Renal & Urology News March 2012 Issue by Haymarket Media

MARCH 2012

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VOLUME 11, ISSUE NUMBER 3

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www.renalandurologynews.com

Radium Drug Called ‘A Big Deal’ for PCa

Radium-223 is much less toxic to bone than other radioactive bone-targeting drugs

A NEW DRUG for PCa bone metastases (shown above) prolonged overall survival.

CKD Incidence Higher in Blacks RESEARCHERS WHO analyzed 20-year follow-up data from a prospective study found that African Americans have a higher incidence of chronic kidney disease (CKD) than whites in part because of albuminuria. “This finding provides an important contrast to cross-sectional studies reporting a higher CKD prevalence

CME FEATURE

among whites compared with African Americans,” the authors concluded in a paper published in the Clinical Journal of the American Society of Nephrology (2012;7:101-107). The study compared the incidence of CKD among young African-American and white adults who participated in continued on page 10

Earn 1 CME credit in this issue

Clinical Challenges and Renal Considerations in Managing Gout PAGE 28

BY JODY A. CHARNOW SAN FRANCISCO—A novel medication may provide a new standard of care for the treatment of patients with castrationresistant prostate cancer (CRPC) and bone metastases, researchers concluded in a presentation here at the annual Genitourinary Cancers Symposium. In a phase 3 study, radium-223 chloride (Alpharadin)—a first-in-class drug—significantly prolonged overall survival and time to first skeletal event (SRE) in CRPC patients with bone metastases, according to lead investigator Chris Parker, MD, of The Royal Marsden NHS Foundation Trust in Sutton, U.K. The drug was well tolerated and associated with a low incidence of bone toxicities.

Proton Beam Superiority Questioned BY JODY A. CHARNOW SAN FRANCISCO—Two studies comparing various treatment modalities for prostate cancer (PCa) could help doctors and patients make more informed treatment decisions, according to presentations at the 2012 Genitourinary Cancers Symposium. In one study, investigators led by Ronald C. Chen, MD, Assistant Professor of Radiation Oncology at the University of North Carolina in Chapel Hill, found that proton therapy is no better than intensity modulated radiotherapy (IMRT) as a treatment for localized PCa, and it is associated with greater gastrointestinal (GI) toxicities. The other study, led by Jay P. Ciezki, MD, a staff member of the Department of Radiation Oncology at Cleveland Clinic, demonstrated that brachytherapy is less toxic and less costly than either external beam radiotherapy (EBRT) or radical prostatectomy (RP). continued on page 10

“Radium-223 is, chemically-speaking, like calcium, so it localizes to bone, and specifically to bone metastases,” Dr. Parker said. “And radium-223 is an alpha emitter, so once in the bone it emits alpha particles, which are highly lethal and highly localized because they are very, very short range.” Researchers analyzed data from 809 patients randomized to receive radium-223 (541 men) or placebo (268 men). The primary endpoint was overall survival. The median overall survival was 14 months in the radium-223 group compared with 11.2 months in the placebo recipients, which translated into a 30% decreased death risk. The median time to first SRE was 13.5 months in the continued on page 10

IN THIS ISSUE 3

Pulmonary hypertension in HD patients hikes death risk

Renal decline associated with TNF receptors

HD patients are at higher risk for herpes zoster

Heavy alcohol use may raise prostate cancer risk

Empiric antibiotics for elevated PSA not warranted

Men with ED more likely to have atopic dermatitis

Web-based tools are enhancing donor screening

Adrenal CT scan showing adenoma PAGE 23

www.renalandurologynews.com

MARCH 2012

Renal & Urology News 3

Pulmonary Hypertension Common in HD Patients PULMONARY hypertension is common in hemodialysis (HD) patients and it is associated with an increased death risk, a study found. In a study led by Rajiv Agarwal, MD, of the Indiana University School of Medicine in Indianapolis, pulmonary hypertension was present in 110 (38%)

of 288 HD patients, according to a report in Nephrology Dialysis Transplantation (published online ahead of print). Dr. Agarwal defined pulmonary hypertension as an estimated systolic pulmonary artery pressure greater than 35 mm Hg using echocardiograms performed within an hour after the end of dialysis.

PROVENGEÂŽ (sipuleucel-T) Suspension for Intravenous Infusion

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Over a median follow-up period of 2.1 years, 97 patients (34%) died, for a crude mortality rate of 114.2 per 1,000 patientyears. Of these, 58 deaths occurred among the 110 patients with pulmonary hypertension and 39 occurred among subjects without it. After adjusting for multiple variables, pulmonary hypertension sig-

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Any Adverse Event Chills Fatigue )HYHU %DFN SDLQ Nausea Joint ache Headache Citrate toxicity Paresthesia Vomiting $QHPLD Constipation Pain Paresthesia oral Pain in extremity 'L]]LQHVV Muscle ache $VWKHQLD Diarrhea ,QĹśXHQ]D OLNH LOOQHVV Musculoskeletal pain Dyspnea Edema peripheral Hot ďŹ&#x201A;ush Hematuria Muscle spasms

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(Table 1 continued on next page.)

nificantly and independently predicted a twofold increased risk of all-cause mortality. Pulmonary hypertension was strongly associated with an enlarged left atrium. â&#x20AC;&#x153;Reducing left atrial size such as through volume control may be an attractive target to improve pulmonary hypertension,â&#x20AC;? Dr. Agarwal concluded. â&#x2013;

4 Renal & Urology News

MARCH 2012

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Stents May Benefit Renal Transplant Patients Ureteral stents in recipients of deceased donor organs lower the risk of ureteral complications RECIPIENTS OF deceased donor kidneys who have ureteral stents implanted are at lower risk of ureteral complications, but are more likely to experience urinary tract infection (UTI), according to researchers.

In a study of 961 renal transplant recipientsâ&#x20AC;&#x201D;310 with ureteral stents and 651 without the stentsâ&#x20AC;&#x201D;investigators found that the ureteral complication rate was 1.9% in stent recipients compared with 5.8% of those without

Table 1 Incidence of Adverse Events Occurring in â&#x2030;Ľ5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

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Grade 3-5 n (%)

stents. After adjusting for confounders, the stent group overall had a significant 60% decreased risk of ureteral complications. Further analysis revealed that stents benefited primarily recipients of deceased donor kidneys, who had

a 66% decreased risk of ureteral complications compared with non-stented recipients, investigators reported online ahead of print in Transplantation. â&#x20AC;&#x153;Routine stenting in deceased donor transplants is recommended as its protective effect was observed in this group,â&#x20AC;? the authors concluded. The protective effect of stents was related primarily to a significant reduction in stricture but not leak. â&#x20AC;&#x153;We speculate that the stent affects the healing process in the early postoperative period in such a way that stricture is less likely to occur at a later time point,â&#x20AC;? Sameh A. Fayek, MD, and colleagues at the University of Maryland School of Medicine in Baltimore, stated. Deceased donor kidneys are more prone to ischemic insult secondary to long cold ischemia time and as certain donor characteristics, such as age and diabetes mellitus with possible microvasculature disease. This insult is manifested by the higher delayed graft

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To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dendreon Corporation Seattle, Washington 98101

References: 1. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 2. PROVENGE [package insert]. Dendreon Corporation; June 2011.

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Ureteral stents, however, are linked to an increased risk of UTI. function rate in the stent group than in the no-stent group (46% vs. 28.6%), the authors noted. The UTI rate was 14.2% in the stent group compared with 7.9% in the nostent group, a difference that translated into a significant 79% increased risk of UTI in the stent group, after adjusting for potential confounders. The finding of an increased UTI risk in renal transplant patients who had ureteral stents implanted is consistent with findings from previous studies, Dr. Fayekâ&#x20AC;&#x2122;s group observed. A major strength of the study was its relatively large cohort of both deceased and living donor recipients, the researchers said. However, the study is limited by its retrospective design and the fact that patients were operated on by different surgeons with variable practices and thresholds for stenting. According to the authors, the value of stents in recipients of living donor kidneys remains to be determined given the low rate of stent utilization in this group. â&#x2013;

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Renal & Urology News 5

FROM THE EDITOR EDITORIAL ADVISORY BOARD

Highlights of the GU Cancers Symposium

his issue features coverage of the 2012 Genitourinary (GU) Cancers Symposium, which was held in San Francisco. On the cover are two news articles, one of which reports on two studies comparing prostate cancer (PCa) treatment modalities. Among the chief findings: Brachytherapy is less toxic and less costly than either external beam radiotherapy or radical prostatectomy, and proton beam therapy—the most expensive PCa treatment of all—is no better than intensity-modulated radiotherapy. Although clinicians may be averse to letting cost be an overriding issue in the treatment they recommend, they might have no choice in the future. These data could be considered by public and private health insurers as they develop reimbursement policies aimed at cutting health care spending. They could formulate payment guidelines that encourage the use of one treatment over another. Symposium news coverage continues on pages 12 and 13, where you will find a report on a large study showing that clinicians are not following the U.S. Preventive Services Task Force recommendation against PSA screening for men aged 75 years and older. The study did not look at why, but the lead investigator suspects that one reason may be that clinicians do not believe that the controversy surrounding the value of PSA screening in this subpopulation has been resolved. And be sure to read about the study showing that 11% of men with metastatic PCa receive no anticancer treatment. The study found that Medicaid, Medicare, and uninsured patients were more likely than the privately insured to go without treatment. I thought it was particularly interesting that Medicare patients were more likely than Medicaid patients to be untreated. I would have thought the reverse given that the Medicaid population tends to be more disadvantaged socioeconomically. Lastly, we have a report on a study suggesting that everolimus may be the first effective pharmacologic treatment for angiomyolipoma (AML). Nearly 42% of patients with this benign tumor had an AML response compared with none of the placebo recipients. For additional news reports from the symposium, I invite you to visit our web site (www.renalandurologynews.com), where you can view video podcasts of colleagues providing details of their studies. Yours sincerely,

Jody A. Charnow Editor Renal & Urology News welcomes letters to the editor. Send to: Jody A. Charnow, 114 West 26th Street, 4th Floor, New York, NY 10001 or e-mail jody.charnow@haymarketmedia.com

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 3. 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

MARCH

2012

■

VOLUME

11, ISSUE

NUMBER

Nephrology Pulmonary Hypertension Common in HD Patients In a study, 38% of hemodialysis patients had the condition, and it was associated with an increased death risk.

Stents May Beneﬁt Renal Transplant Patients The devices lower the risk of ureteral complications in recipients of deceased donor kidneys

this month at renalandurologynews.com 9

Expert Q&A Renal & Urology News talks with a leading authority on brachytherapy

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 January winner: Randy Chudler, MD

Non-Cancer Death Less Likely with PN Patients who undergo partial nephrectomy for localized renal cell carcinoma are more likely to die from causes other than their cancer compared with patients treated with radical nephrectomy.

No Change in PSA Testing for Men 75+ Prostate cancer screening using PSA tests has not declined despite a 2008 U.S. Preventive Services Task Force recommendation against such screening in this age group.

News Coverage Visit our website for on-site coverage of the 27th Annual Congress of the European Association of Urology in Paris, Feb. 24-28.

“

Not ALL ESRD Patients May Want Dialysis Some patients would accept a shorter life expectancy in exchange for a better quality of life.

28 CME Feature Clinical Challenges and Renal Considerations When Managing Gout William F. Finn, MD, Professor of Medicine in the Division of Nephrology and Hypertension at the University of North Carolina School of Medicine at Chapel Hill, discusses the etiology of gout, the pathogenesis of hyperuricemia, risk factors in renal transplant recipients, patient workup, and other aspects of care.

Urology

The Medical Minute Visit renalandurologynews.com /the-medical-minute to hear podcast reports on new studies. Our latest include: • Prostate Health Supplement No Better than Placebo • Stroke Risk Significant Higher in Hemodialysis Patients • A New Radiotherapy Option for Prostate Cancer

Inﬂammatory Markers, CKD Linked Chronic kidney disease is more likely to develop in patients with elevated levels of tumor necrosis factor alpha receptor 2 and interleukin-6.

Empiric Antibiotic Use May Be Unjustiﬁed New findings challenge the widespread practice of placing men on an empiric course of antibiotics for a newly elevated PSA level. PSMs Predict PCa Recurrence in Some Men Positive surgical margins are a risk factor for biochemical recurrence in men who have undergone radical prostatectomy for intermediate-risk disease.

“

ONLINE

At this time, we cannot recommend the addition of rituximab to MMF for the initial therapy of proliferative lupus nephritis. See our story on page 24

Departments 5

From the Editor Genitourinary Cancers Symposium highlights

News in Brief Biomarkers identify AKI

Renal Nutrition Update Salt reduction should be promoted

On the Forefront A puzzling case of primary aldosteronism

Malpractice News A $9 million Wyoming verdict

Your Money Weighing the benefits of target-date funds

8 Renal & Urology News

MARCH 2012

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

Short Takes Vytorin Label Will Include Kidney Data

from food was associated with a

The FDA has approved new labeling

PCa in a comparison of high-grade

for the cardiovascular agent Vyto-

cases and biopsy-negative con-

rin (ezetimibe/simvastatin) that will

trols and a 62% decreased risk in

include data from the Study of Heart

a comparison of high-grade cases

and Renal Protection (SHARP), in which

and healthy controls, according to a

Vytorin 10/20 mg reduced the risk for

report in Preventing Chronic Disease

major vascular events in patients with

(2012;9:110125).

63% decreased risk of high-grade

moderate-to-severe chronic kidney disrelated indication for Vytorin because

Renal Decline Linked to TNF Receptors

SHARP did not assess the independent

High levels of tumor necrosis factor

contributions of ezetimibe and simvas-

(TNF) receptors 1 and 2 are

tatin to the observed effect.

associated with an increased risk

ease. The FDA did not approve a new

of kidney disease in patients with

Dietary Calcium May Decrease PCa Risk

type 1 diabetes, according to find-

Dietary calcium is associated with

the Journal of the American Society

lower risk for prostate cancer (PCa),

of Nephrology. In a study by Andrzej

particularly among black men, and

S. Krolewski, MD, and colleagues,

with a lower risk for high-grade PCa

patients with TNF receptor 2 levels in

among all men, according to a study

the highest quartile were three times

involving 108 U.S. veterans with

more likely to experience renal decline

biopsy-positive prostate cancer, 161

than patients in other quartiles. The

biopsy-negative controls, and 237

risk associated with TNF receptor 1

healthy controls.

was slightly less than that associated

The highest tertile of calcium

ings published online ahead of print in

with TNF receptor 2 values.

