Renal & Urology News - October 2016 issue

O C T O B E R 2016

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VOLUME 15, ISSUE NUMBER 8

ADT Failure Tied to Genetic Variant

Disease progression linked to HSD3B1 (1245C) allele

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DECREASED PROGRESSION-FREE SURVIVAL Prostate cancer patients who receive ADT for disease recurrence following radical prostatectomy have shorter median progression-free survival if they are heterozygous or homozygous for the variant gene HSD3B1 (1245C).* 6.6 years

*Data are from the study’s primary cohort.

4.1 years

BY JODY A. CHARNOW PROSTATE CANCER (PCa) patients with a certain variant genotype are more likely to experience resistance to androgen-deprivation therapy (ADT) following disease recurrence after radical prostatectomy, new study findings suggest.

The genotype, HSD3B1 (1245C), could potentially be a powerful genetic biomarker for distinguishing PCa patients who will respond favorably to ADT from those who have cancer that is more likely to behave aggressively, investigators concluded.

IN THIS ISSUE 7

Adding folic acid to enalapril may lower CKD progression risk

10

Staghorn stones predict a higher infection risk after PCNL

11

Serious side effects uncommon with sacral neuromodulation

20

Ultrasonography alone suboptimal for detecting kidney stones

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Prostate cancer treatment may relieve pre-existing LUTS New equations may improve MRI/US fusion prostate biopsy PAGE 16

The HSD3B1 (1245C) allele encodes an altered enzyme that augments dihydrotestosterone synthesis from nongonadal precursors.

“Overall, these data suggest that there may be a genetically defined subgroup of patients with prostate cancer who might benefit from upfront treatment with a next-generation antiandrogen along with standard medical or surgical castration,” principal investigator Nima Sharifi, MD, of the Glickman Urological and Kidney Institute at Cleveland Clinic, told Renal & Urology News.

Biomarkers Predict AKI Progression THREE URINARY biomarkers measured at the time of acute kidney injury (AKI) diagnosis in patients with acute cardiorenal syndrome (CRS) may help to identify those at highest risk for adverse outcomes, investigators concluded.

In a prospective study of 213 with acute CRS and stage 1 or 2 AKI at diagnosis, the highest tertiles of urinary angiotensinogen (uAGT), urinary neutrophil gelatinase-associated lipocalin (uNGAL), and urinary interleukin-18 (uIL-18) were associated, respectively, with a significant 10.8-, 4.7-, and 3.6fold increased risk of AKI progression, continued on page 11

2.5 years

Homozygous wild-type

Heterozygous variant

Homozygous variant

Source: Hearn JWD et al. HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study. Lancet Oncol. 2016; published online ahead of print.

Dr Sharifi and his colleagues genotyped 443 PCa patients who received ADT for biochemical failure after radical prostatectomy (RP), then correlated genotype with long-term clinical outcomes. Of these, 118 were

in the primary cohort (those who underwent RP), 137 were in a post-RP validation cohort, and 188 were in a metastatic validation cohort. The primary endpoint was progression-free continued on page 11

BCG Alone Best for Bladder CIS BACILLUS Calmette-Guérin (BCG) monotherapy is associated with better long-term efficacy than alternating therapy with mitomycin C (MMC) and BCG in patients with carcinoma in situ of the bladder, according to a new study.

The finding is from a study of 321 CIS patients from Finland, Norway, and Sweden enrolled in a prospective multicenter trial and randomized to receive either BCG monotherapy or alternating MMC/BCG therapy. After a median follow-up of 9.9 years (maximum 19.9 years) in the BCG monotherapy arm and 8.9 years (maximum 20.3 years) in the alternating treatment arm, investigators found that the risk

of disease recurrence was significantly lower in the BCG monotherapy arm than the alternating treatment arm (49% vs. 59%) at 15 years). This difference in recurrence rates corresponded to a significant 26% decreased risk of recurrence, investigators led by Eero Kaasinen, MD, of Helsinki University Hospital in Helsinki, Finland, reported in the Scandinavian Journal of Urology (2016;50:360-368). The researchers observed no significant difference in progression risk and disease-specific and overall mortality between the groups.

Patients who experienced disease progression after 2 years compared continued on page 11

A PROMISING TREATMENT ALTERNATIVE FOR BPH

Encouraging results reported for prostate artery embolization PAGE 19

4 Renal & Urology News

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PD Patient Mortality, Thyroid Dysfunction Linked BOTH LOW and high thyroid hormone levels are associated with elevated mortality risk among patients on peritoneal dialysis (PD), researchers concluded.

Connie M. Rhee, MD, MS, of the University of California Irvine, and colleagues examined the association between thyroid function, as reflected

by serum thyroid-stimulating hormone (TSH) levels, and all-cause mortality in a national cohort of 1,484 PD patients. At baseline, 18% and 7% of patients had hypothyroidism and hyperthyroidism, respectively.

Compared with TSH levels of 0.5<3.0 mIU/L (reference), levels <0.1,

0.1-<0.5, 3.0-<5.0, 5.0-<10, and ≥10.0 mIU/L were associated with 2.09, 1.53, 1.05, 1.63, and 3.1 times increased risk of all-cause mortality in case-mix adjusted analyses, according to a paper published online ahead of print in the Journal of Clinical Endocrinology and Metabolism.

In addition, compared with euthyroid patients, hypothyroid and hyperthyroid patients, respectively, had a 1.69 and 2.08 times increased risk of all-cause mortality. The researchers defined euthyroidism, hypothyroidism, and hyperthyroidism as TSH levels of 0.5-<5.0, <0.5, and ≥5.0 mIU/L, respectively. ■

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Renal & Urology News 5

Study: Better Cancer Screening Guidelines Needed

BY NATASHA PERSAUD EXISTING CANCER screening guidelines for solid organ transplant (SOT) recipients fall short in several key ways, according to a new review.

Investigators found varying recommendations for screening of breast, cervical, colorectal, and other cancers.

Among 13 guidelines reviewed, only annual skin cancer screening with clinical skin exam was endorsed routinely, Nancy N. Baxter, MD, and Sergio A. Acuna, MD, of St. Michael’s Hospital in Toronto, and colleagues concluded in an online report in the American Journal of Transplantation. Consistent evidence of

increased cancer incidence and mortality existed solely for colorectal cancer.

In addition, many of the screening recommendations were based on elevated risks of cancer rather than evidence of benefits from screening. Randomized clinical trials on screening might clarify matters, but they require large numbers

of participants, and the numbers of transplant recipients are relatively small, according to the investigators. There are ethical considerations, as well. The risk and benefit profile of specific cancer screening modalities for this population are largely unknown.

Cancer development and deaths are higher among transplant recipients than the general population, the researchers noted. Cancer screening of these patients remains controversial, however, because they often have multiple comorbidities and lower life expectancy.

“Transplant recipients should be aware they have a heightened risk of developing and dying from cancer and should advocate with their health-care providers to be screened for cancer,” Dr. Baxter commented in a St. Michael’s press release.

“Even though transplant recipients often have other serious medical conditions that could shorten their life expectancy, they also need to be screened for cancer to ensure early detection.”

Recommendations for SOT recipients need improvement, researchers say.

The researchers found that screening recommendations varied considerably by transplanted organ. Five guidelines specifically addressed kidney transplant recipients, and they showed some consistency, although screening frequency differed. The risks of developing and dying from breast and cervical cancers are similar to those observed in the general population. “For these cancers, similar screening to that recommended for the general population would be adequate,” Dr. Acuna told Renal & Urology News.

Screening for lung and renal cancer was not recommended. But low-dose computed tomography for lung cancer is an option that may warrant re-evaluation, the researchers suggested.

Subgroups of SOT recipients, such as those with pre-transplant malignancies or hepatitis B or C infection, would likely benefit from tailored screening advice, they added. Individual risk factors based on family or smoking history, for example, also should be considered.

Concerted research efforts still are needed to define optimal approaches to cancer screening and aid decision making, the researchers emphasized. ■

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FROM THE EDITOR EDITORIAL ADVISORY BOARD

Progress to More Nuanced Medicine

M

edicine in many ways moves in the direction of nuanced patient care. Hardly a week goes by without seeing a paper in a peer-reviewed journal reporting the identification of novel factors for improving risk stratification and predicting how patients with genitourinary diseases will respond to treatment. These findings often help to fine-tune patient management.

Such is the case with Gleason score 7 prostate tumors. Over the years, studies have documented that Gleason pattern 3 + 4 = 7 is associated with better prognoses than Gleason pattern 4 + 3= 7 tumors. This difference is reflected in a proposed and widely supported new prostate cancer (PCa) grading system consisting of 5 grade groups, with grade group 1 reflecting the lowest risk disease and grade group 5 the highest. The new grading system separates 3 + 4 and 4 + 3 cancers into grade groups 2 and 3, respectively, a distinction that could affect treatment decisions.

Recent examples of the stepwise advances in understanding that promise more nuanced medical care are numerous. In a paper published in The Lancet Oncology, investigators showed that PCa patients with a certain variant genotype are more likely to experience resistance to androgen-deprivation therapy following disease recurrence after radical prostatectomy. The researchers concluded that this genetic biomarker potentially could be useful in identifying patients who might warrant early escalated therapy because their cancer is likely to behave more aggressively. Researchers reported in the Clinical Journal of the American Society of Nephrology that they identified 3 urinary biomarkers that, when measured at the time of diagnosis of acute kidney injury (AKI) and added to a clinical risk model, can predict the likelihood of AKI progression among patients with cardiorenal syndrome. And a study published in Kidney International adds to evidence suggesting that conventional thrice-weekly hemodialysis (HD) may not always be the best option for patients with end-stage renal disease. The study found that mortality risk did not differ significantly between incremental HD (2 or fewer sessions per week) and conventional in-center HD. The authors stated that incremental HD could offer patients better preservation of an arteriovenous fistula and preservation of residual kidney function.

Therapeutic decisions have long been influenced by patient characteristics such as age, life expectancy, and comorbidities, and disease severity as indicated by signs and symptoms and pathologic features.

Mounting evidence of, and a growing appreciation for, the clinical value of novel genetic biomarkers, biochemical indicators, and pathologic features, however, could well move medicine into a new paradigm in patient care in which a one-size-fits-all approach is abandoned in favor of precise nuanced care.

Medical Director, Urology

Medical Director, Nephrology

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

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

Urologists

Nephrologists

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

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

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

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

Orange, Calif.

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

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

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

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

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

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

Renal & Urology News Staff Editor Web editor Production editor

Jody A. Charnow Natasha Persaud Kim Daigneau

Group art director, Haymarket Medical

Jennifer Dvoretz

Production manager

Krassi Varbanov

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

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

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OCTOBER 2016

Folic Acid Cuts CKD Progression Risk Adding folic acid to enalapril cut the odds of CKD progression by 21% FOLIC ACID TREATMENT may delay progression of chronic kidney disease (CKD) among patients with mild to moderate CKD, according to investigators.

“Our study is the first to show significant renal protection from folic acid therapy in a population without folic acid fortification,” a team led by Fan Fan Hou, MD, PhD, of Southern Medical University in Guangzhou, China, reported online ahead of print in JAMA Internal Medicine.

In the Renal Substudy of the China Stroke Primary Prevention Trial, hypertensive patients treated with a combination of enalapril and folic acid had a 21% decrease in the odds of CKD progression—the primary outcome—compared with those who received enalapril alone.

They also had a significantly slower rate of decline in estimated glomerular filtration rate (eGFR): 1.28% vs 1.42% per year. Among individuals with CKD at baseline, folic acid therapy was associated with a significant 56% reduction in the odds of CKD progression, a significant 33% reduction in the odds of a rapid decline in renal function (defined as an average decline in eGFR of 5 mL/ min/1.73 m2 or more per year), and a significant 44% slower decline in renal function (0.96% vs 1.72% per year). Dr.

