RUN June-July 2015 Issue

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V O L U M E 14, I S S U E N U M B E R 5

Kidneys Usable Despite Donor AKI

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GRAFT SURVIVAL BY DONOR TYPE A new study shows that recipients of kidneys from deceased donors with acute kidney injury had 1- and 3-year death-censored graft survival rates similar to those of recipients of deceased standard criteria donor (SCD) and expanded criteria donor (ECD) kidneys.

1-year graft survival rate 3-year graft survival rate

Outcomes are similar to those of non-AKI kidneys

BY JODY A. CHARNOW PHILADELPHIA—Transplanted kidneys from deceased donors with acute kidney injury (AKI) are associated with patient and graft survival rates similar to those of non-AKI deceased donor kidneys, according to study findings presented at the 2015 American Transplant Congress.

Carlo Ramirez, MD, of the Division of Transplantation at Thomas Jefferson University Hospital in Philadelphia, and colleagues compared the outcomes of 65 transplanted kidneys from a donor with AKI with the outcomes of 62 expanded criteria

IN THIS ISSUE 7 11

Pre-transplant weight loss may lower NODAT risk Acute kidney injury implicated in nearly one-third of post-PCI deaths

15

Kidney transplants found to reduce the risk of stroke

15

Dialysis patients are more likely to die during winter months

21

Study finds low adherence to medical therapy for stones Initiation of antihypertensive drugs may increase the risk of serious fall injuries PAGE 11

donor (ECD) kidneys and 270 standard criteria donor (SCD) kidneys.

The investigators defi ned AKI as a donor terminal creatinine level of 2 mg/dL or higher.

The 6-month and 1- and 3-year death-censored graft survival rates were 96.9%, 96.9%, and 96.9% in the AKI group, 97.7%, 96.5%, and 91.8% in the SCD group, and 95.1%, 93.2%, and 90.1% in the ECD group, respectively, the investigators reported. The 6-month and 1- and 3-year patient survival rates were 98.5%, 96.8%, and 92% in the AKI group, 98.1%, 97%, and 93.4% in the SCD group, and

www.renalandurologynews.com

96.9%

96.5%

93.2%

AKI

SCD

ECD

96.9%

91.8%

90.1%

Source: Safra A et al. Transplantation of kidneys from donors with acute renal failure: five-year results from double center experience. Data presented in poster format at the 2015 American Transplant Congress in Philadelphia.

98.4%, 93.2%, and 77.7% in the ECD group, respectively.

In addition, the investigators found that kidneys from donors with AKI are associated with a higher risk of delayed graft function (DGF) than non-AKI kidneys (58.5% vs. 41.5%) as well as

© PHOTO CREDIT

J U N E /J U LY 2 015

longer cold ischemia time (857.79 vs.

589.32 minutes) and younger donor age (32.25 vs. 40.65 years).

Dr. Ramirez told Renal & Urology News that kidney grafts from donors with elevated creatinine due to AKI— continued on page 7

High BMI, CKD Advance Linked Risk of Graft Loss No Longer HIGH BODY MASS index (BMI) may 64.7% had 2 eGFR results more than patients who are at increased 3 months apart. The cohort had a mean Differs by Race identify risk of progressive chronic kidney BMI of 28.2 kg/m , and 28.7%, 38.8%, 2

BY JODY A. CHARNOW PHILADELPHIA—Racial disparities in the rate of renal graft loss have improved dramatically in the United States, with white and black kidney recipients now experiencing similar 1and 3-year risks of graft loss, researchers concluded from a study presented at the 2015 American Transplant Congress.

Tanjala Purnell, PhD, MPH, of Johns Hopkins University School of Medicine in Baltimore, and colleagues examined 22-year trends in kidney transplant outcomes using data from the Scientific Registry of Transplant Recipients. The study population included 145,489 continued on page 7

disease (CKD), British researchers reported at the 52nd congress of the European Renal Association-European Dialysis and Transplant Association in London.

Rupert W. Major, MBChB, a Kidney Research U.K. Fellow at the University of Leicester in the U.K., and colleagues studied a cohort of 31,274 patients with an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m 2 (mean 51.1) as calculated using the Modification of Diet in Renal Disease study equation. Of these patients,

and 30.8% had a BMI of 18–25 (normal), 25-30 (overweight), and greater than 30 kg/m2 (obese or severely obese).

Results showed that the mean decline in eGFR was greater in the higher BMI categories. The mean eGFR declined by 0.11 and 0.08 mL/min/1.73 m2 per year in patients with a BMI of 30–35 and greater than 35 kg/m2, respectively, compared with no change or even slight increases in eGFR in the other BMI categories. The decline in eGFR in the higher BMI categories was especially continued on page 7

THE BENEFITS OF PUFAs

PAGE 10

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© THINKSTOCK

High intake of marine PUFAs improve odds of kidney transplant patient survival.

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J U N E /J U LY 2 015

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V O L U M E 14, I S S U E N U M B E R 5

Tumor Shrinkage Prognostic in mRCC

IN THIS ISSUE 5

Adjuvant radiotherapy underused in men with high-risk PCa

5

Urinary tract infection linked to worse bladder cancer outcomes

17

Treating RCC metastases found to improve survival

18

Long-term lithium use does not raise urinary cancer risk

21

Study finds low adherence to medical therapy for stones Initiation of antihypertensive drugs may increase the risk of serious fall injuries PAGE 11

In a study of patients with metastatic renal cell carcinoma (mRCC), researchers found that after 3 months of treatment, the greater the degree of tumor shrinkage, the longer the survival, as shown here.

Biopsy Urged For Small Renal Masses

BY JODY A. CHARNOW RENAL TUMOR biopsy (RTB) for the characterization of small renal masses (SRMs) is safe and reliable and avoids unnecessary treatment, researchers concluded.

A team led by Antonio Finelli, MD, of the University of Toronto, retrospectively studied 509 patients who underwent 529 biopsies for solid SRMs 4 cm or less in diameter. RTBs yielded an overall diagnostic rate of 94%.

Following RTB, treatment could have been avoided in at least 26% of cases because the lesion was benign, the researchers found. continued on page 7

■ 50% –100% tumor shrinkage ■ 25% –49% tumor shrinkage ■ 0% –24% tumor shrinkage

60 50 40 Months

sunitinib and 65 received sorafenib for 3 or more months. Three patients had a complete response to therapy and 40 had a partial response. Another 105 patients showed stable disease, while 37 progressed. The median progression-free survival was 7.3 months, and overall survival was 33.6 months, the investigators reported.

After 3 months on the medications, 9 patients experienced tumor shrinkage of 50%–100%; 43 patients, 25%–49%; and 61 patients, 0%–24%. The remaining 72 patients had tumor enlargement or new metastatic lesions. The median overall survival times by level of tumor

www.renalandurologynews.com

EARLY TUMOR SHRINKAGE AND SURVIVAL

Degree of early shrinkage can predict survival odds

BY NATASHA PERSAUD NEW ORLEANS—Tumor shrinkage may be a useful predictor of outcomes in patients receiving treatment for metastatic renal cell carcinoma (mRCC), according to new studies presented at the American Urological Association 2015 annual meeting.

One study, led by Hideaki Miyake, MD, of Kobe University Graduate School of Medicine in Japan, examined early tumor shrinkage as a predictor of overall survival among 185 mRCC patients who received first-line therapy with tyrosine kinase inhibitors. Of the 185 patients, 120 received

■ ■ ■

30 20 10 0

59 months

39 months

31months

Source: Miyake H. Early tumor shrinkage under first-line tyrosine kinase inhibitor as a surrogate endpoint of overall survival in patients with metastatic renal cell carcinoma. Data presented at the American Urological Association 2015 annual meeting in New Orleans. Abstract PD35-02

shrinkage at 3 months (from greatest to least) were 59, 39, 31, and 16 months, respectively.

In multivariate analysis, Memorial Sloan Kettering Cancer Center classification, C-reactive protein level, liver metastasis, and early tumor shrinkage

were significantly and independently associated with overall survival.

“Considering the potential impact of early tumor shrinkage on the subsequent prognosis of patients with mRCC, it is very important to select continued on page 7

Early ADT May Hike Death Risk

BY JODY A. CHARNOW NEW ORLEANS—Early androgen deprivation therapy (ADT) may increase the risk of death among men who receive it after experiencing biochemical recurrence (BCR) of prostate cancer following radical prostatectomy, according to study data presented at the 2015 American Urological Association annual meeting.

This adverse effect appears to be limited to men younger than 65 years when they experience BCR and those with low-risk disease, reported a research team led by Stephen J. Freedland, MD, of Cedars-Sinai Medical Center in Los Angeles.

Dr. Freedland and his colleagues retrospectively analyzed data from 468 patients who experienced BCR after RP. The median follow-up after BCR was 70 months. Of the 135 men who received early ADT (defined as receipt of ADT when PSA levels were less than 5 ng/mL), 42 died. In adjusted analyses, early ADT was associated with a significant 68% increased risk of death compared with the 333 men who received conventional therapy (no ADT or ADT started when PSA levels were 5 ng/mL or higher). When the researchers stratified the men by age, early ADT was associated with a significant 5.6 times continued on page 7

THE BENEFITS OF PUFAs

PAGE 10

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© THINKSTOCK

High intake of marine PUFAs improve odds of kidney transplant patient survival.

6/19/15 10:38 AM

www.renalandurologynews.com JUNE/JULY 2015

Renal & Urology News 3

FROM THE EDITOR EDITORIAL ADVISORY BOARD Medical Director, Urology

Medical Director, Nephrology

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

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

Nephrologists

Urologists

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

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

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

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

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

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

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

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

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

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

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

Renal & Urology News Staff

Editor Jody A. Charnow

Web editor

Natasha Persaud

Production editor Kim Daigneau

Group art director, Haymarket Medical Jennifer Dvoretz

Production manager Krassi Varbanov

Production director Kathleen Millea Grinder

Circulation manager Paul Silver National accounts manager William Canning

Publisher Dominic Barone

Editorial director

Jeff Forster

Senior VP, medical journals & digital products

Jim Burke, RPh

Senior VP, clinical communications group

John Pal

CEO, Haymarket Media Inc.

Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 14, Number 5. 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 © 2015.

MH-Editorial_RUN0715.indd 3

The Ongoing Problem of Non-Adherence

T

herapeutic non-adherence is a clinical challenge that likely has vexed doctors for centuries, perhaps millennia. If patients fail to take their medications or keep appointments to receive maintenance therapies, the conditions for which they are prescribed treatment cannot be controlled, potentially leading to increased morbidity and mortality.

As with other medical specialties, nephrology and urology have their share of non-adherent patients, as illustrated by 2 studies presented at the American Urological Association (AUA) annual meeting and which we report on in this issue.

In a study of patients with non-muscle invasive bladder cancer (page 16), Alexander M. Helfand, BA, a fourth-year medical student, and colleagues found poor adherence to maintenance therapy, with “realworld” rates of adherence lower than those observed in most clinical trials. Only 10% of patients on the Lamm schedule completed 3 years of treatment with 21 maintenance instillations, Helfand’s group reported.

In the other study (page 21), Yooni Yi, MD, and colleagues found that only 50% of patients with kidney stones adhered to their prescribed medical therapy. Being placed on combination therapy and female gender were independently associated with lower odds of adherence.

These findings resonate with some of the published literature on nonadherence. Last year, in the Journal of Nephrology (2014;27:673-679), investigators published the results of an 8-week study of 135 hemodialysis (HD) patients showing that each week, about half of patients were adherent (missing less than 1 total daily dose per week) to phosphate binder treatment. Over the 8-week period, only 22% of patients were totally adherent (missing less than 1 total daily dose per week, every week). Living with a partner, greater social support, and better physical quality of life were associated with being totally adherence, the investigators reported.

Pill burden has emerged as a possible reason for non-adherence to phosphate binder therapy. A study of 233 dialysis patients found that the median daily pill burden was 19, with phosphate binders accounting for about half of this, according to a study published in the Clinical Journal of the American Society of Nephrology (2009;4:1089-1096). “The daily pill burden in dialysis patients is one of the highest reported to date in any chronic disease state,” the authors concluded. Results showed that 62% of subjects were non-adherent. A study of 8,616 HD patients found that a higher pill burden was associated with lower adherence, and lower adherence was associated with higher mean phosphorus levels, researchers reported in Nephrology Dialysis Transplantation (2014;29:2092-2099).

The aforementioned new studies presented at the AUA meeting should serve as reminders that no matter how much pharmacologic therapy advances, patient behavior will remain a significant factor in the outcomes achieved.

Jody A. Charnow Editor

6/19/15 10:22 AM

4 Renal & Urology News

JUNE/JULY 2015

www.renalandurologynews.com

Contents

J U N E / J U LY 2 0 1 5 ■ V O L U M E 1 4 , I S S U E N U M B E R 5

Nephrology 7

ONLINE

8

this month at renalandurologynews.com Clinical Quiz

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

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

Congratulations to our June winner: Cornel Rusan, MD

15

20

CALENDAR

Weight Loss May Decrease Post-Transplant NODAT Risk Significant weight loss prior to kidney transplantation may lessen the risk of newonset diabetes post-operatively.

Younger Donor Kidneys Better for Elderly Patients Elderly kidney transplant recipients have worse survival odds if they receive organs from elderly rather than younger deceased donors.

Kidney Transplants May Cut Stroke Risk Kidney recipients have nearly half the risk of stroke compared with patients remaining on hemodialysis.

New Study Shows Tolvaptan’s ADPKD Benefits Sufferers with lower levels of kidney function may benefit from long-term treatment.

Urology

Videos

Some of our recent postings include:

5

ART Underused in High-Risk PCa Only 7.4% of patients receive adjuvant radiation therapy after radical prostatectomy despite the presence of adverse pathologic features.

5

UTI Found to Predict Worse Bladder Cancer Outcomes Urinary tract infection may predict higher stage bladder cancer and greater mortality among older patients.

• Testosterone Supplements Don’t Decrease Abdominal Fat

10

ESRD Risk with RN, PN Comparable Radical and partial nephrectomy for renal cell carcinoma is associated with a similar risk of end-stage renal disease.

