Renal & Urology News - June-July 2016 issue

J U N E /J U LY 2 016

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VOLUME 15, ISSUE NUMBER 5

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AKI Patients Benefit from Early RRT Study demonstrates improved 90-day survival and greater likelihood of recovering renal function EARLY RRT IMPROVES OUTCOMES Early initiation of renal replacement therapy (RRT) improves 90-day survival and recovery of renal function compared with delayed initiation, data show.

70 60

61%

Survival at 90-days 54%

50

45%

40

Renal function recovery at 90 days 39%

30 20 10 0

Early RRT

Delayed RRT

Percentages have been rounded off.

Source: Zarbock A, et al. Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury. The ELAIN Randomized Clinical Trial. JAMA 2016;315:2190-2199. Data also presented May 22, 2016 at the ERA-EDTA 53rd Congress in Vienna. Abstract LB02.

Obesity-CKD Link Challenged

BY JODY A. CHARNOW BOSTON—Study findings presented at the National Kidney Foundation’s 2016 Spring Clinical Meetings challenge whether obesity has an association with chronic kidney disease (CKD).

“Much of the medical literature states that there is a direct effect of obesity on CKD, independent from the

effects of diabetes and hypertension as a result of obesity,” lead researcher Patrick Albertus, MPH, of the Kidney Epidemiology and Cost Center at the University of Michigan in Ann Arbor, told Renal & Urology News. “Our fi ndings from a large survey, which is demographically representative of continued on page 11

EXPERT Q&A

Ishir Bhan, MD, MPH, explains why SHPT remains a management challenge.

PAGE 12

BY JODY A. CHARNOW EARLY INITIATION of renal replacement therapy (RRT) improves 90-day survival among critically ill patients with acute kidney injury (AKI), according to study findings presented at the 53rd Congress of the European Renal Association-European Dialysis and Transplant Association in Vienna.

In a randomized single-center trial that enrolled 231 patients, Alexander Zarbock, MD, of the University of Muenster in Germany, and colleagues found that early initiation of RRT was associated with a significant 34% decreased risk of death compared with delayed initiation.

The investigators defined early RRT as RRT started within 8 hours of a diag-

Statins May Lower Kidney Stone Risk

BY JODY A. CHARNOW SAN DIEGO—Individuals who take statins may be at lower risk of kidney stone formation, according to study findings presented at the American Urological Association 2016 annual meeting.

The study, by Andrew Cohen, MD, of the University of Chicago Medical Center, and colleagues, compared 1,785 recurrent stone formers and 97,563 patients with no history of stones.

Patients prescribed statins were significantly older (60.7 vs. 51.9 years) and had a significantly higher body mass index (BMI, 29.2 vs. 28.1 kg/m2).

In the stone-former group, new stones developed in 33.8% of those on statins compared with 53% of non-statin users.

In the stone-naïve patients, new stones developed in 3.8% of those on statins compared with 4.7% of non-statin users.

In multivariable analysis, statin use was associated with a significant 43% and 47% decreased odds of new stones among stone naïve patients and recurcontinued on page 11

nosis of Kidney Disease: Improving Global Outcomes (KDIGO) stage 2 AKI and delayed RRT as RRT started within 12 hours of KDIGO stage 3 AKI or no RRT initiation. To be included in the trial, patients had to have a plasma level of neutrophil gelatinase-associated lipocalin—an early biomarker for AKI in the adult intensive care unit population—greater than 150 ng/mL. Of the 231 patients, 112 and 119 were randomly assigned to the early and delayed RRT groups, respectively. RRT for all patients was continuous venovenous hemodiafiltration. At 90 days, 68 patients in the early group (60.7%) were alive compared with 54 (45.3%) in the delayed group. continued on page 11

IN THIS ISSUE 4

Elevated FGF23 levels increase the risk of respiratory infection

5

Low fitness levels in midlife raise risk of late life CKD

7

CKD not linked to urologic procedures for kidney stones

11

ESA doses are lower for patients living at higher elevations

20

Warfarin, diabetes identified as calciphylaxis risk factors

21

Smoking found to increase CKD risk in blacks

25

High uric acid ups non-fatal stroke risk in CKD patients

A new study has independently validated a proposed new grading system for prostate cancer.

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J U N E /J U LY 2 016

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VOLUME 15, ISSUE NUMBER 5

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Renal Stone ‘Dusting’ Shows Benefits

© IMAGE COURTESY OF KHURSHID GHANI, MBCHB, MS

Laser technique may reduce need for basket extraction and ureteral access sheaths, new data suggest

DUSTING DURING LASER ureteroscopic lithotripsy results in sub-millimeter stone fragments.

BY JODY A. CHARNOW SAN DIEGO—Data from studies presented at the American Urological Association 2016 annual meeting may help to clarify the role of ureteroscopic laser lithotripsy “dusting” for the treatment of kidney stones.

Ureteroscopy with laser lithotripsy is an established procedure for breaking apart kidney and ureteral stones.

Traditionally, the technique involves basket extraction of fragments. With the new dusting technique, urologists employ low-pulse, high-frequency laser energies utilizing more powerful laser systems to pulverize stones into extremely fine fragments that can pass spontaneously in the urine, potentially obviating the need for basket

Testosterone Rx, PCa Not Linked Landmark PSA SAN DIEGO—Testosterone treatIn a study of 147,593 U.S. veterans Trial Outcomes ment is not associated with an with low total testosterone, Thomas increased likelihood of being diag- J. Walsh, MD, of the University of Challenged nosed with prostate cancer (PCa), and Washington in Seattle, and colleagues it may lower the risk aggressive PCa, according to the findings of separate studies presented at the American Urological Association 2016 annual meeting.

found that PCa incidence was per 1,000 person-years was 2.27 among men who ever received testosterone treatment and 2.60 in those who never continued on page 11

EXPERT Q&A

Ishir Bhan, MD, MPH, explains why SHPT remains a management challenge.

PAGE 12

BY JODY A. CHARNOW RECOMMENDATIONS AGAINST routine PSA screening from the U.S. Preventive Services Task Force (USPSTF) are based largely on a landmark trial showing that such screening does not decrease the risk of death from prostate cancer (PCa), but this conclusion may be invalid, according to the authors of a Letter to the Editor in The New England Journal of Medicine.

(2016; 374:1795-1796).

The trial in question is the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, in which 76,693 men in the United States were randomly assigned to receive either annual screening (intervention arm) or usual care. Men in the intervention arm were offered annual PSA testing for 6 years and digital rectal examinations for 4 years. Results of that study were published in NEJM in 2009.

Jonathan E. Shoag, MD, and Sameer Mittal, MD, of New York Presbyterian continued on page 11

extraction and the use of ureteral access sheaths.

“It’s a much more efficient way of dealing with a stone,” said Khurshid Ghani, MBChB, MS, of the University of Michigan in Ann Arbor, lead author of one of the studies. “We can tackle any medium- to large-size stones quite rapidly.”

Dr. Ghani and his colleagues presented findings of a study of 71 patients who underwent 83 laser dusting procedures with a 120W holmium laser. Patients had a mean stone size of 12.5 mm (range 5–50 mm). The stones were present in the kidney in 73% of patients and in the ureters in 27%. Ureteral access sheaths were used in 21% of cases. After a mean continued on page 11

IN THIS ISSUE 7

Urologic procedures for kidney stones do not raise CKD risk

15

Proposed new grading system for prostate cancer validated

16

Carbohydrate restriction may ease adverse effects of ADT

16

New studies confirm the benefits of prostatic urethral lift for BPH

19

Guidelines for non-muscle-invasive bladder cancer updated

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Multiple comorbidities predict high-grade prostate cancer

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Bariatric surgery improves LUTS in obese men

A new study has independently validated a proposed new grading system for prostate cancer.

PAGE 15

4 Renal & Urology News

JUNE/JULY 2016 www.renalandurologynews.com

Respiratory Infections Linked to Higher FGF23 Levels BOSTON—Higher levels of fibroblast growth factor 23 (FGF23) may increase the risk of respiratory infection among older adults, researchers reported at the National Kidney Foundation 2016 Spring Clinical Meetings.

In a study of 55 elderly individuals (mean age 80 years) living in long-term

care facilities, Anna Jovanovich, MD, and colleagues at the University of Colorado Denver found that approximately each 5 mg/mL increment in FGF23 was associated with a significant 5-fold increased odds of respiratory infection in a fully adjusted model. “Our study is the first to report a link between

higher FGF23 levels and increased risk of infection in a non-dialysis population,” Dr. Jovanovich said. “This observational study cannot prove causation but it adds to the existing literature that FGF23 may be involved in immune function.”

The study included participants in a randomized controlled trial evaluating

the effect of high versus standard dose vitamin D on infection. Active vitamin D plays a role in the destruction of bacteria by immune cells, Dr. Jovanovich said.

Previous research demonstrated that higher levels of FGF23 have been linked with an increased risk of infection among hemodialysis patients. n

www.renalandurologynews.com JUNE/JULY 2016

Renal & Urology News 5

Low Midlife Fitness Found to Predict Future CKD MODERATE AND HIGH fitness in midlife may predict a lower risk for chronic kidney disease decades later, even in at-risk populations such as individuals with diabetes mellitus, researchers concluded.

Laura F. DeFina, MD, of The Cooper Institute in Dallas, and colleagues stud-

ied 17,979 participants in the prospective Cooper Center Longitudinal Study seen initially from 1971 to 2009 and who received Medicare coverage from 1999 to 2009. A total of 2,022 cases of incident CKD occurred during 116,973 person-years of observation. Compared with subjects who had low fitness lev-

els, those with moderate and high levels had a 24% and 34% lower risk of CKD, respectively, in a fully adjusted model, the researchers reported online in Preventive Medicine.

Given the high cost of managing endstage renal disease, prevention is critical, the authors noted.

“Our findings support a role for enhancing fitness through regular physical activity in preventive strategies for CKD,” the authors concluded.

For the study, the researchers stratified individuals into age- and sexspecific quintiles of fitness based on treadmill times during exercise stress testing. They considered subjects in quintile 1 to have low fitness and those in quintiles 2–3 and quintiles 4–5 to have moderate and high fitness, respectively. Dr. DeFina’s group used the final treadmill speed and grade to estimate maximal metabolic equivalents (METs).

The average time from baseline examination to the end of surveillance in Medicare was 21.4 years, with a mean follow-up of 7.2 years within the Medicare surveillance period.

High vs. low fitness levels in midlife lowered CKD risk in later life by 34%.

After adjusting for age, gender, and year of baseline examination, each 1-MET increase in fitness was associated with a 13% lower risk of CKD, the researchers reported. The risk of CKD later in life was decreased by 8% per 1-MET increment without intervening DM and by 6% per 1-MET increment following a DM diagnosis.

At baseline, participants in the low fit, moderate fit, high fit categories had a mean age of 46.8, 49.4, and 51.6 years, respectively. The low fit group had more prevalent hypertension and hyperlipidemia than the moderate and high fit groups, study results showed.

The 3 groups did not differ significantly with respect to markers of renal function, including estimated glomerular filtration rate, creatinine levels, and urine protein levels, according to the investigators.

The authors acknowledged limitations of their study. They obtained outcome diagnoses from administrative claims data, not adjudicated clinical data, which may have led to underreporting of CKD because early-stage CKD is known to be under-diagnosed, they noted. In addition, the researchers pointed out that they did not have medication data available to determine the use of drugs potentially affecting renal function. n

6 Renal & Urology News

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FROM THE EDITOR EDITORIAL ADVISORY BOARD

New Discoveries Provide Insights into Calciphylaxis

P

erhaps nothing is more frustrating to clinicians than not being able to ease patients’ suffering or stave off death from a debilitating medical condition.

No medical subspecialty faces this dilemma more than nephrologists.

They care for more than 450,000 endstage renal disease patients on chronic dialysis in the United States, arguably one of the most clinically challenging groups of patients in medicine. These patients have mortality rates of 20% or more per year. On top of the multiple comorbidities from which most dialysis patients suffer, a few develop a painful and often-fatal condition for which no generally accepted disease-altering treatment exists: calciphylaxis, also referred to as calcific uremic arteriolopathy.

It is not precisely clear how calciphylaxis develops and why it occurs in some patients and not others. Previous studies have found a link between warfarin use and calciphylaxis, but these studies were too small to allow identification of other potential risk factors. In this issue (page 20), we report on the largest study by far to examine risk factors for calciphylaxis. The study, led by Sagar U. Nigwekar, MD, MMSc, of Harvard University Medical School and Massachusetts General Hospital in Boston, included 1,030 hemodialysis (HD) patients with newly diagnosed calciphylaxis.