Baseline Patient Characteristics No. patients:

15,104

• Male:

5902

• Female:

9202

No. patients with CKD (%)

1671 (11.1%)

Mean age (range):

60 years (45–75 years)

No.(%) with self-reported • Diabetes

564 (3.7%)

• Hyperlipidemia

445 (2.9%)

Hou and colleagues observed no significant between-group differences among participants without CKD at baseline.

“Given the magnitude of renal protection suggested by this study as well as the safety and the low cost, the potential role of folic acid therapy in the clinical management of patients with CKD in regions without folic acid fortification should be vigorously examined,” Dr. Hou’s team concluded.

The study included 15,104 hypertensive without a history of major cardiovascular disease who were randomly assigned to daily treatment with either

10 mg enalapril plus 0.8 mg folic acid (7545 participants) or 10 mg enalapril alone (7559 participants). The study population had a median follow-up of 4.4 years. Of the 15,104 participants, 1671 had CKD at baseline and 13,433 did not. The researchers defined CKD as an eGFR less than 60 mL/min/1.73 m2 and/ or proteinuria at baseline.

Dr. Hou and colleagues defined CKD progression as a decrease in eGFR of 30% or more and to a level below 60 mL/ min/1.73 m2 if the baseline eGFR was 60 mL/min/1.73 m2, or a decrease in eGFR of 50% of more if the baseline eGFR was less than 60 mL/min/1.73 m2; or the development of end-stage renal disease.

In an editorial accompanying the new report, Patrick J. Stover, PhD, of the Division of Nutritional Sciences at Cornell University in Ithaca, New York, and colleagues noted the study showed that enalapril interacts with folate in human physiology. They pointed out that enalapril treatment alone in the absence of supplemental folic acid increased serum folate by 5.1 ng/mL. “While the mechanisms for this interaction are unknown and should be explored, this drug-nutrient interaction may underlie the secondary prevention of renal function decline observed in this study,” they wrote. ■

Renal & Urology News 7

Drug Aids Uric Acid Lowering ADDING LESINURAD to allopurinol improves uric acid lowering in patients with gout, according to a new study.

Lesinurad is a novel selective uric acid reabsorption inhibitor for the treatment of gout in combination with xanthine oxidase inhibitors. In a randomized phase 3 trial of 603 gout suffers, Kenneth G. Saag, MD, MSc, of the University of Alabama at Birmingham, and collaborators found that the combination of both drugs was significantly more effective at bringing patients to a target serum uric acid level of less than 6 mg/dL. Investigators randomly assigned patients to receive allopurinol alone or allopurinol plus lesinurad at a dose of either 200 or 400 mg. The study’s primary outcome was the proportion of patients achieving a serum uric acid level below 6 mg/dL. At baseline, the study participants, who had a mean age of 51.9 years and gout duration of 11.8 years, had baseline serum uric levels of 6.94 mg/dL. Higher proportions of patients who received lesinurad 200 or 400 mg in addition to allopurinol achieved target serum uric acid

CKD Ups Likelihood of Gastrointestinal Bleeding

levels compared with those who

PATIENTS WITH MILD to moderate chronic kidney disease (CKD) are at increased risk for gastrointestinal (GI) bleeding, new data suggest.

The data are from a study of 11,088 participants in the Atherosclerosis Risk in Communities (ARIC) study. During a median follow-up of 13.9 years, 686 first incident hospitalizations for GI bleeding occurred, an incidence rate of 4.9 episodes per 1000 person-years. In multivariable analysis, lower estimated glomerular filtration rate (eGFR) and higher albumin-to-creatinine ratio (ACR) were independently associated with a high risk of hospitalization for GI bleeding.

Compared with individuals who had an eGFR of 90 mL/min/1.73 m2 or higher, those with an eGFR of 30 to 59 and less than 30 mL/min/1.73 m2 had a 51% and 7-fold increased risk of hospitalization for GI bleeding, respectively, a team led by Kunhiro Matsushita, MD, of the Johns Hopkins Bloomberg School of Public

Saag’s group reported online ahead

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

In addition, compared with individuals who had an ACR below 10 mg/g, those with an ACR of 10 to 29, 30 to 299, and 300 mg/g or higher had a 36%, 2-fold, and 2-fold increased risk of hospitalization for GI bleeding, respectively.

“To our knowledge, this is the first study demonstrating the association of higher albuminuria with risk for GI bleeding,” the investigators stated.

The ARIC study includes a populationbased cohort of individuals aged 45 to 64 years at the time of enrollment from 1987 to 1989 in 4 U.S. communities.

The patients who experienced GI bleeding were significantly older than those who did not (mean 64.8 vs. 62.7 years) and significantly more likely to be using aspirin (65% vs. 56%), anticoagulants (6% vs 2%) and proton pump inhibitors (5% vs. 3%).

The investigators discussed the possible clinical implications of their study findings. For example, physicians should be aware of the high risk of GI bleeding in individuals with decreased kidney function even at a moderate stage. In addition, they said their findings demonstrate that albuminuria is a potent predictor of GI bleeding. Its contribution to risk discrimination was similar to or even greater than most of the established predictors, they stated.

In an acknowledgement of study limitations, Dr. Matsushita’s group noted that they relied on ICD-9 codes to ascertain the outcome of GI bleeding.

Since their study was observational, they could not exclude the possibility of residual confounding. Lastly, their study looked at a middle-aged biethnic population, so it is unclear if their results can be generalizable to other races and age ranges. ■

received allopurinol alone (54.2%, 59.2%, and 27.9%, respectively), Dr. of print in Arthritis & Rheumatology.

The combination treatment was not superior to allopurinol alone with regard to rates of gout flares and complete tophus resolution.

Lesinurad was generally welltolerated, according to the investigators. The safety profile of the 200 mg dose was similar to that of allopurinol alone, except for higher incidences of mostly reversible serum creatinine elevation, the researchers said.

Combination therapy with lesinurad and allopurinol may represent a treatment option for patients with gout who are unable to achieve target serum uric acid levels on a xanthine oxidase inhibitor alone and warrant additional therapy, Dr. Saag and his colleagues concluded. ■

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Contents

OCTOBER 2016 ■ VOLUME 15, ISSUE NUMBER 8

Urology

ONLINE

11

Sacral Neuromodulation Causes Few Serious AEs Overactive bladder treatment with the InterStim System is associated with a 30% rate of reported device-related adverse events after 1 year, but most are minor.

18

PCa Mortality Higher in Blacks in Most Big Cities During 2005–2009, black men had a significantly higher prostate cancer death rate than whites in all but 4 of 41 cities.

this month at renalandurologynews.com 19

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

24

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

Congratulations to our September winner: Kaul Sanjeev, MD

9 Breaches of patient information can result in lawsuits filed in state courts.

Graft Size Decrease Ominous Decreases rather than increases in kidney graft size during the first year after deceaseddonor kidney transplantation strongly predict subsequent graft dysfunction.

20

Longer HD May Offer Survival Benefit Patients treated with extended-hours hemodialysis had a 33% lower adjusted risk of death compared with those who had conventional thrice-week sessions.

News Coverage 25

Sexual Medicine Society of North America Annual Fall Scientific Meeting Scottsdale, AZ November 3–6 American Society of Nephrology Kidney Week 2016 Chicago November 15–20 Genitourinary Cancers Symposium Orlando, FL February 16–18, 2017 Annual Dialysis Conference Long Beach, CA March 11–14, 2017 National Kidney Foundation 2017 Spring Clinical Meetings Orlando, FL April 18–22, 2017 American Transplant Congress Chicago April 29–May 3 American Urological Association Annual Meeting Boston May 12–16

Extracorporeal Therapy for Poisoning A workgroup has developed guidelines for using such modalities as hemodialysis and charcoal hemoperfusion to treat common toxicities

15

Job Board

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

BMI Predicts RCC Patient Death Risk A body mass index of 25 kg/m2 or above is associated with significantly prolonged survival following targeted treatment for renal cell carcinoma.

Nephrology

HIPAA

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

PAE Is a Promising BPH Treatment Alternative Prostate artery embolization, which uses microspheres to block arterioles, is particularly efficacious in men with very large prostates.

CALENDAR

Poor ESA Response, Mortality Linked Researchers found the association using a new definition of suboptimal response to erythropoiesis-stimulating agents.

At a minimum, ESA hyporesponsiveness, as

defined here, can be considered to be a prognostic marker with important clinical and economic implications.

See our story on page 25

26

Departments 6

From the Editor Medical research and nuanced patient care

10

News in Brief Staghorn stones predict post-PCNL infections

23

Ongoing Clinical Trials A listing of trials currently enrolling patients

26

Practice Management Patients can sue in state court for HIPAA violations

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■ Kidney Week, Chicago

OCTOBER 2016

Renal & Urology News 9

American Society of Nephrology Annual Meeting

Extracorporeal Therapy for Poisoning A workgroup has developed guidelines for the use of hemodialysis treatments for common toxicities Editor’s note: This article is a summary of a presentation Dr. Goldfarb is scheduled to give at the 2016 Kidney Week conference in Chicago, November 15, 1:30 to 2:00 p.m.

BY ALEKSEY ETINGER, DO, AND DAVID S. GOLDFARB, MD HEMODIALYSIS (HD) has been used for the treatment of poisoning since the 1940’s. Despite this long history, its utility generally has not been demonstrated by randomized controlled trials. The application of extracorporeal treatments (ECTR), including hemodialysis (HD) and charcoal hemoperfusion (HP), in the treatment of poisoning, therefore, has proceeded without underlying data confirming its appropriate use. Without data, consensus cannot easily be achieved and guidelines cannot be formulated.

In 2011, Marc Ghannoum, MD, a nephrologist on the faculty of the University of Montreal, decided to apply the principles of evidence-based medicine to the field. He heads the EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup (www.extripworkgroup.org). The EXTRIP workgroup developed a detailed methodology for formulating recommendations, which begins with a thorough literature review of ECTR use in the setting of poisoning.

Each member of the group reviews the available evidence and voices an anonymous opinion. This results in a robust discussion regarding the evidence and the final statements. The votes are tallied and recommendations developed.1 The result of this concerted effort has been the publication of a wealth of reviews and recommendations, to date regarding 13 potential toxins: acetaminophen, barbiturates, carbamazepine, digoxin, lithium, metformin, methanol, phenytoin, salicylates, thallium, theophylline, tricyclics, and valproic acid. Here we highlight a few of the recent publications and controversies.

Tricyclic antidepressants Tricyclic antidepressants (TCAs) remain in widespread use, although they are not considered first-line

agents due to their side effect profile and the development of superior agents. Though reviews have suggested a benefit of ECTR, EXTRIP recommended against its use ECTR in TCA poisoning. The evidence was based on 77 studies (a majority are case reports and 1 observational study), which included a total of 108 patients. TCAs are extensively protein bound and lipophilic, resulting in low dialyzability. They may appear to be dialyzable because they are small molecules (200-400 Daltons) that can freely cross HD membranes. But due to their large volume of distribution, there is no significant effect of ECTR on the total body burden. The treatment of severe TCA poisoning should instead be focused on aggressive supportive care and reversal of sodium channel blockade with sodium salts, particularly sodium bicarbonate.2

Acetaminophen Acetaminophen (APAP) is one of the most common drug poisonings among adults and children. APAP is metabolized by the liver to an active and toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). This toxin requires glutathione to be conjugated and inactivated. Sizable ingestions deplete glutathione stores, leading to accumulation of NAPQI and hepatotoxicity and liver failure. The standard of care is administration of N-acetylcysteine (NAC), which acts as a source of glutathione.

