Renal & Urology News - May 2016 Issue

MAY 2016

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VOLUME 15, ISSUE NUMBER 4

Pioglitazone Use, Bladder CA Linked Large population-based study reveals association

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BLADDER CANCER AND PIOGLITAZONE The risk of bladder cancer associated with pioglitazone increased along with duration of use, a study found.

80 70 60

66%

50

78%

IN THIS ISSUE 7 11

Higher NLR predicts more aggressive RCC tumors Prostatic artery embolization may ease nocturia symptoms

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Larger upper urinary tract tumors predict lower survival

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Optimal PSA nadir after salvage PCa cryotherapy identified

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Increased ejaculation frequency found to lower PCa risk Poor gum health is associated with an increased risk of erectile dysfunction.

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In adjusted analyses, researchers found a 63% increased risk of bladder cancer associated with pioglitazone use.

Use of pioglitazone for 1 year or less, 1–2 years, and more than 2 years was associated with a 33%, 66%, and 78% higher risk of bladder cancer, respectively, according to the researchers.

A cumulative dose of 10,500 mg or less, 10,500–28,000, and greater than 28,000 mg was associated with a 63%, 58%, and 70% increased risk of bladder cancer, respectively.

Rosiglitazone, another drug from the thiazolidinedione class, was not asso-

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© SOPHIE JACOPIN / SCIENCE SOURCE

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BY JODY A.CHARNOW PATIENTS WHO take the antidiabetes drug pioglitazone are at higher risk of bladder cancer, according to the findings of a large population-based study.

The risk rises with longer duration of use and increasing cumulative dose.

In a large population-based cohort study using data from the United Kingdom Clinical Practice Research Datalink, the incidence of bladder cancer was significantly higher among users of pioglitazone—a thiazolidinedione drug—rather than antidiabetes drugs other than thiazolidinediones.

33%

10 0

≤1

1–2 >2 Duration of use (years)

Source: Tuccori M et al. Pioglitazone use and risk of bladder cancer: Population based cohort study. BMJ. 2016;352:i1541.

ciated with a higher risk of bladder cancer. “The absence of an association with rosiglitazone suggests that the increased risk is drug specific and not a class effect,” Marco Tuccori, MD, of Jewish General Hospital in Montreal, Canada, and colleagues concluded in

a paper published online in the British Medical Journal.

In addition, compared with rosiglitazone, pioglitazone was associated with a 48% increased risk of bladder cancer in adjusted analyses. continued on page 10

NSS May Decrease ESRD Risk Circumcision Preserves Penile BY NATASHA PERSAUD Europe. Of these, 1,334 (65.8%) underNEPHRON-SPARING surgery (NSS) went NSS and 693 (34.2%) underwent Sensitivity for patients with renal tumors pre- RN with limited or no hilar clamping.

NEONATAL CIRCUMCISION is not associated with changes in adult penile sensitivity, according to new study that provides preliminary evidence that the penile foreskin is not the most sensitive part of the adult penis.

A team led by Jennifer A. Bossio, a PhD candidate in clinical psychology at Queen’s University in Kingston, Ontario, studied 62 men aged 18–37 years: 30 circumcised and 32 not circumcised as neonates. Most study participants were Canadian born and religiously unaffi liated. The circumcised and uncircumcised men did not differ significantly with respect to continued on page 10

serves kidney function and reduces the risk of end-stage renal disease (ESRD) compared with radical nephrectomy (RN), a new study suggests.

Using a collaborative database, Umberto Capitanio, MD, of University Vita-Salute, San Raffaele Scientific Institute in Milan, Italy, and colleagues determined the ESRD rate and predictors among 2,207 patients free of pre-existing chronic kidney disease (CKD) who had surgery for nonmetastatic clinical T1 unilateral kidney cancer during 1984–2010 at 5 centers in

Patients in both treatment arms had a median age of 61 years. The mean follow-up was 72 months.

Unadjusted ESRD rates at 5 and 10 years were similar in the NSS group (1.5% and 2.5%, respectively) and the RN group (1.9% and 2.7%, respectively), according to a paper published online in European Urology. In multivariate analysis, however, NSS was associated with a significant 60% decreased risk of ESRD compared with RN, after adjusting for baseline continued on page 10

EXPERT Q& A

Neal Shore, MD, discusses novel uses of radium-223 in metastatic CRPC. PAGE 16

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Premature Tooth Loss Common Among ESRD Patients PREMATURE TOOTH loss is common among end-stage renal disease patients (ESRD) on hemodialysis (HD), and severe periodontal disease may be a contributing factor, researchers reported online in Oral Diseases.

Pedro Diz, MD, of the School of Medicine and Dentistry at Santiago de

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Compostela University in Spain, and colleagues compared with 44 adult ESRD patients on HD with 44 age- and sex-matched control patients with a glomerular filtration rate above 90 mL/ min/1.73 m2. The mean number of missing teeth was significantly higher in the ESRD patients than controls (13.9 vs.

9.7). The researchers detected 6 (13.6%) fully edentulous patients in the study group compared with only 1 (2.2%) in the control arm. In addition, the investigators found that the mean number of decayed teeth was similar in both groups, although the mean number of teeth with fillings was significantly

lower in the HD group. When the researchers considered the active and inactive (filled) caries the total number of decayed teeth was significantly lower in the HD patients. “Our results indicate that tooth loss in patients with ESRD is not the result of a higher prevalence of caries,” the authors wrote. n

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www.renalandurologynews.com MAY 2016

Renal & Urology News 5

Multiple Comorbidities Predict Higher-Risk PCa COMORBIDITY BURDEN is associated with pathologic upgrading and up staging in men with clinically low-risk prostate cancer (PCa) eligible for active surveillance, new findings suggest.

Using the National Cancer Data Base (NCDB), a team led by Robert Abouassaly, MD, of University

Hospitals Case Medical Center in Cleveland, studied 29,447 men with low-risk PCa who underwent radical prostatectomy (RP) from 2010 to 2011.

Of these, 449 (1.5%) had more than 1 comorbidity. At RP, 44% of cases were upgraded/up staged (UGUS).

The researchers used the Charlson

comorbidity index (CCI) to evaluate comorbidity burden.

In multivariate analysis, men with a Charlson score of 2 or higher had a significant 1.4 times increased odds of UGUS to higher-risk disease, Dr. Abouassaly and his colleagues reported in The Journal of Urology

(2016;195:919-924). Age, race, PSA level, and percentage of positive biopsy cores also were significant predictors of UGUS. Men aged 70 years and older had 32% increased odds of URUS compared with those younger than 70 years. Non-whites had 12% increased odds versus whites. A PSA level of 4 ng/ mL or higher was associated with 66% increased odds compared with lower PSA levels. Patients with 33%–67% and greater than 67% positive cores had 51% and 50% increased odds, respectively, compared with those who had less than 33% positive cores.

After further adjustment for age, race, PSA level and core involvement, only white men younger than 70 years with comorbidities demonstrated significant UGUS. In this group, men with a Charlson score of 2 or more had a significant 31% increased risk of UGUS versus those with a score 1 or less.

Study reveals 40% increased odds of upgrading and up staging at RP. The investigators said their results suggest that comorbidity burden may be another variable to consider when assessing PCa risk, “and that incorporating comorbidity assessment into current practice may improve the accuracy of risk stratification in men eligible for active surveillance.”

They pointed out, however, that as higher comorbidity burden also predicts non-cancer-related deaths, UGUS may not be clinically significant for all PCa patients with comorbidities, especially those with a Charlson score of 3 or higher, who are unlikely to benefit from aggressive treatment.

In a discussion of study limitations, Dr. Abouassaly’s group noted that due to selection bias favoring healthier patients for RP, the prevalence of comorbidities in their study population was about 15% lower than in the general population with PCa in the United States. Because men with comorbidities may be less likely to undergo surgery, other factors not captured in the NCDB, such as positive family history, PSA velocity or density, and lower urinary tract symptoms, may have influenced the use of RP and the risk of UGUS in patients selected for surgery. n

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6 Renal & Urology News

MAY 2016 www.renalandurologynews.com

FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD

Clinical Trials in Surgery: A New Paradigm

W

e hold evidence obtained through randomized clinical trials (RCTs) to be the highest level upon which current medical care should be changed and future care should be based. Unfortunately, the performance of interventional RCTs in surgery comparing modality A versus B is often hampered by poor accrual. It is estimated that one fifth of surgical randomized treatment trials are prematurely terminated.1 A number of barriers to completion of surgical randomized treatment trials have been identified, including inadequate infrastructure, time, and funding.

Increasing emphasis has recently been placed on excess variation in care as a potential source of medical errors. Not surprisingly, policy makers, regulatory agencies, and payers have sought to standardize care delivery processes as a way to potentially impact healthcare outcomes and quality. As an example, the National Quality Forum endorsed 69 surgical quality metrics for 2015; 24 of these involved care processes.2 In response, clinical investigators have begun to address provider- and health care system-risk within the context of randomized treatment trials. These processes-of-care trials more explicitly seek to control and mitigate provider- and healthcare system-risk as a way to standardize surgical care and potentially optimize surgical quality.

Why are processes-of-care trials (POCTs) meaningful? First, they present an opportunity for physicians within a system to rally around a common problem with no obvious solution and try to study it systematically. For example, post-operative ileus is a very common cause of prolonged hospitalization. While it is simple to explain, it remains difficult to improve. Second, POCTs emphasize the use of level 1 evidence and move us away from practice by anecdote. Third, and most importantly, POCTs reshape the culture of acceptance of “meaningless” or “minor” post-operative complications such as catheter associated urinary tract infections, superficial skin infections, and post-op retention. These “initiating” complications often prolong hospitalization and permit “spiraling” complications to set in.

We all espouse scientific rigor in the pursuit of the highest quality of care. Abundant business models focusing on Six Sigma, the Toyota Production System, and best practices have been shown to optimize outcomes, enhance productivity, and even improve revenue. We are uniquely situated in medicine to systematically study processes and then adapt the findings to improve care.

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

1. Kasenda B, von Elm E, You J, et al. Prevalence, characteristics, and publication of discontinued randomized trials. JAMA 2014;311(10):1045-1051.

2. National Quality Forum: NQF-Endorsed Measures for Surgical Procedures. 2015

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Medical Director, Urology

Medical Director, Nephrology

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

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

Nephrologists

Urologists

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

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

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

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

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

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

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

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

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

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

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

Renal & Urology News Staff Editor Web editor Production editor

Jody A. Charnow Natasha Persaud Kim Daigneau

Group art director, Haymarket Medical

Jennifer Dvoretz

Production manager

Krassi Varbanov

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

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

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

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Renal & Urology News 7

Higher NLR Predicts More Aggressive RCC Tumors A PRE-TREATMENT elevated neutrophil-to-lymphocyte ratio (NLR) predicts larger and aggressive renal cell carcinoma (RCC) at the time of nephrectomy, according to researchers.

A team led by Matthew K. Tollefson, MD, of Mayo Clinic in Rochester, Minn., studied 2,402 patients who underwent radical or partial nephrectomy for localized renal tumors from 1995 to 2008. Of these, 2,039 had an NLR determination made within 90 days prior to surgery.

