Renal & Urology News - Jan-Feb 2016 Edition by Haymarket Media

J A N UA R Y/F E B R UA R Y 2 016

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V O L U M E 15, I S S U E N U M B E R 1

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Lethal PCa Risk Lower in Aspirin Users Regular use by men without a prostate cancer diagnosis cut the risk of dying from the malignancy by 24%

REGULAR ASPIRIN USE may inhibit lethal PCa by preventing cancer progression.

Flavonoids Found to Cut ED Risk BY NATASHA PERSAUD MEN WHO regularly consume foods rich in flavonoids, such as fruit, vegetables, tea, and wine, may have a lower risk of erectile dysfunction (ED), a new study finds. In particular, anthocyanins (found in blueberries, cherries, blackberries, black currants, and radishes), flavanones

(found in citrus fruits), and flavones (found in parsley, thyme, celery, and hot peppers) were linked with the greatest benefits for ED prevention. “Men who regularly consumed foods high in these flavonoids were 10% less likely to suffer erectile dysfunction. In terms of quantities, we’re talking continued on page 6

PLANT PROTEIN BENEFITS

Increased intake of plant protein may decrease death risk in CKD patients. PAGE 13

REGULAR ASPIRIN use may decrease the risk of dying from prostate cancer (PCa), according to study findings presented at the 2016 Genitourinary Cancers Symposium in San Francisco. Researchers led by Christopher B. Allard, MD, a urologic oncology fellow at Brigham and Women’s Hospital and Massachusetts General Hospital in Boston, analyzed data from 22,071 men enrolled in the Physicians’ Health Study. Over 27 years of follow-up, PCa was diagnosed in 3,193 men, Dr. Allard reported during a presscast. Lethal PCa, defined as metastatic disease or death from PCa, developed in 403 of these men. Men without a diagnosis of PCa who took aspirin regularly— more than 3 tablets per week—had a

Data Support Upfront CN for mRCC CYTOREDUCTIVE nephrectomy (CN) offers a survival advantage over targeted therapy as initial treatment for clear-cell metastatic renal cell carcinoma (mRCC), researchers reported at the 2016 Genitourinary Cancers Symposium in San Francisco. A team led by Liam C. Macleod, MD, MPH, of the University of Washington School of Medicine in Seattle, noted that previous randomized trials have demonstrated a survival benefit for upfront CN preceding immunotherapy, but it is unclear whether this survival benefit persists in the targeted therapy era. Dr. Macleod and his colleagues studied 492 clear-cell mRCC patients aged 65 years and older using 2006–2011 data from the Surveillance, Epidemiology, and End Results (SEER) Program. The cohort included 227 patients who received upfront CN and 265 who received upfront targeted therapy. The investigators identified targeted therapy from Medicare Part D claims. continued on page 6

significant 24% decreased risk of developing lethal disease, after adjusting for age, race, body mass index, and smoking status. Regular aspirin use did not influence the overall incidence of PCa or the risk of being diagnosed with high-grade or locally advanced PCa. Among men with PCa, regular aspirin use after diagnosis was associated with a significant 39% decreased risk of dying from PCa. Aspirin use prior to diagnosis did not have a measurable benefit, results showed. “In conclusion, our study demonstrates that regular aspirin intake may inhibit lethal prostate cancer probably by preventing cancer progression,” Dr. Allard said. continued on page 6

IN THIS ISSUE 5

Shock wave lithotripsy suitable for moderate-sized stones

Poor mental health predicts post-cystectomy complications

Larger prostates are associated with increased risk of LUTS

Clinical chronic prostatitis is linked to lower PCa risk in blacks

Regular non-aspirin NSAID use may raise he risk of fatal RCC

Prolonged abiraterone treatment duration observed in statin users

Enzalutamide found more effective than bicalutamide

Diet and exercise may reduce the risk of death from prostate cancer after diagnosis. PAGE 14

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FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD Medical Director, Urology

Medical Director, Nephrology

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

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

Adjuvant Therapies: Time to Fold or Double Down?

djuvant therapies are the elusive holy grail of cancer surgery. To date, level 1 evidence demonstrates benefit only in breast, colorectal cancer, GIST and melanoma. Improvements in disease-free and overall survival are modest, ranging from 0%–11% and 0%–6%, respectively. No adjuvant strategies for urologic tumors exist, though not for lack of trying. Decades of clinical trials evaluating hormones, chemo- Benjamin T. Ristau, MD therapy, vaccines and other immunotherapies have failed to yield an effective systemic strategy to improve post-operative survival metrics in kidney, bladder or prostate cancers. The result is that we simply measure, communicate, and monitor a patient’s risk of recurrence. The new era of targeted therapies, particularly in kidney cancer, brought hope and anticipation that improved survival observed in metastatic disease with these agents would be translatable to the adjuvant setting. At least Robert G. Uzzo, MD, FACS 6 clinical trials were launched evaluating various agents as well as their dosing and timing schedules. The largest of these studies, sponsored by the Eastern Cooperative Oncology Group (the ASSURE trial), recently reported negative results early.i Other trial results are expected soon. So why have adjuvant therapies been so ineffective? First, we are currently unable to optimize patient selection. The most robust measures of recurrence risk remain tumor stage, grade, and type. While gene arrays and other biomarkers have been proposed, developed, and marketed, no clinically compelling predictive tool has emerged for genitourinary tumors. Second, the timing, dose, and duration of adjuvant therapies have not been established. Third, solid tumors are heterogeneous, pathways are promiscuous, and resistance emerges. Finally, current systemic agents may simply be too ineffective. So, do we fold or double down on urologic adjuvant systemic therapies? If the strategy of adjuvant therapy remains to follow incompletely effective surgery with incompletely effective systemic therapy, then existing data suggest it is time to put our resources elsewhere. However, when effective biomarkers improve patient selection and novel therapies decrease the evasiveness of micrometastases, it will be time to double down. We can all hope that time will be soon.

Nephrologists

Urologists

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

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

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

R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto Stanton Honig, MD Department of Urology Yale University School of Medicine New Haven, CT J. Stephen Jones, MD, FACS President, Cleveland Clinic Regional Hospitals & Family Health Centers Professor & Horvitz/Miller Distinguished Chair in Urological Oncology Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology University of California Irvine

Csaba P. Kovesdy, MD Chief of Nephrology Memphis VA Medical Center Fred Hatch Professor of Medicine University of Tennessee Health Science Center, Memphis Edgar V. Lerma, MD, FACP, FASN, FAHA Clinical Associate Professor of Medicine Section of Nephrology Department of Medicine University of Illinois at Chicago College of Medicine, Chicago Allen Nissenson, MD Emeritus Professor of Medicine The David Geffen School of Medicine at UCLA, Chief Medical Officer, DaVita Inc.

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

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

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

Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center, Detroit Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J.

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

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

Renal & Urology News Staff Editor

Jody A. Charnow

Web editor

Natasha Persaud

Production editor

Kim Daigneau

Group art director, Haymarket Medical

Jennifer Dvoretz

Production manager

Krassi Varbanov

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

Benjamin T. Ristau, MD Fellow, Urologic Oncology Fox Chase Cancer Center, Philadelphia

Kathleen Millea Grinder Paul Silver William Canning Chad Holloway

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

Kathleen Walsh Tulley Jim Burke, RPh John Pal Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 15, Number 1. 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

JANUARY/ FEBRUARY 2016 ■ VOLUME 15, ISSUE NUMBER 1

Urology 9

ONLINE

this month at renalandurologynews.com Clinical Quiz

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

Congratulations to our January winner: Michael Blute, MD

Prostate Size Predicts LUTS Risk Prostate volumes of 40.1–80 mL are associated with a 67% higher risk of lower urinary tract symptoms versus smaller prostates. NSAIDs May Raise Risk of Fatal RCC Likelihood of dying from renal cell carcinoma is increased 4-fold by regular use of non-aspirin non-steroidal antiinflammatory drugs for 10 or more years. Statin Use Found to Prolong Abiraterone Therapy The median duration of treatment with the drug was 5 months longer in statin users compared with non-users. Enzalutamide More Effective than Bicalutamide In men with metastatic castration-resistant prostate cancer, enzalutamide decreased the risk of disease progression by 56% compared with bicalutamide.

An expert discusses low-cost solutions to help small practices comply with the rules.

Job Board

AKI Diagnostic Testing May Be Excessive Many diagnostic tests for investigating acute kidney injury have limited clinical utility, according to a new study.

Even Mild GFR Declines Up CV Risk Small reductions in kidney function are associated with an increase in cardiovascular risks, independent of blood pressure and atherosclerosis, researchers report.

Plant Protein Good for CKD Patients Each 33% increase in plant protein to total protein ratio decreases death risk by 23%, data show.