Nephrologist Earnings Rise From 2009 to 2010, median annual income rose by 5.1% for nephrologists and fell by 4.6% for urologists, according to data from the Medical Group Management Association. Median income rose by 9.5% for all specialists combined.

2009

2010 $400,000

$372,455

$300,000

$356,885 $325,916

$290,986

$250,000 $200,000 $150,000 $100,000 $50,000 0

Nephrologists

atients undergoing prostate cancer surgery face similar risks for incontinence and sexual problems whether they undergo robotic-assisted laparoscopic radical prostectomy (RP) or open RP. Michael J. Barry, MD, and colleagues studied 406 Medicare patients who had undergone robotic-assisted laparoscopic RP and 220 who had undergone open RP. Of those who responded to questions on a mail survey, 31.1% reported a moderate or big problem with incontinence and 88% reported a moderate or big problem with sexual function, according to an online report in the Journal of Clinical Oncology. Adjusted analyses showed that robotic and open surgery were associated with similar likelihoods of greater problems with urinary and sexual function. “Medicare-age men should not expect fewer adverse effects following robotic prostatectomy,” the authors concluded.

Biomarkers Identify AKI in Emergency Patients I

n an international study of 1,635 emergency-department patients, urinary neutrophil gelatinase-associated lipocalin (uNGAL) was the most useful of five urinary biomarkers in predicting the severity and duration of acute kidney injury (AKI) at the time of hospital admission, with 81% specificity and 68% sensitivity at a cutoff of 104 ng/mL. In the study by Thomas L. Nickolas, MD, MS, and colleagues, which was published in the Journal of the American College of Cardiology (2012;59:246-255), uNGAL and another biomarker, urinary kidney injury molecule 1, predicted a composite outcome of dialysis initiation or death during hospitalization, improved the net risk classification compared with conventional assessments, and identified a substantial subpopulation of patients who had low serum creatinine at hospital admission but were at risk of adverse events.

Study: Form of Bladder Cancer Increased by 56%

$390,678

$350,000 $306,046

Adverse RP Effects Not Lessened with Robotics P

Urologists

All specialists (excludes primary care doctors)

Source: Medical Group Management Association. Physician Compensation and Production Survey (2010 and 2011).

lthough a detailed trend analysis of 127,614 U.S. cases of first primary bladder cancer demonstrated a 9% overall drop in disease occurrence between 1973 and 2007, papillary transitional cell carcinoma (PTCC)—one of two main subtypes—increased by 56% over that period. In contrast, the other main subtype, non-papillary transitional cell carcinoma (NPTCC), fell by about 53%. The results suggest that external and internal bladder tumors are two disease entities with separate causes, according to a report in BJU International (2012;109:52-56). Lead investigator Yawei Zhang, MD, of the School of Public Health and School of Medicine at Yale University, in New Haven, Conn.,observed that “no epidemiological studies have investigated the risk factors for these two subtypes separately. Our study suggests that future research must make clear distinctions between PTCC and NPTCC and not just treat them as subtypes of transitional cell carcinoma.”

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MARCH 2012

Renal & Urology News 9

Non-Cancer Death Less Likely with PN Partial nephrectomy should be offered for RCC whenever technically feasible, researchers conclude PATIENTS WHO UNDERGO partial nephrectomy (PN) for localized renal cell carcinoma (RCC) are more likely to die from causes other than their cancer compared with patients treated with radical nephrectomy (RN), data show. Maxine Sun, MD, of the University of Montreal Health Center, and colleagues compared other-cause mortality (OCM) among 1,068 PN patients and 1,068 RN patients, adjusting for cancer-specific mortality (CSM), age, baseline Charlson comorbidity index (CCI), race, gender, socioeconomic status, tumor grade, and year of surgery. Subjected were propensity matched. The two- and five-year OCM rates were 5% and 16%, respectively, for the PN group compared with 6.9% and 18.1% for the RN group. In multivariate analyses, PN patients had a significant 17% decreased likelihood of OCM compared with RN patients, the investigators reported online ahead of print in European Urology.

PSMs Rare After Partial Nephrectomy POSITIVE SURGICAL margins (PSMs) are rare in patients undergoing partial nephrectomy (PN) for kidney cancer, researchers found. A nonsystematic literature review by Martin Marszalek, MD, of Donauspital, Vienna, Austria, and colleagues revealed that PSMs are present in 0%-7% of patients following open PN, 0.7%-4% after laparoscopic PN, and 3.9%-5.7% after robot-assisted PN, according to a report in European

Additionally, higher CCI, increasing age, female gender, and baseline hypercalcemia and baseline hyperlipidemia were independent predictors of OSM. As a result of their findings, the researchers concluded that PN should be offered as a treatment for localized RCC whenever technically feasible. The authors noted that previous studies have suggested that PN may not be associated with a survival benefit and in fact may be associated with increased overall mortality compared with RN. In a randomized, prospective study of 541 patients with small solitary renal tumors, Hendrik Van Popple, MD, and colleagues (Eur Urol 2011;59:543-552) found no significant difference in survival between PN and RN. A study by William C. Huang, MD, and colleagues (J Urol 2009;181:55-61) showed that RN was associated with a significant 38% increased risk of overall mortality compared with PN, and a study by Laurent Zini, MD, PhD, and colleagues (Cancer 2009;115:1465-1471) demonstrated a

Partial vs. Radical Nephrectomy Partial nephrectomy for renal cell carcinoma is associated with a lower risk of death from non-cancer causes compared with radical nephrectomy, a study found.

Partial nephrectomy Radical nephrectomy

15 10 5 0

Two-year Five-year Other-cause mortality rates Source: Sun M, Trinh Q-D, Bianchi M, et al. A non-cancer-related survival benefit is associated with partial nephrectomy. Eur Urol. 2011 [Epub ahead of print]

significant 23% increased risk of overall mortality associated with RN compared with PN. Dr. Sun’s group pointed out, however, that previous studies have either failed to account for inherent patient and sociodemographic differ-

ences between PN and RN patients, did not consider baseline conditions, or did not account for the effect of CSM. In their discussion of limitations of their study, Dr. Sun’s group noted that their study sample was restricted to Medicare beneficiaries, which have an age of 65 years and older. “This restriction may have compromised the generalizability of the results and may represent a major difference relative to previous studies that did not have an age restriction applicable to their analyses,” the authors wrote. In addition, the investigators pointed out, “the lack of information on baseline kidney functions and serum creatinine levels to identify patients with preexisting and treatment-induced chronic kidney disease may have influenced the rates of OCM events. As such, the observed effect between treatment type and OCM cannot be inferred as a direct causal relationship but only as a mere correlation, which would need to be confirmed in future studies.” ■

Inflammatory Markers, CKD Linked ELEVATED LEVELS OF certain inflammatory markers are associated with an increased risk of developing chronic kidney disease, a study found. The population-based study, which included a cohort of 4,926 individuals, divided subjects into tertiles based on their baseline serum levels of C-reactive protein (CRP), tumor necrosis factoralpha receptor 2 (TNF-αR2), interleukin-6 (IL-6), and serum white blood cell (WBC) count, all markers of inflammation. After adjusting for multiple variables, including diabetes and hypertension, subjects in the highest tertile

of TNF-αR2 and WBC count had a twofold increased risk of developing CKD over a 15-year follow-up period compared with subjects in the lowest tertile, according to a research team led by Anoop Shankar, MD, of the West Virginia School of Medicine in Morgantown. Patients in the highest tertile of interleukin-6 levels had a 45% increased risk. CRP level was not associated with CKD risk. “Results from our study further extend the current understanding of the role of inflammatory markers in the pathogenesis of CKD,” Dr. Shankar’s team wrote in Kidney International (2011;80:1231-1238).

In addition, the authors concluded: “A practical application of our findings is that, if replicated in other studies, these markers may be a potential future way of assessing subjects who are more likely to develop CKD.” Strengths of the study, the researchers noted, include its population-based sample, high participation rate, the availability of specific markers of inflammation, and the use of standardized protocols for exposure and outcome measurement. Lack of information on a marker of kidney injury, such as 24-hour urine protein or urinary albumin/creatinine ratio, was a main study limitation, they wrote. ■

Urology (published online ahead of print). Intermediate follow-up data show that the vast majority of patients with PSMs after PN remain without local or distant tumor recurrence. “Therefore,” the authors concluded, “a surveillance strategy with adherence to a vigilant follow-up protocol seems to be preferable over surgical reintervention.” ■

HD Patients at Higher Risk for Herpes Zoster PATIENTS ON long-term hemodialysis (HD) are at increased risk of herpes zoster compared with the general population, according to researchers. Chien-Chun Kuo, MD, and colleagues at Kaohsiung Medical University in Kaohsiung, Taiwan, studied 843 patients who began HD in 1999-2003 and a com-

parison group of 3,372 patients without end-stage renal disease matched for age and gender. Mean follow-up was 4.73 and 5.49 years for the HD and comparison groups, respectively. The incidence rate of herpes zoster was 73.34 events per 1,000 person-years in the HD group, which was significantly greater

than that of the 31.03 events/1,000 person-years in the comparison group, the investigators reported online ahead of print in the American Journal of Kidney Diseases. After adjusting for confounders, herpes zoster was twice as likely to develop in the HD patients than the comparison group. ■

10 Renal & Urology News

MARCH 2012

Proton Beam continued from page 1

“Today, proton radiation is receiving a lot of attention as a new way to treat prostate cancer and it is the most expensive radiation technique to date,” Dr. Chen said. The number of proton radiation centers has been increasing rapidly in the United States despite no evidence of proton therapy superiority over IMRT, he added. The study also showed that IMRT is superior to conformal radiation therapy (CRT) in terms of adverse effects and cancer control.

Less bowel morbidity with IMRT “To compare treatment-related toxicities and cancer control among the three radiotherapy modalities, the researchers analyzed data from the Surveillance, Epidemiology, and End Results (SEER)Medicare linked database for patients with non-metastatic PCa. Using prospensity-score analysis to adjust for patient characteristics, the researchers found that IMRT patients had a 34% decreased risk for bowel morbidity than

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patients who underwent proton therapy. The study revealed no significant difference in the need for additional cancer treatment, which the investigators used as a surrogate for cancer recurrence. In a propensity-score adjusted analysis, IMRT patients had a significant 9% decreased risk of bowel morbidity and a 22% decreased risk of hip fractures compared with CRT patients, Dr. Chen said. IMRT, however, was associated with a significant 12% increased risk of erectile dysfunction (ED). IMRT patients had a significant 19% decreased risk of receiving additional cancer treatments. Dr. Chen concluded that the study “supports the use of IMRT as the current standard radiation technique for prostate cancer.” He also stated that,“IMRT causes fewer side effects and achieves better cancer control compared to the older conformal radiation technique. Currently, there is no clear evidence that proton therapy is better than IMRT.” Additionally, Dr. Chen noted that more comparative effectiveness studies are needed to directly compare patient outcomes of proton therapy versus IMRT.

Prostate Cancer Treatment Costs A study found that brachytherapy is the least costly of the common treatments for prostate cancer. The average cost per patient per year by treatment modality is shown here. Brachytherapy

EBRT

Open Prostatectomy

$2,557

$6,412

$3,205

Source: Ciezki JC et al. Long-term toxicity and associated cost of initial treatment and subsequent toxicity-related intervention for patients treated with prostatectomy, external beam radiotherapy, or brachytherapy: A SEER/Medicare database study. Data presented at the 2012 Genitourinary Cancers Symposium in San Francisco. Abstract 4.

Radium Drug continued from page 1

radium-223 group versus 8.4 months in the placebo arm, a 39% reduction in SRE risk. Radium-223 significantly reduced time to three of four SRE components: time to first use of external beam radiotherapy to relieve skeletal symptoms; time to first spinal cord compression; and time to first symptomatic pathologic bone fracture. With respect to adverse events (AEs), grade 3 or 4 neutropenia was observed in only 2% of patients in the radium-223 arm and 1% of placebo recipients. Grade 3 or 4 thrombocytopenia was observed in 4% and 2% of these groups, respectively. Sixty-eight patients (13%) in the radium-223 arm and 51 (20%) in the placebo group dropped out of the study because of AEs. Leonard G. Gomella, MD, a prostate cancer specialist who headed the

symposium’s program committee and is Chair of the Department of Urology at Thomas Jefferson University’s Kimmel Cancer Center in Philadelphia, said the new agent “is a big deal in prostate cancer and probably will be a big deal in other cancers that tend to go to the bone.” Existing radiation-based treatments that target bone are so-called beta emitters, Dr. Gomella said. Although these agents helped to control pain and limit fractures, they were very toxic to bone marrow. “What is very exciting and very important about radium-223 is that it’s an alpha emitter, so it does not have the same effect on the bone marrow that some of these earlier radiationbased treatments have on the bone,” Dr. Gomella told Renal & Urology News. “So this is going to be a very important step forward not only for the potential for the survival, as we saw in the study, but also from the potential quality of life in controlling SRE.” ■

Jay P. Ciezki, MD

In the other study, Dr. Ciezki’s team used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify patients aged 65 years and older treated for PCa from 1991 to 2007. Of 137,427 patients identified, 60,806 (44.2%) received EBRT, 59,559 (43.3%) underwent RP, and 17,062 (12.4%) were treated with brachytherapy.

Brachytherapy the safest GI toxicity occurred in 1.7%, 0.1%, and 0.3% of patients treated with EBRT, RP, and brachytherapy, respectively, after a median follow-up of 71 months. Genitourinary toxicity occurred in 7.1%, 6.7%, and 3.4% of these groups, respectively. Within treatment modalities, the percentages receiving toxicity-related intervention were 8.8% for EBRT, 6.9% for RP, and 3.7% for brachytherapy. The average cost per patient per year was $2,557 for brachytherapy, $6,412

CKD Incidence Higher continued from page 1

the community-based Coronary Artery Risk Development in Young Adults (CARDIA) study. The study population included 4,119 subjects aged 18-30 years with an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m2 or higher. The researchers, led by Paul Munter, PhD, of the University of Alabama in Birmingham, defined development of CKD as a decrease in eGFR to below 60 and a 25% or greater decline in eGFR at study visits conducted 10, 15, and 20 years after baseline. Forty-three CKD cases developed during follow-up: 29 (1.4%) among African Americans and 14 (0.7%) among whites, a significant difference between the races. After adjusting for age, gender, body mass index, systolic blood pressure, fasting plasma glucose, and high-density lipoprotein cholesterol, researchers found that CKD was 2.5 times more likely to

for EBRT, and $3,205 for open prostatectomy, investigators found. Prostate cancer specialist Leonard G. Gomella, MD, who headed the symposium’s program committee, noted that “many times, there’s an assumption that the newest or perhaps the most expensive modalities that we have to offer are the best for our patients. These two studies suggest from a side effect standpoint that the more expensive technologies, be they proton therapy or external beam radiation therapy, may in fact be associated with a higher risk of side effects.”