The investigators found significantly lower NLR in patients with benign rather than malignant renal masses (median 2.92 vs. 3.12), with the greatest difference observed among renal lesions larger than 7 cm (median 2.79 vs. 3.87), Dr. Tollefson and his colleagues reported online ahead of print in the World Journal of Urology.

The investigators noted a significant difference in NLR among RCC subtypes. Cystic clear-cell RCC (ccRCC)

had the lowest NLR (median 2.48) and collecting duct RCC had the highest NLR (median 5.99). Results also showed that NLR increased significantly with larger tumor size and greater nuclear grade. Specifically, in patients with ccRCC, an incremental increase in tumor size was associated with greater

NLR (2.80 for tumors 4 cm or less, 3.09 for tumors larger than 4 but not more than 7 cm, and 3.95 for tumors larger than 7 cm). G1, G2, G3, and G4 tumors were associated with an NLR of 2.68, 2.87, 3.48, and 5.18, respectively.

“An elevated NLR is associated with RCC pathology, higher-grade tumors,

and more aggressive histologic subtypes at the time of nephrectomy,” the authors concluded. “Therefore, NLR appears to be a preoperative marker of biologically aggressive RCC and may be useful in predicting malignancy and guiding management among patients with suspicious renal tumors.” n

AKI After RCC Surgery On the Rise RATES OF ACUTE kidney injury (AKI) following partial or radical nephrectomy for renal cell carcinoma (RCC) are increasing, according to researchers.

Using the Nationwide Inpatient Sample, Marianne Schmid, MD, Brigham and Women’s Hospital in Boston, and colleagues studied 253,046 patients who underwent partial nephrectomy (PN) or radical nephrectomy (RN) from January 1998 to December 2010. AKI developed in 5.5% of the patients (3,525 PN patients and 14,303 RN patients), the researchers reported online ahead of print in Urologic Oncology. AKI rates increased significantly from 2.0% in 1998 to 10.4% in 2010.

Dr. Schmid’s group identified male sex, black race, RN, older age, higher preoperative chronic kidney disease stage, and more contemporary years (2004–2010) as predictors of AKI. Postoperative AKI during hospitalization was associated with increased rates of any complications and transfusion, an increased rate of inhospital mortality, prolonged length of stay, and higher hospital costs. n

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www.renalandurologynews.com

Contents

M A Y

2 0 1 6

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V O L U M E

Urology

ONLINE

AKI After RCC Surgery On the Rise Acute kidney injury rates increased from 2.0% in 1998 to 10.4% in 2010 in the United States among patients who underwent partial or radical nephrectomy.

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Selected Metastatic UC Cases Respond to Afatinib In patients with specific genetic abnormalities, the drug significantly improved 3-month progression-free survival.

15

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

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

Congratulations to our April winner: Ronny Kafiluddi, MD

Drugs in the Pipeline

21

Job Board

Shorter PCa Radiotherapy Schedule Okay Decreasing a course of external beam radiation therapy from 8 weeks to 5.6 weeks did not lower disease-free survival rates.

12

Sleep Time, eGFR Decline Rate Linked Women who sleep 6 hours or less per night experience more rapid decreases in renal function compared with those who sleep 7–8 hours per night.

15

Curbing Dietary Potassium Questioned Advising hemodialysis patients to restrict intake of high-potassium plants food to prevent hyperkalemia is backed by little evidence, investigators say.

18

COPD Ups Death Risk in CKD Patients Likelihood of overall mortality is increased by 41% in patients with versus without chronic obstructive pulmonary disease.

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

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

Larger Upper Urinary Tract Tumors Predict Worse Survival Patients with tumors larger than 3 cm were 2.3 and 2.4 times more likely to die from their cancer and all causes, respectively, compared with patients who had smaller tumors.

Nephrology

Keep current on the development of investigational medications.

18

Weekend Transplant Outcomes Not Worse Deceased-donor kidney transplantation performed on Saturday or Sunday in the United States do not result in higher risk of patient death or allograft survival.

In the absence of empirical evidence, it is

of course prudent to continue to recommend low-potassium diets to HD patients with hyperkalemia.

See our story on page 15

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I S S U E

N U M B E R

4

CALENDAR

7

this month at renalandurologynews.com

1 5 ,

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 Society of Transplant Surgeons/American Society of Transplantation American Transplant Congress Boston June 11–15 Canadian Urological Association Annual Meeting Vancouver, B.C. June 25–28 International Continence Society Annual Meeting Tokyo September 13–16 Sexual Medicine Society of North America Annual Fall Scientific Meeting Scottsdale, AZ November 3–6 American Society of Nephrology Kidney Week 2016 Chicago November 15–20

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Departments 6

From the Medical Director Barriers to conducting clinical trials in surgery

9

News in Brief Fluoroquinolones for high PSA may be unjustified

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Practice Management Information disclosure rules not as strict as widely believed

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www.renalandurologynews.com MAY 2016

Renal & Urology News 9

News in Brief

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

Short Takes PSA Screening More Likely Among Blacks

coronary angiography with or without percutaneous coronary intervention.

Black males aged 45–60 years are

The NAC patients had a significant

more likely to undergo PSA screen-

34% decreased odds of CIN compared

ing than non-Hispanic white men,

with controls, researchers ­Nelson

researchers reported in The ­Journal of

Wang, MD, of Macquarie ­University

Urology (2016;195:913-918).

in Sydney, Australia, and colleagues reported in the International Journal of

Jesse D. Sammon, MD, of Brigham

Cardiology (2016;209:319-327).

and Women’s Hospital in Boston, and colleagues studied 122,309 asympresponded to a 2012 survey that

Aminosalicylates Cut PCa Risk in Men with IBD

asked about PSA screening. Of these,

Aminosalicylate use by men with

29% of black and 32% of non-Hispanic

inflammatory bowel disease (IBD)

whites reported undergoing PSA

is associated with a decreased risk

screening. The odds of PSA screening

of prostate cancer (PCa), investiga-

among men aged 45–49, 50–54, and

tors reported online in the Journal of

55–59 years were 66%, 58%, and

­Gastroenterology.

tomatic men aged 40–99 years who

36% higher among blacks, respec-

J. Clair Wilson, PhD, of the

tively, than non-Hispanic whites.

­University of Basel in Switzerland, and colleagues identified 1,077

N-Acetylcysteine May Protect Against CIN

cancers among 19,647 patients with

Evidence supports the use of N-acetyl-

randomly matched group of an equal

cysteine (NAC) for preventing contrast-

number of patients without IBD. The

induced nephropathy (CIN), according

researchers observed no associa-

to the findings of a new systematic

tion between IBD and overall cancer

review and trial sequential analysis.

risk, but aminosalicylate use by IBD

a first-time diagnosis of IBD and a

The review included 43 random-

patients was associated with adjusted

ized controlled trials enrolling a total

68% decreased risk of PCa and 28%

of 3,277 patients who underwent

decreased risk of all cancers.

Living Donor Transplant Trends Despite efforts to increase living kidney donation, the proportion of transplants involving living donors has remained stable or declined slightly during 2011–2015, according to the Organ Procurement & Transplantation Network.

35 30 25 20 15 10 5

34.3%

34.0%

33.9%

32.3%

31.4%

2011

2012

2013

2014

2015

0

Source: Organ Procurement and Transplantation Network, U.S. Department of Health & Human Services.

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Parathyroids’ Weight, Blood Flow Not Linked to PTH Level T

otal weight of parathyroid glands and blood supply to the glands do not predict secretion of parathyroid hormone (PTH), new findings suggest.

Farrokhlagha Ahmadi, MD, of Tehran University of Medical Sciences in Iran, and colleagues used high-resolution ultrasonography to determine gland weight and color Doppler imaging to measure parathyroid blood flow in 52 hemodialysis patients with secondary hyperparathyroidism. The investigators found no significant correlation between the total mass of the glands and serum concentration of serum intact PTH (iPTH) and between both total central and peripheral parathyroid gland blood flow and serum iPTH, according to a paper published in the Saudi Journal of Kidney Disease and Transplantation (2016;27:263-269). The authors concluded that iPTH secretion is not dependent on total weight and blood supply of the parathyroid glands.

Fluoroquinolones May Be Unwarranted for High PSA A

course of fluoroquinolone antibiotics may be unwarranted in asymptomatic men with an elevated PSA level, according to researchers.

In a single-center prospective trial of 150 men with an initial elevated PSA level, Alyssa Greiman, MD and colleagues at the Medical University of South Carolina in Charleston randomly assigned patients to receive 6 weeks of ciprofloxacin or observation. Of 136 men who completed the trial, 63 were in the treatment arm and 73 were in the observation arm. PSA level declined by an average of 0.68 ng/ mL in the treatment arm and 0.01 ng/mL in the observation group, a difference that was borderline significant, investigators reported in Urology (2016;90:32-38).

Among the men who underwent biopsy, prostate cancer was diagnosed in the first biopsy In 24 (63%) patients in the treatment group compared with 27 (52%) of the observation group during follow-up, a non-significant difference.

Low Chloride Ups Mortality, CV Risks in CKD Patients L

ow serum chloride levels are associated with increased risk of death and cardiovascular (CV) events in patients with chronic kidney disease (CKD) not on dialysis, according to a new study. Researchers concluded that serum chloride levels may be an additional prognostic indicator in CKD patients.

Shintaro Mandai, MD, of Tokyo Medical and Dental University, and colleagues prospectively studied 923 pre-dialysis CKD patients who had a median serum chloride level of 106 mEq/L at enrollment. The primary outcome was a composite of death and CV events. During a median follow-up of 33 months, 66 deaths, 98 cardiovascular events and 154 composite outcomes occurred. Patients in the first quartile of serum chloride level (less than 103.9 mEq/L) had a significant 72% increased risk for the composite outcome than those in the third quartile (106–108 mEq/L), the researchers reported online in Clinical and Experimental Nephrology.

Among patients with a chloride level of 106 mEq/L or less, higher chloride levels were associated with a lower risk for the composite outcome.

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Bladder CA risk

continued from page 1

The study included a cohort of 145,806 patients newly treated with antidiabetic drugs from January 1, 2000 to July 31, 2013. During 689,616 person-years of follow-up, 622 patients received a diagnosis of bladder cancer (crude incidence rate of 90.2 per 100,000 person-years).

Given the similarities between pioglitazone and rosiglitazone, the authors noted, “it is unlikely that confounding by indication or detection bias can explain the association observed with pioglitazone.”

Although the biological mechanism by which pioglitazone might increase bladder cancer is not clear, “this imbalance in the risk of bladder cancer between these two thiazolidinediones could likely be explained by pharmacological differences,” they wrote.

Studies of the association between pioglitazone and bladder cancer have been contradictory. The IRIS trial, published recently in the New England Journal of Medicine (2016;374:1321-1331), which

NSS cuts ESRD risk

continued from page 1

c­haracteristics affecting CKD risk, such as age diabetes, uncontrolled hypertension, and other comorbidities.

The median time to ESRD, which was defined as an estimated glomerular filtration rate less than 15 mL/min/1.73 m2, was 45 months.

“Considering the important causes of ESRD, such as diabetes, uncontrolled hypertension, and age, NSS appears to decrease the probability of ESRD after surgery,” Dr. Capitanio and colleagues wrote.

