RUN Jan/Feb 2015 Issue by Haymarket Media

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V O L U M E 14, I S S U E N U M B E R 1

CKD Prevalence Projected to Rise

High lifetime risk found among adults aged 30 plus BY JODY A. CHARNOW THE PREVALENCE of chronic kidney disease (CKD) is projected to grow from 13.2% currently to 14.4% by 2020 and 16.7% by 2030 among U.S. adults aged 30 years and older, according to a new study that also found that individuals in this age group have a high lifetime risk for CKD. Combining the projections of CKD prevalence with overall population projections, Thomas J. Hoerger, PhD, of RTI International in Research Triangle Park, N.C., and colleagues estimated that the number of Americans aged 30 years and

Big Waists Up ESRD Risk In Older Women

Low household income strongly predicts ESRD risk

Cardiovascular risks are higher in ESRD patients with osteoporosis

Allopurinol treatment may slow kidney disease progression

Kidney stones raise coronary heart disease risk in women

Renal insufficiency is linked to higher uric acid levels

A history of kidney stones ups CHD risk in women. PAGE 14

IN THIS ISSUE 3

older with CKD will reach 28 million in 2020 and about 38 million in 2030. “This increase suggests that CKD health care costs and quality-of-life losses will increase accordingly and further emphasizes the need to develop new interventions to slow the onset and progression of CKD,” Dr. Hoerger’s team wrote in a report published online ahead of print in the American Journal of Kidney Diseases. The researchers based their projections on a simulation model based on nationally representative data from persons aged 30 years and older who partici-

CENTRAL OBESITY, as measured by waist circumference, is associated with an increased risk of end-stage renal disease (ESRD) among postmenopausal women, even those with a normal body mass index (BMI), according to a recently published study. Nora Franceschini, MD, of the University of North Carolina in Chapel Hill, and collaborators studied 20,117 postmenopausal women who participated in the Women’s Health Initiative (WHI) program, a prospective population-based cohort study investigating postmenopausal women’s health in the United States.

n n n

www.renalandurologynews.com LIFETIME CKD RISK HIGH

Chronic kidney disease (CKD) will likely develop in more than half of U.S. adults aged 30–64 years during their lifetime, according to a recently published report. The lifetime incidence of CKD by age group is shown here.

30 –49 years

50 –64 years

65 years and older

54% 52% 42% Source: Hoerger TJ et al. The future burden of CKD in the United States: A simulation model for the CDC CKD initiative. Am J Kidney Dis. 2014; published online ahead of print.

pated in the 1999–2010 National Health and Nutrition Examination Surveys. Meanwhile, according to the U.S. Renal Data System 2014 Annual Data Report, the prevalence of end-stage renal disease (ESRD), the most severe stage of CKD, continues to rise. On December

31, 2012, the U.S. had 636,905 ESRD cases, an increase of 3.7% since 2011. The prevalent dialysis population (both hemodialysis and peritoneal dialysis) grew to 449,342 in 2012, up 3.8% from 2011 and a 54% increase from 2000. On continued on page 8

Hyperkalemia Drugs Effective BY JODY A CHARNOW NEW investigational drugs show promise for the treatment of hyperkalemia, according to researchers. Sodium zirconium cyclosilicate (ZS9), a novel selective cation exchanger, decreased serum potassium levels significantly compared with placebo in 2 studies of patients with hyperkalemia. Patiromer, a non-absorbed potassium binder, significantly decreased serum potassium levels in a study of hyperkalemic patients with chronic kidney disease (CKD) receiving renin-angiotensin-aldosterone system (RAAS) inhibitors. Compared with placebo, patiromer therapy was associated with

a significant reduction in the recurrence of hyperkalemia. David K. Packham, MD, of Melbourne Renal Research Group in Australia, and colleagues conducted a multicenter, double-blind phase 3 trial in which they randomly assigned 753 patients with hyperkalemia (serum potassium level higher than 5 mmol/L) to receive either ZS-9 at doses of 1.25 2.5, 5, or 10 grams or placebo 3 times daily for 48 hours. At 48 hours, the mean serum potassium level had decreased from 5.3 mmol/L at baseline to 4.9 mmol/L in the patients who received 2.5 grams of continued on page 8

PRACTICE MANAGEMENT

continued on page 8

Bundled payments may present specialists with opportunities PAGE 16 How to set prices for bundled services

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V O L U M E 14, I S S U E N U M B E R 1

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Study: Prostate Cancer Overtreated

NEW FINDINGS CONFIRM an overuse of aggressive prostate cancer treatment.

BY JODY A. CHARNOW MOST MEN aged 66 to 79 years who have low- or intermediate-risk prostate cancer (PCa) and life expectancies of less than 10 years receive treatment with surgery or radiation, despite national guidelines recommending against such aggressive therapy in these patients, according to a new report. Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, Timothy J. Daskivich, MD, of the University of California Los Angeles (UCLA), and colleagues sampled 96,032 men aged 66 years or older with early-stage PCa and Gleason scores of 7 or less. A total of 50,048 men (52%) had life expectancies of less than

MRI-TRUS Fusion Biopsy Accurate Infected Stones BY JODY A. CHARNOW colleagues retrospectively reviewed 135 Raise Post-Op TARGETED BIOPSIES using magnetic consecutive patients who sequentially resonance imaging-transrectal ultra- underwent pre-biopsy MRI, MRI-TRUS Sepsis Risk sound (MRI-TRUS) fusion can reliably image-fusion biopsy and robotic radical predict the location and primary Gleason pattern of an index prostate tumor with 90% or greater accuracy, according to a new study. This approach, however, has limited ability to predict cancer volume. Eduard Baco, MD, of Oslo University Hospital Aker in Oslo, Norway, and

prostatectomy (RP) from January 2010 to September 2013. The investigators performed image-guided biopsies of MRIsuspected index tumor (IT) lesions with tracking via real-time 3D TRUS. The investigators defined IT as the lesion with continued on page 8

PRACTICE MANAGEMENT

Bundled payments may provide specialists with opportunities How to set prices for bundled services

PAGE 16

BY JODY A. CHARNOW POSITIVE KIDNEY stone cultures independently predict an increased risk of sepsis after percutaneous nephrolithotomy (PCNL), Israeli researchers concluded. Ohad Shoshany, MD, and colleagues at Tel Aviv University studied 206 consecutive patients undergoing PCNL. Forty-five patients had a positive stone culture (group A). These patients were compared with 161 patients who had a sterile stone culture (group B). Postoperative sepsis occurred in 31% of group A versus 5.9% of group B. In multivariate analysis, a positive stone culture was independently associated with a significant 6.9 times increased odds of postoperative sepsis, the researchers reported online in Urolithiasis. According to the investigators, all patients responded well to treatment and experienced no septic complications. Among the patients with positive cultures, Enterococcus species and Escherichia coli were the most prevalent

10 years, as determined using patient age and comorbidities at PCa diagnosis. In this group, 68% of men aged 66 to 69 years, 69% of those aged 70 to 74 years, 57% of those aged 75 to 79 years, and 24% of those aged 80 years and older received aggressive treatment (radical prostatectomy, external beam radiotherapy, or brachytherapy), Dr. Daskivich’s group reported online ahead of print in Cancer. Even men with the heaviest comorbid disease burdens were frequently treated aggressively, the researchers noted. For example, among men aged 66 to 69 and 70 to 74 years with a Charlson score of 3 or higher, 60% and 50%, continued on page 8

IN THIS ISSUE 4

Robotic prostatectomy offers good long-term outcomes

Music found to decrease the pain and anxiety of prostate biopsy

Clinical stage T2c tumors should be considered intermediate risk

Shockwave therapy may improve erectile dysfunction in some men

Perioperative chemotherapy for MIBC is on the rise

Kidney stones increase women’s risk of coronary heart disease

Salvage cryotherapy shows promise for recurrent PCa

A history of kidney stones ups CHD risk in women. PAGE 14

Many men undergo radical surgery or radiotherapy despite life expectancies of less than 10 years

continued on page 8

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www.renalandurologynews.com JANUARY/ FEBRUARY 2015

Brief Summary: Please see Full Prescribing Information for additional information

seen in animal studies with doses up to 16 times the maximum recommended clinical dose on a body weight basis. The effects of Velphoro on labor and delivery in humans are not known. Nursing Mothers Since the absorption of iron from Velphoro is minimal, excretion of Velphoro in breast milk is unlikely.

INDICATIONS AND USAGE Velphoro (sucroferric oxyhydroxide) is a phosphate binder indicated for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis. DOSAGE AND ADMINISTRATION Velphoro tablets must be chewed and not swallowed whole. To aid with chewing and swallowing, tablets may be crushed. The recommended starting dose of Velphoro is 3 tablets (1,500 mg) per day, administered as 1 tablet (500 mg) 3 times daily with meals. Adjust by 1 tablet per day as needed until an acceptable serum phosphorus level is reached, with regular monitoring afterwards. Titrate as often as weekly.

Pediatric Use The safety and efficacy of Velphoro have not been established in pediatric patients. Geriatric Use Of the total number of subjects in two active-controlled clinical studies of Velphoro (N=835), 29.7% (n=248) were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. OVERDOSAGE There are no reports of overdosage with Velphoro in patients. Since the absorption of iron from Velphoro is low, the risk of systemic iron toxicity is low. Hypophosphatemia should be treated by standard clinical practice. Velphoro has been studied in doses up to 3,000 mg per day.

WARNINGS AND PRECAUTIONS

HOW SUPPLIED/STORAGE AND HANDLING Velphoro are chewable tablets supplied as brown, circular, bi-planar tablets, embossed with “PA 500” on 1 side. Each tablet of Velphoro contains 500 mg iron as sucroferric oxyhydroxide. Velphoro tablets are packaged as follows: NDC 49230-645-51 Bottle of 90 chewable tablets

Patients with peritonitis during peritoneal dialysis, significant gastric or hepatic disorders, following major gastrointestinal surgery, or with a history of hemochromatosis or other diseases with iron accumulation have not been included in clinical studies with Velphoro. Monitor effect and iron homeostasis in such patients.

Storage Store in the original package and keep the bottle tightly closed in order to protect from moisture. Store at 25°C (77°F) with excursions permitted to 15 to 30°C (59 to 86°F).

ADVERSE REACTIONS

PATIENT COUNSELING INFORMATION Inform patients that Velphoro tablets must be chewed and not swallowed whole. To aid with chewing and swallowing, the tablets may be crushed [see Dosage and Administration]. Velphoro should be taken with meals. Instruct patients on concomitant medications that should be dosed apart from Velphoro [see Drug Interactions]. Inform patients that Velphoro can cause discolored (black) stool.

DOSAGE FORMS AND STRENGTHS Velphoro (sucroferric oxyhydroxide) chewable tablet 500 mg. CONTRAINDICATIONS None.

In a parallel design, fixed-dose study of 6 weeks duration, the most common adverse drug reactions to Velphoro chewable tablets in hemodialysis patients included discolored feces (12%) and diarrhea (6%). To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Medical Care North America at 1-800-323-5188 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Velphoro can be administered concomitantly with oral calcitriol, ciprofloxacin, digoxin, enalapril, furosemide, HMG-CoA reductase inhibitors, hydrochlorothiazide, losartan, metoprolol, nifedipine, omeprazole, quinidine and warfarin. Take doxycycline at least 1 hour before Velphoro. Velphoro should not be prescribed with oral levothyroxine.