Fatalities are rare and mostly occur in patients who experience a delay or interruption in NAC administration.

APAP has a low molecular weight of 151.2 Daltons and is 25% protein bound with a low volume of distribution. Based on EXTRIP criteria, APAP is considered to have moderate dialyzability (10%–30% removal of total dose in a 6-hour ECTR session), although recent reports show rates of APAP extraction over 50% of total ingested dose). EXTRIP published recommendations based on 24 articles (1 randomized controlled trial, 1 observational study, and 22 case reports, including 23 fatalities). The conclusion was that ECTR is indicated only when NAC cannot be administered and in rare

and that ECTR was recommended for severe poisonings (varying salicylate levels with different thresholds for preserved and impaired renal function, altered mental status, acute respiratory distress syndrome, acidemia and failure of supportive therapy. ECTR not only removes salicylates but serves as a source of bicarbonate.4

Aleksey Etinger, DO

David S. Goldfarb, MD

cases where patients develop signs of mitochondrial injury early after ingestion as manifested by acidemia and high lactate levels.3 ECTR should be followed with further NAC administration, as the antidote is itself dialyzable.

Aspirin Acetylsalicylic acid (aspirin, ASA) is another medication responsible for many poisonings and deaths. It is an organic acid with a molecular weight 180 Daltons, 90% protein bound (as low as 30% in the setting of an overdose), and a small volume of distribution. Salicylates interfere with adenosine triphosphate generation leading to lactic acidosis and ketoacidosis. The drop in systemic pH increases entry of salicylates into the brain, resulting in cerebral edema and death. Treatment includes bowel decontamination and the administration of sodium bicarbonate to alkalinize the plasma relative to the brain and the urine relative to the plasma, and to facilitate excretion by the kidneys. EXTRIP’s recommendations were based on 84 articles (1 randomized control study, 80 case reports/series, and others). They concluded that salicylates are dialyzable

Conclusion ECTR for poisoning represents a complicated clinical scenario. The group hopes that future case reports will be detailed in regards to patients’ clinical presentations and the interventions utilized, and be thorough with respect to data collection throughout the case. A checklist of 114 items that should be included in a case report was developed. This checklist should be consulted when ECTR is employed so that the appropriate variables will be observed and toxicokinetic calculations will be accurate, leading to a higher quality and more useful publication.5 ■ Aleksey Etinger, DO, is a fellow in the nephrology division at NYU Langone Medical Center in New York. David S. Goldfarb, MD, is chief of the nephrology section at the New York VA Medical Center and clinical chief of the nephrology division at NYULMC. He is the National Kidney Foundation’s representative to EXTRIP. Dr. Goldfarb also is a member of the Renal & Urology News editorial advisory board.

DISCLOSURES Dr. Goldfarb receives funding from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Advancing Translational Sciences.

REFERENCES 1. Lavergne V, Nolin TD, Hoffman RS, et al. The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: guideline methodology. Clin Toxicol (Phila) 2012 50:403-413.

2. Yates C, Galvao T, Sowinski KM, et al. EXTRIP workgroup. Extracorporeal treatment for tricyclic antidepressant poisoning: recommendations from the EXTRIP Workgroup. Semin Dial 2014;27:381-389.

3. Gosselin S, Juurlink DN, Kielstein JT, et al. EXTRIP Workgroup. Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP workgroup. Clin Toxicol (Phila) 2014;52:856-867.

4. Juurlink DN, Gosselin S, Kielstein JT, et al. EXTRIP Workgroup. Extracorporeal treatment for salicylate poisoning: Systematic review and recommendations from the EXTRIP Workgroup. Ann Emerg Med 2015;66:165-181.

5. Lavergne V, Ouellet G, Bouchard J, et al. Guidelines for reporting case studies on extracorporeal treatments in poisonings: methodology. Semin Dial 2014;27:407-414.

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News in Brief

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

Short Takes Vitamin D Supplements Do Not Raise Stone Risk

in Zhejiang Province, China, and col-

Long-term vitamin D supplementation

had the highest exposure to pesti-

does not increase the risk of kidney

cides had 1.6-fold increased odds of

stones, according to a new systematic

bladder cancer compared with those

review and meta-analysis published

who had the lowest exposure. The

online ahead of print in the American

odds of bladder cancer were 1.7-

Journal of Clinical Nutrition.

fold higher among individuals in the

leagues, found that individuals who

Robert Scragg, MBBS, PhD, and

Americas.

colleagues at the University of Auckland effects related to calcium metabo-

Low Sodium Levels Up PD Patient Mortality

lism—hypercalcemia, hypercalciuria,

Lower serum sodium levels in patients

and kidney stones—in 48 randomized

initiating peritoneal dialysis (PD) are

controlled trials in which participants

associated with an increased risk

were given vitamin D supplements or

of death, according to a new study

placebo for 24 weeks or more. Vita-

published online ahead of print in

min D supplementation increased the

Peritoneal Dialysis International.

in New Zealand analyzed the adverse

risk of hypercalcemia and hypercalciuria

Researchers led by Andrew Daven-

by 54% and 64%, respectively, but did

port, MD, of the Royal Free Hospital

not increase the risk of kidney stones.

in Hampstead, U.K., studied 3108 PD patients enrolled at day 90 of renal

Bladder Cancer Linked to Pesticide Exposure

replacement therapy into the U.K.

High levels of exposure to pesticides

had sodium measurements available.

are associated with an increased risk

After adjusting for covariates, patients

of bladder cancer, according to a new

in the lowest serum sodium group

meta-analysis published online ahead

(137 mmol/L or less) had a 49%

of print in Oncotarget.

increased risk of dying compared

Renal Registry database and who

After pooling data from 9 studies,

with those who had the highest serum

Zhen Liang, MD, of Zhejiang University

sodium levels (140 mmol/L or higher).

Oral Vitamin D Use Increasing U.S. statistics show a trend toward increasing use of oral vitamin D in the dialysis population.

Shown here are the proportions of dialysis patients who used oral vitamin D in the last 3 months for selected months and years.

August 2010:

3.5%

June 2012:

6.3%

December 2014:

9.1%

April 2015: 19.8% June 2016: 31.4% 0

5

Source: DOPPS Practice Monitor

10

15

20

25

30

35

Staghorn Stones May Predict Infections Following PCNL S

taghorn calculi emerged as the only significant independent predictor for postoperative infection in a study of 227 patients who underwent percutaneous nephrolithotomy (PCNL) and were on preoperative antibiotics.

After controlling for pre- and post-PCNL risk factors, staghorn calculi were associated with 3.4 times greater odds of fever, systemic inflammatory response syndrome (SIRS), or sepsis, and 2.9 times greater odds of postoperative infection overall, Marcelina Rivera, MD, and collaborators at Mayo Clinic in Rochester, Minnesota, reported online ahead of print in the Journal of Endourology.

The overall risk of SIRS and sepsis was low (9% and 0.9%, respectively). The presence of multiple stones was associated with nearly 6-fold higher odds of fever/ SIRS/sepsis, an increase in risk that approached statistical significance.

“These data can be used to appropriately counsel patients with large complex stone burdens of their infection-related risks,” Dr. Rivera’s group concluded.

Higher Phosphorus, Creatinine Levels Increase SHPT Risk S

erum levels of phosphorus and creatinine are independently associated with secondary hyperparathyroidism, according to study findings published in Experimental and Therapeutic Medicine. (2016;12:1206-1212).

For the study, Yudan Wei, MD, of the First Hospital of Jilin University in China, and colleagues reviewed data on 498 CKD patients seen at the hospital between 2008 and 2012. Of these, 424 patients had elevated serum parathyroid hormone (PTH) levels above 88 pg/mL, and 74 had normal PTH levels (control group).

Increasing serum levels of phosphorus and creatinine were associated with increasing risk of SHPT in multivariate analysis. Elevated PTH was also positively correlated with biochemical measures, including serum creatinine, serum phosphorus, C-reactive protein, triglycerides, total cholesterol, and LDL cholesterol.

Post-ESWL Renal Hematoma Linked to High, Low BMI H

igh and low body mass index (BMI) are risk factors for renal hematoma among patients undergoing extracorporeal shock wave lithotripsy (ESWL) for kidney stones, researchers reported online ahead of print in Urolithiasis.

Fabio Nussberger, MD, and colleagues at the University of Bern in Switzerland studied 418 patients who underwent ESWL. Ultrasound scans at post-treatment day 1 revealed renal hematomas in 39 (9%) patients. For 37 of them, the researchers selected a control group of patients without hematoma who were matched by age, gender, and number and energy of shock waves, stone burden, and localization.

In the hematoma group, significantly more patients had a high BMI (greater than 30 kg/m2) and a low BMI (less than 21.5 kg/m2) compared with the control group.

Renal hematomas developed in all patients with a BMI less than 21. 5 kg/m2.

The cases and controls did not differ significantly with respect to skin-kidney distance and rates of diabetes, discontinued anticoagulant/antiplatement medications, and arterial hypertension, according to the investigators.

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ADT Failure continued from page 1

survival according to HSD3B1 (1245C) genotype.

Of the 118 men in the primary cohort, 44 were homozygous wild-type (37%), 62 (53%) were heterozygous (had 1 copy of the variant allele) and 12 (10%) were homozygous (had 2 copies of the variant allele).

In the primary cohort, median progression-free survival diminished as a function of the number of variant alleles inherited, the investigators

Homozygous variant men had a 2.4-fold increased risk of disease progression. reported online ahead of print in The Lancet Oncology. It was 6.6 years for homozygous wild-type men, 4.1 years for heterozygous variant men, and 2.5 years for homozygous variant men.

Relative to the homozygous wild-type genotype, inheritance of 1 copy or 2 copies of the variant allele predicted a 1.7fold and 2.4-fold increased likelihood of disease progression, respectively, according to the investigators.

Median progression-free survival in the metastatic validation cohort

AKI biomarkers continued from page 1

the primary endpoint, compared with the lowest tertiles. After adjusting for clinical variables, uAGT was the best predictor for both AKI progression (primary outcome) and AKI progression with death (secondary outcome), with area under the receiver operator curve of 0.78 and 0.85.

Addition of the 3 biomarkers to a clinical model that took into account age, gender, hypertension, diabetes, preadmission estimated glomerular filtration rate, and other variables significantly

BCG monotherapy continued from page 1

with before 2 years had a significantly higher risk of dying from bladder carcinoma (77% vs. 35%).

The study also showed that patients with primary CIS had a significantly increased risk of recurrence compared with those who had comcomitant CIS.

was 1.8 years for homozygous wildtype men compared with 0.8 years for homozygous variant men, a significant difference that corresponded to a 2-fold increased risk for progression among homozygous variant men.

Heterozygous men had a median progression-free survival of 1.4 years, which did not differ significantly from homozygous wild-type men.

Dr. Sharifi’s team examined distant metastasis-free survival only in the primary study cohort. It was 9.1 years for homozygous wild-type men, 6.8 years for heterozygous men, and 3.6 years for homozygous variant men. Compared with homozygous wild-type men, homozygous variant men had a significant 2.7-fold increased likelihood of distant metastasis. Heterozygous men had a non-significant 1.7-fold increase risk of distant metastasis.

The investigators stated that their results are biologically credible because tumor cells carrying the variant allele are able to produce their own dihydrotestosterone more efficiently.

