Renal & Urology News April 2012 Issue by Haymarket Media

CONVENTIO N ISSUE

■

VOLUME 11, ISSUE NUMBER 4

ESRD After Pancreas Tx Tied to Low eGFR Eightfold increased risk within a decade BY ROSEMARY FREI, MSc QUEBEC CITY—End-stage renal disease (ESRD) eventually develops in more than half of patients with moderate kidney dysfunction at the time of pancreas transplantation, according to new findings presented at the Canadian Society of Transplantation’s 2012 Annual Meeting. From an analysis of data from the U.S. Scientific Registry of Transplant Recipients (SRTR) and the United States Renal Data System, investigators discovered that patients undergoing pancreas transplantation

IN THIS ISSUE 12

High-grade prostate cancer, metabolic syndrome linked

How bundling of dialysis services affects clinical practice

Expert Q&A: Neonatal male circumcision

PSA screening reduces prostate cancer mortality

Kidney donation possible despite ARF

Medullary renal carcinoma in a young AfricanAmerican male PAGE 25

who had an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m 2 were eight times more likely than patients with normal renal function to develop ESRD within a decade. This relationship had been strongly suspected but never before quantified using such a large dataset, according to the investigators. “An eightfold increase is almost unheard-of magnitude these days with respect to risk factors,” lead investigator S. Joseph Kim, MD, PhD, Assistant Professor of Medicine at the

NSAID Use May Increase PCa Risk BY JODY A. CHARNOW PARIS—Contrary to the findings of previous epidemiologic research, a new study found that use of nonsteroidal anti-inflammatory agents (NSAIDs) is associated with an increased risk of prostate cancer (PCa) overall and aggressive PCa, Finnish researchers reported at the 27th Annual Congress of the European Association of Urology. A team at the University of Tampere School of Medicine led by Teemu J. Murtola, MD, PhD, identified all newly diagnosed PCa cases in Finland during 1995 to 2002 and matched these with 24,657 controls. After adjusting for continued on page 11

■

www.renalandurologynews.com © CMSP

APRIL 2012

Post-Pancreas Transplant ESRD The cumulative incidence of end-stage renal disease at 10 years after pancreas transplantation correlates to a patient’s eGFR at the time of surgery, a study found. Patients with an eGFR below 60 mL/min/1.73 m2 had the highest percentage of ESRD cases at 10 years.

30%

23% 130

Stage 1 CKD

Stage 2 CKD

54% 60

Stage 3 CKD

Stage 4 CKD

Stage 5 CKD

Estimated glomerular filtration rate (in mL/min/1.73 m2) Based on data presented at the Canadian Society of Transplantation 2012 Annual Meeting in Quebec City. Abstract 1612.

University of Toronto, told Renal & Urology News. “The big question is whether one can predict which specific patients will develop ESRD after pancreas transplantation and the appropriate timing of kidney transplantation in this subset of patients.”

Dr. Kim’s team studied information from the SRTR on all pancreas transplant recipients in the United States between January 1, 1994 and December 31, 2009. They excluded patients who underwent simultaneous pancreascontinued on page 11

Shockwave Therapy May Treat ED PARIS—Low-intensity extracorporeal shockwave therapy (LI-ESWT) is an effective treatment option for men with vasculogenic erectile dysfunction (ED), according to findings presented at the 27th Annual Congress of the European Association of Urology. In a double-blind, placebo-controlled study, Yoram Vardi, MD, and collaborators at Rambam Medical Center in Haifa, Israel, showed that the treatment significantly improved various measures of erectile function, including penile hardness, hemodynamics, and endothelial function. LI-ESWT is the first therapy shown to reverse the pathology in the penis of

CME FEATURE

men with vasculogenic ED, Dr. Vardi said. “It is really a breakthrough in the sense that it is the first treatment that can probably cure or at least improve the erectile mechanism,” he told Renal & Urology News. Dr. Vardi and his team studied 60 men who were randomly assigned to receive LI-ESWT or sham treatment. LI-ESWT was applied to the penile shaft and crura at five different sites. The researchers assessed erectile function prior to the first treatment and at one month after the final treatment session using the International Index of Erectile Function (IIEF) and the continued on page 11

Earn 1 CME credit in this issue

Part II: Clinical Challenges and Renal Considerations in Managing Gout PAGE 32

www.renalandurologynews.com

ZYTIGA® (abiraterone acetate) Tablets Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Low Potassium 28.3 5.3 19.8 1.0 Low Phosphorus 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: ZYTIGA is not indicated in children. Geriatric Use: Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years and over and 28% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (ChildPugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information]. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE: There have been no reports of overdose of ZYTIGA during clinical studies. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations]. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 Issued: December 2011

08Z11205B

APRIL 2012

Renal & Urology News 5

Long-Term Outcomes Similar for ECDs, SCDs BY ROSEMARY FREI, MSc QUEBEC CITY—Kidneys from standard criteria donors (SCDs) and expanded criteria donors (ECDs) are associated with similar rates of long-term patient survival and death-censored graft survival, a study has confirmed. The only significant difference in deathcensored graft survival rates was between ECD and SCD kidneys with slow graft function (SGF) and SCD kidneys with SGF. The rates were approximately 75% and 92%, respectively, 10 years posttransplant. The researchers determined that an estimated glomerular filtration rate (eGFR) decrease of more than 30% between one month and one year post-transplant is a strong predictor of death-censored graft survival. They presented the results at the Canadian Society of Transplantation’s 2012 Annual Meeting. The use of kidneys from ECDs has increased significantly across North America over the past decade, but these kidneys are associated with a significantly increased risk of graft loss. To determine the impact of immediate outcomes on long-term outcomes, a team from the McGill University Health Centre in Montreal led by Nassima Smail, MD, studied the outcomes of the 471 con-

secutive recipients of deceased-donor kidneys at their center from January 1, 1990 to December 31, 2007. Just over half of the patients (253, or 53.7%) received kidneys from SCDs. These recipients included 82 women with an average age of 49 years. The remaining 218 patients (46.3%) received kidneys from ECDs. These recipients had an average age of 52 years. The group included 73 women. The investigators found no significant differences in 10-year survival rates between patients who received kidneys from ECDs and SCDs, regardless of whether the kidneys had immediate, slow, or delayed graft function post-transplant. There were also similar 10-year deathcensored graft-survival rates, with the only exception being between ECD and SCD kidneys with SGF. The analyses also revealed significant predictors of death. Each one-year increment in recipient age was associated with a 5.8% increased risk of death, and each one-unit increment in serum creatinine was associated with a 0.8% increased risk. Patients receiving a second transplant had a twofold increased risk of death. Tacrolimus use the first month posttransplant was associated with a 39.5% decreased risk. ■

Finasteride Prevents Benign Prostatic Hyperplasia, Study Finds FINASTERIDE USE decreases the risk of clinical benign prostatic hyperplasia (BPH), according to researchers. J. Kellogg Parsons, MD, of the University of California in San Diego, and colleagues made the discovery after performing a secondary analysis of data from the Prostate Cancer Prevention Trial (PCPT). In the trial, investigators randomized men to receive finasteride 5 mg per day or placebo. Results showed that finasteride decreased the risk of prostate cancer by about 25%. The secondary analysis focused on 9,253 men. After a mean follow-up of 5.3 years, the rate of clinical BPH was 11 per 1000 person-years in the finasteride arm compared with 19 per 1000 person-years in the placebo arm, a significant difference that translated into a 40% decreased risk of clinical BPH associated with finasteride use, the researchers reported online ahead

of print in European Urology. Finasteride reduced the risk by 44% among men aged 65 or older. “These data provide the first clinical evidence that BPH may be prevented and directly inform the ongoing scientific and health policy dialogue with respect to the use of 5-ARIs for the chemoprevention of prostate cancer,” the authors wrote. The investigators defined clinical BPH as the initiation of medical treatment, surgery, or sustained, clinically significant urinary symptoms (International Prostate Symptom Score of 8 or higher). Dr. Parsons and his colleagues calculated that the number of men that needed to be treated with finasteride to prevent one case of clinical BPH over seven years was 58 for men aged 55-59; 42 for men aged 60-64; and 31 for men aged 65 or older. ■

2/8/12 2:16 PM

6 Renal & Urology News

APRIL 2012

www.renalandurologynews.com

FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD

Is U.S. Nephrology Lagging Behind?

s practicing clinicians in the United States, we have access to a highly developed medical care system along with advanced, cutting-edge technology in the world’s largest economy. In the past several years, however, we have noticed the staggering development of the so-called emerging economies, including those in Asian-Pacific countries, which now challenge the economic superiority of the United States and the rest of the western world. Each time I fly to the modern Asian airports in Seoul, Taipei, Dubai, and Singapore, I feel the urgent need for long-overdue modernization of our once-to-be-proud-of airports LAX and JFK. Similarly, during my visits to hospitals and dialysis clinics in Asian countries, I see another rapidly deepening contrast: the patient care practice differences between the United States and Asia. The technology and resources used in the United States that are considered conventional medicine are falling behind the cutting-edge technology and clinical machinery in much less-affluent countries, such as Thailand and Malaysia, not to mention the highly modern state-of-the-art medicine practiced in Japan and Singapore. I also see enormous differences in nephrology practice. In the United States, we are proud of starting dialysis treatment early and fast, but our Taiwanese colleagues start dialysis therapy with an average eGFR below 5 mL/min/1.73m2. While we are proud of using ACE inhibitors and angiotensin receptor blockers to slow the rate of chronic kidney disease progression, Taiwanese nephrologists implement half a dozen more interventions to this end, including low-protein diet reinforcement and monitoring, keto-analogues of amino acids, and charcoal derivatives to modulate uremic toxins. On the dialysis front, too, other countries appear to be ahead of us. In this country most of us have no clear idea what so-called “on-line hemofiltration” is, whereas in many other countries it has been practiced routinely in outpatient clinics for years. Our dialysis machines are outdated compared with those of some other nations. We do not allow our patients to eat during dialysis, whereas meals are served routinely in many outpatient dialysis centers in other countries. We appear to be disconnected and uninterested in knowing why other nephrology communities are moving forward faster than we are. In terms of income, we feel that we are paid relatively well in this country, yet we do not realize that even Canadian nephrologists, on average, earn 20% to 40% higher income than their counterparts here. On the bright side, however, the rest of the world still looks up to us and our guidelines. Yet, we should not take our leadership position for granted, but we should cherish it and try hard to preserve and reinforce it. Kamyar Kalantar-Zadeh, MD, MPH, PhD Professor of Medicine and Pediatrics, and Director, Dialysis Expansion & Epidemiology, Harbor-UCLA Division of Nephrology & Hypertension Dr. Kalantar-Zadeh is Medical Director, Nephrology, for Renal & Urology News.

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, PhD, MPH Professor of Medicine and Pediatrics, and Director, Dialysis Expansion & Epidemiology Harbor-UCLA Division of Nephrology & Hypertension Los Angeles BioMedical Research Institute, The David Geffen School of Medicine at UCLA

Urologists

Nephrologists

Frank R. Cerniglia Jr, MD Attending Pediatric Urologist Children’s Urology of Virginia Richmond, Va.

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 Associate Clinical Professor of Surgery/Urology University of Connecticut School of Medicine, Urology Center New Haven J. Stephen Jones, MD, FACS Chairman Department of Regional Urology Cleveland Clinic Glickman Urological & Kidney Institute Professor of Surgery Cleveland Clinic Lerner College of Medicine of Case Western Reserve University James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City Kenneth Pace, MD, MSc, FRCSC Assistant Professor Division of Urology St. Michael’s Hospital University of Toronto Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada

R. Michael Hofmann, MD Associate Professor and Medical Director, Living Kidney Donor Program University of Wisconsin School of Medicine and Public Health, Madison Csaba P. Kovesdy, MD Associate Professor of Clinical Medicine University of Virginia, Charlottesville Chief of Nephrology Salem VA Medical Center Salem, Va. 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. Rulan Parekh, MD, MS Associate Professor Johns Hopkins Children’s Center, Baltimore 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. Lynda Anne Szczech, MD, MSCE Associate Professor of Nephrology Duke University School of Medicine Durham, N.C.

Renal & Urology News Staff Editor Executive editor Senior editor Web editor Editorial coordinator Group art director, Haymarket Medical VP, audience development and operations Production manager Product manager, digital products Circulation manager Assistant circulation manager National accounts manager Editorial director Publisher VP medical magazines and digital products CEO, Haymarket Media Inc.

Jody A. Charnow Marina Galanakis Delicia Honen Yard Stephan Cho Candy Iemma Jennifer Dvoretz John Crewe Kathleen Millea Chris Bubeck Paul Silver Monica Bond William Canning Tanya Gregory Dominic Barone Jim Burke Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 11, Number 4. Published monthly 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. For reprints, contact Wright’s Reprints at 1.877.652.5295. 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 © 2012.

Contents

A P R I L

2 0 1 2

■

VO L U M E

1 1 ,

I S S U E

N U M B E R

Urology 11

RFA Successfully Treats Small Benign Renal Tumors Radiofrequency ablation can effectively treat small benign tumors in a single session.

Hospitalization Rare After Prostate Biopsy Hospital admissions related to a prostate needle biopsy (PNB) are on the increase, but they occur in less than 1% of men who undergo PNB and are not associated with increased mortality.

ONLINE

this month at renalandurologynews.com 24

Expert Q&A Alan S. Kliger, MD, Chief Medical Office and Chief Quality Officer for the Saint Raphael Healthcare System in New Haven, Conn., gives advice on the use of erythropoiesis-stimulating agents.

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 February winner: Mark Ehrenpreis, MD

PSA Screening Lowers PCa Mortality Updated results from large European study confirm previous findings that a PSA-based screening significantly decreases prostate cancer mortality risk. Severe Pelvic Fracture Impairs Sexual Function Patients who have suffered an acute pelvic fracture severe enough to require surgery have a significantly increased risk of a decrease in sexual function, British investigators reported.

32 CME Feature Part II: Clinical Challenges and Renal Considerations in Managing Gout James W. Lohr, MD, Professor of Medicine at the State University of New York in Buffalo and Chief of Nephrology at the Buffalo V.A. Medical Center, discusses such topics as treating CKD patients with gout and pharmacologic options for managing acute gout flares.

Nephrology 13

Bundling’s Impact on Clinical Practice The implementation of a bundled payment system for chronic dialysis in January 2011 was not a surprise and has not been associated with a radical change in clinical practice.

DCD Kidneys Can Yield Good Outcomes Canadian researchers report that transplantation of kidneys donated after cardiac death can result in good outcomes.

NEW: Doctors in the News

News Coverage Visit our website for on-site coverage of the National Kidney Foundation’s 2012 Spring Clinical Meetings in National Harbor, Md., May 9-13.

“

Diabetes May Hike Urinary Stone Risk Diabetes mellitus independently predicts an increased risk of urinary tract calculi, according to investigators in Taiwan. Acute Kidney Injury Linked to Antibiotics New data document a strong association between the use of flucloxacillin with singledose gentamicin in patients undergoing joint replacement surgery and the development of acute kidney injury.

“

Shlomo Raz, MD, will receive the 2012 AUA Ramon Guiteras Award during the annual AUA meeting in Atlanta this May. For more news about urologists and nephrologists, visit renalandurologynews.com /doctors-in-the-news/

Consider recruiting in-center [HD] patients with ample educational pamphlets and on site resources, which outline the benefits of home HD. See our story on page 20

Departments 6

From the Medical Director Is American nephrology lagging?

News in Brief Men with heart disease are at higher PCa risk

Renal Nutrition Update A less costly approach to ridding uremic toxins

On the Forefront Sickle cell trait and medullary renal carcinoma

Legal Issues in Medicine Failure to follow up prompts a lawsuit

10 Renal & Urology News

APRIL 2012

www.renalandurologynews.com

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

Short Takes PCa Risk Higher In Men with Heart Disease

of 6.5 years (maximum 17.7 years)

Coronary artery disease (CAD) was

events or death was 34% lower

associated with a 35% increased risk

in donors than in non-donors. The

of a prostate cancer (PCa) diagnosis

risk of major CV events censored

among the 6,390 men taking part

for death did not differ significantly

in the REDUCE trial, which evaluated

between donors and non-donors, the

whether dutasteride reduced PCa

study showed.

showed that the risk of major CV

risk. Overall, 547 enrollees (8.6%) with men who had no heart disease,

FDA Okays Female Incontinence Device

those with CAD were 24% more

The FDA has cleared InTone, a medi-

likely to be diagnosed with PCa two

cal device for treating female urinary

years into the REDUCE trial and 74%

incontinence.

had a history of CAD. Compared

more likely four years into the study,

InTone is the first medical device

Stephen J. Freedland, MD, and col-

that combines mild micro-current

leagues reported in Cancer Epidemi-

stimulation (similar to a transcutane-

ology, Biomarkers & Prevention.

ous electrical nerve stimulation unit), exercises, and guided biofeedback to strengthen the muscles in the

Kidney donors are at no greater risk

physicians customize settings for

for cardiovascular (CV) events or

the device and patients are shown

death than non-donors, a research

how to use it at home. Most patients

team led by Amit X. Garg, MD,

should experience progress in a few

reported online in the British Medical

weeks, and most should experience

Journal. Interim results from a study

effective relief in 90 days, according

of 2,028 living kidney donors in On-

to a press release issued by InControl

tario, Canada, and 20,280 matched

Medical of Brookfield, Wis., the maker

non-donors followed for a median

of the device.

fro St m ra ig t h ht eW eb

Kidney Donation Does Not Increase CV Risk

pelvic floor. After prescribing InTone,

A Active Surveillance Gaining Favor 1.5%

23%

More likely Not more likely

75.5%

Was not in practice five years ago

The vast majority of urologists are more likely today to recommend active surveillance for selected patients with low-risk prostate cancer than they were five years ago, according to a recent Renal & Urology News online poll to which 200 urologists responded.