Distributed by: Fresenius Medical Care North America 920 Winter Street Waltham, MA 02451

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B: Reproduction studies have been performed in rats and rabbits at doses up to 16 and 4 times, respectively, the human maximum recommended clinical dose on a body weight basis, and have not revealed evidence of impaired fertility or harm to the fetus due to Velphoro. However, Velphoro at a dose up to 16 times the maximum clinical dose was associated with an increase in post-implantation loss in pregnant rats. Animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Labor and Delivery No Velphoro treatment-related effects on labor and delivery were

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Renal & Urology News 3

Low Income Raises Risk of ESRD LOW HOUSEHOLD INCOME is a stronger indicator of end-stage renal disease (ESRD) risk than community poverty, according to a new study. “The findings of our study support a focus on individual rather than community resources when attempting to reduce disparities in ESRD, and emphasize the need to prevent and better manage established CKD risk factors such as diabetes and hypertension among low income individuals,” wrote the researchers led by Deidra C. Crews, MD, assistant professor of medicine at Johns Hopkins University School of Medicine in Baltimore. For the study, published online in BMC Nephrology, the investigators analyzed data for 23,314 adults aged 45 and older in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. They looked at demographic factors such as race, household income, and geographically concentrated county poverty. A majority of participants resided in the “stroke belt,” an area of the southeastern United States with a higher-than-usual number of strokes. During follow-up, ESRD developed in 158 individuals. ESRD incidence was 178.8 per 100,000 persons per year in counties of highest poverty and 76.3 per 100,000 persons in the most affluent counties. However, these differences were almost entirely accounted for by race and income. Notably, the odds of ESRD were almost 4 times higher among people with an annual household income of less than $20,000 compared with those making more than $75,000, according to the investigators. Few participants (6.7%) lacked health insurance. The researchers cited some study limitations. For example, many participants did not provide information about their annual household income. Those who did made up a greater proportion of participants living in less affluent communities than did those residing in more affluent communities. The researchers’ measure of annual household income did not take into account household size, and thus may have failed to classify people with larger household incomes and a large family as economic disadvantaged. n

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4 Renal & Urology News

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RARP Offers Good Long-Term Results Study of 4,803 patients reveals oncologic control on par with other radical surgery approaches RARP Outcomes Durable Researchers who studied what they believe to be the largest series of patients to undergo robot-assisted radical prostatectomy (RARP) revealed that this modality is associated with long-term outcomes on par with other radical surgery approaches. Shown here are the 8-year actuarial rates of biochemical recurrence-free survival (BCRFS), metastasis-free survival (MFS), and cancer-specific survival (CSS). 100

■ biochemical

recurrence-free survival

■ metastasis-free

survival

40 20 0

■ cancer-specific

survival

81%

98.5%

99.1%

BCRFS

MFS

CSS

8-year actuarial rates of survival Source: Sukumar S et al. Oncological outcomes after robot-assisted radical prostatectomy: long-term follow-up in 4803 patients. BJU Int. 2014;114:824-831.

BY JODY A. CHARNOW ROBOT-ASSISTED radical prostatectomy (RARP) confers excellent longterm control of prostate cancer, according to a study of what researchers believe is the largest series to date to look at oncologic outcomes after RARP. The study, by investigators at the Henry Ford Health System’s Vattikuti Urology Institute in Detroit, included 4,803 of 5,152 patients who underwent RARP at the institute from 2001 to 2010. After a median follow-up of 26.4 months, biochemical recurrence (BCR) occurred in 470 patients (9.8%) and metastatic disease developed in 31 patients (0.7%); 13 patients died from prostate cancer (0.3%). Results also showed that the actuarial 8-year BCR-free survival (BCRFS), metastasis-free survival (MFS), and cancer-specific survival (CSS) rates were 81%, 98.5%, and 99.1%, respectively, the investigators reported in BJU International (2014;114:824-831). Among men with node-positive disease, the actuarial 5-year BCRFS, MFS, and CSS rates were 26%, 82%, and 97%, respectively. “This evaluation represents the largest of its kind and conclusively establishes that the long-term oncological outcomes following RARP are at par with the outcomes following other modalities of radical prostatectomy,” corresponding author Akshay Sood, MD, told Renal & Urology News. The study cohort had a mean age of 60 years and a preoperative PSA

News-RoboticPCa_RUN0215.indd 1

level of 6.1 ng/mL. Dr. Sood’s group defined BCR as a post-operative serum PSA level of 0.2 ng/mL or higher with a confirmatory value (a PSA value higher than 0.2 ng/mL at 2 different follow-ups). The investigators also identified predictors of BCR, which included preoperative PSA level, surgical margin status, and pathologic primary Gleason score. For example, among patients with organ-confined disease, patients with a preoperative PSA level of 10.1– 20 ng/mL had 2.4 times greater hazard of BCR than those with a level of 10 ng/mL or less. Patients with a positive surgical margin (PSM) had 3.8 times greater hazard of BCR compared with those who had a negative surgical margin. Compared with patients who had a pathologic primary Gleason score of 3, those with a score of 5 had 5.5 times greater hazard of BCR. Previous studies have shown that RARP may offer good PCa control. In a retrospective population-based study of PCa patients published in European Urology (2014;66:666-672), Jim C. Hu, MD, MPH, of the University of California Los Angeles (UCLA), and Maxine Sun, PhD, of the University of Montreal Health Center, used Surveillance Epidemiology and End Results (SEER)-Medicare linked data to study 5,556 men who underwent RARP and 7,878 who underwent open radical prostatectomy (ORP). In propensityscore adjusted analyses, RARP was associated with a significant 34% and 30%

decreased likelihood of PSMs compared with ORP among men with intermediate- and high-risk cancer, respectively. Additionally, results showed that RARP was associated with a 25%, 27%, and 33% decreased likelihood of requiring additional cancer treatment (androgen deprivation and radiation) within 6, 12, and 24 months, respectively. RARP has become the predominant radical surgery approach for PCa in the United States with nearly 60-80% of the surgical candidates undergoing this approach, according to a report in Surgical Endoscopy (2013;27:2253-2257). For the surgeon, RARP offers better ergonomics, precise dissection, and better visualization in narrow cavities such as the pelvis, Dr. Sood observed. For patients, RARP offers a lower rate of complications, better urinary and sexual functional outcomes, and improved cosmesis. In addition, patients experience much less post-operative pain and require less pain medication.

He pointed out that several factors should be considered when comparing outcomes among various RP approaches, the foremost being the effect of surgeon volume. It appears that high-volume surgeons have better or equivalent outcomes regardless of surgical approach. A recent study showed that highvolume surgeons are the predominant users of RARP. The study, published online ahead of print in BJU International, found that by 2010, 73% of high-volume surgeons adopted RARP compared with 45% and 36% of intermediate- and low-volume surgeons. The investigators defined low-, intermediate, and high-volume surgeons as those performing fewer than 5, 5-24, and more than 24 RPs annually, respectively. The retrospective study, by Steven L. Chang, MD, of Harvard Medical School in Boston, and colleagues, included 489,369 men who underwent open or laparoscopic RP or RARP from 2003 to 2010. ■

RARP Has a Long Learning Curve Robot-assisted radical prostatectomy (RARP) has a long learning curve and may be best suited to high-volume surgeons, researchers concluded based on a prospective observational study published recently in European Urology (2014;65:521-531). The study, by Australian researchers, included 1,552 consecutive patients who underwent either RARP (866 patients) or open radical prostatectomy (ORP, 686 patients) by a single high-volume surgeon who had performed more than 3,000 prior ORPs. The investigators administered the Expanded Prostate Cancer Index Composite quality of life questionnaire at baseline, 1.5, 3, 6, 12, and 24 months after surgery. RARP performed better than ORP in each domain (urinary continence, sexual function and oncologic control); RARP sexual function scores surpassed ORP scores after 99 RARPs and increased to a mean difference of 11 points at the 861st case, plateauing at around 600–700 RARPs, the researchers reported. Early urinary incontinence scores for RARP surpassed ORP after 182 RARPs and rose to a mean difference of 8.4 points, plateauing at around 700–800 RARPs. In addition the odds of a pT2 PSM were initially higher for RARP but became lower after 108 RARPs and were 55% lower by the 866th RARP, according to the investigators. “In this single-surgeon analysis, when compared to ORP, RARP had a long learning curve with inferior outcomes initially but then progressively superior sexual, early urinary, and pT2 PSM outcomes, and equivalent pT3 PSM and late urinary outcomes,” the researchers concluded. Although learning RARP was worthwhile for the high-volume surgeon, the researchers stated, the learning curve may not be justifiable for late-career or low-volume surgeons. ■

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www.renalandurologynews.com JANUARY/ FEBRUARY 2015

Renal & Urology News 5

FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD

Dialysis Should Be The Last Resort for AKI

n the past, acute kidney injury (AKI) used to be called acute renal failure or insufficiency. Among the most common causes of acute renal failure is so-called prerenal azotemia, which occurs when renal perfusion is inadequate or compromised, leading to a transient elevation of serum creatinine level. This can happen as a result of reduced intravascular volume caused by relative dehydration or blood or fluid loss. It also can result from low effective arterial volume even if the patient is otherwise fluid overloaded, such as in the setting of heart failure (cardiorenal) or liver disease (hepatorenal syndrome). When there is potential fluid loss or low blood pressure, a trial of fluid resuscitation is the conventional approach. Usually, normal saline or other types of osmotically effective fluids such as albumin infusions are administered. If prerenal azotemia is not corrected effectively, the compromised renal perfusion leads to ischemic injury and ultimately acute tubular necrosis (ATN). When ATN with worsening uremia and electrolyte disarrays persist, dialysis treatment is inevitable and often combined with fluid removal via ultrafiltration. To date, however, no credible study has shown that either intermittent or slow continuous dialysis therapy can improve AKI outcomes. Indeed, most studies have consistently suggested that patient outcome is poorer and mortality is higher when dialysis is initiated. More recently, AKI has been considered any transient elevation in serum creatinine. There is a tendency to avoid fluid administration for AKI and to start dialysis therapy earlier to remove fluid. Published studies and industry-sponsored lectures have suggested that we should start dialysis earlier and remove more fluid even before creatinine is elevated. Not infrequently, other specialists, particularly intensivists, cardiologists, and cardiothoracic surgeons, want more fluid removed so chest X-rays look drier. Loop diuretics often are ineffective, so dialysis therapy with large amounts of ultrafiltration is desired, no matter how harmful such interventions are to the injured kidneys. A good nephrologist and astute clinician is the one who resists all these pressures and defends renal perfusion. Although fluid removal may improve pulmonary vascular congestion or ventricular contractility, renal ischemia will likely lead to prerenal azotemia and ATN and prolonged oligoanuric AKI. The nephrologist should advocate more fluid administration and better renal perfusion, and use dialysis with the least frequency and fluid removal as the last resort in AKI management. If the nephrologist yields to pressure from other specialists to remove fluid, then who else is left to protect the kidney? Kam Kalantar-Zadeh, MD, MPH, PhD Chief, Division of Nephrology & Hypertension Professor of Medicine, Pediatrics and Public Health University of California Irvine School of Medicine

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Medical Director, Urology

Medical Director, Nephrology

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

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

Nephrologists

Urologists

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

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

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

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

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

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

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

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

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

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

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

Renal & Urology News Staff

Editor Jody A. Charnow Production editor Kim Daigneau Web editor

Natasha Persaud

Group art director, Haymarket Medical Jennifer Dvoretz

Production manager Krassi Varbanov

Production director Kathleen Millea Grinder Circulation manager Paul Silver National accounts manager William Canning Publisher Dominic Barone Editorial director

Jeff Forster

Senior VP, medical journals & digital products

Jim Burke, RPh

Senior VP, clinical communications group

John Pal

CEO, Haymarket Media Inc.

Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 14, Number 1. Published monthly, except for the combined January/February, June/July and November/ December issues, by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Periodicals postage paid at New York, NY, and an additional mailing office. The subscription rates for one year are, in the U.S., $75.00; in Canada, $85.00; all other foreign countries, $110.00. Single issues, $20.00. www.renalandurologynews.com. Postmaster: Send address changes to Renal & Urology News, c/o DMD Data Inc., 2340 River Road, Des Plaines, IL 60018. Copyright: All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without the prior written permission of Haymarket Media, Inc. Copyright © 2015.

