Renal & Urology News - March 2016

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AF Risk Higher in PKD Patients

BY JODY A. CHARNOW PATIENTS with polycystic kidney disease (PKD) are at elevated risk of newonset atrial fibrillation (AF), according to researchers.

In a population-based cohort study using inpatient claims data from Taiwan’s National Health Insurance Research Database (NHIRD), investigators found that PKD patients had a significant 31% increased risk of AF compared with individuals who did not have PKD, after adjusting for age, sex, and comorbidities. The risk was higher in patients aged 50 to 64 years

IN THIS ISSUE 5 10

Study links chronic kidney disease to sleep apnea Cocoa may improve vascular function in dialysis patients

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New findings suggest earlier CIN prediction is possible

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Guidelines issued for the use of tolvaptan in ADPKD patients

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Twice-weekly HD could preserve residual kidney function

Flavanols in cocoa may protect dialysis patients’ vascular function.

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and those without any comorbidities, “suggesting that the development of AF in patients with PKD is highly associated with the disease itself,” the investigators reported in Medicine (2016;95:e2623).

The study by Tung-Min Yu, MD, of the China Medical University in Taiwan, and colleagues compared 7,203 PKD patients with 28,739 randomly selected controls frequency matched according to age, sex, and baseline comorbidities. The risk of AF in PKD patients increased as the number of risk factors increased. Compared

© PDSN / PHOTOTAKE

Atrial fibrillation odds increased by 31%

POLYCYSTIC KIDNEY disease (shown here) is a risk factor for atrial fibrillation, study finds.

with patients with no risk factors, those with 1 risk factor had a significant 59% increased risk of AF. Patients with 3 risk factors had a significant 67% increased risk. Patients with 4 and 5 or more risk factors had a 2.2 and 3.6 times increased risk, respectively.

PKD patients with congestive heart failure (CHF) and chronic kidney disease (CKD) had the highest risk of AF, followed by PKD patients with hypertension and CHF, and PKD patients with hypertension, CHF, and CKD, continued on page 5

Agent Shows Promise for SHPT Earlier ESA Use Improves AMG416, AN investigational agent, 350 pg/mL or higher). Of these, 22 tolerated and appears to be had PTH levels of 700 pg/mL or less Renal Outcomes isanwell effective treatment for second- and 15 had levels above 700 pg/mL. EARLIER TREATMENT of anemia with an erythropoiesis-stimulating agent (ESA) may be more effective at decreasing the risk of renal events in patients with chronic kidney disease (CKD) not yet on dialysis, according to investigators.

In a prospective observational study, Tadao Akizawa, MD, of Showa University School of Medicine in Tokyo, and colleagues found that nondialysis CKD patients may have better renal outcomes if ESA treatment is started when hemoglobin (Hb) levels decrease below 11 g/dL but not less than 10 g/dL. continued on page 5

ary hyperparathyroidism (SHPT) in patients on hemodialysis (HD), according to results from a phase 2 study.

AMG416 (etelcalcetide, Amgen, Inc.) is a novel peptide calcimimetic administered intravenously (IV) thriceweekly at the end of each HD session.

The study, led by David A. Bushinsky, MD, of the University of Rochester School of Medicine in Rochester, N.Y., consisted of a 12-week open-label, parent dose-escalation study that enrolled 37 adult HD patients with SHPT (parathyroid hormone [PTH] levels

The parent study was followed by 2 open-label extension periods totaling 2 years. Patients received AMG416 thrice weekly starting at 5 mg per session and titrated based on each patient’s PTH and albumin-corrected calcium (cCa) level to target a PTH level of 150–300 pg/mL. In the parent study, AMG416 treatment resulted in significant decreases in PTH levels, and these decreases were maintained during the 2 extension phases. continued on page 5

EXPERT Q&A

David J. McConkey, PhD, first director of the only institute devoted solely to bladder cancer.

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New PCa Grading System Proposed

BY JODY A. CHARNOW A CONSENSUS PANEL of experts has proposed a new and simpler prostate cancer grading system that could help clinicians give patients a better understanding of their prognosis.

The system, initially proposed by Jonathan I. Epstein, MD, Professor of Pathology, Urology, and Oncology at Johns Hopkins Medical Institutions in Baltimore, and supported by the International Society of Urological Pathology (ISUP), is based largely on the 1967 to 1973 Gleason scoring system, but more accurately reflects PCa biology

IN THIS ISSUE 6

Rosiglitazone may increase risk of bladder cancer

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Testosterone replacement does not worsen LUTS/BPH

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Men have poor knowledge of sexual function after RP

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HIFU hemiablation feasible in selected PCa patients

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PCa risk found to be lower in men with type 2 diabetes

Flavanols in cocoa may protect dialysis patients’ vascular function.

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than the Gleason system. It incorporates the latest understanding of the pathologic and clinical aspects of PCa. The new grading system, first described in BJU International in 2013 and recently verified in a large multi-institutional study described in the March issue of European Urology (2016;69:428-435), consists of 5 “grade groups,” with Grade Group 1 indicating the most favorable prognosis and Grade Group 5 the least favorable. In the Gleason scoring system, 25 grading combinations are possible.

In an interview with Renal & Urology News, Dr. Epstein said the proposed

Frailty May Up Urologic Surgery Risks FRAILTY IS STRONGLY associated with short-term postoperative complications among patients undergoing most urologic surgeries, according to researchers. The association was significant across age groups, type of complications, and various procedure types, they found.

“These findings highlight the importance of preoperative frailty assessment and how this assessment can enhance surgical decision-making among physicians, patients and their families for optimized postoperative procedures,” Anne M. Suskind, MD, of the University of California, continued on page 5

© IMAGE COURTESY OF JONATHAN I EPSTEIN, MD

Tumors would fall into 1 of 5 grade groups

A NEW GRADING SYSTEM distinguishes Gleason score 3+4 (above) from 4+3.

system distills pathologic findings into the key differences in prognosis “that can be intuitive to both patients and clinicians,” he said.

“Clinicians will be forced to look at the grades appropriately in terms of different prognoses,” Dr. Epstein said.

The original Gleason system used PCa-related death as an outcome, whereas the new system uses biochemical recurrence as an outcome, although recent studies have verified that the new system also predict death due to PCa. continued on page 5

Fatal PCa Linked to Balding

BY NATASHA PERSAUD MEN WITH ANY degree of baldness have an increased risk of dying from prostate cancer (PCa), according to a recent study.

“In the future, patterns and degree of male baldness may play a small role in estimating risk of prostate cancer and may contribute to patient-doctor discussions about whether to opt for prostate cancer screening,” lead investigator Michael Cook, PhD, of the National Cancer Institute in Bethesda, Md., told Renal & Urology News.

Using male pattern baldness as a proxy for long-term androgen exposure, Dr. Cook and colleagues studied

PCa-specific mortality and extent of baldness in 4,316 men aged 25–74 years from the National Health and Nutrition Examination Survey Epidemiologic Follow-up Study (1971–1974).

Of 3,284 deaths occurring during 21 years of follow-up, 107 were due to PCa, according to results published online in the American Journal of Epidemiology. Compared with no balding, having any degree of baldness was associated with a 56% higher risk of fatal PCa, after adjusting for potential confounders such as age, race, and body mass index. Moderate balding, defi ned as observable baldness by a continued on page 5

EXPERT Q&A

David J. McConkey, PhD, first director of the only institute devoted solely to bladder cancer.

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FROM THE EDITOR EDITORIAL ADVISORY BOARD Medical Director, Urology

Medical Director, Nephrology

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

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

Nephrologists

Urologists

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

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

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

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

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

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

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

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

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

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

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

Renal & Urology News Staff Editor

Jody A. Charnow

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Renal & Urology News (ISSN 1550-9478) Volume 15, Number 2. Published monthly, except for the combined January/February, June/July and November/ December issues, by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Periodicals postage paid at New York, NY, and an additional mailing office. The subscription rates for one year are, in the U.S., $75.00; in Canada, $85.00; all other foreign countries, $110.00. Single issues, $20.00. www.renalandurologynews.com. Postmaster: Send address changes to Renal & Urology News, c/o DMD Data Inc., 2340 River Road, Des Plaines, IL 60018. Copyright: All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without the prior written permission of Haymarket Media, Inc. Copyright © 2016.

The Psychological Impact of Prostate Cancer

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t would not be hard to guess the psychological impact on patients the moment a doctor tells them they have cancer. Just hearing that word probably leaves most patients stunned and, in the moments that follow, perhaps only half-listening to whatever else the doctor has to say.

To some, cancer equals death. Cancer may or may not be life ending, but it is almost certainly life changing.

The diagnosis may intrude often on patients’ thoughts and reshape their vision about the trajectory of their lives. Some may decide to take that cruise around the world they have been dreaming about sooner rather than later. Rare would be the patient who is not at least a little concerned or frightened about the odyssey of tests and treatment they face. As a result of the diagnosis, some patients may experience harmful physiological effects and contemplate suicide. Men with prostate cancer (PCa) are not immune.

The medical literature on the effects of a PCa diagnosis on the mental health of men is growing. For example, this issue of Renal & Urology News reports on a study published in the Journal of the National Comprehensive Cancer Network showing that elderly men have a significantly higher risk of hospitalizations for non-cancer conditions after receiving a diagnosis of non-metastatic PCa (see article on page 17). The authors, led by Amit D. Raval, PhD, of West Virginia University in Morgantown, gave some plausible explanations for the increased risk, citing research showing that a PCa diagnosis “can trigger psychological distress, anxiety, and suicidal ideations. This increase in psychological stress may increase blood levels of epinephrine and norepinephrine, resulting in increased heart rate, blood pressure, and blood sugar levels.”

In a previous study published online ahead of print in BJU International, Quoc-Dien Trinh, MD, and colleagues at Harvard Medical School in Boston, found that men with PCa are at increased risk of suicide and accidental death within the first year of diagnosis compared with men diagnosed with other solid cancers. The authors concluded that their findings suggest “the need for close monitoring and coordination with mental health professionals in at-risk men with potentially curable disease.”

While mental health professionals may have a role, urologists who deliver to men what may be among the most distressing bits of news they will ever hear could have a big positive impact. The vast majority of men diagnosed with PCa have low-risk disease, which has an extremely favorable prognosis. The cancers can be cured with surgery or radiation or managed with active surveillance. Even patients with more advanced disease often have good long-term outcomes. These facts, couched in the right language and delivered with empathy by the urologist, could do much to put patients at ease.

Jody A. Charnow Editor

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VOLUME

Nephrology 7

ONLINE

this month at renalandurologynews.com

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

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

Congratulations to our February winner: Said Castro, MD

HIPAA The U.S. Office for Civil Rights reminds providers about patients’ rights to access their health records.

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

Cocoa Flavanols Benefit HD Patients Dietary cocoa flavanols may improve vascular function in hemodialysis patients.

Cinacalcet May Lower Testosterone Cinacalcet treatment for secondary hyperparathyroidism in men on chronic hemodialysis is associated with decreased testosterone.

Statins Decrease Death Risk in CKD Patients Statins improve survival and other outcomes in patients with chronic kidney disease, but they do not appear to slow progression to end-stage renal disease.

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

PCa Relapse Not Linked to ED Drugs Phosphodiesterase type 5 inhibitors do not affect the risk of biochemical recurrence in patients who undergo radical prostatectomy for prostate cancer.

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Hemiablation HIFU Called a Valid Therapy High-intensity focused ultrasound hemiablation is a valid treatment for carefully selected patients with clinically localized prostate cancer, researchers report.

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Canadian Urological Association Annual Meeting Vancouver, B.C. June 25–28

RP Patients Largely Unaware of Sexual Complications Researchers report that patient knowledge about sexual function following radical prostatectomy is poor.

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

Belatacept Improves Kidney Transplant Outcomes Immunosuppression regimens based on belatacept rather than cyclosporine are associated with better 7-year outcomes among kidney transplant recipients.

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Job Board

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CALENDAR

Urology 8

15, ISSUE

PCa Diagnosis Increases Risk of Non-Cancer Hospitalizations Elderly men are at elevated risk of hospitalizations for non-cancer conditions after being diagnosed with non-metastatic prostate cancer.

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Departments 3

From the Editor The psychological impact of prostate cancer

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News in Brief Mid-urethral slings for SUI offer long-term efficacy.

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Expert Q&A David J. McConkey, PhD, discusses the future of bladder cancer research.

A change in clinical practice regarding PDE5i use after PCa treatment is not warranted.

18 See our story on page 8

Practice Management Patients’ rights to access their health records

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www.renalandurologynews.com

Contents

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2016

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VOLUME

Urology 8

ONLINE

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this month at renalandurologynews.com Clinical Quiz

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

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

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Congratulations to our February winner: Said Castro, MD

PCa Relapse Not Linked to ED Drugs Phosphodiesterase type 5 inhibitors do not affect the risk of biochemical recurrence in patients who undergo radical prostatectomy for prostate cancer.