News Coverage

17

Treating RCC Metastases Ups Survival Metastasectomy and intensive local therapy to bone lesions found to decrease risk of death.

• ARV-7 Splice Variance and Metastatic Castration-resistant Prostate Cancer Treatment • Ureteroscopic Stone “Dusting” with Laser • Lab-Grown Kidney a Potential Game-Changer for CKD • Benefits of Nocturnal Dialysis

Visit our website for daily updates.

Out of all the risk factors for new-onset

diabetes after transplant, weight is probably the only modifiable risk factor.

International Continence Society Montreal October 6–9 American Society for Radiation Oncology (ASTRO) San Antonio, TX October 18–21 American Society of Nephrology Kidney Week San Diego November 3–8 Genitourinary Cancers Symposium San Francisco January 7–9, 2016 Annual Dialysis Conference Seattle February 27–March 1, 2016 National Kidney Foundation Spring Clinical Meetings Boston April 27–May 1, 2016 European Association of Urology 31st Annual Congress Munich, Germany March 11–15, 2016 American Urological Association Annual Meeting San Diego May 6–10, 2016 American Society of Hypertension Annual Scientific Meeting & Exposition New York May 14–17, 2016

22

Departments 3

From the Editor Patient non-adherence to treatment

6

News in Brief Adverse events common in CRRT patients

22 See our story on page 7

TOC_Neph_RUN0715.indd 4

Practice Management Preparing for ICD-10

6/19/15 10:32 AM

4 Renal & Urology News

JUNE/JULY 2015

www.renalandurologynews.com

Contents

J U N E / J U LY 2 0 1 5 ■ V O L U M E 1 4 , I S S U E N U M B E R 5

Urology 5

ONLINE

5

this month at renalandurologynews.com Clinical Quiz

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

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

Congratulations to our June winner: Cornel Rusan, MD

10

17

CALENDAR

ART Underused in High-Risk PCa Only 7.4% of patients receive adjuvant radiation therapy after radical prostatectomy despite the presence of adverse pathologic features.

UTI Found to Predict Worse Bladder Cancer Outcomes Urinary tract infection may predict higher stage bladder cancer and greater mortality among older patients.

ESRD Risk with RN, PN Comparable Radical and partial nephrectomy for renal cell carcinoma is associated with a similar risk of end-stage renal disease.

Treating RCC Metastases Ups Survival Metastasectomy and intensive local therapy to bone lesions found to decrease risk of death.

Nephrology Videos

Some of our recent postings include: • ARV-7 Splice Variance and Metastatic Castration-resistant Prostate Cancer Treatment

7

Weight Loss May Decrease Post-Transplant NODAT Risk Significant weight loss prior to kidney transplantation may lessen the risk of newonset diabetes post-operatively.

8

Younger Donor Kidneys Better for Elderly Patients Elderly kidney transplant recipients have worse survival odds if they receive organs from elderly rather than younger deceased donors.

• Testosterone Supplements Don’t Decrease Abdominal Fat

15

Kidney Transplants May Cut Stroke Risk Kidney recipients have nearly half the risk of stroke compared with patients remaining on hemodialysis.

News Coverage

20

New Study Shows Tolvaptan’s ADPKD Benefits Sufferers with lower levels of kidney function may benefit from long-term treatment.

• Ureteroscopic Stone “Dusting” with Laser • Lab-Grown Kidney a Potential Game-Changer for CKD • Benefits of Nocturnal Dialysis

Visit our website for daily updates.

Testosterone therapy appears to be safe in

elderly men as long as they are closely followed with regular physical exams and blood tests.

International Continence Society Montreal October 6–9 American Society for Radiation Oncology (ASTRO) San Antonio, TX October 18–21 American Society of Nephrology Kidney Week San Diego November 3–8 Genitourinary Cancers Symposium San Francisco January 7–9, 2016 Annual Dialysis Conference Seattle February 27–March 1, 2016 National Kidney Foundation Spring Clinical Meetings Boston April 27–May 1, 2016 European Association of Urology 31st Annual Congress Munich, Germany March 11–15, 2016 American Urological Association Annual Meeting San Diego May 6–10, 2016 American Society of Hypertension Annual Scientific Meeting & Exposition New York May 14–17, 2016

22

Departments 3

From the Editor Patient non-adherence to treatment

6

News in Brief Adverse events common in CRRT patients

22 See our story on page 5

TOC_Uro_RUN0715.indd 4

Practice Management Preparing for ICD-10

6/19/15 10:35 AM

www.renalandurologynews.com JUNE/JULY 2015

■ AUA 2015

Renal & Urology News 5

American Urological Association 2015 Annual Meeting, New Orleans

ART Underused in High-Risk PCa

Only 7.4% of patients receive ART after radical surgery despite the presence of adverse pathologic features NEW ORLEANS—Patients who undergo radical prostatectomy for high-risk prostate cancer (PCa) seldom receive adjuvant radiation therapy (ART), despite evidence that it is associated with better outcomes, researchers reported at the 2015 American Urological Association annual meeting.

In a study of 105,226 men who underwent radical prostatectomy and had high-risk PCa features found on final pathology, only 7,741 (7.4%) received ART, according to a research team at the University of Chicago Medical Center led by Charles U. Nottingham, MD. For the study, the investigators defined high-risk features as pT2 tumors with a positive surgical margin (PSM) or pT3 and pT4 tumors with or without a PSM. The study excluded patients with lymph node involvement

and metastatic disease. They defined ART as receipt of radiation therapy within 6 months of surgery.

Younger age was among the significant predictors of ART receipt.

Compared with patients younger than

TRT Safe in Hypogonadal Elderly Men

death occurring in the TRT group versus 6 deaths in the control arm.

“Testosterone therapy appears to be safe in elderly men as long as they are closely followed with regular physical exams and blood tests,” Dr. Ramasamy told Renal & Urology News.

Though the study was retrospective and limited by small sample size, it overcomes some of the limitations of large epidemiologic studies that have suggested an elevated risk of cardiovascular events associated with TRT use, he pointed out. For example, the study had a long follow-up and included an age- and comorbidity-matched control group of hypogonadal men naïve to TRT. All men had at least 2 testosterone measurements. In addition, thrombotic events were verified through patient calls, and mortality was verified using the National Death Index. The study is in press in Urology.

At the 2015 American College of Cardiology Scientific Sessions, researchers presented the findings of a meta-analysis and an observational study demonstrating no increased risk of cardiovascular events associated with TRT. The meta-analysis included data from 29 studies that included a total of 122,889 men; the observational study included 7,245 hypogonadal men and compared men who received TRT with those who did not. n

TESTOSTERONE replacement therapy (TRT) is not associated with an increased risk of myocardial infarction (MI) or other serious thrombotic events in men older than 65 years, new findings suggest.

In a retrospective study, a team at Baylor College of Medicine in Houston led by first author Ranjith Ramasamy, MD, and senior author Larry Lipshultz, MD, evaluated the prevalence of thrombotic events—MI, cerebrovascular accidents (CVA), or pulmonary embolism (PE)—among 217 men aged 65 years and older who had hypogonadism (testosterone level below 300 ng/ dL). Of these, 153 were on TRT and 64 were naïve to TRT (controls). The TRT and control groups had mean ages of 74 and 75 years, respectively.

After a mean follow-up of 3.8 years for the TRT group and 3.4 years for the control group, the researchers observed no statistically significant differences between the groups in the occurrence of MI, CVA, or PE. The control group, however, had a significantly higher prevalence of death from any cause, with 1

AUA-AdjuvantRT_RUN0715.indd 5

Men younger than 65 were more likely to receive adjuvant radiation therapy.

65 years, those aged 65–75 and older than 75 years were 24% and 51% less likely to receive ART. Other patient factors that significantly predicted receipt of ART included residing within the zip code of the treatment facility, surgery at

a low-volume facility (50 cases or fewer per year), private insurance, a preoperative PSA level of 10 ng/mL or higher, a Gleason score of 7–10 at prostatectomy, and pT3 and pT4 cancers regardless of margin status.

Compared with patients who had surgery at a facility in their zip code, patients who had surgery at a facility 61–120 miles and more than 120 miles away were 59% and 69% less likely to receive ART. Compared with patients who had surgery at a facility that treats 50 or fewer prostatectomy cases per year (first quartile), those who had surgery at facilities in the second, third, and fourth quartiles were 43%, 58%, and 67% less likely to receive ART. The lower use of ART at higher-volume centers may reflect a propensity to perform surveil-

lance on high-risk patients and preferential treatment with salvage radiation therapy, Dr. Nottingham’s team concluded.

Privately insured patients were 24% more likely to receive ART than uninsured patients. Patients with a preoperative PSA level of 10–20 and more than 20 ng/mL were, respectively, 17% and 49% more likely to receive ART than those with a PSA level below 10 ng/mL. Patients with a Gleason score of 7 and 8–10 were 1.8 and 4.7 times more likely to receive ART than those with a Gleason score of 6.

Patients with pT3 or pT4 tumors with a negative surgical margin and those with pT3 or pT4 tumors with a PSM were 1.3 and 3.9 times more likely to undergo ART than patients with pT2 tumors with a PSM. n

UTI Found to Predict Worse Bladder Cancer Outcomes

BY NATASHA PERSAUD

208% higher in women presenting with

URINARY TRACT infection (UTI) may

UTI. Likewise, bladder cancer-­specific

predict higher stage bladder cancer

mortality was higher in men (50%) and

and greater mortality among older

women (37%) presenting with UTI. The

patients, according to researchers.

chance of dying from any cause was

Additionally, UTI appears to delay the

similarly elevated by 39% to 47%.

diagnosis of bladder cancer in both

When UTI claim was also considered

sexes, but more notably in women.

as a presenting symptom in addition to

For the study, investigators led by

hematuria, time to diagnosis of bladder

Kyle A. Richards, MD, of the University

cancer was longer in women vs. men

of Wisconsin School of Medicine and

(72 vs. 59 days). Time to diagnosis,

Public Health examined Medicare

however, was not linked to worse

claims data linked to the Surveillance,

pathology or mortality.

Epidemiology, and End Results (SEER)

“Symptoms of UTI in older patients

cancer registry. They identified

might be a harbinger of bladder cancer

Medicare patients older than 66 years

and should prompt thorough evaluation

diagnosed with bladder cancer during

if symptoms persist despite short-

2007–2009, who presented initially

term conservative management,” Dr.

with either hematuria or UTI.

Richards told Renal & Urology News.

Researchers discovered that patients

“Timely bladder cancer diagnosis and

presenting with UTI were at the highest

treatment may not always occur due to

risk of adverse bladder cancer patho-

prolonged treatment for presumed UTI.”

logic and oncologic outcomes com-

An alternate theory is that patients

pared to patients presenting with hema-

presenting with a true UTI might have

turia. The odds of stage 2 or higher

different bladder tumor biology that

disease was 71% higher in men and

leads to negative outcomes. n

6/19/15 10:43 AM

6 Renal & Urology News JUNE/JULY 2015 www.renalandurologynews.com

News in Brief

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

Short Takes Sacral Neuromodulation Testing Increasing

associated with a 60% and 51%

Using a 20% sample of national Medi-

kidney stones in RCTs and observa-

care claims, Anne M. Suskind, MD,

tional studies, respectively. It also

of the University of California San

was associated with a 60% and 80%

Francisco, found that the number of

decreased risk of recurrent kidney

physicians who performed neuromod-

stones, respectively.

decreased relative risk of incident

ulation test procedures increased to an online report in Urology. The

Finasteride Can Decrease TURP-Related Blood Loss

average rates of procedures in-

Pretreatment with finasteride, but not

creased significantly from 4.0 to 6.4

dutasteride, appears to decrease

procedures per physician per year,

perioperative blood loss related to

but the rates of device implantation

transurethral resection of the prostate

remained stable.

(TURP) in men with benign prostatic

4-fold from 2005 to 2010, according

hyperplasia (BPH), Chinese research-

High Fluid Intake Cuts Kidney Stone Risk

ers concluded in a paper published in BMC Urology (2015;15:47).

In a meta-analysis of 17 random-

High fluid consumption significantly reduces the risk of incident and

ized controlled trials that included

recurrent kidney stones, according to

1,489 patients, Yi-Ping Zhu, MD, and

a new systematic review and meta-

colleagues at Fudan University in

analysis published online in the Journal

Shanghai also found that finasteride

of Nephrology.

can decrease blood loss per gram of resected tissue, microvessel den-

Wisit Cheungpasitporn, MD, of Mayo Clinic in Rochester, Minn., and

sity (MVD), and vascular endothelial

colleagues, analyzed data from 9

growth factor level. Pre-TURP dutas-

studies: 2 randomized controlled

teride did not decrease total blood

trials (RCTs) with 269 patients and 7

loss or MVD. Neither drug decreased

observational studies with 273,685

operative time, prostate volume, or

individuals. High fluid intake was

weight of gland resected.

Gender Disparities in OAB Treatment In the United States, men are less likely than women to receive a medication to treat overactive bladder (OAB), according to a recent study. The study also revealed other gender differences in OAB management, as shown here.

35

33.8

31.6

Women

30

Percent

25

19.5

20

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Post-void residual measured

Diagnostic cystoscopy

Urodynamic testing

Source: Goldman H et al. Real-world patterns of overactive bladder (OAB) care in the United States (US) based on an observational study. Data presented at the American Urological Association annual meeting, New Orleans.

Abstract PD27-06.

35

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HILADELPHIA—Proton pump inhibitor (PPI) use is associated with decreased magnesium absorption and increased arterial stiffness in renal transplant recipients, according to a new study presented at the 2015 American Transplant Congress.

Siren Sezer, MD, and colleagues at the Baskent University in Ankara, Turkey, retrospectively studied 354 renal transplant recipients with a mean age of 38.6 years and stable graft function. All had received their transplant at least 36 months previously. The researchers divided subjects into 3 groups: PPI users; H2 receptor blocker users; and a control group not taking any stomach-protecting agents).

The PPI group had a significantly lower mean serum magnesium level compared with the H2 receptor block group and control group (1.5 vs. 1.7 and 1.7 mg/dL).

The researchers measured pulse wave velocity (PWv) to assess arterial stiffness.