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Contents

JANUARY/FEBRUARY 2015

Nephrology 3

ONLINE

this month at renalandurologynews.com 14

Clinical Quiz

Take our latest quiz at renalandurologynews.com /clinical-quiz/. Answer correctly and you will be entered to win a $50 American Express gift card. Congratulations to our December winner: Troy Sofinowski, MD

Videos

Some of our recent postings include: • CHAARTED Study for Advanced Prostate Cancer

• The Growing Testosterone Debate

• Team-Based Care After Discharge Doesn’t Reduce Readmission

Visit our website for daily updates.

Strict BP Control Cuts Death Risk Following ESRD Onset It is associated with a significant 28% decreased risk of death compared with usual blood pressure control. Lupus Nephritis ESRD Rates Stable Rates of end-stage renal disease from lupus nephritis in the United States have stopped increasing and may be declining, but racial disparities in outcomes persist. Higher Uric Acid Raises Odds of Renal Insufficiency Researchers observe an increased risk even when uric acid levels are in the normal range.

RARP Offers Good Long-Term Results A study of 4,803 patients reveals oncologic control on par with other radical surgery approaches.

VA Study Reveals No PCa Racial Disparities Researcher found no significant differences in tumor burden, treatment choice, or survival outcomes.

Study: ADT-RT Combination Superior Androgen-deprivation therapy plus radiotherapy prolonged cancer-specific and overall survival in older men with locally advanced or high-risk prostate cancer.

EF Recovery Depends On PCa Surgical Approach Robot-assisted laparoscopy is associated with a greater likelihood of recovering erectile function compared with open surgery.

• Wearable Artificial Kidney: First Clinical Trial

News Coverage

Low Income Raises Risk of ESRD Individuals with a household income below $20,000 versus more than $75,000 had 4-fold higher odds of end-stage renal disease.

• Panel: Renal Cell Carcinoma Immunotherapy

“The findings of our study support a focus

on individual rather than community resources when attempting to reduce disparities in ESRD. See our story on page 3

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VOLUME 14, ISSUE NUMBER 1

CALENDAR

Urology

• Multiparametric MRI for Prostate Cancer Diagnosis

■

Genitourinary Cancers Symposium Orlando, Fla. February 26 –28 European Association of Urology 30th Annual Congress Madrid March 20 –24 National Kidney Foundation 2015 Spring Clinical Meetings Dallas March 25 –29 American Transplant Congress Philadelphia May 2– 6 American Urological Association 110th Annual Meeting New Orleans May 15 –19 American Society of Hypertension Annual Scientific Meeting New York May 16 –19 European Renal Association-European Dialysis and Transplant Association 52nd Congress London May 28–31 American Society of Clinical Oncology Annual Meeting Chicago May 29–June 2

6 Renal & Urology News

Departments 5

From the Medical Director Dialysis should be the last resort for AKI

News in Brief Music found to ease prostate biopsy pain

Practice Management Bundling services may offer opportunities.

1/23/15 5:09 PM

JANUARY/ FEBRUARY 2015

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Contents

JANUARY/FEBRUARY 2015

Urology 4

ONLINE

this month at renalandurologynews.com

Clinical Quiz

Some of our recent postings include:

• CHAARTED Study for Advanced Prostate Cancer • Multiparametric MRI for Prostate Cancer Diagnosis

RARP Offers Good Long-Term Results A study of 4,803 patients reveals oncologic control on par with other radical surgery approaches. VA Study Reveals No PCa Racial Disparities Researcher found no significant differences in tumor burden, treatment choice, or survival outcomes. Study: ADT-RT Combination Superior Androgen-deprivation therapy plus radiotherapy prolonged cancer-specific and overall survival in older men with locally advanced or high-risk prostate cancer. EF Recovery Depends On PCa Surgical Approach Robot-assisted laparoscopy is associated with a greater likelihood of recovering erectile function compared with open surgery.

• Team-Based Care After Discharge Doesn’t Reduce Readmission

Lupus Nephritis ESRD Rates Stable Rates of end-stage renal disease from lupus nephritis in the United States have stopped increasing and may be declining, but racial disparities in outcomes persist.

Higher Uric Acid Raises Odds of Renal Insufficiency Researchers observe an increased risk even when uric acid levels are in the normal range.

• Wearable Artificial Kidney: First Clinical Trial

News Coverage

Visit our website for daily updates.

Low Income Raises Risk of ESRD Individuals with a household income below $20,000 versus more than $75,000 had 4-fold higher odds of end-stage renal disease. Strict BP Control Cuts Death Risk Following ESRD Onset It is associated with a significant 28% decreased risk of death compared with usual blood pressure control.

• Panel: Renal Cell Carcinoma Immunotherapy

“The findings of our study support a focus

on individual rather than community resources when attempting to reduce disparities in ESRD. See our story on page 3

006_Uro_RUN0215.indd 6

• The Growing Testosterone Debate

VOLUME 14, ISSUE NUMBER 1

CALENDAR

Nephrology

Videos

■

American Society of Clinical Oncology Annual Meeting Chicago May 29–June 2

6 Renal & Urology News

Departments 5

From the Medical Director Dialysis should be the last resort for AKI

News in Brief Music found to ease prostate biopsy pain

Practice Management Bundling services may offer opportunities.

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Renal & Urology News 7

VA Study Reveals No PCa Racial Disparities RESEARCHERS WHO studied prostate cancer (PCa) patients receiving care in the Veterans Affairs (VA) healthcare system found no significant differences in tumor burden, treatment choice, and survival outcomes between black and white men. “The observed lack of disparity in outcomes between African Americans and Caucasians may be due to their receipt of care in the equal-access VA healthcare system, which may eliminate or reduce major barriers in access to care

ease, more equitable provision of costly treatments and the resultant improvement in long-term outcomes.” An alternative explanation is that Caucasians have comparatively worse disease characteristics in the VA system than in other settings, thus decreasing the apparent disparity, they noted.

Dr. Daskivich’s group pointed out that their study had limitations, such as selection bias associated with the observational study design, which may decrease the apparent magnitude of racial disparities. “Veterans with worse disease at diagnosis may not seek care at the VA, which would falsely reduce racial dispar-

ity in all of our main outcomes beyond tumor burden at diagnosis.” Dr. Daskivich and his colleagues commented that their findings contrast with those from the non-VA setting, “which show strong evidence of racial disparity in tumor risk, treatment choice and survival.” ■

Blacks and whites found to have similar tumor burden and survival outcomes. for African Americans,” the investigators, led by Timothy J. Daskivich, MD, of the University of California, Los Angeles, wrote in a new online report in Prostate Cancer and Prostatic Disease. Previous studies have shown that, compared with whites, blacks have a 48% higher incidence of PCa and a 2.5fold higher risk of death from the cancer, Dr. Daskivich’s team pointed out. At diagnosis, blacks have been found to have higher PSA values and tumor volumes and are 3 times more likely to present with advanced disease, they noted. Dr. Daskivich and his colleagues sampled 1,258 men with nonmetastatic PCa diagnosed at the Greater Los Angeles and Long Beach VA medical centers from 1998 to 2004. African Americans and Caucasians had similar odds of higher tumor risk, Gleason score, and clinical stage, and similar odds of receiving aggressive treatment for low-, intermediate-, and high-risk disease. The 2 racial groups also had similar risks of cancer-specific and other-cause mortality. “It is remarkable that we found no significant disparity for any of these outcomes despite lack of control for socioeconomic status and education, which would tend to reduce disparities if included,” the authors commented. A plausible explanation for their findings, the investigators stated, “is that the adverse effects of low socioeconomic status, poor insurance, low education and lack of usual source of care that traditionally are associated with AfricanAmerican race are diminished in the VA setting. This may lead to improved rates of screening, earlier detection of dis-

News-PCA-Ra_RUN0215.indd 7

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Projected CKD growth continued from page 1

the plus side, ESRD incidence appears to have leveled off or declined slightly, with the number of incident ESRD cases lower in 2011 and 2012 than in 2010. “If these incidence and prevalence trends are substantiated in coming years, this would be good news indeed as it implies likely improvements in prevention of ESRD as well as longer survival among patients who have reached ESRD,” the report stated. The study by Dr. Hoerger’s team also found that the lifetime incidence of CKD among those currently aged 30–49, 50–64, and 65 years and older is estimated at 54%, 52%, and 42%, respectively. “Knowing the lifetime incidence of CKD may raise individuals’ awareness and encourage them to take steps to prevent CKD,” they wrote. A previous study of 1,852 patients

Hyperkalemia Drugs continued from page 1

ZS-9, 4.8 mmol/L in the 5-gram group, and 4.6 mmol/L in the 10-gram group, for mean reductions of 0.5, 0.5, and 0.7 mmol/L, respectively, according to an online report in The New England Journal of Medicine (NEJM). The mean potassium level declined to 5.1 mmol/L in the 1.25-gram group and the placebo group, for a mean reduction of 0.3 mmol/L. Additionally, in patients who received 5 grams of ZS-9 and those who received 10 grams of ZS-9, serum potassium levels were maintained at 4.7 and 4.5 mmol/L, respectively, during days 3–15, compared with a level of more than 5.0 mmol/L in the placebo group. Adverse rates were similar among the ZS-9 and placebo recipients.

ESRD risk continued from page 1

During a mean follow-up of 11.6 years, ESRD developed in 212 women, and 3,104 women died. In adjusted analyses, compared with women who had a waist circumference of 88 cm or less, those with a larger waist circumference had a 2.6 times increased risk of ESRD and a 42% increased risk of death, researchers reported online ahead of print in the Journal of the American Society of Nephrology. The model adjusted for age, race, education, smoking, estimated glomerular filtration rate, and other factors.

FC_Neph_RUN0115.indd 8

with CKD (estimated glomerular filtration rate less than 60 mL/min/1.73 m2) found that 90% of those with 2 to 4 clinical markers of CKD and 84% of those with 5 or more clinical markers of CKD were unaware of their kidney disease, according to a paper published in the Clinical Journal of the American Society of Nephrology (2011;6:1838-1844). CKD markers included hyperkalemia, acidosis, anemia, hyperphosphatemia, albuminuria, uncontrolled hypertension, and elevated blood urea nitrogen. Whether the United States will have an adequate nephrology workforce to handle increases in the CKD and ESRD populations remains unclear. Mark G. Parker, MD, chair of the American Society of Nephrology’s Workforce Committee, said he does not know if the study by Dr. Hoerger’s group necessarily indicates that more nephrologists will be needed. “I think we’re at an odd nexus as regards what we truly will need for a

workforce in the future,” Dr. Parker told Renal & Urology News. Dr. Parker explained that much of the effort his committee has put into addressing nephrology workforce issues has focused on recruitment of future nephrologists. “A few years ago, we

formulated a hypothesis that we would need more nephrologists to handle the increasing CKD and ESRD population as time goes on,” he said. Some developments in recent years, however, have prompted the committee to rethink this. The current job market for graduating nephrology fellows is rather soft, he said,

and although the committee has worked to improve recruitment strategies to establish a pipeline of future nephrologists, nephrology training programs have had low numbers of applicants. Dr. Parker pointed out, however, that more and more advanced practitioners, specifically nurse practitioners and physician assistants, are entering the nephrology workforce, a trend that could help ensure the availability of sufficient numbers of caregivers for a growing population of CKD and ESRD patients. Nevertheless, according to Dr. Parker, efforts should continue to be made to attract medical students to a career in nephrology. “It still behooves us to focus on recruiting a strong quality pipeline of nephrologists, especially since the interest is low right now,” he said. “We’re going to need an adequate number of nephrologists, however we decide to define adequate.” n

In another ZS-9 study, 258 hyperkalemic patients received 10 grams of ZS-9 3 times daily in an initial 48-hour openlabel phase. Then, 237 patients achieving normokalemia (3.5–5.0 mEq/L) were randomized to receive 5, 10, or 15 grams

of ZS-9 or placebo daily for 28 days. In the open-label phase, serum potassium levels declined from 5.6 mEq/L at baseline to 4.5 mEq/L at 48 hours, Mikhail Kosiborod, MD, of Saint Luke’s Mid America Heart Institute in Kansas City, Mo., and collaborators reported online

in the Journal of the American Medical Association. The median time to normalization was 2.2 hours, with 84% of patients achieving normokalemia by 24 hours and 98% by 48 hours. In the randomized phase, serum potassium was significantly lower during days 8–29 with all 3 ZS-9 doses compared with placebo: 4.8, 4.5, and 4.4 mEq/L for the 5, 10, and 15-gram doses versus 5.1 mEq/L for placebo. Furthermore, the proportion of patients with mean potassium levels below 5.1 mEq/L during days 8-29 was significantly higher in all ZS-9 groups compared with placebo: 80%, 90%, and 94% for the 5- 10-, and 15-gram groups versus 46% of placebo recipients. The patiromer trial, led by Matthew R. Weir, MD, of the University of Maryland Medical Center in Baltimore, consisted of an initial treatment phase and a randomized withdrawal phase.

