Renal & Urology News - August 2016 issue

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VOLUME 15, ISSUE NUMBER 6

Study Links ESRD to Red Meat Intake

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DIETARY CHANGES MAY LOWER RISK According to researchers, replacing 1 serving of red meat with other food items can decrease the risk of end-stage renal disease. Shown here are the ESRD risk reductions.

High dietary acid load cited as a potential explanation

IN THIS ISSUE 11

Empagliflozin found to slow kidney disease progression in diabetics

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Risk factors for fractures in kidney transplant recipients identified

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Low magnesium in hemodialysis patients linked to PPIs

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Delayed RRT for acute kidney injury does not increase mortality

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Patiromer lowers aldosterone in CKD patients with hyperkalemia

Significant prostate cancer may be less likely with higher selenium intake.

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Nephrology. Consumption of poultry, fish, eggs, or dairy products was not associated with ESRD risk.

In addition, the investigators found that substituting 1 serving of red meat with poultry or fish resulted in a 62.4% and 48.6% reduction in ESRD risk, respectively. Replacing 1 serving of red meat with soy and legumes or eggs was associated with a 50.4% and 44.9% reduction in ESRD risk, respectively.

“We embarked on our study to see what advice should be given to CKD patients or to the general population worried about their kidney health

Sarcopenia Ups Waitlist Death Risk

BY JODY A. CHARNOW GREATER MUSCLE density is independently associated with lower mortality among waitlisted kidney transplant candidates, researchers reported at the 2016 American Transplant Congress (ATC) in Boston.

“Our results suggest that radiologic measures of sarcopenia, such as lean muscle mass versus adiposity, improve mortality risk prediction among waitlisted ESRD [end-stage renal disease] patients,” said lead investigator Jayme E. Locke, MD, MPH, Assistant Professor of Surgery and Director of Transplant Analytics, Informatics & continued on page 8

Poultry

62.4%

Fish

Soy/ legumes

48.6%

50.4%

Eggs

44.9%

© PHOTO CREDIT

BY JODY A. CHARNOW GREATER RED MEAT consumption is associated with an increased risk of end-stage renal disease (ESRD), new finding suggest.

Individuals in the highest quartile of red meat intake have a 40% increased risk of ESRD compared with those in the lowest quartile, researchers led

by Woon-Puay Koh, MBBS, PhD, of Duke-NUS Medical School and Saw Swee Hock School of Public Health at the National University of Singapore reported online ahead of print in the Journal of the American Society of

Source: Lew QJ et al. Red meat intake and risk of ESRD. J Am Soc Nephrol 2016; published online ahead of print.

regarding types or sources of protein intake,” Dr. Koh said in a press release from the American Society of Nephrology. “Our findings suggest that these individuals can still maintain protein intake but consider switching to plant-based sources; however, if they

still choose to eat meat, fish/shellfish and poultry are better alternatives to red meat.”

Dr. Koh and colleagues studied 60,198 Chinese adults who participated in the prospective Singapore Chinese continued on page 8

Metformin Protective in NMIBC

BY JODY A. CHARNOW METFORMIN USE decreases the risk of grade progression in patients with non-muscle invasive bladder cancer (NMIBC), but it does not impact disease-specific survival, according to the findings of separate studies presented at the Canadian Urological Association 2016 annual meeting in Vancouver.

Samer L. Traboulsi, MD, and colleagues at McGill University Health Centre in Montreal conducted a retrospective analysis of 1356 NMIBC patients with a median age of 69.5 years. The cohort consisted of 1197 patients (88.3%) without diabetes, 93 patients (6.9%) with diabetes on

metformin, and 66 patients (4.9%) with diabetes and not on metformin who served as a reference group.

In multivariate analysis, metformin use was not associated with disease recurrence and stage and disease progression, but it was associated with a significant 68% decreased risk of grade progression compared with the reference group. In addition, patients without diabetes had a significant 42% lower risk for disease progression compared with the reference group.

“Investigations in clinical trials are needed to show whether metformin mitigates the deleterious effect of diabetes continued on page 8

MUTATIONS AND METASTATIC PCa

Study implicates genes that maintain DNA integrity PAGE 25

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Metformin Helps NMIBC Patients

IN THIS ISSUE 10

Erectile dysfunction predicts an increased risk of osteoporosis

11

Low socioeconomic status ups risk of invasive penile cancer

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Novel oral testosterone formulation shows long-term safety

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Current smokers face delayed continence recovery after RARP

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Selenium may lower the risk of aggressive prostate cancer

Significant prostate cancer may be less likely with higher selenium intake.

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(6.9%) with diabetes on metformin, and 66 patients (4.9%) with diabetes and not on metformin who served as a reference group.

In multivariate analysis, metformin use was not associated with disease recurrence and stage and disease progression, but it was associated with a significant 68% decreased risk of grade progression compared with the reference group. In addition, patients without diabetes had a significant 42% lower risk for disease progression compared with the reference group.

“Investigations in clinical trials are needed to show whether metformin

Dutasteride Lowers Biopsy UTI Risk

BY JODY A. CHARNOW SAN DIEGO—Dutasteride use is associated with a decreased risk of urinary tract infection (UTI) and related hospitalizations resulting from transrectal prostate biopsy, researchers reported at the American Urological Association 2016 annual meeting.

Daniel M. Moreira, MD, of Mayo Clinic in Rochester, Minnesota, and colleagues retrospectively studied the effect of dutasteride on transrectal prostate biopsy-associated UTI (TPBA-UTI) in a cohort of 6422 men aged 50–75 years with a PSA level of 2.5–10 ng/mL. The men were participants in the REDUCE continued on page 8

© DR. P. MARAZZI / SCIENCE SOURCE

BY JODY A. CHARNOW METFORMIN USE decreases the risk of grade progression in patients with non-muscle invasive bladder cancer (NMIBC), but it does not impact disease-specific survival, according to the findings of separate studies presented at the Canadian Urological Association 2016 annual meeting in Vancouver.

Samer L. Traboulsi, MD, and colleagues at McGill University Health Centre in Montreal conducted a retrospective analysis of 1356 NMIBC patients with a median age of 69.5 years.

The cohort consisted of 1197 patients (88.3%) without diabetes, 93 patients

© PHOTO CREDIT

Researchers find lower grade progression risk

METFORMIN PROTECTS against grade progression in non-muscle invasive bladder cancer.

mitigates the deleterious effect of diabetes on stage progression,” Dr. Traboulsi’s group concluded in a poster presentation.

In the other study, Patrick Richard, MD, and colleagues at the University of Toronto found that that cumula-

tive use of metformin does not impact disease-specific or overall survival among diabetic patients with NMIBC. Using administrative databases, the investigators conducted a retrospective, population-based study that included continued on page 8

PD-1 Blockade Works in mCRPC FOR THE FIRST TIME, a study has provided evidence of meaningful clinical activity for programmed death 1 (PD-1) blockade in men with metastatic castration-resistant prostate cancer (mCRPC), according to a new report.

In an ongoing phase 2 study, a team led by Julie N. Graff, MD, of the Oregon Health & Science University (OHSU) Knight Cancer Institute in Portland, observed robust responses to treatment with pembrolizumab, a monoclonal antibody that binds to the PD-1 receptor, among 3 of the first 10 men with enzalutamide-resistant mCRPC enrolled in the study. All 3

experienced rapid drops in PSA level to below 0.1 ng/mL after treatment, Dr. Graff and her colleagues reported in Oncotarget. At enrollment, the men had PSA levels of 46, 71, and 2503 ng/mL. The investigators noted that currently approved agents for mCRCP generally do not produce PSA reductions to 0.2 ng/mL or below after enzalutamide is no longer effective.

Imaging scans showed that tumors shrank in 2 of the patients, including metastatic liver tumors in 1 patient.

In addition, 2 of the men had relief from cancer-related pain and were able to discontinue opiate therapy. The continued on page 8

MUTATIONS AND METASTATIC PCa

Study implicates genes that maintain DNA integrity PAGE 25

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AUGUST 2016 www.renalandurologynews.com

Deceased-Donor Age Affects Transplant Outcomes R ECIPIENTS OF KIDNEYS donated after cardiac death by individuals older than 50 years are more likely to experience graft loss and delayed graft function (DGF), researchers reported at the Canadian Urological Association 2016 annual meeting in Vancouver.

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David M. Mikhail, MD, and collaborators at Western University in London, Ontario, studied transplant outcomes involving 6,800 cardiac-death donors.

The group included 1,832 donors older than 50 years and 4,968 donors younger than 50 years. The mean donor ages were 55 and 31 years, respectively, and

mean recipient ages were 56 and 50 years, respectively. The median Kidney Donor Profile Index was 37% for donors younger than 50 year and 74% for those older than 50 years. These values predicted 1-, 3-, and 5-year graft survival rates of 91%, 82%, and 71%, respectively, among recipients of kidneys from

the under-50 donors and 86%, 73%, and 60%, respectively, among recipients of kidneys from the over-50 donors.

The DGF rate was significantly higher among recipients of kidneys from the over-50 donor group (49% vs.

37%). In both groups, DGF correlated with worse graft survival. n

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www.renalandurologynews.com AUGUST 2016

Renal & Urology News 5

Hereditary Risks for Aggressive PCa Quantified SWEDISH RESEARCHERS have provided new estimates of the hereditary risk of significant prostate cancers (PCa) that may aid in patient counseling.

Clinicians have long known that having a father or brother with PCa doubles a man’s risk for the disease,

but many of these cancers would turn out to be indolent. So Ola Bratt, MD, PhD, of Lund University, Par Stattin, MD, PhD, of Umea University, and colleagues used Prostate Cancer data Base Sweden, a compilation of populationbased registries that captures a vast majority of PCa cases in the ­country,

to estimate the risks of significant PCa requiring treatment. The investigators calculated risks of any PCa, non-low risk PCa, and high-risk PCa for 51,897 brothers of 32,807 men with PCa. The probabilities are in essence absolute risks, they noted. Non-low risk disease was defined as Gleason score 7 or

above, prostate-specific antigen (PSA) level 10 ng/mL or above, T3–4, N1, and/or M1. High-risk PCa included cases that were Gleason score 8 and above, T3–4, PSA level above 20 ng/ mL and above, N1, and/or M1.

The probability of any PCa was 4.8% by age 65 years and 12.9% by age 75 years, according to results published online in the Journal of the National Cancer Institute. The chances of nonlow-risk PCa were lower: 2.8% by age 65 years and 8.9% by age 75 years. For highrisk PCa, the probabilities were 1.4% by age 65 years and 5.2% by age 75 years.

If a man had a brother with PCa, the probabilities of any PCa by age 75 were 30.3%, non-low-risk PCa, 18.8%, and high-risk PCa, 8.9%. By age 65, those risks were 14.9%, 7.3%, and 3.0%, respectively.

Probability estimates could aid in patient counseling, according to investigators.

Risk increased when a man had more than 1 sibling with PCa. Men with 2 affected brothers had a 55.1%, 33.2%, and 13.6% probability of any PCa, non-low-risk PCa, and high-risk cancer at age 75, respectively, according to the researchers.

“Clearly, the probabilities of nonlow-risk and, in particular, high-risk cancer are highly relevant when counseling men with familial prostate cancer,” the investigators wrote. “We suggest that these probabilities are included in future clinical guidelines.”

The investigators were surprised to find that any PCa can confer substantial hereditary risks regardless of its severity. “We expected that the risk of aggressive prostate cancer would not be much increased in brothers of men with the indolent form, but it turned out to [be] almost as high as the risk among men with aggressive prostate cancer in the family,” Dr. Bratt said in a Lund University press release.

He urged clinicians to share this risk information with patients.

The investigators noted that use of nationwide, population-based highquality registry data with almost complete capture rates was a study strength. “The statistical precision of our calculations was therefore high,” they wrote. n

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6 Renal & Urology News

AUGUST 2016 www.renalandurologynews.com

FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD

Later HD, Less HD, No HD: A New Paradigm?

F

or more than half a century, we have regarded dialysis therapy as the life-saving intervention, assuming that without maintenance dialysis treatment survival would be impossible in patients with advanced kidney failure. To that end, more dialysis and earlier dialysis have been considered better patient care, whereas delayed initiation or less frequent hemodialysis (HD) treatment than at least thrice-weekly is unwanted.

Emerging studies in recent years, however, have cast doubt on the universal superiority of the conventional approach to the initiation to dialysis. A study in 2009 suggested that, among nursing home residents with advanced kidney insufficiency, initiation of dialysis was associated with a substantial and sustained decline in functional status. A provocative clinical trial from Australia and New Zealand in 2010 suggested that planned early initiation of dialysis in patients with stage 5 chronic kidney disease (CKD) was not associated with an improvement in survival or other clinical outcomes. These data have been supported by an increasing number of observational analyses in different dialysis populations.

Recently, there has been a resurgence of data about twice-weekly HD, a taboo subject in many nations where anything less than thrice-weekly HD is considered substandard and inferior. There are even data on once weekly or less frequent HD as a smoother transition to renal replacement therapy (RRT). Some experts have revisited the old school of the nutritional management of CKD and have advocated the use of low protein and low salt diets to slow progression of the kidney disease or to manage uremic symptoms conservatively and without dialysis initiation.

There have been more talks about the preservation of the native kidney function as long as possible even after the dialysis initiation. Are we on the verge of a major paradigm shift in RRT? I do not expect a revolution in the field, but we will likely experience important adjustments in the way dialysis treatment has been employed in this country and probably worldwide, as our ways are often followed by other nations.

We will likely see an increased practice of twice-weekly HD in the first several months of dialysis initiation, along with more attention to the preservation of the residual kidney function, more frequent and longer use of conservative management of kidney disease, and maybe more use of hospice in lieu of transitioning to dialysis. There is a challenging but exciting future before us.

Kam Kalantar-Zadeh, MD, MPH, PhD Medical Director, Nephrology Professor & Chief Division of Nephrology & Hypertension University of California, Irvine School of Medicine

Renal & Urology News welcomes opinions related to issues relevant to urologists or nephrologists. If you have a viewpoint you would like to share, please contact Jody A. Charnow, editor, at jody.charnow@haymarketmedia.com.