The authors added that an even greater benefit is possible with the

Circumcision’s effects continued from page 1

mean age, education level. Bossio and her colleagues used quantitative sensory testing protocols to assess touch and pain thresholds as well as warmth detection and heat pain thresholds at a control site (forearm) and 3–4 penile sites (glans penis,midline shaft, proximal to midline shaft, and, if present, the foreskin.

Results showed that penile sensitivity did not differ by circumcision status for any stimulus type of penile site, the investigators reported online ahead of print in The Journal of Urology. The

Cv-jumps_vUro_RUN0516.indd 10

randomized 3,895 individuals without diabetes to either pioglitazone or placebo, found a higher number of new bladder cancers in the pioglitazone group compared with the placebo group—12 (0.6%) vs. 8 (0.4%)—but the difference was not statistically

r­esearchers reported on a study of 193,099 patients with diabetes showing no significantly higher risk of bladder cancer associated with pioglitazone use.

Connie M. Rhee, MD, MSc, a nephrologist at the University of California Irvine who has investigated the comparative effectiveness of various diabetes management strategies, stated that the study “is a notable contribution to the antidiabetic regimen medical literature.”

Dr. Rhee pointed out that the major strengths of the study were its exclusion of prevalent pioglitazone users (a population that may not capture patients who died or had adverse effects from pioglitazone, as opposed to incident “new users” of the drug), which could bias towards a protective association. Another strength, she said, was the incorporation of a lag period between pioglitazone initiation and the commencement of at-risk time (as short-term pioglitazone use is unlikely to cause incident bladdre cancer).

In addition, the findings were robust across an extensive number of

r­ igorous sensitivity analyses, Dr. Rhee highlighted.

In a joint statement, Edmund C. P. Chedgy, MBBS, MSc, and Peter C. Black, MD, of the University of British Columbia in Vancouver, who published a paper in Urology (online ahead of print) titled “Pioglitazone: No Longer a Worry for Bladder Cancer?” told Renal & Urology News: “There is now a wealth of conflicting literature on this topic of varying quality. So what should physicians do? On the face of it, given that doctors practice with ‘primum non nocere’ at the core of their beliefs, where there is doubt with respect to the safety of a particular medication and alternate medications exist, it can be argued that the riskier medication should not be used.

Pioglitazone is one such medication, and, as demonstrated by this latest study, rosiglitazone does not have such a risk. We would therefore suggest that physicians avoid the use of pioglitazone unless absolutely necessary given its potential significant increased risk of bladder cancer.” n

novel surgical techniques of no clamp or selective clamping, which were described recently in a paper published in The Lancet (2016;387:894-906).

Preoperative medical conditions are the most important determinants for ESRD, according to the researchers. Previous studies, which found little difference in ESRD risk between NSS and RN, did not account for such comorbidities or tumor size.

Dr Capitanio and colleagues noted that a recent subanalysis of 514 patients included in a European Organization for Research and Treatment of Cancer (EORTC) randomized trial found that the incidence of ESRD was nearly identical for patients treated with NSS

or RN (1.6% vs. 1.5%). This study, which was published in European Urology (2014;65:372-377), included patients treated prior to 2003, when

surgical experience with NSS techniques and outcomes were limited, Dr Capitanio’s group pointed out. In addition, some patients had preoperative impaired renal function. The current

series included patients treated more recently, had normal preoperative renal function, and who did not have hilar clamping or who had limited clamping.

“Those main differences may explain the discordance between the benefit we found in the NSS group and the EORTC trial findings,” Dr. Capitanio and colleagues wrote.

Strengths of the current study include its multi-institutional design, the relatively long follow-up, and the inclusion of patients without baseline CKD, Dr. Capitanio’s team noted.

Limitations include the study’s retrospective design, which cannot exclude the presence of residual confounders, such as proteinuria at diagnosis. n

authors noted that the foreskin of uncircumcised men was more sensitive to tactile stimulation than other penile sites, but this finding did not extend

“The results of the current study concerning the sensitivity of the control site compared to the rest of the genital sites do not support the idea that foreskin removal is detrimental to penile sensitivity,” the authors wrote.

Bossio’s group pointed out that little is known about the sexual correlates of neonatal circumcision, penile sensitivity in particular. A widely accepted but largely untested hypothesis is that keratinization of the exposed glans penis epithelium occurs after circumcision, leading to decreased penile sensitivity, they noted. Another hypothesis is that removal of the highly innervated foreskin results in reduced penile sensitivity.

In an editorial comment accompanying the report by Bossio’s group, Ranjiv Mathews, MD, professor of urology and pediatrics at the Southern Illinois University School of Medicine in Springfield, said he suspects the findings “will not placate those opposed to newborn circumcision.”

Dr. Mathews added that previous findings from a study published in BJU International (2007;99:864-869) of the foreskin being a source of significant sensation also are reason for concern.

“Men circumcised in infancy have never had this added source of sensation and, therefore, may not be able to determine that sensitivity was lost.” n

The increased risk appears to be drug specific and not a class effect. significant. A 10-year observational follow-up study of patients who completed the PROactive trial found that pioglitazone users had a 35% decreased risk of bladder cancer and a 47% increased risk of prostate cancer (PCa) compared with placebo recipients, according to a report in Diabetes, Obesity & Metabolism (2016;18:266-273).

In the Journal of the American Medical Association (2015;314:265-277),

Study suggests the foreskin is not the most sensitive part of the penis. to any other stimuli. The investigators also found no difference in sexual function as evaluated with the International Index of Erectile Function.

Preoperative medical conditions are the most important ESRD determinants.

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Renal & Urology News 11

Periodontitis May Increase ED Risk Gum infections are associated with a 1.5-3.4 times higher risk of erectile dysfunction, new review finds dysfuncti on. In an animal model, mild systemic inflammation associated with PD reduced nitric oxide synthase activity in penile tissue.

Andrological examination “should include comprehensive oral evaluation, and physicians detecting erectile dysfunction should refer the patient to a dentist for further evaluation and treatment,” Dr Varela Kellesarian told Renal & Urology News.

A few of the studies suggested that nonsurgical periodontal treatments can reduce inflammation in ED patients.

Chronic PD weakens the supporting structures of teeth, such as the cememtum, gingiva, periodontal ligament, and alveolar bone.

More well-designed, controlled, and longitudinal studies are needed, however. More than half of the included studies did not account for tobacco and alcohol use, and a fifth did not adjust for diabetes or heart disease. Smoking, alcohol, uncontrolled diabetes, and

Prostatic Artery Embolization May Ease Nocturia Symptoms PROSTATIC ARTERY embolization (PAE)

68 patients at 1 month after treat-

may decrease nocturia in older men with

ment. Of the 46 patients, 25 (54.4%)

lower urinary tract symptoms and benign

reported improvements in nocturnal

prostatic hyperplasia (BPH), researchers

urination frequency, with an average

reported at the Society of Interventional

absolute reduction of 0.85 episodes

Radiology’s 2016 Annual Scientific

per night. The 46 patients reported

Meeting in Vancouver, British Columbia.

an average 10-point reduction in AUA

In a retrospective study, PAE

score and an average QoL score

decreased nocturia frequency signifi-

improvement of 2.1, indicating that

cantly in a majority of patients at 3

their urinary symptoms bothered them

months, according to a research team

less and their quality of life showed

led by Sandeep Bagla, MD, an inter-

improvement, the researchers noted.

ventional radiologist at the Vascular

At the 3-month mark, 28 of the

Institute of Virginia in Woodbridge.

38 patients (73.7%) who followed

Dr. Bagla and colleagues enrolled

up reported an average nocturia

68 patients who underwent PAE.

frequency reduction of 1.4 episodes

Participants had an average age of

a night, a 13.4-point reduction in

64.6 years, American Urological

AUA score, and a 2.8-point improve-

Association (AUA) symptom score of

ment in QoL score, according to the

23.9, an average quality of life (QoL)

investigators.

score of 4.8, an average prostate

Dr. Bagla’s group concluded that

volume of 86.4 cc, and an average

their results are comparable to those

nocturnal frequency of 3.3 episodes.

achieved with transurethral resection

Dr. Bagla and colleagues conducted a follow-up with 46 of the original

News_ED-perio_RUN0516.indd 11

of the prostate and photoselective vaporization of the prostate. n

Gum health may affect erectile function.

coronary heart disease, are risk factors for both ED and PD. In addition, the researchers noted that the 9 studies in their review were conducted in Asia and the Middle East for relatively short period of times and with relatively small study samples, limiting generalizability.

Prostate Biopsy Rates Decrease

BY NATASHA PERSAUD PROSTATE BIOPSY rates have fallen following the updated American Urological Association (AUA) guidelines and U.S. Preventive Services Task Force (USPSTF) recommendations, a new study confirms. Although biopsy complication rates have decreased as well, the proportion of men experiencing them has risen.

“Taken together, these findings support a reduction in the morbidity of biopsy following publication of revised PSA screening guidelines but highlight the continued need to reduce the relative morbidity of biopsy,” lead investigator R. Jeffrey Karnes, MD, of Mayo Clinic in Rochester, MN, and colleagues wrote in a paper published online ahead of print in European Urology.

Dr Karnes and his team analyzed prostate biopsy and 30-day complication rates using U.S. claims data from 2005 to 2014 for 5,279,315 commercially insured men older than 40. Of these, 104,584 underwent prostate

Future studies should establish ED diagnosis with medical and psychological exam, nocturnal penile rigidity test, and Doppler ultrasound. ED diagnosis in many of the studies was made using less ideal methods such as the International Index of Erectile Function or Sexual Health Inventory for Men. In a separate review and meta-analysis published recently in the Journal of Clinical Periodontology (2016;43;206215), investigators reported finding an association between CP and ED. The study showed that CP was asssociated with a significant 3-fold increased odds of ED. In another previous study, researchers in Taiwan who compared 5,105 patients with ED and 10,210 controls found that the ED patients had a significant 79% increased odds of being diagnosed with chronic periodontal disease compared with controls, according to findings published in Andrologia 2015;47:513-518). n

biopsy. From 2005 to 2014, biopsy rates fell 33% from 64.1 to 42.8 per 100,000 persons per month, with immediate reductions following the 2008 and 2012 USPSTF recommendations and 2013 AUA guidelines.

This rate decrease is larger than previous reports, suggesting that thresholds for urology referral and/ or performance of biopsy may have changed. Likewise, complication rates decreased 10% from 8.7 to 7.8 per 100,000 persons per month, with notable decreases following the 2012 USPSTF recommendations.

Despite the absolute reduction in 30-day complication rate, the proportion of biopsied men who experienced complications rose from 14% to 18%, driven by non-sepsis infections.

Further analysis of the current study revealed that prior fluoroquinolone use increased the odds of complications by 27% and anticoagulant use by 14%. Advanced age above 70 years also increased the chances by 25% of complications perhaps due to more comorbidities in this population.

They noted that men who have previously taken a fluoroquinolone may benefit from pre-biopsy rectal swabs.

For men with comorbidities such as peripheral vascular disease or cancer, clinicians might reconsider biopsy. n

© THINKSTOCK

BY NATASHA PERSAUD CHRONIC PERIODONTITIS (PD) may be a risk factor for erectile dysfunction (ED), a new review suggests.