Among 237 patients receiving patiromer in the initial treatment phase and who had at least 1 potassium measurement at a scheduled visit after day 3, the mean serum potassium level decreased by a significant 1.01 mmol/L, Dr. Weir’s group reported online in NEJM. At week 4, 76% of patients had achieved the target potassium level of at least 3.8 but less than 5.1 mmol/L. In the subsequent randomized withdrawal phase, the investigators assigned 107 patients to receive either patiromer (55 patients) or placebo (52 patients). The median increase in the potassium level from baseline of that phase was significantly greater in the placebo than patiromer arm. In addition, 60% of the placebo arm experienced a recurrence of hyperkalemia (potassium level of 5.5 mmol/L or higher) through week 8 compared with 15% in the patiromer arm. n

In addition, each 1 cm increment in waist circumference was independently and significantly associated with a 3% increased risk of ESRD, even after additional adjusting for BMI, according to the researchers. BMI also associated with ESRD and death. Compared with women who had a BMI of 18.5–24.9 kg/m2, those with a BMI of 30 kg/m2 or higher had a nearly 2-fold increased risk of ESRD and 21% increased risk of death. “Waist circumference is a simple, easy to measure, low-cost, and feasible measure to implement in clinical care with potential added prognostic value for ESRD risk,” Dr. Franceschini’s

team wrote. “Although interventions to reduce central adiposity are difficult to implement in clinical practice, increased awareness and prevention of central obesity postmenopausal women could be important public health targets to reduce ESRD risk in aging populations.” The study population had a mean age of 63.9 years. Of the 20,117 subjects, 1,154 had chronic kidney disease (CKD), defined as an eGFR of 60 mL/min/1.73 m2 or less. Investigators obtained information on BMI and waist circumference at baseline and obtained information on new ESRD cases from the U.S. Renal Data System.

Strengths of the study by Dr. Franceschini’s group include a large sample size of postmenopausal women, use of a multicultural cohort, standardized measures of adiposity and other risk factors, prospectively obtained data, and a large number of ESRD events. Study limitations include the use of only a single measure of adiposity obtained at a screening visit and the fact that waist circumference cannot distinguish between subcutaneous and intra-abdominal fat. The researchers noted that their findings cannot be generalized to men or premenopausal women, who were not included in the WHI cohort. n

ZS-9 and patiromer lowered potassium levels significantly versus placebo.

The estimated lifetime CKD incidence is 54% among adults currently aged 30–49.

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MRI-TRUS accurate continued from page 1

the highest Gleason score or the largest volume or extraprostatic extension. MRI-TRUS targeted biopsy accurately identified the IT location in 95% of cases the investigators reported online ahead of print in European Urology. In the remaining 5%, the IT was not visible on MRI. Each of these tumors was very small, the researchers stated. Results showed a 90% concordance of primary Gleason pattern between targeted biopsy and RP specimens. The study also demonstrated that the largest tumors had the highest Gleason score

in 98% of patients, which reaffirms the findings of some previous studies, according to the researchers. Dr. Baco’s team noted that discordance between biopsy and RP-specimen Gleason scores is common, ranging from 47% to 56% in the literature. Their study revealed a Gleason score discordance rate of 30.5%. They noted that their data suggest that MRI-TRUS image-fusion biopsies “could become a valuable tool in identifying the location of clinically important cancer in patients.” With respect to study limitations, the researchers pointed out that their study involved retrospective evaluation of a

selected heterogeneous population, which may lessen the generalizability of their results because of potential selection bias. The study by Dr. Baco and his colleagues adds to a growing literature supporting the use of magnetic resonance/ultrasound fusion prostate biopsy. At the 2014 annual meeting of the American Urological Association, for example, researchers reported on a study of 132 patients who underwent 12-core MR-TRUS fusion biopsy and subsequent RP. Fusion biopsy resulted in the upgrading of 40 patients (30.3%) from 12-core biopsy, 12 of whom had a negative 12-core biopsy. n See related commentary on this page.

C O M M E N TA R Y

Study Validates MRI-TRUS Fusion Biopsy BY JOHN M. DIBIANCO, BS, AND ARVIN K. GEORGE, MD

John M. Dibianco, BS, left, and Arvin K. George, MD

THE STUDY by Eduard Baco, MD, and col-

correlation of MRI tumor volume with

use from initial diagnosis to intraopera-

leagues1 adds to the important growing

histologic volume, and overall Gleason

tive surgical planning. Fusion biopsy

body of literature that provides histopatho-

score concordance of 69.5%.

provides accurate histologic sampling

logic correlation for biopsy with the radical

This study provides additional and

resulting in better risk stratification and

prostatectomy (RP) reference standard.

validation of MP-MRI TRUS fusion prostate

informed clinical decision making. Its

Their retrospective review of 135 patients

biopsy as a valuable diagnostic tool, with

use is clinical practice will continue to

who underwent multiparametric magnetic

findings consistent with data from tertiary

grow as costs decline and patients seek

resonance imaging (MP-MRI)-transrectal

centers with considerable experience

out a better biopsy. n

ultrasound (TRUS) fusion prostate biopsy

with prostate MRI and fusion biopsy. In an

and subsequent RP at 2 institutions was

earlier study, Turkbey et al. demonstrated

John M. DiBianco, BS, is a 4th year medi-

performed to investigate whether this

the ability of multiparametric MRI to iden-

cal student at Ross University School

technique can accurately characterize

tify prostate cancer in patients ultimately

of Medicine, Roseau, Commonwealth

not only Gleason score but also location

undergoing RP using a customized,

of Dominica, West Indies and Arvin

and volume of the indexed lesion. The

patient-specific, 3D printed mold gener-

K. George, MD, is a researcher in the

study reported fusion biopsy identifying

ated from preoperative MRI data, with

Urologic Oncology Branch of the National

the index lesion at an overall rate of 95%,

subsequently whole mount sectioning.

with only 7 patients having an MRI-invisible

Identifying the optimal patient popula-

cancer. However, the study population

tion and cost efficacy of MRI remain top-

reflects a cohort of patients who had prior

ics of debate. Recent FDA approval of

fusion biopsy (indicating the presence

various fusion platforms has spurred its

of a suspicious lesion identified on MRI).

adoption among academic centers and

Results of patients undergoing RP in those

community practices alike. The benefits

with a negative MRI were not reported.

of fusion biopsy are significant and the

Additionally, the authors demonstrated

growing body of literature supports its

Post-Op Sepsis Risk continued from page 1

gram positive and gram negative bacteria, respectively, isolated from 29.4% and 21.6% of patients, respectively. For the study, researchers ordered a preoperative urine culture for all patients 2–4 weeks prior to surgery. Patients with a negative preoperative urine culture received prophylactic anti-

FC_Uro_RUN0215.indd 8

biotics with 1 gram cefamezin in according to American Urological Association/ European Association of Urology guidelines. Those with a positive urine culture or a history consistent with an infected stones were treated preoperatively with a full course of antibiotics for a minimum of 7 days, the researchers stated. Dr. Shoshany’s team reported that quinolone resistance was high in both gram negative and gram positive bacteria.

Cancer Institute in Bethesda, Md. REFERENCES 1. Baco E, Ukimura O, Rud E, et al. Magnetic resonance imaging-transrectal ultrasound image-fusion biopsies accurately characterize the index tumor: correlation with step-sectioned radical prostatectomy specimens in 135 patients. Eur Urol. published online ahead of print. 2. Turkbey B, Mani H, Shah V, et al. Multiparametric 3T prostate magnetic resonance imaging to detect cancer: histopathological correlation using prostatectomy specimens processed in customized magnetic resonance imaging based molds. J Urol. 2011;186(5):1818-24.

“One of the important measures to reduce the risk of postoperative infection is the preoperative antibiotic treatment to sterilize the urine,” the authors wrote. “However, infected stone patients pose a specific challenge, as in some patients the urine cannot be sterilized despite repeat antibiotic courses, due to stone colonization and poor antibiotic penetration into the stone.” n

PCa overtreated continued from page 1

respectively, received aggressive treatment, despite other-cause mortality rates of 81% and 86%, respectively, at 10 years after diagnosis. The authors said they hope study findings “will promote greater awareness of the role of life expectancy in treatment decision-making for men with low- and intermediate-risk prostate cancer.” In a press release issued by UCLA, Dr. Daskivich observed, “Life expectancy is poorly integrated into treatment decision-making for prostate cancer, yet it is one of the primary determinants of whether a patient will benefit from treatment with surgery or radiation.” Guidelines from the American Urological Association, National Comprehensive Cancer Network, and the European Association of Urology recommend conservative management of early-stage disease in patients with life expectancies of less than 10 years. Among men aged 66 to 69, 70 to 74, 75 to 79, and 80 years or older with life expectancies less than 10 years, 50%, 53%, 63%, and 69% received radiation treatment and 30%, 25%, 13%, and 9% underwent surgery, respectively. “The disparity in receipt of radiation over surgery increased with both advancing age and increasing comorbidity,” the authors wrote in their report. “The finding that surgery was less common that radiation therapy in older and sicker men is not surprising because these men are often poor surgical candidates; the lack of a similar inherent check on treatment with radiation therapy may be enabling the overtreatment of older and sicker men with radiation.” In an accompanying editorial, Matthew R. Danzig, a medical student, and James M. McKiernan, MD, both of Columbia University in New York, commended the work by Dr. Daskivich and colleagues “for its thoughtfully articulated design and rigorous statistical methodology.” For example, the editorial writers pointed out, the investigators calculated noncancer-specific mortality using competing-risks regression analysis, which is superior to an alternative method of calculating cause-specific mortality commonly used in the clinical literature. “A novel element of the study is that inferred life-expectancy values, vis-àvis rates of other-cause mortality, are calculated from the actual outcomes of the sample population.” n

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Renal & Urology News 9

News in Brief

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

Short Takes Music Eases Prostate Biopsy Pain, Anxiety

tions and complicated intra-abdominal

Music may provide a simple, inex-

cephalosporin and tazobactam is a

pensive and effective adjunct to

beta-lactamase inhibitor.

infections in adults. Ceftolozane is a

The Zerbaxa label includes a warn-

anesthesia during transrectal ultrasound (TRUS)-guided prostate biopsy,

ing about decreased efficacy in pa-

researchers concluded in an online

tients with renal impairment. The most

report in Urologia Internationalis.

common adverse effects identified in clinical trials were nausea, diarrhea,

Korean researchers led by Whi-An Kwon, MD, of the Wonkwang Universi-

headache, and fever. Zerbaxa is marketed by Cubist Phar-

ty Sanbon Hospital, Gunpo, randomly

maceuticals, Lexington, Mass.

assigned 76 men undergoing transrectal ultrasound (TRUS)-guided prosplayed during the procedure (38 men)

Screen Asian Americans for Diabetes at Lower BMI

or to hear no music (38 men). Lido-

The American Diabetes Association

caine gel was instilled into the rectum

has recommended lowering the body

prior to biopsy. Using the State-Trait

mass index (BMI) at which Asian-Amer-

Anxiety Inventory and a visual analog

icans should be considered for type 2

scale, the researchers found that the

diabetes screening.

tate biopsy to hear classical music

music group had significantly lower

The new recommendation, published

mean pain and anxiety scores and

in Diabetes Care (2015;38:150-

higher mean scores for satisfaction

158), calls for Asian-Americans to

and willingness to undergo a repeat

be screened if they have a BMI of

biopsy than the non-music group.