PWv values were significantly higher in the PPI group than the H2 receptor block group and control group (7.3 vs. 6.3 and 6.2 cm/sec, respectively).

Statin-Metformin Combo Lowers PCa Death Risk S

tatins either alone or in combination with metformin may decrease the risk of dying from prostate cancer (PCa), according to study findings presented at the American Society of Clinical Oncology annual meeting in Chicago.

In a study of 22,110 high-risk PCa patients, of whom 1,365 died from the cancer, Grace L. Lu-Yao, PhD, an epidemiologist at the Rutgers Cancer Institute of New Jersey in New Brunswick, and colleagues found that the reduction in the risk of PCa-specific mortality (PCSM) was most pronounced among patients who were obese or had metabolic syndrome. For the cohort overall, statin treatment alone and combination statin/metformin treatment were associated with a 40% and 43% decreased risk of PCSM, respectively, compared with non-users of the medications, Dr. Lu-Yao’s group reported. Among patients who were obese or had metabolic syndrome, statin treatment alone and combination statin-metformin treatment were associated with a 91% and 70% decreased risk, respectively.

High Incidence of AEs Found Among Patients on CRRT I

ntensive care unit patients who require continuous renal replacement therapy (CRRT) experience a high incidence of adverse events (AEs), according to a new study.

In a study of 595 patients who underwent CRRT, a team at Mayo Clinic in Rochester, Minn., led by Kianoush Kashani, MD, found that the most common clinically significant electrolyte derangements were ionized hyperphosphatemia (44% of patients) hypocalcemia (22%), and ionized hypercalcemia (23%). Additionally, 97% of patients had at least 1 additional AE, including new-onset hypotension in 43% of patients, hypothermia (44%), new-onset arrhythmias (29%), new-onset anemia (31%), and thrombocytopenia (40%), the researchers reported in Blood Purification (2015;39:333-339).

“Although the extent to which these complications are attributable to CRRT is not known, clinicians need to be cautious and aware of their high prevalence in this patient population,” the authors concluded.

Women Men

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Low Serum Magnesium Linked to PPIs in Transplant Patients P

19.5

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Weight Loss May Decrease Post-Transplant NODAT Risk PHILADELPHIA—Significant weight

diabetics on recipient follow-up (the

loss prior to kidney transplantation may

NODAT group) and a comparison group

lessen the risk of new-onset diabetes

of 61,992 recipients without diabetes.

after transplantation (NODAT), accord-

The investigators defined pre-transplant

ing to study findings presented at the

weight change as the percentage differ-

2015 American Transplant Congress.

ence in body mass index (BMI) between

A study by investigators at the

waitlisting and transplant. They stratified

University of California Los Angeles led

recipients into quartiles according to

by Edmund Huang, MD, found that renal

pre-transplant weight change, with quar-

transplant recipients with the most pro-

tile 1 including patients with the greatest

found weight loss had a significant 25%

weight gain and quartile 4 including

decreased odds of NODAT compared

those with the greatest weight loss. The

with recipients with the most weight

95% confidence interval for the pre-

gain in multivariate analysis.

dicted probability of NODAT ranged from

“Out of all the risk factors for newonset diabetes after transplant, weight is probably the only modifiable risk

9.2%–23.5% for quartile 1 compared with 7.1%–18.9% for quartile 4.

They also stratified recipients accord-

factor,” Dr. Huang told Renal & Urology

ing to BMI (less than 18.5, 18.5–24.9,

News. Weight loss may contribute to a

25.0–29.9, 30.0–39.9, and 40 kg/

decrease in NODAT risk by improving

m2 or higher). Although NODAT risk

insulin sensitivity, he noted.

increased with increasing BMI, pre-

Dr. Huang’s team studied 9,681

transplant weight loss among recipi-

recipients without diabetes at wait

ents in quartile 4 had a mitigating effect

listing who were later identified as

on NODAT in all BMI categories. n

Graft loss and race continued from page 1

white and 63,910 black adults who received a first-time living donor kidney transplant (LDKT) or deceaseddonor kidney transplant (DDKT) from January 1, 1990 to December 31, 2012.

Results showed that black recipients experienced greater improvement in 5-year graft loss rates after LDKT and DDKT (15.2% and 20.8%, respectively) compared with whites (6.9% and 12.3%, respectively). In addition, blacks who received a DDKT during 1990–1992 were 39% more likely than whites to experience 5-year graft loss, whereas blacks who received a DDKT during 2007–2008 were only 10% more likely to experience 5-year graft loss than whites, in adjusted analyses.

Blacks who received a LDKT during 1990–1992 were 52% more likely than whites to experience 5-year graft loss, but this disparity fell to 38% during 2007–2008.

By the end of the study period, the researchers observed no statistically significant racial differences in 1- or 3-year graft loss after LDKT or DDKT. In an interview with Renal & Urology News, Dr. Purnell explained that the improvement in racial disparity in

BMI Mismatch Ups Allograft Loss Risk PHILADELPHIA—Body mass index (BMI) mismatch in deceased kidney donors and recipients is an independent risk factor for kidney graft loss, German researchers reported at the 2015 American Transplant Congress.

Oliver Staeck, MD, and colleagues at Charite Universitaetsmedizin in Berlin conducted a retrospective study of 549 patients who received a kidney from deceased donors from 2000–2013.

The cohort had a mean follow-up of 6.4 years. The researchers categorized subjects into 2 groups based on BMI mismatch: 265 patients who received a kidney from a donor with a BMI that differed by 4 kg/m2 or more and 284 patients who received a kidney from a donor with BMI mismatch of less than 4 kg/m2. At 7 years after transplantation, the death-censored graft survival rate was 82% among recipients with

a BMI mismatch of 4 kg/m or more compared with 89% among those with a BMI mismatch of less than 4 kg/m2, a significant difference between the groups. The researchers also found that each 1 kg/m2 increment in BMI mismatch was associated with a significant 6% increased risk of graft loss. In addition, each 1 kg/m2 increment in recipient BMI was associated with a significant 5% increased risk of graft loss. n

Donor AKI

College in New York led by Meredith J. Aull, PharmD, also demonstrated that transplantation of kidneys from deceased donors with AKI is associated with death-censored graft survival rates similar to those of non-AKI kidneys, but with an increased risk of DGF. Dr. Aull and her colleagues examined the outcomes of 688 deceased donor kidney transplants.

The investigators defined AKI as a terminal donor creatinine level of 2.0 mg/dL or higher.

The researchers broke donors down into 4 groups: (1) ECD with a termi-

nal creatinine level below 2 mg/dL; (2) ECD with a terminal creatinine level of 2 mg/mL or higher; (3) SCD with a terminal creatinine level below 2 mg/dL; and (4) SCD with a terminal creatinine level of 2 mg/dL or higher.The 3-year death-censored graft survival rates were similar among groups 1–4: 83.3%, 79%, 88.6%, and 87.4%, respectively, according to the investigators. DGF rates were 50% and 37.8% in groups 2 and 4 (the AKI groups), respectively, compared with 40.7% and 27.9% in groups 1 and 3 (the non-AKI groups), Dr. Aull’s group reported. n

continued from page 1

with acceptable biopsy results and machine perfusion pump parameters—may be transplanted safely with outcomes similar to those associated with non-AKI kidneys. “The use of these kidneys may help decrease the high discard rates for this type of kidneys that are already in short supply,” Dr. Ramirez said.

In another study presented at the meeting, researchers at New YorkPresbyterian/Weill Cornell Medical

Cv-Jump_Neph_RUN0715.indd 7

2

Renal & Urology News 7

graft loss may be attributable, at least in part, to a change in United Network for Organ Sharing (UNOS) policy in 2003 that eliminated priority points for HLA-B matching to address racial disparities in kidney transplant rates. A previous study led by Dorry L. Segev, MD, PhD, of Johns Hopkins, which was published in the American Journal of Kidney Diseases (2011;58:813-816), found a significant 23% reduction in the disparity in DDKT rates between blacks and whites after the UNOS policy change.

“It [the policy change] actually reduced the amount of time that patients were spending on dialysis,” Dr. Purnell said, noting that shorter dialysis vintage has been associated in prior studies with better kidney transplant outcomes.

In addition, during the study period, Medicare expanded coverage of immunosuppressive medications and immunosuppressive treatment and posttransplant care have improved over time, said Dr. Purnell, an Assistant Professor of Transplant Surgery and Epidemiology. This may have differentially benefited black transplant patients who historically had been disproportionately burdened by immunologic issues, she said. n

BMI, CKD link

continued from page 1

pronounced in younger patients with higher levels of proteinuria, according to the investigators.

“The association we found suggests that reducing BMI might slow the progression of CKD,” Dr. Major told Renal & Urology News. “Lifestyle interventions, such as exercise and dietary programs, are potential areas for intervention in this area, particularly in primary care. At the University of Leicester, and other international renal research centers, we are running structured exercise program clinical trials in CKD to investigate the effect on outcomes, including CKD progression.”

Dr. Major noted that previous studies have focused on the relationship of BMI and the diagnosis of CKD, including a study by his colleagues suggesting that waist circumference may be a potential CKD screening tool. In contrast, the current study, funded by the U.K.’s National Institute for Health Research, focused on progression of disease in patients with known CKD, and the study included what is probably the largest cohort to date to examine the association, he said. n

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continued from page 1

“Routine RTB should be considered in all patients with an indeterminate SRM for which treatment is being considered,” the investigators concluded in a paper published online ahead of print in European Urology.

Study results showed that 175 patients underwent surgery following RTB. Surgical pathology was unavailable in 3 cases. RTB histology was concordant with final pathology in 93% of 167 tumors and nuclear grade was concordant for 63% of 101 tumors that were analyzed.

Of the masses not initially treated with surgery, 230 were managed with active surveillance and 94 underwent thermal ablation. Fifteen patients were referred to an oncologist for systemic therapies because of non-primary renal cell carcinoma. Adverse events (AEs) occurred in 8.5% of cases; in all cases except 1, the AEs were self-limited.

Biopsies not widely adopted Despite their potential benefits, RTBs have not been widely adopted in the management of RTBs, Dr. Finelli and his colleagues stated. “The lag in uptake is likely due to concerns regard-

Early ADT ups death risk continued from page 1

increased risk of death compared with conventional therapy among men younger than 65 years and a significant 61% decreased risk among those aged 65 years and older.

Early ADT was associated with a significant 3.2 times increased mortality in patients with low-risk disease, but did not significantly affect survival in those with high-risk disease.

Early ADT increased the risk of death by 68% compared with conventional therapy.

Finally, data suggest that men with a PSA doubling time of less than 9 months fared better with early ADT, whereas those with longer PSA doubling times fared worse.

In a poster presentation, Dr. Freedland’s team concluded that the “risks and benefits of ADT must be weighed and taken into account when deciding timing of treatment.”

Cv-Jump_Uro_RUN0715.indd 7

ing the lack of sufficient tissue for diagnosis, discordance with final pathology, safety, and, most importantly, the lack of perceived impact on clinical management,” they wrote. They noted that their results demonstrate that these concerns are exaggerated.

Paradigm shift needed “In view of our results, it seems difficult to continue to justify a timid uptake of routine SRM biopsies and the use of this information to implement treatment strategies. … Given the current evidence, it is our strong belief that it is now time to shift the clinical paradigm.

We believe that RTB should be considered the initial step in the management of patients with radiographically indeterminate SRMs in whom a therapeutic approach is being considered.”

The researchers said that, to the best of their knowledge, their study is the largest single-institution study published on SRM biopsy. Dr. Finelli’s team acknowledged some study limitations. For example, it is possible that biopsy success rates may have been affected by non-captured variables, such as the lesion’s echogenicity, anterior versus posterior location, and amount of peri-nephric adipose tissue, they stated.

Whether the harmful effect of early ADT is due to true harm, treatment bias, or unmeasured confounding is not known, they noted.

“These data support other recent data that ADT can come with a price, and is not appropriate for all men and should be used selectively for those men at the highest risk of death from prostate cancer,” Dr. Freedland told Renal & Urology News.

An observational study published recent in the European Journal of Cancer (2015;51:817-824), however, found that PCa patients who underwent immediate ADT (within 3 months after PSA relapse) had 5-year survival odds similar to those of patients who had deferred ADT (initiated after clinical progression). The study, by Xabier GarcíaAlbéniz, MD, PhD, of the Harvard School of Public Health in Boston, and colleagues, included 2,096 patients with a median age of 69 years, a mean time from primary treatment to PSA relapse of 37.4 months, and mean follow-up time from primary treatment of 91.4 months.

Noting that ADT is associated with adverse effects, Dr. Freedland said the take-home message from both studies is the same: The risks are real and the benefits are unclear. n

A new study suggests that renal mass biopsies are safe and can accurately distinguish malignant and benign tumors.

E. Jason Abel, MD, Assistant Professor of Urologic Oncology at the University of Wisconsin in Madison, who was not involved in the new study, said the investigation by Dr. Finelli’s team was well conducted, and he agreed with the conclusions. He noted, however, that “the non-diagnostic rate is somewhat hard to interpret because the authors excluded 152 biopsies from the analysis, including biopsies of cystic masses, and the authors did not describe how many biopsies ‘missed the target’ and identified only normal renal parenchyma.”

mRCC tumor shrinkage

continued from page 1

first-line agents with an ability to induce prompt tumor remission in order to achieve a favorable prognosis,” Dr. Miyake said.

In a separate study of 199 patients with mRCC receiving first-line systemic therapy, Takafumi Yagisawa, MD, and colleagues at Tokyo Women’s Medical University, found that maximum tumor shrinkage (MTS) within 3 months (early MTS) during first-line targeted therapy was associated with shorter overall and progression-free survival times compared with MTS after 3 or more months (late MTS).

The study included 81 patients with early MTS and 48 with late MTS as measured by computed tomography.

The median overall and progression-free survival times were 14.3 and 6.1 months, respectively, in the early MTS group and 22.8 and 11.5 months, respectively, in the late MTS group.

The agents used for first-line therapy included sunitinib (71 patients), sorafenib (47 patients), pazopanib (4 patients), and temsirolimus (7 patients).

