Renal & Urology News - September 2016 issue

S E P T E M B E R 2 016

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VOLUME 15, IS SUE NUMBER 7

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Delayed mRCC Treatment An Option

© LIVING ART ENTERPRISES, LLC / SCIENCE SOURCE

Patients had a median overall survival time of 44.5 months from the start of active surveillance

SELECTED CASES OF metastatic RCC can be managed safely with active surveillance.

BY JODY A. CHARNOW ACTIVE SURVEILLANCE (AS) may be a safe management approach for selected cases of metastatic renal cell carcinoma (mRCC), according to a new study.

The phase 2 trial, which investigators believe is the first prospective assessment of observation for patients with mRCC, identified clinical characteristics of patients for whom AS was a successful strategy, including limited sites of metastasis and fewer adverse prognostic features.

“There is a perception that all cancers should be treated immediately because they are equally lethal,” lead investigator Brian I. Rini, MD, of Cleveland Clinic, said in a press release

Low Vitamin D May Raise ED Risk High-Grade VITAMIN D DEFICIENCY is asso- have a significant 30% and 80% PCa, Diabetes ciated with an increased prevalence of greater prevalence of ED and severe erectile dysfunction (ED) independent ED, respectively, compared with men Drugs Linked of risk factors for atherosclerotic cardio- who have optimal levels (30 ng/mL or vascular disease (ASCVD), new study findings suggest.

Men with vitamin D deficiency— defined as a 25-hydroxyvitamin D [25(OH)D] level below 20 ng/mL—

higher), after adjusting for comorbidities, ­lifestyle ­variables, and medication use, investigators reported in Atherosclerosis (2016;252:61-67). In addition, each 10 continued on page 11

HEPATITIS C AND CKD

Annette Bruchfeld, MD, PhD, reviews and comments on the latest research.

PAGE 22

USE OF DIABETES drugs, especially metformin, prior to surgery for prostate cancer is associated with an increased risk of high-grade tumors, investigators reported.

In a study of 1314 PCa patients who underwent radical prostatectomy, a team led by Teemu Murtola, MD, PhD, of Tampere University Hospital in Tampere, Finland, found that preoperative use of diabetes drugs was associated with 83% increased odds of Gleason 7–10 disease compared with non-use, according to a paper published online ahead of print in Prostate Cancer and Prostatic Diseases.

Preoperative use of metformin was associated with 3-fold greater odds of high-grade PCa compared with preoperative use of other diabetes drugs.

Despite this, Dr. Murtola’s group found no difference in PSA levels or pathologic stage between metformin users and uses of other diabetes drugs. Users of diabetes drugs had a decreased risk

from The Lancet Oncology, which published the study findings. “But what we’ve seen in this small phase 2 study is that a subset of adults with advanced kidney cancer have slow-growing disease that can be safely managed using active surveillance, which could spare them the inconvenience and debilitating side effects of aggressive treatments for about a year, and in some cases several years, without worsening anxiety and depression.”

The study enrolled 52 patients with treatment-naïve, asymptomatic disease who were placed on AS. Of these, 4 were excluded from all analyses.

Patients were assessed radiographically at baseline, every 3 months for year 1, continued on page 11

IN THIS ISSUE 9

Abnormal CT findings predict bacteremia in UTI patients

11 Postop infections occur in 24% of radical cystectomy patients 15 Glomerulonephritis increase the likelihood of ESRD

16

Prostate cancer radiotherapy found to raise cardiac risks

16 TURP often causes asymptomatic bacteremia

18 RCC is associated with exposure to metalworking fluids

19 Prostate cancer risk not linked to use of ED drugs

Gleason 9-10 PCa outcomes similar with radiation, radical prostatectomy PAGE 12

continued on page 11

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Gout Found to Increase Type 2 Diabetes Risk GOUT INCREASES the risk for type 2 diabetes, and this effect is more pronounced in women than men, according to a new study.

Using a population-based representative insurance claims database, HungPin Tu, PhD, of Kaohsiung Medical University, Kaohsiung, Taiwan, and

Xtandi_004-5_RUN0916.indd 4

colleagues studied 29,765 patients with gout and 59,530 without gout (controls).

Type 2 diabetes developed in 3940 gout patients (13.24%) and 6334 controls (10.64%). Compared with controls, gout patients overall had a significant 70% increased risk of type 2 diabetes in multivariable analysis, the i­nvestigators

reported online ahead of print in the American Journal of Medicine. Gout increased the risk of type 2 diabetes nearly 2-fold in women compared with 1.62 times in men, a significant difference.

In addition, compared with men who did not have gout, women without gout

and both men and women with gout had a significantly higher risk of type 2 diabetes.

“Gout is a strong and independent risk factor for type 2 diabetes, and female patients with gout are at a higher risk of type 2 diabetes than are male patients with gout,” the investigators concluded. n

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Renal & Urology News 5

ESA Resistance Linked to Vitamin B6 Treatment

BY NATASHA PERSAUD INTRAVENOUS (IV) vitamin B6 administered 3 times per week to hemodialysis patients may reduce response to erythropoiesis-stimulating agents (ESA).

In a pilot study, Japanese investigators led by Yoshitsugu Obi, MD, PhD, of Osaka University, and Satoshi Mikami,

MD, PhD, of Higashikouri Hospital, tested whether vitamin B6 supplementation could improve response to anemia treatment. They randomly assigned 56 maintenance hemodialysis (HD) patients with relatively high resistance to ESA agents to a treatment arm in which patients received 60 mg of IV

pyridoxal 5’-phosphate (PLP) at the end of each dialysis session or to a control arm in which patients received standard care but received no PLP. Overall, 40% of patients were vitamin B6 deficient.

The vitamin B6 group experienced a rise in the ESA resistance index (ERI) over 6 months compared with the control

group, according to results published in the Journal of Renal Nutrition. IV vitamin B6 treatment was associated with higher ERI at week 13 by 0.97 x 10–2 µg darbepoetin-alpha per kg of weight per g/dL of hemoglobin, regardless of patients’ vitamin B6 status at baseline. Meanwhile, endogenous erythropoietin levels increased in the B6 group (after adjustment for hemoglobin and ESA dose), perhaps as a compensatory response.

“Intravenous vitamin B6 administration did not offer significant benefit, even in patients with deficiency in terms of anemia and bone metabolism, suggesting that vitamin B6 deficiency may not always be involved in the pathways causal of these complications,” Dr Obi, Dr Mikami, and colleagues stated.

Alternatively, the cutoff for deficiency may be inappropriate, they noted.

No serious adverse effects associated with vitamin B6 toxicity were reported.

Certain markers of bone turnover— bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b—trended downward in the vitamin B6 group among those without vitamin B6 deficiency. “These results suggested vitamin B6 toxicity in the intervention group,” the investigators stated. The dose of PLP used in the study may be too high for HD patients, they noted. No serious adverse events associated with vitamin B6 toxicity were reported, however. The investigators concluded that IV treatment with vitamin B6 may blunt the response of bone to parathyroid hormone.

Most previous studies have shown no benefit for vitamin B supplementation, and some potential harms. A single study of oral pyridoxine conducted in 2001 showed no changes in hemoglobin (Nephron. 2001;87:328-332).

The researchers acknowledged that a possible interpretation of their pilot trial is that their results are the product of chance, but noted that the study is, to the best of their knowledge, the largest trial of vitamin B6 alone in HD patients. “Although per-protocol analyses might have overestimated the effect of vitamin B6 administration, the estimated effect on ERI (the primary outcome) was consistent across subgroups, suggesting the robustness of our findings,” they wrote. n

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www.renalandurologynews.com

Contents

SEPTEMBER 2016 ■ VOLUME 15, ISSUE NUMBER 7

Urology

ONLINE

15

Sexual Problems Linked to 5ARI Use for BPH Sexual dysfunction, erectile dysfunction, and decreased libido occurred in men who use a 5-alpha-reductase inhibitors for benign prostatic hyperplasia.

16

RARP Offers Good 5-Year Outcomes Largest Asian series to day demonstrates a 5-year biochemical recurrence-free survival rate of 76.4%.

18

Metalworking Fluids May Increase RCC Risk White men with a mean exposure of 18.80 mg/m3 per year had a significant 11% higher risk of renal cell carcinoma.

19

Robotic vs Open PN for Endophytic Tumors Partial nephrectomy (PN) performed with robotic assistance by skilled surgeons leads to favorable outcomes similar to those achieved with open PN.

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

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

Congratulations to our August winner: Jorge Frías Jullian, MD

HIPAA

5

ESA Resistance Linked to Vitamin B6 Treatment A pilot study demonstrated a rise in ESA resistance index in hemodialysis patients regardless of their vitamin B6 status at baseline.

10

Parathyroidectomy for SHPT May Reduce PAD Risk Researchers observed a 34% decreased risk of peripheral arterial disease among hemodialysis patients who had the procedure.

14

More Intensive RRT Possibly Harmful Urine output is lower during the first 7 days of treatment for acute kidney injury compared with less intensive RRT.

15

Glomerulonephritis Raises ESRD Risk Pimary GN is more likely than secondary GN to progress to end-stage renal disease, a new study suggests.

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

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

American Society for Radiation Oncology (ASTRO) Annual Meeting Boston September 25–28 Sexual Medicine Society of North America Annual Fall Scientific Meeting Scottsdale, AZ November 3–6 American Society of Nephrology Kidney Week 2016 Chicago November 15–20 Genitourinary Cancers Symposium Orlando, FL February 16–18, 2017 Annual Dialysis Conference Long Beach, CA March 11–14, 2017 National Kidney Foundation 2017 Spring Clinical Meetings Orlando, FL April 18–22, 2017

Nephrology

Encrypting health information offers a safeguard for protecting patient privacy.

Job Board

CALENDAR

26

Departments 8

From the Editor Challenges to the status quo drive medical advancement

9

News in Brief Contrast-induced nephropathy linked to low hemoglobin

26

Practice Management Participating in CMS’ Chronic Care Management program

There is biologic rationale for radiotherapy to increase cardiovascular and skeletal-related events.

See our story on page 16

TOC_007_RUN0916.indd 6

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8 Renal & Urology News

SEPTEMBER 2016 www.renalandurologynews.com

FROM THE EDITOR EDITORIAL ADVISORY BOARD

Medical Advancements Versus the Status Quo

S

cientific research is a challenge to the status quo. It is based on an innate desire to know more or an assumption that improvements always can be made. In medicine, this translates into a perpetual impetus to improve patient health outcomes and quality of life. In this regard, investigators often question the wisdom of current clinical practice and test whether alternative patient management approaches could be better.

In this issue are news reports on just such efforts. A phase 2 study led

by Brian I. Rini, MD, of Cleveland Clinic (see cover), tested whether active surveillance (AS) can be an appropriate management strategy for patients who have metastatic renal cell carcinoma (mRCC), for whom immediate systemic treatment is usually recommended. As Dr. Rini stated, the study demonstrated that a subset of patients with mRCC have slow-growing disease that can be managed safely using active surveillance, “which could spare them the inconvenience and debilitating side effects of aggressive treatments for about a year, and in some cases several years, without worsening anxiety and depression.” The study, which was published in The Lancet Oncology, included only 52 patients, but the results, if confirmed by larger trials, could give clinicians another option to offer selected mRCC patients, one that could delay systemic therapy and its adverse effects.

In another study (see page 19), published in European Urology, Pär Stattin, MD, of Uppsala University in Uppsala, Sweden, and colleagues demonstrated that radical local treatment may decrease mortality in men with very high-risk prostate cancer, for whom clinical guidelines recommend only androgen deprivation therapy (ADT). The study was a semiecologic population-based investigation, and, as Dr. Stattin’s group pointed out, the findings need confirmation in randomized controlled trials. Still, their study may represent an important step forward in providing these men with a possible way to avoid the complications associated with ADT. Lastly, in a study published in the Clinical Journal of the American Society of Nephrology, Matthew J. Oliver, MD, of Sunnybrook Health Sciences Centre in Toronto, and colleagues compared hospitalization rates associated with assisted peritoneal dialysis (PD) and in-center hemodialysis (HD) and found no significant difference (see page 10).

Assisted PD is a treatment option for patients who would like to receive dialysis at home but have significant barriers to self-care. Evidence that this modality can be a safe alternative to in-center HD could promote its use among certain populations—such as the elderly—for whom traveling to an HD center can be disruptive and inconvenient.

At this point, these studies only offer the promise of better patient management, but they also exemplify how advancements in medicine stem from researchers’ nonacceptance of the status quo.

Jody A. Charnow Editor

Mast-Edit_RUN0916.indd 8

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

Urologists

Nephrologists

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

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

R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto

David S. Goldfarb, MD Professor, Department of Medicine Clinical Chief New York University Langone Medical Center Chief of Nephrology, NY Harbor VA Medical Center

Orange, Calif.

Stanton Honig, MD Department of Urology Yale University School of Medicine New Haven, CT J. Stephen Jones, MD, FACS President, Cleveland Clinic Regional Hospitals & Family Health Centers Professor & Horvitz/Miller Distinguished Chair in Urological Oncology Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology University of California Irvine James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City

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.

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

Rulan Parekh, MD, MS Associate Professor of Pediatrics and Medicine University of Toronto Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center, Detroit

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

Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J.

Renal & Urology News Staff Editor Web editor Production editor

Jody A. Charnow Natasha Persaud Kim Daigneau

Group art director, Haymarket Medical

Jennifer Dvoretz

Production manager

Krassi Varbanov

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

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

Renal & Urology News (ISSN 1550-9478) Volume 15, Number 7. Published monthly, except for the combined January/February, June/July and November/ December issues, by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. Periodicals postage paid at New York, NY, and an additional mailing office. The subscription rates for one year are, in the U.S., $75.00; in Canada, $85.00; all other foreign countries, $110.00. Single issues, $20.00. www.renalandurologynews.com. Postmaster: Send address changes to Renal & Urology News, c/o DMD Data Inc., 2340 River Road, Des Plaines, IL 60018. Copyright: All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without the prior written permission of Haymarket Media, Inc. Copyright © 2016.

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Renal & Urology News 9

News in Brief

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

Short Takes Hypertension May Raise Prostate Cancer Risk

and 2.4 times increased risk of atrial

Hypertension may be associated with

those who had normal kidney func-

an increased risk of prostate cancer

tion (90 mL/min/1.73 m2 or higher).