23 kg/m2 or higher rather than a BMI of 25 kg/m2 or higher in the general

Two-Drug Combo Cleared for Complicated UTIs

population. The recommendation

The FDA has approved Zerbaxa

develops in many Asian-Americans at

(ceftolozane/tazobactam) for the treat-

a lower BMI than other racial or ethnic

ment of complicated urinary tract infec-

groups in the United States.

is based on evidence that diabetes

On-Call Coverage Disruptive In a recent online poll, Renal & Urology News asked readers, “How do you find on-call emergency department coverage?” Here are the results based on 208 responses.

Not bothersome at all: 3.85%

Somewhat disruptive to my practice or quality of life: 30.29%

Very disruptive to my practice or quality of life: 55.29%

I do not provide on-call coverage: 11.0% 0

NIB_RUN0215.indd 9

Osteoporosis in ESRD Found To Raise Cardiovascular Risks O

steoporosis is associated with an increased risk of cardiovascular events in patients with end-stage renal disease (ESRD), according to researchers in Taiwan. Chia-Hung Kao, MD, of China Medical University Hospital in Taichung, and colleagues studied 12,535 patients with ESRD undergoing incident dialysis. Of these, 4,153 (33%) had osteoporosis. After adjusting for gender, age, related comorbidities, patients with osteoporosis had a significant 32%, 26%, 13%, and 7% increased risk of coronary artery disease, congestive heart failure, stroke, and mortality, respectively, compared with subjects who did not have osteoporosis, the investigators reported online in Osteoporosis International. “When encountering patients with ESRD and osteoporosis, physicians should be alert to the cardiovascular risk factors in incident dialysis patients to prevent the subsequent occurrence of these adverse events,” the authors concluded.

Higher BMI Lowers ESRD Risk in Some Patients H

igher body mass index (BMI) is associated with a lower risk of end-stage renal disease (ESRD) among individuals without the metabolic syndrome, researchers reported online in Kidney International. Bhupesh Panwar, MD, of the University of Alabama at Birmingham, and colleagues studied 21,840 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. ESRD developed in 247 of these participants over a mean follow-up of 6.3 years. Among subjects without metabolic syndrome, each 5 kg/m2 increment in BMI was associated a 30% decreased risk of ESRD. Higher BMI was not associated with ESRD risk among participants with metabolic syndrome. Compared with normal-weight individuals (BMI 18.5–24.9 kg/m2) without metabolic syndrome, overweight individuals (BMI 25–29.9 kg/m2) and obese individuals (BMI of 30 kg/m2 or higher) with metabolic syndrome had a 2-fold increased risk of ESRD. Obese individuals without the metabolic syndrome had a 53% lower risk of ESRD.

Study: PN May Be a Better Choice for Some RCC Cases P

artial nephrectomy (PN) should be the surgery of choice for renal cell carcinoma (RCC) tumors up to 7 cm in diameter, researchers concluded in a report published online in BMC Nephrology. Radical nephrectomy (RN), by comparison, is associated with significantly more cases of acute kidney injury (AKI) and new-onset chronic kidney disease (CKD), and it is an independent risk factor for kidney function decline. Chang Seong Kim, MD, PhD, and colleagues from Chonnam National University Medical School in South Korea, analyzed the medical records of 557 patients with RCC tumors up to 7 cm in diameter. PN was performed on 39% of patients; the remaining 61% underwent RN. During 3 years of follow-up, RN patients experienced greater kidney function decline than PN patients, and their incidences of AKI and new-onset CKD were significant higher (70.1% vs. 24.3% and 55.7% vs. 6.2%, respectively).

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10 Renal & Urology News

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Researchers: cT2c Tumors Are Intermediate Risk MEN WITH CLINICAL stage T2c (cT2c) prostate cancer (PCa) should be considered at intermediate risk of biochemical recurrence after radical prostatectomy if other high-risk factors are absent, according to a new study. Study findings suggest that patients with cT2c disease should be counseled appropriately and offered treatment options for intermediate-risk disease, concluded a research team led by Stephen J. Freedland, MD, of Duke University Medical Center in Durham, N.C. Dr. Freedland and his colleagues examined whether cT2c tumors without other high-risk factors (cT2c not otherwise specified [NOS]) behaved as an intermediate- or high-risk cancer though an analysis of biochemical

of Urology (EAU), and the D’Amico PCa risk stratification schema have similar PCa guidelines, although there is inconsistent classification of cT2c disease among these organizations. According to the original D’Amico risk stratification schema and AUA guidelines, cT2c disease is defined as high risk, whereas

the NCCN and EAU guidelines consider cT2c disease intermediate risk. Determining whether cT2c disease is an intermediate or high risk has important implications for treatment decisions, so it is essential to define the exact risks that cT2c disease portends, Dr. Freedland’s team stated.

Differences in classification, the authors pointed out, may determine the extent of lymph node dissection at the time of RP, the duration of androgen-deprivation therapy given concomitantly with external beam radiotherapy, or eligibility for enrolling in clinical trials. n

B:15.5”

S:14.625”

F w

Study findings suggest that patients should be counseled appropriately. recurrence (BCR) after radical prostatectomy (RP). Their study included 2,759 men in the Shared Equal Access Regional Cancer Hospital (SEARCH) database and 12,900 men from Johns Hopkins Hospital (JHH) in Baltimore. A total of 99 men from SEARCH (4%) and 202 from JHH (2%) had tumors classified as cT2c-NOS. The cT2c-NOS patients had BCR rates similar to that of the intermediate-risk patients, Dr. Freedland’s group reported online ahead of print in Cancer. During a median follow-up of 66 months in the SEARCH cohort, 37% of cT2c-NOS patients and 40% of intermediate-risk patients experienced BCR. During a median follow-up of 48 months in the JHH cohort, 30% of cT2c-NOS patients and 21% of intermediate-risk patients experienced BCR. In multivariate analysis, men with cT2c-NOS tumors did not differ significantly in BCR risk from those with intermediate-risk tumors in either cohort, but they had a significantly lower risk of BCR than men with high-risk disease. Men in the SEARCH cohort with cT2cNOS disease had a 41% decreased risk of BCR compared with high-risk men. In the JHH cohort, men with cT2cNOS disease had a 61% decreased risk of BCR compared with high-risk men. The researchers noted that the National Comprehensive Cancer Network (NCCN), American Urological Association (AUA), European Association

I T P M

•

R 1 2 M W m

INDICATION AURYXIA is a phosphate binder indicated for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis. IMPORTANT SAFETY INFORMATION Contraindication: AURYXIA is contraindicated in patients with iron overload syndromes. Iron Overload: Iron absorption from AURYXIA may lead to excessive elevations in iron stores. Assess iron parameters, serum ferritin and TSAT, prior to and while on AURYXIA. Patients receiving IV iron may require a reduction in dose or discontinuation of IV iron therapy.

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

a a t e

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

P n

Patients with Gastrointestinal Bleeding or Inflammation: Safety has not been established. Pregnancy Category B and Nursing Mothers: Overdosing of iron in pregnant women may carry

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F:7.3125” 1/23/15 5:20 PM

A w c G c

Renal & Urology News 11

Allopurinol May Slow Kidney Disease Progression B:15.5”

S:14.625”

LONG-TERM treatment with allopurinol may slow the rate of progression of kidney disease and decrease cardiovascular (CV) risks, according to a new study published online ahead of print in the American Journal of Kidney Diseases. The study, which was a post-hoc analysis of long-term follow-up of a 2-year

randomized controlled trial of allopurinol, included 113 participants with an estimated glomerular filtration rate below 60 mL/min/1.73 m2. Of these, 57 received treatment with allopurinol and 56 continued on their standard treatment (controls). During a median follow-up of 84 months, the allopurinol group experi-

enced a significant 68% decreased risk of a renal event and 57% decreased risk of a CV event compared with the control arm in adjusted analyses. The investigators, led by Marian Goicoechea, MD, PhD, of Hospital General Universitario Gregorio Marañón in Madrid, Spain, defined a renal event as

initiation of dialysis, and/or a doubling of serum creatinine, and/or a 50% or greater decrease in estimated glomerular filtration rate. They defined CV events as myocardial infarction, coronary revascularization or angina pectoris, congestive heart failure, cerebrovascular disease, or peripheral vascular disease. n

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

INTRODUCING AURYXIA (FERRIC CITRATE), THE FIRST AND ONLY ABSORBABLE-IRON–BASED PHOSPHATE BINDER CLINICALLY PROVEN TO MANAGE HYPERPHOSPHATEMIA1-6 • Proven control of serum phosphorus within KDOQI guidelines (4.88 mg/dL at Week 56)7,8 • Demonstrated safety and tolerability profile over 52 weeks B:10.25”

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

S:10”

www.renalandurologynews.com JANUARY/ FEBRUARY 2015

References: 1. Fosrenol [package insert]. Wayne, PA: Shire US, Inc.; 2014. 2. Phoslyra [package insert]. Waltham, MA: Fresenius Medical Care North America; 2011. 3. PhosLo Gelcaps [package insert]. Waltham, MA: Fresenius Medical Care North America; 2012. 4. Renagel [package insert]. Cambridge, MA: Genzyme Corporation; 2014. 5. Renvela [package insert]. Cambridge, MA: Genzyme Corporation; 2014. 6. Velphoro [package insert]. Waltham, MA: Fresenius Medical Care North America; 2014. 7. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 Suppl 3):S1-S201. 8. Data on File 1, Keryx Biopharmaceuticals, Inc.

a risk for spontaneous abortion, gestational diabetes, and fetal malformation. Rat studies have shown the transfer of iron into milk. There is possible infant exposure when AURYXIA is taken by a nursing woman. Pediatric: The safety and efficacy of AURYXIA have not been established in pediatric patients. Adverse Events: The most common adverse events with AURYXIA were diarrhea (21%), nausea (11%), constipation (8%), vomiting (7%), and cough (6%). Gastrointestinal adverse reactions were the most common reason for discontinuing AURYXIA (14%).

Drug Interactions: Doxycycline should be taken at least 1 hour before AURYXIA. Consider separation of the timing of the administration of AURYXIA with drugs where a reduction in their bioavailability would have a clinically significant effect on safety or efficacy. Please see Brief Summary on following page. You may report side effects to Keryx at 1-844-44KERYX (844-445-3799).

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12 Renal & Urology News

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Shockwave Therapy May Improve ED in Some Men SHOCKWAVE THERAPY may help improve erectile dysfunction (ED) in some men, according to a new study. The study, which was a prospective, randomized, double-blind, placebocontrolled investigation, included 112 ED sufferers unable to have intercourse with or without the aid of medication. A

team led by Lars Lund, MD, of Odense University Hospital in Odense, Denmark, assessed subjects’ ED at screening and 5, 12, and 24 weeks after treatment by interview and using the Erection Hardness Scale (EHS), and International Index Erectile Function-Erectile Function (IIEF-EF) questionnaire.