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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 Kathleen Millea Grinder Circulation manager Paul Silver National accounts manager William Canning Group Publisher Chad Holloway Editorial director

Kathleen Walsh Tulley

Senior VP, medical journals & digital products

Jim Burke, RPh

Senior VP, medical communications

John Pal

CEO, Haymarket Media Inc.

Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 15, Number 6. 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.

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Contents

www.renalandurologynews.com

AUGUST

2016

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this month at renalandurologynews.com

BP Drug Use Not Optimal in Dialysis Transition Only 40% of older patients starting maintenance dialysis were on renin-angiotensin system blockade.

International Continence Society Annual Meeting Tokyo September 13–16

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Fracture Risk Factors in Transplant Patients ID’d Older donor age, female sex, and end-stage renal disease caused by diabetes or cystic kidney disease increase the risk of major bone fractures.

American Society for Radiation Oncology (ASTRO) Annual Meeting Boston September 25–28

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PPI Use Linked to Low Magnesium in HD Patients Evidence also suggests that low magnesium in the presence of inflammation increases 1-year mortality risk.

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Answer correctly and you will be entered to win a $50 American Express gift card.

Congratulations to our July winner: S.C. Karan, MD

HIPAA

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

Invasive Penile Cancer, Socioeconomic Factors Linked Men with low disposable income had 23% increased odds of T1–T4 penile cancer versus men with high disposable income.

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Water Vapor Ablation Eases BPH/LUTS The treatment provides durable symptom improvement while preserving sexual function, data show.

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Selenium May Cut Aggressive PCa Risk Each 80th percentile increase in blood and nail selenium levels are associated with 57% and 82% decreased odds of advanced stage prostate cancer or death from the disease.

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Sexual Medicine Society of North America Annual Fall Scientific Meeting Scottsdale, AZ November 3–6 American Society of Nephrology Kidney Week 2016 Chicago November 15–20 Genitourinary Cancers Symposium Orlando, FL February 16–18, 2017 Annual Dialysis Conference Long Beach, CA March 11–14, 2017 National Kidney Foundation 2017 Spring Clinical Meetings Orlando, FL April 18–22, 2017

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

Non-Adherence Predicts Worse Transplant Outcomes Acute rejection risk is greater among kidney transplant recipients who do not adhere to follow-up care and medication regimens.

Urology

How to manage business associates to reduce liability.

Job Board

CALENDAR

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

Prostatic Abscess Risk Factors Identified Longer symptom duration and voiding disturbance in men suspected of having acute prostatitis increase the likelihood that a prostatic abscess has developed.

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Departments 6

From the Medical Director A new hemodialysis paradigm may be emerging.

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News in Brief Shockwave therapy eases pain of Peyronie’s disease.

We found a single baseline PSA-level

measurement during midlife could accurately predict future risk of lethal prostate cancer.

See our story on page 13

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Renal & Urology News 7

VOLUME 15, ISSUE NUMBER 6

Nephrology

ONLINE

AUGUST 2016

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Practice Management Specific coding is key to getting paid and avoiding audits.

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Contents

www.renalandurologynews.com

AUGUST

2016

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ONLINE

18

this month at renalandurologynews.com 22

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

25

Answer correctly and you will be entered to win a $50 American Express gift card.

Congratulations to our July winner: S.C. Karan, MD

HIPAA

Selenium May Cut Aggressive PCa Risk Each 80th percentile increase in blood and nail selenium levels are associated with 57% and 82% decreased odds of advanced stage prostate cancer or death from the disease.

Prostatic Abscess Risk Factors Identified Longer symptom duration and voiding disturbance in men suspected of having acute prostatitis increase the likelihood that a prostatic abscess has developed.

17

Fracture Risk Factors in Transplant Patients ID’d Older donor age, female sex, and end-stage renal disease caused by diabetes or cystic kidney disease increase the risk of major bone fractures.

21

PPI Use Linked to Low Magnesium in HD Patients Evidence also suggests that low magnesium in the presence of inflammation increases 1-year mortality risk.

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CALENDAR International Continence Society Annual Meeting Tokyo September 13–16 American Society for Radiation Oncology (ASTRO) Annual Meeting Boston September 25–28 Sexual Medicine Society of North America Annual Fall Scientific Meeting Scottsdale, AZ November 3–6 American Society of Nephrology Kidney Week 2016 Chicago November 15–20 Genitourinary Cancers Symposium Orlando, FL February 16–18, 2017 Annual Dialysis Conference Long Beach, CA March 11–14, 2017 National Kidney Foundation 2017 Spring Clinical Meetings Orlando, FL April 18–22, 2017

BP Drug Use Not Optimal in Dialysis Transition Only 40% of older patients starting maintenance dialysis were on renin-angiotensin system blockade.

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

Water Vapor Ablation Eases BPH/LUTS The treatment provides durable symptom improvement while preserving sexual function, data show.

10

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

Invasive Penile Cancer, Socioeconomic Factors Linked Men with low disposable income had 23% increased odds of T1–T4 penile cancer versus men with high disposable income.

Nephrology

How to manage business associates to reduce liability.

Non-Adherence Predicts Worse Transplant Outcomes Acute rejection risk is greater among kidney transplant recipients who do not adhere to follow-up care and medication regimens.

26

Departments 6

From the Medical Director A new hemodialysis paradigm may be emerging.

9

News in Brief Shockwave therapy eases pain of Peyronie’s disease.

We found a single baseline PSA-level

measurement during midlife could accurately predict future risk of lethal prostate cancer.

See our story on page 13

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Renal & Urology News 7

VOLUME 15, ISSUE NUMBER 6

Urology 11

AUGUST 2016

26

Practice Management Specific coding is key to getting paid and avoiding audits.

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8 Renal & Urology News

AUGUST 2016 www.renalandurologynews.com

30% eGFR Decline Predicts Kidney Transplant Outcomes A 30% OR GREATEr decline in estimated

In multivariable analysis, a 30% or

glomerular filtration rate (eGFR) during

greater decrease in eGFR over 6 to 24

6 to 24 months after kidney trans-

months post-transplant was associated

plantation is a surrogate for long-term

with a 21.3 mL/min/1.73 m2 lower

transplant outcomes, according to find-

5-year eGFR compared with those who

ings presented at the 2016 American

had a smaller decrease in eGFR, after

Transplant Congress in Boston.

adjusting for peak PRA and donor age.

In an observational, prospective

The 30% or greater decrease also was

study, Geovani Faddoul, MD, of the

associated with a greater likelihood

Icahn School of Medicine at Mount

of chronic kidney disease stage IIIb

Sinai in New York, and colleagues,

(66.6% vs. 24.5%). The proportion of

analyzed 5-year outcome data from

patients who experienced graft loss

183 kidney transplant recipients with

was significantly larger in the group

a mean age of 42 years. Overall,

with a 30% or greater decline in eGFR

2-year eGFR and a 30% or greater

(31% vs. 4%).

decline in eGFR over 6 to 24 months

The investigators concluded that their

post-transplant, but not early immune

findings support the use of a 30% or

marker status, each was associated

greater decline in eGFR over the initial 2

with lower 5-year eGFR, Dr. Faddoul’s

years post-transplant as a surrogate for

group reported.

long-term kidney transplant outcomes. n

Metformin in NMIBC continued from page 1

on stage progression,” Dr. Traboulsi’s group concluded.

In the other study, Patrick Richard, MD, and colleagues at the University of Toronto found that that cumulative use of metformin does not impact disease-specific or overall survival among diabetic patients with NMIBC. Using administrative databases, the investigators conducted a retrospective, population-based study that included 1742 diabetic patients with NMIBC, of whom 813 were exposed to metformin. This study was restricted to patients aged 66 or older given the limitations of the databases used. After a median follow-up of 63 months, 1122 patients had died, 247 from bladder cancer. Each additional

Sarcopenia, death risk continued from page 1

Quality at the University of Alabama at Birmingham (UAB). “These findings are novel and clinically useful as they may help inform decision-making with regard to candidate selection.”

Dr. Locke and colleagues studied 80 kidney transplant candidates waitlisted from 2008 to 2009 and who had computed tomography (CT) imaging available at the time of listing. Investigators followed up patients to the earliest of

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6 months of metformin use was associated with a non-significant 6% increased risk of cancer-specific death. Conversely, increasing use of glyburide was associated with worse cancer-specific survival.

ESRD, red meat linked continued from page 1

Health Study. ESRD developed in 951 individuals over a mean follow-up of 15.5 years. The mean age at ESRD diagnosis was 69.3 years.

Individuals in the highest quartile of red meat intake were slightly younger than those in the lowest quartile (55.7 vs. 56.5 years) and less likely to be physically active (31% vs. 39% reporting at least 30 minutes of moderate activity, vigorous activity, or strenuous sports per week). At baseline, individuals in the highest quartile had a lower prevalence of self-reported hypertension than those in the lowest quartile (22% vs. 24%), but a higher prevalence of self-reported diabetes (9% vs. 7%).

Endogenous acid production resulting from red meat consumption is among the possible explanations for the observed association between red meat consumption and ESRD risk, according to the researchers. They cited studies showing that high dietary acid load was associated with an increased ­incidence

of ESRD in a population-based U.S. cohort of adults with chronic kidney disease and that red meat generally yields greater acid production than other animal-sourced protein.

The strengths of the study include its prospective design, large sample size, and long-term and complete ­follow-up of outcomes, the ­investigators noted.

Highest vs. lowest quartile of intake associated with a 40% increased risk.

In addition, dietary intake was assessed using a validated food frequency questionnaire developed specifically for the study population.

Limitations include the observational nature of the study, the use of participant self-report, and a single assessment of diet, which could lead to misclassification bias to due measurement error, the investigators stated. n

Previously, in a paper published in Urologic Oncology (2015;33:386.e7-386. e13), Canadian researchers led by Madhur Nayan, MD, of the University of Toronto, reported on a study of 421 patients undergoing radical cystectomy for bladder cancer showing that

­ etformin users had a 62% decreased m risk of disease recurrence and 43% decreased risk of death from bladder cancer. In a separate study of 1117 patients with NMIBC, which was published in BJU International (2013;112:1105-1112), researchers showed that, among the 125 patients who also had diabetes, metformin use was independently associated with a significant 50% decreased risk of disease recurrence.

“While there are conflicting results in the literature, these studies lend support to further explore metformin as an agent for chemoprevention in NMIBC,” commented Dr. Nayan in an interview with Renal & Urology News. “Metformin is an ideal agent for chemoprevention as it is inexpensive and generally well tolerated.”

He pointed out, however, that certain limitations restrict the interpretation

of study results. Some of these studies included diabetic and non-diabetic patients. While this increases sample size, it also risks selection bias, he said. Those without diabetes may have an inherently different prognosis compared to those with diabetes, Dr. Nayan said, citing a paper published in the International Journal of Urology (2011;18:769-776).

“Furthermore, other than the study

by Richard et al., it is unlikely that these studies accounted for intermittent or cumulative use, as reliable data on medication exposure is difficult to obtain using institutional data,” Dr. Nayan said. “Indeed, it is certainly possible that a patient classified as a user may have discontinued the medication during follow-up, and that a non-user started the medication during follow-up, raising the potential for misclassification bias.” n

transplant, death, or administrative end of the study. After a median of 3.8 years of follow-up, 31 patients died while waiting for a transplant, 23 received transplants, and 26 were still awaiting transplants. Morphometric measures assessed on CT included abdominal adipose tissue, paraspinous and psoas muscle composition, and aortic calcification.

After controlling for multiple factors, only higher psoas muscle attenuation— which indicates leaner muscle mass— remained significantly associated with waitlist mortality, with each Hounsfield

unit increase in attenuation associated with a 6% increased risk of death.

“This ATC poster highlights a novel way of evaluating for sarcopenia though the use of radiographic morphometric measurements in helping to assess kidney waitlist mortality,” commented Uttam Reddy, MD, Medical Director of the Kidney Transplant Program at the University of California Irvine. “As a kidney transplant provider, I find the results innovative and potentially applicable in the evaluation of pre transplant patients.”

Predicting outcomes of waitlisted ESRD patients remains an important part of pre-transplant screening, said Dr. Reddy, who was not part of the study by Dr. Locke’s team. He noted that a previous study led by Kamyar Kalantar-Zadeh, MD, PhD, also of the University of California Irvine, demonstrated an association of low muscle mass and low body mass index (BMI) with ESRD patient waitlist mortality in a paper published in the American Journal of Transplantation (2011;11:725-736). n

Metformin does not impact cancer-specific survival in diabetic NMIBC patients.

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8 Renal & Urology News

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TRT Does Not Worsen Prostate Cancer Outcomes TESTOSTERONE replacement therapy (TRT) does not worsen oncologic outcomes in hypogonadal men with prostate cancer, according to study findings presented at the Canadian Urological Association 2016 annual meeting in Vancouver.

Jesse Ory, MD, of the University of British Columbia in Vancouver, and

­colleagues identified 82 hypogonadal men with prostate cancer (PCa) who received TRT. The group included 50 men who had radiation therapy (RT), 22 who underwent radical prostatectomy (RP), 8 placed on active surveillance (AS), 1 who had cryotherapy, and 1 treated with high-intensity focused ultrasound.

The median follow-up was 41 months.

The investigators observed an increase in both testosterone and PSA levels in the entire cohort, but only patients with low-risk PCa had a statistically significant increase in PSA. PSA increased in the AS patients, but none of these patients were upgraded to a higher Gleason score on subsequent prostate biopsies and none have yet gone on to definitive treatment,

the researchers reported. No RP patient experienced biochemical recurrence, but 3 RT patients (6%) did, as defined by 2006 Phoenix criteria (PSA nadir plus 2 ng/mL).

Dr. Ory’s group said it is unclear whether these recurrences were related to TRT or reflected the natural biology of their disease. n

Metformin for NMIBC

Previously, in a paper published in Urologic Oncology (2015;33:386.e7-386. e13), Canadian researchers led by Madhur Nayan, MD, of the University of Toronto, reported on a study of 421 patients undergoing radical cystectomy for bladder cancer showing that metformin users had a 62% decreased risk of disease recurrence and 43% decreased risk of death from bladder cancer. The study included 85 patients (20%) with diabetes, of whom 39 (46%) were on metformin. In a separate study of 1117 patients with NMIBC, which was published in BJU International (2013;112:1105-1112), researchers showed that, among the 125 patients who also had diabetes, metformin use was independently associated with a significant 50% decreased risk of disease recurrence.