“The next step is to determine if the adverse biology and outcomes associated with inheritance of the HSD3B1(1245C) variant are pharmacologically reversible, and how we should use these data to individualize patient therapy based on their genetics,” said Dr. Sharifi, co-leader of the Cleveland Clinic’s Prostate Cancer Research Center of Excellence.” ■

OCTOBER 2016

Renal & Urology News 11

Sacral Neuromodulation Causes Few Serious AEs OVERACTIVE BLADDER (OAB) patients

infection, which occurred in 9 patients

who undergo sacral neuromodulation

(3%). The overall surgical intervention

therapy with the InterStim System have

rate was 13%, with pain at the surgical

a 30% rate of reported device-related

site, lack/loss of efficacy, and infection

adverse events (AEs) after 1 year, but

being the most common reasons, the

most are minor, according to the find-

investigators reported.

ings of prospective InSite trial.

In the trial, which included 272 patients

Dr Noblett’s team noted that the AEs and surgical intervention rates in their

with OAB treated with sacral neuromod-

study are much lower than those found

ulation, only 1 patient experienced an AE

in earlier trials. Overall rates of AEs

that was considered serious.

and the rates of infection, implant site

The primary aim of the study, which

pain, and surgical intervention were

was led by Karen Noblett, MD, of the

much lower that the rates observed in

University of California Riverside, was

the MDT-103 pivotal trial (30% vs. 52%;

to provide a detailed analysis of the

3% vs. 6.1%; 7% vs. 15.3; and 13% vs.

AEs and surgical intervention out to

54%, respectively), Dr. Noblett and her

12 months.

colleagues reported.

Of the 272 patients, 82 (30%)

“These data suggest that the new

reported device-related AEs. Fifty-

techniques and devices related to this

six percent of device-related AEs

therapy have substantially reduced

occurred between implant and 3

overall AEs and most importantly

months, Dr. Noblett’s group reported

reduced AEs that lead to more

in Neurourology and Urodynamics. The

intensive interventions,” the investiga-

most frequent device-related AEs were

tors concluded. “These data also give

an undesirable change in stimulation,

insight into how we may reduce device-

which occurred in 32 patients (12%);

related AEs and gives a realistic basis

implant site pain, which occurred in

for counseling patients on the risks

20 patients (7%); and implant site

associated with this therapy.” ■

improved risk stratification for AKI progression and AKI progression with death, with uAGT performing the best, investigators led by Fan Fan Hou, MD, of Southern Medical University in Guangzhou, China, reported.

Of the 213 patients, 50 (23.5%) experienced AKI progression. Patients who progressed to a higher AKI stage and those who did not were similar with respect to mean age (66.8 and 70.6 years, respectively), primary diseases of heart failure, preadmission medication use, and baseline renal function. Compared with patients who did not have AKI progression, those

who did had significantly higher levels of N-terminal pro-B-type natriuretic peptide (mean 9000 vs. 6647 pg/mL) and significantly lower levels of serum albumin (2.9 vs. 3.2 g/dL) and hemoglobin (10.8 vs. 11.8 g/dL), Dr. Hou and colleagues reported online ahead of print in the Clinical Journal of the American Society of Nephrology.

The mortality rate was 36% among patients who presented with stage 1 or 2 AKI and progressed to higher stages compared with 15% in patients who did not progress. “It is therefore critical to identify patients at highest risk of both AKI progression and death so

as to guide prognosis and treatment decisions,” the investigators wrote.

“Unfortunately, the lack of objective tests to predict progression of acute CRS delays initiation of intervention and hinders clinical trials.”

In a discussion of study limitations, the researchers noted that the number of outcomes was relatively small, although there were sufficient events for the primary endpoint. “As is true in the case of most AKI studies, we were not able use urine output for AKI diagnosis because an indwelling urinary catheter was not present in most of the patients.” ■

In addition, Dr. Kaasinen’s team found that patients in the MMC/BCG group were significantly less likely to terminate in the instillation regimen prematurely because of adverse effects.

The probability of non-cessation of instillations at 6, 12, and 15 months for MMC/BCG compared with BCG alone was 99% vs. 90%, 95% vs. 75%, and 94% vs. 73%, respectively.

Of the 321 patients, 91 (29.9%) had primary CIS, 129 (42.4%) had secondary CIS, and 84 (27.6%) had concomitant CIS. Alternating therapy consisted of 6 weekly instillations of mitomycin C 40 mg followed by 10 instillations of BCG or MMC alternating monthly for 1 year.

The same 6 + 10 schedule was followed for BCG monotherapy. Doctors evaluated patients every 3 months during the

first 2 years; thereafter, evaluations were according to local practice.

In an accompanying editorial, Kesavan Esuvaranathan, MD, of the National University of Singapore, wrote: “Kaasinen and colleagues are to be congratulated for contributing one of the best descriptions of the longterm, treatment-modified history of carcinoma in situ (CIS) of the bladder.” ■

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OCTOBER 2016

Renal & Urology News 15

Graft DASH-Style Diet May Lower Kidney Size Decrease Chronic Kidney Disease Risk Ominous It can reduce uric acid, a possible CKD risk factor, according to researchers CKD—defined by a decline in estimated glomerular filtration rate of 25% or more to a level below 60 mL/ min/1.73m2, end-stage renal disease, or a related hospitalization or death— was 16% more likely to develop in low adherers to the diet. Dr. Rebholz and colleagues adjusted for established CKD risk factors such as comorbid

© THINKSTOCK

BY NATASHA PERSAUD FOLLOWING A DIET similar to the Dietary Approaches to Stop Hypertension (DASH) eating plan—which emphasizes fruits, vegetables, and whole grains and discourages intake of red and processed meats—may stave off chronic kidney disease (CKD), according to 2 new studies.

A diet rich in fruits and vegetables may offer protection from chronic kidney disease.

“Our results provide support for promotion of a DASH-style diet in an even broader segment of the US population for reduced risk for kidney disease in addition to blood pressure reduction and cardiovascular disease prevention,” Casey M. Rebholz, PhD, MS, MPH, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, and colleagues concluded in a report published online ahead of print in the American Journal of Kidney Diseases.

The investigators assessed the development of CKD in 14,882 black and white adults from the Atherosclerosis Risk in Communities (ARIC) study over 23 years of follow up. At baseline and an additional visit, participants self-reported their intake of red and processed meat, sweet drinks, sodium, fruits, vegetables, whole grains, nuts, legumes, and low-fat dairy products in a validated 66-item food frequency questionnaire. None were given dietary advice.

After comparing participants whose diets most and least reflected the DASH diet, the investigators discovered that

conditions (e.g., diabetes and hypertension), systolic blood pressure, antihypertensive medication, baseline kidney function, sociodemographic factors, as well as lifestyle factors (e.g., smoking, calorie intake, overweight, and physical activity). They were unable to assess albuminuria.

High intake of red and processed meats (e.g., cold cuts) was associated with a 22% greater risk of CKD. Conversely, frequent consumption of nuts and legumes, and low-fat dairy products were linked with 9% and 16% lower risks, respectively.

Several possible mechanisms may be responsible for reduction in CKD risk, Dr. Rebholz and colleagues explained.

The DASH diet is known to reduce blood pressure. It also has a lower dietary acid load than typical American diets, and previous research has linked acid load with kidney disease.

In the other study, published online ahead of print in Arthritis & Rheumatology, investigators found that a DASH-style diet can lower uric acid,

which has been linked to increased CKD risk.

“A number of studies have shown that urate-lowering therapy can improve kidney function and reduce albuminuria, suggesting that uric acid itself may cause direct kidney damage,” study author Stephen P. Juraschek, MD, PhD, of Johns Hopkins Medical Institutions in Baltimore, told Renal & Urology News. “Our study shows that the DASH diet can significantly lower uric acid levels, particularly among adults with hyperuricemia.”

Dr. Juraschek and colleagues performed an ancillary study of the DASH-sodium trial, a randomized control trial that originally examined the influence of a DASH diet and varying amounts of sodium on blood pressure. For the current study, 103 adults with pre- or stage 1 hypertension were randomly assigned to the DASH diet or a control diet typical of the average American diet to assess the impact on uric acid levels. Participants consumed meals at low, medium, and high sodium levels of 60, 120, and 180 mmol of sodium per day for 30 days each in a crossover design. Body weight was kept constant.

While the study did not directly measure kidney function, the investigators reported that the DASH diet effectively lowered serum uric acid by 1.3 mg/dL in adults with elevated uric acid above 7 mg/dL. The effect size was comparable to that achieved with medications.

Adults with advanced kidney disease, diabetes, or cardiovascular disease were excluded from the study.

The researchers also found that higher levels of sodium, reflective of a typical American diet, reduced serum uric acid, especially in those with high blood pressure at baseline. The mechanism is unclear, but may involve reduction in sodium and urate reabsorption. The findings do not support consuming typical or excess amounts of sodium to lower uric acid, the investigators emphasized.

Rather, clinicians should be aware that acute changes in uric acid can occur.

“The study establishes the DASH diet as an effective dietary intervention to lower uric acid in patients with hyperuricemia,” Dr. Juraschek said. ■

DECREASES rather than increases in kidney graft size during the first year after deceased-donor kidney transplantation strongly predicts subsequent graft dysfunction, new findings suggest.

Compared with transplant recipients who experienced an increase in graft size, those who had a decrease had a significant 4.5 times higher risk of a composite outcome of a 50% or greater reduction in estimated glomerular filtration rate (eGFR) or end-stage graft failure during the first year post-transplant in adjusted analyses, researchers reported in Transplantation (2016;100:1759-1766).

They had a significant 4.4 times higher risk of a 50% or greater reduction in eGFR and 5.4 times higher risk of endstage graft failure.

In an observational study of 319 deceased-donor kidney transplant recipients, a team at University Medical Centre in Ljubljana, Slovenia, led by

Decline in size of transplanted kidney predicts graft dysfunction.

Miha Arnol, MD, PhD, found that 121 patients (38%) experienced a decrease in graft size and 198 (62%) had an increase at 1 year post-transplant. After a median follow-up of 53 months, 41 patients with a decrease in graft size reached the composite outcome compared with 12 who had an increase (34% vs 6%, respectively).

The investigators measured graft size by ultrasound-Doppler examination.

They defined graft size as the longest bipolar of the kidney, measured as the maximum diameter in a sagittal plane parallel to the long axis of the kidney.

Dr. Arnol’s team noted that the mechanisms by which graft size affects transplant outcomes have long been a matter of investigation. Some researchers have suggested that intraglomerular hypertension and hyperfiltration leading to nephron loss has a role.

“Data from our study suggest that variation in kidney [graft size] during the first year after transplantation may influence the development of immunemediated injury.” ■

16 Renal & Urology News

OCTOBER 2016

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Defining Deliverables of Prostate Cancer Fusion-Targeted Biopsy Two new equations could better descriminate between clinically significant and indolent prostate cancer

BY BENJAMIN T. RISTAU, MD, ASEEM MALHOTRA, MD, JEFFREY ELLIS, BS, AND ALEXANDER KUTIKOV, MD THE GOAL OF maximizing detection of clinically significant prostate cancer (PCa) and minimizing the diagnosis of indolent disease underpins the enthusiasm with which the urologic community has embraced magnetic resonance imaging/ultrasound (MRI/US) fusion technology. Indeed, refinement of multiparametric magnetic resonance imaging (mpMRI) for PCa diagnosis and its coupling to live ultrasound imaging holds great promise for improving tissue sampling during prostate biopsy (Figure 1).

While standard assessment parameters such as sensitivity, specificity, and positive/negative predictive value of mpMRIassisted targeted biopsy techniques have now filled the urologic literature, practical deliverables of this technology have yet to be fully crystallized.