The researchers randomly assigned 51 men to receive low-intensity extracorporeal shockwave therapy (LI-ESWT) and 54 to receive a placebo treatment. The men received 5 treatments over 5 weeks. After 10 weeks, the placebo group received active treatment (active placebo group).

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BRIEF SUMMARY AURYXIA™ (ferric citrate) tablets contain 210 mg of ferric iron equivalent to 1 g ferric citrate for oral use. INDICATIONS AND USAGE AURYXIA is a phosphate binder indicated for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis. CONTRAINDICATIONS AURYXIA is contraindicated in patients with iron overload syndromes (eg, hemochromatosis). WARNINGS AND PRECAUTIONS Iron Overload: Iron absorption from AURYXIA may lead to excessive elevations in iron stores. Increases in serum ferritin and transferrin saturation (TSAT) levels were observed in clinical trials. In a 56-week safety and efficacy trial in which concomitant use of AURYXIA and IV iron was permitted, 55 (19%) patients treated with AURYXIA had a ferritin level >1500 ng/mL as compared with 13 (9%) patients treated with active control. Assess iron parameters (eg, serum ferritin and TSAT) prior to initiating AURYXIA and monitor iron parameters while on therapy. Patients receiving IV iron may require a reduction in dose or discontinuation of IV iron therapy. Accidental Overdose of Iron: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6 years of age. Keep this product out of the reach of children. In case of accidental overdose, call a doctor or poison control center immediately. Patients with Gastrointestinal Bleeding or Inflammation: Patients with inflammatory bowel disease or active, symptomatic gastrointestinal bleeding were excluded from clinical trials. Safety has not been established in these populations. ADVERSE REACTIONS Adverse reactions to a drug are most readily ascertained by comparison with placebo, but there is little placebo-controlled experience with AURYXIA, so this section describes adverse events with AURYXIA, some of which may be disease-related, rather than treatment-related. A total of 289 patients were treated with AURYXIA and 149 patients were treated with active control (sevelamer carbonate and/or calcium acetate) during the 52-week, randomized, open-label, active control phase of a trial in patients on dialysis. A total of 322 patients were treated with AURYXIA for up to 28 days in three short-term trials. Across these trials, 557 unique patients were treated with AURYXIA; dosage regimens in these trials ranged from 210 mg to 2,520 mg of ferric iron per day, equivalent to 1 to 12 tablets of AURYXIA. In these trials, adverse events reported for AURYXIA were similar to those reported for the active control group. Adverse events reported in more than 5% of patients treated with AURYXIA in these trials included diarrhea (21%), nausea (11%), constipation (8%), vomiting (7%), and cough (6%). During the 52-week active control period, 60 patients (21%) on AURYXIA discontinued study drug because of an adverse event, as compared to 21 patients (14%) in the active control arm. Patients who were previously intolerant to any of the active control treatments (calcium acetate and sevelamer carbonate) were not eligible to enroll in the study. Gastrointestinal adverse events were the most common reason for discontinuing AURYXIA (14%). AURYXIA is associated with discolored feces (dark stools) related to the iron content, but this staining is not clinically relevant and does not affect laboratory tests for occult bleeding, which detect heme rather than non-heme iron in the stool.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. It is not known whether AURYXIA can cause fetal harm when administered to a pregnant woman. Animal reproduction studies have not been conducted. The effect of AURYXIA on the absorption of vitamins and other nutrients has not been studied in pregnant women. Requirements for vitamins and other nutrients are increased in pregnancy. An overdose of iron in pregnant women may carry a risk for spontaneous abortion, gestational diabetes, and fetal malformation. Labor and Delivery: The effects of AURYXIA on labor and delivery are unknown. Nursing Mothers: Data from rat studies have shown the transfer of iron into milk by divalent metal transporter-1 (DMT-1) and ferroportin-1 (FPN-1). Hence, there is a possibility of infant exposure when AURYXIA is administered to a nursing woman. Pediatric Use: The safety and efficacy of AURYXIA have not been established in pediatric patients. Geriatric Use: Clinical studies of AURYXIA included 106 subjects aged 65 years and older (33 subjects aged 75 years and older). Overall, the clinical study experience has not identified any obvious differences in responses between the elderly and younger patients in the tolerability or efficacy of AURYXIA. OVERDOSAGE No data are available regarding overdose of AURYXIA in patients. In patients with chronic kidney disease on dialysis, the maximum dose studied was 2,520 mg ferric iron (12 tablets of AURYXIA) per day. Iron absorption from AURYXIA may lead to excessive elevations in iron stores, especially when concomitant IV iron is used. In clinical trials, one case of elevated iron in the liver as confirmed by biopsy was reported in a patient administered IV iron and AURYXIA. PATIENT COUNSELING INFORMATION Dosing Recommendations: Inform patients to take AURYXIA as directed with meals and adhere to their prescribed diets. Instruct patients on concomitant medications that should be dosed apart from AURYXIA. Adverse Reactions: Advise patients that AURYXIA may cause discolored (dark) stools, but this staining of the stool is considered normal with oral medications containing iron. AURYXIA may cause diarrhea, nausea, constipation, and vomiting. Advise patients to report severe or persistent gastrointestinal symptoms to their physician. Keryx Biopharmaceuticals, Inc. ©2014 Keryx Biopharmaceuticals, Inc. Printed in USA

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LI-ESWT is said to be patient friendly and has no side effects requiring treatment.

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DRUG INTERACTIONS Doxycycline is an oral drug that has to be taken at least 1 hour before AURYXIA. Oral drugs that can be administered concomitantly with AURYXIA are: amlodipine, aspirin, atorvastatin, calcitriol, clopidogrel, digoxin, doxercalciferol, enalapril, fluvastatin, levofloxacin, metoprolol, pravastatin, propranolol, sitagliptin, and warfarin. There are no empirical data on avoiding drug interactions between AURYXIA and most concomitant oral drugs. For oral medications where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, consider separation of the timing of the administration of the two drugs. The duration of separation depends upon the absorption characteristics of the medication concomitantly administered, such as the time to reach peak systemic levels and whether the drug is an immediate release or an extended release product. Consider monitoring clinical responses or blood levels of concomitant medications that have a narrow therapeutic range.

At the 5-week follow-up, the EHS showed that 29 men (57%) in the LI-ESWT group were able to obtain an erection after treatment and to have sexual intercourse without the use of medication compared with only 5 men (9%) in the placebo group, Dr. Lund’s group reported online ahead of print in the Scandinavian Journal of Urology. Assessment using the IIEF-EF questionnaire showed no significant improvement in ED in either group. After 24 weeks, 7 men in the LI-ESWT group (19%) and 9 (23%) in the active placebo group were still able to have intercourse without medication, the researchers noted. “The treatment is patient friendly, has no side-effects requiring treatment and can be used for all patients,” the authors concluded. The effect of LI-ESWT on ED remains unclear, Dr. Lund and his colleagues noted. They explained

that the basis for its use as an ED treatment is the notion that it could induce the release of endothelial nitric oxide synthase, vascular endothelial growth factors, and proliferating cell nuclear antigen, and thereby enhance neovascularization. In a previous prospective study published recently in the International Journal of Urology (2014;21:1041-1045), Chi-Hang Yee, MD, and colleagues at The Chinese University of Hong Kong found that LI-ESWT benefited a subgroup of men with severe ED. The study included 58 men with ED who received either LI-ESWT (30 patients) or a sham treatment (28 patients). The two groups did not differ significantly in baseline IIEF erectile function domain score and EHS. At week 13, the mean IIEF-EF domain score in the shockwave therapy and sham arms was 17.8 and 15.8, respectively and the mean EHS was 2.7 and 2.4. These differences were not statistically significant. The shockwave therapy, however, was superior to sham treatment in a subgroup of men with severe ED (mean IIEF-EF domain score 10.1 vs. 3.2). n

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Renal & Urology News 13

Study: ADT-RT Combination Superior Longer cancer-specific and overall survival seen in older men with locally advanced or high-risk PCa ANDROGEN-DEPRIVATION therapy (ADT) in combination with radiotherapy (RT) is associated with better cancer-specific and overall survival compared with ADT alone in older men with locally advanced or screendetected high-risk prostate cancer, according to a new study. Using the Surveillance Epidemiology and End Results (SEER)-Medicare database, Justin E. Bekelman, MD, of the University of Pennsylvania in Philadelphia, and colleagues identified 3 groups of older men with locally advanced or high-risk prostate cancer (PCa) diagnosed from 1995 to 2007 and observed through 2009. These groups included a randomized clinical trial (RCT) cohort of 4,642 men aged 65–75 years; an elderly cohort of 8,694 men older than 75 years with locally advanced PCa; and a cohort of 2,017 men aged 65 years and older with

screen-detected high-risk PCa. ADT plus RT was used in 64.1% of the RCT cohort, 52.8% of the screendetected cohort, and 39.4% of the elderly cohort. In the RCT cohort, ADT plus RT was associated with a 57% decreased risk of cancer-specific mortality and a 37% decreased risk of all-cause mortality compared with ADT alone in propensity score-adjusted analyses, Dr. Bekelman’s team reported online ahead of print in the Journal of Clinical Oncology. In the elderly cohort, ADT plus RT was associated with a 49% and 37% decreased risk of cancer-specific and all-cause mortality, respectively. In the screen-detected cohort, ADT plus RT was associated with a 75% and 50% decreased risk of cancer-specific and all-cause mortality, respectively. The researchers commented that their findings “raise a provocative

Strict BP Control Cuts Death Risk Following ESRD Onset STRICT BLOOD PRESSURE control in

onset, 142 deaths occurred in the

patients with chronic kidney disease

strict BP control arm and 182 deaths

(CKD) does not prevent progression to

occurred in the usual BP control arm,

end-stage renal disease (ESRD), but it

which translated into a significant 28%

does decrease the risk of death after

decreased risk of death in the strict BP

ESRD onset, researchers concluded.

control arm.

Elaine Ku, MD, of the University of

Overall, regardless of ESRD status,

California San Francisco, and col-

212 deaths occurred in the strict BP

leagues studied 840 CKD patients

control arm and 233 deaths occurred

in the Modification of Diet in Renal

in the usual BP control arm, which trans-

Disease (MDRD) trial. Patients were ran-

lated into a significant 18% decreased

domly assigned to strict versus usual

risk of death in the strict BP control arm.

blood pressure (BP) control from 1989

The researchers pointed out that

to 1993. Investigators defined strict

their results may not generalize to the

control as mean arterial pressure below

entire CKD population because of the

92 mm Hg and usual control as mean

unique characteristics of the MDRD

arterial pressure below 107 mm Hg.

cohort, which included mainly Caucasian

Dr. Ku’s team conducted an extended

patients with a high prevalence of

follow-up of study enrollees by linkage

polycystic kidney disease and glomerulo-

with the U.S. Renal Data System and

nephritis as the cause of kidney disease

National Death Index to determine

and high rates of transplantation and

ESRD and vital status through 2010.

survival post-ESRD. “Nevertheless,

ESRD developed in 627 patients

these data suggest that trials with lon-

through 2010, with a median follow-

ger follow-up are needed to understand

up of 19.3 years, Dr. Ku’s group

and assess the potential impact and

reported online ahead of print in

benefit of interventions implemented

Kidney International. After ESRD

during CKD,” the authors concluded. n

News-ADT-RT_RUN0215.indd 13

hypothesis” that in the United States, men older than 75 years with locally advanced PCa or men older than 65 years with high-risk screen-detected PCa who receive ADT alone are at risk for decrements in cancer-specific and overall survival.