“While there are conflicting results in the literature, these studies lend support to further explore metformin as an agent for chemoprevention in NMIBC,” commented Dr. Nayan in an interview with Renal & Urology News.

studies included diabetic and nondiabetic patients. While this increases sample size, it also risks selection bias, he said. Those without diabetes may have an inherently different prognosis compared to those with diabetes, Dr. Nayan said, citing a paper published in the International Journal of Urology (2011;18:769-776).

“Furthermore, other than the study

by Richard et al., it is unlikely that these studies accounted for intermittent or cumulative use, as reliable data on medication exposure is difficult to obtain using institutional data,” Dr. Nayan said. “Indeed, it is certainly possible that a patient classified as a user may have discontinued the medication during follow-up, and that a non-user started the medication during follow-up, raising the potential for misclassification bias.” n

continued from page 1

1742 ­diabetic patients with NMIBC, of whom 813 were exposed to metformin.

This study was restricted to patients aged 66 or older given the limitations of the databases used. After a median followup of 63 months, 1122 patients had died, 247 from bladder cancer. Each additional 6 months of metformin use was associated with a non-significant 6% increased risk of cancer-specific death. Conversely, increasing use of glyburide was associated with worse cancer-specific survival, and the authors concluded that external validation of these results is necessary.

Given the limitations of the administrative databases, the protective effect of metformin on disease recurrence could not be evaluated, the researchers noted.

PD-1 in mCRPC continued from page 1

patients remained free of progression at 16, 30, and 55 weeks of follow-up.

“It’s pretty remarkable, especially in light of the fact that many people doubted this approach could work at all,” Dr. Graff said in an OHSU press release. “You don’t get responses like this with almost any other treatment.”

Of the remaining 7 patients, 3 had stable disease at 30, 47, and 50 weeks.

Four patients showed no evidence of clinical benefit, with 1 dying from prostate cancer.

Three of the 10 patients had significant immune-related adverse events. Grade 2 myositis occurred in 1 patient, grade 3 hypothyroidism in 1 patient, and grade 2 hypothyroidism in 1 patient.

To be included in the study, patients needed to have at least 1 distant metastatic lesion, castrate levels of testosterone (less than 50 ng/dL), a PSA response to enzalutamide (defined as a PSA decrease of 50% or less), and, at the time of enrollment, must have had progression on enzalutamide. Additionally, they could not have received chemotherapy

Cvr_jumps_vUro_RUN0816.indd 8

for castration-resistant cancer, but previous chemotherapy for castration-sensitive cancer was allowed. Patients were continued on enzalutamide 80–160 mg orally per day; pembolizumab was given as a dose of 200 mg intravenously every 3 weeks for a total of 4 doses.

Profound PSA drop occurred in 3 of 10 men who progressed on enzalutamide.

In a previous report published in The New England Journal of Medicine (2012;366:2443-2454), ­i nvestigators reported the findings of a phase 1 study showing that PD-1 inhibition with nivolumab showed activity in melanoma, renal cell cancer, and non– small-cell lung cancer. The researchers observed no objective responses in the 17 patients with CRPC. In subsequent phase 3 studies, PD-1 blockade has demonstrated improved survival for non– small-cell lung cancer, renal cell carcinoma, melanoma, and bladder cancer. n

Metformin does not impact cancer-specific survival in diabetic NMIBC patients.

“Metformin is an ideal agent for chemoprevention as it is inexpensive and generally well tolerated.”

He pointed out, however, that certain limitations restrict the interpretation of study results. Some of these

Dutasteride, UTI risk continued from page 1

[Reduction by Dutasteride of Prostate Cancer Events] trial. They were randomly assigned to receive oral dutasteride 0.5 mg or placebo daily.

Fifty-four men (0.8%) experienced TPBA-UTI: 15 (0.5%) in the dutasteride arm and 39 (1.2%) in the placebo arm. Dutasteride use was associated with a significant 61% decreased relative risk of any TPBA-UTI compared with non-use. Results also showed that 14 patients (0.2%) had severe TPBAUTI: 2 (0.06%) in the dutasteride arm and 12 (0.4%) in the placebo group.

Dutasteride use was associated with a significant 83% decreased relative risk of severe TPBA-UTI versus non-use.

According to the investigators, 137 patients would need to be treated with dutasteride to prevent 1 case of TPBAUTI and 326 would need to be treated to prevent 1 case of severe TPBA-UTI. The researchers defined TPBA-UTI as the presence of urinary symptoms and the prescription of antibiotics by the treating physician, both within 30 days after a prostate biopsy. They

defined severe TPBA-UTI as a TPBAUTI requiring hospitalization.

“The mechanisms by which dutasteride reduces urinary tract infections are not entirely understood,” Dr. Moreira told Renal & Urology News. “There are several factors that may play a role.”

For example, he noted that dutasteride use is associated with a reduction in prostate size and lower post-void residual (PVR). “In our study, we adjusted our analyses for prostate size and PVR, and the results were virtually unchanged compared to unadjusted ones. This suggests that other mechanisms may be play a role in the relationship between dutasteride and lower UTI rate.”

Dr Moreira’s group noted that previous research demonstrated that dutasteride use is associated with a decreased risk of UTI in men with benign prostatic hyperplasia (BPH). A post-hoc analysis of the REDUCE study by Paul Toren, MD, and colleagues at the University of Toronto found that dutasteride use by men with asymptomatic BPH was associated with a significant 38% decreased risk of UTI compared with those who received placebo, according to a paper published in BMJ (2013;346:f2109). n

7/20/16 11:33 AM

www.renalandurologynews.com AUGUST 2016

Renal & Urology News 9

News in Brief

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

Short Takes Shockwave Therapy May Ease Peyronie’s Disease

RAYALDEE by its manufacturer, OPKO

Extracorporeal shockwave therapy

Health Inc., based in Miami, is not

(ESWT) may be a safe and effective

indicated for the treatment of SHPT in

treatment for reducing penile plaques

patients with CKD stage 5 or end-stage

and relieving pain in men with Peyronie’s

renal disease on dialysis.

The drug, which is being marketed as

The approval is based on a 2

disease, according to a new meta-analysis published online in the International

randomized, double-blind, placebo-

Journal of Impotence Research.

controlled phase 3 studies and an open-label extension study.

The meta-analysis, by Liang Gao, MD, and colleagues at Sichuan University that included 443 patients. Pooled data

Intestinal Autoimmunity Possibly Linked to ADT

from these studies showed that ESWT

Androgen deprivation therapy (ADT)

was associated with a significant 2-fold

for prostate cancer may be associ-

increased odds of lessening of plaques,

ated with a reduced risk of inflamma-

4.5-fold increased odds of pain relief,

tory bowel disease (IBD), according a

and 5.9-fold increased odds of com-

recent report in the American Journal

plete remission of pain, the investiga-

of Epidemiology (2016;184:15-22).

tors reported. ESWT was not associ-

In a study of 31842 men newly

in Sichuan, China, included 6 studies

ated with improved penile curvature and

diagnosed with prostate cancer, Lau-

sexual function.

rent Azoulay, MD, of Jewish General Hospital in Montreal, and colleagues

SHPT Drug Approved For Use in CKD Patients

found men exposed to ADT had a sig-

Calcifediol extended-release capsules

ative colitis and a non-significant 62%

have received FDA approval for the

decreased risk of Crohn’s disease.

nificant 48% decreased risk of ulcer-

treatment of secondary hyperparathy-

“These findings indicate that the

roidism (SHPT) associated with vitamin

use of ADT may be associated with

D insufficiency in patients with chronic

intestinal autoimmunity,” the research-

kidney disease (CKD) stages 3 and 4.

ers concluded.

Lifetime Risk of CKD The cumulative lifetime risk of chronic kidney disease (CKD) is 41.3% among individuals without CKD at age 50, researchers concluded from a new analysis of data from participants in the Framingham Offspring Study. The risk is higher for those with CKD risk factors at baseline, as shown below.

Diabetes: 52.6% Hypertension: 50.2% Obesity: 46.5% 0

10

20

30

40

50

Source: McMahon GM et al. Residual lifetime risk of chronic kidney disease. Nephrol Dial Transplant 2016; published online ahead of print.

NewsBrief_RUN0816.indd 9

60

High BMI, Post-Transplant Viral Infections Linked M

orbidly obese kidney transplant recipients are at increased risk of posttransplant opportunistic viral infections, researchers reported at the 2016 American Transplant Congress in Boston.

Sara Strout, PharmD, and collaborators at the Medical University of South Carolina in Charleston studied 308 kidney transplant recipients, of whom 103 had a body mass index of 35 kg/m2 or higher (morbidly obese) and 205 patients had a BMI less than 35 kg/m2.

The overall rate of infections did not differ significantly between the morbidly obese and non-morbidly obese groups (51.2% and 55.3%), but the morbidly obese group experienced more opportunistic viral infections overall (52.4% vs. 37.1%) and more cytomegalovirus (CMV) infections (27.2% vs. 16.1%). The rates of CMV syndrome or disease did not differ significantly between the groups.

Data Support Bladder-Sparing Trimodal Therapy for MIBC B

ladder-sparing trimodal therapy with endoscopic resection, radiation therapy, and chemotherapy for muscle-invasive bladder cancer (MIBC) results in survival outcomes similar to those of selected matched patients undergoing radical cystecomy, investigators reported at the Canadian Urological Association 2016 annual meeting in Vancouver.

Girish S. Kulkarni, MD, and colleagues at Princess Margaret Cancer Centre in Toronto, compared 48 MIBC patients who underwent full bladder preservation with trimodal therapy (TMT) and a propensity score matched group of 48 MIBC patients who underwent RC, with no imbalances. After a median follow-up of 3.6 years, 19 patients in the RC group (39.6%) died (7 from bladder cancer) and 15 (31.3%) died in the TMT group (6 from bladder cancer). The 5-year diseasespecific survival was 84.7% and 85.2% in the RC and TMT groups, respectively, a between-group difference that was not statistically significant.

Venous Thromboembolism Linked to High Uric Acid E

levated serum uric acid (SUA) is associated with an increased risk for venous thromboembolism (VTE), suggesting that SUA could be a novel risk factor or marker for the condition, researchers concluded in Thrombosis Research (2016;144:144-148).

Yasuhiko Kubota, MD, of the University of Minnesota in Minneapolis, and colleagues analyzed data from 14,126 participants in the Atherosclerosis Risk in Communities Study aged 45 to 64 years without a history of VTE or gout. They obtained information on incident gout from 1987 to 1998 from 10,247 participants. The researchers documented 632 incident cases of VTE. In a fully adjusted model, individuals with the highest level of SUA (8.7 mg/dL or higher) had a 2-fold increased risk for total VTE compared with those with the lowest level (4.9 mg/dL or less). Individuals with incident gout had a nonsignificant increased risk for total VTE.

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Expectant Management for PCa More Likely At Academic Centers Odds of using this strategy are 2.7-fold greater versus community facilities MEN WITH LOW-RISK prostate cancer (PCa) are more likely receive expectant management (EM) for their disease if they are evaluated at academic rather than community centers, new findings suggest.

The finding is not attributable to known demographic or clinical characteristics, researchers concluded in a report published online ahead of print in Urology.

Using the National Cancer Data Base (NCDB), Nathaniel H. LesterColl, MD, of Yale University School of Medicine in New Haven, Connecticut, and colleagues performed a retrospective analysis of 2010-2013 data on 91,556 men with low-risk PCa. Of these, 39,139 were evaluated at academic centers and 52,417 were evaluated at community facilities. In all, 10,880 received EM (active surveillance/watchful waiting) and 80,676 received treatment.

A significantly higher proportion of men evaluated at academic facilities received EM (17% vs. 8%), Dr. LesterColl’s group reported. After adjusting for pertinent covariates, patients evaluated at an academic versus community facility had 2.7 times increased odds of being placed on EM.

A possible explanation for greater EM use at academic centers, according to the researchers, is that men with low-risk PCa may be referred to these centers because of greater medical complexity and burden of comorbid illness, and thus may be less amenable to definitive treatment. They pointed out, however, that their study found no significant differences in Charlson/Deyo comorbid-

The finding is not attributable to known demographic factors or clinical features. ity scores between patients evaluated at academic and community centers.

“Therefore, our results do not support the hypothesis that differences in patientlevel comorbidity between community and academic centers are responsible for the observed differences in EM use.”

Additional unmeasurable patient characteristics are another possibility. “For example, patients who seek opinions at academic centers may be more ­motivated

to obtain multiple opinions and/or are more hesitant to pursue treatment,” Dr. Lester-Coll and his colleagues wrote.

“It is also possible that physicians in academic practices are more shielded or less concerned with the difference in reimbursement of EM and definitive treatment,” the researchers wrote.

“Because academic salaries are less directly dependent on clinical revenue, the pressure to treat patients may be reduced in academic practice.”

The NCDB defines an academic facility as an academic/research program including National Cancer Institutedesignated comprehensive cancer centers. Community facilities include community cancer programs, comprehensive community cancer programs, and integrated cancer centers.

With respect to study limitations, Dr. Lester-Coll’s team pointed out that the NCDB does not differentiate between active surveillance and watchful waiting, adding that “it is possible these strategies are associated with distinct practice patterns.” In addition, 3,398 men were coded ambiguously as have received “no treatment” and excluded from the study. n

ED Found To Predict Osteoporosis MEN WITH a history of erectile dysfunction (ED) are at higher risk of osteoporosis, according to a new study.

“ED can be considered an early predictor of osteoporosis,” the investigators concluded in Medicine (2016;95:p e4024).

Using the Taiwan National Health Insurance Research Database, investigators led by Chih-Lung Lin, PhD, of Kaohsiung Medical University in Taiwan, compared 4460 men aged 40 years or older diagnosed with ED from 1996 to 2010 with 17,480 randomly selected age-matched patients without ED. During follow-up, osteoporosis developed in 264 patients with ED (5.92%) and 651 without ED (3.65%).