RP Patients Largely Unaware of Sexual Complications Researchers report that patient knowledge about sexual function following radical prostatectomy is poor.

Hemiablation HIFU Called a Valid Therapy High-intensity focused ultrasound hemiablation is a valid treatment for carefully selected patients with clinically localized prostate cancer, researchers report.

PCa Diagnosis Increases Risk of Non-Cancer Hospitalizations Elderly men are at elevated risk of hospitalizations for non-cancer conditions after being diagnosed with non-metastatic prostate cancer.

15, ISSUE

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

Nephrology

HIPAA The U.S. Office for Civil Rights reminds providers about patients’ rights to access their health records.

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

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Belatacept Improves Kidney Transplant Outcomes Immunosuppression regimens based on belatacept rather than cyclosporine are associated with better 7-year outcomes among kidney transplant recipients.

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Cocoa Flavanols Benefit HD Patients Dietary cocoa flavanols may improve vascular function in hemodialysis patients.

11

Cinacalcet May Lower Testosterone Cinacalcet treatment for secondary hyperparathyroidism in men on chronic hemodialysis is associated with decreased testosterone.

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

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Statins Decrease Death Risk in CKD Patients Statins improve survival and other outcomes in patients with chronic kidney disease, but they do not appear to slow progression to end-stage renal disease.

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Departments 3

From the Editor The psychological impact of prostate cancer

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News in Brief Mid-urethral slings for SUI offer long-term efficacy.

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Expert Q&A David J. McConkey, PhD, discusses the future of bladder cancer research.

A change in clinical practice regarding PDE5i use after PCa treatment is not warranted.

18 See our story on page 8

Practice Management Patients’ rights to access their health records

www.renalandurologynews.com MARCH 2016

AF risk in PKD patients continued from page 1

according to the researchers. In addition, the odds of dying from AF was 69% higher in the PKD patients than in the comparison cohort.

“The current study is the first to provide clinical evidence of the association between AF and PKD,” the authors wrote.

Previous research has identified crucial risk factors associated with newonset AF, including advanced age, hypertension, and CHF. Cardiovascular complications remain the major problems contributing to mortality and morbidity in PKD patients, the researchers stated. Studies have demonstrated that enlargement of renal cysts in adults with ADPKD is associated with increased circulating and intrarenal renin-angiotensinaldosterone system (RAAS) activity,

Dr. Yu’s team noted. A study published in the American Journal of Nephrology (1998;18:391-398) revealed enhanced sympathetic activity in ADPKD patients, with higher plasma concentrations of epinephrine and norepinephrine found in patients with

Atrial fibrillation risk increases along with the number of patient risk factors. essential hypertension, with or without renal failure. In addition, in a paper published in Journal of Molecular and Cellular Cardiology (2013;58:199-208), researchers reported that idiopathic dilated cardiomyopathy was more prevalent in ADPKD patients than in the general population.

Neera K. Dahl, MD, PhD, Associate Professor of Medicine (Nephrology) at the Yale School of Medicine in New Haven, Conn., who has a research interest in ADPKD but was not part of the new study, said the paper by Dr. Yu and colleagues “provides evidence that ADPKD is an independent risk factor for AF.” A limitation of the study, however, was the lack of information on structural heart disease in the cohort. It is not known if patients with PKD were more likely to have left ventricular hypertrophy, reduced ejection fraction, or valvular heart disease, which may also predispose to AF, and whether the findings from the Taiwanese population would be generalizable to other populations.

“Cardiovascular disease is still the major cause of mortality in ADPKD. Focusing on arrhythmia opens new areas for research,” Dr. Dahl said. n

Renal & Urology News 5

Sleep Apnea, CKD Linked, Study Finds SLEEP APNEA may be a novel risk factor for chronic kidney disease (CKD), a new Taiwanese study suggests.

The risk of CKD was 58% greater among sleep apnea (SA) patients compared with similar patients without the sleep disorder. The contribution of SA was equivalent to hypertension.

Therefore, SA should be added to the list of factors considered in CKD risk assessment, enhancing the ability to prevent CKD, lead researcher Yung-Tai Chen, MD, from Taipei City Hospital in Taiwan, and colleagues concluded in Respirology.

Using Taiwan’s National Health

Earlier ESA use continued from page 1

At baseline, patients had a mean PTH level of 853 pg/mL. From baseline to the efficacy assessment period (EAP), patients had a mean 53.6% decrease in PTH level, the researchers reported in the American Journal of Nephrology (2015;42:379-388). The proportion of patients with a 30% or greater reduction in PTH from baseline to the efficacy assessment period (EAP) was 89%. At the EAP, 56% of patients had achieved a PTH level of 300 pg/mL or less.

The researchers also compared patients with PTH values of 700 pg/mL or less and those with values above 700 pg/mL and found comparable results.

The mean percent changes from baseline to EAP for cCa and phosphorus were −15% and −10%, respectively.

The most common treatment-emergent adverse events (AEs), occurring in at least 10% of patients, were asymptomatic blood calcium decreases (24%), diarrhea (14%), and symptomatic hypocalcemia (11%). AEs were mild to moderate in severity, according to the researchers.

“AMG416 appears to be a promising agent to effectively manage SHPT in subjects treated with hemodialysis and potentially offers substantial advantages over currently available treatments,” the authors concluded.

Dr. Bushinsky’s group noted that the only commercially available calcimimetic agent, cinacalcet, is formulated

for oral administration, “placing the burden of daily adherence on patients who already take a large number of oral medications.”

In addition, the investigators said, nausea and vomiting are common AEs associated with cinacalcet use, especially at higher doses, and this limits its utilization. Over the 2-year extension periods, no patient had to withdraw because of nausea or vomiting, Dr. Bushinsky and his colleagues reported.

The researchers acknowledged that a limitation of their study was their small sample size, which may have under- or overestimated the frequency of AEs that may not become evident until a larger number of patients are treated.

The study was funded by Amgen, Inc. n

Insurance Research Database 20002010, the investigators identified 8,687 patients with SA and 34,747 matched controls without SA. During a median 3.9 years, CKD developed in 157 patients with SA and 298 without SA. SA patients were 1.58 times more likely to be diagnosed with CKD. The researchers accounted for hypertension, diabetes, medications, demographic factors, and other potential confounding variables.

Dr. Chen and colleagues determined that the relative contribution of SA to CKD was 17%, similar to that of hypertension, whereas diabetes conferred a 117% greater risk of CKD. Patients who had all 3 conditions had a 479% greater risk of CKD.

Agent promises SHPT continued from page 1

Dr. Akizawa and colleagues noted that the 2012 guidelines from the Kidney Disease: Improving Global Outcomes initiative states that introduction of ESA therapy should be considered when Hb levels drop below 10 g/dL in non-dialysis CKD patients, but provide no evidence to support this recommendation.

“Although early detection and management of anemia is considered to be vital,” the authors wrote, “the best time for starting ESA therapy is still uncertain, and it is now imperative that we collect data on the appropriate Hb level for starting ESA therapy.”

The study included 1,113 non-dialysis CKD patients with anemia treated

with epoetin beta. The investigators divided subjects into 3 groups based on Hb levels at initiation of therapy: Group I, 10 g/dL or more but less than 11 g/dL; group II, 9 g/dL or more but less than 10 g/dL; and group III, less

AMG416 lowered PTH significantly with no serious adverse events. than 9 g/dL. The primary endpoint was time to first occurrence of any renal event (initiation of renal replacement therapy, doubling of serum creatinine level, or a measurement of

estimated glomerular filtration rate (eGFR) less than 6.0 mL/min/1.73 m2).

Renal events occurred in 32.4%, 45.1%, 60.6% of patients in group I, II, and III, respectively, the researchers reported online in Clinical and Experimental Nephrology. Compared with patients in group I, those in group III had a significant 2.5 times increased risk of renal events. Patients in group II had a 48% increased risk, but this was not significant.

“Initiation of ESA therapy when Hb levels decreased below 11 g/dL but not below 10 g/dL could be more effective at reducing the risk of renal events in non-dialysis CKD patients with anemia compared with initiation of ESA therapy at below 9 g/dL or even 10 g/ dL,” the researchers concluded. n

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The purported harmful effects of SA toward CKD risk appear independent from hypertension and diabetes. The findings support previous research showing increased CKD risk with SA. For example, a U.S. study published in Thorax (2015;70:888895) of mostly male veterans found 2.3 and 2.8 times greater risks of incident CKD among those with untreated and treated obstructive SA, respectively.

Dr. Chen’s group acknowledged they were unable to account for SA severity, obesity, tobacco use, and family history. As the study involved the population of Taiwan, the results may not pertain to non-Asians. n

www.renalandurologynews.com MARCH 2016

PCa grading system continued from page 1

A noteworthy aspect of the new grading system is the distinction it makes between Gleason score 3 + 4 and 4 + 3 cancers, which often are simply called Gleason score 7 disease in discussions with patients. Dr. Epstein emphasized that Gleason 3 + 4 tumors are associated with substantially better prognoses than Gleason 4 + 3 tumors. The new grading system separates these cancers into Grade Group 2 and 3, respectively.

This distinction could affect patient decisions whether to be placed on active surveillance if their doctors recommend it. Patients may feel more comfortable with this approach if they are told their cancer is a grade 2 out of 5 instead of a Gleason 7 out of 10, Dr. Epstein said.

Another important feature of the new system is the placement of Gleason score 6 cancers into Grade Group 1.

Dr. Epstein pointed out that patients with Gleason score 6 disease often believe their prognosis is worse than it is because Gleason score 6 is half way along the Gleason scoring scale of 2 to 10, when, in fact, a Gleason score 6 tumor is the lowest-grade cancer currently assigned with an excellent prognosis. The new system reflects this.

The new grading system has been in use at Johns Hopkins since 2013, with

Urologic surgery risks continued from page 1

San Francisco, and colleagues concluded in an online report in BJU International.

Not all urologic surgeries were significantly associated with an increased risk of complications. These exceptions include prostatectomy with lymph node dissection, prostatectomy with extended lymph node dissection, cystectomy, sling procedures for urinary incontinence, and orchiectomy.

Dr. Suskind’s group analyzed data from 95,108 cases representing 21 different urologic procedures in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP).

They assessed frailty using a frailty index (FI) designed specifically for use with NSQIP data. The index includes 11 items: history of diabetes; impaired functional status; history of chronic obstructive pulmonary disease or pneumonia; history of congestive heart failure; history of myocardial infarction within 6 months of surgery; history of percutaneous coronary intervention

biopsy reports including both Gleason scores and grade groups, and clinicians at the institution have embraced it, Dr. Epstein said. “It helps them to explain to patients in simple terms the relative prognosis of their tumors,” he said.

The consensus panel was convened in 2014 by ISUP and included 65 PCa pathology experts as well as 17 clinicians, including urologists, radiation oncologists, and medical oncologists from 19 countries.

The new grading system and terminology of Grade Groups 1 through 5 have been accepted by the World Health Organization for the 2016 edition of Pathology and Genetics: Tumours of the Urinary System and Male Genital Organs. As for how quickly the new system will be adopted by U.S. clinicians, Dr. Epstein noted that this depends largely on its adoption by the College of American Pathologists checklists, to which every medical institution adheres.

This often follows what the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) do with respect to the TNM Classification of Malignant Tumors, which both groups maintain.

“The new grading system has some significant advantages over the Gleason grading system,” said David F. Penson, MD, Chair of the

cardiac surgery or angina; receipt of hypertensive medications; peripheral vascular disease or rest pain; impaired sensorium; transient ischemic attack or cerebrovascular accident (CVA); and CVA with deficit defined by history of CVA with persistent residual dysfunction. Items are summed and divided by 11 for the composite score. For example, an FI score of 1/11 would be 0.09 and a score of 2/11 would be 0.18, the researchers explained. “This index has been shown to have excellent correlation with both mortality and morbidity in all surgical subspecialties,” the authors noted.

Increasing frailty was associated with significantly increasing odds of complications. Patients with an FI of 0.09 had 28% increased odds of complications in adjusted analyses, whereas patients with an FI of 0.18 or higher had 74% increased odds.

The researchers classified complications as either minor or major. The most frequent minor complication was blood transfusion, which was required in 4.6% of cases; the most frequent major complication was hospital readmission, which was required in 6.2% of cases. n

Jonathan I. Epstein, MD

Department of Urologic Surgery and Director of the Center for Surgical Quality and Outcomes Research at Vanderbilt University Medical Center in Nashville, Tenn. “The Gleason system can be quite confusing to patients. Patients often misinterpret the news of a Gleason 3 + 3 = 6 tumor as bad news, as the scale runs from 2 to 10 and 6 is in the middle, implying intermediate-risk disease. Resetting the grading system so the lowest risk cancers are a Grade Group 1 will be very helpful for patient counseling and will aid in the further uptake of active surveillance in appropriate men with low-risk disease.”

Fatal PCa, balding link continued from page 1

dermatologist at baseline, was associated with an 83% increased risk.

Patterned hair loss was not associated with all-cause mortality.