CKD Risk Following AKI Characterized Even mild acute kidney injury with rapid recovery increases the risk of chronic kidney disease stage 3 or higher.

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

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

Annual Dialysis Conference Seattle February 27–March 1 European Association of Urology 31st Annual Congress Munich, Germany March 11–15 National Kidney Foundation Spring Clinical Meetings Boston April 27–May 1 American Urological Association Annual Meeting San Diego May 6–10 American Society of Hypertension Annual Scientific Meeting New York May 13–17 European Renal Association–European Dialysis and Transplant Association 53rd Congress Vienna, Austria May 21–24 American Transplant Congress Boston June 11–15

Nephrology

HIPAA

CALENDAR

Despite the widespread use of bicalutamide,

evidence of its clinical benefits is scarce in the context of castration-resistant prostate cancer. See our story on page 17

Departments 3

From the Medical Director Adjuvant Therapies: Time to Fold or Double Down?

News in Brief RCC surgery outcomes not worsened by extreme obesity.

Practice Management How to use Medicare’s star ratings for dialysis facilities.

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Renal & Urology News 5

News in Brief

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

Short Takes Hypospadias Prevalence Found to Vary Widely

matched 6,342 statin users with 6,342

Hypospadias prevalence shows wide

years, statin users had 30% increased

geographic variation, according to an

odds of acute kidney injury and 36%

online report in the Journal of Pediatric

increased odds of chronic kidney

Urology.

disease compared with non-users.

non-users. A fter a follow-up of 8.4

Based on a systematic literature

“These findings are cautionary and

review, Alexander Springer, MD, of the

suggest that long-term effects of statins

Medical University of Vienna in Austria,

in real-life patients may differ from

and colleagues found that the mean

shorter term effects in selected clinical

prevalence of hypospadias, per 10,000

trial population,” the authors concluded.

live births, was 19.9 in Europe, 34.2 in 0.6–69 in Asia, 5.9 in Africa, and 17.1–

PAE Effect on Prostate Zones Characterized

34.8 in Australia. The researchers said

Prostatic arterial embolization (PAE)

the true prevalence of hypospadias and

decreases the volume of various pros-

trends were difficult to estimate. No

tate anatomical zones and the whole

epidemiologic data were available from

gland, according to researchers who

many parts of the world, they noted.

reviewed magnetic resonance imaging

North America, 5.2 in South America,

(MRI) scans obtained from 25 patients

Statin Use May Raise Kidney Disease Risk

before and after PAE.

Statin use is associated with an

of median lobes, central zones, periph-

increased risk of acute and chronic

eral zones, and whole prostate glands

kidney disease, researchers reported

by 26.2%, 18.8%, 16.4%, and 19.1%,

online in the American Journal of

respectively, Yen-Ting Lin, MD, of the

Cardiology.

Hôpital Européen Georges-Pompidou in

PAE significantly reduced the volumes

Tushar Acharya, MD, of the University

Paris, and colleagues reported online

of California San Francisco–Fresno

ahead of print in European Radiology.

Medical Education Program, Fresno,

A larger reduction in prostate volume

Calif., and colleagues propensity score

was associated with clinical success.

U.S. Kidney Disease Prevalence The 2014 National Health Interview Survey showed that an age-adjusted 1.8% of U.S. adults aged 18 years and older were told they had kidney disease.* The age-adjusted percentages increased with increasing age, as shown here. 8

6.8%

7 6 5

3.9%

4 3

1.7%

2 1 0

0.7% 18 – 44

45– 64 65–74 Age Group (in years)

75 and older

*Respondents were asked if they had been told in the previous 12 months by a health professional that they had weak or failing kidneys (excluding kidney stones, bladder infections, or incontinence). Source: National Center for Health Statistics; National Health Interview Survey, 2014

Study Supports Use of SWL For Moderate-Sized Stones S

hock wave lithotripsy (SWL) is an efficacious treatment for moderate-sized kidney stones, according to British researchers. In a study of 130 patients, Vera Y. Chung, MBBS, and Benjamin W. Turney, PhD, FRCS, of the University of Oxford, Headington, Oxford, U.K., evaluated the efficacy of SWL in treatment of kidney stones 10–20 mm in maximum diameter. The mean stone size was 12.8 mm. The overall treatment success (combined complete stone clearance and clinically insignificant residual fragments) was 66.4% The success rate was 70.4% and 53.1% for stones less than 15 mm and 15 mm or larger, respectively, the investigators reported online in Urolithiasis. “This study suggests that SWL has an efficacy for treating larger renal stones (10–20 mm) that is equivalent to success rates for smaller stones in other series,” the authors wrote.

Hyperkalemia-Diabetes Link Found in CKD Patients D

iabetes mellitus is associated with a significantly increased prevalence of hyperkalemia among patients with stage 3 chronic kidney disease (CKD), a new study found. The study, published online ahead of print in the American Journal of Nephrology, also found that stage 4 CKD and ACE inhibitor use are major determinants of hyperkalemia occurrence in multivariate analysis. Charalampos Loutradis, MD, of Aristotle University of Thessaloniki in Greece, and colleagues conducted a nested case-control study of 180 type 2 diabetic and 180 non-diabetic patients with CKD. The prevalence of hyperkalemia—defined as a serum potassium level above 5 mEq/L—was not significantly higher in the diabetic than non-diabetic patients (27.2% vs. 20%), but it was significantly higher between diabetic and non-diabetic patients with stage 3 CKD (28.6% vs. 17.5%).

RCC Surgery Outcomes Not Worsened by Extreme Obesity E

xtreme obesity is not associated with worse outcomes after surgery for renal cell carcinoma (RCC), according to a study published online ahead of print in BJU International. A team led by E. Jason Abel, MD, of the University of Wisconsin School of Medicine and Public Health in Madison, studied 843 patients who underwent surgery for RCC. Of these, 100 had a body mass index (BMI) of 40 kg/m2 or higher (extreme obesity) and 743 patients had a lower BMI. Extreme obesity was not associated with an increased likelihood of blood transfusion, longer hospital length of stay, or 30-day hospital readmission rate compared with the lower-BMI group. The groups showed no significant differences in major complications, 90-day mortality, and overall, cancer-specific, or recurrence-free survival. The 5-year overall, cancer-specific, and recurrence-free survival rates for the extremely obese group were 70%, 87.9%, and 90.6%, respectively. The rates for the patients with a BMI less than 40 kg/m2 were 69%, 78.4%, and 84.1%, respectively. None of these between-group differences was statistically significantly.

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Aspirin and lethal PCa

continued from page 1

Although the biological basis for the protective effect of aspirin is not known, preclinical research suggests aspirin may prevent the spread of cancer to the bone, according to Dr. Allard.

Flavonoids cut ED risk

continued from page 1

just a few portions a week,” stated lead researcher Aedin Cassidy, PhD, professor of nutrition at the University of East Anglia in Norwich, UK, in a press release. For the joint study with Harvard T.H. Chan School of Public Health, Dr. Cassidy and colleagues examined food-frequency questionnaires completed every 4 years by 25,096 mostly Caucasian men from the Health Professionals Follow-Up Study (HPFS). In 1998, none of the men had ED, cardiovascular disease, or prostate, bladder, or testicular cancers. During 10 years of follow-up, ED developed in 35.6% of subjects, according to results published online in the American Journal of Clinical Nutrition.

Men with the PCa who already may benefit from the cardiovascular effects of aspirin could have another reason to consider regular aspirin use, he said. Men should consider the potential risks of regular aspirin use when discussing with their physicians the potential benefits of aspirin with respect to cardiovascular health and

After adjusting for cardiovascular and other factors (such as caffeine and alcohol consumption, body mass index, smoking, and physical activity), the investigators discovered that specific classes of flavonoids—flavones, flavanones, and anthocyanins—were associated with a reduced incidence of ED. In multivariate analysis, individuals in the highest quintile of flavone, flavanone, and anthocyanin intake had a significant 9%, 11%, and 9% decreased risk of ED, respectively, compared with those in the lowest quintile. Men in the highest quintile of fruit intake had a significant 14% lower risk of ED compared with those in the lowest quintile. This impact is equivalent to 2 to 5 hours of brisk walking each week. The investigators performed an analysis by age and discovered a higher

Specialized Immunonutrition May Benefits RC Patients SPECIALIZED immunonutrition may

Dr. Hamilton-Reeves and her col-

provide a way to improve immune

leagues randomly assigned 29 men

response and decrease infection rates

scheduled to undergo RC for primary

after radical cystectomy (RC), accord-

bladder cancer to receive an arginine-

ing to a small pilot study.

enriched SIM beverage or an oral nutri-

Infections account for up to 25% of

tion supplement (ONS, control arm)

postoperative complications at 30

beverage before and after surgery.