Sergio Varela Kellesarian, DDS, of Eastman Institute for Oral Health in Rochester, NY, and colleagues identified 9 studies published from 2009 to 2015 that assessed ED and oral health.

Two were randomized controlled trials and the remainder cross-sectional studies. All studies reported a positive and statistically significant relationship between PD and ED, according to results published online in the American Journal of Men’s Health.

Researchers reported odds ratios in 4 studies, with odds of ED ranging from 1.5–3.4 times higher in men with PD. Regarding how chronic PD might contribute to ED, the investigators cited hypotheses such as increased production of reactive oxygen species in tissues that reduce the bioavailability of nitric oxide, promoting endothelial

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12 Renal & Urology News

MAY 2016 www.renalandurologynews.com

Sleep Time, eGFR Decline Rate Linked More rapid decrease in renal function seen in women who sleep 6 hours or less vs. 7–8 hours per night

SHORTER SLEEP duration is associated with more rapid declines in renal function in middle-aged women, according to researchers.

In a study of 4,238 women in the Nurses’ Health Study, Ciaran J. McMullan, MD, and colleagues at Brigham and Women’s Hospital in Boston, analyzed the association of selfreported sleep duration with decline in renal function over an 11-year period (1989–2000).

The NHS began in 1976 when 121,700 registered nurses aged 30–55 years returned an initial questionnaire. The 4,238 women in the current analysis provided information on sleep duration in a 1986 questionnaire and had serum creatinine levels measured in 1989 and 2000.

Individuals who reported shorter sleep duration were more likely to have a rapid decline (30% or more) in estimated glomerular filtration rate (eGFR), Dr. McMullan’s team reported online ahead of print in Kidney International.

Compared with sleeping 7–8 hours per

Protein Type May Affect Diabetes Risk HIGHER DIETARY INTAKE of animal protein is associated with an elevated risk of type 2 diabetes (T2D), whereas increased consumption of vegetable protein is associated with a slightly reduced risk, a recent study suggests.

The findings suggest that adopting a diet rich in plant-based proteins should be considered for T2D prevention, according to a research team led by Vasanti S. Malik, MD, of the Harvard T.H.Chan School of Public Health in Boston.

Dr. Malik and colleagues studied 72,992 women in the Nurses’ Health Study (1984–2008), 92,088 women in the Nurses’ Health Study II (1991– 2009), and 40,722 men in the Health Professionals Follow-up Study (1986– 2008). Investigators documented 15,580 new cases of T2D during 4,146,216 person-years of follow-up.

Subjects in the highest quintile of percentage of energy derived from total protein and animal protein had 7% and 13% increased risks of T2D, respec-

News-sleep_renal_RUN0516.indd 12

Less Sleep Ups Renal Function Decline Risk In a study, less sleep was associated with a more rapid decline in renal function. Shown here is the annual rate of decline in estimated glomerular filtration rate by sleep duration.

1.5 1.2 0.9

1.3%

1.1%

0.9%

0.6 0.3 0.0

7–8 hours

6 hours Sleep duration

≤ 5 hours

Source: McMullan CJ et al. Association of short sleep duration and rapid decline in renal function. Kidney Int. (published online ahead of print).

night, sleeping for 5 or fewer hours and 6 hours per night was associated with a significant 79% and 31% increased odds of a rapid decline in eGFR, respectively, in adjusted analyses.

Women who reported sleeping 7–8 hours per night had an eGFR decline of 0.9 mL/min/1.73m2 per year, which was significantly slower than the annual rate of decline for subjects who reported

tively, compared with those in the lowest quintile, Dr. Malik’s team reported online ahead of print in the American Journal of Epidemiology. Subjects in the highest quintile of percentage of energy intake from vegetable protein had a 9% decreased risk of T2D compared with those in the lowest quintile.

The investigators also calculated the effect of substituting 5% of energy from protein for equal exchanges of total and different-quality carbohydrates and substituting vegetable protein for animal protein. Substituting vegetable protein for animal protein was associated with a significant 23% decreased risk. Substituting total and animal protein for total carbohydrate was not associated with T2D risk, but substitution with vegetable protein was associated with a significant 22% decreased risk. Substituting total and animal protein for carbohydrate from whole grains was associated with 20% and 18% increased risks of T2D. “To our knowledge, this is the first study that has examined long-term intake of protein in relation to T2D risk using repeated measurements taken over many years of follow-up and that has examined the role of substitution of protein and protein type by carbohydrate type in T2D risk,” the authors wrote. n

6 hours of sleep per night (1.1 mL/ min/1.73 m2) and 5 or fewer hours of sleep per night (1.3 mL/min/1.73 m2).

“To our knowledge, this is the first prospective study to find that shorter sleep duration is associated with a more rapid decline in eGFR,” the authors wrote.

Results also showed that women who, in 1986, reported slept 5 or fewer hours per night had a significant 2.5 times

higher odds of having albuminuria compared with those who reported sleeping 7–8 hours per night. The finding is consistent with a study of 6,834 Japanese adults showing that proteinuria was 1.7 times more likely to develop in individuals who slept 6 or fewer hours per night than those who slept 7–8 hours per night, the investigators noted.

Dr. McMullan’s group explained that most renal physiologic processes follow a diurnal rhythm, including regulation of the renin-angiotensin-system, sodium reabsorption, glomerular filtration, and renal blood flow. “Coordination of the circadian periodicity of these processes allows the kidney to anticipate changes in metabolic and physiological demands through a 24-hour cycle,” they explained.

“However, changes to lifestyle and work practices have diminished the amount of nightly sleep many people obtain, thereby altering the times at which workers are required to be awake and desynchronizing basic physiologic rhythms from environmental demands.” n

Acthar Gel May Be an Option for Nephrotic Syndrome ACTHAR GEL (adrenocorticotropic

50% or greater reduction in proteinuria

hormone) may be an option for treating

from baseline and final proteinuria 500–

nephrotic syndrome (NS).

3,500 mg/day, and clinical response as

Arvind Madan, MD, of Nephrology

a 30% or greater reduction in proteinuria

Associates of Central Florida in

from baseline that did not meet criteria

Orlando, and colleagues studied 44

for complete or partial remission).

adult NS patients treated with Acthar

A total of 37 patients completed

gel. Of these, 30 (68.2%) had received

treatment. Complete remission occurred

prior treatment with immunosup-

in both MCD patients and partial remis-

pressive or cytotoxic therapies. NS

sion occurred in both MLN patients and

etiologies included idio­pathic focal

the patients with MPGN, the research-

segmental glomerulosclerosis (FSGS,

ers reported in BMC Nephrology (2016

15 patients), idiopathic membranous

17:37). Partial remission or clinical

nephropathy (iMN, 11), IgA nephropathy

response was observed in 12 (80%) of

(IgAN, 5), diabetic nephropathy (DN, 4),

the 15 FSGS patients. Complete or partial

systemic lupus erythrematosus class

remission or clinical response occurred

V membranous lupus nephritis (MLN,

in 8 (72.7%) of the 11 iMN patients.

2), minimal change disease (MCD, 2),

“Acthar gel may meet an impor-

membranoproliferative glomerulone-

tant treatment need in patients with

phritis (MPGN, 1), fibrillary glomerulone-

treatment-resistant NS in response

phritis (FGN, 1), and unbiopsied NS (3).

to first-line therapies, patients unable

The investigators defined complete

to tolerate first-line therapies, and in

remission as final proteinuria less than

patients with advanced disease,” the

500 mg/day), partial remission as a

authors concluded. n

4/19/16 4:32 PM

14 Renal & Urology News

MAY 2016 www.renalandurologynews.com

Selected Metastatic UC Cases Respond to Afatinib

BY NATASHA PERSAUD AFATINIB, a drug approved in 2013 to treat lung cancer, may help patients with metastatic urothelial carcinoma (UC) who have 1 of 2 genetic abnormalities, a small study finds.

“Compared to other drugs which have been tried for refractory metastatic

bladder cancer, including immune therapies which will likely be approved, the time to disease progression is significantly longer with afatinib in patients carrying the genetic abnormalities,” lead researcher Peter O’Donnell, MD, of the University of Chicago, stated in a press release. “There have been

no other drugs approved in the U.S. in decades in this disease setting, and only one drug approved in Europe. Its progression-free time was half of what we are seeing with afatinib in this same population of patients.”

For the phase 2 trial, Dr O’Donnell and his team enrolled 23 patients with

UC of the bladder, upper tract, or urethra whose disease had progressed despite platinum-based combination chemotherapy. Each patient received afatinib 40 mg per day continuously until their cancer progressed or intolerance developed.

Afatinib is an oral, irreversible tyrosine kinase inhibitor of the ErbB receptor family. The main endpoint was 3-month progression-free survival (PFS3).

Five of the 23 patients experienced delayed tumor progression for at least 3 months: 2 with partial response to the drug and 3 with stable disease, according to results published online ahead of print in the Journal of Clinical Oncology.

Based on an analysis of tumor specimens, the investigators determined that 3 of 4 patients with multiple copies of human epidermal growth factor receptor (HER2) and all 3 patients with somatic mutations of ERBB3 met the PFS3 endpoint. None of the patients without the molecular alterations responded to treatment.

In a small study, the drug benefited patients with certain genetic mutations.

The single patient with both HER2 amplification and ERBB3 mutation did not progress with afatinib, but treatment was stopped after 10.3 months due to depressed ejection fraction.

No unexpected toxicities occurred.

Two patients had dose reductions for grade 3 rash and fatigue. The most common side effect was diarrhea, experienced by 83% of patients.

The potential contribution of ERBB3 to afatinib sensitivity is a novel finding, according to Dr O’Donnell and colleagues.

“Molecular characterization of tumors is becoming increasingly used and more feasible to perform,” the authors concluded. “In the era of personalized medicine, a nuanced understanding of molecular studies is vital for identifying patients most likely to benefit from selected therapies. With this in mind, to our knowledge, this report is the first to show that afatinib has significant activity in patients with platinumrefractory UC with somatic ERBB3 and HER2 genomic alterations.”

The study was funded in part by Boehringer Ingelheim Pharmaceuticals, Inc., manufacturers of afatinib. n RU_7x10_Legal.indd 1

News_afatinib_metUC_RUN0516.indd 14

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Renal & Urology News 15

Curbing Dietary Potassium Questioned Researchers contend that little evidence exists to support this approach to prevent hyperkalemia ing high-potassium, plant-based foods, such as seeds, nuts, beans, and peas, as well as many commonly consumed fruits and vegetables.

Targeting of high-potassium foods is based on the assumption that all dietary potassium is therapeutically equivalent, the team noted. “Dietary potassium is not alone in being regarded this way,” the authors wrote. “HD patients with hyperphosphatemia are advised to avoid many high-phosphorus foods that may contribute minimally to hyperphosphatemia due to their relatively low phosphorus bioavailability.”

Dr. St-Jules’ group cited prior research demonstrating that potassium excretion in stool was 3 times higher in HD patients compared with normal controls.