Benefits observed in each of 3 large cohorts of men aged 65 and older. Dr. Bekelman’s group observed that their results are consistent with and extend the findings of previous studies looking at the role of ADT and RT in the management of older men with locally advanced or high-risk PCa. One such study is the Scandinavian

Perioperative Chemotherapy For MIBC Rises PHYSICIAN USE of perioperative chemotherapy (POC) for muscle-invasive bladder cancer (MIBC) increased by 35% from 2006 to 2010, following the 2003 landmark SWOG-8710 trial favoring the treatment. The shift was driven mainly by neoadjuvant chemotherapy administration, which almost doubled. Adjuvant chemotherapy usage changed little. “Although a rising trend in guideline adherence is reassuring, the optimal rate of POC administration for MIBC is not known,” a research team led by Zachary D. Reardon, MD, of Vanderbilt University Medical Center in Nashville, wrote in an online report in European Urology. “In an era where physicians are subject to performance measures contingent on both qualityof-care metrics and patient outcomes, reconciliation of guideline adherence, patient selection, and execution of appropriate therapy in the setting of MIBC will become increasingly complex. It is clear that shared decision making between individual patients and physicians as well as a risk-strati-

Prostate Cancer Group Study 7, in which investigators randomly assigned 875 men with locally advanced or highrisk localized PCa and a mean age of 66 years to receive ADT alone or ADT plus RT. Results showed that ADT plus RT was associated with a large and significant reduction in cancer-specific and all-cause mortality, according to a report published in The Lancet (2009;373:301-308). In an editorial accompanying the report by Dr. Bekelman and colleagues, Dean A. Shumway, MD, and Daniel A. Hamstra, MD, of the University of Michigan in Ann Arbor, commented that the study “contributes significantly to our understanding of both the age-dependent bias against treatment as well as the benefits of RT added to ADT in elderly men with locally advanced or screen-detected high-risk prostate cancer.” n

fied approach to the administration of POC will optimize outcomes.” For the study, the investigators analyzed data on 5,692 patients from the National Cancer Database with no prior malignancy who ultimately underwent radical cystectomy for stage 2 MIBC or greater without node involvement or metastases. POC administration increased significantly from 29.5% of cases in 2006 to 39.8% of cases in 2010, according to the investigators. Neoadjuvant chemotherapy usage rose from 10.1% to 20.8% over the same period. Adjuvant chemotherapy use remained stable between 18.1% and 21.3%. Increasing age beyond 59 years was negatively associated with POC receipt. Comorbidities were another factor. For example, prior analyses show that 30% to 50% of patients with MIBC are ineligible for standard chemotherapy due to poor performance status and impaired renal function, Dr. Reardon and his colleagues found. The researchers also confirmed several other nonclinical patient factors associated with lack of chemotherapy, including no insurance, residing outside the northeastern United States, and increasing distance from treatment facilities. By contrast, increasing income above $35,000 a year predicted a greater likelihood of chemotherapy receipt, the study showed. n

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Lupus Nephritis ESRD Rates Stable The rates may even be declining, but outcomes continue to differ by race, a new study suggests ESRD Rates Level Off for SLE Patients

ESRD SIR

In 2-year periods subsequent to 1995–1996, the rates of end-stage renal disease resulting from systemic lupus erythematosus have remained stable and may be in decline in the United States, as indicated by the standardized incidence ratio (SIR) for selected periods (shown below). 1.2 1.0 0.8 0.6 0.4 0.2 0.0

1.19

1.17

1.18

1997–1998

2001–2002

2005–2006

1.05

2009–2010

Source: Sextan DJ et al. ESRD from lupus nephritis in the United States, 1995–2010. Clin J Am Soc Nephrol. Published online ahead of print.

RATES OF END-STAGE renal disease (ESRD) from lupus nephritis in the United States have stopped increasing and may be declining, but racial disparities in outcomes persist, according to researchers. In a retrospective study using the U.S. Renal Data System database, investiga-

tors at the Chronic Disease Research Group of the Minneapolis Medical Research Foundation in Minneapolis, analyzed data from 1,557,117 individuals who initiated renal replacement therapy (RRT) from 1995–2010. Of these, 16,649 had ESRD from systemic lupus erythematosus (SLE). The

Stones Raise CHD Risk In Women

in females and may impact clinical management.” The investigators suggested plausible explanations for the findings. For example, kidney stones may be associated with CHD risk factors, such as features of the metabolic syndrome, including obesity, hypertension, and dyslipidemia. Stone formers, particularly those with uric acid stones, have a higher prevalence of diabetes and glucose intolerance. In addition, a history of kidney stones has been independently associated with CHD, raising the hypothesis that kidney stone formation has a vascular pathogenesis. The process leading to calcium buildup in the coronary arteries may be the same mechanism contributing to calcium buildup in renal tubules, Dr. Cheungpasitporn’s team explained. A recent study found that the composition of vascular plaques is identical to Randall’s plaque, the nidus of stone formation. In addition, a deficiency of pyrophosphates, which are inhibitors of calcification, in both blood and urine could explain the link between CHD and kidney stone formation. The investigators said it is surprising that females with kidney stones were more likely to develop CHD because both CHD and kidney stones are more common in males. Female stone formers may be exposed to unknown factors that increase their CHD risk. n

WOMEN WITH a history of kidney stones have a significantly increased risk of coronary heart disease (CHD), a new meta-analysis confirms. For the meta-analysis, investigators led by Wisit Cheungpasitporn, MD, of Mayo Clinic in Rochester, Minn., calculated CHD risk based on 52,791 patients with kidney stones. Data was pooled from observational cohort studies and a crosssectional study, each with control groups. Compared with individuals without kidney stones, stone formers had a 24% greater risk of CHD, according to results published in the North American Journal of Medical Sciences (2014;6:580-585). A history of kidney stones was associated with a significant 43% increased risk of CHD in females and a non-significant 14% increased risk in males. “Our study demonstrates a statistically significant increased risk of CHD in female patients with prior kidney stones,” the authors concluded. “This finding suggests that a history of kidney stones is a risk factor for CHD

News-Lupus-ESRD_RUN0215.indd 14

researchers, led by Robert N. Foley, MD, calculated standardized incidence ratios (SIRs) to 1995–1996, when the rate of SLE-related ESRD was 3.2 cases per million per year. Rates per million during 1995–1996 were higher for African Americans (11.1), female subjects (4.9), and individuals aged 20–29 (4.9), 30–44 (4.6), and 45–64 (4.0), according to the investigators. For the overall population, the SIRs of SLE-related ESRD requiring RRT were 1.19 in 1997–1998, 1.17 in 1999–2000, 1.17 in 2001–2002, 1.21 in 2003–2004, 1.18 in 2005–2006, 1.16 in 2007–2008, and 1.05 in 2009–2010, according to findings published online ahead of print in the Clinical Journal of the American Society of Nephrology. The rates for whites during these same biennial periods were 1.19, 1.14, 1.16, 1.12, 1.13, 1.14, and 1.03, respectively. The rates for African Americans were 1.22, 1.20, 1.19, 1.31, 1.23, 1.23, and 1.10, respectively.

During a median follow-up of 4.4 years, 42.6% of individuals with ESRD from SLE died, 45.3% were listed for renal transplantation, and 28.7% underwent transplantation. Compared with white patients, African-American patients were 23% more likely to die, after adjusting for age, sex, and other variables, according to the investigators. Although African-American patients were 11% more likely than white patients to be listed for a renal transplant, they were 46% less likely to receive one. The SLE patients were matched to a control group of patients who initiated RRT for ESRD not due to SLE. These controls were matched to SLE patients according to year of RRT initiation, sex, age, race, and ethnicity. Compared with controls, the SLE patients were more likely to be listed for a renal transplant, more likely to undergo transplantation, and just as likely to die, the researchers reported. n

Lower Creatinine Clearance Ups Odds of Muscle Atrophy LOWER SERUM creatinine clearance

with significantly slower mean 7-m

is associated with muscle atrophy,

and 400-m walk and knee extension

decreased walking speed, and more

strength during follow-up.

rapid declines in lower-extremity

During a mean follow-up of 7.1 years,

strength over time in older adults,

each 10-mL/min/1.73 m2 lower base-

according to a new study.

line creatinine clearance was associ-

The study, by Baback Roshanravan, MD, MS, of the Division of Nephrology at the University of Washington in

ated with a significant 0.024 kg/year greater decline in knee strength. This investigation included individuals

Seattle, and colleagues, included 826

aged 65 years and older who enrolled

community-living adults with a mean

in the Invecchiare in Chianti Study

age of 74 years. Of these, 183 had a

(InCHIANTI). Researchers determined

creatinine clearance of less than 60

baseline creatinine clearance based on

mL/min/1.73 m2. After adjusting for

24-hour urine collection. They chose

potential confounders, each 10-mL/

creatinine clearance “to account for

min/1.73 m decrement in creatinine

creatinine production within an individ-

clearance was associated with a 28

ual, reducing the potential for confound-

mm lower calf muscle area, 0.15 mg/

ing in analyses of muscle structure and

cm lower calf muscle density, 0.01 m/

performance.”

sec slower 7-m usual walking speed,

Dr. Roshanravan’s team said they

and 0.008 m/sec slower 400-m walk-

believe their study is the first to evalu-

ing speed, the researchers reported

ate associations of kidney function by

online ahead of print in the American

creatinine clearance with long-term

Journal of Kidney Diseases. Lower

changes in objectively measured physi-

creatinine clearance was associated

cal performance measures over time. n

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Renal & Urology News 15

Salvage Prostate Cryo Promising Focal and whole-gland approaches may provide alternatives for recurrent PCa after radiotherapy SALVAGE PROSTATE cryoablation as a focal or whole-gland therapy may be an effective treatment for patients with recurrent prostate cancer (PCa) following radiotherapy, according to the findings of 2 new studies. In a study of 91 men who underwent salvage focal cryoablation for biopsyproven recurrent PCa after radiotherapy, J. Stephen Jones, MD, of Cleveland Clinic, and colleagues found that the patients had biochemical disease-free survival rates of 95.3%, 72.4%, and 46.5% at 1, 3, and 5 years, respectively. In addition, 4 (28.6%) of 14 patients who underwent prostate biopsies had positive biopsies after salvage treatment, Dr. Jones’ group reported in The Prostate (2015;75:1-7). The researchers observed rectourethral fistula in 3 cases (3.3%), urinary retention in 6 cases (6.6%), and urinary incontinence requiring pad use in 5 cases (5.5%). Of 20 patients who reported potency prior to salvage treatment, 10 (50%) reported successful intercourse afterward. “The outcomes from this observational study indicate that salvage focal cryoablation can be an effective treatment with encouraging potency preservation for patients with locally recurrent PCa after radiotherapy,” the investigators concluded. “However,

Salvage Focal Cryoablation Offers Encouraging Outcomes In a study, researchers found that salvage focal prostate cryoablation for recurrent prostate cancer after radiotherapy offers good biochemical disease-free survival rates. Shown here are the 1-, 3-, and 5-year rates. 100

95.3%

72.4.3%

46.5%

40 20 0

1 year

3 year

5 year

Source: Li YH et al. Salvage focal prostate cryoablation for locally recurrent prostate cancer after radiotherapy: Initial results from the Cryo On-Line Data Registry. Prostate. 2014;75:1-7.

other morbidity including rectourethral fistula and incontinence are not clearly lower than for patients treated with salvage whole gland cryoablation.” The researchers observed that studies with longer follow-up times, more patients, and direct comparisons with salvage whole-gland cryoablation are needed before recommending salvage focal cryoablation as a standard treatment option for these patients. For the study, the researchers used data from the Cryo On-Line Data Registry. “To our knowledge, this is the largest data set assembled for salvage focal cryoablation for the treat-

ment of localized PCa recurrence after radiotherapy.” The other study, by Göran Ahlgren, MD, PhD, of Skåne University Hospital, Malmö, Sweden, included 30 men who received whole-gland transperineal cryotherapy at the hospital for biopsy-verified local PCa recurrence after radiotherapy. The patients had a median age of 70 years (range 61–80 years). The median follow-up after cryotherapy was 2.7 years (maximum 6.6 years). The median time from primary radiotherapy to cryotherapy was 7 years. Of 23 patients without hormonal treatment at the time of cryotherapy,