and 90 days, a research team led

The primary study endpoint was the

by Jill M. Hamilton-Reeves, PhD, RD,

change in total MDSC counts.

of the University of Kansas Medical

The researchers observed a sig-

Center in Kansas City, noted in a

nificantly smaller difference between

report published online ahead of print

MDSC counts at baseline and postop-

in European Urology. Post-RC accumu-

erative day 2 in the SIM group versus

lation of myeloid-derived suppressor

the ONS group. The change in MDSC

cells (MDSCs), which suppress T cells,

counts during surgery (3 hours after

may contribute to lower resistance to

the first incision) and postoperative

infection, they explained. In addition,

day 2 was significantly less in the SIM

surgery-induced arginine deficiency

group than the ONS group, accord-

impairs lymphocyte proliferation and

ing to the investigators. In addition,

T-cell receptor integrity. The research-

patients in the SIM arm experienced a

ers hypothesized that arginine-

significant 39% decrease in infection

enriched specialized immunonutri-

rate compared with the control group

tion (SIM) will modulate the immune

at 90 days after surgery, according to

response to surgery.

the investigators. n

risk of death from PCa, he pointed out. Sumanta Pal, MD, who moderated the presscast, cautioned that while the new findings are provocative, the findings are from an observational study in which surveys and reviews of hospital records were used to obtain information. Such studies “are perhaps best followed by formal clinical trials where

Flavonoid-rich foods such as citrus fruits may improve erectile function.

intake of these flavonoids was significantly associated with lower ED risk only in men younger than 70 years. “Our data strengthen the knowledge that a healthy diet, specifically one rich in several flavonoids, together with

CN for mRCC continued from page 1

The median survival time was significantly longer in the upfront CN than the upfront targeted therapy group (18 vs. 10 months). In adjusted analyses, upfront targeted therapy was associated with a 70% increased risk of death compared with upfront CN. A propensity matched analysis showed that upfront CN was associated with a significant 6.4 month survival advantage, according to the researchers. “We attempt to account for a number of factors affecting treatment selection bias, and do find improved overall survival among those receiving cytoreductive nephrectomy,” Dr. Macleod told Renal & Urology News. “These findings will need to be placed in context with upcoming clinical trials examining the role of surgery relative to sunitinib in the mRCC setting.” “Although retrospective, this study is strengthened by its ability to include patient comorbidity and specific targeted therapy use,” said Stephen H. Culp, MD, PhD, an assistant professor of urology at the University of Virginia in Charlottesville who led a study of the factors associated with survival in patients undergoing CN in the targeted

we compare use of aspirin to either no treatment or perhaps a placebo.” Dr. Pal, who is a spokesperson for the American Society of Clinical Oncology, a co-sponsor of the symposium, pointed out that important unknowns remain, such as the right dose of aspirin and which patients would derive the most benefit from it. n

increased physical activity and maintenance of body weight are important components of health to improve sexual health and CVD risk factor reduction,” Dr. Cassidy’s group wrote. “These lifestyle modifications will likely provide benefit regardless of use of current drug therapies, including phosphodiesterase type 5 inhibitors.” Emerging evidence suggests flavonoids improve endothelial function and blood pressure, which may protect erectile function. Consuming these particular flavonoids as part of a healthy diet also reduces the risk of diabetes and cardiovascular disease. The HPFS is a prospective cohort study that began in 1986 with the recruitment of 51,529 male pharmacists, optometrists, dentists, osteopath physicians, podiatrists, and veterinarians. n

therapy era but was not involved in the new study. The inclusion only of patients aged 65 years and older is a study limitation, Dr. Culp said. In addition, as the investigators acknowledge, they lacked information to classify patients according to established prognostic criteria (such as those developed by Memorial Sloan-Kettering Cancer Center and Cleveland Clinic), Dr. Culp said. This is particularly important because patients undergoing upfront CN likely would be favorable/intermediate risk, he said. “Nonetheless, this study does provide additional population-based data on outcomes in the era of targeted therapy which is essential given different practice patterns and availability of multiple therapeutic agents,” Dr. Culp said. He pointed out that CN remains a mainstay in the multi-modal management of patients with mRCC despite an absence of level 1 evidence demonstrating a survival benefit in the context of targeted therapy. Although prospective randomized clinical trials are ongoing, results are not yet available and there is concern as to whether the results will be reliable because only 1 targeted therapeutic—sunitinib—is being studied, Dr. Culp stated. n

6 Renal & Urology News

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Renal & Urology News 7

Study: AKI Diagnostic Testing May Be Excessive MANY DIAGNOSTIC tests for investigating acute kidney injury (AKI) have limited clinical utility, even when results are positive or abnormal, a new study found. “In particular, selected urine and blood tests are unlikely to impact AKI diagnosis or management,” investigators led by David E. Leaf, MD, of Brigham and Women’s Hospital in Boston, and colleagues reported online in BMC Nephrology. In addition, the study found that the frequency of testing increases with higher AKI stages for nearly all diagnostic tests. Dr. Leaf and his colleagues characterized AKI diagnostic testing among 4,903 adult in-patients who experienced 5,731 AKI episodes, assessing the frequency of testing and the frequency of abnormal test results overall and by AKI stage.

with abnormal results found in 11%. Renal ultrasound was performed in 567 AKI episodes (10%), and abnormal results were detected in 196 (35%) of tests. Hydronephrosis was detected in 109 tests (19%); of these, 35 (32%) resulted in a procedural intervention. Computerized tomography of the

pelvis/abdomen (CTAP) was ordered in 54 AKI episodes (0.9%), with abnormal results detected in 18 (33%) of the scans. Among the abnormal tests, 61% resulted in an intervention. CTAP was more likely than renal ultrasonography to show abnormalities among patients with higher AKI stages.

Some urine and blood tests are unlikely to impact AKI diagnosis and management. The most commonly ordered tests were urinalysis and automated urine sediment examination. The researchers performed a sensitivity analysis to evaluate the appropriateness of testing and diagnostic yield of selected glomerulonephritis and paraproteinemia tests in a random subcohort of 100 patients (50 each). Using prespecified criteria, the investigators concluded that glomerulonephritis and paraproteinemia testing was appropriate in 50% and 54% of tests, respectively. Among patients who had a glomerulonephritis test, results were normal in 45 (90%) out of 50 tests. Results affected AKI diagnosis or management in only 1 (2.2%) of the normal tests and none of abnormal tests). For patients who had a paraproteinemia test, testing was normal in 39 (78%) of 50 tests. Results affected AKI diagnosis or management in none of the normal tests and in 4 of the abnormal tests. Clinicians ordered urine eosinophil tests in 7% of AKI episodes (3%, 9%, and 24% among patients with AKI stages 1, 2, and 3, respectively), with abnormal results detected in 7% of those tests. Clinicians ordered serum protein electrophoresis tests in 6% of all AKI episodes—with abnormal results found in 19% of those tests— and anti-neutrophil cytoplasmic antibody testing in 3% of AKI episodes, Mount Sinai Renal & Urology News Trim: 7 x10

The authors stated that “development of better diagnostic tests that provide reliable and actionable data on AKI diagnosis and management should be a priority in AKI research. “The dearth of such tests may be a key reason why therapeutic advances to improve outcomes in AKI have been largely unsuccessful.” n

8 Renal & Urology News

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CV Mortality Linked to Post-Op AKI Acute kidney injury alone was associated with a 31% higher risk of cardiovascular death at 10 years BY NATASHA PERSAUD ACUTE KIDNEY injury (AKI) commonly occurs in patients undergoing vascular surgery and is associated with a high risk of cardiovascularspecific death similar to that observed with chronic kidney disease (CKD), researchers reported. The relationship appears to strengthen with worsening kidney function and appears independent of other factors, such as the type of operation or co-existing conditions. Matthew Huber, BS, of the University of Florida in Gainesville, and colleagues examined perioperative AKI, CKD occurrence, and cardiovascular (CV) mortality among 3,646 patients who underwent vascular surgery (open or endovascular) at a single teaching hospital from 2000 to 2010. The researchers defined AKI as a least a 50% and/or a 0.3-mg/dL increase in serum creatinine per Kidney Disease: Improving Global Outcomes (KDIGO) criteria.

AKI and Cardiovascular Mortality Acute kidney injury (AKI), with or without chronic kidney disease (CKD), that develops after vascular surgery is associated with increased adjusted 10-year cardiovascular mortality rates, as shown here. 50

41% 40

31%

30%

AKI/no CKD

CKD/no AKI

17%

20 10 0

No kidney disease

Source: Huber MH et al. Cardiovascular-specific mortality and kidney disease in patients undergoing vascular surgery. JAMA Surg. 2015; published online ahead of print.