The overall incidence of osteoporosis was 3-fold higher in the ED group than the non-ED group (9.74 vs. 2.47) per 1000 person-years) after controlling for covariates. Osteoporosis was 3 times more likely to develop in men with either psychogenic or organic ED compared with those who did not have ED. The risk varied by age. ED patients aged 40 to 59 years had a 3.6 times increased risk of osteopo-

BP Drug Use Not Optimal in Dialysis Transition

BY NATASHA PERSAUD USE OF BLOOD PRESSURE drugs among older adults initiating dialysis may need improvement, according to a new analysis.

Using Medicare claims data reported to the U.S. Renal Data System, Tara I. Chang, MD, of Stanford University in Palo Alto, California, and colleagues looked for patterns in antihypertensive medication use among 13,554 lowincome patients older than 67 years initiating dialysis from 2008 and 2010.

Prescriptions for antihypertensive drugs increased as patients approached end-stage renal disease (ESRD), cresting at 3.4 the quarter before dialysis initiation. That number declined to 2.2 drugs by 2 years after the transition.

Use of ACE inhibitors or angiotensin II receptor blockers (ACEI/ARB) stayed constant at approximately 40%, even among patients with coronary ­disease and ­systolic heart failure.

AS-community_RUN0816.indd 10

Renin-angiotensin system blockade did not correlate with the development of acute kidney injury or hyperkalemia.

Diuretic use declined by 40% with the start of dialysis and continued to dwindle.

Additionally, the researchers observed that 3- and 4-drug combinations including a diuretic commonly were prescribed before ESRD, whereas 1- and 2-drug ß-blocker or calcium-channel blocker– based combinations prevailed afterward.

“We showed that ACEI/ARB and ß-blocker use could be improved, particularly in subgroups in whom clinical guidelines recommend first-line treatment, such as patients with coronary heart disease or systolic heart failure,” Dr. Chang and colleagues reported online in the Clinical Journal of the American Society of Nephrology. “We also show a precipitous drop in diuretic use after incident ESRD, which may not always be appropriate if the patient still has significant residual renal function.”

With respect to study limitations, all patients were seniors, so the findings may not pertain to the ESRD population as a whole. In addition, insurance claims lacked laboratory or blood pressure results, limiting interpretation of clinical relevance.

In an accompanying editorial, Jordana B. Cohen, MD, and Raymond R. Townsend, MD, of the University of Pennsylvania in Philadelphia, pointed out that the study by Dr. Chang and colleagues “is the first to follow patients longitudinally over several months leading up to and after dialysis initiation, while also taking into account highly relevant comorbidities.”

They noted, however, that the study is “somewhat limited it its generalizability to the dialysis population as a whole, because patients were required to be eligible for Medicare with low-income medication subsidy 2 years before initiating dialysis.” n

rosis and those aged 60 years and older had a 3.5 times increased risk compared with the non-ED group.

“Because of the easy and noninvasive evaluation of osteoporosis, patients with ED should be examined for bone mineral density, and men with osteoporosis should be evaluated for ED,” the investigators wrote.

Dr. Lin and colleagues discussed possible mechanisms underlying the relationship between ED and osteoporosis. For example, men with ED have lower naturally available free testosterone than those without ED, they noted, adding that androgens may have a key role in regulating bone formation in men. In addition, men with low testosterone have a marked increase in the risk of fragility fractures, and androgen deprivation therapy and orchiectomy have been associated with an increased risk of osteoporosis and fractures.n

7/19/16 11:37 AM

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Renal & Urology News 11

Drug Slows Kidney Disease Advance Renal benefit of empagliflozin seen in patients with type 2 diabetes at high cardiovascular risk

BY NATASHA PERSAUD TYPE 2 DIABETES patients at high risk of cardiovascular events receiving empagliflozin along with standard care experienced slower progression of kidney disease and lower rates of renal events, according to a study published online by the New England Journal of Medicine.

For the EMPA-REG OUTCOME trial, Christoph Wanner, MD, from Würzburg University in Germany, and colleagues randomly assigned patients with type 2 diabetes, established cardiovascular disease, and an estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m² to once daily placebo or empagliflozin at a dose of 10 mg or 25 mg (median treatment duration, 2.6 years). Patients also received standard of care comprising glucose-lowering and cardiovascular drugs, such as hypertension and lipid-lowering medication.

Secondary renal outcomes of the trial included nephropathy, development or worsening (i.e., macroalbuminuria, doubling of serum creatinine, initiation of renal replacement therapy (RRT), or death from renal disease), and incident albuminuria.

Results showed that nephropathy developed or worsened in 525 of 4124 patients (12.7%) in the pooled

Improved Renal Outcomes Empagliflozin use is associated with a significantly lower incidence of adverse renal outcomes among patients with type 2 diabetes at high risk of cardiovascular events.

Compared with placebo, empagliflozin use was associated with the following reductions in the risk of renal outcomes: Incident/worsened nephropathy

39%

Doubling of serum creatinine

44%

Renal replacement therapy initiation

55%

Source: Wanner C et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016; published online ahead of print.

e­ mpagliflozin group and in 388 of 2061 patients (18.8%) in the placebo group over a median 3.1 years. The difference represents a significant 39% risk reduction. In addition, doubling of serum creatinine occurred in 1.5% of the empagliflozin group vs. 2.6% of the placebo group, for a significant 44% risk reduction. RRT commenced in 0.3% of empagliflozin users vs. 0.6% of placebo users, for a significant 55% risk reduction.

The researchers observed no significant difference in the rate of incident albuminuria (51.5% vs. 51.2%). Three patients in the empagliflozin group

(0.1%) and none in the placebo group died from renal disease.

“The mechanisms behind the renal effects of empagliflozin are probably multifactorial, but direct renovascular effects may play an important role,” Dr. Wanner and colleagues suggested. The drug was used along with background blockade of the renin–angiotensin– aldosterone system, which supports its potential use in type 2 diabetes patients with kidney disease, they noted.

Empagliflozin, a selective sodiumglucose cotransporter 2 inhibitor, lowers elevated blood glucose by reducing

the renal reabsorption of glucose and increasing its urinary excretion. The drug’s adverse-event profile in patients with impaired kidney function at baseline was similar to that of the overall trial population. In line with previous reports, more patients taking empagliflozin experienced genital infection. Fewer occurrences of acute renal failure or hyperkalemia were reported with the drug.

The purported renal benefits of empagliflozin cannot be extended to type 2 diabetes patients at lower cardiovascular risk, the investigators stated.

They recommended further research in broader populations, including black patients, who comprised only a small percentage of the EMPA-REG OUTCOME sample.

In an accompanying editorial, Julie R. Ingelfinger, MD, and Clifford J. Rosen, MD, commented: “We are left with differences that appear encouraging, yet are not a ‘home run’ with regard to the management of diabetes. In the coming years, controlled and comparative effectiveness trials that uniformly combine newer agents with older agents may help to delineate an even more effective treatment plan for the millions of people whose lives are affected by type 2 diabetes.” n

Invasive Penile Cancer, Socioeconomic Factors Linked LOW EDUCATION LEVEL and low disposable income are among the socioeconomic factors associated with an increased risk for invasive penile cancer, a new study found.

Men who are divorced or never married or who live in a single-person household also are at higher risk.

The findings, from a large population-based of 11,548 Swedish men, possibly reflect social differences in lifestyle, health awareness, and healthseeking patterns, according to a paper published online in BJU International

by Christian Torbrand, MD, of Skåne University Hospital in Malmö, and colleagues.

The study population included 1676 men diagnosed with penile cancer from 2000 to 2012 and 9872 randomly selected controls. Compared with men who had a high education level (13 or more years of schooling), men with a

Empaglifozin_RUN0816.indd 11

low level (9 or fewer years of schooling) had 25% increased odds of invasive (T1–T4) penile cancer in adjusted analyses. Men with a low disposable income level (lowest 50% income among the controls) had 23% increased odds of T1–T4 penile cancer compared with men who had a high income level (highest 50% income among the controls).

Compared with married men, divorced men and men who never married had 42% and 46% increased odds of penile cancer, respectively, 69% and 67% increased odds of in situ disease (Tis), and 34% and 39% increased odds of T1–T4 disease.

Results also showed that men in multiple-person households had a lower risk for penile cancer overall and for Tis and T1–T4 disease than those in a single-person household. For example, men in a household of 3 or more people had 24%, 43%, and 12% decreased

odds of any penile cancer, Tis disease, and T1–T4 disease, respectively, versus those in a single-person household.

Among the 928 men with invasive penile cancer, the 1- and 3-year cancer-specific mortality rates were lower in men with a high education level

Men with less education and disposable income are at higher risk. and high disposable income as well as those who were married and living in household with 2 or more individuals, but these associations did not reach statistical significant after adjusting for age TNM stage, and comorbidities, the researchers reported.

“Our present findings provide evidence of socioeconomic gradients, not only in the risk of developing penile cancer, but also regarding primary tumour stage at presentation,” the investigators wrote.

Dr. Torbrand and colleagues noted that the population-based design and large number of patients were strengths of the study. “By means of record linkage, individual level data on socioeconomic factors, concomitant disease and vital status, were retrieved from highquality population-based registries.”

Regarding study limitations, the researchers acknowledged that no data were available on smoking history, an established risk factor for penile cancer. They noted, however, that they used a history of previous hospitalization with a diagnosis of chronic obstructive pulmonary disease as a proxy for smoking. n

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SHPT Parathyroidectomy Rates Stable The trend follows an abrupt decline following introduction of cinacalcet, according to a new study Parathyroidectomy for SHPT Rates of parathyroidectomy for secondary hyperparathyroidism in the United States have been stable in recent years despite the advent of medical therapy for the condition, researchers reported. Shown here are the rates per 1000 patients for the last 6 years of the 2002–2011 study period.

6

Rate per 1000 patients

BY NATASHA PERSAUD DESPITE CHANGES in medical therapy for secondary hyperparathyroidism (SHPT), rates of parathyroidectomy have remained stable in recent years, a new study finds.

Sun Moon Kim, MD, and colleagues at Stanford University in Palo Alto, California, sought to obtain a broader view using the Healthcare Cost and Utilization Project’s Nationwide Inpatient Sample, a national database representing a fifth of U.S. hospitals serving patients of all ages and insurance types, as well as the uninsured.

The investigators looked for trends from 2002 to 2011 in parathyroidectomy, in-hospital mortality, length of stay, and hospitalization costs.

Excluding cancer cases, surgeons performed 32,971 parathyroidectomies for SHPT during the study period. Overall, the parathyroidectomy rate was approximately 5.4 per 1000 patients, using dialysis and transplant recipient counts from U.S. Renal Data System reports as the denominator.

Results showed that parathyroidectomy rates rose from 7.3 to 7.9 procedures per 1000 patients from 2002 to 2003, declined to a low of 3.3 procedures per 1000 patients in 2005, then rebounded before becoming stable

5.4%

5.5%

5.6%

5

4.4%

4.8%

4.9%

2010

2011

4 3 2 1 0

2006

2007

2008

2009

Source: Kim SM, et al. Rates and outcomes of parathyroidectomy for secondary hyperparathyroidism in the United States.

Clin J Am Soc Nephrol. 2016;11 (published online ahead of print).

from 2006 onward, with rates of 5.4, 5.5, 5.6, 4.4, 4.8, and 4.9 per 1000 patients observed in years in 2006, 2007, 2008, 2009, 2010, and 2011, respectively.

Dr. Kim and colleagues attributed the abrupt decline in parathyroidectomy rates to the introduction of cinacalcet.

“During 2004 and 2005, clinicians might have deferred parathyroidectomy in some patients, anticipating improved control of sHPT,” they wrote in an online report in the Clinical Journal of the American Society of Nephrology.

Unlike the current findings, the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial found a sizeable drop in parathyroidectomy with cinacalcet compared with placebo. EVOLVE specified titration of cinacalcet to a maximum daily dose of 180 mg during the first 20 weeks, which rarely occurs in clinical practice, the investigators noted. Release of SHPT guidelines also may have influenced parathyroidectomy trends.

Rates of in-hospital mortality decreased from 1.7% in 2002 to 0.8%

in 2011. In the current study, in-hospital mortality rates were significantly higher in patients with heart failure and peripheral vascular disease and lower among patients with prior kidney t­ransplants.

The study lacked information on patients’ SHPT severity. Lengths of hospital stay decreased over time, whereas parathyroidectomy costs increased.

In an accompanying editorial, James B. Wetmore, MD, of the Minneapolis Medical Research Foundation, commented that the risk to benefit ratio of parathyroidectomy might be more unfavorable than anticipated in light of mortality, treatment failure, and the prospect of hypocalcemia.

“The nephrology community should engage in a robust discussion about the appropriate role of PTX [parathyroidectomy] in patients on maintenance dialysis with SHPT,” Dr. Wetmore wrote. “More work is needed examining which types of patients might benefit from PTX, such as those likely to live longest, and which types might incur undue risk, such as those who are nonadherent with therapy and who may be at elevated risk of lifethreatening adverse events after surgery.”

Among the disclosures, Dr. Chertow, the study’s senior author, noted research support from Amgen, Inc., the manufacturer of cinacalcet (Sensipar). n

Study: Rituximab May Have MN Treatment Role NEW STUDY FINDINGS may represent a step forward in the use of rituximab as first-line therapy for severe membranous nephropathy (MN).

The study, which was the first randomized controlled trial (RCT) of rituximab in primary MN, demonstrated a positive treatment effect after 6 months and identified early markers of rituximab effect. The study also demonstrated that adding this drug to nonimmunosuppressive antiproteinuric treatment (NIAT) does not affect safety.

Karine Dahan, MD, of Tenon Hospital in Paris, and colleagues randomly assigned patients with biopsy-proven primary MN and nephrotic syndrome after 6 months of NIAT to receive 6 months of therapy with either NIAT and 375 mg/m2 intravenous rituximab on days 1 and 8 (37 patients) or NIAT alone (38 patients). The median time to last follow-up was 17 months in both groups.

Parathyroidectomy_RUN0816.indd 12

The primary outcome was a combined endpoint of complete or partial remission of proteinuria at 6 months. The researchers defined complete and partial remission using 2012 Kidney Disease: Improving Global Outcomes (KDIGO) criteria on the basis of proteinuria.