The investigators believe their findings support their hypothesis that PCa and androgenic alopecia have overlapping pathophysiologic mechanisms from heritable factors and endogenous hormones; both hair follicles and the prostate gland are androgen responsive.

The authors noted that the “moderate association and relatively high prevalence of male pattern baldness in Western populations does not currently support the use of male pattern baldness in prostate cancer screening decisions.”

The new findings support some previous studies linking PCa to balding (such as vertex or frontal balding patterns). For example, in a study of 39,070 men in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, a team led by Dr. Cook found that, compared with no baldness, frontal

Renal & Urology News 5

The differentiation between Gleason 3 + 4 and 4 + 3 as Grade Groups 2 and 3 is also an important advance that will improve patient education and future studies of PCa, Dr. Penson said.

“Specifically, many administrative and institutional databases fail to differentiate between 3 + 4 and 4 + 3 disease, reporting both as Gleason score 7,” he said. “This is probably not the optimal approach given that studies show that there are differences in outcomes between the 2 groups.”

Although the proposed Grade Group system is an advance, some questions still remain, Dr. Penson said. The validation data presented by Dr. Epstein uses biochemical recurrence-free survival as the endpoint, Dr. Penson pointed out. “As we know, not all biochemical recurrences result in a clinical event such as metastasis or death and, of course, the definition of a biochemical recurrence differs between surgery and radiation. It’s also not entirely clear to me how patients who have a tertiary Gleason pattern on prostatectomy will be graded in the new system.”

Given these and other remaining questions, further study of the new system is needed. “That being said, however, it is definitely time for us to take a critical look at the Gleason grading system and develop better approaches to the pathologic grading of prostate cancer,” Dr. Penson said. n

plus moderate vertex baldness at age 45 years was associated with a significant 39% increased risk of aggressive PCa, according to a paper published in the Journal of Clinical Oncology (2015;33:419-425). In an earlier study of 4,421 men aged 25–75 years without a history of PCa who participated in the first National Health and Nutrition Examination Survey, Ernest Hawk, MD, MPH, and colleagues at the National Cancer Institute found that male pattern baldness was associated with a 50% increased relative risk of PCa, regardless of baldness severity and independent of other risk factors, such as race and age, according to a report in Cancer Epidemiology, Biomarkers & Prevention (2000;9:523-527).

Not all studies examining the relationship between balding and PCa have found a connection, however.

For example, Dr. Cook and colleagues reported in The Prostate (2015;75:415423) that they found no significant association between pattern baldness and overall PCa and PCa subtypes in a study of 32,583 men aged 50–76 years in the VITamins And Lifestyle (VITAL) cohort study. n

6 Renal & Urology News

MARCH 2016 www.renalandurologynews.com

News in Brief

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

Short Takes Rosiglitazone May Up Bladder Cancer Risk

Bariatric surgery overall was associated

Diabetics who use rosiglitazone have

risk (RR) of kidney stones versus no

an increased incidence of bladder

surgery. RYGB, however, was associ-

cancer, Korean researchers reported

ated with a 73% increased pooled RR

in Medicine (2016;95:e2786).

of kidney stones, but restrictive proce-

with a 22% increased pooled relative

In a nested case-control study that

dures such as laparoscopic banding or

included 47,738 patients with diabe-

sleeve gastrectomy were associated

tes, investigators found that exclusive

with a 63% decreased pooled RR.

rosiglitazone use was associated cancer compared with non-use. The

Poor Appetite, Lower GFR Linked in Children with CKD

risk of bladder cancer started to rise

Self-reported appetite in children with

after less than 3 months of use and

chronic kidney disease (CKD) worsens

peaked at 3–12 months of use (4.5-

with lower glomerular filtration rate.

with 3-fold increased odds of bladder

fold increased odds).

Bariatric Surgery Type Influences Stone Risk

study, Frank W. Ayestaran, MD, of

Bariatric surgery using the Roux-en-

colleagues found that children with

Y gastric bypass (RYGB) procedure

an iohexol or estimated glomerular

increases the risk of kidney stones,

filtration rate (ieGFR) below 30 mL/

whereas restrictive procedures

min/1.73 m2 was associated with

decrease the risk, according to a

nearly 4.5-fold greater odds of having

systematic review and meta-analysis

a worse appetite than those with an

published in Renal Failure (2016;

ieGFR above 90 mL/min/1.73 m2, ac-

online ahead of print).

cording to an online report in Pediatric

Emory University in Atlanta, and

Charat Thongprayoon, MD, of Mayo

Nephrology. Patients who did not have

Clinic in Rochester, Minn., and col-

a very good appetite had more hospi-

leagues analyzed data from 4 studies

talizations over the following year than

that included 11,348 participants.

those with a very good appetite.

Urinary Cancers in the U.S. Shown here are the estimated numbers of new cases of urinary tract cancers that will be diagnosed in 2016 in the United States, by sex, according to the American Cancer Society:

180,890

n Male

n Female

150000

100000

58,950 50000

0

18,010 Prostate

mong patients undergoing robotic partial nephrectomy (RPN) for renal tumors, African-American (AA) patients are more likely than non-AA patients to have papillary renal cell carcinoma (RCC), a study found.

Investigators at Cleveland Clinic in Ohio led by Jihad H. Kaouk, MD, examined the possible effects of race on pathologic outcomes and kidney function preservation in patients undergoing RPN. Of 1,005 patients, 84 were AA. The AA and non-AA patients were comparable in age and tumor size (2.7 vs. 3 cm). The proportion of patients with papillary RCC was significant higher in the AA than the non-AA patients (43.3% vs. 19.4%), the researchers reported online in the Journal of Robotic Surgery. After matching AA patients with non-AA counterparts, the preservation of estimated glomerular filtration rate (eGFR) after surgery between the groups was similar (84.3% vs. 85%). On multivariate analysis, AA race, male gender, and low preoperative eGFR predicted papillary RCC. The researchers observed no difference in kidney function recovery after RPN.

In a study of 879 participants in the Chronic Kidney Disease in Children

200000

Study: Papillary RCC More Common in African Americans A

Urinary bladder

39,650

23,050

Kidney and renal pelvis

Source: American Cancer Society, Cancer Facts & Figures 2016.

65 –74

Hyperkalemia Linked to Use of Aldosterone Antagonists U

se of aldosterone antagonists is associated with an increased risk of hyperkalemia and acute renal failure among older patients with reduced ejection fraction after acute myocardial infarction (MI), according to a new study published online ahead of print in the Journal of the American Heart Association.

Tracy Y. Wang, MD, MS, of Duke University Medical Center in Durham, N.C., and colleagues studied 12,081 MI patients aged 65 years and older with an ejection fraction (EF) of 40% or less. Of these, 1,310 (11%) were prescribed aldosterone antagonists—predominantly spironolactone—at discharge. In adjusted analyses, patients prescribed aldosterone antagonists had a 2-fold increased risk of hyperkalemia at 30 days and a 39% increased risk of acute renal failure at 2 years.

Mid-Urethral Slings for SUI Offer Long-Term Efficacy M

id-urethral slings have excellent long-term efficacy in the management of stress urinary incontinence (SUI), researchers concluded.

Ingrid Schauer, MD, and colleagues at Kaiser-Franz-Joseph Hospital in Vienna, Austria, studied 256 women who had 10 years of follow-up following a mid-urethral sling operation. At the 2, 5, and 10-year follow-up, the percentages of women report the use of 0-1 pads per day were 96.4%, 97.1%, and 88.5%, respectively, the investigators reported online ahead of print in Neurourology and Urodynamics.

More than 95% of women reported no SUI at the 2-, 5-, and 10 year follow-up. At baseline, urgency was reported by 61.2% of patients; this declined to 17.3% at 2 years and increased subsequently to 32.4% and 41.7% at 5 and 10 years, respectively. De novo urgency developed in 3.6%, 10.8%, and 14.4% of patients after 2, 5, and 10 years, respectively. The proportion of women who had a high degree of treatment satisfaction decreased from 79.1% at 2 years to 70.5% and 62.6% at 5 and 10 years, respectively.

www.renalandurologynews.com MARCH 2016

Renal & Urology News 7

Belatacept Improves Kidney Transplant Outcomes IMMUNOSUPPRESSION regimens based on belatacept rather than cyclosporine are associated with better 7-year outcomes among kidney transplant recipients, according to final results from BENEFIT, a phase 3 study.

In that study, Flavio Vincenti, MD, of the University of California San Francisco, and colleagues randomly assigned 666 patients to receive a lessintensive or more intensive belatacept regimen or a cyclosporine regimen.

Of these, 447 could be evaluated at 7 years: 163 in the less-intensive belatacept group, 153 in the more-intensive belatacept group, and 131 in the cyclosporine group.

Results showed a significant 43% reduction in the risk of death or graft loss in both of the belatacept treatment arms compared with the cyclosporine

The study had originally enrolled 738 patients, of whom 666 underwent randomization to a treatment arm: 226 to a less-intensive belatacept regimen, 219 to a more-intensive belatacept regimen, and 221 to a cyclosporine-based regimen.

The less-intensive belatacept regimen consisted of 10 mg/kg of the medica-

tion on days 1 and 5 and at weeks 2 and 4 during month 0–1; 10 mg/kg at weeks 8 and 12 during months 2–3; and 5 mg/kg every 4 weeks beyond 3 months. The more-intensive belatacept regimen consisted of 10 mg/kg on days 1 and 5 and weeks 2, 4, 6, 8, 10, and 12 during months 0–3; 10 mg/kg at weeks

Researchers report lower risk of death and graft loss versus cyclosporine. group, the investigators reported in The New England Journal of Medicine (2016;374:333-343). The less-intensive and more intensive belatacept groups had a significant 45% and 38% decreased risk of death, respectively, and a 41% and 44% decreased risk of graft loss, respectively, compared with the cyclosporine group.

In addition, the mean estimated glomerular filtration rate (eGFR) increased in patients in both belatacept groups but decreased in those treated with cyclosporine. From month 1 to month 84, patients in the less-intensive and more-intensive belatacept groups experienced mean eGFR increases of 1.39 and 130 mL/min/1.73 m2 per year, respectively, whereas the cyclosporine arm had a mean eGFR decline 1.04 mL/min/1.73 m2 per year, according to the researchers.

The 3 treatment arms had similar cumulative frequencies of serious adverse events at 7 years.

The investigators acknowledged that a limitation of the trial was that it did not compare belatacept with tacrolimus, the current the standard-of-care calcineurin inhibitor, but patient and graft outcomes with contemporary tacrolimus-based regiments, they noted, are similar to those observed with cyclosporine-based regimens.

Mount Sinai Renal & Urology News Trim: 7 x10

16, 20, and 24 during months 4–6; and 5 mg/kg every 4 weeks beyond month 6. The cyclosporine regimen consisted of an initial daily dose of 4–10 mg/ kg, with the dose adjusted to 150 – 300 ng/mL during months 0–1. The dose was adjusted to 100–250 ng/mL beyond month 1. n

8 Renal & Urology News

MARCH 2016 www.renalandurologynews.com

PCa Relapse Not Linked to ED Drugs Biochemical recurrence risk after radical surgery unaffected by PDE5i use ORAL DRUGS to treat erectile dysfunction after radical treatment for prostate cancer (PCa) do not affect the risk of biochemical recurrence (BCR) of disease, regardless of the cumulative number of pills taken, a new study suggests.

Stacy Loeb, MD, of New York University, and colleagues conducted a nested case-control study using the National Prostate Cancer Registry (NPCR) of Sweden—which includes 98% of PCa cases nationwide—linked to the Prescribed Drug Register, which the investigators used to identify filled prescriptions for sildenafil, vardenafil, and tadalafil. The study compared 293 men who experienced BCR after radical prostatectomy (RP) or radiation therapy with 5,767 BCR-free controls.

Practice change unwarranted After adjusting for marital status, income, education, PSA level, clinical stage, Gleason score, and proportion of positive biopsies, Dr. Loeb’s group found no significant association between phosphodiesterase type 5 inhibitor (PDE5i) use and BCR following either RP or radiation treatment, according to a paper published online ahead of print in European Urology.

Patients with a greater cumulative number of PDE5i pills were not at higher risk of BCR following RP, after adjusting for pathologic tumor features.

“A change in clinical practice regarding PDE5i use after PCa treatment is not warranted,” the authors concluded.

Cumulative number of PDE5i pills taken had no effect on BCR risk, study found.

Conflicting findings The new study conflicts with a study

by Uwe Michl, MD, of the MartiniClinic Prostate Cancer Center, University Hospital HamburgEppendorf, Hamburg, Germany.

That study, which was published in the Journal of Urology (2015;193:479483), found that PDE5i use was associated with a significant 38% increased risk of BCR risk after RP. The study included 4,752 patients with localized PCa who underwent bilateral nervesparing RP. Of these, 1,110 (23.4%) received PDE5i postoperatively and 3,642 (76.6%) did not.