HD Is An Independent Risk Factor for Atherosclerosis H

emodialysis (HD) is an independent risk factor for atherosclerosis in patents who have chronic renal failure (CRF), researchers reported in the North American Journal of Medicine Science (2012;4:77-80). In a study of 78 CRF patients, those on HD had significantly greater carotid artery intima media thickness (CAIMT) than age- and sex-matched non-dialyzed CRF patients (mean 1136.3 vs. 959.3 µm), investigators at Burdwan Medical College in West Bengal, India, observed. “Measurement of CAIMT has a value to diagnose the atherosclerosis in CRF patients on hemodialysis after traditional risk factors have been taken into consideration,” the authors concluded. “Aggressive control of modifiable risk factors may reduce the progression of atherosclerosis in hemodialysis patients because they are also independent risk factors of atherosclerosis.”

Researchers: Colorectal Cancer Linked to CP/CPPS C

hronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) may put men at increased risk for colorectal cancer, a study found. The association was most prominent among men younger than 60 years. Herng-Ching Lin, MD, of Taipei Medical University in Taiwan, and collaborators conducted a study that included 2,899 men with colorectal cancer (cases) and 14,995 randomly selected men as controls. Case patients were 45% more likely than controls to have had a prior diagnosis CP/CPPS, after adjusting for hypertension, diabetes, renal disease, monthly income, geographic location and other potential confounders, the researchers reported online ahead of print in BJU International. In a subgroup analysis, the association was strongest among men younger than 60 than other age groups. Case patients aged 40-49 and 50-59 were twice as likely as controls to have CP/CPPS.

Physician Reminders Fail to Increase ACE/ARB Use T

reatment reminders fail to increase the rate at which primary care physicians (PCPs) prescribe ACE inhibitors or angiotensin receptor blockers (ARBs) for elderly patients with chronic kidney disease (CKD), according to an online report in the Clinical Journal of the American Society of Nephrology. In a study of 5,444 CKD patients older than 65 years and who had diabetes or proteinuria, ACE inhibitors or ARBs were prescribed for 77.1% of those whose PCPs received a standard laboratory prompt with kidney test results and for 76.9% of those whose PCPs received an enhanced prompt that recommended prescribing one of these agents, a nonsignificant difference. Braden Manns, MD, of Foothills Medical Center in Calgary, Alberta, and coinvestigators found that for the subset of patients with an estimated glomerular filtration rate of less than 30 mL/min/1.73 m2, ACE inhibitor/ARB use was higher in the enhanced-prompt group.

www.renalandurologynews.com

ESRD/ Post Pancreas Tx kidney transplants, received a pancreas after a kidney, or were younger than 18 years. Their other exclusion criteria were the presence of ESRD prior to transplant, previous pancreas transplant, and not having serum creatinine data available from the time of pancreas transplant. The investigators focused on differences in patients’ outcomes based on whether at the time of pancreas transplant their eGFR (in mL/min/1.73 m2) was below 60, 60-89.9, or above 90, as determined using the Chronic Kidney Disease Epidemiology Collaboration equation. The three categories included 269, 338, and 528 patients, respectively. Overall, the patients had a mean and median eGFR of 83.3 and 87.1, respectively.

Patients with an eGFR greater than 90 were significantly younger than the others (average 38.5 vs. 43.7 years for those with an eGFR below 60 and 43.6 years for patients with an eGFR of 60-89.9). Furthermore, a smaller proportion was female (52.7% vs. 59.1% and 59.5%), and fewer were white (93.6% vs. 95.5% and 94.4%). Moreover, fewer of the donors to recipients with an eGFR above 90 were female (32.8% vs. 37.2% and 35.2%). The cumulative incidence of ESRD was significantly higher among patients who at the time of pancreas transplant had an eGFR below 60: about 54% at 10 years post-transplant compared with 30% for recipients with an eGFR of 60-89.9 and 23% for those with an eGFR above 90. “The survival curve for people in the group with the lowest eGFR at time of transplant is quite different from

the curves for the other two groups, with a very statistically significant increase in ESRD incidence over time”, Dr. Kim noted. Recipients with an eGFR below 60 had an eightfold greater risk of developing

Shockwave Therapy for ED

NSAID Use and PCa Risk

continued from page 1

Erection Hardness Scale (EHS). They also assessed penile hemodynamics and endothelial function using the flow mediated dilatation technique (FMD). The main outcome measure of treatment success was a change in IIEF-ED Domain score of more than five points. The LI-ESWT group showed a greater increase in total IIEF and IIEF-ED score compared with the sham group and significantly greater improvement in FMD. Combining

potential confounders, men who had ever used NSAIDs had a 31% increased risk of PCa overall and a 63% increased risk of advanced PCa. For the study, Dr. Murtola’s group estimated the cumulative COX-2 inhibition by multiplying the total cumulative amount (in milligrams) of each NSAID used with the drug-specific COX-1/COX-2 inhibition ratios. They also estimated the propensity to NSAID use among users of medications to treat benign prostatic hyperplasia, diabetes, hypercholesterolemia, and hypertension. From this, the researchers calculated a propensity score for each subject. “The major difference between our study and most of the previous studies is the source of information on NSAID usage,” Dr. Murtola said. “In our study, the information came from a

national prescription database, whereas most of the previous studies relied on survey information, i.e., on selfreported data.” Although the researchers did not have knowledge of over-the-counter NSAID usage—the most common way these drugs are used—their data was far more detailed than in any previous study, enabling them to estimate even the cumulative COX-2 inhibition based on total amount of NSAID use in milligrams. “Because all NSAIDs in our study were prescribed by a physician, all users for certain had an indication for the usage,” Dr. Murtola said. “We believe this was often some chronic condition possibly associated with chronic systemic inflammation. An example of this could be arthrosis caused by excess obesity. Therefore, the NSAID users in our study likely were, as a group, different from previous studies where most users had been

continued from page 1

The treatment improved penile hardness and hemodynamics. the objective and subjective parameters, the researchers found that 22 patients in the LI-ESWT group (56%) showed significant improvement in both IIEF and FMD compared with only one (5%) in the sham group. In addition, 13 patients in the LI-ESWT group had an EHS of 3 or greater before treatment compared with 31 after treatment. In the sham group, there was no significant difference in the number of patients with an EHS of 3 or greater (eight before sham treatment, seven after). The LI-ESWT group experienced a significantly greater increase in the IIEF Total Satisfaction category than the sham group. ■

New findings do not point to a need for a simultaneous kidney transplant. ESRD compared with those with an eGFR above 90 in a multivariable Cox proportional hazards model. Each 10 mL/min/ 1.73 m2 increase in eGFR at the time of pancreas transplantation was associated with a 20% reduction in ESRD risk. These results remained consistent when the investigators re-analyzed the data

APRIL 2012

Renal & Urology News 11

using the Modification of Diet in Renal Disease study equation for calculating eGFR and used a statistical model that explicitly accounted for the competing risk of death. Venkatesh Krishnamurthi, MD, Director of the Kidney and Pancreas Transplant Programs at the Cleveland Clinic, said the new findings are robust but do not point to the need for simultaneous kidney-pancreas transplants in patients with suboptimal kidney function. “Patients undergoing isolated pancreas transplants are doing so because their diabetes control is very brittle,” Dr. Krishnamurthi said. “They don’t have kidney failure, nor have they undergone a prior kidney transplant. There are plenty of patients who need a kidney transplant immediately, so it may not be fair to give a kidney instead to someone who might not need one for many years. It’s a rough situation due to limited resources.” ■

using prescription-free NSAIDs most often in short-term.” Dr. Murtola and his colleagues said they do not think COX-2 inhibition, by itself, caused the increased PCa risk observed in the study. “If this really were the case, we would have expected dose-dependence between COX-2 inhibition and the risk, but this was not observed,” Dr. Murtola said.

Comorbidities responsible Instead, they believe the elevated risk was caused by underlying comorbidities for which NSAIDs were prescribed. “Therefore, our main message is that COX-2 inhibition by NSAID usage does not decrease prostate cancer risk at the population level,” Dr. Murtola told Renal & Urology News. “Other factors that associate [with] and cause the medication use affect the risk more, leading to [a] net effect of increased risk,”he added. ■

Many Patients Initially Choose PD, but Start on HD MANY PATIENTS start dialysis treatment with hemodialysis (HD) even though they initially had opted for peritoneal dialysis (PD), according to researchers. Scott E. Liebman, MD, and colleagues at the University of Rochester in New York studied 217 patients who received dialysis modality education at their institution and subsequently started dialysis. The study’s outcome measure was HD use at dialysis initiation and day 91 of dialysis therapy in

patients initially selecting PD. At the time of education, 124 patients chose PD, 41 chose HD, and 52 were undecided. Of the 124 patients who chose PD at the time of education, 59 started dialysis therapy with PD and 65 started on HD, the researchers reported online ahead of print in the American Journal of Kidney Diseases. On day 91, 60 patients were on PD and 55 were on HD. Nine patients either died, had a renal transplant, or not yet reached 91 days of dialysis therapy.

Nonglomerular cause of end-stage renal disease, age older than 75 years, and being unemployed predicted starting on HD therapy; age older than 75 years, nonwhite race, and nonglomerular causes of ESRD predicted HD use at day 91. “These findings help define a group that should be monitored carefully to ensure that they start PD therapy if this remains their modality choice,” the authors concluded. ■

12 Renal & Urology News

■ EAU 2012, Paris

APRIL 2012

www.renalandurologynews.com

News coverage of 27th Annual European Association of Urology Congress written by Jody A. Charnow, editor of Renal & Urology News.

Novel Drug Works for Refractory OAB Mirabegron reduces incontinence and micturition episodes regardless of prior antimuscarinic therapy MIRABEGRON, AN experimental drug for overactive bladder (OAB), can effectively treat the condition in patients whether or not they failed previous antimuscarinic therapy, according to new findings. The findings are from a post-hoc analysis of a randomized, double-blind phase 3 trial comparing mirabegron, the first in a new class of OAB agents with a distinct mechanism of action, with tolterodine slow release (SR) or placebo. The study, which included 1,978 patients in 26 European countries and Australia, found that mirabegron at daily doses of 50 or 100 mg reduced the mean number of micturitions and incontinence episodes compared with placebo in OAB patients with and without prior antimuscarinic therapy. Investigators led by Vik Khullar, MD, of Imperial College in London, U.K., randomized 493 patients to receive mirabegron 50 mg, 496 to receive mirabegron 100 mg, 495 to receive tolterodine SR

RCC Death Not Greater in HD Patients HEMODIALYSIS (HD) patients are no more likely to die from renal cell carcinoma (RCC) as patients with normal renal function, but they have decreased overall survival, investigators reported. Shingo Hatakeyama, MD, of the Hirosaki University Graduate School of Medicine in Hirosaki, and colleagues reviewed the oncologic outcomes of pT1NOMO RCC detected by annual

4 mg, and 494 to receive placebo orally once a day for 12 weeks. Among patients who had no prior treatment with antimuscarinics, the mean number of micturitions per 24 hours decreased significantly from baseline by 0.52, 0.37, and 0.29 in the mirabegron 50 and 100 mg groups and

Mirabegron was well tolerated at both 50 and 100 mg doses, researchers found. the tolterodine group, respectively, compared with placebo. Among patients who had discontinued prior antimuscarinic therapy because of insufficient effect, the mean number of micturitions per 24 hours decreased significantly by a mean of 0.59 and 0.58 in the mirabegron 50 and 100 mg groups, respectively, where-

as it declined nonsignificantly by only 0.08 in the tolterodine group. The mean number of incontinence episodes per 24 hours in antimuscarinic-naïve patients decreased by 0.29, 0.15, and 0.08 in the mirabegron 50 and 100 mg groups and the tolterodine group, respectively, compared with placebo. Among the patients who discontinued prior antimuscarinic therapy because of insufficient effect, the mean number of incontinence episodes decreased significantly by 0.76 and 0.62 in the mirabegron 50 and 100 mg groups, and nonsignificantly by only 0.06 in the tolterodine group. “Patients who had previously not found antimuscarinics efficacious found that mirabegron 50 [or] 100 mg gave them greater efficacy over placebo, whereas the tolterodine group did not find such an effect,” Dr. Khullar said. Mirabegron was well tolerated at both doses. The percentage of patients with treatment-emergent adverse effects was

Key Points ■ Study compared mirabegron

50 and 100 mg with tolterodine SR 4 mg and placebo ■ Mirabegron, but not tolterodine

SR, benefited patients despite prior antimuscarinic therapy. ■ The percentage of patients with

treatment-emergent adverse effects was similar across study arms.

similar in all study arms (42.8%, 40.1%, 46.7% and 43.3% of the mirabegron 50 and 100 mg groups, tolterodine group, and placebo group, respectively). The study was funded by Astellas Pharma, which is developing mirabegron. The FDA is reviewing the company’s New Drug Application seeking approval of the drug. ■

PCa Linked to Metabolic Syndrome METABOLIC SYNDROME does not increase men’s risk of prostate cancer (PCa) overall, but it does increase their risk of aggressive PCa, researchers reported. Investigators at Vall D’Hebron Hospital in Barcelona, Spain, studied 2,408 men who underwent prostate biopsy for an elevated PSA, an abnormal digital rectal examination, or both. Of these men, 1,480 (61.5%) had metabolic syndrome and 928 did not. Prostate cancer was diagnosed in 34.3% of men with metabolic syndrome and 36.6% of those without it, a nonsignificant difference between

the groups. Among the patients with PCa, high-grade disease was found in 33.1% of those with metabolic syndrome compared with 21.2% of men without it, a significant difference that translated into an 83% increased risk for high-grade PCa associated with metabolic syndrome. At last year’s EAU congress, Italian investigators reported similar findings from a study of 195 men undergoing prostate biopsy. In that study, metabolic syndrome was associated with a 3.8 times increased risk of high-grade PCa but not with PCa risk overall.

Another Italian study, however, found that men with metabolic syndrome had a 66% increased PCa risk overall compared with men who did not have the syndrome, according to a report in the Annals of Epidemiology (2011;21:835841). The study, which compared 1,294 PCa cases with 1,451 controls (men hospitalized for acute, non-neoplastic conditions), also showed that the risk varied with the number of metabolic syndrome components present. For example, men with four components had a fourfold increased risk of PCa compared with men who had no component. ■

computed tomography (CT) screening. The study population consisted of 119 patients with incidentally detected pT1NOMO RCC: 13 HD patients and 106 age-matched patients without renal dysfunction (controls). Cancer-specific survival rates were 92% and 95% in the HD patients and controls, respectively, a nonsignificant difference between the groups. Overall five-year survival rates did differ significantly: 54% vs. 96%. ■

Data Support Pre-Brachytherapy Cystoscopy CYSTOSCOPY PRIOR to low-doserate (LDR) brachytherapy for prostate cancer is feasible and useful in identifying patients who require further investigation or intervention before seed implantation, researchers reported. Nicholas J. Mehan, MD, and colleagues, reported data from a prospective study of

440 men treated with LDR brachytherapy. As part of a routine protocol, all patients underwent pretreatment cystoscopy, which revealed abnormalities in 59 (13.4%) of the 440 patients. Thirty-two patients (7.2%) had a prominent middle lobe of the prostate, nine (2%) had anterior urethral strictures, seven (1.6%) had

bladder calculi, four (0.9%) had transitional cell carcinoma of the bladder, and eight (1.8%) had benign urothelial abnormalities. Based on the cystoscopic findings, 46 patients (10.5%) had interventions, such as middle lobe resection and stricture dilation, and transurethral resection of the bladder. ■

www.renalandurologynews.com

APRIL 2012

Renal & Urology News 13

■ FEATURE

Bundling’s Impact on Clinical Practice Some changes have occurred, such as decreased use of ESAs, but many of the radical predictions have not been borne out BY JAY B. WISH, MD

Editor’s note: The author of this article and another one starting on page 19 are scheduled to speak on the topics covered in the articles at the 2012 National Kidney Foundation’s Spring Clinical Meetings in National Harbor, Md.

he implementation of a bundled payment system (“bundling”) for chronic dialysis in January 2011 has not been associated with a radical change in clinical practice. The legislative mandate for bundling was clearly spelled out in the Medicare Improvement for Patients and Providers Act of 2008, and most of the end-stage renal disease (ESRD) stakeholders were familiar with the specific provisions of bundling following the release by the Centers for Medicare and Medicaid Services (CMS) of the draft regulations in 2009 and the final regulations in 2010. Moreover, their comfort with the bundling regulations led over 95% of providers to “opt-in” 100% to a bundled payment system in 2011, rather than choosing to phase in the bundled payment between 2011 and 2014. The cost basis for the bundled payment in 2011 was actual dialysis provider costs in 2008. There had already been a secular trend toward lower erythropoiesis-stimulating agent (ESA) use and lower hemoglobin (Hb) targets in dialysis patients between 2008 and 2011 due to the results of random-

ized clinical trials of ESAs such as CHOIR and CREATE published in 2006, changes in the FDA labeling of ESAs that followed the publication of those studies, and the implementation by CMS in 2007 of a payment penalty for ESAs for dialysis patients with hemoglobin (Hb) levels greater than 13 g/dL for three consecutive months. Many dialysis providers anticipated even greater ESA cost savings following the implementation of bundling in 2011 through the use of lower Hb targets, greater use of IV iron with higher targets for transferrin saturation (TSAT) and serum ferritin, placing a ceiling on ESA doses in ESA resistant patients, and the administration of ESAs via the subcutaneous (SC) rather than the intravenous (IV) route.