“Fecal potassium content was directly proportional to dietary potassium intake and stool weight.” The increase in bowel potassium excretion in patients with chronic kidney disease was later shown to be primarily the result of potassium

Larger Upper Urinary Tract Tumors Predict Worse Survival TUMOR SIZE greater than 3 cm pre-

had tumors larger than 3 cm and

dicts worse survival among patients

only 49 patients (23.6%) had smaller

surgically treated for upper urinary

tumors, indicating that tumor size

tract urothelial carcinoma (UTUC), new

could be used as an objective variable

findings suggest.

for identifying candidates for lymph

In a study of 795 patients who

node dissection, the researchers

underwent nephroureterectomy for

reported online ahead of print in BJU

UTUC, Yan Shibing, MD, of West China

International.

Hospital, Sichuan University, Chengdu,

Dr. Shibing and collaborators noted

and colleagues found that patients with

that newly updated UTUC guidelines,

tumors larger than 3 cm were 2.3 and

for the first time, include tumor size

2.4 times more likely to die from their

as a preoperative risk factor, based

cancer and all causes, respectively,

on its impact on survival outcomes.

compared with patients who had

The authors pointed out, however,

smaller tumors. In addition, they were

that no solid evidence has been avail-

2.2 times more likely to experience

able to support this except for a few

cancer recurrence.

studies with small sample sizes and

The study population had a median

indefinite conclusions. Dr. Shibing and

follow-up of 32 months, during which

colleagues said their results represent

313 (39.4%) patients died from UTUC,

important new evidence.

321 (40.4%) experienced cancer

Tumor size “is a readily available

recurrence, and 359 (45.1%) died from

parameter, can be accurately mea-

all causes.

sured and has the great advantage of

Of the 208 patients who underwent lymph node dissection, 159 (76.4%)

News_hyperk_RUN0516.indd 15

little discrepancy among observers,” they noted. n

Many plant foods are rich in potassium.

secretion into the bowel rather than reduction of small intestine absorption of dietary potassium. “Given the relatively high prevalence of constipation in HD patients, infrequent bowel movements may be an important determinant of hyperkalemia in HD patients.”

Study Probes Novel Combo for CRPC COMBINED TREATMENT with bicalutamide and everolimus has “encouraging efficacy” in patients with bicalutamide-naïve castration-resistant prostate cancer (CRPC), researchers concluded from a phase 2 study.

The study, led by Chong-Xian Pan, MD, PhD, of the University of California Davis, and colleagues, included 24 men with progressive CRPC and a mean serum testosterone levels at study entry of 43.4 ng/dL. None of the patients had prior treatment with either bicalutamide (except to prevent flare) or everolimus, an inhibitor of the mammalian target of rapamycin (mTOR) pathway.

The men were prescribed oral bicalutamide 50 mg and oral everolimus 10 mg, both once daily, on a 4-week cycle. The primary endpoint was PSA response, defined as a 30% or greater reduction in PSA from baseline.

The mean length of treatment was 8 cycles. Of the 24 patients, 18 (75%) had a PSA response and 15 (62.5%) had a

“In addition to impairing nutrition status and quality of life,” they wrote, “advising HD patients to limit or avoid many plant-based foods, especially fruits and vegetables, may contribute to adverse metabolic status, such as oxidative stress, inflammation, metabolic acidosis, dyslipidemias, and conditions that negatively impact HD patient health, such as constipation and hypertension.”

The authors pointed out that other nutrients in food influence potassium distribution and excretion. Unlike meat, which when metabolized leads to net acid production and which are low in carbohydrates and contain no fiber, plant foods, especially fruits and vegetables, tend to yield net base production and are high in both carbohydrates and fiber. They researchers noted, for example, that although the pH of oranges is acidic, the net result of orange juice ingestion is urinary alkalinization. n

PSA decrease of 50% or greater, the investigators reported online ahead of print in Cancer. The cohort had a mean overall survival time of 28 months; 14 patients experienced grade 3 (13 patients) or 4 (1 patient) adverse events attributable to treatment.

Dr. Pan’s team concluded that combination therapy with bicalutamide and everolimus “represents a promising new era of treatment” for men with bicalutamide-naïve CRPC, and stated that a randomized phase 3 trial with everolimus in combination with antiandrogen therapy is warranted.

“However, because of significant toxicity, modification of the study design is needed,” they added. “One option is to reduce the everolimus dose, because toxicity improved in the vast majority of patients after the everolimus dose, but not the bicalutamide dose, was reduced.”

The researchers noted that overexpression of androgen receptors (AR) and AR mutation are among the mechanisms proposed to explain castrationresistance. A previous study showed that inhibiting the mTOR signaling pathway also up-regulated the AR signaling pathway. “This compensatory mechanism explained why an mTOR inhibitor alone has little therapeutic effect in CRPC.” n

@ THINKSTOCK

RESEARCHERS AT New York University School of Medicine question the practice of advising hemodialysis (HD) patients to restrict intake of highpotassium plant foods to prevent hyperkalemia, according to a recent review.

In a paper published online ahead of print in the Journal of Renal Nutrition, David E. St-Jules, RD, PhD, and colleagues concluded that evidence linking high dietary potassium intake to hyperkalemia in HD patients is “virtually non-existent.”

“In the absence of empirical evidence, it is of course prudent to continue to recommend low-potassium diets to HD patients with hyperkalemia; however, the practice of advising patients to eliminate so many plant foods from the diet may be harmful, and must be evaluated.”

The authors noted that patients with end-stage renal disease (ESRD) treated with intermittent HD are advised to follow a low-potassium diet (2,000– 3,000 mg/day), which involves avoid-

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16 Renal & Urology News

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Novel Approaches to Using Radium-223 Neal Shore, MD, is the National Urology Research Director for 21st Century Oncology in Myrtle Beach, SC. He has

patients now are receiving radium 223 prior to chemotherapy. The full course of therapy is 6 monthly infusions. Each infusion takes about 45 to 60 seconds.

been extensively involved in clinical trials of medications

Who is the optimal candidate for radium-223?

for treating prostate cancer, including the clinical trial

Dr. Shore: Patients converting from androgen sensitive to castration-resistant disease, converting from M0 to M1 CRPC, and also converting from truly asymptomatic to symptomatic disease are potential candidates for radium-223, who have symptomatic bone metastases. Patients to whom radium-223 could be administered are those who progress after either abiraterone or enzalutamide and who have demonstrable bone metastases, some level of symptomatology and a rising PSA. In my practice, I am frequently combining the use of radium-223 at that point with enzalutamide or abiraterone.

of radium-223, which on May 15, 2013 received FDA approval for the treatment of treatment of bone metastases in patients with symptomatic castration-resistant prostate cancer (CRPC). He spoke with Renal & Urology News about the place of radium-223 in the therapeutic armamentarium and how he uses the drug in his practice.

What has been your clinical experience with radium-223?

Dr. Shore: In May 2013, we were the first site worldwide to administer radium-223 to a CRPC patient post-FDA approval. I had previously administered radium-223 to patients in the expanded access program. It was very well tolerated, consistent with the data that we saw from the ALSYMPCA (ALpharadin in SYMPtomatic Prostate CAncer) phase 3 registration trial. My initial experience was with patients who had received essentially all other approved lines of CRPC therapeutics. So these were folks who had progressed with usually at least 1, but almost invariably 2 lines of chemotherapy consisting of docetaxel and cabazitaxel. Many of these patients had also progressed beyond the novel hormonal lines of therapy, abiraterone and enzalutamide. So they had high tumor burdens and obviously had a high likelihood of having a degree of immunosuppression.

I was very pleased at how well they tolerated the infusions. Radium-223 emits alpha particles, which are much larger than the beta and gamma particles emitted by other radiopharmaceuticals. The interesting thing about it from a safety and tolerability standpoint is that it was theoretically less penetrating into the myeloproliferative tissue in the bone marrow and thus [associated with] less risk of having myelosuppressive side effects, such as neutropenia and thrombocytopenia. And that’s exactly what we saw.

It’s helpful to explain to patients that in addition to monitoring PSA for progression and response to therapeutics

ExpertQA_RUN0416.indd 16

such as androgen-receptor-targeted drug, we’re now also able to measure another biomarker, alkaline phosphatase, to monitor bone metastasis response to radium-223, which is a calcium mimetic and its mechanism of action is designed to create an apoptotic effect on bone metastatic lesions.

Are there any contraindications?

Dr. Shore: According to the label and due to limited clinical trial data, the only absolute contraindication to the use of radium-223 would be concomitant use of a chemotherapeutic such as docetaxel or cabazitaxel.

How do you use radium-223?

How does radium-223 improve survival?

Dr. Shore: I don’t look at this as an agent that’s primarily given to reduce pain, although it can in some patients. The main reason for giving it is the same reason why I’m thinking about using the other CRPC approved therapies: to first and foremost prolong survival, and then of course to ameliorate or prevent pain as well as to maintain quality of life parameters. I have been using radium-223 more frequently for my prechemotherapy patients. I am very proactive in using sipuleucel-T, abiraterone, and enzalutamide in my asymptomatic and minimally asymptomatic patients.

Of course, those patients will eventually progress. They may progress with PSA elevations, suggesting some level of biological progression. Of course, monitoring for both symptomatic progression as well radiologic progression with new lesions are still the most accepted indication for switching antineoplatic therapies. It might seem intuitive now that these drugs … because of their marked differences in mechanism of action and their completely different safety tolerability profiles, one might expect that they would be very good to use in combination. I would say that about 75% of my

Dr. Shore: The hypothesis is that radium-223 exposure to CRPC patients

The main reason for giving the drug is to prolong survival. ­—Neal Shore, MD

with bone metastases are experiencing a higher degree of apoptotic effect on these lesions, due to the proposed increased in double-stranded DNA disruptions. With double-stranded breaks, theoretically, there should be less chance for repair mechanisms to occur.

We’re not eradicating the disease; we’re stabilizing the disease by creating an equilibrium in disease progression as well as maintaining performance status.

By slowing down disease progression and not creating or worsening comorbidities and toxicities, the combined effect is to improve overall survival.

What research have you been conducting at your center?

Dr. Shore: At my research site, we’ve completed an investigator-initiated study of 31 patients who received abiraterone acetate with prednisone 5 mg b.i.d. concomitantly with a course of radium-223. We evaluated those patients in terms of quality of life parameters, including the Brief Pain Inventory and FACT-P questionnaires, as well as the usual serologic parameters, CBC, CMP, PSA, alkaline phosphatase, and also with baseline CT scan, bone scan, and end-ofstudy CT scan and bone scan, as well as a CT scan at the 4-month mark. We presented our interim analysis at ASCO GU [the American Society of Clinical Oncology Genitourinary Cancers Symposium] this year. We demonstrated excellent combined tolerability, no unanticipated adverse events or safety profile issues associated with combining the 2 drugs, stabilization of disease, and improvement in several interesting quality of life parameters.

We’ve now submitted a final analysis for presentation.

To date, I believe our investigator-initiated study of combining abiraterone acetate and radium-223 in 31 patients is the largest prospective combination study to date that’s been rigorously monitored and presented in a peerreviewed forum, and we’ll present our final analysis hopefully later this year.

We are now doing a similar investigator-initiated study of enzalutamide with radium-223. I started doing this prior to the publication of the expanded access program literature, so when we submitted our grant no one had any published or presented literature in any sort of a public forum regarding combined use of these therapies. n

4/19/16 4:43 PM

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Renal & Urology News 17

Hospital- vs. Community-Acquired AKI Poor long-term outcomes found even in patients with community-acquired AKI but not hospitalized INDIVIDUALS WHO MEET acute kidney injury (AKI) criteria in the community may not always require hospitalization, but they remain at high risk of poor long-term outcomes, according to a new study.