Positive effect on remission in severe cases observed after 6 months.

At month 6, 13 patients in the NIATrituximab arm (35.1%) and 8 (21.1%) in the NIAT-only arm achieved the primary endpoint, a non-significant difference between the groups, Dr. Dahan’s team reported online in the Journal of the American Society of Nephrology.

During a post-RCT observational phase, however, remission rates based on the last follow-up differed significantly between the combination-therapy and NIAT-only arms (64.9% vs.

34.2%). The median time to remission was 7 months in both groups.

Rates of full antiphospholipase A2 receptor antibody (PLA2R-Ab) depletion—indicating complete immunologic remission—at months 3 and 6 were 56% and 50%, respectively, in the NIATrituximab arm compared with 4.3% and 12%, respectively, in the NIAT-only arm, a significant difference between the groups. Eight serious adverse events occurred in each treatment arm.

In addition, the study showed that adding 2 infusions of rituximab to NIAT was associated with a higher percentage increase in serum albumin at months 3 and 6 compared with NAIT alone, the investigators reported.

“These data suggest that PSA2R-Ab levels are early markers of rituximab effect and that addition of rituximab to NIAT does not affect safety,” the researchers concluded.

In addition, trial data suggest criteria for defining remission should include serum albumin and PLA2R-Ab levels, they said.

Dr. Dahan’s group offered some explanations for lack of effect of the NIAT-rituximab regimen on the rate of proteinuria remission at 6 months, including a high rate of remission in the NIAT-only group. Another explanation could be the lower rate of remission than expected in the combination arm. The researchers calculated sample size from initial studies of rituximab, which they said probably overestimated the rate of remission in the NIATrituximab group and led to a lack of statistical power. n

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Renal & Urology News 13

Midlife PSA Foretells PCa Death Risk Values above the median at age 40 to 59 increase the odds of lethal prostate cancer 6.9 to 12.6 times

BY NATASHA PERSAUD LETHAL PROSTATE cancer (PCa) is more likely to develop in men with a PSA level above the median in midlife, according to a new study.

Using data from the Physicians’ Health Study, Mark A. Preston, MD, MPH, of Brigham and Women’s Hospital in Boston, and colleagues performed a case-control analysis of 234 mostly white men diagnosed with PCa and 711 controls aged 40 to 59 at baseline. Then, 71 men with lethal PCa (including cases of metastatic PCa) were re-matched to 213 controls for further analysis.

Median PSA levels among agematched controls were 0.68, 0.88, and 0.96 ng/mL for men aged 40 to 49, 50 to 54, and 55 to 59 years, respectively, according to results published online ahead in the Journal of Clinical Oncology. Over 30 years of follow-up, the investigators found that the risk of lethal PCa was strongly associated with baseline PSA in midlife. Among all cases of lethal PCa, 82%, 71%, and

Fat Predicts PCa Therapy Outcomes PROSTATE CANCER PATIENTS with greater visceral fat volume and density are less likely to experience biochemical recurrence of their cancer following radical prostatectomy (RP) or radiation therapy, researchers reported at the Canadian Urological Association 2016 annual meeting in Vancouver.

Daniel Taussky, MD, and colleagues at Université de Montréal, Québec,

86% occurred in men with PSA levels above the median at ages 40 to 49, 50 to 54, and 55 to 59 years, respectively.

Compared with PSA values at or below the median, PSA values above the 90th percentile at ages 40 to 49, 50 to 54, and 55 to 59 years were associated with 8.7, 12.6, and 6.9 times increased odds of lethal PCa, respectively.

A PSA measurement during middle age may be less confounded by benign prostatic hyperplasia, according to background information in paper. “We found a single baseline PSA-level measurement during midlife could accurately predict future risk of lethal prostate cancer,” Dr. Preston stated in a Brigham and Women’s press release. “These data identify subgroups of men, based on their PSA levels at a given age, who could benefit from screening intervals tailored to their actual magnitude of risk.”

The ideal screening interval based on midlife PSA level is unknown at this point. Men in the study had opportunistic PSA screening.

Midlife PSA and Lethal Prostate Cancer A new study found that men aged 40 to 59 years with PSA levels above the median are at elevated risk of dying from prostate cancer (PCa). Shown here are the proportions of the lethal PCa cases that developed in men according to the age at which they had PSA levels above the median.

100 80

82%

86% 71%

60 40 20 0

40–49

50–54

55–59

Patient age in years

Source: Preston MA, et al. Baseline prostate-specific antigen levels in midlife predict lethal prostate cancer. J Clin Oncol. 2016; published online ahead of print.

In the same release, senior author Lorelei Mucci, ScD, of the Harvard T.H. Chan School of Public Health in Boston, said the study findings support the recommendation that risk-stratified screening for PCa based on midlife PSA should be considered for men aged 45 to 59.

“Our study does not imply prostate biopsy or definitive treatment is

i­mmediately required in younger men with higher PSA levels at baseline, as this could lead to over diagnosis.

Rather, these men should undergo more intensive PSA screening to enable earlier identification of cancer and potential cure while still possible.”

The Physicians’ Health Study included mostly white men, so additional research needs to be conducted in black men. n

Bariatric Surgery May Up Graft Loss PATIENTS WHO UNDERGO bariatric surgery prior to kidney transplantation may be more likely to experience graft loss at 1 year than those with a body mass index (BMI) higher than 35 kg/m 2 who do not have the surgery, researchers reported at the 2016 American Transplant Congress in Boston.

A team at the Medical University of South Carolina in Charleston led by Titte R. Srinivas, MD, studied 1,167 renal transplant patients, of whom 31 patients underwent bariatric surgery prior to transplantation, 974 had a

BMI of 35 kg/m2 or less, and 162 had a BMI above 35 kg/ m2. Of the 1,167 patients, 5% experienced 1-year graft loss. The bariatric surgery patients had 3.4 times increased odds of 1-year graft loss compared with patients who had a BMI above 35 kg/m2 who did not undergo the surgery.

Dr. Srinivas and colleagues noted that bariatric surgery could lead to decreased absorption of immunosuppressive drugs due to the operation itself or increased oxalate absorption that results in oxalate crystallization in the transplanted kidneys.

Although the increased likelihood of 1-year graft loss did not reach statistical significance, Dr. Srinivas said this is because of the relatively small numbers of bariatric surgery patients.

Still, the findings indicate a clinically significant trend that underscores a need for careful patient selection and improved management of immunosuppression, dietary oxalate, and risk factors for oxaluria post-transplant, Dr. Srinivas said. In addition, he said the study findings confirm the clinical experiences shared by many in the transplant community. n

randomly selected 201 patients treated with RP or external beam radiation therapy, all of whom had their visceral adipose tissue (VAT) and subcutaneous adipose tissue volumes manually contoured and corresponding tissue densities in Hounsfield units calculated.

Patients with a VAT volume and density values above the median were 2.5 times and 2.4 times less likely to experience biochemical recurrence, respectively. n

Midlife-PSA_RUN0816.indd 13

SREs Linked to Higher Mortality in mCRPC SKELETAL-RELATED events (SREs) are associated with increased mortality in men with bone metastatic castration-resistant prostate cancer (mCRPC), according to study findings published online in Prostate Cancer and Prostatic Diseases.

The study, by Lauren E. Howard, MD, of Duke University School of Medicine in Durham, North Carolina,

and colleagues, included 233 men with nonmetastatic castration-resistant prostate cancer who later progressed to bone metastases.

During follow-up, SREs occurred in 88 patients (38%) and 198 (85%) died. SREs were associated with a 67% increased mortality risk, after adjusting for age, race, biopsy Gleason score, primary treatment to the prostate, PSA,

months from androgen deprivation therapy to CRPC, and other covariates, according to the investigators. After adjusting for bone pain, SREs were associated with a 42% increased risk.

The researchers noted that SREs, including pathologic fracture, spinal cord compression, radiation and surgery to bone, are common in bone mCRPC patients. n

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New Hyperkalemia Drugs May Help To Optimize Use of RAAS Inhibitors High potassium levels limit the use of the antihypertensive drugs in CKD patients NOVEL AGENTS introduced recently for managing hyperkalemia in outpatient settings will create new opportunities to get the most benefit from renin-angiotensin-aldosterone system (RAAS) inhibition in patients with chronic kidney disease (CKD), according to the authors of a review article published in Current Hypertension Reports (2016;18:55).

Optimizing RAAS inhibition is one of the important therapeutic goals in the CKD population, but development of hyperkalemia as a result of treatment is a major impediment, wrote Anjay Rastogi, MD, PhD, and colleagues at David Geffen School of Medicine at the University of California Los Angeles.

Dr Rastogi, along with Farid Arman, MD, and Setareh Alipourfetrati, MD, reviewed the risks and benefits of the 4 classes of FDA-approved RAAS inhibitors: ACE inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and direct renin inhibitors, of which only aliskiren is FDA approved.

They also reviewed the trial data for patiromer and sodium zirconium cyclosilicate, new hyperkalemia treatments that can reduce the risk associated with the use of RAAS inhibitors.

Dr Rastogi and his colleagues explained that the potential risk of potassium retention is an important limiting factor in the use of RAAS inhibitors. The overall incidence and severity of hyperkalemia associated with RAAS inhibitor use is low in patients with relatively normal kidney function, but is more prominent in those with renal insufficiency and/or diabetes, they wrote.

New report cites the promise of patiromer and sodium zirconium cyclosilicate.

Rapidly acting transient therapies for hyperkalemia are available for use in emergency situations, Dr Rastogi and his co-authors pointed out, but therapeuties for preventing and treating hyperkalemia in the long term are limited.

One of the treatments for hyperkalemia is sodium polystyrene sulfonate (SPS), which is administered orally or as a retention enema. It takes up potassium and releases sodium in the colon.

SPS, however, requires multiple doses and it has a noxious taste, causes diarrhea, and has been associated with rare but serious adverse effects.

The recent introduction of patiromer (Veltassa) and sodium zirconium cyclosilicate has been promising. Patiromer, which was recently approved by FDA, is a nonabsorbable organic polymer administered as a powder that easily mixes with water. Patiromer binds with potassium in exchange for calcium in the colon, thereby decreasing the amount of potassium available for gastrointestinal absorption. Sodium zirconium cyclosilicate, which has not yet received FDA approval, is an orally administered, nonabsorbable polymer that selectively traps potassium ions. The drug has a potassium binding capacity 9 times that of SPS, the authors noted. It exchanges sodium for potassium in the GI tract, beginning in the duodenum.

“If proven safe and effective for longterm use, these therapies may be administered together with RAAS inhibitors to reduce the risk of adverse effects and to allow for the utilization of maximum renal and cardiovascular protective effects of RAAS inhibitors.” n

Fracture Risk Factors in Transplant Patients ID’d OLDER DONOR AGE and end-stage renal disease (ESRD) caused by diabetes or cystic kidney disease are among the risk factors for major bone fractures in kidney transplant recipients, researchers reported in the World Journal of Transplantation (2016;6:370-379).

Kyla L. Naylor, MD, of the Institute for Clinical Evaluative Sciences in London, Ontario, Canada, and colleagues studied 2723 adults who received kidney-only transplants from 2002 to 2009. They examined general risk factors (such as age, sex, and prior major fracture) and transplant-specific risk factors (such as donor age and cause of ESRD) for major fractures.

Major fractures included those of the proximal humerus, forearm, and hip, as well as clinical vertebral fractures.

During an average follow-up of 6 years, 132 patients (4.8%) suffered a major fracture (8.1 fractures per 1000 personyears) and 402 patients died (14.8%).

hyperkalemia_RAAS_RUN0816.indd 17

Compared with recipients who did not suffer a major fracture, those who did were significantly older (median age 56.5 vs. 50.5 years), were more likely to be women (48.5% vs. 35.8%), and were less likely to have glomerulonephritis as their cause of ESRD (29.6% vs. 36.7%).

In multivariable analysis, each 5-year increment in recipient age was associated with a significant 11% increased risk of major fracture. Women had an 81% increased risk of major fracture compared with men. Compared with recipients whose ESRD was caused by glomerulonephritis, those with ESRD caused by diabetes or cystic kidney disease had a 72% and 73% increased risk of major fracture, respectively. Each 5-year increment in donor age was associated with a 9% increased risk.

The investigators also assessed risk factors for fractures in other locations (excluding major fractures and fractures of the skull, hands, or feet). Diabetes

and a fall with hospitalization in the year prior to transplantation were the general risk factors associated with an greater risk of these other fractures, and length of time on dialysis and renal vascular disease and other causes of ESRD were the transplant-specific risk factors associated with a greater risk of other fractures. The researchers found no association between recipient age and female sex and the risk of other fractures.

“Our findings suggest that both general and transplant-specific risk factors for fracture should be considered by clinicians when assessing fracture risk in kidney transplant recipients,” Dr. Naylor’s team wrote. “However, different risk factors may need to be taken into account when considering different fracture locations.”

The investigators commented that, unfortunately, “none of the risk factors for major fractures found in this study are easily modifiable.” n

Renal & Urology News 17

Restricting Fat May Cut CKD Risk HIGHER CONSUMPTION of advanced glycation end products (AGEs) through dietary fat is associated with higher risk of chronic kidney disease (CKD), according to a new study.

Hanieh-Sadat Ejtahed, MSc, of the Shahid Beheshti University of Medical Sciences in Tehran, Iran, and colleagues studied 1692 participants in the Tehran Lipid and Glucose Study who were free of CKD at baseline. The individuals had a mean age of 43.4 years and mean dietary intake of energy-adjusted AGEs was 8336 kU/day. The mean dietary AGE intake from fat and meat was 3518 and 3609 kU/day, or 42.2% and 43.3% of total AGE intake, respectively. After 3 years of followup, 172 individuals (10.2%) were diagnosed with CKD. Participants in the highest quartile of AGEs intake from fat was associated with 2-fold increased odds of CKD compared with those in the lowest quartile, the investigators reported online in the Journal of Renal Nutrition. Total AGE intake and AGE intake from meats was not associated with CKD risk.

The researchers concluded that “restricting dietary AGEs by decreasing fat intake is a practical strategy for decreasing CKD incidence.”