Quality incentive payment The quality incentive payment (QIP) for 2012, based on provider data from 2010 (which is before bundling actually “kicked in”), rewards facilities for having the maximum percentage of patients with Hb in the 10-12 g/dL range. However, following the publication of the TREAT study in 2009, the FDA changed the ESA labeling in June 2011 and eliminated the target Hb range of 10-12 g/dL for patients receiving ESAs, the range upon which CMS based its QIP for 2012. The current FDA recommendation for ESRD patients with anemia is to start ESAs when the Hb level is below 10 g/dL and to discon-

Jay B. Wish, MD

tinue or decrease the ESA dose when the Hb level is above 11 g/dL. The FDA has removed the lower limit of the Hb target range for ESRD patients receiving ESA therapy, stating instead that the clinician should individualize therapy to use the lowest ESA dose required to avoid red blood cell transfusions. CMS followed the FDA ruling in July 2011 by eliminating the floor of the Hb target range for the QIP. For 2013 (based on 2011 data), dialysis facilities will be financially penalized for having more patients with Hb levels above 12 g/dL, but will not be penalized for having more patients with Hb levels below any particular value. The point of the above introduction is that the changes in clinical practice in dialysis that have occurred over the past year of so since the onset of bundling may also be reactions to other events that occurred both

before and after January 1, 2011. Most facilities were aware of the particulars of the bundled payment regulations well before January 1, 2011 and were already testing or implementing new protocols for cost-containment. Medicare claims data for 2011, which will be the most comprehensive description of how clinical practice changed under bundling, will not be available for another 12-18 months and will not be reported in the U.S. Renal Data System (USRDS) Annual Data Report until 2013. Elab, the electronic laboratory data collection system that reports laboratory data on anemia, adequacy, nutrition, and bone/mineral metabolism for most prevalent dialysis patients during the fourth quarter of each calendar year, will not complete its 2011 report until mid-2012. This means that data for 2011 that are currently available are not national and are based on what has been released by individual provider organizations, surveys, and the Dialysis Outcomes and Practice Patterns Study (DOPPS) Practice Monitor.

Decreased monthly ESA use In one poster presented at the American Society of Nephrology 2011 Renal Week, a group of investigators reported a 29% decrease in mean monthly ESA dose and 48% increase in mean monthly IV iron dose between January-April 2010 and January-April 2011 in two private nonprofit dialysis centers. Most other reports have not been this dramatic,

14 Renal & Urology News

APRIL 2012

since the large dialysis organizations, which care for around 70% of dialysis patients in the United States, had already been implementing anemia management protocols to increase IV iron use and decrease ESA use during 2010. In an on-line survey of 303 nephrologists by BioTrends Research Group fielded Dec. 5-12, 2011, about onequarter stated that their ESA use had not changed since implementation of bundling, but around 50% stated that it had decreased by 10% or more. In addition, 25% of these nephrologists stated that their IV iron use had increased by more than 10% since the onset of bundling, but 40% reported that IV iron use did not change. The most common change in anemia management reported in this survey was the targeting of lower Hb levels since the onset of bundling, which includes initiating ESAs at lower Hb levels, holding ESAs at lower Hb levels, and down-titrating ESA doses at lower Hb levels. These nephrologists reported an increase in “some hemodialysis patients receiving ESAs via the SC route” from 12% in the fourth quarter of 2010 to 21% in the fourth quarter of 2011. Thirty-seven percent of the nephrologists reported that they observed an increase in blood transfusions in the previous six months compared with 13% who made the same observation in the survey during the first quarter of 2011. Furthermore, 84% of respondents in the December 2011 survey attributed the increase in blood transfusions to the FDA labeling change for ESAs and the change in the QIP that eliminated the target Hb floor, not to bundling per se.

Changes in Hb levels DOPPS reports data on a stratified random sample of 145 U.S. dialysis facilities that are representative of a national sample by facility type (dialysis organization size, rural/urban, free standing/hospital based). The data are collected monthly and the DOPPS Practice Monitor (www. dopps.org/dpm), a website reporting data trends over the prior 12 months, is updated quarterly. The key findings from the DOPPS Practice Monitor are summarized in Table 1. The most recent data are through August 2011 and show a decrease in the mean Hb only from 11.5 to 11.4 g/dL between August 2010 and July 2011, but a decrease to 11.2 g/dL in August 2011 following the change in the FDA product information on ESAs and the discontinuation of the target Hb floor for the QIP by CMS. In addition, the mean Hb level fell from 11.2 to 10.9 g/dL between June and

www.renalandurologynews.com

Other issues

Table 1: DOPPS Practice Monitor Data Pre- and Post-Bundling August 2010

August 2011

11.5

11.2

13.2

12.0

52.6

40.6

Percent of patients receiving IV iron in past month

Median monthly IV iron dose prescribed (mg)

197

199

487

582

Indicator Mean hemoglobin (g/dL) Percentage of patients receiving ESAs Median weekly epoetin dose (1000 units) th

Upper 90 percentile weekly epoetin dose (1000 units)

Upper 90 percentile monthly IV iron dose (mg) Median serum ferritin (ng/mL)

555

647

1,049

1,235

Median PTH (pg/mL)

246

305

IV vitamin D use (percent of patients)

Oral active vitamin D use (percent of patients)

4.2

7.0

Cinacalcet use (percent of patients)

30-day annualized hospitalization rate

1.5

1.9

Upper 90th percentile serum ferritin (ng/mL)

ESAs=erythropoiesis stimulating agents; IV=intravenous; PTH=parathyroid hormone.

August 2011 among dialysis providers with 10 or more facilities, but only from 11.3 to 11.2 g/dL during the same period among dialysis providers with fewer than 10 facilities. This suggests that the larger dialysis organizations are more nimble in adapting to regulatory changes. There was a 15% decrease in the median dose of ESA prescribed among all the providers in the DOPPS sample between August 2011 and 2011, but the 90th percentile of ESA dose decreased by 23% during this period. It can be inferred that a ceiling on ESA dosing among patients with “ESA resistance” is driving much of the decrease in the mean dose.

Subcutaneous EPO dosing Since smaller dialysis organizations may be under increased cost pressures from bundling than their larger counterparts with economies of scale, SC EPO dosing has increased to 15% of patients in dialysis organizations with fewer than 10 facilities, while it remains less than 2% among patients in dialysis organizations with 10 or more facilities. IV iron use peaked in June 2011 prior the changes in FDA and CMS QIP policy regarding target Hb levels. The median monthly IV iron dose has increased only 1% between August 2010 and August 2011 to 199 mg. Nonetheless, the median serum ferritin level has increased 17% during that period to 646 ng/mL, and 34% of patients had serum ferritin levels greater than 800 ng/mL in August 2011.

Active vitamin D Although anemia management was expected to undergo the greatest change under bundling because ESAs are the

biggest ticket item that was previously separately billable by dialysis providers, other aspects of clinical practice have also undergone changes. According to the BioTrends survey of nephrologists in December 2011, there has been very little change in the use of active vitamin D since the onset of bundling, although many providers have changed the brand of active vitamin D used because of more favorable contracting terms. Cinacalcet use was expected to increase in 2011-2013 (the period during which active vitamin D is in the bundle but cinacalcet is not) due to its vitamin D sparing properties, but a significant increase in cinacalcet use has failed to materialize, according to the BioTrends survey. This is confirmed by the DOPPS Practice Monitor, which also demonstrates a small but significant trend towards the increased use of oral as opposed to IV active vitamin D agents, especially among patients in dialysis organizations with fewer than 10 facilities where the use of oral active vitamin D approaches 20%.

Phosphate binder use The DOPPS Practice Monitor does not show a significant change in phosphate binder use, choice of phosphate binder agent, serum phosphorus levels, or serum calcium levels since the onset of bundling. Serum parathyroid hormone (PTH) levels are rising, which may be due to the adoption of the more liberal international KDIGO range for PTH (around 100-500 pg/mL) compared with the U.S. KDOQI range for PTH (150-300 pg/mL) as well as cost-containment efforts directed at active vitamin D use.

Of some concern is an increase in hospitalization rate reported by DOPPS from around 1.5 events per year in August 2010 to around 1.9 events per year in August 2011. The reason for this is not clear since the trend predates the decrease in mean Hb levels that occurred in July and August 2011. According to the Fistula First dashboard, central venous catheter (CVC) prevalence has remained stable at around 20% between September 2010 and September 2011. Since CVCs are expensive to the dialysis provider under bundling due to the use of antibiotics for infection, thrombolytics for flow problems and missed treatments due to hospitalizations, there had been some concern that the prevalence of arteriovenous grafts (AVGs) might rise under bundling in an attempt to decrease CVC prevalence, since AVGs mature more rapidly than do arteriovenous fistulas (AVFs). Fortunately, this has not proved to be the case, as the prevalent AVG rate has continued to decrease slightly between 2010 and 2011 and the prevalent AVF rate continues to increase.

Summary The shift of many items such as ESAs, IV iron, active vitamin D, thrombolytics for CVCs and ESRD-related antibiotics from a profit center under fee-for-service to a cost center under bundling has decreased the use of some of these agents, as was intended. The challenge to caregivers is to provide smarter, more cost-effective care with improved patient outcomes and satisfaction. The full impact of bundling on clinical practice has yet to be seen, since national claims data are incomplete, most providers are receiving total payments comparable to pre-bundling, and the reduction in payments from the QIP just began. Many of the more radical predictions regarding extensive SC ESA use, greater AVG prevalence, and increased patient complaints/grievances to the ESRD Networks have not been borne out. The increase in hospitalizations does provide some cause for concern and needs to be investigated thoroughly. Otherwise, for most patients and providers, it’s been pretty much business as usual. ■ Jay B. Wish, MD, is Medical Director, Dialysis Program, University Hospitals Case Medical Center, and Professor of Medicine at Case Western Reserve University in Cleveland.

18 Renal & Urology News

APRIL 2012

www.renalandurologynews.com

â&#x2013; 2012 Genitourinary Cancer Symposium, San Francisco

Immunotherapy May Improve mRCC Outcomes, Data Show BY JOHN SCHIESZER AN IMMUNOTHERAPY (AGS-003) in combination with sunitinib may help prolong the lives of men with unfavorable risk, metastatic renal cell carciBrief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in Full Prescribing Information). DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions). Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25Â°C/77Â°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2Â°C to 8Â°C (36Â°F to 46Â°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25Â°C/77Â°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS: Hypocalcemia. Xgeva can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/ min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis. Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, 2.2% of patients receiving Xgeva developed ONJ; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse Reactions). Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling: s (YPOCALCEMIA (see Warnings and Precautions) s /STEONECROSIS OF THE *AW (see Warnings and Precautions) The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia. Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reďŹ&#x201A;ect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Information) in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion.

noma (mRCC), according to new data from an open-label phase 2 study. â&#x20AC;&#x153;We observed encouraging clinical and immunologic responses which correlated with prolonged survival,â&#x20AC;? said lead invesEntry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 â&#x20AC;&#x201C; 41) and median duration onstudy was 13 months (range: 0.1 â&#x20AC;&#x201C; 41). Of patients who received Xgeva, 46% WERE FEMALE %IGHTY lVE PERCENT WERE 7HITE (ISPANIC ,ATINO !SIAN and 3% Black. The median age was 63 years (range: 18 â&#x20AC;&#x201C; 93). Seventy-ďŹ ve percent of patients who received Xgeva received concomitant chemotherapy.

tigator Robert Figlin MD, Director of the Division of Hematology/Oncology at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute in Los Angeles. â&#x20AC;&#x153;In this study, AGS-003 in comanticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormone therapy (see Clinical Pharmacology [12.2] in full Prescribing Information).

USE IN SPECIFIC POPULATIONS: Pregnancy: Category C. There are no adequate and well-controlled trials of Xgeva in pregnant women. Use Xgeva during pregnancy only if the potential beneďŹ t justiďŹ es the potential risk to the fetus. Encourage women who become pregnant during Xgeva treatment to enroll in Amgenâ&#x20AC;&#x2122;s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800772-6436) to enroll. In an embryofetal developmental study, cynomolgus Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any monkeys received subcutaneous denosumab weekly during organogenesis at Severity (Trials 1, 2, and 3) doses up to 6.5-fold higher than the recommended human dose of 120 mg every 4 weeks, based on body weight (mg/kg). No evidence of maternal toxicity Xgeva Zoledronic Acid OR FETAL HARM WAS OBSERVED (OWEVER THIS STUDY ONLY ASSESSED FETAL TOXICITY Body System n = 2841 n = 2836 during the ďŹ rst trimester, and fetal lymph nodes were not examined. Potential % % adverse developmental effects resulting from exposures during the second and third trimesters have not been assessed in animals (see Nonclinical Toxicology GASTROINTESTINAL [13.2] in full Prescribing Information). In genetically engineered mice in which Nausea 31 32 the gene for RANK ligand (RANKL) has been deleted (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?), the Diarrhea 20 19 absence of RANKL caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice also showed altered maturation of the maternal mammary gland, leading to GENERAL impaired lactation postpartum (see Use in Nursing Mothers). 45 46 Fatigue/ Asthenia Nursing Mothers. It is not known whether Xgeva is excreted into human milk. INVESTIGATIONS Because many drugs are excreted in human milk and because of the potential 18 9 (YPOCALCEMIAb for serious adverse reactions in nursing infants from Xgeva, a decision should 32 20 (YPOPHOSPHATEMIAb be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva NEUROLOGICAL during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling 13 14 (EADACHE pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum (see Nonclinical Toxicology [13.2] in RESPIRATORY full Prescribing Information). 21 18 Dyspnea 15 15 Cough Pediatric Use. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in a Adverse reactions reported in at least 10% of patients receiving Xgeva in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL with a construct of osteoprotegerin bound to Trials 1, 2, and 3, and meeting one of the following criteria: Fc (OPG-Fc) at doses less than or equal to 10 mg/kg was associated with s !T LEAST GREATER INCIDENCE IN 8GEVA TREATED PATIENTS OR inhibition of bone growth and tooth eruption. Adolescent monkeys dosed with s "ETWEEN GROUP DIFFERENCE EITHER DIRECTION OF LESS THAN AND MORE THAN denosumab at 5 and 25 times (10 and 50 mg/kg dose) higher than the 5% greater incidence in patients treated with zoledronic acid compared to recommended human dose of 120 mg subcutaneously every 4 weeks (based on placebo (US Prescribing Information for zoledronic acid) body weight mg/kg) had abnormal growth plates (see Nonclinical Toxicology b Laboratory-derived and below the central laboratory lower limit of normal [8.3 â&#x20AC;&#x201C; [13.2] in full Prescribing Information). 8.5 mg/dL (2.075 â&#x20AC;&#x201C; 2.125 mmol/L) for calcium and 2.2 â&#x20AC;&#x201C; 2.8 mg/dL (0.71 â&#x20AC;&#x201C; Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 0.9 mmol/L) for phosphorus] (44%) were 65 years of age or older. No overall differences in safety or efďŹ cacy were observed between these patients and younger patients. Severe Mineral/Electrolyte Abnormalities s 3EVERE HYPOCALCEMIA CORRECTED SERUM CALCIUM LESS THAN MG D, OR LESS THAN Renal Impairment. In a trial of 55 patients without cancer and with varying degrees 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of of renal function who received a single dose of 60 mg denosumab, patients with a patients treated with zoledronic acid. Of patients who experienced severe creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia of severe hypocalcemia with denosumab compared to patients with normal renal and 16% experienced 3 or more episodes (see Warnings and Precautions and function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg Use in SpeciďŹ c Populations). every 4 weeks has not been evaluated in patients with a creatinine clearance of less s 3EVERE HYPOPHOSPHATEMIA SERUM PHOSPHORUS LESS THAN MG D, OR LESS than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and Reactions, and Clinical Pharmacology [12.3] in full Prescribing Information). 7.4% of patients treated with zoledronic acid. OVERDOSAGE: There is no experience with overdosage of Xgeva. Osteonecrosis of the Jaw PATIENT COUNSELING INFORMATION: In the primary treatment phases of Trials 1, 2, and 3, ONJ was conďŹ rmed in Advise patients to contact a healthcare professional for any of the following: 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic acid group (see Warnings and Precautions). When events occurring during an s 3YMPTOMS OF HYPOCALCEMIA INCLUDING PARESTHESIAS OR MUSCLE STIFFNESS extended treatment phase of approximately 4 months in each trial are included, twitching, spasms, or cramps (see Warnings and Precautions and Adverse the incidence of conďŹ rmed ONJ was 2.2% in patients who received Xgeva. The Reactions) median time to ONJ was 14 months (range: 4 â&#x20AC;&#x201C; 25). s 3YMPTOMS OF /.* INCLUDING PAIN NUMBNESS SWELLING OF OR DRAINAGE FROM the jaw, mouth, or teeth (see Warnings and Precautions and Adverse Immunogenicity. As with all therapeutic proteins, there is potential for Reactions) immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with s 0ERSISTENT PAIN OR SLOW HEALING OF THE MOUTH OR JAW AFTER DENTAL SURGERY (see denosumab doses ranging from 30 â&#x20AC;&#x201C; 180 mg every 4 weeks or every 12 Warnings and Precautions) weeks for up to 3 years tested positive for binding antibodies. No patient with s 0REGNANCY OR NURSING (see Use in SpeciďŹ c Populations) positive binding antibodies tested positive for neutralizing antibodies as Advise patients of the need for: assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic proďŹ le, toxicity proďŹ le, or clinical s 0ROPER ORAL HYGIENE AND ROUTINE DENTAL CARE response associated with binding antibody development. The incidence of s )NFORMING THEIR DENTIST THAT THEY ARE RECEIVING 8GEVA antibody formation is highly dependent on the sensitivity and speciďŹ city of the s !VOIDING INVASIVE DENTAL PROCEDURES DURING TREATMENT WITH 8GEVA assay. Additionally, the observed incidence of a positive antibody (including ÂŽ . Patients should neutralizing antibody) test result may be inďŹ&#x201A;uenced by several factors, Advise patients that denosumab is also marketed as Prolia ÂŽ including assay methodology, sample handling, timing of sample collection, inform their healthcare provider if they are taking Prolia . concomitant medications, and underlying disease. For these reasons, Amgen Manufacturing Limited, a subsidiary of Amgen Inc. comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading. One Amgen Center Drive DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There was no evidence that various