Perioperative AKI developed in 49.4% of patients, according to results published online ahead of print in JAMA Surgery. The researchers calculated that CKD was present in 13.6% of patients. Estimated cardiovascular mortality at 10 years was 31%, 30%, and 41%,

Post-Cystectomy Complications Linked to Poor Mental Health A BLADDER CANCER patient’s self-

that measures physical and mental

reported mental health prior to radical

components of health, in the months

cystectomy might be a better harbin-

before surgery.

ger of postoperative complications

Results showed that 16.8% of patients

than physical health, according to a

experienced a high-grade complication

new study published in The Journal of

within 30 days of radical cystectomy

Urology (2016;195:47-52).

with urinary diversion, as identified by

“Prior studies have suggested that

the Clavien-Dindo classification. The

poor baseline mental health can lead to

median mental composite score on the

more significant postoperative complica-

SF-12 was significantly lower in patients

tions possibly due to impaired immune

with a high-grade complication (44.8 vs.

response associated with higher levels

49.8), whereas the physical composite

of stress,” lead researchers Scott M.

score was no different (39.2 vs. 43.8).

Gilbert, MD, MS, of the H. Lee Moffitt

To determine whether components of

Cancer Center in Tampa, Fla., explained

the SP-12 were clinically relevant predic-

in a press release from the American

tors of complications, the investigators

Urological Association, the journal’s

employed an expert model of known

publisher. “This may delay both wound

factors associated with high-grade com-

healing and the ability to fight infection in

plications (e.g., age, body mass index,

the postoperative state, for example.”

Charlson comorbidity index, preopera-

Dr. Gilbert and colleagues examined

AKI/CKD

tive albumin, and clinical stage). The

responses from 274 bladder cancer

model itself did not significantly predict

patients treated at their center who

complications. When the mental health

completed the Medical Outcomes Study

component of the SP-12 was added,

Short Form (SF-12), a 12-question survey

however, it became significant. n

respectively, for patients with AKI and no CKD, CKD without AKI, and AKI with CKD compared with just 17% for patients without any kidney disease. Compared with patients who had no kidney disease, those with AKI without CKD and CKD without AKI had

Even Small GFR Declines Up CV Risk BY NATASHA PERSAUD SMALL REDUCTIONS in k idney function are associated with an increase in cardiovascular risks, independent of blood pressure and atherosclerosis, according to a study of living kidney donors. “Even in very healthy people, a small reduction in kidney function from normal to just a bit below normal was associated with an increase in the mass of the left ventricle, a change that makes the heart stiffer and impairs its ability to contract,” explained senior author Jonathan Townend, MD, in a press release from the American Heart Association (AHA). For the Chronic Renal Impairment in Birmingham (CRIB)-Donor study, Dr. Townend, professor of cardiology at the Queen Elizabeth Hospital Birmingham in Edgabaston, UK, and colleagues looked for a direct link between decreases in kidney function after donation and heart and blood vessel changes. They compared 68 kidney donors (average age 47) with

a 2-fold increased risk of cardiovascular mortality in adjusted analyses. Patients with both AKI and CKD had a 3-fold increased risk. In an editorial accompanying the study, Christian de Virgilio, MD, and Dennis Yong Kim, MD, of HarborUCLA Medical Center in Torrance, Calif., commented: “The results of the study by Huber and colleagues should prompt a call to action in terms of earlier diagnosis, treatment, and prevention of postoperative AKI.” The editorial writers noted that urinary markers of cell cycle arrest recently have been validated for identifying AKI far in advance of clinical manifestations such as oliguria or azotemia. “These novel biomarkers may furnish physicians with a narrow window to reverse or altogether avoid the development of AKI.” “Regardless of the strategies used, it is readily apparent that it is time to start paying closer attention to postoperative AKI,” they added. n

56 healthy controls fit for donation and who did not have nephrectomy (average age 44). At 12 months, the average decline in isotopic glomerular filtration rate (GFR) in donors was −30 mL/min/1.73m2, according to results published online in Hypertension, which is published by the AHA. Few donors reached an estimated GFR less than 45 mL/min/1.72m2. Compared with controls, donors experienced significant increases in left ventricular mass (7 vs. −3 g, measured with magnetic resonance imaging by a blinded reviewer) and mass to volume ratio (0.06 vs. 0.09 g/mL) that were graded with decreases in GFR. In addition, aortic distensibility and global circumferential strain decreased. Donors also had greater risks of developing detectable troponin T, a predictor of cardiovascular events and mortality, and microalbuminuria. Serum uric acid, parathyroid hormone, fibroblast growth factor-23, and C-reactive protein increased significantly. Dr. Townend and colleagues observed no change in ambulatory blood pressure, which was less than 140/90 mm Hg mg for all participants. “This is evidence that reduction in kidney function itself leads directly to measurable adverse effects on the heart and blood vessels, even without other risk factors. n

www.renalandurologynews.com JANUARY/ FEBRUARY 2016

Warfarin Safe for CKD Patients BY NATASHA PERSAUD WARFARIN DOES NOT significantly increase the risk of major bleeding in patients with both atrial fibrillation (AF) and non-end-stage chronic kidney disease (NECKD) compared with placebo or anti-platelet drugs, according to a new systematic review and meta-analysis. Investigators led by Chang-Sheng Ma, MD, of Beijing Tongren Hospital in China, examined 12 studies of warfarin use compared with warfarin “non-use” (i.e., low-dose warfarin, placebo, antiplatelet drugs, aspirin, or direct oral anticoagulants (DOACs) such as dabigatran, apixaban, and rivaroxaban) in patients with NECKD and AF. The investigators looked for major bleeding events, including intracranial or extracranial hemorrhage and gastrointestinal hemorrhage, whether fatal or non-fatal. An analysis of pooled data from 3 studies showed no significant difference in major bleeding risk from warfarin compared with placebo or antiplatelet drugs, according to results in Thrombosis Research, published online ahead of print. Information on aspirin was inadequate to determine relative risks. DOACs reduced the risk of major bleeding by 19% compared with war-

Renal & Urology News 9

Prostate Size Predicts LUTS Risk Each 10 mL increase is associated with a 12% higher risk, study finds LOWER URINARY tract symptoms (LUTS) are more likely to develop in men with larger prostates, according to a post hoc analysis of data from the REDUCE trial. The randomized, double-blind trial compared the effect of dutasteride versus placebo on reducing the risk of prostate cancer. The post hoc analysis, led by Stephen J. Freedland, MD, of the Cedars-Sinai Medical Center in Los Angeles, included 3,090 participants with mild to no LUTS at baseline. Among the 1,550 placebo recipients, those with a baseline prostate size of 40.1–80 mL had a significant 67% increased risk of developing incident LUTS compared with men who had smaller prostates, after adjusting for potential confounders, the researchers reported online ahead of print in European Urology. Each 10 mL increment in baseline prostate size was associated with a significant 12% increased risk of incident LUTS. The investigators observed no association between prostate size and incident LUTS risk among the 1,540 dutasteride recipients. “These findings suggest that prostate size may predict the development of incident LUTS and this effect may be negated by dutasteride use,” the authors stated. The researchers defined mild to no LUTS using an International Prostate Symptom Score (IPSS) less than 8 and incident LUTS as the first report of medical treatment, surgery, or sus-

Larger Prostates Up LUTS Risk In a study of 1,550 men in the placebo arm of the REDUCE trial, incident lower urinary tract symptoms (LUTS) developed in 193 men, with substantially more cases observed in men with larger prostates. n All incident LUTS cases

200

n Prostates 40.1– 80 mL n Prostates 40 mL or less

150

100

193

124

Source: Simon RM et al. Does prostate size predict development of incident lower urinary tract symptoms in men with mild to no current symptoms? Results from the REDUCE trial. Eur Urol. 2015; published online ahead of print.

tained, clinically significant benign prostatic hyperplasia (BPH) symptoms. “Our findings suggest that the question of whether or not there is clinical utility in being able to predict incident LUTS in a man with mild to no symptoms must be discussed,” Dr. Freedland’s team wrote. “First, and most importantly, such a prediction could potentially allow for closer follow-up in a man who perhaps would not normally be followed for LUTS/BPH because of few current symptoms.” Dr. Freedland’s team noted that previous studies have found conflicting results when correlating prostate size to LUTS severity. In the Olmsted County study of urinary symptoms and health status among men, the researchers pointed out, even central-zone prostate volume only weakly correlated

with IPSS and peak flow rate, according to results published in the Journal of Urology (1999;161:831-834). “While this lack of correlation between prostate size and LUTS severity argues against the effect of a growing prostate leading to urinary complications, several studies have highlighted the relationship between increased prostate size and LUTS/BPH progression in symptomatic individuals.” For example, the researchers cited a secondary analysis of the placebo arm of 3 randomized finasteride trials study, which was published in European Urology (2000;38:563-568), showing that patients with a prostate size of 40 mL or greater were twice as likely to develop acute urinary retention at 2 years compared with men with smaller prostates. n

farin, according to an analysis of 3 randomized controlled trials. DOACs proved superior to warfarin even as renal function declined during mild to moderate CKD. “Therefore, we confirmed that DOACs were alternatives to warfarin for AF anticoagulation from the perspective of safety even in the case of NECKD,” the researchers stated. “It can be inferred from this metaanalysis that DOACs reduce the risk of major bleeding by 19% compared to warfarin and the reduction remains stable from mild to moderate CKD,” the investigators wrote. “But it appears reasonable to monitor renal function when DOACs are used in AF patients, as their renal function may deteriorate.” n