Simon Sawhney, MBBS, of the University of Aberdeen, U.K., and colleagues studied a cohort of 50,835 individuals, applying the NHS England AKI “e-alerts” based on Kidney Disease: Improving Global Outcomes (KDIGO) criteria to identify and follow 3 AKI groups: individuals with hospital-acquired AKI (HA-AKI); individuals with community-acquired AKI hospitalized within 7 days (CAAAKI); and individuals with communityacquired AKI not hospitalized within 7 days (CANA-AKI). The researchers compared 30-day, 1- and 5-year mortality, 90-day renal recovery, and need for chronic renal replacement therapy

(RRT). The researchers defined the start of an AKI episode as the first blood test meeting AKI criteria.

AKI developed in 4,550 patients (9%). Of these, 2,779 (61.1%) were in the HA-AKI group, 1,042 (22.9%) in

Implications of using KDIGO-based AKI criteria in outpatient settings characterized. the CAA-AKI group, and 729 (16%) in the CANA-AKI group. The 30-day mortality rates were similar for the HA-AKI and CAA-AKI groups (24.2% and 20.2%, respectively), but significantly lower for the CANA-AKI group (2.6%), Dr. Sawhney’s team reported online ahead of print in Nephrology

Positive Surgical Margins After PN Increase Mortality Risk POSITIVE SURGICAL margins (PSM) are

5-year OS compared with NSM (89% vs.

associated with worse overall survival

92%). On multivariable analysis, PSM

following partial nephrectomy (PN), a

was associated with a significant 34%

new study suggests.

increased risk of all-cause mortality, Dr.

Using the National Cancer Data Base (NCDB), investigators led by Robert

Abouassaly and colleagues concluded.

The authors cautioned that the asso-

Abouassaly, MD, MS, of University

ciation between PSM and worse OS

Hospitals Case Medical Center in

does not imply causation. “Since the

Cleveland, studied 6,038 cases of

NCDB does not include information on

pathologic T1–T3a of non-metastatic

cancer recurrence, cause of death, or

renal cell carcinoma (RCC) who

secondary treatments, the exact cause

underwent PN during 2003–2006. Of

of the excess mortality rate in PSM

these patients, 302 (5.3%) had PSM.

patients is unknown and not necessarily

The median follow-up was 71 months.

due to RCC,” they wrote.

At last contact, 699 patients (11.6%)

Still, the authors stated that their study

died—51 (17.2%) PSM patients and

is the first to detect a significant differ-

647 (11.3%) of the 5,736 patients with

ence in OS patients with PSM, which may

negative surgical margins (NSM), the

be attributed to the inclusion of a large

investigators reported online ahead of

cohort, “ample prevalence of PSM,” a

print in the Journal of Endourology.

“statistically sufficient event rate,” longer

Higher pathologic T stage and higher comorbidity score were the only fac-

term follow-up data, and other variables.

Limitations of the study include suscep-

tors significantly associated with PSM,

tibility to bias because of its retrospective

according to the researchers.

design and the limitations of the NCDB.

The unadjusted 5-year overall survival

“Since follow-up information in the NCDB

(OS) for the cohort was 92%. PSM was

is limited to vital status, we were only able

significantly associated with decreased

to assess OS as our primary outcome.” n

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Dialysis Transplantation. Five-year mortality rates followed a similar pattern: 67.1%, 64.7%, and 46.2%, respectively.

Compared with the CAA-AKI group, those in the CANA-AKI group had significantly higher rates of renal nonrecovery at 90 days (11.8% vs. 3.5%) and chronic RRT at 5 years (3.7% vs. 1.2%).

In addition, CANA-AKI patients were much less likely to undergo repeat testing at 7 days and 90 days. At 7 days, 81.7% of CANA-AKI patients did not have repeat testing compared with 18.6% and 20.4% of the HA-AKI and CAA-AKI groups, respectively. At 90 days, the proportions were 31%, 10.8%, and 14.1%, respectively.

“Despite AKI frequently initiating in the community, and despite the need for early recognition of AKI, this is the first large population-based study to explore the implications of applying the same systematic AKI criteria to patients

both admitted and not admitted within 7 days,” the authors noted.

Dr. Sawhney and his colleagues commented that the high rate of chronic RRT and lack of repeat testing in the CANA-AKI group was unexpected.

“One explanation could be misclassification of rapidly progressing CKD patients when the AKI criteria are applied outside the hospital setting,” they stated. The low 30-day mortality might also suggest a less “acute” insult in CANA-AKI, according to the investigators.

Patients in the HA-AKI group were significantly older than those in the CAA-AKI and CANA-AKI groups (median age 77 years vs. 73 and 72 years, respectively). The proportion of patients aged 70 years and older was 71.8% in the HA-AKI group compared with 58.2% and 56% in the CAA-AKI and CANA-AKI groups, respectively. n

Best Salvage Cryo PSA Nadir Identified

The researchers stratified bPFS by presalvage PSA (psPSA). Among patients with a PSA nadir below 0.4 ng/mL, the estimated 5-year bPFS rates were 78.5%, 77.1%, and 77.8% for patients with a psPSA less than 4, 4–10, and more greater than 10 ng/ mL, respectively. Among patients with a PSA nadir of 0.4 ng/mL or higher, rates were 17.9%, 15.7%, and 16.8%, respectively.

The study cohort had a median age of 72 years and mean and median psPSA of 6.09 and 4.7 ng/mL, respectively.

Noting that, historically, the preferred salvage therapy for men with an intact prostate has been radical prostatectomy (RP), the researchers said they believe “that salvage prostate cryotherapy represents a viable alternative to salvage RP, and previous studies have reported similar disease-specific survival rates following salvage RP and salvage cryotherapy. The results of our analysis suggest that salvage cryoablation may be beneficial to patients with a wide range of psPSA values and who reach a postsalvage PSA nadir <0.4 ng/mL.” The authors noted that the retrospective nature of their analysis, which lends itself to inherent biases, was a limitation of their study. They also noted that the COLD registry does not contain information on salvage cryotherapy biopsy findings, which would provide more definitive proof of treatment success. n

RESEARCHERS HAVE identified the optimal PSA nadir following wholegland salvage prostate cryoablation for recurrent prostate cancer that predicts which patients will have the best longterm biochemical progression-free survival (bPFS).

In a retrospective study using the Cryo On-Line Database (COLD), Evan Kovac, MD, of the Glickman Urological and Kidney Institute at Cleveland Clinic, and colleagues analyzed outcomes among 486 hormone-naïve patients who underwent salvage whole-gland cryoablation following primary radiotherapy.

They used Kaplan-Meier (KM) analysis to calculate 5-year bPFS using Phoenix criteria (PSA nadir plus 2 ng/mL).

KM analysis identified a nadir PSA of less than or greater than 0.4 ng/mL as the nadir PSA threshold, with the greatest difference in bPFS. The KM estimated 5-year bPFS rates were 75.5% and 22.1% for PSA nadir less than 0.4 and 0.4 ng/mL or higher, respectively, Dr. Kovac’s group reported online ahead of print in the Journal of Endourology.

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COPD Ups Death Risk in CKD Patients Likelihood of overall and respiratory-related mortality is increased 41% and 4-fold, respectively CHRONIC obstructive pulmonary disease (COPD) is associated with an increased risk for death among patients with chronic kidney disease (CKD), new findings suggest. The association is more pronounced in younger patients and women.

In a study that included 56,960 patients with stages 3 and 4 CKD, researchers led by Sankar D. Navaneethan, MD, MS, MPH, of the Baylor College of Medicine in Houston, found that the presence COPD was associated with a 41% increased risk for all-cause mortality and a 4-fold increased risk for respiratory-related deaths after adjusting for potentially confounding variables.

“These data highlight the need for further prospective studies to understand the underlying mechanisms and potential interventions to improve outcomes in this population,” the authors concluded in a paper published in the American Journal of Nephrology (2016;43:39-46).

Of the 56,960 patients, 2,667 (4.7%) had underlying COPD. During a median

Study: CKD a Risk Factor for UTUC CHRONIC KIDNEY disease (CKD) is a risk factor for upper tract urothelial carcinoma (UTUC), a study found.

Using Taiwan’s Longitudinal Health Insurance Database, Jeng-Sheng Chen, MD, of Sinying Hospital in Sinying, and colleagues compared 45,321 CKD patients and 181,284 age- and gender-matched controls.

The CKD group had a significantly

A chest x-ray showing COPD, a mortality risk factor in patients with stages 3 or 4 CKD.

f­ollow-up of 3.7 years, 15,969 patients died. The mean ages of the patients with and without COPD were 74.6 and 72.2 years, respectively.

Factors significantly associated with having COPD include older age, diabetes, coronary artery disease (CAD), congestive heart failure (CHF), hypertension, and ­smoking.

Each 10-year increment in age was associated with 26% increased odds of having COPD, Dr. Navaneethan and colleagues reported. Diabetics had a 19% increased odds compared with non-diabetics. Patients with CAD, CHF, and hypertension had 1.6, 2.3, and 3.0 times increased odds, respectively, compared with patients without these conditions. Smokers had a 2.9 times increased odds compared with non-smokers.

Given their lack of spirometry data, the COPD prevalence found in the new study probably is an underestimate, according to the investigators.

They pointed out that even in the general population, COPD is underdiagnosed, with about 63% of adults showing evidence of impaired lung function but do not have a diagnosis of lung disease such as asthma, chronic bronchitis, or emphysema.

The effect of COPD on mortality differed by age and gender. In adjusted analyses, COPD was associated with a 2-fold increased risk of death among patients aged 45–60 years and 62%,

35% and 28% increased risk among those aged 61–70, 71–80, and 81 years or older, respectively.

“It appears that with aging, the effect of COPD on outcomes become less relevant in those with CKD,” Dr. Navaneethan’s team commented.

COPD in male and female patients was associated with a 29% and 55% increased risk of death, respectively, the study found.

As for possible explanations for the increased risk for overall mortality and respiratory deaths among CKD patients, Dr. Navaneethan and colleagues pointed out that “higher infection-related deaths, especially with pneumonia, have been reported in the CKD population.”

The additional presence of COPD, they noted, could further increase the risk for pneumonia or other infection due to immunosuppression from long-term use of COPD medications.

Further, they stated that “COPD is a known contributor to pulmonary hypertension and could contribute to adverse outcomes in CKD.” n

Most Gout Inadequately Controlled GOUT IS inadequately controlled in more than two-thirds of sufferers, adversely affecting their healthrelated quality of life (HRQOL), daily functioning, and work productivity, researchers found.

In a study of 1,204 gout sufferers with a mean age of 61.9 years, Robert Wood, BSc, of Adelphi Real World in Cheshire, U.K., and colleagues found that 836 (69%) had inadequately controlled and 368 (31%) had adequately controlled gout, according to an online report in The Journal of Rheumatology. The authors defined inadequate control as a

serum uric acid (SUA) level greater than 6 mg/dL on the most recent SUA test or 2 or more flares in the past 12 months and adequate control as an SUA level of 6 mg/dL or less and no flares.