Treat patients as individuals Dr. Gomella, who is Chair of the Department of Urology at Thomas Jefferson University’s Kimmel Cancer Center in Philadelphia, stressed that “at the end of the day we really need to look at each patient as an individual and pick for that individual patient what may be the best for them looking at both cancer control and quality of life.” Although brachytherapy turned out to be the lowest cost option in the study by Dr. Ciezki and colleagues, men who might choose this treatment may not be a good candidate for it, Dr. Gomella observed. For example, brachytherapy probably is not good for men who have a lot of urinary symptoms. “If they choose brachytherapy, those symptoms may actually get much worse. So we have to be very careful in that we can’t paint a broad brush stroke here on all of the competing treatment options for prostate cancer.” ■

develop in African Americans than in whites, Dr. Munter’s group reported. In a multivariable analysis that accounted for albuminuria at year 10, however, CKD was only 12% more likely to develop in African Americans than in whites at year 15 or 20. At the year 10 visit, the geometric mean albuminuria level was 8.2 mg/g among African Americans compared with 6.6 mg/g among whites. It is well established that African Americans have a higher incidence of end-stage renal disease than whites, the researchers noted. Recent data from the U.S. Renal Data System shows that ESRD is four times more likely to develop in African Americans than in whites, they pointed out. It is possible that African Americans have more severe kidney disease that progresses more rapidly to ESRD. It is noteworthy that six of the seven participants with ESRD in their study were African American, researchers stated. ■

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MARCH 2012

Renal & Urology News 11

Not All ESRD Patients May Want Dialysis BY ROSEMARY FREI, MSc SOME INDIVIDUALS with end-stage renal disease (ESRD) are willing to give up a few months of life rather than live with the logistical difficulties that can be associated with dialysis, according to a survey. The survey findings, which were published online in the Canadian Medical Association Journal, showed that patients would be willing to forgo seven months of life expectancy in exchange for having fewer hospital visits for dialysis and forgo 15 months of life expectancy so they could travel more. It is the first study of its kind to examine the choices pre-dialysis patients make between dialysis and no dialysis. “Our research has shown that patients are particularly interested in knowing their expected survival, the number of visits to a dialysis facility that they would have to make, the resultant restrictions on their ability to travel for work or vacation, and the time of day dialysis can be performed,” noted lead investigator Rachael Morton, PhD, of the Sydney School of Public Health at the University of Sydney in Australia. “In addition, patients have the right to know that a pathway of care is available should they choose not to initiate dialysis.”

The survey was completed by 105 subjects, all of whom had stage 3-5 chronic kidney disease. Their average age was 63 years, 56% were men, and 44% had private health insurance. The study is what is known as a discrete choice experiment in which participants are asked to choose between several hypothetical scenarios. The participants were presented with 12 choice sets (scenarios) involving tradeoffs between life expectancy, number of visits to hospital per week for dialysis, travel restrictions, number of hours on treatment and whether subsidized transportation was available for hospital visits. The alternative to dialysis was presented as supportive non-dialysis medical management. The patients chose dialysis as their preferred option 90% of the time. Six patients chose conservative care with every scenario. Some of the reasons the patients gave, when filling in the optional comments section at the end of the survey, were—in this case, from a 67-year-old man—“I think dialysis would be very restrictive to my quality of life. I am very active in my community and also love to travel and head bush whenever I like. At the moment I have a very unrestrictive lifestyle and want to keep it that way.” As the investigators expected, higher

For some, freedom from the hassles of treatment is worth a shorter life expectancy, study finds

Patients have a right to know dialysis is not the only option, according to researchers.

average estimated life expectancy was associated with an 84% greater likelihood that the patients would choose dialysis. Subjects were nearly nine times as likely to opt for dialysis if it was available during the day or evening, versus only during the day or overnight and 55% more likely if subsidized transportation was available. The researchers also used the survey responses to calculate the tradeoffs between life expectancy and other characteristics. They found patients were willing to forgo seven months of life expectancy in exchange for reducing the number of hospital visits for dialysis from four to three. They were willing to forgo 15 months of

life expectancy to decrease their travel restrictions by one level, for example, from “very restricted” to “somewhat restricted.” The investigators concluded that dialysis should not be the presumed treatment for all patients approaching ESRD. “We acknowledge that instigating such conversations [about non-dialysis options] with patients and their families may be difficult. However, further support is available for nephrologists through the ‘shared decision making’ clinical practice guideline (2010) issued by the Renal Physicians Association,” said Dr. Morton, referring to the Rockville, Md.-based organization. ■

Cryotherapy Is An Option for Small Renal Masses BY NAYANAH SIVA LONDON—Cryotherapy can be used to treat small renal tumors or masses successfully with relatively low rates of complications and recurrence, a urologist skilled in the technique told attendees at the Renal and Bladder Cancer 3rd National conference here. Neil Barber, FRCS, Consultant Urological Surgeon at Frimley Park Hospital, Surrey, UK, spoke about his experience with cryotherapy for renal cancer. Since 2008, he has used this modality to treat 52 patients, 75% of whom had a small malignant mass (4 cm or less). Patients had an average age of 70 years. The typical procedure time was two hours and 20 minutes and no blood transfusions were required. The average hospital stay was one night. Three patients experienced complications: two patients had bleeding, which

was managed conservatively, and one had a ureteric injury. With the incidence of small renal masses (2-4 cm) rising in both men and women, particularly in elderly patients, Dr. Barber said he believes treatment

It is associated with low rates of complications and recurrence. options other than surveillance could reasonably be considered when managing this group of patients. “Surveillence is the talk of the town [at the moment] when we talk about how to manage small renal masses, and there is increasing evidence that surveil-

lance is a safe option although there are no randomised trials to confirm this.” Data have shown that most of these tumors grow very slowly. Dr. Barber cited data from the Surveillance, Epidemiology, and End Results (SEER) database showing that up to 75% of patients with small renal masses had malignant small renal masses. Of those that were malignant, about 55% had low-grade malignancy. However, up to 20% of patients had high-grade tumors, with some smaller tumors were already metastatic at presentation. Treatment options for small renal tumors or masses include nephronsparing surgery or partial nephrectomy, but these, too, are not without their complications, Dr. Barber said. Dr. Barber’s cryotherapy involves freezing and thawing the renal mass.

By using hollow needles, he uses argon to freeze the mass. Ice crystals form inside and outside of cells as well as in the surrounding blood supply. During the thawing stage, helium is placed into the mass. Extracellular fluid re-enters cells, further damaging the mass and causing necrosis in the entire tumor. Overfreezing can be an issue, and there may be complications with bleeding, he noted. The overall complication rate is 9.4%, but this appears to be less than with radiofrequency ablation. Dr. Barber said he thinks cryotherapy is an important option for patients, particularly elderly patients who have a high incidence of small renal tumors. Cryotherapy is minimally invasive and is associated with rapid hospital discharge, and low complication rates, he said. In addition, it is not very technically demanding for surgeons. ■

12 Renal & Urology News

MARCH 2012

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■ 2012 Genitourinary Cancers Symposium, San Francisco

No Change in PSA Testing for Men 75+ The articles on these pages report on studies presented at the 2012 Genitourinary Cancers Symposium in San Francisco, which was sponsored by the American Society of Clinical Oncology, the American Society of Radiation Oncology, and the Society of Urologic Oncology. Renal & Urology News editor Jody A. Charnow provided news coverage.

PROSTATE CANCER screening using PSA tests has not declined among men aged 75 years and older despite a 2008 U.S. Preventive Services Task Force (USPSTF) recommendation against such screening in this age group. Using data from the 2005 and 2010 National Health Interview Survey, a cross-sectional household survey providing a representative sample of the U.S. population, investigators found that PSA tests were ordered for 40.6% of men aged 75 years and older in 2010 compared with 40.4% in 2005. In addition, the study, led by Michael W. Drazer, a fourth-year medical student at the University of Chicago, found that PSA testing in 2010 was significantly more common in men aged 75 and older than in men aged 40 to 49

(9.2%) and 50-59 (26.2%). “Despite the USPSTF recommendation against prostate cancer screening in men aged 75 or older, there was no decrease in PSA testing rates in these men,” the researchers concluded in a poster presentation. “A significant proportion of elderly men continue to receive PSA screening despite a very low likelihood of benefit.” Speculating as to why PSA testing has not waned for men aged 75 and older, Drazer said physicians may believe “the controversy hasn’t really been resolved yet” regarding the value of PSA testing in elderly men. “They’re more likely to err on the side of caution,” Drazer added. He observed that sometimes men want to continue with their screening past age 75. Commenting on the study’s findings, Leonard G. Gomella, MD, chairman of the symposium’s program committee, said the task force chose 75 years as the cutoff because that is when the average man in the United States reaches his 10-year life expectancy. Caution should be exercised, however, in making broad determinations about men who have 10-year life expectancies, said Dr. Gomella, chairman of the Department of Urology and Associate Director of the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia.

PSA Testing in the Very Old PSA testing remained unchanged among men aged 75 and older despite recommendations against such screening from the U.S. Preventive Services Task Force, a study found. Shown here are the testing rates by age group for 2005 compared with 2010.

50 43.9%

46.7%

2005

40.4% 40.6%

27.8%

2010

26.2%

20 9.8%

10 0

75+

60-74

50-59

9.2%

40-49

Source: Drazer MW et al. Impact of U.S. Preventive Services Task Force recommendation on screening for prostate cancer in men aged 75 or older. Data presented at the 2012 Genitourinary Cancers Symposium in San Francisco. Abstract 216.

“They’re not all the same,” Dr. Gomella said. “Older men do die from aggressive prostate cancer. While we can’t say that screening will eliminate the risk of death in these men, certainly to ignore the men in that older age group who may ultimately suffer from prostate cancer at this point in time seems a little bit premature. Having said that, the 10-year life expectancy and looking at patients’ overall health is very important in deciding when you stop screening.”

He pointed out that the life expectancy of men in the United States is going up dramatically in part because improvements in cardiovascular care have reduced their risk of dying from heart attacks and strokes. Dr. Gomella said he thinks that in the next couple of years PSA screening will used more thoughtfully and providers and patients will be engaged in more dialogue in deciding whether screening is the right thing to do given a patient’s age and health status. ■

PCa-Related Deaths Uncommon Post-Treatment ELDERLY MEN who receive definitive local treatment for prostate cancer (PCa) are much more likely to die from causes other than their cancer, a finding that could inform doctor-patient discussions about treatment for localized PCa, according to researchers. Investigators who studied 4,237 men aged 65 years or older who were treated with radical prostatectomy (1,634 men), external beam radiotherapy (1,570 men), or brachytherapy (1,033 men) found that the risk of PCa-specific mortality (PCSM) compared with competing causes of mortality (CCM) is low, especially for patients with moderateto-severe comorbidity. “Even if you had high-risk prostate cancer and no comorbidities, you were

still much more likely to die of other causes than you were from prostate cancer,” observed investigator Joseph C. Klink, MD, a urologic oncology fel-

Patients are much more likely to die from causes other than prostate cancer. low at Cleveland Clinic, who presented study findings. Over a median follow-up of 72 months, investigators observed 88 and 748 PCSM and CCM events, respectively. Among healthy men with low-

risk PCa, 10-year PCSM was 2% and CCM was 19%. Among healthy men with high-risk PCa, PCSM was 11% and CCM was 27%. In a group of patients with moderate-to-severe comorbidities, PCSM was 1%, 3%, and 21% for men with low-, intermediate-, and high-risk PCa, respectively, whereas CCM was 49%, 59%, and 58%, respectively. The investigators noted that current evidence suggests that local treatment for PCa is associated with a 25% reduction in PCSM at best. Therefore, they observed, with active surveillance, it is unlikely that PCSM would exceed 5%-7% in patients with low- and intermediate-risk PCa. The study by Dr. Klink and colleagues is not the first to show that men treated

for localized PCa are more likely to die from non-PCa causes than from their cancer. In a study of 120,392 men who underwent radical prostatectomy for localized PCa, Sergey Shikanov, MD, and colleagues at the University of Chicago showed that 15-year PCaspecific mortality was 5.3% and the 15-year non-PCa mortality was 30.6%, according to recent report published online ahead of print in Prostate Cancer and Prostatic Diseases. In addition, 15 years after surgery, mortality related to cardiovascular disease was 11%, other cancers, 9.1%, and other causes, 10.5%. Among men aged 65 years and older, 15-year PCSM was 6% and 15-year non-PCa mortality was 40.8%. ■

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MARCH 2012

Renal & Urology News 13

■ 2012 Genitourinary Cancers Symposium, San Francisco

HEAVY ALCOHOL use is associated with an increased risk of prostate cancer (PCa) among low-risk men with at least one prior negative prostate biopsy, according to researchers. It also is associated with an elevated risk for highgrade PCa. The findings emerged from a study of data from 6,729 men who had at least one on-study biopsy while participating in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial. Of these, 49% were moderate drinkers and 26% were heavy drinkers. The researchers, led by Lionel L. Bañez, MD, of Duke University Medical Center in Durham, N.C., found that as ethanol intake increased, so did the risk

for PCa overall and for high-grade disease. Dutasteride decreased overall PCa risk significantly by 27% and alcohol did not interfere with the protective effect of dutasteride. Compared with non-drinkers, heavy drinkers had a 21% greater risk of PCa overall and a 34% greater risk of high-grade PCa (Gleason score of 7 or higher). For the study, the investigators defined alcohol intake in terms of units (half pint of beer, glass of wine, for example). They classified subjects as nondrinkers, moderate drinkers (seven units or less per week), and heavy drinkers (more than seven units per week). The study is not the first to find a link between alcohol

Prostate Cancer Linked to Heavy Alcohol Use

Drinking too much may hike PCa risk.

use and prostate cancer risk. In a prospective study published recently in the American Journal of Epidemiology (2011;174:1044-1053), researchers found that higher-frequency drinking (three or

