Renal & Urology News December 2011 Issue

■ ■ ■

VOLUME 10, ISSUE NUMBER 12

Anemia Care Shifts After Bundling Epoetin use has declined, IV iron use is up

BY JODY A. CHARNOW PHILADELPHIA—The prospective payment system for dialysis services (“bundling”), which went into effect on January 1, 2011, already may be affecting how dialysis centers treat anemia in dialysis patients, according to study findings presented at Kidney Week, the annual meeting of the American Society of Nephrology.

In a study, Katie E. Cardone, PharmD, of the Albany College of Pharmacy and Health Sciences in Albany, N.Y., and colleagues found that epoetin alfa (EPO) use has decreased and intrave-

IN THIS ISSUE 3

Antibiotics may increase kidney stone risk

8

Hyponatremia in cancer patients shown to worsen outcomes

16

Overactive bladder linked to metabolic syndrome

18

PSA testing in the United States and abroad

29

Anonymous kidney donors act out of altruism

36

Healthier eating may improve male fertility A multidisciplinary approach to intractable stone disease PAGE 22

nous (IV) iron use has increased substantially in private dialysis units since the implementation of bundling.

The investigators examined data from two private nonprofit dialysis centers for the periods January to April 2010 (pre-bundling) and January to April 2011 (post-bundling). They evaluated 1,470 patient-months.

Among in-center hemodialysis patients receiving EPO, mean monthly doses decreased from 62,758 IU before bundling to 44,140 IU after bundling was introduced. For those on IV iron, mean monthly doses rose from 306

High FGF-23 in AKI Raises Death Risk

BY JODY A. CHARNOW PHILADELPHIA—Levels of fibroblast growth factor 23 (FGF-23) are elevated in acute kidney injury (AKI) and are associated with an increased risk of death or need for renal replacement therapy (RRT), data presented at Kidney Week 2011 suggest.

FGF-23 is a hormone released by osteocytes that has an important role in phosphate and vitamin D homeostasis.

FGF-23 levels are independently associated with increased mortality in chronic kidney disease and end-stage renal disease. FGF-23 has not been studied in AKI, according to investigators. continued on page 15

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■

■

Epoetin Doses Decline Mean monthly doses of epoetin alfa have declined and mean monthly doses of IV iron have increased since the implementation of a bundled payment system for dialysis services, a study found.

Shown here are the data for patients on in-center hemodialysis.

www.renalandurologynews.com

62,758

453

pre-bundling

post-bundling

Mean monthly epoetin dose (IU) Mean monthly IV iron dose (mg)

44,140 44 140

306

post-bundling

pre-bundling

PHOTO: © BIOPHOTO ASSOCIATES / PHOTO RESEARCHERS, INC.

DECEMBER 2011

Source: Cardone KE et al. Effects of the ESRD Medicare Bundling Rule on Anemia Management agement in Private Dialysis Units Units. Poster presented at American Society of Nephrology’s Kidney Week in Philadelphia, November, 11, 2011.

to 453 mg. Mean hemoglobin (Hb) concentrations were significantly lower after implementation of bundling (11.1 vs. 11.6 g/dL before bundling), but remained within the target range. Both the home hemodialysis and peritoneal dialysis groups had a 0.5 g/dL decrease

in Hb levels in the post-bundle observation period.

In another study presented at the conference, researchers showed that the use of IV iron for managing anemia in HD patients has increased steadily continued on page 13

Testosterone May Not Improve ED

BY JOHN SCHIESZER ORLANDO, FLA.—Testosterone supplementation in elderly men with borderline low testosterone levels may not improve erectile dysfunction (ED) compared with placebo, new findings suggest.

“The existing data on this are mixed,” said study investigator Lauren Roth, MD, a second-year fellow in reproductive endocrinology and infertility at the University of Colorado in Denver. “We expected there would be an improvement.”

Dr. Roth reported study findings at the American Society for Reproductive Medicine annual meeting.

CME FEATURE

She and her colleagues found scores on the Sexual Health Inventory for Men (SHIM) instrument did not improve despite bringing men into the normal androgenic range using transdermal testosterone.

In this study, men aged 60 years or older with borderline low testosterone (T) were treated with low-dose testosterone gel (25 mg/day), conventionaldose testosterone gel (50 mg/day), or placebo gel for one year.

The researchers used two dosing regimens to determine if side effects were dose-dependent. Testosterone levels were measured and SHIM continued on page 14

Earn 1 CME credit in this issue

A Nephrologic Perspective on the Management of Gout PAGE 37

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DECEMBER 2011

Renal & Urology News 3

Antibiotics Could Increase Kidney Stone Risk

BY JODY A. CHARNOW ANTIBIOTIC TREATMENT can decrease colonization of a common intestinal bacterium that metabolizes oxalate, perhaps rendering patients more susceptible to the formation of calcium oxalate kidney stones, according to researchers.

The bacterium, Oxalobacter formigenes (OF) is a commensal organism that colonizes the human colon in a large proportion of the normal adult population. OF bacteria metabolize oxalate as their sole energy source. By decreasing the availability of dietary oxalate for absorption, these bacteria

could lower the risk of hyperoxaluria and thus prevent development of calcium oxalate stones.

In a prospective study of patients undergoing upper endoscopy, investigators led by David S. Goldfarb, MD, Clinical Chief, Nephrology Division, New York University (NYU) Medical

Center and Professor of Medicine and Physiology at the NYU School of Medicine compared the effect of antibiotics on OF colonization in two groups: patients receiving antibiotics to treat gastric infection with Helicobacter pylori and patients without H. pylori who did not receive antibiotics (controls). The researchers identified OF colonization in stool by oxalate degradation at baseline, with confirmation by polymerase chain reaction assay.

The prevalence of OF intestinal colonization was 43.1% among all patients. Among the 12 patients who tested positive for OF but were not receiving antibiotics, 11 (92%) had the bacteria present on stool tests at one and six months. Of the 19 subjects who tested positive for OF and received

The drugs eradicate intestinal bacteria that metabolize oxalate, study finds. antibiotics, only seven (36.8%) continued to be colonized by the bacterium on follow-up stool testing at one and six months, a significant difference between the groups, according to a report in the Journal of Endourology (2011;25:1781-1785).

“Antibiotics markedly reduced the colonization rates with OF, while the control group— people who were [endo]scoped but did not have H. pylori—did not receive antibiotics and did not have elimination of colonization with OF,” said Dr. Goldfarb, Director of the Kidney Stone Prevention Program at Lenox Hill Hospital in New York. “The suggestion here is that antibiotics can leave one at increased risk of stones.”

Previous studies have shown that people who took antibiotics had less colonization by OF, but this had never been shown prospectively, he said.

Additionally, Dr. Goldfarb’s group found that a combination of amoxicillin and clarithromycin caused 62.5% of subjects to become negative for OF at one month; at six months, 56.2% remained negative.

“We did not measure urine oxalate because these patients are not stone formers and measuring oxalate would require careful attention to diets, and for this group that was not tenable,” Dr. Goldfarb noted. ■

4 Renal & Urology News

DECEMBER 2011

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FROM THE EDITOR EDITORIAL ADVISORY BOARD

Dialysis Care in the Post-Bundling Era

F

or the ninth straight year, I came away from Kidney Week (formerly Renal Week), the annual scientific meeting of the American Society of Nephrology, feeling badly that Renal & Urology News can only report on a fraction of the thousands of studies presented at the meeting. This year, as part of our on-site news coverage of Kidney Week for our web site (www.renalandurologynews.com), we prepared reports on 36 of the approximately 4,000 studies presented.

Kidney Week ended toward the end of the production cycle for this issue, but we had enough time to include on our front page a report on three studies presented at the conference suggesting that the care of dialysis patients has changed following implementation of the bundled payment system for dialysis services by the Centers for Medicare & Medicaid Services (CMS). Under this system, dialysis centers are paid a flat fee to cover all dialysis services and drugs.

In one study, a team led by Katie E. Cardone, PharmD, of the Albany College of Pharmacy and Health Sciences found that the use of ESAs has declined and the use of IV iron has increased since the debut of bundling on Jan. 1, 2011. A number of factors might explain these trends, such as FDA changes in prescribing information reducing the recommended hemoglobin level at which epoetin dose is decreased or withheld. In another study, investigators showed that the prevalence of uncontrolled secondary hyperparathyroidism increased sharply among black dialysis patients after the debut of bundling. The researchers suggested that financial constraints resulting from bundling might be a factor in the use of vitamin D analogues.

The January issue will carry full coverage of Kidney Week 2011, which includes a report on a study linking high salt intake with a lower risk of chronic kidney disease. Also, you may want to visit our website to hear Kidney Week podcasts of researchers talking about their studies and attendees responding to a survey question that asked: Do you think many CKD patients are being placed on dialysis too soon?

As 2011 draws to a close, the staff and editorial advisory board of Renal & Urology News would like to thank you for your continued readership. As always, feel free to e-mail me with any suggestions or comments. We hope you have a great holiday season.

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 Assistant art director VP production and manufacturing Production manager Product manager, digital products Audience development director 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 Natasha Marcano-Dillon Louise Morrin Kathleen Millea Chris Bubeck John Crewe Paul Silver Monica Bond William Canning Tanya Gregory Dominic Barone Jim Burke Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 10, Number 12. 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 © 2011.

Contents

DECEMBER 2011

■

VOLUME 10, ISSUE NUMBER 12

Nephrology

ONLINE

16

Biologic Lowers Acute Rejection Rate Alemtuzumab use is associated with a lower incidence of acute rejection compared with rabbit anti-thymocyte globulin induction in unselected kidney and pancreas transplant recipients.

23

Low eGFR Raises Risk of Serious Infections A study of 5,142 community-dwelling individuals aged 65 and older revealed that diminished renal function is associated with a higher risk of infection-related hospitalization.

this month at renalandurologynews.com Expert Q&A Aaron Tobian, MD, PhD, a pathologist at the Johns Hopkins Center for Global Health in Baltimore, argues that the benefits of male circumcision are undeniable.

24

26

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 October winner: Mabel Bodell, MD

3

16

18

News Coverage

“

Anthony J. Bleyer, MD, Professor of Medicine in the Section of Nephrology at Wake Forest University School of Medicine in WinstonSalem, N.C., reviews urate metabolism and excretion as well as the causes, pathophysiology, diagnosis, and treatment of gout.

36

Antibiotics May Increase Kidney Stone Risk The medications can decrease colonization by bacteria that metabolize oxalate, increasing the bioavailability of oxalate and thus raising the risk of kidney stone formation, a study found.

OAB Linked to Metabolic Syndrome Metabolic syndrome is associated with a 2.5 times increased odds of overactive bladder, according to a study of 274 female patients

by Turkish researchers.

PSA Testing: Why the U.S. and Europe Differ Solid evidence for a survival benefit from PSA screening for prostate cancer is lacking, but the practice is more widespread in the United States than in many European countries.

Exercise May Boost Sperm Motility Men who engage in moderate exercise have better sperm motility than sedentary men, according to a new prospective study.

“

Visit our website for on-site reporting from the annual Genitourinary Cancers Symposium in San Francisco, Feb. 2-4.

Kidney Transplants Fail to Stop CAC Researchers who studied 150 renal transplant recipients found that the prevalence of coronary artery calcification increased after receiving their allograft.

A Nephrologic Perspective on the Management of Gout

Urology

The Medical Minute Visit renalandurologynews.com/ the-medical-minute to hear podcast reports on new studies. Our latest include: • Rethink Use of Vitamin Supplements to Ward Off Prostate Cancer • Novel Treatment Promotes Blood Vessel Growth in Diabetics

Drug-Eluting Stents Safe for Older CKD Patients The devices are safe to use in older patients undergoing percutaneous coronary interventions, regardless of renal function.

37 CME Feature

This study suggests that depending on a man’s sperm count, the chances of having a son may not just be a coin flip.

See our story on page 36

27

Departments 4

From the Editor Anemia care after debut of bundling

8

News in Brief Cancer patient mortality, hyponatremia linked

22

On the Forefront Team approach to intractable stone disease

25

Renal Nutrition Update The possible benefits of soy protein

34

Legal Issues in Medicine Trouble for a doc who listened to a salesman

42

Your Money Investing in consumer companies

8 Renal & Urology News

DECEMBER 2011

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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 High Testosterone Could Decrease CV Risk

patients taking the product, a combi-

Total testosterone and sex hormone-

is manufactured by Merck & Co.,

binding globulin (SHBG) levels were

Inc., in Whitehouse Station, N.J. This

inversely associated with the risk

finding contrasts with a 2008 clinical

of cardiovascular (CV) events in a

trial that raised concern because

population-based study of 2,416

cancer developed in substantially

men in Sweden aged 69-81 years.

more patients taking Vytorin than pla-

For the 485 CV events that oc-

cebo. Merck is seeking FDA approval

curred over a median five-year

for use of Vytorin in patients with

follow-up, men in the highest quartile

chronic kidney disease, which would

of testosterone—550 ng/dL or

make it the first treatment of its kind

greater—had a 30% lower risk than

for this indication.

nation simvastatin and ezetimibe that

men in the lower three quartiles. In terone and SHBG, testosterone but

Repeat UTIs May Not Raise Kids’ CKD Risk

not SHBG predicted CV risk, ac-

Although urinary tract infections

cording to a report in the Journal of

(UTIs) in childhood are considered

the American College of Cardiology

a risk factor for chronic kidney

2011;58:1674-1681).

disease (CKD), a literature search

models that included both testos-

revealed that in the absence of

No Increased Cancer Risk with Vytorin

structural kidney abnormalities

The FDA has found no evidence for

the first UTI, the etiologic fraction

elevated cancer risk with Vytorin,

of recurrent childhood UTIs as a

a combination drug that helps to

main cause of CKD appears small,

lower cardiovascular problems, ac-

investigators reported in Pediatrics

cording to a written statement.

(2011;128:840-847). In 1,576

In an evidence review of three clinical

reviewed cases, childhood UTIs were

trials, the FDA found that there was

not the main cause of subsequent

no increase in cancer incidence in

CKD for any patient.

evident in imaging studies after

Prostate Volume Has Little Impact on Laser PVP Efficacy P

rostate volume in men with benign prostatic hyperplasia has little effect on the safety and efficacy of GreenLight HPS laser photoselective vaporization prostatectomy (PVP), researchers reported in the Journal of Endourology (online ahead of print).

Xiao Gu, MD, PhD, of the University of Oklahoma Health Sciences Center in Oklahoma City, and colleagues based that conclusion on a study of 207 men undergoing PVP. The researchers stratified the men into two groups based on prostate volume: 80 mL or greater (57 patients) or less than 80 mL (150 patients). Clinical outcomes (American Urological Association Symptom Score, Quality of Life score, maximum flow rate, and post-void residual volume) showed immediate and stable improvement from baseline in each group, and investigators observed no significant differences between the groups during follow-up. The incidence of adverse events was low and similar in both groups. The authors noted that their study was limited by its observation and retrospective design, and the inability to adjust for all comorbidities.

Hyponatremia Raises Death Risk in Cancer Patients H

yponatremia in cancer patients is associated with longer hospital stays and increased mortality, data show.

The study analyzed 4,702 hospital admissions by 3,357 cancers patients.

Using first admission data, the mean length of stay of 5.6 days for patients with eunatremia (serum sodium levels of 135-147 mEq/L) compared with 9.9, 13, and 11.5 days for those with mild, moderate, and severe hyponatremia (134-130, 129-120, and less than 120 mEq/L, respectively). Compared with patients who had eunatremia, those with mild, moderate, and severe hyponatremia had a 2.0, 4.7, and 3.5 times increased risk of death within 90 days, Simit M. Doshi, MD, MPH, of the University of Texas M.D. Anderson Cancer Center in Houston, and colleagues reported in the American Journal of Kidney Diseases (published online ahead of print).

The Most Costly Ailments Heart disease is the most costly health condition in the United States, according to federal statistics. Shown here are the expenditures, in billions of dollars, for the top most costly medical problems.

100 80

90.9 71.4

T

67.3 59.9

60

56.2 47.3

45.5

44.5

40

34.6

20 0

PCa Diagnosis Risk in BPH Patients Higher In Blacks

Heart Cancer Trauma Disease

Mental Disorders

Ostoarthritis

Hyper- Diabetes COPD, tension Asthma

Back Problems

Source: Center for Financing, Access, and Cost Trends, AHRQ, Household Component of the Medical Expenditure Panel Survey, 2008

he likelihood of men with benign prostatic hyperplasia (BPH) being diagnosed with prostate cancer (PCa) is greater among blacks than whites, researchers reported.

In a study of 398 black men and 1,656 white men followed for a mean of 10.2 years in a health maintenance organization, the risk of a PCa diagnosis was 2.2 times greater for the blacks, after adjusting for serum PSA level, investigators reported in BJU International (2011;108:1302-1308).

In addition, black men were more likely than white men to receive medical therapy for BPH symptoms (43.7% vs. 37.2%), but the researchers observed no clinically meaningful differences with respect to subsequent acute urinary retention or BPH-related surgery.

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Anemia care shifts continued from page 1

from 2002 to 2008, even after declines in the use of erythropoiesis-stimulating agents (ESAs). Their analysis of U.S. Renal Data System data from approximately 250,000 HD patients per year for a seven-year period (2002-2008) revealed that the percentage of patients receiving IV iron increased from 63% in the first quarter of 2002 to 76% in the fourth quarter of 2008.

Mean iron doses rise The mean quarterly iron dose rose from about 500 mg in 2002 to 660 mg in 2008, Janet K. Freburger, PhD, of the University of North Carolina in Chapel Hill, and colleagues reported in a poster presentation. The mean quarterly EPO dose increased from nearly 65,000 IU/month in 2002 to just over 77,000 IU/month in the last quarter of 2006 and then declined to about 71,000 IU/month in 2008. Mean monthly Hb levels trended with EPO dose, increasing from 2002 to the first

Key Points ■ The percentage of patients receiv-

ing IV iron increased from 63% in the first quarter of 2002 to 76% in the fourth quarter of 2008.

■ The mean quarterly iron dose

rose from about 500 mg in 2002 to 660 mg in 2008.

■ The mean quarterly EPO dose

declined from just over 77,000 IU/month in the last quarter of 2006 and to about 71,000 IU/month in 2008.

quarter of 2007 and then subsequently decreasing.

Subgroup differences The investigators say they observed the same general patterns in iron doses, EPO doses, and Hb levels across demographic and clinical subgroups, but noted important differences between subgroups in the amount of iron and EPO received, especially between white and black patients and between shorter and longer dialysis vintage groups. The mean quarterly iron and EPO dose for white patients ranged from 760-850 mg and 61,000-72,000 IU/month, respectively.

Comparatively, doses administered among black patients were higher ranging from 785-890 mg for iron and from 70,000-85,000 IU/month for EPO. Iron dosing was highest and EPO dosing lowest in the shorter (one to two years) dialysis vintage groups.

“The temporal trends in EPO dosing,” Dr. Freburger told Renal & Urology News, “likely represent changes in response to the results of high-target hemoglobin studies among pre-dialysis patients which resulted in changes to ESA labeling, clinical practice guidelines, and the Centers for Medicare & Medicaid Services reimbursement policy for ESA therapy. The reasons behind the growing use of iron are unclear and need further investigation, especially in light of the declining hemoglobin levels in the later years of the study.”

Major dialysis provider’s view Jeffrey L. Hymes, MD, Senior Vice President, Associate Chief Medical Officer and Chairman, Pharmacy and Therapeutics Committee, Fresenius Medical Care North America, a major provider of dialysis services in

Untreated SHPT Increases Mortality Risk in HD Patients PHILADELPHIA—Untreated secondary hyperparathyroidism (SHPT) is associated with increased mortality risk in hemodialysis (HD) patients, according to a report presented at Kidney Week 2011.

Compared with HD patients with parathyroid hormone (PTH) levels of 150-299 pg/mL (reference), those with levels of 500 pg/mL or higher had a significant 33% increased death risk after adjusting for potential confounders.