(PCa), a recent meta-analysis published

­Patients with a urinary ­albumin/creati-

in Scientific Reports suggests.

nine ratio (ACR) of 300 mg/g or higher

fibrillation, respectively, compared with

The meta-analysis, by Zhen Liang,

had a 2-fold increased risk of atrial fibril-

MD, of Zhejiang University, Hangzhou,

lation compared with those who had an

China, and colleagues, included data

ACR below 30 mg/g.

from 21 observational studies, includstudies and 4 case-control studies.

Prostate Cancer BCR Risk Not Linked to Statin Use

Individuals with hypertension had a

Preoperative statin use at the time of

significant 8% increased risk of PCa.

radical prostatectomy (RP) for prostate

ing 17 cohort/nested case-control

cancer does not affect the risk of

Reduced Kidney Function Ups Likelihood of AFib

biochemical recurrence (BCR) or patho-

Decreased kidney function is a risk

online ahead of print in Urology.

factor for atrial fibrillation, inves-

logic upgrading, investigators reported Timothy D. Lyon, MD, of the

tigators reported in Nephrology

­University of Pittsburgh Medical ­Center,

(2016;21:717-720).

and colleagues studied 3042 men who

In a prospective study of 1840

underwent RP. Of these, 824 (27%)

patients aged 61–82 years, Jari

reported using statins at the time of RP.

­Laukkanen, MD, of the University of

Over a median follow-up of 70 months,

Eastern Finland in Kuopio, Finland, and

455 men (15%) experienced BCR. The

colleagues observed 159 incident cas-

investigators found no significant dif-

es of atrial fibrillation during a median

ference in BCR rates. Of the men with

follow-up of 3.7 years. Patients with a

biopsy Gleason 3 + 3 disease, 52%

glomerular filtration rate of 15–59 mL/

were upgraded to higher-grade disease

min/1.73 m estimated using c ­ ystatin C

after RP, but statin use was not associ-

and creatinine measurements had a 2.7

ated with pathologic upgrading.

2

Uncontrolled High BP in the U.S. Federal statistics show that the rates of uncontrolled high blood pressure among individuals aged 20 years and older with hypertension vary by gender and race/ethnicity. Rates during the period 2011–2014 are shown here.

60 50 40 30 20 10 0

58.1%

45.5%

48.4%

58.7%

57.5%

Male

Female

White

Black

Hispanic

Source: Centers for Disease Control and Prevention/National Center for Health Statistics; National Health and Nutrition Examination Survey.

NewsInBrief_RUN0916.indd 9

Bacteremia in UTI Patients Tied to Abnormal CT Findings B

acteremia in adult patients with a urinary tract infection (UTI) is associated with certain abnormal findings on computed tomography (CT), data show.

In a study of 189 adult UTI patients who underwent CT scans within 24 hours after hospital admission, investigators at Wonkwang University College of Medicine in South Korea, identified concurrent bacteremia in 40.2%. Abnormal CT findings were present in 96.3% of the patients, and 62.4% had 2 or more abnormal findings. In multivariable analysis, the presence of 2 or more abnormal CT findings was associated with 2.1-fold increased odds of bacteremia, investigators reported online in the European Journal of Clinical Microbiology and Infectious Diseases. Hydronephrosis was associated with 12-fold increased odds.

“Physicians should be aware that appropriate early management is necessary to prevent fatality in patients with these CT findings,” the investigators concluded.

Low Hemoglobin Associated With Elevated Risk of CIN L

ow hemoglobin levels may increase the risk of contrast-induced nephropathy (CIN) following administration of iodinated contrast media.

Jinzhong Xu, MD, of Wenzhou Medical University, Wenling, Zhejiang, China, and colleagues divided 841 patients undergoing coronary angiography and/or percutaneous coronary intervention (CAG/PCI) into 2 groups: patients with low hemoglobin levels (less than 120 g/L for men, less than 110 g/L for women) and normal levels (120–160 g/L for men, 110–150 g/L for women). CIN developed in 14.7% of patients with low hemoglobin levels compared with 5% of those with normal levels. On multivariable analysis, low hemoglobin was associated with a 3-fold increased risk of CIN, according to a report in Experimental and Therapeutic Medicine (2016;12:603-610).

The investigators determined that the optimal cut-off at which the hemoglobin level resulted in a high probability of developing CIN was 115.5 g/L in men and 111.5 g/L in women.

Tight Glycemic Control May Help Diabetic NMIBC Patients P

oor glycemic control in diabetic patients with non-muscle invasive bladder cancer (NMIBC) is associated with shorter progression-free survival, new findings suggest.

Ji Hoon Ahn, MD, and colleagues at Chonnam National University Medical School in Gwangju, Korea, reviewed data from 645 patients with NMIBC. Patients with diabetes mellitus had a significant 42% increased risk of recurrence and 79% increased risk of progression, the investigators reported in the Journal of Korean Medical Science (2016;31:1464-1471). Among patients with diabetes mellitus, those with preoperative and postoperative HbA1c values of 7% or higher had 2.6 and 2.4 times increased odds of progression, respectively, compared with those who had lower values. Metformin use was not associated with recurrence or progression.

The investigators concluded that “tight glycemic control and close follow-up for bladder tumor may be beneficial in patients with poor glycemic control.”

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Assisted Peritoneal Dialysis Is a Safe Alternative to In-Center Hemodialysis Hospitalization risks are similar for both strategies, according to a study ASSISTED PERITONEAL dialysis (PD), a treatment option for patients who wish to receive dialysis at home but have significant barriers to self-care, is associated with a hospitalization rate similar to that of in-center hemodialysis (HD), researchers reported.

In a study comparing 203 assisted PD patients and 872 in-center HD patients, investigators found that the hospitalization rate was 11.1 days per year in the PD group and 12.9 days per year in the HD group, a non-significant difference, according to a paper published online ahead of print in the Clinical Journal of the American Society of Nephrology.

The study, led by Matthew J. Oliver, MD, of Sunnybrook Health Sciences Centre in Toronto, also showed that patients on assisted PD were more likely to be hospitalized for dialysisrelated reasons compared with the HD group (admitted for 2.4 days per year vs. 1.6 days per year). The difference was explained in part by more hospital days due to peritonitis. The PD patients had a hospitalization rate of 1.2 days per year for peritonitis

whereas the HD group had a hospitalization rate of 0.4 days per year for catheter-related bacteremia, according to the investigators.

Modality switching was associated with high hospitalization rates in both groups. In the HD group, 179 patients (21%) transferred to PD after a median

High hospitalization rates were observed among patients who switched modalities. time of 136 days on HD. In the PD group, 51 patients (25%) transferred to HD after a median of 350 days, the investigators reported. Patients who transferred from PD to HD spent an average of 17.8 days in the hospital per year, and those who transferred from HD to PD had a rate of 17.7 days in the hospital per year.

Dr. Oliver’s team noted that assisted PD expands home dialysis in the older

population with barriers to self-care.

“It seems to be a safe alternative to in-center HD in terms of hospitalization risk,” they wrote. “Peritonitis and technique failure are major drivers of hospitalization and should be monitored closely to maintain equivalent outcomes to in-center HD.” In an accompanying editorial, Edwina A. Brown, MBChB, of Hammersmith Hospital in London, UK, and Martin Wilkie, MBChB, PhD, of Sheffield Teaching Hospitals National Health Service Foundation Trust, Sheffield, UK, said the new study “adds to the expanding literature on this fledgling dialysis modality [assisted PD] and supports its use as an alternative to in-center HD for people with barriers to self-care.”

With the population aging worldwide, growing numbers of older individuals are requiring dialysis, Drs. Brown and Wilkie observed. “Assisted PD can avoid the need for transport, which not only adds to treatment times but is also disruptive to a person’s daily routine, particularly when considering the often antisocial hours of dialysis sessions.” n

Good HRQoL With Active Surveillance PATIENTS WITH prostate cancer who opt for active surveillance (AS) rather than definitive therapy experience a health-related quality of life (HRQoL) over the short term similar to that of men with a negative prostate biopsy who ostensibly had the same stresses from testing.

In a novel, prospective, multi-center study, a team led by Christopher R. Porter, MD, of Virginia Mason Medical Center in Seattle, compared 89 racially-diverse men with low-risk PCa on AS (mean age 64 years, at baseline) with 420 clinically and psychologically similar men (mean age 61 years) without cancer who also underwent transrectal ultrasound-guided biopsy from 2007 to 2014. All were military health beneficiaries enrolled in the Center for Prostate Research Multicenter National Database. Low-risk PCa was defined as clinical stage T1 to T2a, biopsy Gleason score 6 or less, and PSA less than 10 ng/mL, in accordance with National Comprehensive Cancer Network criteria.

“The potential clinical impact of

Parathyroidectomy for SHPT May Reduce PAD Risk

these results is significant and will

BY NATASHA PERSAUD PARATHYROIDECTOMY is associated with a decreased risk of peripheral arterial disease (PAD) in hemodialysis patients with secondary hyperparathyroidism (SHPT), according to a new study.

Yueh-Han Hsu, MD, MPH, of China Medical University in Taichung, Taiwan, and colleagues used Taiwan’s nationwide health insurance claims database to compare the incidence of PAD among patients with end-stage renal disease (ESRD) on hemodialysis and who had SHPT. They matched 947 patients who newly underwent parathyroidectomy (PTx) from 2000 to 2007 with 3746 patients who did not, by sex, age, year of diagnosis, and index date. None of the patients had pre-existing PAD. During an average follow-up of 4.6 years, PAD developed in 59 patients in the PTx group and 408 in the nonPTx group, the investigators reported in PLOS One 11(6): e0156863). The incidence rate of PAD was in 12.26 per 1000

HRQoL outcomes associated with AS,”

AssistedPDvsHD_RUN0916.indd 10

persons per year in the PTx group compared with 24.09 per 1000 persons per year in the non-PTx group. In multivariable analysis, PTx was associated with a significant 34% decreased risk for PAD compared with no PTx. The investigators adjusted for sex, age, income, urban residence, and comorbidities.

Peripheral arterial disease risk was lowered by 34% in ESRD patients.

PTx might be particularly beneficial for female patients and those with comorbidities. Women who underwent PTx had a significant 40% decreased risk of PAD in adjusted analyses compared with women who did not. Men who underwent PTx had a non-significant 25% decreased risk of PAD versus those who did not. PTx was associated with a

non-significant 21% decreased risk of PAD among patients without comorbidities, but a significant 51% decreased risk among those with comorbidities.

The investigators noted that a multidisciplinary approach likely is necessary to address other factors contributing to PAD, such as poor glycemic control.

“Though we have [previously] reported reduced risk of stroke in ESRD patients who received PTx, the findings in the present study provide further evidence for the association of controlling SHPT and the risk of PAD,” Dr. Hsu and colleagues wrote.

In addition to a retrospective design, other study limitations included a higher prevalence of diabetes—a PAD risk factor—in the non-PTx group, although the investigators attempted to minimize this bias. Further, pertinent patient data were lacking, such as smoking history, body mass index, diet, laboratory data, and certain treatment information. The investigators also noted that wealthier patients were more likely to afford PTx. n

allow clinicians to counsel patients effectively in regard to the potential Dr. Porter explained in a press release.

Investigators assessed HRQoL at biopsy and annually for 3 years using validated metrics. Except for a slight difference in bowel function at year 1, the investigators found no significant differences in most HRQoL subscales between men on AS and those without PCa over 3 years, even after adjusting for demographic factors, according to a report in The Journal of Urology (2016;196:392-398).

In an editorial comment accompanying the new report, Nachiketh Soodana Prakash, MD, and colleagues at the University of Miami School of Medicine Sylvester Comprehensive Cancer Center stated that, despite its limitations, “this study will be helpful to men contemplating AS who are worried about the impact of this decision on HRQoL.” n

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mRCC treatment delay continued from page 1

every 4 months for year 2, and then every 6 months thereafter. The primary endpoint was time to initiation of systemic therapy.

The median time on AS was 14.9 months, with 22 patients (46%) dying during the study period, all from mRCC, the investigators reported.

Results showed that the 29 patients who had 2 or fewer organs affected and 1 or no International Metastatic Database Consortium risk factor at the start of the study, on average, remained nearly 3 times longer on AS than the other patients (22.2 vs 8.4 months).

The estimated overall median survival from the start of AS was 44.5 months, according to the researchers.

Of the 43 patients who experienced disease progression, 32 (74%) had growth in existing sites of metastases, 8 (19%) had new sites of disease, and 3 (7%) had both a worsening of existing sites and development of metastases in new sites. New sites included the lungs in 4 patients, lymph nodes in 2, and central nervous system (CNS) in 2.

High-risk PCa continued from page 1

of pathologic stage T3-T4 and/or N1 in an analysis adjusted for HbA1c. The study found no association between insulin use and Gleason grade, pathologic stage, or PSA level.

During a median follow-up of 8.6 years after surgery, 551 men experienced biochemical recurrence and 244 died, 32 from PCa. On multivariable analysis, preoperative use of diabetes drugs was associated with an 81% increased risk of death due to any cause compared with non-use. The investigators reported that, generally, they observed no association between risk of disease recurrence and preoperative use of diabetes drugs. In stratified analysis, preoperative use of diabetes drugs was associated with an increased risk of disease recurrence in men with low-grade disease, but not among those with Gleason 7–10 disease.

Men who discontinued diabetes drugs after surgery had a nearly 4.7-fold increased risk of death compared with non-users, whereas no risk difference was observed in those who kept using the drugs. “This probably reflects the patients’ increased likelihood to stop preventive medication use at terminal phase of cancer,” the investigators explained.

Cov-jumps_vUro_RUN0916_r081716.indd 11

Dr. Rini and his colleagues concluded that “for some select patients with mRCC, AS might be the optimum approach to avoid the certain toxicity of systemic therapy without clearly compromising the benefit of therapy when initiated. Appropriate selection of patients and adequate monitoring, which should include CNS surveillance, is crucial in application of this approach.”

In an accompanying editorial, Paul Russo, MD, of Memorial SloanKettering Cancer Center in New York, observed: “Although no patients were cured, they achieved a degree of prolonged survival not imaginable a decade ago.”

