Renal and Urology News - May 2015 Edition

MAY 2015

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VOLUME 14, IS SUE NUMBER 4

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Data Back Transplantation for HIV Pts Renal allograft and overall survival rates are similar to those of patients not infected with the virus TRANSPLANT OUTCOMES SIMILAR IN HIV PATIENTS Researchers who compared HIV-infected kidney transplant recipients with a matched group of HIV-negative recipients (controls) found that HIV-infected patients who were not coinfected with hepatitis C virus (HCV) had 5- and 10-year graft survival rates similar to those of controls not infected with either virus. Recipients infected with both viruses, however, had significantly worse 5- and 10-year graft survival.

80

75%

5-year graft survival 10-year graft survival

70 60

55.9%

50

75.8% 64% 56%

52%

40

36.2% 27%

30 20 10 0

HIV+ only

HIV+/HCV+

HIV−/HCV− controls

HIV−/HCV+ controls

Kidney transplant subgroups Source: Locke JE, et al. A national study of outcomes among HIV-infected kidney transplant recipients.

J Am Soc Nephrol. (published online ahead of print).

Warfarin Ups Calciphylaxis Risk DIALYSIS PATIENTS treated with vitamin K antagonists (VKAs) such as warfarin are at increased risk of calciphylaxis, a rare but serious complication associated with a high mortality rate, according to a new study.

A team led by Thomas F. Hiemstra, MD, of the University of Cambridge in the U.K., performed a retrospective

cohort study of 2,234 dialysis patients.

Of these, 5 experienced calciphylaxis and 142 were treated with VKAs (141 with warfarin and 1 with acetocoumarol). Calciphylaxis occurred in 4 of the 142 patients. In all cases, vitamin K antagonists were discontinued and treatment instituted with sodium continued on page 9

MEN’S HEALTH

Food pesticide residues linked to diminished semen quality PAGE 17

BY JODY A. CHARNOW TWO RECENT studies provide evidence for expanding the use of renal transplantation in patients infected with HIV. In one study, Jayme E. Locke, MD, of the University of Alabama at Birmingham, and colleagues demonstrated that renal transplantation in HIV-infected patients is associated with graft and overall survival rates similar to those of HIV-negative patients, except in cases of co-infection with hepatitis C virus (HCV). The other study, led by Deirdre Sawinski, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, found that HIV-infected patients have better kidney transplant outcomes than HCV-

HD Patient Mortality, Low Mg Linked LOW SERUM magnesium levels are associated with an increased risk of death among hemodialysis (HD) patients, especially among patients with low serum albumin levels, according to study findings reported at the National Kidney Foundation’s 2015 Spring Clinical Meetings in Dallas.

The study, led by Kamyar KalantarZadeh, MD, PhD, of the University of California Irvine, and presented by Lin Li, MD, of the same institution, included 9,359 HD patients who initiated dialysis at DaVita facilities. The cohort had a median follow-up of 19 months, during which 2,636 deaths occurred. Compared with patients who had a serum magnesium level of at least 2.2 but less than 2.4 mg/dL (reference), patients with a level below 2.0 mg/dL had a significantly increased risk of all-cause mortality over time after adjusting for baseline characteristics and co-morbidities. The risk was increased by about 20% for patients with a magnesium level of at least 1.8 but

infected patients, even though HIVinfected patients are required to have an undetectable viral load to be eligible for a kidney transplant and HCV-infected patients are not.

The study by Dr. Locke’s group is the first national study examining outcomes among the entire U.S. cohort of HIVpositive kidney transplant recipients and comparing their outcomes to appropriately matched HIV-negative controls.

The study included 510 HIV-infected renal transplant patients and 94,948 HIVnegative controls. The 5- and 10-year graft survival among the HIV-infected patients was 68.9% and 49.5%, respectively, but was highest among those who were infected only with HIV (monoinfected) continued on page 9

IN THIS ISSUE 5

Hyponatremia prolongs cancer patient hospitalizations

6

CKD found to be less likely to develop in fitter veterans

8

Less television watching could lower diabetes risk

9

Dialysis modalities offer similar outcomes in acute kidney injury

15

Phosphate binder use is associated with lower mortalilty odds

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A “phosphorus pyramid” nutrition guide has been proposed

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Nephron-sparing surgery may not eliminate CKD risk

PCa relapse more likely in smokers PAGE 14

continued on page 9

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PCa-Obesity Link Stronger in Blacks

© THINKSTOCK

High BMI places African-American men at higher prostate cancer risk versus non-Hispanic whites

OBESITY MAY PARTIALLY EXPLAIN racial disparities in prostate cancer risk.

PCa Test May Avert Biopsies THE PROSTATE Health Index (phi), a blood test that combines 3 PSA measurements into a single score, improves detection of clinically significant prostate cancer (PCa) and could help decrease the number of unnecessary prostate biopsies, researchers reported.

In a study of 658 men aged 50 years and older with PSA levels of 4–10 ng/

mL, Stacy Loeb, MD, of New York University, and colleagues investigated whether phi can improve specificity for detecting clinical significant PCa and reduce PCa over diagnosis. The researchers used the Epstein definition of clinically significant PCa (Gleason score 7 or higher, 3 or more positive cores, and continued on page 9

MEN’S HEALTH

Food pesticide residues linked to diminished semen quality PAGE 17

BY JODY A. CHARNOW OBESITY IS more strongly associated with elevated prostate cancer (PCa) risk among African-American than non-Hispanic white men, according to a new study.

African-American (AA) men have the highest incidence of PCa of any racial or ethnic group in the United States, the study’s investigators noted.

“Findings from this study suggest that increased obesity could partially explain the substantially higher risk of prostate cancer among AA men,” the researchers concluded.

The findings are based on a prospective analysis of data from 22,673 non-Hispanic white (NHW) men and 3,398 AA men who participated in the Selenium

LUTS May Up Men’s Bladder Cancer Risk SEVERE LOWER urinary tract symptoms (LUTS) are associated with an increased risk of developing bladder cancer, new findings suggest.

In a study of 30,183 men in the Health Professionals Follow-up Study (HPFS), men with severe LUTS had a 64% higher relative risk of bladder cancer compared with men who did not have LUTS in multivariate analysis. Men who had both voiding and storage dysfunction had a significant 60% higher risk of bladder cancer. In addition, among individual urinary symptoms, urinary hesitancy was strongly associated with bladder cancer risk: men who had urinary hesitancy at least 50% of the time had a 2.2 times increased risk, a team led by Dominique S. Michaud, ScD, of Tufts University Medical School in Boston, reported online ahead of print in Urology.

Dr. Michaud and her colleagues concluded that their findings suggest that urinary voiding symptoms may raise the risk of bladder cancer. “If this

and Vitamin E Cancer Prevention Trial (SELECT). Study subjects had a median follow-up of 5.6 years, during which 1,723 were diagnosed with PCa. The study’s primary author, Wendy E. Barrington, PhD, of the University of Washington School of Nursing and the Fred Hutchinson Cancer Research Center in Seattle, and colleagues found that among AA men a body mass index (BMI) of 35 kg/m2 or higher increased risk of low-grade PCa by 122% and increased risk of high-grade PCa by 81% compared to a BMI less than 25 which is considered normal weight.

Among NHW men, having a BMI of 35 kg/m2 or higher was associated with a 20% reduced risk of low-grade and continued on page 9

IN THIS ISSUE 8

Vitamin E added to antibiotics may improve UTI treatment

9

Adjuvant drugs fail to improve outcomes after RCC surgery

14 Screening erectile dysfunction

sufferers for CVD is cost-effective

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New findings confirm obesity as a risk factor for bladder cancer

15 PCa recurrence not associated with metabolic syndrome

16 Nephron-sparing surgery may not eliminate CKD risk

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Expert Q&A: Narrow-band imaging for bladder cancer

PCa relapse more likely in smokers PAGE 14

continued on page 9

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www.renalandurologynews.com APRIL 2015

Renal & Urology News 3

FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD Medical Director, Urology

Medical Director, Nephrology

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

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

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 4. Published monthly, except for the combined January/February, June/July and November/ December issues, by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Periodicals postage paid at New York, NY, and an additional mailing office. The subscription rates for one year are, in the U.S., $75.00; in Canada, $85.00; all other foreign countries, $110.00. Single issues, $20.00. www.renalandurologynews.com. Postmaster: Send address changes to Renal & Urology News, c/o DMD Data Inc., 2340 River Road, Des Plaines, IL 60018. Copyright: All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without the prior written permission of Haymarket Media, Inc. Copyright © 2015.

MH-Editorial_003_RUN0515.indd 3

To Treat or Not to Treat Edema

Y

ou can’t be a clinician and not have any patient with swollen ankles. We often manage patients’ ankle edema ourselves by restricting salt and giving diuretics, or we send the patient to other specialists who can do it for us. We feel good about it, especially when patients report that the swelling has improved. But do we really know why we diurese patients?

Many types of edematous states are associated with symptoms. Pulmonary edema may lead to respiratory distress.

Ascites and increasing trunk girth result in discomfort, sensation of fullness, and breathing difficulties. Anasarca in nephrotic syndrome can limit physical activities. When we see mild ankle edema, we often start with dietary salt and fluid restriction, and if this doesn’t work we prescribe diuretics, starting with thiazides followed by more potent loop diuretics. In extreme circumstances with worsening pulmonary edema and imminent intubation and mechanical ventilation, we may consider ultrafiltration via dialysis or hemodiafiltration. In some countries, ambulatory ultrafiltration centers are available to edematous outpatients so that fluid can be conveniently removed without hospital admission. But does removing fluid have any impact on the deleterious effects of the underlying disease or its progression. Most clinical trials involving heart failure have failed to show significant benefit of diuresis or ultrafiltration.

Is fluid retention really harmful? A 2009 paper in Circulation detailing a study of 34,107 hemodialysis (HD) patients (conducted by a team I led) showed that the greater the fluid retention between 2 consecutive dialysis treatment days, the worse the patient mortality. But I would argue that the increased mortality also could be due to a harmful effect of the removal of greater fluid volumes by ultrafiltration. Although there are such controversies related to severe types of fluid overload in heart failure and HD patients, I am still not sure why I even need to treat lower extremity edema. Oral diuretics can cause harm such as hypokalemia and muscle weakness, hyponatremia and altered mental state, deep vein thrombosis and pulmonary embolism, and many other direct and indirect side effects of these pharmacologic agents. Even restricted salt intake to less than 2 grams per day is associated with worse outcome according to recent findings. So where is the benefit of diuresis?