Francesca Tentori, MD, of Arbor Research Collaborative for Health in

Ann Arbor, Mich., and colleagues analyzed data from 17,476 participants in the Dialysis Outcomes and practice Patterns Study (DOPPS). Of these, 5,728 subjects had no evidence of treatment for SHPT (no vitamin D or cinacalcet prescription for 12 months following study entry).

Compared with subjects receiving SHPT therapy, untreated patients had shorter duration of HD and lower serum PTH levels (mean 217.0 vs. 306.9 pg/mL), according to the investigator. ■

DECEMBER 2011

Renal & Urology News 13

Change in SHPT Care Researchers have found that treatment of secondary hyperparathyroidism (SHPT) in black dialysis patients may have changed after the introduction of bundled payments for dialysis services.

Using data from the DOPPS Practice Monitor, which follows a nationally representative sample of about 140 U.S. dialysis centers service 20 or more chronic HD patients, Francesca Tentori, MD, of the Ann Arbor Research Collaborative for Health in Ann Arbor, Mich., and colleagues found that uncontrolled SHPT has been on the rise among black HD patients since the implementation of bundling. Increased financial constraints resulting from bundling may lead to reduced use of IV vitamin D analogs and thus poorer control of SHPT, they noted in a presentation at Kidney Week. Black patients on average require higher doses of these analogues, so they may be particularly susceptible to this change, they stated.

The researchers examined trends in parathyroid hormone (PTH) values and SHPT therapies from July 2010 to February 2011. The median PTH value increased from 296 to 379 pg/mL among blacks and from 244 to 283 pg/mL among non-black. The prevalence of severe uncontrolled SHPT (defined as a PTH level above 600 pg/mL) increased sharply from 16% on July 2010 to 26% on February 2011, but only slightly from 9% to 11% among non-blacks.

The investigators stated that these changes do not appear to be related to decreased overall use of SHPT treatments—as the proportion of patients prescribed IV vitamin D increased slightly in both blacks and non-blacks—or to changes in serum calcium or phosphorus.

the United States, said that since the implementation of bundling, “We have observed a slight fall in mean hemoglobin values, reflecting fewer patients at levels above 12 g/dL, while the percentage of patients below 10 has remained stable. The average dose of EPO has fallen and iron administration per treatment has increased.”

Factors influencing these trends, according to Dr. Hymes, include FDA changes in prescribing information reducing the recommended Hb level at which EPO dose is reduced or withheld; the recognition that more liberal use of iron can overcome functional

iron deficiency and reduce the need for higher EPO doses in patients’ hyporesponsive to ESAs; and the availability to prescribing physicians of Fresenius’ Corporate Medical Advisory Board algorithms for ESA and iron use, resulting in more timely and accurate dose adjustments.

“We continue to closely monitor trends in these important values,” Dr. Hymes said.

A spokesperson for DaVita, another major American dialysis provider, said none of DaVita’s medical personnel at this time could comment on the trends in ESA and IV iron use. ■

Gout Prevalence High in CKD PHILADELPHIA—Patients with chronic kidney disease (CKD) have a relatively high prevalence of gout compared with the general population, according to data presented at Kidney Week 2011.

In a study of 1,827 patients hospitalized between 2009 and 2010 at St. Elizabeth Health Center in Youngstown, Ohio, Erdal Sarac, MD, of the Northeastern Ohio Universities College of Medicine, Rootstown, and collaborators found that 251 of them (13.7%) had gout. Gout was significantly more prevalent among male than female patients (59.8% vs. 40.2%).

Hyperlipidemia was significantly more

common in CKD patients with gout than without gout (46.2% vs. 38.7%).

Diabetes mellitus was significantly more common in CKD patients without gout than with gout (36.3% vs. 29.8%).

Only 65% of CKD patients with gout received treatment in accordance with guidelines established by the European League Against Rheumatism.

The guidelines contain 12 key recommendations for gout management, such as which drugs to use for acute and recurrent acute attacks and discontinuation of diuretics, if possible, in cases of gout associated with the use of these medications. ■

14 Renal & Urology News

DECEMBER 2011

Testosterone continued from page 1

administered at baseline and six and 12 months.

A total of 56 subjects were in the placebo group (P), 56 were in the lowdose T group (T25), and 55 were in the conventional-dose T group (T50). The three groups did not differ significantly in age or in levels of total or free T at baseline. Additionally, all three groups demonstrated mild to moderate ED based on SHIM scores at baseline.

Over the course of the study, total and free T did not change in the placebo

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ies before that have looked at a similar cohort and [found] an improvement in sexual function, but that included men who were hypogonadal. This was a different group of men who had borderline low testosterone. Men with erectile dysfunction and low testosterone commonly are supplemented with testosterone in an attempt to improve their erectile dysfunction. These data would suggest that it is not beneficial.”

Dr. Roth, who presented the study findings at the meeting, noted that currently there is no defined standard for diagnosing hypogonadism. Most clinicians rely on a laboratory diagnosis (total testosterone below 200 ng/ dL) and symptomatic diagnosis or a combination of both.

Commenting on the study, Dolores J. Lamb, PhD, President-Elect of ASRM, said these findings may affect clinical

practice. “Studies in animal models show that the neural control of sexual motivation and functioning is complex with ‘cross-talk’ of many signaling pathways that ultimately influence sexual behavior,” said Dr. Lamb, Professor, Department of Urology, Baylor College of Medicine in Houston. “This study indicates that perhaps testosterone supplementation is needed for some men, some of the time. ■

Treatment failed to benefit men with borderline low testosterone. group but increased significantly in both treatment groups. However, the investigators observed no change in SHIM scores in any group. “This was surprising,” Dr. Roth told Renal & Urology News. “There have been small stud-

SWL Does Not Raise Diabetes Risk SHOCK WAVE lithotripsy is not associated with an increased risk of developing diabetes mellitus, the researchers reported.

The investigators noted that there is concern about diabetes mellitus resulting from SWL because cases studies have shown that the pancreas is vulnerable to injury from the treatment.

Amy E. Krambeck, MD, of the Mayo Clinic College of Medicine in Rochester, Minn., and colleagues studied 5,287 cases of stone formation in patients without pre-existing diabetes mellitus and at least three months of follow-up. After an average follow-up of 8.7 years, 423 patients (8%) underwent SWL treatment, according to findings published in Urology (online ahead of print). Newonset diabetes mellitus developed in 743 (12%). For 77 patients, the diabetes diagnosis followed SWL. After controlling for age, gender, and obesity, the investigators found no significant association between SWL and diabetes mellitus. ■

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CO, cardiac output; PVR, peripheral vascular resistance; RAAS, renin-angiotensin-aldosterone system.

Not an actual health care professional.

www.renalandurologynews.com

DECEMBER 2011

Renal & Urology News 15

High Uric Acid Level Lowers Mortality in HD Patients HIGH URIC ACID concentrations are associated with lower all-cause and cardiovascular mortality among hemodialysis (HD) patients, according to an international study.

The findings contrast with those of studies of individuals in the general population and “raise the possibility

that higher uric acid concentrations may be cardioprotective in dialysis patients,” researchers concluded in the Clinical Journal of the American Society of Nephrology (2011; ;6;2470-2477).

In a study of 5,827 HD patients from six countries, those with uric acid levels below 8.2 mg/dL had a 24% and 54%

increased risk of all-cause and cardiovascular mortality, respectively, compared with patients who had higher uric acid levels, after adjusting for multiple variables.

Each 1 mg/dL increment in uric acid was associated with a 5% decreased risk of all-cause mortality and 8% decreased risk of cardiovascular mortality.

For additional hypertension control,

In addition, the study showed that younger age, higher body mass index, residual renal function, and diuretic use were significant predictors of high uric acid (above 8.2 mg/dL).

The investigators, led by Rajiv Saran, MD, of the University of Michigan in Ann Arbor, examined data from patients who participated in the Dialysis Outcomes and Practice Patterns Study (DOPPS), which is administered by Arbor Research Collaborative for Health.

Dr. Saran’s group noted that the paradoxical association between high uric acid and lower all-cause and cardiovascular mortality is yet another example of so-called “reverse epidemiology” in the dialysis population.

They speculate that higher uric acid among HD patients is a surrogate for better nutritional status. ■

FGF-23 and AKI continued from page 1

– Renin triggers RAAS activation1

– Many untreated hypertensive patients, including those with diabetes, have an overactive RAAS4 – ACE inhibitors and ARBs only partially block the RAAS1

References: 1. Jackson EK. Renin and angiotensin. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill Companies, Inc; 2006:789-822. 2. Data on file. Clinical study report 2327. Novartis Pharmaceuticals Corp.

3. Chrysant SG, Melino M, Karki S, Lee J, Heyrman R. The combination of olmesartan medoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, double-blind, placebo-controlled, 8-week factorial efficacy and safety study. Clin Ther. 2008;30(4):587-604. 4. Alderman MH, Cohen HW, Sealey JE, Laragh JH. Plasma renin activity levels in hypertensive persons: their wide range and lack of suppression in diabetic and in most elderly patients. Am J Hypertens. 2004;17(1):1-7.

©2011 Novartis

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XHV-1064621

David E. Leaf, MD, of Columbia University Medical Center in New York, and colleagues studied 30 patients with AKI and 30 controls from the medical intensive care unit and general hospital wards at Columbia. The investigators measured FGF-23 levels at baseline and again five days later.

AKI patients had a median FGF-23 level of 1,471 RU/mL, which was significantly greater than the 263 RU/mL level in the control arm. The proportion of AKI patients progressing to death or need for RRT was about 70% for those in the highest tertile of FGF-23 level compared with about 10% among AKI patients in the lowest tertile. After adjusting for age and baseline serum creatinine levels, FGF-23 remained a significant independent predictor of death or need for RRT, with an adjusted odds ratio of 13.7. In addition, the study showed that FGF-23 correlated positively with phosphate and parathyroid hormone levels and negatively with 1,25-hydoxyvitamin D. When asked to comment, Dr. Leaf stated: “This work builds on existing literature suggesting that FGF-23 is an incredibly important hormone in patients with kidney disease. Our study is unique in that it demonstrates the importance of FGF-23 among patients with acute rather than chronic kidney disease, an area in which it has not previously been studied.” ■

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Biologic Reduces Acute Rejection Risk Incidence was lower with alemtuzumab than rabbit anti-thymocyte globulin in transplant recipients

BY JOHN SCHIESZER BOSTON—Alemtuzumab (Alem) use is associated with a lower incidence of acute rejection and infection compared to rabbit anti-thymocyte globulin (rATG) induction in unselected kidney and pancreas transplant recipients, regardless of age or ethnicity, according to a new study presented at the Infectious Diseases Society of America annual meeting.

“What we found somewhat surprising was that there was a lower incidence of biopsy-proven acute rejection in patients receiving alemtuzumab induction,” said study investigator Robert Stratta, MD, Director of Transplantation at Wake Forest University in Winston-Salem, N.C. “This finding was consistent in a number of patient subpopulations.

We looked at low and high immunologic responders, younger and older patients, as well as African Americans and Caucasians.”

An increased risk of infectious complications (ICs) after kidney/pancreas transplantation is an ongoing major concern when using lymphocyte depleting antibody induction agents

Study: Stone Type Linked To Obesity IN PATIENTS WHO form renal and ureteral stones, obesity is associated with a higher risk of stones composed of uric acid (UA) compared with other compounds, according to report in the Korean Journal of Urology (2011;52:622-625).

In a study of renal and ureteral stones removed surgically from 490 patients, obese patients

such as Alem and rATG, according to the investigators.

In a randomized trial that enrolled 222 adult kidney/pancreas transplant patients, 113 subjects received single-dose Alem (30 mg) and 109 received alternate day rATG (1.5 mg/kg) induction. All patients received maintenance therapy consisting of tacrolimus, mycophenolic acid, and risk stratification to determine early steroid elimination. The two treatment arms were similar with respect to demographic characteristics.

Patients received prophylaxis for fungal infections for four to eight weeks, pneumocystis prophylaxis for 12 months, and prophylaxis against cytomegalovirus for three to six months. ICs were graded according to National Institute of Health (NIH) Clinical Toxicity Criteria (CTCAE version 3.0).

After a minimum follow-up of 24 months, the overall patient survival rate was 95%, the kidney survival rate was 90%, and the pancreas survival rate was 85%. The researchers observed no significant survival differences between study arms.

Robert Stratta, MD

“We also found that the single most important risk factor for infection was the presence of biopsy proven acute rejection,” Dr. Stratta told Renal & Urology News.

The incidence of biopsy proven acute rejection (BPAR) was lower in the Alem recipients (16%) than in the rATG group (26%). The presence of BPAR increased the overall risk of ICs from 41% to 72%.

ICs developed in 61 Alem patients (54%) and 81 rATG patients (74%).

The investigators found no significant differences in the incidence or severity of ICs according to recipient ethnicity or age either in the Alem or rATG induction groups.

Among patients older than 60 years, the researchers observed no differences in the number of patients with infection or in the rate of hospitalization for infection compared with younger patients.

The severity of ICs in older patients compared with younger patients was similar regardless of recipient ethnicity.

It had been theorized that older adults, because of their aging immune systems, would be less likely to reject their transplanted organ and therefore would require less immunosuppression, Dr. Stratta said. “However, because older adult patients are receiving more expanded criteria donor kidneys, their risk of rejection is actually higher with these types of kidneys. Consequently, under-immunosuppressing older patients will have a negative effect on outcomes,” he explained. ■

OAB Tied to Metabolic Syndrome METABOLIC SYNDROME is associated with overactive bladder (OAB) in women, according to researchers.

In a study of 274 female patients, investigators Hakki Uzun, MD, and Orhan Unal Zorba, of Rize University in Rise, Turkey, metabolic syndrome was diagnosed in 201 (64%) of 313 with OAB compared with 73 (35%) of 208 patients without OAB, a significant difference between the groups. In multivariate analysis, metabolic syndrome was associated with a 2.5 times increased odds of OAB, the researchers reported online ahead of print in Urology.

The OAB group had significantly greater waist circumference and body mass index compared with the non-OAB patients (98.73 vs. 91.55 cm and 31.37 vs. 27.71 kg/ m2, respectively), as well as a significantly higher incidence of hypertension (53% vs. 5%), and lower level of high-density lipoprotein (52.75 vs. 57.25 mg/dL).

“The metabolic syndrome can be an etiologic pathway for the onset of symptoms, and avoiding a sedentary lifestyle and poor eating habits with weight loss or improvement in the treatment targeted toward the metabolic syndrome might be a worthwhile research area

to develop into a potential therapeutic modality,” the authors concluded.

In a discussion of possible reasons for the link between metabolic syndrome and OAB, Drs. Uzun and Zorba said it is postulated that pro-inflammation and myopathy of the bladder can precipitate detrusor overactivity. Previous studies have suggested an association between OAB and obesity.

For the study, the researchers defined OAB as urinary urgency with or without urgency incontinence that is usually associated with increased daytime frequency and nocturia. ■

were nearly 3.5 times more likely to form UA stones than stones made of both calcium oxalate and calcium phosphate (COP) and 2.8 times more likely to form UA stones than calcium phosphate (CP) stones. Obese patients also were 2.7 times more likely to form calcium oxalate (CO) than COP stones and two times more likely to form CO than CP stones.

■

Leading Urologists Favor Routine PSA Tests MOST LEADING urologists recommend routine PSA testing for men aged 50 and older, despite a recent U.S. panel’s recommendation, according to a survey

by U.S. News World & Report.

The survey found that 95% of leading urologists disagreed with the U.S. Preventive Services Task Force conclu-

sion, based on a review of evidence, that PSA screening served no benefit for men under the age of 75. In addition, 97% of the urologists said that they would undergo PSA testing themselves.

The magazine conducted the survey through “America’s Top Doctors,” a peer-nominated rankings directory

developed by Castle Connolly Medical Ltd. and managed by a physician-led research team.

Nearly 40% of leading internists— usually the doctors who order PSA testing for patients—expressed uncertainty as to whether or not the test exposed men to potential harm. ■

18 Renal & Urology News

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■ FEATURE

PSA Testing: Why the U.S. and Europe Differ Solid evidence for a survival benefit from PSA screening for prostate cancer is lacking, but the practice is more widespread in the U.S. BY DELICIA HONEN YARD

xpert guidelines panels of the American Urological Association and the European Association of Urology (EAU) have concluded that using the PSA test for prostate cancer (PCa) detection remains controversial. Still, different PSA screening patterns have evolved in the United States and Europe, observes Gerhard J. Fuchs, MD, Co-Director of Cedars-Sinai Urology Center in Los Angeles. Dr. Fuchs is certified through both the American and German boards of urology.

“Both guideline panels concluded as recently as 2009, that there is, to date, no evidence-based clinical data showing a survival benefit for a population-based

PSA screening program for all men in a given population,” Dr. Fuchs said.

“In reality,” he adds, “these differences are driven by the urologists’ interpretation of the expert guideline recommendations, the role of prostate cancer awareness in the public, medical and economic concerns and interests of the urologists, and also to a great extent by patient demand as a result of public awareness.”

Generally speaking, the AUA supports prostate screening in men aged 40 years and older. Yet the EAU does not recommend mass screening (European Urology 2011;59 [1]:e1-e4; available at www.europeanurology.com/article /S0302-2838(10)01004-3/fulltext).

“The AUA as well as the American Cancer Society (ACS) currently recommend that patients make informed deci-

sion regarding screening,” says Richard Hoffman, MD, MPH, Associate Professor of Epidemiology and Preventive Medicine at the University of New Mexico (UNM) School of Medicine in Albuquerque. “In the early 1990s these organizations did indeed recommend mass screening. At the time, the data suggested that PSA was far more sensitive than digital rectal examination in detecting cancer and more likely to detect cancers at an earlier stage—when men could be offered curative therapies.”

However, the benefit of screening had not been evaluated in randomized trials, and such organizations as the U.S. Preventive Services Task Force and the American College of Physicians did not endorse the practice. “Over time, evidence accumulated indicat-

Richard Hoffman, MD, is Associate Professor at the University of New Mexico School of Medicine in Albuquerque.

J. Brantley Thrasher, MD, is Chair of the Department of Urology at the University of Kansas Medical Center in Kansas City.

Gerhard J. Fuchs, MD, is Co-Director of the Cedars-Siani Urology Center in Los Angeles.

This is Part 2 of a series. Part 1 of this feature appeared in our November issue.

E

ing that PSA testing could lead to overdiagnosis, thus unnecessarily subjecting men to the harms of treatment,” observes Dr. Hoffman, a general internist with a focus in prostate disease. “This led AUA and ACS to change their position away from mass screening towards informed decision making.”

The EAU policy on PSA screening isn’t enacted uniformly throughout the continent. “Austria basically has a nationwide ability to screen, whereas in other countries you may have doctors that are saying, ‘I’m sorry, but we refuse to draw a PSA or do a screening on you at this age,’ and they send the patient home,” observed J. Brantley Thrasher, MD, the William L. Valk Chair of the Department of Urology at the University of Kansas Medical Center in Kansas City and a member of the American Urological Association (AUA) board of directors.

Dr. Hoffman explains this. “The Europeans from the start recognized the lack of evidence for screening—and the potential harms—which is indicated in the wording of various European guidelines,” he says. “I think this is one of the major factors accounting for lack of European endorsements for screening.”