Results of the study by Dr. Loeb and colleagues, however, corroborate recently published findings by Andrea Gallina, MD, and colleagues at IRCCS Ospedale San Raffaele, Milan, Italy, who examined PDE5i use and BCR in 2,579 men who underwent bilateral nerve-sparing RP. The number of PDE5i pills taken was not significantly associated with BCR, after adjusting for clinicopathologic features, the researchers reported in European Urology (2015;68:750-753).

Strengths of the study by Dr. Loeb’s team include the availability of population-based data from healthcare registries and demographic databases in Sweden, “which are real-world data of high quality. Comprehensive linkages provide complete and detailed data, including PCa treatment outcomes, exact cumulative PDE5i exposure, and information on putative confounders including socioeconomic factors.”

The researchers also acknowledged study limitations, including assessment of PDE5i use based on records for filled prescriptions and an insufficient sample size to examine the association between cumulative PDE5i pills and BCR after radiotherapy. In addition, data regarding pretreatment PDE5i use were not available for the study population. n

Study: TRT Safe in Men with LUTS

BY NATASHA PERSAUD A RECENT REVIEW finds no evidence that testosterone replacement therapy (TRT) causes or worsens lower urinary tract symptoms (LUTS) or benign prostatic hyperplasia (BPH).

Furthermore, although the Endocrine Society and other associations have suggested severe LUTS as a contraindication to TRT treatment, investigators found little evidence to support it after reviewing the limited research.

Martin Kathrins, MD, of University of Illinois at Chicago, and colleagues identified and examined 35 prospective trials of hypogonadal men with LUTS/BPH using TRT published from 1995–2015. The investigators discovered that men with mild LUTS experienced either no change or an improvement in their symptoms following TRT. International Prostate Symptom Scores did not significantly worsen, nor did prostate size increase. Limited urodynamic studies also indicated that TRT helped rather than harmed bladder physiology.

Remarkably, patients with metabolic syndrome (MetS) experienced

BOO More Severe in Men with Small Prostates

symptomatic improvement after TRT.

BY NATASHA PERSAUD UROLOGISTS frequently manage pa­tients with bladder outlet obstruction (BOO) similarly regardless of their prostate size. A new study, however, suggests that men with small prostates and BOO have more severe symptoms and voiding problems compared with men who have larger prostates.

Researchers found that maximal flow rate (Qmax) and serum PSA level predicted BOO in men with small prostates.

The study presents “thought-provoking” evidence that men with LUTS/ BPH and small prostates and refractory symptoms should be checked for bladder functions with urodynamic studies, lead researcher Seung-June Oh, MD, PhD, of Seoul National University Hospital in South Korea, and colleagues concluded in a paper published online ahead of print in Urology.

The investigators evaluated data from 2,039 patients with benign prostatic

suggested. Writing in a paper pub-

hyperplasia (BPH) or lower urinary tract symptoms (LUTS) refractory to medication. All patients underwent urodynamic study from 2004 to 2013 at the hospital. Patients were then divided into 3 groups by their prostate volume: small (30 mL or less), moderate (30–80 mL), or large (80 mL or greater). The groups had mean total prostate volumes of 24.53 mL, 49.12, and 112.80 mL, respectively.

Prostate volume correlated with BOO. Men with small prostates and BOO, however, had higher post-void residual urine, lower voiding efficiency, and similar Qmax compared with men who had larger prostates, the researchers reported. Additionally, urodynamic studies showed that bladder abnormalities, including low compliance and involuntary detrusor contraction, were similar regardless of prostate size. Notably, the small prostate group had more detrusor underactivity.

In multivariate analysis, the investigators found that the risk of BOO increased by 34% per unit increase in serum PSA and decreased by 23% per unit increase in Qmax.

While BOO is less common in men with small prostates, it might be more severe because it has different causes, the researchers hypothesized. These include high bladder neck elevation, increased prostate-urethral angle, and elevated smooth muscle tone in the prostatic stroma.

The researchers acknowledged some limitations of the study, such as its retrospective design. The evaluation protocol for patients with LUTS/BPH was not consistent over the study period.

Their data, which came from medical records, were obtained for clinical purposes, not for research. In addition, selection and attribution biases were unavoidable because the study enrolled on those patients who visited their tertiary care center. n

TRT may reduce prostatic inflammation associated with MetS, the investigators lished online ahead of print in Urology, they explained that the therapy “may improve voiding symptoms while also improving the underlying metabolic and biometric abnormalities of MetS.” Half of trials excluded men with severe LUTS due to concerns TRT might worsen symptoms. Androgens influence prostate development, so some investigators feared TRT would promote prostate enlargement.

According to preliminary research discussed by the researchers, serum testosterone may not have a strong impact on levels of intra-prostatic testosterone or dihydrotestosterone.

The investigators acknowledged several study limitations, including the exclusion of retrospective trials, short trial durations, and small numbers of patients. n

www.renalandurologynews.com MARCH 2016

Renal & Urology News 9

The Future of Bladder Cancer Research The Johns Hopkins University in Baltimore recently appointed David J. McConkey, PhD, as the first ­director of The Johns Hopkins Greenberg Bladder Cancer Institute. The institute, which was established in 2014 with a $15 million gift from Erwin L. Greenberg and his wife, Stephanie Cooper Greenberg, and a $30 ­million investment from The Johns Hopkins University, is the world’s only center devoted exclusively to ­bladder cancer research, diagnosis, and treatment. Dr. McConkey is the former director of urologic research at the University of Texas MD Anderson Cancer Center in Houston. In an interview with Renal & Urology News, he discussed the institute’s mission and what he sees as research priorities.

Why the need for an institute dedicated to bladder cancer?

Dr. McConkey: Bladder cancer has historically been drastically under-recognized as a significant health problem.

The institute is needed because the field needs to grow quickly. We’ve got a great opportunity to generate substantial clinical impact, and all the pieces are in place to do that. The bladder cancer research community is very clearly collaborative, and we’ve made grass-roots networks already that have been very effective at doing collaborative research. About 2 years ago, the Cancer Genome Atlas Project on bladder cancer was completed and published, and that started a very strong wave of interest in bladder cancer. And then the 1-2 punch came with [data showing] the clinical activity of immune checkpoint blockade, which was published in the fall of 2014 in a high-profile Nature paper (Powles T et al. 2014;515:558-562) pointing out the results of an active clinical trial. The genomic project, combined with the clinical activity of immune checkpoint blockade, has raised a lot of awareness of bladder cancer. The folks behind… the institute recognized that this was the perfect time to establish a focal point for collaborative bladder cancer

research, not just within this country, but around the world, and that this serves as a kind of a catalyst for synergistic collaborations worldwide.

to milestones of clinical impact. For example, right now, there’s Level 1 evidence for the use of neoadjuvant chemotherapy in patients with muscleinvasive bladder cancer, but the utilization of neoadjuvant chemotherapy is really pretty poor. So the question is, how do we get people to pay attention to Level 1 evidence and use the chemotherapy? The challenge has been the perception that the long-term impact of chemotherapy on survival is somewhat modest, an estimated 5%–15%.

Personally, I wouldn’t be that satisfied with the benefit observed in unselected patients. The solution in my opinion is to identify the patients who are going to benefit the most from neoadjuvant chemotherapy and then make sure that those patients are getting it.

How much progress has been made in identifying patients who could benefit from neoadjuvant chemotherapy?

Dr. McConkey: As a global community, we’re starting to get good biomarkers that identify patients who are most likely to respond to and require neoadjuvant chemotherapy. We should be pouncing on this nationwide. The Southwest Oncology Group, for which I am chair of translational medicine for the genitourinary committee, has a clinical trial called the “CoXEN”

What is the goal?

Dr. McConkey: The goal is to assemble a program internally that is going to model how we want to aggressively address these clinical issues as efficiently as possible, and then integrate with all the other research teams like this across the country. Some of the funding will be sent out to various investigators in the form of grants, and we are interested in coordinating some of that with the Bladder Cancer Advocacy Network (BCAN) and local research programs (i.e., the MD Anderson Bladder Cancer SPORE) that also have grant funding mechanisms. The grants are solicited through a request for applications, which are circulated not only around Johns Hopkins but worldwide. I oversee the review of the process. The decision-making ultimately is informed by peer review. And we’ll be investing in research efforts at home.

What is your vision for the direction of bladder cancer research?

Dr. McConkey: The need here is to stop thinking incrementally, to really have ambitious goals that are tied

trial (S1314). This trial is specifically designed to test a biomarker panel that was developed by Dan Theodorescu [at the University of Colorado] to predict response to and long-term benefit from neoadjuvant chemotherapy.

As another example, from our own work at MD Anderson, we’ve identified an intrinsic subtype of muscleinvasive bladder cancer called the basal subtype that is similar to the basal subtype that was originally identified in breast cancer, and, doing genomics experiments on these tumors in patients untreated and treated with neoadjuvant chemotherapy, we discovered that patients with those tumors are actually the ones who probably benefit the most from neoadjuvant chemotherapy, because patients with basal tumors who did not receive neoadjuvant chemotherapy had the worst prognoses. Interestingly, that’s not at all dissimilar to what we see in breast cancer, where patients whose tumors belong to the basal subtype appear to also derive the most benefit from neoadjuvant chemotherapy. There is also preliminary evidence for the existence of an aggressive basal subtype of pancreatic cancer, and it has been suggested these tumors may also be sensitive to chemotherapy.

Therefore, the biology seems very consistent across disease types.

Patients with these basal cancers do the worst if they don’t get neoadjuvant chemotherapy, but get the most benefit from it. By combining genomics tests, we should be able to more precisely identify patients who will not only benefit the most, but also respond to neoadjuvant chemotherapy. This is an action item that should be rolled out immediately.

Will there be a core group of bladder cancer specialists working solely at the institute?

“The institute is needed because the field needs to grow quickly.” ­—David J. McConkey, PhD

Dr. McConkey: There is already a core group of faculty that will serve as leadership: Noah Hahn (medical oncologist), Trinity Bivalacqua (urologist), Charles Drake (immunotherapy), and George Netto (pathology). We’ve got dedicated support for administration.

We hope to bring in other faculty members and other high-profile basic scientists. The mission is to grow the program, but the core group is already on the ground, and we’re already designing collaborative research projects. n

10 Renal & Urology News

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Cocoa Flavanols Benefit HD Patients Researchers observe significant improvements in chronic and hemodialysis-induced vascular dysfunction ­dysfunction in this high-risk population.”

The trial consisted of 2 parts: a baseline cross-over acute study to determine safety and efficacy of CF (11 patients) and a subsequent chronic parallel group study with a 30-day follow-up period (52 patients) to study effects of CF on HD-mediated vascular dysfunction.

Acute ingestion of the cocoa flavanols improved FMD by a significant 53% (from 3.2% to 4.8%); 30-day (chronic) ingestion increased FMD by a significant 18% (from 3.4% to 3.9%), and this increase was accompanied by a significant reduction in diastolic blood pressure (from 73 to 69 mm Hg) and increase in heart rate (from 70 to 74 beats per minute) compared with placebo. Placebo recipients experienced no significant increase in FMD. “Impressively, the degree of reversion of vessel dysfunction was comparable to the effects observed through administering statins or making dietary and lifestyle changes,” Dr. Rassaf said in a

Fixed-Dose Phosphate Binder Schedules Less than Ideal

BY NATASHA PERSAUD

Software along with other dietary

PHOSPHATE AMOUNTS typically con-

reference tools to gauge the phosphate

sumed in meals and snacks varies, but

content of each meal.

dialysis patients do not appear to adjust

When researchers looked at how

their phosphate binders to match the

closely phosphate binder dose

food phosphate content, a new study

matched the actual phosphate content

suggests.

of meals, they discovered a mismatch

Deborah Zimmerman, MD, of Ottawa

for lunch and dinner. They used the

Hospital in Ontario, Canada, and col-

Intra Class Correlation Coefficient (ICC),

leagues asked 60 peritoneal dialysis

in which 0 indicated maximal variability

patients to keep a detailed 3-day

and 1 indicated no variability, and found

food diary of all foods and beverages

notable discrepancies.

consumed as well their portion sizes.

“The standard practice of prescribing

Patients also recorded the amount of

fixed doses of phosphate binders at

phosphate binders taken with each meal.

meals is an inappropriate management

For half of patients, diabetic nephropathy

strategy for the control of serum phos-

was the cause of end-stage renal disease.

phate concentration as meal phosphate

The recommended daily limit of phos-

intake is highly variable as was demon-

phate from foods is 800 to 1,100 mg.

strated in this study,” the investigators

According to results published online

concluded.

BMC Nephrology, the dietary intake in

The investigators plan to use the

this study was somewhat higher: 959

results of this 3-phase study to create

to 1,144 mg. One snack could range up

a mobile app that matches phosphate

to 463 mg of phosphate. A registered

binders to the amount of phosphate in

dietitian used the ESHA Food Processor

foods to improve phosphate control. n

Flavanols in cocoa may protect dialysis patients’ vascular function.

press release from the American Society of Nephrology., which publishes CJASN. In an accompanying editorial, Carmine Zoccali, MD, and Francesca Mallamaci, MD, of Ospedali Riuniti, Calabria, Italy, said the findings by Dr.