We physicians often feel obsessed to get the fluid out. There is little doubt that a swollen ankle doesn’t look good esthetically. With worsening ankle edema shoes feel tight especially as the day progresses. Most of my patients feel happier when I help them to have thinner ankles and nicer legs, and they give me better reviews, so I can maintain my high ranking among Top Physicians, Best Doctors, and Best Physicians.

That should be good enough reason to diurese.

Kam Kalantar-Zadeh, MD, MPH, PhD Chief, Division of Nephrology & Hypertension Professor of Medicine, Pediatrics and Public Health University of California Irvine School of Medicine

4/23/15 11:24 AM

4 Renal & Urology News

MAY 2015

www.renalandurologynews.com

Contents

M A Y

2 0 1 5

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V O L U M E

Nephrology

ONLINE

Greater Fitness Associated with Lower CKD Risk A study of male U.S. veterans found chronic kidney disease was less likely to develop in those with greater exercise capacity.

9

Dialysis Modalities Show Similar Outcomes in AKI Extended daily dialysis and continuous renal replacement therapy are associated with similar rates of death and kidney recovery, a new meta-analysis found.

Clinical Quiz

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

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

Congratulations to our April winner: Shaun Maloney, MD

13

16

Dementia Risk Lower in PD Initiators Starting renal replacement therapy on peritoneal dialysis was associated with a 25% lower dementia risk compared with starting on hemodialysis, a study showed.

CKD ‘Phosphorus Pyramid’ Developed It is a visual, user-friendly tool for nutritional education designed to help healthcare providers teach patients how to decrease their phosphorus intake.

Urology

Videos

Some of our recent postings include:

8

• Blood Test Identifies Circulating Prostate Cancer Cells • Lymph Node Dissections in MuscleInvasive Bladder Cancer

• Early Efficacy Signals in Advanced Kidney Cancer

PCa Relapse More Likely in Smokers Current smokers are twice as likely as patients who never smoked to experience biochemical recurrence after radical prostatectomy.

14

Erectile Dysfunction Sufferers Benefit from CVD Screening Such an approach could significantly decrease national healthcare costs and disease burden with significant societal implications.

• Bladder Cancer Guidelines Updated

News Coverage

Visit our website for daily updates.

15

Obesity Increases Likelihood of Bladder Cancer Bladder cancer risk increased by 4.2% with every 5 kg/m2 increment in BMI, according to a recent meta-analysis.

NBI [for bladder cancer detection]

can potentially improve patient outcomes, which can hopefully translate into an improved quality of life for a variety of reasons.

See our story on page 18

TOC_004_Neph_RUN0515.indd 4

N U M B E R

4

European Renal Association – European Dialysis and Transplant Association 52nd Congress London May 28–31 American Society of Clinical Oncology Annual Meeting Chicago May 29–June 2 Canadian Urological Association Annual Meeting Ottawa June 27–30 International Continence Society Montreal October 6–9 American Society for Radiation Oncology (ASTRO) San Antonio, TX October 18–21 Kidney Week San Diego November 3–8

Vitamin E May Improve UTI Therapy In a study of girls with their first episode of pyelonephritis, researchers found that vitamin E supplementation added to antibiotics significantly improved symptoms.

14

• Aerobic Fitness and Risk of Chronic Kidney Disease in Veterans

I S S U E

CALENDAR

6

this month at renalandurologynews.com

1 4 ,

18

Departments 3

From the Medical Director To treat or not to treat edema

5

News in Brief Nephropathy case linked to iced-tea consumption

17

Men’s Health Update Sex hormones predict erectile dysfunction risk

18

Q&A In a new light: NBI for bladder cancer

4/23/15 11:25 AM

4 Renal & Urology News

MAY 2015

www.renalandurologynews.com

Contents

M A Y

2 0 1 5

■

V O L U M E

Urology

ONLINE

Vitamin E May Improve UTI Therapy In a study of girls with their first episode of pyelonephritis, researchers found that vitamin E supplementation added to antibiotics significantly improved symptoms.

14

PCa Relapse More Likely in Smokers Current smokers are twice as likely as patients who never smoked to experience biochemical recurrence after radical prostatectomy.

14

Erectile Dysfunction Sufferers Benefit from CVD Screening Such an approach could significantly decrease national healthcare costs and disease burden with significant societal implications.

Clinical Quiz

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

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

Congratulations to our April winner: Shaun Maloney, MD

Videos

15

• Blood Test Identifies Circulating Prostate Cancer Cells

Greater Fitness Associated with Lower CKD Risk A study of male U.S. veterans found chronic kidney disease was less likely to develop in those with greater exercise capacity.

9

Dialysis Modalities Show Similar Outcomes in AKI Extended daily dialysis and continuous renal replacement therapy are associated with similar rates of death and kidney recovery, a new meta-analysis found.

• Aerobic Fitness and Risk of Chronic Kidney Disease in Veterans 13

• Bladder Cancer Guidelines Updated

News Coverage

Visit our website for daily updates.

16

Dementia Risk Lower in PD Initiators Starting renal replacement therapy on peritoneal dialysis was associated with a 25% lower dementia risk compared with starting on hemodialysis, a study showed.

CKD ‘Phosphorus Pyramid’ Developed It is a visual, user-friendly tool for nutritional education designed to help healthcare providers teach patients how to decrease their phosphorus intake.

NBI [for bladder cancer detection]

can potentially improve patient outcomes, which can hopefully translate into an improved quality of life for a variety of reasons.

See our story on page 18

TOC_004_URO_RUN0515.indd 4

N U M B E R

4

European Renal Association – European Dialysis and Transplant Association 52nd Congress London May 28–31 American Society of Clinical Oncology Annual Meeting Chicago May 29–June 2 Canadian Urological Association Annual Meeting Ottawa June 27–30 International Continence Society Montreal October 6–9 American Society for Radiation Oncology (ASTRO) San Antonio, TX October 18–21 Kidney Week San Diego November 3–8

6

• Lymph Node Dissections in MuscleInvasive Bladder Cancer

• Early Efficacy Signals in Advanced Kidney Cancer

Obesity Increases Likelihood of Bladder Cancer Bladder cancer risk increased by 4.2% with every 5 kg/m2 increment in BMI, according to a recent meta-analysis.

Nephrology

Some of our recent postings include:

I S S U E

CALENDAR

8

this month at renalandurologynews.com

1 4 ,

18

Departments 3

From the Medical Director To treat or not to treat edema

5

News in Brief Nephropathy case linked to iced-tea consumption

17

Men’s Health Update Sex hormones predict erectile dysfunction risk

18

Q&A In a new light: NBI for bladder cancer

4/23/15 11:27 AM

www.renalandurologynews.com

MAY 2015

Renal & Urology News 5

News in Brief

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

Short Takes Low Physical Function Not Tied to Muscle Mass

England Journal of Medicine.

Patients on maintenance hemodialysis

tory of kidney stones or any family his-

(MHD) have worse physical function

tory of kidney disease, said he drank

than elderly non-hemodialysis (non-

16 8-ounce glasses iced tea daily. A

HD) patients independent of muscle

renal biopsy revealed many oxalate

mass and co-morbidity, researchers

crystals, interstitial inflammation with

reported online ahead of print in the

eosinophils, and interstitial edema

Journal of Renal Nutrition.

consistent with a diagnosis of oxalate

The man, who had no personal his-

nephropathy, the authors wrote.

A team led by Srinivasan Beddhu,

Black tea is a rich source of oxalate,

MD, of the University of Utah School of Medicine in Salt Lake City, compared

and the authors estimated that the

108 MHD and 122 elderly non-HD pa-

patient’s daily intake of oxalate was

tients. They used magnetic resonance

more than 1,500 mg, much higher

image to measure subjects’ mid-thigh

than that of the average American.

muscle area and evaluated physical subjects walked in 6 minutes. Although

FDA Approves Label Update for Abiraterone

the MHD patients had a greater mid-

The FDA has approved a label update

thigh area than the elderly group, they

for abiraterone acetate (Zytiga)

walked a significant 117 meters less

to include data showing that the

than the elderly group after adjusting

drug is associated with significantly

for mid-thigh muscle area, comorbid

prolonged overall survival compared

conditions, and demographics.

with placebo plus prednisone in men

functioning by measuring the distance

with chemotherapy-naïve metastatic

Nephropathy Case Linked to Iced Tea Consumption

castration-resistant prostate cancer.

Excessive consumption of iced tea

Lancet Oncology (online ahead of

is the suspected cause of nephropa-

print), showed that abiraterone treat-

thy in a 56-year-old man, physicians

ment prolonged survival in mCRPC

in Arkansas reported in The New

patients by a median of 4.4 months.

The data, published recently in The

Would You Be A Doctor Again?

In a recent online poll, Renal & Urology News asked nephrologists and urologists, “If you had your career to do over, would you choose to become a doctor?” Here are the results based on 126 responses.

Definitely: 35% Most likely: 24% Unlikely: 24% Definitely not: 17%

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Hyponatremia May Prolong Cancer Patient Hospital Stay H

yponatremia at hospital admission or during hospitalization is a significant predictor of length of stay in cancer patients, according to a recent study published online in Supportive Care in Cancer.

Rossana Berardi, MD, and colleagues at Azienda Ospedaliero-Universitaria Ospedali Riuniti in Ancona, Italy, studied 105 cancer patients hospitalized at their institution from June 2013 to December 2013. The researchers defined hyponatremia as a serum sodium level below 135 mEq/L. Among patients whose hospital stay was 1–5 days, none had hyponatremia at admission (sodium level of 136 mEq/L or higher) compared with 16% and 45% of those who had a hospital stay of 6–15 days and longer than 15 days, respectively.

Among patients whose hospital stay was 1–5, 6–15, and more than 15 days, less than 4%, 35%, and 75%, respectively, had hyponatremia during hospitalization.

PAE Effective in BPH Patients with Medium or Large Prostates P

rostatic arterial embolization (PAE) is safe and effective for treating benign prostatic hyperplasia (BPH) in men with medium and large prostates, according to the findings of a Chinese study published online in BJU International.