In addition to warfarin use, diabetes mellitus, skin trauma, higher body mass index, and use of nutritional vitamin D and cinacalcet at the time of HD initiation were independently associated with an increased risk of calciphylaxis, Dr. Nigwekar and his colleagues reported in the Journal of the American Society of Nephrology. The identification of additional risk factors is a noteworthy advance that could better enable researchers to develop strategies to prevent and treat calciphylaxis.

In a separate report published recently in the Journal of Dermatological Treatment, researchers reported on a series of 8 calciphylaxis patients treated with sodium thiosulfate, a drug indicated for cyanide toxicity, at University Hospital of Leuven in Belgium. Four patients achieved complete healing of skin lesions, 2 had stabilization of disease while experiencing pain relief. The remaining 2 had progression of the disease. Four patients eventually died due to calciphylaxis-related causes.

Anecdotally, Dr. Nigwekar said he has had some success using sodium thiosulfate to treat calciphylaxis; however, more rigorous studies are needed to ascertain its efficacy.

Calciphylaxis is quite rare, but it is likely that many nephrologists will encounter at least 1 case during their careers. With the progress being made in the understanding of the condition, nephrologists in the nottoo-distant future may well have something in their armamentarium to offer their patients with calciphylaxis.

Medical Director, Urology

Medical Director, Nephrology

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

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

Nephrologists

Urologists

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

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

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

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

Edgar V. Lerma, MD, FACP, FASN, FAHA Clinical Associate Professor of Medicine Section of Nephrology Department of Medicine University of Illinois at Chicago College of Medicine, Chicago Allen Nissenson, MD Emeritus Professor of Medicine The David Geffen School of Medicine at UCLA, Chief Medical Officer, DaVita Inc.

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

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

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

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

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

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

Renal & Urology News Staff Editor Web editor Production editor

Jody A. Charnow Natasha Persaud Kim Daigneau

Group art director, Haymarket Medical

Jennifer Dvoretz

Production manager

Krassi Varbanov

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

Jody A. Charnow Editor

Csaba P. Kovesdy, MD Chief of Nephrology Memphis VA Medical Center Fred Hatch Professor of Medicine University of Tennessee Health Science Center, Memphis

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

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Renal & Urology News 7

Phosphorus Values Linked to Blood Sample Timing PHOSPHORUS LEVELS in dialysis patients are higher when blood is collected after the weekend (interdialytic period) compared with blood samples taken on other days, researchers reported at the European Renal AssociationEuropean Dialysis and Transplant Association 53rd Congress in Vienna. The timing of blood collection also affects the relationship between phosphorus level and mortality, investigators found.

The results are from COSMOS, a prospective 3-year, observational, opencohort study including 6,797 dialysis patients from 227 centers in 20 European countries. Adriana Dusso, MD, of the Hospital Universitario Central de Asturias in Spain, and colleagues divided

CKD, Stone Procedures Not Linked UROLOGIC PROCEDURES to treat patients with urolithiasis increase the risk for elevated serum creatinine, but they do not appear to increase the incidence of chronic kidney disease (CKD), according to a new study.

Matthew D’Costa, MD, of Marshfield Clinic in Marshfield, Wis., and colleagues conducted a retrospective observational cohort study that included 1,340 patients diagnosed with urolithiasis, of whom 446 (33.28%) underwent urologic procedures for kidney stones.

The patients who underwent procedures had a significant 49% increased risk for elevated serum creatinine compared with those who did not undergo procedures, after adjusting for age, gender, and comorbidities, the investigators reported online in Clinical Medicine & Research. The researchers found no significant between-group differences in the incidence of CKD or death from any cause.

Although elevated serum creatinine may be the result of procedural intervention, it is just as likely, if not more so, to be the result of renal injury secondary to the urolithiasis event itself, the investigators wrote. n

patients into 2 groups depending on whether dialysis centers drew blood specimens midweek (MW) or postweekend (PW). Mean serum phosphorus levels were significantly higher in the PW than MW group (5.5 vs 5.2 mg/dL).

The PW group had a higher proportion of patients with phosphorus levels

above the upper targets recommended by guidelines. Despite these differences, the prescription of phosphate binders was similar between the groups: 85% for the PW and 84.8% for MW arm.

The lowest mortality ranges for serum phosphorus were 3.5–4.9 mg/dL when blood was sampled MW and 3.8–5.7 mg/

dL when sampled PW. The association between high phosphorus and mortality risk was stronger for MW phosphorus measurements. For serum phosphorus in the 5.5–6.3 mg/dL range (quintile 4), MW collection was associated with a significant 35% increased relative risk of mortality versus PW collection. n

8 Renal & Urology News

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Contents

J U N E / J U LY 2 0 1 6 ■ V O L U M E 1 5 , I S S U E N U M B E R 4

Nephrology 20

ONLINE

21

this month at renalandurologynews.com 25

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

25

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

Congratulations to our recent winners: May: Nabet Kasabian, MD June: Lawrence Greenberg, MD

Smoking May Up CKD Risk in Blacks Compared with black individuals who did not smoke, those who currently smoked had a 83% higher incidence of rapid renal function decline.

CKD Progression After AKI Defined Male gender, diabetes mellitus, and decline in renal function at 3 months are associated with an increased likelihood of CKD progression at 3 years.

High Uric Acid Raises Stroke Risk in CKD Patients Compared with patients in the second quartile of serum uric acid, those in the fourth quartile had a significant 49% increased odds of nonfatal stroke.

15

New PCa Grading System Independently Validated Findings from a recent study support the use of a 5 grade-group system that more accurately predicts patients’ risk of adverse outcomes.

16

Low-Carb Diet May Ease ADT Effects Extreme carbohydrate-restricted diets may ameliorate the adverse effects of androgen deprivation therapy for prostate cancer.

19

Bladder Cancer Guidelines Updated New recommendations for the diagnosis and management of non-muscle-invasive bladder cancer may enable more individualized treatment.

Keep current on the development of investigational medications.

Job Board

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

Calciphylaxis Risk Factors Identified The largest calciphylaxis study to date found that warfarin use, diabetes mellitus, and recurrent skin trauma are among the independent predictors of the potentially fatal condition.

International Continence Society Annual Meeting Tokyo September 13–16 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

Urology

Drugs in the Pipeline

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

CALENDAR

22

High-Grade PCa Linked to Greater Comorbidity Burden Patients with 2 or more comorbidities have 2.8 greater odds of a Gleason score 8 to 10 versus a Gleason score of 6 or less, researchers reported.

One of the major problems we have with the

management of non-muscle-invasive bladder cancer in the United States is that it is all over the map.

See our story on page 19

26

Departments 6

From the Editor Recent evidence provides insights into calciphylaxis.

10

News in Brief Hidden hypercalcemia common in hemodialysis patients.

12

Expert Q&A Ishir Bhan, MD, MPH, explains why treating SHPT is still a challenge.

26

Practice Management Consultants offer advice for collecting what patients owe.

8 Renal & Urology News

JUNE/JULY 2016

www.renalandurologynews.com

Contents

J U N E / J U LY 2 0 1 6 ■ V O L U M E 1 5 , I S S U E N U M B E R 4

Urology

ONLINE

this month at renalandurologynews.com

15

New PCa Grading System Independently Validated Findings from a recent study support the use of a 5 grade-group system that more accurately predicts patients’ risk of adverse outcomes.

16

Low-Carb Diet May Ease ADT Effects Extreme carbohydrate-restricted diets may ameliorate the adverse effects of androgen deprivation therapy for prostate cancer.

19

Bladder Cancer Guidelines Updated New recommendations for the diagnosis and management of non-muscle-invasive bladder cancer may enable more individualized treatment.

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

22

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

Congratulations to our recent winners: May: Nabet Kasabian, MD June: Lawrence Greenberg, MD

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

20

Calciphylaxis Risk Factors Identified The largest calciphylaxis study to date found that warfarin use, diabetes mellitus, and recurrent skin trauma are among the independent predictors of the potentially fatal condition.

21

Smoking May Up CKD Risk in Blacks Compared with black individuals who did not smoke, those who currently smoked had a 83% higher incidence of rapid renal function decline.

25

CKD Progression After AKI Defined Male gender, diabetes mellitus, and decline in renal function at 3 months are associated with an increased likelihood of CKD progression at 3 years.

Departments

High Uric Acid Raises Stroke Risk in CKD Patients Compared with patients in the second quartile of serum uric acid, those in the fourth quartile had a significant 49% increased odds of nonfatal stroke.

10

News in Brief Hidden hypercalcemia common in hemodialysis patients.

12

Expert Q&A Ishir Bhan, MD, MPH, explains why treating SHPT is still a challenge.

26

Practice Management Consultants offer advice for collecting what patients owe.

Keep current on the development of investigational medications.

Job Board

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

International Continence Society Annual Meeting Tokyo September 13–16

Nephrology

Drugs in the Pipeline

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

High-Grade PCa Linked to Greater Comorbidity Burden Patients with 2 or more comorbidities have 2.8 greater odds of a Gleason score 8 to 10 versus a Gleason score of 6 or less, researchers reported.

CALENDAR

25

One of the major problems we have with the

management of non-muscle-invasive bladder cancer in the United States is that it is all over the map.

See our story on page 19

26 6

From the Editor Recent evidence provides insights into calciphylaxis.

10 Renal & Urology News

JUNE/JULY 2016 2016 www.renalandurologynews.com

News in Brief

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

Short Takes Lupus Nephritis ESRD Has Worse Outcomes

in Halifax, Nova Scotia, de novo OAB—

End-stage renal disease (ESRD) due to

frequency and nocturia—developed in

lupus nephritis is linked to worse sur-

19% of patients. Those who under-

vival outcomes compared with other

went subsequent radiotherapy had a

causes, investigators concluded in a

nearly 5.6-fold increased relative risk

paper published in Kidney International

of de novo OAB, after adjusting for

(2016;89:1337-1345).

age, body mass index, smoking sta-

defined as urgency with or without

tus, cancer stage, and nerve-sparing

In a study of patients with ESRD

status, Dr. Hosier’s team reported.

starting renal replacement therapy in Australia and New Zealand, a team of Princess Alexandra Hospital in

Hip Fracture Rate Higher in Non-Dialysis CKD

Brisbane, Australia, found that ESRD

Patients with non-dialysis chronic kid-

caused by lupus nephritis was associ-

ney disease (CKD) may be at elevated

ated with a 33% increased risk of dial-

risk for hip fracture, according to a

ysis patient death and 87% increased

new study published online in the Jour-

risk of renal transplant patient death

nal of Bone and Mineral Research.

led by David W. Johnson, MD, PhD,

versus ESRD due to other causes.

Analyzing 2010 data from the Nationwide Inpatient Sample, research-

Post-RP Radiotherapy May Raise OAB Risk

ers led by Glenn M. Chertow, MD,

Adjuvant or salvage radiotherapy fol-

Medicine in Palo Alto, CA, found that

lowing radical prostatectomy (RP) may

the age-standardized incidence (per

increase the likelihood of overactive

1,000 person-year) of hip fracture

bladder (OAB), according to study find-

was 1.81 among patients with non-

ings published online ahead of print in

dialysis CKD compared with 1.18 for

Urology.

patients with normal or near normal

MPH, of Stanford University School of

In a study of 875 men who under-

kidney function. The incidence was

went open RP, Gregory W. Hosier, MD,

highest (3.89) in patients with end-

and colleagues at Dalhousie ­University

stage renal disease.

Physician Competence and Aging In a recent online poll, Renal & Urology News asked readers, “Should doctors’ competence be evaluated when they reach a certain age?” Here are the results based on 162 responses:

Yes: 46%

No: 40%

Do not know: 14% 0

10

20

30

40

50

Drug Cleared for Refractory Advanced Bladder Cancer A

tezolizumab has received accelerated FDA approval for treating advanced bladder cancer that is progressing despite platinum-based chemotherapy.

The drug, which will be marketed under the name Tecentriq, is indicated for patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or following platinum-based chemotherapy or whose disease has worsened within 12 months of receiving this chemotherapy before or after surgery.

Atezolizumab is a monoclonal antibody that binds with a protein called PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking interaction with both PD-1 and B7.1 receptors, according to a press release issued

by Genentech, the drug’s manufacturer. By inhibiting PD-L1, the drug may enable T cell activation.

The approval is based on the phase 2 IMvigor 210 study, an open-label, multicenter trial that enrolled 310 patients.