11 achieved a PSA nadir of less than 0.5 ng/mL, Dr. Ahlgren’s group reported online ahead of print in the Scandinavian Journal of Urology. At the end of followup, 5 of these 23 patients still had a PSA level below 0.5 ng/mL and 10 were free from recurrence according to the Phoenix definition (PSA nadir plus 2 ng/ mL). The investigators detected clinical recurrence—verified with imaging or biopsies—in 13 patients, of whom 6 had local recurrence. Death from PCa occurred in 1 patient. With respect to complications, urinary incontinence grade 1–2 and 3–4 occurred in 11 and 3 patients, respectively. Severe but transitory tissue sloughing occurred in 3 patients. In addition, 3 patients experienced a urethral stricture or had prolonged urinary retention, and 1 patient developed a urinary fistula 4.5 years after cryotherapy. “The results from Skåne University Hospital in Malmö compare well with those reported from centres with longer experience,” the authors wrote. “Proper patient selection is crucial for obtaining optimal results.” The researchers acknowledged that their study is limited by the small number of treated patients and lack of prospective, patient-reported evaluation of side effects. n

Higher Uric Acid Raises Odds of Renal Insufficiency EVEN A SLIGHT increase within the normal range of serum acid levels may be a risk factor for kidney damage in the general population, according to Japanese researchers. Using a nationwide database of 165,847 individuals aged 29–74 years who participated in the annual “Specific Health Check and Guidance in Japan” checkup from 2008–2010. Keita Kamei, MD, of Yamagata University School of Medicine in Yamagata, Japan, and colleagues examined the relationship between serum uric acid levels at baseline and the 2-year change in estimated glomerular filtration rate (eGFR). Compared with the first quintile of serum uric acid level, the fourth and fifth quintiles were associated with a significant 10% and 20% increased odds of incidental renal insufficiency (eGFR below 60 mL/ min/1.73 m2), after adjusting for age,

News-salvage-cryo_RUN0215.indd 15

gender, obesity, hypertension, and other variables, Dr. Kamei’s group reported online ahead of print in Nephrology Dialysis Transplantation. Each 1 mg/dL increment in uric acid level was associated with a significant 5% increased odds of renal insufficiency. The first quintile of uric acid level was 4.9 mg/dL or less in men and 3.7 mg/dL or less in women. The fourth quintile was 6.3–7.0 mg/dL in men and 4.9–5.4 mg/dL in women. The fifth quintile was 7.1 mg/dL or higher in men and 5.5 mg/dL or higher in women. Normal uric acid levels are 3.4–7.0 mg/dL in men and 2.4–6.0 mg/dL in women. The researchers noted that a strength of the study was the large nationwide study population that was followed prospectively, but the study had some limitations. Serum uric levels were measured only at baseline, so changes

in serum levels during the follow-up period that might have an independent effect on renal outcome were not evaluated, according to the investigators. In addition, eGFR was evaluated only at baseline and at 2 years.

Even uric acid levels in the normal range can increase the risk, study finds. In a previous study published in Nephrology Dialysis Transplantation (2010;25:3593-3599), a U.S. team found that higher serum uric acid (SUA) levels may independently contribute to the development of chronic kidney disease (CKD). The finding was based on an analysis of data from the C8 Health

Study, a population-based study of 49,295 Appalachian adults free from cardiovascular disease. The investigators, led by Anoop Shankar, MD, of the West Virginia University School of Medicine in Morgantown, observed a positive association between increasing quartiles of SUA and CKD, independent of age, gender, smoking status, alcohol intake, diabetes mellitus, hypertension, BMI, total cholesterol, and education. Compared with the patients in SUA quartile 1 (reference), those in quartiles 2, 3, and 4 had a 1.53, 2.16, and 4.67 times increased risk of CKD, the investigators reported. Dr. Shankar and his colleagues noted that an association between SUA and kidney disease is biologically plausible. They cited a study showing that mild elevations of SUA in rats, even levels within normal limits, can cause hypertension and renal microvascular disease. n

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JANUARY/FEBRUARY 2015

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Practice Management Bundled payments may offer opportunities to individual specialists and help practices stay afloat as healthcare reform moves forward BY TAMMY WORTH

How to Charge For Bundled Care Cass Schaedig, director of Data Solutions for HealthTronics IT, Inc., offers some tips for deciding what to charge for bundled care: • Choose a trigger for the bundle • Define a window of time for the length of care needed to treat a condition • Establish what should be included in a bundle • Calculate cost based on relative value units

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A CMS initiative under development would provide for bundled payments to physicians.

programs because many are focused on [primary care providers] and across specialties,” she said. “But there is a huge role for specialists to play because they are responsible for a lot of the care provided and the more costly care that is provided.” CMS is “pushing and driving” the change in the way physicians are paid, but Brennan said she is encouraging practices to explore opportunities with both Medicare and private payers. Feefor-service reimbursements likely will not be gone anytime soon, but having flexibility to try different kinds of payment models may help practices remain afloat as healthcare reform moves forward. In addition to conditions such as diabetes and UTIs, Teresa Koenig, senior vice president of The Camden Group, said bundled payments could easily span procedures and radiation for such illnesses such as end-stage renal disease and cancer. CMS is currently exploring an oncology model that could include common diagnoses like prostate cancer. Cass Schaedig, director of Data Solutions for HealthTronics IT, Inc.,

is a data cruncher who has worked with hospitals to figure out what they should be charging for bundled care. Understanding the cost of a bundled payment begins with choosing the trigger for the bundle, like the presence of benign prostatic hyperplasia (BPH) in

based on relative value units (RVUs). When figuring the costs, she said providers have to take into account how that relates to what they are currently paid for the services and if it will cover their overall costs. Schaedig has helped develop a simulation of what a BPH bundle might look like. She culled data over a 2-year period from more than 200 urology groups to see what an episode of care would cost. She looked at both large and small practices and asked for their average reimbursement under fee-for-service arrangements. They included covered services beginning with a diagnosis of BPH with urinary obstruction and ending 90 days later. She found that the average payment per episode was approximately $691 and included just more than 18 RVUs and from 7 to 8 work RVUs. More than 80% of the total payments came from surgery and evaluation/management. It is important, particularly when negotiating with private payers, to “carve out” things that should not be included in the diagnosis, Schaedig said. This way, pro-

Among other considerations, a physician has to define a window of time for the length of care needed to treat a condition. a new patient or initiation of care for the condition in a current patient. Next, a physician has to define a window of time for the length of care needed to treat the condition. Third, and most importantly, they need to establish what should be included in the bundle. Providers will need to go through their records to find out what kind of services were provide to patients after the diagnosis and how often these services occur. They then need to calculate the cost

viders are not responsible for the cost of things that are out of their control like external labs or other services. In her accounting, she excluded patients with other conditions like prostate malignancy from her tabulations. Some services can be carved out of the bundle, and patients with too many other diagnoses may have to be left out altogether, she said. ■ Tammy Worth is a freelance medical journalist based out of Blue Springs, MO.

he Centers for Medicare and Medicaid Services (CMS) has been laser focusing on ways to reduce healthcare costs and improve the quality of treatment provided to patients. One way CMS is doing this is by revamping the way physicians are being paid. The “bundle” appears to be emerging as a favorite type of payment. CMS’ Bundled Payment Care Initiative was rolled out in 2013, but focused on hospitals and post-acute care facilities. The bundles centered on episodes of care for conditions including urinary tract infections (UTIs), renal failure, and diabetes. A new program is currently under development that would, for the first time, focus bundling on individual physicians for procedures and chronic condition management: The Specialty Practitioner Payment Model. This may be new territory for many specialists, but one that they should be actively exploring, according to Allison Brennan, senior advocacy adviser for the Medical Group Management Association. “One of the challenges for specialists is to find where their niche is in these

Want to improve your practice? Look for our tips on how to handle equipment issues, adjust to EHRs, comply with HIPAA, and more at www.renalandurologynews.com/practice.

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EF Recovery Depends On PCa Surgical Approach RECOVERY OF erectile function (EF) may be more likely among prostate cancer patients who undergo nerve-sparing radical prostatectomy by robot-assisted laparoscopy rather than open surgery, new findings suggest. Jens-Uwe Stolzenburg, MD, of University Hospital Leipzig in Germany, and colleagues studied 422 patients younger than 68 years who had normal preoperative EF prior to nervesparing surgery for localized prostate cancer. In a 9-month double-blind trial, investigators randomly assigned patients to receive tadalafil (once daily or on demand) or placebo after surgery, followed by a 6-week drug-free washout and 3-month open-label once daily tadalafil treatment for all patients. The researchers defined EF recovery as an International Index of Erectile Function (IIEF)-EF domain score of 22 or higher and normal orgasmic function based on IIEF Question 10. Of the 422 patients, 115 had robotic-assisted laparoscopy, 88 had conventional laparoscopy, and 189

had open surgery. For 30 patients, the type of surgery was classified as “other.” Patients who had robotassisted laparoscopy had a significant 2.4 times increased odds of EF recovery at the end of the drugfree washout compared with the open surgery group, the researchers

Erectile function is more like to recover after robot-assisted laparoscopy. reported online ahead of print in BJU International. In addition, men who had robot-assisted laparoscopy had a significant 2-fold increased likelihood of EF recovery during the doubleblind treatment compared with those who had open surgery. The investigators observed no favorable effect of conventional laparoscopy compared with open surgery. n

Early HD Visits May Promote Arteriovenous Fistula Creation WHEN PATIENTS ARE seen more

could lead to improvements in health

frequently by a nephrologist or advanced

outcomes.”

practitioner in the first 90 days of

More face-to-face encounters could

hemodialysis (HD), they are more likely to

help providers stabilize sick patients so

have early surgery for the creation of an

they are better candidates for surgery,

arteriovenous (AV) fistula or placement of

the researchers noted. Patients also

an AV graft, a new study found.

may be more willing to undergo surgery

Previous studies have shown that pre-dialysis visits increase the likelihood of AV fistula creation and AV graft placement. “Current reimbursement encour-

when it is recommended by a provider they learn to trust. For the study, published online ahead of print in the Journal of the American Society of Nephrology, Dr. Erickson’s

ages visits to all patients, irrespec-

team analyzed national registry records

tive of their health needs,” wrote the

for 35,959 patients aged 67 or older

researchers led by Kevin Erickson, MD,

who were starting HD.

of the Center for Primary Care and

Each additional nephrologist or

Outcomes Research, Department of

advanced practitioner visit per month

Medicine, Stanford University School

in the first 90 days of HD was associ-

of Medicine in Stanford, Calif. “Policies

ated with a 21% increase in the odds

that encourage more frequent visits

of AV fistula creation or graft place-

to patients who actually benefit from

ment during that period, the research-

additional visits, such as patients who

ers reported. It increased the absolute

recently started dialysis or who were

probability of the vascular access

recently discharged from the hospital,

surgery by an average 4.5%. n

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treatment with XTANDI. Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day,and cleft palate and absent palatine bone at 30 mg/kg/ day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC). Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide 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 XTANDI, 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 XTANDI in pediatric patients have not been established. Geriatric Use Of 1671 patients who received XTANDI in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these 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 Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology (12.3)]. Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology (12.3)]. OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day

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(0.3 times the human exposure based on AUC). Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Medivation, Inc., San Francisco, CA 94105 Revised: September 2014 14B006-XTA-BRFS Rx Only © 2014 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

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