The report by Dr. Rini and his colleagues, Dr. Russo wrote, “provides guidance to both medical and surgical oncologists who, when faced with a newly diagnosed patient with metastatic renal cell carcinoma who has good performance status and limited metastatic disease, can offer a period of close surveillance with the potential for prolonged survival before disease progression and the initiation of systemic therapies.” n

Despite the increased frequency of high-grade tumors among users of diabetes drugs, the investigators found no difference in median PSA level at diagnosis. “This supports the idea that reliability of PSA as a tumor marker might be lower among diabetics compared with non-diabetics,” they wrote.

“However, this did not have impact on risk of PSA recurrence.”

Men who used the medications were more like to have Gleason 7–10 tumors.

Dr. Murtola and his colleagues noted that important strengths of the study included the availability of comprehensive information on disease characteristics and progression, detailed information on medication use, and information on glycemic control among users of diabetes drugs. “We were able to analyze the effect of drug use both before and after surgery.”

The investigators acknowledged study limitations, including a low number of PCa deaths, an inability to differentiate between types of diabetes mellitus, and lack of information on diet management. n

Renal & Urology News 11

Infection Occurs in One Fourth of Radical Cystectomy Patients APPROXIMATELY 1 in 4 patients under-

Oncology. Infections included surgical

going radical cystectomy (RC) experi-

site infection (SSI), which occurred in

ence an infection within 30 days of

404 patients (12.7%); sepsis/septic

surgery, new study findings suggest.

shock (SSI, 405 patients, 12.7%);

Factors associated with the development of infection include perioperative blood transfusion and prolonged operative time.

Using the American College of

and urinary tract infection (UTI, 309 patients, 9.7%).

On multivariable analysis, body mass index of 30 kg/m2 or higher, receipt of a perioperative blood transfusion (PBT),

Surgeons National Surgical Quality

and operative time of 480 minutes or

Improvement Project database, a team

more were associated with a statisti-

led by Stephen A. Boorjian, MD, of

cally significant 1.52, 1.27, and 1.72

Mayo Clinic in Rochester, Minnesota,

times increased odds of infection.

identified 3187 patients who underwent

Operative time of 480 minutes or

RC and examined factors associated

more was independently associated with

with infection within 30 days of surgery.

a significant 1.63, 2.1, and 1.8 times

Of the 3187 patients, 366 (24%) were

increased odds of SSI, UTI, and sepsis/

diagnosed with postoperative infec-

septic shock, respectively. PBT was

tion at a median of 13 days following

associated with a significant 1.33 and

surgery, according to a report pub-

1.29 times increased odds of SSI and

lished online ahead of print in Urologic

sepsis/septic shock, respectively. n

ED, vitamin D link continued from page 1

ng/mL decrease in 25(OH)D was associated with a significant 12% increased prevalence of ED. “Our findings have potentially important clinical and public health implications for men,” Erin D. Michos, MD, of Johns Hopkins University School of Medicine in Baltimore, and colleagues wrote. “25(OH)D is an easy biomarker to screen for through simple commerciallyavailable laboratory tests, and deficiencies can be treated with supplementation and/or modest sunlight exposure.”

They pointed out, however, that additional research, such as randomized controlled clinical trials, is needed to determine whether treating vitamin D deficiency can improve erectile function.

Dr. Michos’ team studied 3390 men aged 20 years or older free of ASCVD who participated in the 2001–2004 National Health and Nutrition Examination Survey. For the study, investigators measured serum 25(OH)D using the DiaSorin radioimmunoassay and assessed self-reported ED using a single question from the Massachusetts Male Aging Study: “How would you describe your ability to get and keep an erection adequate for satisfactory intercourse?” Men who answered “never” or “sometimes able” were considered

to have ED. Investigators defined severe ED as never being able to get and keep an erection.

The weighted prevalence of 25(OH)D deficiency and ED were 30% and 15.2%, respectively. Levels of 25(OH)D were significantly lower among men with versus without ED (mean 22.8 vs 24.3 ng/mL).

Dr. Michos and her colleagues discussed various mechanisms that could explain a biologic relationship between vitamin D deficiency and ED. For example, vascular ED results from endothelial dysfunction and/or atherosclerosis. Diabetes mellitus is a strong risk factors for both of these conditions, diabetic men are 3 times more likely than non-diabetic men to have ED, they pointed out. “The association of 25(OH)D with ED and with ASCVD may be mediated by impaired glucose metabolism,” they stated.

The investigators also noted that men with ED have an increased prevalence of endothelial dysfunction, and vitamin D may improve endothelial function. “One mechanism linking low vitamin D levels with ED may be via reduced synthesis of nitric oxide,” they wrote. “Secretion of nitric oxide is needed for relaxation of the smooth muscles of the corpora cavernosa and subsequent penile erection, and vitamin D may be a regulator of endothelial nitric oxide synthase.” n

8/22/16 9:57 AM

12 Renal & Urology News

SEPTEMBER 2016 www.renalandurologynews.com

Gleason 9–10 PCa Outcomes Similar with Radiation, RP External beam radiation therapy (EBRT) plus brachytherapy found to offer improved systemic control versus EBRT alone and radical prostatectomy RADIATION THERAPY and radical prostatectomy (RP) offer men with Gleason score 9–10 prostate cancer (PCa) equivalent cancer-specific and overall survival, according to a new study.

Findings also suggest that extremely dose-escalated radiation therapy plus androgen deprivation therapy (ADT) might be the optimal upfront treatment for these patients, researchers concluded in a paper published online ahead of print in European Urology.

The investigators noted that their study is the largest comparative study of outcomes exclusively for patients with Gleason score 9–10 PCa. The study, led by Amar U. Kishan, MD, of the University of California Los Angeles, included 487 patients with biopsy Gleason 9–10 disease. Of these, 230 underwent external beam radiation therapy (EBRT), 87 were treated with EBRT and brachytherapy (BT), and 170 underwent RP. Most radiation therapy patients received androgen deprivation therapy and dose-escalated radiation therapy.

The median follow-up was 4.6 years.

Local salvage and systemic salvage were performed more frequently among RP patients (49% vs. 30.1%) when compared with EBRT patients (0.9% and 19.7%) or EBRT plus BT patients (1.2% and 16.1%), Dr. Kishan’s group reported.

Survival rates The 5- and 10-year rates of cancerspecific and overall survival were similar across the 3 cohorts after adjusting for age, clinical stage, biopsy Gleason score, initial PSA level, year of treatment, and use of salvage therapies, according to the investigators. For example, the 10-year rates of cancerspecific mortality were 8.4%, 4.4%, and 8.3% in the EBRT, EBRT + BT, and RP groups, respectively. The 10-year rates of overall survival were 79.9%, 84.7%, and 90.3%, respectively.

The 5-year and 10-year distant metastasis-free survival rates were significantly higher with EBRT plus BT (94.6% and 89.8%) than with EBRT (78.7% and 66.7%) or RP (79.1% and 61.5%).

the dose delivered as well as the use of androgen deprivation therapy.”

They noted that nearly 94% of EBRT patients in their study had upfront ADT with a median duration of 24 months and 97% of EBRT patients received doses isoeffective to, or higher than, 75.6 Gy in 1.8-Gy fractions.

Amar U. Kishan, MD

“Our finding that EBRT + BT provides improved systemic control over both EBRT and RP in this setting is novel, and suggests that optimal local control (offered by extreme dose-escalation) and an upfront method of systemic control (offered by a frequent use of ADT in this cohort) may represent the best upfront treatment strategy for these patients who are at high risk of harboring micrometastatic disease at presentation,” the investigators wrote.

The equivalence of cancer-specific and overall survival following EBRTbased treatments and RP in the current study differs from most prior comparative studies, the investigators pointed out. “Importantly, the majority of EBRT patients in prior studies received neither long-course ADT nor highdose RT,” they wrote. “In contrast, the majority of RT patients treated in our series were treated in accordance with contemporary standards.”

An important implication of the study findings is that investigators should be cautious when drawing conclusions from comparative series of radiationbased treatments versus surgical treatments that include patients treated years ago, Dr. Kishan said. “Radiation treatments in particular have changed significantly over time with respect to

Implications for patient counseling “Patients with Gleason 9–10 prostate cancer should be counseled that they can expect equal survival outcomes whether they receive upfront radiation therapy and androgen deprivation therapy or radical prostatectomy,” Dr. Kishan told Renal & Urology News. “Surgical patients should be counseled that they will most likely require postoperative radiation therapy, and a significant portion will require some form of androgen deprivation therapy as well. Highly dose-escalated radiotherapy, which can be achieved with a brachytherapy boost following an initial course of external beam radiotherapy, in combination with androgen deprivation therapy, may offer the highest chance of remaining free of metastatic disease.”

Usually, he added, the inclusion of patients treated years ago is necessary for practical purposes. PCa, in general, can have a slow natural history, and long follow-up times are needed to identify enough clinical events to draw conclusions. “We were able to restrict our analysis to patients treated in the modern era [since 2000] because aggressive lesions such as Gleason 9–10 prostate cancers lead to clinical events on a shorter time scale. In this framework, surgery and radiation-based treatments offered equivalent survival, and in fact, highly dose-escalated radiation seems to offer the highest chance of remaining free of metastatic disease.”

As the study was retrospective, the findings are hypothesis-generating, Dr. Kishan said. He and his collaborators said they hope to verify their findings in a larger cohort of patients with Gleason 9–10 PCa, and to further investigate the role that systemic therapies (including ADT) may play in treating these patients. n

Race Found To Impact PCa Therapy Switch BLACK MEN WITH low-risk prostate cancer (PCa) are slightly more likely than their white counterparts to switch to active treatment after initial observational management, independent of baseline and follow-up clinical measures, according to a new study.

“A primary reason that we examined whether sociodemographic and clinical factors predicted switching to active treatment was that studies have primarily been performed in non-ethnically diverse populations,” co-principal investigator Scott P. Kelly, PhD, of the Lombardi Comprehensive Cancer Center at Georgetown University Medical Center in Washington, DC, said in a press release. “We wanted to determine whether observational management like active surveillance is underused in minority populations, particularly within the framework of an equal access health care system.”

Black men are more likely to move from initial observation to active treatment.

Dr. Kelly and his colleagues retrospectively studied 2,228 PCa patients in the Kaiser Permanente Northern California health system initially managed with observation. Of these, 27% switched to active treatment after a median follow-up of 2.9 years. Compared with non-Hispanic white men, non-Hispanic black men were 30% more likely to switch to active treatment, the investigators reported in The Journal of Urology (2016;196:734-740).

In addition, results showed that Gleason grade progression, PSA doubling time less than 48 months, and higher baseline PSA levels (8 to 10 ng/ mL) were associated with switching to active treatment independent of race.

“While the current study may not be completely generalizable to the larger population of men with prostate cancer, it underscores the need to develop patient navigation tools for prostate cancer that are racially and culturally tailored to individual patients,” David F. Penson, MD, of Vanderbilt University in Nashville, Tennessee, wrote in editorial comments accompanying the new report. n

14 Renal & Urology News

SEPTEMBER 2016 www.renalandurologynews.com

More Intensive RRT Possibly Harmful This approach is associated with lower urine output during the first 7 days of therapy for acute kidney injury RRT and Daily Urine Output Less versus more intensive RRT is associated with greater mean daily urine output in AKI patients. Shown here are the differences in output between less and more intensive RRT (in mL/day) overall and according to the presence or absence of oliguria at baseline, all favoring the less intensive RRT arm.

50 40

mL/day

MORE VERSUS LESS intensive renal replacement therapy (RRT) for acute kidney injury is associated with greater reduction in urine output during the first week of therapy, according to a new study. More intensive RRT also is associated with a 50% or greater risk of a decline in daily urine output.

“These results suggest that lower urine output is a potential early adverse effect of more intensive RRT,” investigators led by Finnian R. McCausland, MD, of Brigham and Women’s Hospital in Boston, and colleagues wrote.

The team studied 1124 critically ill patients requiring RRT initiation. The patients, who participated in the Acute Renal Failure Trial Network Study, were randomly assigned to more intensive RRT (hemodialysis [HD] or sustained low-efficiency dialysis 6 times per week or continuous venovenous hemodiafiltration [CVVHDF] at 35 mL/kg per hour) or less intensive RRT (HD or sustained low-efficiency dialysis 3 times per week or CVVHDF

45.7* 36.3*

30 20

11.4

10 0

Overall

Source: McCausland FR et al. Clin J Am Soc Nephrol 2016; published online ahead of print.

at 20 mL/kg per hour). The primary outcome was the rate of change in daily urine output in patients who survived from randomization up to and including day 7 (871 patients: 436 in the less intensive and 435 in the more intensive group).

ROBOTIC-ASSISTED laparoscopic

between groups at 12 weeks after

prostatectomy (RALP) results in similar

prostatectomy (83.8 vs. 82.5 for open

functional outcomes at 12 weeks to

and RALP, respectively),” investigators

open radical retropubic prostatectomy,

John W. Yaxley, MBBS, and colleagues

according to new findings published in

reported. Sexual function scores also

The Lancet.

appeared similar between groups

clinically localized prostate cancer

(35.0 vs. 38.9, respectively).

Neither procedure proved superior

(aged 35 to 70) from the Royal

in the short-term in the proportion of

Brisbane & Women's Hospital in

patients with positive surgical margins,

Queensland, Australia, were randomly

according to the investigators.

assigned to RALP and 163 to open

RALP patients appeared to have

prostatectomy. To minimize heteroge-

better perioperative outcomes, such

neity, the same surgeon performed

as shorter operation time, fewer

all RALPs and another surgeon

adverse events, less blood loss, fewer

performed all open procedures from

complications, and shorter hospital

2010 to 2015. In the 12 weeks after

stay. Fourteen patients (9%) in the

surgery, 131 and 121 men, respec-

open surgery group and 6 (4%) in

tively, completed questionnaires, such

the RALP group had post-operative

as the Expanded Prostate Cancer

complications and 8% and 2% of men,

Index Composite and International

respectively, experienced intraopera-

Index of Erectile Function.

tive adverse events. These outcomes

Results showed that urinary function scores did not differ significantly

UrineOutput_RUN0916.indd 14

Oliguria absent at baseline

*Statistically significant difference

RALP, Open Surgery for PCa Offer Similar Early Results

For the phase 3 trial, 163 men with

Oliguria at baseline

did not translate into an earlier return to work, however. n

In a model adjusting for baseline covariates such as sex, race, age, and numerous comorbid conditions, the mean urine output in the less intensive group was, on average, 36.3 mL/day higher compared with the more intensive group, Dr. McCausland’s group reported online

Aspirin Does Not Up RPN Bleeding Risk PERIOPERATIVE administration of aspirin for patients undergoing robotic partial nephrectomy (RPN) does not significantly increase the overall risk of bleeding complications, new data suggest.