Possible First Drug Therapy for AML EVEROLIMUS IS the first potential pharmacologic treatment option for patients with angiomyolipoma (AML), a benign tumor that usually occurs in the kidney. John J. Bissler, MD, of the Cincinnati Children’s Hospital Medical Center, and colleagues conducted a prospective, double-blind study of 118 patients with AML randomized to receive everolimus 10 mg daily (79 patients) or placebo (39 patients). The study population included patients who had tuberous sclerosis complex or lymphangioleiomyomatosis. The

primary efficacy endpoint was the proportion of patients with an AML response, defined as a 50% or greater reduction in the sum of volumes of all target AML relative to baseline. The mean duration of treatment 38.1 weeks for the everolimus group and 34 weeks fo the placebo group. Results showed that 41.8% of everolimustreated patients had an AML response compared with none of the placebo recipients. Additionally, the mean time to AML progression was 11.4 months for placebo and was not reached in the everolimus group. Everolimus-treated

subjects also had significantly higher best overall skin lesion response rate (complete or partial response) than placebo (26% vs. 0%), according to the investigators. The drug was associated with an acceptable safety profile consistent with previous reports in tuberous sclerosis complex. Most adverse effects (AEs) were grade 1 or 2. The incidence of AEs was similar in both groups. Angiomyolipomas rarely cause symptoms, but they can bleed or grow large enough to cause pain or renal failure, the study noted. ■

more days per week compared with less than one day per week) was associated with a significant 55% increased risk of prostate cancer. In another prospective study published in the same journal (2010;172:773-780), researchers who studied 294,707 U.S. men found that those who consumed six or more drinks per day had a 25% higher risk of nonadvanced PCa than nondrinkers. The authors observed no association between alcohol intake and advanced prostate cancer among heavy drinkers. However, based on a meta-analysis published online in the European Journal of Cancer Prevention, researchers concluded that there is no evidence of a material association between alcohol drinking and prostate cancer, even at high doses. The meta-analysis considered data from 50 case-control and 22 cohort studies that included a total of 52,899 PCa cases. ■

Metastatic PCa Often Goes Untreated MANY PATIENTS with metastatic prostate cancer (PCa) never receive anticancer treatment. “This is an important observation because these patients are basically falling through the cracks,” said Alexander C. Small, a fourth-year medical student at Mount Sinai School of Medicine in New York, one of the investigators. The National Cancer Database was used to identify patients diagnosed with stage IV PCa between 2000 and 2008. Of 1,201,732 patients with

Empiric Antibiotic Use May Be Unjustified NEW FINDINGS challenge the widespread practice of placing men on an empiric course of antibiotics for a newly elevated PSA level. Scott E. Eggener, MD, of the University of Chicago, and colleagues studied 77 men with a newly elevated PSA level. Of these, 38 were randomized to receive ciprofloxacin 500 mg twice daily for two weeks or no antibiotic (control group). PSA was measured 21-45 days following randomization and immediately prior to prostate biopsy.

Prostate biopsy revealed prostate cancer in 36 men (47%). Detection rates did not differ significantly between patients with an increasing PSA or decreasing PSA between the two measurements, said Michael Christopher Large, MD, a urologic oncology fellow at the University of Chicago, who presented study findings. Mean PSA levels at randomization into the study were 7.6 ng/mL in the antibiotic group and 6.5 ng/mL in the control arm. The mean PSA lev-

els at biopsy were 8.5 and 6.9 ng/mL, respectively. In the antibiotic group, cancer was found after a PSA increase in seven (44%) of 16 patients after a PSA decrease in five (24%) of 21 patients. In the control arm, cancer was found after a PSA increase in 12 (60%) of 20 patients and after a PSA decrease in 11 (58%) of 19 patients. “Prescription of empiric antibiotics in asymptomatic men with elevated PSA is not of any clinical benefit,” Dr. Large said. ■

PCa diagnosed during this period, 59,074 (4.8%) had metastatic disease. Among these, 6,582 (11.1%) received no anticancer treatment. With each 10year increment in age, the prevalence of untreated metastatic PCa increased by 43%. Blacks and Hispanics were, respectively, 32% and 41% more likely than whites to have untreated metastatic PCa. Medicaid patients, Medicare patients, and uninsured patients were, respectively, 57%, 82%, and 96% more likely to be untreated compared with privately insured patients. ■

18 Renal & Urology News

MARCH 2012

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Renal Nutrition Update H

ow important is it for the average person to limit salt? Worldwide, more than one billion adults have hypertension, and, in 17%-30% of cases, the hypertension is related to excess dietary intake of salt. Historically, salt has been a commodity, a preservative, and a flavor enhancer. The salt shaker has a special place in most kitchens or dining room tables. Therefore, when dietitians or other health-care providers suggest to patients that they should reduce or limit salt intake to lower blood pressure (BP) and prevent fluid retention, they are often very resistant. However, it is not just patient resistance that makes salt reduction difficult. Salt, or sodium chloride, is used by food manufacturers in all types of food products. This means that much of the sodium patients consume comes from processed or restaurant food items. In fact, 77% of sodium intake is from processed foods in most developed countries (J Am Coll Nutr 1991;10:383-393). Through these food items, Americans may consume double the recommended intake of sodium, potentially contributing to more than 7.6 million premature deaths and billions of dollars in health care costs (CMAJ 2009;181:605-609). It has been well documented that salt-sensitive patients benefit from a reduction in sodium, but in patients who are not salt sensitive, one may question whether reductions in salt or sodium should be recommended for hypertension. A 2011 meta-analysis found that reductions in salt intake result in decreased

urinary sodium excretion and decreased systolic BP in normotensive individuals and those with hypertension or heart failure. This reduction in urinary sodium excretion and BP did not appear to translate into decreased cardiovascular or all-cause mortality (Am J Hypertens 2011;24:843-853). A limitation of this meta-analysis was the lack of end points; therefore, while large effects could be detected, small or moderate effects may not be found. It is these small effects, which over a lifetime, may cumulatively impact quality of life, mortality, and health care costs for a nation. In fact, Frohlich and Susic (Circulation 2011;124:1882-1885) suggest that more attention needs to be paid to the “subtle adverse end points of dietary salt excess.” Within this review, the authors outline the organs impacted by excessive salt intake (heart, arteries, and kidneys) and highlight experimental studies conducted in animal models demonstrating that salt loading results in local pathophysiological changes. Years of continuous excessive salt consumption may lead to elevated BP and multi-organ structural and functional damage. Due to this potential organ damage and subsequent impact on health care costs and mortality, communities and countries have begun instituting public policy regarding salt reductions. It has been estimated that a “population-wide decrease of 2 mm Hg diastolic blood pressure could lower the prevalence of hypertension by 17%, coronary artery disease by 6%, and the risk of stroke by 15%” (CMAJ 2009;181:605-609).

Salt Intake in the U.S. • The 2010 Dietary Guidelines for Americans recommend limiting sodium intake to 1,500 mg per day for individuals aged 51 year or older. • Most Americans consume more than twice the recommended sodium limit each day. • 77% of an individual’s salt intake comes from restaurant or processed food; only 6% is added to food at the table and 5% during cooking. Sources: Mattes RD, Donnelly D. Relative contributions of dietary sodium sources. J Am Coll Nutr 1991;10:383–93 and the Centers for Disease Control and Prevention.

Health care workers should promote dietary salt reduction, an inexpensive, practical way to impact health BY ALISON L. STEIBER, PhD, RD, LD

Sodium in American diets comes mainly from restaurant food and from the large amount of processed foods we eat. A recent analysis by Asaria et al (Lancet 2007; 370:2044-2053) demonstrated that 8.5 million deaths worldwide could be avoided (2006-2015) with public policies directed at reducing salt intake. It has been suggested, and exemplified by Finland, that for a populationbased sodium reduction to occur there must be a partnership formed with the food industry. Finland began to have a countrywide sodium reduction in the 1970’s that resulted in a 40% decrease in sodium intake and a 70% reduction in mortality from stroke and coronary artery disease (Prog Cardiovasc Dis 2006;49:5975). Other countries such as the United Kingdom, France, and Canada have begun similar programs. In the new Affordable Care Act, a key indicator of the National Prevention Strategy is to reduce the average daily sodium intake in the United States population from the current 3,641 mg to 2,300 mg within 10 years. This goal is in line with the Institute of Medicine, which set the “upper tolerable intake”

for adults at 2,300 mg, the World Health Organization goal of 2000 mg or less daily, and the United Kingdom goal of 2,400 mg daily. As health care providers we must work with our patients to identify foods (both processed and fresh) that are lower in sodium; support food manufacturers that lower sodium without raising other potentially harmful additives (potassium or phosphorus); and advocate for government controlled food labeling that gives clear and accurate nutrient information. Lowering salt is an inexpensive, practical way to have a major impact on population health, mortality and overall health care costs. It behooves the health care community to stand up and loudly applaud this initiative within the Affordable Care Act, but even more so to engage in activities which will ensure its success. ■ Dr. Steiber is Coordinator of the Dietetic Internship/Master’s Degree Program at Case Western Reserve University in Cleveland.

22 Renal & Urology News

MARCH 2012

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ED Highly Prevalent Among Men on Hemodialysis MOST MEN ON hemodialysis (HD) have erectile dysfunction (ED) and do not receive treatment for the condition, a multinational study found. Of 946 male HD patients who provided complete data on ED, 83% reported ED and 47% reported severe ED, according to a report published Brief 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.

online ahead of print in Nephrology Dialysis Transplantation. The prevalence of ED was highest among unmarried men (94%). Compared with unmarried men, married men had a 51% lower risk of ED. Each one-year increment in age was associated with a 6% and 10% increased risk of ED Entry 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.

and severe ED, respectively, according to the researchers. The strongest predictor of ED was depressive symptoms. ED was 2.4 times more likely to occur in men with depressive symptoms than in those without these symptoms. Additionally, compared with employed men, those anticancer 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 a Table 1. Per-patient Incidence of Selected 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, s 0 ERSISTENT PAIN OR SLOW HEALING OF THE MOUTH OR JAW AFTER DENTAL SURGERY (see less than 1% (7/2758) of patients with osseous metastases treated with 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.

receiving a pension or who were unemployed had a 2.0 and 1.8 times increased risk of ED, respectively. The study also revealed that only 3% of those with ED and 2% of those with severe ED reported receiving pharmacologic treatment. â&#x20AC;&#x153;The reasons behind such a lower intervention rate are that we still have suboptimal evidence about the benefits and harms of drugs used to treat ED in people on hemodialysis, there is low awareness from treating clinicians, patient embarrassment and the importance of symptoms relative to the patientsâ&#x20AC;&#x2122; overall health concerns,â&#x20AC;? said lead investigator Prof. Giovanni F. M. Strippoli, MD, PhD, Senior Vice President Scientific Affairs of Diaverum AB, a provider of renal services. The researchers observed that the ED prevalence in men on HD is markedly higher than that of the general population, in which 10%-40% of

Erectile dysfunction was most strongly associated with depressive symptoms. men report one or more features of sexual dysfunction. The authors proposed that men receiving HD should be routinely asked about ED using existing and easily accessible validated instruments. Dr. Strippoli and his colleagues reported that they were not able to confirm previous observations that anemia, hypertension, or dyslipidemia were associated with ED risk. They noted that their study of ED in HD patients is the largest of its kind to date and included men from several HD centers and countries, â&#x20AC;&#x153;facilitating our ability to identify the key correlates of erectile dysfunction by adjusting for important confounding variables that have not previously been accounted for, particularly depressive symptoms.â&#x20AC;? Of particular importance, the researchers noted, they collected data on ED and depression using validated instruments. The researchers evaluated ED using the erectile function domain of the International Index of Erectile Function questionnaire and evaluated depressive symptoms using the Center for Epidemiological StudiesDepression Scale. â&#x2013;

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On the Forefront

MARCH 2012

Renal & Urology News 23

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

Resistant Hypertension Secondary to Primary Aldosteronism BY JIWAN K. THAPA, MD, GEORGE THOMAS, MD, ROBERT STEIN, MD, AND EMMANUEL L. BRAVO, MD

43-year-old man was evaluated for uncontrolled hypertension (HTN) despite multiple drug therapy, which included amlodipine 10 mg daily, clonidine 0.3 mg BID, and metoprolol XL 200 mg BID. He had several episodes of hypokalemia (2.73.0 mmol/L) over the years that persisted despite oral potassium supplementation and discontinuing diuretics. On examination, he had elevated blood pressure (BP) in both arms (160/110 mm Hg) with a heart rate of 60 beats/minute. Physical examination was otherwise unremarkable. His laboratory tests showed serum potassium (K) of 2.8 mmol/L, serum bicarbonate of 33 mmol/L, and serum creatinine of 1.48 mg/dL with estimated GFR of 55 mL/min/1.73 m2.

Plasma aldosterone (PAC) was 33 ng/dL and plasma renin activity (PRA) was less than 0.1 µg/L/hour. A 24-hour urine collection with salt loading showed urinary potassium wasting (60 mmol) and high aldosterone excretion (42 µg). An adrenal computed tomography scan revealed a low-density 1.5 × 1.2 cm nodule in the left adrenal gland (Figure 1). He was started on eplerenone 100 mg BID, which controlled his BP (123/78 mm Hg on sitting and 122/70 mm Hg on standing). Serum K normalized (4.0 mmol/L) without need for supplementation. The patient wished to undergo surgery. Adrenal venous sampling showed lateralization to the left (See table). Surgical pathology after laparoscopic unilateral left adrenalectomy confirmed the diagnosis of adrenocortical adenoma. Eplerenone was stopped post-operatively. Plasma aldosterone

Aldosterone Versus Cortisol Levels Aldosterone ng/dL

Cortisol ug/dL

A/C ratio

Left Adrenal

15,230

545

27.9

Right Adrenal

426.3

615

0.69

Low IVC

64.6

16.5

3.9

Left adrenal vein A/C ratio divided by Right adrenal vein A/C ratio (value >4 indicates lateralization to left adrenal) Right adrenal vein A/C ratio divided by low Inferior Vena Cava (IVC) A/C ratio (value <1.0 indicates suppression of aldosterone secretion from the right adrenal)

decreased to 3.3 ng/dL with a PRA of 0.8 µg/L/hour. Over the next year, his serum potassium remained normal (4.0-5.0 mmol/L) without supplementation and his BP was well-controlled (below 120/80 mm Hg) on amlodipine 10 mg alone.

