Renal & Urology News - April 2016 Issue by Haymarket Media

APRIL 2016

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VOLUME 15, ISSUE NUMBER 3

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Nephrology Attracting Fewer Doctors Fellowship positions go unfilled as the U.S. faces expanding population of kidney disease patients BY JODY A. CHARNOW RESEARCHERS EXPECT the population of patients with kidney disease to swell in coming years as a result of a growing elderly population, increasing diabetes incidence and prevalence, and other factors. The trend has raised concerns about whether the nation will have sufficient nephrologists and other kidney care specialists to keep pace with this expanding population of complex patients. A report titled “US Nephrology Workforce 2015: Developments and Trends,” which was prepared for the American Society of Nephrology (ASN), noted that “changes in the general health care system and delivery of kidney care make it unclear how increases in need will be translated into demand

INTEREST IN NEPHROLOGY WANING The proportion of filled nephrology fellowship positions in the United States has been in decline. 100 80

91%

89% 76%

68%

40 20 0

2012

2013

2014

2015

Source: National Resident Matching Program Specialties Matching Service.

PD Growing Faster than HHD SEATTLE—The number of patients on home hemodialysis (HHD) grew rapidly while the number of those on peritoneal dialysis (PD) grew slowly in the United States prior to the debut of the Medicare prospective payment system for dialysis care in 2011, but the pattern subsequently reversed, according to data presented at the 2016 Annual Dialysis Conference.

Possible explanations for the trend include a higher profit margin potentially associated with PD and lack of adequate reimbursement for HHD training, said Eric D. Weinhandl, PhD, MS, who presented study findings. Under the prospective payment system (PPS), PD is reimbursed at the same rate continued on page 7

MANAGEMENT OF ADPKD

An analysis and interpretation of the latest evidence by Ronald D. Perrone, MD. PAGE 15

Incompatible Live Donors a Good Option BY JODY A. CHARNOW RECIPIENTS OF a kidney from an HLA-incompatible live donor have substantially better survival than individuals who receive a kidney from a deceased donor or who remain on the transplant waiting list, according to a study. After 8 years, patients who received a kidney from an HLA-incompatible donor had a survival rate of 76.5%, which was significantly higher than the survival rates for 2 control groups: patients who remained on the transplant waiting list or received a kidney from a deceased donor (62.9%) or those who remained on the waiting list and did not receive a transplant from a deceased donor (43.9%). The survival benefit was observed across all donorspecific antibody levels, researchers reported in The New England Journal of Medicine (2016;374:940-950). “For the first time, we have definitively shown that incompatible live continued on page 7

for nephrologists.” If the demand does increase, however, the country may not have enough young doctors entering the subspecialty to meet it. The number of medical residents filling nephrology fellowship positions has been declining. The proportion of filled nephrology fellowship positions dropped from about 91% in 2012 to 89% in 2013, 76% in 2014, and 68% in 2015, according to the National Resident Matching Program Specialties Matching Service. Reasons for the relative lack of interest in nephrology are varied and speculative. Ruediger W. Lehrich, MD, director of the nephrology fellowship program at Duke University Medical Center in Durham, N.C., offered some possible explanations. continued on page 7

IN THIS ISSUE 5

Sildenafil may improve passage of distal ureteric stones

Death risk higher among black vs. white children on dialysis

Intradialytic hypotension predicts greater long-term mortality

NKF Preview: Treating anemia in cancer patients with CKD

NKF Preview: Update on the management of ADPKD

A chewable iron-based binder improves phosphorus control

Finasteride may lower the risk of bladder cancer diagnosis in men A review of anemia management for cancer patients with CKD by Jeffrey S. Berns, MD. PAGE 11

APRIL 2016

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VOLUME 15, ISSUE NUMBER 3

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www.renalandurologynews.com

Saturation Prostate Biopsy Not Better Detection of high Gleason grade tumors is not significantly improved versus standard 12-core biopsy GLEASON UPGRADING UNAFFECTED BY NUMBER OF BIOPSY CORES In a study, patients who underwent standard 12-core and saturation prostate biopsies (18–33 cores, median 20) had similar rates of high Gleason grade prostate cancer detected at biopsy and final pathologic examination of radical prostatectomy specimens. 80

12-core biopsy

Saturation biopsy

70 60 50 40 30

69.5% 65.1% 49.1%

50%

20 10 0

Biopsy

Final pathology

Source: Quintana L. Gleason misclassification rate is independent of number of biopsy cores in systematic biopsy. Urology. 2016 (published online ahead of print).

Frailty Predicts RC Outcomes STRATIFYING BLADDER cancer patients according to how frail they are can predict their likelihood of serious adverse outcomes following radical cystectomy (RC), according to a new study. “As the patient population with bladder cancer continues to age, it is increasingly important to identify those patients at increased risk of severe

complications and mortality in the perioperative period,” investigators Meera R. Chappidi, a medical student at Johns Hopkins University School of Medicine in Baltimore, Max Kates, MD, and Trinity J. Bivalacqua, MD, PhD, of the same institution, and colleagues wrote in a paper published online ahead of continued on page 7

MANAGEMENT OF ADPKD

An analysis and interpretation of the latest evidence by Ronald D. Perrone, MD. PAGE 15

BY JODY A. CHARNOW SATURATION PROSTATE biopsy does not increase the likelihood of detecting high Gleason grade tumors, according to a new study. Unusual tumor location outside of biopsy grids, such the anterior lobes, apex, bladder neck, and para-sagittal zones, is among the main reasons for missing high Gleason grade tumors, a finding that supports the need for improved detection methods, such as magnetic resonance imaging (MRI)guided targeted biopsy, a research team led by Huihui Ye, MD, of Beth Israel Deaconess Medical Center in Boston, reported. Dr. Ye’s group compared the diagnostic accuracy of the standard 12-core

Incompatible Live Donors a Good Option BY JODY A. CHARNOW RECIPIENTS of a kidney from an HLA-incompatible live donor have substantially better survival than individuals who receive a kidney from a deceased donor or who remain on the transplant waiting list, according to a study. After 8 years, patients who received a kidney from an HLA-incompatible donor had a survival rate of 76.5%, which was significantly higher than the survival rates for 2 control groups: patients who remained on the transplant waiting list or received a kidney from a deceased donor (62.9%) or those who remained on the waiting list and did not receive a transplant from a deceased donor (43.9%). The survival benefit was observed across all donorspecific antibody levels, researchers reported in The New England Journal of Medicine (2016;374:940-950). “For the first time, we have definitively shown that incompatible live donor kidney transplantation provides almost continued on page 7

prostate biopsy and saturation biopsy (18–33 cores, median 20) among 375 consecutive patients who underwent radical prostatectomy (RP). Of these, 269 had 12-core biopsies and 106 had saturation biopsies. The researchers compared biopsy findings with final pathologic findings of RP specimens. A similar proportion of patients in the 12-core and saturation biopsy groups had high Gleason grade prostate cancer (PCa) on biopsy (49.1% vs. 50%) and at RP (69.5% vs. 65.1%). Among patients with high Gleason grades on final pathology, the 12-core and saturation biopsy schemes had comparable sensitivity, specificity, and negative and positive predictive continued on page 7

IN THIS ISSUE 5

Sildenafil may improve passage of distal ureteric stones

Silodosin found safe and effective for BPH-related LUTS

Prostate cancer radiotherapy raises risk of secondary cancer

Most post-cystectomy VTE cases occur after hospital discharge

NKF Preview: Treating anemia in cancer patients with CKD

NKF Preview: Update on the management of ADPKD

Finasteride may lower the risk of bladder cancer in men A review of anemia management for cancer patients with CKD by Jeffrey S. Berns, MD. PAGE 11

www.renalandurologynews.com APRIL 2016

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 Medical Director, Nephrology Professor & Chief Division of Nephrology & Hypertension University of California, Irvine School of Medicine Orange, Calif.

Nephrologists

Urologists

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

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

Suphamai Bunnapradist, MD Director of Research Department of Nephrology Kidney Transplant Research Center The David Geffen School of Medicine at UCLA

R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto 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 Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J.

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

Lynda Anne Szczech, MD, MSCE Medical Director, Pharmacovigilence and Global Product Development, PPD, Inc. Morrisville, N.C.

Renal & Urology News Staff Editor

Jody A. Charnow

Web editor

Natasha Persaud

Production editor

Kim Daigneau

Group art director, Haymarket Medical

Jennifer Dvoretz

Production manager

Krassi Varbanov

Production director Circulation manager National accounts manager Group Publisher Editorial director Senior VP, medical journals & digital products Senior VP, medical communications CEO, Haymarket Media Inc.

Kathleen Millea Grinder Paul Silver William Canning Chad Holloway Kathleen Walsh Tulley Jim Burke, RPh John Pal Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 15, Number 3. Published monthly, except for the combined January/February, June/July and November/ December issues, by Haymarket Media, Inc., 114 West 26th Street, 4th 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 © 2016.

The Looming Battle for ESRD Fountains Each year, approximately 120,000 Americans transition to maintenance dialysis therapy while 90,000 dialysis patients die and 20,000 undergo kidney transplantation. The result is a small positive balance of 10,000 added dialysis patients each year on top of the nation’s prevalent dialysis population of 450,000. The trivial differential, a narrow margin of growth of 2% to 3%, is the basis on which the dialysis industry capitalizes its growth and expansion in the United States. Now imagine that, in the not-too-distant future, fewer people transition to dialysis and mortality and transplantation rates remain the same. The margin of growth will be even narrower. The positive balance will shrink and may even go into the negative zone. This likely scenario leads to unfilled dialysis chairs and increasing vacancies in hemodialysis shifts. Dialysis centers struggling for survival will try hard to go directly to the source of new dialysis patients, the so-called “ESRD fountains,” such as large community hospitals. An ESRD fountain can be defined as a medical center complex where each month 4 or more people are started on chronic dialysis treatment in that center. These new dialysis patients are then discharged to 1 of the 6,000 dialysis clinics in the country. An ESRD fountain that sends out 4 or more new dialysis patients each month contributes to at least 45-50 new patients a year. This is the number needed to keep a 150-patient dialysis clinic operational, given that each year a center will lose about one third of its patients due to death, transplantation, geographic relocations, and other factors. There are also “near-fountains,” such as medical centers with 2–3 new ESRD patients a month. A dialysis center needs to be linked to at least 1 ESRD center or several near-fountains to survive, let alone grow or expand beyond its usual modalities to offer, for example, home dialysis. Nephrology groups often compete for access to ESRD fountains. The competition can be tough to the point that some nephrology groups provide free CKD clinics in some of the mega-fountains (more than 6 new ESRD patients a month). Dialysis companies try hard to contract with nephrology groups that have more secure access to ESRD fountains. The geographic location of a dialysis clinic also plays a role. A dialysis clinic in the middle of a neighborhood with more minorities, including African Americans and Hispanics, have a better chance of surviving or even growing than a dialysis unit in an upscale area even if the population is elderly. As the rate of acceleration in ESRD incidence continues to drop, we should expect heightened battles for the ESRD fountains. Kam Kalantar-Zadeh, MD, MPH, PhD Medical Director, Nephrology Professor & Chief Division of Nephrology & Hypertension University of California, Irvine School of Medicine

4 Renal & Urology News

APRIL 2016

www.renalandurologynews.com

Contents

A P R I L

2 0 1 6

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VO L U M E

Nephrology

ONLINE

Intradialytic Hypotension Ups Long-Term Death Risk Intradialytic hypotension independently predicts an increased long-term risk of death among patients on maintenance hemodialysis.