Vignesh T. Packiam, MD, and colleagues at the University of Chicago reviewed data from 214 patients who underwent RPN at their institution from May 2012 to March 2015. They compared 49 patients continuing aspirin at a dose of 81 mg, 34 patients holding aspirin for at least 7 days prior to surgery, and 131 patients who had never taken aspirin.

Overall bleeding complications included a greater than 3 g/dL drop in postoperative hemoglobin during admission, postoperative blood transfusion, or necessity for urgent selective angiographic embolization.

Patients who continued aspirin had a rate of overall bleeding complications that did not differ significantly from those who held or never took aspirin (27% vs. 15% vs. 14%), Dr. Packiam’s

ahead of print in the Clinical Journal of the American Society of Nephrology. More intensive RRT was associated with a 37% increased risk of a 50% or greater decline in daily urine output.

“An important factor that may contribute to differences in urine output according to RRT intensity could be the presence of more hemodynamic instability associated with greater intensity or frequency of dialytic therapy,” the researchers explained.

In an accompanying editorial, Christine K. Federspiel, MD, of the University of Copenhagen in Denmark and the University of California San Francisco (UCSF), and Kathleen D. Liu, MD, of UCSF, commented that the new study shows “yet another way in which more intensive RRT is not beneficial and may be harmful: through a decline in urine output. Although this analysis does not show an association with longer-term outcomes, including dialysis dependence at day 28 or 60, there certainly seems to be no benefit with more intensive dialysis.” n

team reported online ahead of print in the Journal of Endourology. The rates also did not differ significantly with respect to a hemoglobin drop greater than 3 g/dL (24% vs. 15% vs. 14%, and postoperative blood transfusion (4% vs. 3% vs. 2%).

The 3 groups did not differ significant with regard to estimated blood loss, operating room time, or intravenous fluid administration.

On multivariate analysis controlling for Charlson Comorbidity Index (CCI) and R.E.N.A.L. nephrometry score, aspirin administration was not significantly associated with bleeding complications, although continuation of aspirin was associated with a higher rate of overall 30-day complications compared with those who held or never took aspirin (24% vs. 12% vs. 8%). They also had a higher rate of Clavien 3–4 complications (10% vs. 6% vs. 1.5%).

“We demonstrate that continuing perioperative aspirin was not associated with significantly higher bleeding complications,” the investigators wrote.

“To our knowledge, this series evaluates the largest group of patients continuing aspirin for partial nephrectomy to date.”

Patients who continued aspirin had higher overall CCI than those who held or never took aspirin (median 5 vs. 4 vs. 2). n

8/22/16 10:28 AM

www.renalandurologynews.com SEPTEMBER 2016

Renal & Urology News 15

Glomerulonephritis Raises ESRD Risk Data suggest primary GN may be more likely than secondary GN to result in end-stage renal disease.

Rates of Progression to ESRD A new study has determined the rates of progression to end-stage renal disease among patients with primary and secondary glomerulonephritis (GN). Shown below are the rates per 1000 patient-years for Medicare patients and those enrolled in a commercial health plan.

80

Rate per 1000 patient-years

GLOMERULONEPHRITIS (GN) is associated with an increased likelihood of progression to end-stage renal disease (ESRD) and death, researchers concluded.

James B. Wetmore, MD, MS, and colleagues from the Chronic Disease Research Group in Minneapolis examined the incidence and period prevalence of GN and resultant ESRD and death rates in a 20% Medicare sample (5,442,495 individuals) and an Optum Clinformatics Employer Group Health Plan (EGHP) sample of 13,712,946 individuals. The Medicare and EGHP cohorts had 31,409 and 5,246 patients with incident GN, respectively. The mean ages of these patients were 75.9 and 54.6 years, respectively.

The incidence rates of primary and secondary GN, per 100,000 patientyears, were 57 and 134, respectively, in the Medicare cohort and 20 and 10, respectively, in the health plan cohort, Dr. Wetmore’s group reported online ahead of print in Kidney International.

The period prevalence, per 100,000 individuals, was 306 and 917 in the Medicare cohort and 70 and 52 in the health plan cohort, respectively.

72.9

n Medicare cohort n Health plan cohort

70 60 50

46.2

40

24.1

30 20

19.5

10 0

Primary GN

Secondary GN

Source: Wetmore JB et al. The incidence, prevalence, and outcomes of glomerulonephritis derived from a large retrospective analysis. Kidney Int 2016; published online ahead of print.

The death rates in incident Medicare patients were 2.7-fold higher for primary GN compared with no GN. In the Medicare cohort, women with incident secondary GN had a significant 30% and 18% decreased likelihood of progressing to ESRD and death, respectively, than men. Black patients with primary or secondary GN had a significant 1.6-fold greater likelihood of progressing to ESRD than white patients, but they were not more likely to progress to death.

In the Medicare cohort, the rate of progression to ESRD, per 1000 patientyears, was 72.9 and 24.1 for patients with primary and secondary GN, respectively, compared with 2.2 for non-GN patients, according to the investigators.

In the EGHP cohort, the rates were 46.2 and 19.5 for those with primary and secondary GN, respectively, compared with 0.2 for non-GN patients.

“In addition to highlighting the additional risks GN confers for ESRD,” the

Hyperkalemia Increases Mortality HYPERKALEMIA is associated with an elevated risk of death in the general population, investigators reported online ahead of print in Mayo Clinic Proceedings.

A team led by Morgan E. Grams, MD, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, studied 15,539 adult participants in the Atherosclerosis Risk in Communities (ARIC) Study, a prospective epidemiologic study conducted in 4 U.S. communities.

At baseline, 321 (2.1%) patients had hyperkalemia and 413 (2.7%) had hypokalemia. In a fully adjusted model, hyperkalemia (serum potassium level 5.5 mmol/L or higher) was associated with a significant 24% increased risk of death compared with normokalemia, but not sudden cardiac death (SCD), chronic kidney disease (CKD), or endstage renal disease (ESRD).

Hypokalemia (serum potassium level below 3.5 mmol/L) was associated with all-cause mortality and kidney

­ utcomes in participants not taking o potassium-wasting diuretics. In this group, hypokalemia was associated with a significant 74% increased risk of mortality, 2.4-fold increased risk of SCD, 65% increased risk of CKD, and 2.6-fold increased risk of ESRD compared with normokalemia.

“Although our study suggests that both hypokalemia and hyperkalemia may lead to adverse outcomes, our data are observational and cannot demonstrate causality,” Dr. Grams’ group wrote.” n

investigators wrote, “our findings raise the possibility that incident primary GN may be more likely to result in ESRD than secondary GN, as primary GN was over twice as likely to result in ESRD in the EGHP cohort and about 3 times as likely in the Medicare cohort.”

Using their approach, Dr. Wetmore’s group noted, it cannot be determined definitively whether incident primary GN is more likely than secondary GN to lead to ESRD because the higher death rate among patients with secondary rather than primary GN would yield an underestimate of the former’s rate of ESRD. The researchers discussed some potential reasons why patients with primary GN may have a higher ESRD rate. For example, treatment for secondary GN, which conventionally consists of treating the underlying systemic disorder, may be more successful, on average, than treatment for primary GN, the investigators stated.

Another possibility, they noted, is that physicians may be more likely to prescribe potent immunosuppressive drugs to patients with systemic disorders and take a more conservative approach in renal-limited disease. n

Proton Pump Inhibitors May Up CKD Risk INDIVIDUALS WHO take proton pump inhibitors (PPIs) are at elevated risk for chronic kidney disease (CKD), researchers reported online in BMC Nephrology.

Pradeep Arora, MD, of the University at Buffalo and the VA Medical Center in Buffalo, New York, and colleagues studied 76,462 patients without pre-existing CKD at

Sexual Problems Linked to 5ARI Use for BPH USE OF 5α-reductase inhibitors (5ARIs) to treat benign prostatic hyperplasia (BPH) is associated with a significantly increased risk of sexual dysfunction, researchers reported online in the Journal of Sexual Medicine.

In a meta-analysis and systematic review, Luhao Liu, MD, of Guangzhou

GN_incidence_RUN0916.indd 15

Medical University in Guandong, China, and colleagues analyzed data from 17 randomized controlled trials with 17,494 patients. Of these, 9 evaluated the efficacy of 5ARIs in men with BPH and 8 looked at the use of 5ARIs in treating androgenetic alopecia (AGA).

Use of 5ARIs for BPH was associated with a significant 2.5, 1.5, and 1.7 times increased pooled relative risk for sexual dysfunction, erectile dysfunction, and decreased libido, respectively, compared with placebo. The study found no significant association between 5ARI use for AGA and sexual dysfunction. n

baseline. The investigators identified PPI use in 22,734 patients: 4,711 CKD patients and 18,023 controls. PPI use versus non-use was associated with 10% increased odds of CKD and 76% increased odds of death.

The most likely explanation for the increased risk of CKD is unrecognized or partially recovered acute interstitial nephritis, the researchers stated. n

8/22/16 10:32 AM

16 Renal & Urology News

SEPTEMBER 2016 www.renalandurologynews.com

RARP Offers Good 5-Year Outcomes Robotic-assisted radical prostatectomy effectively controls prostate cancer, even in high-risk patients ROBOTIC-ASSISTED radical prostatectomy (RARP) is an oncologically safe procedure that provides effective 5-year prostate cancer (PCa) control, even among patients with high-risk disease, according to the findings of Asia’s largest RARP series.

Ali Abdel Raheem, MD, of Yonsei University College of Medicine in Seoul, Korea, and colleagues retrospectively analyzed 800 Asian men (mean age 64.3 years) who underwent RARP from July 2005 to May 2010. Of these, 197 (24.65%) were classified as lowrisk patients, 218 (27.3%) as intermediate-risk, and 385 (48.1%) as high-risk according to D’Amico risk stratification criteria. The primary endpoint was biochemical recurrence (BCR).

The study had a median follow-up of 64 months. The cohort had an overall 36.6% incidence of positive surgical margins (PSM). A total of 183 (22.9%) patients experienced BCR at a median time of 19 months, 38 (4.8%) had distant

Bacteremia Often Caused

By TURP ASYMPTOMATIC bacteremia is commonly caused by transurethral resection of the prostate (TURP) and occurs despite prophylaxis, researchers concluded.

The findings challenge a commonly held view that urine is the primary source of bacteremia in TURP-associated sepsis and raise the possibility of occult prostatic infection as a cause of bacteraemia, according to Amar Raj Mohee, MBChB, of The Christie NHS Foundation Trust in Manchester, U.K., and colleagues.

The investigators studied 73 TURP patients from whom 276 blood samples were obtained. Patients had a mean age of 72.7 years. Prior to surgery, patients received standard of care antibiotic prophylaxis.

No symptomatic bacteremia developed in any patient during the procedure, but asymptomatic bacteremia developed in 17 patients (23.2%). The most common organisms cultured were Enterococcus faecalis and Pseudomonas aeruginosa. Bacteremia was 5.38 and

RARP_Asian_RUN0916.indd 16

Five-Year RARP Outcomes Based on the largest Asian series to date of men undergoing robot-assisted radical prostatectomy (RARP), researchers concluded that RARP offers safe and effective cancer control. Shown here are the 5-year actuarial rates of biochemical recurrence-free, metastasis-free, and cancer-specific survival.

100

94.6%

96.7%

Metastasis-free

Cancer-specific

80

76.4% 60 40 20 0

BCR-free

SURVIVAL Source: Abdel Raheem A et al. Stratified analysis of 800 Asian patients after robot-assisted radical prostatectomy with a median of 64 months of follow up. Int J Urol 2016; published online ahead of print.

metastasis, and 24 (3%) died from PCa, the investigators reported.

The actuarial BCR-free, metastasis-free, and cancer-specific survival rates at 5 years were 76.4%, 94.6%, and 96.7%, respectively, Dr. Abdel

6.46 times more likely to be detected at 10 and 20 minutes after the start of the procedure compared with before the procedure, the investigators reported online in PLoS One. The finding that bacteremia most often developed from 10 to 20 minutes after the start of TURP and less frequently after the end of the procedure suggests a causal relationship between TURP and bacteremia, according to the investigators. TURP, however, did not explain bacteremia in all patients because 3 patients were bacteremic prior to the start of the procedure.

Dr. Mohee’s group noted that 34 patients (46.6%) had preoperative bacteriuria, with E. faecalis the commonly cultured organism. Eleven of these patients (32.3%) did not have a urinary catheter in situ.

With respect to prostatic pathology, 20 patients (27.4%) had prostate cancer and 26 (35.6%) had evidence of prostatic inflammation. Patients with malignant histology had a 4.9 times increased likelihood of bacteremia than those without malignant histology, the investigators reported.

Results also showed that the presence of a urinary catheter and recent antibiotic use were associated with 4.92 and 4.34 increased odds of intra-operative bacteremia, respectively. n

Raheem’s group reported online in the International Journal of Urology. The 5-year BCR-free survival rate for men with high-risk disease was 54%.

Results showed that positive lymph nodes (LN) were associated with lower

5-year BCR-free, metastasis-free, and cancer-specific survival: 9.1%, 61.9%, and 75.7%, respectively. On multivariable analysis, positive LN status was the strongest predictor of BCR and metastasis-free and cancer-specific survival.

Compared with patients who had negative LN, those with positive LN had a significant 5.4 times, 6.7 times, and 7.6 times increased risk of BCR, metastasis, and death from PCa. In addition, PSM was associated with a significant 1.67 times and 3.1 times increased risk of BCR, respectively, compared with negative margins.

Men with high-risk disease had a 2.35 times increased risk of BCR compared with those who had low-risk disease. The risk of metastasis and PCa death did not differ significantly among the risk groups.