The study, by Maoqiang Wang, MD, and colleagues, included 115 men diagnosed with lower urinary tract symptoms due to BPH refractory to medical treatment.

Researchers divided the patients into 2 groups: Group A included patients with large prostates (mean volume of 129 mL) and group B included patients with a medium-size prostate (mean volume of 64 mL). Results showed no significant difference in technical success rate between groups A and B (93.8% and 96.8%). Of the 115 men, 101 (55 in group A and 46 in group B) completed follow-up (mean 17 months). After PAE, both groups experienced significant improvements from baseline in International Prostate Symptom Score (IPSS), quality of life (QoL), post-void residual (PVR), prostate volume (PV), and maximum flow rate (Qmax). Outcomes in group A were significantly better with respect to IPSS, Qmax, PVR, PV, and QoL compared with group B.

Portugal’s RRT Incidence Rate Is Highest in Europe P

ortugal has the highest incidence rate of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in Europe, and Montenegro has the lowest, newly published findings in the Clinical Kidney Journal show.

According to the 2012 European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report, the overall unadjusted incidence and prevalence of patients receiving RRT for ESRD in Europe was 109.6 per million population (pmp) and 716.7 pmp (on December 31, 2012), respectively. The unadjusted incidence rate was 219.9 pmp in Portugal and 24.2 pmp in Montenegro. On December 31, 2012, Portugal also had the highest unadjusted prevalence (1670.2 pmp), and Ukraine had the lowest (146.7 pmp).

The ERA-EDTA Registry collected data from national and regional registries in 30 countries in Europe and from 20 other European countries without registries.

4/23/15 11:30 AM

6 Renal & Urology News

MAY 2015 www.renalandurologynews.com

Greater Fitness Associated with Lower CKD Risk GREATER exercise capacity is associated with a lower risk of developing chronic kidney disease (CKD), according to a new study of male U.S. veterans.

“The findings of the present study demonstrate that health benefits associated with higher exercise capacity also extend to lowering the risk of developing CKD,” Peter Kokkinos, PhD, of Veterans Affairs Medical Center in Washington DC, and colleagues said in a report published in Mayo Clinic Proceedings (2015;90:461-468).

The investigators prospectively assessed peak exercise capacity for 5,812 male veterans (mean age 58.4 years) at the center using a standard treadmill test.

The men were referred for exercise testing for clinical reasons. All participants were free of CKD stage 3 and above at baseline with an estimated glomerular filtration rate (eGFR) of 60 mL/min per 1.73 m2 or higher. CKD developed in 1,010 men (17%) during follow-up.

they pointed out, are more likely to develop cardiorenal metabolic syndrome and low-grade systemic inflammatory response, which sets the stage for increased risk of cardiovascular disease and CKD. “If metabolic factors play a role in the association between poor exercise

capacity and the development of CKD, it is reasonable to hypothesize that improved metabolic and cardiovascular profiles exert a protective effect on renal function over time,” the investigators stated.

Noting that moderate intensity exercise programs are effective S:7”in improv-

ing cardiorespiratory fitness regardless of age or comorbidities, Dr. Kokkinos and his colleagues propose that “exercise interventions for individuals at risk for CKD and those with preclinical CKD may be implemented to prevent or at least attenuate the rate of developing CKD.” n

CKD risk declined by 22% with every 1 MET increase in exercise capacity.

The risk of CKD declined by 22% with every 1 metabolic equivalent (MET) increase in exercise capacity.

Compared with the least fit individuals, the odds of CKD were 13%, 45%, and 58% lower in the low-, moderately-, and high-fit groups, respectively, according to the investigators.

Researchers adjusted the fitness groupings for age. They also adjusted their models for CKD predictors, such as race, diabetes, hypertension, dyslipidemia, alcoholism, glucose-lowering medication, and lipid-lowering medication.

“The findings of the present study support an inverse, independent, and graded association between the development of CKD stage 3 or higher and exercise capacity,” Dr. Kokkinos’ group wrote. “The decline in risk was precipitous with only modest increases in exercise capacity.”

The dose-response association between increased exercise capacity and reduced risk of CKD suggests the presence of causal mechanism, they noted. The investigators said their study cohort included a significant number of veterans with an elevated body mass index and diabetes mellitus. Overweight and obese patients,

exercise-Auryxia_006-7_RUN0515.indd 6

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

4/23/15 11:33 AM

B:15.5” T:15.5”

www.renalandurologynews.com MAY 2015

Renal & Urology News 7

Preoperative MRI May Benefit Some RP Patients B:15.5” T:15.5”

MAGNETIC RESONANCE imaging (MRI) of the prostate prior to surgery for prostate cancer does not significantly decrease the likelihood of positive surgical margins (PSMs) overall, but it may be beneficial for men with cT1 tumors, researchers reported online ahead of print in European Urology.

The study is the first randomized controlled trial to evaluate the benefit of MRI prior to robot-assisted laparoscopic prostatectomy (RALP), according to a research team led by Erik Rud, MD, of Oslo University Hospital in Oslo.

Dr. Rud and his colleagues preoperatively randomly S:7”assigned 438 men

scheduled for RALP to undergo preoperative MRI (222 men) or no MRI (216 men). PSMs were identified in 19% of the MRI group and 23% of the no-MRI group, a non-significant difference. In a subgroup analysis of men with cT1 tumors—which made up 55% of the cohort—16% of the MRI group

had PCMs versus 27% of the no-MRI group, a difference that translated into a 41% relative risk reduction in the MRI group, Dr. Rud’s group reported.

The authors acknowledged that their study cannot explain the precise mechanisms for the decreased rate of PSMs in men with cT1 tumors. 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%).

exercise-Auryxia_006-7_RUN0515.indd 7

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

4/23/15 11:33 AM

8 Renal & Urology News

MAY 2015 www.renalandurologynews.com

Watching Less TV May Reduce Diabetes Risk PEOPLE WHO SPEND less time watching television have a lower risk of developing diabetes, according to a recent analysis of the Diabetes Prevention Program.

Previous results from the program showed that increasing physical activity to at least 150 minutes per week

at moderate intensity helped prevent or delay the development of diabetes in overweight men and women. Since then, new research has shown that exercise level is not the only important factor. Sedentary behavior itself, such as sitting in front of the television or at work, may be an independent risk facT:7”

tor for both metabolic syndrome and diabetes.

For this analysis, researchers with the Diabetes Prevention Program Research Group led by Andrea M. Kriska, PhD, MS, of the University of Pittsburgh, specifically examined sedentary time for the 3,232 participants,

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.

TV_Auryxia_008_RUN0515.indd 8

PP-AUR-US-0075

VITAMIN E supplementation may help ameliorate the symptoms of urinary tract infection (UTI), according to findings published in the Iranian Journal of Kidney Diseases (2015;9:97-104).

Parsa Yousefichaijan, MD, and colleagues at Arak University in Arak, Iran, tested the effect of vitamin E on UTI in 152 girls aged 5–12 years with a first acute episode of pyelonephritis. The researchers randomly assigned 76 girls to receive antibiotics only (controls) and 76 to receive vitamin E in addition to antibiotics.

During follow-up, the mean number of episodes of fever, urinary frequency, dribbling, and urgency were significantly lower in the vitamin E group than the control arm.

The investigators found no significant difference in the results of urine culture 3–4 days after the start of treatment and 7–10 days after its termination. They also observed no significant difference between the

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

Vitamin E May Improve UTI Therapy 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.

who were randomly assigned to 3 groups: a group engaging in increased lifestyle activity, a group taking metformin, and a placebo group.

Across all groups, the more time spent watching TV, the greater the chances of diabetes: 3.4% per hour of TV—even after controlling for other factors, according to results published in Diabetologia.

After 3 years of follow-up, sitting time declined more in the active group, according to the investigators. The decrease in time watching television was 22 minutes per day, on average, and was greater than that achieved by the other 2 groups.

“This effort suggests that modest improvements in domain-specific sedentary time, such as TV watching, may lead to reduced diabetes incidence in individuals at high risk of developing the disease,” the researchers stated. n

groups in DMSA scan findings 4–6 01/15

months after treatment. n

4/23/15 11:36 AM

www.renalandurologynews.com MAY 2015

t­ hiosulphate (STS), cinacalcet, and supportive measures. All 5 patients recovered, but 1 experienced a sudden cerebrovascular death during follow-up.

Calciphylaxis occurs most commonly in patients with end-stage renal disease (ESRD) requiring dialysis, but it also is associated with primary hyperparathyroidism, malignancy, and connective tissue disorders, the researchers pointed out. The condition is characterized by vascular calcification, thrombosis, and inflammation.

“Our findings added to a growing body of evidence that supports the avoidance of VKA treatment in patients with ESRD,” the authors concluded in a paper published in Nephron (2015;129:197-201).

“Where calciphylaxis does occur, VKAs should be withdrawn.”

Previous studies have implicated VKAs in the development of calciphylaxis, the investigators noted. For example, a matched case-control study of maintenance hemodialysis (HD)

patients by Sagar U. Nigwekar, MD, of Massachusetts General Hospital in Boston, and colleagues found that warfarin treatment was associated with a 4.3 times increased odds of calciphylaxis, according to a report in the American Journal of Nephrology (2013;37:325-332).

The researchers compared 62 patients with calciphylaxis and 124 hospitalized patients without calciphylaxis (controls).

Hypercalcemia, hypoalbuminemia, and calcitriol use also were positively associated with calciphylaxis.

Dr. Hiemstra and his colleagues noted that patients with ESRD often require systemic anticoagulation for atrial fibrillation or recurrent venous thromboembolism, and some clinicians continue to use warfarin for maintenance of vascular access patency. “Our data demonstrated that, where continued anticoagulation is required, the use of newer anticoagulants such as dabigatran in conjunction with STS, cinacalcet, avoidance of oral calcium intake, and definitive treatment of resistant hyperparathyroidism can result in resolution of cutaneous lesions,” they wrote. n

5- and 10-year graft survival rates were significantly worse for patients coinfected with HIV and HCV than for matched HIV-negative controls infected with HCV (52.0% vs.64.0% and 27.0% vs. 36.2%, respectively).

Patient survival rates among all HIV-infected recipients were 83.3% and 51.5% at 5 and 10 years, respectively. The rates were higher among the mono-infected HIV patients (88.7% and 63.5%, respectively) than the coinfected patients (66.3% and 29.3%).