Retesting PSA May Lower PCa Diagnosis Risk

BY NATASHA PERSAUD FOR MEN WITH an elevated PSA, retesting PSA levels within a year may reduce the risk of prostate biopsy and a prostate cancer (PCa) diagnosis, a new study finds.

“Men with an elevated PSA level should be given a repeated PSA test before proceeding to biopsy,” lead researcher Rodney H. Breau, MD, MSc, of Ottawa Hospital in Ontario, Canada, and colleagues, wrote in a report published online ahead of print in Mayo Clinic Proceedings.

The investigators looked at 1,268 patients referred to the Ottawa Regional Prostate Cancer Assessment Center from April 1, 2008 through May 31, 2013 who had initial PSA levels of 4–10 ng/mL. After repeat PSA testing, 315 (24.8%) had normal results, finding consistent with results from other studies.

A multivariable analysis revealed that men with a normal PSA upon re-testing had a 58% lower risk of prostate biopsy, a 77% lower risk of a PCa diagnosis,

Rassaf’s group, if confirmed by other studies, “may be a turning point” in the management of cardiovascular (CV) disease in patients on dialysis.

“Cocoa flavanols seem to be remarkably beneficial for the endothelium in these patients,” they wrote.

Study findings suggest that endothelial dysfunction and perhaps atherosclerosis should not be considered non-modifiable alterations in patients with chronic kidney disease, they noted. “Patients with heart failure were excluded from the trial, but a beneficial effect in these patients seems likely,” they stated.

Drs. Zoccali and Mallamaci observed that some caveats remain. They pointed out, for example, that FMD has not been established as a valid surrogate biomarker in ESRD patients. In spite of the caveats, “the burden of CV disease in patients on dialysis is so devastating that a promising intervention like cocoa flavanols deserves full attention by the nephrology community,” they wrote. n

and an 84% lower risk of a Gleason score of 7 or higher compared with men who received a second abnormal PSA result. Men with normal results tended to be younger (61.5 vs. 65.2 years) and have lower initial PSA results (5.5 vs.

6.6 ng/mL).

“These findings indicate that routine repeated PSA testing influences patient management and should be adopted by physicians who make decisions regarding prostate biopsy,” the authors concluded.

A normal PSA result does not rule out the possibility of cancer, the investigators acknowledged, but “repeating a PSA test will avoid or delay many prostate biopsies in patients whose PSA level may have been transiently elevated.”

The researchers noted several study limitations, including an inability to assess the impact of a concerning digital rectal examination finding or a family history of PCa. They also could not comment on patients with PSA results below 2.5 or above 10 ng/mL. “To our knowledge, this is the first study to examine the impact of prompt repeated PSA testing in an unselected cohort of patients being screened for prostate cancer,” the investigators stated.

“It is also the first to report patient outcomes such as prostate biopsy and prostate cancer diagnosis.” n

© THINKSTOCK

DIETARY COCOA flavanols may improve vascular function in patients on hemodialysis (HD), according to a new study.

In a randomized, double-blind study that enrolled 57 HD patients, Tienush Rassaf, MD, of the West German Heart and Vascular Center Essen, University Hospital, Essen, Germany, and colleagues found that acute and chronic ingestion of a cocoa flavanol (CF)-rich beverage (900 mg/day) improved flowmediated dilation (FMD) compared with placebo.

The researchers concluded that their results demonstrate that CF ingestion is well tolerated and improves endothelial functions in patients with end-stage renal disease (ESRD). “CFs mitigate chronic and HD-induced vascular dysfunction in ESRD,” they wrote in a paper published online ahead of print in the Clinical Journal of the American Society of Nephrology (CJASN). “CFs may, thus, have the potential to ameliorate ­vascular

www.renalandurologynews.com MARCH 2016

Renal & Urology News 11

Pre-ADT Low Testosterone Predicts Poor Survival LOW PRE-TREATMENT serum testosterone levels significantly predict poor survival after primary treatment with androgen deprivation therapy (ADT) for metastatic, castration-resistant prostate cancer (mCRPC).

Akira Yokomizo, MD, PhD, and colleagues of Kyushu University in Fukuoka, Japan, examined the relationship of various parameters to prognosis for 56 patients with mCRPC treated with primary ADT at their institution from 2000 to 2012. These factors included pre-treatment serum testosterone, body mass index (BMI), PSA level at diagnosis, pathologic Gleason score, clinical stage, and age.

Corroborating previous research, the new study, which was published online

Cinacalcet May Lower Testosterone CINACALCET treatment for secondary hyperparathyroidism (SHPT) in men on chronic hemodialysis (HD) is associated with decreased serum total and free testosterone, according to a small study.

Piotr Kuczera, MD, and colleagues at the Medical University of Silesia in Katowice, Poland, studied the effect of 6 months of treatment with cinacalcet on serum total and free teosterone in 38 male HD patients with SHPT, defined as a serum parathyroid hormone (PTH) level above 300 pg/mL. Among 33 patients who completed the study, cinacalcet treatment was associated with a significant decrease in mean serum PTH level from 1,143 pg/mL at baseline to 607 pg/mL after 6 months of treatment, the researchers reported in Kidney & Blood Pressure Research (2016;41:18). During the same period, serum total testosterone decreased significantly from 4.95 to 4.39 ng/ mL and serum free testosterone decreased significantly from 6.95 to 5.60 pg/mL, respectively. These decreases were associated with the magnitude of serum PTH decrease and dose of cinacalcet, according to the researchers. n

in Anticancer Research, found that low pre-treatment serum testosterone predicted poor overall, cancer-specific, and progression-free survival after primary ADT. The median serum testosterone level was 397 ng/dL. The median overall, cancer-specific, and progression-free survival rates were 68.1, 68.9, and 23.2

months, respectively. Men with higher testosterone levels in the second to fourth quartiles showed similar survival.

“Therefore, pre-treatment testosterone may reflect the nature of how much the tumor is dependent on androgens,” the investigators suggested. “Accordingly, low serum testosterone may mean less

dependency on androgen.” It is also possible that low testosterone is a cause of prostate cancer progression.

Although BMI previously has been reported to be associated with serum testosterone, the investigators found no correlation. Ethnic differences in obesity may play a role. n

12 Renal & Urology News

MARCH 2016 www.renalandurologynews.com

ESRD Anemia Responds to Oral Drug In a phase 2 trial, roxadustat maintained hemoglobin levels over 19 weeks as well as epoetin alfa ROXADUSTAT, an investigational oral drug, is well tolerated and can maintain hemoglobin (Hb) levels for up to 19 weeks in patients with end-stage renal disease (ESRD) and anemia, according to the findings of a phase 2 trial comparing the drug with epoetin alfa.

The effect of roxadustat is independent of inflammation, a condition known to increase dose requirements of epoetin alfa. In addition, roxadustat treatment is associated with a significantly greater decline in levels of hepcidin, a key regulator of iron metabolism, compared with epoetin alfa. The study establishes that roxadustat can treat patients who, because of inflammation, are hyporesponsive to erythropoiesis-stimulating agents, according to researchers.

The study, by Robert Provenzano, MD, of St. John Hospital & Medical Center in Detroit, and colleagues had 2 parts. Part 1 was a 6-week dose-ranging study of 54 patients who received thrice-weekly oral roxadustat doses (41 patients) or continuation of intravenous (IV) epoetin alfa (13 patients).

Part 2 enrolled 90 patients treated for 19 weeks with various starting doses and dose-adjustment rules in individuals with a range of epoetin alfa

responsiveness. Of the 90 patients, 67 received roxadustat at various starting doses and 23 continued on epoetin alfa. IV iron use was prohibited.

The primary endpoint was Hb level response, which the investigators defined as end-of-treatment Hb level change of −0.5 g/dL or greater from baseline (part 1) and as mean Hb level of 11.0 g/dL or higher during the last 4 treatment weeks (part 2).

In part 1, mean baseline epoetin alfa doses were 138.3 and 136.3 U/kg/wk in part 1 and 152.8 and 173.4 U/kg/wk in part 2 in patients randomly assigned to receive roxadustat and epoetin alfa, respectively.

During part 1, recipients of roxadustat doses of 1.5 mg/kg or higher had a pooled responder rate of 79%, which was significantly higher than 33% responder rate among patients in the epoetin alfa arm.

In part 2, for roxadustat-treated patients overall, 31 (51%) of 61 efficacyevaluable patients achieved an average Hb level of 11.0 g/dL or higher over the last 4 weeks of the 19-week treatment period (the primary endpoint) versus 8 (36%) of 22 epoetin alfa recipients, the investigators reported online ahead of print in the American Journal of Kidney

Roxadustat may be effective in treating anemia in patients hyporesponsive to ESAs.

Diseases. The researchers observed a progressive decrease in hepcidin levels in patients receiving higher doses of roxadustat for 6 weeks compared with epoetin alfa. At the end of the 19-week treatment period, roxadustattreated patients had an overall mean 60.4 ng/mL decrease in hepcidin levels, whereas the epoetin alfa recipients had a 35.6 ng/mL increase, a significant difference between the treatments.

Dr. Provenzano and his colleagues also examined the effect of roxadustat

and epoetin alfa in patients with and without inflammation, as reflected

by C-reactive protein (CRP) levels.

Impairment in iron export from macrophages, where most iron is stored, is an important mechanism leading to increased epoetin alfa requirements during inflammation, the investigators noted. Their analysis included all patients randomly assigned to 19 weeks of roxadustat treatment and dosed beyond 12 weeks. Results also showed that baseline CRP levels correlated with pre-enrollment epoetin alfa maintenance dose requirements— with higher CRP levels associated with increased epoetin alfa requirements—but roxadustat maintenance dose requirements did not. “This independence of response from CRP levels suggests the potential for roxadustat to overcome the therapeutic barrier to erythropoiesis from the inflammatory component present in ESRD,” the authors stated.

The investigators acknowledged limitations of their study, such as its relatively small sample size and short treatment duration.

Roxadustat is being developed by FibroGen Inc., which sponsored the study. n

PATIENTS WHO UNDERGO radical prostatectomy (RP) have unrealistic expectations about their sexual function after the operation, new study findings reveal.

Serkan Deveci, MD, and colleagues at Memorial Sloan-Kettering Cancer Center in New York surveyed 336 consecutive patients who underwent either open RP (216 patients) or robot-assisted laparoscopic prostatectomy (RALP, 120 patients). Subjects had a mean age of 64 years, with no significant difference between the groups. Investigators questioned patients about erectile function (EF), post-operative ejaculatory status, organsm, and post-operative penile morphologic changes. The mean elapsed time after RP at the time of postoperative assessment was 3 months.

Patient knowledge about sexual function after RP was poor, according to the investigators, with significant differences between the open RP and

RALP groups. Compared with open RP patients, RALP patients expected a shorter erectile function (EF) recovery time (6 vs. 12 months), a higher likelihood of recovery of back to baseline EF (75% vs. 50%), and a lower potential need for intracavernosal

Most men surveyed did not know their surgery rendered them anejaculatory. injection (ICI) therapy (4% vs. 20%), Dr. Deveci’s group reported online in BJU International. Findings showed that only 38% of patients had an accurate recollection of their nerve-sparing status.

With respect to ejaculation and orgasm, only 70% of open RP and 60%

of RALP patients were aware they were rendered anejaculatory by their operation. None of the RALP patients and only 10% of those who underwent open RP recalled being informed of the potential for penile length loss. In addition, the researchers found that no patient was aware of the recently described association between RP and Peyronie’s disease.

“These data are illuminating and should give us reason to think about our approach to the education of the patient before RP,” the authors wrote.

“Irrespective of whether we as clinicians routinely have a sexual dysfunction discussion or not, patients are not remembering or appreciating the information the way that it is intended and undertake the operation with poor expectations regarding multiple domains of sexual health.”

Surgeons should be encouraged to be thorough in counseling patients

prior to RP and to document that such discussion is held, the authors concluded. “Indeed, we go one step further and encourage all clinicians to use written instructions to transmit sexual health information to patients, lest they receive the orally transmitted information in a state of anxiety, where failure to process the information may be highly likely.”

Study strengths included enrollment of a significant number of men consecutively and use of a standardized , although non-validated, instrument for all patients, according to the researchers. Study limitations included the absence of an instrument to define expectations, an inability to differentiate between what patients were told and what they remember, and the inability to ascertain whether some patients did their own research before or after they had seen their surgeon prior to their RP. n

© THINKSTOCK

RP Patients Largely Unaware of Sexual Complications

www.renalandurologynews.com MARCH 2016

Botox Does Not Improve BPH/LUTS BOTULINUM TOXIN TYPE A provides no clinical benefit for lower urinary tract symptoms (LUTS) or benign prostatic hyperplasia (BPH), a new review and meta-analysis found.