www.XGEVA.com

REFERENCES: 1. Saad F, Gleason DM, Murray R, et al, for the Zoledronic Acid Prostate Cancer Study Group. Long-term efďŹ cacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96:879-882. 2. Ibrahim A, Scher N, Williams G, et al. Approval summary for zoledronic acid for treatment of multiple myeloma and cancer bone metastases. Clin Cancer Res. 2003;9:2394-2399. 3. Yu EY, Nathan FE, Higano CS. Role of detection of metastatic disease as a leading cause of screening failure in an ongoing phase III trial of zibotentan versus placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC). J Clin Oncol. 2011;29(suppl 7). Abstract 135. 4. Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: â&#x20AC;&#x153;RECISTâ&#x20AC;?ing a step backwards. Clin Cancer Res. 2005;11:5223-5232. 5. Tannock IF, de Wit R, Berry WR, et al, for the TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512. 6. Petrylak DP, Tangen CM, Hussain MHA, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-1520. 7. XGEVAÂŽ (denosumab) prescribing information, Amgen. 8. Saad F, Gleason DM, Murray R, et al, for the Zoledronic Acid Prostate Cancer Study Group. A randomized, placebocontrolled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458-1468.

bination with sunitinib was associated with a median overall survival longer than has been reported for sunitinib alone in unfavorable risk, metastatic RCC patients.â&#x20AC;? He and his colleagues found that AGS003 was well tolerated in combination with sunitinib. Observed adverse events were consistent with expected sunitinib toxicities, with the notable exception being grade 1 injection site reactions in approximately 50% of study subjects. In addition, adverse reports and laboratory assessments for markers of autoimmune responses found no evidence of emergent autoimmune disease.

Personalized therapy The combination of AGS-003 plus sunitinib is designed to relieve immune suppression in the tumor itself and stimulate the patientâ&#x20AC;&#x2122;s immune response to the tumor. Each production of a patientâ&#x20AC;&#x2122;s fully personalized immunotherapy generates up to five years of treatment for each patient. The study enrolled 21 patients (16 men) with newly diagnosed metastatic clear cell RCC. The median age was 56 years (range 22-68 years). Following nephrectomy or metastasectomy to harvest tumor mRNA, autologous monocytes were collected by leukapheresis to produce RNA-loaded dendritic cells specific to each patientâ&#x20AC;&#x2122;s disease. Treatment consisted of six-week cycles of sunitinib, four weeks on and two weeks off, plus AGS-003. This fully personalized immunotherapy was administered as an intradermal injection every three weeks for five doses, and then every 12 weeks until progression in combination with sunitinib. Dr. Figlin, who presented the study findings, said there were multiple partial responses observed with this combination regimen. Of 15 patients with serial immune assessments, 11 (73%) had increases in their CD28+ memory T cells. These immune responses correlated directly with prolonged survival. Overall, the median progression-free survival was 11.2 months, and the estimated Kaplan-Meier median overall survival was 29.3 months, based on follow-up through January 2012. â&#x20AC;&#x153;Targeted therapy has been an important step but not a final step. A personalized vaccine offers the opportunity for hopefully long-term durable maintained remissions and even the possibility of a cure,â&#x20AC;? Dr. Figlin said. â&#x2013;

www.renalandurologynews.com

APRIL 2012

Renal & Urology News 19

Setting Up a Home Hemodialysis Program The author will be giving a presentation on this topic at the National Kidney Foundation’s 2012 Spring Clinical Meetings in National Harbor, Md., May 9-13.

BY JOEL D. GLICKMAN, MD I BEGIN this article hoping that you are impressed with the improvement in patient quality of life and cardiovascular outcomes of more frequent home hemodialysis (HD), and that you recognize that many, but not all, of your patients will greatly benefit from this modality. As you develop and grow a home HD program, not only will you have wonderful successes, but there will also be challenges and disappointments. To stay on course the program needs a philosophy and, as trite as it might seem, a mission statement. Patient-centric medicine Our program keeps it very simple: “It’s all about the patient.” That is, we practice “patient-centric” medicine and try to incorporate the patient’s vantage point in every aspect of the program. Every project, miscue, and opportunity for improvement in the process of setting up a home program will turn into a success if the entire home HD team focuses on the patient’s needs (and not necessarily ours). There are three major components of a home HD program: the people, the physical infrastructure, and the policies and procedures by which the clinic is run. For certain, the people are most important and patients are paramount because without patients there is no program (Table 1). A dialysis facility needs to project census prior to developing space and hiring staff. The last thing one should do is build a space you will outgrow within a year, or

have to mothball because of inadequate utilization. You need to set a goal. Based on some studies, personal experience, and discussions with colleagues, I believe a realistic number is 8%-10% of dialysis patients will embrace home HD. That number will vary according to demographics, and some practices will have higher utilization. Do not think that a beautiful home and a college education is a requirement. We have single mothers with barely high school educations who succeed tremendously on home HD. There are several sources of patients. The largest is probably transfers from in-center dialysis, but CKD education programs, both outpatient and inpatient, will help attract patients.

In-center recruitment Consider recruiting in-center patients with ample educational pamphlets and on site resources, which outline the benefits of home HD. For patients who are highly motivated, but not 100% confident, consider investing in a trial of short daily HD training. If patients like it, they can complete training. If they do not feel any better (which is unlikely), they will return to in-center HD. Finally, a relatively high proportion of our patients have failed kidney transplants or other solid organ transplants that have renal failure as a consequence of chronic immunosuppression. We seek to develop programs to attract these patients (Table 2). “Leader” or “champion” needed The medical staff needs at least one “leader” or “champion,” and preferably two, but everyone on the team needs to understand the special needs of the home patient. For example, one of our home HD patients had a beautiful arteriovenous fistula placed in his dominant arm because “the vein was

For such a venture to be successful, the entire team must focus on the patient’s needs

Home hemodialysis improves not only quality of life, but cardiovascular outcomes too.

better.” Luckily, he was ambidextrous because otherwise he would not have been able to self-cannulate. Our vascular surgeon knows that the fistula needs to be in the non-dominant arm and a transposed vein needs to be placed in a position that the patient can get to. The leaders of the team should be both the physician and the nurse champion. The physician needs to be the point person for patient recruitment, but along with the nurse champion develop staff education programs, policies and procedures, program development, and quality assurance (QA) projects. The day-to-day operation of the program rests on the shoulders of the nurse. Having a great nurse is the key to success so make sure you recruit the right nurses and invest in their education. Dietary restrictions improve but do not disappear with home HD, so a dietitian knowledgeable about frequent HD is essential. But the social worker is the key to identifying potential changes in the home that may lead to patient burnout or dropout from the program.

On site recruiting program, consider “lobby days” where patients can receive educational materials and see the home HD machines. For those patients who are great candidates, do an up-close demonstration while they receive in-patient hemodialysis.

To enlist patients from your in-center

Physical infrastructure In keeping with the theme of “it’s all about the patient,” we strongly believe that the physical infrastructure—the clinic space and its layout, as well as dialysis equipment—needs to be beautiful, comfortable, warm, and appealing. Patients should feel that we are committed to our program so the space should be front and center and not relegated to a remote corner of the dialysis facility. It is often difficult to retrofit existing space for home HD in most dialysis facilities because a storage closet converted to a multiuse training and examination room is rarely attractive and does not allow for growth. A new program should focus primarily on training patients, but eventually the nursing staff will spend a significant portion of their time with monthly, routine, and urgent clinic visits. A space that focuses only on training rooms and not the workflow of the staff during clinic visits will fall short of needs and will lead to tremendous inefficiencies and frustrations for the nurses. At our new facility, University City Dialysis, we elected to have a central nursing station with work spaces and rooms surrounding the nursing station. The nurses also have laptops with a wireless connection so they can document and enter orders easily in every room. We also like having two training rooms connected by sliding pocket doors so they can be used to take care of two patients at once during training yet also provide privacy when needed.

20 Renal & Urology News

APRIL 2012

Table 1. The Medical Team At least one person needs to be the program champion Nurses Physician Social worker Dietitian Administrator Biomedical engineering Administrative assistant Patient-care technician Interventional radiologist Vascular surgeon

We have designated clinic rooms that are not used for training, but the training rooms can be used for clinic visits during very busy days. The training rooms should obviously have appropriate drains for used dialysate and, if you plan to use the Fresenius 2008K@Home machine make sure there is appropriate water and electric connections. The Nxstage

Whatever you invest in your home HD program you will get back 10-fold. machine does not require special plumbing and it runs on standard electric outlets. The machine’s size, simplicity, and portability make it the machine of choice for almost all of our patients.

The multidisciplinary model Developing policies and procedures is beyond the scope of this limited article. Suffice to say some policies are universal and apply to both in-center and home HD. But there needs to be home HD-specific policies, procedures, and protocols. We believe in the multidisciplinary model of home dialysis care and schedule monthly patient visits at the home dialysis center with the nurse, physician, social worker, and dietitian all present. Some programs call for a separate nursing visit at the facility and a physician visit at the physician’s office or at the facility on another day. We mandate that physicians participate in the multidisciplinary visit because we find that we are much more effective and thorough when we see the patient at the same time. We also

www.renalandurologynews.com

Table 2. Sources and Strategies to Recruit Patients 1) In-center hemodialysis • “Lobby days” • Chairside machine demonstrations • “Try it you will like it” programs • Patient support groups 2) CKD patients • CKD education 3) Acute start patients • In-hospital modality education • Maintain contact with patients interested but not ready to commit 4) Transplant patients • Develop relationships with transplant program

train our nephrology fellows from the University of Pennsylvania, so we find that their educational experience is enhanced by the opportunity to learn directly from the nurses, dietitians, and social workers. Finally, QA and CQI projects are especially important in the early, developmental phase of the program. Identify quality indicators other than the usual Kt/V, anemia, and albumin, for example, which you feel are important and specific to your program such as drop out, blood pressure control and adherence with treatments. If you outcomes fall short of your goals develop projects and teams to fix them. The quality of your program helps increase the size of your program because dropout rates will be lower. Having a larger program will not guarantee better outcomes if you don’t have the right staff, facility, and procedures. QA and CQI projects are a win-win situation: They improve patient care as well as the professional satisfaction of your team.

Conclusion From experience, I know that whatever you invest in your home HD program you will get back 10-fold. Investing in staff education will make your job easier in the long run. Lastly, giving patients the opportunity to live better and longer will give you tremendous, everlasting professional fulfillment. ■ Joel D. Glickman, MD, is Associate Professor of Clinical Medicine and Director of Home Dialysis Programs at the University of Pennsylvania in Philadelphia and Medical Director for the Davita University City Dialysis Center in Philadelphia.

Study: DCD Kidneys Can Yield Good Outcomes BY ROSEMARY FREI, MSc QUEBEC CITY—Transplantation of kidneys donated after cardiac death (DCD) can result in good outcomes, according to a study by Canadian investigators. DCD kidney donation was common until the 1960s but just regained popularity across North America recently. Surgeons at the London Health Sciences Centre, London, Ontario, have transplanted 63 DCD kidneys since July 2006. The one-year graft and patient survival were 96.4% and 98.2%, respectively. The rate of delayed graft function (DGF) was 65.1%. In a multivariate analysis, the surgeons found that machine perfusion of the kidneys prior to transplantation and reduced time from asystole to flushing have contributed to their gradually improved outcomes over time. They presented the findings at the Canadian Society of Transplantation’s 2012 Annual Meeting. Mike Moser, MD, and his colleagues examined their DCD kidney transplant learning curve. They compared the outcomes of the 31 procedures they performed between July 2006 and January 2009, and those of 32 they performed between March 2009 and October 2011. Donor and recipient characteristics from the two time periods have not changed significantly. The time from asystole to flushing has also decreased significantly, from 16 to 12 minutes on average. Furthermore, a perfusion pump

was used in 81.3% of the more recent cases compared with 25.8% of the earlier cases. The average time with mean arterial pressure (MAP) below 55 mm Hg decreased from 25 to 18 minutes, and cold ischemic time increased from 464 to 725 minutes on average. The average length of stay dropped from 16 to 13 days. The recipients’ average creatinine clearance at three days post-op has also improved, from 7.8 to 11.9 µmol/L. Multivariate analysis showed that the two factors that contributed significantly to this increase was use of machine perfusion and reduced asystole to flush time. The average creatinine clearance rate at one month was 42.8 µmol/L and at one year is 67 µmol/L, the researchers noted.

DGF-related factors Factors associated with DGF include longer time with MAP below 55 mm Hg and recipient pre-transplant urine output, a novel finding, the study showed. In addition, creatinine clearance from DGF kidneys catches up to that of earlyfunction kidneys within a year. “Patients on the waiting list got 63 kidneys that they wouldn’t otherwise have gotten, and they did work well,” concluded Dr. Moser, now a transplant surgeon at the University of Saskatchewan, in Saskatoon. “The lessons learned over time have been invaluable—in London they now use the pump on every single DCD kidney they retrieve.” ■

Thiazide-Related Hyponatremia More Likely in Older Patients RESEARCHERS HAVE identified risk factors for hospitalizations related to thiazide-associated hyponatremia, according to a report in the Journal of Clinical Hypertension (2012;14:158-164). In a respective case-control study of 10,805 patients—including 1,802 hospitalized with thiazide-associated hyponatremia and 9,003 who did not experience hyponatremia while treated with a thiazide (controls)—the strongest risk factors were older age, use of ACE inhibitors, and hypokalemia. Each 10-year increment in age was associated with a 75% increased risk of hospitalizations related to thiazide-

associated hyponatremia. ACE inhibitor use was associated with a 53% increased risk. Hypokalemia increased the risk 41-fold. The study, by Divaker Rastogi, PharmD, of Kaiser Permanente Woodland Hills Medical Center in Woodland Hills, Calif., and colleagues, also showed that potassium supplement use and increasing weight were protective. Potassium supplement use was associated with a 40% decreased risk and each 5 kg increment in weight was associated with a 9% decreased risk, according to the investigators. ■

www.renalandurologynews.com

APRIL 2012

Renal & Urology News 21

Hospitalization After Prostate Biopsy Uncommon HOSPITAL ADMISSIONS related to a prostate needle biopsy (PNB) are on the increase, but they occur in less than 1% of men who undergo PNB and are not associated with increased mortality, researchers concluded in an online report in European Urology. “Thus for healthy men with sufficient life expectancy to benefit from early prostate cancer detection, the risk of biopsyrelated complications should not deter men from undergoing a recommended prostate biopsy,” researchers led by Stacy Loeb, MD, of New York University Langone Medical Center, wrote. Dr. Loeb and her colleagues from

the European Randomized Study of Screening for Prostate Cancer (ERSPC) examined the risk of infectious complications and hospital admissions after PNB in a this European screening trial. Febrile complications and hospital admissions were assessed by questionnaires two weeks after PNB.