Discussion Resistant HTN is defined as persistent elevation of BP above goal in spite of concurrent use of three anti-hypertensive agents, each of unique class, including a diuretic, with all drugs at maximally tolerated doses. HTN that is controlled with the use of four or more medications is also considered resistant to treatment. It is so defined to identify patients who are more likely to have reversible causes of HTN. Consultation with a HTN specialist should be considered if goal BP cannot be achieved. Evaluation for secondary causes should be done in patients with resistant HTN, and a high suspicion of primary aldosteronism (1°A) should be entertained in patients with the following clinical history: 1) spontaneous or unprovoked hypokalemia with renal potassium wasting, 2) severe diureticinduced hypokalemia (potassium 3.0 mEq/L or less), which does not normal-

Figure 1. CT scan showing left adrenal adenoma

ize after discontinuation of diuretics for at least four weeks and is unresponsive to angiotensin blockers, 3) hypertension with adrenal adenoma, and 4) family history of 1°A. ■ The authors are affiliated with the Cleveland Clinic’s Glickman Urological and Kidney Institute REFERENCES 1. Bravo EL. Primary aldosteronism. Issues in diagnosis and management. Endocrinol Metab Clin North Am. 1994;23:271-283. Review. 2. Thomas G, Bravo EL. Outpatient evaluation of secondary causes of resistant hypertension. US Cardiology 2011;8:102–107. Review 3. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008;51:1403-1419.

Unusual Manifestation of an Aldosterone-Producing Adenoma BY SURAFEL GEBRESELASSIE, MD, EMMANUEL BRAVO, MD, AND JIHAD KAOUK, MD

rimary aldosteronism was first described by Jerome Conn in 1955 in a patient with an aldosteroneproducing adrenal adenoma. It’s now a widely recognized cause of secondary hypertension. The following case illustrates the challenges of making clinical diagnosis of aldosterone producing adrenal adenoma. A middle-aged woman with medullary sponge kidney and nephrocalcinosis was first diagnosed with adrenal mass on a computed tomography scan performed for kidney stone evaluation about 10 years previously (Figure 2). She had normal

serum potassium and serum bicarbonate levels. Subsequently, she was found to have elevated blood pressure and was referred to the Department of Nephrology and Hypertension for further evaluation. Her serum aldosterone level was 475.5 ng/dL. Despite achieving 290 mmol/day of urinary sodium, she had no kaliuresis following an oral salt loading test. The urinary aldosterone level was 231 µg/day. After further discussion with colleagues in the Department of Urology, the patient successfully underwent robotic-assisted laparascopic adrenalectomy. She became normotensive requiring no further antihypertensive medication. Aldosterone is a potent mineralocorticoid secreted by the zona glomerulosa

of the adrenal cortex. Unlike cortisol, which is inactivated to cortisone by 11-β hydroxysteroid dehydrogenase, aldosterone avidly binds to the mineralocorticoid receptor in the distal nephrone leading to sodium retention resulting in anti-natri-

Figure 2. Adrenal CT showing left adrenal adenoma and bilateral nephrocalcinosis.

uresis, volume expansion, hypertension, metabolic alkalosis and renal potassium wasting. The patient had a very high levels of circulating serum aldosterone (475.5 ng/dL) but did not present with hypokalemia or metabolic alkalosis, and did not have resistant hypertension, which delayed the diagnosis of aldosterone-producing adenoma. We thought that the renal tubular disease resulting from nephrocalcinosis caused the distal tubule to be resistant to the action of aldosterone even in the presence of high distal sodium delivery and high aldosterone levels. ■ The authors are affiliated with the Cleveland Clinic’s Glickman Urological and Kidney Institute

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Rituximab Ineffective as an LN Add-On Used with MMF and corticosteriods, the drug did not boost partial renal response rates BY ROSEMARY FREI, MSc ADDING RITUXIMAB to mycophenolate mofetil (MMF) and corticosteroids does not improve outcomes in patients with lupus nephritis (LN), data show. As part of the Lupus Nephritis Assessment with Rituximab (LUNAR) trial, American and Mexican investigators led by Brad H. Rovin, MD, Director of Nephrology at the Ohio State College of Medicine in Columbus, Ohio, studied 144 patients (aged 16-75 years) with class III or IV LN who were taking MMF and corticosteroids. They randomized 72 subjects to receive add-on therapy with 1000 mg rituximab on days 1, 15, 168, and 182, and 72 to receive placebo on the same schedule. Rituximab treatment was not associated with a higher rate of complete or partial renal responses at the end of the study, with a 56.9% rate compared to 45.8% for placebo, the researchers reported online ahead of print in Arthritis & Rheumatism. “At this time, we cannot recommend the addition of rituximab to MMF for

ED Linked to Atopic Dermatitis MEN WITH ERECTILE dysfunction (ED) are more likely to have had prior atopic dermatitis than men without ED, according to study findings published online in the Journal of Sexual Medicine. Investigators led by Herng-Ching Lin, PhD, of Taipei Medical University in Taiwan, compared 3,997 men with

the initial therapy of proliferative lupus nephritis,” Dr. Rovin concluded. “We suspect that there are patients who may benefit from rituximab, but we still need to develop methods to identify who they are.” LN can occur in up to 50% of patients with systemic lupus erythematosus and is not associated with a good prognosis. Furthermore, standard proliferative treatment of LN achieves renal response rates of only 50%-80%, and many patients achieve partial rather than full remission. Because B cells have been shown to play a key role in LN, and because rituximab depletes CD20-positive B cells while sparing stem cells and plasma cells, Dr. Rovin’s team opted to study rituximab as addon LN therapy.

Brad H. Rovin, MD

Treatment protocol MMF was first given at 1.5 g/day in three divided doses and increased, as tolerated, to 3 g/day by week 4 and continued until at least week 52. In addition, patients received oral prednisone 0.75 mg/kg/day up to a maxi-

mum of 60 mg until day 16, and were tapered to 10 mg/day or less by week 16. Other immunosuppressive agents were not permitted. Rituximab depleted peripheral CD19+ B cells in 98.6% of rituximab-treated patients (71/72). The

study, however, demonstrated no significant difference in the rate of the primary endpoint—complete and partial renal responses—between the two groups. Moreover, the small difference in the rate was primarily due to more partial responses with rituximab, according to the investigators. Rates of serious adverse events, including infections, were similar in both groups. Neutropenia, leucopenia, and hypotension were more frequent in the rituximab group. “Further randomized trials with rituximab can help clarify the role of rituximab in LN treatment, including whether rituximab should be used in place of MMF or cyclo phosphamide instead of as add-on therapy, and whether rituximab has a role in salvaging patients with refractory LN,” Dr. Rovin stated. “These studies remain to be set up, but the results of an ongoing U.K. investigation of rituximab as a primary therapy will be reported soon; results presented in abstract form at scientific meetings indicate this approach has promise.” ■

Deceased Donor Tx Rates Declining DIALYSIS PATIENTS waiting for a deceased donor kidney transplant face a declining likelihood of receiving one, according to a recent study. The study, by researchers at the Medical College of Wisconsin in Milwaukee, examined data from 70,891 patients receiving dialysis and who were waitlisted for their first deceased donor renal transplant between January 1996 and December 2005. Patients waitlisted in 1998, 2000, 2002, and 2004 were, respectively, 15%, 27%, 37%, and 42% less likely than patients

waitlisted in 1996 to receive a kidney within 12 months, researchers reported in The American Journal of Medicine (2012;125:57-65). “It is apparent that current efforts are not enough and creative strategies are needed to improve transplantation rates,” the authors wrote. “These should include enhancing organ donation from both living and deceased donors. Increased effort to enhance public education that might result in increasing deceased donor donation is an important consideration.”

Investigators also observed that certain subgroups receiving long-term dialysis have a greater likelihood of dying before receiving a kidney transplant. These include the elderly and blacks and those with diabetic end-stage renal disease. In addition, although the transplantation ratio is nearly equal for male and female patients, women have a higher death ratio than men. “As a result, women are disadvantaged such that the chance of dying before receiving the benefit of a transplant is greater compared with men,” the researchers observed. ■

newly diagnosed ED and 19,985 men without a history of ED (controls). Of the 23,982 subjects, 1,758 had been previously diagnosed with atopic dermatitis: 425 (10.6%) in the ED group versus 1,333 (6.7%) in the control group. Men with ED were 60% more likely to have prior atopic dermatitis than controls, after adjusting for hypertension, diabetes, coronary heart disease, and other potential confounding factors. ■

PSMs Predict PCa Recurrence in Some Men POSITIVE SURGICAL margins (PSMs) are a risk factor for biochemical recurrence of prostate cancer (PCa) in patients who have undergone radical prostatectomy for intermediate-risk disease, researchers reported online in BJU International. Niall Corcoran, MD, of the Leslie and Gordon Diamond Health Care

Centre in Vancouver, British Columbia, and colleagues studied 1,514 patients who underwent radical prostatectomy for PCa. Of these, 276 (18.2%), 761 (50.3%), and 477 (31.5%) had low-, intermediate-, and high-risk disease, respectively. Investigators identified PSMs in 370 men (24.4%). The PSM rate rose from 11% in men with low-

risk disease to 43% in those with highrisk disease. After a median follow-up of 22.2 months, 165 (7%) experienced biochemical recurrence. Multivariate analysis revealed that PSMs were a significant predictor of biochemical recurrence only men with intermediaterisk disease. ■

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Renal & Urology News 25

■ FROM THE EDITORIAL ADVISORY BOARD

What the ‘HD Marathon Man’ Teaches Us Adherence to diet, medicine, scheduling, and follow-up helped Ed Strudwick survive 39 years on hemodialysis BY ROBERT S. RIGOLOSI, MD

s Ed Strudwick’s nephrologist for every day of his remarkable 39 years and nine months on dialysis (Renal & Urology News, “The Hemodialysis Marathon Man,” October 2007; (www.renalandurologynews. com/search/marathon+man/) until his recent death from septicemia at age 71, I would like to revisit some of the valuable lessons that this experience has reinforced for me. Remind your dialysis patients that adherence is key. Ed’s longevity was due to his full adherence to diet, medicine, scheduling, and follow-up. If you have a compliant patient like this, you can expect long-term survival. We have about 200 patients on dialysis in our center, and I would guess that 10% or 15% of them have been on dialysis for more than 35 years. We may have another 10% that have been on 20 to 30 years. Patients do best when they embrace their new disease-driven lifestyle and accept what they have to do. Be sure they understand that they can’t be too careful. For example, if they go off their diet by eating a high-potassium-containing food and then become hyperkalemic, all the work they have done during the course of their dialysis time—whether months or years—is wasted because they’re hyperkalemic, and that can be fatal. So these things have to be avoided. Staff diligence matters. Dialysis patients don’t have much leeway in terms of how much they can cheat. We’ve had patients gain 15 pounds kin the 48 hours between sessions. They can’t do that repeatedly and survive a long time. They might be able to get away with it once or twice,

or maybe even five or six times, but the staff has to be very attentive and get right on top of them, pointing out why they can’t do what they’re doing, educating them, and encouraging them. Nutritionists are key, as are the nurses getting involved with the care. Certainly Ed was down in the dumps on many occasions. The staff would bring it to the doctors’ attention and would try to help him work through those issues, which I believe

with the patient. Talk to your patients and their families regularly, and try to stay engaged with them. Let the patient know that he or she can call you to discuss a problem. You have a social worker who can always help them through personal issues and family issues. Ed Strudwick had a personal rapport with the staff that made it less of a chore for him to come in three times a week, 156 times a year, for 39 years. His nurse, Karen, could tell you

Dialysis in the U.S. • As of December 31, 2009, the U.S. had 370,274 patients on hemodialysis and 22,522 on peritoneal dialysis • The adjusted rates of all-cause mortality for dialysis patients in the 2009 were 6.5-7.4 times greater than those of the general population • In 2004, the adjusted survival five-year survival probability for hemodialysis patients was 34%. Source: U.S Renal Data System 2011 Annual Data Report

contributed to his longevity. Patients really have two supportive teams: One is their family and friends, and the other is their professional team—the nephrologist, the nurse, the dietitian, the social worker. Don’t lose the patient relationship. Today, we’re being encouraged to use electronic systems to record our patients’ visits. And what’s happening is, physicians are losing that personal contact. For example, I’ve seen young doctors take a patient’s history while keeping their eyes on their computer as they input the data, only occasionally glancing at the patient. In this age of computerization, I hope we don’t lose that personal eye-to-eye contact

everything that was going on with his family, down to his grandchildren. And when Ed reached his 30th or 35th year on dialysis, we even marked the occasion by buying him and his wife tickets to a Broadway show and a nice dinner. Encourage home dialysis. I think home dialysis treatment is preferable. Ed had a cadaver transplant in 1977, only about four years into his dialysis treatment. The testing between the donor and the recipient wasn’t as good as it is now, and Ed had a very bad experience: His body rejected the kidney before he ever got out of the hospital. We tried to send him back for another transplant, but he refused.

But at the time, we had a large home hemodialysis program. We taught his wife how to do his home hemodialysis, and he was happy with that. He was able to get back to work and dialyze at home. He stayed on that for about 15 years after the failed transplant. We don’t have many home hemodialysis patients anymore, but now we have a large peritoneal dialysis program here, and the patients love doing home peritoneal dialysis because they can eat more, they can drink more, they’re more independent, they can dialyze around their own schedule; everything is much more flexible. And home peritoneal dialysis is more rehabilitative and less expensive for the government than in-center hemodialysis. Give patients hope. I share the example of Ed Strudwick with predialysis patients, because when you’re telling these people that they’re about to start a treatment that requires them to come in three times a week to survive, and that they have to do that for the rest of their lives if they don’t get a kidney transplant, you do have to give them hope. I can tell them, “You can do well with this treatment as long as you follow certain instructions and listen to your staff members; I had a patient who lived 39 years that way.” Ed saw two daughters get married and four or five grandchildren born during his time on dialysis, something many people would not expect could happen. ■ Dr. Rigolosi is Director of the Regional Hemodialysis Center at Holy Name Hospital in Teaneck, N.J. He is a member of the Renal & Urology News Editorial Advisory Board.