Clinical Prostatitis May Lower PCa Risk in Blacks CLINICAL CHRONIC prostatitis is associated with a significantly decreased risk of prostate cancer (PCa) in African American men, according to a new study. Among white men, clinical prostatitis significantly increased PCa risk in those without evidence histologic prostatic inflammation. Benjamin A. Rybicki, MD, of the Henry Ford Health System in Detroit, and collaborators analyzed data from 574 PCa case-control pairs (345 white and 229 African-American men). In adjusted analyses, clinical chronic prostatitis in African-American men was associated with a significant 53% decreased risk of PCa compared with

the absence of prostatitis, the researchers reported online ahead of print in Prostate Cancer and Prostatic Diseases. Clinical prostatitis did not significantly increase PCa risk in white men overall, but it was associated with a significant 3.5-fold increased risk in those who had no evidence of histologic inflammation. In addition, the investigators found that clinical prostatitis increased PCa risk nearly 3-fold in white men with a low PSA velocity and nearly 2-fold in white men with more frequent PSA testing. PSA velocity and PSA testing frequency did not significantly modify the effect of clinical prostatitis on PCa risk in African American men.

“Prostatitis is a biologically and clinically heterogeneous condition; as a result, determining its role in prostate carcinogenesis is challenging,” the authors wrote. “As clinically-reported prostatitis is more likely when the underlying prostatic inflammation is extensive, the factors that influence the spread of prostatic inflammation, and how these factors may promote carcinogenesis need to be better understood.” The authors noted that their assessment of clinical prostatitis was limited to medical chart review at a single institution. “Although this reduces recall bias, prostatitis diagnoses could have been missed if they occurred at another medical facility,” they wrote. n

www.renalandurologynews.com JANUARY/ FEBRUARY 2016

Renal & Urology News 13

Plant Protein Good for CKD Patients

The death risk decreases 23% with each 33% increase in plant protein to total protein ratio, data show GREATER PROPORTIONS of plant protein in the diet are associated with a decreased death risk among individuals with chronic kidney disease (CKD), a new study found. The study, led by Srinivasan Beddhu, MD, of the University of Utah School of Medicine in Salt Lake City, examined data from 14,866 participants in the National Health and Nutrition Examination Survey III. In a subpopulation of 1,065 patients with CKD (estimated glomerular filtration rate [eGFR] less than 60 mL/min/1.73 m2), each 33% increase in plant protein to total protein ratio was associated with a 23% decreased death risk among individuals, after adjusting for demographics, alcohol use, smoking, body mass index, and other potential confounders. In addition, compared with individuals in the lowest quartile of plant protein ratio (less than 24.4%), those in highest quartile (greater than 41.3%) had a 33% decreased death risk in adjusted analyses. The researchers observed no significant association between plant protein intake and death risk among individuals without CKD. The researchers published their study findings online ahead of print in the

American Journal of Kidney Diseases (AJKD), where they stated: “The results of this study suggest that at a given total protein intake, [a] higher proportion of protein from plant sources is associated with lower mortality in CKD.” The researchers noted that plant protein is defined as the amount of protein contributed by plant products, including vegetables, grains, fruits, nuts, legumes, and seeds. Animal protein sources include eggs, meats, and dairy foods. High-protein plant-based diets have been investigated as way to slow CKD progression and maintain adequate nutrition, Dr. Beddhu’s group pointed out. Some studies suggest that plant proteins do not accelerate CKD progression as animal proteins do. In the Nurses’ Health Study, high animal protein intake in women with mild CKD was associated with significantly greater decreases in eGFR than high plant protein intake. Moderate restriction of total protein intake is probably important to preserve kidney function in people with CKD, but the effect of sources of protein on overall health in CKD has not been well studied, Dr. Beddhu, MD, said in a statement issued by the National Kidney

Eating more fruits and vegetables may decrease mortality in kidney disease patients.

Foundation, which publishes AJKD. “Our research indicates that plant-based proteins could play an important role in improving the health outcomes for people with decreased kidney function.” “Previous studies have shown that the rate of intestinal phosphorus absorption is higher from animal protein than plant-based protein.” said Thomas Manley, director of scientific activities for NKF. “Higher blood phosphorus

levels are associated with increased mortality in both people with CKD and the general population. This may be one plausible explanation for the higher death rates in CKD patients who consume larger amounts of animal protein.” Dr. Beddhu’s team advised caution in interpreting the study findings. “Whether the results are related to the plant protein itself or to the higher polyunsaturated fatty acid and lower saturated fatty acid or increased fiber levels associated with more plant-based diets is difficult to establish without intervention trials that increase solely plant protein,” they wrote. Various mechanisms have been proposed for the potential benefits of high plant protein intake in CKD patients, according to the investigators. “The differences in amino acid composition of plant protein and animal protein might explain their different effects on kidney function,” they wrote. In addition, plant proteins have a significant effect on cholesterol metabolism. Research has shown that greater intake of plant protein from gluten lowers oxidized low-density lipoprotein cholesterol, serum triacylglycerol, and uric acid levels. n

RESEARCHERS have identified racial/ ethnic disparities in the likelihood of receiving a kidney transplant among patients undergoing home dialysis. Compared with whites undergoing peritoneal dialysis (PD), blacks and Hispanics undergoing PD, respectively, had a significant 46% and 48% decreased likelihood of receiving a kidney transplant, after adjusting for age, gender, and diabetes, Rajnish Mehrotra, MD, of the University of Washington in Seattle, and colleagues reported online ahead of print in the Journal of the American Society of Nephrology. Among patients undergoing home hemodialysis (home HD), blacks had a significant 43% decreased likelihood of receiving a kidney transplant compared with whites, but the researchers found no disparity in kidney transplantation among Hispanics, Asians, and other racial/ethnic groups. Among patients receiving home HD, the finding of a disparity in kidney transplantation only in blacks and

no other racial/ethnic minorities compared with whites may be due to the relatively small number of events in these other groups, “making our analyses underpowered to make definitive conclusions.” In the subgroup of patients receiving in-center HD, all racial/ethnic groups were significantly less likely than whites to receive a transplant.

White patients have an advantage over minorities in getting a kidney transplant. Dr. Mehrotra’s team noted that although racial disparities in access to transplantation are well established and evident in their cohort of patients receiving in-center HD, “the persistence of this difference in the subgroup of patients undergoing PD is surprising.”

Patients treated with PD in the United States, they pointed out, are significantly more likely to receive a kidney transplant, “probably because these patients are younger and healthier, have a higher socioeconomic status, and are motivated to engage in self-care—medical and social characteristics that are all associated with a higher probability of receiving a kidney transplant.” The study population included 17,791 patients undergoing PD, 2,536 undergoing home HD, and 140,389 treated with in-center HD. Blacks undergoing PD or home HD had a significantly higher risk of transfer to in-center HD compared with their white counterparts. The researchers found no significant difference in the risk of transfer to in-center HD between Hispanics and whites treated with PD or home HD. Asians and other racial groups undergoing PD had lower risks for transfer to in-center HD, but the researchers observed no significant difference in risk for these groups treated with

home HD compared with whites, Dr. Mehrotra’s group reported. In addition, among patients undergoing PD, every racial/ethnic group had a significantly lower risk of death compared with whites, the study found. Among patients treated with home HD, the risk of death was significantly lower among blacks but similar for other racial/ethnic groups. Among patients receiving in-center HD, the risk of death was significantly lower in every racial/ethnic group compared with whites. “Our analysis is the first multicenter and nationally representative cohort study to compare the racial/ethnic differences in mortality among patients treated with PD or home HD in the United States,” the authors noted. The lower risk of death among racial minorities treated with PD compared with whites is consistent with what has previously been reported using data from the U.S. Renal Data System and other studies, according to the investigators. n

Racial/Ethnic Disparities in Home Dialysis Outcomes ID’d

14 Renal & Urology News ■ GCS 2016, San Francisco

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Genitourinary Cancers Symposium 2016, San Francisco

Post-PCa Diagnosis Lifestyle Matters Through diet and exercise, prostate cancer patients can decrease the risk of dying from their illness

ADOPTING a healthy lifestyle after being diagnosed with prostate cancer (PCa) can reduce the risk of dying from the malignancy, researchers concluded. To realize this survival benefit, PCa patients need to engage in frequent vigorous physical activity, abstain from smoking, maintain a healthy body weight, and consume a diet rich in cruciferous vegetables, healthy fats from vegetable sources, coffee, and wine, according to a research team led by Stacey A. Kenfield, ScD, of the Harvard School of Public Health in Boston. Patients should reduce intake of processed meat, poultry with skin, and whole milk and avoid excess supplemental selenium.