The United States, however, has enthusiastically supported prostate cancer screening. “The U.S. Postal Service even issued a stamp endorsing screening,” Dr. Hoffman points out. “Unfortunately, as Otis Brawley, chief medical

20 Renal & Urology News

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PSA Testing Milestones Two large studies of PSA screening published Proportion of men

U.S. Preventive

in the New England Journal

aged 50-79 years who

of Medicine: a European study

Services Task Force

had a PSA test within the

showing that PSA screening

recommends that healthy

FDA approved the first

FDA approved the

past two years: 49%,

reduced the risk of prostate

men should not undergo

PSA test for monitoring

PSA test for use in

according to the 2005

cancer death by 20%, and a

PSA screening, saying

patients diagnosed with

diagnosing prostate

National Health

U.S. study showing no

the potential harms

prostate cancer

cancer

Interview Survey

PCa survival benefit

outweigh any benefits

1986

1992

2005

2009

2011

Sources: National Cancer Institute; Cancer Epidemiology, Biomarkers & Prevention (2008;17:636-644).

officer of the ACS, pointed out in an October 20, 2009, New York Times interview [www.nytimes.com/2009/10/21 /health/21cancer.html], screening has probably been oversold: The actual benefits are far less substantive than the public has been led to believe and there are indeed harms resulting from screening.”

Nevertheless, Dr. Brawley’s words may not be strong enough to make much of a dent in our national prostate cancer consciousness. “In the USA, there is much more public awareness about prostate cancer through celebrity prostate cancer cases, prostate cancer support groups, public fundraising events, and television advertisements from pharmaceutical companies than there is in the European Union [EU],” Dr. Fuchs says.

“This has led to a very significant direct patient demand to be tested. In the EU, patient awareness and patient advocacy for prostate cancer early detection is rudimentary in comparison.”

In addition, Dr. Fuchs notes, an increasing amount of government and private funding for targeted prostate cancer research has further fueled the interest of the academic urological community and public awareness, thereby raising again the demand for early detection in the hope of an eventual survival benefit.

“In comparison, prostate cancer awareness in the European Union is more sporadic and geographically diverse, and by far not as much of a driver for PSA testing demand,” Dr. Fuchs concludes.

Medicolegal influence Perhaps a less litigious environment in the United States would bring our testing practices more in line with that in Europe.

As it is, however, U.S. physicians are better off toeing the line, as Dr. Thrasher illustrates with a hypothetical scenario.

“If I don’t give a PSA test and the patient is diagnosed with prostate cancer, or if the patient asks for a test and I refuse him because he’s not in the age range or high-risk group, and it turns out he does have prostate cancer, what sort of medicolegal problem do I get myself into?”

U.S. practitioners may have no choice but to think that way. “The fear of getting sued is much more of an issue here than just about anywhere else that I’ve been in the world,” Dr. Thrasher says. “When I was in Egypt, for example, the doctors there said that this is absolutely not an issue for them.”

Once a PSA test has been performed, many U.S. urologists feel obligated to conduct serial testing to avoid later legal issues should the patient eventually develop prostate cancer, a situation that could lay the groundwork for a claim of negligent follow-up. “In the EU, these issues are far less prominent, as health-care expenditures for the most part are not point-of-care but bundled, with no financial incentive, and patient demand is by far less,” Dr. Fuchs says.

UNM’s Dr. Hoffman agrees that malpractice concerns are a driving force in American screening practices. “One of the issues is that discussing screening is challenging and time-consuming, and tests are often ordered without any discussion,” he says. “One remedy for this, pointed out by the [March 2010] ACS guidelines, is to provide patients with decision aids to support informed decision making [CA: A Cancer Journal for Clinicians. 2010;60(2):70-98; available at http://caonline.amcancersoc .org/cgi/content/full/caac.20066v1]. Some legal experts argue that a decision made after reviewing a decision aid is more binding than an informed consent.”

During his visit to Egypt, Dr. Thrasher heard many questions as to whether the

nation should adopt PSA and mammography screening to help reduce mortality from prostate and breast cancers—a prospect that could put Egypt’s health-care system on a slippery slope. “You have to then start looking at where the lines cross between early detection and screening and end-of-life issues, and keeping these people alive or treating the latter part of their disease process, and how much it’s costing the government,” Dr. Thrasher says.

“But I will say this,” he adds. “In the places where PSA screening has not been done, such as Mexico or the continent of Africa, you still see death rates from prostate cancer climb. In countries where it is being done, you’re seeing the prostate cancer death rate continue to decline.”

Economics has a hand in these survival trends in the United States, according to Dr. Hoffman. “PSA screening has detected millions of early-stage cancers, which has led to marked increases in

building radiation therapy facilities, for which prostate cancer is the major indication; increased use of robotic surgeries—again, for which prostate cancer is the leading indicator; and increased use of androgen deprivation,” he confirms. “Because prostate cancer is being diagnosed at such an early stage, all surgical treatments and radiation therapies will be associated with high five-year survivals, as is the option of no treatment—and we certainly lack sufficient evidence to conclude that the newer techniques lead to better outcomes than the older techniques.”

As Dr. Fuchs points out, large patient cohort PSA screening studies are under way here (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) and in the EU (the European Randomized Study of Screening for Prostate Cancer). Prostate cancer mortality is a main endpoint to be assessed, with analyses expected by 2013, he says. ■

Beyond PSA While researchers debate whether PSA screening prevents deaths from prostate cancer (PCa), new urine tests may enable clinicians to better discriminate clinically insignificant prostate tumors with low metastatic potential from aggressive prostate cancers. Such tests could identify men who can be placed on active surveillance, thus avoiding treatment-related complications such as urinary incontinence and erectile dysfunction.

One such test is the prostate cancer gene 3 (PCA3) assay (Progensa), which is being developed by Gen-Probe Inc., of San Diego. In a European study of 516 men, an increasing PCA3 score corresponded with an increasing probability of a positive prostate biopsy, according to a report in The Journal of Urology (2011;185:2119-2125). The mean PCA3 score was significantly higher in men with a positive compared with a negative biopsy and significantly higher in men with a biopsy Gleason score of 7 or greater than in those with a biopsy Gleason score below 7. The authors concluded that the assay is superior to total PSA, PSA density, and percent-free PSA in predicting initial biopsy outcome and may reflect PCa aggressiveness.

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On the Forefront

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

Renal ATPV for Patients with Intractable Stone Disease

BY MARK J. NOBLE, MD, STUART M. FLECHNER, MD, ALVIN WEE, MD, KATHY COFFMAN, MD, JAMES SIMON, MD, AND MICHELLE ANTHONY, RN

S

ome patients have recurrent nephrolithiasis that may prove refractory to all known preventive strategies. Such individuals can experience frequent bouts of renal colic that result in narcotic dependency, long-term disability, and depression.

As a long-term solution, we offer such patients the option of renal preservation by means of autotransplantation with pyelovesicostomy (ATPV) (Figure 1).

At Cleveland Clinic, we employ a multidisciplinary approach to deal with such cases. Nephrologists focus on medical and dietary prophylaxis against new kidney stone formation, aiming for correction of any detectable metabolic risk factors plus ensuring adequate hydration and dietary modification.

Patients who continue with frequent stone events despite such measures are then considered by the urology department for the above procedure.

This is a complex, lengthy, and highly-technical surgery that can be life-

Figure 1. Autotransplant with modified pyelovesicostomy (detail in inset)

changing in its scope. Hence, all patients considered for ATPV are first screened by our transplant psychiatrist, by a urologist who subspecializes in endourology, and by a second urologist who subspecializes in renal transplantation.

For example, eight years ago, a 31-yearold female patient with cystinuria refractory to optimal medical management, underwent left nephrectomy, ex-vivo removal of all stones, ex-vivo reconstruction for multiple renal arteries, and then transplantation into the ipsilateral iliac

fossa. The technique of pyelovesicostomy was modified from that originally described by Boari and utilized the upper third of the transplant ureter incorporated longitudinally into the bladder flap to create a fully-refluxing, large diameter, tubularized connection with the bladder lumen. The opposite kidney was moved in similar fashion four months later. The patient became narcotic-free and rejoined the workforce.”

To date, we have mean follow-up of 42 months on 12 such patients and 15 renal

Volume Loss as the Predominant Determinant of Ultimate Renal Function after PN

BY STEVEN C. CAMPBELL, MD, AND MATTHEW N. SIMMONS, MD

T

he objectives of partial nephrectomy (PN) for kidney cancer are to optimize cancer control by obtaining negative margins while preserving as much renal function as possible. Most conventional PNs are facilitated by temporary clamping of the renal vasculature along with hypothermia if the ischemic interval is likely to extent beyond 20-25 minutes. This allows the surgery to be performed in a bloodless field and minimizes the potential for ischemic damage.

Until recently, the main focus in this field has been on minimizing the warm isch-

emic time (WIT), because this appeared to be the most important modifiable factor during PN. Indeed, most studies demonstrated a strong correlation between ischemic interval and ultimate renal function. In one such study, each additional minute of warm ischemia correlated with a 5%-6% increase in the risk of acute renal failure or new onset chronic kidney disease. Such data argue strongly in favor of any surgical approach that could minimize or eliminate warm ischemia.

However, most of these studies did not incorporate parenchymal volume loss into the analysis, and allowed ischemia time to serve to some extent as a surrogate predictor of ultimate renal function. Our recent analysis of large

subgroups of patients undergoing PN in a solitary kidney has demonstrated a strong correlation between volume loss and ischemia time, which is intuitive.

A more difficult PN requiring greater parenchymal volume loss will take longer, whereas a simple PN will be associated with a very brief ischemic interval.

When both volume loss and WIT were incorporated into the analyses, volume loss stood out as the predominant factor determining ultimate renal function after PN, whereas WIT only achieved statistical significance on multivariate analysis when it was extended beyond 25 minutes. Most previous studies in this literature were misleading in that they did not incorporate the volume loss factor

units (three patients underwent staged, bilateral procedures). There have been no failures, and renal function has been the same or better in all cases. Narcotic use was reduced in these patients, as were subsequent stone events per year.

Although ileal ureteral substitution provides a large conduit for stone passage and can relieve painful colic, it can result in reabsorption of urea and other solutes, thus placing a greater load on kidneys. Further, ileal ureteral substitution does little to prevent future stone formation, whereas our ATPV technique, with freely-refluxing systems, provides a measure of mechanical prevention due to crystal washout, thus compensating for the failure of metabolic approaches in these difficult cases.

In summary, renal autotransplantation and modified pyelovesicostomy offers patients with intractable stone disease the opportunity to experience improvement in their quality of life by reducing pain and narcotic use and by preventing many stone interventions in this group of individuals. ■ The authors are affiliated with the Glickman Urological and Kidney Institute of Cleveland Clinic.

and thereby allowed WIT to subsume all of the predictive capacity.

In summary, recent studies suggest a more nuanced appreciation of the factors that determine renal function after PN, and this has direct implications with respect to surgical technique. Given the predominance of volume loss, precision during tumor excision and reconstruction of the kidney to preserve as much vascularized parenchyma, appears to be of primary importance. As long as the ischemic interval is short or a hypothermic approach is applied, most nephrons will recover. A short ischemic interval, by providing a bloodless field, may facilitate a precise PN and thus allow for optimal recovery of renal function. ■ The authors are with the Center for Urologic Oncology at Cleveland Clinic’s Glickman Urological and Kidney Institute.

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DECEMBER 2011

Renal & Urology News 23

Low eGFR Increases Risk of Serious Infections DECREASED KIDNEY function places elderly individuals at higher risk of infection-related hospitalization, according to a study.

The study, which included 5,142 community-dwelling individuals aged 65 and older who participated in the Cardiovascular Health Study (CHS), found that the risk increases with declining estimated glomerular filtration rate (eGFR). Compared with individuals with an eGFR of 90 mL/ min/1.73 m2 or higher, those with an eGFR of 60-89, 45-59, and 15-44 are at 16%, 37%, and 64% greater risk, respectively, of infection-related hospitalization, researchers reported online in the American Journal of Kidney Diseases. Each 10 mL/min/1.73 m2 decrease in eGFR was associated with an 8% increased risk.

“These findings highlight that even moderate degrees of decreased kidney function are associated with clinically

plication of late-stage kidney disease as indicated by markedly high rates of infection and infection-related deaths in persons with end-stage renal disease on dialysis. Few studies have looked at whether less severe renal impairment is associated with infection risk, they stated.

“Kidney disease is a continuum, and alterations in immune cellular function may develop well before end-stage renal disease, similar to other metabolic abnormalities associated with kidney disease,” the researchers noted.

A major strength of the study, the investigators observed, was the use of

For your OAB patients with urge urinary incontinence

Any moment is an accident waiting to happen.

Help reduce their concern with the powerful efficacy of TOVIAZ1-4

The risk increased by 8% for each 10 mL/min/1.73m2 decrease in eGFR. significant higher risks of serious infection in older individuals,” the authors, led by Lorien S. Dalrymple, MD, MPH, of the University of California at Davis, concluded.

During a median follow-up of 11.5 years, 20% of the CHS participants had one infection-related hospitalization and 10% had two or more infection-related hospitalizations, the study found.

The association between kidney function and infection-related hospitalization may be due to increased susceptibility to infection, increased severity of infection, or both, in older patients with chronic kidney disease, according to the investigators.

They pointed out that altered immune cell function is a known clinical com-

Be sure to visit renalandurologynews.com for our on-site coverage of the Genitourinary Cancers Symposium in San Francisco, Feb. 2-4.

cystatin C rather than serum creatinine to estimate kidney function. This allowed them to examine more directly the association between kidney function and infection in older adults, as older populations may have low serum creatinine levels because of low muscle mass or malnutrition. ■

TOVIAZ is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

Important Safety Information TOVIAZ is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma, and in patients with known hypersensitivity to the drug or its ingredients or to DETROL® (tolterodine tartrate) tablets or DETROL® LA (tolterodine tartrate extended release capsules).

Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine, in some cases after the first dose. Patients should be advised to promptly discontinue fesoterodine therapy and seek immediate medical attention if they experience edema of the tongue, laryngopharynx, or difficult breathing.

TOVIAZ tablets should be used with caution in patients with clinically significant bladder outlet obstruction, decreased gastrointestinal motility, controlled narrow-angle glaucoma, or myasthenia gravis.

The recommended starting dose of TOVIAZ is 4 mg once daily swallowed whole. Based upon individual response and tolerability, the dose may be increased to 8 mg once daily. Doses greater than 4 mg are not recommended in patients with severe renal insufficiency (CLCR <30 mL/min), or in patients taking a potent CYP3A4 inhibitor; in patients taking a weak or moderate CYP3A4 inhibitor, careful assessment at 4 mg is advised prior to increasing to 8 mg. TOVIAZ is not recommended for use in patients with severe hepatic impairment (Child-Pugh C).

The most frequently reported adverse events (≥4%) for TOVIAZ were: dry mouth (placebo, 7%; TOVIAZ 4 mg, 19%; TOVIAZ 8 mg, 35%) and constipation (placebo, 2%; TOVIAZ 4 mg, 4%; TOVIAZ 8 mg, 6%).

OAB=overactive bladder.

References: 1. Chapple C, Van Kerrebroeck P, Tubaro A, et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol.

2007;52(4):1204-1212. 2. Dmochowski RR, Peters KM, Morrow JD, et al. Randomized, double-blind, placebo-controlled trial of flexible-dose fesoterodine in subjects with overactive bladder. Urology. 2010;75(1):62-68. 3. Herschorn S, Swift S, Guan Z, et al. Comparison of fesoterodine and tolterodine extended release for the treatment of overactive bladder: a headto-head placebo-controlled trial. BJU Int. 2010;105(1):58-66. 4. Kaplan SA, Schneider T, Foote JE, et al. Superior efficacy of fesoterodine over tolterodine extended release with rapid onset: a prospective, head-to-head, placebo-controlled trial. BJU Int. 2011;107(9):1432-1440.

For more information, visit www.ToviazHCP.com.

Please see brief summary of prescribing information on next page.

PUSH BACK ON OAB

24 Renal & Urology News

DECEMBER 2011

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Drug-Eluting Stents Safe for Older CKD Patients DRUG-ELUTING stents are safe to use in older patients undergoing percutaneous coronary interventions regardless of renal function, researchers concluded.

In addition, use of these stents are associated with lower risks of death and myocardial infarction (MI) in patients

with normal renal function and most subgroups of patients with chronic kidney disease (CKD) compared with the use of bare-metal stents, according to a report in the Journal of the American College of Cardiology (2011;58:1859-1869).

Drug-eluting stents have emerged as the stent of choice for CKD patients in

TOVIAZ® (fesoterodine fumarate) extended release tablets Rx only BRIEF SUMMARY OF PRESCRIBING INFORMATION. The following is a brief summary only; see full Prescribing Information for complete product information.

INDICATIONS AND USAGE: Toviaz is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

DOSAGE AND ADMINISTRATION: The recommended starting dose of Toviaz is 4 mg once daily. Based upon individual response and tolerability, the dose may be increased to 8 mg once daily.

The daily dose of Toviaz should not exceed 4 mg in the following populations: s 0ATIENTS WITH SEVERE RENAL IMPAIRMENT #,#2 M, MIN s 0ATIENTS TAKING POTENT #90 ! INHIBITORS SUCH AS KETOCONAZOLE ITRACONAZOLE AND CLARITHROMYCIN 4OVIAZ IS NOT RECOMMENDED FOR USE IN PATIENTS WITH SEVERE HEPATIC IMPAIRMENT #HILD 0UGH # ;SEE WARNINGS AND PRECAUTIONS; USE IN SPECIFIC POPULATIONS; and DRUG INTERACTIONS].

4OVIAZ SHOULD BE TAKEN WITH LIQUID AND SWALLOWED WHOLE 4OVIAZ CAN BE ADMINISTERED WITH OR WITHOUT FOOD AND SHOULD not be chewed, divided, or crushed.

CONTRAINDICATIONS Toviaz is contraindicated in patients with urinary retention, gastric retention, or uncontrolled NARROW ANGLE GLAUCOMA 4OVIAZ IS ALSO CONTRAINDICATED IN PATIENTS WITH KNOWN HYPERSENSITIVITY TO THE DRUG OR ITS INGREDIENTS OR TO TOLTERODINE TARTRATE TABLETS OR TOLTERODINE TARTRATE EXTENDED RELEASE CAPSULES ;SEE MECHANISM OF ACTION].

WARNINGS AND PRECAUTIONS: Angioedema: !NGIOEDEMA OF THE FACE LIPS TONGUE AND OR LARYNX HAS BEEN REPORTED WITH FESOTERODINE )N SOME CASES ANGIOEDEMA OCCURRED AFTER THE FIRST DOSE !NGIOEDEMA ASSOCIATED WITH UPPER AIRWAY SWELLING MAY BE LIFE THREATENING )F INVOLVEMENT OF THE TONGUE HYPOPHARYNX OR LARYNX OCCURS FESOTERODINE SHOULD BE PROMPTLY DISCONTINUED AND APPROPRIATE THERAPY AND OR MEASURES TO ENSURE A PATENT AIRWAY SHOULD BE PROMPTLY PROVIDED Bladder Outlet Obstruction: Toviaz should be administered with caution to patients with clinically significant bladder OUTLET OBSTRUCTION BECAUSE OF THE RISK OF URINARY RETENTION ;SEE CONTRAINDICATIONS].

Decreased Gastrointestinal Motility: 4OVIAZ LIKE OTHER ANTIMUSCARINIC DRUGS SHOULD BE USED WITH CAUTION IN patients with decreased gastrointestinal motility, such as those with severe constipation.

Controlled Narrow-Angle Glaucoma: 4OVIAZ SHOULD BE USED WITH CAUTION IN PATIENTS BEING TREATED FOR NARROW ANGLE GLAUCOMA AND ONLY WHERE THE POTENTIAL BENEFITS OUTWEIGH THE RISKS ;SEE CONTRAINDICATIONS].

Hepatic Impairment: Toviaz has not been studied in patients with severe hepatic impairment and therefore is not RECOMMENDED FOR USE IN THIS PATIENT POPULATION ;SEE USE IN SPECIFIC POPULATIONS and DOSAGE AND ADMINISTRATION].

response to the high stenosis rates of 13% to 35% observed with bare-metal stents, the researchers noted.