MARCH 2012

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Malpractice News While the innovation of such things as cell phones, iPads, social networking sites, and the Internet can often be a boon when it comes to gaining or sharing clinical information on the go, they can also be a distraction to health care professionals. A recent New York Times report highlighted this issue, which was termed “distracted doctoring.” According to the report, clinicians have been found to use their smart phones and tablet computers for personal reasons—social networking, checking news, airfare prices, and the like—while engaging in patient care, and not simply to access drug information or patient data. When used to obtain clinical information, these devices can be strong support tools, but individual browsing (while on the job) can compromise patient safety and has led to errors. A recent study of 439 perfusionists and supporting technicians illuminates this problem (Perfusion 2011;26:375-380). This survey of clinicians who perform cardiopulmonary bypass (CPB) showed that more than 55% of respondents admitted to using a cell phone while performing CPB. In addition, 49% reported sending text messages during the procedure. For those who had smart phone features, 21% admitted to checking e-mail, 15% used the Internet, and 3% posted on social networking sites during surgery. And yet more than 78% of the surveyed participants stated that cell phone use in the operating room (OR) could introduce a significant safety risk to patients. The New York Times case cited above prolifes an incident where a patient was left partially paralyzed after surgery, during which a distracted neurosurgeon used a wireless headset to make at least 10 personal calls. This case was settled out of court. Many hospitals are addressing this new safety issue by instituting policies

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Many clinicians admit to using social media sites during surgical procedures.

Distracted Care Can Lead To Increase in Malpractice

that restrict the use of cell phones, smart phones, and other electronic devices in hospital. The Oregon Health and Science University (OHSU) Hospital in Portland instituted a policy establishing operating rooms as “quiet zones,” after complaints that staff clinicians were using smart phones (to check or send e-mails) while intubating patients. After the policy was firmly in place, an OHSU nurse was formally reprimanded for checking airline prices (on an OR computer) during a spinal operation. Younger clinicians are more apt to use these new devices, so medical schools are starting to incorporate policy edicts during training, stressing the importance of using technology only for garnering patient-related information.

Malpractice Attorney Charged with Theft A New York attorney is charged with stealing $70,000 from his clients, according to Rockland County District Attorney, Thomas P. Zugibe. The clients, a husband and wife, were plaintiffs in a medical malpractice case. The defendant sent a $70,000 check directly to the couple in an effort to settle the case. The plaintiffs did not want to settle for less than $350,000 and told their attorney this when they

BY ANN W. LATNER, JD

handed the check over to him. The prosecutor allegedly told his clients that he would return the check to the other party in the lawsuit, but instead deposited the money into his personal bank account. The attorney in question then falsely filed an agreement and release to settle the case for $70,000—without the knowledge or consent of his clients. The counselor was subsequently charged with grand larceny in the second degree, criminal possession of a forged instrument, and offering a false instrument for filing. He faces up to 15 years in prison. In a press release, Zugibe said the defendant in this case “is accused of betraying his clients. Having already been injured by the negligent acts of others, this unsuspecting couple was again victimized by their lawyer. This arrest should serve as a warning to unscrupulous professionals who seek to prey on their clients.”

in his left arm. Further tests revealed that the man had a broken neck and he then underwent emergency neckfusion surgery. Because of the initial failure to diagnose the fracture, the plaintiff suffered permanent C5 nerve root injuries and had to undergo a second neck fusion. In fact, the plaintiff will need additional surgeries, including the implantation of a spinal cord stimulator in hopes of reducing intense, chronic pain. At trial date, the plaintiff was still not back at work due to disability, and, because of chronic pain, was largely confined to his home. At trial, the doctor denied that he had failed to perform a physical exam; however, on cross-examination, his own defense expert testified that if the exam An ER physician missed an injured worker’s broken neck.

$9 Million Wyoming Verdict Is Largest on Record A jury recently found in favor of a Wyoming man, the plaintiff in a malpractice lawsuit, and awarded a recordbreaking $9 million in damages. The plaintiff was a 51-year old oilfield worker whose truck slid off an icy road and rolled over several times before landing upside down. Emergency medical service (EMS) workers arrived on the scene, freed the man from the truck and immediately immobilized him with a backboard. The EMS team then put a brace on the man’s neck. The plaintiff was conscious when he arrived at Campbell County Memorial Hospital in Gillette and was complaining of neck pain. The attending ER physician immediately ordered X-rays and CT scans of the accident victim’s head, thoracic spine, and facial bones—but not of his neck. The physician ultimately released the patient without a cervical collar and without performing a full physical exam. The patient returned to the hospital four days later with extreme pain in his left shoulder and neck and weakness

26 Renal & Urology News

had actually been performed, the plaintiff’s obvious and intense pain should have prompted would have indicated that X-rays were required. The jury found the physician and the hospital negligent and awarded the plaintiff damages in the amount of $7 million plus an additional $2 million to the plaintiff’s wife for loss of consortium. Prior to this, the record-high malpractice award in Wyoming had been $1.5 million. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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Renal & Urology News 27

Web-Based Tools Speed Donor Screening Potential kidney donors fill out an online form that helps transplant centers evaluate eligibility BY ROSEMARY FREI, MSc MIAMI BEACH, FLA.—Web-based preliminary screening of potential kidney donors has resulted in a flood of applications at two U.S. transplant centers. It only takes potential donors a couple of minutes to confidentially answer questions about whether they have hypertension, diabetes, frequent kidney stones or hepatitis, and whether they are current smokers or users of illicit drugs. The websites differentiate between absolute ineligibility—for example, having hepatitis C, HIV, or diabetes—and relative ineligibility, such as being obese or currently smoking. Potential donors can then either proceed to a longer webbased health-status questionnaire or are brought to a webpage stating they are not currently suitable candidates. The paperless format makes it easy to screen large numbers of people quickly and for people needing kidneys to alert friends and family by simply e-mailing the screening website’s URL. Details of web-based donor screening programs at the University of CaliforniaSan Francisco (UCSF) and Vanderbilt University in Nashville, Tenn., were presented at the American Society of Transplant Surgeons’ 2012 Annual State of the Art Winter Symposium.

“We’re having to redo some of our workflow because we’re getting so many potential donors—for example, one of the people on our transplant wait list has 19 potential donors,” said John Roberts, MD, Chief of Transplantation at UCSF. “It’s much more unlikely to get multiple potential donors stepping forward when the screening questionnaire is on paper. That’s why we’re really excited about online screening.” The Vanderbilt Kidney/Pancreas Transplant Program is having a similar experience with their online kidney donor intake form, available at https://www.vanderbilthealth.com/ transplant/30936. “We are very excited about this new web-based tool and feel that it can be easily incorporated into many transplant programs,” noted Deonna Moore, MSN, a nurse practitioner for the Vanderbilt program who has been instrumental in the development and application of the web-based tool that has been in use since January 2011. In the past year, the tool has been used to screen more than 600 potential donors. “The features of the web-based application increase the transplant center’s ability to attract donors and process them efficiently, with the ultimate goal

Donna Moore, MSN

John Roberts. MD

being to potentially increase living kidney donation,” she said. “One of the things I’ve been amazed about is the percentage of people who have Internet access and seem able to use it,” Dr. Roberts noted. The UCSF website uses a BREEZE Transplant (MedSleuth, Inc., San Francisco; http:www.medsleuth.com/ transplant/) platform. An analysis by Dr. Roberts’ team of 200 consecutive users of the website showed there was a 98% satisfaction rating and a 96% rating for ease of use. Moreover, since

the web-based approach was implemented there has been a 41% increase in rate of donor-questionnaire completion and 50% increased productivity of the transplant nurse coordinators. Another benefit is the immediate availability of donor information to clinicians compared with the previous several-week delay with paper-based screening. Both the UCSF and Vanderbilt programs have found that approximately 25% of people screened online are not suitable donors. ■

Transplant-Related Urinary Complications Defined BY ROSEMARY FREI, MSc MIAMI BEACH, FLA.—A review of 635 kidney transplants performed at the University of Florida, Gainesville, has confirmed that transplanted kidneys with more than one renal artery places recipients at increased risk for urinary complications. The researchers found that renalartery multiplicity in transplanted kidneys is associated with a statistically significant 2.5-fold higher risk of urinary complications compared with organs that have only one renal artery, according to a poster presentation at the American Society of Transplant Surgeons’ 2012 Annual State of the Art Winter Symposium. Rupak Kulkarni, MD, and three other transplant surgeons analyzed the urinary complication outcomes of transplants performed between December 1, 2006 and December 31, 2010. All patients had at least six

months of follow-up data available. They evaluated 34 characteristics of the donors and recipients. These included some parameters that have been evaluated in previous research–including donor and recipient age, donor and recipient race, and cold ischemia time of more than 24 hours. They also analyzed some that had not been previously exam-

ined, including whether the kidneys had been imported from outside of the local catchment area. Urinary complications developed in 19 (4.6%) of the 635 transplants. These included 17 strictures (58.6%), seven leaks (24.1%), and five (17.2%) stones or internal hematomas. Univariate analysis revealed only two factors associated with a statistically

Post-Transplant Urinary Problems Strictures were the most common urinary complication among 635 renal transplants studied at the University of Florida, Gainesville. Shown here are the proportions of each type of urinary complication.

17.2%

Strictures 58.6%

24.1%

Leaks Stones or internal hematomas

Source: Kulkarni R, et al. Data presented at the American Society of Transplant Surgeons’ 2012 Annual State of the Art Winter Symposium.

significant increased risk of urinary complications: double-kidney transplantation, which was associated with a 2.72 times increased risk, and the presence of more than one renal artery, which was associated with a 2.48-fold increased risk. On multivariate analysis, however, only renal-artery multiplicity remained statistically significant, with a 2.5-fold increased risk. The researchers observed trends toward urinary complications with donor age of 60 years or older, re-transplants, and ligation of the lower pole artery, but these trends did not reach statistical significance possibly because of the small sample size of subgroups with these complications. “The results confirm that our judgment regarding kidney choice—such as preservation of the inferior pole renal artery if previously transected— is resulting in excellent outcomes,” Dr. Kulkarni said. ■

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CME FEATURE

Clinical Challenges and Renal Considerations in Managing Gout A case study examines the treatment of hyperuricemia and gout in a 57-year-old postmenopausal renal transplant recipient with intermittent gout attacks

Release Date: March 2012 Expiration Date: March 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 the 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 • William F. Finn, MD

Reported Financial Relationship Consultant: Takeda Pharmaceuticals Speakers’ Bureau: Takeda Pharmaceuticals

• Anthony J. Bleyer, MD (Faculty Chair)

Consultant: Takeda Pharmaceuticals, Savient Pharmaceuticals

BY WILLIAM F. FINN, MD

out, a chronic, progressive disease and the most prevalent form of inflammatory arthritis, causes significant morbidity and impaired quality of life.1,2 Because of its association with hyperuricemia and crystallization of uric acid within joints, gout is considered a rheumatologic manifestation of renal disease.2,3 Hyperuricemia and gout are particularly common among those with chronic kidney disease (CKD), and persons with gout have a much higher incidence of CKD. While the prevalence of CKD in the US general population is approximately 13%,4 it approaches 40% among patients with gout.5

Etiology of gout onset Chronic hyperuricemia is a prerequisite for the development of gout.1 Hyperuricemia can result from either overproduction or underexcretion of uric acid, or both, any of which may predispose the individual to gout.6 Overproduction of uric acid accounts for only 10% of gout cases. More commonly, the causative factor is a decrease

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 March 2012 through March 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/marchgout (March 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.

William F. Finn, MD, is Professor of Medicine in the Division of Nephrology and Hypertension at University of North Carolina School of Medicine at Chapel Hill.

in the kidney’s ability to secrete urate as a consequence of drugs or disease. Both hyperuricemia (generally defined as a urate level >7.0 mg/dL in men and >6.0 mg/dL in women) and gout are significant problems in recipients of renal and other solid organ transplants. The general incidence of hyperuricemia is between 2% and 18% with gout occurring in 0.1%-0.3%; in renal allograft recipients, hyperuricemia occurs in 19%85% of patients, with the highest incidence in those treated with calcineurin inhibitors.7-9 Of these patients, between 3.5% and 28% are reported to have gout post-transplant.10,11 Patients without hyperuricemia prior to renal transplantation appear to have the same incidence of gout as the general population.12 Based on Medicare claims data, new-onset gout may occur in as many as 13% of renal transplant recipients, with a cumulative incidence of 7.6% at 3 years post-transplant.13 Gout in renal recipients has been described as more aggressive than in the general population, with early onset, fast tophaceous progression, and involving unusual joints such as the hip, shoulder, and sacroiliac.14,15 Independent correlations with new-onset gout were found for use of cyclosporine compared with use of tacrolimus after discharge, male

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sex, age >34.3 years, higher body mass index (BMI) (>28.6 kg/m2), and more recent year of transplant (after 1996).13 Furthermore, new-onset gout was independently associated with decreased patient survival, with a 1-year mortality rate of 14.3%, as well as a 22% increased risk for graft loss.13 The improved quality of life gained through renal transplantation may be offset by gout that becomes severe and debilitating.16

Pathogenesis of hyperuricemia Uric acid is the end product of purine metabolism. The pKa of uric acid is approximately 5.3. At the physiologic pH of 7.4, the equilibrium between the undissociated acid and the salt form is significantly shifted towards the salt form as monosodium urate. Because the amount of urate in the body is regulated by a balance between dietary purine intake, endogenous purine synthesis, and urate excretion (Figure 1), purine metabolism plays a significant role in the pathogenesis of hyperuricemia leading to gout.2 Approximately 95% of uric acid produced by purine metabolism is freely filtered through the glomerulus.16 Urate is absorbed extensively in the proximal tubule via the organic anion transporter URAT1, then further reabsorbed by the kidney with sodium-dependent reabsorption of anions, resulting in renal clearance of only 7% to 10% of the filtered load.2,16 Supersaturation of urate (which may occur at plasma levels >6.8 mg/dL) leads to the formation of monosodium urate crystals that may be deposited in joints and periarticular tissues, depending on the temperature, pH, and concentrations of sodium and calcium within those structures.2,16 Urine pH may be as low as 4.4—a hydrogen gradient of 1000:1 compared to the 7.4 pH of plasma. At this pH, the equilibrium shifts from monosodium urate to uric acid. Uric acid nephrolithiasis is principally due to a low urinary pH, leading to a predominance of uric acid in the urine, which is much less soluble than urate.

Case study: gout onset in a postmenopausal Tx patient Mrs. G, a 57-year-old postmenopausal Caucasian woman, is 5’4” tall and weighs 138 lb, with a BMI of 23.7 kg/m2, and does not smoke or drink alcohol. She underwent renal transplantation

2 years ago for progressive kidney failure after an 11-year history of polycystic kidney disease. Her immunosuppressant regimen consists of tacrolimus 8 mg/day and azathioprine 100 mg/day. Mrs. G also takes a daily multivitamin and calcium and vitamin D supplements. She reports acute onset of redness, swelling, and pain in her right big toe that began 2 days ago. She has had similar episodes intermittently over the past 3 months and is concerned that they may be becoming more frequent.