At the American Society of Clinical Oncology annual meeting in Chicago,

Biopsy limitations This study demonstrated that renal mass biopsy is safe and that it can accurately differentiate malignant and benign tumors, Dr. Abel said.

However, the optimal use of biopsy remains unclear for many urologists, he said. “Proper utilization of biopsy for small renal masses is being studied and continues to evolve,” Dr. Abel told Renal & Urology News. “Biopsy is very useful in clinical situations that are not black and white, such as patients who are borderline candidates for treatment. Furthermore, one underappreciated benefit of renal mass biopsy is that it provides more information to patients and doctors so that they can make more informed decisions among the treatment options. Biopsy definitely improves the informed consent process for many patients.”

Dr. Abel pointed out renal mass biopsy has limitations, including the small possibility of undergrading or understaging. “Undergrading of biopsy was demonstrated in the series but not mentioned in the conclusions,” Dr. Abel said. “The risk of undergrading/ understaging must be considered when using renal mass biopsy for risk stratification, especially in otherwise healthy patients.” n Viktor Gruenwald, MD, and colleagues at the Medical School of Hannover in Hannover, Germany, reported on a study of 4,736 mRCC patients demonstrating that RCC early tumor shrinkage of 7% or 8% provides the optimal cut-off for predicting progression-free and overall survival, and that the conventional 30% tumor

The current tumor shrinkage threshold for prognosis is too high, data suggest. shrinkage threshold is too high. The researchers used data from Pfizersponsored clinical trials with sorafinib, axitinib, sunitinib, interferon-alfa, and temsirolimus. The researchers evaluated early tumor shrinkage at the first post-baseline scan. They classified patients as responders if progressionfree and overall survival times (7 and 20 months, respectively) were above the median.

The study cohort was 71% male and had a median age of 59 years; 67% of patients were treatment naïve. n

© BSIP / SCIENCE SOURCE

Small renal masses

Renal & Urology News 7

6/19/15 10:17 AM

8 Renal & Urology News JUNE/JULY 2015 www.renalandurologynews.com

Younger Donor Kidneys Better for Elderly Patients PHILADELPHIA—Elderly kidney transplant recipients have worse survival odds if they receive organs from elderly rather than younger deceased donors, study findings presented at the 2015 American Transplant Congress suggest.

In addition, elderly recipients who receive elderly donation-after-cardiacdeath (DCD) kidneys have a greater risk of graft loss and worse renal function.

Using the Dutch Organ Trans­plan­ta­ tion Registry, Stefan P. Berger, MD, of University Medical Center Groningen in The Netherlands, and colleagues, analyzed patient and graft survival and renal function of elderly renal transplant recipients (aged 65 years and older) who received a DCD or donation-after-brain-death (DBD) kidneys from a donor aged 65 years and older.

They compared outcomes with the outcomes of DCD or DBD kidneys from donors younger than 65 years transplanted into elderly recipients.

Compared with elderly recipients of DBD kidneys from younger donors (reference group), elderly recipients of DCD and DBD kidneys from elderly donors had a 2.2 and 1.7 times increased risk of death, respectively, in adjusted analyses. Transplantation of elderly DCD kidneys was associated

with a 1.75 times higher 5-year crude graft loss risk compared with the reference group. Additionally, results showed that 63.8% of elderly recipients of elderly DCD kidneys had an estimated glomerular filtration rate below 30 mL/min/1.73 m 2 at 1 year posttransplant compared withS:7” 26% of the

reference group, a significant difference between the groups.

Dr. Berger’s team noted that 19% of all Dutch deceased-donor kidneys from 2011 to 2013 were from elderly donors, and these accounted for 63% of Dutch deceased-donor kidneys transplanted into elderly recipients. n

GFR Decline Greater with Warfarin PATIENTS WITH atrial fibrillation receiving oral anticoagulation therapy experience a significantly greater decline in renal function with warfarin than dabigatran, according to a study published in recently in the Journal of the American College of Cardiology (2015;65:2481-2493).

Michael Böhm, MD, of the Universitätsklinikum des Saarlandes, Homburg, Germany, and colleagues, studied 16,490 patients enrolled in the RE-LY trial. Investigators randomized patients to receive warfarin or dabigatran 110 mg or 150 mg twice daily.

The glomerular filtration rate (GFR) decreased in all groups. After an average of 30 months, mean GFR declined by 3.68 mL/min among warfarin recipients compared with a 2.57 and 2.46 mL/min decline in the dabigatran 110 mg and 150 mg groups, respectively.

Patients in the dabigatran 110 mg and 150 mg groups had a significant 19% and 21% lower risk of experiencing a greater than 25% decrease in GFR

INDICATION AURYXIA is a phosphate binder indicated for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis.

IMPORTANT SAFETY INFORMATION Contraindication: AURYXIA is contraindicated in patients with iron overload syndromes.

Iron Overload: Iron absorption from AURYXIA may lead to excessive elevations in iron stores. Assess iron parameters, serum ferritin and TSAT, prior to and while on AURYXIA. Patients receiving IV iron may require a reduction in dose or discontinuation of IV iron therapy.

Overdose: AURYXIA contains iron. Iron absorption from AURYXIA may lead to excessive elevations in iron stores, especially when concomitant IV iron is used.

Accidental Overdose of Iron: Accidental overdose of iron containing products is a leading cause of fatal poisoning in children under 6 years of age. Keep this product out of the reach of children.

Patients with Gastrointestinal Bleeding or Inflammation: Safety has not been established.

Pregnancy Category B and Nursing Mothers: Overdosing of iron in pregnant women may carry

compared with warfarin recipients. n

Auryxia_News_RUN0715.indd 8

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B:15.5” T:15.5”

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Renal & Urology News 9

Study: Patient Survival Better with HHD than PD B:15.5” T:15.5”

HOME hemodialysis (HHD) is associated with better patient survival than peritoneal dialysis (PD), a new study suggests.

The study included 11,416 patients on incident home dialysis at 90 days after initiating renal replacement therapy (RRT). The group included 10,710

patients on PD (median age 62 years) and 706 on HHD (median age 50 years). The patients were enrolled in the Australian and New Zealand Dialysis and Transplantation Registry study.

The PD and HHD groups had 4,970 and 86 deaths, respectively. Results showed that 5-year S:7”survival rates were

significantly higher among HHD than PD patients (85% vs. 44%). HHD was associated with a significant 53% decreased risk of death and a significant 66% decreased risk of technique failure, the researchers, led by David W. Johnson, MBBS, PhD, of Princess Alexandra Hospital in Brisbane,

Australia, reported online ahead of print in the Clinical Journal of the American Society of Nephrology.

The investigators noted that few studies have directly compared clinical outcomes associated with HHD and PD, and none have specifically evaluated patients starting RRT with a home-based modality.n

For the control of serum phosphorus levels in patients with chronic kidney disease on dialysis

AURYXIA™ (ferric citrate) IS THE FIRST AND ONLY ABSORBABLE-IRON–BASED PHOSPHATE BINDER CLINICALLY PROVEN TO MANAGE HYPERPHOSPHATEMIA1-6

• Proven control of serum phosphorus within KDOQI guidelines (4.88 mg/dL at Week 56)7,8 • Demonstrated safety and tolerability profile over 52 weeks B:10.25”

S:10”

T:10.25”

• Each AURYXIA tablet contains 210 mg ferric iron, equivalent to 1 g ferric citrate

References: 1. Fosrenol [package insert]. Wayne, PA: Shire US, Inc.; 2014. 2. Phoslyra [package insert]. Waltham, MA: Fresenius Medical Care North America; 2011. 3. PhosLo Gelcaps [package insert]. Waltham, MA: Fresenius Medical Care North America; 2012. 4. Renagel [package insert]. Cambridge, MA: Genzyme Corporation; 2014. 5. Renvela [package insert]. Cambridge, MA: Genzyme Corporation; 2014. 6. Velphoro [package insert].

Waltham, MA: Fresenius Medical Care North America; 2014. 7. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 Suppl 3):S1-S201. 8. Data on File 1, Keryx Biopharmaceuticals, Inc.

n

a risk for spontaneous abortion, gestational diabetes, and fetal malformation. Rat studies have shown the transfer of iron into milk. There is possible infant exposure when AURYXIA is taken by a nursing woman.

e atal his

Pediatric: The safety and efficacy of AURYXIA have not been established in pediatric patients.

Adverse Events: The most common adverse events with AURYXIA were diarrhea (21%), nausea (11%), constipation (8%), vomiting (7%), and cough (6%).

Gastrointestinal adverse reactions were the most common reason for discontinuing AURYXIA (14%).

Auryxia_News_RUN0715.indd 9

Drug Interactions: Doxycycline should be taken at least 1 hour before AURYXIA. Consider separation of the timing of the administration of AURYXIA with drugs where a reduction in their bioavailability would have a clinically significant effect on safety or efficacy.

Please see Brief Summary on following page.

You may report side effects to Keryx at 1-844-44KERYX (844-445-3799).

©2015 Keryx Biopharmaceuticals, Inc. 01/15 PP-AUR-US-0075

6/19/15 10:52 AM

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High n-3 PUFA Intake Improves Post-Tx Survival RENAL TRANSPLANT recipients may benefit from marine n-3 polyunsaturated fatty acids (PUFAs) in terms of reduced overall and cardiovascular mortality risk, according to a new study.

Ivar A. Eide, MD, of Oslo University Hospital in Norway, and colleagues conducted an observational cohort

study of 1,990 Norwegian recipients of a renal transplant. The investigators measured the marine n-3 PUFA levels in plasma phospholipids using gas chromatography 10 weeks after transplantation. Of the 1,990 patients, 406 (20.4%) died during a median followup period of 6.8 years.

T:7”

Compared with patients in the bottom quartile of PUFA level, those in the top quartile had a significant 67% and 88% lower risk of all-cause and cardiovascular mortality, respectively, in a fully adjusted model. Dr. Eide’s team reported online ahead of print in the Clinical Journal of the American Society

BRIEF SUMMARY AURYXIA™ (ferric citrate) tablets contain 210 mg of ferric iron equivalent to 1 g ferric citrate for oral use.

INDICATIONS AND USAGE AURYXIA is a phosphate binder indicated for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis.

CONTRAINDICATIONS AURYXIA is contraindicated in patients with iron overload syndromes (eg, hemochromatosis).

WARNINGS AND PRECAUTIONS Iron Overload: Iron absorption from AURYXIA may lead to excessive elevations in iron stores. Increases in serum ferritin and transferrin saturation (TSAT) levels were observed in clinical trials. In a 56-week safety and efficacy trial in which concomitant use of AURYXIA and IV iron was permitted, 55 (19%) patients treated with AURYXIA had a ferritin level >1500 ng/mL as compared with 13 (9%) patients treated with active control.

Assess iron parameters (eg, serum ferritin and TSAT) prior to initiating AURYXIA and monitor iron parameters while on therapy. Patients receiving IV iron may require a reduction in dose or discontinuation of IV iron therapy.

Accidental Overdose of Iron: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6 years of age.

Keep this product out of the reach of children. In case of accidental overdose, call a doctor or poison control center immediately.

Patients with Gastrointestinal Bleeding or Inflammation: Patients with inflammatory bowel disease or active, symptomatic gastrointestinal bleeding were excluded from clinical trials. Safety has not been established in these populations.

ADVERSE REACTIONS Adverse reactions to a drug are most readily ascertained by comparison with placebo, but there is little placebo-controlled experience with AURYXIA, so this section describes adverse events with AURYXIA, some of which may be disease-related, rather than treatment-related. A total of 289 patients were treated with AURYXIA and 149 patients were treated with active control (sevelamer carbonate and/or calcium acetate) during the 52-week, randomized, open-label, active control phase of a trial in patients on dialysis.

A total of 322 patients were treated with AURYXIA for up to 28 days in three short-term trials. Across these trials, 557 unique patients were treated with AURYXIA; dosage regimens in these trials ranged from 210 mg to 2,520 mg of ferric iron per day, equivalent to 1 to 12 tablets of AURYXIA. In these trials, adverse events reported for AURYXIA were similar to those reported for the active control group. Adverse events reported in more than 5% of patients treated with AURYXIA in these trials included diarrhea (21%), nausea (11%), constipation (8%), vomiting (7%), and cough (6%).

During the 52-week active control period, 60 patients (21%) on AURYXIA discontinued study drug because of an adverse event, as compared to 21 patients (14%) in the active control arm. Patients who were previously intolerant to any of the active control treatments (calcium acetate and sevelamer carbonate) were not eligible to enroll in the study. Gastrointestinal adverse events were the most common reason for discontinuing AURYXIA (14%).

AURYXIA is associated with discolored feces (dark stools) related to the iron content, but this staining is not clinically relevant and does not affect laboratory tests for occult bleeding, which detect heme rather than non-heme iron in the stool.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. It is not known whether AURYXIA can cause fetal harm when administered to a pregnant woman. Animal reproduction studies have not been conducted.

The effect of AURYXIA on the absorption of vitamins and other nutrients has not been studied in pregnant women. Requirements for vitamins and other nutrients are increased in pregnancy. An overdose of iron in pregnant women may carry a risk for spontaneous abortion, gestational diabetes, and fetal malformation.

Labor and Delivery: The effects of AURYXIA on labor and delivery are unknown.

Nursing Mothers: Data from rat studies have shown the transfer of iron into milk by divalent metal transporter-1 (DMT-1) and ferroportin-1 (FPN-1).

Hence, there is a possibility of infant exposure when AURYXIA is administered to a nursing woman.

Pediatric Use: The safety and efficacy of AURYXIA have not been established in pediatric patients.

Geriatric Use: Clinical studies of AURYXIA included 106 subjects aged 65 years and older (33 subjects aged 75 years and older). Overall, the clinical study experience has not identified any obvious differences in responses between the elderly and younger patients in the tolerability or efficacy of AURYXIA. OVERDOSAGE No data are available regarding overdose of AURYXIA in patients. In patients with chronic kidney disease on dialysis, the maximum dose studied was 2,520 mg ferric iron (12 tablets of AURYXIA) per day. Iron absorption from AURYXIA may lead to excessive elevations in iron stores, especially when concomitant IV iron is used.