Incident HD Patients Often Have Hidden Hypercalcemia H

idden hypercalcemia is common among new hemodialysis (HD) patients and it is associated with an increased mortality risk similar to that of apparent hypercalcemia, researchers reported at the National Kidney Foundation’s Spring Clinical Meetings in Boston.

Using data from a large dialysis organization (DaVita), Yoshitsugu Obi, MD, PhD, of the University of California Irvine School of Medicine, and collaborators studied 869 incident HD patients. Among patients with high ionized calcium (levels above 1.32 mmol/L), 88% and 70% were incorrectly categorized as being normocalcemic using uncorrected and corrected total calcium, respectively, according Dr. Obi’s group. The researchers considered these patients to have hidden hypercalcemia.

Compared with patients who had normocalcemia (ionized calcium level 1.16– 1.32 mmol/L), those with hidden hypercalcemia on the basis of uncorrected and corrected total calcium had a significant 71% and 75% increased mortality risk, respectively, in adjusted analyses.

Surgeons Perform First Penile Transplant in the U.S. S

urgeons at Massachusetts General Hospital in Boston performed the first reconstructive penile transplant in the nation this month. The 64-year-old patient underwent a 15-hour operation to connected the arteries, veins, nerves, urethra, and skin graft pedicle to form an anatomically correct penis. Blood flow was established to the donor organ with no signs of bleeding, rejection, or infection. The intricate surgery involved more than 30 healthcare professionals, including 7 attending surgeons, 6 fellows or residents, anesthesiologists, nurses, physician assistants, scrub nurses, circulators, and organ bank personnel.

The testes were not transplanted, so reproduction is not a major concern. The risk of organ rejection is 6%–18% in the first year, so the patient will receive immunosuppressive therapies.

www.renalandurologynews.com JUNE/JULY 2016

Renal & Urology News 11

Proposed Regimen May Cut Risk of Hypercalcemia in CKD A PROPOSED paricalcitol-based treatment protocol for secondary hyperparathyroidism (SHPT) that includes limited use of calcium-based phosphate binders may reduce the risk hypercalcemia in non-dialysis chronic kidney disease (CKD) patients, according to the findings of a prospective cohort study presented at the

Elevation Influences ESA Dose BOSTON—Doses of erythropoiesisstimulating agents (ESAs) are lower among anemic hemodialysis (HD) patients living at higher elevations, new findings suggest that are presented at the National Kidney Foundation’s 2016 Spring Clinical Meetings.

It remains unclear, however,

European Renal Association-European Dialysis and Transplant Association 53rd Congress in Vienna.

Pablo Molina, MD, of the Valencian Society of Nephrology and Dr Peset University Hospital in Valencia, Spain, and colleagues compared a treatment cohort of 249 stage 3 and 4 CKD patients who received the proposed

protocol and a control cohort of 498 CKD patients who had no restriction on the use of calcium-based binders and vitamin D metabolites. The treatment and control arms were matched for age, gender, comorbidities, and CKD stages.

A significantly higher proportion of patients receiving the proposed regi-

men achieved target calcium levels compared with the control arm at 6 months (65% vs. 55%) and 12 months (64% vs.

55%). At the end of the study, the rate of hypercalcemia was significantly higher in the control arm than the study group (12% vs. 4%). Both groups had similar mean parathyroid hormone, calcium, and phosphorus levels. n

Early RRT Benefits

Presentation of the study’s findings coincided with publication of the findings in the Journal of American Medical Association (2016;315:2190-2199), where the investigators concluded: “Our study provides important feasibility data for an AKI stage-based, biomarker-guided intervention trial in AKI. However, an adequately powered multicenter trial is needed to confirm our results and establish the best time point for the initiation of RRT in critically ill patients with AKI.” With regard to study limitations, the researchers noted that although they detected a large mortality difference, “this was not a multicenter trial, and

as with many single-center studies, the observed effect size is likely inflated.”

Larger trials are needed because small trials cannot avoid small baseline differences, according to the investigators.

In an accompanying editorial, Glenn M. Chertow, MD, MPH, of Stanford University School of Medicine in Palo Alto, CA, and Wolfgang C. Winkelmayer, MD, MPH, ScD, of Baylor College of Medicine in Houston, wrote: “Whether the findings reported by Zarbock et al represent a plausible effect or not, the investigators have performed a rigorous trial and have presented their results appropriately, with responsible and conservative reporting.” n

tial confounders and mediators, the researchers found a positive association between obesity (defined as a body mass index [BMI] above 30 kg/m 2) and CKD. After adjustment, however, the association diminished or became negative, except among underweight individuals (BMI less than 18.5 kg/m2).

Noting that their study was crosssectional, Albertus said a longitudinal cohort and more advanced statistical methods are needed to truly understand the direct effect of obesity on CKD. Importantly, Albertus noted, the study found that the observed associa-

tion between BMI and CKD prevalence differed depending on the measure of kidney function used as an outcome. For example, urine albumin-to-creatinine ratio (uACR) measurements resulted in a strong positive association for underweight subjects compared with those of normal weight, whereas estimated glomerular filtration rates (eGFR) did not.

“Our findings related to the outcome measure suggest that we need to be aware of the measure of kidney function used to evaluate the association between obesity and CKD. Ideally, eGFR and uACR would need to be used.” n

matory and anti-oxidative properties, and animal models on stone formation have shown that statins decrease renal tubular injury and inhibit crystal formation.

“Because there are data suggesting an association of kidney stones with vascular disease, these data have some credibility,” commented kidney stone specialist David S. Goldfarb, MD, professor of medicine and physiology at New York University and chief of the nephrology section at the New York Harbor VA Healthcare System.

Dr. Goldfarb said he does not think the association between stone formation and vascular disease is causal, but rather that the conditions share risk factors that

may be influenced by statins. “If statins prevent stones, then these data may suggest more about the mechanisms of stone initiation,” Dr. Goldfarb said.

A previous study of 57,232 subjects with hyperlipidemia and 1,904 with nephrolithiasis demonstrated that patients taking statins had a significant 49% decreased odds of stone formation, after adjusting for sex, age, and comorbidities, according to a report in Clinical Nephrology (2013;79;351-355).

Compared with non-users, statin users were significantly older (mean 59 vs.

45 years) and had a significantly higher proportion of female patients (38% vs.

34%), researchers reported. n

continued from page 1

In addition, 60 patients in the early group (53.6%) had recovered renal function at day 90 versus 46 (38.7%) in the delayed group. Early RRT was associated with a significant 83% increased likelihood of recovering renal function compared with delayed RRT. Duration of RRT and length of hospital stay were significantly shorter in the early group than the delayed group (median 9 vs 25 days and median 51 vs 82 days, respectively), but investigators observed no significant effect on requirement for RRT after day 90.

whether decreased ESA dosing at higher elevations are attributable to increased endogenous production of erythropoietin or increased ESA responsiveness.

Yue Jiao, PhD, of Fresenius Medical Care North America (FMCNA), and colleagues analyzed ESA dosing data from 98,303 patients on chronic HD receiving care at FMCNA in-center dialysis facilities from June 1 to August 31 of 2015.

Results showed that ESA doses decreased with increasing elevation.

For example, HD patients at sea

Obesity-CKD Link

continued from page 1

the U.S. population, suggest that this direct effect is in question. Clinically, this could mean that control of diabetes, hypertension, and other mediators of this obesity-CKD pathway may be sufficient for a reduced risk of CKD.” Albertus and his colleagues analyzed data from 16,700 participants in the National Health and Nutrition Examination Survey (2007–2012). Of these, 18.1% had CKD and 81.9% did not. Before adjusting for poten-

level had a normalized mean ESA dose of about 0.1, whereas patients living at 1,000 meters (3,281 feet)

Statins and stone risk

or 2,000 meters (6,562 feet) had a

continued from page 1

normalized mean ESA dose of about

rent stone formers, respectively, compared with no statin use, after adjusting for race, BMI, gender, and comorbidities.

“Our data substantiates previous work suggesting that statins are protective against renal stone formation,” the investigators concluded in their study abstract. “Their protective effect is greater among recurrent stone formers compared to stone naïve patients.”

The authors explained that obesity and hyperlipidemia are pro-inflammatory states that may increase the likelihood of stone formation. Statins have anti-inflam-

−0.08 and −0.25, respectively.

“The most notable findings are that differences in the geography of residence can affect the treatment of end-stage renal disease patients,” Dr. Jiao told Renal & Urology News.

“In this case, we found that the required dosing of erythropoietinstimulating agents decreases as the elevation of residence increases in chronic hemodialysis patients.” n

www.renalandurologynews.com JUNE/JULY 2016

Renal stone ‘dusting’ continued from page 1

follow-up of 102 days, the patient population had a 74% rate of stone clearance, defined as 2 mm residual fragments or smaller. The rate of grade 1 and 2 complications was 10%.

The investigators concluded that their findings suggest dusting may be an attractive alternative to basket extraction, sparing patients possible morbidity associated with the routine use of ureteral access sheaths.

Laser dusting is good for mixed calcium, calcium phosphate, and uric acid stones.

In a separate study comparing basket retrieval and dusting for the treatment of 5–20 mm renal stones, investigators from the Endourology Disease Group for Excellence (EDGE) Consortium found that basket retrieval results in a higher stone free rate than dusting (86.3% vs. 59.2%). The researchers, however, found no difference in readmission or re-intervention rates, or patients becoming symptomatic from residual stone fragments.

The study included 80 patients who underwent basket retrieval and 72 who underwent dusting. A ureteral access

Landmark PSA trial continued from page 1

Hospital, and Jim C. Hu, MD, MPH, of Weill Cornell Medical College, New York, contend that the rates of PSA testing in the control arm have been misinterpreted and are substantially higher that currently recognized. As interpreted by the USPSTF, approximately 50% of controls received at least 1 PSA test during the study. Drs. Shoag, Mittal, and Hu, however, conclude that close to 90% of controls had at least 1 PSA test before or during the trial. Men in the control group, they stated, reported having had more cumulative PSA testing than those in the intervention arm.

In an interview with Renal & Urology News, Dr. Hu said such excessive “contamination” results in an unfair groupto-group comparison, making conclusions about the effect of routine PSA testing on PCa mortality unreliable.

“The study design set out to compare apples to oranges and ended up comparing apples to apples, which isn’t

sheath was used in 100% of patients in the basket group and 18.2% of the dusting group.

One of the investigators, Brian H. Eisner, MD, of Massachusetts General Hospital in Boston, explained that the objective of the trial was not to demonstrate whether dusting was better or not better than basket retrieval. “We showed that each procedure has its advantages,” he said.

Residual fragments controversial The consequences of residual stone fragments remain controversial, Dr. Eisner said. Urologists who are advocates of dusting believe the tiny fragments are not going to cause problems, but other urologists contend that even a single fragment in the kidney is bad.

“I think our study clearly showed that in the short term, it [dusting] didn’t cause any unanticipated problems,” he said, adding that long-term follow-up is needed.

Dr. Eisner explained how he performs ureteroscopic laser lithotripsy procedures. “You have to pick a strategy when you’re operating on a stone, and this includes choosing your initial laser settings. I tend to start with the dusting settings—settings of 0.3 Joules and 30 Hz or 0.4 Joules and 40 Hz were commonly used in our study.

In my practice, if I find that the stone is amenable to rapid fragmentation, I leave it on those settings and try to dust it into very tiny pieces. If the stone the intent of a randomized controlled trial,” said Dr. Hu, the Ronald Lynch Professor of Urologic Oncology and Professor of Urology at Weill Cornell.

“I think the original study investigators didn’t anticipate that PSA [testing] would be so widely used.”

Excessive contamination in the control arm, Dr. Hu pointed out, could explain why the European Randomized Study of Screening for Prostate Cancer (ERSPC)—which included 162,388 men in 8 countries and had a median follow-up of 11 years—found that regular PSA testing (every 4 years in 87% of subjects and every 2 years in the remaining 13%) was associated with a significant 21% decrease in the risk of PCa mortality compared with controls. In that study, the contamination rate in the control arm was lower, he noted.

“It was a head scratcher that the outcomes of 2 randomized trials were so different,” Dr. Hu commented.

In their NEJM letter, Dr. Hu and his co-authors said their clarifications

doesn’t break that well, or it is a harder stone, then I switch to fragmenting the stone and basketing the pieces out.”

Not all stones are amenable to ureteroscopic laser lithotripsy, Dr. Ghani emphasized. These include stones in the lower pole of the kidney.