Additionally, compared with appropriately matched HIV-negative controls, the HIV-infected patients had similar 5-year patient survival rates (83.5% and 86.2%), but significantly lower 10-year survival rates (51.6% vs. 72.1%). The 5- and 10-year patient survival rates did not differ significantly between the monoinfected HIV patients and

HIV-negative/HCV-negative controls (88.7% and 89.1% and 63.5% and 77.6%). Coinfected patients, however, had significantly worse survival at 5 and 10 years compared with HIV-negative/ HCV-positive controls (67.0% vs.78.6% and 29.3% vs. 56.2%, respectively).

In an editorial accompanying the paper by Dr. Locke’s team, Alissa J. Wright, MD, and John S. Gill, MD, of the University of British Columbia in Vancouver, commented that the researchers “should be commended for providing a national perspective on the study of HIV transplantation which supports expanded use of kidney transplantation in this group.”

The study by Dr. Sawinski and her colleagues, which was published in Kidney International (online ahead of print), included 124,035 adult kidney transplant recipients—492 infected with HIV, 5,605

infected with HCV, 147 infected with both HIV and HCV, and 117,791 without infection with either virus (reference group). The 3-year survival rate of the HIV-infected patients was 89%, which was not statistically different from the 90% rate in the reference group. By comparison, the 3-year survival rates were notably lower in HCV and HIV/HCV groups (84% and 73%, respectively).

“These findings show that HIV patients are being unfairly perceived to have worse kidney transplant outcomes than non-infected groups, and as a result, they often have to wait the longest for transplants and there are fewer living donors,” Dr. Sawinski said in a university press release. She added that her group hopes their findings inspire the kidney transplant community to focus on eradicating hepatitis C in transplant recipients to ensure better outcomes. n

magnesium level below 2.0 mg/dL had a significant 17% increased risk of death compared with those who had a magnesium level of 2.0 mg/dL or higher.

“These findings may help identify HD patients with higher mortality risk for potential interventions,” the investigators concluded.

In a separate study published recently in PLOS One, Yoshitaka Isaka, MD, of Osaka University Graduate School of Medicine in Japan and colleagues reported that higher magnesium levels,

via their effect on phosphorus levels, may lower all-cause and cardiovascular mortality in HD patients. The investigators analyzed data from more than 142,000 HD patients They categorized patients into 3 groups by serum magnesium levels: the lower group had less than 2.7 mg/ dL magnesium; the intermediate group had 2.7 to less than 3.1 mg/dL; and the higher group had 3.1 mg/dL or more.

Within a year, 11,401 patients died, 41.7% from cardiovascular causes.

Among patients in the 4th quartile of

serum phosphorus (6 mg/dL or higher), those in the lower- and intermediatemagnesium groups had a significant 52% and 58% increased odds of allcause mortality, respectively, and 64% and 42% increased odds of cardiovascular mortality, respectively, compared with patients in the 2nd quartile of serum phosphorus (reference, 4.1 to less than 5.1 mg/dL). In contrast, patients in the higher-magnesium group had no significantly increased risk of all-cause or cardiovascular mortality. n

Dialysis Modalities Show Similar Outcomes in AKI DATA FROM randomized controlled

and 10 observational studies. The 17

trials show that extended daily dialysis

studies included 634 patients undergo-

and continuous renal replacement

ing EDD and 574 undergoing CRRT.

therapy for acute kidney injury (AKI)

RCTs revealed no significant differ-

are associated with similar outcomes,

ence in the risk of death between EDD

according to the authors of a recently

and CRRT, but observational studies

published meta-analysis.

show that EDD was associated with a

Extended daily dialysis (EDD) was associated with decreased mortality compared with continuous renal

16% decreased relative risk of mortality compared with CRRT. Both the RCTs and observation studies

replacement therapy (CRRT) in obser-

demonstrated no significant difference

vational studies, but such studies are

between the modalities with respect to

potentially subject to allocation or

kidney recovery, fluid removal, length

selection bias, researchers reported

of stay in the intensive care unit, and

online ahead of print in the American

laboratory findings (serum urea, serum

Journal of Kidney Diseases.

creatinine, and serum phosphate).

A team led by Rinaldo Bellomo, MD,

The investigators stated that, to their

PhD, Austin Health, Heidelberg, Victoria,

knowledge, their study is the first to sys-

Australia, analyzed data from 17 studies:

tematically evaluate the effect of EDD

7 randomized controlled trials (RCTs)

versus CRRT on patients with AKI. n

Tx use in HIV patients continued from page 1

but not HCV (75% and 55.9%, respectively), Dr. Locke and colleagues reported online ahead of print in the Journal of the American Society of Nephrology. Among patients coinfected with HIV and HCV, the 5- and 10-year graft survival rates were 49.9% and 25.9%, respectively.

The researchers compared the HIV group with a matched group of HIVnegative controls. Compared with the control group, the HIV-infected patients overall had significantly lower 5- and 10-year graft survival rates (69.2% vs.

75.3% and 49.8% vs. 54.4%, respectively). The monoinfected HIV-positive patients had 5- and 10-year graft survival rates similar to those of HIV-negative/ HCV-negative controls (75.0% vs. 75.8% and 55.9% vs. 56.0%, respectively). The

Mortality, low Mg link continued from page 1

less than 2.0 mg/dL and 40% for those with a level below 1.8 mg/dL. The association between magnesium level and mortality, however, was not statistically significant after additional adjustment for other laboratory analytes, especially serum albumin, Dr. Kalantar-Zadeh’s group reported.

Among patients with low serum albumin (less than 3.5 g/dL), patients with a

Cv-Jump_Neph_RUN0515.indd 9

Calciphylaxis risk

Renal & Urology News 9

continued from page 1

4/23/15 12:32 PM

www.renalandurologynews.com MAY 2015

association is confirmed,” they wrote, “LUTS might be used as a simple test to identify men who are at higher risk of bladder cancer.”

The investigators pointed out that about 15%–60% of men older than 40 years report suffering from LUTS in various studies, with the prevalence and severity increasing with age.

Investigators used a slightly modified American Urological Association Symptom Score Index (AUA-7) to assess LUTS information. The index consists of 7 questions assessing storage and voiding dysfunction symptoms. Each question is scored on a 0–5 scale, with 0, 1, 2, 3, 4, 5 corresponding, respectively, to 0%, 10%, 25%, 50%, 75%, and almost 100% of the time that a symptom was experienced. The maximum possible total score is 35. Patients with AUA-7 scores greater than 1 but not more than 7, higher than 7 but not more than 19, and higher than 19 had mild, moderate, and severe LUTS, respectively.

At baseline, 1,892 men reported experiencing urinary hesitance for at least 50% of the time, among which 1,069 men (56.5%) had mixed storage and voiding dysfunctions and 642 (33.9%) had isolated voiding dysfunction. Men reporting experiencing hesitance for at least 50% of the time had the highest overall total AUA-7 score.

“These results suggest that the presence of severe urinary hesitancy might indicate higher volume of postvoid residual urine, which can increase the contact time of potential carcinogens in urine and the bladder urothelium and the risk of bladder cancer,” they wrote.

Previous studies have revealed bladder wall thickening and bladder mass increases among men with LUTS, Dr. Michaud’s group noted.

The researchers found that men who urinated 3 or more times per night had a nonsignificant 18% decreased risk of bladder cancer compared with men who had no nighttime urination.

Initiated in 1986, the HPFS enrolled 51,529 male health professionals aged 40–75 years across the United States. n

unique contribution of obesity prevention and treatment to the health of their AA patients. Such targeted efforts may contribute to reductions in prostate cancer disparities.”

The investigators said the mechanisms underlying their findings are unknown, but a possible explanation is that the biological effects of obesity differ in AA and NHW men. “Inflammation plays a role in prostate carcinogenesis, and the effect of obesity on systemic inflammation could be stronger in AA than in NHW men,” they wrote. “Similarly, insulin may play a role in prostate carcinogenesis and it is possible that the effect of obesity on insulin secretion is stronger in AA than in NHW men.”

Another possible explanation is that the PCa detection rate in SELECT may be higher among AA compared with

NHW men, they said. Additionally, mean PSA levels, adjusted for age and other covariates, are lower among NHW compared with AA men, which may increase the likelihood of diagnostic biopsies among AA men. Moreover, it is well established that obesity is inversely related to PSA concentration.

Strengths of the study include a large sample size, standardized assessment of height and weight, active follow-up for incident PCa, and consideration of bias due to differential detection, the researchers noted. The study also had limitations, such as the use of BMI, which is a nonspecific measure of obesity. It does not discriminate more metabolically active abdominal fat from other body fat, and it does not distinguish whether excess body weight relative to height is due to nonfat tissues.

Stephen J. Freedland, MD, who has conducted research on the influence of obesity on PCa risk but was not involved in the latest investigation, said the new study was well-done and “is intriguing but needs validation.”

Non-biological reasons, such as what prompted men to get a biopsy, could explain the study findings, he said.

“Factors that influence who gets a biopsy have a tremendous effect on who is diagnosed with cancer,” said Dr. Freedland, professor of surgery (urology) at Cedars-Sinai Medical Center in Los Angeles, where he is director of the Center for Integrated Research on Cancer and Lifestyle.

These factors, such as health insurance, access to care, and especially willingness to undergo a biopsy, could differ by race, he said. n

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, the investigators reported.

The new study builds on previous research showing that phi improves specificity and provides a greater net benefit for PCa detection compared with total and percent free PSA, the researchers pointed out.

“Phi is a simple blood test that we recommend for use as part of a multivariable approach to reduce unneces-

sary biopsies and over diagnosis,” the authors concluded.

Dr. Loeb’s group acknowledged some study limitations, including the use of biopsy criteria to define clinical significance. “Although biopsy criteria are frequently used, these end points are not perfect and other factors such as life expectancy also have a key role in defining over diagnosis,” they wrote.

With regard to study strengths, the researchers noted that their study used a prospectively enrolled source population, including a large number of men from

multiple centers across the United States.

The study population had a median age of 63 years. Of the 658 men, 324 (49.2%) had PCa detected on biopsy.

Among the men with PCa, 52.5% had clinically significant disease and 33.7% had Gleason 7 or higher tumors.