NKF Preview: Managing Anemia in Patients with Cancer and Chronic Kidney Disease Jeffrey S. Berns, MD, advises the benefits of ESA's must be weighed against the increased risk of death and thrombosis.

Clinical Quiz

Take our latest quiz at renalandurologynews.com /clinical-quiz/. Answer correctly and you will be entered to win a $50 American Express gift card.

Congratulations to our March winner: Enayat Osanloo, MD

NKF Preview: An Update on the Management of ADPKD in 2016 and Beyond Ronald D. Perrone, MD, discusses evidence showing that intensive blood pressure control in selected patients may slow total kidney volume growth. Iron-Based Binder Improves Phosphorus Control Data suggest a chewable iron-based phosphate binder can improve serum phosphorus levels in patients with hyperphosphatemia and decrease their pill burden.

Urology

HIPAA Experts offer recommendations for entering into agreements with Health Information Organizations.

Job Board

Sildenafil Aids Ureteric Stone Passage Sildenafil may be useful as medical expulsive therapy for distal ureteric stones 5–10 mm in diameter.

Most Post-Cystectomy VTE Occurs After Discharge A total of 55% of venous thromboembolism cases that develop after radical cystectomy occur after hospital discharge.

Finasteride May Cut Risk of Bladder CA Likelihood of the malignancy was 37% lower in men who reported finasteride use, after adjusting for age and smoking status.

News Coverage Visit our website for daily updates as well as on-site coverage of major medical meetings.

Urologists Perform 85% of RPs Using Robotics Robot-assisted laparoscopic prostatectomy is performed 5 times more than open radical prostatectomy (RP) and accounts for 85% of all RPs performed by urologists in 2013.

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

I S S U E

N U M B E R

CALENDAR

this month at renalandurologynews.com

1 5 ,

Counseling patients in smoking cessation

prior to the procedure may provide an avenue for quality improvement to limit readmissions. See our story on page 18

National Kidney Foundation Spring Clinical Meetings Boston April 27–May 1 American Urological Association Annual Meeting San Diego May 6–10 American Society of Hypertension Annual Scientific Meeting New York May 13–17 European Renal Association–European Dialysis and Transplant Association 53rd Congress Vienna, Austria May 21–24 American Society for Clinical Oncology Annual Meeting Chicago June 3–7 American Transplant Congress Boston June 11–15 Canadian Urological Association Annual Meeting Vancouver, B.C. June 25–28

Special Feature 19

Reporting clinical depression screening and pain assessment data via CROWNWeb CMS will review submitted data for Payment Year 2018 to analyze whether dialysis facilities screened patients for clinical depression and whether a follow-up plan was documented.

Departments 3

From the Medical Director The Battle for ESRD Fountains

News in Brief Mirabegron effective for refractory overactive bladder in children.

4 Renal & Urology News

APRIL 2016

www.renalandurologynews.com

Contents

A P R I L

2 0 1 6

■

VO L U M E

Urology

ONLINE

Sildenafil Aids Ureteric Stone Passage Sildenafil may be useful as medical expulsive therapy for distal ureteric stones 5–10 mm in diameter.

Clinical Quiz Take our latest quiz at renalandurologynews.com /clinical-quiz/.

Answer correctly and you will be entered to win a $50 American Express gift card. Congratulations to our March winner: Enayat Osanloo, MD

Experts offer recommendations for entering into agreements with Health Information Organizations.

Intradialytic Hypotension Ups Long-Term Death Risk Intradialytic hypotension independently predicts an increased long-term risk of death among patients on maintenance hemodialysis.

NKF Preview: Managing Anemia in Patients with Cancer and Chronic Kidney Disease Jeffrey S. Berns, MD, advises the benefits of ESA's must be weighed against the increased risk of death and thrombosis.

Iron-Based Binder Improves Phosphorus Control Data suggest a chewable iron-based phosphate binder can improve serum phosphorus levels in patients with hyperphosphatemia and decrease their pill burden.

News Coverage Visit our website for daily updates as well as on-site coverage of major medical meetings.

Finasteride May Cut Risk of Bladder CA Likelihood of the malignancy was 37% lower in men who reported finasteride use, after adjusting for age and smoking status.

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

Most Post-Cystectomy VTE Occurs After Discharge A total of 55% of venous thromboembolism cases that develop after radical cystectomy occur after hospital discharge.

Nephrology

HIPAA

I S S U E

N U M B E R

CALENDAR

this month at renalandurologynews.com

1 5 ,

Counseling patients in smoking cessation

prior to the procedure may provide an avenue for quality improvement to limit readmissions. See our story on page 18

Special Feature 19

Departments 3

From the Medical Director The Battle for ESRD Fountains

News in Brief Mirabegron effective for refractory overactive bladder in children.

www.renalandurologynews.com APRIL 2016

Renal & Urology News 5

Urologists Perform 85% of RPs Using Robotics ROBOT-ASSISTED laparoscopic prostatectomy (RALP) is performed 5 times more frequently than open radical prostatectomy (RP) and accounts for 85% of all RPs performed by urologists in 2013, according to investigators. Daniel T. Oberlin, MD, and colleagues from Northwestern University Feinberg School of Medicine in Chicago examined 6-month case logs from 6,563 urologists or two thirds of urologists in the United States certified by the American Board of Urology from 2003–2013. Of these, 68% had performed at least 1 RP in 6 months. Relatively few surgeons performed a high volume of procedures, however. Overall, 39% of surgeons performed

Sildenafil Aids Ureteric Stone Passage SILDENAFIL MAY be useful as medical expulsive therapy for distal ureteric stones 5–10 mm in diameter, according to research findings published in the Arab Journal of Urology (2016;14:1-6). Ahmed A. Shokeir, MD, and colleagues at Mansoura University in Mansoura, Egypt, compared sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, with placebo in a randomized, double-blind study that enrolled 100 patients with distal ureteric stones: 50 who received sildenafil 50 mg daily and 50 who received placebo. The groups were comparable with respect to age and stone characteristics. Of the 100 patients, 49 and 47 patients in sildenafil and placebo arms, respectively, were available for analysis. Spontaneous stone expulsion occurred in 33 patients (67.3%) in the sildenafil group compared with 19 (40.4%) placebo recipients, a significant difference between the groups. In multivariable analysis, sildenafil treatment was associated with a significant 2.7 times increased likelihood of stone expulsion compared with placebo, according to the researchers. n

2 or fewer open RPs within 6 months and 19% performed 2 or fewer RALPs, the researchers reported online ahead of print in Urological Oncology. The median number of open RPs was 2 and RALPs, 8. The highest volume robotic surgeons performed 41% of RALPs. Open RP was

more likely to be performed by lower volume surgeons. Oncologists represented just 4.1% of surgeons but performed 15.1% of RP. General urologists performed the majority (57.8%) of RPs. “The influence of surgeon volume on patient outcomes is a hotly debated

topic in surgery today, with studies showing that surgeons who perform a low volume of specialized procedures per year have increased mortality, postoperative infections, and revision rates,” Dr. Oberlin and colleagues wrote. A minimal surgical volume for proficiency has yet to be established. n

6 Renal & Urology News

APRIL 2016 www.renalandurologynews.com

News in Brief

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

Short Takes Black Kids on Dialysis Are More Likely to Die

suprapubic tube (SPT) and 35 who

SEATTLE—African-American children on

that bother by the catheter with re-

dialysis are more likely to die than their

spect to personal and genital hygiene

white counterparts, according to study

was significantly less for SPT patients

findings presented at the 2016 Annual

on post-operative day (POD) 5 and

Dialysis Conference. Hispanic children

POD 1–6, respectively, researchers

on dialysis, however, may fare better

reported.

had a urethral catheter (UC)—found

or at least no worse than white children. Zadeh, MD, MPH, PhD, of the

Prediabetic CKD Patients Have Higher SBP at Night

University of California, Irvine, included

SYSTOLIC BLOOD PRESSURE (SBP)

895 African-American, 778 Hispanic,

is higher at night in elderly patients

and 1,024 white children on dialysis.

who have both prediabetes and

Compared with white children, African-

chronic kidney disease (CKD), re-

American children had a significant

searchers reported online in the Clini-

64% increased risk of death. Hispanic

cal Journal of the American Society

children had a non-significant 27%

of Nephrology.

The study, led by Kamyar Kalantar-

decreased risk of death.

Kenji Obayashi, MD, and colleagues from the Nara Medical University

Suprapubic Tubes May Be Better for RALP Patients

School of Medicine in Nara, Japan,

SUPRAPUBIC TUBES may be a better

data from 1,227 Japanese men and

option than urethral catheters for

women older than 60 years. Mean

urinary drainage in patients under-

nighttime SBP measurements in pa-

going robot-assisted laparoscopic

tients with both prediabetes and CKD

prostatectomy, new study findings

and patients with both diabetes and

published in the World Journal of Urol-

CKD were significantly elevated by

ogy (2016;34:407-411) suggest.

2.9 mm Hg and 7.8 mm Hg, respec-

collected clinical and laboratory

The prospective randomized study of 62 RALP patients—27 who had a

tively, compared with normoglycemic individuals who had no CKD.

Diagnosed Diabetes in the U.S. An estimated 9.7% of U.S. adults aged 18 and older have been diagnosed with diabetes, a non-significant increase over the estimated 9.1% prevalence in 2014, according to the January–September 2015 National Health Interview Survey. The age- and sex-adjusted prevalence varied by race and ethnicity, as shown here. 15 12 9 6 3 0

12.3%

7.3%

12.7%

Hispanic

Non-Hispanic whites

Non-Hispanic Blacks

Source: National Center for Health Statistics. Early release of selected estimates based on data from the January–September National Health Interview Survey 2015.

65–74

Mirabegron Found to Relieve Refractory OAB in Children M

irabegron may be an effective treatment for children with idiopathic overactive bladder (OAB), according to a new study. The prospective off-label study, by Anne-Sophie Blais, MD, CHU de QuébecUniversité Laval, Québec, Québec, and colleagues, recruited 58 pediatric OAB patients who had no symptom improvement with behavioral or medical treatments and/or significant side effects with at least 2 different antimuscarinic agents. The patients had a median age of 10.1 years and were on mirabegron for a median of 11.5 months. Patients’ median bladder capacity improved from 150 to 200 mL and continence improved in 52 patients (89.6%), with 13 being completely dry, the researchers reported online ahead of print in European Urology. “Mirabegron, a novel first-in-class therapy, appeared as a safe and effective alternative for children with idiopathic OAB refractory to antimuscarinics,” the authors concluded.

Intradialytic Hypotension Ups Long-Term Death Risk S

EATTLE—Intradialytic hypotension (IDH) independently predicts an increased long-term risk of death among patients on maintenance hemodialysis, researchers reported at the 2016 Annual Dialysis Conference. In a study of 293 patients, Jin-bo Yu, MD, and colleagues at Fudan University in Shanghai, China, found that patients with IDH had a significant 1.6 times increased risk of 5-year mortality compared with those who did not have IDH in multivariable analysis. The study found that increasing left ventricular mass index also independently predicted an elevated risk of death. Of the 293 patients, 117 (39.9%) experienced IDH, which the investigators defined as a sudden drop in systolic blood pressure of more than 20 mm Hg or in mean arterial pressure of more than 10 mm Hg. The researchers monitored intradialytic blood pressure over a 3-month period. During a 5-year follow-up, 84 patients died, for a mortality rate of 5.9% per year. The overall mortality rate rose as IDH incidence increased.