AGEs are proteins or lipids that become glycated and oxidized after exposure to sugars. They contribute to oxidative stress and inflammation and promote atherosclerosis, insulin resistance, and renal dysfunction.

Diets rich in fats and meats are likely to contribute more AGEs, especially when cooked under drug heat, according to investigators.

The researchers cited studies showing that AGEs can increase the thickness of glomerular basic membrane, glomerular sclerosis, and tubular interstitial fibrosis. AGE accumulation is associated with renal insufficiency and correlated positively with serum creatinine and negatively with glomerular filtration rate, they noted. n

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18 Renal & Urology News

■ AUA 2016, San Diego

AUGUST 2016 www.renalandurologynews.com

American Urological Association 2016 Annual Meeting

Water Vapor Ablation Eases BPH/LUTS Symptomatic improvements, including preservation of sexual function, durable to 24 months TRANSURETHRAL convective water vapor energy (WAVE) ablation of prostate tissue offers an effective minimally invasive alternative for treating lower urinary tract symptoms secondary to benign prostatic hyperplasia, according to the findings of separate studies.

The studies showed that treatment with the Rezum System (NxThera, Inc.), which uses the thermal energy of steam to ablate prostate tissue, provides durable symptom improvement while preserving sexual function.

In a study of 197 men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH), Kevin McVary, MD, of the Southern Illinois University School of Medicine in Springfield, and colleagues randomly assigned patients to undergo WAVE ablation (136 men) and 61 to receive a control procedure consist-

Sleep Apnea May Increase Risk of UI OBSTRUCTIVE SLEEP APNEA (OSA) is associated with an increased risk of urinary incontinence (UI), according to a new study.

Using data from Taiwan’s Longitudinal Health Insurance Database, researchers compared 1,499 individuals with obstructive sleep apnea (1,210 men and 289 women) with 7,495 age- and gendermatched controls without OSA.

ing of rigid cystoscopy with mimicked active treatment sounds. At 3 months, LUTS improved by 11 points in the WAVE group compared with 4.3 points in the control arm. In patients with severe LUTS (International Prostate Symptom Score [IPSS] greater than 19), 85% achieved a 30% or greater reduction in symptoms. At 3 months, peak flow rate increased 68% (6.2 mL/sec) in the WAVE group compared with no change in the control group. These improvements were sustained in 96% of treated subjects who completed their 1 year follow-up.

At study entry, 52% of treatment subjects had a history of erectile dysfunction (ED) and 26% had ejaculatory dysfunction. Dr. McVary’s group included only sexual active men (91 of the 136 WAVE patients) in sexual function analyses. In these

men, the International Index of Erectile Function baseline mean score was 17.2 and the Male Sexual Health Questionnaire for Ejaculatory

In a study, no new cases of ED were reported following the procedure.

Dysfunction mean score was 7.8. The researchers reported no clinically meaningful negative changes in scores over 12 months. Modest decreases in ejaculatory volume occurred in 6 men (4.4%), anejaculation in 4 men (2.9%).

No new cases of ED were reported.

In another study, Christopher Dixon, MD, of Bronx-Lebanon Medical

Center in Bronx, NY, and colleagues found that WAVE ablation provides effective and sustained relief of BPH/ LUTS for 2 years with no deterioration in sexual function. The study included 65 men with moderate-to-severe LUTS who underwent WAVE treatment.

The researchers observed significant clinical improvements at 1, 3, 6, 12, and 24 months in IPSS, which decreased at those time points by 7.2, 13.4, 13.1, 12.5, and 12.1 points, respectively. At 24 months, these results were equivalent to a significant 55% improvement in IPSS and a 58% improvement in peak flow rate. Additionally, patients reported an improved quality of life, which was sustained at 24 months with a 58% improvement. Sexual function was preserved. One patient had prolonged urinary retention that required transurethral resection of the prostate. n

Robotic RC Gaining in Popularity SURGEONS ARE performing a growing proportion of radical cystectomies robotically, an approach associated with short-term outcomes similar to those of open surgery, according to a study of New York State data.

From 2009 to 2012, the number of surgeons performing robotic-assisted radical cystectomy (RARC) in the state increased from 56 to 66, whereas the number performing open radical cystectomy (ORC) decreased from 117 to 109, investigators at the Mount Sinai Icahn School of Medicine in New York reported.

The proportion of patients undergoing RARC increased from 19.9% to 28.9%,

Jamie S. Pak, a fourth-year medical student, and colleagues reported.

Across the study period, the median approach-specific surgeon volume was significantly lower for RARC than ORC (3 vs. 8 cases per year).

Results also showed that the proportion of patients undergoing pelvic lymph node dissection and ileal conduit creation was significantly higher with RARC than ORC (80% vs. 70.4% and 80.5% vs. 76.6%, respectively).

The proportion of patients requiring blood transfusion was significantly lower with RARC than ORC (34.3% vs.

47.4%). In multivariate analysis, RARC

was associated with 40% lower odds of blood transfusion compared with ORC. Researchers found no significant differences in inpatient complication rate, hospital length of stay, hospital charges at the index stay, readmission rates, or mortality rates during the index stay or at 30 or 90 days.

For the study, the researchers analyzed data from an all-payer statewide reporting system database. The study included 2,525 patients, 610 who underwent RARC and 1,915 who underwent ORC. The cohorts did not differ significantly with respect to age, gender, race, comorbidities, and primary payer. n

The mean follow-up was 5.6 years.

Results showed that individuals with OSA had a significantly higher incidence of UI than controls (3.6% vs.

1.8%). The incidence of UI was 2.3% among men and 9% among women.

After adjusting for heart disease, ischemic stroke, hyperlipidemia, diabetes, and hypertension, OSA patients had a nearly 2-fold increased risk of UI compared with controls, the researchers reported. n

AUA_BPH_Wave_RUN0616.indd 18

C. Difficile Risk Not Linked to Pre-RC Chemo PATIENTS WHO RECEIVE neoadjuvant chemotherapy prior to radical cystectomy (RC) for bladder cancer are not at increased risk for post-operative Clostridium difficile infection, researchers reported.

Previous studies have shown that RC alone and just having cancer increases the risk of C. difficile infection, lead

investigator Katherine J. Cotter, MD, noted. “With the added component of immunosuppression from neoadjuvant chemotherapy, our hypothesis was that this factor may increase C. difficile incidence,” she told Renal & Urology News.

Dr. Cotter and her colleagues at the University of Minnesota in Minneapolis studied 144 patients undergoing RC.

Of these, 14 (12%) experienced C. difficile infection within 30 days postoperatively, a rate higher than the 1.7% to 8.8% rate reported in the literature.

C. difficile infection developed in 6 (12.2%) of the 49 patients who received neoadjuvant chemotherapy and 8 (8.4%) of the RC-only patients, a non-significant difference between the groups. n

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Renal & Urology News 19

PCa Risk Linked to PSA at Age 55–60 As baseline PSA in this age range increases, so does the likelihood of any or significant prostate cancer BASELINE PSA levels in men aged 55–60 years strongly predict the future risk of being diagnosed with prostate cancer (PCa), researchers reported.

For example, among men in this age group with a baseline PSA level less than 0.5 ng/mL, the 5- and 13-year risk of any PCa diagnosis is 0% and 0.8%, respectively, according to Eric Kovac, MD, of Cleveland Clinic Foundation, and colleagues at Memorial SloanKettering Cancer Center in New York and Göteborg University in Göteborg, Sweden. The risks of an important PCa diagnosis are 0% and 0.4%. respectively.

In contrast, among men with a baseline PSA level of 2.0–3.0 ng/mL, the 5- and 13-year risk of any PCa diagnosis is 8.4% and 24%, respectively. The corresponding risks of an important PCa diagnosis are 2.7% and 11%. The 5- and 13-year risks among men with a baseline PSA level greater than 4 ng/mL are

Incontinence Care Varies

by Specialty MEDICAL SPECIALTIES vary considerably in their management of urinary incontinence (UI) in women, despite the availability of UI treatment guidelines, new study findings suggest.

In addition, the study showed that most women do not have their type of UI categorized and urinalysis is underused.

Researchers at Weill Cornell Medical College/New York Presbyterian Hospital in New York led by Bilal Chughtai, MD, analyzed 1999–2010 data from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medicare Care Survey. They identified visits by adult female patients to physician practices or hospital outpatient departments where UI was the chief complaint or primary diagnosis.

The number of UI visits increased from 10.7 million in 1999–2000 to 13.6 million in 2009–2010.

Overall, the use of antimuscarinic agents increased significantly from

AUA_baselinePSA_RUN0816_vG.indd 19

Midlife PSA and Future Prostate Cancer The higher a man’s PSA level in middle age, the greater his risk for an important prostate cancer (PCa) diagnosis in later years, according to a new study. Below is an example of the 5- and 13-year risks of important PCa associated with midlife PSA values.

29.5%

30 25

21.3%

20 15

n 5-year risk n 13-year risk

11%

10 5 0

2.7% 2.0–3.0 ng/mL

>4 ng/mL

Source: Kovac E, et al. Baseline PSA before age 60 as a predictor of important prostate cancer diagnosis and prostate cancer-specific mortality in the intervention arm of the Prostate, Lung, Colorectal and Ovarian Trial. Presented at the American Urological Association 2016 annual meeting in San Diego. MP39-11.

40.5% and 53.7%, respectively, for any PCa diagnosis and 21.3% and 29.5% for an important PCa diagnosis.

For the study, which included 10,968 men in the intervention arm of the

16.7% of UI visits in 1999–2000 to 35% in 2009–2010. Urinalysis use decreased significantly from 53% of cases in 1999–2000 to 37.2% in 2009–2010.

The investigators examined trends in the management of UI by physician specialty: primary care doctors, urologists, and gynecologists. Antimuscarinic use among gynecologists was less than that of the other specialties.

Data showed that antimuscarinic use among primary care doctors rose from 24.9% of cases in 1999–2000 to 42.4% in 2009–2010, a trend that was not statistically significant. Urologists’ use of antimuscarinic agents rose significantly from 23.5% of cases in 1999–2000 to 44.2% in 2009–2010. Gynecologists used antimuscarinics in 10% of cases in 1999–2000 and 25.3% in 2009–2010.

Urinalysis use by primary care doctors declined from 49.7% of cases in 1999–2000 to 19.5% in 2009–2010.

Urinalysis use by urologists decreased from 81.1% in 1999–2000 to 63.7% in 2009–2010. Urinalysis use by gynecologists decreased from 50.6% of cases in 1999–2000 to 29.4% in 2009–2010.

The increase in antimuscarinic use, Dr. Chughtai noted, may be due, in part, to the more widespread availability and marketing of these medications. n

Prostate, Lung, Colorectal, and Ovarian (PLCO) trial aged 55–60 years at study entry, Dr. Kovac and his colleagues defined an important PCa diagnosis as cT2b or higher or pT3 or higher tumors,

biopsy or pathologic Gleason score of 7 or higher, or death from PCa. The median follow-up time from study enrollment to PCa diagnosis was 71 months, Dr. Kovac’s group reported. The median survival time was 141 months. Only 15 men died from PCa after 13 years of follow-up. Eight of these men had a baseline PSA level above 4.0 ng/mL. “Nomograms predicting the outcomes of screening should include baseline PSA information,” the investigators concluded in a poster presentation. “This information may be used to refine existing screening paradigms to reduce overdiagnosis and over-treatment.”

In a paper published recently in the Journal of Clinical Oncology, Mark A. Preston, MD, MPH, and colleagues reported on a study showing that men with a PSA level above the median in midlife are at increased risk of dying from PCa. n

Novel Oral Testosterone Shows Long-Term Safety, Tolerability LPCN 1021, A NOVEL oral testosterone

In a 52-week phase 3 open-label

formulation, demonstrates a favorable

randomized trial comparing LPCN 1021

safety and tolerability profile for the

with an active control (testosterone

long-term treatment of hypogonadal

gel [T gel]), a team led by Mohit Khera,

men, study findings suggest.

MD, of the Baylor College of Medicine

A phase 3 study, which previously

in Houston, found comparable rates of

established the drug’s efficacy in raising

adverse events (AEs) in both treatment

testosterone levels, found that LPCN

arms: 67% of LPCN 1021 patients

1021 causes no liver toxicities, a well-

and 65% of T gel patients. No hepatic,

recognized problem associated with oral

cardiac, or drug-related serious AEs

testosterone preparations. The formula-

occurred, Dr. Khera said.

tion bypasses the liver and is absorbed mainly by the lymphatic system.

The drug, which is being developed

The study included 315 men: 210 randomly assigned to receive LPCN 1021 twice daily and 105 randomized

by Lipocine, Inc., of Salt Lake City, is

to receive T gel (Androgel 1.62%).

under FDA review.

Following a 13-week efficacy phase,

An advantage of the drug is that it

men continued to receive their

would avoid the potential danger of

assigned treatment for up to 52 weeks,

transferring testosterone to family

returning at weeks 26, 39, and 52 for

members and others, as is potentially

safety assessments.

the case with testosterone gels,

The effects of the drugs on lipid and

patches, and implants, according to

androgenic parameters were similar

investigators.

between treatment arms. n

7/20/16 10:54 AM

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Renal & Urology News 21

PPI Use Linked to Low Magnesium in HD Patients PROTON PUMP inhibitor (PPI) use by hemodialysis patients is associated with low serum magnesium levels, which in the presence of inflammation predict increased 1-year mortality risk, according to a new study.

Rika Ago, MD, of Miyoshi Central Hospital in Hiroshima, Japan, and

colleagues studied 399 hemodialysis patients, of whom 243 were using PPIs when magnesium measurements were obtained. Mean serum magnesium levels were significantly lower in patients who used PPIs than in those who did not (2.39 vs. 2.56 mg/dL), the researchers reported online in Hemodialysis

International. In addition, lower serum magnesium levels were associated with elevated levels of high-sensitivity C-reactive protein (hs-CRP), which is a marker of systemic inflammation, and lower albumin and potassium levels.

“These results indicate that low serum magnesium levels are related to

malnourishment and inflammation in these patients,” the investigators noted.

During follow-up, 29 deaths occurred.