The study was funded by Beckman Counter Inc., of Carlsbad, Calif., which markets the phi test. The test received FDA premarket approved in June 2012 and the company announced the test’s availability in the United States in May 2014. n

Adjuvant Medications Fail to Improve RCC Outcomes ORLANDO, Fla.—Adjuvant treatment

for 1 year. The patients were at high risk

with sorafenib or sunitinib does not

for cancer recurrence based on tumor

improve outcomes in patients who have

size and grade, lymph node involve-

undergone surgery for locally advanced

ment, and other factors. The sorafenib,

kidney cancer, researchers reported

sunitinib, and placebo arms included

at the 2015 Genitourinary Cancers

649, 647, and 647 patients, respec-

Symposium.

tively. The median disease-free survival

“These drugs didn’t reduce disease

times did not differ significantly among

recurrence, but on average they did not

the study arms: 5.6, 5.6, and 5.7

appear to worsen patient outcomes

years, respectively. The 5-year disease-

either,” said lead author Naomi B. Haas,

free and overall survival rates for the

MD, associate professor of medicine

sorafenib, sunitinib, and placebo arms

at the Abramson Cancer Center of the

also did not differ significantly: 52.8%,

University of Pennsylvania in Philadelphia.

53.8%, and 55.8%, respectively, and

In the phase 3 ASSURE clinical trial, Dr. Haas and her colleagues randomly

80.7%, 76.9%, and 78.7%, respectively.

“The findings from this study suggest

assigned 1,943 patients who underwent

that patients with locally advanced kid-

surgery for locally advanced, non-

ney cancer completely resected should

metastatic renal cell carcinoma (RCC) to

not be treated with either adjuvant

receive sorafenib, sunitinib, or placebo

sorafenib or sunitinib,” Dr. Haas said. n

PCa-obesity link continued from page 1

only a 33% increased risk of high-grade PCa compared to being of normal weight. Compared with normal weight NHW men, AA men with a BMI less than 25, 25.0 to less than 27.5, 27.5 to less than 30.0, 30 to less than 35.5, and 35.0–50.0 had a significant 28%, 49%, 58%, 75%, and 103% increased risk of PCa, respectively, the researchers reported online in JAMA Oncology.

“This study reinforces the importance of obesity prevention and treatment among AA men, for whom the health benefits may be comparatively large,” Dr. Barrington’s group concluded. “Although obesity is linked to poor health outcomes in all populations, clinicians might consider the

PCa test

continued from page 1

more than 50% involvement of any core).

The test measures total, free, and [-2] proPSA (p2PSA), the latter being an isoform of free PSA identified as the most PCa-specific form found in tumor extracts.

Phi outperformed its individual components in detecting clinically significant PCa, the researchers reported in The Journal of Urology (2015;193:11631169). Using a 90% sensitivity cutoff for

Cv-Jump_URO_RUN0515.indd 9

LUTS

Renal & Urology News 9

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4/23/15 12:28 PM

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Renal & Urology News 13

Dementia Risk Lower in PD Initiators Researchers say new findings stress the need to assess dialysis patients’ cognitive function regularly Dr. Wolfgram’s team noted that their study “emphasizes the need for clinicians to regularly assess cognitive function among persons undergoing dialysis.” By helping clinicians tailor management to patients’ cognitive abilities, early recognition of dementia may improve patient outcomes, they stated.

PD was the initial dialysis modality for 8,663 of the 121,623 study subjects.

The mean age of the total cohort was 69.2 years.

The researchers used U.S. Renal Data System data for incident ESRD patients during calendar years 2006–2008. For all patients, they obtained Medicare claims data for 2004 through 2009, which includes ICD-9 comorbid disease diagnosis codes.

“Our use of Medicare data allowed us to exclude people who carried a dementia diagnosis at baseline, or who were recognized as having dementia during the 90 days after they initiated

Abnormal K Raises Death Risk in CKD

to increased mortality usually as a consequence of the arrhythmogenic effects of potassium.

“The results are not surprising for mortality,” commented Csaba P. Kovesdy, MD, who has conducted research on potassium levels and mortality in patients with renal disease but was not involved in the new study. “But I was surprised that [the researchers] did not find associations with ESRD.” The study has the advantage of a moderately large study sample and fairly good representation of confounders, said Dr. Kovesdy, Director of the Clinical Outcomes and Clinical Trials Program in the Division of Nephrology at the University of Tennessee Health Science Center in Memphis and Nephrology Section Chief at the Memphis VA Medical Center. The study, however, relied on data from a single center, which limits interpretation of study findings. Another limitation is the use of a single baseline serum potassium value, which may or may not represent long-term potassium levels and may not be the best way to evaluate the effects on mortality.

Both higher and lower potassium are known to increase mortality through arrhythmias, for which short-term changes in potassium are most relevant, he pointed out. n

LOW AND HIGH serum potassium levels are associated with increased mortality risk in patients with chronic kidney disease (CKD), researchers reported at the National Kidney Foundation’s 2015 Spring Clinical Meetings in Dallas.

In a study of 42,912 patients with stage 3 or 4 CKD, Georges N. Nakhoul, MD, and colleagues at Cleveland Clinic found that hypokalemia (potassium levels below 3.5 mmol/L) and hyperkalemia (potassium levels 5.5 mmol/L or above) were associated with a 26% and 22% increased risk of death, respectively, compared with a potassium level of 4.0–4.9 mmol/L (reference).

The investigators found no association between serum potassium and risk of end-stage renal disease.

The study population, which had a mean age of 72 years, was 54% female and 13% African American. Dr. Nakhoul’s group obtained data from their institution’s electronic health record-based CKD registry.

The researchers noted that hypokalemia and hyperkalemia have been linked

News-dementia_RUN0514.indd 13

In a study, patients who started on peritoneal dialysis rather than hemodialysis were 25% less likely to develop dementia.

dialysis,” they wrote. “Thus we were not simply documenting that persons with dementia are unlikely to be able to initiate PD, a therapy which requires greater involvement of patients in care.”

The investigators also acknowledged study limitations. For example, they pointed out that non-medical factors impact the choice between PD and HD. “Physicians are more likely to encourage patients with subtle evidence of cognitive impairment to choose HD as their initial modality, biasing our results toward higher dementia risk in those initiated on HD. Although we excluded patients with pre-existing dementia from our analysis, it is possible that significant differences in baseline cognitive function between the PD and HD groups affected our results.”

Another limitation was that the researchers required 2 years of Medicare eligibility prior to the diagnosis of ESRD. As a result, their cohort was substantially older than the overall ESRD population and may have been healthier due to a survival effect, they noted.

“Thus we cannot extrapolate our findings to younger persons with ESRD.” n

New Tool Could Spare Men Unnecessary Prostate Biopsies A NEW TOOL called the 4Kscore

School of Medicine, who presented

could help avoid unnecessary pros-

study findings.

tate biopsies by enabling clinicians to

Biopsies revealed high-grade PCa in

more accurately discriminate which

231 men (23%). The 4Kscore showed

patients are likely to have high-grade

excellent calibration, with the predicted

prostate cancer (PCa) found at biopsy,

probability of high-grade PCa being sim-

according to a new study presented

ilar to what was observed, Dr. Punnen’s

at the 2015 Genitourinary Cancers

group reported. In fact, the 4Kscore

Symposium.

demonstrated greater discrimination

The study is the first prospective evaluation of the 4Kscore for detecting high-grade PCa (Gleason score

than the widely used Prostate Cancer Prevention Trial Risk Calculator.

The number of unnecessary biopsies

7 or higher) among men referred for

that could be avoided varied depending

prostate biopsy in the United States.

on the threshold used for biopsy. If the

It enrolled 1,012 men scheduled for

threshold for biopsy was a 6% or greater

prostate biopsy at 26 U.S. centers.

probability that high-grade PCa would

The 4Kscore combines the results

be found, 30% of biopsies would be

of blood assays of 4 kallikrein proteins

avoided and only 1.3% of Gleason 3+4

(total, free, and intact PSA and hK2)

or higher cancers would be missed. If

with clinical information (such as age,

the threshold was 9% or higher, 43% of

digital rectal examination findings,

biopsies would have been avoided and

prior biopsy status, and family history),

only 2.4% of high-grade cancers would

into an algorithm. “It actually provides

be missed, according to investigators.

you with a personalized risk predic-

If the threshold was 15%, nearly 60%

tion,” said lead author Sanoj Punnen,

of unnecessary biopsies could have

MD, of the University of Miami Miller

been avoided. n

© AARON HAUPT / SCIENCE SOURCE

PATIENTS WITH end-stage renal disease (ESRD) who initiate renal replacement therapy on peritoneal dialysis (PD) are at lower risk of dementia than those who start on hemodialysis (HD), researchers concluded.

In a retrospective study of 121,623 patients initiating dialysis, Dawn F. Wolfgram, MD, of the Medical College of Wisconsin in Milwaukee, and colleagues found that those who started on PD had a 25% decreased risk of dementia compared with those who started on HD, after adjusting for age, gender, and other potential confounders. They obtained similar results when patients were matched by propensity score.

“This is the largest study to date in support of the hypothesis that the HD process itself, rather than simply the presence of ESRD, may contribute to the wellknown higher prevalence of dementia among persons with ESRD,” the authors wrote in Peritoneal Dialysis International.

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14 Renal & Urology News

MAY 2015 www.renalandurologynews.com

PCa Relapse More Likely in Smokers Even patients who quit smoking less than 10 years after radical prostatectomy are at increased risk Switzerland, stated that this new analysis “seems to confirm results we have seen in many other types of cancer: basically, smoking increases the risk of cancer recurrence after initial treatment. … It’s just another reason not to smoke at all, but the fact that the risk drops after 10 years means that anyone who has prostate cancer would be well advised to quit immediately.”

Current smokers had a significantly higher proportion of patients who had biopsy and RP Gleason scores of 8 or higher and seminal vesicle invasion.