Silodosin Safe, Effective for LUTS in Men with BPH S

ilodosin is safe and effective for treating lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH), findings from a European phase 4 study published online ahead of print in the International Journal of Urology. The study, by Francesco Montorsi, MD, of IRCCS Ospedale San Raffaele in Milan, Italy, and colleagues, included 1,036 men aged 60 years and older with BPH and an International Prostate Symptom Score (IPSS) of 12 or higher. Patients received silodosin 8 mg for 24 weeks. Of the 1,036 patients, 766 (77.1%) had a 25% or greater decrease in IPSS, the primary endpoint of the study. The mean IPSS decreased from 18.9 to 10.6. The storage subscore declined from 8.1 to 4.9 and the voiding subscore decreased from 10.8 to 5.7. The mean IPSS quality of life suubscore decreased from 4.0 to 2.2. Results showed that 74.2% of men were satisfied with treatment.

www.renalandurologynews.com APRIL 2016

Fewer nephrologists First, nephrology may not be viewed as an innovative field, at least not like such popular subspecialties as oncology and cardiology. “It might be perceived by applicants that nothing really has happened in nephrology for a long time,” Dr. Lehrich told Renal & Urology News. Fewer “breathtaking” trials take place in nephrology, and many yield negative results, he added.

dialysis providers, Dr. Lehrich said. Lastly, Dr. Lehrich noted that foreign medical school graduates historically have gravitated toward nephrology, perhaps because they find obtaining a fellowship position in this subspecialty less competitive. The number of these international graduates is shrinking, however, possibly because the number of U.S. medical school graduates is nearly identical to the number of PGY 1 positions, “meaning there is less room for foreign graduates to train in the U.S.,” Dr. Lehrich said.

Perceived inadequate pay Another reason for nephrology’s relative unpopularity may be the view that nephrology does not measure up to other subspecialties in terms of compensation, said Dr. Lehrich, adding that this is a misperception. “I think nephrologists are very, very handsomely compensated,” he said. Young physicians may see nephrology as particularly demanding, with obligations to travel to different dialysis units and hospitals to provide care, as well as frequent call duty. “I think it is perceived that the compensation does not match up to the heavy workload and the limitations as it pertains to lifestyle,” he said. A third factor that may discourage interest in nephrology may be the stringent regulatory burdens imposed on nephrologists by the Centers for Medicare and Medicaid Services (CMS) and the large

Skewed view of nephrology In response to declining applications to nephrology fellowship programs, the ASN’s Workforce Committee began looking at the trend systematically about 5 or 6 years ago, said committee chair Mark G. Parker, MD, nephrology division chief and nephrology fellowship director at Maine Medical Center in Portland and clinical associate professor of medicine at Tufts University School of Medicine in Boston. The committee started out by surveying fellows, residents, and medical students and found that the content of nephrology education and perceptions of the balance between professional obligations and personal life contribute to a negative view of nephrology. Committee members speculated that students and residents were getting a skewed view of a day in the life of a nephrologist, Dr. Parker said. Many

PD growing faster

increase of 19%) and 45,247 in 2014 (an increase of 69% compared with 2004). Among HHD patients, the annual growth rate was 24.9% in 2004–2010; this decreased to 7.9% in 2010–2014. In contrast, among PD patients, the annual growth rate was 2.8% in 2004–2010; this increased to 10.1% in 2010–2014.

continued from page 1

as in-center HD (3 sessions per week), Dr. Weinhandl told attendees. “So there certainly is the potential for added profit margin with peritoneal dialysis,” he said. Another reason may be the combined effect of increased acceptance of starting patients on PD and a PPS onset of dialysis adjustment during the first 120 days of dialysis, which had increased the base pay for PD by 51% from 2011 to 2015, he explained. For the study, Dr. Weinhandl and Allan J. Collins, MD, both from the University of Minnesota in Minneapolis, used data from the ESRD Network Organization Programs Summary Annual Reports for 2004– 2012 and individual ESRD Network Annual Reports for 2013 and 2014. The number of HHD patients in the United States increased from 1,529 in 2004 to 5,844 in 2010 (an increase of 282%) and 8,080 in 2014, an increase of 428% compared with 2004. The number of PD patients increased from 26,710 in 2004 to 31,867 in 2010 (an

In 2004–2010, the annual growth rate of PD surpassed that of HHD, data show. Additionally, in 2004–2010, the study showed that the HHD annual growth rates ranged from 12.5% to 41.8% across ESRD networks; in 2010–2014, the change in growth rates ranged from a decline of 2.5% to an increase of 18%. Among PD patients, growth rates ranged from a decline of 1.5% to an increase of 6.2% across ESRD networks in 2004– 2010; in 2010–2014, the rates ranged from an increase of 3.7% to 14%. n

institutions were giving students and residents narrow clinical experiences, exposing them mostly to acute care inpatients and dialysis populations, especially subsets of those populations that were most critically ill and frequently using acute care services. “Students and residents weren’t really seeing the full breadth of what we do in nephrology in the outpatient realm, in the transplantation realm, and interventional nephrology realm,” Dr. Parker said.

“The perception is that nephrologists work harder, but for relatively less money.” Another negative view of nephrology that emerged from the surveys was that the subspecialty is not adequately compensated, he said. “The perception is that nephrologists work harder, but for relatively less money,” he said.

Programs to inspire interest Through the workforce committee, the ASN started programs to inspire students “about the exciting things that there are to do in nephrology,” Dr. Parker said. The major program is Kidney TREKS (Tutored Research and Education for Kidney Scholars), whereby medical stu-

Live donor options continued from page 1

donor kidney transplantation p rovides almost twice the survival of a patient’s next best option,” lead investigator Dorry L. Segev, MD, PhD, an abdominal transplant surgeon at Johns Hopkins University School of Medicine in Baltimore, said in a university-issued press release. “This is great news for patients who have healthy, willing live donors but who have been relegated to the waiting list because of HLA incompatibilities. Through this study, we now know that those donors can donate today, those transplants can happen and those lives can be saved.” In the study, which involved 22 transplant centers, Dr. Segev and his colleagues compared survival rates among 1,025 recipients of kidneys from incompatible live donors, 5,125 patients on a transplant waiting list or received a deceased-donor kidney, and 5,125 patients on a waiting list and did not receive a deceased-donor kidney. HLA incompatibilities are not accounted for in case-mix-adjusted

Renal & Urology News 7

dents are invited to a scientific retreat at Mount Desert Island in Maine, near Bar Harbor, for about a week. Students take a course at Mount Desert Island Biologic Research Laboratory called “Origins of Renal Physiology.” In addition, the students are matched with a nephrologist mentor at their home institutions who will interact with them over the course of medical school, graduate school, or postdoctoral training. “That’s been so successful in our estimation that the ASN has invested more funding into it and we’re now going to have a second site for students to consider as an option at the University of Chicago,” Dr. Parker said. Another ASN program is Kidney STARS (Students and Residents), which is held in conjunction with Kidney Week. The goal is “to stimulate interest in nephrology careers by targeting medical students, residents, and graduate students with an interest in nephrology but have not yet committed to applying to a fellowship,” according to the society’s website. A third program is Kidney MAPS (Mentor and Assessment Program for Students), aimed at promoting interest in nephrology through student-organized community screening programs. “We developed all of these programs to try to grab students at the earliest levels, at the earliest stages of their training and nurture their interest in nephrology,” Dr. Parker said. n

benchmarks, so centers performing transplants with kidneys from incompatible donors may be subjected to regulatory scrutiny and loss of certification from the Centers for Medicare and Medicaid Services, the researchers stated. “Given such pressures, many transplant centers have avoided transplanting kidneys from incompatible live donors,” the authors wrote in their report. “However, for most sensitized patients, receiving a compatible kidney is not an option: their choice is to undergo desensitization or remain on the waiting list, which is associated with a high mortality rate.” For the study, the investigators matched each recipient of a kidney from an incompatible live donor with 5 waiting-list-or-transplant controls and 5 waiting-list-only controls. The researchers defined recipients of kidney transplants from HLA-incompatible live donors as individuals undergoing perioperative desensitization therapy for donor-specific antibodies detected prior to transplantation. Each transplant center classified the donor-specific antibody level as low, moderate, or high prior to giving a desensitization protocol. n

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Live donor continued from page 1

twice the survival of a patient’s next best option,” lead investigator Dorry L. Segev, MD, PhD, an abdominal transplant surgeon at Johns Hopkins University School of Medicine in Baltimore, said in a university-issued press release. “This is great news for patients who have healthy, willing live donors but who have been relegated to the waiting list because of HLA incompatibilities. Through this study, we now know that those donors can donate today, those transplants can happen and those lives can be saved.” In the study, which involved 22 transplant centers, Dr. Segev and his colleagues compared survival rates among 1,025 recipients of kidneys from incompatible live donors, 5,125 patients on a transplant waiting list or received a deceased-donor kidney, and

Saturation prostate Bx continued from page 1

values (69.5% vs. 72.5%, 97.6% vs. 91.9%, 58.4% vs. 64.2%, and 98.5% vs. 94.3%, respectively) in detecting high Gleason grades, the investigators reported online ahead of print in Urology. On multivariate analysis, prebiopsy serum PSA level and clinical T stage (cT2 vs. cT1) independently predicted Gleason upgrading. Saturation biopsy was not a significant predictor. Dr. Ye and colleagues pointed out some study limitations, including the use of data from a single tertiary-care academic hospital in which men with PCa were most treated by 4 urologists. “Therefore, our study results may not be representative of other urological

Frailty predictions continued from page 1

print in Urologic Oncology. “Risk stratification is especially important for RC, as most patients experience at least 1 postoperative complication within 30 days of surgery.” Chappidi’s group used the modified frailty index (mFI) to evaluate the frailty of 2,679 RC patients included in the National Surgical Quality Improvement Program database. The mFI consists of 11 risk factors identified pre-operatively, each with a score of 1. The investigators tallied the number of risk factors each patient had and used the total value as the mFI score. They divided patients into 4 groups based on mFI score:

Renal & Urology News 7

5,125 patients on a waiting list and did not receive a deceased-donor kidney. HLA incompatibilities are not accounted for in case-mix-adjusted benchmarks, so centers performing transplants with kidneys from incompatible donors may be subjected to regulatory scrutiny and loss of certification from the Centers for Medicare & Medicaid Services, the researchers stated. “Given such pressures, many transplant centers have avoided transplanting kidneys from incompatible live donors,” the authors wrote in their report. “However, for most sensitized patients, receiving a compatible kidney is not an option: their choice is to undergo desensitization or remain on the waiting list, which is associated with a high mortality rate.” For the study, the investigators matched each recipient of a kidney from an incompatible live donor with 5 waiting-list-or-transplant controls and 5 waiting-list-only controls.