“Some stones can be quite tricky to get into,” Dr. Ghani said. “More importantly, we don’t like to break up the stones and dust them in the lower pole because they don’t really drain out, they don’t pass. So it’s important in those cases to actually pick up the stones and move them to another location in the kidney to then treat it with the laser. This is done with a basket during ureteroscopy.”

Stone composition matters In addition, dusting may not be appropriate for harder stones, such as calcium oxalate monohydrate stones.

“In those cases, you have to crack and retrieve fragments,” Dr. Ghani said.

Dusting procedures are good for mixed calcium, calcium phosphate, and uric acid stones.

Computed tomography (CT) scans can provide clues to whether a stone is a candidate for dusting. “We can tell how well a stone will respond based on Hounsfield units on a CT scan,” Dr. Ghani said. In his experience, dusting works well for stones in the 900 to 1100 Hounsfield unit range, but is less effective for stones in the 1400 to 1500 Hounsfield unit range. n

Jim C. Hu, MD, MPH

about control group contamination “should be considered by policymakers and payers debating reimbursement and meaningful use of PSA testing, particularly given the mounting evidence that intermittent PSA testing decreases the costs and harms of screening while preserving the benefits of annual testing.” n

Renal & Urology News 11

Testosterone Rx continued from page 1

received treatment. In adjusted analyses, ever-treatment with testosterone was not associated with increased the overall PCa risk and risk of aggressive PCa compared with no testosterone treatment.

Of the entire cohort, 56,833 men (40%) received testosterone therapy.

Of these, 40% received intramuscular testosterone only, 38% received topical testosterone only, and 22% received both types of preparations. The median follow-up for all men was 3.0 years, 3.2 years for men testosterone treated men and 2.8 years for untreated men. A total of 1,439 PCa cases were diagnosed (1%). Of these, 313 were aggressive.

The finding of no association between testosterone therapy and PCa risk held regardless of testosterone formulation and lifetime cumulative dose.

“Among veterans with low testosterone levels, compared to no treatment, testosterone treatment was not associated with increased risk of subsequent prostate cancer diagnosis, any prostate cancer or high grade,” Dr. Walsh said at a press conference.

In another study, Ahmad Haider, MD, a urologist in private practice in Bremerhaven, Germany, and colleagues found that long-term treatment with testosterone was associated with a lower incidence of PCa and less aggressive PCa among those diagnosed with the malignancy. The study included 656 hypogonadal men. Of these, 360 received testosterone treatment and 296 opted against treatment and served as controls.

PCa was diagnosed in 7 men (1.9%) in the testosterone group and 12 (4.1%) of the control group. The PCa incidence per 10,000 patient-years was 30.0 in the testosterone group versus 63.5 among controls.

All PCa patients underwent radical prostatectomy. Among those treated with testosterone, the predominant Gleason score was 3 and the tumor grade was 2 in all patients, Dr. Haider reported. All had negative lymph nodes and surgical margins. In the control arm, the predominant Gleason score was 3 in 3 patients, 8 in 4, and 5 in 1. The tumor grade was 2 in 5 men and 3 in 7 men. In addition, 7 men had positive lymph nodes and 7 had positive surgical margins.

“Long-term treatment with testosterone in hypogonadal men may reduce the incidence of prostate cancer and protect against high-grade prostate cancer,” Dr. Haider concluded. n

12 Renal & Urology News

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Why SHPT Remains Difficult to Treat Ishir Bhan, MD, MPH, is Director of Nephrology Informatics at Massachusetts General Hospital and Assistant Professor

because there’s a greater likelihood of finding something that people are willing to take. If they’re more willing to take it, it’s more likely to be effective.

in Medicine at Harvard Medical School in Boston. His

What are the challenges in developing better pharmacotherapies?

research focuses on the biological actions of vitamin D.

Dr. Bhan: Like with any therapy, the main limiting factor is side effects. With the vitamin D agents, the main side effect has been an undesirable increase in phosphorus levels. One aspect of management that has become increasingly clear over the past few years is that phosphate seems to be a particularly bad culprit in the development of complications in kidney disease. High phosphorus levels have been associated with increased mortality. Phosphorus appears to drive fibroblast growth factor 23, which has been strongly associated with bad outcomes in kidney disease. The concern with treating secondary hyperparathyroidism with activated vitamin D is that you will end up with worse control of hyperphosphatemia because vitamin D agents increase the absorption of phosphorus. That’s been a big challenge because you can’t just give as much vitamin D as you want to control secondary hyperparathyroidism. One of the new agents that has come on the scene in the past decade is

Dr. Bhan recently gave a presentation on the management of secondary hyperparathyroidism (SHPT) at the National Kidney Foundation’s 2016 Spring Clinical Meetings in Boston. He spoke with Renal & Urology News about the challenges in treating SHPT. What is the current status of SHPT management?

Dr. Bhan: I think there is a lot of confusion right now. In large part, that is driven by uncertainties surrounding the benefits of vitamin D. There was a lot of excitement over the past decade about the potential effects of vitamin D beyond just the control of secondary hyperparathyroidism. Its role in secondary hyperparathyroidism has been pretty stable for some time, but there was a lot of enthusiasm for using it beyond SHPT management because a number of observational studies had suggested there were potential benefits to the cardiovascular system, survival, and the immune system. So its potential use had broadened beyond just the traditional role. In the last couple years, there have been several randomized controlled trials suggesting that all those benefits that looked promising in observational studies and animal studies did not materialize when tested under the rigor of a randomized controlled trial.

The mainstay of therapy in secondary hyperparathyroidism has been the active vitamin D compounds: calcitriol, paracalcitol, doxicalciferol. The question has been whether there has been an additional benefit in using the so-called nutritional vitamin D’s, and those are the precursors to active vitamin D—ergocalciferol and cholecalciferol—which are used in the general population. The hope was that those formulations would provide additional benefit on top of the active vitamin D in advanced kidney disease. While they may have some effect early in

chronic kidney disease, it doesn’t look like those additional effects have been proven in advanced kidney disease.

There is a new agent, calcifidiol, which is partially activated vitamin D. It does seem to have some benefit in relatively early kidney disease, but we don’t know if it will have benefit in later kidney disease.

Where do you think nephrologists fall short in their management of SHPT?

Dr. Bhan: We need to look not just at absolute [parathyroid hormone] values but at trends, and sometimes we can miss patterns until someone has severe secondary hyperparathyroidism. The control of phosphorus is underappreciated. This can have effects on secondary hyperparathyroidism separate from the effects of vitamin D treatment. If phosphorus levels get too high, this can stimulate the parathyroid glands and it’s going to be more difficult to control the secondary hyperparathyroidism. So control of phosphorus is something that should be considered part of the strategy to control secondary hyperparathyroidism.

Newer phosphate binders have emerged on the market recently, but whether there’s any difference in the efficacy of these binders—iron-based binders, for example, compared to the older binders—is not totally clear.

One thing I’ve found, at least, is that a major limiting factor in the treatment of hyperphosphatemia is peoples’ ability to tolerate specific binders. Certain people seem to be able to tolerate some classes compared to other classes. So having more options available is always helpful

cinacalcet. How to combine vitamin D with cinacalcet, or when to use one versus the other, is still an evolving area, and there haven’t been a lot of studies looking at how to best combine those therapies.

What about the role of calcium-containing medications or supplements?

Dr. Bhan: The main concern has been that the calcium that we give may not end up just suppressing the parathyroid glands. It may deposit in tissues and cause vascular calcification, including calcific uremic arteriolopathy (CUA).

A study by my colleague Dr. [Sagar] Nigwekar found that CUA is increasing, and one of the associated factors is the use of vitamin D. In our attempt to control secondary hyperparathyroidism, we may be inadvertently increasing vascular calcification. That’s a big concern. Cinacalcet can be a very useful agent in someone who you are worried about giving too much calcium, or calcium levels getting too high, or phosphorus levels getting too high. It might be an important adjunctive treatment, perhaps in combination with vitamin D to bring down PTH levels.

Have you been testing combinations?

Dr. Bhan: Not as part of a research study. In my patient population, there have been several patients who I’ve started on cinacalcet as an additional agent, and I have found it useful, but there are not a lot of data to guide us in this area. We need more studies looking at how best to combine these therapies and whether it’s really an optimal strategy for controlling the adverse effects.

At what point should a patient be referred for a parathyroidectomy?

Like with any therapy, the main limiting factor is side effects. ­—Ishir Bahn, MD, MPH

Dr. Bhan: I would first try cinacalcet because that has essentially become a chemical parathyroidectomy. But there are patients who either early on or after some time do not seem to respond to cinacalcet alone. With patients who have extremely high PTH levels, I would be very concerned about effects on bone and mineral metabolism, and would consider a parathyroidectomy in that situation. In addition, I would look for evidence where the bone disease has become problematic. I would have a lower threshold for considering parathyroidectomy for patients who develop fractures or who have advanced bone disease. n

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Low HRQoL Found to Worsen CKD Patient Outcomes AMONG PATIENTS with mild to moderate chronic kidney disease (CKD), those who report low healthrelated quality of life (HRQoL) have higher risks of cardiovascular events and death, a new study finds.

Anna C. Porter, MD, of the University of Illinois at Chicago, and colleagues

analyzed data from 3,837 patients with CKD stages 2–4 from the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic Chronic Renal Insufficiency Cohort (H-CRIC), robust and ethnically diverse prospective studies.

Investigators measured HRQoL at baseline using the Kidney Disease

and Quality of Life (KDQOL-36) questionnaire, which gauges kidney disease-specific domains. The questionnaire includes 5 subscales: a mental component summary (e.g., depression and anxiety, energy level, and social activities); physical component summary; burden of kidney disease

(e.g., the degree to which fluid or diet restrictions are taxing); effects of kidney disease (how CKD interferes with daily life); and symptoms and problems of kidney disease (e.g., lack of appetite and shortness of breath).

The primary outcomes were CKD progression (defined as a 50% decline from baseline in estimated glomerular filtration rate [eGFR] or ESRD); cardiovascular (CV) events (myocardial infarction, stroke, heart failure, atrial fibrillation, or revascularization procedure for peripheral arterial disease); and all-cause mortality.

Factors associated with low HRQoL The investigators found that both sociodemographic and clinical factors were associated with low HRQoL at baseline. Patients of younger age, low education, and female gender reported worse quality of life on KDQOL-36.

Those with diabetes, vascular disease, congestive heart failure, obesity, and lower eGFR also complained of low HRQoL, according to investigators.

Researchers observe an increased risk of cardiovascular events and death.

During a median follow-up of 6.2 years, the researchers observed higher crude rates of all outcomes across all 5 subscales. In fully adjusted models, however, low scores on 3 subscales— physical component summary, effects, and symptoms—were associated with higher risk of CV events and death.

Low scores on the mental component summary were associated with higher risk of death only.

“Collectively, these findings underscore the importance of heightened attention to HRQoL in patients with low socioeconomic status, certain comorbid diseases, and more advanced CKD,” Dr. Porter and colleagues wrote in a paper published online in the Clinical Journal of the American Society of Nephrology.

The investigators speculated that poor scores on mental health may reflect unhealthy lifestyle choices, such as smoking or medication noncompliance, which might contribute to mortality. Likewise, they noted, physical inactivity might be partly to blame for CV events and death. n

www.renalandurologynews.com JUNE/JULY 2016

New PCa Grading System Independently Validated Patients’ risk of adverse outcomes are predicted more accurately, study finds 4 + 3 = 7, 4 + 4 = 8, and 9–10). The researchers performed separate analyses using biopsy grade and RP grade for group assignment. The primary outcome was biochemical recurrence-free survival (bRFS). The study population had a median follow-up of 52.7 months.

The 5-year actuarial bRFS rates for biopsy-grade groups 1– 5 were 94.2%,

© IMAGE COURTESY OF JONATHAN I. EPSTEIN, MD

BY JODY A. CHARNOW RESEARCHERS have independently validated a proposed new grade-group system for predicting prostate cancer (PCa) outcomes, according to a new report published online ahead of print in BJU International.

The system, which was first proposed in 2013, classifies PCa patients into 5

A proposed system places Gleason 6 prostate cancer (above) in the lowest-risk grade group.

groups based on the current application of the Gleason score, which has been modified several times since its inception.

Patients at lowest risk for adverse outcomes are placed into group 1 (Gleason score 6 or less), and those at highest risk are placed in group 5 (Gleason score 9–10). An important feature of the new system is the distinction made between Gleason 3+4 and 4+3 tumors. Patients with the 3+4 pattern are placed in group 2, whereas those with 4+3 pattern are placed in the higher-risk group 3.