The findings, by Thomas Tsai, MD, MSc, of the Denver VA Medical Center, and colleagues emerged from an analysis of data from 283,593 patients aged 65 years and older who received stents

0ATIENTS ALSO RECEIVED 4OVIAZ FOR UP TO THREE YEARS IN OPEN LABEL EXTENSION PHASES OF ONE 0HASE AND TWO 0HASE CONTROLLED TRIALS )N ALL OPEN LABEL TRIALS COMBINED

AND PATIENTS RECEIVED 4OVIAZ FOR AT LEAST MONTHS YEAR YEARS AND YEARS RESPECTIVELY 4HE ADVERSE EVENTS OBSERVED DURING LONG TERM OPEN LABEL STUDIES WERE SIMILAR TO THOSE OBSERVED IN THE WEEK PLACEBO CONTROLLED STUDIES AND INCLUDED DRY MOUTH CONSTIPATION DRY eyes, dyspepsia, and abdominal pain. Similar to the controlled studies, most adverse events of dry mouth and constipation were mild to moderate in intensity. Serious adverse events, judged to be at least possibly related to study MEDICATION BY THE INVESTIGATOR AND REPORTED MORE THAN ONCE DURING THE OPEN LABEL TREATMENT PERIOD OF UP TO YEARS

INCLUDED URINARY RETENTION CASES DIVERTICULITIS CASES CONSTIPATION CASES IRRITABLE BOWEL SYNDROME CASES

AND ELECTROCARDIOGRAM 14 CORRECTED INTERVAL PROLONGATION CASES Post-marketing Experience: The following events have been reported in association with fesoterodine use in WORLDWIDE POST MARKETING EXPERIENCE Eye disorders: Blurred vision; Cardiac disorders 0ALPITATIONS General disorders and administrative site conditions: hypersensitivity reactions, including angioedema with airway obstruction, face edema; Skin and subcutaneous tissue disorders: Urticaria, pruritus. Because these spontaneously reported events are FROM THE WORLDWIDE POST MARKETING EXPERIENCE THE FREQUENCY OF EVENTS AND THE ROLE OF FESOTERODINE IN THEIR CAUSATION cannot be reliably determined.

DRUG INTERACTIONS Antimuscarinic Drugs: #OADMINISTRATION OF 4OVIAZ WITH OTHER ANTIMUSCARINIC AGENTS THAT PRODUCE DRY MOUTH

CONSTIPATION URINARY RETENTION AND OTHER ANTICHOLINERGIC PHARMACOLOGICAL EFFECTS MAY INCREASE THE FREQUENCY AND OR SEVERITY OF SUCH EFFECTS !NTICHOLINERGIC AGENTS MAY POTENTIALLY ALTER THE ABSORPTION OF SOME CONCOMITANTLY ADMINISTERED drugs due to anticholinergic effects on gastrointestinal motility.

CYP3A4 Inhibitors: $OSES OF 4OVIAZ GREATER THAN MG ARE NOT RECOMMENDED IN PATIENTS TAKING POTENT #90 !

INHIBITORS SUCH AS KETOCONAZOLE ITRACONAZOLE AND CLARITHROMYCIN #OADMINISTRATION OF THE POTENT #90 ! INHIBITOR KETOCONAZOLE WITH FESOTERODINE LED TO APPROXIMATELY A DOUBLING OF THE MAXIMUM CONCENTRATION #max AND AREA UNDER THE CONCENTRATION VERSUS TIME CURVE !5# OF HYDROXYMETHYL TOLTERODINE (-4 THE ACTIVE METABOLITE OF FESOTERODINE #OMPARED WITH #90 $ EXTENSIVE METABOLIZERS NOT TAKING KETOCONAZOLE FURTHER INCREASES IN THE EXPOSURE TO (-4 WERE OBSERVED IN SUBJECTS WHO WERE #90 $ POOR METABOLIZERS TAKING KETOCONAZOLE ;SEE WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].

4HE EFFECTS OF WEAK OR MODERATE #90 ! INHIBITORS WERE NOT EXAMINED CYP3A4 Inducers: .O DOSING ADJUSTMENTS ARE RECOMMENDED IN THE PRESENCE OF #90 ! INDUCERS SUCH AS RIFAMPIN AND CARBAMAZEPINE &OLLOWING INDUCTION OF #90 ! BY COADMINISTRATION OF RIFAMPIN MG ONCE A DAY #max AND !5# OF THE ACTIVE METABOLITE OF FESOTERODINE DECREASED BY APPROXIMATELY AND RESPECTIVELY AFTER ORAL ADMINISTRATION OF 4OVIAZ MG 4HE TERMINAL HALF LIFE OF THE ACTIVE METABOLITE WAS NOT CHANGED CYP2D6 Inhibitors: 4HE INTERACTION WITH #90 $ INHIBITORS WAS NOT TESTED CLINICALLY )N POOR METABOLIZERS FOR #90 $

REPRESENTING A MAXIMUM #90 $ INHIBITION #max AND !5# OF THE ACTIVE METABOLITE ARE INCREASED AND FOLD

RESPECTIVELY .O DOSING ADJUSTMENTS ARE RECOMMENDED IN THE PRESENCE OF #90 $ INHIBITORS Drugs Metabolized by Cytochrome P450: In vitro data indicate that at therapeutic concentrations, the active METABOLITE OF FESOTERODINE DOES NOT HAVE THE POTENTIAL TO INHIBIT OR INDUCE #YTOCHROME 0 ENZYME SYSTEMS

Renal Impairment: Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment ;SEE USE IN SPECIFIC POPULATIONS and DOSAGE AND ADMINISTRATION].

Oral Contraceptives: )N THE PRESENCE OF FESOTERODINE THERE ARE NO CLINICALLY SIGNIFICANT CHANGES IN THE PLASMA concentrations of combined oral contraceptives containing ethinyl estradiol and levonorgestrel.

Concomitant Administration with CYP3A4 Inhibitors: Doses of Toviaz greater than 4 mg are not recommended IN PATIENTS TAKING A POTENT #90 ! INHIBITOR E G KETOCONAZOLE ITRACONAZOLE CLARITHROMYCIN

Drug-Laboratory Test Interactions: )NTERACTIONS BETWEEN 4OVIAZ AND LABORATORY TESTS HAVE NOT BEEN STUDIED

)N PATIENTS TAKING WEAK OR MODERATE #90 ! INHIBITORS E G ERYTHROMYCIN CAREFUL ASSESSMENT OF TOLERABILITY AT THE MG daily dose is advised prior to increasing the daily dose to 8 mg. While this specific interaction potential was not EXAMINED BY CLINICAL STUDY SOME PHARMACOKINETIC INTERACTION IS EXPECTED ALBEIT LESS THAN THAT OBSERVED WITH POTENT #90 ! INHIBITORS ;SEE DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION].

Pregnancy: 0REGNANCY #ATEGORY # 4HERE ARE NO ADEQUATE AND WELL CONTROLLED STUDIES USING 4OVIAZ IN PREGNANT WOMEN

Myasthenia Gravis: Toviaz should be used with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.

ADVERSE REACTIONS Clinical Trials Experience: 4HE SAFETY OF 4OVIAZ WAS EVALUATED IN 0HASE AND CONTROLLED TRIALS IN A TOTAL OF PATIENTS WITH OVERACTIVE BLADDER OF WHICH WERE TREATED WITH FESOTERODINE /F THIS TOTAL RECEIVED 4OVIAZ MG DAY AND RECEIVED 4OVIAZ MG DAY IN 0HASE OR STUDIES WITH TREATMENT PERIODS OF OR WEEKS !PPROXIMATELY OF THESE PATIENTS HAD WEEKS EXPOSURE TO 4OVIAZ IN THESE TRIALS ! TOTAL OF PATIENTS PARTICIPATED IN TWO WEEK 0HASE EFFICACY AND SAFETY STUDIES AND SUBSEQUENT OPEN LABEL EXTENSION STUDIES )N THESE TWO STUDIES COMBINED PATIENTS RECEIVED 4OVIAZ MG DAY AND PATIENTS RECEIVED 4OVIAZ MG DAY )N 0HASE AND PLACEBO CONTROLLED TRIALS COMBINED THE INCIDENCES OF SERIOUS ADVERSE EVENTS IN PATIENTS RECEIVING PLACEBO 4OVIAZ MG AND 4OVIAZ MG WERE

AND RESPECTIVELY !LL SERIOUS ADVERSE EVENTS WERE JUDGED TO BE NOT RELATED OR UNLIKELY TO BE RELATED TO STUDY MEDICATION BY THE INVESTIGATOR EXCEPT FOR FOUR patients receiving Toviaz who reported one serious adverse event each: angina, chest pain, gastroenteritis, and QT PROLONGATION ON %#' The most commonly reported adverse event in patients treated with Toviaz was dry mouth. The incidence of dry mouth WAS HIGHER IN THOSE TAKING MG DAY AND IN THOSE TAKING MG DAY AS COMPARED TO PLACEBO $RY mouth led to discontinuation in 0.4%, 0.4%, and 0.8% of patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg, respectively. For those patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment.

4HE SECOND MOST COMMONLY REPORTED ADVERSE EVENT WAS CONSTIPATION 4HE INCIDENCE OF CONSTIPATION WAS IN THOSE TAKING PLACEBO IN THOSE TAKING MG DAY AND IN THOSE TAKING MG DAY 4ABLE LISTS ADVERSE EVENTS REGARDLESS OF CAUSALITY THAT WERE REPORTED IN THE COMBINED 0HASE RANDOMIZED

PLACEBO CONTROLLED TRIALS AT AN INCIDENCE GREATER THAN PLACEBO AND IN OR MORE OF PATIENTS TREATED WITH 4OVIAZ OR MG ONCE DAILY FOR UP TO WEEKS Table 1. Adverse events with an incidence exceeding the placebo rate and reported by â&#x2030;¥1% of patients from double-blind, placebo-controlled Phase 3 trials of 12 weeks treatment duration Placebo N=554 %

Toviaz 4 mg/day N=554 %

Toviaz 8 mg/day N=566 %

Dry mouth

#ONSTIPATION

Dyspepsia

Nausea

!BDOMINAL PAIN UPPER

Urinary tract infection

Upper respiratory tract infection

System organ class

'ASTROINTESTINAL disorders

)NFECTIONS

Preferred term

.O DOSE RELATED TERATOGENICITY WAS OBSERVED IN REPRODUCTION STUDIES PERFORMED IN MICE AND RABBITS )N MICE AT TO TIMES THE EXPECTED EXPOSURE AT THE MAXIMUM RECOMMENDED HUMAN DOSE -2($ OF MG BASED ON !5# MG KG DAY ORAL INCREASED RESORPTIONS AND DECREASED LIVE FETUSES WERE OBSERVED /NE FETUS WITH CLEFT PALATE WAS OBSERVED AT EACH DOSE

AND MG KG DAY AT AN INCIDENCE WITHIN THE BACKGROUND HISTORICAL RANGE )N RABBITS TREATED AT TO TIMES THE -2($ MG KG DAY ORAL INCOMPLETELY OSSIFIED STERNEBRAE RETARDATION OF BONE DEVELOPMENT WERE OBSERVED IN FETUSES )N RABBITS AT TO TIMES THE -2($ MG KG DAY SUBCUTANEOUS MATERNAL TOXICITY AND INCOMPLETELY OSSIFIED STERNEBRAE WERE OBSERVED IN FETUSES AT AN INCIDENCE WITHIN THE BACKGROUND HISTORICAL RANGE )N RABBITS AT TIMES THE -2($ MG KG DAY SUBCUTANEOUS DECREASED MATERNAL FOOD CONSUMPTION IN THE ABSENCE OF ANY FETAL EFFECTS WAS OBSERVED /RAL ADMINISTRATION OF MG KG DAY FESOTERODINE TO MICE IN A PRE AND POST NATAL development study resulted in decreased body weight of the dams and delayed ear opening of the pups. No effects were noted on mating and reproduction of the F dams or on the F offspring.

4OVIAZ SHOULD BE USED DURING PREGNANCY ONLY IF THE POTENTIAL BENEFIT OUTWEIGHS THE POTENTIAL RISK TO THE FETUS Nursing Mothers: )T IS NOT KNOWN WHETHER FESOTERODINE IS EXCRETED IN HUMAN MILK 4OVIAZ SHOULD NOT BE ADMINISTERED DURING NURSING UNLESS THE POTENTIAL BENEFIT OUTWEIGHS THE POTENTIAL RISK TO THE NEONATE

No Benefit To Adding Niacin to Statin Rx

Pediatric Use: 4HE PHARMACOKINETICS OF FESOTERODINE HAVE NOT BEEN EVALUATED IN PEDIATRIC PATIENTS 4HE SAFETY AND effectiveness of Toviaz in pediatric patients have not been established.

ADDING NIACIN to statin therapy

Geriatric Use: .O DOSE ADJUSTMENT IS RECOMMENDED FOR THE ELDERLY 4HE PHARMACOKINETICS OF FESOTERODINE ARE NOT significantly influenced by age.

offers no incremental clinical benefit

/F PATIENTS WHO RECEIVED 4OVIAZ MG DAY OR MG DAY IN THE 0HASE AND PLACEBO CONTROLLED EFFICACY AND SAFETY STUDIES WERE YEARS OF AGE OR OLDER AND WERE YEARS OF AGE OR OLDER .O OVERALL DIFFERENCES IN SAFETY OR EFFECTIVENESS WERE OBSERVED BETWEEN PATIENTS YOUNGER THAN YEARS OF AGE AND THOSE years of age or older in these studies; however, the incidence of antimuscarinic adverse events, including dry mouth, CONSTIPATION DYSPEPSIA INCREASE IN RESIDUAL URINE DIZZINESS AT MG ONLY AND URINARY TRACT INFECTION WAS HIGHER IN PATIENTS YEARS OF AGE AND OLDER AS COMPARED TO YOUNGER PATIENTS ;see ADVERSE REACTIONS].

to patients with atherosclerotic cardio-

Renal Impairment: )N PATIENTS WITH SEVERE RENAL IMPAIRMENT #,#2 M, MIN #max AND !5# ARE INCREASED AND FOLD RESPECTIVELY $OSES OF 4OVIAZ GREATER THAN MG ARE NOT RECOMMENDED IN PATIENTS WITH SEVERE RENAL IMPAIRMENT )N PATIENTS WITH MILD OR MODERATE RENAL IMPAIRMENT #,#2 RANGING FROM M, MIN #max AND !5# OF THE ACTIVE METABOLITE ARE INCREASED UP TO AND FOLD RESPECTIVELY AS COMPARED TO HEALTHY SUBJECTS .O DOSE ADJUSTMENT IS RECOMMENDED IN PATIENTS WITH MILD OR MODERATE RENAL IMPAIRMENT ;SEE WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].

Hepatic Impairment: 0ATIENTS WITH SEVERE HEPATIC IMPAIRMENT #HILD 0UGH # HAVE NOT BEEN STUDIED THEREFORE 4OVIAZ IS NOT RECOMMENDED FOR USE IN THESE PATIENTS )N PATIENTS WITH MODERATE #HILD 0UGH " HEPATIC IMPAIRMENT #max and !5# OF THE ACTIVE METABOLITE ARE INCREASED AND FOLD RESPECTIVELY AS COMPARED TO HEALTHY SUBJECTS .O DOSE ADJUSTMENT IS RECOMMENDED IN PATIENTS WITH MILD OR MODERATE HEPATIC IMPAIRMENT ;SEE WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].

vascular disease and LDL cholesterol levels below 70 mg/dL, according to study findings published in the New England Journal of Medicine (online ahead of print).

The study included 3,414 patients who were randomly assigned to receive extended-release niacin or pla-

Race: !VAILABLE DATA INDICATE THAT THERE ARE NO DIFFERENCES IN THE PHARMACOKINETICS OF FESOTERODINE BETWEEN #AUCASIAN AND "LACK HEALTHY SUBJECTS FOLLOWING ADMINISTRATION OF 4OVIAZ

cebo in addition to simvastatin. The

PATIENT COUNSELING INFORMATION: See FDA-Approved Patient Labeling

Information for Patients: 0ATIENTS SHOULD BE INFORMED THAT FESOTERODINE MAY PRODUCE ANGIOEDEMA WHICH COULD RESULT IN LIFE THREATENING AIRWAY OBSTRUCTION 0ATIENTS SHOULD BE ADVISED TO PROMPTLY DISCONTINUE FESOTERODINE THERAPY AND SEEK IMMEDIATE MEDICAL ATTENTION IF THEY EXPERIENCE EDEMA OF THE TONGUE OR LARYNGOPHARYNX OR DIFFICULT BREATHING

trial was stopped after a mean follow-

Dry eyes

0

2ENAL AND URINARY disorders

Dysuria

Urinary retention

2ESPIRATORY disorders

#OUGH

Dry throat

0.4

'ENERAL DISORDERS

Edema peripheral

-USCULOSKELETAL disorders

"ACK PAIN

0.4

0SYCHIATRIC DISORDERS

)NSOMNIA

0.4

)NVESTIGATIONS

!,4 INCREASED

''4 INCREASED

0.4

0.4

2ASH

!,4 ALANINE AMINOTRANSFERASE ''4 GAMMA GLUTAMYLTRANSFERASE

USE IN SPECIFIC POPULATIONS

Gender: .O DOSE ADJUSTMENT IS RECOMMENDED BASED ON GENDER 4HE PHARMACOKINETICS OF FESOTERODINE ARE NOT significantly influenced by gender.

Eye disorders

3KIN DISORDERS

from 2004-2007. The study population included 162,147 patients with normal renal function, 73,751 with mild CKD, 34,004 with moderate CKD, and 8,509 with severe CKD, and 5,182 on longterm dialysis.

Compared with the use of bare-metal stents, the use of drug-eluting stents was associated with lower 30-month death rates in patients with normal renal function (11.9 vs. 14.6%), mild CKD (15% vs. 18.6%) and moderate CKD (24.7% vs. 26.8%).

Drug-eluting stents also were associated with significantly lower 30-month MI rates compared with bare-metal stents for all groups except patients on long-term dialysis: 5.7 vs. 7.0 for patients with normal renal function; 6.5 vs. 7.3 for patients with mild CKD; 9.6 vs. 11.9 for individuals with moderate CKD; and 15.0 vs. 12.8 for those with severe CKD. At 30-month follow-up, patients on dialysis had a 3.6-fold increased risk of death, a 2.1-fold increased risk of MI, and a 2.3-fold increased risk of major bleeding compared with patients who had normal renal function, the authors noted. â&#x2013;

0ATIENTS SHOULD BE INFORMED THAT 4OVIAZ LIKE OTHER ANTIMUSCARINIC AGENTS MAY PRODUCE CLINICALLY SIGNIFICANT ADVERSE EFFECTS RELATED TO ANTIMUSCARINIC PHARMACOLOGICAL ACTIVITY INCLUDING CONSTIPATION AND URINARY RETENTION 4OVIAZ LIKE OTHER antimuscarinics, may be associated with blurred vision, therefore, patients should be advised to exercise caution until THE DRUG S EFFECTS ON THE PATIENT HAVE BEEN DETERMINED (EAT PROSTRATION DUE TO DECREASED SWEATING CAN OCCUR WHEN 4OVIAZ LIKE OTHER ANTIMUSCARINIC DRUGS IS USED IN A HOT ENVIRONMENT 0ATIENTS SHOULD ALSO BE INFORMED THAT ALCOHOL MAY ENHANCE THE DROWSINESS CAUSED BY 4OVIAZ LIKE OTHER ANTICHOLINERGIC AGENTS 0ATIENTS SHOULD READ THE PATIENT LEAFLET ENTITLED h0ATIENT )NFORMATION 4/6)!:v BEFORE STARTING THERAPY WITH 4OVIAZ

up of three years because of a lack of efficacy. The primary endpointâ&#x20AC;&#x201D;the first event of the composite of death from coronary heart disease, nonfatal

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myocardial infarction, ischemic

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stroke, and other eventsâ&#x20AC;&#x201D;occurred

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16.2%, respectively). â&#x2013;

www.renalandurologynews.com

DECEMBER 2011

Renal & Urology News 25

Renal Nutrition Update V

egetarian diets and soy as a source of protein have long been a topic of interest in the general population, and interest in this dietary source of protein recently has increased in the chronic kidney disease (CKD) population. In my July 2011 column, I described some recently emerging literature on vegetarian versus animalbased diets. The article explored the benefits of vegetable protein.