Men with a pathologic Gleason score of 8–10 had a 6.58 times increased risk of BCR compared with those who had a score of 6. n

Radiation Treatment for PCa Linked to Higher Cardiac Risk RADIATION TREATMENT for clinically

cardiac death, fractures, and fractures

localized prostate cancer (PCa) is

requiring hospitalization, but not MI.

associated with an increased risk of

The investigators found no evidence of

cardiac and skeletal-related events

a significant interaction between local

compared with radical surgery,

treatment and ADT.

according to study findings presented

For the study, the investigators used

at the Canadian Urological Association

the Surveillance, Epidemiology and

annual meeting in Vancouver.

End Results (SEER)-Medicare linked

In a population-based cohort study,

databases for men aged 65 to 79 years

a team led by Christopher J.D. Wallis,

to examine outcomes from 14,403

MD, and Robert K. Nam, MD, of the

patients who underwent RP and 45,753

University of Toronto, found that,

who underwent radiation treatment. A

patients treated with radiation had

significantly higher proportion of radia-

a significant 18% increased risk of

tion therapy patients than RP patients

coronary heart disease, 20% increased

received ADT (52% vs. 12%). The cohort

risk of myocardial infarction (MI), 28%

had a median follow-up of 6 years.

increase risk of sudden cardiac death,

As for what might explain the study’s

and 16% increased risk of both fracture

findings, Dr Wallis told Renal & Urology

and fracture requiring hospitalization

News: “There is biologic rationale for

compared with men who underwent

radiotherapy to increase cardiovascular

radical prostatectomy (RP).

and skeletal-related events. Work in

Results showed that patients

testis cancer has shown that abdominal

receiving androgen-deprivation

radiotherapy, without mediastinal radio-

therapy (ADT) had an increased risk

therapy, increases rates of cardiovas-

of coronary heart disease, sudden

cular disease.” n

8/22/16 10:33 AM

18 Renal & Urology News

SEPTEMBER 2016 www.renalandurologynews.com

Metalworking Fluids May Increase RCC Risk GREATER EXPOSURE to metalworking fluids (MWF), which are used to cool and lubricate metal in occupational settings, may increase the risk of renal cell carcinoma (RCC), especially among white men, researchers found.

A team led by Katie M. Applebaum, ScD, of George Washington University

in Washington, DC, studied a prospective cohort of 33,421 Michigan autoworkers (27,148 white, 6273 black, 28,908 men, 4513 women) who were followed up from 1985 to 2009. During the follow-up period, 135 RCC cases occurred: 114 among whites and 21 among blacks.

White men with a mean and median cumulative MWF exposure of 18.80 and 9.60 mg/m3 per year had a significant 11% and 6% increased risk of RCC, respectively, according to a paper published online in Occupational and Environmental Medicine. The small number of exposed cases among black

men and among women provided limited statistical power for estimating RCC risk associated with MWF exposure, the investigators noted.

The individuals in the study were part of the United Autoworkers-General Motors cohort, which is unique because it is a large cohort followed for decades with quantitative exposure estimates for each of the 3 main types of MWF, Dr. Applebaum and her colleagues stated.

These types are straight (mineral oils), soluble (a mixture of mineral oil and water), and synthetic (water-based, no oil).

The investigators noted that the International Agency for Research on Cancer classified mineral oils as a human carcinogen in 1984, based on previous research showing a link to cancers of the skin, stomach, rectum, bladder, larynx, and pancreas. n

Metastatic PCa Is On the Rise METASTATIC PROSTATE cancer (PCa) has been increasing in incidence since 2007, particularly among men in an age group believed most likely to benefit from definitive treatment, according to a new report.

Using the National Cancer Data Base (2004–2013), researchers led

by Edward M. Schaeffer, MD, of the Northwestern University Feinberg School of Medicine in Chicago, identified 767,550 men diagnosed with PCa at 1089 different healthcare facilities in the United States.

Of these, 3% had metastatic disease at diagnosis.

From 2007 to 2013, the incidence of metastatic PCa increased by 7.1% annually, the investigators reported online ahead of print in Prostate Cancer and Prostatic Diseases.

In 2013, the incidence was 72% higher than in 2004. The greatest incidence of metastatic PCa was found among men aged 55–69 years (a 92% increase from 2004 to 2013). The incidence of low-risk PCa decreased by 9.3% annually from 2007 to 2013, and was 37% lower than in 2004. n

www.renalandurologynews.com SEPTEMBER 2016

Radical Local Therapy Ups Survival In Men with Very High-Risk PCa Findings challenge view that this approach is ineffective in these patients GUIDELINES recommend androgen deprivation therapy (ADT) only for men with very high-risk prostate cancer (PCa), but new findings from a population-based study suggest that radical local treatment can lower mortality in these patients, according to researchers.

The study, by Pär Stattin, MD, of Uppsala University in Uppsala, Sweden, and colleagues, included 7500 men with very high-risk PCa (local clinical stage T4 and/or PSA level 50–200 ng/mL, any nodal involvement, and no known metastases) and 10,316 men with locally advanced PCa (local clinical stage T3 and PSA level less than 50 ng/mL, any nodal involvement, and no known metastases) who served as positive controls.

Dr. Stattin’s group examined the proportion of men who received primary radical local therapy—radical prostatectomy or full-dose radiotherapy with or without ADT—within 1 year of diagnosis for very high-risk and locally advanced PCa in 640 experimental units defined by county, diagnostic period, and age at diagnosis.

PCa-specific and all-cause mortality rates were 49% and 44% lower in units in the highest tertile of exposure

to radical local treatment (67%–100%) compared with units in the lowest tertile (0%–33%), Dr. Stattin and colleagues reported online ahead of print in European Urology.

Decreased rates of cancer-specific and all-cause mortality observed.

The PCa-specific and all-cause mortality rates observed for locally advanced PCa were 25% and 15% lower in units in the highest versus lowest tertile of exposure.

In the very high-risk PCa group, the association between radical treatment and PCa mortality for highest versus lowest tertile of exposure was observed in all age groups up to 75 years, the investigators reported. Among men younger than 65 years and those aged 65–69 years and 70–74 years, those in the highest tertile of exposure had PCa-specific mortality rates 36%, 68%, and 12% lower than those in the lowest tertile, respectively.

The absolute PCa-specific mortality for men with very high-risk PCa was 30 per 1000 person-years in the highest tertile compared with 58 per 1000 person-years in the lowest tertile. The absolute allcause mortality for these men was 44 and 79 per 1000 person-years, respectively.

The investigators concluded that their study findings suggest “that radical local treatment decreases mortality in men with very high-risk PCa for whom radical treatment has previously been considered ineffective.”

With respect to study strengths, Dr. Stattin’s group noted that exposure to treatment could be assessed on a population level, which minimized selection bias on an individual level, while at the same time they had available comprehensive, high-quality individual-level data for cancer characteristics, comorbidity, cancer treatment, and cause of death.

The investigators acknowledged that the effects of diagnostic and therapeutic activity could not be separated.

“High exposure to radical local treatment was linked to high exposure to staging investigations including bone and lymph node imaging and complete Gleason classification,” they wrote. n

Robotic vs Open PN for Endophytic Tumors

BY NATASHA PERSAUD FOR PATIENTS WITH completely endophytic kidney tumors, robotassisted partial nephrectomy (RAPN) by skilled surgeons leads to favorable outcomes similar to those achieved with open partial nephrectomy (OPN), according to a new study.

“Robotic partial nephrectomy results match the open approach for small localized endophytic renal masses, while affording a minimally invasive approach and shorter hospital stay,” lead investigator Jihad Kaouk, MD, of Cleveland Clinic in Ohio, said in a news release.

Since excising endophytic tumors is challenging, OPN has been preferred.

These tumors are not easily identifiable on visual inspection of the capsular surface, and the depth of resection is not immediately apparent, which increases the technical difficulty of the surgery as well as complication risk, Dr. Kaouk’s team explained in a paper

PCa_HighRisk_RUN0916.indd 19

published online ahead of print in BJU International.

Dr. Kaouk and colleagues compared surgical, oncological, and functional outcomes of 87 RAPN and 56 OPN cases performed at a single center between 2011 and 2016. The groups had a similar mean age (58.3 and 61.1 years, respectively) and a similar racial composition, with white patients predominating (82.8% and 87.5%, respectively). Surgeon experience was high for both approaches, beyond the learning curve. For all RAPN, surgeons employed a transperitoneal route, a drop-in ultrasound probe, and selective use of intracorporeal renal parenchyma cooling. The investigators found no significant differences in tumor size, grade, stage, subtype, and margin status by approach.

Endophytic tumors have been linked with prolonged ischemia and longer operative time. , Although there was

a trend toward longer warm ischemia time with RAPN, analyses revealed no significant differences in warm or cold ischemia time between procedures. Duration of surgery was similar between groups, possibly due to surgeon experience. Intraoperative and posteroperative complication rates also did not differ. RAPN patients did experience shorter hospital stays (median 3 vs 5 days), less blood loss (mean 175 vs. 341 mL), and lower rates of intraoperative blood transfusion (0 vs. 7.1%), the researchers reported.

In addition, neither local cancer recurrences nor distant metastases occurred within the median follow-up of 15.2 and 18.1 months in the RAPN and OPN groups, respectively. The researchers also found no difference in preservation of estimated glomerular filtration rate by procedure at these time points. The study may have been underpowered to detect some differences. n

Renal & Urology News 19

PCa Risk Not Linked to Use of ED Drugs RESEARCHERS REPORT finding no link between prostate cancer (PCa) risk and the use of a phosphodiesterase type 5 inhibitor (PDE-5i).

“In vitro mouse studies have suggested that these drugs might have some anticancer activity, but the evidence in human subjects is mixed,” lead investigator Stephen J. Freedland, MD, of Cedars-Sinai Medical Center in Los Angeles, stated in a press release. “Given the routine use of PDE-5i and the possibility that these agents may have anticancer activity, we wanted to test the association between their use and risk of developing prostate cancer.”

Dr. Freedland and his colleagues conducted a post-hoc analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, a multicenter, randomized trial comparing daily dutasteride with placebo in men with benign prostatic hyperplasia. Of 6501 mostly white men with PSA levels of 2.5 to 10.0 ng/mL and negative prostate biopsy at baseline, 364 were taking a PDE-5i, including tadalafil, sildenafil, and vardenafil.

REDUCE participants then underwent repeat transrectal ultrasound-guided biopsies at 2 and 4 years.

Results published online ahead of print in the Journal of Urology showed that PDE-5i use was not associated with PCa diagnosis. PCa developed in 19.5% of PDE-5i users and 22.7% of nonusers, a statistically insignificant difference. ED drugs also did not influence development of low- or high-grade disease, whether the Gleason score cut point was 7 or 8. The investigators adjusted for baseline PSA, prostate volume, family history of PCa, and dutasteride use, in addition to smoking, diabetes, coronary artery disease, age, race, and world region.

Men from North America had higher rates of PDE-5i use, so a secondary analysis was performed on this subset. Although fewer PCa diagnoses were made in the group, results did not reach statistical significance. n

8/22/16 10:35 AM

www.renalandurologynews.com SEPTEMBER 2016

Hyponatremia Increases Mortality Risk in Some Cancer Populations Link found in patients with lymphoma and breast, lung, and colorectal cancer HYPONATREMIA develops frequently and predicts an increased risk of death among patients with some common cancer types, according to a new study.

Findings also suggest that hyponatremia may adversely impact progressionfree survival.

Among patients with lymphoma and breast, colorectal, and lung cancer, development of hyponatremia was associated with a 4.5, 3.7, 2.4, and 2.4 times increased risk of death, respectively, investigators reported in BMC Cancer (2016;16:564).

The study, by Jorge J. Castillo, MD, of the Dana-Farber Cancer Institute in Boston, and colleagues, included 1758 patients with lymphoma or breast, colorectal, or lung cancer. Of these, 943 had 1 or more hyponatremia episodes during follow-up and 815 did not.

Overall, the incidence of euvolemic or hypervolemic hyponatremia was 54%.

The hyponatremia incidence was highest (76%) among patients with small-cell and non-small cell lung cancer; 37% for patients with breast cancer; 64% among those with colorectal cancer; and 60% among those with lymphoma. The incidence observed in the lung cancer

Renal & Urology News 21

Cystatin C Is Best Death Predictor CYSTATIN C is a better predictor of all-cause mortality risk than creati-

Hyponatremia and Mortality Shown here are the magnitudes by which hyponatremia increases the risk of death, according to cancer type: 5

4.5×

The study, led by Marika Salminen, Turku, Finland, included 1260 individuals with a mean age of 74 years.

3

2.4×

2.4×

During a 9-year follow-up, 275 died, 192 from cardiovascular disease

2

(CVD). The investigators compared

1 0

filtration rate, a study found.

MD, of Turku University Hospital,

3.7×

4

nine-based estimates of glomerular

cystatin C with the Modification of Lymphoma

Breast

Colorectal

Lung

Source: Castillo JJ et al. The occurrence of hyponatremia and its importance as a prognostic factor in a cross-section of cancer patients. BMC Cancer 2016;16:564.

group was considerably higher than the 20% to 50% incidence previously reported, Dr. Castillo’s group stated.

Hyponatremia was not statistically associated with progression-free survival, but patients with stage 3 or 4 cancer diagnosis had a significantly increased likelihood of disease progression.

The investigators defined hyponatremia as a serum sodium value of 135 mEq/L or less, and classified hyponatremia as mild, moderate, or severe (131–135, 125–130, and less than

125 mEq/L, respectively), based on the lowest observed serum sodium value during the episode. Hyponatremia was mild in 84% of cases. The median time to first hyponatremia episode was 59 days and the median duration was 16 days.

For the study, Dr. Castillo’s group excluded patients with hypovolemic hyponatremia because this type of hyponatremia generally responds to treatment with intravenous fluids, whereas euvolemic and hypervolemic hyponatremia tend be more difficult to manage. n

Diet in Renal Disease study equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the combined creatinine-serum cystatin C (CKD-EPIcr-cys) equations.

After multivariable adjustment, only cystatin C values predicted all-cause mortality in fully adjusted models. Each 0.1-unit increment in cystatin C concentration was associated with an approximately 10% increased the risk of death from all causes, Dr. Salminen’s group reported online ahead of print in the European Journal of Internal Medicine.