In a study of 694 men who underwent radical prostatectomy (RP), Daniel E. Spratt, MD, and colleagues at the University of Michigan in Ann Arbor demonstrated a step-wise, increased risk of biochemical recurrence (BCR) in these groupings based on both biopsy and RP grade.

“This new system may allow for improved prognostication, and these results support their clinical implementation,” the authors concluded.

For the study, Dr. Spratt’s group placed patients into groups 1– 5 according to Gleason grades (6 or less, 3 + 4 = 7,

89.2%, 73.1%, 63.1%, and 54.7%, respectively. The 5-year actuarial bRFS rates based on RP grade groups were 96.1%, 93%, 74%, 64.4%, and 49.9% for grade groups 1–5, respectively.

In adjusted analyses, compared with patients in biopsy grade group 1, those in grade groups 2, 3, 4, and 5 were at 1.98, 4.20, 5.57, and 9.23 times higher risk of BCR. Compared with patients in RP group 1, those in RP grade groups 2, 3, 4, and 5 were at 2.0, 5.2, 5.9, and 10.4 times increased risk, respectively.

The 5-grade-group system had a higher prognostic discrimination than the widely used 3-tier system (Gleason 6 vs.

7 vs. 8–10), according to the investigators.

The new grading system has been endorsed by the International Society of Urological Pathology and accepted by the World Health Organization. “Our present study provides an independent external validation of this new grading schema from a distinct surgical cohort.”

The original Gleason score, which was introduced in the 1960s, used PCarelated death as an outcome, whereas the new system uses BCR.

In an interview earlier this year with Renal & Urology News, Jonathan I. Epstein, MD, who initially proposed the 5-grade system in 2013 based on a study performed at Johns Hopkins University in Baltimore, said the new system distills pathologic findings into the key differences in prognosis “that can be intuitive to both patients and clinicians.”

An important feature of the new system is the placement of Gleason score 6 cancers into grade group 1. Dr. Epstein pointed out that patients with Gleason score 6 disease often believe their prognosis is worse than it is because Gleason score 6 is half way along the Gleason scoring scale of 2 to 10, when, in fact, a Gleason score 6 tumor is the lowest-grade cancer currently assigned with an excellent prognosis.

“The study by Spratt et al. is one of a growing number of studies that validate the new grading system and helps to support its routine adoption, initially to be used in concert with the Gleason grading system,” Dr. Epstein said in a recent e-mail.

In addition, he noted that a large multinational study of more than 20,000 men he led also supports the concept of the 5 grade-group system. The study was published this year in European Urology.

A weakness of the study by Dr. Spratt and colleagues, which they acknowledged, was that some patients were graded prior to 2005, when grading was different from what is currently recommended, Dr. Epstein said. Even in the pre-2005 cohort, however, the 5 grade groups were distinct in their discrimination of the risk of biochemical recurrence, although the post2005 graded specimens showed better discrimination.

“Another weakness of the Spratt study, as well as our initial study proposing the new grading system and our subsequent validation study, was that the outcome was BCR, and not death due to prostate cancer,” Dr. Epstein said.

More recently, a report published online ahead of print in the British Journal of Cancer by Daniel M. Berney, MD, and colleagues, documented that the new 5 grade-group system correlates with PCa-specific mortality in a cohort of men treated conservatively. n

Renal & Urology News 15

PCNL Use Increasing, Data Show PERCUTANEOUS nephrolithotomy (PCNL) procedures nearly doubled in incidence in the United States from 1998 to 2011, according to a new study.

During these 2 decades, the overall annual procedure rate increased from 17 to 31 per million adults, a research team led by Mitchell R. Humphreys, MD, of Mayo Clinic Hospital in Phoenix, concluded in a paper published online ahead of print in Urology.

“The increase in percutaneous nephrolithotomy is likely attributable to several factors, including the overall increase in stone prevalence and the more complex nature of affected patients over time,” the authors noted.

The investigators added that the increasing costs of stone disease management should encourage the use of PCNL as well as boost training and further advances in percutaneous stone treatment. In addition, they noted that PCNL “offers a more definitive surgical treatment and higher stone-free rate compared with other treatment modalities.”

Procedure incidence rose from 17 to 31 per million adults from 1998 to 2011.

Dr. Humphreys and his colleagues analyzed data from the Nationwide Inpatient Sample and identified 105,180 patients who underwent PCNL from 1998 to 2011. The incidence of PCNL increased from 17 to 30 per million among adult males and 17 to 32 per million among adult females. The incidence increased from 39 to 70 per million adults among individuals aged 18–64 years and from 52 to 113 per million among those older than 65, according to the researchers.

Dr. Humphrey’s team noted that the increase in PCNL use “has important implications for planning research, developing percutaneous nephrolithotomy technology, and training physicians. On a larger scale, knowledge of percutaneous nephrolithotomy trends can help tailor stone management to the evolving patient population, one that may require more definitive stone management beyond what is attainable with less-invasive techniques.” n

16 Renal & Urology News

■ AUA 2016, San Diego

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American Urological Association 2016 Annual Meeting

Low-Carb Diet May Ease ADT Effects PCa patients on an extreme carbohydrate-restricted diet showed improvement in insulin sensitivity

PUL Benefits For BPH/LUTS Confirmed TWO NEW STUDIES support the use of prostatic urethral lift as a surgical option for men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH).

In the first prospective, randomized trial comparing prostatic urethral lift (PUL) and standard transurethral resection of the prostate (TURP), 46% of the 40 BPH/LUTS suffers who underwent PUL responded to the BPH6 primary endpoint at 2 years compared with 22% of 35 men who underwent TURP, Jens Sønksen, MD, PhD, of Herlev Hospital in Herlev, Denmark, and colleagues reported. The BPH6 endpoint measures symptom relief, quality of recovery, erectile function, ejaculatory function, continence preservation, and safety.

With respect to individual components of BPH6, PUL resulted in superior quality of recovery and ejaculatory function, whereas TURP was superior at reducing International Prostate Symptom Score (IPSS) and improving peak flow rate.

side effects of hormonal therapy,” Dr. Freedland told Renal & Urology News.

The prospective Carbohydrate and Prostate Study I (CAPS1) randomized 42 men starting ADT to follow a low-carbohydrate diet (20 total grams per day) or a standard diet (controls).

To be included in the study, the men had to be overweight and not diabetic.

The primary outcome was the difference between 6-month and baseline (pre-ADT) insulin sensitivity as measured by homeostasis model assessment (HOMA) between study arms.

Decreases in insulin sensitivity can progress to diabetes. Dr. Freedland noted that hormonal therapy increases the risk of diabetes by 40%.

Of the 42 men, 2 dropped out before the baseline visit (1 in each arm). Thus, of the 40 men who completed the baseline

PUL and TURP did not differ significantly in their effects on erectile function, continence, and safety.

The new findings are consistent with 12-month results reported last year in European Urology (2015;68:643-652).

PUL involves placement of small, permanent metallic implants into the lateral lobes of the prostate that retract the lobes and thereby reduce urinary obstruction.

The second study, the largest and longest trial of the PUL procedure, showed that PUL patients on average achieve rapid and clinically meaningful LUTS relief that can be sustained to 4 years. Claus Roehrborn, MD, of the University of Texas Southwestern Medical Center in Dallas, and colleagues prospectively studied 206 patients randomly assigned to undergo PUL (140 patients) or a sham control (66 patients).

Compared with controls, the PUL patients had an average reduction in IPSS was 44% by 1 month, 50% at 3 months, 47% at 1 year, and 46% at 4 years, the researchers reported.

Peak flow rates increased by 64% at 3 months, 59% at 1 year, and 69% at 4 years. PUL patients experienced little morbidity, and sexual function with respect to erection and ejaculation was preserved, they noted. n

Avoiding carbohydrates during androgendeprivation therapy may prevent diabetes.

visit, 14/19 (79%) in the low-carbohydrate group and 20/21 (95%) in the control arm completed the 6-month study. A few men were excluded due to missing baseline or 6-month blood draws. From baseline to 3 months after ADT initia-

tion, the low-carbohydrate group experienced a mean 19% decrease in HOMA, whereas the control arm had a mean 7% increase, a significant between-group difference. At the 6-month mark, the low-carbohydrate group had a mean 4% decrease in HOMA and the controls had a 36% increased, but the difference was not significant.

In addition, the low-carbohydrate group experienced a mean 9.3 kg weight loss at 6 months, whereas those in the control group had a mean 1.3 kg weight gain, Dr. Freedland reported.

During the 6-month period, bone mineral content increased 0.1% in the lowcarbohydrate arm and declined 2.3% in the control group. Fat body mass decreased 16.2% in the low-carbohydrate arm and increased 11% in the control arm. n

Elevated PSA Levels Predict Increased Risk of LUTS MEN WITH mild or no lower urinary

6 ng/mL had a 49% increased risk of

tract symptoms (LUTS) but who have

incident LUTS in multivariable analysis.

PSA levels above 6 ng/mL are at

A baseline PSA level of 4.1–6.0 ng/mL

increased risk of developing incident

was associated with a nonsignificant

LUTS believed to be secondary to

33% increased risk.

benign prostatic hyperplasia (BPH), investigators reported.

Tom Feng, MD, a urology resident at Cedars-Sinai Medical Center in Los Angeles, and colleagues analyzed

Of the 3,060 men in the study, 1,534 (50.1%) were in the placebo arm of the REDUCE trial and 1,526 (49.9%) were in the dutasteride arm.

“BPH poses a significant burden to

data from 3,060 men in the REDUCE

public health,” Dr. Feng told Renal &

[Reduction by Dutasteride of Prostate

Urology News. “Studies have looked at

Cancer Events] trial, a 4-year random-

risk factors for development of LUTS,

ized, placebo-controlled study looking

such as increased prostate size. We

at the effect of dutasteride on the risk of

know that prostate size correlates with

prostate cancer in biopsy-negative men.

PSA, but the relationship of PSA to the

Of these men, 329 (10.7%) progressed

development of LUTS in asymptomatic

to incident LUTS, defined as the first

men is unknown. We found that baseline

report of medical treatment, surgery,

PSA was a significant predictor of inci-

or sustained clinically significant LUTS

dent LUTS. Higher PSA was associated

(2 reports of an International Prostate

with a greater risk of developing signifi-

Symptom Score greater than 14).

cant LUTS presumed due to BPH. Our

Compared with men who had a

study reveals that men with greater PSA,

baseline PSA level of 4 ng/mL or less,

especially greater than 6, are potential

those with a baseline PSA level above

candidates for closer follow-up.”

© THINKSTOCK

BY JODY A. CHARNOW CARBOHYDRATE-restricted diets may be effective in ameliorating adverse effects associated with androgen-deprivation therapy (ADT) for prostate cancer, according to a new study.

Study results suggest that a very lowcarbohydrate diet (phase I induction phase of the Atkins diet) in men starting ADT can result in significant loss of body weight and fat mass, protection against osteoporosis, and improvement in insulin sensitivity, said lead investigator Stephen J. Freedland, MD, Professor of Urology at Cedars-Sinai Medical Center in Los Angeles and Director of the Center for Integrated Research on Cancer and Lifestyle.

“In summary, we have an intervention—an extreme low carbohydrate diet—that actually blocks a lot of the

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American Urological Association 2016 Annual Meeting

Salvage RP Offers Good Long-Term Outcomes SALVAGE RADICAL prostatectomy (SRP) offers good long-term oncologic outcomes among patients who experience recurrence of prostate cancer (PCa) after radiotherapy, researchers concluded.

Antoni Vilaseca, MD, and colleagues at Memorial Sloan-Kettering Cancer Center in New York, studied 251 men with a median age of 65 years who underwent SRP for biopsy-proven

radiorecurrent PCa after external beam radiation therapy, brachytherapy, or both. Of these, 221 underwent open SRP and 30 had minimally invasive surgery (MIS). In addition to long-term

oncologic outcomes of SRP, the investigators looked at whether MIS can reduce the incidence of bladder neck contracture (BNC).

The 5- and 10-year cancer-specific survival rates were 92% and 78%, respectively, and the 5- and 10-year overall survival rates were 87% and 64%, respectively, the investigators reported. The 1- and 3-year BNC-free survival rates were 81% and 73%, respectively. Patients who underwent MIS had significantly better BNC-free survival compared with those who had open surgery.