High hs-CRP levels (above 4.04 mg/L) in association with low magnesium were associated with a nearly 3-fold increased risk of 1-year mortality.

The study was limited by its observational design and the fact that serum magnesium measurements were obtained once at baseline. In addition, the researchers could not assess specific mortality risks because of the small number of patients who died.

Dr. Ago’s group noted that the FDA in 2011 warned that low magnesium levels may be associated with long-term use of PPIs, and some observational data have linked PPI use with hypomagnesemia. n

Smokers Face Prolonged UI After RARP URINARY INCONTINENCE (UI) following robotic-assisted radical prostatectomy (RARP) is more likely to be prolonged in men who are current smokers, new data presented at the Canadian Urological Association 2016 annual meeting suggest.

A team at the Université de Montréal in Quebec led by Assaad El-Hakim, MD, analyzed continence data from 322 RARP patients who were interviewed at 1, 3, 6, 12, and 24 months after surgery. In multivariate analysis, active smokers at the time of surgery had a significant 42% decreased likelihood of continence recovery compared with non-smokers, Dr. El-Hakim’s group reported in a poster presentation.

Results also showed that bladder neck sparing, large prostate size, and longer operative time independently predicted delayed continence recovery after surgery.

Active smokers who undergo RARP and who have 1 or more additional risk factors for delayed continence recovery, such as large prostate glands and prolonged operative times, should be counseled on the increased risk of urinary incontinence postoperatively, they wrote. n RU_7x10_Legal.indd 1

hypomagnesemia_RUN0816.indd 21

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Selenium May Cut Aggressive PCa Risk MEN WITH higher selenium levels have a lower risk of aggressive prostate cancer (PCa), according to a new study.

Each 80th percentile increase in blood and nail selenium concentrations is associated with a significant 57% and 82% decreased odds of aggressive PCa, respectively, after adjusting for body mass index, age, height, smoking status, education, and marital status, Naomi E. Allen, MSc, DPhil, of the University of Oxford in Oxford, U.K., and colleagues reported in the Journal of the National Cancer Institute (2016;108:djw153). The researchers defined aggressive PCa as advanced stage disease and/or PCarelated death.

The concentration of selenium in nail, but not blood, was inversely associated with the risk of total PCa. Each 80th percentile increase in nail selenium associated with a significant 71% decreased odds of total PCa and 67% decreased odds of non-aggressive PCa.

Brazil nuts are rich in selenium, a trace element with antioxidant properties.

“Because a substantial proportion of PSA-detected cancers remain biologically indolent for many years, the identification of factors that are associated with the development of clinically

Non-Adherence Predicts Worse Transplant Outcomes NON-ADHERENCE to follow-up visits

vs. 50%). The proportion of patients

and medication regimens by kidney

with a history of diabetes mellitus was

transplant recipients is associated with

significantly higher in the adherent than

worse transplant outcomes, and rates of

non-adherent group (36% vs. 30%).

non-adherence differ by race, accord-

In the other study, David J. Taber,

ing to the results of separate studies by

PharmD, MS, and colleagues found

researchers at the Medical University

that black kidney transplant recipients

of South Carolina in Charleston pre-

appear to have higher rates of early

sented at the 2016 American Transplant

non-adherence than non-blacks, and

Congress in Boston.

these higher rates are driven mainly by

In a study of 1410 kidney transplant

missed appointments.

recipients, Raghavesh Pullalarevu, MD,

The study included 1407 kidney

and collaborators found that 737 had

transplant recipients, of whom 687

documented adherence to laboratory

(53%) were black and 620 were not. The

assessments, clinic appointments,

researchers observed non-adherence in

and medication regimens and 673 had

19.5% of the black patients within 1 year

documented non-adherence.

(18% non-adherent with appointments

Compared with adherent patients,

and 2.2% non-adherent with medica-

non-adherent patients had a significant

tions) compared with 12.1% of non-black

40% increased odds of acute rejection

patients, a significant difference between

and 3-fold and 7.7-fold increased odds

the groups. Black patients had 76%

for second and third rejection episodes,

increased odds of non-adherence.

respectively, the investigators found.

The non-adherent group had a

Early non-adherence was significantly associated with acute rejection and

significantly higher proportion of black

hospital readmission among black

patients than the adherence group (57%

patients but not non-black patients. n

PCa-selenium_RUN0816.indd 22

aggressive cancers is important,” Dr. Allen’s group wrote. “Hence, our finding that both blood and nail concentrations were associated with a lower risk of aggressive prostate cancer is of potential etiological relevance.”

The results are based on an analysis of individual participant data from 15 prospective studies in which data were available for 4527 case patients and 6021 control patients for blood selenium and 1970 cases and 2086 controls for nail selenium.

The researchers acknowledged that it is possible that the inverse association of blood and nail selenium level and risk of aggressive PCa might be due to confounders, but noted that they adjusted their analyses for a range of lifestyle factors as well as the matching factors used in the individual studies, “none of which materially influenced the risk estimates.”

Dr. Allen and her collaborators pointed out that nails are a more reliable marker of long-term selenium exposure, and

this might explain why nail, and not blood, selenium levels are inversely associated with the risk of total PCa. Nail clippings provide a measure of exposure over several weeks and up to 12 months prior to sample collection, they noted. Blood levels reflect shorterterm (1–2 weeks) selenium exposure.

According to the researchers, the absence of an association between blood selenium levels and total PCa risk is consistent with the findings of the Selenium and Vitamin E Cancer Prevention Trial (SELECT). In this phase 3 trial, investigators randomly assigned 35,533 men to 1 of 4 groups: placebo plus placebo; vitamin E plus placebo; selenium plus placebo; and selenium plus vitamin E. The median follow-up was 5.5 years. Selenium was dosed at 200 µg/day and vitamin E was dosed at 400 IU/day. Selenium or vitamin E, alone or in combination, did not significantly affect PCa risk. n

SCr Doubling Ups CV Risks In Diabetics

(2016;8177-184). The groups with and without a doubling of serum creatinine had similar risks of angina pectoris and transient ischemic attack.

The researchers also looked at CV risk estimates by sex, and found the most pronounced sex disparity for MI. Among patients who had a doubling of serum creatinine, women had a 3.32 times increased risk of MI compared with a 1.84 times increased risk for men compared with patients who did not have a doubling of serum creatinine.

Dr. Meier’s group noted that their results are based on data from the primary care setting, and acknowledged “there is a possibility that we may have missed some cases with cardiovascular outcomes, particularly milder forms of the outcomes of interest. However, as most cardiovascular outcomes in this study represent acute and rather severe diseases, we are confident that few cases with an outcome of interest have been missed.”

For the study, the investigators considered patients to have CKD if they had at least 2 estimated glomerular filtration rate values below 90 mL/min/1.73 m2, separated by at least 90, but not more than 730 days. Most patients (56.4% and 71.8% in the groups with and without doubling of serum creatinine, respectively) had an eGFR of 75 to 89 mL/ min/1.73 m2 at or prior to baseline. n

DOUBLING OF SERUM creatinine is associated with an increased risk of cardiovascular (CV) events in patients with chronic kidney disease (CKD) and type 2 diabetes, according to a new study.

Using the Clinical Practice Research Datalink, a U.K. database of some 8 million individuals enrolled with general practitioners, a team led by Christoph R. Meier, PhD, of University Hospital Basel in Basel, Switzerland, identified 27,811 adult patients with CKD and type 2 diabetes. Of these, 21,215 had a follow-up of time of at least 3 years. Doubling of serum creatinine occurred in 1,262 patients.

Angina pectoria, congestive heart failure (CHF), myocardial infarction (MI), stroke, and transient ischemic attack developed in 693, 1069, 508, 970, and 578 patients, respectively. Compared with patients who did not have a doubling of serum creatinine, those who did had a nearly 3 times increased risk of CHF, 2.5 times increased risk of MI, and 1.9 times increased risk of stroke, the investigators reported in Clinical Epidemiology

© THINKSTOCK

An analysis of individual participant data from 15 prospective studies suggests a protective effect

7/20/16 10:57 AM

www.renalandurologynews.com AUGUST 2015

Low Sodium Ups Death Risk in PD LOW SERUM SODIUM LEVELS are associated with a higher risk of death among adult patients on peritoneal dialysis (PD), independent of sociodemographic factors and comorbidities, according to a new study.

In this study, incrementally lower baseline and time-dependent serum sodium categories below 140 mEq/L were increasingly associated with higher death risk compared to a reference category of 140 to less than 142 mEq/L independent of case-mix covariates, lead investigator Connie M. Rhee, MD, MSc, of the University of California Irvine School of Medicine and colleagues reported in Nephrology Dialysis Transplantation. For example, in time-dependent analyses, sodium categories of 138-<140, 136-<138, 134-<136, and <134 mEq/L were associated with a 1.5-, 2.0-, 2.8-, and 4.1-fold higher death risk compared to the reference category.

The study included 4687 adult incident PD patients who underwent at least 1 serum sodium measurement within the first 3 months of dialysis.

Renal & Urology News 23

Hyperkalemia Drug Lowers Aldosterone Study demonstrates a novel effect of patiromer treatment in CKD patients PATIROMER treatment decreases aldosterone levels in patients with chronic kidney disease (CKD) and hyperkalemia on renin-angiotensinaldosterone system (RAAS) inhibitors, a new study suggests. The effect is independent of plasma renin activity.

Matthew R. Weir, MD, of the University of Maryland Medical Center in Baltimore, and colleagues analyzed data from the phase 3 OPAL-HK study. The study consisted of a 4-week initial treatment phase in which 243 patients received patiromer—a novel potassium-binding polymer that uses calcium as the cation for exchange with potassium in the gastrointestinal tract—and an 8-week randomized placebo-controlled withdrawal phase with 107 patients, of whom 55 continued on patiromer and 52 switched to placebo.

Most patients had advanced CKD and diabetes mellitus.

In the treatment phase, the mean serum potassium level decreased concordantly with serum aldosterone (−1.99 ng/dL), systolic/diastolic blood pressure (−5.64/−3.84 mm Hg), and albumin-to-creatinine ratio (−203.7 mg/g), Dr. Weir’s group reported online in Kidney International. All of these decreases were statistically significant.

In the withdrawal phase, mean aldosterone levels were sustained with patiromer (+0.23 ng/dL) but increased significantly with placebo (+2.78 ng/dL). In addition, patiromer-treated patients had significant decreases in mean systolic/ diastolic blood pressure (−6.70/−2.15 mm Hg), whereas placebo recipients did not (−1.21/+1.72 mm Hg). The investigators observed significant changes in plasma renin activity only in the placebo group.

Patiromer use was associated with decreases in BP and albuminuria.

“Although patiromer and other agents are documented to reduce potassium levels in individuals with CKD, there are no previously published reports that demonstrate a reduction in aldosterone, blood pressure, and albuminuria with these agents,” the investigators wrote.

The researchers noted that, based on their study, there is no direct evidence to determine whether reductions in blood pressure and albuminuria were secondary to decreases in aldosterone.

Patiromer was well tolerated with a low rate of discontinuation due to adverse events: 6% in the initial treatment phase and 2% in the randomized withdrawal phase.

Aldosterone production is not only regulated by the RAAS, but also by potassium, “which is equally potent in modulating aldosterone secretion,” the researchers explained.

Higher levels of serum aldosterone are associated with increased mineralocorticoid receptor stimulation, which has been shown to promote cardiovascular and renal disease progression in experimental and clinical studies, according to background information provided by the researchers.

“By blocking this interaction, mineralocorticoid receptor antagonists have demonstrated benefits in patients with heart failure and post-acute myocardial infarction,” Dr. Weir and colleagues stated.

The use of mineralocorticoid receptor antagonists, however, in patients with renal dysfunction is associated with a substantial incidence of hyperkalemia, which limits their use either alone or combined with angiotensinconverting enzyme inhibitors or angiotensin receptor blockers, according to the researchers. n

Dr. Rhee’s team suggested a number of potential mechanisms by which low serum sodium may lead to greater mortality among PD patients. For example, they noted that severe hyponatremia may be directly toxic to the brain, resulting in cerebral edema and herniation, encephalopathy, seizure, and coma. In addition, emerging data suggest that hyponatremia leads to derangements in cardiac conduction and function as a result of inhibition of calcium channel circuits. The investigators also cited research showing that hyponatremia is a risk factor for worse outcomes in patients with PD-related peritonitis and infectionrelated mortality risk in PD patients.

With regard to study limitations, the researchers noted that atients were required to have at least 1 serum sodium value, “and while the indications for which sodium measurement within the study population cannot be ascertained, this was likely at the discretion of medical providers.” n

Patiromer_RUN0816.indd 23

Delayed RRT for AKI Does Not Increase Mortality EARLY AND DELAYED initiation of renal-replacement therapy (RRT) for critically ill patients with severe acute kidney injury (AKI) are associated with similar mortality risks, a new French study suggests.

In a multicenter trial, Stéphane Gaudry, MD, of Hôpital Louis Mourier, Colombes, France, and colleagues randomly assigned 620 intensive care unit patients with stage 3 AKI to receive early (immediately after randomization) or delayed RRT. In the delayed group, RRT was initiated when at least 1 of the following criteria was met: severe hyperkalemia, metabolic acidosis, pulmonary edema, blood urea nitrogen level higher than 112 mg/dL, or oliguria for more than 72 hours after randomization. The primary outcome was overall survival at day 60.

Patients in the early-strategy group underwent their first RRT session within a median of 2 hours after randomization, and those in the delayed-strategy group received RRT within a median of

57 hours after randomization, according to the investigators. A total of 150 deaths occurred among the 311 patients in the early-strategy group (48.5%) and 153 deaths occurred among the 308 patients in the delayed-strategy group (49.7%), the investigators reported online in the New England Journal of Medicine. In addition, 151 patients (49%) in the delayed-strategy group did not receive RRT. The rate of catheter-related bloodstream infections was significant higher in the early- versus delayed-strategy group (10% vs. 5%).

Results showed that diuresis, a marker of improved renal function, occurred significantly earlier in the delayed-strategy group.