To this end, in a presentation at the American Urological Association 2016 annual meeting,1 our group sought to define metrics that could quantitate deliverables of fusion-targeted biopsy (TB). First, we defined the value added

by TB techniques over traditional transrectal US-guided prostate biopsy (TRUSB). We termed this measure, the Actionable Intelligence Metric (AIM).

This metric quantifies the clinically actionable data provided by TB over what was seen on TRUSB. More specifically, AIM measures the percentage of time that TB uncovered clinically actionable information that was different from that garnered through TRUSB alone.

For example, the burden, procedural acumen, and expense of TB is likely justified when Gleason 8 disease is found on TB but not on TRUSB. In contrast,

AIM =

ReM =

[

FIGURE 1: A 64-year-old man with multiple previous negative standard template prostate biopsies and multiparametric MRI demonstrating a PIRADS 5 lesion in the right anterior transitional zone (left). TB of lesion demonstrated Gleason 3+4=7 disease, while 12-core template did not demonstrate evidence of cancer. A specimen from robotic nerve-sparing prostatectomy is shown (right), with the arrow indicating a notable subcapsular bulge at the site of the pathologically-proven Gleason 3+4=7 lesion (right).

the increased process of care intensity inherent to TB is probably not worth the effort when both TB and TRUSB demonstrate high risk disease features. In short, this metric reports what standard test characteristic measures such as PPV and NPV are not able to describe.

The second measure we sought to describe is the TB’s ability to replace TRUSB entirely. Stated differently, how many clinically significant tumors are found on the concomitantly performed TRUSB that are not picked up

by TB? In our experience, this is one of the most commonly asked questions by both patients and urologists in every day clinical practice. We termed this new instrument the Reduction Metric (ReM), which defines the percentage of patients whose biopsies were appropriately graded with TB alone.

Equations for calculated AIM and RM are shown in Figure 2. Once the metrics were defined, we then evaluated performance of AIM and ReM for 3 clinical scenarios in which TB is most commonly employed: (1) biopsy naïve

(BN) patients, (2) patients with elevated PSA and prior negative biopsy (EPNB), and (3) patients on active surveillance (AS) for “very low” and “low” risk PCa. A prospectively collected, consecutive institutional cohort of 249 patients with documented PIRADS 3–5 lesions on prostate mpMRI were included in the study. All men underwent UroNav (Invivo; Gainesville, FL) TB with concomitant 12-core TRUSB. Patients were stratified into the 3 previously described cohorts. Clinically significant PCa was defined as Gleason Score 3+4=7 or higher. AIM and ReM were calculated for the overall cohort and for each clinical scenario (See Figure 2 for equations). The overall cancer detection rate for all patients was 61.8%.

For the entire cohort, AIM and ReM were 34.1% and 81.1%, respectively.

Stratified by clinical situation, the AIM was 30.8% (BN), 46.7% (EPNB), and 20.5% (AS) and the ReM was 88.9% (BN), 85.7% (EPNB), and 72.3% (AS).

These percentages compared favorably to previously reported studies that

# pts with higher GS on TB (minimum GS ≥ 3 + 4 = 7) relative to TRUSB

1−

Total pts with GS ≥ 3 + 4 = 7

*100

# pts with higher GS on TRUSB (minimum GS ≥ 3 + 4 = 7) relative to TB

FIGURE 2: Equations for calculating AIM and ReM

Total pts undergoing prostate biopsy

]

offered enough published information to perform accurate calculations.

Based on the AIM calculation, TB harbors potential for improvement over traditional TRUSB techniques. Our data reveal that TB yields the most actionable information in patients with elevated PSA and prior negative biopsy (EPNB cohort AIM 46.7%) and is least helpful in AS patients (AS cohort AIM, 20.5%).

Furthermore, at our institution, the ReM predicts that approximately 15% of clinically significant cancers would fail to be detected if TB was performed in the absence of concomitant TRUSB. Therefore, as shown by other investigators, TRUSB remains a necessary adjunct to TB at this time, particularly in the AS setting where up to 28% of clinically significant cancers may be missed.

In conclusion, we have introduced two new metrics—AIM and ReM—to help quantify, communicate, and compare deliverables of TB technology. It is our hope that further validation proves these metrics to be useful additions in refining the detection of clinically significant prostate cancers and minimizing overdiagnosis of indolent tumors. ■ The authors are affiliated with Fox Chase Cancer Center in Philadelphia.

REFERENCE

*100

1. Ristau BT, Malhotra A, Ginzburg S, et al. Defining deliverables of multiparametric magnetic resonance imaging (mpMRI)/ultrasound fusion-guided targeted prostate biopsy: Actionable intelligence metric (AIM) and reduction metric (RM). J Urol. 2016;195(4):e697.

18 Renal & Urology News

OCTOBER 2016

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PCa Mortality Higher in Blacks in Most Big Cities BLACK MEN die from prostate cancer (PCa) at a significantly higher rate than white men in the United States, and the degree of this racial disparity varies considerably across cities, new study findings suggest.

At the national level, the PCa death rate during 2005–2009 was nearly 2.4 times

higher among black men than white men. The city with the least disparity was Minneapolis, where the rate of PCa death was 13% higher among black men than white men, a non-significant difference, Maureen R. Benjamins, PhD, of the Sinai Urban Health Institute in Chicago, and colleagues reported in

Cancer Epidemiology (2016;44:125-131).

The city with the greatest disparity was Los Angeles, the nation’s second-most populated city, where the PCa death rate was a significant 3.24 times higher in blacks than whites.

During 2005–2009, the PCa mortality rate in New York and Chicago, the

largest and third-largest U.S. city by population, was 2.75 times and 2.61 times higher among blacks than whites, respectively.

“This type of specific city-level data can be used to motivate public health professionals, government officials, cancer control agencies, and communitybased organizations in cities with large or increasing disparities to demand more resources, focus government efforts, and implement effective policy and programmatic changes in order to combat this highly prevalence condition,” Dr. Benjamins’ team concluded.

The investigators found no association between socioeconomic factors, such as education and income at the city level,

Racial disparity is largest in Los Angeles, smallest in Minneapolis. and PCa mortality disparities, but the level of disparity within a city was associated with the degree of black segregation, according to the researchers.

The investigators analyzed PCa mortality data from 1990–1994 and 2005–2009. They included 41 of the nation’s largest cities in their analysis. The PCa mortality rate declined for both races over the 20-year period from 1990 to 2009, but still remained higher for blacks than whites in most cities. During 1990–1994, blacks had a significantly higher PCa death rate than whites in all but 2 cities (Las Vegas and Fresno, CA). During 2005–2009, blacks had a significantly higher PCa death rate than whites in all but 4 cities (Minneapolis, Las Vegas, Portland, OR, and Sacramento, CA).

In 1990–1994, the PCa mortality rate among blacks in Memphis was 1.91 times higher than among whites. This rate was 3.18 times higher in 2005– 2009, making it the city with the second largest racial disparity and the city that experienced the largest increase in racial disparity among the 41 cities.

Due to the racial disparity, an estimated 2820 annual excess PCa deaths nationwide occurred among black men during 2005–2009, according to the investigators. The number of annual excess black deaths from PCa during the same period was 62 in Los Angeles, 172 in New York, and 109 in Chicago, the researchers reported. ■

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CURRENT consumer and researchrelated nutritional databases cannot be relied upon to list accurate amounts of phosphorus in beverages and likely foods, according to the latest product review in the Journal of Renal Nutrition (2016;26:e27-e30).

Recent studies have reported inaccuracies in databases, so Caitlin Krekel, MSPH, RD, and colleagues examined them. For 46 drinks, they compared actual phosphorus measurements from Medallion Laboratories in Minneapolis with listed amounts in databases and calorie-counting sites. Beverages included popular colas, fruit-flavored drinks, coffee drinks, iced teas, lemonades, vitamin-containing waters, and sports drinks, all available at grocery stores.

The researchers found just 28 of the 46 beverages in the Nutrient Data System for Research (NDSR). Of these, listed phosphorus amounts were lower than measured amounts for 78%.

Similarly, the USDA Standard Nutrient Reference Database yielded exact

Listed phosphorus amounts in beverages may be lower than measured amounts. matches for just 5 beverages and sometimes underestimated phosphorus content. The Web sites MyFitnessPal and CalorieKing provided no phosphorus information for any of the beverages.

Manufacturers supplied phosphorus amounts for 14 of the beverages that were remarkably similar to measured amounts. When products provided no such information, the investigators calculated phosphorus content based on cation values listed on the nutrition facts labels. These calculations approached actual phosphorus amounts, but they were time-consuming to produce.

Increasing awareness among food manufacturers about the importance of dietary phosphorus restriction in patients with kidney disease may help encourage self reporting of phosphorus content and consequently improve the quality of dietary phosphorus content information available to both researchers and consumers,” Krekel and colleagues concluded. ■

Renal & Urology News 19

PAE Is a Promising BPH Treatment Alternative The procedure may be particularly efficacious for men with very large prostates

BY REGGIE WILSON, MS AMELIA ISLAND, FL—Prostate artery embolization (PAE) has been emerging as a minimally invasive alternative for patients suffering from benign prostatic hyperplasia (BPH).

Via femoral or radial artery access, an interventional radiologist deploys microspheres endovascularly to block the arterial supply to the prostate using a small diameter micro catheter.

With blood supply curbed, the prostate shrinks, relieving the symptoms of BPH such as slow or weak urinary stream, urgency and frequent urination.

Shivank Bhatia, MD, Associate Professor of Interventional Radiology and Urology at the University of Miami Miller School of Medicine, who has been at the forefront of the implementation of this procedure in United States, spoke about his 3 years of experience with PAE during a presentation at the Florida Urological Society (FUS) annual meeting.

All the patients treated by Dr. Bhatia are assessed in a multidisciplinary fashion with urologists, interventional and diagnostic radiologists, and primary care physicians. This multidisciplinary approach helps providers to offer all the possible treatment alternatives, including PAE when appropriate, and helps patients to make an informed decision regarding their condition, he said. “With BPH affecting so many men, having another option that is minimally invasive is a real benefit to patients,” Dr. Bhatia said.

Dr. Bhatia highlighted how PAE has been able to alleviate symptoms and improve the quality of life of his patients. For example, an 80-year old patient had presented with refractory urinary retention for three months.

Shivank Bhatia, MD

© BSIP SA / ALAMY STOCK PHOTO

Phosphorus Information Often Wrong

OCTOBER 2016

Prostate artery embolization involves the use of microspheres to block arterioles.

The patient’s MRI revealed a prostate volume of 571 mL, and he had declined open prostatectomy. PAE was performed and the patient was able to urinate freely within 10 days of the procedure. At 3 months follow-up, the patient’s prostate volume dropped to 270 mL, his BPH symptoms were mild, and his quality of life score had improved from “terrible” to “pleased.”

Although this patient was unique in having such a large prostate, Dr. Bhatia said many of the patients he has treated with PAE have similar favorable outcomes. Since first performing PAEs in 2014, Dr. Bhatia has treated patients with a variety of prostate-related issues ranging from lower urinary tract symptoms and urinary retention to gross hematuria and as a pre-operative measure to reduce blood loss during radical prostatectomy for prostate cancer. The majority of the patients treated with PAE can go home few hours after the procedure and report significant improvement in urinary function within a month of the procedure.

“PAE offers a non-invasive alternative to treatment of BPH in men who are refractory to medical therapy,” said Sanoj Punnen, MD, attending urologist at the University of Miami and the FUS program co-chair. “For many men who may find the surgical options to be less appealing, this technology provides them with a safe and effective alternative to standard therapies.”