In a recently published study (Clin J Am Soc Nephrol 2011;6:257-264), Moe et al. demonstrated that one week of a vegetarian diet led to lower serum phosphorus levels and decreased levels of fibroblast growth factor 23 in patients with stage 3 or 4 CKD. The study included nine patients with a mean estimated glomerular filtration rate of 32 mL/min/1.73 m2. Patients were randomized to initially receive either a grain/soy- or meat/dairy-based diet for one week. After a washout period, they were placed on the opposite diet.

Clinicians may be concerned that long-term plant-based diets lead to insufficient protein intake or an increase in potassium and phosphorus concentrations. Therefore, an exploration of plant-based proteins, specifically soy, is warranted.

Soy comes from soybeans and is made of 3-sn-phosphatidyl choline, phosphatidyl ethanolamine, and phosphatidyl-inositol. It is not uncommon as a meat replacement additive to diets, as the texture and protein content are comparable. Textured vegetable protein, tempeh, and tofu are examples of soy protein foods used in plantbased diets.

Soy consumption may be beneficial because of the high amounts of isoflavones and phytoestrogens.

Phytoestrogens in soy products are thought to be responsible for reducing the menopausal symptoms in women, in addition to their potentially beneficial effects on osteoporosis and cardiovascular disease. However, data on the benefits or risks of high soy intake in CKD patients has been slow to accumulate.

Reduced coagulation factor In recent years, a few small trials have been published on soy supplementation in hemodialysis (HD) and peritoneal dialysis (PD) patients. A study published in 2009 (J Ren Nutr. 2009;19:389-395) highlighted a potential risk with the use of soy. The study was an unblinded, randomized trial looking at the impact of soy on plasma coagulating factors.

The eight-week study included 36 PD patients (18 on soy and 18 as controls).

The soy group received 28-g packets of raw, textured soy flour containing 14 g of soy protein and 233 mg of phosphorus.

At baseline, the two groups had no significant differences in any demographic characteristics. At the end of the eight weeks, researchers observed no significant difference in serum phosphorus between the soy group and controls (3.5 vs. 3.7 mg/dL, respectively). The study revealed, however, a significant 17% decrease in coagulation factor IX in the soy group, a reduction that was significant compared with controls. This decrease in coagulation factor IX may be a risk factor for patients on dialysis, especially if they are receiving other anticoagulant medications.

Effect on oxidized LDL In an another small trial (J Med Food.

2006;9:368-372), investigators compared soy with whey protein in HD patients to study the effect on oxidized

Š IGOR DUTINA / SHUTTERSTOCK

Soy protein may benefit kidney disease patients, but some data suggest that it can have negative effects BY ALISON L. STEIBER, PhD, RD, LD

Consuming soy may improve cardiovascular risk factors.

which significantly decreased in the whey group. A significant difference in mean change of oxidized LDL was found between groups, with the soy group decreasing by 31% and the whey group increasing by 11%.

Improved CV risk factors Finally, in a 2008 longitudinal study of 41 patients with type 2 diabetes and nephropathy, a soy treatment arm received 35% animal proteins, 35% textured soy protein, and 30%

Soy may have a negative impact on coagulation factors, so careful monitoring of clotting parameters would be warranted in some patients.

LDL concentrations. The study randomized 17 HD patients to receive either soy (seven patients, 25 mg protein and 52 mg flavones) or whey (nine patients) for four weeks. The study demonstrated no statistically significant changes in laboratory values between pre- and post-intervention for either group, except for serum creatinine,

vegetable proteins and a control arm received 70% animal proteins and 30% vegetable proteins for four years (Diabetes Care. 2008;31:648-54). This small, randomized, clinical trial demonstrated significantly improved cardiovascular risk factors associated with the consumption of soy, including plasma glucose (-18 vs. 11 mg/dL for controls),

total cholesterol (-23 vs. 10 mg/dL for controls), LDL cholesterol (-20 vs. 6 mg/dL for controls), serum triglycerides (-24 vs. -5 mg/dL for controls), serum C-reactive protein concentrations (-1.31 vs. 0.33 mg/L for controls), proteinuria (-0.15 vs. 0.02 g/day for controls), and urinary creatinine (-1.5 vs. 0.6 mg/dL for controls).

Despite the limitations of these studies, including small size, unblinded design, and limited data on the effect of soy protein on potassium and phosphorus, the data seem to indicate that in pre-dialysis and dialysis patients, soy use may have some benefit. It should be noted, however, that soy may impact coagulation factors, so careful monitoring of clotting parameters would be warranted in patients consuming high amounts of soy. If patients are vegetarian, would like to become vegetarian, or are just interested in including more plant-based protein sources in their diet, soy may be a reasonable choice to consider. â&#x2013; Dr. Steiber is Coordinator of the Dietetic Internship/Masterâ&#x20AC;&#x2122;s Degree Program at Case Western Reserve University in Cleveland.

26 Renal & Urology News

DECEMBER 2011

www.renalandurologynews.com

Kidney Transplants Fail to Prevent CAC Progression RENAL TRANSPLANTATION does not stop or reverse coronary artery calcification (CAC), according to researchers.

In a study that included 150 renal transplant recipients, CAC prevalence increased from 35.3% with a mean score of 60.0% to 64.6% with a mean score of 94.9 after about 2.8 years of follow-up. At a baseline scan, 34 patients with no baseline CAC converted to a positive score at follow-up, for an incidence rate of about 12.5% a year.

In addition to baseline CAC score, higher triglyceride level and bisphosphonate use were associated with CAC progression. Other lipid parameters such as low-density lipoprotein (LDL) cholesterol had a negative association with CAC in patients.

Headed by Nurhan Seyahi, MD, the authors published their findings in Nephrology Dialysis Transplantation

(published online ahead of print). To their knowledge, this was the largest study with the longest follow-up to examine CAC progression in renal transplant recipients.

Only two renal transplant patients (1.3%) had a regression in CAC score, a finding that contrasts with a previ-

ous study in which 14.5% of patients experience regression.

The researchers noted that while they lacked a control group, CAC progression in non-kidney disease patients is lower, which is consistent with previous studies that report a 6.6% incidence rate per year.

The researchers stated that further analysis of these associations is necessary to develop strategies that prevent progression of CAC in kidney disease patients, and that “renal transplantation can improve CAC in some patients in the short term but in the long term, progression is the usual process.” ■

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t Soliris is the first and only approved therapy for pediatric and adult patients with BUZQJDBM )FNPMZUJD 6SFNJD 4ZOESPNF B)64

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t *O B)64 VODPOUSPMMFE UFSNJOBM DPNQMFNFOU BDUJWBUJPO SFTVMUT JO UISPNCPUJD NJDSPBOHJPQBUIZ 5."

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Traditional opioid treatment options have many unwanted side effects and Exparel has the “potential to reduce or delay the use of opioids following inpatient and outpatient surgical procedures,” according to Sonia Ramamoorthy, MD, Associate Professor of Surgery at the University of California, San Diego.

Exparel was evaluated in 21 clinical trials with more than 1,300 subjects.

Common adverse reactions such as nausea, constipation, and vomiting had an incidence rate of 10% or more. ■

For more information, contact your Alexion representative or call 1-888-SOLIRIS (1-888-765-4747) today.

www.renalandurologynews.com

DECEMBER 2011

Renal & Urology News 27

Chronic Inflammation Linked to Truncal Fat TRUNCAL FAT MASS is significantly and independently associated with chronic inflammation in hemodialysis (HD) patients, researchers reported.

Eiji Ishimura, MD, of Osaka City University in Japan, and collaborators measured fat and lean masses of 452 HD patients and examined their association

with high-sensitivity C-reactive protein (hsCRP), a marker of systemic inflammation. Researchers divided patients into two groups: those with normal hsCRP (less than 0.3 mg/dL) and those with high hsCRP (0.3 mg/dL or higher).

Patients with high hsCRP levels had significantly higher total fat mass than

those with normal hsCRP levels (14.8 vs. 13.4 kg), according to findings published in Nephron: Clinical Practice (2011;119:c283-c288). Truncal fat mass was significantly higher in the high hsCRP group than the normal hsCRP group (7.69 vs. 6.67 kg), after adjusting for various factors, including diabetes and nontrun-

IMPORTANT SAFETY INFORMATION WARNING: SERIOUS MENINGOCOCCAL INFECTIONS See full prescribing information for complete boxed warning Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. t $PNQMZ XJUI UIF NPTU DVSSFOU "EWJTPSZ $PNNJUUFF PO *NNVOJ[BUJPO 1SBDUJDFT "$*1

recommendations for meningococcal vaccination in patients with complement deďŹ ciencies. t *NNVOJ[F QBUJFOUT XJUI B NFOJOHPDPDDBM WBDDJOF BU MFBTU XFFLT QSJPS UP BENJOJTUFSJOH UIF m STU EPTF PG 4PMJSJT VOMFTT UIF SJTLT PG EFMBZJOH 4PMJSJT UIFSBQZ PVUXFJHI UIF SJTL PG EFWFMPQJOH B NFOJOHPDPDDBM JOGFDUJPO 4FF Serious Meningococcal Infections for BEEJUJPOBM HVJEBODF PO UIF NBOBHFNFOU PG UIF SJTL PG NFOJOHPDPDDBM JOGFDUJPO

t .POJUPS QBUJFOUT GPS FBSMZ TJHOT PG NFOJOHPDPDDBM JOGFDUJPOT BOE FWBMVBUF JNNFEJBUFMZ JG infection is suspected.

4PMJSJT JT BWBJMBCMF POMZ UISPVHI B SFTUSJDUFE QSPHSBN VOEFS B 3JTL &WBMVBUJPO BOE .JUJHBUJPO 4USBUFHZ 3&.4 6OEFS UIF 4PMJSJT 3&.4 QSFTDSJCFST NVTU FOSPMM JO UIF QSPHSBN &OSPMMNFOU JO UIF 4PMJSJT 3&.4 QSPHSBN BOE BEEJUJPOBM JOGPSNBUJPO BSF BWBJMBCMF CZ UFMFQIPOF 40-*3*4

Indications and usage 4PMJSJT JT JOEJDBUFE GPS UIF USFBUNFOU PG QBUJFOUT XJUI QBSPYZTNBM OPDUVSOBM IFNPHMPCJOVSJB 1/)

to reduce hemolysis.

4PMJSJT JT JOEJDBUFE GPS UIF USFBUNFOU PG QBUJFOUT XJUI BUZQJDBM IFNPMZUJD VSFNJD TZOESPNF B)64

to inhibit complement-mediated thrombotic microangiopathy.

5IF FGGFDUJWFOFTT PG 4PMJSJT JO B)64 JT CBTFE PO UIF FGGFDUT PO UISPNCPUJD NJDSPBOHJPQBUIZ 5."

BOE SFOBM GVODUJPO 1SPTQFDUJWF DMJOJDBM USJBMT JO BEEJUJPOBM QBUJFOUT BSF POHPJOH UP DPOm SN UIF CFOFm U PG 4PMJSJT JO QBUJFOUT XJUI B)64 -JNJUBUJPO PG 6TF Soliris is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic TZOESPNF 45&$ )64

Adverse reactions 5IF NPTU GSFRVFOUMZ SFQPSUFE BEWFSTF SFBDUJPOT JO UIF 1/) SBOEPNJ[FE USJBM Ăś PWFSBMM BOE HSFBUFS UIBO QMBDFCP BSF IFBEBDIF OBTPQIBSZOHJUJT CBDL QBJO BOE OBVTFB 5IF NPTU GSFRVFOUMZ SFQPSUFE BEWFSTF SFBDUJPOT JO B)64 TJOHMF BSN QSPTQFDUJWF USJBMT Ăś DPNCJOFE QFS QBUJFOU JODJEFODF BSF IZQFSUFOTJPO VQQFS SFTQJSBUPSZ USBDU JOGFDUJPO EJBSSIFB IFBEBDIF BOFNJB WPNJUJOH OBVTFB VSJOBSZ USBDU JOGFDUJPO BOE MFVLPQFOJB Please see brief summary of Prescribing Information, including Boxed WARNING, on the following page.

References: 1. SolirisÂŽ [package insert]. Cheshire, CT: Alexion Pharmaceuticals, Inc; 2011. 2. US Food and Drug Administration. FDA approves Soliris for rare pediatric blood disorder [press release]. September 23, 2011. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm272990.htm.

Accessed October 13, 2011.

SolirisÂŽ JT B SFHJTUFSFE USBEFNBSL PG "MFYJPO 1IBSNBDFVUJDBMT *OD $PQZSJHIU ÂŞ "MFYJPO 1IBSNBDFVUJDBMT *OD "MM SJHIUT SFTFSWFE 40-

cal fat mass. The researchers observed no significant difference between the groups with respect to nontruncal fat mass and truncal and nontruncal lean mass.

The new findings indicate that the visceral or truncal fat mass is an important contributor to increased chronic inflammation, the authors noted. â&#x2013;

28 Renal & Urology News

DECEMBER 2011

www.renalandurologynews.com

Cancer Risk is Elevated in Transplant Recipients CANCERS DEVELOP more frequently in solid organ transplant recipients than in the general population, according to researchers.

In a study of data from 175,732 solid organ transplant recipients (58.4% kidney, 21.6% liver, 10% heart, and 4.0% lung), investigators found that 10,656

ÂŽ

( e c u l i z u m a b ) Concentrated solution for intravenous infusion Brief summaryâ&#x20AC;&#x201D;please see full prescribing information IMPORTANT SAFETY INFORMATION WARNING: SERIOUS MENINGOCOCCAL INFECTIONS See full prescribing information for complete boxed warning Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. t $PNQMZ XJUI UIF NPTU DVSSFOU "EWJTPSZ $PNNJUUFF PO *NNVOJ[BUJPO 1SBDUJDFT "$*1 SFDPNNFOEBUJPOT GPS NFOJOHPDPDDBM WBDDJOBUJPO JO patients with complement deďŹ ciencies. t *NNVOJ[F QBUJFOUT XJUI B NFOJOHPDPDDBM WBDDJOF BU MFBTU XFFLT QSJPS UP BENJOJTUFSJOH UIF mSTU EPTF PG 4PMJSJT VOMFTT UIF SJTLT PG EFMBZJOH 4PMJSJT UIFSBQZ PVUXFJHI UIF SJTLT PG EFWFMPQJOH B NFOJOHPDPDDBM infection. (See Serious Meningococcal Infections for additional HVJEBODF PO UIF NBOBHFNFOU PG UIF SJTL PG NFOJOHPDPDDBM JOGFDUJPO

t .POJUPS QBUJFOUT GPS FBSMZ TJHOT PG NFOJOHPDPDDBM JOGFDUJPOT BOE evaluate immediately if infection is suspected.

4PMJSJT JT BWBJMBCMF POMZ UISPVHI B SFTUSJDUFE QSPHSBN VOEFS B 3JTL &WBMVBUJPO BOE .JUJHBUJPO 4USBUFHZ 3&.4 6OEFS UIF 4PMJSJT 3&.4 prescribers must enroll in the program. Enrollment in the Soliris REMS program and additional information are available by telephone: 40-*3*4

INDICATIONS AND USAGE Paroxysmal Nocturnal Hemoglobinuria (PNH) Soliris is indicated for the treatment of patients with paroxysmal nocturnal IFNPHMPCJOVSJB 1/) UP SFEVDF IFNPMZTJT Atypical Hemolytic Uremic Syndrome (aHUS) Soliris is indicated for the treatment of patients with atypical hemolytic uremic TZOESPNF B)64 UP JOIJCJU DPNQMFNFOU NFEJBUFE UISPNCPUJD NJDSPBOHJPQBUIZ 5IF FGGFDUJWFOFTT PG 4PMJSJT JO B)64 JT CBTFE PO UIF FGGFDUT PO UISPNCPUJD NJDSPBOHJPQBUIZ 5."

BOE SFOBM GVODUJPO 1SPTQFDUJWF DMJOJDBM USJBMT JO BEEJUJPOBM QBUJFOUT BSF POHPJOH UP DPOmSN UIF CFOFmU PG 4PMJSJT JO QBUJFOUT XJUI B)64 -JNJUBUJPO PG 6TF: Soliris is not indicated for the treatment of patients with Shiga toxin E. coli SFMBUFE IFNPMZUJD VSFNJD TZOESPNF 45&$ )64

CONTRAINDICATIONS Soliris is contraindicated in: t 1BUJFOUT XJUI VOSFTPMWFE TFSJPVT Neisseria meningitidis infection t 1BUJFOUT XIP BSF OPU DVSSFOUMZ WBDDJOBUFE BHBJOTU Neisseria meningitidis, VOMFTT UIF SJTLT PG EFMBZJOH 4PMJSJT USFBUNFOU PVUXFJHI UIF SJTLT PG EFWFMPQJOH B meningococcal infection [see Warnings and Precautions].

WARNINGS AND PRECAUTIONS Serious Meningococcal Infections The use of Soliris increases a patientâ&#x20AC;&#x2122;s susceptibility to serious meningococcal JOGFDUJPOT TFQUJDFNJB BOE PS NFOJOHJUJT -JGF UISFBUFOJOH BOE GBUBM meningococcal infections have occurred in patients treated with Soliris.

"ENJOJTUFS B QPMZWBMFOU NFOJOHPDPDDBM WBDDJOF BDDPSEJOH UP UIF NPTU DVSSFOU "EWJTPSZ $PNNJUUFF PO *NNVOJ[BUJPO 1SBDUJDFT "$*1 SFDPNNFOEBUJPOT GPS patients with complement deďŹ ciencies. Revaccinate patients in accordance XJUI "$*1 SFDPNNFOEBUJPOT DPOTJEFSJOH UIF EVSBUJPO PG 4PMJSJT UIFSBQZ 7BDDJOBUF QBUJFOUT XJUIPVU B IJTUPSZ PG NFOJOHPDPDDBM WBDDJOBUJPO BU MFBTU XFFLT QSJPS UP SFDFJWJOH UIF mSTU EPTF PG 4PMJSJT *G VSHFOU 4PMJSJT UIFSBQZ JT indicated in an unvaccinated patient, administer the meningococcal vaccine BT TPPO BT QPTTJCMF *O DMJOJDBM TUVEJFT QBUJFOUT XJUI B)64 XFSF USFBUFE XJUI 4PMJSJT MFTT UIBO XFFLT BGUFS NFOJOHPDPDDBM WBDDJOBUJPO BOE PG UIFTF QBUJFOUT SFDFJWFE BOUJCJPUJDT GPS QSPQIZMBYJT PG NFOJOHPDPDDBM JOGFDUJPO VOUJM BU MFBTU XFFLT BGUFS NFOJOHPDPDDBM WBDDJOBUJPO 5IF CFOFmUT BOE SJTLT of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving Soliris have not been established.

7BDDJOBUJPO SFEVDFT CVU EPFT OPU FMJNJOBUF UIF SJTL PG NFOJOHPDPDDBM JOGFDUJPOT *O DMJOJDBM TUVEJFT PVU PG 1/) QBUJFOUT EFWFMPQFE TFSJPVT meningococcal infections while receiving treatment with Soliris; both had been vaccinated [see Adverse Reactions> *O DMJOJDBM TUVEJFT BNPOH OPO 1/) QBUJFOUT NFOJOHPDPDDBM NFOJOHJUJT PDDVSSFE JO POF VOWBDDJOBUFE QBUJFOU *O BEEJUJPO B QSFWJPVTMZ WBDDJOBUFE QBUJFOU XJUI B)64 EFWFMPQFE NFOJOHPDPDDBM sepsis during the post-study follow-up period [see Adverse Reactions]. $MPTFMZ NPOJUPS QBUJFOUT GPS FBSMZ TJHOT BOE TZNQUPNT PG NFOJOHPDPDDBM infection and evaluate patients immediately if an infection is suspected.

Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Discontinue Soliris in patients who are undergoing treatment for serious meningococcal infections.

Soliris REMS #FDBVTF PG UIF SJTL PG NFOJOHPDPDDBM JOGFDUJPOT 4PMJSJT JT BWBJMBCMF POMZ UISPVHI B SFTUSJDUFE QSPHSBN VOEFS B 3JTL &WBMVBUJPO BOE .JUJHBUJPO 4USBUFHZ 3&.4 6OEFS the Soliris REMS, prescribers must enroll in the program.

1SFTDSJCFST NVTU DPVOTFM QBUJFOUT BCPVU UIF SJTL PG NFOJOHPDPDDBM JOGFDUJPO provide the patients with the REMS educational materials, and ensure patients are vaccinated with a meningococcal vaccine.

Enrollment in the Soliris REMS program and additional information are available by UFMFQIPOF 40-*3*4

Other Infections 4PMJSJT CMPDLT UFSNJOBM DPNQMFNFOU BDUJWBUJPO UIFSFGPSF QBUJFOUT NBZ IBWF increased susceptibility to infections, especially with encapsulated bacteria. $IJMESFO USFBUFE XJUI 4PMJSJT NBZ CF BU JODSFBTFE SJTL PG EFWFMPQJOH TFSJPVT JOGFDUJPOT due to Streptococcus pneumoniae and Haemophilus inďŹ&#x201A;uenza UZQF C )JC "ENJOJTUFS vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus inďŹ&#x201A;uenza UZQF C )JC JOGFDUJPOT BDDPSEJOH UP "$*1 HVJEFMJOFT 6TF DBVUJPO XIFO administering Soliris to patients with any systemic infection.

Monitoring After Soliris Discontinuation Treatment Discontinuation for PNH: Monitor patients after discontinuing Soliris for at MFBTU XFFLT UP EFUFDU IFNPMZTJT 5SFBUNFOU %JTDPOUJOVBUJPO GPS B)64 "GUFS EJTDPOUJOVJOH 4PMJSJT NPOJUPS QBUJFOUT XJUI B)64 GPS TJHOT BOE TZNQUPNT PG UISPNCPUJD NJDSPBOHJPQBUIZ 5."

DPNQMJDBUJPOT GPS BU MFBTU XFFLT *O B)64 DMJOJDBM TUVEJFT QBUJFOUT JO UIF QSPTQFDUJWF TUVEJFT EJTDPOUJOVFE 4PMJSJT USFBUNFOU 5." DPNQMJDBUJPOT PDDVSSFE GPMMPXJOH B NJTTFE EPTF JO QBUJFOUT BOE 4PMJSJT XBT SFJOJUJBUFE JO PG UIFTF QBUJFOUT $MJOJDBM TJHOT BOE TZNQUPNT PG 5." JODMVEF DIBOHFT JO NFOUBM TUBUVT TFJ[VSFT BOHJOB EZTQOFB PS UISPNCPTJT *O BEEJUJPO UIF GPMMPXJOH DIBOHFT JO MBCPSBUPSZ

were diagnosed with malignancies, twice the number of malignancies expected to occur in the same number of individuals in the general population.

The incidence of cancers of the kidney and urinary bladder were 4.65 and 1.52 times higher in the transplant population than would be expected in the gen-

QBSBNFUFST NBZ JEFOUJGZ B 5." DPNQMJDBUJPO PDDVSSFODF PG UXP PS SFQFBUFE NFBTVSFNFOU PG BOZ POF PG UIF GPMMPXJOH B EFDSFBTF JO QMBUFMFU DPVOU CZ PS NPSF DPNQBSFE UP CBTFMJOF PS UIF QFBL QMBUFMFU DPVOU EVSJOH 4PMJSJT USFBUNFOU BO JODSFBTF JO TFSVN DSFBUJOJOF CZ PS NPSF DPNQBSFE UP CBTFMJOF PS OBEJS EVSJOH 4PMJSJT USFBUNFOU PS BO JODSFBTF JO TFSVN -%) CZ PS NPSF PWFS CBTFMJOF PS OBEJS during Soliris treatment. *G 5." DPNQMJDBUJPOT PDDVS BGUFS 4PMJSJT EJTDPOUJOVBUJPO DPOTJEFS SFJOTUJUVUJPO PG Soliris treatment, plasma therapy [plasmapheresis, plasma exchange, or fresh GSP[FO QMBTNB JOGVTJPO 1& 1* > PS BQQSPQSJBUF PSHBO TQFDJmD TVQQPSUJWF NFBTVSFT

eral population, researchers reported in The Journal of the American Medical Association (2011;306(17):1891-1901).

The study, led by Eric A. Engels, MD, MPH, of the National Cancer Institute in Bethesda, Md., found that the incidence of kidney cancer was 6.6 times greater among kidney transplant recipi-

TABLE 1 (CONT.): ADVERSE REACTIONS OCCURRING IN AT LEAST 15% OF PATIENTS LESS THAN 18 YEARS OF AGE ENROLLED IN aHUS STUDY 3 MedDRA Number (%) of Patients ver. 11.0 < 2 yrs 2 to < 12 yrs 12 to<18 yrs Total (n=5) (n=10) (n=4) (n=19) Respiratory, Thoracic and Mediastinal Disorders $PVHI

Thrombosis Prevention and Management The effect of withdrawal of anticoagulant therapy during Soliris treatment has not /BTBM DPOHFTUJPO

been established. Therefore, treatment with Soliris should not alter anticoagulant $BSEJBD %JTPSEFST management.

5BDIZDBSEJB

a.

Laboratory Monitoring includes the preferred terms upper respiratory tract infection and nasopharyngitis.

PNH: Serum LDH levels increase during hemolysis and may assist in monitoring 4PMJSJT FGGFDUT JODMVEJOH UIF SFTQPOTF UP EJTDPOUJOVBUJPO PG UIFSBQZ *O DMJOJDBM Immunogenicity studies, six patients achieved a reduction in serum LDH levels only after a decrease in "T XJUI BMM QSPUFJOT UIFSF JT B QPUFOUJBM GPS JNNVOPHFOJDJUZ 5IF JNNVOPHFOJDJUZ PG UIF 4PMJSJT EPTJOH JOUFSWBM GSPN UP EBZT "MM PUIFS QBUJFOUT BDIJFWFE B SFEVDUJPO Soliris has been evaluated using two different immunoassays for the detection of JO TFSVN -%) MFWFMT XJUI UIF EBZ EPTJOH JOUFSWBM <TFF Clinical Pharmacology and BOUJ FDVMJ[VNBC BOUJCPEJFT B EJSFDU FO[ZNF MJOLFE JNNVOPTPSCFOU BTTBZ &-*4"

using the Fab fragment of eculizumab as target was used for the PNH indication; Clinical Studies].

B)64 &BSMZ TJHOT PG UISPNCPUJD NJDSPBOHJPQBUIZ 5."

JODMVEF B EFDSFBTF JO BOE BO FMFDUSP DIFNJMVNJOFTDFODF &$- CSJEHJOH BTTBZ VTJOH UIF FDVMJ[VNBC platelet count, and increases in serum LDH and creatinine levels. Follow patients for XIPMF NPMFDVMBS BT UBSHFU XBT VTFE GPS UIF B)64 JOEJDBUJPO -PX UJUFST PG BOUJCPEJFT TJHOT PG 5." CZ NPOJUPSJOH TFSJBM QMBUFMFU DPVOUT TFSVN -%) BOE DSFBUJOJOF EVSJOH UP 4PMJSJT XFSF EFUFDUFE JO PG BMM 1/) QBUJFOUT USFBUFE XJUI 4PMJSJT CZ UIF &-*4" BTTBZ *O QBUJFOUT XJUI B)64 USFBUFE XJUI 4PMJSJT BOUJCPEJFT UP 4PMJSJT Soliris therapy and following discontinuation of Soliris.

XFSF EFUFDUFE JO CZ UIF &$- BTTBZ "O &$- CBTFE OFVUSBMJ[JOH )")" BTTBZ XJUI B MPX TFOTJUJWJUZ PG NDH N- XBT QFSGPSNFE UP EFUFDU OFVUSBMJ[JOH Infusion Reactions "T XJUI BMM QSPUFJO QSPEVDUT BENJOJTUSBUJPO PG 4PMJSJT NBZ SFTVMU JO JOGVTJPO SFBDUJPOT BOUJCPEJFT GPS UIF QBUJFOUT XJUI B)64 /P OFVUSBMJ[JOH BDUJWJUZ UP 4PMJSJT XBT JODMVEJOH BOBQIZMBYJT PS PUIFS IZQFSTFOTJUJWJUZ SFBDUJPOT *O DMJOJDBM USJBMT OP EFUFDUFE JO QBUJFOUT XJUI B)64 USFBUFE XJUI 4PMJSJT /P BQQBSFOU DPSSFMBUJPO PG patients experienced an infusion reaction which required discontinuation of Soliris. antibody development to clinical response was observed in both indications. The *OUFSSVQU 4PMJSJT JOGVTJPO BOE JOTUJUVUF BQQSPQSJBUF TVQQPSUJWF NFBTVSFT JG TJHOT PG immunogenicity data reďŹ&#x201A;ect the percentage of patients whose test results were DPOTJEFSFE QPTJUJWF GPS BOUJCPEJFT UP 4PMJSJT JO BO &-*4" CBTFE BTTBZ BOE PS BO &$- cardiovascular instability or respiratory compromise occur. based assay are highly dependent on the sensitivity and speciďŹ city of the assay ADVERSE REACTIONS VTFE "EEJUJPOBMMZ UIF PCTFSWFE JODJEFODF PG BOUJCPEZ QPTJUJWJUZ JO UIF BTTBZ NBZ CF Clinical Trial Experience inďŹ&#x201A;uenced by several factors including sample handling, timing of sample collection, Meningococcal infections are the most important adverse reactions experienced concomitant medications and underlying disease. For these reasons, comparison CZ QBUJFOUT SFDFJWJOH 4PMJSJT *O 1/) DMJOJDBM TUVEJFT UXP QBUJFOUT FYQFSJFODFE of the incidence of antibodies to Soliris with the incidence of antibodies to other meningococcal sepsis. Both patients had previously received a meningococcal products may be misleading.

WBDDJOF *O DMJOJDBM TUVEJFT BNPOH QBUJFOUT XJUIPVU 1/) NFOJOHPDPDDBM NFOJOHJUJT occurred in one unvaccinated patient. Meningococcal sepsis occurred in one Postmarketing Experience QSFWJPVTMZ WBDDJOBUFE QBUJFOU FOSPMMFE JO UIF SFUSPTQFDUJWF B)64 TUVEZ EVSJOH UIF $BTFT PG TFSJPVT PS GBUBM NFOJOHPDPDDBM JOGFDUJPOT IBWF CFFO SFQPSUFE post-study follow-up period [see Warnings and Precautions].

USE IN SPECIFIC POPULATIONS PNH 5IF EBUB EFTDSJCFE CFMPX SFnFDU FYQPTVSF UP 4PMJSJT JO BEVMU QBUJFOUT XJUI 1/) BHF PG XIPN XFSF GFNBMF "MM IBE TJHOT PS TZNQUPNT PG Pregnancy intravascular hemolysis. Soliris was studied in a placebo-controlled clinical study (in 1SFHOBODZ $BUFHPSZ $ XIJDI QBUJFOUT SFDFJWFE 4PMJSJT BOE QMBDFCP B TJOHMF BSN DMJOJDBM TUVEZ BOE There are no adequate and well-controlled studies of Soliris in pregnant women.

B MPOH UFSN FYUFOTJPO TUVEZ QBUJFOUT XFSF FYQPTFE GPS HSFBUFS UIBO POF ZFBS "MM 4PMJSJT B SFDPNCJOBOU *H( NPMFDVMF IVNBOJ[FE BOUJ $ BOUJCPEZ JT FYQFDUFE UP DSPTT UIF QMBDFOUB "OJNBM TUVEJFT VTJOH B NPVTF BOBMPHVF PG UIF 4PMJSJT NPMFDVMF patients received the recommended Soliris dose regimen.

Because clinical trials are conducted under widely varying conditions, adverse NVSJOF BOUJ $ BOUJCPEZ TIPXFE JODSFBTFE SBUFT PG EFWFMPQNFOUBM BCOPSNBMJUJFT reaction rates observed in the clinical trials of a drug cannot be directly compared BOE BO JODSFBTFE SBUF PG EFBE BOE NPSJCVOE PGGTQSJOH BU EPTFT UJNFT UIF IVNBO to rates in the clinical trials of another drug and may not reďŹ&#x201A;ect the rates observed dose. Soliris should be used during pregnancy only if the potential beneďŹ t justiďŹ es UIF QPUFOUJBM SJTL UP UIF GFUVT in practice.

The most frequently reported adverse reactions in the PNH randomized trial "OJNBM SFQSPEVDUJPO TUVEJFT XFSF DPOEVDUFE JO NJDF VTJOH EPTFT PG B NVSJOF Ăś PWFSBMM BOE HSFBUFS UIBO QMBDFCP BSF IFBEBDIF OBTPQIBSZOHJUJT CBDL QBJO BOUJ $ BOUJCPEZ UIBU BQQSPYJNBUFE UJNFT MPX EPTF BOE UJNFT IJHI EPTF

the recommended human Soliris dose, based on a body weight comparison. When and nausea. animal exposure to the antibody occurred in the time period from before mating until *O UIF QMBDFCP DPOUSPMMFE DMJOJDBM TUVEZ TFSJPVT BEWFSTF SFBDUJPOT PDDVSSFE BNPOH early gestation, no decrease in fertility or reproductive performance was observed.

QBUJFOUT SFDFJWJOH 4PMJSJT BOE QBUJFOUT SFDFJWJOH QMBDFCP 5IF When maternal exposure to the antibody occurred during organogenesis, two cases serious reactions included infections and progression of PNH. No deaths occurred PG SFUJOBM EZTQMBTJB BOE POF DBTF PG VNCJMJDBM IFSOJB XFSF PCTFSWFE BNPOH in the study and no patients receiving Soliris experienced a thrombotic event; one offspring born to mothers exposed to the higher antibody dose; however, the exposure thrombotic event occurred in a patient receiving placebo. did not increase fetal loss or neonatal death. When maternal exposure to the antibody "NPOH QBUJFOUT XJUI 1/) USFBUFE XJUI 4PMJSJT JO UIF TJOHMF BSN DMJOJDBM TUVEZ occurred in the time period from implantation through weaning, a higher number of or the follow-up study, the adverse reactions were similar to those reported in the NBMF PGGTQSJOH CFDBNF NPSJCVOE PS EJFE DPOUSPMT MPX EPTF HSPVQ IJHI QMBDFCP DPOUSPMMFE DMJOJDBM TUVEZ 4FSJPVT BEWFSTF SFBDUJPOT PDDVSSFE BNPOH PG EPTF HSPVQ 4VSWJWJOH PGGTQSJOH IBE OPSNBM EFWFMPQNFOU BOE SFQSPEVDUJWF GVODUJPO the patients in these studies. The most common serious adverse reactions were: viral Nursing Mothers JOGFDUJPO IFBEBDIF BOFNJB BOE QZSFYJB

B)64 5IF TBGFUZ PG 4PMJSJT UIFSBQZ JO QBUJFOUT XJUI B)64 XBT FWBMVBUFE JO UXP *U JT OPU LOPXO XIFUIFS 4PMJSJT JT FYDSFUFE JOUP IVNBO NJML *H( JT FYDSFUFE JO QSPTQFDUJWF TJOHMF BSN TUVEJFT B)64 4UVEJFT BOE BOE POF SFUSPTQFDUJWF TUVEZ IVNBO NJML TP JU JT FYQFDUFE UIBU 4PMJSJT XJMM CF QSFTFOU JO IVNBO NJML )PXFWFS B)64 4UVEZ 5IF EBUB EFTDSJCFE CFMPX XFSF EFSJWFE GSPN BEVMU BOE BEPMFTDFOU QVCMJTIFE EBUB TVHHFTU UIBU BOUJCPEJFT JO IVNBO NJML EP OPU FOUFS UIF OFPOBUBM QBUJFOUT XJUI B)64 FOSPMMFE JO B)64 4UVEZ BOE B)64 4UVEZ "MM QBUJFOUT SFDFJWFE BOE JOGBOU DJSDVMBUJPO JO TVCTUBOUJBM BNPVOUT $BVUJPO TIPVME CF FYFSDJTFE XIFO UIF SFDPNNFOEFE EPTBHF PG 4PMJSJT .FEJBO FYQPTVSF XBT XFFLT SBOHF XFFLT 4PMJSJT JT BENJOJTUFSFE UP B OVSTJOH XPNBO 5IF VOLOPXO SJTLT UP UIF JOGBOU GSPN gastrointestinal or limited systemic exposure to Soliris should be weighed against Because clinical trials are conducted under widely varying conditions, adverse UIF LOPXO CFOFmUT PG IVNBO NJML GFFEJOH reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reďŹ&#x201A;ect the rates observed Pediatric Use in practice.

The safety and effectiveness of Soliris for the treatment of PNH in pediatric patients 5IF NPTU GSFRVFOUMZ SFQPSUFE BEWFSTF SFBDUJPOT JO B)64 TJOHMF BSN QSPTQFDUJWF USJBMT below the age of 18 years have not been established. Ăś DPNCJOFE QFS QBUJFOU JODJEFODF BSF IZQFSUFOTJPO VQQFS SFTQJSBUPSZ USBDU Three clinical studies assessing the safety and effectiveness of Soliris for the infection, diarrhea, headache, anemia, vomiting, nausea, urinary tract infection, USFBUNFOU PG B)64 JODMVEFE B UPUBM PG QFEJBUSJD QBUJFOUT BHFT NPOUIT UP BOE MFVLPQFOJB ZFBST 5IF TBGFUZ BOE FGGFDUJWFOFTT PG 4PMJSJT GPS UIF USFBUNFOU PG B)64 BQQFBS *O B)64 4UVEJFT BOE DPNCJOFE PG QBUJFOUT FYQFSJFODFE B TFSJPVT similar in pediatric and adult patients [see Dosage and Administration, Adverse BEWFSTF FWFOU 4"& 5IF NPTU DPNNPOMZ SFQPSUFE 4"&T XFSF IZQFSUFOTJPO Reactions, and Clinical Studies].

BOE JOGFDUJPOT 0OF QBUJFOU EJTDPOUJOVFE 4PMJSJT EVF UP BEWFSTF FWFOUT EFFNFE "ENJOJTUFS WBDDJOBUJPOT GPS UIF QSFWFOUJPO PG JOGFDUJPO EVF UP Neisseria meningitidis, unrelated to Soliris.

Streptococcus pneumoniae and Haemophilus inďŹ&#x201A;uenza UZQF C )JC BDDPSEJOH UP "$*1 "OBMZTJT PG SFUSPTQFDUJWFMZ DPMMFDUFE BEWFSTF FWFOU EBUB GSPN QFEJBUSJD BOE BEVMU guidelines [see Warnings and Precautions].