Patients with inadequately controlled gout reported significantly worse functioning and HRQOL as measured by the EQ-5D and Patient Reported Outcomes Measurement Information System Health Assessment Questionnaire (PROMIS HAQ) scales.

Significantly more inadequately controlled versus adequately controlled patients reported problems with pain/

discomfort, self-care, anxiety/depression, mobility, and performing usual activities.

In addition, patients with inadequately controlled gout missed significantly more work time than those with adequately controlled group (4.5% vs.

1.3%). They also had greater overall work impairment due to gout.

“Improved gout treatment strategies remain a critical unmet need; steps to enhance the control of hyperuricemia may lead to gout symptom improvements and a resultant increase in HRQOL and work productivity,” the authors concluded. n

higher incidence UTUC than the conanalysis, CKD was associated with a 63% increased risk UTUC, investigators reported in Medicine (Baltimore) (2016;95:e3255). The risk increased to 72% after excluding patients who progressed to dialysis and kidney transplantation. Results also showed that female gender was associated with a 38% increased UTUC risk. n

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Weekend Kidney Transplant Outcomes Not Worse DECEASED-DONOR kidney transplantation performed on weekends in the United States do not result in worse outcomes, according to a study published in BMJ Open (2016;6(4):e010482).

Seema Baid-Agrawal, MD, of the University of Gothenburg, Gothenburg, Sweden, and colleagues

analyzed outcomes of 136,715 recipients of deceased-donor kidneys, of whom 72.5% underwent transplantation on a regular weekday (Monday– Friday) and 27.5% on a weekend (Saturday–Sunday). In adjusted analyses, the study revealed no significant difference in patient survival and death-

censored and overall allograft survival between patients who received their organs on a weekday or weekend. They also found no significant association between weekend transplantation and patient and graft survival at 1 month and 1 year, delayed graft function, or acute rejection within the first year. n

© SCOTT CAMAZINE / SCIENCE SOURCE

trols (0.22% vs. 0.07%). In multivariate

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Ejaculation May Decrease PCa Risk Inverse association found with a monthly frequency of 13 times or more vs. 4–7 times MEN WHO REPORT a higher frequency of ejaculation as adults are less likely to be diagnosed with prostate cancer (PCa), a new study confirms.

“More frequent ejaculation in the absence of risky sexual behaviors could represent an important means of reducing the profound medical costs and physical and psychological side effects of unnecessary diagnosis and treatment of low-risk tumors, even though it appears to be less strongly associated with aggressive disease,” the researchers concluded in a report published online ahead of print in European Urology.

Jennifer R. Rider, ScD, MPH, of the Boston University School of Public Health, and her colleagues conducted a prospective cohort study of 31,925 men who participated in the Health Professionals Follow-up Study (HPFS).

All answered questions about ejaculation frequency on a 1992 questionnaire and were followed through to 2010. The questionnaire asked men how many ejaculations, on average, per month they had during ages 20–29 and 40–49, and in the year prior to distribution of the questionnaire (1991).

During 480,831 person-years of followup, 3,839 men were diagnosed with PCa: 1,585 with localized low-risk disease,

1,493 with localized intermediate-risk disease, 604 with localized high-risk PCa, and 157 with evidence of regional or distant metastases at diagnosis.

Results showed that an ejaculation frequency of 13 more times per month at age 20–29 and 40–49 years and in 1991 was associated with a significant 12%, 20%, and 11% decreased risk of a prostate cancer diagnosis, respectively, compared with a frequency of 4–7 times per month in adjusted analyses, according to researchers. At these same time points, a monthly ejaculation frequency of 21 times or more was associated with a 19%, 22%, and 24% decreased risk. The associations were driven mostly by low-risk PCa. Compared with an ejaculation frequency of 4–7 times per month, a frequency of 13 times or more per month was associated with a significant 27% lower risk of a diagnosis of intermediaterisk PCa among men aged 20–29 years and a non-significant 17% decreased risk among men aged 40–49 years.

Ejaculation frequency was not significantly associated with a diagnosis of high-risk PCa or regional/distant metastases, according to the investigators.

“This large prospective study provides the strongest evidence to date of a

Ejaculation Frequency and PCa Risk In a study, an average monthly ejaculation frequency of 13 times or more (red) and 21 times or more (blue) during 3 time points* was associated with a decreased risk of a prostate cancer diagnosis compared with a frequency of 4–7 times per month. The magnitude of risk reduction is shown here.

25

19%

20 15

20%

24%

22%

12%

11%

10 5 0

20–29

40–49

1991

*In 1992, men answered a question asking how many times, on average, they ejaculated each month at ages 20–29 and 40–49 and in 1991.

Source: Rider JR et al. Ejaculation frequency and risk of prostate cancer: Updated results with an additional decade of follow-up.

Eur Urol. 2016; published online ahead of print.

beneficial role of ejaculation in prevention of PCa, a disease for which relatively little is understood about etiology generally and knowledge of modifiable risk factors is particularly scant.”

The new findings build on an initial study of the HPFS cohort published in 2004 in which researchers led by Michael F. Leitzmann, MD, of the National Cancer Institute in Bethesda, Md., found a statistically significant inverse relation-

ship between monthly ejaculation frequency and PCa risk based on 8 years of follow-up. That study, published in the Journal of the American Medical Association (2004;291:1578-1586), found that men reporting 21 or more ejaculations per month at ages 20–29 and 40–49 years and in 1991 had an 11%, 32%, and 51% lower risk of PCa, respectively, than those reporting 4–7 ejaculations per month. n

Hip Fracture, Mild Prolonged Hyponatremia Linked MILD PROLONGED hyponatremia is independently associated with an increased risk of hip fracture among individuals older than 60 years, according to a new study.

Juan Carlos Ayus, MD, the Renal Consultants of Houston in Texas and the Italian Hospital of Buenos Aires (IHBA) in Buenos Aires, Argentina, retrospectively studied of 31,527 patients older than 60 years who had 2 or more measurements of plasma sodium levels during 2005–2012.

Of these, 228 (0.9%) had prolonged chronic hyponatremia, defined as a sodium level below 135 mmol/L for more than 90 days. The mean plasma sodium level was 132 mmol/L in the hyponatremic patients and 139 mmol/L in the normonatremic patients.

Hip fractures occurred in 7 (3%) of the 228 hyponatremic patients and 411 (1%) of the 31,299 normonatremic. In adjusted analyses, prolonged chronic

News_PCa_RUN0516.indd 20

hyponatremia was associated with a 4.5 times increased risk of hip fracture compared with normonatremia, Dr. Ayus’ team reported online ahead of print in Nephrology Dialysis Transplantation. Chronic moderate hyponatremia (sodium level less than

Researchers observed a 4.5 times increased risk of hip fracture vs. normonatremia.

130 mmol/L) was associated with 7.6 times higher risk.

The findings suggest that duration of hyponatremia is an additional risk for hip fracture, the authors concluded. “Although the present study cannot establish a causal relationship, the results raise questions about the

c­ urrent i­ndication for the treatment of mild hyponatremia in older patients and suggest the need for interventional studies to evaluate whether systematic surveillance and active correction of mild hyponatremia could help to reduce hip fractures in the elderly.”

The investigators described 2 proposed mechanisms by which hyponatremia contributes to bone fractures: by causing subtle neurologic impairment, with gait abnormalities and falls, and by contributing directly to osteoporosis and increased bone fragility. Animals studies have shown that prolonged chronic hyponatremia (3 months’ duration) leads to abnormal bone histomorphology and decreased bone mineral density, but no human studies have examined whether hyponatremia duration contributes to bone abnormalities, they pointed out.

“In the present study, all hip fractures were caused by a mechanical fall, sug-

gesting abnormal gait was present in these subjects,” the authors wrote.

Dr. Ayus and his colleagues explained that the brain adapts to chronic hyponatremia with the loss of osmolytes, such as glutamate, a neurotransmitter involved in gait function. “Thus, loss of glutamate may play a role in gait abnormalities that lead to falls in patients with chronic hyponatremia.”

The study population consisted of patients receiving care at IHBA, a general tertiary-level hospital. The patients with chronic hyponatremia were older than those with normonatremia (mean 78 vs. 70 years). The median follow-up times for the hyponatremic and normonatremic groups were 510 days and 1,421 days, respectively. The hyponatremic patients had a higher incidence of previous fractures (17% vs. 12%) and alcohol use (2.6% vs. 0.8%), factors known to increase fracture risk. n

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Ferritin Rising in HD Patients

Renal & Urology News 21

Effects of Longer CIT on Transplant Results Linked to Living Donor Age Worse outcomes found in recipients of kidneys from donors older than 50 years

SERUM FERRITIN levels in new hemodialysis (HD) patients increase over time, a trend independent of intravenous iron use, exposure to erythropoiesis-stimulating agents (ESAs), and other potential confounders, according to researchers.

A team led by Kamyar KalantarZadeh, MD, MPH, PhD, of the University of California Irvine, analyzed data from a 5-year (January 2007–December 2011) cohort of 81,864 incident U.S. HD patients.

The researchers examined changes in ferritin averaged over 3-month intervals as well as ferritin trends across strata of baseline ferritin level, dialysis initiation year, cumulative intravenous (IV) iron and ESA use in the first dialysis year, and baseline hemoglobin level.

Among patients with baseline ferritin levels lower than 200, 200 but less than 500, and 500 but less than 800 ng/mL, the mean change in those levels following dialysis

LONGER COLD ischemic time (CIT) is associated with an increased likelihood of delayed graft function (DGF) and graft loss among recipients of kidneys from living donors older than 50 years, according to a new study.

Using data from the Australia and New Zealand Dialysis and Transplant registry, a team led by Wai Lim, MBBS, PhD, of the Sir Charles Gairdner Hospital in Perth, Western Australia, studied 3,717 patients who received live-donor kidney transplants from 1997–2012. The median follow-up was 6.6 years.

Of the 3,717 patients, 224 (25%) had a CIT of more than 4 hours but not more than 8 hours. Among recipients who received kidneys from donors older than 50 years, each hour increase in CIT was associated with a significant 28% increased odds of DGF in adjusted analyses, Dr. Lim’s team reported online in the American Journal of Transplantation. In addition, compared with a CIT of 1–2 hours, a CIT of more than 4 hours but not more than

8 hours was associated with a nearly 2-fold increased risk of both overall and death-censored graft loss, according to the investigators. The researchers observed no association between CIT and graft loss among recipients of kidneys from younger donors.

“Attempts to reduce CIT in live-donor kidney transplants involving older donor

Transplant patients who received older kidneys had a higher risk of graft loss. kidneys may lead to improvement in graft outcomes,” the authors concluded.

Dr. Lim and colleagues observed an inverse association between CIT and acute rejection among recipients of kidneys from donors older than 50 years, with each hour of CIT associated with a significant 8% decreased risk of any acute rejection and 27% decreased

risk of multiple rejections in adjusted analyses.

“Given the acceptance of paired kidney exchange program worldwide where regional transport of live-donor kidneys may lead to extended CIT, it is critical to understand the association between CIT and live-donor graft and patient outcomes,” the authors noted.