The researchers defined recipients of kidney transplants from HLAincompatible live donors as individuals undergoing perioperative desensitization therapy for donor-specific anti-

bodies detected prior to transplantation. Each transplant center classified the donor-specific antibody level as low, moderate, or high prior to giving a desensitization protocol. n

practices, particularly private practice and community hospitals,” the researchers noted. In addition, the saturation biopsy approach was performed by a single urologist, whereas 12-core biopsies were performed by multiple urologists. “The operator factor could lead to differences in biopsy core quality,” the authors cautioned. The investigators defined a Gleason upgrade as the presence of high-grade tumors in RP specimens who had Gleason 3 disease only on biopsy. They defined a Gleason downgrade as final pathology of Gleason 3 disease only on RP specimens from patients who had high-grade tumors diagnosed on biopsy. The 12-core biopsy and saturation biopsy groups were similar with respect to median age at PCa diagnosis

(60 vs. 59 years). Compared with the saturation group, the 12-core group had a significantly higher proportion of African American patients than the saturation group (19.3% vs. 6.6%), a significantly higher median pre-biopsy PSA level (5.4 vs. 4.6 ng/mL), and a significantly higher proportion of patients with cT2 tumors (26.6% vs. 12.3%). The median prostate volume was significantly higher in the saturation than the 12-core group (42 vs. 36 mL). “The authors are to be congratulated for their unexpected but clinically important findings,” commented Judd W. Moul, MD, the James H. Semans, MD, Professor of Surgery at Duke University Medical Center in Durham, N.C., who was not part of the new study but has conducted research look-

ing at the correlation between biopsy and pathologic Gleason sums. Over the past few years, multiple studies have shown that about 40% of men thought to have Gleason 6 cancer on initial biopsy are upgraded if they undergo radical prostatectomy, said Dr. Moul, who also is director of the Duke Prostate Center. The new study found that the Gleason misclassification rate was about 40% regardless of whether patients had the standard 12-core or saturation biopsy. “The authors use these data to suggest that prostate MRI may improve the selection for active surveillance,” Dr. Moul said. “However, prostate MRI has yet to be proven prospectively to help improve the care of our surveillance patients.” n

0 (843 patients), 1 (1,176 patients), 2 (555 patients), and 3 or higher (105 patients). The researchers examined the relationship between mFI score and the rate of Clavien grade 4 and 5 complications.

patients who had an mFI score less than 2, those with an mFI score of 2 or higher had a significantly higher rate of Clavien grade 4 or 5 complications (14.6% vs. 8.3%) and overall mortality rate (3.5% vs. 1.8%) in the 30-day post-operative period, according to the investigators. In multivariable analysis, patients with an mFI score of 2 had a significant 1.8 times increased risk of Clavien grade 4 or 5 complications, compared with patients who had an mFI score of 0. Patients with an mFI score of 3 had a 2.6 times increased risk. In addition, patients older than 80 years had a 1.6 times increased risk of Clavien grade 4 or 5 complications and a 2.7 times increased risk of death compared with patients younger than 50 years.

“For this study, an mFI score of 2 represents a cutoff at which the highgrade postoperative complication and mortality rates significantly increased among patients,” the authors wrote. “These types of cutoffs provide clinical utility when creating future guidelines for taking care of patients who are of questionable surgical candidacy.” A cutoff above an mFI score of 2 would not be an absolute or relative contraindication to RC, but it would be an important clinical indicator that a patient may want to strongly consider potential treatment options other than RC “if oncological principles for treatment of bladder cancer would not be compromised with these alternative treatment options.” n

Researchers risk stratified patients using the modified frailty index. Overall, 1,585 patients (59%) experienced a Clavien complication. When stratified with an mFI score cutoff of 2 or higher, the overall complication rate did not differ significantly. Compared with

Incompatible Live Donor Kidneys Offer Survival Edge End-stage renal disease patients who receive a kidney from an incompatible live donor have better survival than those who remain on the kidney transplant waiting list or receive a deceased-donor kidney, a study found. 100 80

5-year survival rate

86%

75%

74.4%

8-year survival rate

62.9%

59.2% 43.9%

40 20 0

Recipients of incompatible live donor kidneys

Waiting list or recipient of deceaseddonor kidneys

Waiting list only

Source: Orandi BJ et al. Survival benefit with kidney transplants from HLA-incompatible donors. N Engl J Med. 2016;374:940-950.

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PCa Radiotherapy Ups Risk of Secondary Cancers BY NATASHA PERSAUD PROSTATE CANCER (PCa) patients treated with radiotherapy may have increased risks of bladder, colorectal, and rectal cancers, a new systematic review and meta-analysis finds. The study is not the first to show an association, but results from previous research have been mixed. So investigators led by Robert Nam, MD, of the University of Toronto, pooled results from 21 mostly large, multiinstitutional, observational studies published up to April 6, 2015. The studies compared PCa patients treated with any radiotherapy (conformal external beam, intensity modulated, brachytherapy, or a combination), regardless of dose or duration, with patients who did not undergo radiotherapy (including those who opted for surgery).

Meta-analysis shows increased likelihood of bladder, colorectal, and rectal cancers. The investigators found 67%, 79%, and 79% increased risks of cancers of the bladder, colorectum, and rectum, respectively, after radiotherapy compared with no radiotherapy or surgery. The absolute risks of these cancers were low, however, according to results published online in BMJ. The absolute rates for bladder, colorectal, and rectal cancers ranged from 0.1%– 3.8%, 0.3%–4.2%, and 0.3%–1.2%, respectively, and depended on the type of radiotherapy, control group, and lag time to secondary cancer. Dr. Nam and colleagues did not find consistent evidence for an association between radiotherapy and lung and hematologic cancers. External beam radiotherapy was associated consistently with greater risk of bladder, colorectal, and rectal cancers, while brachytherapy was not. Although the researchers did not separately analyze intensity modulated radiotherapy, they cited a study by Michael J. Zelefsky, MD, and colleagues at Memorial SloanKettering Cancer Center in New York showing no increased risk (BJU Int 2012:110:1696-1701). “It can be speculated that brachy therapy could pose a lower risk of secondary malignancy related

to radiation than external beam radiotherapy because it delivers much less integral radiation to normal tissues (outside the prostate) than external beam radiotherapy,” Dr. Nam and colleagues suggested. Some evidence suggests radiation scatter and radiation-induced genetic

alterations can occur outside the irradiated area of the prostate, they noted. With regard to clinical implications, these findings should be discussed with PCa patients who have a long life expectancy, according to the investigators and an accompanying

editorial by Christine E. Eyler, MD, a clinical fellow of the Harvard Radiation Oncology Program, and Anthony L. Zietman, MD, professor of radiation oncology at Harvard Medical School in Boston. The results also support tightly targeted external radiation techniques.

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“Perhaps most important, this study confirms our belief that second malignancy should be added to the already long list of avoidable hazards associated with treatment for those men with low risk prostate cancer who simply need no treatment at all,” Drs. Eyler and Zietman wrote. “Concern about second malignancies should not, however, stand in the way of an effective and well studied treatment being

given to men with higher grade, lethal prostate cancer for whom the potential benefit simply dwarfs the risk.” Dr. Nam and his colleagues acknowledged a moderate risk of bias in their systematic review and metaanalysis due to factors such as the lack of explicit demonstration that cancer was not present at the start of the study and the length of follow-up. The researchers noted that they lacked

important information on confounders and comorbidities and other risk factors associated with cancers other than PCa, which might be more common in patients who undergo radiotherapy. In a related development, a Canadian population-based study published online ahead of print in Cancer by Danielle Desautels, MD, of the University of Manitoba in Winnipeg, and colleagues found that the risk of

Renal & Urology News 9

colorectal cancer is increased following a PCa diagnosis, and is highest for rectal cancer among those treated with radiation. Radiotherapy was associated with a 2-fold increased risk of rectal compared with PCa cases not treated with radiation. The authors concluded that colorectal cancer screening should be considered soon after a PCa diagnosis, especially for men planning to under radiotherapy. n

T:10.875”

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Most Post-Cystectomy VTE Occurs After Discharge MORE THAN HALF of the cases of venous thromboembolism (VTE) that develop after radical cystectomy (RC) occur after hospital discharge, a study found. D. Robert Siemens, MD, and his colleagues from Queen’s University in Ontario, Canada, used the Ontario

Cancer Registry to identify 3,879 patients from the Ontario general population who underwent RC during 1994–2008. VTE occurred in 3.6% of patients within a month of their surgery, according to an analysis of hospital diagnostic codes. B:6.875” That rate rose to 4.7% at 2 months and 5.4% at 3 T:6.875”

months. A total of 55% of VTE events presented after hospital discharge. Results published online ahead of print in BJU International showed that patients who experienced VTE experienced a 35% and 27% increased odds of cancer-specific and overall mortality, respectively.

Multivariate analysis revealed that only longer length of stay (LOS) in the hospital and higher surgeon volumes were significant predictors of VTE. Compared with an LOS less than 9 days, an LOS of 9–13 days and 14 or more days was associated with a 1.5 times and 4.6 times increased odds of VTE within 30 days of RC, respectively, and a 1.4 times and 3.4 times increased odds of VTE within 90 days, respectively. Compared with patients whose surgeons were in the fourth quartile of surgical volume, patients whose surgeons were in the first, second, and third quartiles had 34%, 41%, and 33% decreased odds of VTE, respectively, within 30 days of RC, and 30%, 54%, and 12% decreased odds of VTE, respectively, within 90 days of RC.

Predictors include longer hospital LOS and higher surgeon volume.

T:9.875”

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In addition, VTE also was associated with higher surgeon volume, but that may reflect complex cases or usage of academic centers, according to the researchers. The type of urinary diversion with RC possibly plays a role, but the researchers were unable to assess it. “Although the findings in this population-based study confirmed some previous understanding of the frequency of VTE for this complex surgery, we were surprised at the number that were diagnosed after hospital discharge,” Dr. Siemens said in a press release. “Furthermore, we were unable to identify strong predictive factors associated with VTE, suggesting to us that most all patients should receive prolonged VTE prophylaxis well beyond their hospital discharge.” Until RC research reveals the optimal duration of VTE prophylaxis, the investigators recommend following guidelines for other major pelvic surgery. VTE was not linked with pathologic stage as assessed by lymph node count, an inexact marker of the extent of pelvic lymph node dissection. The findings also did not support a significant additional risk from adjuvant chemotherapy. Perioperative VTE might be a marker of more aggressive disease, the investigators suggested, warranting further research. n

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Renal & Urology News 11

National Kidney Foundation 2016 Spring Clinical Meetings Preview

Managing Anemia in Patients With Cancer and Chronic Kidney Disease The benefits of ESAs must be weighed against the increased risk of death and thrombosis Editor’s note: This article is a summary of a presentation that Dr. Berns is scheduled to give at the National Kidney Foundation’s 2016 Spring Clinical Meetings in Boston, in a Lunch Workshop session titled, “Onco-Nephrology Cancer, Chemotherapy and the Kidney,” (April 30, 11:30 a.m. to 1 p.m.).