In clinical trials, one case of elevated iron in the liver as confirmed by biopsy was reported in a patient administered IV iron and AURYXIA. PATIENT COUNSELING INFORMATION Dosing Recommendations: Inform patients to take AURYXIA as directed with meals and adhere to their prescribed diets. Instruct patients on concomitant medications that should be dosed apart from AURYXIA. Adverse Reactions: Advise patients that AURYXIA may cause discolored (dark) stools, but this staining of the stool is considered normal with oral medications containing iron.

AURYXIA may cause diarrhea, nausea, constipation, and vomiting. Advise patients to report severe or persistent gastrointestinal symptoms to their physician.

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RADICAL AND PARTIAL nephrectomy for renal cell carcinoma are associated with a similar risk of end-stage renal disease (ESRD), according to a study conducted in Taiwan.

Wei-Yu Lin, MD, of Chang Gung

Memorial Hospital in Chiayi, and colleagues studied a nationwide population-based cohort of 7,670 patients with RCC who underwent radical nephrectomy (RN) or partial nephrectomy (PN). From this group, the researchers propensity score matched 1,212 PN patients to 2,424 RN patients. The median follow-up for this cohort was 48 months.

ESRD developed in 70 patients (2.9%) in the RN group, for an incidence rate of 6.9 cases per 1,000 person-years, and 23 patients (1.9%) in the PN group, for an incidence rate of 5.5 cases per 1,000 personyears, the researchers reported in PLOS One (2015;10:e0126965). In adjusted analyses, the difference between treatment groups was not statistically significant.

The authors stated that their

Keryx Biopharmaceuticals, Inc. ©2015 Keryx Biopharmaceuticals, Inc. Printed in USA

ESRD Risk With RN, PN Comparable

T:10”

DRUG INTERACTIONS Doxycycline is an oral drug that has to be taken at least 1 hour before AURYXIA. Oral drugs that can be administered concomitantly with AURYXIA are: amlodipine, aspirin, atorvastatin, calcitriol, clopidogrel, digoxin, doxercalciferol, enalapril, fluvastatin, levofloxacin, metoprolol, pravastatin, propranolol, sitagliptin, and warfarin. There are no empirical data on avoiding drug interactions between AURYXIA and most concomitant oral drugs.

For oral medications where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, consider separation of the timing of the administration of the two drugs. The duration of separation depends upon the absorption characteristics of the medication concomitantly administered, such as the time to reach peak systemic levels and whether the drug is an immediate release or an extended release product. Consider monitoring clinical responses or blood levels of concomitant medications that have a narrow therapeutic range.

of Nephrology. In addition, patients in the top quartile had a significant 93% lower risk of sudden cardiac death and a 92% lower risk of stroke-related death.

The study had a number of strengths, the most important of which, according to the investigators, was the use of gas chromatography to measure individual plasma phospholipid fatty acids, “which in contrast to dietary questionnaires, correlates very well with actual marine n-3 PUFA intake.” Other strengths included a relatively long follow-up period and a well defined and large study population. Study limitations included a lack of dietary data to adjust for the full matrix of nutrients and the fact that they performed only a single measurement of plasma phospholipid marine n-3 PUFAs, they wrote. n

investigation is the first Asian study 01/15

on this topic. n

6/19/15 10:53 AM

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Renal & Urology News 11

BP Drug Start, Serious Falls Linked Initiating antihypertensive therapy increases the short-term risk in elderly patients, study finds all 16% increased odds of a serious fall injury; it was associated with a 15% and 20% increased odds among those with a diagnosis of hypertension and in those not hospitalized within 365 days prior to their fall, the researchers reported at the American Society of Hypertension 2015 Annual Scientific Meeting. Initiation of antihypertensive medication was not associated with increased odds of a serious fall injury beyond 15 days.

Dr. Shimbo’s group defined serious fall injuries based on emergency department and inpatient claims with an injury code for a non-pathologic fracture, brain injury, or dislocation of the hip, knee, shoulder, or jaw, along with a fall-related code, or with the requirement that there was no motor vehicle accident code in the absence of a fallrelated code. Patients were included in the study only if they had full Medicare free-for-service and pharmacy coverage.

The study findings are consistent with those of a study published in JAMA

Nearly One-Third of Deaths After PCI Due to AKI

increased odds of death, with 31.4% of deaths attributable to AKI, Dr. Gurm’s group reported.

Although the study showed that a high contrast dose at time of PCI significantly increases the risk of AKI, the researchers stated that contrast dosing is only a minor contributor to the overall burden of AKI in this population. “Thus, efforts to reduce contrast dose, although worthwhile, would only moderately impact in-hospital mortality rates,” they wrote. “This suggests that efforts to reduce the incidence and impact of AKI need to move beyond contrast media choice and dosing and be targeted at other mechanistic pathways of AKI, such as inflammation and the potential role for statin preloading.”

The researchers found that the mortality risk associated with AKI was highest in those with cardiogenic shock, cardiac arrest, or presenting with ST-segment elevation myocardial infarction.

The researchers explained that AKI following PCI has a number of potential causes, including acute tubular necrosis from poor perfusion, nephrotoxicity from contrast media, use of nephrotoxic medications, cholesterol embolization, procedure-related factors, or a combination of these. n

ALMOST ONE-THIRD of in-hospital mortality after percutaneous coronary intervention (PCI) is attributable to acute kidney injury (AKI), according to new study findings.

Researchers calculated that 1 death could be prevented for every 9 cases of AKI that is successfully avoided, according to a report published online in Circulation. Cardiovascular Interventions (2015;8:e002212).

“These study findings stress the need for developing effective AKI preventive strategies beyond minimization of contrast dose,” the authors concluded.

Using a regional registry of all patients undergoing PCI in Michigan, a team led by Hitinder S. Gurm, MD, of the University of Michigan Cardiovascular Center in Ann Arbor, identified 92,317 PCI patient who underwent PCI from 2010 to 2013. AKI developed in 2,141 (2.3%) of these patients. The researchers propensity score-matched 1,371 of the patients with AKI to 5,484 controls.

AKI was associated with a 12.5 times

ASH-Falls-News_RUN0715.indd 11

The risk of serious fall injuries is higher within 15 days of starting antihypertensive therapy.

Internal Medicine (2014;174:588-595), which found that moderate-intensity and high-intensive antihypertensive drug treatment were associated with a 40% and 28% increased risk of serious fall injuries compared with not tak-

ing antihypertensive medications. The study included 4,961 community-living hypertensive adults older 70 years.

In a study published recently online ahead of print in Hypertension, however, researchers found that in relatively healthy elderly individuals, antihypertensive drugs were not associated with an increased risk of falls. The study, led by Lewis A. Lipsitz, MD, of the Hebrew SeniorLife Institute for Aging Research in Boston, included 598 hypertensive community-dwelling patients aged 70–97 years. Patients taking ACE inhibitors had a significant 38% decreased 1-year risk of injurious falls, and those taking calcium channel blockers had a significant 38% decreased risk of all falls and 43% decreased risk of indoor falls compared with individuals not taking these drugs, the researchers reported. In addition, higher doses of both classes of these drugs were associated with a lower fall risk. n

Post-Transplant 30% eGFR Decline May Worsen Outcomes PHILADELPHIA—A 30% or greater

plant, 10% of patients experienced

decline in estimated glomerular

at least a 30% decline in eGFR. This

filtration rate (eGFR) between years

decline was associated with a 6-fold

1 and 3 after kidney transplantation

increased risk in death-censored graft

is associated with an increased risk

loss and a 2.3 times increased risk of

of death-censored graft failure and

patient death compared with stable

patient death, according to study find-

eGFR, the researchers reported.

ings presented at the 2015 American Transplant Congress.

This magnitude of decline in eGFR potentially may be useful as a surro-

Greater rates of eGFR decline were associated with progressively higher risks of these outcomes, according to the investigators.

gate marker in clinical trials looking at

The findings of the new study echo

the impact of interventions to prevent

those of a recent study examining how

these outcomes, according to co-

eGFR declines affect the subsequent

investigator Steven J. Chadban, MBBS,

risk of end-stage renal disease (ESRD)

PhD, who presented study findings.

and mortality in patients with chronic

Using data from the Australia and

kidney disease (CKD). The study, pub-

New Zealand Dialysis and Transplant

lished in the Journal of the American

Registry, Dr. Chadban and his col-

Medical Association (2014;311:2518-

leagues studied 7,949 kidney trans-

2531), demonstrated that a 30%

plants performed from 1995–2009.

or greater decline in eGFR from a

During a total follow-up of 71,845

baseline of less than 60 mL/min/1.73

patient-years, recipients experienced

m2 over 2 years was associated with

1,121 graft losses and 1,192 deaths.

an increased risk of both outcomes in

Between years 1 and 3 post-trans-

adjusted analyses. n

© THINKSTOCK

NEW YORK—Initiating or adding antihypertensive medications is associated with an increased short-term risk of serious fall injuries in elderly patients, according to new study findings.

Daichi Shimbo, MD, of Columbia University Medical Center in New York, and collaborators studied 90,127 Medicare beneficiaries aged 65 years and older who suffered a serious fall injury.

Initiation of antihypertensive medication and a diagnosis of hypertension in the 365 days prior to filling a first antihypertensive medication prescription were associated with 36% increased odds of a serious fall injury within 15 days. Initiation of antihypertensive medication was associated with a significant 38% increased odds of a serious fall injury within 15 days among beneficiaries not hospitalized in the 365 days before their fall.

For beneficiaries already on antihypertensive medication, starting a new class of medication was associated with an over-

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■ ERA-EDTA 2015

Renal & Urology News 15

European Renal Association-European Dialysis and Transplant Association 52nd Congress, London

Post-Transplant UTI Risk Factors ID’d Female kidney recipients have a nearly 7-fold higher risk of UTI than their male counterparts FEMALE GENDER, ureteral catheterization, and comorbidities are among the risk factors for urinary tract infection (UTI) among renal transplant recipients, new study findings suggest.

The observational, cross-sectional study, by Alparslan Ersoy, MD, of Uludag University Medical School in Bursa, Turkey, and colleagues, included 213 patients who underwent renal transplantation. Of these, 106 were diagnosed with 171 episodes of UTI, with recurrent UTI in 39 cases (36.8%). First UTIs occurred at a mean of 13.7 months after transplantation. The UTI group had a significantly greater proportion of female recipients than the non-UTI group (60.4% vs. 21.5%).

The rate and duration of ureteral catheterization were significantly greater in the UTI than non-UTI group (48.1% vs. 28% and 66.1 vs.

55.9 days, respectively), as was the pro-

Vitamin C May Improve Anemia Care ASCORBIC ACID may help to manage anemia in hemodialysis (HD) patients, according to a study.

Romanian researchers randomized 69 HD patients with anemia to receive, for 12 months, 300 mg intravenous ascorbic acid 3 times a week, or placebo.

After the first 3 months, the ascorbic acid group had a sig-

portion of patients with comorbidities (43.4% vs. 27.1%).

In regression analysis, female gender, ureteral catheterization, and co-morbid diseases were independently associated with a significant 6.8, 2.8, and 2.3 times increased risk of UTI, respectively. The risk of recurrent UTIs was 4.2 times higher among diabetic than non-diabetic recipients. Among patients with recurrent UTI, 1 had 5 episodes, 4 had 4 episodes, 15 had 3 episodes, and 19 had 2 episodes.

The UTI and non-UTI groups were similar with respect to donor type, primary disease, diabetes mellitus, acute rejection, and surgical complications, according to the investigators.

In a separate study of 1,019 transplant recipients presented at the meeting, researchers in Kuwait identified age, female gender, thymoglobulin induction, pretransplant urologic problems, and hepatitis C as risk factors for recurrent UTI in renal transplant recipients.

The investigators divided patients into 2 groups: patients who had recurrent UTI (group 1) and those who had no or non-recurrent UTI) (group 2). Group 1 was significantly younger than group 2 (34.9 vs. 42.8 years); they also had a significantly higher proportion of

Recurrent UTIs are 4.2 times more likely to occur in diabetics than non-diabetics. female patients. Recurrent UTI did not adversely impact graft or patient survival.

These new studies add to a growing body of literature on UTI risk factors after kidney transplantation. In a recently published study in Medicine (2015;94:e594), researchers demonstrated that vitamin D

deficiency is an independent risk factor for post-transplant UTI. A study published in Transplantation Proceedings (2014;46:3455-3458) found that the only risk factor for UTI after renal transplantation was gender, with female recipients at higher risk than male recipients.

Also in Transplantation Proceedings (2014;46:1757-1759), investigators reported on a study that identified older age (independent of gender), biopsy-proven acute rejection episodes, and receipt of kidneys from deceased donors as UTI risk factors. For female recipients, an additional risk factor was the number of pretransplant pregnancies. Researchers reported in Transplantation (2013;96:732-738) that their study of 1,166 kidney transplant recipients showed that post-transplant UTI risk factors included female gender, prolonged use of Foley catheters, ureteral stents, age, and delayed graft function. n

Dialysis Pt Mortality Higher in Winter MORTALITY among dialysis patients follows a seasonal pattern, with higher death rates during winter months, according to a new Austrian study presented at the European Renal AssociationEuropean Dialysis and Transplant Association 52nd congress in London.

The retrospective cohort study,

by Claudia Friedl, of the Medical University of Graz, Austria, and colleagues, included 2,438 dialysis patients: 902 women and 1,536 men. Patients had a mean age of 63.9 years. During the study, 1,836 patients died. The researchers reported that all-cause mortality was

highest in winter (1.60 deaths per 100 patient-months) and lowest in summer (1.06 deaths per 100 patient-months).

The monthly mortality rate per 100 patient months was calculated by dividing the number of deaths in a specified month by the number of patients at risk at the start of the respective month and then multiplying by 100.

The investigators concluded that physicians may need to pay more attention to preventive measures like seasonal vaccination or intensive control of cardiovascular risk factors such as high blood pressure, especially in winter.

Dr. Friedl’s team noted that their study findings are similar to those of a U.S. study. That study, by Len A. Usvyat, PhD, of the Renal Research Institute in New York, and colleagues, included 15,056 dialysis patients from 6 states of varying climates. All-cause mortality was significantly higher in winter compared with other seasons: 14.2 deaths per 100 patient-years in winter compared with 13.1 in spring, 12.3 in autumn, and 11.9 in summer, the authors reported in the Clinical Journal of the American Society of Nephrology (2012;7:108-115). n

nificantly greater rise in hemoglobin compared with the control group.