The new study adds to mounting evidence of a link between smoking to an increased risk of biochemical recurrence of PCa after RP. In a retrospective study of 1,450 patients who underwent RP for PCa—including 549 who were active cigarette smokers and 1,121 who were nonsmokers at the time of surgery—Daniel M. Moreira, MD, of The Arthur Smith Institute for

Erectile Dysfunction Sufferers Benefit from CVD Screening SCREENING FOR cardiovascular

Dr. Pastuszak’s group found that

disease (CVD) in men who present with

men with CVD had a 47% increased

erectile dysfunction (ED) can be a cost-

relative risk of ED. They estimated that

effective intervention for the secondary

the co-prevalence of ED and CVD was

prevention of both conditions, accord-

1,991,520 men. Additionally, 44% of

ing to a new study.

men with CVD risk factors are unaware

“As the link between the etiologies of

of their risk, they noted. CVD screening

ED and CVD grows stronger, both the

of all men who presented with ED would

healthcare community and patients stand

identify 5.8 million men with previously

to benefit from screening for and treat-

unknown CVD risk factors over 20 years

ing CVD in men with ED,” researchers

at a cost of $2.7 billion to screen, the

wrote in the Journal of Sexual Medicine

researchers reported. Assuming that

(2015;12:975-984). “Such an approach

screening and subsequent treatment

could significantly decrease national

results in a 20% decrease in cardiovas-

healthcare costs and disease burden

cular events, 1.1 million cardiovascular

with significant societal implications.”

events would be avoided, for a cost

Using the known incidence and

savings of $21.3 billion over 20 years.

prevalence of ED and CVD, the rate

The investigators stated that based

of undiagnosed CVD, and the effects

on their model, “we call for a paradigm

of CVD, Alexander W. Pastuszak, MD,

shift that moves research and treat-

PhD, of the Center for Reproductive

ment of ED away from merely deriving

Medicine at Baylor College of medicine

symptomatic improvement in the dis-

in Houston, and colleagues modeled

ease to a proactive and comprehensive

the change in prevalence of acute CVD

view that appreciates and attempts to

events and ED as a function of the

reverse the underlying and concurrent

number of men with ED and CVD.

vascular pathology.” n

News-EAU_RUN0514.indd 14

In a study of RP patients, smokers had a 2.2 times increased risk of biochemical recurrence compared with never-smokers.

Urology at North Shore Long Island Jewish Health System in New Hyde Park, and colleagues found that active smoking was associated with a significant 25% increased risk of biochemi-

Study: Post-RP Cause of Death Linked to Age HIGH-RISK PROSTATE cancer (PCa) patients younger than 60 years are more likely to die from their malignancy than from other causes during the first 10 years after radical prostatectomy (RP). Once past that point, however, other causes of death become more likely, according to research presented at the European Association of Urology congress in Madrid.

The findings have important clinical implications. “These results confirm that if you are under 60 when you undergo a radical prostatectomy you need close follow-up, concentrating on possible cancer recurrence for the first 10 years,” stated lead researcher Marco Bianchi, MD, of Ospedale San Raffaele in Milan, Italy, in a news release. “After that time, patients should worry less about prostate cancer and priorities may need to shift to other health risks, even though regular urological check-ups should be continued.”

For the international, multicenter study, the investigators identified 612 patients aged 39–60 treated with RP for high-risk PCa (defined as PSA above

cal recurrence, a significant 2.6 times increased risk of both metastasis and castration-resistant PCa, and a significant 2.1 times increased risk of overall mortality, according to a report in Cancer (2014;120:197-204).

In an previous retrospective study of 1,416 patients who underwent RP, a team led by Elizabeth A. Platz, ScD, MPH, of the Johns Hopkins Bloomberg School of Public Health in Baltimore found that at 1 year after surgery, current smokers had a 2.3 times increased risk of PCa recurrence than never-smokers in adjusted analyses. The authors, who published their findings in the Journal of the National Cancer Institute (2011;103:835-838), wrote that their work “may contribute to the development of evidence-based recommendations for the prevention of prostate cancer recurrence after treatment for potentially curable prostate cancer.” n

20 ng/mL, clinical stage 3 or higher, or biopsy Gleason score 8–10) from 1987 to 2013. During the study period, 57 (9.3%) patients died of cancer and 37 (6%) of other causes. At 5, 10, and 15 years, cancer-specific survival rates were 93.9%, 87%, and 82.2% respectively.

Overall survival rates at the same time points were 91%, 82.1%, and 69.6%.

Significant factors predicting PCarelated death included year of surgery, Gleason score, clinical stage, surgical margins status, and lymph-node invasion.

Among patients who survived 5 and 8 years after surgery, the probability of dying from PCa within the next 5 years was higher than dying of other causes (7.3 and 6.7% vs. 2.6 and 5.8%, respectively). In contrast, once patients survived 10 years after RP, other-cause mortality became the main cause of death during the next 5 years (9.9% vs.

5.3% for cancer-specific mortality).

The researchers suggest strict followup of patients in the first 10 years after RP. Thereafter, with periodic urology check-ups, a comorbidity profile reassessment should be made to stratify patient prognosis.

“This is particularly important especially with increasing time after surgery, since new comorbidities, such as heart disease, may develop and become a more immediate risk to the patient’s health,” Dr. Bianchi said. n

© THINKSTOCK

CURRENT SMOKERS and those who quit smoking less than 10 years before radical prostatectomy (RP) for prostate cancer (PCa) are twice as likely as patients who never smoked to experience biochemical recurrence, according to study findings presented at the European Association of Urology 2015 congress in Madrid.

The study included 7,191 men who underwent RP. Of these, 2,513 (34.9%) had never smoked, 2,269 31.6%) were former smokers, and 3,409 (33.5%) currently smoked. After a median followup of 28 months, current smokers and those who had quit smoking within the last 10 years had a 2.2 times and 2.0 times increased risk of biochemical recurrence of PCa, respectively, compared with never-smokers. Men who quit smoking 10 or more years had a non-significant 20% increased risk.

Lead researcher Malte Rieken, MD, of University Hospital in Basel,

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Binders Cut Mortality, Up ESRD Risk PHOSPHATE BINDER use was associated with lower mortality risk but a higher risk of end-stage renal disease (ESRD) among patients with chronic kidney disease (CKD) and high phosphorus levels, according to study findings presented at the National Kidney Foundation’s 2015 Spring Clinical Meetings in Dallas.

In a retrospective longitudinal cohort study, Ardeshir Khosraviani, MD, and colleagues at Kaiser Permanente Southern California compared phosphate binder use and non-use among 3,026 non-dialysis CKD patients with hyperphosphatemia (phosphorus levels 5.5 mg/dL or higher). Compared with patients who did not use phosphate binders, those who did had a 15% decreased mortality risk and a nearly 3-fold increased risk of ESRD, the investigators reported.

“These findings underscore the need to better understand whether earlier phosphorus management may impact morbidity and mortality in advanced CKD,” the authors concluded in a poster presentation.

Of the 3,026 subjects, 596 used

Renal & Urology News 15

PCa Recurrence, MetS Not Linked High LDL cholesterol and blood glucose, however, increased PSA relapse risk

BY NATASHA PERSAUD A NEW STUDY of veterans demonstrated no link between prostate cancer (PCa) recurrence and metabolic syndrome (MetS), but elevated low-density lipoprotein (LDL) levels and impaired fasting glucose might increase recurrence risk.

“This analysis of a large cohort of veterans supports a role for lipid and glucose metabolism in PCa recurrence and contributes to a developing body of evidence that may support preventive recommendations if these findings are confirmed,” stated lead researcher Liam Macleod, MD, of the University of Washington School of Medicine in Seattle, and colleagues.

For the retrospective study, the investigators analyzed the relationship between MetS and biochemical recurrence of localized PCa (after prostatectomy or radiotherapy) among 1,706 predominantly Caucasian veterans.

Most men had clinical stage T1a–T2a disease, Gleason 7, and PSA less than 10 ng/mL. Patients receiving active surveillance or androgen-deprivation therapy were excluded.

MetS was defined as any 3 of the following features: • blood pressure greater than 130/85 mm Hg

• fasting blood glucose 100 mg/dL or higher • waist circumference above 102 cm (40 inches) • high-density lipoprotein (HDL) less than 40 mg/dL • triglycerides 150 mg/dL or above.

The researchers also separately examined LDL cholesterol levels (greater than 130 mg/dL).

Findings support a role for lipid and glucose metabolism in PCa recurrence.

After a median 41 months, 279 men experienced PCa recurrence. Contrary to previous research, the investigators found no associations between recurrence and MetS or its components, according to results published in Prostate Cancer and Prostatic Disease.

Although the researchers could not confirm a link between hypertension and PCa recurrence, for example, “the role for hypertension merits further investigation,” they stated.

Having a high LDL cholesterol level was associated with 33% greater odds

of disease recurrence. “Our findings of an association between elevated LDL and PCa recurrence support the concept that cholesterol interactions may have a role in the protective effects of statins noted by some researchers,” the investigators stated.

In addition, having an impaired fasting glucose level was linked to 54% greater odds of PCa recurrence.

The cytotropic effects of glucose and insulin-mediated stimulation of cancer growth factors are among the possible mechanisms, according to the researchers.

The new findings contrast with those of some other recent studies. For example, in a study published recently in European Urology ((2015;67:64-70), Bimal Bhindi, MD, of the University of Toronto, and colleagues found that men with MetS versus no component of MetS had 54% increased odds of a PCa diagnosis, 56% increased odds of clinically significant PCa, and 56% increased odds of intermediate- or high-grade PCa. The study included 2,235 men without a prior PCa diagnosis who underwent a prostate biopsy.

“Our findings suggest that men with MetS may require a lower threshold for performing biopsy,” Dr. Bhindi’s group concluded.” n

binders and 2,430 did not. Study subjects had a mean age was 65.5 years; 49% were female, 49% were white, 24% were Hispanic, 17.3% were black, and 8.5% were Asian.

The binder group had higher rates of diabetes, hypertension, and coronary artery disease.

“Our study raises the question of whether earlier management and control of hyperphosphatemia in the CKD population with binder therapy may improve patient survival in terms of mortality prior to and after [transition to ESRD],” Dr. Khosraviani told Renal & Urology News.

He said he and his colleagues believe their study adds to the literature on the topic because it looked at a real-world practice environment using a large and heterogeneous CKD population, and the results provide insights into CKD mineral-bone management strategies as patients transition to ESRD. n

News-PCa_RUN0514.indd 15

Obesity Increases Likelihood of Bladder Cancer

BY NATASHA PERSAUD OBESITY IS ASSOCIATED with an increased risk of bladder cancer, a new systematic review and meta-analysis has confirmed.