Dr. Kenfield’s group based their findings on a study of 3,583 men in the Health Professionals Follow-up Study who were diagnosed with non-metastatic PCa from 1986 to 2008 and followed through 2012. The median follow-up was 11 years. Of these men, 240 died from PCa. The investigators calculated scores based on patients’ adherence to 11 lowrisk factors, each of which was assigned a score of 1 point. These factors included not currently smoking or quit 10 or more years ago; a body mass index less than 30 kg/m2; 3 or more hours per week of vigorous activity and/or brisk walking for 7 or more hours per week; consuming 1 or more servings per day of cruciferous vegetables; consuming 3 or more servings per week of nuts and oil-based salad dressing; consuming fewer than 2 servings per week of processed meat; 0 servings per week of poultry with skin or

BAT Promising for Advanced Hormone-Sensitive PCa BIPOLAR androgen therapy (BAT)—the

Each round of BAT-ADT consisted of

intermittent use of high-dose testoster-

3 cycles of BAT and 12 weeks of ADT

one therapy—is safe and possibly effec-

alone. The primary endpoint was the

tive in patients with advanced hormone-

percentage of patients with a PSA level

sensitive prostate cancer (PCa), new

below 4 ng/mL at the end of the study.

findings from a small study suggest.

Of the 33 patients, 29 went on to the

The study, conducted at Johns

BAT phase of the study, and 17 of these

Hopkins University in Baltimore,

men (59%) achieved the primary end-

enrolled 33 patients with advanced

point, according to lead author Michael

hormone-sensitive PCa. Twenty-two

T. Schweizer, MD, now at the University

patients had undergone radical prosta-

of Washington/Fred Hutchinson Cancer

tectomy, 8 received radiation therapy,

Research Center in Seattle, and his

and 3 received no treatment. The

colleagues. Three patients (10%) had

cohort had a median PSA level of 27.6

undetectable PSA (less than 2 ng/mL).

ng/mL at study baseline. All patients received a 6-month andro-

Adverse events thought to be at least possibly related to testosterone

gen deprivation therapy (ADT) lead-in.

occurred in 23 (79%) of the 29 men,

Patients with a PSA level below 4 ng/

although all events were low grade.

mL or 50% or more below baseline at

The authors noted that previous

the end of the lead-in went on to receive

research demonstrated a paradoxical

2 rounds of alternating BAT-ADT. During

anti-tumor effect in patients with castra-

rounds of BAT, testosterone cypionate or

tion-resistant PCa treated with BAT. An

testosterone enanthate was administered

adaptive increase in androgen receptor

intramuscularly at the FDA-approved

expression following chronic ADT may

dose of 400 mg every 28 days.

underlie this effect, they stated. n

A healthy lifestyle after a PCa diagnosis may lower the risk of PCa-related death.

chicken/turkey sandwiches; intake of less than 140 µg per day of supplemental selenium; consuming less than 4 servings per week of whole milk; drinking 4 or more servings per day of coffee; and drinking 7 or more servings per week of wine.

NSAIDs May Raise Risk of Fatal RCC LONG-TERM regular use of nonaspirin non-steroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of fatal renal cell carcinoma (RCC). The finding is from an analysis of data from 2 large prospective cohorts: the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). In the NHS and HPFS, use of aspirin and other NSAIDs was ascertained in 1990 and 1986, respectively, and every 2 years thereafter. “We found a strong statistical association between regular use of non-aspirin NSAIDs beyond 4 years and development of total and fatal renal cell carcinoma,” lead investigator Mark A. Preston, MD, MPH, of Brigham and Women’s Hospital in Boston, told Renal & Urology News. “No statistically significant increased risk was seen with aspirin or acetaminophen. While this does not establish causality, the results are provocative and warrant further study.”

In multivariable analysis, patients who had a score of 4–7 and 8–11 had a 48% and 75% decreased risk of a PCa death compared with those who had a score of 0–3, the investigators reported. Prudent diet and exercise choices have a “profound impact” on the risk of lethal PCa, Dr. Kenfield told Renal & Urology News. “These results should be empowering to men with this diagnosis and can serve as a reminder to clinicians to counsel their patients on health behaviors.” Regarding how changes in diet and lifestyle might influence the PCa death risk, Dr. Kenfield observed: “These healthy behaviors potentially act through similar biologic mechanisms including hyperinsulinemia, insulin resistance, insulin-like growth factors and associated binding proteins, sex hormone regulation, inflammation, adipokine production and signaling, and oxidative stress.” n

During follow-up of 22 years among 77,527 women and 26 years among 45,913 men, the investigators documented 438 cases of RCC (230 in women and 208 in men). Of these cases, 106 were fatal (56 in women, 40 in men). In a pooled multivariate analysis, regular use of aspirin was not significantly associated with RCC risk, but regular use of non-aspirin NSAIDs was associated with a significant 34% increased risk. In addition, subjects who regularly used non-aspirin NSAIDs for at least 4 years but less than 10 years and 10 or more years had a nearly 2 times and 4 times increased relative risk of fatal RCC, respectively, compared with those who did not regularly use the drugs, Dr. Preston’s team reported. Women who regularly used non-aspirin NSAIDs for at least 4 years but less than 10 years and 10 or more years had a significant 1.9 times and 4.8fold times increased relative risk of fatal RCC, respectively. The researchers found no significant association between regular use of non-aspirin NSAIDs and fatal RCC in men who reported less use overall compared to women. Regular aspirin use had no significant effect on the risk of fatal RCC in either women or men. n

The articles on pages 14 and 15 report on studies presented at the 2016 Genitourinary Cancers Symposium in San Francisco.

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Renal & Urology News 15

Statin Use Found to Prolong Abiraterone Therapy STATIN USE may prolong duration of abiraterone treatment in men with castration-resistant prostate cancer (CRPC), new findings suggest. In a retrospective study of 224 CRPC patients treated with abiraterone, Lauren C. Harshman, MD, of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, and colleagues found a trend toward longer median duration of treatment in statin users compared to non-users (14.2 vs. 9.2 months). Of the 224 patients, 92 (41%) used statins and 96% had metastatic disease at the time of abiraterone administration. Additionally, 26% had previously received docetaxel and 7% had prior enzalutamide treatment.

Statin use was associated with a nonsignificant 18% reduced likelihood of abiraterone treatment cessation after adjusting for prior use of docetaxel, enzalutamide, and site of metastases. Prior docetaxel use was associated with significantly shorter abiraterone duration.

Based on prior preclinical work out of the Kantoff Laboratory at Dana-Farber, Dr. Harshman and colleagues hypothesized that statins may compete with uptake of the adrenal androgen dehydroepiandrosterone sulfate (DHEAS), a precursor to more potent androgens, such as dihydroxytestosterone, leading

5-ARIs Cut Risk of PCa Progression MEN ON ACTIVE surveillance (AS) long-term who take 5-alpha-reductase inhibitors (5-ARIs) have a lower rate of prostate cancer progression and are less likely to quit AS than those not taking the drugs, researchers reported. Investigators led by Antonio Finelli, MD, of the University of Toronto, retrospectively studied 288 men on AS for PCa at a single institution. Over a median follow-up of 61.2 months, 124 men (43%) experienced pathologic progression. A total of 119 men (41.3%) quit the AS program. Men taking a 5-ARI experienced a lower rate of pathologic progression (24.3% vs. 49.1%) and were less likely to abandon AS compared with nonusers (25.7% vs. 46.3%). On multivariable analysis, not taking a 5-ARI was associated with a nearly 2.6 times increased risk of pathologic progression compared with 5-ARIDelicious use. When

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investigators accounted for prostate gland size, non-use of 5-ARIs was Facebook

associated with an approximately 2.8 times increased risk of progression. The researchers accounted for time Slash Dot

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on active surveillance. Reddit finding DeliciousFriendFeed The investigators reported

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to increased time to progression on androgen deprivation therapy. Another possible explanation for the current study’s findings is that statins may inhibit hepatic uptake of abiraterone, thereby prolonging drug exposure and increasing effectiveness, according to the investigators. ■