Of 9,241 completed questionnaires, 392 (4.2%) reported fever and 78 (0.8%) reported hospital admission. Most fevers were managed on an outpatient basis, but 81% of hospital admissions were for infection. Only two patients required admission to an intensive care unit. No patient died from biopsy-related complications.

In a multivariable analysis, an enlarged prostate and diabetes each was associated with a significant 48% increased risk of fever. Later year of biopsy was the only factor significantly associated with an increased risk of hospital admission, and the researchers believe this is likely due to increasing antibiotic resistance. ■

Need to know which drug to treat that bug?

Diabetes May Hike Urinary Stone Risk DIABETES MELLITUS independently predicts an increased risk of urinary tract calculi (UTC), according to a study conducted in Taiwan. The study included 12,257 cases of diabetes mellitus newly diagnosed in 2000-2002 and 96,781 controls followed to the end of 2007. Over nearly eight years of follow-up, 8.9% of diabetics and 7.2% of control subjects sought ambulatory care or were hospitalized for UTC. After adjusting for comorbidities, urinary tract infections (UTIs), sociodemographic characteristics, diabetic patients had an 18% increased risk of UTC compared with nondiabetics, researchers reported in Urology (2012;79:86-92). In addition, UTI and pyelonephritis were independently associated with an adjusted 1.68 and 2.26 times increased risk of UTC.

MONTHLY PRESCRIBING REFERENCE PRESENTS

THE DRUGS & BUGS APP The Drugs & Bugs App includes: • A database of more than 100 antibiotics and nearly 200 bacterial pathogens • Smart Search capability by pathogen, type of infection, brand and generic drug names • Quick-to-read spectrum of activity results • Comprehensive drug monographs for anti-infectives • Useful comparative charts by drug class • Clinical calculators

Additionally, compared with diabetics without UTI, male and female diabetics with UTI had a 35% and 74% increased risk of UTC, respectively. “This cohort study provides epidemiologic support for the causal relation between diabetes and UTC, and such relation was independent of UTI,” the authors concluded. “In addition, diabetes accompanied by UTI may further increase the rate of UTC, especially in women, and these patients should be screened for UTC.” ■

Download today at eMPR.com/drugsandbugs, the iTunes App Store, Android Market, BlackBerry App World, Nook Store, and Kindle Store

22 Renal & Urology News

APRIL 2012

www.renalandurologynews.com

Renal Nutrition Update Oral adsorbents and pre- and probiotics could provide an inexpensive way to eliminate uremic toxics in CKD patients BY ALISON L. STEIBER, PhD, RD, LD

atients on a traditional renal diet often find that they are consuming a relatively “unhealthy diet,” meaning the diet is low in fresh fruits and vegetables, whole grain, and dairy products. Ultimately, this translates into a diet low in fiber and micronutrients and high in fat. While the conventional diet, if followed as prescribed, may keep serum potassium and phosphorus within normal ranges, it can also contribute to altered gastrointestinal (GI) function and, potentially, micronutrient inadequacies. The GI tract is a metabolically active organ that contributes to immune function and availability of amino acids, glucose, lipids, and micronutrients for further metabolic conversion by the liver. Additionally, the GI tract harbors huge populations of bacteria, which in turn contribute to the metabolic status of the body. It is thought that the human intestinal tract contains over 1014 bacteria with more than 500 different types (J Renal Nutr 2005;15:77-80). It has been suggested that derangements of the GI tract occur when chronic kidney disease (CKD) develops. For instance, bacteria in the gut become more aerobic versus anaerobic. Escherichia coli and Bifidobacterium are examples of aerobic and anaerobic bacteria, respectively. The balance between these two bacteria types can become altered and may result in an increase in toxins and a decrease in available nutrients. Potential therapies to improve mortality and overall health could target the GI tract by correct-

Probiotics, such as Lactobacillus acidophilus bacteria in yogurt, could correct derangements of the GI tract that lead to the production of uremic toxins. ing the balance between aerobic and anaerobic microbes via bacteria supplementation (e.g., probiotics), eliminating toxins through fecal waste (gut sorbents), or providing substrate, such as fiber, to support a particular type of bacteria (e.g. prebiotics). Indoxylsulfate and p-cresolsulfate are two uremic toxins that have been studied as they relate to CKD. Both toxins are associated with negative

Oral Drug Delays Dialysis

Source: Hatakeyama S, et al. Effect of an oral adsorbent, AST-120, on dialysis initiation and survival in patients with chronic kidney disease. Int J Nephrol 2012; published online ahead of print.

12 months

25%

24 months

Percent

A recently published Japanese study of 560 patients with chronic kidney disease demonstrated that AST-120, an oral adsorbent, can delay initiation of dialysis. Shown here are the dialysis-initiation-free rates at 12 and 24 months for patients who received AST-120 and those who did not.

15 13.7%

10.5%

5.7%

0 AST-120

No AST-120

Dialysis-initiation-free rate

outcomes in the CKD population. Indoxylsulfate causes inflammation, endothelial dysfunction, and disturbances of bone metabolism, and is associated with a loss of renal function (Blood Purif 2010;29:130-136); p-cresolsulfate is a pro-inflammatory molecule that impacts monocytes and lymphocytes. Additionally, in observational studies, p-cresol, which is converted to p-cresolsulfate, is associated with mortality, cardiovascular disease, infectious complications, and uremic symptoms. The production of indoxylsufate and p-cresolsulfate begins in the GI tract. Aerobic bacteria have an enzyme called tryptophanase, which converts tryptophan in the bowel to indole. Indole is absorbed into the blood from the GI tract and travels to the liver, where it is converted into indoxyl sulfate. Similarly, tryosine in the bowel is converted to p-cresol. To reduce the amount of toxins produced, patients

would need to consume less tryptophan or tyrosine, both of which are found in high-protein foods, or absorb and eliminate the precursors before they leave the bowel. Low-protein diets are recommended for pre-dialysis patients; however, that type of diet would not be recommended for dialysis patients. Therefore, oral adsorbents and preand probiotics have been suggested. An oral adsorbent “absorbs” the urea and other toxins and eliminates them via feces. AST-120 is an oral adsorbent that has been studied in rats and humans. In a Japanese study with CKD patients, AST-120 was compared with standard care. The dialysisinitiation-free rate was significantly higher in the AST-120 group compared with the non-AST-120 group at 12 and 24 months (25% and 13.7%, respectively vs. 10.5% and 5.7%, respectively). However, this improved rate did not translate into improved survival rates in the AST-120 group (Int J Nephrol 2012; published online ahead of print. Curr Med Res Opin. 2009;25:1913-1918). Finally, pre- and probiotics together in a symbiotic have been tested in hemodialysis (HD) patients to see if the amount of p-cresol could be reduced (Nephrol Dial Transplant 2011;26:1094-1098). The symbiotic was tested in nine HD patients for two weeks. The patients were surveyed on their bowel habits and p-cresol was measured pre and post treatment. At the end of treatment, p-cresol significantly decreased and stool volume and consistency had improved. These types of interventions may be less expensive and have far reaching positive effects on patients’ overall health, but substantially more research needs to be done in this area before these therapies can become standard practice. ■ Dr. Steiber is Coordinator of the Dietetic Internship/Master’s Degree Program at Case Western Reserve University in Cleveland.

www.renalandurologynews.com

APRIL 2012

Renal & Urology News 23

The Case for Neonatal Male Circumcision & QA

Less than a decade ago, Aaron Tobian, MD, PhD, would not have been a proponent of male circumci-

sion. But now the benefits of this procedure are undeniable to the Johns Hopkins Center for Global Health pathologist, who has studied the matter extensively both in the United States and in Uganda. Dr. Tobian spoke with Renal & Urology News senior editor Delicia Honen Yard hours after returning from his most recent trip to sub-Saharan Africa.

Are you promoting circumcision for all male newborns, or are you just more concerned that people are considering the proper evidence in making a decision? Dr. Tobian: It has been well known for a long time that male circumcision reduces urinary tract infections among infants. However, the other benefits of male circumcision have not been clear up until about the last 10 years. Three randomized controlled trials have demonstrated that male circumcision reduces multiple sexually transmitted infections. However, the American Academy of Pediatrics (AAP) has not revised its policy since these trials have been published, and increasing numbers of states have eliminated Medicaid insurance coverage for male circumcision.

What is the AAP policy? Dr. Tobian: The current policy states that they’re equivocal on male circumcision—they say that there aren’t major benefits, but there aren’t major risks, either. However, when they discuss the sexually transmitted infections, they say the data are complex and conflicting. The medical benefits of male circumcision to reduce sexually transmitted infections are overwhelming clear since the publication of the first randomized trial in 2005.

How can a whole organization of professionals come to this conclusion, which you ﬁnd erroneous? Dr. Tobian: Primarily the American Academy of Pediatrics focuses on young

children, whereas sexually transmitted infections are more of an issue as an adult. So I think the AAP is focusing on the short term and not the whole life span. However, they are in the process of revising their policy. We primarily want to clarify the evidence and correct misconceptions about male circumcision. There are clearly benefits of male circumcision: It reduces HIV, genital herpes, and human papillomavirus [HPV] in men. In female partners, male circumcision can reduce the risk of bacterial vaginosis, trichomoniasis, and human papillomavirus, which causes cervical cancer.

In a recent editorial published in the Journal of the American Medical Association (2011;306:1479-1480), you and Ronald H. Gray, MD, MSc, stated that it is important for circumcision to occur early in life rather than in adulthood. What is your main reason for taking this position? Dr. Tobian: There are multiple reasons to be circumcised as a neonate compared to an adult. One is that neonatal male circumcision provides some benefits during childhood, such as reduced urinary tract infections and penile inflammatory disorders. Second, approximately 50% of high school students report having sex prior to age 18 years. So delaying male circumcision until after 18 would deny these adolescents the potential benefits of circumcision during often the highest-risk period of sexual activity. A third advantage is that the complication rate of male circumcision is substantially lower as a neonate than as an adult. So delaying the procedure would only add to surgical risk.

In that same JAMA editorial, you contend that if a vaccine were available that reduced HIV risk by 60%, genital herpes

When you are with colleagues, what is the general sense you get about the medical community’s stance on male circumcision? Dr. Tobian: I think most people outside of the HIV field think that male circumcision is fine, but there are not substantial benefits.

Dr. Tobian: Some say these trials were performed in Africa, and they do not apply to the United States. However, despite decades of safe-sex education, sexually transmitted infections continue to have substantial morbidity and mortality in the United States. So, there clearly is a problem in the United States. Several observational studies in the United States—in Maryland, Florida, and Arizona—have shown that male circumcision reduces the risk of heterosexually acquiring HIV and human papillomavirus (J Infect Dis 2009;199:713;59-65). Those estimates are almost identical to the male circumcision trial. Thus, they demonstrate that the trial efficacy estimates are applicable to the United States.

Do you think you would have been as supportive of neonatal male circumcision before HIV, herpes, and HPV were on the public health radar? Dr. Tobian: The short answer is no, I would not have been as supportive of male circumcision. The benefits of male circumcision have not been very clear up until the last five years. The first randomized trial was not published until 2005, and that showed a benefit for reducing HIV. Subsequently, just in the past few years, we’ve seen benefits for reducing genital herpes and human papillomavirus among the men, and then of course the female benefits that we discussed earlier: bacterial vaginosis, trichomoniasis, and human papillomavirus. The data just were not available [before] that point.

What do you see as the greatest misconception about male circumcision held by health care professionals? Dr. Tobian: I think most healthcare professionals know that male circumcision reduces urinary tract infections among male infants. The rate of urinary tract infections among infants is low, so they think overall there’s not a huge benefit for male circumcision. However, they are less aware of the randomized trial data, which are relatively new and shows that male circumcision has a substantial impact on reducing common sexually transmitted infections.

risk by 30%, and high-risk HPV risk by 35%, as male circumcision reportedly does, “it would be promoted as a game-changing public health intervention.” How do opponents who are health-care professionals argue this point with you?

There are many benefits to circumcision in neonates. —Aaron Tobian, MD, PhD

What is the best argument you’ve heard from those who favor banning circumcision among males younger than age 18? Dr. Tobian: The one concern about male circumcision is that there are medical risks to every procedure. So if there are no benefits to a procedure in medicontinued on page 24

24 Renal & Urology News

APRIL 2012

www.renalandurologynews.com

Acute Kidney Injury Linked to Antibiotics BY JILL STEIN SAN FRANCISCO—New data document a strong association between the use of high-dose flucloxacillin with singledose gentamicin in patients undergoing joint replacement surgery and the development of acute kidney injury (AKI). The investigators, who are with the Dumfries & Galloway Royal Infirmary in Dumfries, Scotland, reported their findings at the American Academy of Orthopaedic Surgeons 2012 Annual Meeting. Principal investigator Chris Isles, MD, consultant nephrologist, said his institution had recently decided to replace cefuroxime for the prevention of superficial and deep wound infection after joint replacement surgery with flucloxacillin plus single-dose gentamicin. The decision was made in order to decrease the incidence of Clostridium difficile diarrhea, which can be asymptomatic in some patients or life-threatening in others when pseudomembranous colitis is present. Although their use is now considered routine for primary joint arthroplasty, some antibiotics, including second- and third-generation cephalosporins, may increase the risk of C. difficile diarrhea. However, the unintended consequence of the switch to flucloxacillin/gentamicin was an increase in the incidence of AKI, which Dr. Isles’ team had initially noticed when AKI requiring hemodialysis developed in three patients after arthroplasty. To explore the issue more closely, they examined the incidence of AKI sequentially in 198 patients under-

going elective hip or knee replacement surgery at their institution over a recent 12-month period. The study included 52 patients who received high-dose flucloxacillin and single-dose gentamicin in whom the investigators had first noticed an increased incidence of AKI; a group of 48 consecutive patients who received cefuroxime prophylaxis; 46 patients who were given low-dose flucloxacillin

Neonatal continued from page 23

that time, the California legislature has acted to prevent these types of ballot initiatives. My bigger concern is the lobbying efforts by the anti-circumcision activists who are continuing to lobby state legislatures to eliminate Medicaid insurance coverage. It is the reduced insurance coverage that is much more concerning.

cine, you should not perform it. The complication rate of neonatal male circumcision is extremely low—about tenfold lower than even adult male circumcision. The risk of morbidity from a sexually transmitted infection is much higher and worse than the risk of [male circumcision] complications. So, the concern is the medical risk, but I think that if you weigh it against the benefits the answer is very clear in favor of male circumcision.

Higher risk found with certain regimen of flucloxacillin and gentamicin. with single-dose gentamicin. In addition, because the problem of AKI did not appear to have been completely resolved, an additional 52 patients received cefuroxime. The four groups were similar with respect to age, gender, type of operation, American Society of Anesthesia grade, mode of anesthesia, baseline serum creatinine, pre-operative comorbidity, pre-operative medication, and post-operative hypotension. Overall, 27 (52%) patients receiving high-dose flucloxacillin with single-dose gentamicin experienced AKI by RIFLE criteria (a 1.5 times increase in serum creatinine level or a fall in glomerular filtration rate by more than 25% relative to baseline values). Recipients of high-dose flucloxacillin plus single-dose

Are you concerned that a ban on neonatal male circumcision may be adopted, or do you think that is unlikely?

Should urologists proactively recommend circumcision for their uncircumcised male patients, or just proactively point out the risks and beneﬁts, or should they leave the topic unaddressed unless the patient speciﬁcally asks for information?