QBUJFOUT FOSPMMFE JO B)64 4UVEZ / SFWFBMFE B TBGFUZ QSPmMF UIBU XBT TJNJMBS Geriatric Use UP UIBU XIJDI XBT PCTFSWFE JO UIF UXP QSPTQFDUJWF TUVEJFT B)64 4UVEZ JODMVEFE 4JYUFFO QBUJFOUT ZFBST PG BHF PS PMEFS XJUI 1/) BOE XJUI B)64 XFSF USFBUFE pediatric patients less than 18 years of age. Overall, the safety of Soliris in pediatric XJUI 4PMJSJT "MUIPVHI UIFSF XFSF OP BQQBSFOU BHF SFMBUFE EJGGFSFODFT PCTFSWFE JO QBUJFOUT XJUI B)64 FOSPMMFE JO 4UVEZ BQQFBSFE TJNJMBS UP UIBU PCTFSWFE JO BEVMU UIFTF TUVEJFT UIF OVNCFS PG QBUJFOUT BHFE BOE PWFS JT OPU TVGmDJFOU UP EFUFSNJOF QBUJFOUT 5IF NPTU DPNNPO Ăś BEWFSTF FWFOUT PDDVSSJOH JO QFEJBUSJD QBUJFOUT whether they respond differently from younger patients. are presented in Table 1.

HOW SUPPLIED/STORAGE AND HANDLING Table 1: Adverse Reactions Occurring in at Least 15% of Patients Less 4PMJSJT FDVMJ[VNBC JT TVQQMJFE BT NH TJOHMF VTF WJBMT DPOUBJOJOH N- PG than 18 Years of Age Enrolled in aHUS Study 3 mg/mL sterile, preservative-free Soliris solution per vial.

MedDRA Number (%) of Patients Soliris vials must be stored in the original carton until time of use under refrigerated ver. 11.0 < 2 yrs 2 to < 12 yrs 12 to<18 yrs Total DPOEJUJPOT BU Â? $ Â? ' BOE QSPUFDUFE GSPN MJHIU %P OPU VTF CFZPOE UIF expiration date stamped on the carton. Refer to Dosage and Administration (2) for (n=5) (n=10) (n=4) (n=19) information on the stability and storage of diluted solutions of Soliris.

General Disorders DO NOT FREEZE. DO NOT SHAKE. and Administration Site Conditions /%$ 4JOHMF VOJU NH DBSUPO $POUBJOT POF N- WJBM PG 4PMJSJT 1ZSFYJB

NH N-

.BOVGBDUVSFE CZ "MFYJPO 1IBSNBDFVUJDBMT *OD Gastrointestinal ,OPUUFS %SJWF $IFTIJSF $5 64" Disorders %JBSSIFB

7PNJUJOH

Infections and SolirisÂŽ JT B SFHJTUFSFE USBEFNBSL PG "MFYJPO 1IBSNBDFVUJDBMT *OD Infestations $PQZSJHIU ÂŞ "MFYJPO 1IBSNBDFVUJDBMT *OD 6QQFS SFTQJSBUPSZ "MM SJHIUT SFTFSWFE 40-

tract infectiona

ents than would be expected in the general population.

The incidences of non-Hodgkin lymphoma and lung cancer were 7.54 and 1.97 times higher.

Liver cancer risk was elevated only among liver transplant recipients, in whom the incidence of the malignancy was nearly 44 times greater than would be expected in the general population, according to the investigators.

The authors concluded: â&#x20AC;&#x153;Some malignancies arise from the loss of immunologic control of oncogenic viruses, but others are unrelated to known infections. Additional contributing factors for some cancers may include other effects of chronic immune disturbance or inflammation, underlying medical conditions, or medication toxicity.â&#x20AC;? â&#x2013;

Study: HoLEP Offers Durable BPH Relief HOLMIUM LASER enucleation of the prostate (HoLEP) is an effective treatment for benign prostatic hyperplasia (BPH) with long-term durable clinical outcomes, researchers concluded.

The procedure is associated with little complication risk and has a reoperation rate of 0.7% at 10-year followup, a rate lower than the 10%-16% rate associated with transurethral resection of the prostate (TURP).

The study, by researchers at McGill University in Montreal led by Mostafa M. Elhilali, MD, included 949 patients treated with HoLEP over a 12-year period. Patients had a mean preoperative post-void residual volume of 311 mL, maximal flow rate of 7.9 mL/sec, and an International Prostate Symptom Score (IPSS) of 19. Postoperatively, all variables showed significant improvement beginning after one month of follow-up remained improved for the entire follow-up period, the researchers reported in the Journal of Urology (2011;186:5;1972-1976). At 10 years, mean postoperative post-void residual volume was 52 mL, mean maximal flow rate was 23.4 mL/sec, and mean IPSS was 3.8. A total of 343 men (36%) experienced acute urinary retention. â&#x2013;

www.renalandurologynews.com

DECEMBER 2011

Renal & Urology News 29

Anonymous Kidney Donors Altruistic Their rate of psychological problems is not higher than that of other types of donors

BY ROSEMARY FREI, MSc VANCOUVER, B.C.—Individuals who wish to donate a kidney anonymously are motivated by altruism rather than psychopathology, according to new studies.

A case series presented by a Vancouver team at the Canadian Psychiatric Association’s 2011 annual meeting indicated that six out of 10 people who stepped forward to be anonymous donors (ADs) were motivated only by the desire to help someone else. This finding corroborates the results of a study published last year that showed carefully screened ADs are individuals acting out of positive motivations (Transplantation 2011;91: 772-778).

“Most donors were middle-aged, well psychologically and physically, and motivated primarily by altruism,” said Maria Corral, MD, who headed the Vancouver team. “In our sample, because they were all anonymous donations, the issues of pressures for donation or financial exchange were not present. This also eliminated any issues of a need for recognition as a motive, as the donors cannot publicize their donation.”

The term AD is somewhat broader in the United States than in Canada. In the United States, it includes not only people who are giving an anonymous, non-

Sources of Living Donor Kidneys Unknown 3.3% Other unrelated 26.1%*

Spouse unrelated 12%

Related 58.6%

*Includes such non-spousal relationships as friends and in-laws, or anonymous donors.

Source: Organ Procurement and Transplantation Network

directed donation, but also those giving directed donations to a stranger.

James Rodrigue, PhD, Associate Professor of Psychiatry at Harvard Medical School and a psychologist at the Transplant Institute of Beth Israel Deaconess Medical Center in Boston, is the lead investigator of the other study that involved 39 ADs and 52 non-anonymous or traditional donors (TDs) from two transplant programs in the United States. His team found that members of both groups had positive donation motivations and relatively few had donation-related psychological problems such as anxiety, depression or marital or financial difficulties.

“Our ADs are not much different from more traditional donors in terms of the reasons for exclusion,” Dr. Rodrigue told Renal & Urology News. “That is, our data suggest that the rate of psychological disturbance is not significantly higher than we see in other donor candidates.”

Dr. Corral, Clinical Professor of Psychiatry at the University of British Columbia, and Interim Head of the Department of Psychiatry at St. Paul’s Hospital, and other members of the Consultation Liaison Psychiatry Team at St. Paul’s Hospital first began psychological evaluation of potential ADs in 2008. In the subsequent two years they assessed 10 patients.

The potential ADs ranged in age from 21-62 years; seven were women and three were men. Three were rejected because they were found to have psychopathology: one suffered from antisocial personality disorder; another had a major depressive disorder and avoidant personality disorder; and third had a cognitive disorder not otherwise specified. A fourth person who was not accepted as a donor was motivated by a need for recognition and was found to have incomplete individuation.

The remaining six all had a clean bill of psychological and motivational health—

including one with major depressive disorder in remission—and had indeed stepped forward primarily due to the desire to help others, the team reported in a poster. For example, one potential donor had not been a good match for a family member with kidney disease so decided to continue the process as an anonymous donor. Another had watched a distant relative die of kidney disease and wanted to ‘do something to help,’ the investigators noted.

The study by Dr. Rodrigue and his colleagues uncovered similar results. The team found both ADs and TDs were both primarily motivated by altruism and were psychologically healthy. However, TDs were more likely to except something in return for the donation, such as financial assistance or preferential treatment from the recipient, or better health care.

Overall, 85% of the ADs and 94% of the TDs felt “very” or “extremely” satisfied with the donation experience.

Dr. Rodrigue and his colleagues recently received a grant from the National Institutes of Health for a study of surgical, medical, and psychological outcomes over the first two years after either traditional or anonymous kidney donation. When completed, it should be the most comprehensive study of ADs, Dr. Rodrigue said. ■

Study Supports AVF Use in Pediatric HD Patients

BY JOHN SCHIESZER BOSTON—Central venous catheters (CVCs) for hemodialysis (HD) access are responsible for a high incidence of catheter-related bloodstream infections in children, according to data presented at the Infectious Diseases Society of American annual meeting.

As a result, greater efforts are needed to encourage the use of arteriovenous fistulas (AVFs) in pediatric HD patients, researchers at the State University of New York Downstate Medical Center in Brooklyn, N.Y., concluded. “With children there is reluctance for cosmetics reasons to give them a fistula,” said study investigator Margaret Hammerschlag, MD, Professor of Pediatrics and Medicine.

Infection rates with AVFs are dramatically lower than with CVCs in all HD populations, she noted. Her colleagues reviewed data on catheter-

related bloodstream infections (CRBSIs) in children on HD at their pediatric dialysis clinic. The investigators collected data on demographic characteristics, types and sites of central venous catheter, duration of catheter use, causative organisms and sensitivities.

The study included 25 individuals aged 2-21 years seen between January 2009 and April 2011. Of these, 24 used CVCs for vascular access. A total of 108 catheters were placed: 105 were tunneled and three were not tunneled. In addition, 13 were placed in femoral veins, 77 were placed in internal jugular veins, and 15 were placed in subclavian veins.

The mean duration of catheter use was 773 days (range 24-3,265 days).

CRBSIs developed in 16 patients (64%) for a total of 130 episodes (mean five per patient) and an incidence of 6.9 per 1,000 catheter-days. In addition, the incidence of CRBSIs (per 1,000

catheter-days) was 6.6 with tunneled catheters, 15.3 for non-tunneled catheters, 13.9 for femoral catheters, 6.0 for internal jugular catheters, and 6.1 for subclavian catheters.

The incidence of CRBSI during the study period for pediatric HD patients

High incidence of CVC-related bloodstream infections found. was higher than the estimated national CRBSI incidence for pediatric and adult patients, she said. In one case, repeated episodes led to removal of a child from the transplant list because of thrombosis.

In adults on HD, the incidence of CRBSIs with CVCs has been reported

to be 1.05-5.5/1,000 catheter-days compared with only 0.04-0.6 in adults with AVFs, Dr. Hammerschlag said, Coagulase-negative staphylococci were responsible for 36.4% of episodes, Staphylococcus aureus, 22%, methicillin-resistant S. aureus, 28%, Gram negative bacilli, 35%, and Candida species (5%). They also found uncommon organisms, including Delftia acidovorans, Chryseobacterium meningosepticum, Providencia stuartii, Morganella morganii, Neisseria sicca, and Bacillus cereus.

Co-investigator Kobkul Chotikanatis, MD, a second-year pediatric infectious disease fellow, said many nephrologists may use a CVC in a child because they believe the child has a chance for an early transplant and will only be on dialysis for short time. “But it turned out that could be a significant burden for the patients,” Dr. Chotikanatis said. ■

34 Renal & Urology News

DECEMBER 2011

www.renalandurologynews.com

Legal Issues in Medicine A urologist listens to a salesman pitching reusable plastic needle guides and winds up in serious trouble BY ANN W. LATNER, JD

D

A urologist took a polygraph test to prove that a vendor told him what he said he did.

Dr. M was informed that the Board of Medical Examiners, in conjunction with the FDA was investigating a rumor that the physician was reusing plastic needle guards, which are single use only.

“Why yes,” Dr. M said. “I’ve been using them for the past few months. We use them on average between three to five times per needle guard. I was told by the vendor that they were reusable.”

Dr. Y was incredulous. “You’ve been in

Even well-educated people can fall prey to believing what they hear. In this case, a physician should have read the product’s reference guide. the needle guards could be reused three to five times. The office staff was told to wash the needle guides in hot water, scrub them to remove blood or tissue, and then soak them in a disinfecting solution before the next use. Once the needle guards became “too bloody,” they should be discarded, the physician said.

About three months after the office started using the plastic needle guards, Dr. M received a visit from Dr. Y, from the state Board of Medical Examiners.

single-use plastic needle guards, also on the information of the vendor.

Based on this information, the polygraph, and Dr. M’s cooperation and openness about the situation, and after negotiations with his attorney, the Board of Medicine reinstated Dr. M’s license a month after it had been suspended. The reinstatement was based on a voluntary agreement that if Dr. M were to perform an invasive procedure in his office, it would be under the supervision of a third-party monitor who was an expert in infectioncontrol procedures. This supervision was to last for three months.

© AARON HAUPT / PHOTO RESEARCHERS, INC.

r. M, 59, was an experienced urologist with a busy private practice. He had been in the field for close to 30 years and was well known and respected in the community.

His office was staffed by several nurses, some of whom had been working there for decades.

Drug reps or equipment vendors regularly showed up in the waiting room hoping get some time with the physician.

One afternoon, Dr. M had a few minutes between patients and spent this time with a vendor for a company that made endocavity needle guards. For many years, Dr. M. had used biopsy and treatment equipment that included using stainless steel needle guides that were reused after cleaning and disinfecting. His previous equipment, however, had worn out and he was interested in purchasing something new. Dr. M had not previously purchased needle guards from this company before, but the salesman was engaging and among his claims for the superiority of these particular plastic needle guards was the assertion that, like the metal ones, they were reusable. Dr. M put in an order.

For the next few months, Dr. M used the new needle guards during procedures for prostate biopsies, implantable markers, and gold seed radiation implants. He instructed his staff that, per the salesman,

practice for over 20 years and you listened to a salesman when it came to the sterilization of medical equipment?”

Dr. Y returned to the Board of Medical Examiners and reported that Dr. M had admitted reusing the single-use guards.

The board reviewed the evidence and summarily suspended Dr. M’s license to practice medicine and charged him with malpractice for reusing the disposable needle guides, and with the “continual failure to exercise the skill or

diligence” normally exercised by physicians in good standing. They reviewed his records and discovered that about 100 patients had had procedures utilizing the needle guards. The board sent letters to the patients, advising them to get tested for hepatitis and HIV. Dr. M was devastated. His thriving practice was suddenly shut down. His reputation was potentially ruined. He hired an attorney to help with the damage control. The attorney made some inquiries and then told Dr. M that the board did not believe that a salesman had told him that the needle guards were reusable. The attorney recommended a public relations campaign to restore Dr. M’s good name.

“I suggest we put an ad in the paper, explaining the situation, but first, I think you should take a polygraph to prove that the vendor told you what you said he did,” the attorney said.

Dr. M took the polygraph, which he passed, and his attorney orchestrated the creation of a newspaper ad with testimonials from patients and other physicians, testifying about the dedication and professionalism of Dr. M. Two weeks after Dr. M’s license was suspended, another local urologist came forward to the board to report himself.

He, too, had been reusing the same

Legal background Dr. M is still facing the two pending charges by the Board of Medicine, which could carry penalties, but are not the same as being sued by a patient and facing civil (or possibly criminal) charges.

At the time of the writing of this article, none of the affected patients had tested positive for hepatitis or HIV; however, if one ultimately did, that patient could certainly sue Dr. M in civil court for negligence and malpractice. The current charges against the physician are medical board actions, not court lawsuits.

Protecting yourself The bottom line? Don’t believe a salesman. While this should be common sense, it is clear from this case that even well-educated people can fall prey to believing what they hear. Regardless of what a salesperson or vendor states, it is essential to take the extra step to confirm it. In this case, that extra step would merely have been to read the enclosed reference guide that came with the needle guides clearly stating that “disposable components are packaged sterile and are single-use only.” ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y. Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended.

www.renalandurologynews.com

DECEMBER 2011

Renal & Urology News 35

Study: Phone Intervention Can Aid Weight Loss

BY JILL STEIN ORLANDO—A weight loss program delivered over the phone can be just as effective in obese patients with at least one cardiovascular risk factor as a weight loss program delivered with in-person support, researchers reported at the American Heart Association Scientific Sessions 2011.

The results, also published simultaneously online in the New England Journal of Medicine, showed that patients who enrolled in a weight loss program delivered over the phone by health coaches and with website and physician support lost weight and kept it off just as well as patients who participated in a program involving in-person coaching sessions.

Patients assigned to both active interventions did better than a control group of patients who received only brief advice, the study showed.

“Perhaps most impressive was the high percentage of patients who lost 5% or more of their initial body weight—about 40% in both the

were randomized to the two active interventions or controls. Study participants were drawn from six local primary care practices.

At 24 months, the mean weight loss was 4.6 kg in the group receiving remote support only, 5.1 kg in the group receiving in-person support, and 0.8 kg in the con-

Moving Forward

trol group, the investigators reported.

To date, few weight loss trials have investigated the effect of behavioral interventions in clinical practice, and results have been highly variable, Dr. Appel observed. Thus, practicing physicians have not had effective, evidencebased tools to draw upon in assisting

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group receiving remote support only and in the group receiving in–person support versus about 20% in the control group,” principal investigator Lawrence J. Appel, MD, MPH, Professor of Medicine at Johns Hopkins University in Baltimore, told Renal & Urology News. “A weight loss of 5% or more has been shown to produce multiple health benefits, including improved control of diabetes and hypertension, a reduced risk of these conditions, and a decrease in cardiovascular risk factors.”

Sustained weight loss In addition, although the magnitude of weight loss with the active interventions is essentially the same as that in several early efficacy studies, this study differs from most earlier ones in that patients sustained the weight loss until the end of the two-year study, according to the researchers.

The study included 415 patients— mostly middle-aged women—with a mean body mass index of 36.6 kg/m2 and a mean weight of 103.8 kg who

their obese patients in achieving and sustaining weight loss.

Remote weight loss support has particular appeal, he said, because it offers patients flexibility and may also help primary care doctors better manage obesity and related cardiovascular disease. ■

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36 Renal & Urology News

DECEMBER 2011

■ ASRM 2011, Orlando, Florida

www.renalandurologynews.com

News coverage of the American Society for Reproductive Medicine annual meeting by John Schieszer

Better Nutrition May Improve Semen BETTER NUTRITION may make for better semen, according to two new studies.

One study was conducted by researchers at the Harvard School of Public Health in Boston, the University of Rochester in Rochester, N.Y., and the University of Murcia in Murcia, Spain. The University of Rochester’s Young Men’s Study recruited men aged 18-22 years. Investigators assessed diets using a questionnaire and assessed semen quality using standard measures of sperm concentration, motility, and morphology in semen samples.

The Prudent diet The researchers categorized subjects’ diets into two types: a Western diet, characterized by high intakes of red meat and refined grains, or a Prudent diet, with high intakes of fish, vegetables, and whole grains.

Adherence to a Prudent diet was significantly associated with higher sperm motility, but not sperm morphology or sperm concentration. Men in the second, third, and fourth quartiles had a 2.2%, 6.0%, and 11.3% higher percentage motile sperm, respectively compared with men in the lowest quartile after adjusting for abstinence time, multivitamin use, race, smoking status, body mass index, year of recruitment, and exercise level.

“This is the first study to look at this issue in an unselected group of men,” said lead investigator Audrey Gaskins, a doctoral candidate at Harvard School of Public Health. “Nutrition could possibly be a safe and inexpensive way to improve semen quality.”

“The main reason I wanted to look at this association is because there is some evidence that semen quality has been declining for a number of years,” Ms. Gaskins told Renal & Urology News.