“Although some studies have shown efficacy, the scientific evidence for botulinum toxin type A in BPH is low,” lead researcher Jae Heon Kim, MD, PhD, assistant professor at Soonchunhyang University in South Korea, told Renal & Urology News. “The indication for botulinum toxin type A in BPH patients should be recommended as third line.”

Improving on previous reviews, Dr Kim and colleagues pooled results from 3 double-blind, randomized, controlled trials comparing botulinum toxin type A with placebo. Of 522 men with LUTS/BPH, 260 were treated with a single dose of botulinum toxin type A (200 U) and 262 received a placebo injection.

After 8 to 24 weeks, the group that received botulinum toxin barely

Renal & Urology News 13

Tolvaptan Lowers ADPKD Albuminuria New findings suggest the medication induces beneficial renal structural changes TOLVAPTAN DECREASES albuminuria over time in patients with autosomal dominant polycystic kidney disease (ADPKD), independent of blood pressure (BP), according to a post-hoc analysis of the TEMPO 3:4 Trial. The finding contrasts with the initial trial report, which concluded that tolvaptan had no effect on albuminuria.

The trial was a 3-year prospective, randomized, placebo-controlled study that included 1,375 ADPKD patients randomized to receive the V2 receptor antagonist tolvaptan or placebo.

Researchers measured albuminuria in a spot morning urine sample prior to tolvaptan dosing and expressed as albumin-to-creatinine ratio (ACR).

The investigators who conducted the post-hoc analysis noted that the initial TEMPO 3:4 Trial looked at categorical “albuminuria events,” which may have resulted in a loss of sensitivity to detect changes. The post-hoc analysis, led by Ron T. Gansevoort, MD, of University Medical Center Groningen in The Netherlands, examined the effect of tolvaptan on albuminuria as a continuous variable.

At baseline, the patients had a median ACR of 3.2 mg/mmol, and 47.9%, 48.7%, and 3.4% of patients had normal, moderately increased, and severely increased ACR, respectively, Dr. Gansevoort and his colleagues reported online in Nephrology Dialysis Transplantation. Patients with a higher baseline ACR had higher BP and total kidney volume (TKV) and lower estimated glomerular filtration rate (eGFR).

Post-hoc analysis results contrast with those in the initial trial report.

Over 3 years, ACR rose in the placebo arm and decreased in the tolvaptan arm (+23 vs. −0.40 mg/mmol). The difference in ACR increased over time, reaching a maximum of 24% at month 36. At that time, the researchers observed only a minor difference in blood pressure (BP). The decrease in ACR was similar in all subgroups and remained after

withdrawal of tolvaptan. During followup, higher baseline ACR was associated with more rapid eGFR loss, but not TKV growth rate. Compared with placebo, tolvaptan was associated with a significant beneficial effect on TKV growth in all ACR subgroups, but was stronger in patients with a higher ACR, Dr. Gansevoort’s team reported.

“In our opinion, the gradual onset of the ACR lowering response that remains after drug withdrawal indicates that the reduction in albuminuria with V2 receptor antagonists is a reflection of structural benefits that have obtained, such as less growth in TKV during tolvaptan treatment,” the authors wrote.

ADPKD is a relatively low albuminuria disease, so the effect of tolvaptan on albuminuria per se is of limited clinical relevance, the authors pointed out. The new findings are particularly important because they indicate that, in ADPKD patients, tolvaptan induces structural renal benefits and assessing albuminuria status in this disease may help to identify ADPKD patients who may benefit more from tolvaptan treatment, according to the researchers. n

showed improvement over the group that received placebo based on International Prostate Symptom Score (IPSS). There were no significant differences between groups in maximal urinary flow rate (Qmax), prostate volume, and post-void residual volume.

The researchers discovered that the placebo effect was substantial, ranging from 0 to 28% for IPSS and up to 29% for Qmax. “It is well known that patients with LUTS/BPH can have a significant placebo response,” the investigators explained in International Urology and Nephrology (2016;48:19-30).

Dr. Kim’s group observed no significant differences in any reported adverse events between the groups.

Among the study limitations, the investigators could not conclusively determine whether botulinum toxin is suitable for LUTS/BPH refractory to medications.

The authors concluded that their study does not provide evidence of clinical benefits with the use of botulinum toxin type A injections for LUTS/ BPH in real clinical practice. n

Statin Use Decreases Death Risk in CKD Patients

BY NATASHA PERSAUD STATINS IMPROVE survival and other outcomes in patients with chronic kidney disease (CKD), but they do not appear to slow progression to end-stage renal disease (ESRD), a new meta-analysis finds.

Since previous research yielded inconsistent results, Zhenhong Zhang, MD, Pinsheng Wu, MD, and colleagues at Southern Medical University in China, pooled data from 23 randomized controlled trials (1995–2014) including 39,419 participants for an updated metaanalysis. The causes of CKD included diabetes, hypertension, glomerulonephritis, autosomal dominant polycystic kidney disease, idiopathic membranous nephropathy, and metabolic syndrome.

Eight types of statins were examined.

According to results published in Pharmacological Research, statins improved proteinuria, reducing urinary protein excretion to 682.68 mg daily.

Statin treatment also reduced all-cause mortality by 22%.

“Statins unquestionably reduce the risk of death in populations with, or at

low risk of, cardiovascular disease,” the researchers stated.

The findings also showed that statins lower lipid levels, protect the vascular endothelium, stabilize plaques, and suppress inflammation.

Drs. Zhang, Wu, and colleagues were less certain about statins’ effect on microalbuminuria. Statin use lowered the urine albumin excretion ratio to 26.73

Treatment with the medications lowered the risk of all-cause by 22%, data show. µg/min. Statins provide podocyte protection, prevent tuberinterstitial injury, and improve endothelial dysfunction, the investigators noted, but use of statins at large doses may increase microalbuminuria due to reduced protein trafficking across tubular cells.

Statins did not reduce renal health events, including kidney failure leading

to dialysis or transplantation, a doubling of creatinine level, or a halving of glomerular filtration rate (GFR). One study, the Study of Heart and Renal Protection (SHARP), accounted for most of the finding.

“These findings support the recommendations in the present guidelines for the use of statins in hyperlipidaemic early stage CKD patients,” the researchers concluded.

Other recent meta-analyses have shown the cardiovascular benefit of statins in CKD patients. For example, statin therapy decreased the risk of major cardiovascular events by 18% in CKD patients with coronary diseases and by 23% in those with CKD only, according to a meta-analysis by Wanyin Hou, MD, and colleagues published in the European Heart Journal (2013;34:1807-1817). A study

by Giovanni F. M. Strippoli, MD, and colleagues published in BMJ (2008;336:645-651) demonstrated that statins reduced the risk of fatal and non-fatal cardiovascular events by 19% and 23%, respectively. n

14 Renal & Urology News

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New Findings May Enable Earlier Prediction of CIN Risk linked to small changes in serum creatinine and eGFR and colleagues studied 860 patients who underwent cardiac catheterization. They measured SCr and eGFR before catheterization, on the following day, and 48–72 hours after the procedure.

CIN developed in 40 patients. From baseline to the day following the procedure, SCr levels increased significantly from 1.55 to 1.79 mg/dL, but decreased

© DOUG MARTIN / SCIENCE SOURCE

BY JODY A. CHARNOW CHANGES IN SERUM creatinine level and estimated glomerular filtration rate (eGFR) on the day following cardiac catheterization can predict a patient’s risk of developing contrastinduced nephropathy (CIN), a common form of acute kidney injury, researchers concluded.

Researchers have linked contrast-induced nephropathy risk after cardiac catheterization to changes in serum creatinine and eGFR on the day after contrast media exposure.

CIN is often defined as a 0.5 mg/dL or greater or 25% or greater increase in serum creatinine (SCr) from baseline 48–72 hours after contrast exposure.

“Therefore, CIN cannot be diagnosed on the day of cardiac catheterization or on the following day, when the majority of patients who undergo elective cardiac catheterization are discharged from the hospital in the real-world setting,” the authors pointed out in a report published online ahead of print in the Journal of Cardiology.

Investigators established cut-off values for SCr and eGFR changes that could aid in deciding which patients could be discharged without concern about CIN. They believe these cut-offs may have greater discriminatory power than the Mehran risk score, currently the most widely used risk score for predicting CIN. Makoto Watanabe, MD, PhD, of Nara Medical University in Kashihara, Japan,

significantly from 1.21 to 1.18 mg/ dL in those without CIN. The eGFR decreased significantly from 47.3 to 40.6 mL/min/1.73 m2 in patients with CIN, but increased significantly from 53.1 to 53.6 mL/min/1.73 m2 in those without CIN. The researchers’ analyses showed that the cut-off value for change in SCr was 0.1 mg/dL, which has a sensitivity and specificity of 72.5% and 86.1%, respectively. The cut-off value for change in eGFR was −1.1 mL/min/1.73 m2, which has a sensitivity and specificity of 85% and 64.9%, respectively. The negative predictive value was high for both cutoff values, according to the investigators. The authors stated that patients with a change in SCr less than 0.1 mg/ dL or eGFR less than −1.1 mL/min/1.73 m2 could be discharged from the hospital without concern about CIN. On multivariate analysis, a 0.1 mg/ dL or greater increase in SCr and a

1.1 mL/min/1.73 m2 or greater decrease in eGFR on the day following cardiac catheterization independently predicted CIN. These changes were associated with a significant 29.3 and 69.7 times increased odds of CIN, respectively. Cut-offs for changes in SCr and eGFR had a relatively high C-statistic of 0.853 and 0.789, respectively.

“The present study demonstrates for the first time that the small changes in SCr or eGFR on the day following contrast use can predict subsequent development of CIN,” the authors wrote.

The authors noted that more than 80% of patients with an eGFR below 60 mL/min.1.73 m2 received saline or bicarbonate before and up to several hours after contrast use, but some of them developed CIN, suggesting current methods of hydration cannot completely prevent CIN. “It would be ideal to determine which patients will develop CIN before the procedure and prevent CIN from developing, but such an approach is not realistic. Second best is diagnosing CIN as soon as possible after contrast use. In this context, the new cut-offs for change in SCr and eGFR will help diagnose CIN on the day following the procedure and before hospital discharge.

Chi-yuan Hsu, MD, MSc, who has conducted research on acute kidney injury but was not involved in the new study, commented that the usefulness of risk scores such as the Mehran risk score is that they inform the operator prospectively what should be done prior to cardiac catheterization, he pointed out. Using data after catheterization to predict a complication from the procedure is less useful because one cannot go back to change anything, such as deciding not to do the procedure or varying the dose of contrast and the rate or type of intravenous hydration prior to administering contrast.

Dr. Hsu, who is professor and chief of the division of nephrology at the University of California San Francisco, also questioned the importance of this type of AKI because the vast majority of CIN cases seem to be clinically benign, and patients currently are discharged home without even knowing if CIN occurred or not. n

Hemiablation HIFU Called a Valid Therapy HIGH-INTENSITY focused ultrasound (HIFU) hemiablation can offer mid-term disease control in carefully selected patients with clinically localized prostate cancer (PCa), researchers concluded.

They based that conclusion on a prospective cohort study of 50 patients who underwent ablation of a single lobe of the prostate. Patients had a mean followup of 40 months. The 5-year actuarial metastases-free survival, cancer-specific survival, and overall survival rates were 93%, 100%, and 87%, respectively, Roland van Velthoven, MD, and colleagues at the Jules Bordet Institute in Brussels, Belgium, reported in Prostate Cancer and Prostatic Diseases (2016;19:7983). The researchers documented complete continence (no pads) and erections

The 5-year actuarial cancer-specific and overall survival rates were 100% and 87%. sufficient for intercourse in 94% and 80% of patients, respectively.

“Our study suggests that hemiablation HIFU is a valid mini-invasive focal therapy strategy, feasible in day-to-day practice with satisfactory functional outcomes,” the investigators concluded.

The study included patients with localized PCa, a life expectancy of at least 5 years, and a prostate volume less than 40 cm3. The researchers used both multiparametric magnetic resonance imaging (MRI) and MRI-targeted biopsy to localize tumors.

The patients had a mean nadir PSA value of 1.6 ng/mL, a 72% reduction compared with initial PSA pretreatment values. The median time to achieve PSA nadir was 3 months.

Biochemical recurrence, according to the Phoenix definition (PSA nadir plus 2 ng/mL) and Stuttgart definition (nadir plus 1.2 ng/mL), occurred in 28% and 36% of patients, respectively.

The 5-year actuarial recurrence-free survival rates for patients with lowand intermediate-risk disease were 75% and 36%, respectively, according to the Phoenix definition and 58% and 27%, respectively, according to the Stuttgart definition. n

www.renalandurologynews.com MARCH 2016

Renal & Urology News 15

Tolvaptan Guidelines Issued for ADPKD ERA-EDTA makes recommendations for patient selection, timing of treatment initiation, and dosing THE EUROPEAN Renal AssociationEuropean Dialysis and Transplant Association (ERA-EDTA) has published a consensus document containing recommendations for the use of tolvaptan in patients with autosomal dominant polycystic kidney disease (ADPKD).