BY JEFFREY S. BERNS, MD ANEMIA IS ONE OF the most common and clinically important complications of chronic kidney disease (CKD), due primarily to impaired synthesis of the glycoprotein hormone erythropoietin by the damaged kidneys. The approval of the first erythropoiesis-stimulating agent (ESA) epoetin alpha in the United States nearly 30 years ago drastically changed the management of anemia in patients with CKD and end-stage renal disease (ESRD). With higher hemoglobin (Hgb) levels resulting from use of supplemental iron and ESA, the need for red cell transfusion has decreased and symptoms related to severe anemia have been mitigated. While first used in patients with kidney disease, ESAs were subsequently approved for use in patients with cancer and chemotherapy-related anemia. More recently, though, concern has been raised about risks of ESA in patients with cancer, including those with CKD. ESAs and mortality risk A recent meta-analysis of randomized trials of ESAs in patients with cancer concluded that ESAs increased mortality during active study periods and decreased overall survival.1 Subsequent analyses have generally, although not

On The Web

uniformly, confirmed a higher mortality with ESAs in patients with cancer and have also identified a significantly greater risk of venous thromboembolism in these patients. The mortality risks may vary depending on the type of cancer and achieved Hgb level. Although more research is needed, there seems to be a general consensus that while ESAs do not have a proven adverse effect on cancer progression, they do increase mortality in patients with cancer (and risk of thromboembolism). The FDA-approved prescribing information for ESAs now states that their use shortens overall survival and/or increases risk of progression or recurrence of several specific malignancies, and that they should be used only for myelosuppressive chemotherapy related anemia but not when the anticipated outcome is cure. The FDA

Mortality risks may vary depending on the type of cancer and achieved Hgb level. also requires prescriber enrollment in a Risk Evaluation and Management Strategy (REMS) program when using ESAs in patients with cancer.

Darbepoetin trial raised concerns Concern about use of ESAs in patients with CKD and cancer first arose when the findings of a randomized controlled trial of darbepoetin versus placebo in patients with type 2 diabetes mellitus and CKD were reported in 2009.2 The primary composite cardiovascular endpoint and most other primary end-point

caution, if at all, in CKD patients with active malignancy, particularly when cure is anticipated, or in those with a history of cancer.5

Jeffrey S. Berns, MD

outcomes did not differ significantly between the groups, but among patients with a history of cancer who died, 14 (7.4%) of 188 died from recurrent or new cancer in the darbepoetin group compared with only 1 (0.6%) of 160 with recurrent cancer in the placebo group, a significant difference between the groups (P = 0.002). Patients with known active malignancy were excluded. In addition, there were more deaths attributed to cancer in the darbepoetin-treated patients, but this was not statistically significant (P = 0.08). While a Japanese cross-sectional study did not find ESA use to be associated with greater risk of new or worsened cancer,3 a U.S. study found ESA use in patients with CKD to be associated with a significantly greater risk of risk of stroke in those who also had cancer but not in those who did not.4 Based on these findings, the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for Anemia in CKD recommends that ESAs be used with great

Balancing benefits and risks Clinical decisions typically involve assessment of the balance between potential benefits and risks. With ESAs in cancer patients with CKD, there is the potential to reduce symptoms of severe anemia and the need for blood transfusions which must be balanced against a potential increase in the risk of mortality and thrombosis. ESAs may be appropriate to use in some patients with CKD and active malignancy or who are thought to be in remission after careful consideration of the risks. The target of ESA therapy probably should be a Hgb level of 10 g/dL or less with treatment under the FDA’s REMS Assisting Providers and cancer Patients with Risk Information for the Safe use of ESAs (APPRISE) program. ■ Jeffrey S. Berns, MD is Professor of Medicine and Pediatrics in the University of Pennsylvania’s Perelman School of Medicine in Philadelphia. REFERENCES 1. Bohlius J, Schmidlin K, Brillant C, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet 2009;373:1532-1542. 2. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361:2019-2032. 3. Imai E, Yamamoto R, Suzuki H, Watanabe T. Incidence of symptomatic stroke and cancer in chronic kidney disease patients treated with epoetins. Clin Exp Nephrol 2010;14:445-452. 4. Seliger SL, Zhang AD, Weir MR, et al. Erythropoiesisstimulating agents increase the risk of acute stroke in patients with chronic kidney disease. Kidney Int 2011; 80:288-294. 5. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int (Suppl) 2012; 2: 279–335

Go to www.renalandurologynews/NKF-spring-2016 for daily coverage of the National Kidney Foundation 2016 Spring Clinical Meetings in Boston, April 26 – May 1.

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Renal & Urology News 15

National Kidney Foundation 2016 Spring Clinical Meetings Preview

Update on the Management of ADPKD in 2016 and Beyond Studies suggest intensive blood pressure control in selected patients may slow total kidney volume growth

BY RONALD D. PERRONE, MD, FASN, FNKF AUTOSOMAL dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, affecting 1–2/1000 individuals in the general population. Growth and expansion of multiple kidney cysts results in increased volume of both kidneys, complications such as gross hematuria, cyst infection, nephrolithiasis, and pain, and the development of end-stage renal disease (ESRD) in half of affected individuals by the time they are in their mid-to-late 50s. Advances in the diagnosis and management of ADPKD are readily translatable to everyday clinical practice. Diagnosis Diagnosis of ADPKD is readily accomplished by the detection of multiple kidney cysts throughout the parenchyma using available imaging technologies, including ultrasound, computerized tomography, and magnetic resonance imaging (MRI). Refinements in the cyst number required to make a specific diagnosis by ultrasound or MRI in younger individuals with small numbers of cysts will be reviewed. In the common situation of an ADPKD family where the genotype is not known, the presence of 3 or more kidney cysts (unilateral or bilateral) is sufficient for establishing the diagnosis in individuals aged 15–39 years.1 For individuals aged 40 years or older, having no cysts or 1 cyst is sufficient to exclude the diagnosis of ADPKD. In individuals under age 30 years with a family history of ADPKD, a new study

reports that the presence of more than 10 cysts as demonstrated by MRI confers a diagnostic sensitivity and specificity of 100%.2 Quantitative criteria for individuals without a family history of ADPKD remain to be developed.

Management The completion of the HALT PKD study provides important insights to the management of hypertension in ADPKD. Intensive blood pressure (BP) control (95/60–110/75 mm Hg) versus standard BP control (120/70 –130/80 mm Hg) in HALT Study A (ages 15–49 years; estimated glomerular filtration rate [eGFR] greater than 60 mL/min/1.73 m2) using treatment based on use of the angiotensin-converting enzyme inhibitor (ACEI) lisinopril with or without the angiotensin receptor blocker (ARB) telmisartan slowed the annual rate of total kidney volume (TKV) growth by 14.2% over the 5-year study period.3 The chronic eGFR slope, after accounting for the acute drop in eGFR in the intensive BP group, was marginally reduced (P = 0.05). The HALT Study A (early PKD) and HALT Study B (advanced PKD: eGFR 25–60 mL/min/1.73 m2; ages 18–64 years)4 showed neither benefit nor increased incidence of adverse

Ronald D. Perrone, MD, FASN, FNKF

events (AKI and hyperkalemia) of combined ACEI/ARB use. These findings indicate that intensive BP control in closely monitored younger individuals with preserved eGFR is safe, reduces the rate of TKV growth, and might have a beneficial effect on eGFR. In practice, the option of more intensive BP control should only be offered to compliant individuals matching the HALT Study A entry criteria who are willing to undergo frequent home BP assessment and possibly increased frequency of laboratory assessment of eGFR and serum potassium.

Diagnosis of ADPKD is readily accomplished via the detection of multiple kidney cysts throughout the renal parenchyma on radiographic imaging.

The vasopressin receptor blocker tolvaptan was found to slow the enlargement of TKV by 50% and the rate of eGFR loss by 30%.5 Tolvaptan has not been approved by FDA for use in ADPKD. The drug cannot be used for ADPKD in the United States. Further, there is a 30-day limitation on its use due to concerns about hepatotoxicity. Tolvaptan is available for clinical use in Europe, Japan, and Canada after approval by the respective regulatory agencies. A global trial of tolvaptan in more advanced ADPKD (late stage 2 to early stage 4 CKD) is underway (REPRISE; NCT02160145). Vasopressin blockade or elimination slows progression in cystic kidney disease in animal models.6 Provision of increased water intake (2.5–3 L/day) to individuals with an eGFR greater than 30 mL/min/1.73 m2 to suppress vasopressin is a reasonable strategy in clinical practice.7 Serum sodium should be monitored, and those with risk factors for hyponatremia (preexisting hyponatremia, reduced eGFR, use of diuretics) should not have high water intake. Reduction of sodium intake to 2–3 grams per day will reduce the amount of water required to lower urine osmolarity and suppress vasopressin.

TKV, genetics, and prognosis An abundance of evidence demonstrates that a TKV greater than about 1100 cc (height-corrected TKV of 600 cc/m) predicts a high likelihood of future GFR decline.8 Evidence from the PKD Outcomes Consortium has been used to qualify TKV as a biomarker for the selection of participants for clinical studies evaluating progression of ADPKD. Large TKV in younger individuals with preserved eGFR predict an increased likelihood of the development of a 30% decline in eGFR and ESRD. Measurements of TKV are not routinely available in the clinical setting. However, an image classification system developed by investigators at the Mayo Clinic allows the relatively

Editor’s note: This article is a summary of a presentation that Dr. Perrone is scheduled to give at the National Kidney Foundation’s 2016 Spring Clinical Meetings in Boston as part of the “Updates in PKD” program (April 28, 10:00 a.m. to 11:30 a.m.).

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HD Patients Show Cognitive Deficits Neuropsychological tests show poor scores for attention and memory, meta-analysis reveals

Management of ADPKD continued from page 15

simple estimation of TKV and prediction of future GFR decline using measurements of kidney length, width and depth readily available from CT or MR images of polycystic kidneys (http:// www.mayo.edu/research/documents/ pkd-center-adpkd-classification/doc20094754).9 This classification system is applicable only to cystic kidneys with diffuse symmetrical distribution of cysts throughout the kidneys (class 1) but not those with solitary kidneys, severe atrophy, asymmetric or lopsided cyst distribution, or unilateral cystic disease (class 2). Entering kidney size measurements into the classification web form along with age, gender, and eGFR, yields an estimate of heightcorrected TKV and a rough estimate of future GFR decline. Although designed for selection of patients into clinical trials, nephrologists and patients could use such a system for estimating time to ESRD, recognizing inter-patient variability and unforeseen clinical events that could alter the accuracy of the prediction. Recent studies have clarified genetic factors impacting prognosis. It is well known that PKD1 mutations result in progression to ESRD at a younger

Impaired cognitive function can reduce health literacy and medication adherence.

School in Australia, and colleagues concluded in an online report in the American Journal of Kidney Diseases. The investigators reviewed 42 studies and pooled data from 3,522 participants for the analysis. They adjusted results

age, and larger TKV at any given age as compared to PKD2. Further classification of PKD1 mutations into truncating (which markedly reduce the amount of polycystin 1) and nontruncating (with lesser impact on the amount of functional polycystin 1) demonstrates that patients with non-

Caution must be exercised in applying risk projections to individual patients. truncating PKD1 mutations have a slower course, intermediate between that of PKD1 and PKD2 patients.10,11 The Genkyst investigators have incorporated mutation type (PKD1 truncating, PKD1 non-truncating, or PKD2) along with markers of ADPKD severity, including onset of hypertension before age 35, or first urological complication (e.g., gross hematuria) before age 35, to develop a risk assessment tool designated the PROPKD score.12 An individual with a PKD1 truncating mutation, and hypertension and first urological complication before age 35 would have the highest risk of ESRD at a younger age. An individual with a

for age, but were unable to determine the influence of education and co-existing illnesses, such as cardiovascular diseases. Many studies excluded patients with dementia; however, the investigators did consider the potential impact of aluminum-related dementia from aluminum used in dialysate. HD patients have risk factors for cognitive impairment, including hypertension, diabetes, and dyslipidemia, Dr. O’Lone and colleagues noted in the review’s background information. HD patients also are exposed to hypoxemia, fluid and osmolar shifts, fluctuating uremic toxin titers, and a proinflammatory state. These patients need cognitive skills to access health services, understand clinicians’ instructions, and make health care decisions. Impairment can reduce health literacy, medication adherence, harm health, and increase the risk of early death. Clinicians treating HD patients need to bear this in mind, especially when discussing options in renal

replacement therapy or transplantation and when educating patients about these therapies. The difference in scores between dialyzed and non-dialyzed patients suggests that cognitive deficits may be partially reversible. Previous research by the inves-

PKD2 mutation and absence of hypertension or first urological complication before age 35 would have the lowest risk of ESRD at a younger age. At present, assessment of risk for progression is most germane to recruitment of participants into clinical trials, although some patients would like to know what the future may hold. TKV, in concert with age and eGFR, can be used to assess likelihood of future decline in GFR. Genotyping is not widely available because of expense and because knowing the specific mutation does not currently impact clinical care. Caution must be exercised in applying risk projections to individual patients because of wide confidence bands for such projections and the likelihood of making erroneous predictions that potentially impact life planning and other important decisions. Nonetheless, discussions of level of risk for progression may provide a useful framework to guide management and to employ more intensive treatments (rigorous BP control, high water intake, low sodium diet) in those patients predicted to have a worse outcome. n

Tufts Medical Center and Professor of Medicine at Tufts University School of Medicine in Boston.