Dr. Tobian: During this past summer, I was quite concerned about a possible ban in California. However, since

Dr. Tobian: Male circumcision as an adult is common in sub-Saharan Africa, primarily to reduce HIV. It

gentamicin had a 14.5 times increased risk of AKI compared with patients in the first cefuroxime group after adjusting for confounders. Additionally, AKI was found in four (8%) patients in the first cefuroxime group, 10 (22%) patients in the lowdose flucloxacillin with single-dose gentamicin group, and seven (14%) in the second cefuroxime group. RIFLE class F AKI (defined as a rise in serum creatinine level to three times baseline value) developed in seven patients. Of these, six had received high-dose and one had received lowdose flucloxacillin. Three patients in the high-dose flucloxacillin group needed temporary dialysis, and two of the three underwent a renal biopsy that indicated acute tubulo-interstitial nephritis. No patient in the study experienced C. difficile diarrhea. Dr. Isles emphasized that the findings must be interpreted cautiously given that the study was neither randomized nor controlled. Furthermore, it was not possible to rule out a seasonal effect because the study was conducted over a single 12-month period. Meanwhile, he said “the finding of an odds ratio of 14.5 linking high-dose flucloxacillin plus single-agent gentamicin with AKI after adjusting for possible confounders supports the view that one or the other or both antibiotics may be nephroxotic in this setting.” Finally, he noted that, since the study, his institution has reverted back to the use of cefuroxime as prophylaxis for primary joint arthroplasty. ■

Men should be aware of the risks of undergoing circumcision as an adult. is the World Health Organization’s policy to promote male circumcision among adult men. However, the HIV epidemic is substantially different in the United States compared to subSaharan Africa. If adult men are requesting circumcision in the United States, urologists should explain both the risks and benefits of the procedure. However, male

PSA-Based Screening Cuts PCa Mortality BY JODY A. CHARNOW PSA-BASED screening significantly decreases the risk of dying from prostate cancer, according to updated results of a large European study. The European Randomized Study of Screening for Prostate Cancer involved 186,160 men aged 50 to 74 years at enrollment, with a predefined core age group of 162,388 men aged 55 to 69 years. Investigators randomly assigned subjects to a screening group or a control group. Men in the screening group were offered PSA-based screening and those in the control arm were not. After a median follow-up of 11 years in the core age group, those in the screening arm had a 21% decreased risk of PCa death relative to controls, researchers reported in The New England Journal of Medicine (2012;366:981-990). Additionally, the researchers calculated that to prevent one death from PCa at 11 years of follow-up, 1,055 men would need to be invited for screening and 37 cancers would need to be detected. The investigators stated that the controversy regarding PCa screening has been renewed by the publication of the draft report of the U.S. Preventive Services Task Force, which, after a literature-based analysis of the benefits and harms, recommended against PSA screening of asymptomatic men. ■

circumcision is not 100% protective against HIV or other sexually transmitted infections. Safe-sex education is also important.

But should this topic be addressed as part of the patient visit, whether the man asks or not? Dr. Tobian: I think men should be aware of the risks and benefits. The risks of circumcision are higher as an adult than as a neonate, and depending on the person’s sexual activities, safe-sex education is important. So, I don’t really like saying the urologists should go out of their way or they should not go out of their way.

So perhaps it’s something to keep in mind if a patient comes in and falls into some high-risk group. Dr. Tobian: Exactly. ■

www.renalandurologynews.com

On the Forefront

APRIL 2012

Renal & Urology News 25

Urologists and nephrologists working together: an emerging model of patient care

Sickle Cell Trait and Medullary Renal Carcinoma BY MATTHEW SIMMONS, MD, PhD AND SURAFEL GEBRESELASSIE, MD ince the discovery of Hemoglobin S (HbS) by Linus Pauling and colleagues in 1949 and identification of the abnormality in the amino acid sequence by Vernon Ingram in 1956 (replacement of the hydrophilic glutamic acid at position 6 in the β-globin chain by the hydrophobic valine residue), it has been known that the abnormal polymerization of deoxy-HbS is the main cause for vaso-occlusive crisis involving many organs, including the kidneys in sickle cell disease (SCD). Medullary renal carcinoma (MRC) is a rare and fatal cancer that occurs primarily in patients with sickle cell trait (SCT) and SCD. The typical patient with MRC is a young male (mean age of 22 years) of African or Mediterranean descent. Most patients with this disease present initially with gross hematuria, weight loss, or abdominal pain. In symptomatic patients, 80% will have retroperitoneal lymphadenopathy and visceral metastasis. The disease is uniformly fatal, with a life expectancy from the time of initial diagnosis of only 15 weeks. There are no known effective radiation or chemotherapy treatments for the disease. The renal manifestations of SCD are not limited to MRC. The hypertonic, acidic and hypoxic environment in the inner medulla favors red blood cell sickling, leading to occlusion and necrosis of the vasarecta. The resulting ischemia leads to release of vasodilators such as prostaglandin. This, in turn, increases the glomerular filtration rate (GFR),

leading to microalbuminuria, proteinuria, and eventually low GFR, particularly among patients in the fourth decade of life. Sickle cell patients can have supranormal proximal tubular function resulting in increased creatinine secretion and hyperphosphatemia. Such patients can also have impaired distal hydrogen ion-potassium secretion. Diminished urinary concentrating ability is one of the early renal involvements in SCD and this is often irreversible after age 10. Less severe, impaired urinary concentrating ability is also seen in patients with SCT, which is a benign carrier condition in which one sickle cell beta globulin gene is inherited along with a normal beta globulin gene. The prevalence of SCT is as high as 8%-10% in African Americans. Hematuria is common in both patients with SCD and SCT and could be from papillary necrosis, renal infarct, or MRC, which is seen more often in those with the trait. Investigation has focused on why MRC behaves so aggressively. Data support that chronic renal medullary hypoxia may play a role in tumorigenesis. Conditions in the renal medulla, including low oxygen tension, high acidity, and high osmolarity, promote sickling of red cells in patients with SCT. Sickled cells conglomerate and occlude capillaries. This leads to tubular epithelial hypertrophy and hyperproliferation. The nature and extent of mutations in MRC are variable, but the net result is activation of the hypoxiainducible factor 1 pathway.

Sperm Banking To Remote Sites BY ASHOK AGARWAL, MD, AND EDMUND SABANEGH, MD nfertility is a stressful experience for many couples, a situation made particularly difficult by the need to produce a semen sample in a clinical setting. We set out to develop a system that allows semen specimens to remain viable through a short transport cycle and to retain adequate viability prior to cryopreservation at our sperm bank.

Twenty-two samples were subjected to preliminary testing to optimize transport media, temperatures, and the most ideal kit constructions. Once the appropriate kit components were formalized, nine additional samples were subjected to overnight shipment and analyzed for motility, count, and viability on the basis of normal semen analysis according to World Health Organization guidelines.

This image shows a large multilocular right renal mass in a 27-year-old African-American male. The arrow points to a metastatic liver lesion.

Clinical strategies are limited currently to prevention and early detection. Medullary hypoxia in these patients may be lessened with daily bicarbonate supplementation and increased fluid hydration. General screening for MRC would be difficult to justify given the high cost of imaging and the low incidence of disease. Patient selection for screening plays a clear role. Most young males with SCT have gross hematuria with associated papillary necrosis or hypertrophy. Cross-sectional imaging with and without contrast is mandatory in these patients as part of their formal hematuria evaluation. It could be argued

that these patients be placed on a surveillance protocol involving annual renal US. There is no current data to support that early detection impacts survival of MRC. Indeed, there are no data that describe outcomes of curative-intent surgery for low-stage localized MRC. Nonetheless, in young patients with SCT and gross hematuria, surveillance seems a prudent course of action. ■

We standardized the transport media used in the kit (called the NextGenSM Home Banking Kit) as well as the proper cooling components necessary during overnight transportation that could take up to 24 hours and mimic a temperature of 37° C. Semen samples were analyzed before treatment (0 hour) to establish a baseline on which to compare the overnight shipping (24h). Average preshipment total motile sperm (TMS) was 59.46 million. The percent recovery of TMS was 41.28%. Sperm motility and viability showed a decrease of approxi-

mately 50% during in vitro incubation via overnight shipment. This decrease was consistent with the percentage change in motility seen in samples collected on site. Overnight shipment of sperm in transport media in the kit preserves sperm motility and viability for securing future fertility. More information can be obtained about the NextGenSM program by visiting clevelandclinic.org/nextgen. ■

Matthew Simmons, MD, is in the Department of Urology and Surafel Gebreselassie, MD, is in the Department of Nephrology at the Cleveland Clinic’s Glickman Urological and Kidney Institute.

The authors are affiliated with the Cleveland Clinic’s Glickman Urological and Kidney Institute.

30 Renal & Urology News

APRIL 2012

www.renalandurologynews.com

Newer BP Drugs Might Not Be Better A calcium channel blocker and an ACE inhibitor were similar to a diuretic in lowering CV mortality BY ROSEMARY FREI, MSc CALCIUM CHANNEL blockers (CCBs) and ACE inhibitors may be no better than diuretics at preventing cardiovascular (CV) deaths in patients with hypertension, according to a follow-up study of patients in a seminal antihypertensive trial. In addition, CCBs and ACE inhibitors may increase cardiovascular risks. The follow-up study looked an additional 8-13 years of follow-up data for participants in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) and found no significant difference in CV mortality for the calcium channel blocker amlodipine and the ACE inhibitor lisinopril, each compared with the diuretic chlorthalidone. In addition, amlodipine was associated with a higher rate of heart failure and lisinopril was associated with a higher rate of stroke mortality compared with chlorthalidone, research-

ers led by William Cushman, MD, of the Memphis Veterans Affairs Medical Center reported in The Journal of Clinical Hypertension (2012;14:2031). The new findings are similar to those from the original ALLHAT study,

Persistently Low iPTH Is a Bad Sign

ACC progression and mortality, compared with patients who had iPTH levels between 60 and 150 pg/mL. In addition, each one-year increment in age was associated with an 8% increased likelihood of ACC progression. The study population had a mean age of 51 years and a median follow-up of 46.9 months. All patients had iPTH levels below 300 pg/mL during their first year on dialysis. The investigators scored AAC using posterior-anterior plain chest X-rays. They determined baseline AAC score within three months before and after HD initiation. Previous studies have demonstrated that vascular calcification is closely related to cardiovascular and all-cause mortality, the researchers pointed out. Their study, however, did not find a significant association between AAC progression and death, and they believe this might be due to the relatively shorter follow-up period and small sample size. The authors stated that there are two possible explanations for increased mortality in patients with persistently low iPTH. One is that persistent uremic hypoparathyroidism may be associated indirectly with mortality by its association with prolonged malnutrition. The other explanation is that uremic hypoparathyroidism is associated with vascular calcification. ■

PERSISTENTLY LOW LEVELS of intact parathyroid hormone (iPTH) are independently associated with progression of aortic arch calcification (AAC) and death among incident hemodialysis (HD) patients, according to a new study. The study of 94 HD patients by Sang Heon Song, MD, PhD, of Pusan National University Hospital in Busan, Republic of Korea, and colleagues found that persistently low iPTH (below 150 pg/mL) was associated with a significant fivefold increased risk of AAC progression and a significant eightfold increased risk of death compared with patients who had optimal iPTH levels (between 150 and 300 pg/mL). AAC at baseline was associated with a significant threefold increased risk of AAC progression, the researchers reported in Clinical and Experimental Nephrology (published online ahead of print). Within the persistently low iPTH group, patients with iPTH levels below 60 pg/mL had significantly lower serum phosphate, albumin, and total cholesterol, as well as significantly greater

For some outcomes, a diuretic proved superior to a CCB or ACE inhibitor. which was published in the Journal of the American Medical Association (2002;288:2981-2997). Together, the results suggest that more clinicians should consider using diuretics to treat hypertension rather than newer agents. “Our data do not show that these newer agents [amlodipine and lisinopril] are better,” Dr. Cushman noted.

“In fact, there were some outcomes where the diuretic was better than the calcium-channel blocker or the ACE inhibitors. Even though these differences were in secondary outcomes, they are still important clinically.” The original ALLHAT results—which involved an average follow-up of 4.9 years—showed no difference in the rates of the primary endpoint of fatal coronary heart disease or nonfatal myocardial infarction or in the rates of allcause mortality among the three types of medications. However, researchers found a 38% higher heart failure rate with amlodipine than with chlorthalidone, and 10%, 15%, and 19% higher rates, respectively, of cardiovascular disease, stroke, and heart failure with lisinopril than with chlorthalidone. The follow-up study revealed a 12% higher risk for heart failure in patients taking amlodipine compared with those using chlorthalidone. Additionally, the study demonstrated a 20% higher risk

for stroke mortality with lisinopril compared with chlorthalidone. “The higher stroke mortality with lisinopril was something new that appeared in the follow-up to ALLHAT, but there was a trend toward that in the original trial,” said Dr. Cushman, Professor of Preventive Medicine at the University of Tennessee College of Medicine in Memphis. “However, the total mortality wasn’t significantly elevated with lisinopril. So we don’t think there’s anything particularly bad about lisinopril.” Some clinicians hypothesize that “because chlorthalidone increases glucose and can ‘cause’ diabetes, that long-term chlorthalidone could increase mortality,” Dr. Cushman said. “But we didn’t see that. Also, in another paper that we’re going to publish that focuses on diabetes, we show that those who developed diabetes while using chlorthalidone had an average increase in blood glucose of 6 mg/dL, which is small.” ■

EPO Resistance May Predict Heart Problems in HD Patients EARLY IDENTIFICATION of erythropoietin

and third tertiles was 63.0% and 60.8%,

(EPO) resistance may help clinicians

respectively, compared with 65.8%

predict cardiovascular risk (CV) in hemo-

among patients in the first tertile. Addi-

dialysis (HD) patients.

tionally, during a median follow-up period

In a prospective study of 72 HD

of 53 months, 29 patients (40.3%) had

patients, investigators at The Catholic

CV events (sudden cardiac death, acute

University of Korea in Seoul led by

myocardial infarction, stroke, and pulmo-

Young Kyun Kim, MD, found that EPO

nary edema). Compared with patients in

resistance index (ERI) is associated with

the first ERI tertile, those in the third ter-

left ventricular mass index (LVMI), left

tile had a significant threefold increased

ventricular ejection fraction (LVEF), and

risk of cardiovascular events, after

CV events. Dr. Kim’s group defined ERI

adjusting for age, gender, body mass

as the weekly weight-adjusted dose of

index, and diabetes status. The risk was

EPO (U/kg/week) divided by hemoglobin

not increased significantly for patients in

concentration (g/dL). They assigned

the second tertile. ERI was not signifi-

subjects one of three groups according

cantly associated with all-cause or CV

to ERI tertiles.

mortality or with left ventricular diastolic

Patients in the second and third tertiles (6.06-19.97 and 1997-30.72

function, according to the investigators. “The monitoring of the ERI may be

U/kg/week/g/dL) had a mean LVMI of

useful for the early detection of the EPO

50.4 and 48.7 g/m2.7, respectively,

resistance in patients on chronic hemodi-

2.7

compared with 40.9 g/m for those in

alysis,” the authors observed. Moreover,

the first tertile (0-6.06 U/kg/week/g/

early detection of EPO resistance may be

dL), the researchers reported in Hemo-

helpful in avoiding the use of high doses

dialysis International (online ahead of

of EPO, which usually is associated with

print). The LVEF for those in the second

decreased survival, they stated. ■

www.renalandurologynews.com

APRIL 2012

Renal & Urology News 31

Legal Issues in Medicine D

r. V, 68, was a general practitioner who had been running his own medical practice for the past 30 years. Many of his patients had been coming to him for years. One such patient was Mr. G, 55. Dr. V had been seeing this patient for several years for routine matters and to manage his diabetes, hypertension, and morbid obesity. One day, Mr. G came in complaining of abnormal urination and back pain. The physician ordered a PSA test, which revealed a PSA level of 10.96 ng/mL. Dr. V referred the patient to a urologist, Dr. K. The urologist met with the patient and explained what the elevated PSA level could indicate. The patient elected to have a repeat PSA test rather than an immediate biopsy. The second PSA showed a level of 12. The next month, January 2001, a biopsy was performed, with benign results. Dr. K told the patient that he intended to personally perform repeat PSA tests and instructed the patient to return for such testing. However, the patient was non-compliant and never returned. In April of the same year, the urologist sent Dr. V a letter stating, “This is

and blood in his urine. The physician admitted Mr. G into the hospital, where a PSA test was performed, indicating a reading of 2,400. Mr. G was diagnosed with advanced prostate cancer that had metastasized to his bones and kidneys. Mr. G died a little over a year later. Prior to his death, he filed a medical malpractice case against Dr. V. After his death, the suit was dismissed, but a new lawsuit was brought a year later by Mr. G’s adult children. Dr. V met with the defense attorney provided by his insurance company. The attorney explained to the physician that he was being sued for wrongful death based on medical malpractice. “Specifically,” the attorney said, “the complaint says that you owed Mr. G the duty to properly advise and treat him at the early stage of his prostate cancer. What the case will hinge on is at what point he could still have possibly been treated successfully.” The case dragged on. Over a year was spent with discovery and depositions. One deposition was from the medical expert for the plaintiff, who testified that Mr. G would more likely than not have died had his prostate cancer been

Simply referring a patient to a specialist does not absolve a clinician from following up with a patient, the specialist, or both. a follow-up on Mr. G. He had a prostate ultrasound and biopsy on 1-12-01 and this was negative. Enclosed is a copy of the report.” Dr. V put the letter in the patient’s folder and promptly forgot about it. Over the next several years, Mr. G returned to see Dr. V routinely for treatment of his diabetes, hypertension, and high cholesterol, as well as for a skin infection and swelling of the patient’s hand. Blood work was done often, but the patient’s PSA was not tested. In April 2004, Mr. G came to see Dr. V with complaints of left flank pain

diagnosed after December 2001. After that deposition, the defense attorney called Dr. V in to update him. “I think we’ve caught a break,” the attorney said. “The plaintiff’s expert physician testified that the cancer would have to have been diagnosed prior to December 2001 in order for Mr. G to have had a chance at survival. Our state has a three-year statute of limitations on malpractice cases. The statute begins to run when the injury or act of negligence allegedly took place, not when it was discovered. In this case, the time will start running from when Mr. G no longer had

A physician is sued when he fails to follow-up on patient after referring him to a urologist BY ANN W. LATNER, JD

A physician put a copy of a report from a urologist into a patient’s folder and forgot about it.

a chance of survival (December 2001), as their expert testified. The plaintiffs didn’t file this case until 2006. I believe they missed the window of opportunity to sue – hopefully, the judge will agree, too. I’ll file a motion to dismiss.” The judge did agree, and dismissed the case, much to the relief of Dr. V and the disappointment of the plaintiffs.