In May 2015, the European Medicines Agency approved the use of tolvaptan, a vasopressin V2 receptor antagonist, for slowing progression of cyst development and renal insufficiency in adult ADPKD patients with CKD stages 1–3 at initiation of treatment and evidence of rapidly progressing disease. This makes tolvaptan the first pharmaceutical agent approved for slowing disease progression in ADPDK. Tolvaptan was originally approved for the treatment of hyponatremia, and in the United States, it is only approved for that use.

The recommendations are based on the consensus of ADPKD experts and

methodologists in the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice. In the consensus document, which was published online in Nephrology Dialysis Transplantation (NDT), the ERA-EDTA suggests that

Consensus document includes suggested definitions of rapid disease progression. tolvaptan can be prescribed to adult ADPKD patients younger than 50 years with CKD stages 1–3a (an estimated glomerular filtration rate [eGFR] greater than 45 mL/min/1.73 m2) who have demonstrated or who are likely to have rapidly progressing disease.

Parathyroidectomy for SHPT Confers a Survival Benefit DIALYSIS PATIENTS with refractory

ous cohort studies and the inconclusive

secondary hyperparathyroidism (SHPT)

results of the EVOLVE (Evaluation of

experience a survival advantage with

Cinacalcet Hydrochloride Therapy to

parathyroidectomy, a new Taiwanese

Lower Cardiovascular Events) trial.

study confirms.

Parathyroidectomy (PTx) was associ-

To minimize selection bias, the investigators enrolled only patients with

ated with a significant 20% to 25%

severe SHPT confirmed by radionuclide

lower risk for mortality from any cause

parathyroid scanning. Of 2,786 hemodi-

in the long term. To minimize con-

alysis and peritoneal dialysis patients in

cerns that surgery patients might be

the Taiwanese National Health Insurance

healthier, the researchers adjusted for

system during 1999-2010, 1,707 had

co-existing diabetes and cardiovascular

PTx and 1,079 were matched controls

diseases (such as myocardial infarc-

who did not have the surgery.

tion, congestive heart failure), as well as demographic factors.

“Corroborating the effectiveness of

The results corroborate findings from a study published by Bryan Kestenbaum, MD, and colleagues in Kidney

PTx in the treatment of SHPT is of spe-

International (2004;66:2010-2016) that

cial importance in the era of calcimimet-

found a 10% to 15% lower risk of early

ics,” lead researcher Junne-Ming Sung,

death. They also complement a more

MD, professor of medicine at National

recent Japanese study by Hirtotaka

Cheng Kung University in Taiwan, and

Komaba, MD, and colleagues published

colleagues wrote in Scientific Reports.

in the same journal (2015;88:350-359)

Both PTx and calcimimetics aim to

demonstrating a survival benefit.

improve survival by suppressing intact

How SHPT increases mortality is still

parathyroid hormone (iPTH) levels, but

unclear, according to the researchers,

their efficacies have been questioned

but some evidence points to a predis-

because of the potential bias of previ-

position to cardiovascular disorders. n

ERA-EDTA recommends not starting tolvaptan in patients aged 30–40 years with CKD stage 1 (eGFR greater than 90 mL/min/1.73 m2) or patients aged 40–50 years with CKD stages 1 or 2 (eGFR greater than 60 mL/min/1.73 m2).

The organization recommends that rapid disease progression be defined as a confirmed annual eGFR decline of at least 5 mL/min/1.73 m2 in 1 year, and/or at least 2.5 mL/min/1.73 m2 per year over a period of 5 years. It can also be defined as a greater than 5% increase in total kidney volume per year by repeated measurements (preferably 3 or more, each at least 6 months apart and by magnetic resonance imaging). ERA-EDTA suggests tolvaptan be started at a dose of 45 mg in the morning and 15 mg in the evening, uptitrating the dose to 50/30 and 90/30 when tolerated, and discontinuing tolvaptan when patients approach endstage renal disease.

In the NDT paper, the working groups proposed a hierarchical decision algorithm to assess whether treatment is warranted.

“Even though consensus documents are inherently weak for producing recommendations for clinical practice, these treatment recommendations may be useful to doctors and patients,” NDT Editor-in-Chief Carmine Zoccali, MD, said in an ERA-EDTA press release. He noted that tolvaptan has a number of limitations and side effects and it probably is only suitable for a minority of patients.

“Besides, we know that mainly the patients with rapid disease progression might profit from tolvaptan treatment.”

Among these patients, physicians need to identify those willing to cope with the side effects, namely excessive urination and immensely increased fluid intake (over 5 liters a day in most patients), he said. n

Rising Stone Incidence in Young Found

for age and race, the incidence increased 15% per 5 years among females, but remained stable for males, according to the investigators. The incidence among blacks increased 15% more per 5 years compared with whites.

“These changes in incidence resulted in doubling of the risk of nephrolithiasis during childhood and a 45% increase in the lifetime risk of nephrolithiasis for women over the study period,” the authors concluded.

The authors stated that the emergence of nephrolithiasis as a disease that begins in childhood is worrisome because there is limited evidence about how to best treat the disease in children.

Use of South Carolina Medical Encounter Data was a strength of the study because it includes unite patient identifiers and dated encounters for care received at every hospital in the state over a 16-year period. Consequently, the authors were able to describe annual changes in the distribution and frequency of nephrolithiasis in the population, which are obscured in analyses using the National Health and Nutrition Examination Survey and Healthcare Cost and Utilization Project databases.

Among study limitations, the researchers acknowledged that their observations are on the basis of data from a single state and they cannot completely rule out that changes in imaging use contributed to changes in nephrolithiasis incidence. n

THE INCIDENCE OF kidney stones has increased among young patients, especially girls, and among blacks, according to a new study.

Gregory E. Tasian, of the Children’s Hospital of Philadelphia, and colleagues performed a population-based study using U.S. Census data and South Carolina Medical Encounter Data, which capture all emergency department visits, surgeries, and hospital admissions in the state.

Among an at-risk population of 4,625,364 people, 152,925 unique patients received emergency, inpatient, or surgical care for kidney stones during the 1997– 2012 study period, Dr. Tasian’s group reported online ahead of print in the Clinical Journal of the American Society of Nephrology. The mean annual incidence of nephrolithiasis increased 1% annually from 206 to 239 per 100,000 persons.

The researchers observed the greatest increase among 15–19 year olds, in whom the incidence rose 26% per 5 years. In this age group, the incidence increased 23% per 5 years among boys and 28% per 5 years for girls. Adjusting

16 Renal & Urology News

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Twice-Weekly HD Could Preserve RKF Patients with substantial residual kidney function experience a survival benefit, study shows INCREMENTAL hemodialysis (HD) —the initiation of HD at a lower frequency—may be a safe treatment regimen for incident HD patients with substantial residual kidney function (RKF), according to a new study.

In these patients, incremental HD is associated with greater preservation of RKF, investigators reported.

In a study of 23,645 HD patients, a research team led by Kamyar Kalantar-Zadeh, MD, MPH, PhD, of the University of California Irvine, compared incremental HD—whereby patients were placed on routine twiceweekly HD for more than 6 continuous weeks during the first 91 days upon transition to dialysis—with conventional thrice-weekly HD. The incremental HD group included 351 patients. Baseline renal urea clearance and urine volume were higher in these patients in the first patient-quarter compared with the 23,294 patients in the conventional group. The incremental regimen was associated with an average 17-minute shorter dialysis treatment time, less weekly cumulative percentage interdialytic weight gain (IDWG), and lower standard Kt/V. The prevalence

of patients with 2.1 or higher total standard Kt/V—the recommended minimum level of urea removed according to National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guidelines—was greater than 95% in patients with a

Incremental approach may be inappropriate for patients who have little or no RKF. renal urea clearance greater than 3.0 mL/min/1.73 m 2 regardless of HD schedule, but differed greatly between schedules among patients with renal urea clearance of 3.0 mL/min/1.73 m2 or less (30% in the incremental group vs. 90% in the conventional group).

Investigators matched the 351 incremental HD patients with 8,068 conventional HD patients according to baseline renal urea clearance, urine volume, age, sex, diabetes status, and central venous catheter use. Both renal urea clearance and urine volume showed signifi-

cantly slower declines over time in the incremental versus conventional HD regimens, Dr. Kalantar-Zadeh and colleagues reported online ahead of print in the American Journal of Kidney Diseases.

In survival analyses after year 1, the investigators found no significant difference in all-cause mortality between the incremental and conventional HD groups. Among the incremental HD patients, however, subgroup analyses revealed that the incremental approach was associated with greater mortality risk among patients with inadequate RKF, renal urea clearance of 3.0 mL/ min/1.73 m2 or less, and urine volume of 600 mL/day or less, but not among patients with higher baseline RKF. In addition, results showed a significant trend toward better survival among patients in the incremental group across higher increments of renal urea clearance and lower increments of weekly IDWG, but not in urine volume categories.

“Our results suggest that twice-weekly hemodialysis may be a safe and even preferred regimen to preserve RKF over time following the initiation of maintenance dialysis therapy, especially in patients with substantial RKF,” the authors wrote.

“However, caution against twice-weekly hemodialysis may be needed for patients with little or no RKF.” Dr. Kalantar-Zadeh’s group noted that less frequent HD has been commonly prescribed in some other countries, such as China and India. NKF-KDOQI guidelines suggest a twice-weekly schedule for patients with substantial residual renal urea clearance (at least 3.0 mL/min/1.73 m2). In the United States, though, most patients initiating maintenance HD are prescribed thrice-weekly dialysis regardless of RKF. The researchers pointed out that the estimated glomerular filtration rate is greater than 10 mL/min/1.73 m2 upon initiation of maintenance dialysis in up to 45% of patients in the United States, so the incremental HD regimen may preserve RKF and offer both clinical and economic benefits.

The authors explained that more frequent HD may lead to more rapid loss of RKF through several mechanisms, include the release of nephrotoxic inflammatory mediators during HD and ischemic kidney damage caused by intradialytic hypotension and postdialytic hypovolemia. n

Prostate Cancer Risk Lower in Type 2 Diabetics INDIVIDUALS WITH type 2 diabetes mellitus (T2DM) are at increased risk for a number of cancers, but older men with T2DM have a reduced risk of prostate cancer (PCa), according to a retrospective, population-based cohort study.

At least 3 years after a T2DM diagnosis, men aged 65–74 years had a 27% decreased risk of PCa compared with non-diabetic men, researchers led by Diego Serraino, MD, of the Epidemiology and Biostatistics Unit, IRCCS CRO National Cancer Institute, Aviano, Italy, reported in Cancer Epidemiology (2016;41:80-87).

The reason for this inverse relationship may be the reduced androgen levels among diabetics, the researchers said.

They pointed out, however, that the mechanisms underlying this association remain unclear.

In contrast, among individuals with T2DM for 3 or more years, the risk of colorectal, lung, pancreatic, kidney, and bladder cancer was 56%, 37%, 55%, 43%, and 30% higher, respectively,

compared with non-diabetic subjects.

The risk of liver cancer was 2.6 times higher. Women with T2DM had a 24% increased risk of breast cancer.

The study included 32,247 T2DM patients (17,827 men, 14,420 women) and 1,018,518 people without diabetes in northeastern Italy. Serraino’s group obtained data from administrative health-related databases covering the entire population living in the Friuli Venezia Giulia region in northeastern Italy. The median duration of followup was 3.65 years. The investigators documented 2,069 cancer cases (6.4%) among the 32,247 T2DM patients during the study period.

For the T2DM group overall (regardless of the time elapsed since T2DM diagnosis), the risk of cancer at any site was 28% higher and the risks of bladder and kidney cancer were 36% and 47% higher, respectively, compared with individuals who did not have T2DM. The risk of pancreatic cancer was 2.6 times higher.

The investigators noted that previous studies support a relationship between diabetes and the risk of kidney and bladder cancer, “making our results comparable with existing epidemiological evidence.”

Diabetic men aged 65-74 had a 27% lower risk of PCa vs. non-diabetics.

The study found sex differences in the risk of various cancers. For example, among patients with T2DM for 3 years or more, men had a 47% increased risk of bladder cancer whereas women had a 31% decreased risk. In the T2DM group overall, the risk of pancreatic cancer was 3-fold higher among women versus 2-fold higher among men.

Among the T2DM patients, the overall probability of surviving 5 years after

diagnosis of T2DM was 88.7%, accordign to the investigators. With respect to the impact of T2DM on cancer survival, the researchers observed no differences in survival probabilities for prostate, colorectal, liver, pancreatic, and bladder cancers.

“Considering the high prevalence of T2DM in Italy, even a small increase in cancer risk could have severe consequences at a population level,” the authors concluded. “Therefore, specific primary and secondary cancer prevention programs are a priority among T2DM patients.”

Strengths of the study include its large study population and the use of a database covering the entire population in their region of interest, thus eliminating selection bias, the researchers noted.