The investigators stated that their study should not be interpreted as suggesting that a “wait and see” approach is safe for all patients. Indeed, they noted that careful surveillance is mandatory when deciding to delay RRT in patients with severe AKI so that any complication will be detected and RRT initiated

without delay. “In our trial, delaying the initiation of therapy allowed many patients to recover from acute kidney injury without embarking on such a treatment course,” they stated.

Dr. Gaudry and colleagues cautioned that their findings may not be generalizable because more than half of the patients in the study received intermittent hemodialysis as the first mode of therapy, and only 30% of patients received continuous RRT as the sole method, with no intermittent dialysis at any time.

In an accompanying editorial, Ravindra L. Mehta, MD, of the University of California San Diego, said the trial provides new data “to unravel the complexity of the timing” of RRT initiation in the context of AKI. “The findings highlight a need for dynamic risk-stratification tools to identify patients who will not need renal-replacement therapy for management of their acute kidney injury,” Dr. Mehta wrote. n

7/20/16 10:59 AM

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DNA-Repair Gene Mutations Occur Often in Men with Metastatic PCa Genetic testing results could help guide therapy for advanced disease

BY NATASHA PERSAUD GERMLINE MUTATIONS in genes that maintain DNA integrity appear in a significant proportion of men with metastatic prostate cancer (PCa), according to a new study published online ahead of print in the New England Journal of Medicine.

Among men with metastatic PCa, 11.8% had inherited mutations that are presumed to be harmful compared with just 4.6% of men with localized PCa and 2.7% of the general population.

“The result is surprising and important for men with prostate cancer as this information may prioritize certain therapies,” Peter S. Nelson, MD, of Fred Hutchinson Cancer Research Center in Seattle, and senior author of the study stated in a press release. “These findings present a compelling argument for updating prostate cancer screening guidelines to include germline DNA testing as a part of standard care for men with metastatic prostate cancer.”

For the study, Dr. Nelson and colleagues determined the incidence of DNA-repair gene mutations in 692 men with metastatic PCa from 7 case series across multiple institutions in the United

Peter S. Nelson, MD

States and United Kingdom. They then compared it to the frequencies among patients with localized PCa using public data on 499 patients from the Cancer Genome Atlas PCa study and a general population of 53,105 without known cancer from the Exome Aggregation Consortium. Men with metastatic PCa were recruited without regard to family history, age, or genetic background.

The investigators isolated germline DNA and used multiple sequencing assays to assess mutations in 20 DNA-

repair genes linked with syndromes that predispose to autosomal dominant cancer. A total of 84 pathogenic mutations were found in 16 genes, such as BRCA2 (prevalent in 44% of men with these mutations), ATM (13%), CHEK2 (12%), and BRCA1 (7%). The chances of having these mutations did not differ by age at diagnosis or family history of PCa, according to the investigators.

The study has important clinical implications, according to Dr Nelson and colleagues. Genetic testing for these mutations could identify patients who may benefit from precision treatments. For example, other research indicates these patients may respond to poly-ADP ribose polymerase inhibitors, which target vulnerabilities in the DNA repair process within cancer cells, and platinum-based chemotherapy.

“It is also important for family members as they may have inherited a gene that predisposes them to developing one of several types of cancer [breast, ovarian, pancreatic] and heightened awareness could enhance early detection and treatment,” Dr. Nelson stated. n

Prostatic Abscess Risk Factors Identified LONGER SYMPTOM duration and voiding disturbances in men suspected of having acute prostatitis predict an increased likelihood that prostatic abscess is present and should prompt clinicians to consider performing imaging studies, according to researchers.

“Early diagnosis is beneficial because prostatic abscesses require prolonged treatment protocols, or even require surgical drainage,” Dong Sup Lee, MD, of The Catholic University of Korea in Suwon, South Korea, and colleagues wrote in BMC Urology (2016;16:38).

The investigators reviewed 31 prostatic abscess cases that developed in 142 patients with acute prostatitis. All patients underwent computed tomography (CT) or transrectal ultrasonography (TRUS) to discriminate acute prostatic abscesses from acute prostatitis without abscess formation.

Multivariate analysis showed that longer symptom duration and voiding distur-

metastatic-PCa_RUN0816.indd 25

bances were associated with significantly increased odds of abscess formation.

The antibiotic treatment period in general was longer in cases of prostatic abscess than in those without abscess, regardless of surgical intervention, the investigators reported.

Patients with abscesses smaller than 20 mm did not undergo surgery and were cured without any complications.

Patients with abscesses larger than 20 mm who underwent transurethral resection had a shorter duration of antibiotic therapy compared with men who did not have surgery. The incidence of septic shock did not differ significantly between the groups.

The vast majority of the acute prostatitis cases were caused by gram negative bacteria, the researchers stated.

A wide range of microorganisms may be detected in prostatitis with abscess formation. “Therefore, physicians should perform urine culture prior to

administering empirical antibiotics,” they wrote. “These cultures should be repeated, if possible, during treatment.

With appropriate treatment, the prognosis of acute prostatitis with and without abscess would not differ.”

The investigators noted that prostatic abscesses often are found in patients who do not improve with initial therapy. “Therefore, without [a] routine imaging study, a prostate abscess present initially may be missed rather than developing from acute prostatitis during the follow-up period.” In their 111 cases of confirmed acute prostatitis without abscess, abscess formation was not identified during the treatment period, the authors noted.

“Routine imaging studies such as CT or TRUS should be considered in cases of acute prostatitis for this reason, especially in patients with longterm symptom duration and voiding disturbances,” they wrote. n

Renal & Urology News 25

VUR Scans Not Good Alternatives NEITHER RENAL-BLADDER ultrasound nor dimercaptosuccinic acid scans are sufficiently accurate to detect vesicoureteral reflux (VUR), investigators concluded based on a systematic review.

Nader Shaikh, MD, and colleagues at Children’s Hospital at Pittsburgh, analyzed data from 42 cross-sectional or cohort studies comparing results of the index tests—renalbladder ultrasound (RBUS) or dimercaptosuccinic acid (DMSA) scans—with the findings from radiographic voiding cystourethrography (VCUG), the gold standard, in children younger than 19 years with a culture-confirmed urinary tract infection (UTI).

Of the 42 studies, 20 reported data on the test performance of RBUS in detecting VUR. The summary sensitivity and specificity estimates for RBUS scans were 44% and 78%, respectively, the authors reported online in the Cochrane Database of Systematic Reviews.

The 11 studies that reported data on the test performance of RBUS in detecting high-grade VUR found that the summary sensitivity and specificity estimates were 59% and 79%, respectively. The 19 studies that looked at the test performance of DMSA in detecting VUR showed that the summary sensitivity and specificity estimates were 75% and 48%, respectively. Ten studies reported data on the accuracy of DMSA in detecting high-grade VUR. The summary sensitivity and specificity estimates were 93% and 44%, respectively.

The investigators noted that a child with a negative DMSA test has a less than 1% probability of having highgrade VUR, performing a screening DMSA scan will result in a large number of children falsely labeled as being at risk for high-grade VUR. “Accordingly, the usefulness of the DMSA [scan] as a screening test for high-grade VUR should be questioned,” they concluded. n

7/20/16 11:17 AM

26 Renal & Urology News

AUGUST 2016 www.renalandurologynews.com

Practice Management Medicare and other payers may be scrutinizing claims more closely now that they are becoming comfortable with ICD-10. BY TAMMY WORTH

T

bring more granularity to the system, meaning payers will have more data on treatment.

They may begin changing or fine tuning policies that could call for more information in areas like medical necessity or experimental treatments.

A good dialogue with payers can help understand when this is occurring.

“Many payers have this information posted on their website,” Daley said.

“There may not be adjustments, but watch out in case there are.”

Nonspecific diagnoses may invite closer inspection, so coding must be as specific as possible.

End of grace period To ease everyone into ICD-10, Medicare created a grace period allowing providers to be paid even when their codes weren’t as specific as they should be. In other words, as long as they were close, the claims were being paid.

But that will change come October 1, when the Centers for Medicare and

“Are you always picking certain codes because they seem to be working and you are getting paid, or are you picking them because of the specifics of that encounter?” he asks. It should be the latter.

Nonspecific diagnoses, for example, may invite greater scrutiny. The error rate with that code is about 30%, according to

Providers should identify the most commonly used codes that are getting paid now, but may be denied after the grace period has ended.

Medicaid Services (CMS) will be starting post-payment audits that allow them to more closely scrutinize claims and audit those that require greater specificity. The result of this could just be more “back and forth” when things come into question, said Jim Daley, past chair of the Workgroup for Electronic Data Interchange (WEDI), based in Reston, Virginia, and co-chair of the WEDI ICD-10 workgroup. But if a pattern is found, it could cause big problems. To avoid major issues, you need to make sure you are capturing enough documentation to make coding as specific as possible.

PracticeMan_RUN0816.indd 26

Stuart Newsome, vice president of Alpha II LLC, based in Tallahassee, Florida.

“Those are a target because it’s like saying you don’t really know what is wrong with the patient,” he said.

Additions and deletions CMS also created a code freeze set to last through October 1. Instead of the typical annual changes, the organization created a moratorium while people were getting used to ICD-10.

In October, there will be more than 3,500 new procedure codes and 1,900 new diagnosis codes. Jackie Stack, education specialist for the American Academy of Professional Coders, said there will also be more than 400 codes revised and 300 deleted. Providers can keep up with the changes by checking CMS’ website, where there is a listing of the new codes.

New policies As payers become increasingly com­ fortable with ICD-10, they may begin creating new medical policies, Daley said. The new codes were meant to

Helpful sites NueMD ICD-10 code lookup

http://www.nuemd.com/icd-10/codes

ICD-9 to ICD-10 converter

http://www.icd10data.com

New ICD-10 codes for FY 2017

https://www.cms.gov/Medicare/Coding/ ICD10/index.html

Preparation The good news about preparing for the coming changes is you can do what you should be doing already. This includes checking frequency reports to identify where problems can arise, Stack said.

Rather than looking for codes that are not getting paid, providers should identify the most commonly used codes that are getting paid now, but may be denied after the grace period has ended.

Newsome tells his clients to create an escrow account before the changeover in case payments are delayed. If you have such an account, he recommends not cashing it in quite yet. If you do not, you might want to open one. Calculate your error rate from Medicare and put that money into an account. Also, find your “bad payers” and assume they will be late for a couple of months after the change. Put that amount aside as well.

Daley recommends communicating with staff so they know changes are coming and understand their responsibilities. Communicate with payers and vendors to ensure they are ready for the change, and monitor key performance indicators for any changes.

“You want to have a point person assigned who is the one who knows what is going on and can assure you continue business as usual,” Daley said. “You have to make sure that happens so you don’t have people standing around pointing fingers at each other if something goes wrong.” n Tammy Worth is a freelance medical journalist based in Blue Springs, MO.

© THINKSTOCK

he expectation of doom that came with the move to ICD-10 was nothing short of the hoopla surrounding Y2K (when people feared the world’s computers would shut down or malfunction). But October came and went and … silence. The industry adapted surprisingly well to the new codes and little has been reported on major problems for either payers or providers.

But experts say things went so smoothly because everyone was becoming acclimated to the changes.

Now that Medicare and other payers are becoming comfortable with the new system, they will begin making changes and more closely scrutinizing claims. Here’s what to prepare for in the coming months.

7/20/16 11:19 AM

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7/14/16 1:18 PM

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For men with mCRPC who have progressed on ADT

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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.

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IMPORTANT SAFETY INFORMATION Hepatotoxicity—In postmarketing experience, there have been ZYTIGA®-associated severe hepatic toxicities, including fulminant hepatitis, acute liver failure and deaths. 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. Re-treatment with ZYTIGA® 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. Permanently discontinue ZYTIGA® for patients who develop a concurrent elevation of ALT greater than 3X ULN and total bilirubin greater than 2X ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation.

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

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2016 06/16 044350-160421

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Let’s do this Established safety profile Contraindicated in women who are or may become pregnant; Warnings and Precautions include Mineralocorticoid Excess, Adrenocortical Insufficiency, and Hepatotoxicity 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

ZYTIGA® in geriatric patients

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IMPORTANT SAFETY INFORMATION—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®.

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

051320-160413

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.

* Greater sensitivity of some older individuals cannot be ruled out.

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

STRONG T O G E T H E R

Learn more today at www.zytigahcp.com

Date: 07/25/16 Customer Code: 044350-160421 Group 360 Job #: 761662 File Name: 044350-160421_Zytiga-Urology_761662_v1c (pg 3 - right hand page) Size: 7” W x 10” H Colors: CMYK Description: Zytiga & Prednisone Pub: Renal and Urology News (8/1/16 - Online issue) K

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Of the total number of patients receiving ZYTIGA® in phase 3 trials, 73% of patients were aged 65 years and over and 30% were aged 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

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 ­ZYTIGA. 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 postmarketing experience, there have been ZYTIGAassociated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths [see Adverse Reactions].

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 Z­ YTIGA, 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 ­ZYTIGA. 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].

Permanently discontinue ZYTIGA for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation [see Dosage and Administration (2.2) in full Prescribing Information].

ZYTIGA® (abiraterone acetate) Tablets 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].

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 Z­ YTIGA was 8 months.

Table 1: Adverse Reactions due to ­ZYTIGA in Study 1 ­ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 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

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

Table 1: Adverse Reactions due to Z­ YTIGA in Study 1 (continued) ­ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % 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

Table 3: A dverse Reactions in ≥5% of Patients on the ­ZYTIGA Arm in Study 2 (continued) 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 % % % % 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.

1 Adverse

events graded according to CTCAE version 3.0. 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.

6 Includes 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.

2 Includes

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 Z­ YTIGA 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

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 Z­ YTIGA arm.

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 ­ZYTIGA 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.

Postmarketing 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.

Hepatobiliary Disorders: fulminant hepatitis, including acute hepatic failure and death.

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].

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

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].

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. ­ZYTIGA 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 Z­ YTIGA, 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 ­ZYTIGA. 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, ­ZYTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle Z­ YTIGA 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 Z­YTIGA and prednisone.

• Patients should be informed that Z­ YTIGA should not be taken with food and that no food should be consumed for at least two hours before the dose of ­ZYTIGA 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.

• Patients should be informed that ­ ZYTIGA is taken once daily and 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 Z­ YTIGA 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: May 2016 051318-160413