Extraprostatic extension, lymph node invasion, seminal vesicle invasion, and positive surgical margins were present in 69%, 22%, 32%, and 17% of patients, respectively, according to the investigators. Fifty patients died, 27 from PCa. n

Bodybuilder Death Rate 34% Higher BODYBUILDERS HAVE have a mortality rate 34% higher than that of the age-matched U.S. male population, data show.

Daniel Gwartney, MD, and colleagues at Baylor College of Medicine in Houston identified 1,578 professional male bodybuilders who competed from 1948 to 2014. Complete mortality data was available for 597.

Of the 597 men, 58 (9.7%) were reported dead. Only 40 deaths were expected in this population based on age-matched data, for a standardized mortality rate of 1.34. The mean age of death was 47.7 years (range 26.6 – 75.4 years). The researchers found no significant difference in mortality rates above age 50 years.

Although the cause is unclear, the researchers noted, the increased mortality supports the possibility that use of performance-enhancing drugs, such as high-dose testosterone, and unique competitive training may contribute to deaths among younger professional bodybuilders. n RU_7x10_Legal.indd 1

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Renal & Urology News 19

Bladder Cancer Guidelines Updated New AUA/SUO recommendations promise to enable clinicians to provide more individualized patient care or what the implications are.”

By the time tumors become muscle invasive, 50% of patients already have microscopic metastatic disease, he said.

“I think the guidelines just do a very nice job of creating algorithms that are easy to follow, easy to understand for all urologists.”

New bladder cancer guidelines incorporate the use of blue light cystoscopy (Cysview). The images show bladder tissue using white light alone (left) and with blue light as an adjunct (right).

Urinary biomarkers The guidelines also address the use of urinary biomarkers following a diagnosis of bladder cancer. In surveillance of NMIBC, the guidelines strongly recommend that clinicians not use urinary biomarkers in place of cystoscopic evaluation. Clinicians should not routinely use a urinary biomarker or cytology during surveillance in a patient with a history of low-risk cancer and normal cystoscopic findings. In a patient with NMIBC, a clinician may use biomarkers to assess response to intravesical bacillus Calmette-Guérin (BCG) and adjudicate equivocal cytology.

For NMIBC patients who underwent an incomplete initial resection (not all visible tumor treated), clinician should perform repeat TUR or endoscopic treatment of all remaining tumor if technically feasible.

Intravesical therapy For patients with known or suspected low- or intermediate-risk tumors,

Gary D. Steinberg, MD

­clinicians should consider administering a single postoperative instillation of intravesical chemotherapy, such as mitomycin C or epirubicin, within 24 hours of TUR. Clinicians should not use postoperative chemotherapy for patients with a suspected perforation or extensive resection.

In addition, clinicians should not administer induction intravesical therapy in low-risk patients.

For intermediate-risk patients, clinicians should consider administering a 6-week course of induction intravesical chemotherapy or immunotherapy.

The guidelines strongly recommend administration of a 6-week induction course of BCG to high-risk patients with newly diagnosed carcinoma in situ, high-grade T1, or high-risk Ta urothelial carcinoma.

Gary D. Steinberg, MD, Director of Urologic Oncology at the University of Chicago Medical Center, praised the new guidelines, saying they provide urologists with standardized algorithms that can enhance management of NMIBC. “One of the major problems we have with the management of non-muscleinvasive bladder cancer in the United States is that it is all over the map,” Dr. Steinberg told Renal & Urology News.

‘Red flags’ missed Dr. Steinberg, who was not involved in the development of the new guidelines, commented that, too often, urologists do not get serious about bladder cancer until it is muscle invasive. Patients show red flags before the cancer advances to that point, he said, but if patients are not managed according to a standardized algorithm, “you never learn what these red flags are, or what they mean,

Blue light cystoscopy Urologists could do a better job diagnosing and staging of tumors, which is important for charting the management course, Dr. Steinberg said. Enhanced detection with cystoscopy, notably blue light cystoscopy—which is mentioned for the first time in the bladder cancer guidelines—is a key element in the patient workup, he said.

Blue light cystoscopy (Cysview, Photocure) was FDA approved in 2010 in the United States, but has been adopted slowly. It involves the use of hexaminolevulinate HCL, which enhances visual contrast between benign and malignant cells compared with white light cystoscopy.

Induction intravesical therapy should not be given to patients with low-risk disease.

“Once you begin using it, to me, it’s like the difference between watching television in black and white versus watching in color and high-def,” Dr. Steinberg said.

An important aspect of blue light cystoscopy is its specificity for bladder cancer, which sets it apart from other cystoscopic technologies, such as narrowband imaging (NBI). NBI is specific for blood vessels and is used to detect hypervascularity, which is assumed to indicate bladder cancer. That is not necessarily the case, Dr. Steinberg said, especially in patients who have had prior cystoscopies and biopsies, inflammation, infection, and intravesical therapy.

Blue light cystoscopy enhances surgeons’ ability to do a better transurethral resection so that patients are diagnosed and staged more accurately.

Improved resection, Dr. Steinberg said, can help in deciding on subsequent prophylactic measures, such as intravesical BCG. n

IMAGES COURTESY OF PHOTOCURE

BY JODY A. CHARNOW UPDATED CLINICAL practice guidelines for the diagnosis and management of non-muscle-invasive bladder cancer (NMIBC) may enable clinicians to provide patients with more individualized treatment.

The guidelines, developed by the American Urological Association (AUA) and the Society for Urologic Oncology (SUO), make 38 recommendations regarding diagnosis, risk stratification, surgical intervention, and intravesical therapy.

“We’ve come a long way in understanding bladder cancer and how to treat and manage this disease and this guideline takes our knowledge one step further by refining our approach and allowing us to provide more individualized treatment to our patients,” said Sam S. Chang, MD, said in an AUA press release. Dr. Chang, of Vanderbilt University Medical Center in Nashville, Tenn., led the AUA/SUO panel that developed the guidelines.

With respect to diagnosis, the guidelines state that at the time of transurethral resection (TUR) of suspected bladder cancer, a clinician should perform a thorough cystoscopic examination of a patient’s entire urethra and bladder that evaluates and documents tumor size, location, configuration, number, and mucosal abnormalities. At initial diagnosis, when technically feasible, clinicians should perform complete visual resection of the tumor. As part of an initial evaluation of a bladder cancer patient, clinicians should perform upper urinary tract imaging.

“In a patient with a history of NMIBC with normal cystoscopy and positive cytology, a clinician should consider prostatic urethral biopsies and upper tract imaging, as well as enhanced cystoscopic techniques (blue light cystoscopy, when available), ureteroscopy, or random bladder biopsies,” the guidelines state.

On the basis of expert opinion, the guidelines recommend that clinicians perform the first surveillance cystoscopy with 3–4 months after completion of the initial evaluation and treatment of a patient with NMIBC. At the time of each cancer occurrence or recurrence, clinicians should assign a clinical stage and classify a patient as low-, intermediate-, or high-risk, according to the guidelines.

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Calciphylaxis Risk Factors Identified Largest study of calciphylaxis to date links the condition to warfarin use, recurrent skin trauma

BY JODY A. CHARNOW RESEARCHERS WHO have conducted the largest study to date on calciphylaxis in hemodialysis (HD) patients have identified risk factors for this life-threatening condition, findings that could be useful in directing the design of preventive strategies, according to a paper published online ahead of print in the Journal of the American Society of Nephrology.

In a study of 1,030 HD patients with newly diagnosed calciphylaxis, also called calcific uremic arteriolopathy (CUA), Sagar U. Nigwekar, MD, MMSc, of Harvard University Medical School and Massachusetts General Hospital in Boston, and colleagues found that warfarin use, diabetes mellitus, higher body mass index (BMI), higher levels of serum calcium, phosphorus, and parathyroid hormone (PTH), and use of nutritional vitamin D and cinacalcet at the time of HD initiation were independently associated with increased risk of calciphylaxis development in multivariable analysis.

The study cohort was 67% female, 49% white, 28% black, and 23% other races. Calciphylaxis patients were matched by age, sex, and race to 2,060 HD patients without calciphylaxis. The median duration between HD initiation and development of calciphylaxis

Sagar U. Nigwekar, MD, MMSc

was 925 days. The mortality rates were 27% and 45% at 6 and 12 months after calciphylaxis diagnosis, respectively.

The median time to death was 151 days from calciphylaxis diagnosis.

Warfarin use at HD initiation was associated with a greater than 3-fold increased risk of calciphylaxis, and diabetes was associated with a greater than 2-fold increased risk.

“Now we can confidently state that warfarin is likely the most dominant risk factor for calciphylaxis,” Dr. Nigwekar told Renal & Urology News during an interview at the National Kidney Foundation’s 2016 Spring

Sodium Thiosulfate Promising Small case series suggest that sodium thiosulfate could be an effective treatment for calciphylaxis, a rare but potentially fatal condition seen mostly in dialysis patients. No standardized therapy exists.

In a recent study of 8 calciphylaxis patients (2 without related renal risk factors) who received sodium thiosulfate in different dosing schemes, 4 achieved complete healing of skin lesions, and 2 had stabilization of disease while experiencing pain relief, Pieter Bourgeois, MD, and Petra De Haes, MD, of University Hospital Leuven, Leuven, Belgium, reported in the Journal of Dermatological Treatment. In the 2 remaining patients who had disease progression, sodium thiosulfate treatment resulted in analgesia. Overall, 7 patients had some benefit from the drug, although 4 patients eventually died from causes related to calciphylaxis.

Promising results also emerged from a recent French study of 4 end-stage renal disease patients with calciphylaxis. All patients experienced complete resolution of pain and trophic disorders following treatment with sodium thiosulfate, Stéphanie Malbos, MD, Hôpital Lariboisière in Paris, and colleagues reported in Joint Bone Spine (2016;83:89-92). Two patients experienced nausea and vomiting. No recurrences developed during a follow-up of 5–17 months after treatment discontinuation.

Clinical Meetings in Boston, where he chaired a workshop focusing on calciphylaxis risk factors, pathogenesis, diagnosis, and treatment.

Warfarin use, he said, is a potentially modifiable risk factor. He pointed out that the decision to place patients on warfarin is mainly made by a cardiology team, and nephrologists—who could provide input about potential calciphylaxis risk—are not directly involved in the process.

At HD initiation, the risk of calciphylaxis increased by 38% for each 5 kg/m2 increment in BMI, 33% with each 1 mg/dL increment in albumincorrect serum calcium, 11% with each 1 mg/dL increment in serum phosphorus, and 12% with each 100 pg/mL increment in PTH. The use of nutritional vitamin D and cinacalcet at HD initiation each was associated with a 2-fold increased risk.

Additionally, compared with diabetics receiving no insulin injections, patients who injected insulin 1 or 2 times per day had 49% increased risk, whereas those injecting 3 times per day and more than 3 times per day had 88% and greater than 3.5-fold increased risk, respectively of calciphylaxis at the typical sites of insulin injections suggesting a possible relationship between recurrent skin trauma and calciphylaxis risk.

Dr. Nigwekar’s team concluded that “risk factors for CUA are present months to years prior to CUA development in patients receiving hemodialysis. CUA has a predilection for white, female, diabetic, and obese patients and, especially in these patients, research and clinical attention should focus on avoiding additional CUA triggers such as vitamin K antagonism or deficiency, skin trauma, and mineral bone deficiencies.”

To conduct this large-scale investigation of calciphylaxis, a rare disease, Dr. Nigwekar collaborated with investigators from the Fresenius Medical Care North America, a large dialysis organization and through this collaboration could identify more than 1,000 patients diagnosed with calciphylaxis.

The underlying mechanism by which warfarin is believed to increase calciphylaxis risk is via its antagonist effect on vitamin K, Dr. Nigwekar said. In addition to its key role in activating clotting factors, vitamin K activates matrix

Gla protein (MGP), which blocks calcification. When warfarin inhibits vitamin K, it also impairs MGP activation, potentially promoting calcification, including calciphylaxis, he explained.

Even without warfarin, calciphylaxis patients have severe vitamin K deficiency, Dr. Nigwekar pointed out, adding that early research is showing that the level of active MGP is reduced in calciphylaxis patients.

In 2015, Dr. Nigwekar and his collaborators initiated a randomized, placebo-controlled proof-of-concept clinical trial to test whether vitamin K supplementation could be a potential treatment for calciphylaxis.

No widely accepted disease-modifying treatment exists for calciphylaxis, Dr. Nigwekar said, but sodium thiosulfate—a drug approved for treating cyanide toxicity—has emerged in small studies as a promising therapy. The drug breaks down calcium phosphate,

Supplementation with vitamin K is being tested as a potential treatment. the salt deposited in tissues in calciphylaxis. It makes the calcium more soluble so it can be eliminated in the urine. “At our center, we use it because there is nothing else available at this point,” Dr. Nigwekar said.