Each 0.1-unit increment in cystatin C concentration was associated with a significant 10% increased risk of both cardiovascular and non-cardiovascular

Phosphorus Control Tied to Binder Adherence

death in men and a significant 9% and

BY NATASHA PERSAUD PATIENTS WHO REPORT incomplete adherence to phosphate binder therapy are more likely to have poor phosphorus control, according to a small study.

As part of an initiative to improve phosphorus control, dietitians at Kaiser Permanente Los Angeles Medical Center in California administered questionnaires on phosphorus management to 79 ethnically diverse patients (average age 64.2) receiving hemodialysis in October 2012. A modified Morisky Medication Adherence Scale captured adherence to phosphate binders. At the time, 77.2% of patients had controlled average phosphorus levels at or below 5.5 mg/dL, whereas 22.8% had uncontrolled levels above 5.5 mg/dL. Average phosphorus in the hyperphosphatemia group was 6.69 mg/dL. Compliance to phosphate binder therapy was suboptimal, with 61%

tively, in women. The CKD-EPIcr-cys

Hyponatremia_ca_RUN0916.indd 21

a­ccidentally forgetting to take their medication or otherwise skipping doses unintentionally. Nearly half (48%) also reported intentionally skipping their phosphate binder, typically when they experienced side effects, felt no symptoms, or were inconvenienced. Patients with poor medication adherence were 29% less likely to have controlled phosphorus. Those who intentionally skipped doses appeared no more or less likely to have controlled phosphorus.

Knowledge of hyperphosphatemia was low: nearly half of patients failed to name 2 high-phosphorus foods or identify a risk of having the condition.

Lack of knowledge did not appear to influence phosphorus control, nor did medication refill rates.

The findings may help inform strategies to improve phosphorus control. “In particular, the findings presented here suggest that strategies to reduce the chances of forgetting to dose medica-

tion and, to a lesser extent, to improve phosphorus-specific knowledge, could be particularly useful at improving phosphorus control,” Cherriday G. Joson, RN, BSN, of Kaiser, and colleagues wrote in the Journal of Renal Nutrition. They suggested trying interventions such as patient support groups centered on adherence and a “phosphorus fair” to show how binders work.

“Patient actions are, in part, influenced by our collective efforts to inform them about the harmful effects of excessive dietary phosphorus intake on health outcomes,” Juan Jesus Carrero, Pharm, PhD, of the Karolinska Institutet in Stockholm, Sweden, and colleagues observed in an accompanying editorial. “Provision of pill boxes or calendar-based dispensers to help them track their daily medications is useful in other contexts, but the nature of phosphorus binder dosing requires a more sophisticated approach.” n

13% increased risk of cardiovascular and non-cardiovascular death, respecequation remained a significant predictor of non-CVD deaths among women, with each 0.1-unit increase in CKDEPIcr-cys value associated with an 8% increased risk of non-CVD death.

“Our results suggest that cystatin C is an accurate measure of the risk of death in elderly men and women, and using the combined CKD-EPIcrcys equation does not provide any additive prognostic information,” Dr. Salminen’s team wrote.

It has been argued that cystatin C may have toxic effects that contribute to its association with death, they noted. “We cannot exclude the possibility that the prognostic ability of cystatin C may be mediated in part by some other factor than impaired kidney function.” n

8/22/16 10:41 AM

22 Renal & Urology News

SEPTEMBER 2016 www.renalandurologynews.com

n FEATURE

Hepatitis C Virus in CKD: Challenges and Opportunities Direct-acting antiviral drugs may enable eradication of HCV and improve outcomes

BY ANNETTE BRUCHFELD, MD, PHD

I

nfection with the hepatitis C virus (HCV) affects more than 170 million people worldwide. After acute infection, 80% to 85% of individuals do not clear the virus and progress to chronic infection and its associated complications.1 The risk of liver-related complications such as cirrhosis and hepatocellular carcinoma is well known, but it has become apparent that HCV is also associated with extrahepatic complications, including chronic kidney disease (CKD).

the metabolic syndrome, and diabetes.3 These are known risk factors for CKD in the general population, but a large cohort study in Taiwan concluded that there is a significant and independent association between HCV and CKD in the absence of traditional CKD risk factors.4 It is now well recognized that HCV is associated with glomerular disease, most commonly membranoproliferative glomerulonephritis with or without cryoglobulinemia. Other reported lesions include membranous nephropathy, focal segmental glomerulosclerosis, fibrillary or immunotactoid glomerulopathies, and thrombotic microangiopathy.5 HCV is thought to cause renal injury through the

action of cryoglobulins, HCV-antibody immune complexes, and direct cytopathic effects, including endotheliitis, mesangial inflammation and podocyte injury.6 Worldwide, diabetes mellitus is the most common cause of end-stage renal disease (ESRD),7 and HCV adds to the risk in these patients. In a study, the risk of ESRD was 44% greater in patients with both diabetes and HCV patients than in those without HCV (HCV−).

The risk was 2.0 and 1.8 times as great for patients younger than 50 years and those infected within 4 years of their diabetes diagnosis, respectively.8 In my view, the presence of diabetes may therefore be a strong indication for antiviral treatment.

HCV and chronic kidney disease According to a recent systematic review and meta-analysis, individuals who are seropositive for anti-HCV antibodies (HCV+) have a significant 23% greater relative risk of having and/or developing CKD compared with uninfected individuals.2 At the 53rd Congress of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) in Vienna, I advised delegates that chronic HCV infection should be seen as a metabolic disease that causes chronic systemic inflammation through direct viral effects on the vasculature and indirect effects via the immune system and the liver. The result is a pro-inflammatory state that increases the risk of atherosclerosis, cardiovascular disease,

HepC in CKD-Feature_RUN0916.indd 22

Hepatitis C virus, shown here infecting cultured liver cells, is significantly associated with chronic kidney disease (CKD) in the absence of traditional CKD risk factors, a study found.

A study from Taiwan demonstrated that patients treated for HCV infection had a significant 84% reduction in the risk of ESRD, a significant 47% reduction in the risk of ischemic stroke, and a nonsignificant 36% reduction in the risk of acute coronary syndromes.9

HCV and hemodialysis HCV has long been a challenge for nephrologists because of the risk of transmission of this blood-borne virus in hemodialysis (HD) centers. HCV prevalence among HD patients has been falling in many countries, but overall it remains higher than in the general population. Prevalence also varies across the world: from less than 5% in northern Europe, Canada, Australia and New Zealand, to 8% to 16% in the United States, Southern Europe, and Japan, and up to 70% in some African, South American, and Asian countries.10, 11 One explanation for the decline in nosocomial HCV transmission is the implementation by dialysis centers of universal infection control precautions, as recommended by Kidney Disease Improving Global Outcomes (KDIGO) guidelines.12 During ERAEDTA 2016, Nejra Prohic´, MD, of University Clinical Centre, Sarajevo, Bosnia and Herzegovina, reported that strict adherence to infection control procedures resulted in a decline in the incidence of HCV among incenter dialysis patients, from 0.55% in 2006 to 0.15% in 2015.13 A second study presented during ERA-EDTA 2016 by Boris Bikbov, MD, of the A.I. Evdokimov Moscow State University of Medicine and Dentistry, Moscow, Russian Federation, also reported a fall in seroconversion rates in patients

© THOMAS DEERINCK, NCMIR / SCIENCE SOURCE

This review and commentary includes study data presented at the 53rd Congress of the European Renal Association-European Dialysis & Transplant Association (ERA-EDTA 2016) in Vienna, Austria, May 21–24. 2016, and reflects discussions that took place at the congress.

8/22/16 10:43 AM

www.renalandurologynews.com SEPTEMBER 2016

s­ tarting dialysis, from 2.7 events per 100 patient-years in 2004–2008 to 2.2 events per 100 patient-years in 2009–2013.14 HD patients are at increased risk of death compared with the age-matched general population,15 and chronic HCV infection worsens this already poor prognosis. A meta-analysis of 14 studies concluded that HCV infection independently predicts a significant 1.35, 1.26, and 3.82 times increased relative risk for all-cause mortality, cardiovascular death, and liver disease-related death, respectively, in adjusted analyses.16 These adverse outcomes are most likely due to HCV-associated inflammation and the cumulative cardiovascular effects of the combination of ESRD and HCV. HCV may also be a factor in the cognitive impairment that occurs more frequently in HD patients than in the general population.17 In a study presented during ERA-EDTA 2016, severe impairment on the Mini-Mental State Examination was more frequent in HCV+ HD patients compared with matched HCV- controls: 10 of 22 (45.4%) versus 3 of 23 (13%).

HCV+ patients also had significantly greater impairment on visual attention and psychomotor speed scores, and borderline significant impairment on working memory scores. According to Mohammed Ibrahim, MD, of Ain Shams University in Cairo, Egypt, these findings may reflect subclinical encephalopathy in HCV+ HD patients, suggesting that treatment to clear the virus should be initiated early after the infection is detected.18

HCV and kidney transplantation HCV eradication is recommended before and after kidney transplantation, but few waitlisted patients currently receive treatment,10 and they are consequently at higher risk of death and graft loss after transplantation. In a Swedish study that includes 571 kidney and kidney-pancreas transplant recipients, HCV significantly reduced patient and graft survival. HCV remained an independent risk factor for lower patient and graft survival after adjusting for sex, previous transplant history, and time in renal-replacement therapy.19 Although cardiovascular disease was the main cause of death in this study, post-transplant immunosuppression also adversely influenced viremia, increasing the risks of infection and septicemia.

Another reason for the lower patient and graft survival seen in HCV+ recipients may be their increased risk of new-onset glomerulonephritis after transplantation. In a study, this complication developed in 15 (34%) HCV+ patients at a mean of 47 months compared with only 8 (6.6%) of 121 HCV− patients at

HepC in CKD-Feature_RUN0916.indd 23

a mean of 60 months, a significant difference between the groups. The HCV+ group also had significantly impaired graft survival. In contrast, the incidence of recurrent primary glomeronephritides was significantly higher in HCV− patients (29% vs. 6.8% in HCV+ patients).20 HCV after transplantation is also associated with a higher risk of posttransplant diabetes mellitus (PTDM), a well-recognised risk factor for reduced patient and graft survival.21 A systemic review of 10 studies in which the adjusted odds ratio of PTDM in HCV+ patients was 3.97.22 While no prospective study has investigated the impact of pre-transplant HCV clearance on the incidence of PTDM, retrospective reports suggest that treatment could reduce the risk of this potentially serious complication.23,24 During a presentation at ERA-EDTA 2016, I reminded delegates that, compared with remaining on the waiting list, kidney transplantation improves survival in HCV+ patients.25 Therefore, HCV has not been seen as a contraindication to kidney transplantation although treatment options were limited especially after transplantation. Recent advances in treatment have changed this as it is potentially feasible to eradicate the virus before and after transplantation in nearly all patients.

Therapeutic options Over the last 20 years, there has been a dramatic improvement in sustained virologic response (SVR) or cure rates of HCV, rising from 7%–10% with interferon to 40%–50% with pegylated interferon and ribavirin, and to more than 90% with interferon-free combinations of direct-acting antiviral drugs (DAAs). As a result, HCV has become the first chronic viral infection to be cured by medical therapy in most patients.1 According

HCV Worsens Transplant Outcomes Renal transplant recipients who are positive for hepatitis C virus (HCV+) experience inferior outcomes compared recipients who are negative for the virus, according to a study published online ahead of print in Experimental and Clinical Transplantation.

The study, by Ali Khalil, MD, of Indiana University, Indianapolis, Indiana, and colleagues, included 61,775 renal transplant recipients, of whom 3334 were HCV+ at the time of transplantation.

HCV+ recipients had a significantly higher rate of delayed graft function compared with HCV− recipients (23.9% vs. 16.0%) and a significantly higher 1-year acute rejection rate (17.2% vs. 14.6%). In multivariate analysis, HCV+ recipients had a 34% increased risk of graft loss compared with HCV− recipients.

In addition, within the HCV+ group, graft survival was inferior for those who received an HCV+ donor kidney compared with an HCV− donor kidney and those who received a deceased-donor kidney compared with a living-donor kidney, the investigators reported.

“Given the inferior outcomes in HCV+ patients, every HCV infected patient on a wait list for kidney transplant should be considered for antiviral therapy to reduce HCV-associated posttransplant morbidity and mortality as the new interferon-free agents are promising,” the investigators concluded.—Jody A. Charnow

Dr. Roth explained that SVR rates reported in recent clinical trials in the general population have been achieved by targeting different parts of the HCV genome with fixed-dose DAA combinations, such as elbasvir-grazoprevir, ledipasvir-sofosbuvir, and paritaprevirombitasvir-ritonavir (with or without dasabuvir). With the exception of sofosbuvir, these drugs are cleared by the liver. In the observational, prospective HCV-TARGET study, sofosbuvir-containing regimens achieved SVR in 82% to 83% of patients with an estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m2 or less and HCV genotype 1 regardless of renal function.

However, anemia, worsening renal function, and serious adverse events (AEs) occurred more frequently regardless of ribavirin use.26

The first consideration in HCV+ kidney transplant candidates is an accurate assessment of the extent of their liver disease. to David Roth, MD, of the University of Miami Miller School of Medicine, despite advances in treatment, there remains a high unmet need among HCV+ renal patients. Of the 49,762 HD patients included in the international Dialysis Outcomes and Practice Patterns (DOPPS) study, 9.5% were HCV+, but only 1% of 4,589 patients with prescription data and 3.7% of waitlisted patients were receiving antiviral medication.10

Renal & Urology News 23

Although paritaprevir has not been well studied in patients with an eGFR below 15 mL/min/1.73 m2 and in HD patients, no dosage adjustments are recommended in mild to severe renal impairment.27 Dr. Roth reported that in the open-label RUBY-1 trial, paritaprevir-ombitasvir-dasabuvir (with ribavirin in HCV genotype 1a and without ribavirin in HCV genotype 1b) achieved SVR in 18 of 20 patients with an eGFR of 30 mL/min/1.73 m2 or less.