16 Renal & Urology News

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CKD Risk Following AKI Characterized Even mild AKI with rapid recovery increases the risk of chronic kidney disease stage 3 or higher

DEVELOPMENT OF acute kidney injury (AKI) during a hospitalization is associated with an increased risk of developing chronic kidney disease (CKD) by 1 year after discharge, and the risk is influenced by the timing of AKI recovery, new findings suggest. Michael Heung, MD, MS, of the University of Michigan in Ann Arbor, and colleagues studied 104,764 patients in the Veterans Health Administration (VHA) system hospitalized in 2011 who had a baseline estimated glomerular filtration rate above 60 mL/min/1.73 m2 and no diagnosis of end-stage renal disease or non–dialysis-dependent CKD. AKI developed in 17,049 patients (16.3%), of whom 91% had stage 1 AKI, the researchers reported online in the American Journal of Kidney Diseases. At 1 year, CKD stage 3 or higher developed in 18.2% of the study popu-

lation (31.8% and 15.5% of the CKD cases developed in the AKI and nonAKI patients, respectively). Among patients with stage 1 AKI, those with AKI that recovered in 2 days or less had a significant 43% increased relative risk of CKD stage 3 or higher by 1 year after hospital discharge. Patients with AKI that recovered in 3–10 days had a 2-fold increased relative risk. Patients whose AKI persisted beyond 10 days had a 2.6-fold increased relative risk. “This study demonstrates the significant risk of CKD development following an episode of AKI,” the authors concluded. “This risk increases with worsening severity of AKI, as defined by duration of injury and time to recovery, and this was present with even the mildest forms of AKI with fast recovery.” These results should raise awareness of the potential long-term development

of CKD following AKI, they added. Dr. Heung’s team pointed out that it remains unclear whether the relationship between AKI and CKD is causal, but they stated: “Regardless of the nature of the relationship between

The risk increases with worsening severity of acute kidney injury. AKI and CKD, recognition of at-risk patients will allow optimization of preventive strategies, such as more aggressive CKD risk factor modification, stricter avoidance of nephrotoxic exposures, and increased monitoring of kidney function.”

Newer Anticoagulants Safer in CKD NEWER ANTICOAGULANTS are associated with lower bleeding risk compared with conventional medications in patients with chronic kidney disease (CKD), researchers reported at the American Society of Hematology annual meeting in Orlando, Fla. The study showed that newer oral anticoagulants (NOACs) posed significantly less bleeding risk compared to conventional treatment in patients with mild renal insufficiency and appeared to be more efficacious in preventing arterial thrombosis in patients with mild to moderate renal insufficiency. Furthermore,

the rates of venous thromboembolism with NOACs was comparable to conventional treatment, if not better,” lead investigator Srinath Sundararajan, MD, of the University of Arizona in Tucson, told Renal & Urology News. Dr. Sundararajan and colleagues performed a meta-analysis of 16 randomized controlled trials that included 48,403 patients with mild to moderate renal insufficiency. Rivoroxaban, apixaban, edoxaban, and dabigatran were the newer oral anticoagulants studied. Patients with mild renal insufficiency who received the newer agents had a sig-

nificant 19% decreased bleeding risk and 32% decreased risk of arterial thromboembolism compared with those treated with conventional medications. Patients with moderate renal insufficiency treated with the newer agents had a significant 26% lower risk of arterial thromboembolism and a trend toward a decreased bleeding risk. Among patients with mild and moderate renal insufficiency, Dr. Sundararajan’s team observed a trend toward a decreased risk of venous thromboembolism in patients treated with the newer agents versus those treated with conventional medications. n

An important strength of the study, the authors stated, was the ability to account for baseline albuminuria in a subset of the study population, in contrast to previous studies. Proteinuria, they noted, is an important risk factor for CKD and CKD progression. “Proteinuria has gained recognition as an independent risk factor for AKI and thus could be a common element accounting for the association between AKI and CKD.” The study also had some limitations. For example, the authors pointed out that the VHA database represents a predominantly male population, thereby limiting generalizability. In addition, because their study was observational, the researchers did not have prescribed follow-up of patients, and results depended on the availability of follow-up laboratory testing. n

Caution Urged In the Use of Megestrol ORAL MEGESTROL acetate (MA) should be used with caution in the management of protein-energy wasting in patients with chronic kidney disease (CKD) and only when other treatment options are unavailable, researchers concluded from a systematic literature review. The review, by Lori D. Wazny, PharmD, of the University of Manitoba in Winnipeg, British

Weekly ESA Dosing May Offer Time Savings

Columbia, and colleagues, found

DIALYSIS CENTERS may experience time savings by switching patients from thrice-weekly epoetin alfa (EPO) to onceweekly darbepoetin alfa (DPO) because fewer administrations are required, a new study found. Time savings would provide opportunities to redirect nurse time towards activities aimed at improving patient care, according to researchers. J. Mark Stephens, BS, of Prima Analytics of Weymouth, Mass., and colleagues conducted a time and motion study of staff time required to prepare, administer, and document erythro-

is sparse, with few high-quality

poiesis-stimulating agent (ESA) doses. Dialysis centers using intravenous administration of thrice-weekly EPO or once-weekly DPO were selected in pairs (1 EPO, 1 DPO) from the same organization to help control for differences in ESA protocols and staffing patterns across organizations, Stephens’ group noted. Trained observers timed ESA-related tasks. Researchers observed a total of 200 ESA administrations (81 DPO, 119 EPO). Each administration required a mean of 2.26 minutes. ESA process

time per administration did not vary significantly between EPO and DPO. The estimated potential monthly staff time savings for an average facility with 70 patients totaled 23 hours because of fewer ESA administrations using onceweekly DPO, the investigators reported online in Current Medical Research and Opinion. “Patient education and fulfillment of care plans were identified as opportunities for improved care processes that could be implemented if staff time was freed up from the ESA process,” the authors wrote. n

that the current evidence for treatment with MA in dialysis patients trials. Use of MA is associated with significant adverse effects. The review included 9 studies, all of which were limited by small sample sizes, short duration, a high degree of bias, and absence of clinical outcomes, according to findings published online in the Journal of Renal Nutrition. No data were available on the use MA in non-dialysis CKD patients. n

www.renalandurologynews.com JANUARY/ FEBRUARY 2016

Renal & Urology News 17

Enzalutamide More Effective than Bicalutamide DATA SUPPORT the use of enzalutamide instead of bicalutamide in patients with asymptomatic or mildly symptomatic metastatic castrationresistant prostate cancer (mCRPC), researchers concluded. The data are from the TERRAIN trial, which showed that enzalutamide use was associated with significantly longer median progression-free survival compared with bicalutamide. Enzalutamide is an oral androgenreceptor inhibitor approved for patients with mCRPC. Bicalutamide is a non-steroidal oral anti-androgen that is approved for use in conjunction with luteinizing hormone-releasing hormone (LHRH) analogues in men with hormone-treatment naïve prostate cancer. “Despite the widespread use of bicalutamide, evidence of its clinical benefits is scarce in the context of castrationresistant prostate cancer,” Neal D. Shore, MD, of Carolina Urologic Research Center in Myrtle Beach, S.C., and colleagues stated in an online report in Lancet Oncology. TERRAIN, which the investigators believe is the first head-to-head trial comparing the drugs, was a doubleblind phase 2 study of asymptomatic or minimally symptomatic mCRPC patients with cancer progression on androgen-deprivation therapy (ADT). Investigators randomly assigned 375 patients to receive either enzalutamide (184 patients) or bicalutamide (191 patients). Of these, 126 (68%) and 168 (88%), respectively, discontinued their assigned treatment prior to the end of the study, mainly because of progressive disease. The median follow-up time was 20 months in the enzalutamide group and 16.7 months in the bicalutamide group. The enzalutamide recipients had significantly improved median progression-free survival (PFS)—the study’s primary endpoint—compared with those in the bicalutamide arm (15.7 vs. 5.8 months). This difference in PFS translated into a significant 56% decreased risk of disease progression in the enzalutamide arm. Of the most common adverse events, those occurring more frequently in the enzalutamide than bicalutamide group were fatigue, back pain, and hot flushes; those occurring more frequently in the bicalutamide than enzalutamide arm were nausea, constipation, and arthralgia. Serious adverse events were reported by 57 (31%) of 183 patients in the enzalutamide arm

and 44 (23%) of 189 patients in the bicalutamide arm. Data from the TERRAIN trial are consistent with the superior activity of enzalutamide versus bicalutamide in preclinical models of mCRPC, thus continuing to show the importance of inhibiting androgen receptor signaling

in mCRPC patients, according to the researchers. The results from the TERRAIN trial confirm and extend the results of enzalutamide activity in the phase 3 PREVAIL trial in chemotherapy-naïve patients and in the AFFIRM trial in patients who had received docetaxel.