Doses of erythropoiesis-stimulating agent decreased significantly after 6 months only in the intervention arm, but remained stable in the control group. Serum ferritin increased only in patients on ascorbic acid and only after 6 months. Iron requirements decreased significantly only in the intervention group. n

EDTA_RUN0715.indd 15

Kidney Transplants Found to Decrease Stroke Risk PATIENTS with end-stage renal disease (ESRD) who have had a kidney transplant have nearly half the risk of stroke compared with patients on hemodialysis, Australian researchers reported.

Philip Masson, MBChB, of the University of Sydney, and colleagues examined stroke risk factors in a retro-

spective cohort study of 10,745 ESRD patients. The cohort experienced 640 stroke events during 47,472 personyears of follow-up.

Compared with dialysis patients, kidney transplant recipients had a 46% lower risk of stroke. Patients who had a previous stroke had a 2.5 times higher

risk of stroke than those who never had a stroke. Stroke risk was 6 times higher in patients aged 50–70 years than in those aged younger than 30 years.

Smoking increased the risk of stroke by 55% compared with never having smoked. Women were 39% more likely than men to suffer a stroke. n

6/19/15 10:59 AM

16 Renal & Urology News JUNE/JULY 2015 www.renalandurologynews.com

■ AUA 2015

American Urological Association 2015 Annual Meeting, New Orleans

Treating RCC Metastases Ups Survival Metastasectomy and intensive local therapy to bone lesions found to decrease risk of death TREATMENT OF metastatic lesions may have a role in improving survival of patients with metastatic renal cell carcinoma (mRCC), new studies suggest.

For example, in a retrospective study of 119 mRCC patients who underwent radical nephrectomy, Hironori Fukuda, MD, and colleagues at Tokyo Women’s Medical University in Japan found that the 55 patients treated with metastasectomy had a significantly better 5-year overall survival rate compared with the 64 patients who did not (68% vs. 27%).

Of the 119 patients, 48 (40%) had lung-only metastases and 71 (60%) had metastases at sites other than the lung.

For both groups, the overall 5-year survival rate was significantly better among those who underwent metastasectomy than those who did not (82.3% vs.

51.4% for those with lung-only metastases and 57.4% vs. 7.1% for those with non-lung-only metastases).

Of the 55 patients who underwent metastasectomy, 9 (16%) had incomplete metastasectomy whereby all lesions were not resected. The estimated 5-year cancer-specific survival rate of these patients was lower than those who had complete resection (68.6% vs. 78.2%), but higher than patients who did not undergo metastasectomy (28.5%).

In multivariate analysis, complete metastasectomy was independently associated with a significant 69% decreased risk of death.

In a separate study, investigators at Asan Medical Center, University of Ulsan College of Medicine in Seoul, South Korea, reviewed the medical records of 323 mRCC patients who received no systemic treatment. Of these, 13 underwent complete metastasectomy followed by targeted therapy, 48 underwent partial metastasectomy followed by targeted therapy, and 262 received targeted therapy only. The median overall survival was 70.9, 29.9, and 19.4 months in the complete, partial, and non-metastasectomy groups, respectively. On multivariate analysis, complete metastasectomy was associated with a significant 70% decreased risk of death.

The investigators concluded that aggressive metastasectomy should be considered in mRCC patients if the metastases are surgically resectable.

In a third study, Japanese researchers found that intensive local therapy to bone lesions in mRCC patients with bone metastases was associated with a significant 55% decreased risk of death compared with less intensive or

Metastasectomy Results Promising A study by South Korean investigators found that patients with metastatic renal cell carcinoma who undergo either complete or partial metastasectomy have increased median overall survival rates compared with those who do not.

80 70

n Complete metastasectomy

60

n Partial metastasectomy

50

n No metastasectomy

40 30 20 10 0

70.9 months

29.9 months

19.4 months

Source: You D. Impact of metastasectomy on prognosis of patients with metastatic renal cell carcinoma in the targeted therapy era. Presented at the American Urological Association 2015 annual meeting in New Orleans. Abstract MP69-13.

no local therapy in multivariate analysis. The retrospective study, by Hiroshi Fukushima, MD, and colleagues at Tokyo Metropolitan Cancer and Infectious Diseases Center, included 70 mRCC patients with bone metastases. Of these, 27 (39%) had multiple bone metastases. Bone metastasis sites included the vertebra (38 patients), pelvis (18 patients), long bones (21 patients), and other sites (23 patients).

The investigators defined intensive local therapy as surgical resection with a wide margin or radiotherapy with a biologically effective dose of 140 Gy or

greater to sites of metastasis. The investigators classified patients into 3 groups: intensive local therapy to bone metastases with curative intent to the other lesions (level 1, 19 patients); intensive local therapy to bone metastases without curative intent to the other lesions (level 2, 15 patients); and less intensive or no local therapy (level 3, 36 patients).

During a median follow-up of 13 months, 37 patients (53%) died. The median overall survival rate was 22 months. Patients in level 1, 2, and 3 had 1-year overall survival rates of 84%, 70%, and 51%, respectively. n

Adherence to Maintenance NMIBC Therapy Poor ADHERENCE TO maintenance therapy for non-muscle invasive bladder cancer (NMIBC) is poor in real-world clinical practice, according to new findings.

In fact, adherence rates were worse than those observed in most clinical trials. The study also showed that patients tended to be more compliant with a monthly schedule than a Lamm schedule, but both protocols were associated with similar adherence rates at 1 year, suggesting that overall length of therapy drives compliance more than the difference between schedules, said Alexander M. Helfand, BA, a fourth-year medical student at the Sackler School of Medicine at Tel Aviv University in Israel and a research fellow in urology at the University of Michigan in Ann Arbor, who presented study findings.

RC-metastases-News_RUN0715.indd 16

AUA guidelines recommend that NMIBC patients at high risk for progression receive bacillus CalmetteGuérin (BCG) maintenance therapy and patients with recurrent, multifocal, or large- volume Ta low-grade malig-

‘Real-world’ rates are lower than those observed in most clinical trials. nancy receive BCG or mitomycin induction with optional maintenance.

Still, in clinical trials, adherence to maintenance schedules has been poor in clinical trials. Little is known about compliance with maintenance therapy

in a real-world clinical practice setting, outside the controlled environment of clinical trials, Helfand noted.

Helfand and his colleagues at Beilinson Hospital in Israel conducted a retrospective review of 729 patients in their clinic who received BCG or mitomycin for bladder cancer stage T1 or below. They defined the complete maintenance protocol as an induction of 6 weekly instillations, followed by either a Lamm schedule consisting of 3 weekly BCG instillations at 3 and 6 months after induction and every 6 months thereafter for 3 years or 9 monthly treatments starting 3 months after induction. They defined compliance as receiving 9 months of monthly or 21 weeks of Lamm maintenance.

The cohort started a total of 861 induction cycles (63% with BCG and 37%

with mitomycin) and received 8,247 instillations. Results showed that 54% of patients on the Lamm schedule completed at least 9 BCG instillations in the first year after induction, 26% completed 15 instillations in 2 years, and only 10% completed 3 years of treatment with 21 maintenance instillations. The 10% compliance rate was lower than that observed in most prospective trials using the 3-year maintenance protocol.

With regard to the patients undergoing monthly maintenance, patients received a median of 6.9 monthly BCG instillations or 6.6 mitomycin instillations. Helfand’s group found that 55% of patients completed 1 year of monthly maintenance, a rate similar to that observed among patients on the Lamm schedule. In addition, 47% of patients on monthly mitomycin completed 1 year of treatment. n

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Renal & Urology News 17

PHI Predicts Prostate Cancer Recurrence Risk PREOPERATIVE Prostate Health Index (PHI) levels may predict early biochemical recurrence (BCR) in prostate cancer patients, according to a new study.

For the study, investigators led

by Giovanni Lughezzani, MD, of Humanitas University in Milan, Italy, examined the value of the Beckman

Coulter PHI, a blood test that measures total, free, and [-2]proPSA, to predict BCR. A total of 313 patients had the preoperative test and subsequently underwent robot-assisted radical prostatectomy (RARP) for clinically localized prostate cancer (PCa). Patients receiving neoadjuvant or adjuvant therapy were

excluded. On biopsy, Gleason score was 6 in 55% of patients, 7 in 39%, and 8 or higher in 6%. The cohort had a median follow-up time of 28 months. Overall, 34 patients (10.9%) experienced BCR, including 16 (7%) of the 228 patients found to have organ-confined cancer at final pathology. The investigators defined

BCR as total PSA (tPSA) level of 0.2 ng/ mL or higher and rising after RARP. The 2-year biochemical-free survival rates were 92.5% overall and 96.7% among patients with organ-confined cancer, according to findings published online ahead of print in Urologic Oncology.

According to the researchers, the most significant PHI cutoff for discriminating between patients with and without BCR was 82. In the overall population, the 2-year BCR-free survival rate was 97.7% in patients with a preoperative PHI level less than 82 compared with 69.7% in patients with a PHI level of 82 or higher. In the subgroup with organ-confined PCa, the 2-year BCRfree survival rate was 98.0% in patients with a preoperative PHI level less than 82 compared with 83.3% in patients with a PHI level of 82 or higher, the investigators reported.

PHI levels may be useful in evaluating the need for early adjuvant radiotherapy.

The authors noted that “PHI level emerged as an independent predictor of BCR and was significantly more accurate than the currently used predictors of BCR, such as tPSA level, clinical/pathological category, and Gleason score, in both the preoperative and the postoperative settings.” They suggested that PHI levels may be useful in evaluating the need for early adjuvant radiotherapy and determining follow-up schedules post-prostatectomy.

Dr. Lughezzani’s team said their study provides the first evidence supporting the role of PHI level in predicting oncologic outcomes after RARP. As a next step, the researchers urge further validation of the PHI in studies with larger, more diverse populations, other treatment modalities, and with follow-up longer than 2 years.

Recently, another team of investigators reported in The Journal of Urology (2015;193:1163-1169) that the PHI improves detection of clinically significant PCa and could help decrease the number of unnecessary prostate biopsies. Using a 90% sensitivity cutoff for significant versus insignificant PCa (a PHI threshold of 28.6) could potentially avoid 30% of biopsies with indolent or no PCa compared with 21.7% using free PSA alone. n

PHI-BCR_RUN0715.indd 17

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18 Renal & Urology News JUNE/JULY 2015 www.renalandurologynews.com

Renal Cancers, Lithium Not Linked Findings from a new Danish study contrast with those of previous research were then matched by age and sex to 259,080 controls. Based on the Danish Prescription Registry, less than a quarter percent of cases and controls were taking lithium for at least 5 years.

According to findings published online ahead of print in the Journal of the American Society of Nephrology, longterm use of lithium was linked to a nonsignificant 30% increased odds of the cancers. Even in the worst case scenario, researchers estimated that it would take 3,091 person-years of lithium exposure to see 1 additional cancer case. Analyses by cancer stage and subtype also revealed only slight, non-significant increased odds. Results were adjusted for other drugs, diseases, and socioeconomic factors believed to affect the kidney.

“In conclusion, we can exclude any major effect of long-term lithium use on the risk of renal cancer or cancers of the renal pelvis or ureter,” the investigators wrote. “Although long-term lithium use may be associated with other renal

Non-Dialysis CKD-MBD Care Suboptimal

targets. Each of the 19 nephrology clinics involved in the study had their own clinical targets, although most generally followed Kidney Disease Outcomes Quality Initiative (KDOQI) recommendations.

The prevalence of therapeutic inertia was 34% at 6 months. It was defined as lack of phosphate binder prescriptions despite hyperphosphatemia; lack of calcium and vitamin D supplements despite hypocalcemia; or lack of phosphate binders and calcium and vitamin D supplements despite hyperparathyroidism.

Therapeutic inertia was highest for hyperphosphatemia at 54%. For example, 51% of the 212 patients with serum phosphate greater than 4.1 mg/dL received neither phosphate binders nor a prescription for a low-protein diet. PTH was off-target in two-thirds of patients.

“This significant difference between PTH and phosphate-calcium control in the follow-up of our cohort is likely the consequences of early onset of PTH elevation in the course of CKD,” the researchers wrote.

The likelihood of inadequate treatment overall decreased as CKD worsened to stages 4 and 5 (by 40% and 68%, respectively). The management of CKD-MBD in non-dialysis patients appears subpar, especially compared with the care of dialysis patients, according to the investigators. n

BY NATASHA PERSAUD A SIGNIFICANT proportion of nondialysis chronic kidney disease (CKD) patients have inadequately managed mineral bone density (MBD), according to a new Italian study. Therapeutic inertia appears to be a barrier to good care of these patients, researchers concluded.

For the study, Maurizio Gallieni, MD, of the Nephrology and Dialysis Unit, Ospedale San Carlo Borromeo, University of Milan, and colleagues prospectively evaluated CKD-MBD management in 727 non-dialysis, Caucasian patients over 2 visits occurring 6 months apart. All patients had 1 or more markers of MBD, including hyperphosphatemia, hypocalcemia, and/or hyperparathyroidism, and all were considered compliant with prescribed therapy.

According to results published online ahead of print in the Journal of Nephrology, more than 65% of the patients did not reach parathyroid hormone (PTH) targets, 19% missed calcium targets, and 15% missed phosphate

Lithium-News_RUN0715.indd 18

Long-term use of lithium does not appear to induce renal cancer, researchers conclude.

adverse effects, it is reassuring that lithium use does not appear to induce renal cancer, and that lithium can be kept on the armamentarium for conditions as debilitating as bipolar disorder and severe unipolar depression.”

The researchers noted that their findings might be affected by surveillance bias, “as lithium users frequently undergo renal function tests and generally have more frequent contact with the health care system compared with individuals without bipolar disorder or severe depression, and no lithium use.”