Ronald D. Perrone, MD, FASN, FNKF, is Associate Chief of the Division of Nephrology and Medical Director of Kidney Transplantation at

Investigators reviewed 42 studies and analyzed pooled data from 3,522 participants. tigators published in Transplantation also found cognitive improvement after kidney transplantation (2014;98:845-846). The investigators acknowledged high heterogeneity between studies due to the variety of neuropsychological tests used. They suggested future research would benefit from an agreed standard tool for measuring cognition in CKD. n

REFERENCES 1. Pei Y, Obaji J, Dupuis A, et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol. 2009;20:205-212. 2. Pei Y, Hwang Y, Conklin J, et al. Imaging-based diagnosis of autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2015;26:746-753. 3. Schrier RW, Abebe KZ, Perrone RD, et al. Blood pressure in early autosomal dominant polycystic kidney disease. N Engl J Med. 2014;371:2255-2266. 4. Torres VE, Abebe KZ, Chapman AB, et al. Angiotensin blockade in late autosomal dominant polycystic kidney disease. N Engl J Med. 2014;371:2267-2276. 5. Torres V, Chapman A, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367:2407-2418. 6. Chebib F, Sussman C, Wang X, et al. Vasopressin and disruption of calcium signalling in polycystic kidney disease. Nat Rev Nephrol. 2015;11: 451-464. 7. Torres V, Bankir L, Grantham J. A case for water in the treatment of polycystic kidney disease. Clin J Am Soc Nephrol. 2009;4:1140-1150. 8. Chapman A, Bost J, Torres V, et al. Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. CJASN. 2012;7: 479-486. 9. Irazabal M, Rangel L, Bergstralh E, et al. Imaging classification of autosomal dominant polycystic Kidney Disease: A simple model for selecting patients for clinical Trials. J Am Soc Nephrol. 2014:Epub ahead of print. 10. Heyer C, Sundsbak J, Abebe K, et al. Predicted mutation strength of nontruncating PKD1 mutations aids genotype-phenotype correlations in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2016;[Epub ahead of print]. 11. Hwang Y, Conklin J, Chan W, et al. Refining genotypephenotype correlation in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2015;Epub ahead of print. 12. Cornec-Le Gall E, Audrézet M, Rousseau A, et al. The PROPKD score: A new algorithm to predict renal survival in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2016;27:942-951.

BY NATASHA PERSAUD HEMODIALYSIS (HD) patients demonstrate impaired cognitive function, particularly in the domains of orientation and attention and executive function, a new review and meta-analysis confirms. The impairments particularly affect attention, processing speed, and working memory. HD patients’ scores on neuropsychological tests for attention and memory were worse than the general population’s, but better than scores from non-dialyzed kidney failure patients. HD patients also performed slightly worse in memory than people with non-dialysis-dependent chronic kidney disease (CKD). Data on peritoneal dialysis patients were insufficient for a meaningful comparison. “Cognitive deficits in specific domains should be further explored in this population and should be considered when approaching education and chronic disease management,” Emma O’Lone, MBChB, of Sydney Medical

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Iron-Based Binder Improves Phosphorus Control SEATTLE—New studies presented at the 2016 Annual Dialysis Conference suggest that a chewable iron-based phosphate binder can improve serum phosphorus levels in patients with hyperphosphatemia and decrease their pill burden. Linda H. Ficociello, DSc, of Fresenius Medical Care North America, and

c olleagues conducted a retrospective analysis of pharmacy data from 943 adult in-center hemodialysis patients who switched to sucroferric oxyhydroxide (SO) after using other phosphate binders. Prior to switching to SO, patients had a mean serum phosphorus level of 6.93 mg/dL (putting

13.8% of patients in-range) and took a mean number of 9.7 pills per day. After switching to SO, 25.1% of patients achieved in-range serum phosphorus levels (3.5–5.5 mg/dL, as recommended by Kidney Disease Outcomes Quality Initiative guidelines), an 81% increase. Patients’ pill burden dropped a mean

of 3.8 pills per day, a 61% decrease, Dr. Ficociello reported. Similar findings emerged in a separate and similarly conducted retrospective study of 338 peritoneal dialysis patients with hyperphosphatemia by the same research team. Before switching to SO from other phosphate binders, patients had a mean serum phosphorus level of 6.8 mg/dL (with 14.5% in-range) and took a mean 7.9 phosphate binder pills per day. After switching, the proportion of patients achieving in-range serum phosphorus rose to 26.3%, an 81% increase, and the pill burden dropped to 3.7 pills per day, a 53% decrease. n

Readmissions After RC Tied to Smoking INFECTIOUS COMPLICATIONS account for almost half of the readmissions following radical cystectomy (RC), and the risk of these complications is linked to current smoking, according to a new study. Using the American College of Surgeons National Surgical Quality Improvement Program database, Sij Hemal, MD, of the Wake Forest School of Medicine in Winston-Salem, N.C., and colleagues analyzed data from 961 patients who underwent RC for bladder, of whom 159 (17%) required readmission at a median of 16 days post-RC. Of the 159 patients, 71 (45%) were readmitted for infectious complications, Dr. Hemal’s group reported online in Therapeutic Advances in Urology. Smoking was more significantly common in patients readmitted because of infectious complications compared with those readmitted for a non-infectious complication (37% vs. 25%). Smoking was independently associated with a significant 2.3 times increased odds of post-RC readmission due to an infectious cause. “Counseling patients in smoking cessation prior to the procedure may provide an avenue for quality improvement to limit readmissions,” the authors wrote. n

www.renalandurologynews.com APRIL 2016

MEN WHO TAKE finasteride to reduce prostate size or promote hair growth are less likely to be diagnosed with bladder cancer than men who do not use the medication, according to recent novel findings. A team led by Michael A. Liss, MD, of University of Texas Health Science Center at San Antonio analyzed data from 72,370 men who participated in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial and met the researchers’ study inclusion criteria. Of these, 6,069 (8.4%) reported using finasteride. Bladder cancer was diagnosed in 65 (1.07%) of the 6,069 finasteride versus 966 (1.46%) of the 66,301 of those who reported no use of finasteride during the trial, Dr. Liss and his colleagues reported in European Urology (2016;69:407-410). In analyses that controlled for age and smoking, self-reported finasteride use was associated with a significant 37% decreased risk of bladder cancer.

The malignancy was 37% less likely to be diagnosed in men who used the drug. The findings are the first from a largescale trial to demonstrate a possible preventive or therapeutic role of finasteride for bladder cancer, the authors stated. Dr. Liss’ group noted hat their study was limited by its observational design, lack of available data on many confounding variables for bladder cancer, such as alcohol use, and the reliance on annual self-reported use of finasteride, which is subject to missing values and error. The authors pointed out that finasteride use may have reduced lower urinary tract symptoms and/or microscopic hematuria and thus decreased the rate of cystoscopy. Commenting on the study in an accompanying editorial (pp.411-412), Carlo La Vecchia, MD, of the University of Milan in Italy, stated: “Repetition of its findings using either a case-control approach including an adequate number of relevant covariates or, more likely, a record-linage approach with large regional or national administrative databases … is required to confirm the inverse association between finasteride and bladder cancer.” n

Statin Therapy Does Not Stop Progression to Kidney Failure Statins do appear to reduce proteinuria and mortality in CKD patients BY NATASHA PERSAUD STATIN USE by patients with chronic kidney disease (CKD) does not lower the likelihood of progression to kidney failure, but it appears to decrease proteinuria and all-mortality, according to recent meta-analyses. A meta-analysis by Zhenhong Zhang, MD, Pinsheng Wu, MD, and colleagues at Southern Medical University in China pooled data from 23 randomized controlled trials (1995–2014) including 39,419 participants with CKD. The causes of CKD included diabetes, hypertension, glomerulonephritis, autosomal dominant polycystic kidney disease, idiopathic membranous nephropathy, and metabolic syndrome. Eight types of statins were examined. According to results published online in Pharmacological Research, statins decreased proteinuria, reducing 24-hour urinary protein excretion by 682.68 mg daily compared with controls. Statin treatment reduced allcause mortality by 22%. Statin use lowered the urine albumin excretion ratio by 26.73 µg/min compared with controls. Statins provide podocyte protection, prevention of tuberinterstitial injury, and improvement of endothelial dysfunction, the investigators noted; however, use of large dose statins may raise microalbuminuria due to reduced protein trafficking across tubular cells. “Statins unquestionably reduce the risk of death in populations with, or at low risk of cardiovascular disease,” the researchers stated. “Our study further indicated that statins had the same effect on non-end stage CKD.” Notably, statins did not reduce renal health events, including kidney failure leading to dialysis or transplantation, a doubling of creatinine level, or halving of glomerular filtration rate (GFR). “These findings support the recommendations in the present guidelines for the use of statins in hyperlipidaemic early stage CKD patients,” the researchers concluded. Several recent meta-analyses support this finding. For example, statin therapy reduced major cardiovascular events by 18% in CKD patients with coronary diseases and by 23% in those with CKD only, according to an analysis by

Although statin use by CKD patients did not lower the risk of kidney failure, it was associated with slower declines in estimated glomerular filtration rates, according to a meta-analysis.