Program co-chair Christopher S. Gomez, MD, a BPH specialist, works closely with Dr. Bhatia to offer a mul-

tidisciplinary approach to patients suffering with BPH. “PAE has emerged as a minimally invasive treatment option for men that I routinely discuss when counseling them regarding surgical alternatives to TURP,” Dr. Gomez said.

When compared with surgical options like TURP, PAE has a vastly diminished risk of long-term side effects, such as retrograde ejaculation, incontinence, or sexual dysfunction, Dr. Bhatia explained. Post-procedural adverse effects of PAE most commonly include urethral burning and urinary frequency.

Within 2 weeks of the procedure, however, these effects usually resolve.

PAE seems to have a role in a select cohort of patients, Dr. Bhatia pointed out. Specifically, PAE could be an option for elderly patients who have an increased risk of morbidity with conventional surgery. PAE may be most beneficial in patients with larger prostates. Dr. Bhatia said he plans to continue performing PAEs and examine its long-term efficacy. Randomized controlled studies comparing PAE versus TURP are still in progress.

“These studies will enable us to introduce an alternative treatment option for the patients with an enlarged symptomatic prostate,” Dr. Bhatia said. “PAE needs to be studied in more detail before it can be adopted as an approved mainstream alternative for management of BPH; however, initial results are very encouraging. This treatment alternative might have niche applications in patients with very enlarged glands.” ■

20 Renal & Urology News

OCTOBER 2016

www.renalandurologynews.com

Longer HD May Offer Survival Benefit In a study, extended-hours versus conventional HD was associated with a 33% decreased mortality risk EXTENDED-HOURS hemodialysis (HD) is associated with decreased mortality risk relative to conventional HD, according to a new study.

Matthew B. Rivara, MD, of the University of Washington in Seattle, and collaborators compared mortality risk among 1206 patients with endstage renal disease (ESRD) undergoing thrice-weekly extended-hours HD and 111,707 receiving conventional HD. The average treatment time per session for extended-hours HD was 399 minutes compared with 211 minutes for conventional HD. The crude mortality rate with extended-hours HD was 64 deaths per 100 patient-years versus 14.7 per 100 patient-years for conventional HD. Patients treated with extended-hours HD had a 33% lower adjusted risk of death compared with those who had conventional HD, Dr. Rivara and his colleagues reported online ahead of print in Kidney International.

An important potential benefit of thrice-weekly extended-hours HD over other forms of dialysis intensification

ESRD Patients Visit the ER More Often

BY NATASHA PERSAUD NEWLY DIAGNOSED end-stage renal disease (ESRD) patients use the emergency room (ER) 4 times more frequently than other Medicare beneficiaries and 6 times more than adults overall in the United States, researchers reported online in JAMA Internal Medicine.

Brendan P. Lovasik, MD, of Emory University School of MERicine, Atlanta, and colleagues searchER the US Renal Data System and identified 769,228 adults diagnosed with ESRD from 2005 to 2011 receiving Medicare. Of these, 69% visited the ER at least once by 2015.

More than half (55%) visited the ER in their first year of treatment. Annual visits per patient averaged 2.89, 2.48, and 2.54 in the first, second, and third years of ESRD, respectively. Investigators excluded from the study those patients who visited the ER more than 50 times in a year because they probably used the ER for regular dialysis services.

lengthening of HD treatment is much greater than what is possible to achieve within the context of conventional in-center HD or more frequent HD, whether performed in-center or at home.

Dr. Rivara and his collaborators discussed some potential mechanisms by which substantially longer HD treatments may lead to improved clinical outcomes, independent of any increase in dialysis frequency.

For example, nocturnal extendedhours HD has been shown to enhance phosphorus removal and decrease arterial stiffness, which are potential mediators in the pathway between ESRD and clinical cardiovascular events. Dr. Rivara’s group noted that in their study, patients who switched from conventional in-center HD to extended-hours HD, serum phosphorus levels decreased into the range associated with lower risk for death in prior observational studies.

As far as the investigators are aware, their study is the largest to date of extended-hours HD. ■

Extended-Hours vs Conventional HD Extended-hours hemodialysis (HD) is associated with decreased mortality rates compared with conventional HD, according to a new study.

399

400

■ Conventional HD ■ Extended-Hours HD

80

64 60

300 200

211

40

0

14.7

20

100

Average treatment time (in minutes)

0

Crude mortality rate (deaths per 100 patient-years)

Source: Rivara MB et al. Extended-hours hemodialysis is associated with lower mortality risk in patients with end-stage renal disease.

Kidney Int. 2016; published online ahead of print.

is avoidance of the need for more frequent use of the patient’s vascular access, the investigators noted. In the Frequent Hemodialysis Network trials, they pointed out, patients undergoing more frequent HD were more likely to experience complications related to vascular access versus patients undergoing conventional HD. In contrast,

The investigators found that certain sociodemographic factors correlated with higher ER use, including being younger, female, black, or on Medicaid.

Tobacco use and institutionalization were other red flags.

Clinical factors included having a catheter or graft hemodialysis (HD) access, a recent diagnosis of ESRD, or comorbid conditions. The catheter-related problems could reflect infections and inadequate dialysis, Dr. Lovasik and colleagues stated. During the first year of ESRD, the most common comorbid conditions were respiratory abnormalities (6.6%), congestive heart failure (3.1%), and chest pain (2.9%). The underlying causes for 1.2% of ER visits were preventable: hyperkalemia (0.7%) and fluid overload (0.5%).

The team also identified factors associated with lower ER usage, including pre-ESRD nephrology care, erythropoietin use before ESRD, and private insurance coverage.

Almost half of ER visits by ESRD patients resulted in hospital admissions—a rate 4 times higher than the national average. The top reasons for admission during the first year of treatment were HD access complications (12.6%), septicemia (7.8%), and congestive heart failure (7.5%). ■

there is no evidence that thrice-weekly extended-hours HD is associated with an increase in access-related complications versus conventional HD. Noting that the average treatment times of patients treated with extendedhours HD exceeded those of conventional HD by more than 3 hours, they explained that this substantial

Study: Ultrasonography Alone for Kidney Stones Suboptimal ■

USING ULTRASONOGRAPHY (US) alone

researchers reported. CT detected 299

to detect kidney stones and determine

stones, whereas US detected 184.

their size may result in the inappro-

Assuming observational manage-

priate management of one-fifth of

ment would be recommended to

patients, investigators reported online

patients with 0–4 mm stones and

in BJU International.

patients with 5 mm or larger stones

In a retrospective study of 552 stone

could be counseled on the alterna-

patients comparing US with computed

tive of intervention, the investigators

tomography CT)—the gold standard

found that in 14% of cases where CT

for diagnosing kidney stones—Vishnu

would suggest observation, US would

Ganesan, BS, and colleagues at

lead to a recommendation for inter-

Cleveland Clinic in Ohio found that

vention. In contrast, when CT results

US had an overall sensitivity of 54%,

would suggest intervention, US would

although this increased with stone size.

suggest observation in 39% of cases,

In addition, US significantly overesti-

according to the investigators. On the

mated the size of stones in the 0–10

basis of US alone, 22% of patients, on

mm range. US had a specificity of 91%.

average, could have been inappropri-

Stone location and patients’ body

ately counseled.

mass index did not significantly affect

Stones classified as 5–10 mm based

US sensitivity, a finding consistent with

on US had the highest probability (43%)

previous studies.

of having their management recom-

The median time from US to CT scan was 11 days (range 5–23 days), the

mendation changed when CT was performed, the investigators reported.” ■

22 Renal & Urology News

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www.renalandurologynews.com

PCa Treatment Can Relieve Pre-Existing LUTS

BY NATASHA PERSAUD MEN WITH pre-existing lower urinary tract symptoms (LUTS) who undergo prostate cancer (PCa) treatment may on average experience relief rather than worsening of symptoms.

“Practitioners should consider the full spectrum of urinary symptom burden

evident before PCa treatment in treatment decisions,” Peter Chang, MD, MPH, of Beth Israel Deaconess Medical Center in Boston, and colleagues concluded in a report published online ahead of print in The Journal of Urology.

In a new analysis of a prospective, multicenter quality-of-life study, the

investigators compared patients’ perception of urinary symptoms before and 2 years after radical prostatectomy (RP), external beam radiation therapy (EBRT), and brachytherapy (BT), in 1021 American men with T1 or T2 PCa from the PROSTA-QA (Prostate Cancer Outcomes and Satisfaction with

Treatment Assessment) cohort. In addition to patient-reported urinary bother, the researchers monitored changes in urinary medication usage (alphablockers, 5-alpha reductase inhibitors, and anticholinergics) and urinary procedural interventions. Most men undergoing RP had nerve-sparing procedures. A majority of EBRT patients had intensity-modulated radiation treatment, with a third also receiving neoadjuvant hormonal therapy. Men selecting BT received permanent, lowdose radioactive implants. Less than 5% of men overall had adjuvant or salvage hormonal therapy. The median age of the entire cohort at study enrollment was 63 years. The patients who underwent RP, EBRT, and BT had median ages at enrollment of 60, 69, and 66 years, respectively.

Greatest symptom relief found in men who had a radical prostatectomy.

Rates of urinary medication usage before and 2 years after PCa treatment were 15% and 6%, respectively, for RP, 22% and 26% for EBRT, and 19% and 46% for BT. Urinary procedural intervention rates did not differ significantly among treatment groups.

The investigators compared urinary symptom burden before and after treatment by patients’ response to the following Expanded Prostate Cancer Index Composite (EPIC-26) question: “Overall, how much of a problem has your urinary function been for you?”, a global question that captures both LUTS and incontinence. For all patients across treatment groups, results showed urinary symptom burden improved for 23% and worsened for 28% following PCa treatment.

Using ordinal logistic regression analyses, the investigators identified pre-treatment urinary medication usage and pre-treatment moderate LUTS as favorable predictors of urinary symptom relief. On average, those men with moderate to severe pre-treatment LUTS perceived relief of their overall urinary symptoms after PCa treatment. Men with pre-existing LUTS who had RP experienced the greatest overall urinary symptom relief, even after considering new urinary incontinence in some men. ■ RU_7x10_Legal.indd 1

4/18/16 12:12 PM

www.renalandurologynews.com

OCTOBER 2016

Renal & Urology News 23

Ongoing Clinical Trials The following listings of clinical trials are based on information from the ClinicalTrials.gov Web site maintained by the National Institutes of Health. Only trials that are currently enrolling patients are included.

Spotlight

PROSTATE CANCER Novel Screening MRI for the Detection of Prostate Cancer Sponsor Case Comprehensive Cancer Center, Cleveland Collaborator National Cancer Institute, Bethesda, MD Estimated study completion date July 2017 Principal investigator Robert Abouassaly, MD robert.abouassaly@uhhospitals.org ClinicalTrials.gov Identifier NCT02131207

Trial Probes Web-Based Behavior Change Tool for PCa Patients RESEARCHERS at the Oregon Health & Science University Knight Cancer Institute in Portland, in collaboration with the National Cancer Institute, in Bethesda, Md., recently launched a randomized pilot study to examine how well a computer-based behavior change guide works in increasing physical activity in men with prostate cancer (PCa) who have received androgen-deprivation therapy (ADT).

The trial, whose principal investigator is Esther L. Moe, PhD, will have an estimated enrollment of 110 patients.

In a development phase, patients will view mock-ups of a computer-based behavior change guide (BCG) web design on a computer, iPad, or printed color paper and provide feedback with a one-on-one interview or separately using the think/talk aloud method followed by a one-on-one interview. After completion of these design

Phase II Open Label Investigation of the Safety and Efficacy of Pre-Operative Prostate Artery Embolization (PAE) Before Radical Prostatectomy in Prostate Cancer Patients

rounds, patients will use the BCG website and provide individual feedback.