In a study published recently in Kidney International (2014;86:184-190), French researchers found an increased risk of solid renal tumors associated with lithium treatment. The study included 170 patients treated with lithium for a mean duration of 21.4 years. Over a 16-year period, renal tumors developed in 14 subjects, reported Mohamad Zaidan, MD, of Necker Hospital, APHP, Paris Descartes University in Paris, and colleagues. Of these tumors, 7 were malignant and 7 were benign. The ratio of renal cancer was significantly greater in the lithium-treated patients compared with the general population, according to the researchers. n

Short-Term ADT Plus Radiation Associated with Better Outcomes SHORT-TERM androgen deprivation

13.5%, 11%, and 23.5% in arms 1, 2,

therapy (STADT) combined with radio-

and 3, respectively. The differences

therapy (RT) in men with intermediate-

between arms 1 and 3 and arms 2

risk prostate cancer is associated with

and 3 were statistically significant, but

superior outcomes compared with

the differences between arms 1 and 2

dose-escalated RT alone, researchers

were not, according to the investiga-

reported at the American Society of

tors. The 5- and 10-year disease-free

Clinical Oncology annual meeting in

survival (DFS) rates for arms 1, 2,

Chicago.

and 3 were 92.8%, 97.1%, and 85.5%,

Abdenour Nabid, MD, of Centre

respectively, and 78.4%, 78.3%, and

Hospitalier Universitaire de Sherbrooke

65.9%, respectively. The differences

in Sherbrooke, Quebec, Canada, and

in 5- and 10-year DFS rates between

colleagues studied 600 men with inter-

arms 1 and 3 and arms 2 and 3 were

mediate-risk prostate cancer (IRPC)

statistically significant, but the differ-

who were randomized to 6 months

ences between arms 1 and 2 were

of STADT and 2 levels of prostate RT

not. The researchers found no signifi-

doses of 70 (arm 1) or 76 Gy (arm 2)

cant differences among the 3 arms

or prostate dose-escalated RT alone at

with respect to overall survival.

76 Gy (arm 3). Subjects had a median

“In patients with IRPC, the use of

age of 71 years and median PSA level

STADT in association with RT, even

of 10 ng/mL. Patient characteristics

at lower doses, leads to a superior

were well balanced among the 3 arms.

biochemical control and DFS as com-

At a median follow-up of 6.5 years,

pared to dose-escalated RT alone,” the

biochemical failure occurred in 96

researchers concluded in their study

patients (16%). The failure rates were

abstract. n

© GIPHOTOSTOCK / SCIENCE SOURCE

BY NATASHA PERSAUD A LARGE, NATIONWIDE Danish study found no association between long-term lithium use and the risks of upper urinary tract cancers.

Previously, a small-scale study had found a strong link between lithium, a medication commonly used to treat bipolar affective disorders, and genitourinary cancers. Preliminary animal and human studies had also raised the possibility that lithium’s nephrotoxic effects extended to malignancy.

In Denmark, medical care is nationalized, allowing for comprehensive data capture on a population level. For the current study, investigators led by Anton Pottegård, PhD, a clinical pharmacist at the University of Southern Denmark, identified 6,477 histologically-verified upper urinary tract cancers cases from the Danish Cancer Registry between 2000 and 2012. The cancers included a first-time diagnosis of invasive cancer of the kidney, renal pelvis, or ureter. Cases

6/19/15 11:07 AM

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Renal & Urology News 19

AKI Linked to Anabolic Steroids, Supplements PHYSICIANS IN IRAQ have linked acute kidney injury (AKI) in 4 bodybuilders to anabolic steroid injections and excessive protein and creatine intake, according to a new online report in the Clinical Kidney Journal.

The researchers, led by Michael D. Hughson, MD, of Shorsh General

Hospital in Kurdistan, said the patients presented with serum creatinine levels of 2.6–3.8 mg/dL and estimated glomerular filtration rate (eGFR) of 22–34 mL/min/1.73 m2. Renal biopsies revealed acute tubular necrosis.

The bodybuilders had injected testosterone proprionate and/or nandrolone

deconate at doses exceeding 400 mg per week. They also took commercial whey protein (78–104 g/day) and creatine (15 g/day) products at doses moderately higher than recommended.

Four weeks after the men discontinued the steroids and nutritional supplements, their serum creatinine returned

to the normal range below 1.4 mg/dL and eGFR rose to 60 mL/min per 1.73 m2), including in 2 of the patients who had more than 30% interstitial fibrosis and tubular atrophy on biopsy.

“The findings highlight a risk for acute and potentially chronic kidney injury among young men abusing anabolic steroids and using excessive amounts of nutritional supplements,” the authors wrote.

They considered the possibilities of hypervitaminosis-D induced nephrocalcinosis, calcium-alkali syndrome, and acute phosphate nephropathy, but found no compelling evidence for these conditions. They pointed rather to a combination of factors: “Our patients’ biopsies showed acute tubular necrosis that could be nephrotoxic or ischemic. In either case, this type of kidney injury…is a rare event and points to a causal relationship with supplement and steroid use.” The researchers believe inadequate hydration rather than direct toxicity probably precipitated the kidney injuries. n

Active IBD Harms Sexual Function ACTIVE INFLAMMATORY bowel disease (IBD) is associated with impaired sexual function, according to a new study published online ahead of print in the Journal of Sexual Medicine.

The study, led by Stephanie Both, PhD, of Leiden University Medical Centre in The Netherlands, included 168 female and 119 male IBD patients and a control group without IBD. The investigators assessed sexual function using the Female Sexual Function Index (FSFI) for women and the International Index of Erectile Function (IIEF) for men.

Overall, IBD patients did not differ significantly from controls in the prevalence of sexual dysfunction, but IBD patients with active disease had significantly lower scores on the FSFI and IIEF than the IBD patients in remission and controls, “indicating impaired sexual function during disease activity,” the researchers reported. Results showed that depression is the most important determinant for impaired sexual function in IBD. n

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6/19/15 11:09 AM

20 Renal & Urology News JUNE/JULY 2015 www.renalandurologynews.com

Diabetic Donor Kidneys Associated With Worse Transplant Outcomes Diabetic recipients are at especially high risk of graft loss and death

BY JODY A. CHARNOW PHILADELPHIA—Kidneys from diabetic donors are associated with an increased risk of graft loss and death compared with kidneys from nondiabetic donors, especially in diabetic recipients, investigators reported at the 2015 American Transplant Congress.

Using United Network for Organ Sharing registry data, Deirdre Sawinski, MD, and colleagues at the University of Pennsylvania in Philadelphia compared outcomes between pairs of recipients receiving a kidney from the same donor. They stratified subjects by the diabetes status of both donor and recipient. Among pairs in which 1 recipient was diabetic and the mate recipient was non-diabetic, 1,539 received diabetic donor kidneys and 21,459 received nondiabetic donor kidneys.

Compared with diabetic recipients of diabetic donor kidneys, non-diabetic recipients of diabetic kidneys had a significant 19% decreased risk of graft loss and a 35% decreased risk of death.

Additionally, results showed that diabetic recipients of a non-diabetic donor kidney had a 49% increased risk of graft loss and 1.9 times increased risk of death

compared with non-diabetic recipients of non-diabetic donor kidneys.

The study found no difference in the risk of graft loss when diabetic recipients of non-diabetic donor kidneys were compared with non-diabetic recipients of diabetic donor kidneys.

It may an advantage to consider a diabetic donor kidney over waiting on dialysis.

“Given the overall shortage of kidneys, these organs [from diabetics] should not be discarded; however, they should be allocated with caution,” Dr. Sawinski told Renal & Urology News.

“In particular I would recommend against their use in younger patients.”

Asked whether diabetic transplant candidates should be advised to wait for a non-diabetic donor, Dr. Sawinski said this would depend on the patient.

Clinicians need to consider that diabetics are at increased risk for death on dialysis, especially those with other comorbid

conditions, and take into account wait times in the patient’s region. “So I would argue that in high-risk patients—those with multiple medical comorbidities—or for those in long-wait areas, it still might be advantageous to consider a diabetic donor kidney over waiting on dialysis.”

A separate study presented at the meeting showed that transplanting kidneys from selected deceased donors with diabetes into recipients with diabetes does not worsen outcomes beyond the effect of recipient diabetes alone. Investigators at Toronto General Hospital studied a cohort of 67,815 kidney transplant recipients, of whom 1,404 were diabetics who received a kidney from a diabetic deceased donor. Compared with recipients who did not have diabetes, recipients with diabetes who received a kidney from a diabetic deceased donor did not have a significantly increased risk of total or death-censored graft failure, total mortality, or death with a functioning graft. Non-diabetic recipients who received a kidney from a non-diabetic donor, however, had a significantly increased risk of total mortality and death with a functioning graft compared with diabetic recipients. n

Readmission Risks Post-Tx Identified PHILADELPHIA—Patients discharged with home health (HH) or to a skilled nursing facility (SNF) after receiving a kidney transplant are more likely those discharged home to be readmitted to a hospital within 30 days, according to a study presented at the 2015 American Transplant Congress.

The study, led by Maha Mohamed, MD, Assistant Professor of Medicine at the University of Wisconsin in Madison, showed that the 30-day readmission rate for patients discharged home was 17.6%. By comparison, the rate for patients discharged with HH or to a SNF were 28.1% and 32.4%, respectively.

“Patients discharged home may be healthier and therefore have a lower readmission rate,” the researchers concluded in a poster presentation.

The authors suggested that the higher risk of readmission found among patients discharged with HH or to an SNF could be related to frequent patient assessments by HH nurse or SNF nurses, enabling them to catch complications and call providers. Dr. Mohamed and her colleagues also pointed out that healthcare providers

New Study Shows Tolvaptan’s ADPKD Benefits

and families may not want to send

PATIENTS WITH autosomal dominant polycystic kidney disease (ADPKD) and lower levels of kidney function may benefit from long-term treatment with tolvaptan, researchers concluded.

In a clinical trial, Wendy E. Boertien, MD, PhD, of University Medical Center Groningen in Groningen, The Netherlands, and colleagues enrolled 29 ADPKD patients who were stratified into 3 groups based on estimated glomerular filtration rate (eGFR) at inclusion: less than 30, 30–60, and greater than 60 mL/ min/1.73 m2. For all study analyses, the researchers used measured GFR (mGFR) determined by 125I-iothalamate clearance.

They evaluated changes in total kidney volume (TKV) with magnetic resonance imaging (MRI). Investigators evaluated subjects at baseline and after 3 weeks of treatment with tolvaptan given in increasing dosages, if tolerated (doses of 60, 90, and 120 mg/day in weeks 1, 2, and 3, respectively). Of the 29 patients, 27 com-

instead opt for HH, which may not be

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pleted the study. They had a mean age of 46 years, and their mGFR at baseline ranged from 18 to 148 mL/min/1.73 m2.

Tolvaptan treatment led to a significant increase in urine volume and free-water clearance and a significant decrease in urine osmolality and total kidney volume (TKV), the investigators reported in the American Journal of Kidney Diseases (2015;65:833-841). From baseline to final treatment, mean urine volume rose from 2,584 to 5,930 mL per 24 hours. Mean free-water clearance increased from -0.5 to 3.0 L/24 hours. Mean urine osmolality decreased from 359 to 139 mOsm/kg, and mean TKV decreased from 2,147 to 2,052 mL. The researchers also observed significant decreases in kidney injury marker excretion.

Changes in urine volume, free-water clearance, urine osmolality, and TKV were less pronounced in patients with lower baseline mGFRs. In subjects with lower mGFRs, however, the increase

in fractional free-water clearance was greater than in patients with higher GFRs. “This latter finding suggests that tolvaptan also is effective in patients with decreased kidney function,” the authors noted.

Although the study had a number of strengths, such as the use of measured GFR at 3 time points instead of using eGFR and inclusion of patients with a wide range of GFRs, the researchers acknowledged some limitations, including the relatively small number of participants and the absence of a control group.

In an accompanying editorial, Bharathi Reddy, MD, and Arlene B. Chapman, MD, of the University of Chicago, called the new findings “informative, hypothesis generating, and exciting and should give impetus for developing predictive models for benefit of tolvaptan therapy and the potential efficacy of tolvaptan use in patients with ADPKD and advanced kidney disease.” n

patients to an SNF so that the patients can have more independence, and the correct decision.

Dr. Mohamed’s group studied 529 initial kidney transplant recipients with 781 hospital discharges. Of these, 158 (20.2%) were readmitted within 30 days. Readmission rates did not differ significantly by race, sex, or marital status.

The researchers also looked at the effect of comorbidities—diabetes, hypertension, chronic kidney disease (CKD), coronary artery disease, peripheral vascular disease, and chronic obstructive pulmonary disease—on readmission risk. CKD was associated with a decreased risk. Patients with CKD had a 17.7% rate of readmission within 30 days compared with a 24.5% rate among those without CKD. n

6/19/15 11:13 AM

www.renalandurologynews.com JUNE/JULY 2015

■ AUA 2015

Renal & Urology News 21

American Urological Association 2015 Annual Meeting, New Orleans

Stone Medication Adherence Rates Low Only 50% of patients adhered to their treatment regimen, with adherence rates differing among agents Adherence Rates by Treatment Regimen A study found that adherence rates to medical therapies for preventing recurrent kidney stones varied by treatment regimen.

60 50 Percent

PATIENT ADHERENCE to selective medical therapy for kidney stones is low, according to researchers.

Yooni Yi, MD, and colleagues at the University of Michigan in Ann Arbor studied a cohort of 21,843 adults with kidney stones who were prescribed selective medical therapy.

Results showed that 50.1% adhered to their treatment regimen, with adherence rates differing among agents.

Adherence was highest for thiazide monotherapy (42%), followed by allopurinol monotherapy (8.2%), and alkali citrate monotherapy (2.9%).

Patient factors independently and significantly associated with lower odds of adherence included female gender, geographic region of residence, and being placed on combination therapy.

Patients who were salaried employees, those with lower Charlson scores, and those taking single agents had significantly greater odds of adherence.

“Our findings have implications for patients with kidney stones and their providers who care for them because non-adherence may mitigate treatment benefit or even cause harm,” Dr. Yi told Renal & Urology News.

Compared with men, women had 14% lower odds of adherence.