“Although not everyone responds, we have seen some dramatic successes. The main improvement that we see, which could be pretty quick, in the first 2 or 3 weeks, is improvement in pain. However, a randomized controlled trial is needed to ascertain the efficacy of sodium thiosulfate for calciphylaxis” Sodium thiosulfate is generally well tolerated, he said. The main symptomatic side effects include nausea and vomiting.

An important consideration in the use of the drug is the delivery of a high sodium load. Each 25-gram dose of sodium thiosulfate that patients receive with dialysis gives them around 5 grams of sodium, Dr. Nigwekar said.

In addition, sodium thiosulfate breaks down into thiosulfuric acid, which can contribute to acidosis, he said. n

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Renal & Urology News 21

CKD Risk in Blacks Linked to Smoking Current smokers had an 83% higher incidence of rapid renal function decline compared with never smokers Additionally, the investigators found the more cigarettes smoked, the greater the kidney injury. African Americans who reported currently smoking up to 19 cigarettes daily had a 75% greater incidence of rapid renal decline than those who never smoked, whereas those who smoked more cigarettes had a 97% greater incidence, according to results published online in the Journal of the American Heart Association.

Higher rates of chronic kidney disease (CKD) among African Americans have been attributed to hypertension, obesity, and diabetes. Dr Hall and his team also investigated the role of systemic inflammation. Current and past cigarette smokers, respectively, had 38% and 10% higher levels of C-reactive protein—a marker of systemic inflammation—compared with never smokers. The researchers again observed a dose-dependent effect. Several cohort studies, such as the Chronic Renal Insufficiency Cohort

Niacin Lowers Phosphorus in Advanced CKD Patients BOSTON—Niacin may be an option

Commenting on the study, Csaba P.

for phosphate control in patients with

Kovesdy, MD, chief of nephrology at

advanced chronic kidney disease

the Memphis VA Medical Center and

(CKD), according to data presented at

The Fred Hatch Professor of Medicine

the National Kidney Foundation’s 2016

at the University of Tennessee Health

Spring Clinical Meetings.

Science Center in Memphis, stated

A team at Edward Hines, Jr. VA

that the effects of niacin on phospho-

Hospital in Hines, Ill., led by Nicholas

rus levels are known and accepted,

J. Burge, PharmD, retrospectively

but the new study, which analyzed a

studied 50 patients with advanced

real-life scenario in the United States,

CKD: 25 treated with niacin and 25

is novel.

controls matched according to CKD

“The study confirms that a low

stage (average age 72 and 74 years,

number of patients use niacin in clini-

respectively). After excluding non-

cal practice, which limits the power

adherent patients, the average serum

of observational studies like the one

phosphorus level over the course of 6

presented,” said Dr. Kovesdy, who has

months was significantly lower in the

conducted research on phosphorus

niacin than the control arm (3.4 vs. 4.2

control in CKD patients but was not

mg/dL), the researchers reported in

involved in this investigation.

a poster presentation. They found no

The limited size makes it impos-

significant association between niacin

sible to account for the presence of

dose and phosphorus level.

confounders, Dr. Kovesdy said. He

Dr. Burge and his colleagues stated

pointed out that the control arm had a

that niacin has the advantages of daily

higher proportion of patients receiving

administration without regard to meals

vitamin D analogues, which could cause

and generic availability.

an increase in serum phosphorus. n

Smoking may impair renal function in blacks.

(CRIC), the Framingham Offspring cohort, and the Multi-Ethnic Study of Atherosclerosis (MESA) have shown similar associations. Potential mechanisms include oxidative stress, endothelial dysfunction, and atherogenesis.

Short Sleep Duration Ups Renal Risk SHORT SLEEP DURATION is associated with an elevated risk of proteinuria, a finding that could impact the clinical management of chronic kidney disease (CKD), researchers concluded from a new meta-analysis.

Wisit Cheungpasitporn, MD, of Mayo Clinic in Rochester, MN, and colleagues analyzed data from 9 observational studies that included 289,272 individuals. They found that short sleepers had a 1.47 times increased risk of proteinuria compared with nonshort sleepers. The study found no significant association between short sleep duration and CKD, which most studies defined as an estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2. Most of the studies included in the review and meta-analysis defined short sleep duration as less than 4–5 hours of sleep per night.

Proteinuria is a strong predictor of clinical progression of CKD. In patients with CKD, it may accelerate kidney disease progression to end-stage renal disease (ESRD).

Overall, African Americans are less likely to smoke than Caucasians.

Their metabolism of substances in cigarettes may differ, however. For example, previous research found differences in enzyme CYP2A6-mediated nicotine metabolism between African Americans and Caucasians.

The researchers noted that popular use of menthol-flavored cigarettes has been linked with increased blood concentrations of cadmium, a toxic metal.

Kidney damage has been linked to low level exposure to cadmium.

“We should be aggressive with screening patients who have risk factors for kidney disease by finding out if they smoke and, if so, encourage them to quit or cut back as much as possible if they can’t quit,” Dr Hall said in a press release, “because there does seem to be a dosedependent effect, meaning patients who smoke more are at higher risk for having worsening kidney injury over time.” n

Adequate sleep is critical for regulating body metabolism and various physiologic functions, the authors explained. Some studies have shown association between short sleep duration (less than 7 hours) and co-morbid conditions such as diabetes mellitus, hypertension, obesity, and cardiovascular disease. In addition, they noted that sleep is a key regular of blood pressure and GFR. “During normal sleep, reduced sympathetic activity and increased vagal tone, particularly during non-rapid eye movement sleep, are responsible for the nocturnal dipping of blood pressure associated with sleep,” Dr. Cheungpasitporn’s team wrote. “Thus, reduced sleep duration may lead to sympathetic nervous system stimulation and attenuation of the sleepinduced decrease in blood pressure.”

In a separate study of women in the Nurses’ Health Study published recently in Kidney International, Ciaran J. McMullan, MD, and colleagues found that shorter sleep duration (6 hours or less) was associated with more rapid declines in eGFR. Compared with sleeping 7–8 hours per night, sleeping for 5 or fewer hours and 6 hours per night was associated with a significant 79% and 31% increased odds of a rapid decline in eGFR, respectively, in adjusted analyses. n

© THINKSTOCK

AFRICAN AMERICANS who smoke cigarettes are prone to kidney function decline, a new study finds.

Michael Hall, MD, MS, of the University of Mississippi Medical Center in Jackson, and colleagues looked at renal function decline in 3,648 African American men and women aged 21 to 84 who participated in the Jackson Heart Study, 2000–2004. Among these, 422 reported current cigarette smoking, 659 past smoking, and 2,567 never smoking.

Compared with those who never lit up, current cigarette smokers had an 83% higher incidence of rapid renal function decline, defined as a 30% drop in estimated glomerular filtration rate (eGFR). The finding was significant, even after adjustment for relevant factors such as body mass index, diabetes, hypertension, and cardiovascular disease. The findings corroborate past studies on smoking and kidney function in various populations.

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High-Grade PCa Linked to Greater Comorbidity Burden MULTIPLE COMORBIDITIES at the time of a prostate cancer (PCa) diagnosis is associated with higher biopsy Gleason scores, independent of age, new study findings suggest.

In a study of 1,482 men diagnosed with non-metastatic PCa from 1998 to 2004, Timothy J. Daskivich, MD, Assistant Professor at Cedars-Sinai Medical Center in Los Angeles, and colleagues found that those with 2 and 3 or more comorbidities (Charlson Comorbidity Index scores of 2 and 3+) had a significant 1.8 times greater odds of having a Gleason score of 7 or higher compared with men who had no comorbidities (Charlson score of 0), after adjusting for age, race, clinical stage, PSA level, mobility status, and smoking history.

Gleason 7-10 tumors are more likely in men with a Charlson score of 2 vs. 0.

Specifically, men with Charlson scores of 2 had 1.6 times greater odds of having a Gleason score of 7 (vs. ≤ 6) and 2.8 times greater odds of having a Gleason score of 8–10 (vs. ≤ 6), compared with those with Charlson scores of 0. Men with Charlson scores of 3+ were at 3-fold increased odds of having Gleason 8–10 (vs. ≤ 6) tumors, compared with those with Charlson scores of 0.

“Our data suggest that men with heavier comorbid disease burdens are more likely to have higher-grade prostate cancers at the time of biopsy,” Dr. Daskivich told Renal & Urology News.

Although it might seem reasonable to omit PCa screening in sicker men to avoid overdiagnosis of low-grade tumors, this approach may result in underdetection of high-grade cancers, he said.

“This is problematic since emerging evidence suggests that even men with life expectancies of less than 10 years may benefit from surgery or radiation for high-grade disease,” said Dr. Daskivich, who is Director of Health Services Research for the Department of Surgery at Cedars-Sinai. “The optimal approach involves screening these men but only treating those who need

it, in order to maximize treatment benefit and minimize morbidity.”

The study also showed that, compared with white men, Hispanic men had 57% increased odds of higher

Gleason score, whereas the risk did not differ significantly between white and black men. Clinical stage T2b and T2c disease were associated with a significant 2.3 and 4.9 times increased

odds of higher Gleason scores, respectively, compared with clinical stage T2a disease. Higher PSA and older age also were significantly associated with higher Gleason scores.

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The study by Dr. Daskivich and colleagues adds to the medical literature showing an association between comorbid disease burden and higher risk PCa. In a paper published in April in The Journal of Urology (2016:195:919924), Matthew J. Maurice, MD, of the Cleveland Clinic’s Glickman Urological

and Kidney Institute, and colleagues reported on a study showing that white men younger than 70 years who had a Charlson score greater than 1 had 1.3fold higher odds of upgrading (Gleason score greater than 6) or up staging (T3– T4/N1) at radical prostatectomy (RP) than men with an index of 1 or less.

The study included 29,447 men with low-risk PCa, of whom 449 (1.5%) had a Charlson score greater than 1. At RP, 44% of cases were upgraded or up staged, the researchers reported.

Previously in the same journal (2015;194:343-349), Kathryn T. Dinh, MD, of Harvard Medical School in

Renal & Urology News 23

Boston, and colleagues reported on a study of 10,273 men diagnosed with clinically low-risk disease showing that 44% of them were upgraded and 9.7% were up staged at RP. A multivariable analysis revealed that age, PSA level, and percent positive cores, but not race, was associated with occult advanced disease. n

B:10.25”

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Poverty Associated with Advanced Prostate Cancer POVERTY is associated with an increased risk of advanced stage or aggressive prostate cancer (PCa), regardless of race, according to investigators.

“Among African American men with prostate cancer, poverty appears to increase the likelihood of high-risk B:7.25” disease,” lead researcher Adam Reese, T:7” MD, Chief of Urologic Oncology at S:7”

Temple University School of Medicine in Philadelphia, said. “Impoverished men may be more likely to benefit from intensive prostate cancer screening and early, aggressive treatment.”

Dr. Reese and his colleagues studied 389 African-American PCa patients who underwent radical prostatectomy. The median household income for the cohort was $40,031 (range $14,297–$162,615).

The researchers divided subjects into low- and high-income groups (below and above the median income, respectively). Adverse pathology—defined as Gleason 3+4 disease, stage pT3 or higher tumors, or lymph node involvement—was found in 40.6% of the lowincome group versus 29.1% of the highincome groups, a significant difference between the groups. Significantly greater proportions of patients in the low-income group than the high-income group had seminal vesicle invasion (17.3% vs.

8.4%), positive surgical margins (35.2% vs. 22.4%), intermediate-risk cancer (38.2% vs. 23.6%), and high-risk cancer (18.8% vs. 13.0%). n

Bariatric Surgery May Ease LUTS BARIATRIC surgery can rapidly and B:10.25”

S:10”

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significantly improve storage phase lower urinary tract symptoms (LUTS) in obese men, data suggest.