For the meta-analysis, Yong-Bing Xiang, MD, and colleagues from the Shanghai Cancer Institute at Renji Hospital in China, pooled results from 15 cohort studies published by September 2014 from North America, Europe (including Scandinavia), Asia, and Australia. Among 14 million people, 38,072 bladder cancer cases were identified. Compared with normal-weight individuals (body mass index [BMI] 18.50–24.99 kg/m2), preobese and obese individuals (BMI 25.00–29.99 and 30 or greater, respectively) had a 7% and 10% increased risk of bladder cancer, respectively, the researchers reported in PLOS One. Researchers observed a linear relationship between body mass index

(BMI) and bladder cancer risk. For each 5 kg/m2 increase in BMI, there was a 4.2% hike in bladder cancer risk.

The findings update and expand a 2013 meta-analysis that reached a similar conclusion. A shortcoming of that study was it did not address confounders.

Investigators in the current study adjusted for smoking and found no meaningful differences. They also examined other possible confounders.

Studies that adjusted for physical activity, alcohol consumption, and family history of cancer, for example, actually showed stronger associations.

The researchers presented several theories for how obesity might promote carcinogenesis. Elevated insulin production, which is linked to obesity, might fuel tumor growth. In addition, obesity might promote chronic lowgrade inflammation, causing disruptions in levels of cytokines and adipokines that promote cancer.

Given the rising rates of pre-obesity and obesity worldwide, “more in-depth studies are warranted to disentangle the roles of the biological mechanisms involved in obesity-related carcinogenesis,” the researchers concluded.

The meta-analysis has a number of strengths, the investigators stated.

They noted that they restricted their analysis to prospective studies and excluded traditional case-control studies, “which would eliminate the influences caused by recall bias.” In addition, to their knowledge, for the first time in a meta-analysis, a doseresponse analysis was performed “to better describe the relationship between BMI and bladder cancer.”

The meta-analysis also had some limitations. For example, BMI usually tends to fluctuate over time, but most studies used a single measure of BMI at baseline, which may not reflect usual adult weight. n

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16 Renal & Urology News

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CKD ‘Phosphorus Pyramid’ Developed A goal is to help healthcare providers teach patients how to decrease their phosphorus intake

BY NATASHA PERSAUD ITALIAN RESEARCHERS have developed a phosphorus pyramid to help healthcare providers teach chronic kidney disease (CKD) patients how to reduce their dietary phosphorus load and stave off mineral and bone disorders (MBD).

“The phosphorus pyramid herein proposed is an original, visual, userfriendly tool for nutritional education.

It can support patients and caregivers in making the right food choices by encouraging adherence to dietary prescriptions, which is a crucial component for CKD-MBD,” Adamasco Cupisti, MD, of the University of Pisa in Italy, and colleagues wrote in BMC Nephrology (2015;16:9).

Phosphorus is a concern at all stages of CKD, the researchers noted. The pyramid can help both CKD and dialysis patients understand what to eat and what to avoid, with appropriate tailoring. The pyramid offers some basic nutrition strategies:

Higher B12 Ups HD Patient Mortality ELEVATED LEVELS of vitamin B12 are associated with an increased risk of death in hemodialysis (HD) patients, study findings presented at the National Kidney Foundation 2015 Spring Clinical Meetings in Dallas suggest.

The study, led by Kamyar KalantarZadeh, MD, PhD, of the University of

• In non-dialysis patients, consider restricting protein intake. (Those on dialysis require extra protein.) In a mixed diet, each gram of protein is usually accompanied by 12–14 mg of phosphorus.

• Shift from phosphorus-rich foods to low phosphorus foods. Take into consideration bioavailability. Plant foods contain phosphorus but less than half of the mineral content is absorbed by the body. The phosphoric acid in soft drinks, by comparison, is almost completely absorbed.

• Boil foods to reduce their mineral content, including phosphorus (then discard the water). According to a study, boiling reduces phosphorus by 51% for vegetables, 48% for legumes, and 38% for meats.

• Try to identify and avoid phosphate additives. Processed foods contain considerable amounts of added phosphorus, including from preservatives.

The food pyramid color codes food items similar to a traffic light: greens for

A food pyramid developed by Italian investigators uses different colors to indicate the phosphorus content of various foods.

go, yellows for slow, and reds for stop. It consists of 6 levels with foods arranged by their phosphorus content, phosphorus to protein ratio (no more than 12 mg/g is favorable) and phosphorus bioavailability. Here is an overview of each level from 1 (low phosphorus) to 6 (high phosphorus): 1. Green: Foods with a very low phosphorus content include protein-free foods, fruit, vegetables, egg white, olive oil, and sugar. These items are

not limited, unless a patient is overweight, diabetic, or receiving dialysis.

2. Light green: Foods with phytate, a less absorbable form of phosphorus, include cereal, rice, pasta, white bread, and legumes. 2–3 servings per day.

3. Yellow: Among meats, choose lamb, rabbit, ham, or fish (e.g., trout, tuna, cod, hake, and sole). Avoid farmed fish because it has been fed with phosphorus to promote growth. Also choose milk and yogurt. No more than 1 serving per day.

4. Orange: Foods with a higher phosphorus to protein ratio include turkey, offal, shrimp, squid, salmon, and soft cheeses. No more than 1 serving per week.

5. Orange-Red: Foods with a very high phosphorus content include nuts, egg yolk, and hard cheeses. No more than 2–3 servings per month.

6. Red: Processed foods with phosphorus-containing additives include colas, processed meat, and processed cheese. Avoid as much as possible. n

CKD Risk May Remain Despite PN Use PATIENTS WITH medical risk factors for chronic kidney disease (CKD) are at higher risk of progressive renal impairment despite the use of partial nephrectomy (PN), according to a new study published online in BJU International.

The study, by Prassannah Satasivam, MD, of Monash Health in Melbourne, and colleagues, included 488 patients undergoing surgery for renal cell carcinoma (RCC). Of these, 156 underwent PN and 332 underwent radical nephrectomy (RN). RN was associated with a 2.7 times increased risk of a new-onset CKD

(estimated glomerular filtration rate [eGFR] below 60 mL/min/1.73 m2) compared with PN. Patients undergoing PN, however, were still at risk of new-onset CKD. The proportion of PN patients who experienced new-onset CKD more than 6 months after surgery was 7% for those without CKD risk factors, including hypertension, diabetes mellitus, cardiovascular disease, obesity, high cholesterol, family history of CKD, and age, the researchers reported. This proportion rose to 24%, 30%, and 42% for patients older than 60 years and those with hyper-

tension or diabetes mellitus, respectively.

“These findings complement emerging evidence that renal impairment arising purely as a result of surgery may not have the same adverse outcomes as that which occurs in patients with pre-existing medical renal disease,” the authors noted.

The researchers stated that in patients with pre-existing renal impairment or those with normal renal function who have CKD risk factors, “PN may be required to reduce the risk of progression to moderate and severe renal impairment.” n

California Irvine School of Medicine, incident HD patients receiving dialysis at DaVita facilities. Compared with HD patients who had a vitamin B12 level below 400 pg/mL, those with levels of at least 550 but less than 650 pg/mL had a significant 26% increased risk of all-cause mortality in a fully adjusted model, Dr. Kalantar-Zadeh’s team reported in a poster presentation. n

News-phosphorus_RUN0514.indd 1

Dialysis for AKI Does Not Raise Major CV Risks TREATMENT OF acute kidney injury (AKI) with temporary dialysis in hospitalized patients with normal or nearnormal estimated glomerular filtration rate is not associated with an increased risk for subsequent major adverse cardiovascular events (MACE), according to study findings presented at the National Kidney Foundation’s 2015 Spring Clinical Meetings in Dallas.

Bolanle A. Omotoso, MD, of the University of Virginia Medical Center in Charlottesville, and colleagues conducted an observational cohort study of 125,880 adults admitted to the hospital from January 1, 2002 to December 31, 2012. All had an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or higher. AKI developed in 24,631 (19.57%). The researchers propensity

score matched 253 AKI patients who received temporary dialysis with 759 AKI patients who did not.

After a median follow-up 299 days, the researchers observed no significant difference between the groups in the risk of MACE, defined as subsequent admission for myocardial infarction, transient ischemic attack, stroke, and heart failure. n

© D’ALESSANDRO ET AL. BMC NEPHROLOGY

included a 5-year cohort of 12,968

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Renal & Urology News 17

Men’s Health Update Please visit us at www.renalandurologynews.com for the latest news updates from the fields of urology and nephrology

Bicycles were not designed with male genitalia in mind, and they account for more than 4,000 genitourinary injuries each

vessels. In a paper published in Urology (2015;85:725-730),

© THINKSTOCK

year. A recent comprehensive review looked for conclusive

Mathias Michiels, MD, and Frank Van der Aa, MD, PhD, of KV Leuven in Leuven, Belgium, concluded that bicycle seats may result in transient genital numbness, but that there is no evidence the effects are permanent. Cyclists with occasional numbness should select a seat that fully supports the ischial tuberosities, then tilt the seat’s nose downward, avoid leaning forward for too long, and regularly stand up on the pedals.

Researchers Take Another Look at Average Penis Size Men often joke about penis size, but for some the fear of not sizing up is significant enough to seek medical attention. Most physicians have enough experience to provide basic reassurance, but a new report combines data from 20 studies to provide definitive nomograms of the flaccid, flaccid stretched, and erect penis length and girth across ages and races. The average length was 9.16 cm when flaccid, 13.24 cm when stretched, and 13.12 cm when erect, investigators reported in BJU International (2015; published online ahead of print). Flaccid length was correlated with erect length; despite popular belief, foot size was not predictive.

Food Pesticide Residues Linked to Diminished Semen Quality Increasing evidence suggests pesticides can impact semen quality. In a new study published in Human Reproduction (2015; published online ahead of print), researchers who stud© THINKSTOCK

ied men attending the Massachusetts General Hospital Fertility Center in Boston found that, overall, fruit and vegetable intake did not correlate with semen quality, but those who ate the most high pesticide-residue foods (spinach, strawberries, blueberries, celery, apples, potatoes, peaches) had lower sperm counts, fewer normal-appearing sperm, and lower ejaculate volume. The authors noted, however, that they relied on self-reporting of dietary intake and did not assess pesticide levels in patients’ food.