Legal background Cases are dismissed on technicalities all the time. Filing after the statute of limitations has run out, not filing the case properly, and not having an expert certify a medical malpractice case in states that require it are but a few of the numerous reasons why a case can fail before it ever gets to trial. While it sometimes seems unfair, particularly to the plaintiffs, the rules are in place for a reason, mainly to limit the number of unnecessary lawsuits. Protecting yourself While Dr. V was not found liable in this case, he still had to go through the unpleasant experience of being sued. In all likelihood he could have prevented this from happening in the first place by doing one of several things: he should have been regularly testing Mr. G’s PSA, especially knowing that there had been

an issue; he could have contacted the urologist to find out whether the urologist was doing the PSA testing; he could have discussed with the patient (and, very importantly, noted in the patient’s medical file) whether the PSA level was being monitored by the urologist and the importance of the continued testing. But instead, after referring the patient to the urologist in 2001, Dr. V never discussed the issue with the patient, had the patient’s PSA retested, or wrote anything relating to the prostate issue in the file until three years later when the patient showed up with an obvious problem, and it was too late. Simply referring a patient to a specialist does not absolve a clinician from following up with the patient, the specialist, or both. Unfortunately, although the end result would not likely have changed for Mr. G, it doesn’t alter the fact that Dr. V should have taken some action. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y. Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended.

32 Renal & Urology News

APRIL 2012

www.renalandurologynews.com

CME FEATURE

Part II: Clinical Challenges and Renal Considerations in Managing Gout A case study involving a 65-year-old man with chronic kidney disease and acute attacks of pain, swelling, and erythema in the first metatarsophalangeal joint.

Release Date: April 2012 Expiration Date: April 2013 Estimated time to complete the educational activity: 1 hour This activity is jointly sponsored by Medical Education Resources and Haymarket Medical Education and is supported by an educational grant from Savient Pharmaceuticals. STATEMENT OF NEED: Clinicians today face an increasing number of patients with gout. Nephrologists in particular must contend with complex cases in patients with varying degrees and stages of renal dysfunction in addition to other comorbidities and individual characteristics that affect treatment decisions and, ultimately, treatment success. As gout occurs in tandem with renal disorders, nephrologists must be able to appropriately identify and treat these patients. TARGET AUDIENCE: This activity has been designed to meet the educational needs of nephrologists and other clinicians involved in the treatment of patients with gout. EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Describe how renal function affects the management of gout. • Evaluate current and emerging options for urate-lowering therapy with regard to their benefits and limitations in patients with varying degrees of renal impairment. • Discuss ways to motivate patient adherence to a long-term treatment plan that incorporates lifestyle considerations and pharmacotherapy. ACCREDITATION STATEMENT: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Medical Education Resources (MER) and Haymarket Medical Education. MER is accredited by the ACCME to provide continuing medical education for physicians. CREDIT DESIGNATION: Medical Education Resources designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. DISCLOSURE OF CONFLICTS OF INTEREST: Medical Education Resources ensures balance, independence, objectivity, and scientific rigor in all our educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure all scientific research referred to, reported, or used in a CME activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality CME activities that promote improvements or quality in health care and not a commercial interest. The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Faculty • James W. Lohr, MD

Reported Financial Relationship No financial relationships to disclose

• Anthony J. Bleyer, MD (Faculty Chair)

Consultant: Takeda Pharmaceuticals, Savient Pharmaceuticals

BY JAMES W. LOHR, MD

out is an inflammatory arthritis most often caused by the inability of the kidney to properly excrete uric acid. Acute symptoms are due to deposition of monosodium urate crystals in joints and tissues. Gout typically develops after years of sustained hyperuricemia.1 Each year, gout accounts for approximately 3.9 million ambulatory care visits in the U.S., predominantly by men but increasingly by women, too. Treatment occurs primarily in the primary care setting.2,3 Aging is an important risk factor in the development of hyperuricemia, with age-related decline in renal function also a consideration. For women, declining estrogen levels contribute to the rise in uric acid levels. The current epidemic of obesity—an additive risk factor—and the increasing population of older Americans mean hyperuricemia and gout will likely become more prevalent.1 Hyperuricemia is associated with myriad comorbid conditions, including chronic kidney disease (CKD), hypertension (HTN), heart failure, diabetes

mellitus (DM), and hyperlipidemia.4-7 CKD, for example, occurs in about 4% of the general US population but in nearly 40% of patients with gout.2,7 Patients with gout and CKD tend to be older, female, and have more comorbidities than patients with gout but without CKD.7 Moreover, these associated conditions can complicate gout management.5 For example, diuretics may increase the risk of hyperuricemia and acute gout flares. CKD itself may affect prescribing patterns for uratelowering therapies.8,9

CASE INTRODUCTION: Chronic gout in a CKD patient Mr. M, a 65-year-old retired postal worker, was diagnosed with gout 4 years ago after experiencing pain, swelling, and erythema in the first metatarsophalangeal joint; the presence of monosodium urate crystals in synovial fluid; and a serum uric acid level of 9.2 mg/dL. Initially, a nonsteroidal anti-inflammatory drug (NSAID) was effective in relieving the symptoms, but he experienced several more acute attacks over the next year and began treatment with allopurinol orally 100 mg/day. Mr. M complains

The content managers, Marjorie Hale, Jill Rovitzky Black, Susan Basilico, Jody A. Charnow, and Marina Galanakis of Haymarket Medical Education, and Victoria Smith, MD, of Medical Education Resources, have disclosed that they have no relevant financial relationships or conflicts of interest. METHOD OF PARTICIPATION: There are no fees for participating in and receiving CME credit for this activity. During the period April 2012 through April 2013, participants must: 1) read the learning objectives and faculty disclosures, 2) study the educational activity, 3) complete the posttest and submit it online. Physicians may register at www.myCME.com/aprilgout (April 2012), and 4) complete the evaluation form online. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better.

James W. Lohr, MD, is Professor of Medicine at the State University of New York in Buffalo and Chief of Nephrology at the Buffalo V.A. Medical Center.

www.renalandurologynews.com

of mild-to-moderate pain, inflammation, and swelling of the same joint; he has had three acute gout flares in the past 5 months. His medical history includes stage 3 CKD, diagnosed 2 years ago after he presented with fatigue and lower extremity edema, with an estimated glomerular filtration rate (eGFR) of 48 mL/min/1.73 m2. His current serum creatinine level is 1.7 mg/dL.

Discussion: serum urate level can predict ESRD Numerous studies have established a link between hyperuricemia and CKD.6,10 Most patients with gout have a relative impairment of renal clearance of urate due to abnormalities in renal tubular transport, explaining the association of hyperuricemia with decreased GFR and progressive kidney disease.5 Notably, serum urate levels correlate with risk for kidney failure and predict end-stage renal disease, even when adjusting for multiple covariates and comorbidities.4 Serum urate levels >8.5 mg/dL are associated with a >8-fold increased risk for kidney failure, whereas reduction of serum urate levels has been reported to be associated with slowing the progression of kidney failure.4,5 In animal models, treatment with the urate-lowering agents allopurinol and febuxostat ameliorated systemic and glomerular HTN; in patients with kidney impairment, treatment with allopurinol reduced the proportion of patients with further deterioration of kidney function or progression to dialysis.11,12 While these data suggest that allopurinol or other agents may slow the progression of CKD, there are no large, randomized, doubleblind, prospective trials to confirm or deny this association. It should be emphasized that allopurinol and febuxostat are recommended only for the treatment of gout (defined by the presence of inflammatory arthritis caused by deposition of monosodium urate crystals) and not for asymptomatic hyperuricemia.

CASE: Comorbidity and medication factors Mr. M’s medical history also includes hypertension. For 12 years, his blood pressure (BP) has been well controlled with a combination of the angiotensin

receptor blocker (ARB) valsartan and hydrochlorothiazide (HCTZ) 80 mg/12.5 mg.

APRIL 2012

Renal & Urology News 33

Table. Drugs for Managing Gout in Patients with CKD Indications and Drugs TO TREAT ACUTE GOUT FLARES

Discussion: serum urate levels and hypertension There is a linear relationship between serum urate level and systolic BP, and hyperuricemia has been identified as an independent risk factor for HTN4 and other cardiovascular (CV) risk factors, including age, male gender, obesity, DM, and insulin resistance.4 Several landmark trials established an independent risk relationship between serum urate levels and cardiovascular disease (CVD).13-15

CASE: routine examination and lab results Mr. M’s height is 5’9”, weight is 195 lb, body mass index is 28.8 kg/m2, and BP is 128/78 mm Hg. The left great toe is swollen, warm, erythematous, and tender to touch, with chronic synovial changes. A complete blood count (CBC) and blood chemistry profile are unremarkable except for a serum uric acid level of 8.2 mg/dL and a serum creatinine of 1.5 mg/dL. Mr. M expresses concern that his acute gout flares have become more frequent. The clinician discusses the patient’s medication and dietary history. Asked about his allopurinol regimen, Mr. M admits that he sometimes “forgets” to take the medication when he feels well between acute flares.

Discussion: treating CKD patients with gout Clinicians face several challenges when treating gout in patients with impaired kidney function (Table).5,8,16 The first is a failure to understand that gout is a chronic condition, requiring ongoing rather than intermittent treatment. The second is that chronic urate-lowering therapies with xanthine oxidase inhibitors such as allopurinol and febuxostat may be associated with gout exacerbation upon initiation of therapy, which should be recognized as a consequence of lowering uric acid levels and a sign of effective treatment. These complicated issues must be discussed at length with patients, and compliance must be addressed and reinforced regularly. In the event of acute flares, the proper course is to add an anti-inflammatory agent.

NSAIDs

Relatively contraindicated

Colchicine

Best avoided; risk for myopathy and neuropathy; commonly used dosing regimens of 0.6 to 1.2 mg/day should be reduced

Corticosteroids

Mainstay of treatment for acute flares in CKD; generally well tolerated with reasonable short-term safety; long-term safety issues are common

TO LOWER SERUM URATE LEVELS LONG-TERM Allopurinol

• Optimal dosage is uncertain; target serum urate level of approximately 6.0 mg/dL • Alert patients to potential for severe rash

Uricosuric agents (probenecid)

Ineffective if GFR is <50 mL/min

Febuxostat

• Effective in mild-to-moderate CKD • No dose adjustment needed for mild-to-moderate kidney impairment

Pegloticase

• No dose adjustment needed for patients with kidney impairment • Infusion reactions and allergic reactions may occur • Contraindicated in patients with G6PD deficiency

CKD = chronic kidney disease; NSAIDs = nonsteroidal anti-inflammatory drugs; GFR = glomerular filtration rate; G6PD = glucose-6-phosphate dehydrogenase Source: Adapted from El-Zawawy 2010, Gaffo 2008, Reinders 2010.

Concerns about dosing of allopurinol, colchicine, and nonsteroidal agents in CKD also pose a challenge to clinicians. Consequently, many patients with hyperuricemia—with or without comorbidities— are not treated optimally and continue to experience attacks of gout.9 A study of 177,637 patients with gout found 58.1% had HTN, DM, dyslipidemia, and/or ischemic heart disease.9 During the 12-month study, 37% of patients reported an outpatient visit for a first gout claim. Of these, 42% of patients were prescribed NSAIDs, 31% received allopurinol, 21% were prescribed corticosteroids, and 17% were treated with colchicine. Overall, 39% of patients received no treatment for their gout complaint. Patients with cardiometabolic comorbidities, DM, or CKD were less likely to be treated than those without comorbidities, despite a higher risk for flares in patients with comorbidities that indicated a higher disease burden.9 Gout is often considered the chronic disease with the worst rate of adherence,17 which contributes to suboptimal management. The laboratory “reference range,” which includes up to 20% of the U.S. population with asymptomatic hyperuricemia, should not be confused with

a “normal range.” Indeed, for decades it has been advised that patients with gout should be treated toward a uric acid level no greater than 6.0 mg/dL. Persistent elevation of serum uric acid and gout flares tend to occur in patients with self-reported prior noncompliance, longer disease duration, and kidney failure.17 Some patients even suspend treatment due to worsening of disease.16 The “intercritical” phase of gout—an asymptomatic phase following recovery from an acute flare—is an excellent time to address secondary causes of hyperuricemia other than adherence, including medications for comorbid conditions, dietary considerations, and alcohol consumption.18

CASE: medication effectiveness Mr. M asks what medication he can use to treat acute flares and if there are any new medications to lower his serum uric acid level, since the allopurinol seems to be losing effectiveness. The clinician reminds him that adherence to any longterm therapy for hyperuricemia is critical to prevent acute flares and worsening of the disease. This is especially important because elevated serum uric acid may adversely affect his kidney function.4

34 Renal & Urology News

APRIL 2012

www.renalandurologynews.com

CME FEATURE The clinician explains that because of his CKD, NSAIDs are not a preferred therapy for an acute flare, and they discuss corticosteroid treatment to alleviate his current symptoms.5,8

Discussion: pharmacologic options Pharmacologic options for management of acute gout flares include NSAIDs, colchicine, corticosteroids, and corticotropin; colchicine and NSAIDs must be used very carefully (or not at all) in older individuals and those with impaired kidney function (Table). NSAIDs, for example, are associated with an increase in BP, decreased response to diuretics, and when used in combination with angiotensin-converting enzyme inhibitors and diuretics, can precipitate acute kidney injury.9 The importance of judicious use of NSAIDs or avoiding them entirely in CKD is well known to nephrologists. Up to 20% of a dose of colchicine is excreted by the kidneys in individuals with normal kidney function.5,8 Colchicine clearance is reduced in patients with CKD and may accumulate in serum and cause gastrointestinal (GI) toxicity, even at low doses; dosing should be reduced in patients with kidney impairment. Neutropenia, neuropathy, and myopathy can occur with long-term use, and may only partially resolve with discontinuation of treatment. Patients with CKD receiving colchicine at any dose should therefore be monitored regularly for leukopenia and myopathy. This is particularly true in kidney transplant recipients treated with cyclosporine. Colchicine is not a preferred agent for prophylaxis against gout and should not be used as prophylaxis for acute flares in patients with a GFR <50 mL/min.8 Colchicine should not be used in patients on hemodialysis. Corticosteroids are used increasingly for acute gout attacks when comorbid conditions preclude NSAID or

colchicine use.5,8 Intra-articular injections of a long-acting corticosteroid are useful for acute flares limited to a single joint or bursa, after septic arthritis has been ruled out by culture of aspirated synovial fluid. Oral, intramuscular, or intravenous corticosteroids can provide complete relief from acute attacks. Corticosteroids are typically given as prednisone or its steroid equivalent for 7-10 days. Lack of corticosteroid effectiveness often results from inadequate dosing, or tapering too soon after initial resolution of acute symptoms. Because short courses of corticosteroids are used for acute gout flares, steroid-related adverse events are less of a concern than with longterm use, but blood glucose levels can rise significantly in patients with or without diabetes. Corticotropins have similar indications for use as corticosteroids, although they are more costly than generic corticosteroids.5,8 Available in subcutaneous and intramuscular formulations, a single corticotropin dose is rapid, efficient, and well tolerated. Adverse effects include hyperglycemia, rebound arthritis, hypokalemia, and fluid retention, which pose a concern for patients with CKD or congestive heart failure.

CASE: new treatment approach Mr. M and the clinician agree that treatment of his acute gout symptoms with an intra-articular corticosteroid is a sensible approach, eliminating concerns about compliance to an oral regimen or systemic effects of steroids. Mr. M returns one month later, his acute flare resolved. The clinician discusses changing Mr. M’s medications in order to reduce his serum uric acid level to the goal of 6 mg/dL.5 The thiazide diuretic in his combination antihypertensive decreases distal sodium reabsorption, which is compensated for by increased proximal

Key Points ■ Decreased renal excretion of uric acid is the primary problem leading to gout,

not lifestyle choices. ■ Proper management is aimed at treating the underlying condition (hyperuricemia). ■ The “reference range” for uric acid is not a “normal range.” ■ Uric acid levels less than 6.0 mg/dL are associated with decreased gout frequency.

tubular sodium and, secondarily, urate reabsorption. Thus, thiazide diuretics increase serum urate levels.8 Changing to another antihypertensive agent may help to lower his serum urate level. As the patient has not been compliant with his allopurinol in the past, they consider beginning allopurinol again for chronic treatment of his symptomatic hyperuricemia.