Sponsor Shivank Bhatia, MD, University of Miami Collaborators Merit Medical Systems, Inc., South Jordan, UT Society of Interventional Radiology Foundation, Fairfax, VA Estimated study completion date September 2017 Principal investigator Shivank Bhatia, MD SBhatia1@med.miami.edu ClinicalTrials.gov Identifier NCT02173522

(American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer

KIDNEY TRANSPLANTATION Combined HLA-Matched Bone Marrow and Kidney Transplantation for Multiple Myeloma or Other Hematologic Disorders With End Stage Renal Disease Sponsor Massachusetts General Hospital, Boston Estimated study completion date February 2021 Principal investigator Thomas Spitzer, MD tspitzer@partners.org

Patients will be randomly assigned to 1 of 2 groups. Patients in group 1 will use the BCG website, which will collect personal information such as individual health priorities and goals, demographic data, health information, individual capabilities, physical activity level, and exercise preferences. Patients then receive a report with a personalized physical activity plan. Patients in group 2 will use a passive website Survivors). After completion of the trial, patients will be followed up at 2 months.

Lifestyle Management of CKD in Obese Diabetic Patients Sponsor NYU School of Medicine New York Estimated study completion date October 2019 Principal investigator Mary Ann Sevick, ScD, RN mary.sevick@nyumc.org ClinicalTrials.gov Identifier NCT02276742

Pathways to Improving Functional Capacity in Older Patients With Chronic Kidney Disease and Cardiovascular Disease Sponsor Wake Forest School of Medicine, Winston-Salem, NC Estimated study completion date June 2017 Principal investigator Killian Robinson, MD ClinicalTrials.gov Identifier NCT02473705

The estimated study completion date is July 2017. The ClinicalTrials.gov identifier is NCT02869412. Dr. Moe’s email address is moe@oshu.edu. ■

ClinicalTrials.gov Identifier NCT02158052

Non-Invasive Evaluation of the Transplant Kidney Using OCT Sponsor Georgetown University, Washington, DC Estimated study completion date May 2018 Principal investigator Peter M. Andrews, PhD andrewsp@georgetown.edu ClinicalTrials.gov Identifier NCT02084966

Transplant Society Worker Support for Live Kidney Donation in African Americans Sponsor Duke University, Durham, NC Collaborator National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD

Estimated study completion date November 2017 Principal investigator Leigh E. Boulware, MD, MPH ClinicalTrials.gov Identifier NCT02369354

CHRONIC KIDNEY DISEASE The COMBINE Study: The CKD Optimal Management With BInders and NicotinamidE Sponsor John Kusek, PhD National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD Estimated study completion date June 2018 Principal investigator Jennifer J. Gassman, PhD Cleveland Clinic ClinicalTrials.gov Identifier NCT02258074

KIDNEY STONES The EDGE Consortium: A Randomized Trial of Preoperative Prophylactic Antibiotics Prior to Percutaneous Nephrolithotomy: Part 1 Sponsor University of California San Diego Estimated study completion date March 2017 Principal investigator Roger L. Sur, MD rlsur@mail.ucsd.edu ClinicalTrials.gov Identifier NCT02384200

Validation of the Wisconsin StoneQOL, a Quality of Life Survey for Kidney Stone Formers Sponsor University of Wisconsin, Madison Estimated study completion date June 2018 Principal investigator Stephen Y. Nakada, MD ClinicalTrials.gov Identifier NCT02188108 ■

24 Renal & Urology News

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BMI Predicts RCC Patient Death Risk Study demonstrates improved survival following targeted treatment among overweight patients RENAL CELL carcinoma (RCC) that develops in individuals with a high body mass index (BMI) is associated with better survival after targeted treatment for metastatic disease than RCC that develops in those with a low BMI, data show.

The study, led by Toni K. Choueiri, MD, of the Dana-Farber Cancer Institute in Boston, included 1975 RCC patients in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) who received targeted therapy and an external validation cohort of 4657 RCC patients who received targeted treatment in clinical trials.

In the IMDC cohort, median overall survival (OS) following first-line treatment was 25.6 months in patients with a high BMI (25 kg/m2 or higher) compared with 17.1 months in those with a low BMI (less than 25 kg/m2), Dr. Choueiri’s group reported online ahead of print in the Journal of Clinical Oncology. Following second-line therapy, median OS was 16.4 months in the high-BMI group compared with 8.7 months in the low-BMI group. The differences in survival corresponded to a 16% and 42% decreased risk of death among patients with a high BMI. In the validation cohort, the median OS after first-line treatment was 23.4

Body Mass Index and Survival Renal cell carcinoma (RCC) diagnosed in patients with a body mass index (BMI) of 25 kg/m2 or higher is associated with longer survival compared with RCC diagnosed in patients with a BMI less than 25 kg/m2, according to a new study. Shown here are the median survival times in months following first- and second-line treatment in the study’s IMDC* cohort.

30 25 20

30

25.6

25

17.1

20

15

15

10

10

5

5

0

First-line treatment

0

■ BMI 25 kg/m2 or higher ■ BMI less than 25 kg/m2 16.4 8.7

Second-line treatment

*International Metastatic Renal Cell Carcinoma Database Consortium Source: Albiges L et al. Body mass index and metastatic renal cell carcinoma: Clinical and biological correlations.

J Clin Oncol. 2016; published online ahead of print.

months in the high-BMI group compared with 14.5 months in the low-BMI group. After second-line treatment, median OS was 19.8 and 14.9 months, respectively. The survival differences corresponded to a 17% decreased risk of death in the high-BMI group.

In the IMDC cohort, the median time to failure of first-line treatment was 8.1 months in the high-BMI group compared with 5.7 months in the low-BMI group, which corresponded to a 14% decreased risk of primary treatment

among patients with a high BMI. In the validation cohort, median progressionfree survival times were 8.2 and 5.5 months in the high- and low-BMI groups, respectively, a significant difference that corresponded to an 18% decreased risk of progression in the high-BMI group.

“We demonstrated that patients with high BMI had a more favorable survival outcome than patients with low BMI. This finding is consistent in the firstand second-line settings for all end points examined including OS, even

after adjusting for IMDC prognostic criteria and other baseline characteristics.”

The researchers also examined relationship between of fatty acid synthase (FASN) and BMI using specimens from the IMDC biospecimen cohort.

FASN gene expression has been shown to be associated with poor prognosis in various tumor types, including RCC, they noted. The investigators used tissue microarrays from 146 patients who received targeted therapy. At the time of analysis, 122 deaths had occurred (84%). FASN immunohistochemistry staining positivity was recorded in 45 (31%) of the 146 patients. The investigators detected FASN positivity more frequently in poor- and intermediaterisk patients than in favorable risk patients. OS was 27.5 months in FASNnegative patients compared with 14.5 months in FASN-positive patients.

In adjusted analyses, FASN-positive patients had a 28% increased risk of death versus FASN-negative patients.

As for how obesity could be associated with improved outcomes in patients with mRCC, the researchers cited a previous study suggesting that longer survival among obese patients versus normalweight patients is due to a less aggressive disease subtype. ■

Bisphosphonates Benefit Kidney Transplant Patients

BY NATASHA PERSAUD BISPHOSPHONATE drugs increase bone mineral density (BMD) in kidney transplant recipients, a new systematic review and meta-analysis confirms.

Early bisphosphonate therapy within the first 6 months of transplant is the most beneficial.

Study findings strengthen the case for bisphosphonate therapy in kidney transplantation recipients, said investigator Craig Gordon, MD, MS, of Boston University School of Medicine. Selection of this treatment needs to be individualized, however, because concerns remain about these agents causing higher rates of adynamic bone disease. “So, the benefit in BMD may be offset by this increase in adynamic bone disease, which is perhaps why at this point the evidence is not strong enough to recommend bisphosphonates universally to all kidney transplant recipients with reduced BMD,” Dr. Gordon told Renal & Urology News.

Mineral and bone disorders develop in kidney transplant patients due to a combination of factors, he explained, such as abnormal bone turnover from chronic kidney disease that is exacerbated by corticosteroid use or tertiary hyperparathyroidism after transplantation, among

The drugs improved bone mineral density at the lumbar spine and femoral neck. other causes. BMD of the lumbar spine drops in the first 6 months of transplant and declines still further for up to 18 months. Fracture rates are high among kidney recipients, ranging up to 44%, likely due to the bone loss.

To update estimates of BMD and fracture rates, Dr. Gordon and colleagues

performed a systematic review of 12 randomized controlled trials and prospective studies with a reference group published before October 2015. All 12 studies of 625 patients reported on lumbar spine BMD, whereas 7 studies with 287 patients also reported on femoral neck BMD. At baseline, mean creatinine was 1.49 mg/dL, calcium was 9.66 mg/dL, and phosphorus was 4.83 mg/ dL. Pre-treatment BMD in the femoral neck and lumbar spine was 0.845 and 1.057 g/cm2, respectively.

Results published in Clinical Transplantation showed that bisphosphonate therapy improved femoral neck and lumbar spine BMD in transplant recipients compared with control patients by 0.055 g/cm2 and 0.053 g/ cm2, respectively, without worsening serum creatinine in the allograft or serum calcium levels. By percentage, BMD improved by 6.0% and 7.4%, respectively. BMD did not differ by

route of bisphosphonate administration (oral or intravenous). The investigators found no difference in fracture incidence between groups. “The studies in our meta-analysis had relatively small sample sizes, relatively short followup times, and did not assess for occult fractures, each of which might have increased the statistical power to detect a difference in fracture risk, if one exists,” Dr. Gordon said.

The findings corroborate 2 previous meta-analyses that showed an association between bisphosphonate therapy and increased BMD (Nephrol Dial Transplant 2006;21:2275-2281 and Cochrane Database Syst Rev 2007;3:CD005015).

The 2009 KDIGO (Kidney Disease Improving Global Outcomes) guidelines on Caring for the Kidney Transplant Recipient suggest clinicians consider bisphosphonate therapy in kidney transplant recipients based on limited evidence. ■

www.renalandurologynews.com

OCTOBER 2016

Renal & Urology News 25

Poor ESA Response, Mortality Linked Researchers develop a new definition of suboptimal response to erythropoiesis-stimulating agents INVESTIGATORS HAVE identified a new definition of erythropoiesis-stimulating agent (ESA) hyporesponsiveness in hemodialysis (HD) patients, and, using that definition, found that this condition is “potently and persistently” associated with increased mortality, according to a new report.

“This study represents the first analysis of ESA hyporesponsiveness since the 2011 changes in the US ESA labels and reimbursement policy and the concomitant changes in ESA dosing practices,” a team led by Jiacong Luo, MD, MS, MPH, of DaVita Clinical Research in Minneapolis, Minnesota, reported online in the American Journal of Kidney Diseases. “In the context of these changes, we identified a new operational definition of ESA hyporesponsiveness that is conceptually aligned with the underlying construct, meets with expectations regarding its historical prevalence, and is

relevant in contemporary practice.”

During 2011, the Centers for Medicare & Medicaid Services changed the reimbursement policy for injected drugs for dialysis patients, and the FDA required changes to ESA product labeling, resulting in marked ESA dose reductions for treating the anemia of kidney disease.

It is unclear if ESA hyporesponsiveness has a causal role in patient deaths.