Compared with patients living in

40

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20 10 0

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Source: Yi Y et al. Adherence rates for selective medical therapy among patients with kidney stones. Presented as a poster at the American Urological Association 2015 annual meeting in New Orleans. Abstract MP16-19.

the Midwest, those in the Northeast, South, and West had 15%, 23%, and 20% lower odds of adherence. Salaried employees had 16% increased odds of adherence compared with non-salaried employees. Patients with a Charlson score of 0, 1, and 2 had 19%, 40%, and 5% increased odds of adherence compared with those who had a Charlson score of 3 or more. Patients on combination had 68% lower odds of adherence compared with those taking a single agent.

“Our study serves to inform providers about the potential opportunities to increase adherence,” Dr. Yi said.

“Urologists could consider a variety

of patient-level interventions, such as mobile applications tracking patients dosing schedules.”

The investigators used the proportionof-days covered (PDC) formula to measure adherence within the first 6 months of starting treatment. They defined adherence as a PDC of 80% or higher.

Dr. Yi’s group noted that AUA guidelines recommend a trial of thiazide diuretic, citrate, or allopurinol in patients with selected metabolic abnormalities.

They hypothesized that medication adherence rates are low because the benefits of preventive pharmacologic therapy may not be apparent to patients between stone episodes. The researchers said

their study is the first to evaluate adherence rates of preventive pharmacologic therapy for nephrolithiasis.

David S. Goldfarb, MD, a kidney stone specialist who was not involved in the new study, commented that the adherence rate found by Dr. Yi’s group is not necessarily low. He pointed out that the study lacked a control group for adherence that included patients with some other chronic condition, such as gout, that similarly is intermittent and not usually lethal. In addition, it is not known if the stone formers had urologic procedures performed or had single or multiple stones. “And we don’t know who wrote the prescription and under what circumstances,” said Dr. Goldfarb, Professor of Medicine and Physiology at the New York University (NYU) School of Medicine and clinical chief of nephrology at NYU Langone Medical Center. “At least these patients had a prescription for stone prevention written.”

Dr. Goldfarb cited a previous study published in The Journal of Urology (2014;191:376-380) showing that more than 90% of patients at high risk for stone recurrence did not have a 24-hour urine collection obtained. Without such a metabolic evaluation, these patients would not have had an opportunity to have a prescription written. n

PCa Metastasis Predictors Identified In AS Patients

BY JODY A. CHARNOW RESEARCHERS HAVE identified risk factors for the development of metastatic disease in men with low- or intermediate-risk prostate cancer (PCa) being managed with active surveillance.

These factors include a PSA doubling time of 3 years or less, a Gleason score of 7 at baseline, and more than 2 positive biopsy cores, according to Toshihiro Yamamoto, MD, and colleagues at Sunnybrook Health Science Centre, University of Toronto. In multivariate analysis, a PSADT of 3 years or less was associated with a significant 3.7 times increased risk of metastasis compared with a PSADT of more than 3 years. A Gleason score of 7 was associated with a significant 3 times increased risk of metastasis compared with a

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Gleason score of 6 or less. A biopsy finding of more than 2 positive cores was associated with a significant 2.7 times increased risk of metastasis compared the finding of 2 or fewer positive cores. Patients with intermediate-risk disease had a 2.7 times greater risk of metastases than the low-risk group.

Dr. Yamamoto’s group prospectively studied a cohort of 980 evaluable PCa patients, 22% of whom had intermediate-risk cancer. Of the 980 patients, 30 (3.1%) progressed to metastatic disease after a median of 6.9 years. Of these, 11 were still alive at last follow-up, 15 died from PCa, and 4 died from other causes. Bone was the most common site of metastasis, occurring in 17 patients.

“For low-risk patients managed with AS, the risk of prostate cancer metas-

tasis is very low,” Dr. Yamamoto told Renal & Urology News. “For intermediate-risk patients, more detailed subclassification will be needed to validate this approach.”

The proportion of Gleason pattern 4 on the diagnostic biopsy should be considered in decision making, he said. A PSA level greater than 10 ng/mL had no impact on metastasis.

Among intermediate-risk patients, those with a PSA level above 10 ng/mL and a Gleason score of 6 have an excellent outcome with AS, Dr. Yamamoto said. The rate of progression to metastatic disease was no greater than those with a PSA level below 10 ng/mL. Patients who had a Gleason score of 3+4 had a 3-fold greater risk of eventually developing metastatic disease, and

caution is warranted for those patients, he said.

Although the investigators believe AS is still appropriate for selected men with Gleason 3 plus small amounts of 4, extra scrutiny is required, either with magnetic resonance imaging (MRI), template biopsies, or genetic biomarkers, Dr. Yamamoto said. Although their data did not address this specifically since MRI was not part of the algorithm until recently, they believe that patients with a Gleason 3+4 cancer—with a low percentage of Gleason 4 (10% or less) and a negative multiparametric MRI or favorable genetic score—can be managed safely using this approach. Other patients may also be candidates, particularly older individuals, he said. n

6/19/15 11:16 AM

22 Renal & Urology News JUNE/JULY 2015 www.renalandurologynews.com

Practice Management ICD-10 replaces ICD-9 coding on October 1, but providers can take steps now to ensure a smooth transition BY TAMMY WORTH

O

n October 1, healthcare providers will need to switch from ICD-9 to ICD-10 coding, but they can take administrative measures to prepare for the transition, said Jim Daley, IT director for BlueCross BlueShield of South Carolina and workgroup co-chair for the Workgroup for Electronic Data Interchange. The first is to be mindful of the dates and staffing.

Providers would be remiss to have key staff members going on a 2-week vacation beginning October 1. It will also be important to have vendor and insurance contacts and their information readily available. If questions arise, providers will want to know whom to call and how to reach him or her quickly.

Daley also advises eliminating as much claim backlog prior to October 1 as possible. Any claims not submitted take away from cash on hand, which will be helpful if there are problems after the change. Healthcare providers should be prepared for potential changes in technology. This could be the case if practices get new billing systems or revise current systems to support ICD-10.

Training Providers do not have to learn all of the new 68,000 codes in ICD-10. The point is to know the codes that are used frequently in a particular office. An

impact assessment can show the most commonly used codes under ICD-9 and whether or not they will change under ICD-10. Most of these changes are related to increased documentation.

Shift in note taking For instance, a nephrourectomy is 1 code in ICD-9 and 12 codes in ICD-10, said Ed Hock, senior director at The Advisory Board Company. The change is related to new notes physicians will have to make to document such surgical aspects as the resection site, laterality, and approach used during the operation.

Coders will be responsible for assigning the correct codes under the new system, but it will be incumbent on physicians to understand how their documentation needs to change. The conversion won’t change the way providers practice, just the way they record it.

Many providers are worried about testing with vendors and insurers to guarantee they are prepared for the transition. Hock, however, said he worries less about vendor’s preparedness than a provider’s.

“You have to test the human element,” he said. “They worry about how ready the vendor is for them, but they should worry how ready they are for the vendor.”

With ICD-10, physicians have to understand how their documentation needs to change.

When the Centers for Medicare and Medicaid Services (CMS) tested their systems for readiness, 81% of claims submitted were accepted. Of those rejected, only about 6% failed because of ICD coding issues. There may be only a small number of denials, but Hock recommends providers have an “open” conversation about this with payers. This will allay some fears providers might have of working with payers on problems after the transition.

“Mistakes will be made no matter how prepared everyone is,” he said.

“They are going to have to talk about how they will go through this transition together.”

Daly recommends that providers test codes with payers, but not necessarily all of them. CMS is doing extensive testing and offering results publicly.

Odds are, if their systems work with hundreds of other users, they will work with yours. He recommends trying ICD-10 codes with a few payers to determine if the results are different than they would be under ICD-9.

It is possible that facilities could take revenue hits after switching from ICD-9 to ICD-10. Hock said a study conducted by his organization for a 250-bed hospital found that the facility would lose $1.5 million to $2 million during the year after the change because of things like insufficient documentation, payer denials, and coding problems. Hock said it will likely be “a series of small cuts” that will lead to losses.

As for vendor upgrades, they should have either already taken place or the vendor should be able to offer a very specific plan regarding their process.

Providers should be asking what the plan and costs are, when they will receive an upgrade, and what their testing plan is for your specific office.

Vendors should have precise answers to those questions. n

United States Bankruptcy Court, Middle District of Florida, Fort Myers Division, www.flmb.uscourts.gov, In re: Naples Nephrology, P.A., Debtor.; Chapter 11; Case No. 9:15-bk-707-FMD

NOTICE OF PROPOSED SALE OF ASSETS OF NAPLES NEPHROLOGY, P.A.

On May 8, 2015, the Debtor filed with the Bankruptcy Court (i) a term sheet executed April 30, 2015 (“Term Sheet”) by and between the Debtor and Total Kidney Oversight, P.A. (the “Purchaser”); (ii) a motion (the “Sale Motion”), seeking among other things, the authority of the Bankruptcy Court for the Debtor to sell the Assets (as defined in the Term Sheet), free and clear of all liens, claims, interests, and encumbrances, to the Purchaser in exchange for $25,000 in cash and assumption of certain non-employment-related liabilities, pursuant to the Term Sheet. The Bankruptcy Court has approved certain bidding procedures in connection with the Sale (the “Bidding Procedures”).

The Debtor owns and operates a medical practice that specializes in the care of patients with kidney disease, hypertension, kidney transplants, and kidney dialysis in

PracticeMan_RUN0715.indd 22

the Naples, Florida area. The Debtor currently employs four doctors and nine staff members. Further information on the Debtor’s practice is available upon request in compliance with the Bidding Procedures.

Prospective purchasers and other interested parties should review the Term Sheet, the Sale Motion, the Bidding Procedures, and other relevant documents on file with the Clerk of the Bankruptcy Court and available at www.srbp.com. Any party wishing to submit a competing bid (“Competing Bid”) to acquire the Assets should contact Daniel R. Fogarty, Esq., Stichter Riedel Blain & Prosser, P.A, 110 East Madison Street, Suite 200, Tampa, Florida 33602 TEL: 813/229-0144; FAX 813/229-1811; E-MAIL dfogarty@srbp.com.

An auction to consider any Competing Bids in respect of the Assets will be held in Tampa, Florida at 11:00 a.m. (Eastern Standard Time) on September 22, 2015 at the offices of Stichter, Riedel, Blain & Prosser, P.A. The Bankruptcy Court will conduct a hearing to consider approval of the Sale Motion, the results of the Auction, if any, and to consider any timely-filed objections thereto, at the Bankruptcy Court, on September 23, 2015 at 10:30 a.m.

© THINKSTOCK

NOTICE IS HEREBY GIVEN that NAPLES NEPHROLOGY, P.A., as debtor and debtor in possession (“Debtor”), has sought the approval of the United States Bankruptcy Court for the Middle District of Florida, Fort Myers Division (“Bankruptcy Court”), for the sale of substantially all of its assets (excluding cash and accounts receivable) and the assumption and assignment of certain non-employment-related agreements therewith (the “Sale”).

6/19/15 11:19 AM

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In men with mCRPC who progressed on ADT

The story for ZYTIGA® has significantly evolved.

Presenting…

mCRPC = metastatic castration-resistant prostate cancer; ADT = androgen-deprivation therapy.

INDICATION

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.

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.

Please see additional Important Safety Information on the next pages.

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

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IMPORTANT SAFETY INFORMATION

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

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In men with mCRPC who progressed on ADT, consider ZYTIGA® (abiraterone acetate) first.

Final analysis of the pivotal phase 3 trial.*

Every day tells a story.

* Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were OS and radiographic progression-free survival (rPFS). Select exclusion criteria included AST and/or ALT ≥ 2.5X ULN, liver metastases, moderate or severe pain, opiate use for cancer pain, and visceral organ metastases. † At a prespecified final analysis for OS, 65% (354/546) of patients treated with ZYTIGA® + prednisone compared with 71% (387/542) of patients treated with placebo + prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer. § rPFS was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 [PCWG2] criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally reviewed radiographic assessment of progression.

IIAt the prespecified rPFS analysis, 150 (28%) of patients treated with ZYTIGA® + prednisone and 251 (46%) of patients treated with placebo + prednisone had radiographic progression.

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

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2015 3/15 028723-150129

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Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

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.

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IMPORTANT SAFETY INFORMATION

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After a median 4 years (49 months) of follow-up…

ZYTIGA® (abiraterone acetate) + prednisone achieved a median overall survival (OS) of almost 3 years (34.7 months).1† • 4.4 months improvement in median OS—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—rPFS: 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

With a median 49 months of follow-up, there were no notable changes in the safety profile of ZYTIGA® + prednisone since the previously reported interim analyses.1 In your patients with mCRPC…

CONSIDER ZYTIGA® FIRST.

003307-150130

Learn more today at

www.zytigahcp.com.

Every day tells a story.

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Reference: 1. Ryan CJ, Smith MR, Fizazi K, et al; for the COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152-160.

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Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%.

Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

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

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

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

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

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

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ­­ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information].

In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ­ZYTIGA [see Adverse Reactions].

Co-administration of a corticosteroid suppresses adrenocorticotropic ­­ hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ­ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of Z­ YTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ­ZYTIGA. Adrenocortical Insufficiency: ­Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ­ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving Z­ YTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with Z­ YTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

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

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ­ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced Z­ YTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt Z­ YTIGA treatment and closely monitor liver function.

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

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

Increased ­ZYTIGA Exposures with Food: ­ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ­ZYTIGA is taken and for at least one hour after the dose of Z­ YTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ZYTIGA® (abiraterone acetate) Tablets ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralo­ corticoid Excess [see Warnings and Precautions].

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

• Increased ­ZYTIGA Exposures with Food [see Warnings and Precautions].

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

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

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

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

Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5 XULN 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 Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

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

Table 3: A dverse Reactions in ≥5% of Patients on the Z­ YTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Musculoskeletal discomfort, and Musculoskeletal stiffness terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable.

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

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ­ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 4 Includes

Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases.

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

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

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

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

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

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

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

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

Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis.

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

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

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

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

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

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

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

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

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

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

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

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

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

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

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

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

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

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

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

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

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

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

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

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

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

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

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

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

• Patients should be informed that ­ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle Z­ YTIGA 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: March 2015 030924-150310