Discussion: risk factors in renal Tx patients Mrs. G is representative of a renal transplant patient with gout. Transplant recipients and the general population share several risk factors for the development of hyperuricemia and gout, including increased BMI, hypertension, and insulin resistance or diabetes mellitus, all clinical features of the metabolic syndrome.1,16 Treatment with loop or thiazide diuretics also increase the risk for hyperuricemia by inhibiting renal excretion of urate via the organic anion transporter OAT4.1,16 Renal impairment is associated with hyperuricemia, particularly in postmenopausal women, and CKD is a significant risk factor for gout.1,16 Interestingly, hyperuricemia is common in patients with end-stage renal disease (ESRD), but gout is not.16 Calcineurin inhibitors: In transplant recipients, immunosuppressive therapy (particularly the calcineurin inhibitor [CNI] cyclosporine) is the most important risk factor for gout.6,16 Gout risk correlates with exposure to cyclosporine over time rather than the absolute dose or serum level. Due to its vasoactive properties and effect on interstitial structures, cyclosporine may decrease the renal clearance of urate by both reducing glomerular filtration rate (GFR) and impairing the handling of urate in the proximal tubules.6,16 Symptomatic hyperuricemia has been reported in 51% to 84% of patients treated with cyclosporine and 11% to 55% of those treated without a CNI. From 1.7% to 28% of those treated with cyclosporine developed gout compared with 0% to 23% of those not given a CNI.16 Medicare claims data indicated that the prevalence of new-onset gout

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Table 1. Considerations in Selecting Uric Acid-Lowering Therapy Class and Agent

Consideration

Drugs Used to Treat or Prevent Gout Flares NSAIDs

• Use with caution or may be contraindicated in patients with severe heart failure, ulcer disease, GI bleeding, aspirin- or NSAID-induced asthma, renal impairment • May worsen renal function temporarily or permanently • Drug interaction with warfarin

Colchicine

• Contraindicated in patients on dialysis • Dose adjustment needed for renal impairment • Can cause serious GI adverse effects • Drug interactions with cyclosporine, statins, macrolides

Corticosteroids

• Use with caution in patients with diabetes or infection • Dose should be tapered to avoid rebound flare

Drugs Used for Ongoing Management of Hyperuricemia Xanthine oxidase inhibitors Allopurinol • Effective in patients who underexcrete or overproduce uric acid • Dose adjustment needed for impaired renal function • Should not be used with azathioprine, 6-mercaptopurine • Target serum uric acid levels not achieved in some patients without high doses • Rare but potentially fatal hypersensitivity syndrome Febuxostat

Uricosuric Probenecid

Urate transporter Pegloticase

• Option for allopurinol hypersensitivity or intolerance • Effective in patients with or without renal insufficiency • Contraindicated for use with azathioprine, 6-mercaptopurine, and theophylline • Loses effectiveness as renal function declines • May not be effective in patients treated with cyclosporine • Risk for nephrolithiasis in patients with high uric acid production • Adequate fluid intake necessary • Twice-daily dosing required • Administered by IV infusion every 2 weeks • Relatively rapid dissolution of tophi • Infusion reactions and allergic reactions reported • Gout flares common in early months of treatment • May exacerbate CHF

NSAIDs = nonsteroidal anti-inflammatory drugs; GI = gastrointestinal; IV = intravenous; CHF = congestive heart failure Sources: Dubchak N, Flasca GF. 2010; Reindeers MK, Jansen TL. New advances in the treatment of gout: review of pegloticase. Ther Clin Risk Manag 2010;6:543-550.; Schumacher HR Jr, Chen LX. The practical management of gout. Cleve Clin J Med 2008;75 Suppl 5:S22-S25.; Terkeltaub R. 2009.

was significantly lower in renal transplant patients treated with tacrolimus than those treated with cyclosporine (6.1% vs. 7.9%, P<0.05) within 3 years of transplantation. 13 Some studies in small patient populations have reported a decrease in serum uric acid after switching from cyclosporine to tacrolimus 16; others have found no advantage to tacrolimus over cyclosporine. 17 In a 3-month trial, hyperuricemia occurred in 18.9% of patients treated with sirolimus (structurally similar to tacrolimus but with a different mechanism of action) and 54.1% of those treated with cyclosporine.16

Inhibitors of purine metabolism: Azathioprine is a prodrug, converted in the body to the active metabolites 6-mercaptopurine and 6-thioinosinic acid (Figure 2).16 Azathioprine interferes with nucleic acid metabolism although the exact mechanism of action is not known. Xanthine oxidase inhibitors potentiate azathioprine toxicity, so patients with gout must discontinue azathioprine before treatment with a xanthine oxidase inhibitor. Mycophenolate mofetil is a prodrug converted to mycophenolic acid, a potent and reversible uncompetitive inhibitor of inosine monophosphate dehydrogenase. Unlike azathioprine, its metabolism is

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CME FEATURE not affected by allopurinol, a significant advantage in patients with gout.18 Among transplant recipients and the general population alike, gout is more common in men; in women, it occurs predominantly after menopause.16,19 Premenopausal gout is unusual. The first metatarsophalangeal joint is most often involved, although wrists, knees, and elbows may be affected.6,16

Case: initial patient workup Examination reveals erythema, swelling, warmth, and tenderness of the right first metatarsophalangeal joint with no evidence of tophi. Laboratory studies revealed a serum creatinine of 1.8 mg/dL, BUN of 25 mg/dL, albumin 4.0 g/dL, and an estimated GFR of 32 mL/min. The serum uric acid level of 7.2 mg/dL indicates hyperuricemia, and analysis of synovial fluid aspiration confirms the presence of monosodium urate crystals.6,19 The clinician explains that Mrs. G is experiencing acute symptoms of gout because the level of uric acid in her blood is elevated and crystals have formed in the joint, causing local damage leading to inflammation, redness, and pain. The clinician recommends an increase in the prednisone dosage to help treat the acute flare of gout. He gives Mrs. G information on uric acid-lowering drugs that they can discuss at her followup visit and recommends substituting mycophenolate mofetil for azathioprine.

They also review dietary changes that may limit the hyperuricemia.

Discussion: identifying urate levels A serum uric acid level >6 mg/dL in both men and women favors crystallization of monosodium urate; the higher the urate level, the greater the risk of an acute attack. The presence of monosodium urate crystals in synovial fluid is required for a definitive diagnosis of gout.6,16 Monosodium urate crystals damage bone and periarticular tissue through local mechanical pressure and acute or chronic inflammation.6,16 Acute attacks of gout result from an inflammatory response, in which monocytes and synoviocytes initially release proinflammatory cytokines in response to the monosodium urate crystals.16,20 The subsequent accumulation of neutrophils within the synovial fluid and membrane induces the release of several inflammatory mediators, of which interleukin-1Î˛ plays a central role.20 While acute attacks of gout may be self-limiting and respond rapidly to short-term anti-inflammatory therapy, the chronic presence of monosodium urate crystals in joints can damage cartilage, bone, and soft tissues.16 Just as not all patients with hyperuricemia develop gout, not all patients with gout develop tophi.16 Patient education plays an important role in preventing the development of gout, particularly regarding

Figure 1. Overview of the Pathogenesis of Gout

Dietary purine load

dietary precautions for renal transplant recipients.21 Increased serum uric acid levels are associated with red meat, fructose-sweetened beverages, and alcohol; dairy products, coffee, and vitamin C seem to decrease uric acid levels.22 Alcohol should be avoided or consumed only occasionally.16,21 (Go to www.renalandurologynews.com /gout1 for a more extensive list of dietary precautions.) Unfortunately, even if successful, dietary precautions may result in a decline in serum urate concentrations of only 1 mg/dL.

Case: pharmacotherapy regimen Mrs. G expresses concern over her hyperuricemia persisting and triggering more attacks of gout, but she is reluctant to add another drug to her regimen. She asks if she can use pain medications as needed. The clinician and Mrs. G discuss the benefits and risk of analgesics known to be effective for acute attacks of gout. The clinician emphasized that these agents do not treat the underlying chronic condition.

Discussion: managing inďŹ&#x201A;ammation The medical management of acute gout attacks in renal transplant recipients is similar to that for most patients, with anti-inflammatory therapy initiated at the time of diagnosis (Table 1).6 Colchicine, a plant-derived product with a rapid onset

of action (usually within 48 hours), is effective in most patients.6,16,22 However, colchicine is associated with diarrhea, abdominal cramping, or nausea that may be related to its extensive enterohepatic recirculation.6,16 In some patients, the gastrointestinal (GI) symptoms precede pain relief.16 For the treatment of gout flares, the recommended doses have recently undergone revision (Table 1). Colchicine treatment in renal transplant patients is associated with myotoxicity, manifesting as weakness and reduced deep tendon reflexes, sometimes accompanied by an elevated creatine kinase level; diagnosis is confirmed by muscle biopsy.6,16 Although reversible, myotoxicity may be significantly disabling.6 Patients receiving cyclosporine may be predisposed to colchicine myotoxicity, and dose reduction is necessary in patients with advanced CKD.1 Nonsteroidal anti-inflammatory drugs (NSAIDs) are an effective alternative to colchicine but can adversely affect renal hemodynamics, particularly in patients with diminished allograft function (Table 1).6,16 COX-2 inhibitors have not been well-studied in renal transplant patients and generally are thought to offer no advantage over traditional NSAIDs in terms of renal adverse effects. If used, renal function should be closely monitored and the agents discontinued with an increase in the serum creatinine concentration.16,20 Furthermore, the association of COX-2 inhibitors with an

Figure 2. Metabolism of Azathioprine and Site of Action of the Xanthine Oxidase Inhibitor Allopurinol.

Renal excretion Azathioprine Urate level

Endogenous purine synthesis

Gut Mercaptopurine

Urate supersaturation and crystallization

6-Thiouric acid (inactive metabolite)

Gout

Source: Adapted from Choi HK, et al. 2005

Xanthine oxidase

Allopurinol

Source: Adapted from Stamp L, et al 2005.

increased risk for adverse cardiovascular events signals judicious use in patients with existing risk.16 Corticosteroids are another antiinflammatory treatment option for acute gout attacks (Table 1).16,21 Many renal transplant recipients are on maintenance doses of corticosteroids. An increased dose may be effective for acute gout symptoms, but must be tapered after symptom resolution to avoid rebound attacks.16,21 Oral corticosteroids should be limited to short courses for acute episodes, and intra-articular formulations are useful when joint involvement is limited and they are accessible.16

Case: monitoring drug protocols The clinician understands Mrs. G’s desire to limit her medications. He indicates that there is a high likelihood that gout will recur, and he asks her to call if she develops symptoms again. He provides her with extra glucocorticoid tablets to take if she has a recurrence, reiterating that she should call.

Discussion: more treatment options Gout is the only chronic form of arthritis that can be cured.16 When serum uric acid levels are reduced over the long term, monosodium urate crystals in joints, soft tissue, and tophi dissolve, and acute attacks of gout subside.16 Uric acid-lowering therapy may be considered after the first acute gout attack, since attacks will recur in most organ transplant recipients.16 Serum uric acid levels should be maintained below 6 mg/dL by reducing uric acid formation with the xanthine oxidase inhibitors allopurinol and febuxostat or increasing urate excretion with the uricosuric agent probenecid (Table 1).16,22 Xanthine Oxidase Inhibitors: Allopurinol is a purine analog that reduces uric acid production by inhibiting xanthine oxidase and is considered first-line therapy for most gout patients.20 Serum uric acid decreases markedly within the first 24 hours after administration and a peak effect occurs at 2 weeks.19 In controlled clinical trials, allopurinol 300 mg/day lowered serum uric acid by about 33% in a population in which 25% to 30% had detectable tophi.20

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The formation of uric acid crystals (shown above) in the synovial fluid.

Allopurinol is metabolized in the liver to its active agent, oxypurinol, which is excreted predominantly by the kidney. Because serum oxypurinol levels vary inversely with renal function, dose adjustments of allopurinol are recommended for patients with CKD. GI disturbance and rash are common adverse effects.22 Allopurinol hypersensitivity syndrome, although rare, has been associated with higher doses, diuretic use, renal insufficiency, and higher concentrations of oxypurinol.22 Because studies identifying this relationship may have been flawed, it remains uncertain whether higher doses are a risk factor for this syndrome. Mercaptopurine is the active metabolite of the immunosuppressant azathioprine (Figure 2). Xanthine oxidase inactivates the conversion of mercaptopurine to inactive 6-thiopurine. Inhibiting xanthine oxidase increases circulating levels of mercaptopurine that can induce myelosuppression and other toxic effects relatively quickly.11,21 The availability of mycophenolate mofetil obviates the need to reduce the starting dose of allopurinol.16,21 Febuxostat, a non-purine selective xanthine oxidase inhibitor, is an appropriate option for patients with allopurinol ineffectiveness, hypersensitivity, or intolerance.20,22 Clinical trials have demonstrated improved efficacy of febuxostat over allopurinol to meet target serum uric acid concentrations in many patients, including those with CKD, and without an increased incidence of hypersensitivity reactions.20,22 Febuxostat 40 or 80 mg/day produced similar uric acid-lowering effects in patients with and without renal insufficiency.22 In

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addition, chronic febuxostat therapy may result in dissolution of tophi and has a favorable impact on quality-of-life parameters with prolonged (5 years) treatment.20,22 Unlike allopurinol, febuxostat is metabolized primarily in the liver with little renal elimination, so there is no need for dose adjustment in patients with CKD.20 Possible side effects include elevations in hepatic enzymes and GI disturbances.22 Febuxostat may have a lower propensity for drug toxicity than allopurinol because it neither directly regulates pyrimidine metabolism nor is incorporated into nucleotides.20 However, febuxostat is contraindicated for use with azathioprine and 6-mercaptopurine because it prolongs the half-life of these purine analogs.22 Uricosuric Agents: Rather than decreasing uric acid formation, uricosuric agents increase uric acid excretion. Probenecid, most commonly used, interferes with renal uric acid or anion exchange to block reabsorption of uric acid in the proximal tubules.22 Uricosuric agents are not advised in patients who are overproducers of uric acid and whose urinary uric acid levels are already high (ie, >800 mg/day) because of the risk of nephrolithiasis. This risk can be reduced through adequate hydration, alkalinization of the urine, and renal sonograms at regular intervals.6,22 Uric acid excretion should be monitored periodically in probenecid users; high fluid intake is advised for patients with 24-hour uric acid excretion >750 mg.6 Probenecid becomes progressively less effective with declining GFR, and it may be ineffective in patients taking cyclosporine.6, 20 There are a number of potential drug interactions with probenecid. Clinicians prescribing probenecid should make sure that patients alert them of medication changes made by other clinicians. These issues, coupled with the availability of allopurinol and febuxostat, have limited the use of this agent.22 Probenecid requires more than once-daily dosing; treatment is initiated at low doses and titrated upward gradually, with maintenance doses ranging from 500 mg/day to 3 g/day.22