AEs were primarily mild or moderate, and

no patient discontinued treatment due to an AE. Ribavirin therapy was interrupted due to anemia in 9 patients, 4 of whom received erythropoietin.28 Renal function does not influence the dosage of the fully oral, ribavirin-free combination of elbasvir-grazoprevir. The prospective C-SURFER trial randomized 224 patients with an eGFR below 30 mL/min/1.73 m2 and HCV genotype 1 to receive either immediate treatment with elbasvir-grazoprevir (111 patients) or deferred treatment (113 patients), with 11 patients assigned to intensive pharmacokinetic investigation. Dr. Roth commented that C-SURFER patients were typical of those seen in clinical practice: 76% were HD dependent, 52% had HCV genotype 1a, 80% were HCVtreatment naïve, and 6% had cirrhosis.

After 12 weeks treatment, SVR was 99% in the combined immediate-treatment and intensive pharmacokinetic group, with 1 relapse 12 weeks after the end of treatment. The most common AEs were headache, nausea, and fatigue, which occurred at similar frequencies in patients receiving active treatment and placebo.29 Presenting further C-SURFER data during the ERA-EDTA congress, I reported that at entry to the study, 11.7% of patients with HCV genotype 1a had NS5A resistance-associated variants (RAVs). These are known to impair treatment response in regimens that include an NS5A inhibitor such as elbasvir, but the effect on SVR was modest at 84.5% versus 100% in patients without baseline RAVs. Pharmacokinetic analysis confirmed that elbasvir-grazoprevir does not require dose adjustment in HD patients.

Compared with placebo, active ­treatment

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had a generally positive effect on healthrelated quality of life, with trends towards improvements from baseline in physical component summary and health domain scores. The exception was social functioning, role limitations, emotional and mental component summary.30

Treatment guidelines Current KDIGO HCV guidelines, published in 2008, do not take into account the availability of DAA combinations.

Dr. Roth advised delegates that treatment recommendations for HCV+ patients with renal impairment are available from the American Association for the Study of Liver Disease (AASLD). Depending on HCV genotype, elbasvir-grazoprevir, paritaprevir-ombitasvir-dasabuvir or pegylated interferon and dose-adjusted ribavirin are recommended for patients with creatinine clearance less than 30 mL/min for whom the urgency to treat is high and kidney transplantation is not an immediate option.31 The latest guidelines from the European Association for the Study of the Liver (EASL) recommend an interferon-free and preferably ribavirin-free regimen, which should if possible be given to potential kidney transplant candidates before wait listing.32 According to Dr. Roth, the differences between the US and European guidelines reflect the availability of DAAs: while elbasvir-grazoprevir is approved in the United States, it not yet available in Europe (though the European Medicines Agency issued a positive opinion in May 2016). However, both the AASLD and EASL strongly recommend HCV eradication in transplant candidates to avoid the surge in viral replication in patients receiving induction therapy and potent maintenance immunosuppression.

In a recent statement, the ERA-EDTA described patients with CKD stages 4–5 as a priority group for treatment with DAAs, but suggested that in the DAA era, treatment could be postponed until after transplantation if this enables earlier transplantation with an HCV+ donor kidney.33 Dr. Roth agreed that a deceaseddonor HCV+ kidney transplant could significantly reduce waiting time and avoid the AEs that an HCV+ kidney recipient would experience by remaining on dialysis.

However, HCV+ patients are at higher risk of complications in the early posttransplant period. Vigilant and frequent post-transplant monitoring by nephrologists is also essential because of potentially serious drug-drug interactions between DAAs and immunosuppressant drugs, especially the calcineurin inhibitors.

Dr. Roth advised delegates that, based on published experience in liver

HepC in CKD-Feature_RUN0916.indd 24

HCV and Mortality Outcomes A meta-analysis of 14 studies concluded that hepatitis C virus (HCV) infection independently predicts a significantly increased relative risk for death from all causes, cardiovascular death, and liver disease-related death. Shown here are the magnitudes by which HCV infection increases those risks:

3.82x

4.0 3.5

Mortality Type

24 Renal & Urology News

3.0 2.5 2.0 1.5

1.35x

1.26x

All-cause

Cardiovascular

1.0 0.5 0.0

Liver diseaserelated

Source: Fabrizi F et al. Impact of hepatitis C on survival in dialysis patients: a link with cardiovascular mortality? J Viral Hepat 2012;19:601-607.

t­ ransplantation, the first consideration in HCV+ kidney transplant candidates is an accurate assessment of the extent of their liver disease. If the patient does not have cirrhosis and has a living donor, it may be appropriate to eradicate HCV before transplantation. In the absence of a living donor, patients have the choice of receiving an HCV+ kidney following post-transplant treatment to achieve SVR or of undergoing HCV eradication before transplantation and accepting the longer waiting time for an HCV− donor kidney.34 In Dr. Roth’s opinion, the DAA era raises important questions for nephrologists. There is accumulating evidence that DAAs effectively eradicate HCV after kidney transplantation,35 but the logistics of identifying HCV genotype in an RNA-positive donor might be challenging for some transplant centres. The outcomes of HCV+ transplantation compared with receiving a non-infected donor kidney are not well studied, and there is potential for super-infection if the recipient has a different HCV genotype from that of the donor. The latter risk may, however, be reduced by limiting HCV+ donor organs to recipients with the majority genotype within the local population; for example, genotype 1 in Europe and the US.36 There are also ethical issues, especially if an HCV+ kidney is offered to an HCV− recipient. Nephrologists must be confident that they will be able to cure HCV infection post-transplant and, to ensure fully informed consent, patients must be educated about the risks as well as benefits.

Conclusions The availability of DAAs offers the opportunity for successful eradication of HCV in renal patients before and after kidney transplantation, but this raises important

questions for nephrologists, transplant centers, and healthcare systems. There has been criticism of the acquisition costs of curative DAA therapy, but Dr. Roth noted that these are comparable to the costs of novel palliative oncology therapies, and DAAs have been judged cost effective in health technology assessment.37 Given the potential benefits for renal patients of HCV eradication, nephrologists must become involved in decisions about patient selection for DAA therapy. n Annette Bruchfeld, MD, PhD, is Associate Professor, Karolinska Institutet, Depart­ment of Renal Medicine, Karolinska University Hospital, Sweden, and Scientific Secretary, Swedish Society of N ­ ephrology . Sue Lyon, a freelance medical writer in London, UK, assisted in the preparation of the manuscript.

REFERENCES 1. Webster DP, Klenerman P, Dusheiko GM. Hepatitis C. Lancet 2015;385(0073):1124-1135.

2. Park H, Adeyemi A, Henry L, et al. A meta-analytic assessment of the risk of chronic kidney disease in patients with chronic hepatitis C virus infection.

J Viral Hepat 2015;22:897-905.

3. Voulgaris T, Sevastianos VA. Atherosclerosis as extrahepatic manifestation of chronic infection with hepatitis C virus. Hepat Res Treat 2016;2016:7629318.

4. Chen YC, Chiou WY, Hung SK, et al. Hepatitis C virus itself is a causal risk factor for chronic kidney disease beyond traditional risk factors: a 6-year nationwide cohort study across Taiwan. BMC Nephrol 2013;14:187.

5. Cacoub P, Gragnani L, Comarmond C, Zignego AL. Extrahepatic manifestations of chronic hepatitis C virus infection. Dig Liver Dis 2014;46 Suppl 5:S165-173.

6. Barsoum RS. Hepatitis C virus: from entry to renal injury--facts and potentials. Nephrol Dial Transplant 2007;22:1840-1848.

7. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet 2013;382(9888):260-272.

8. Hwang JC, Jiang MY, Lu YH, Weng SF. Impact of HCV infection on diabetes patients for the risk of end-stage renal failure. Medicine (Baltimore) 2016;95(3):e2431.

9. Hsu YC, Lin JT, Ho HJ, et al. Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients. Hepatology 2014;59:1293-1302.

10. Goodkin DA, Bieber B, Gillespie B, et al. Hepatitis C infection is very rarely treated among hemodialysis patients. Am J Nephrol 2013;38:405-412.

11. Marinaki S, Boletis JN, Sakellariou S, Delladetsima IK. Hepatitic C in hemodialysis patients. World J Hepatol 2015;7:548-558.

12. Kidney Disease Improving Global Outcomes. Guideline 3: Preventing HCV transmission in hemodialysis units. Kidney Int 2008;73(Suppl 109):S46-S52.

13. Prohic N, Masnic F, Resic H. Prevalence and incidence of hepatitis C virus in hemodialysis patients in the period of 2007-2015. Presented at 53rd Congress of the European Renal Association-European Dialysis & Transplant Association (ERA-EDTA), Vienna, Austria, May 21–24, 2016.

14. Bikbov B, Tomilina N, Evdokimov AI. Viral hepatitis B and C seroconversion rates in incident hemodialysis patients: a cohort study. Presented at 53rd Congress of the European Renal Association-European Dialysis & Transplant Association (ERA-EDTA), Vienna, Austria, May 21–24, 2016. SP571.

15. Jager KJ, Lindholm B, Goldsmith D, et al., for the EUropean REnal and CArdiovascular Medicine working group of the European Renal Association–European Dialysis and Transplant Association (ERA–EDTA). Cardiovascular and non-cardiovascular mortality in dialysis patients: where is the link? Kidney Int Suppl 2011;1:21-23.

16. Fabrizi F, Dixit V, Messa P. Impact of hepatitis C on survival in dialysis patients: a link with cardiovascular mortality? J Viral Hepat 2012;19:601-607.

17. O’Lone E, Connors M, Masson P, et al. Cognition in people with end-stage kidney disease treated with hemodialysis: a systematic review and meta-analysis.

Am J Kidney Dis 2016;67:925-935.

18. Ibrahim MAM, Heibbah HA, Abdo TA. Effect of hepatitis C seropositivity on cognitive functions in prevalent hemodialysis patients. Presented at 53rd Congress of the European Renal Association-European Dialysis & Transplant Association (ERA-EDTA), Vienna, Austria, May 21–24, 2016. MP635.

19. Bruchfeld A, Wilczek H, Elinder CG. Hepatitis C infection, time in renal-replacement therapy, and outcome after kidney transplantation. Transplantation 2004;785:745-750.

20. Ozdemir BH, Ozdemir FN, Sezer S, et al. De novo glomerulonephritis in renal allografts with hepatitis C virus infection. Transplant Proc 2006;38:492-495.

21. Sharif A, Cohney S. Post-transplantation diabetes—state of the art. Lancet Diabetes Endocrinol 2016;4:337-349.

22. Fabrizi F, Martin P, Dixit V, et al. Post-transplant diabetes mellitus and HCV seropositive status after renal transplantation: meta-analysis of clinical studies. Am J Transplant 2005;5:2433-2440.

23. Gürsoy M, Köksal R, Karaveliog˘lu D, et al. Pretransplantation alpha-interferon therapy and the effect of hepatitis C virus infection on kidney allograft recipients. Transplant Proc 2000;32:580-582.

24. Kamar N, Toupance O, Buchler M, et al. Evidence that clearance of hepatitis C virus RNA after alpha-interferon therapy in dialysis patients is sustained after renal transplantation. J Am Soc Nephrol 2003;14:2092-2098.

25. Roth D, Gaynor JJ, Reddy KR, et al. Effect of kidney transplantation on outcomes among patients with hepatitis C. J Am Soc Nephrol 2011;22:1152-1160.

26. Saxena V, Koraishy FM, Sise ME, et al. HCV-TARGET. Safety and efficacy of sofosbuvir-containing regimens in hepatitis C infected patients with impaired renal function. Liver Int 2016;36:807-816.

27. Saxena V, Terrault NA. Treatment of hepatitis C infection in renal transplant recipients: the long wait is over. Am J Transplant 2016;16:1345-1347.

28. Pockros PJ, Reddy KR, Mantry PS, et al. Efficacy of direct-acting antiviral combination for patients with hepatitis C virus genotype 1 infection and severe renal impairment or end-stage renal disease. Gastroenterology 2016 Mar 11. [Epub ahead of print].

29. Roth D, Nelson DR, Bruchfeld A, et al. Grazoprevir plus elbasvir in treatment-naive and treatmentexperienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study.

Lancet 2015;386(10003):1537-1545.

30. Bruchfeld A. Elbavir/grazoprevir treatment of hepatitis C virus infection in patients with chronic kidney disease stage 4/5: clinical, virologic and health-related quality of life outcomes in the C-SURFER study. Presented at the 53rd Congress of the European Renal AssociationEuropean Dialysis & Transplant Association (ERA-EDTA), Vienna, Austria, May 21–24, 2016.

31. American Association for the Study of Liver Disease.

Recommendations for testing, managing and treating hepatitis C. Unique patient populations: patients with renal impairment. Updated February 24, 2016.

Changes made 25 April 2016. www.hcvguidelines. org (last accessed 4th June 2016).

32. European Association for the Study of the Liver.

EASL recommendations on treatment of hepatitis C 2015. J Hepatol 2015;63:199-236.

33. Pol S, Jadoul M, Vallet-Pichard A. An update on the management of hepatitis C virus-infected patients with stage 4-5 chronic kidney disease while awaiting the revised KDIGO Guidelines. Nephrol Dial Transplant 2016 Mar 22. [Epub ahead of print].

34. Sawinski D, Bloom RD. Novel hepatitis C treatment and the impact on kidney transplantation. Transplantation 2015;99:2458-2466.

35. Sawinski D, Kaur N, Ajeti A, et al. Successful treatment of hepatitis C in renal transplant recipients with direct-acting antiviral agents. Am J Transplant 2016;16:1588-1595.

36. Messina JP, Humphreys I, Flaxman A, et al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology 2015;61:77-87.

37. National Institute for Health and Care Excellence.

NICE recommends three new treatment options for hepatitis C in draft guidance. Press release July 29, 2015. https://www.nice.org.uk/news/press-andmedia/nice-recommends-new-treatment-options-forhepatitis-c (last accessed 3rd June 2016).

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www.renalandurologynews.com SEPTEMBER 2016

Renal & Urology News 25

Study: Intermediate HDL-C Is Best High and low HDL cholesterol both increase mortality across all levels of kidney function

BY NATASHA PERSAUD MAINTAINING AN intermediate level of high-density lipoprotein cholesterol (HDL-C) may offer the best chances of survival, a new study finds.

Investigators led by Ziyad Al-Aly, MD, and Benjamin Bowe, MPH, of the Clinical Epidemiology Center at the Veterans Affairs St. Louis Health Care System in Missouri, examined all-cause mortality among 1,764,986 U.S. male veterans with at least a single measurement of estimated glomerular filtration rate (eGFR) and HDL-C from October 2003 to September 2004.