In background information provided in their paper, the researchers noted that the association between prolonged CIT and adverse graft and patient outcomes is well established among recipients of deceased-donor kidneys, but less well established among recipients of live-donor kidneys.

In a previous study of 38,467 recipients of live-donor kidneys published in the American Journal of Transplantation (2007;7:99–107), Dorry L. Segev, MD, PhD, of Johns Hopkins University in Baltimore, and colleagues found that prolonged CIT was not associated with worse renal function and acute rejection at 1 year following transplantation or with worse allograft survival. n

initiation was 29.7, 32.9, and 19.4 ng/mL per quarter (designated as “patient-quarter”), respectively, Dr. Kalantar-Zadeh and his colleagues reported online ahead of print in Nephrology Dialysis Transplantation.

Among patients with baseline ferritin levels of 800 ng/mL or higher, mean ferritin levels initially decreased by 7.5 ng/mL per patient-quarter. Mean serum ferritin levels decreased from 1,133.8 ng/mL in the first patientquarter to 847 ng/mL in the third patient-quarter. From the fourth patient-quarter onward, however, the levels rose over time, similar to the rest of the baseline ferritin strata, the investigators stated.

Among patients starting HD in 2007, mean ferritin levels rose sharply in the first year of dialysis (56.4 ng/mL/year) versus the second year (13.7 ng/mL/year), after adjusting for case-mix, malnutritioninflammation-cachexia syndrome, and IV iron use. The ferritin slope again rose sharply (20.1 ng/mL/ year) in the fifth year of HD. n

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Shorter PCa Radiotherapy Schedule Okay

BY NATASHA PERSAUD FOR PATIENTS with early-stage prostate cancer (PCa) treated with external beam radiation therapy (RT), a shortened schedule of 5.6 weeks offers cancer control similar to that of an 8-week schedule, a new study finds. Minor side effects increased with hypofractionation, however.

“This study has implications for public policy,” lead researcher W. Robert Lee, MD, professor at Duke University Medical Center in Durham, NC, stated in a press release. “Because the shorter regimen has advantages such as greater patient convenience and lower costs, it’s important to establishing whether we can cure as many patients with the shorter regimen.”

Dr. Lee and his team randomly assigned 1,092 men with low-risk PCa to receive either conventional radiotherapy (C-RT) of 73.8 Gy in 41 fractions over 8.2 weeks or hypofractionated radiotherapy (H-RT) of 70 Gy in 28 fractions over 5.6 weeks. The study excluded patients who had prior

r­adiotherapy, definitive surgery, bilateral orchiectomy, chemotherapy, or cryosurgery. Androgen deprivation was not allowed, except as salvage therapy.

The study population had a median follow-up of 5.8 years. The estimated 5-year disease-free survival (DFS) was 85.3% for C-RT patients and 86.3% for H-RT patients, according to results published online in the Journal of Clinical Oncology. The findings established the noninferiority of H-RT, which the investigators defined as a predefined hazard “These findings have important implications for men with low-risk prostate cancer who are considered for external beam RT,” the authors wrote.

“If disease control is similar, reducing the number of treatments from 41 to 28 and reducing the duration of therapy by 2.5 weeks (a nearly one-third reduction) provides greater patient convenience and reduced cost.”

Late gastrointestinal (GI) and genitourinary (GU) adverse events (AEs) increased by 31%–59% among H-RT

patients compared with the C-RT group. The groups exhibited no differences in severe AEs. The increased late toxicity after treatment with H-RT in this study is “somewhat surprising,” the inves-

Disease-free survival is not diminished with 5.6 rather than 8 weeks of treatment. tigators stated, as most of randomized controlled trials have not found excess GI and GU toxicity with hypofractionation.

Among the study’s limitations, the investigators acknowledged that many men with low-risk PCa may not require treatment and can opt for active surveillance. The findings do not extend to men who progress from low-risk disease after a period of active surveillance. n

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Practice Management T

he idea of disclosing protected health information to patients strikes fear into the hearts of most physicians. And, thanks to HIPAA, releasing information to anyone other than an actual patient is considered nearly taboo. Most doctors do not realize, however, that HIPAA is not just about restrictions and prohibitions. The goal of HIPAA is to strike a good balance between protecting information and facilitating, or even expediting, its movement when appropriate. Following are some guidelines on when to disclose to patients’ family, friends and caregivers.

Whom to tell HIPAA regulations lump people into 3 different categories. The first includes patients, who have the greatest ability to access their information.

The second is patients’ personal representatives, individuals designated to make medical decisions for them. They have rights equal to those of patients to access information under HIPAA. The third category includes friends, family, and others. The law makes very little distinction between them.

provider have in using his or her judgment when sharing information? More than you think, according to HIPAA consultant Abner Weintraub.

“Medical providers have enormous discretion and freedom to share medical and billing information that they are not taking advantage of,” he said.

“It’s disserving because the rules permit a lot of disclosure.”

Weintraub receives nearly a dozen calls each week from patients, parents, and spouses who cannot obtain information they should be able to receive.

Fear of reprisal from employers and enforcement agencies like the U.S. Office of Civil Rights keeps many physicians from disclosing this information, he said.

If a patient is present and can make decisions, a provider is free to share any information as long as the patient says it is okay or does not object given the option.

If the patient is not present, unconscious, or unable to make a decision, a physician can use “professional judgment” to decide if it is in a patient’s best interest to provide information to

Simply making a note in a patient’s medical file is sufficient to document approval or lack of objection to share information.

Physicians can provide information to family and friends when they believe it is in the best interest of a patient. Regarding “others,” the same judgment is required by physicians, but they must be “reasonably sure” a patient has involved the other individuals in his or her care.

Professional judgment The answer to the first question begs another: how much latitude does a

On The Web PracticeManagement_RUN0516.indd 22

another party. In this case, health or payment information should be limited to what the physician believes the person needs to know.

“This is not how the medical world sees the rules right now,” Weintraub said.

Even if a patient is in a coma, HIPAA protects physicians if they share information and the patient later wakes up and objects. As long as the provider has acted in good faith and used good

© THINKSTOCK

Health information disclosure rules established by HIPAA grant physicians more latitude than widely believed BY TAMMY WORTH

If done in a patient’s best interests, physicians can share information with family and friends.

judgment, he or she will be protected under HIPAA, Weintraub said.

Documentation Documentation that an individual has been given rights to a patient’s information is not required. This can be done orally, Weintraub said. Simply making a note in a patient’s medical file is sufficient for providers to document approval or lack of objection to share information. Providers can even share information over the phone if a family member or friend calls to request it. Providers do not need to verify the identity of a person on the phone, but they can establish some way to do so if it makes the staff more comfortable.

Exclusions Physicians have a lot of “freedom and discretion” regarding what information they can provide to family and friends, Weintraub said. Among the areas considered off limits under HIPAA is information that is not part of a patient’s designated record set.

Most billing and clinical information is part of this. Providers should use discretion, however, in sharing information that could be stolen and used for identity theft, like a date of birth or Social Security Number.

“There is generally no good reason a family member or friend should be asking for those things,” he said.

Also, no one, including patients, is allowed to personal notes made by a psychiatrist.

Finally, information being compiled as part of a civil or criminal court proceeding is off limits even to patients. ■ Tammy Worth is a freelance medical journalist based in Blue Springs, MO. Renal & Urology News is researching an article on how HIPAA rules have affected medical practice. If you would like to share your experience, please contact Jody A. Charnow, Editor, at jody.charnow@haymarketmedia.com.

Want to improve your practice? Look for our tips on how to handle equipment issues, adjust to EHRs, improve efficicency, and more at www.renalandurologynews.com/practice.

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www.renalandurologynews.com MAY 2016

Renal & Urology News 23

PCa Metastasis More Likely in Some AS Patients METASTASES DEVELOP in a small proportion of patients placed on active surveillance (AS) for prostate cancer (PCa), but the risk is significantly higher in some men, such as those with Gleason 7 tumors, a new study found.

In a study of 980 men placed on AS—769 with low-risk and 211 with intermediate-risk PCa—a team led by Laurence Klotz, MD, of Sunnybrook Health Sciences Centre in Toronto found that 30 men (3%) progressed to metastatic disease at a median of 6.3 year after diagnosis, according to study findings published in The Journal of Urology (2016;195:1409-1414).

Metastases developed in 13 (10%) of 133 patients with Gleason 7 disease.

Metastases occurred in 16 low-risk and 14 intermediate-risk patients, and developed in bone in 18 patients and lymph nodes in 13. Of the 30 men, 15 died from PCa, 4 died of other causes, and 11 are alive with metastases.

usefulness of AS for managing PCa, but observed: “While the authors have highlighted the risk factors for developing metastases in patients treated with AS, they may be overly optimistic about the safety of this management strategy, particularly in patients with Gleason 7 disease.”

Dr. Koch pointed out that the median follow-up was only 6.3 years, so the number of patients with Gleason 7 disease in whom metastases will develop will grow even more.

“As of now AS would appear to be illadvised in this group of patients,” he noted.

In a separate commentary, Joel B. Nelson, MD, of the University of Pittsburgh Medical Center, stated: “Active surveillance is obviously safe in men who do not progress. The task now is to avoid misclassification of disease as indolent when it is not and detect progression before it is too late.”n

Gleason 7 tumors predict a higher risk of progressing to metastasis.

Patients with intermediate-risk disease were at higher risk for metastasis, but those with Gleason score 6 and PSA level greater than 10 ng/mL were not at increased risk.

In multivariate analysis, a PSA doubling time less than 3 years versus greater than 3 years was associated with a 3.7fold increased risk of metastasis. Gleason score 7 compared with 6 was associated with a 3-fold increased risk. The presence of 3 or more positive biopsy cores was associated with a 2.7-fold increased risk compared with fewer positive cores.

The authors concluded that AS appears safe in patients at low risk and in select patients at intermediate risk, particularly those with Gleason score 6 and PSA levels greater than 10 ng/mL. The presence of Gleason pattern 4 on diagnostic biopsy was associated with a 3-fold to 4-fold increased risk of metastasis.

Patients with Gleason pattern 4 should be offered active surveillance with caution, according to the investigators.

In editorial comments accompanying the new report, Michael O. Koch, MD, of the Indiana University School of Medicine in Indianapolis, said Dr. Klotz and his colleagues contribute to the growing body of knowledge of the

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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

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

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress.

Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. mCRPC = metastatic castration-resistant prostate cancer; ADT = androgen-deprivation therapy.

Please see additional Important Safety Information on the next pages.

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

For men with mCRPC who have progressed on ADT

ZYTIGA® & PREDNISONE: (abiraterone acetate)

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

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

IMPORTANT SAFETY INFORMATION Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. continued on next page

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2016 02/16 044350-151207

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

Let’s do this Prespecified secondary end point¶

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

IMPORTANT SAFETY INFORMATION—continued

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

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Drug Interactions—continued ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8.

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

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

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

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

Analysis of rPFS utilized centrally reviewed radiographic assessment of progression.

§

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

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

Learn more today at www.zytigahcp.com

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

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

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

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

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

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

Hepatotoxicity: ­In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ­ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking Z­ YTIGA. No deaths clearly related to ­ZYTIGA were reported due to hepatotoxicity events.

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

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

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

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

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

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

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

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

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

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

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

ZYTIGA® (abiraterone acetate) Tablets

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