Hou Wanyin Hou, MD, and colleagues published in the European Heart Journal (2013;34:1807-1817). A study by Giovanni F. M. Strippoli, MD, and colleagues published in BMJ (2008;336:645-651) similarly indicated that statins reduce fatal and non-fatal cardiovascular events by 19% and 23%, respectively. Evidence for renoprotective effects has been mixed. With regard to limitations of the current analysis, the researchers observed that variation in populations and interventions, such as the type of statin and dosage, may have influenced the results. In a meta-analysis published online ahead of print in the American Journal of Kidney Diseases, Xiaole Su, MD, and colleagues from Peking University in Beijing, pooled data from 57 randomized controlled trials involving 143,888 adult patients with and without non-dialysis CKD. Most trials compared statins with placebo or usual care; 6 compared statins of various types; and 3 compared different doses of the same statin. Patients took statins for at least 6 months. Statin treatment did not reduce the risk of kidney failure events, including a 25%–50% decrease in eGFR, doubling of serum creatinine level, or end-stage renal disease. Compared with controls, statin users experienced a 0.41 mL/ min/1.73m2 per year slower decline in eGFR and a decline in proteinuria or albuminuria of 0.65 standard deviation units. Statin use had no adverse effects on the kidneys. Consistent with previous research, statin therapy did reduce cardiovascular events, such as myocardial infarction,

stroke, cardiovascular death, and heart failure, in CKD patients by 31%. “Although this study did not show clear renal benefits, the lack of evidence for an adverse effect of statin on kidney outcomes is important, particularly in light of the clear cardiovascular benefits of statins,” the authors wrote. The findings are in line with the Study of Heart and Renal Protection (SHARP), a large trial of 6,245 patients with advanced CKD that found statins did not reduce kidney failure risk or rate of eGFR decline. Other notable research failed to examine clinically relevant renal outcomes. “To our knowledge, the current study represents the largest systematic review of statin administration on kidney disease progression and the first meta-analysis that evaluates the effect of statin treatment on kidney failure events,” Dr. Su’s group stated. Dr. Su and colleagues acknowledged that their review might not be the “final answer” as to whether lowering low-density lipoprotein cholesterol levels with statins would slow progression of kidney disease. Evidence supports dyslipidemia as a risk factor for CKD development or progression. Intensive lipid lowering might reduce the risk for kidney failure compared with the usual dose of statins, they noted. Individual statin medications also may differ in the degree of kidney protection they offer. In the trials examined by Dr. Su’s team, atorvastatin showed the greatest renal benefit, and atorvastatin, pravastatin, and simvastatin showed a trend toward benefit. n

Finasteride May Cut Risk of Bladder CA

Renal & Urology News 19

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■ Special to Renal & Urology News

CMS uses CROWNWeb for reporting clinical depression screening and pain assessment data For Payment Year 2018, CMS will review submitted data to analyze whether dialysis facilities screened patients for clinical depression and whether a follow-up plan was documented BY ONIEL DELVA, BA IN OCTOBER 2015, the Centers for Medicare & Medicaid Services (CMS) expanded the use of its CROWNWeb data collection system by presenting the end-stage renal disease (ESRD) community with a means to capture data on clinical depression screening and pain assessment efforts. Depression affects millions around the world, regardless of age, race, gender, or ethnic background. Furthermore, dealing with the factors that come with having stage 5 chronic kidney failure can add to renal patients’ burden. Depression is a common, under-recognized, and undertreated problem that is independently associated with increased morbidity and mortality in chronic kidney disease patients.1 Furthermore, studies have shown that pain is a significant problem for more than 50% of patients with ESRD, and up to 82% of those patients report moderate to severe chronic pain.2 CMS is interested in whether and how Medicare-certified dialysis providers perform pain assessment and clinical depression screening. To analyze these important issues, CMS incorporated “Clinical Depression Screening and Follow-Up” and “Pain Assessment and Follow-Up” as new reporting measures in the agency’s Payment Year (PY) 2018 ESRD Quality Incentive Program (ESRD QIP). CROWNWeb and the ESRD QIP To comply with these new reporting measures, authorized facility representatives are required to use CROWNWeb to indicate, for each qualified patient, whether they conducted a pain assessment and a clinical depression screening during the performance period, and whether a patient was referred for follow-up for either of these conditions.

Since the early developmental stages of CROWNWeb, CMS envisioned this system serving as a tool that could be used across multiple platforms to support data reporting needs. CROWNWeb serves as the ESRD patient registry and quality reporting system, and supports a multitude of CMS initiatives, including the agency’s Quality Strategy, CMS’ Three Aims for the ESRD Network Program, and the ESRD QIP. CROWNWeb has evolved over the years to include data reporting fields and functionalities that directly support ongoing changes to the ESRD QIP and facilities’ ability to meet the requirements of these programs. PY 2018 of the ESRD QIP presents the latest change to the ESRD QIP and CROWNWeb. The Clinical screen in CROWNWeb has been updated to enable users to report pain assessment and clinical depression screening data via a “Patient Reporting” tab.

Clinical Depression Screening and Follow-Up According to CMS, nearly 30% of beneficiaries with ESRD experience significant symptoms of depression, which can lead to low energy, fatigue, sleep disturbance, and anorexia.3 Additionally, according to Paul L. Kimmel, MD, of the Division of Renal Diseases and Hypertension at George Washington University Medical Center, depression is the most common psychological disorder in patients with ESRD.4 With a focus on working toward improving outcomes in patients’ mental health and to promote person- and family-centered care, CMS adopted a depression measure for PY 2018 of the ESRD QIP that is based on National Quality Forum (NQF)-endorsed measure #0418, “Preventive Care and Screening: Screening for Clinical Depression and Follow-Up Plan.”

Under the Screening for Clinical Depression and Follow-Up reporting measure, authorized facility representatives are required to use CROWNWeb annually to indicate, for each qualified patient, the outcome of a clinical depression screening and whether a follow-up plan is documented. For PY 2018, CMS will review submitted data to analyze whether facilities screened patients for clinical depression and whether a follow-up plan was documented. In support of PY 2018, facility representatives must use CROWNWeb to report one of the following conditions for each eligible patient at least once between January 1, 2016 and January 31, 2017: • Screening for clinical depression is documented as being positive, and a follow-up plan is documented • Screening for clinical depression is documented as positive, a followup plan is not documented, and the facility possesses documentation stating the patient is not eligible for depression screening • Screening for clinical depression is documented as positive, the facility possesses no documentation of a follow-up plan, and no reason is given • Screening for clinical depression is documented as negative, and a follow-up plan is not required • Screening for clinical depression is not documented, but the facility possesses documentation stating the patient is not eligible for depression screening • Clinical depression screening is not documented, and no reason is given.5

Defining Positive vs. Negative and Eligibility According to CMS, positive and negative as they pertain to clinical depression documentation are defined as:3

• Positive—Based on the scoring and interpretation of the specific standardized tool used, and through discussion during the patient visit, a health professional has determined that the patient is deemed positive for signs of depression • Negative—Based on the scoring and interpretation of the specific standardized tool used, and through discussion during the patient visit, a health professional has determined that the patient is deemed negative for signs of depression Additionally, not all patients will be eligible for follow-up or screening, even if they are otherwise eligible for the measure. The following criteria are used to determine if a patient is not eligible for follow-up or screening:3 • Not eligible for follow-up—The patient is not eligible for a followup plan, or it is not appropriate for the patient to undergo treatment for depression because such treatment is medically contraindicated • Not eligible for screening—The patient is not eligible for depression screening if one or more of the following reasons are documented in the patient’s medical record: —— Patient refuses to participate —— Patient is in an urgent or emergent situation where time is of the essence and to delay treatment would jeopardize the patient’s health status —— Situations where the patient’s motivation to improve may impact the accuracy of results of nationally recognized standardized depression assessment tools. For example: certain court appointed cases —— Patient was referred with a diagnosis of depression —— Patient has been participating in on-going treatment with

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February 13, 2015 SelectingConditions Conditions n CROWNWeb for Patients Eligible the Depression Screening andUp Follow Up Measure Selecting in iCROWNWeb for Patients Eligible for thefor Depression Screening and Follow Measure February 13, 2015 Pertains only to m easure eligble patients (I.e., 1. F acilities with a CCN o pen date after July 1, 2016; 2. F acilities treating fewer than 11 qualifying p atients during the performance period; 3. Patients who are younger than age 12; 4. Patients treated at the facility fo r fewer than 90 days

Start

Based on the scoring and interpretation of the specific Standardized tool u sed, and at the discretion of the treating pro vider. R ationale for reaching a particular conclusion is documented in the m edical record.

Follow Up plan Prescribed and Documented

Positive

Yes

Condition 1 Screening for clinical depression is documented as being positive, and a follow-‐up plan is documented

Condition 2 A normalized and v alidated depression screening tool developed for the patient population in which it is being utilized. The name of the age appropriate standardized depression screening tool utilized m ust be documented in the m edical record.

Depression Screening conducted and Documented using a standardized screening tool

A patient is not eligible to undergo treatment or therapy for depression w hen such treatments are medically contraindicated. Reason for ineligibility is documented in the medical record.

Yes

Documentation that patient is Ineligible f or Follow up

Yes

Screening for clinical depression documented as positive, and a f ollow-‐ up plan not documented, and the facility possess do cumentatio n stating the patient i s not eligible

Condition 3 No

Negative No

Screening for clinical depression documented as positive, the facility possesses no documentation o f a follow-‐up plan, and no reason is given

Condition 4

No follow up plan i s required

Documentation that patient is not eligible f or Depression Screening

Screening for clinical depression is documented as negative, and a f ollow-‐ up plan is no t required

Condition 5 Screening for clinical depression not documented, but the facility possesses documentation stating the patient is not eligible

Yes

Condition 6 No

No reason is given

Clinical depression screening not documented, and no reason is given

FIGURE 1: Clinical Depression Screening and Follow-Up Decision Tree. screening of clinical depression in a preceding reporting period — Severe mental and/or physical incapacity where the person is unable to express himself/herself in a manner understood by others. For example: cases such as delirium or severe cognitive impairment, where depression cannot be accurately assessed through use of nationally recognized standardized depression assessment tools Justification for any of these findings should be documented in the patient’s medical record.3 Figure 1 gives an overview of the decision tree users should follow when reporting clinical depression screening and follow-up data to CROWNWeb.

Pain Assessment and Follow-Up Pain is one of the most common symptoms in patients with ESRD.6 Based on this fact, and the findings of clinical

studies, CMS identified a need to incorporate a measure as part of the ESRD QIP that determines whether facilities regularly assess their patients’ pain, and whether they develop follow-up plans as necessary. Recognizing that this measure would address a need indicated by the National Quality Strategy (NQS) (http:// www.ahrq.gov/workingforquality/), CMS adopted a pain measure for PY 2018 of the ESRD QIP that is based on NQF-endorsed measure #0420, “Pain Assessment and Follow-Up.” Under the Pain Assessment and Follow-Up reporting measure, authorized facility representatives must use CROWNWeb to report one of the following conditions for each eligible patient once between January 1, 2016 and July 31, 2016, and once between July 1, 2016 and January 31, 2017: • Pain assessment using a standardized tool is documented as positive and a follow-up plan is documented

• Pain assessment is documented as positive, a follow-up plan is not documented, and the facility possesses documentation that the patient is not eligible for a pain assessment • Pain assessment is documented as positive using a standardized tool, a follow-up plan is not documented, and no reason is given • Pain assessment using a standardized tool is documented as negative, and no follow-up plan required • No documentation of pain assessment, and the facility possesses documentation the patient is not eligible for a pain assessment using a standardized tool • No documentation of pain assessment, and no reason is given.5

Defining Positive vs. Negative and Eligibility According to CMS, positive and negative as they pertain to pain assessment documentation are defined as:3

• Positive—Based on the scoring and interpretation of the specific standardized tool used, and through discussion during the patient visit, the provider should determine if the patient is deemed positive for pain. • Negative—Based on the scoring and interpretation of the specific standardized tool used, and through discussion during the patient visit, the provider should determine if the patient is deemed negative for pain. Additionally, not all patients will be eligible for follow-up or assessment, even if they are otherwise eligible for the measure. The following criteria are used to determine if a patient is not eligible for follow-up or assessment:3 • Not eligible for follow-up—A patient may not be eligible for followup plan, or it may not be appropriate for a patient to undergo treatment or therapy for pain because such treatments are medically contraindicated.