Over 9.1 years of follow up, the most deaths (40.1%) occurred among men with the lowest HDL-C level (25 mg/ dL and below). When the team modeled survival using the lowest HDL-C level as a reference, they discovered that intermediate HDL-C levels (25 to

50 mg/dL) were associated with lower risks of dying across all levels of eGFR. The apparent protection eroded for the highest HDL-C level (50 mg/dL and above). Higher death risks, similar to the reference group, were found

The finding that high HDL-C was associated with greater death risk was unexpected. among men with HDL-C levels of 50 mg/dL and above at the highest and lowest eGFR (below 30 mL/min/1.73m2 or 90 mL/min/1.73m2 and above).

“The finding that high HDL-C was also associated with higher risk of death was not expected and has not been

reported previously in large epidemiologic studies such as the Framingham Heart Study and others,” Dr. Al-Aly stated in a press release.

Additional analyses actually revealed a U-shaped curve between HDL-C and early death. “Our findings may explain why clinical trials aimed at increasing HDL-C levels have failed to show improvement of clinical outcomes,” Bowe added.

A lower eGFR eroded some of the benefit of intermediate HDL-C, but the association was still significant.

The presence of cardiovascular disease also weakened the association between HDL-C and mortality from any cause.

Findings from previous experimental and pharmaceutical research “supports the notion that there may be a range of HDL-C values where HDL-C may have a salutary effect, beyond which higher

Higher Complication Rate Found Data Support with Open Partial Nephrectomy Biopsy Before Renal Cryo

PARTIAL NEPHRECTOMY (PN) using an

glomerular filtration rate, and clinical

open rather than a robot-assisted pro-

tumor size were not.

cedure predicts a higher rate of overall

“For experienced surgeons, the mor-

complications for unifocal T1a renal

bidity associated with nephron-sparing

tumors, investigators concluded.

surgery may be incrementally improved

A team at Cleveland Clinic in Ohio led

by Jihad H. Kaouk, MD, compared 169 patients who underwent PN with an open

using the robot-assisted approach,” Dr. Kaouk and colleagues concluded.

The y stated that, to their knowledge,

approach (OPN) with 545 patients who

the current study is the largest compar-

underwent robot-assisted PN (RAPN).

ing morbidity after OPN and RAPN for

The OPN group had a significantly higher

clinical T1a renal tumors. They pointed

rate of overall complications than the

out, however, that the study had limita-

RAPN group (30.3% vs. 18.2%). Wound

tions. The retrospective design predis-

complications accounted for 11.8% and

posed to selection bias, they said. In

1.8% of these events in the OPN and

addition, their outcomes reflect the expe-

RAPN groups, respectively.

rience of a high-volume, tertiary referral

On multivariable analysis, the open procedure was associated with a sig-

center with experienced surgeons.

Still, they noted that an open surgical

nificant 58% increased odds of overall

procedure was the strongest predictor

complications compared with RAPN,

of overall complications in their study.

Dr. Kaouk’s team reported online ahead

Although some would argue that a

of print in BJU International.

large proportion of patients with T1a

The study also found that non-white

renal tumors could undergo active

race (vs white race), higher Charlson

surveillance or ablative treatments,

Comobidity Index, and higher body mass

“we typically reserve these treatment

index were associated with significantly

options for older patients, poor surgical

increased odds of overall complications,

candidates, or those patients who

whereas age, preoperative estimated

refuse surgery,” they wrote n

HDL-C_survival_RUN0916.indd 25

BIOPSY-BASED RISK stratification of patients prior to percutaneous renal cryoablation may be helpful in identifying patients at higher risk of primary treatment failure, according to a study.

The study, led by Ithaar H. Derweesh, MD, of the University of California San Diego in La Jolla, was a retrospective analysis of 153 patients who had renal cell carcinoma (RCC) documented by perioperative biopsy. Patients had a median follow-up of 48 months. Dr. Derweesh’s team divided the cohort into patients who experienced recurrence (18 patients, 11.8%) and those who did not (135 patients, 88.2%). The groups were similar with respect to demographics, R.E.N.A.L. score, and number of probes used.

Study results showed that the recurrence group had significantly larger tumors than the no-recurrence group (median 3.1 vs. 2.4 cm) as well as a significantly greater proportion of high-grade tumors (33% vs 0.7%) and tumors with clear cell histology (77.8% vs. 45.9%), the investigators reported online ahead of print in the World Journal of Urology.

HDL-C may not be beneficial and may be associated with untoward outcomes,” Dr Al-Aly and colleagues commented in a report in the Clinical Journal of the American Society of Nephrology (published online ahead of print).

HDL-C may be a surrogate rather than a driver of outcomes, they acknowledged.

Men with both low eGFR and low HDLC, for instance, also had more comorbid conditions. Regardless, HDL-C may be useful for risk assessment.

Acknowledging study limitations, the investigators noted that they could not assess HDL size, composition, functional capacity, or subclasses.

They also could not thoroughly examine cause of death, although cardiovascular causes do not appear to be a major culprit. Cancer risks and inflammation are other possibilities that require investigation. n

The 4-year recurrence-free survival (RFS) was 100% for grade 1 tumors compared with 80% for grade 2/3 tumors.

The 4-year RFS for patients with clear cell RCC and those other RCC types did not differ significantly (88% vs. 97%).

“While these findings require further confirmation, they nonetheless suggest a rethinking of the current algorithm of ablative management,” the investigators wrote.

The association of higher grade and clear cell histology with an increased likelihood of disease recurrence and progression suggests a need for increased emphasis on risk stratification based on preoperative biopsy findings, Dr. Derweesh and his colleagues concluded.

Patients with low-grade clear cell or non-clear cell histology may be more effectively treated by ablation, whereas patients with clear cell histology and higher tumor grade may be counseled as to the increased risk of experiencing ablative treatment failure and potentially steered to other management options, according to the investigators.

Dr. Derweesh’s group said that despite increasing importance attached to biopsy as a determine for management of small renal masses, “most research focusing on predictive factors related to ablative success has focused on technical factors, surgical approach, and type of ablative technology, while predictive ability of biopsy detected histology and grade on treatment success has been little studied.” n

8/22/16 1:07 PM

26 Renal & Urology News

SEPTEMBER 2016 www.renalandurologynews.com

Practice Management Participating in CMS’ Chronic Care Management program has logistical challenges, but it can be worthwhile. BY TAMMY WORTH specific signed consent form, so it calls it out as different to patients and creates confusion.”

Currently, as a condition of billing for CCM, a provider must secure a patient’s signature on a written consent form, the terms of which are dictated by the regulations, Ross pointed out. This is the only service for which CMS requires the patient’s signature on a specific form as a condition of provider payment. This is not to be confused with general consent for treatment, he said. CMS now has proposed to eliminate this requirement in the 2017 Medicare Physician Fee Schedule proposed rule, which would take effect January 1, 2017.

Patients’ financial responsibility Patients also may not like being financially responsible for 20% of the $42 monthly fee. Many patients do not like paying when there is no face-to-face contact with a provider, Dr. Shapiro said. They also feel that much of this care management is “part and parcel” of what physicians should be doing already.

A care plan detailing patients’ health issues, treatment, social services, and medications has to be created and updated regularly. last at least a year. To receive the payment providers are required to spend 20 minutes of staff time and create a management plan that is regularly updated.

Here are some of the major issues and points to note about the program.

Signing on Getting patients to sign on to the program and agreeing to their financial responsibility are major impediments for many specialists.

“The consent issue drives people crazy,” said Martie Ross, principal at Pershing, Yoakley & Associates (PYA).

“It is clunky and there is no other service where people have to have a

“It’s not impossible, but it can be tricky to get this [consent form] in writing,” Dr. Shapiro said.

Overstepping boundaries In theory, CCM should be a great option for many specialists who often spend a lot of time coordinating patient care. In reality, however, Dr. Shapiro said many specialist providers have foregone the program because the role is already the purview of primary care physicians. The CCM program allows for only 1 doctor to bill for a patient each month. Patients in medical home or accountable care organizations, or in groups like Kaiser,

© THINKSTOCK

W

hen nephrologist Michael Shapiro, MD, first heard about the Chronic Care Management (CCM) program run by the Centers for Medicare and Medicaid Services (CMS), he was excited for the opportunity. Nephrologists see a lot of patients with multiple chronic conditions and they already are engaged in a lot of communication and care coordination.

“But when you look at the details, it becomes a little less attractive,” Dr. Shapiro said. “In our practice, we decided when it was first introduced that it wasn’t applicable.”

Dr. Shapiro, president-elect of the Renal Physicians Association, has talked with several other large nephrology groups that have investigated it, and not one is taking part, although some are considering it in the future as part of their participation in value-based payment models.

Through the CCM program, CMS pays $42 per month for physicians to manage the care of patients with 2 or more chronic conditions expected to

The CCM program is aimed at improving care for patients with multiple chronic conditions.

for example, are likely receiving the service there.

“If we get it [the consent form and subsequent claim] in first, we may be upsetting the apple cart,” he said.

For specialists, the number of eligible patients might be even smaller.

Nephrologists, for instance, cannot simultaneously bill the CCM and monthly capitation payment for patients with end-stage renal disease, many of whom are on Medicare.

According to PYA, the gross revenue of the CCM program for a physician with 1,742 patients could range from $44,000 if about one-third of the Medicare patients are eligible to as much as $178,000 if two-thirds are.

Ross pointed out that ESRD patients may receive CCM, but CMS will not pay for CCM during the same service period as certain ESRD services.

Building a system Creating a system in which to work the CCM is among the biggest challenges of the program, but providers should not be deterred by the process. Dr. Shapiro said it is similar from an operational perspective to other patient care processes such as integrating a new electronic medical record into the practice. A care

plan detailing patients’ health issues, treatment, social services, and medications has to be created and updated regularly. Basic templates are available online that offer documentation logs, patient letters, consent forms and care plans logs.

Keeping track of documentation Dr. Shapiro said it will be important to know where the documentation will be kept for the 20 minutes of virtual visits during the month. Staff members should prepare a checklist of the patients taking part in the program and who will be in charge of their care.

Staff members taking part in the program are an important component, Dr. Shapiro pointed out. Clinical staff should be gathering information and making patient contact between visits, he said.

“Optimally, the physician as the clinical lead is delegating the interim contacts to others within the practice and may have weekly or daily briefings with the clinical team,” Dr. Shapiro said.

“You are not looking at reducing care, but enhancing and improving it.”n Tammy Worth is a freelance medical journalist based in Blue Springs, MO.

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For men with mCRPC who have progressed on ADT

Z Y T I G A® & P R E D N I S O N E

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

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

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

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

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

Please see additional Important Safety Information on the next pages.

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

Date: 07/25/16 Customer Code: 044350-160421 Group 360 Job #: 761662 File Name: 044350-160421_Zytiga-Urology_761662_v1c (pg 1 - right hand page) Size: 7” W x 10” H Colors: CMYK Description: Zytiga & Prednisone Pub: Renal and Urology News (8/1/16 - Online issue) K

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IMPORTANT SAFETY INFORMATION Hepatotoxicity—In postmarketing experience, there have been ZYTIGA®-associated severe hepatic toxicities, including fulminant hepatitis, acute liver failure and deaths. 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. 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. Permanently discontinue ZYTIGA® for patients who develop a concurrent elevation of ALT greater than 3X ULN and total bilirubin greater than 2X ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation.

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

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2016 06/16 044350-160421

Date: 07/25/16 Customer Code: 044350-160421 Group 360 Job #: 761662 File Name: 044350-160421_Zytiga-Urology_761662_v1c (pg 2 - left hand page) Size: 7” W x 10” H Colors: CMYK Description: Zytiga & Prednisone Pub: Renal and Urology News (8/1/16 - Online issue) K

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Let’s do this Established safety profile Contraindicated in women who are or may become pregnant; Warnings and Precautions include Mineralocorticoid Excess, Adrenocortical Insufficiency, and Hepatotoxicity The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia

ZYTIGA® in geriatric patients

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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).

051320-160413

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.

* Greater sensitivity of some older individuals cannot be ruled out.

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

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Of the total number of patients receiving ZYTIGA® in phase 3 trials, 73% of patients were aged 65 years and over and 30% were aged 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

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

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

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

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

Co-administration of a corticosteroid suppresses adrenocorticotropic ­­ hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia.

Use ­ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ­ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ­ZYTIGA. Adrenocortical Insufficiency: ­Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ­ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ­ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress.

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

Hepatotoxicity: ­In postmarketing experience, there have been ZYTIGAassociated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths [see Adverse Reactions].

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 Z­ YTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ­ZYTIGA. No deaths clearly related to ­ZYTIGA were reported due to hepatotoxicity events.

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

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

Permanently discontinue ZYTIGA for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation [see Dosage and Administration (2.2) in full Prescribing Information].

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

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

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

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

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

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

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

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

Table 1: Adverse Reactions due to ­ZYTIGA in Study 1 ­ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications 5.9 1.4 2.3 0 Fractures5

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

Table 1: Adverse Reactions due to Z­ YTIGA in Study 1 (continued) ­ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 2.3 1.9 1.0 0.3 Cardiac failure8

Table 3: A dverse Reactions in ≥5% of Patients on the ­ZYTIGA 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 % % % % Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0.

2 Includes terms Edema peripheral, Pitting edema, and Generalized edema.

3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness.

1 Adverse

events graded according to CTCAE version 3.0. terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness.

3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness.

4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema.

5 Includes all fractures with the exception of pathological fracture.

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.

2 Includes

Table 2 shows laboratory abnormalities of interest from Study 1.

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

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

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

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

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 Z­ YTIGA 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 ­ZYTIGA 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.

Postmarketing 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.

Hepatobiliary Disorders: fulminant hepatitis, including acute hepatic failure and death.

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].

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

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

Effects of Abiraterone on Drug Metabolizing Enzymes: Z­YTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine).

If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

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

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

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. ­ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss.

Advise females of reproductive potential to avoid becoming pregnant during treatment with ­ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

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

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

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

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

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

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

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ­ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or

AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

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

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ­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, ­ZYTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle Z­ YTIGA 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 should 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 reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests.

• Patients should be informed that Z­ YTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ­ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ­ZYTIGA. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 ©Janssen Biotech, Inc. 2012 Revised: May 2016 051318-160413