals and schedules. They will be able to see where there is space for work-ins or where they might fall behind because of slow or more-challenging patients.

Avoid procrastination Michael DeVries, a partner at VanderLugt, Mulder, DeVries, Elders, based in Grandville, Michigan, said he frequently sees doctors with what he calls the “do later piles.” Whether putting off reading medical journals or finishing charts or patient notes, he said to do it, schedule it, or delegate it as soon as possible.

Attending to patient records Physicians often think that attending to patient records at the end of the day is more efficient, but Borglum said it takes longer to restart something than to do it as part of the original activity.

Starting chart entries and then setting them aside and going back to them later also leaves more room for error.

Finally, he said patients tend to like it

when physicians dictate information into a recorder because this gives them confidence the doctor is saying the same thing to them as what is in the record.

Use technology DeVries also recommends that physicians learn to make the best use of their practice management system. For instance, office staff should be proficient in Excel so physicians can make sense of their data. This will enable doctors to analyze the practice and have a better idea of where changes need to be made.

Another way to improve efficiency is to make templates for all kinds of communications. DeVries finds programs like TextExpander a time saver whether writing letters or sending email. Other simple technology fixes for improving efficiency include dual monitors, which give staff more space to run a practice management system and other software simultaneously; telephone headsets that allow for greater multitasking; and scanners at each desktop, which are reasonably priced and allow for handy, quick access. n Tammy Worth is a freelance medical journalist based in Blue Springs, MO.