The investigators defined ESA hyporesponsiveness as 2 consecutive hemoglobin measurements less than 10 g/dL (every other week) with contemporaneous ESA dose greater than 7700 U per treatment. Among candidate definitions,

Black Men on AS More Likely to Harbor Higher-Risk PCa BLACK MEN WITH clinically localized

(11.2%) were black. Patients transi-

prostate cancer (PCa) initially managed

tioned from active surveillance (AS)

with active surveillance are more likely

and underwent RP from 2010 to 2013.

than non-black men to have higher-risk

The selected endpoints were patho-

disease at radical prostatectomy (RP),

logic upgrading to Gleason scores

according to a new study published

above 6 (primary) or above 7 (second-

online ahead of print in The Journal of

ary) and/or upstaging to pathological

Urology.

T3 or 4 or N1 disease.

The study findings support the

Black men had 20% greater odds

hypothesis that black race itself is an

of upgrading at RP to Gleason score

influential factor in PCa progression.

above 6 and/or upstaging, the study

Previous studies offered conflicting

found. In addition, black race indepen-

results because race often could not

dently predicted upgrading to Gleason

be investigated apart from complicat-

score above 7 and/or upstaging.

ing factors such as low income and

Results held after stratification and

comorbidity burden.

multivariable modeling accounting for

Robert Aboussaly, MD, MS, of University Hospitals Case Medical Center in Cleveland, and colleagues

important confounders, according to the investigators.

Black men with clinically low-risk PCa

queried the robust and nationally

“are more likely to harbor higher-risk

representative National Cancer Data

disease, which may lead to adverse out-

Base, which captures 70% of new

comes,” Dr. Aboussaly and colleagues

cancer diagnoses in the United States.

concluded. “By itself, this finding

Of 48,473 American men with clini-

does not preclude active surveillance;

cally low-risk PCa (clinical stage T2a

however, race should be considered

or below, Gleason score 6 or below,

as men weigh the risks and benefits of

and PSA level below 10 ng/mL), 5411

active surveillance versus treatment.” ■

this combination of factors “met with prior expectations with regard to the prevalence of ESA hyporesponsiveness: approximately 9% to 12% of hemodialysis patients receiving ESA therapy at any time.”

Dr. Luo and colleagues studied 98,972 HD patients, of whom 12,361 (12.5%) had ESA hyporesponsiveness according to the new definition. Patients with ESA hyporesponsiveness were identified during the first quarter of 2012 and followed up through 2013. At baseline, the mean hemoglobin level among those with ESA hyporesponsiveness was about 1 g/dL lower than in patients without ESA hyporesponsiveness. This difference narrowed during follow-up to 0.4 g/dL, the investigators reported.

Initially, mean ESA use was about 3-fold greater for patients with than without ESA hyporesponsiveness, according to investigators. Mean ESA

use decreased to 2-fold greater at the end of the study. Iron use and missed HD treatment rates were greater among patients with than without ESA hyporesponsiveness.

In the second quarter, patients with ESA hyporesponsiveness were 2.2 times as likely to die as those without ESA hyporesponsiveness; by study end, their death risk was 1.5 times greater.

“At a minimum, ESA hyporesponsiveness, as defined here, can be considered to be a prognostic marker with important clinical and economic implications.”

Dr. Luo’s group said it is unclear whether ESA hyporesponsiveness is a causal determinant of mortality, perhaps due to toxic effects of resultantly high ESA doses, or whether the excess mortality is related to the conditions that render patients hyporesponsive to ESAs, or other differences between patients with and without ESA hyporesponsiveness. ■

Phosphorus May Predict LVH Risk

predicted left ventricular mass index, along with gender, systolic blood pressure, and estimated glomerular filtration rate. It also predicted left ventricular end diastolic dimension, although not relative wall thickness. After multivariable analyses, serum phosphorus was significantly and independently associated with greater prevalence of left ventricular hypertrophy (LVH). In a fully adjusted model, each 1 mmol/L increase in serum phosphorus level was associated with a significant 2.4-fold increase in the odds of LVH. Compared with the 1st tertile of phosphorus level, the 3rd tertile was associated with a significant 2.5-fold increased odds of LVH.Neither renal function decline nor systolic blood pressure solely explained changes to cardiac structure and function, although they no doubt contributed. Serum calcium and intact parathyroid hormone levels also did not account for the findings.

“These results suggest that serum phosphorus might be a mediator for left ventricular eccentric remodeling in CKD,” Dr. Jiang and colleagues stated in the International Journal of Cardiology (2016;221:134-140).

Eccentric LVH possibly results from volume overload, whereas concentric LVH may result from afterload, such as hypertension, they explained.

As the current study was cross-sectional in design, it precludes the establishment of cause and effect. ■

BY NATASHA PERSAUD HIGHER SERUM phosphorus levels are associated with a greater likelihood of left ventricular remodeling.

The prevailing theory has been that serum phosphorus increases vascular and valvular calcification. Yet other processes involving phosphorus also may be contributing to cardiovascular damage and, in turn, heart failure, arrhythmias, and sudden cardiac death.

Investigators led by Geng-Ru Jiang, MD, of Xin Hua Hospital in Shanghai, China, studied left ventricular remodeling via transthoracic echocardiography in 296 hospitalized patients (average age 56.4) with pre-dialysis chronic kidney disease (CKD) who were free of symptomatic heart failure. Two-thirds of patients (68.6%) had hypertension.

Of these, 58% took antihypertensive medication; and 21.6% overall had diabetes. Most of the patients were never treated with phosphate binders or calcitriol, and all received no treatment within 2 weeks of hospitalization.

Serum phosphorus, assessed by tertiles from 1.04 to 2.02 mmol/L, independently

26 Renal & Urology News

OCTOBER 2016

www.renalandurologynews.com

Practice Management W

hen it enacted HIPAA, the Department of Health and Human Services (HHS) chose to use a carrot rather than stick approach to enforcing the law. Penalties have been given for major breaches, but aside from that, there is little financial skin in the game for providers. At least until now.

When a provider wrongfully discloses protected health information, HIPAA does not provide patients with a legal remedy other than reporting the incident to HHS. But courts have begun to look at the issue differently, ruling in some cases that providers can be sued under state rules pertaining to privacy and negligence for breaches.

“Courts are beginning to say that just because the federal government didn’t give a remedy, it shouldn’t preclude patients from bringing a suit in states,” said Chad Eckhardt, a member

There are numerous torts for which individuals can seek redress for personal injury, but some are not suitable for filing lawsuits related to HIPAA violations.

Two such torts are invasion of privacy and public disclosure of private facts, Eckhardt said. Plaintiffs must prove damages. Those torts rarely result in physical damage, so plaintiffs have to prove mental or emotional distress. Courts, he said, are reluctant to provide a remedy for nonphysical damage under torts.

Negligence is another category that requires plaintiffs to prove damages.

Under this tort, physicians can be considered negligent because they did not comply with a standard of conduct (HIPAA). “If the federal government says this is the minimum standard of confidentiality and you don’t meet those minimum standards, you are negligent as a matter of fact,” Eckhardt said.

Courts have ruled that providers can be sued under state rules pertaining to privacy and negligence for information breaches. in the regulated business group at Frost Brown Todd, which has its headquarters in Cincinnati, Ohio.

Recourse at the state level It was a 2014 Supreme Court decision in Connecticut that set a precedent allowing providers to be sued for HIPAA violations. A patient filed a lawsuit against her obstetrician when the provider mailed her medical records to a court in response to a subpoena related to paternity suit filed by her ex. She was not informed of the subpoena by her provider and she filed for negligence, negligent emotional distress, breach of contract, and negligent misrepresentation as to the safety of her records. Although originally dismissed, her case ended up at the state supreme court, which ruled that her case stated a claim for which relief may be granted and remanded it for trial.

Breach of contract is another option for plaintiffs, though the damages are much less than with a tort, Eckhardt said. Some states, like Ohio and West Virginia, have also created torts specifically for the unauthorized disclosure of medical records.

“More states are creating this tort for unauthorized released of records and if they don’t have one, courts are going to try to find a remedy for harm done if there is actual damage to an individual,” Eckhardt said.

Setting precedent A case out of Indiana was the first to show that employers can be held accountable for their staffs’ HIPAA violations. A patient sued Walgreens and one of its pharmacists when she found out the pharmacist had looked up and released medical records to the plaintiff’s ex-boyfriend. The pharmacist was

© THINKSTOCK

Patients whose protected health information is wrongfully disclosed can file lawsuits against providers in state courts BY TAMMY WORTH

Courts will try to find a remedy if actual damage is done to an individual.

currently married to the woman’s ex, to whom she provided prescription information. The woman won $1.4 million in damages, holding Walgreens accountable for the employees’ breach of confidentiality under HIPAA for reasons including negligent supervision.

Physicians need to ensure they are training all employees upon hiring them and annually thereafter, he said. Consistent training can help a provider prove they have not been negligent in supervision of their employees and reduce their liability.

As part of training, the importance of caring for hypersensitive information like HIV status and mental health conditions should be emphasized. In addition, practices need to review office processes to determine where people can get tripped up.

“Courts are going to try to find a remedy for harm done if there is actual damage to an individual,” Eckhardt said. ■ Tammy Worth is a freelance medical journalist based in Blue Springs, MO.

HIPAA Lawsuits Following are examples of cases filed by patients at the state level after a breach of their protected health information: • When a Princeton Health Care System employee was hospitalized in 2012, it was noted in her medical records that she was HIV-positive. Two years later, her records were breached by another employee and the information was spread among co-workers. The hospital notified the woman and said corrective action was being taken, but she sued for negligence.

• The Cleveland Clinic was sued by a patient for invasion of privacy after staff released medical records in response to a subpoena. The hospital said it was allowed under HIPAA, but the courts ruled that the stricter state privacy standards superseded federal law.

• A medical group in Indiana sent a patient’s records to collections after failure to pay his bill. Sensitive patient information was not redacted, and when the paperwork was given to the court his HIV-positive status was part of public record.

The man sued the practice and was awarded $1.25 million in damages.

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

LET’S STRONG

DO

THIS

TOGETHER

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)

For more than

5 years,

ZYTIGA® has been prescribed to men battling mCRPC1

5

years

ZYTIGA® has been prescribed for more than

80,000 patients

ZYTIGA® was the

#1 prescribed

oral medication for mCRPC in 20151

in the United States since its approval in April 20111 The median seating capacity of a professional football stadium is 69,000

IMPORTANT SAFETY INFORMATION Hepatotoxicity—In postmarketing experience, there have been ZYTIGA®-associated severe hepatic toxicities, including fulminant hepatitis, acute liver failure and deaths. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Re-treatment with ZYTIGA® at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN. Permanently discontinue ZYTIGA® for patients who develop a concurrent elevation of ALT greater than 3X ULN and total bilirubin greater than 2X ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation.

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

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

Let’s do this Established safety profile

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

ZYTIGA® in geriatric patients

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

IMPORTANT SAFETY INFORMATION—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®.

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

051320-160413

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

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

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

Learn more today at www.zytigahcp.com

STRONG T O G E T H E R

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

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

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

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

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

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

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

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

In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received 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 ZYTIGA 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 ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

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

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

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

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

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

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

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

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

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

Table 1: Adverse Reactions due to 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

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

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

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0.

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

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

1 Adverse

events graded according to CTCAE version 3.0. terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness. terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness.

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

5 Includes all fractures with the exception of pathological fracture.

6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia.

7 Includes terms Angina pectoris, Chest pain, and Angina unstable.

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

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased.

2 Includes 3 Includes

Table 2 shows laboratory abnormalities of interest from Study 1.

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

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

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

Table 3: Adverse 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

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

Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws.

Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%).

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

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

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

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

Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis.

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

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

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

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

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

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

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

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

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

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose.

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

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

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

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

Geriatric Use: Of the total number of patients receiving 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 ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

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

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

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

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

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

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

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

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

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

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

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

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

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

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

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

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

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

• Patients should be informed that 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: May 2016 051318-160413