The authors also acknowledged study limitations, including a lack of information on potentially confounding variables such as body mass index, obesity status, and smoking, as well as clinical information. n

www.renalandurologynews.com MARCH 2016

BY NATASHA PERSAUD MEN UNDERGOING transrectal ultrasound (TRUS)-guided prostate biopsy may experience lower rates of sepsis with targeted antimicrobial prophylaxis instead of standard empirical fluoroquinolone, a new British review suggests.

Investigators led by Timothy J. Dudderidge, MBChB, MSc, FRCS (Urol), consultant urological surgeon at University Hospital Southampton in the UK, compared rates of infective complications, such as urinary tract infection and sepsis, after TRUSguided biopsy. In pooled results from 9 studies (a mix of retrospective and prospective data), 2,484 patients received empirical fluoroquinolone and 2,087 targeted antibiotics based on results of pre-biopsy rectal swab cultures.

Infection and sepsis rates were significantly higher among patients receiving empirical prophylaxis (4.55% and 2.21%) compared with patients receiving targeted antibiotics (0.72% and 0.48%), according to results published in BJU International. Fluoroquinolone resistance was found in 22.8% of men with culture results.

Antibiotic selection based on pre-biopsy rectal swab cultures decrease sepsis risk.

Based on these results, 27 men would need to receive targeted antibiotics to prevent 1 infective complication. The costbenefit ratio likely would be favorable if it prevented a hospital admission for sepsis.

“In light of these findings we are planning to introduce rectal swabs and targeted antibiotic prophylaxis as a necessary preparation for transrectal prostate biopsy,” Dr. Dudderidge stated in a press release. Optimal timing and collection of rectal swab still need to be determined.

Alternatives to targeted antimicrobial therapy such as pre-biopsy rectal cleansing and disinfection and lowresistance, broad-spectrum antibiotics need further study. “The only question is whether techniques involving multiparametric MRI of the prostate and targeted transperineal biopsy will make transrectal biopsy obsolete first,” Dr. Dudderidge said. n

PCa Diagnosis Increases Risk of Non-Cancer Hospitalizations Psychological stress could trigger events leading to admissions ELDERLY MEN ARE at significantly elevated risk of hospitalizations for non-cancer conditions after being diagnosed with non-metastatic prostate cancer (PCa), data suggest.

In a study of 57,489 Medicare beneficiaries aged 67 years or older with incident PCa, the rate of non-cancer hospitalizations (NCHs) was significantly higher during the year after a PCa diagnosis compared with the year before (5.1% vs. 3.2%), Amit D. Raval, PhD, of West Virginia University in Morgantown, and colleagues reported in the Journal of the National Comprehensive Cancer Network (2016;14:186-194).

“These findings highlight the need for targeted research, program, policy, and intervention efforts to reduce the excess NCHs in this group,” Dr. Raval’s group concluded.

Using 2000 through 2010 data from the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database, the researchers conducted a population-based retrospective cohort study of 57,489 male Medicare beneficiaries aged 67 years or older with incident PCa. Dr. Raval’s team identified NCHs in 3 periods before and 3 periods after the incidence of PCa. Each period consisted of 120 days. For the study, the investigators considered NCHs to be any admission to an inpatient facility with a principal diagnosis for conditions other than PCa or hospitalizations for causes other than cancer-related complications.

Results showed that men were 38% more likely to have NCHs in the postcancer period than the pre-cancer period, after adjusting for pre-cancer and post-cancer periods as well as types of chronic conditions and predisposing, enabling, need, and external environment factors.

Predisposing factors were unique characteristics of patients who tend to engage more or less use of health services. These include age, race/ethnicity, and marital status. Enabling factors were those that enable patients to use health services, and include income, education, access to care, and initial cancer treatment. Need factors were conditions affecting the need to use health services at the individual level.

External environmental factors were those that facilitate the use of health ser-

vices as reflected in the structure of services in an individual’s geographic area.

In addition, results showed that patients with cardiometabolic conditions alone or combined with respiratory or mental health conditions had a greater increase in the risk of NCHs during the post-cancer period compared with the pre-cancer period.

ies, including a cohort study of 342,497 PCa patients by Fang Fang, MD, and colleagues at Harvard Medical School in Boston. PCa patients had a 40% increased risk of suicide within 1 year after their diagnosis and a nearly 2-fold increased risk of suicide in the first 3 months after diagnosis, according to a paper published in the Journal of the

After being diagnosed with PCa, men are more likely to be hospitalized for non-cancer causes.

The researchers pointed out that the highest rates of NCHs occurred during the first 4 months after the cancer diagnosis. “There are several plausible explanations for this increased risk,” the authors stated. “It has been documented that the diagnosis of prostate cancer can trigger psychological distress, anxiety, and suicidal ideations.

This increase in psychological stress may increase blood levels of epinephrine and norepinephrine, resulting in increased heart rate, blood pressure, and blood sugar levels.”

Dr. Raval’s group pointed out that previous research suggests that acute emotional or psychological stress experienced by elderly men with preexisting cardiometabolic conditions may trigger the incidence of another heart failure episode, leading to hospitalization. “The study findings reinforce the need for intervention to reduce NCHs among elderly men with incident prostate cancer” the authors wrote.

The potential consequences of psychological stress in men with PCa have surfaced in a number of previous stud-

National Cancer Institute (2010;102:307314). In addition, PCa patients had a 9% increased risk of cardiovascular death within the first year after diagnosis and a 2-fold increased risk within the first month after diagnosis.

“We believe that suicide and cardiovascular death reflect only the tip of the iceberg of anxiety, mood disturbance, and perhaps other mental illness (or suffering) after a prostate cancer diagnosis,” Dr. Fang’s group stated. “Hence, our study suggests the potential importance of providing emotional counseling and support for patients newly diagnosed with cancer.”

In a separate study published online ahead of print in BJU International, investigators found that men with PCa are at increased risk of suicide and accidental death within the first year of diagnosis compared with men diagnosed with other solid cancers. The authors concluded that their findings suggest “the need for close monitoring and coordination with mental health professionals in at-risk men with potentially curable disease.” n

© THINKSTOCK

Targeted Bx Prophylaxis Beneficial

Renal & Urology News 17

18 Renal & Urology News

MARCH 2015 www.renalandurologynews.com

Practice Management The Office for Civil Rights has issued a new document clarifying the rights of patients to access their health records BY TAMMY WORTH

T

within 10 days, state law would trump HIPAA,” she said.

Denials According to OCR, there are very few reasons a provider can deny access of records to a patient (see box below). If providers have not updated their policy regarding patient access to records since HIPAA was enacted, now is the time to make it current.

Providers can request cost-based fees for providing records to patients, but guidelines apply.

and explain how patients can submit a complaint to OCR.

Ease of access OCR reminds providers that there are a few areas they may be tripping up patients and unwittingly making it excessively difficult for them to gain access to protected PHI. One such area is verification of identity. It is the provider’s obligation to verify the ­identity

Providers are obligated to a verify a patient’s identity, but they cannot do this in a way that will be a barrier to obtaining health records. important high points in the document.

Here is what practices need to know about access.

Practices must provide access to the PHI requested, in whole or in part, no later than 30 calendar days from receiving the individual’s request.

If providers deny patients access to their records, they have to explain why in writing within 30 days of the request. They need to inform patients they can have the decision reviewed

of an individual, but the provider cannot do this in a manner that will be a barrier to getting the information. If requests have to be on a provider’s specified form, for instance, that form can request information that allows the provider to verify a person’s identity. If access is available via a portal, authentication controls are appropriate for identity verification.

An increasing number of providers offer information through portals, but

OCR maintains that providers cannot require patients use a portal to gain access to PHI. “Not everyone can use it or has easy access to it,” Goturi said.

Just as portals cannot be the only means for providing access to PHI, neither can requiring patients to visit an office in person. It may be a burden for some patients to come to the office. Records can be mailed at a patient’s request.

E-mail security It is engrained among providers that PHI should be sent in a secure manner. This may be a reason providers are reticent to send this information via e-mail. But OCR has made it clear that PHI can be sent this way. Providers just have to make sure patients are aware the information is unsecured and it is not the providers’ fault if the information is compromised.

State laws While HIPAA is a federal standard, Goturi said the guidelines make it clear that physicians should also look to state laws as well, particularly because some are more restrictive than HIPAA. “A provider has 30 days under HIPAA to provide access to records, but if state law said access has to be given

Fees Providers can request a cost-based fee to provide records to a patient. The fee cannot include things like searching and retrieving the information, maintaining systems, or recovering costs for storage or infrastructure. Providers can recoup labor costs for copying the information, supplies like paper or compact disks, postage and preparation of a summary of the PHI. n Tammy Worth is a freelance medical journalist based in Blue Springs, MO.

When Patient Access to Records Can Be Denied Providers can refuse patients’ access to certain records, such as: • Psychotherapy notes used in a legal proceeding • Records that could jeopardize the health or safety of an inmate • Health information that is part of a study (like a clinical trial) in process • Information is in Privacy Act records that are protected • Records were obtained, confidentially, by a family member or other person and providing access would reveal the source • Information is “reasonably likely” to endanger the safety of or cause harm to the requestor or their representative

© THINKSTOCK

he Office for Civil Rights (OCR) in the U.S. Department of Health and Human Services recently issued a document spelling out HIPAA’s right of access provisions. The document provides clarification for providers based on OCR’s enforcement experience and patient complaints regarding difficulties getting their records.

“That is a common cause of complaints to OCR — people who need them and are entitled and can’t get them will get frustrated,” said Milada Goturi, a partner in Thompson Coburn’s Health Law Practice Group.

“This is one of the reasons people can become subject to investigation.”

According to the OCR website, people have a right to access protected health information (PHI) in a “designated record set,” defined as a group of records maintained by or for a covered entity that comprises medical and billing records about individuals maintained by or for a covered health care provider; enrollment, payment, claims adjudication, and case or medical management record systems maintained by or for a health plan; or other records used in whole or in part by or for the covered entity to make decisions about individuals.

The OCR document offers insight into handling access, but there are some

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

DO

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.

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

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



Median

4 Years (49 months)

of follow-up

034441-150514

IMPORTANT SAFETY INFORMATION 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).

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2015 8/15 037771-150729

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

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

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

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

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.

Learn more today at www.zytigahcp.com

STRONG T O G E T H E R

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ­ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ­ZYTIGA is not indicated for use in women. ­ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ­­ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ­ZYTIGA [see Adverse Reactions].

Co-administration of a corticosteroid suppresses adrenocorticotropic ­­ hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ­ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ­ ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ­ZYTIGA. Adrenocortical Insufficiency: ­Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ­ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving Z­YTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress.

Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ­ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: ­In 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 ­ZYTIGA. No deaths clearly related to ­ZYTIGA were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced Z­ YTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with Z­ YTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ­ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions].

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

ZYTIGA® (abiraterone acetate) Tablets Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 Z­ YTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

The most common adverse reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypo­phosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ­ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with Z­ YTIGA was 8 months.

Table 1: Adverse Reactions due to ­ZYTIGA in Study 1 ­ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications 5.9 1.4 2.3 0 Fractures5 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 2.3 1.9 1.0 0.3 Cardiac failure8 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

6 Includes

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

terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable.

Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ­ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Table 2 shows laboratory abnormalities of interest from Study 1.

Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ­ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases.

Table 3 shows adverse reactions on the ­ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ­ZYTIGA was 13.8 months.

Table 3: A dverse Reactions in ≥5% of Patients on the ­ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Table 4: L aboratory Abnormalities in >15% of Patients in the Z­ YTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ­ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%).

Grade 3-4 cardiac failure occurred in 1.6% of patients taking Z­ YTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ­ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ­ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ­ZYTIGA arms.

Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ­ZYTIGA is a substrate of CYP3A4.

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].

In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information].

Effects of Abiraterone on Drug Metabolizing Enzymes: Z­YTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate.

Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA [see Clinical Pharmacology (12.3) in full Prescribing Information].

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ­ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ­ZYTIGA in pregnant women and ­ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. Z­ YTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ­ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

Nursing Mothers: Z­ YTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ­ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of ­ZYTIGA in pediatric patients have not been established.

Geriatric Use: Of the total number of patients receiving ­ZYTIGA in Phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of Z­ YTIGA increased by approximately 1.1‑fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function.

The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ­ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information.

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of Z­ YTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

There is no specific antidote. In the event of an overdose, stop Z­ YTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].

Based on its mechanism of action, Z­ YTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle ­ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ­ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.

• Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with Z­ YTIGA and prednisone.

• Patients should be informed that ­ZYTIGA should not be taken with food and that no food should be consumed for at least two hours before the dose of Z­ YTIGA is taken and for at least one hour after the dose of ­ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ­ZYTIGA with food causes increased exposure and this may result in adverse reactions.

ZYTIGA is taken once daily and • Patients should be informed that ­ prednisone is taken twice daily according to their physician’s instructions.

• Patients should be informed that in the event of a missed daily dose of ­ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.

• Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests.

• Patients should be informed that ­ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ­ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ­ZYTIGA. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 ©Janssen Biotech, Inc. 2012 Revised: Dec 2015 044724-151215