Asnat Groutz, MD, and colleagues at Tel Aviv Sourasky Medical Center in Israel, prospectively studied 55 obese men who underwent laparoscopic sleeve gastrectomy. Of these, 53 completed all pre- and postoperative questionnaires. Their mean body mass index (BMI) before and 3 months after surgery was 42.8 and 31.3 kg/m2, respectively. Postoperatively, total International Prostate Symptom Score (IPSS) decreased significantly from 5.5 to 2.7, but this change was due to improvement in storage phase LUTS, measured by questions 2 (frequency), 4 (urgency), and 7 (nocturia) of the IPSS questionnaire. The frequency score decreased from 1.39 preoperatively to 0.7 postoperatively. The urgency score decreased from 0.78 to 0.2. The nocturia score decreased from 1.4 to 0.55. The patients also had improvement in sexual function. n

www.renalandurologynews.com JUNE/JULY 2016

Renal & Urology News 25

CKD Progression After AKI Defined Non-recovery of renal function at 3 months is an important predictor, British researchers conclude TWO NEW STUDIES by the same British research team may help to clarify how acute kidney injury (AKI) influences progression of chronic kidney disease (CKD), according to reports presented at the European Renal Association-European Dialysis and Transplant Association 53rd Congress in Vienna.

Researchers led by Nicholas M. Selby, MD, of Royal Derby Hospital in Derby, UK, presented 3-year outcomes from pilot studies preceding the AKI Risk in Derby (ARID) study, a prospective case-control study in a generalized hospitalized population.

One pilot study looked at post-AKI risk factors for CKD progression and found that male gender, diabetes mellitus, and decline in renal function at 3 months independently predicted an increased likelihood of CKD progression at 3 years. The other study demonstrated that even mild episodes of AKI are associated with CKD progression, although few patients reach end-stage renal disease within 3 years.

The risk factor study included 194 patients with a median age of 71 years and mean baseline estimated glomeru-

lar filtration rate (eGFR) of 62.6 mL/ min/1.73 m 2. Of these patients, 138 (71.1%) had AKI stage 1, 31 (16%) had AKI stage 2, and 25 (12.9%) had AKI stage 3. Ninety-one patients (46.9%) had pre-existing CKD and 41 (21%) had diabetes.

At 3 years, CKD progression occurred in 39 patients (24.7%).

Progressors included a significantly higher proportion of men than women (33% vs. 12.5%) and a significantly higher proportion of diabetics (45.7% vs. 17%). The progressors also were significantly older (74 vs. 70 years).

In multivariable analysis, male gender and diabetes were independently associated with 2.9 times and 5.2 times increased odds of CKD progression at 3 years, respectively. In addition, compared with patients who had a 5.22 mL/min/1.73 m2 or greater increase in eGFR at 3 months, those who had an 8.20 mL/min/1.73 m2 or greater decrease in eGFR at 3 months had a significant 28 times increased odds of progression, the investigators reported. Results also showed that recurrent AKI was associated with ongoing CKD progression.

The researchers concluded that nonrecovery of renal function at 3 months is an important predictor of CKD progression, and evaluation at 3 months could be a useful time point as which to perform a patient risk assessment.

Even mild AKI is associated with CKD progression at 3 years, study finds.

For the other study, the investigators identified hospitalized patients with AKI (cases) and without AKI (controls) and matched 300 case-control pairs according to age and baseline eGFR stage. Of the 300 cases, 70%, 16%, and 14% had AKI stage 1, 2, and 3, respectively. The mean eGFR was significantly lower in the AKI group than controls at 3 and 12 months and 3 years. CKD progression was significantly more common in the AKI group than controls at 3 years (23.8% vs. 6.8%). Dr. Selby and his colleagues observed the same trend when only

pairs with stage 1 AKI were examined: CKD progression at 3 years occurred in 23% of cases compared with 8.2% of controls.

AKI occurred significantly more frequently in the AKI than control group during the 3-year follow-up. The investigators observed no significant difference in the proportion of cases and controls experiencing CKD progression between 3 months and 3 years.

Proteinuria and albuminuria occurred significantly more frequently in the AKI group than the control group. At 3 years, 50.7% of cases had albuminuria versus 21.1% of controls. The median albuminto-creatinine ratio was significantly higher in the AKI patients at 3 years (1.8 vs. 0.9 mg/mmol).

Only 2 patients in the AKI group (1.3%) and 3 in the control arm (2%) progressed to a pre-defined renal endpoint (requirement for renal replacement therapy, eGFR less than 15 mL/ min/1.73 m 2, or doubling of serum creatinine). In addition, 20 AKI patients (13.3%) died compared with 16 (10.7%) in the control group. These between-group differences were not statistically significant. n

High Uric Acid Raises Stroke Risk in CKD Patients HIGH URIC ACID LEVELS may increase the risk of non-fatal stroke in patients with chronic kidney disease (CKD), according to study findings presented at the European Renal Association-European Dialysis and Transplant Association 53rd Congress in Vienna.

Compared with patients in the second quartile of serum uric acid level (5.7–6.4 mg/dL in men and 4.5–5.1 mg/dL in women), those in the fourth quartile (7.4 mg/dL or higher in men and 6.0 mg/dL or higher in women) had a significant 49% increased odds of non-fatal stroke, Keita Kamei, MD, of the Yamagata University School of Medicine in Yamagata, Japan, and colleagues reported. These increased odds were preserved after adjusting for age, sex, comorbidities, and other confounders.

The increased odds of non-fatal stroke in the fourth quartile were significant in individuals without proteinuria, but not in those with proteinuria.

Additionally, in subgroup analyses, individuals in the fourth quartile with dyslipidemia, diabetes, and eGFR less than 45 mL/min/1.73 m2 had greater odds of non-fatal stroke than subjects without these factors.

Increased odds of non-fatal stroke found in patients without proteinuria.

For the study, the researchers used a national database of 22,333 individuals with an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2 who participated in an annual health checkup. Subjects’ ages ranged from 39 to 73 years. During follow-up, 432 non-fatal strokes occurred. The lowest incidence rate was in the second quartile of uric acid (8.3 strokes per 1,000 person-years) and the highest rate was

in the fourth quartile (12.3 per 1,000 person-years).

In a previous study published in the American Journal of Nephrology (2012;36:324-331), researchers identified hyperuricemia as an independent risk factor for cardiovascular (CV) events in CKD patients not on medications known to alter endothelial function. The study included 303 patients with stage 3–5 CKD and a mean followed up period of 39 months. Of the 303 patients, 214 had hyperuricemia (uric acid levels above 6 mg/dL for women and above 7 mg/dL for men) and 89 had normal uric acid levels.

Both fatal and non-fatal CV events occurred in 100 hyperuricemic patients (46.7%) compared with 13 patients with normal uric acid levels (14.6%).

The increased likelihood of CV events was independent of eGFR and traditional and non-traditional CV risk factors, according to the investigators.

In a separate presentation at the congress, researchers reported that

high uric acid is significantly associated with increased arterial stiffness in healthy Korean women. The study, by Hyeong Cheon Park, MD, of Yonsei University in Seoul, and colleagues, included 2,704 patients who underwent brachial-ankle pulse wave velocity (baPWV) testing and coronary computed tomography angiography.

The researchers group subjects into quartiles of serum uric acid level. For men, quartiles 1, 2, 3, and 4 were 1.9– 5.2, 5.21–5.9, 5.91–6.7, and 6.71–12.1 mg/dL, respectively. For women, the values were 2.0–3.8, 3.81–4.3, 4.31–4.9, and 4.91–8.7 mg/dL, respectively.

After adjusting for age, systolic blood pressure, body mass index, estimated glomerular filtration rate and other confounders, women with SUA in the fourth quartile had a significant 81% increased odds of having a high baPWV compared with those in the first quartile. The researchers found no significant association between SUA and baPWV in men. n

26 Renal & Urology News

JUNE/JULY 2016 www.renalandurologynews.com

Practice Management Prompt-pay discounts and payment plans are among the ways practices can improve collections of what patients owe BY TAMMY WORTH

Good policy Making sure practices receive money they are owed begins with having a good financial policy that is communicated to patients, said David Zetter, founder of Zetter Healthcare Management Services in Mechanicsburg, PA. He recommends having patients sign off on a policy every other year so they are up to date on the practice’s guidelines.

Physician offices should have strict guidelines for handling self-pay patients with an option for a promptpay discount if possible, said Michelle Colaberardino, director of physician practice services for Revenue Cycle Solutions, LLC, which is headquartered in Pittsburgh.

lengthening the time to pay it off for larger bills, like 3 months for bills under $500 and 6 months for bills $1,500 or more.

If a plan stretches payments out over too much time, physicians can end up being considered a lender by federal or state regulations, Zetter said. “Any practice needs to be very cognizant of what the laws are in their state,” he said. “They need to know how long they can let payments go on a certain balance or bill.”

Office changes Small measures can be taken in the office to improve collections. First, staff should be trained to collect copays at the time of service or patients do not see the doctor, Zetter said. “If a patient has a co-pay of $20, they need to ask, ‘How would you like to handle that today?’” he said. “They shouldn’t ask, ‘Would you like to pay it?’ It just takes some training.”

Staff should also be trained to verify insurance every time a patient visits. A co-pay is listed on most insurance cards, but if patients have an old card, the copay may be out of date. A real-time verification should tell what a co-pay is, so it can be collected at the time of the visit.

If a patient with a balance on his or her bill comes in for an appointment, the front desk should make an attempt to collect at that point.

Another policy to consider is how many statements will be sent to patients if they do not pay. Zetter recommends sending only 1, because “if they ignore it, they will ignore others.”

Then if they don’t pay within 30 days, he suggests sending the bill to collection. And if your state allows it, require patients to pay collection fees.

The policy should also cover any payment plans a practice offers.

Colaberardino recommends basing payment terms on the amount owed,

Likewise, if a patient with a balance on his or her bill comes in for an appointment, the front desk should make an attempt to collect at that point. Zetter recommends that all staff members who have patient contact receive instruction on how they can take part in the collections effort and how to communicate so they do not feel uncomfortable asking patients for money. If patients cannot pay the entire bill at the time of service, use the electronic medical record (EMR) to

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ore and more patients may have insurance now than they did 5 or 10 years ago, but that does not necessarily mean fewer are paying for services out of their own pockets. In recent years, deductibles and co-pays have risen quickly, even among employer-sponsored plans. So how can practices help improve collections of fees for service? Experts offer tips on ways to bring more money into the practice.

Staff should be trained to collect co-pays at the time of service, expert advises.

generate a bill to give to them before they leave the office. By doing this, patients will already have an idea of what is currently due, according to Colaberardino. Some EMR systems can send a bill as a soon as a balance becomes due. This may provide better results and be more cost effective than sending statements out weekly or monthly.

“Don’t wait,” she said. “Statements could be going out every day. This keeps the money flowing in.”

Use credit A practice that Zetter recommends to most of his clients is keeping patients’ credit card information on file. “I have a couple of providers that mandate that they have credit or debit on account or they don’t see patients,” he said. “They have hardly any [accounts receivable]; the only problems they have now are collections with insurance.”

Taking patients’ credit information and keeping it locked in a file somewhere is a huge risk, however, according to Zetter. He recommends working with gateway vendors that keep the information in their system and is responsible for keeping it safe. When a patient signs off on a payment plan,

office staff can simply go into the system each month and charge the flat amount until it is paid off. A vendor then sends a receipt to patients each month alerting them the amount has been debited.

Gateway groups typically charge a monthly fee, but the money spent comes back to an office 10-fold by increasing collections and reducing staff time on the efforts, Zetter said.

Colaberardino is less a fan of having credit card information on file because of the potential for theft of the information. It is beneficial for a practice to gather this information, she said, but patients tend to be skeptical of the process. Many individuals do not want to give a practice the ability to deduct money from their accounts automatically. To do this, staff members need to assure patients their information will be secure, Colaberardino said.

“You have to educate them and let them know the process is going to help provide services in a more efficient manner and allow staff to dedicate less time here and more time on other important jobs,” Zetter said. n Tammy Worth is a freelance medical journalist based in Blue Springs, MO.

For men with mCRPC who have progressed on ADT

Z Y T I G A® & P R E D N I S O N E

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

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

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

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

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

Please see additional Important Safety Information on the next pages.

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

For men with mCRPC who have progressed on ADT

ZYTIGA® & PREDNISONE: (abiraterone acetate)

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

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

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

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

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

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

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

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

Let’s do this Prespecified secondary end point¶

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

IMPORTANT SAFETY INFORMATION—continued

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

034441-150514

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

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

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

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

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

Analysis of rPFS utilized centrally reviewed radiographic assessment of progression.

§

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

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

Learn more today at www.zytigahcp.com

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

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

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

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

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

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

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

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

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

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

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

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

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

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

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

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

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

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

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

6 Includes

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

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

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

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

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

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

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

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

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

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

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

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

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

Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis.

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

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

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

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

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

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

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

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

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

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

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

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

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

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

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

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

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

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

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

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

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

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

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

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

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

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

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

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

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