Prostate Cancer: The Price of Fitness?

horter men are at increased risk of coronary artery disease (CAD), which is partially explained by the association between shorter height and an adverse lipid profile, researchers reported online in The New England Journal of Medicine.

“Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association,” they concluded.

Using a genetic approach in a study of 65,066 men with CAD and 128,383 controls, Christopher P. Nelson, PhD, of the University of Leicester in the U.K., and colleagues observed a 13.5% increased relative risk of CAD with each 6.5 cm decrease in genetically determined height. The researchers also looked at the effect of 12 known cardiovascular risk factors and found that shorter height was significantly associated with increased levels of low-density lipoprotein cholesterol and triglycerides.

The investigators noted that their findings “underscore the complexity underlying the inherited component of CAD.”

© THINKSTOCK

No Permanent Genitourinary Injuries from Bicycle Riding

erectile dysfunction, by compressing the pudendal nerve and

University of California, Irvine, Department of Urology

Coronary Artery Disease More Likely in Shorter Men S

Short Takes

evidence that bicycle seats also cause chronic issues, like

BY JAIME LANDMAN, MD and Christopher R. Kelly, MD, of the

Sex Hormones Predict Erectile Dysfunction Risk H

igh levels of free and bioavailable testosterone independently predict a decreased risk of erectile dysfunction (ED) in younger men, according to new findings published online in the Journal of Sexual Medicine.

In a population-based prospective cohort study of 733 Chinese men followed for 4 years, investigators found that high free testosterone (FT) and bioavailable testosterone (BT) levels were associated with a significant 19% and 22% decreased risk of ED, respectively, in men aged 21–40 years after adjusting for potential confounders. Total testosterone (TT) was not associated with ED risk in these men. Among men aged 41–65 years, TT, FT, and BT were not significantly associated with ED in either adjusted or unadjusted analyses.

The study, by Yawen Luo, BSc, and Haiying Zhang, MD, PhD, both of Guangxi Medical University in Nanning, Guangxi, China, and colleagues, demonstrated that men with both low FT and high sex hormone-binding globulin had the highest ED risk.

Although physical fitness is widely known to prevent cardiovascular disease,

underwent a treadmill-based fitness assessment and were then observed for an average 6.5 years. The men in the best shape had significantly lower rates of lung and colorectal cancer but, surprisingly, had higher rates of prostate cancer (PCa)—even after adjusting for several potentially confounding variables. The researchers hypothesized that physically fit men were more likely to undergo screening tests, presumably resulting in PCa over diagnosis. Fortunately, the fittest men also had the lowest overall cancer and cardiovascular mortality, so even if exercise did somehow contribute to PCa risk, its benefits still prevail.

MenHealth_RUN0515.indd 17

MEDISTAT

in JAMA Oncology (2015; published online ahead of print) nearly 14,000 men

17.7

The percentage of hypogonadal men receiving testosterone replacement therapy in a study of 9,176 men who underwent testing for low testosterone levels.

Source: Malik R et al. Characteristics of men undergoing testosterone replacement therapy and adherence to follow-up recommendations in metropolitan multicenter health care system. Urology 2015; published online ahead of print.

© THINKSTOCK

its impact on cancer is less clear. In an observational cohort study published

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18 Renal & Urology News

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www.renalandurologynews.com

In a New Light: NBI for Bladder Cancer Narrow-band imaging (NBI) recently received FDA approval for improved visualization of bladder cancer. Daniel Canter, MD, who has extensive experience using NBI, recently discussed the technology with Renal & Urology News. Dr. Canter is professor of urology and vice chairman of the Urologic Institute of Southeastern Pennsylvania, a partnership of the Fox Chase Cancer Center and the Einstein Healthcare Network.

What are your thoughts about the recent FDA approval of NBI for use in bladder cancer detection?

Dr. Canter: Anything we can do to improve the earlier detection of bladder cancer, specifically the detection of occult lesions in patients with de novo and recurrent bladder cancer, is welcome. Overall, there have been few advancements in the detection and treatment of bladder cancer. NBI can help detect these lesions; it has been documented to do so to the tune of 24% additional occult tumors and 28% additional carcinoma in situ (CIS or difficult-to-detect flat lesions).

If a practice or hospital was thinking of investing in NBI, what would be the best reasons for doing so?

Dr. Canter: This would be an important investment because it can improve outcomes. With the digital cystoscope, you can use the cystoscope for not only white light cystoscopy but also NBI. You can toggle between the 2 imaging techniques to do a thorough cystoscopic examination of the bladder. NBI does not require the use of dyes, which is convenient. What is also nice about NBI technology is that it is available in both the inpatient and outpatient settings.

Historically what have been some challenges of diagnosing bladder cancer and what impact will NBI have on addressing those?

Dr. Canter: Historically, while considered the gold standard, white light

On The Web QA_RUN0515.indd 18

cystoscopy would miss difficult-todetect occult or flat lesions. These types of recurrences would be missed not infrequently on white light cystoscopy. The addition of NBI should help to detect these lesions earlier and should translate into improved patient outcomes.

What benefits that you haven’t yet mentioned might be derived through NBI use in terms of treatment costs?

And in terms of patient outcomes and/or quality-of-life?

Dr. Canter: Bladder cancer is the most costly cancer to treat. The high rate of its recurrence and the disease’s potential for progression requires long-term patient monitoring, which accounts for its cost as well as increasing patient discomfort and anxiety. NBI can potentially improve patient outcomes which can hopefully translate into an improved quality of life for a variety of reasons.

Also, if visualized early enough, NBI has the potential to reduce expenses.

For example, using a cystoscope with NBI capabilities, small tumors that may have been missed on a surveillance cystoscopy could be fulgurated in-office and could prevent OR visits.

How soon do you think NBI will be a standard-use technology among urologists diagnosing and treating bladder cancer?

Dr. Canter: With any new technology, it’s hard to predict how readily it will be adopted. I do think these types

of techniques are being recognized as an important adjunctive part of endoscopic follow-up for patients. An improved view into the underlying vascularity of the lining of the bladder means an improved ability to detect and treat not just the obvious tumors but also the lesions that may have been missed with traditional white light cystoscopy only. This is something most urologists have known and would agree with, but it is now backed by the FDA. What technical challenges are presented by the anatomy and physiology of the bladder? Is NBI helpful in dealing with these anatomy-specific challenges and how?

Dr. Canter: The bladder, as with any hollow organ, poses its own unique set of anatomic challenges for endoscopic procedures. As we have said, many bladder cancer lesions can be missed during white light cystoscopy, thus the use of any technology to aid in the visualization of these lesions is needed. With NBI, the isolation of the blue and green light bands of wavelength allows for ready visualization

Many bladder tumors can be missed with white light cystoscopy.

—Daniel Canter, MD

NBI At a Glance ■

Filters white light into specific light wavelengths absorbed by hemoglobin

■

Improves visualization of lesion boundaries in non-muscle invasive bladder cancer (NMIBC) patients

■

Not intended to replace histopathological sampling to make a diagnosis

■

Based on a weighted average study, NBI helped identify 24% additional NMIBC tumors.

Source: http://medical.olympusamerica.com/

of blood patterns. The blood absorbs these colors -- blue light [415 nm] highlights the shallow capillaries and green light [540 nm] highlights deeper veins.

Getting a good look at blood vessel patterns is important to help identify occult lesions or tumors.

How can the urology community get the word out about NBI to referring physicians, such as those at family practices?

Dr. Canter: PCPs give referrals to urologists not usually for bladder cancer but for hematuria, and then a portion of these patients will be diagnosed with some type of urologic cancer, such as bladder cancer. General or community urologists do an outstanding job of taking care of patients with bladder cancer, but their access to newer techniques and technology can often be limited by the cost of updating their equipment for things like NBI. So, I think it’s important that community urologists know about NBI and do what they can to learn more about it.

If they don't have the capability for NBI in their practice, it may be worthwhile to refer patients who are not responding to treatment or recurring at a faster rate to places where NBI is used to help detect and treat potential occult lesions. Ultimately, we all want better outcomes for our patients, and technologies like NBI should help us achieve that. ■

Continue the conversation online! We have many experts who weigh in on controversial topics important to you. Catch our discussions at www.renalandurologynews/expertqa.

4/23/15 12:04 PM

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In mCRPC therapy…

Is there more to the story?

mCRPC = metastatic castration-resistant prostate cancer; AST = aspartate aminotransferase; ALT = alanine aminotransferase.

Please see additional Important Safety Information on the next page.

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

Date: 04/07/15 Customer Code: 029979-150220 File Name: 029979-150220_727018_v1 (pg1 Right Hand Start) Size: 7" x 10" Colors: CMYK Description: Is there more to the Story Pub: Renal and Urology News Digital Edition (5/1/15 Issue) K

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

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

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.

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.

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.

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.

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For men with mCRPC who progressed on ADT

In a clinical trial, patients had a median overall survival on ZYTIGA® (abiraterone acetate) of…*

More than 1,000 days.

And every day tells a story.

35.3 5.2 MONTHS IMPROVEMENT IN MEDIAN OVERALL SURVIVAL

MONTHS MEDIAN OVERALL SURVIVAL FOR ZYTIGA® plus prednisone† vs 30.1 MONTHS with placebo plus prednisone (active compound).‡

compared with placebo plus prednisone.

Co-primary end point—overall survival: hazard ratio (HR)=0.792; 95% CI: 0.655, 0.956; P=0.0151; prespecified value for statistical significance not reached.

Co-primary end point—radiographic progression-free survival: median not reached for ZYTIGA® plus prednisone vs a median of 8.28 months for placebo plus prednisone. HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.

*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 overall survival (OS) and radiographic progression-free survival.

ADT = androgen-deprivation therapy.

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

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2015 3/15 029979-150220

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IMPORTANT SAFETY INFORMATION (cont) 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.

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.

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003307-150130

†At a prespecified interim analysis for OS, 37% (200/546) of patients treated with ZYTIGA® plus prednisone compared with 43% (234/542) of patients treated with placebo plus prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

Learn more today at

Every day tells a story.

www.zytigahcp.com.

Date: 04/07/15 Customer Code: 029979-150220 File Name: 029979-150220_727018_v1 (pg3 Right Hand page) Size: 7" x 10" Colors: CMYK Description: Is there more to the Story Pub: Renal and Urology News Digital Edition (5/1/15 Issue) K

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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