Conclusions Hyperuricemia and gout are common among renal transplant recipients and

Renal & Urology News 31

present challenges to the management of both immunosuppression and hyperuricemia. The relatively high prevalences of hyperuricemia and gout in this patient population are attributable to abnormal renal urate transport mechanisms due to the use of CNIs and/or intrinsic renal tubular defects. The risks and benefits of pharmacologic agents used to treat acute attacks of gout and chronic hyperuricemia must be evaluated carefully for their effects on serum uric acid levels and drug-drug interactions. ■ REFERENCES 1. Roddy E, Doherty M. Epidemiology of gout. Arth Res Ther 2010;12:223. 2. Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med 2005;143:499-516. 3. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population. Arthritis Rheum 2011;63:3136-3141. 4. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA 2007;298:2038-2047. 5. Fuldeore MJ, Riedel AA, Zarotsky V, et al. Chronic kidney disease in gout in a managed care setting. BMC Nephrol 2011;12:36. 6. Clive DM. Renal transplant-associated hyperuricemia and gout. J Am Soc Nephrol 2000;11:974-979. 7. Bieber J, Terkeltaub R. Gout: on the brink of novel therapeutic options for an ancient disease. Arthritis Rheum 2004;50:2400-2414. 8. Delaney V, Sumrani N, Daskalakis P, et al. Hyperuricemia and gout in renal allograft recipients. Transplant Proc 1992;24:1773-1774. 9. Lin H, Rocher L, McQuillan M, et al. Cyclosporine induced hyperuricemia and gout. N Engl J Med 1989;321:287-292. 10. Ben Hmida B, Hachicha J, Bahloul Z, et al. Cyclosporine-induced hyperuricemia and gout in renal transplants. Transplant Proc 1995;27: 2722-2724. 11. Stamp L, Ha L, Searle M, et al. Gout in renal transplant recipients. Nephrology 2006;11:367-371. 12. Hernandez-Molina G, Cachafeiro-Vilar A, Villa A, et al. Gout in renal allograft recipients according to the pretransplant hyperuricemic status. Transplantation 2008;86:1543-1547. 13. Abbott KC, Kimmel PL, Dharnidharka V, et al. Newonset gout after kidney transplantation: incidence, risk factors and implications. Transplantation 2005;80:1383-1391. 14. Baethge BA, Work J, Landreneau MD, McDonald JC. Tophaceous gout in patients with renal transplants treated with cyclosporine A. J Rheumatol 1993;20:718-720. 15. Pascual E. Gout update: from lab to the clinic and back. Curr Opin Rheumatol 2000;12:213-218. 16. Stamp L, Searle M, O’Donnell J, Chapman P. Gout in solid organ transplantation: a challenging clinical problem. Drugs 2005;65:2593-2611. 17. Kanbay M, Akcay A, Huddam B, et al. Influence of cyclosporine and tacrolimus on serum uric acid levels in stable kidney transplant recipients. Transplant Proceed 2005;37:3119-3120. 18. Jacobs F, Mamzer-Bruneel MF, Skhiri H, et al. Safety of the mycophenolate mofetil-allopurinol combination in kidney transplant recipients with gout. Transplantation 1997;64:1087-1088. 19. Harris MD, Liegel LB, Alloway JA. Gout and hyperuricemia. Am Fam Physician 1999;59:925-934. 20. Terkeltaub R. Novel therapies for treatment of gout and hyperuricemia. Arthritis Res Ther 2009;11:236. 21. Baroletti S, Bencivenga GA, Gabardi S. Treating gout in kidney transplant recipients. Prog Transplant 2004;14:143-147. 22. Dubchak N, Flasca GF. New and improved strategies for the treatment of gout. Int J Nephrol Renovasc Dis 2010;3:145-166.

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.

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CME FEATURE CME Post-test Expiration Date: March 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 /marchgout. You must receive a score of 70% or better to receive credit. 1. Among renal transplant recipients: a. The progression and clinical features of gout are comparable to those in the general population. b. Tophaceous progression generally occurs at the same rate as in the general population, but manifests in unusual joints, such as the shoulder. c. Gout has been observed to be more aggressive than in the general population. d. Tophi formation tends to be markedly slower, although acute attacks of gout recur more frequently than in the general population. 2 The most important risk factor for gout among renal transplant recipients is: a. Extended duration of pretransplant kidney disease b. Hypertension, elevated body mass index, and other components of the metabolic syndrome c. Treatment with loop or thiazide diuretics d. Use of immunosuppressive agents, especially cyclosporine 3. Dietary regimens used to manage gout: a. Restrict consumption of alcoholic beverages and foods high in vitamins A and C b. Require the elimination of red meat, alcoholic beverages, dairy products, and caffeine c. Offer efficacy comparable to medication use d. May result in only limited reductions in serum urate concentration, even if successfully followed 4. Maintenance doses of corticosteroids used by some renal transplant recipients: a. Are usually sufficient to manage acute symptoms b. Can be increased to treat acute gout symptoms, and then

maintained at the higher dose to reduce risk of recurrence c. Can be increased to treat acute gout symptoms, but must be tapered thereafter to minimize risk of rebound attacks d. Must be tapered in response to acute gout attacks, with therapy resuming after symptom resolution 5. You are asked to see a kidney transplant patient with recurrent gout. His immunosuppressive regimen includes tacrolimus, azathioprine, and prednisone. Which of the following is true? a. Switching from tacrolimus to cyclosporine is likely to decrease gout attacks. b. Adding allopurinol and continuing present immunosuppressants is a good option to prevent future gout attacks. c. Adding febuxostat and continuing current immunosuppressants is a good option to prevent future gout attacks. d. Changing azathioprine to mycophenolate and adding allopurinol is a good option to prevent future gout attacks. 6. When starting therapy with a xanthine oxidase inhibitor (allopurinol or febuxostat), which of the following is NOT true? a. The goal is to reduce uric acid levels below 6.0 mg/dL. b. Combined therapy with an antiinflammatory agent (colchicine, NSAID, prednisone) is necessary to reduce the likelihood of inducing an acute gout flare. c. If an acute gout flare occurs, the xanthine oxidase inhibitor should be held until the flare is over. d. Over time, inflammatory changes may resolve, tophaceous deposits may regress, and anti-inflammatory agents may be stopped.

Active Surveillance for Bladder Cancer BY NAYANAH SIVA LONDON—Low-risk non-muscle invasive bladder cancer (NMIBC) could be safely managed by periods of active surveillance rather than aggressive resection surgery and frequent cystoscopic follow up, Jeremy Crew, MD, a consultant urologist surgeon at Oxford University Hospital, experienced in the technique, told attendees at the Renal and Bladder Cancer 3rd National Conference. Guidelines from the European Association of Urology state that lowrisk NMIBC should be managed by frequent cystoscopy, at three months and (if negative) subsequent cystoscopies at nine months and yearly for a minimum of five years. When a recurrent tumor is detected, a resection under general anesthetic is indicated, allowing for histopathologic examination and grading of the tumor. Active surveillance is not a new concept, Dr. Crew said. “Urologists have been ahead of the game on this, with low-risk prostate cancers and for small renal masses.” He proposes that the strategy could be an option for patients with low-risk NMIBC. Avoiding unnecessary surgery might be beneficial to the patient particularly if the tumor is low risk. “There is a suggestion that by not resecting the tumor you are not going to disseminate blad-

der cancer cells throughout the bladder, which can then implant in the raw area that was just resected. So perhaps by applying a more conservative approach you may actually reduce the rate at which the tumor recurs.” Cost, in terms of managing the patient and the surgeon’s time, is another advantage for active surveillance, Dr. Crew said. Typically, patients with significant comorbidities, where general anesthetic and resection could be a risk, may be managed using more conservative options, such as active surveillance, but Dr. Crew thinks this option could be extended to patients with low-risk NMIBC tumors who are otherwise fit and healthy. There are, however, disadvantages, Dr. Crew said, such as lack of histologic data. Without such data, it cannot be ascertained whether a tumor seen through a cystoscope is a low-grade cancer, and this can cause patient anxiety. “Some patients are not cut out for active surveillance and they may be anxious about leaving the cancer untreated,” he said. By looking at the evidence base, Dr. Crew said that progression rate and growth rate of tumors under 5 mm in diameter was zero or minimal within a one-year surveillance period. “I think low-risk NMIBC can be safely managed by periods of active surveillance,” he said. ■

Living Kidney Donors Not at Higher Acute Dialysis Risk LIVING KIDNEY donors are at no higher risk for requiring acute dialysis than non-donors, according to a recent study. Investigators led by Amit X. Garg, MD, of the University of Western Ontario in London, compared 2,027 living kidney donors with 20,270 matched non-donors. After a median follow-up period of 6.6 years, only one donor received acute dialysis, which translated into 6.5 events per 100,000 person-years, according to an online report in Nephrology Dialysis Transplantation. This rate was no different statistically from the non-donor group, in which 14 subjects required acute dialysis, for a rate of 9.4 events per 100,000 person-years.

“The overall incidence of acute dialysis is very small and will not occur in over 99.99% of donors in the decade following donation,” the investigators wrote. “During this time, living kidney donors are unlikely to suffer from the inciting events that may pre-dispose to acute kidney injury.” Dr. Garg and his colleagues added that when such events occur, “it is possible that the remaining kidney adequately compensates to prevent acute kidney injury.” The researchers said they focused on severe acute kidney injury treated with acute dialysis “as this outcome is well ascertained in our data sources and is the most worrisome event.” ■

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Your Money Target-date funds offer one-stop shopping for investment vehicles and enable investors to own a diverse portfolio BY STAN LUXENBERG

Shifting from stocks to bonds Funds that are designed for people who will retire in 2040 or 2050 start with big allocations to stocks. As the retirement date approaches, the portfolios gradually sell stocks and shift to bonds. Fidelity Freedom 2050 starts with 90% of assets in stocks. By the time the saver retires 40 years later, the fund will only have 49% in stocks. The

icking the right investments for your retirement savings is no easy task. There are more than 10,000 mutual funds and countless stocks and bonds on the market. But to simplify your search, consider a target-date fund. These mutual funds are designed to serve people who will retire in a particular year such as 2020 or 2040. Holding broad collections of stocks and bonds, the funds offer onestop shopping. By buying a single fund, you can own a diverse portfolio that should deliver competitive results and avoid the worst losses in downturns. Because the funds are convenient solutions, they have become favorite investments for 401(k) and other retirement plans. Many employers have selected target funds as default options. Unless employees opt for other choices, plan contributions are automatically invested in target funds. Even during the financial crisis, investors continued pouring into the funds. Now the target funds rank as one of the fastestgrowing fund categories, with $345 billion in assets. A typical target fund achieves diversification by investing in a collection of other funds. T. Rowe Price Retirement 2040 invests in a group of 18 funds. Holdings include T. Rowe Price Growth Stock Fund, T. Rowe Price International Stock Fund, and T. Rowe Price New Income Fund, a bond portfolio. About 40 companies offer target funds. Top choices include Invesco BalancedRisk 2020, Fidelity Freedom 2020, and T. Rowe Price Retirement 2020.

Many employers have selected target funds as default options.

shift is made automatically according to a predetermined plan. Savers need not make any decisions. The funds aim to become more conservative as the saver ages. While stocks tend to deliver bigger returns over the long term, they are riskier than bonds. The target funds seek to focus on bonds during the stage when aging retirees will need reliable income and can’t afford to suffer big losses.

Aggressive funds Though all the funds become more conservative over time, they follow different strategies. Some funds are aggressive and hold relatively large stock positions, while other funds are more cautious and have large bond stakes. At the aggressive end of the spectrum is Goldman Sachs 2040, which has 85% of assets in stocks. A more cautious choice is Fidelity Freedom 2040, which has 71% of assets in stocks. Which fund should you take? That depends on your tolerance for volatility. Either aggressive or cautious funds can work. But before you buy any fund, make sure you pick one that suits your temperament. In bull markets, the aggressive funds should record the best gains. In the difficult markets of recent years, the tamer choices have done the best. The impact

of the divergent approaches became clear during the third quarter of 2011. In a period when most stocks dropped sharply, the aggressive Goldman Sachs fund lost 17.7%, while the cautious Fidelity fund only dropped 13.1%. During the past three years, the cautious Fidelity Freedom fund has returned 11.2% annually, while the Goldman Sachs choice lagged with a return of 9.4%. When you shop for a fund, pay particular attention to the portfolio allocation after the retirement date. Some funds

stays put. Wells Fargo Advantage DJ Target 2050 takes a different approach. The fund starts with 85% of assets in stocks. By the retirement date, there are only 23% of assets in stocks. Then the allocation keeps shifting, so that five years after retirement only 15% of assets are in stocks. For wary investors who worry about losing their nest eggs after retirement, a cautious choice like the Wells Fargo fund may be a sensible solution.

Conservative approaches Faced with volatile markets, some funds have been tinkering with their allocations, shifting to more conservative approaches. But T. Rowe Price has not changed its allocation during the rough times. The company’s 2055 fund has about 90% of assets in stocks. At retirement, the allocation reaches 55%. Then the figure keeps falling, reaching 40% 10 years after retirement. T. Rowe Price argues that clients should prepare for retirements that can last 30 years. Retirees should own stocks that can deliver long-term capital gains. While all the target funds own stocks and bonds, some portfolios hold especially broad mixes that include special-

Some funds are aggressive and hold relatively large stock positions, while other funds are more cautious and have large bond stakes. reach their final allocation on the retirement date. After that the allocation stays fixed—no matter how many years an investor holds the account. Other funds continue lowering their stock allocations after the retirement date. Among funds that are aggressive after the retirement date is American Century LIVESTRONG 2050. The fund starts with 85% of assets in stocks and gradually lowers the figure to 45% on the retirement date. After that the allocation

ized assets. Goldman Sachs 2020 holds emerging market bonds. Those yield more than U.S. securities and can help to diversify portfolios. The managers of Fidelity Freedom 2020 argue that retirees should prepare for inflation, which can erode the purchasing power of people living on fixed income. For protection the Fidelity fund owns commodities. Those can rise along with inflation. Fidelity also holds inflationprotected bonds. ■