IMAGE COURTESY OF THE ESRD QIP

A patient is not eligible for screening if one or more of the following conditions are documented in the medical record: Patient refuses to participate, Patient is in an urgent or emergent situation where time is of the essence and to delay treatment would jeopardize the patient’s health status, Situations where the patient’s functional capacity or motivation to improve may impact the accuracy of results of standardized depression assessment tools. For example: certain court appointed cases or cases of delirium Patient has an active diagnosis of Depression Patient has a diagnosed Bipolar Disorder

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Selecting Conditions in CROWNWeb for Patients Eligible for the Pain Assessment and Follow Up Measure

13, 2015February 13, 2015 Selecting Conditions in CROWNWeb for Patients Eligible for the Pain Assessment and Follow UpFebruary Measure

Examples of standardized assessment tools include but are not limited to the following: The Brief Pain Inventory (BPI); Faces Pain S cale (FPS); McGill Pain Questionnaire (MPQ); Multidimensional P ain Inventory (MPI); Neuropathic P ain S cale (NPS); Numeric R ating S cale (NRS); Oswestry D isability Index (ODI); Roland Morris Disability Questionnaire (RMDQ); Verbal D escriptor S cale (VDS); Verbal Numeric Rating Scale (VNRS); and Visual AnalogScale (VAS). The name of the standardized assessment tool utilized must be documented in the medical record.

A patient is not eligible if one or m ore of the following reason(s) is documented in the m edical record: S evere mental and/or p hysical incapacity where the person is u nable t o express himself/herself in a m anner u nderstood by o thers. F or example, cases where pain cannot b e accurately assessed through use of n ationally recognized standardized pain assessment tools, Patient is in an urgent or emergent situation w here time is of the essence and to d elay treatment would jeopardize the patient’s h ealth status

Start

Pain Assessment conducted and Documented using a standardized a ssessment tool

Follow Up plan Prescribed and Documented

Positive

Yes

A patient is not eligible to undergo treatment or therapy for p ain w hen such treatments are m edically contraindicated. R eason for ineligibility is documented in t he medical record.

Yes

Condition 1 Pain assessment using a standardized tool i s documented as positive and a f ollow-‐up plan is documented

Condition 2

Documentation that patient is Ineligible f or Follow up

Yes

Pain assessment documented as positive, a follow-‐up plan is not documented, and the facility possesses documentation that the patient is not eligible

Condition 3 Pain assessment documented as positive using a standardized tool, a follow-‐up plan is not documented, and no reason is given

No Negative

Condition 4

Pain assessment using a standardized tool i s documented as negative, and no f ollow-‐up plan required

No follow up plan i s required

Condition 5 Documentation that patient is not eligible for Pain Assessment

No documentation of pain assessment, and the facility possesses documentation the patient is not eligible f or a pain assessment using a standardized tool

Yes

Condition 6 No

No documentation of pain assessment, and no reason is given

No reason is given

FIGURE 2: Pain Assessment and Follow-Up Decision Tree. • Not eligible for assessment—The patient is not eligible for pain assessment if one or more of the following reasons are documented in the patient’s medical record: — Severe mental and/or physical incapacity where the person is unable to express himself/ herself in a manner understood by others. For example, cases where pain cannot be accurately assessed through use of nationally recognized standardized pain assessment tools — Patient is in an urgent or emergent situation where time is of the essence and to delay treatment would jeopardize the patient’s health status Justification for any of these findings should be documented in the patient’s medical record.3 Figure 2 gives an overview of the decision tree users should follow when

reporting pain assessment and followup data to CROWNWeb. ■ The work on which this publication was performed under Contract Number HHSM-500-2015-00511G, titled “CROWNWeb Outreach, Communications, and Training,” funded by the Centers for Medicare & Medicaid

Services, Department of Health and Human Services, Janis Grady, CMS COR. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.

For more Information • Further information regarding the ESRD QIP can be obtained from http://www. cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/ESRDQIP/ index.html, which provides a wide variety of information including answers to

Frequently Asked Questions, detailed discussions about the rules for each PY, samples of facility’s Performance Score Certificates, and other helpful references. • ESRD QIP technical specifications can be accessed at http://www.cms.gov/ Medicare/Quality-Initiatives-Patient-Assessment-Instruments/ESRDQIP/061_ TechnicalSpecifications.html.

• Additionally, questions regarding the program can be sent to CMS’s ESRD QIP team at ESRDQIP@cms.hhs.gov.

REFERENCES: 1. Hedayati, S. Susan et. al. A practical approach to the treatment of depression in patients with chronic kidney disease and end-stage renal disease. (2012). Kidney International. Vol. 81, 247 –255. Retrieved February 2, 2016 from http://www.nature.com/ki/ journal/v81/n3/full/ki2011358a.html. 2. Davison, Sarah N. Pain in hemodialysis patients: prevalence, cause, severity, and management. American Journal of Kidney Disease. (2003). Vol. 42, Issue 6, 1239-1247. Retrieved on February 2, 2016, from http://www.ajkd.org/article/S02726386(03)01112-0/fulltext. 3. Centers for Medicare & Medicaid Services. Addressing Depression in Dialysis Patients: A New ESRD QIP Reporting Initiative. (2015). Retrieved February 2, 2016, from https://www.cms.gov/Medicare/QualityInitiatives-Patient-Assessment-Instruments/ESRDQIP/ Downloads/ESRD-QIP-Policy-Update-and-DepressionScreening-CMS-Quality-Conference-v1_5-508.pdf. 4. Kimmel, Paul L. and Rolf A. Peterson. Depression in Patients with End-Stage Renal Disease Treated with Dialysis: Has the Time to Treat Arrived? (2006). Retrieved on February 2, 2016, from http://cjasn. asnjournals.org/content/1/3/349.full. 5. Centers for Medicare & Medicaid Services. Final Measure Specifications for the PY 2018 ESRD QIP. (2014). Retrieved February 2, 2016, from http:// www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/ESRDQIP/Downloads/ESRDQIPPY2018finaltechnicalmeasurespecifications-.pdf. 6. Cohen, S. D., Patel, et al. Pain, sleep disturbance, and quality of life in patients with chronic kidney disease. (2007). Clinical Journal of the American Society of Nephrology, Vol. 2 Number 5, 919-925. Retrieved on February 2, 2016, from http://cjasn. asnjournals.org/content/2/5/919.long.

IMAGE COURTESY OF THE ESRD QIP

Pertains only to m easure eligble patients (I.e., 1. F acilities with a CCN o pen date after July 1, 2016; 2. F acilities treating fewer than 11 qualifying p atients during the performance period; 3. Patients who are younger than age 18; 4. Patients treated at the facility for fewer than 90 days

Based on the scoring and interpretation of the specific Standardized tool u sed, and at the discretion of the treating provider. R ationale f or reaching a particular conclusion is documented in the m edical record.

For men with mCRPC who have progressed on ADT

Z Y T I G A® & P R E D N I S O N E

LET’S STRONG

THIS

TOGETHER

INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. mCRPC = metastatic castration-resistant prostate cancer; ADT = androgen-deprivation therapy.

Please see additional Important Safety Information on the next pages. Please see brief summary of full Prescribing Information on subsequent pages.

For men with mCRPC who have progressed on ADT

ZYTIGA® & PREDNISONE: (abiraterone acetate)

In the final analysis of the pivotal phase 3 trial*…

ZYTIGA® + prednisone achieved a median OS of almost 3 years (34.7 months) after a median 4 years (49 months) of follow-up† 4.4 months improvement in median overall survival—34.7 months with ZYTIGA® + prednisone vs 30.3 months with placebo + prednisone (active compound)‡ — Co-primary end point—median OS: hazard ratio (HR)=0.81; 95% CI: 0.70, 0.93; P=0.0033 Co-primary end point—at the prespecified rPFS analysis, median not reached for ZYTIGA® + prednisone vs a median of 8.28 months for placebo + prednisone; HR=0.425; 95% CI: 0.347, 0.522; P<0.0001§II

IMPORTANT SAFETY INFORMATION Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. continued on next page

Please see brief summary of full Prescribing Information on subsequent pages.

Let’s do this Prespecified secondary end point¶

ZYTIGA® + prednisone significantly delayed median time to initiation of cytotoxic chemotherapy ZYTIGA® + prednisone vs placebo + prednisone: 25.2 vs 16.8 MONTHS Secondary end point—HR=0.580; 95% CI: 0.487, 0.691; P<0.0001

IMPORTANT SAFETY INFORMATION—continued

Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

034441-150514

Drug Interactions—continued ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In a CYP2C8 drug interaction trial in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA®. Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA®.

OS = overall survival; rPFS = radiographic progression-free survival. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, doubleblind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were OS and rPFS. Select exclusion criteria included aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥2.5X ULN, liver metastases, moderate or severe pain, opiate use for cancer pain, prior ketoconazole treatment for prostate cancer, a history of adrenal gland or pituitary disorders, and visceral organ metastases. Concurrent use of spironolactone was not allowed during the study period. † At a prespecified final analysis for OS, 65% (354/546) of patients treated with ZYTIGA® + prednisone compared with 71% (387/542) of patients treated with placebo + prednisone had died. ‡

Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

rPFS was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 [PCWG2] criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally reviewed radiographic assessment of progression.

II At the prespecified rPFS analysis, 150 (28%) of patients treated with ZYTIGA® + prednisone and 251 (46%) of patients treated with placebo + prednisone had radiographic progression. ¶ The secondary efficacy analysis presented here is as of the December 20, 2011, cutoff date.1

Reference: 1. Data on file. Janssen Biotech, Inc.

Learn more today at www.zytigahcp.com

STRONG T O G E T H E R

500 Film-Coated Tablets

Janssen Biotech, Inc. ÂŠ Janssen Biotech, Inc. 2016 1/16 042935-151105

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with Z YTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking Z YTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced Z YTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with Z YTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions]. • Adrenocortical Insufficiency [see Warnings and Precautions]. • Hepatotoxicity [see Warnings and Precautions].

ZYTIGA® (abiraterone acetate) Tablets Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 Z YTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients. The most common adverse reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months. Table 1: Adverse Reactions due to Z YTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications 5.9 1.4 2.3 0 Fractures5 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 2.3 1.9 1.0 0.3 Cardiac failure8 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture

ZYTIGA® (abiraterone acetate) Tablets

6 Includes

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: A dverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Table 4: L aboratory Abnormalities in >15% of Patients in the Z YTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking Z YTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis. Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis. DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information]. Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA [see Clinical Pharmacology (12.3) in full Prescribing Information].

ZYTIGA® (abiraterone acetate) Tablets

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. Z YTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. Nursing Mothers: Z YTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving ZYTIGA in Phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of Z YTIGA increased by approximately 1.1‑fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of Z YTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE Human experience of overdose with ZYTIGA is limited. There is no specific antidote. In the event of an overdose, stop Z YTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, Z YTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with Z YTIGA and prednisone. • Patients should be informed that ZYTIGA should not be taken with food and that no food should be consumed for at least two hours before the dose of Z YTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. ZYTIGA is taken once daily and • Patients should be informed that prednisone is taken twice daily according to their physician’s instructions. • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician. • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 ©Janssen Biotech, Inc. 2012 Revised: Dec 2015 044724-151215