Discussion: long-term management There are several considerations for pharmacologic management of hyperuricemia in patients with CKD (Table). Long-term therapy is recommended for patients with >2 gout flares per year and for those with tophi. A serum urate goal of <6 mg/dL is associated with a marked reduction in acute gout flares.5 Initiation of allopurinol or febuxostat can mean increased likelihood of an acute gout flare. Prophylaxis with NSAIDs or colchicine can prevent flares, but they may be contraindicated in patients with kidney failure or used with extreme caution if there are no alternatives. Low-dose prednisone may prevent acute flares but is associated with long-term toxicity. Another option is to provide patients with a glucocorticoid dose pack to take in anticipation that they may develop an acute gout attack. Patients must understand that they should continue with their allopurinol or febuxostat during the flare. If they do not experience rapid improvement, they should contact their physician to rule out septic arthritis. Allopurinol is effective in both overproducers (10%) and underexcreters (90%) of urate (Table).5,8,19 Allopurinol is considered a first-line therapy because it has a simple dosing regimen, is relatively inexpensive, and is generally well tolerated. Allopurinol is metabolized to the liver to its active metabolite, oxypurinol, which inhibits xanthine oxidase, thus blocking the conversion of hypoxanthine to xanthine to uric acid to decrease serum and urinary levels of urate. One should monitor for GI intolerance, headache, and leukopenia, the most frequent toxicities associated with allopurinol therapy. Patients affected with allopurinol hypersensitivity syndrome, the most dreaded complication of allopurinol usage, develop a rash consistent with Stevens-Johnson syndrome. Hepatic failure may devel-

op, and the condition can be fatal. Patients starting allopurinol should be advised to stop the medication and call their clinician immediately if they develop a rash. Earlier studies linked allopurinol hypersensitivity syndrome to kidney impairment and diuretic usage, though these studies may have been flawed, so it remains unclear what factors are likely triggers for this syndrome. Allopurinol interacts with several drugs, including azathioprine, theophylline, warfarin, and thiazide diuretics. Some patients with CKD, especially those with tophi, may require higher doses of allopurinol than those recommended to meet the serum uric acid goal.20 A study of allopurinol administered at 300 mg/day for 6 weeks in patients with CKD found that patients had oxypurinol concentrations higher than the recommended therapeutic range. There was a linear correlation between oxypurinol levels and changes in serum uric acid levels, with a higher proportion of patients meeting the serum uric acid goal of 6 mg/dL. None of the patients experienced a significant change in creatinine clearance rate or serum albumin level, developed a rash, or experienced allopurinol hypersensitivity syndrome or other serious adverse events, though this study did not have the power to detect these events.20 Allopurinol should not be given with azathioprine or 6-mercaptopurine because both drugs are metabolized by xanthine oxidase. Another trial found that a daily 100-mg dose of allopurinol for 24 months in patients with CKD slowed progression of kidney disease and reduced CV risk compared with placebo.12 At the end of the study, serum uric acid levels had decreased from 7.8 to 6.0 mg/dL in the allopurinol group but showed no change in the placebo group (P=0.016). In addition, the eGFR increased by 1.3 mL/min/1.73 m2 in the allopurinol group but decreased by 3.3 mL/min/1.73 m2 in the placebo group (P=0.018), indicating that allopurinol slowed the progression of kidney disease. In addition, allopurinol reduced C-reactive protein levels compared to both baseline (P=0.04) and placebo (P=0.018), reducing CV risk (P=0.039) in 71% of patients. Effective treatment of gout will reduce the need for analgesic use, which may also slow the decline of renal function.

www.renalandurologynews.com

APRIL 2012

Renal & Urology News 35

CME FEATURE patients requiring pegloticase to clinicians with expertise in its use.

CASE: assessment and new treatment

As shown above, gout can occur in both males and females when crystals of uric acid are deposited on the articular cartilage of joints and tendons.

Probenecid is a uricosuric agent that acts at the level of urate anion transporter 1 (URAT1) in the kidney proximal tubule to increase urinary urate excretion.5 Probenecid loses its effectiveness if the GFR is <50 mL/min (Table). As this agent increases urinary urate excretion, it should not be used in patients with already high levels of urinary uric acid (ie, >800 mg/day). Probenecid use may increase the frequency of both uric acid and calcium oxalate kidney stones, so patients should increase their fluid intake to prevent the development of renal calculi. There are potential interactions with azathioprine, rifampin, salicylates, heparin, penicillins, and indomethacin. Febuxostat is an orally administered, nonpurine, selective xanthine oxidase inhibitor. 21,22 Because it undergoes nearly complete hepatic metabolism, there is no need to adjust febuxostat dosing in patients with mild-tomoderate kidney impairment. In a head-to-head clinical trial, febuxostat 80 or 120 mg/day was more effective than allopurinol 300 mg/day in achieving a serum urate level of 6 mg/dL after 3 months.5 Like allopurinol, febuxostat may induce gout flares on initiation of therapy (an indication of its effectiveness), warranting prophylaxis with an anti-inflammatory agent. Pegloticase, the most recent addition to the antihyperuricemic armamentarium, is a polyethylene glycolmammalian recombinant uricase indicated for treatment-refractory gout.16,23 Pegloticase is administered

by intravenous infusion every 2 weeks and requires no dose adjustment for patients with kidney impairment. Gout flare prophylaxis with an NSAID or colchicine should begin 1 week before initiating pegloticase and continue for 6 months unless contraindicated or not tolerated. This biological agent is contraindicated in patients with glucose6-phosphate dehydrogenase deficiency due to a risk for methemoglobinemia and hemolysis. The development of antibodies against pegloticase is common and is associated with failure to maintain normalized serum uric acid levels and infusion reactions. Data from 26-week, placebo-controlled trials of pegloticase showed that 42% of patients achieved a serum urate level <6 mg/dL and 40% had complete dissolution of tophi. Acute gout flares were highest in the first 3 months of treatment with pegloticase (77%) and decreased by 6 months (41%), compared with an occurrence in 81% of patients in the placebo group. Serious adverse events (flares and infusion reactions) occurred in one-quarter to one-third of patients. No overall differences in efficacy were noted between patients with CKD and patients with normal kidney function.16 Pegloticase is a promising agent, especially for individuals with tophaceous gout who cannot take allopurinol or febuxostat. This agent has resulted in dramatic resolution of tophi in a number of patients. Given the high risk of allergic reactions, it may be advisable to refer

Mr. M’s joint symptoms were treated with a local corticosteroid injection after a culture of the synovial fluid proved negative for bacterial infection. He was switched from valsartan/hydrochlorothiazide to valsartan and a calcium channel blocker, and his dose of allopurinol was gradually titrated upward over a period of weeks. The patient was instructed to take an oral corticosteroid for acute flares, while his CBC and creatinine clearance were monitored closely. Mr. M initially experienced an acute flare when the allopurinol dose was increased but had no flares in the past 5 months. He tolerated allopurinol well, and treatment achieved a serum uric acid level ranging from 5.2 mg/ dL to 5.8 mg/dL. Mr. M agreed to have his serum uric acid level checked every 6 months.

Conclusion In this patient, subtracting a thiazide diuretic plus adding daily treatment with allopurinol was effective in achieving a uric acid level <6.0 mg/dL. Comorbidities such as CKD, HTN, CVD, and DM are common in patients with hyperuricemia. Target serum uric acid levels are the same in patients with or without comorbidities; however, the choice of serum urate-lowering drug and dosage may need to be altered. Often, first-line therapies are contraindicated or not tolerated in patients with these comorbidities. Corticosteroids are increasingly replacing NSAIDs and colchicine for the treatment of acute gout flares because they have little effect on kidney function. In Mr. M, if the uric acid level did not fall to <6.0 mg/dL (even if it fell to within the reference range), the decision would have to be made to either increase the dose of allopurinol or change therapy. In this circumstance, febuxostat is an alternative to allopurinol, as it is in patients with allopurinol intolerance or hypersensitivity. Febuxostat does not require dose adjustment for patients with impaired kidney function. Pegloticase is an important new therapeutic agent for individuals with

severe gout in whom allopurinol and febuxostat have not been tolerated or effective. ■ REFERENCES 1. Wallace KL, Riedel AA, Joseph-Ridge N, Wortmann R. Increasing prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population. J Rheumatol 2004;31:1582-1587. 2. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA 2007;298:2038-2047. 3. Krishnan E, Lienesch D, Kwoh CK. Gout in ambulatory care settings in the United States. J Rheumatol 2008;35:498-501. 4. Edwards NL. The role of hyperuricemia and gout in kidney and cardiovascular disease. Cleve Clin J Med 2008;75(suppl 5):S13-S16. 5. Gaffo AL, Saag KG. Management of hyperuricemia and gout in CKD. Am J Kidney Dis 2008;52:994-1009. 6. Wu CH, Lee CT, Lee CH, et al. Urinary UMOD excretion and chronic kidney disease in gout patients: cross-sectional case-control study. Ren Fail 2011;33:164-168. 7. Fuldeore MJ, Riedel AA, Zarotsky V, et al. Chronic kidney disease in gout in a managed care setting. BMC Nephrol 2011;12:36. 8. El-Zawawy H, Mandell BF. Managing gout: how is it different in patients with chronic kidney disease? Cleve Clin J Med 2010;77:919-927. 9. Primatesta P, Plana E, Rothenbacher D. Gout treatment and comorbidities: a retrospective cohort study in a large US managed care population. BMC Musculoskelet Disord 2011;12:103. 10. Gibson T. Hyperuricemia, gout and the kidney. Curr Opin Rheumatol 2011 Dec 12. [Epub ahead of print] 11. Siu YP, Leung KT, Tong MK, Kwan TH. Use of allopurinol in slowing the progression of kidney disease through its ability to lower serum uric acid level. Am J Kidney Dis 2006;47:51-59. 12. Goicoechea M, García de Vinuesa S, Verdalles U, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol 2010;5:1388-1393. 13. Krishnan E, Baker JF, Furst DE, Schumacher HR Jr. Gout and the risk of acute myocardial infarction. Arthritis Rheum 2006;54:2688-2696. 14. Verdecchia P, Schillaci G, Reboldi G, et al. Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study. Hypertension 2000;36:1072-1078. 15. Bos MJ , Koudstaal PJ, Hofman A, et al. Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam Study. Stroke 2006;37:1503-1507. 16. Reinders MK, Jansen TL. New advances in the treatment of gout: review of pegloticase. Ther Clin Risk Manag 2010;6:543-550. 17. Silva L, Miguel ED, Peiteado D, et al. Compliance in gout patients. Acta Rheumatol Port 2010;35:466-474. 18. Harris MD, Siegel LB, Alloway JA. Gout and hyperuricemia. Am Fam Physician 1999;59(4):925-934. 19. Zyloprim® (allopurinol) [package insert]. San Diego, CA: Prometheus Laboratories, Inc.; 2009. 20. Panomvana D, Sripradit S, Angthararak S. Higher therapeutic plasma oxypurinol concentrations might be required for gouty patients with chronic kidney disease. J Clin Rheumatol 2008;14:6-11. 21. Gaffo AL, Saag KG. Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout. Core Evid 2009;4:25-36. 22. Uloric (febuxostat) tablet for oral use [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2011. 23. Krystexxa™ (pegloticase) Injection, for intravenous infusion [package insert]. East Brunswick, NJ: Savient Pharmaceuticals, Inc.; 2010.

Erratum In the initial article of this three-part series, “Clinical Challenges and Renal Considerations in Managing Gout,” March 2012, the agent pegloticase was inaccurately characterized in a table as a urate transporter. It is in fact a pegylated recombinant mammalian uricase. The table has been corrected in the online version of the article, available at www.mycme.com/marchgout and www.renalandurologynews.com/gout1.

36 Renal & Urology News

APRIL 2012

www.renalandurologynews.com

CME FEATURE CME Post-test Expiration Date: April 2013 Medical Education Resources designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Participants should claim only the credit commensurate with the extent of their participation in the activity. Physician post-tests must be completed and submitted online. Physicians may register at no charge at www.myCME.com/aprilgout. You must receive a score of 70% or better to receive credit.

1. The prevalence of gout in patients with CKD is about _____ times the prevalence in the general U.S. population: a. 20 times b. 10 times c. 2 times d. 1.5 times 2. Patients with increased serum urate levels are likely to have all of the following except: a. An increased risk for acute myocardial infarction b. Insulin resistance or diabetes mellitus c. Increased risk of developing hypertension d. A lower level of systolic blood pressure (BP) 3. Treatment of acute gout flares in patients with CKD with intra-articular injections of corticosteroids: a. Is appropriate for patients with multiple joint involvement b. Is less effective than treatment with nonsteroidal anti-inflammatory agents (NSAIDs) c. Is helpful for patients who cannot be treated with NSAIDs or colchicine d. Requires tapering of the dose after resolution of acute symptoms 4. A key difference between the xanthine oxidase inhibitor febuxostat and the recombinant uricase pegloticase is: a. Dose adjustment of pegloticase but not febuxostat is required for patients with impaired renal function b. Effectiveness may be diminished by the development of antibodies to pegloticase but not to febuxostat c. Acute gout flares are common after initiation of treatment with febuxostat but not with pegloticase d. Febuxostat is more effective that pegloticase for achieving serum urate levels <6 mg/dL 5. Gout is most commonly caused by: a. Overproduction of uric acid b. Poor dietary choices and excessive alcohol intake c. A history of acute kidney injury d. Impaired renal clearance of urate

DISCLAIMER: The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Savient Pharmaceuticals, Medical Education Resources, or Haymarket Medical Education. The authors have disclosed if there is any discussion of published and/or investigational uses of agents that are not indicated by the FDA in their presentations. The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of Savient Pharmaceuticals, Medical Education Resources, or Haymarket Medical Education. Before prescribing any medicine, primary references and full prescribing information should be consulted. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. The information presented in this activity is not meant to serve as a guideline for patient management.

Acute Renal Failure Need Not Stop Kidney Donation BY ROSEMARY FREI, MSc THE USE OF kidneys from deceased donors with acute renal failure (ARF) can be safe and produce good renal function up to one year after transplantation, research has confirmed. A Montreal team reviewed the outcomes from 196 cadaveric kidneys they had transplanted from January 2006 to December 2010. Among these, 29 were from donors with ARF according to the Acute Kidney Injury Network (AKIN) definition. Two of the recipients had venous thrombosis of the transplanted kidneys shortly after surgery and the investigators excluded them from the analysis. Fourteen women and 15 men received the kidneys. Their mean age was 53 years, 25 had a panel reactive antibody percentage at transplant of 1%-19% and the mean cold ischemia time was 942 minutes. Five patients experienced delayed graft function (DGF) post-transplant. Another 11 had slow recovery of function and three had biopsy-proven acute rejection. Overall, six required dialysis immediately post-transplant. The mean creatinine values were 140.8 µmol/L at one month post-transplant, 126.5 µmol/L at three months, 122.5 µmol/L at six months, 123.3 µmol/L at one year, and 127.3 µmol/L at five years.

“If you have data showing the kidney function was normal prior to the event that led to the ARF and death, then you can be reasonably confident of a good outcome,” said lead investigator Lynne Senécal, MD, a nephrologist and Adjunct Clinical Professor at the Hôpital Maisonneuve-Rosemont in Montreal. “Since there are so few organs to choose from, before refusing kidneys from someone with ARF you should think twice, because sometimes, if the donors were young and not sick prior to the fatal event, they can function well.” Dr. Senécal presented the results at the Canadian Society of Transplantation’s 2012 Annual Meeting. The findings mirror those of an earlier French study (Nephrol Dial Transplant 2010;25:1980-1986). It showed an average of 7.6 days’ renal-recovery time among 52 patients who received kidneys from deceased donors with ARF. This study, however, also indicated that renal function was lower posttransplant among patients who received kidneys from donors who were older, whose cause of death was related to cardiovascular factors, cerebral hemorrhage, or stroke, or who had previous cardiovascular disease. ■

Severe Pelvic Fracture Impairs Sexual Function, Study Finds BY JILL STEIN SAN FRANCISCO—Men and women who suffer an acute pelvic fracture that is severe enough to require surgery have a significantly increased risk of a decrease in sexual function, British investigators reported here at the American Academy of Orthopaedic Surgeons 2012 Annual Meeting. Peter V. Giannoudis, MD, and colleagues at the University of Leeds examined sexual function in 67 patients who underwent surgery for a pelvic fracture at their institution over a recent 12-month period. Patients were 18 to 65 years old at the time of their accident and had been injured at least 12 months prior to enrollment. The study excluded patients with co-morbidities linked to sexual dysfunction. Acute pelvic injuries are indicators of high-energy trauma and are most often

caused by motor vehicle accidents, said Dr. Giannoudis, Professor and Chairman of the Trauma & Orthopaedic Surgery Department. Pedestrians who are hit by a car or “crushed” in a motorcycle accident or fall from a significant height are also at increased risk of acute pelvic trauma. Results showed that while no patient in the study had sought medical attention for sexual function prior to their injury, 50 (71.5%) patients showed a decrease in overall sexual function after their fracture. Of these, 47.1% had sexual function below the accepted threshold of dysfunction, defined as a Female Sexual Function Index score of 25.5 or less and International Index of Erectile Function score of 30 or less. Also, 24.3% of patients had a measurable, but milder decrease in sexual function. ■