“These data support the role of enzalutamide use in patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer who had disease progression while on ADT with an LHRH agonist or antagonist, or after bilateral orchiectomy,” the authors wrote. n

18 Renal & Urology News

JANUARY/ FEBRUARY 2016 www.renalandurologynews.com

Practice Management Physicians can use Medicare’s dialysis facility rating system as a starting point to get to know dialysis providers BY TAMMY WORTH

Dialysis centers Robert Provenzano, MD, vice president of medical affairs at DaVita HealthCare Partners Inc., said his organization initially had some misgivings about the processes of developing the ratings, but has since learned to embrace them. At the highest level, the ratings can be used to categorize facilities. They can also indicate which facilities may need more resources.

Medicare evaluates and rates dialysis facilities based on a number of quality measures.

know this and are able to account for what they are doing to improve.

Physicians Referring physicians should understand and use the ratings mainly because the industry is moving rapidly toward integrated kidney care, Dr. Provenzano said. “If you are going to enter into a risk contract, do you think you want to do it with a 1- or 2-star facility?” he said. “Every single provider needs to

Referring physicians should understand and use the ratings mainly because the industry is moving rapidly toward intergrated kidney care. “I don’t accept that the ratings do not reflect quality,” Dr. Provenzano said. “If 2 people are taking a test and one gets an A with a 91% and the other a B% with an 89%, they are equally bright. But if one gets 91% and the other a 20%, there is a meaningful difference.” Public metrics may not be perfect, but they are definable and measurable, so doctors and dialysis centers have to take ownership of them, he said. If ratings are low, it is imperative that facilities

wise up and look at it from a patient’s perspective.” Physicians can choose to work only with highly-rated facilities or continue to work with 2- or 3-star facilities if they understand what is unique in those facilities resulting in lower ratings and the relationship to actual quality, Dr. Provenzano said. Nephrologists can use the ratings to open a dialogue and get to know dialysis providers.

If ratings are low, physicians should call the medical director to find out why. They will usually be honest, and let you know, for example, that they are shortstaffed or have high turnover that is causing problems, Dr. Provenzano said. The facility administrator also can give a good sense of what is happening. The bottom line is that all of the care providers and

support teams transparently communicate to drive higher quality. Kim Fox, vice president of the health care marketing firm Jarrard Phillips Cate & Hancock, Inc., of Brentwood, Tenn., said dialysis centers should at least have information on their website about the rating system and what it means. It is important to convey to patients that ratings are just a single aspect of quality. Fox said she also recommends going beyond the website to create a handout for referring specialists. The handout can discuss why an organization’s ratings are good, and, if they are not, what corrective action is being taken to change them. A center with low ratings can underscore aspects that are not measured but are being done well. For instance, ratings do not take into account patient satisfaction, staff friendliness, and facility cleanliness. “Patients look at quality much differently than doctors do,” Fox said. “A patient thinks quality is when they [staff] are really nice to me there, take really good care of me, are friendly, clean, and they know my name,” she said. n Tammy Worth is a freelance medical journalist based in Blue Springs, MO.

How Medicare Arrives at the Star Ratings The Dialysis Facility Compare star ratings represent a summary of the quality of care provided by dialysis facilities, according to the Centers for Medicare and Medicaid Services (CMS). CMS bases the ratings on the following quality measures: • Standardized mortality ratio • Standardized hospitalization ratio • Standardized transfusion ratio • Percentage of adult hemodialysis patients who had enough wastes removed from their blood during dialysis • Percentage of pediatric hemodialysis patients who had enough wastes removed from their blood during dialysis • Percentage of adult peritoneal dialysis who had enough wastes removed from their blood during dialysis • Percentage of adult dialysis patients who had hypercalcemia • Percentage of adult dialysis patients who received treatment through an arteriovenous fistula • Percentage of adult patients who had a catheter left in vein longer than 90 days for their regular hemodialysis treatment Source: Medicare.gov

he Centers for Medicare and Medicaid Services (CMS) recently updated the Dialysis Facility Compare star ratings for dialysis centers, which were somewhat controversial when released in January 2015. In a press release announcing the star ratings, CMS administrator Marilyn Tavenner stated: “Star ratings are simple to understand and are an excellent resource for patients, their families, and caregivers to use when talking to doctors about health care choices. CMS has taken another step in its continuous commitment to improve quality measures and transparency.” Detractors did not like the points of measurement or bell curve upon which centers are rated, but they can come in handy for physicians and dialysis providers alike. Experts offer tips on how to manage and use the ratings.

For men with mCRPC who have progressed on ADT

Z Y T I G A® & P R E D N I S O N E

LET’S STRONG

THIS

TOGETHER

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

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. 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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For men with mCRPC who have progressed on ADT

ZYTIGA® & PREDNISONE: (abiraterone acetate)

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

ZYTIGA® + prednisone achieved a median OS of almost 3 years (34.7 months) after a median 4 years (49 months) of follow-up† months improvement in median  4.4 overall survival—34.7 months with

Median

ZYTIGA® + prednisone vs 30.3 months with placebo + prednisone (active compound)‡ —Co-primary end point—median OS: hazard ratio (HR)=0.81; 95% CI: 0.70, 0.93; P=0.0033 Co-primary end point—at the prespecified rPFS analysis, median not reached for ZYTIGA® + prednisone vs a median of 8.28 months for placebo + prednisone; HR=0.425; 95% CI: 0.347, 0.522; P<0.0001§II

4 Years



(49 months)

of follow-up

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

034441-150514

Date: 11/03/15 Customer Code: 037771-150729 File Name: 037771-150729_740853_v1a (p2 Left side) Size: 7" x 10" Colors: CMYK Description: Lets Do This Pub: Renal and Urology News - (December Online Issue) K

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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. 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. 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).

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IMPORTANT SAFETY INFORMATION

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Let’s do this With a median 49 months of follow-up…

There were

no notable changes in the safety profile of ZYTIGA® + prednisone

since the previously reported interim analyses1 in women who are or may become pregnant; warnings and Contraindicated precautions include mineralocorticoid excess, adrenocortical insufficiency,



and hepatotoxicity

hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia

OS = overall survival; rPFS = radiographic progression-free survival. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were OS and rPFS. Select exclusion criteria included aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥2.5X ULN, liver metastases, moderate or severe pain, opiate use for cancer pain, prior ketoconazole treatment for prostate cancer, a history of adrenal gland or pituitary disorders, and visceral organ metastases. † At a prespecified final analysis for OS, 65% (354/546) of patients treated with ZYTIGA® + prednisone compared with 71% (387/542) of patients treated with placebo + prednisone had died. ‡ Prednisone, as a single agent, is not approved for the treatment of prostate cancer. § rPFS was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 [PCWG2] criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally reviewed radiographic assessment of progression. II At the prespecified rPFS analysis, 150 (28%) of patients treated with ZYTIGA® + prednisone and 251 (46%) of patients treated with placebo + prednisone had radiographic progression. Reference: 1. Ryan CJ, Smith MR, Fizazi K, et al; for the COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152-160.

STRONG T O G E T H E R

Learn more today at www.zytigahcp.com

Date: 11/3/15 Customer Code: 037771-150729 File Name: 037771-150729_740853_v1a (p3 Right side) Size: 7" x 10" Colors: CMYK Description: Lets Do This Pub: Renal and Urology News - (December Online Issue) K

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most common laboratory abnormalities (>20%) are anemia, elevated alkaline The phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia,

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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

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 Z YTIGA 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 Z YTIGA 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 Z YTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking Z YTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced Z YTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt Z YTIGA treatment and closely monitor liver function. Re-treatment with Z YTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of Z YTIGA 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.

ZYTIGA® (abiraterone acetate) Tablets ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralo corticoid 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 drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months. Table 1: Adverse Reactions due to ZYTIGA in Study 1 Z YTIGA 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 Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3

ZYTIGA® (abiraterone acetate) Tablets

1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia,

Table 3: A dverse Reactions in ≥5% of Patients on the Z YTIGA 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 % % % % 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

Musculoskeletal discomfort, and Musculoskeletal stiffness 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 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) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory 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 4 Includes

Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: A dverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm. Table 4: L aboratory Abnormalities in >15% of Patients in the Z YTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking Z YTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis. Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis. DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information].

ZYTIGA® (abiraterone acetate) Tablets

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. Z YTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving Z YTIGA 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 (ChildPugh 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 ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, Z YTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. • Patients should be informed that ZYTIGA should not be taken with food and that no food should be consumed for at least two hours before the dose of Z YTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. • 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 drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 ©Janssen Biotech, Inc. 2012 Revised: May 2015 034443-150514