Exercise May Benefit Sperm MEN WHO ENGAGE in moderate

The group reporting moderate exercise

exercise have better sperm motility

had the highest average sperm motility

than sedentary men, according to a

as well as a significantly lower percent-

new prospective study.

age of men with less than 40% sperm

The study, by researchers at Kura-

motility (14.3%) compared with the other

moto Women’s Clinic and Yamaguchi

groups. In the groups with the lowest and

University in Japan, included 215 men

highest MET-h/w, 30.8% and 27.1% of

who attended an in vitro fertilization

men had sperm motility under 40%.

clinic in Japan from April 2010 to

“It is well known that regular exercise

April 2011 and completed the Godin

is associated with many health benefits,

Leisure-Time Exercise Questionnaire.

but data on its effects on male fertil-

The men were grouped by their self-

ity are limited,” said lead investigator

reported physical activity measured

Masao Murakami, DVM, PhD, a senior

in metabolic equivalent hours per

research scientist at the women’s clinic.

week (MET-h/w). The MET-h/w was

“Today, many subfertile men can be of-

calculated for each man using the

fered a chance to improve fertility

frequency of his exercise, its duration,

via assisted reproductive technologies

and a MET score for strenuous, moder-

such as intracytoplasmic sperm

ate, or light exercise. Each participant

injection. However, this only bypasses

provided at least two semen samples,

the problem and, in many cases, the

which were evaluated for volume, sperm

underlying cause may be left unre-

concentration, and sperm motility.

solved. Therefore, research to under-

Subjects had a mean age of 37.5 years

stand the lifestyle factors that can

(range 24-59 years). Age and body

potentially affect male fertility may

mass index (BMI) were similar among

ultimately lead to more satisfactory and

the groups.

cost-effective treatments.” ■

General Hospital in Boston. All the subjects completed food journals and underwent semen analysis.

Audrey Gaskins

“We found that a Prudent diet that was high in fruits and vegetables, fish and whole grains was associated with higher motility. We are hoping that will translate into increased fertility but we can’t make that jump based on our findings.”

The other study recruited men attending the Fertility Center at Massachusetts

Low Sperm Count May Lower Odds of Having Sons AS A MAN’S SPERM production declines, so does the proportion of sperm bearing the Y chromosome, thus decreasing the likelihood of siring a son, according to new data.

The finding that the efficiency of male spermatogenesis may partially dictate the gender of the offspring may have implications in the counseling and treatment of infertile couples.

“While it has long been known the important role that sperm plays in selecting the gender of the offspring, this study suggests that depending on man’s sperm count, the chances of having a son may not just be coin flip,” said lead investigator Michael Eisenberg, MD, Assistant Professor of Urology at Stanford University School of Medicine in Stanford, Calif.

“This is the first study to directly look at the sperm and see this association between a man’s sperm production

Trans-fats bad for sperm In addition, semen samples of a subset of subjects were chosen for more detailed analysis to measure the level of trans fats. The study revealed that a diet high in trans-fats was negatively associated with sperm concentrations. It was positively associated with higher levels of trans-fats in the sperm and seminal plasma, the researchers noted.

“We are still exploring the impact of nutrition on male fertility, but even these initial studies point to a link between a good diet and reproductive health for men,” commented Edward Kim, MD, who is President of the Society for Male Reproduction and Urology and Professor of Urology at the University of Tennessee in Knoxville. ■

and his ability to sire a male offspring,” he said.

Dr. Eisenberg and his colleagues conducted a study of 186 men (mean age 37.8 years) who underwent semen fluorescence in situ hybridization (FISH).

The median sperm density was 33.8 million/mL (range 0-227 million/mL) with a mean total motile sperm count of 51 (range 0-349) million sperm, according to Dr. Eisenberg, who conducted this study while he was at Baylor College of Medicine in Houston.

He and his colleagues found that for the entire cohort the proportion of Y chromosome-bearing sperm was 51.5%. Men with less than five million motile sperm were found to have a significantly lower proportion of Y chromosome-bearing sperm (50.7%) compared with men with higher sperm counts (51.6%). After adjusting for age, aneuploidy, and time period of semen analysis, a higher motile sperm count significantly increased the odds of having a Y chromosome-bearing sperm.

“The next step to investigate may be to examine the question of whether interventions known to improve sperm counts may affect this gender ratio,” Dr. Eisenberg told Renal & Urology News. ■

www.renalandurologynews.com

DECEMBER 2011

Renal & Urology News 37

CME FEATURE

A Nephrologic Perspective on the Management of Gout Gout is increasingly recognized in patients with chronic kidney disease, but the proper dosing regimen for traditional agents has not been well studied in this patient group

Release Date: December 2011 Expiration Date: December 2012 Estimated time to complete the educational activity: 1 hour This activity is jointly sponsored by Medical Education Resources and Haymarket Media, Inc. TARGET AUDIENCE: This activity has been designed to meet the needs of nephrologists and other health care professionals involved in the treatment of patients with gout.

EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Discuss the pathophysiology of under-excretion of uric acid by the kidney in different disease states.

• Define relevant clinical approaches to treatment.

• Review the use of allopurinol and febuxostat in the treatment of chronic gout.

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 Media, Inc. 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 • Anthony J. Bleyer, MD

Reported Financial Relationship Speakers Bureau: Genzyme and Takeda Consulting Fees: Genzyme, Takeda, and Savient Royalties: For a genetic test to detect uromodulin (UMOD) mutations

BY ANTHONY J. BLEYER, MD

G

out is an historic medical malady with an impressive clinical presentation of acute, intense pain and erythema, often involving the big toe (podagra). This singular clinical finding made gout easy to recognize and diagnose, and defined it as a rheumatologic disease. However, with advanced understanding of biochemistry and renal function, it has become clear that in most cases, gout is actually the rheumatologic manifestation of renal disease, with hyperuricemia most often the result of decreased renal urate excretion.1

Urate metabolism Urate is a byproduct of nucleic acid metabolism. The production, degradation, and recycling of nucleic acids is critical for reproduction of cells and for directing the synthesis of proteins. For most animal species, uric acid is metabolized by the enzyme uricase2 to allantoin. However, man does not produce uricase, resulting in an accumulation of uric acid.

Figure 1 (on page 39) shows key elements of nucleic acid metabolism. Allopurinol3

and febuxostat4 are xanthine oxidase inhibitors and result in increased concentrations of xanthine, with decreased urate production.

Why do humans not have uricase? The gene for producing uricase is actually found in the human genome, but there are two separate mutations that occurred over time that resulted in the inability to synthesize urate.5 There are a number of theories as to why uric acid might be beneficial to humans. An important theory proposed by Dr. Richard Johnson6, 7 is that in primitive cultures that were in general sodium deficient, uric acid resulted in changes in vascular tone in the renal microvasculature, resulting in an increase in blood pressure and increased salt sensitivity.

These changes allowed for an increase in blood pressure that may have provided an evolutionary advantage. With the marked increases in sodium consumption in modern times, it is postulated that elevated serum urate levels may now contribute to nephrosclerosis and hypertension.8 This theory is highly innovative but is still not proven, though work is proceeding rapidly in this area. A recent investigation performed in adolescents with new-onset hypertension showed that treatment with allopurinol actually resulted in a decline in blood pressure measurements.9

The content managers reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Content Manager • Jody A. Charnow, Haymarket Media, Inc. • Marina Galanakis, Haymarket Media, Inc. • Julie Johnson, PharmD, MER

Reported Financial Relationship No financial relationships to disclose No financial relationships to disclose No financial relationships to disclose

METHOD OF PARTICIPATION: There are no fees for participating in and receiving CME credit for this activity. During the period December 2011 through December 2012, 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/renalandurologynews, 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.

Anthony J. Bleyer, MD, is Professor of Medicine in the Section of Nephrology at Wake Forest University School of Medicine in Winston-Salem, N.C. Dr. Bleyer’s clinical interests include the management of gout in patients with CKD.

38 Renal & Urology News

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CME FEATURE The previous concept of urate proximal tubular reabsorption, secretion, and postsecretory reabsorption has been revised based on recent studies using molecular biologic and genetic techniques. These investigations have shown that there are a number of organic anion transporters in the proximal tubule that participate in urate reabsorption, some on the basolateral and some on the apical surface.

An important organic anion transporter known as URAT1 is highly specific for urate transport and exchanges urate for other organic anions. URAT1 is localized to the apical surface of proximal tubular cells and exchanges urate through a nonvoltage dependent mechanism. A number of uricosuric medications bind to URAT1, including probenecid, indomethacin, and salicylates.10 Unique to angiotensin receptor blockers, losartan inhibits the URAT1 transporter,11 resulting in increased urinary urate excretion and decreased serum urate levels.12 Individuals with mutations in the URAT1 transporter have low serum urate levels, very elevated urinary urate levels, and are prone to acute kidney failure13 and uric acid urolithiasis.14 While there are a number of organic anion transporters in the proximal tubule, the cumulative effect is extensive urate reabsorption that is linked to sodium reabsorption. It is of great practical importance for the clinician to realize that increased proximal tubular sodium reabsorption leads to increased urate reabsorption and hyperuricemia.

Pathophysiology Gout occurs almost exclusively in individuals with hyperuricemia, but only a minority of individuals with hyperuricemia develop gout. The probability of developing gout increases with increasing serum urate levels.

The vast majority of individuals who suffer from gout are under-excreters of uric acid, and hyperuricemia is predominantly the result of reduced renal clearance of urate. The development of chronic kidney disease, even when mild, may be associated with decreased urate excretion and hyperuricemia. As renal failure progresses, hyperuricemia worsens.

Factors that stimulate proximal tubular reabsorption of urate will also increase serum urate levels. As mentioned previously, increased proximal sodium reabsorption is a primary driver of

© DU CANE MEDICAL IMAGING LTD. / PHOTO RESEARCHERS, INC.

Urate excretion

An x-ray showing uric acid build up and joint destruction on the big toe.

proximal urate reabsorption. The following are known to cause increased proximal sodium reabsorption: • Congestive heart failure. While there are a number of mechanisms that may be responsible, increased proximal tubular sodium uptake with secondary increased proximal tubular urate uptake is a known factor. Higher serum urate levels in these patients predict a worse outcome.15 • Use of Diuretics. Diuretics lead to increased sodium losses in the thick ascending limb or distal tubule. The nephron compensates for this by increasing proximal tubular sodium reabsorption and secondarily increasing proximal tubular urate reabsorption.

• Aspirin use. Low-dose aspirin increases proximal tubular urate reabsorption in the elderly. At a dosage of 75 mg/ day, aspirin was found to cause a 15% decrease in urate excretion in elderly in-patients in hospital.16 • Some genetic disorders are associated with increased proximal tubular reabsorption of urate. Patients with uromodulin associated kidney disease have mutations in the gene encoding uromodulin (Tamm Horsfall protein).17 The disease is inherited in an autosomal dominant manner. Mutations in uromodulin decrease the ability to reabsorb sodium in the thick ascending limb, resulting in increased proximal tubular sodium uptake and, secondarily, uric acid. Individuals present with hyperuricemia in childhood and often develop gout in their teenage years.

Chronic kidney failure develops over time, with patients developing endstage renal disease in the 4th through 8th decades of life. Hyperuricemia does not cause the chronic kidney

disease (CKD) in this condition, and allopurinol does not stop progression of kidney failure, though it may slow progression.

Autosomal dominant mutations in the gene encoding renin have also been associated with hyperuricemia. Mutations in renin result in mild hyperkalemia, anemia, and hyperuricemia beginning in youth. Hyperuricemia is due to increased proximal tubular urate reabsorption, but the cause of this is uncertain. Patients with this condition also develop slowly progressive CKD. It is important for the nephrologist to be able to identify potential mechanisms in individual patients that lead to increased proximal tubular urate reabsorption so as to better treat hyperuricemia and gout.

While reduced urate excretion is the predominant factor, increased urate production still remains problematic, and is frequently secondary to consumption of meat products18 and alcohol.19, 20 Beer has a high nucleic acid content that leads to increased urate levels.20, 21 Kidney transplantation is associated with a high prevalence of gout,22 due to factors including decreased glomerular filtration in transplanted kidneys, frequent diuretic use, and the hypouricosuric effects of cyclosporine and tacrolimus. Cyclosporine is more likely to be associated with gout than tacrolimus.23 Importantly, allopurinol Table 1. Causes of Gout Overproduction of uric acid • HPRT deficiency • PRPP synthetase overactivity • Glucose 6 phosphatase deficiency • Excessive protein or purine intake • Excessive beer ingestion Under-excretion of uric acid Chronic kidney disease • Polymorphisms in urate transporter genes • Uromodulin associated kidney disease • Autosomal dominant mutations in the gene encoding renin • Thiazide and loop diuretics • Kidney transplantation

Table 2. Therapies for Gout Acute therapies • Colchicine • Non-steroidal anti-inflammatory agents • Prednisone • Intra-articular corticosteroid injection Chronic therapies • Probenecid • Allopurinol • Febuxostat

and febuxostat should not be used in patients receiving azathioprine, as this can lead to life-threatening leucopenia.

Clinical approaches Once gout has been diagnosed, the cause of the hyperuricemia should be identified. The two most common causes of hyperuricemia are decreased renal elimination of urate and excessive alcohol intake. A basic metabolic panel should be obtained to determine if CKD exists. Potential causes of increased proximal tubular urate reabsorption, such as excessive diuretic usage or congestive heart failure, should be identified. Patients should be questioned about their alcohol intake. In younger individuals with gout, one must consider occult kidney disease.

For diagnostic and therapeutic purposes, a 24-hour urine collection for urate can be performed to determine if the patient over-produces urate, under-excretes urate, or both. A 24-hour urate excretion of greater than 700 mg is suggestive of excessive urate excretion but does not rule out that concomitant increased proximal tubular reabsorption is not occurring.24 In one study, in individuals without gout, the fractional excretion of urate was 7.6 ± 1.9% vs. a fraction excretion of 5.8 ± 1.0% in individuals with gout.24 Acute treatment: Acute treatment is substantially different from chronic prevention. Acute treatment involves decreasing inflammation and pain.

Chronic prevention requires lowering serum urate concentrations. In both forms of therapy, one must consider residual renal function.

Local therapy includes the use of ice on the joint, which has been found to decrease pain and swelling compared to no ice.25 An intra-articular glucocorticoid injection is very effective, though requiring an office visit and a physician proficient in the giving these injections.

The three major therapeutic medicinal choices for acute gout include colchicine, non-steroidal anti-inflammatory agents (NSAIDs), and glucocorticoid therapy.

While colchicine has long been used in the treatment of gout, it is associated with significant gastrointestinal toxicity as well as the potential for life-threatening leucopenia. Traditional dosing regimens of 0.6 mg hourly until nausea or diarrhea develops are ill advised. A recent trial showed that colchicine dosed at

www.renalandurologynews.com

DECEMBER 2011

Figure 1. Uric Acid Metabolism PRPP Synthetase Overactivity

Ribose-5-Phosphate + ATP PRPP synthetase Adenosine triphosphate

PRPP

Guanosine triphosphate

Adenosine monophosphate

Inosine monophosphate

Guanosine monophosphate

5'-nucleotidase APRT +PRPP

Adenosine

5'-nucleotidase

5'-nucleotidase Guanosine

Inosine

HPRT +PRPP

HPRT +PRPP Adenine

Guanine

Hypoxanthine Xanthine oxidase

Allopurinol and Febuxostat

Xanthine

Lesch Nyhan Xanthine oxidase Uric acid

Renal & Urology News 39

in individuals with the risk factors outlined above. For this reason, allopurinol is not recommended in the treatment of asymptomatic hyperuricemia.29 The dosing of allopurinol in CKD remains controversial. Earlier studies suggested that normal doses of allopurinol in patients with CKD resulted in increased accumulation of allopurinol metabolites and placed patients at increased risk of allopurinol hypersensitivity.30 However, these investigations may have been flawed. Despite this, there are no good safety data regarding the correct dosage of allopurinol in CKD. Febuxostat: Febuxostat is another xanthine oxidase inhibitor that has been found to be more effective in preventing gout attacks and lowering serum urate levels than the traditional doses of allopurinol.4, 31, 32 In clinical trials with febuxostat, no severe allergic reactions have been reported, though in these studies there were also no severe allergic reactions with allopurinol.31, 33

Uricase Allantoin

1.2 mg followed by 0.6 mg in one hour was as effective as higher dosing (1.2 mg followed by 0.6 mg every hour for six hours) and associated with much less toxicity.26 NSAIDs are very effective agents for the treatment of gout and should be considered in individuals with normal kidney function. Unfortunately, many individuals with gout have renal insufficiency, and the use of NSAIDs may be contraindicated. NSAIDs may be especially contraindicated in individuals receiving ACE inhibitors and diuretics or individuals with kidney failure, liver failure, or heart failure.

A prednisone taper is being used increasingly as a first-line therapy for gout. The major advantages of prednisone are its efficacy and its rapid efficacy.

Prednisone also has limited effects on kidney function. A major disadvantage is the effect of prednisone on blood glucose control. Diabetic patients who take a prednisone taper need to monitor their blood glucose concentrations closely.

Chronic treatment: The goal of chronic therapy is to lower the bodyâ&#x20AC;&#x2122;s uric acid burden. A goal serum urate level less than 6 mg/dL has been set as a

target for lowering serum urate levels, as levels below this are associated with a low frequency of gout attacks27 and are associated with tophi resolution.

This level is only one factor that should be taken into account in the management of the patient with gout.

When serum urate levels are lowered, for an unknown reason, patients have an increased risk of developing a gout attack. A poor understanding of this phenomenon by both patients and their physicians has resulted in noncompliance and poor long-term therapy of gout patients.

Probenecid: Probenecid is a medication that increases renal urate excretion by inhibiting proximal tubular urate uptake. The medication should be considered in individuals with good kidney function whose hyperuricemia is the result of decreased urate excretion. It is contraindicated in individuals with advanced CKD and in those with urolithiasis.28 The use of probenecid with penicillin or in patients with renal insufficiency is not recommended, and aspirin may decrease the efficacy of probenecid. Due to drug

interactions and the increased urinary uric acid excretion, probenecid is used less commonly than allopurinol. It is important to alert the patient given probenecid to the possible drug interactions that may occur, as the physician prescribing probenecid may not be the sole provider of health care to the patient.

Allopurinol: Allopurinol is probably the most common medication used in the chronic treatment of gout. It is in general well tolerated by patients. Unfortunately, there is the rare possibility of the development of a severe allergic reaction to allopurinol that can be life-threatening.29, 30 This rare reaction results in a Stevens Johnson rash, elevated liver function tests, and can be associated with fulminant hepatic failure and death. While this reaction is rare, it points to the fact that allopurinol should only be used when a clear indication exists. Patients who have had the severe reaction have typically been older, on a diuretic, and suffering from reduced glomerular filtration rates.30 Patients should be instructed to stop allopurinol immediately if a rash develops and to contact their physician.

Close monitoring is especially important

Pegloticase: Pegloticase is a new compound that consists of the enzyme uricase that has been pegylated to decrease immunogenicity. It is indicated for severe gout refractory to other treatments. Pegloticase is given by intravenous infusion and is associated with frequent reactions during infusion. It has been noted to be extremely beneficial in tophaceous gout.

Asymptomatic hyperuricemia: There is no indication for the treatment of asymptomatic hyperuricemia at this time, and this cannot be stressed enough. However, there are a number of studies suggesting that allopurinol may be beneficial in terms of CKD progression and even mortality. In a recent prospective, randomized study,34 113 individuals with an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2 were randomized to 100 mg/day allopurinol or placebo.

After a median follow-up of almost two years, the eGFR decreased by 3.3 mL/min/1.73 m2 in the placebo group and increased by 1.3 mL/min/1.73 m2 in the allopurinol group. Allopurinol was also associated with a 71% reduction in the risk of cardiovascular events during the study. In another study,35 54 hyperuricemic patients with CKD were randomized to receive allopurinol (dosed between 100 and 300 mg/day) and usual therapy for 12 months. Four of 25 patients in the allopurinol group and

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CME FEATURE 12 of 26 in the control group achieved the combined end point of significant deterioration of kidney function or dialysis dependence.

Summary In summary, gout is a disease that has been studied for several millennia, but recent scientific and pharmacologic advances have provided exciting information. Most gout is due to increased proximal tubular reabsorption of urate, and the nephrologist has the best ability to determine why reduced urate excretion is occurring in a given patient. The frequent coexistence of gout and kidney failure results in nephrologists treating many individuals with gout. While allopurinol has been used as a treatment for gout for many decades, the proper dosing regimen in CKD has not been well studied. Future research will try to better define the role of allopurinol and febuxostat in treatment, and address how these agents may potentially slow progression of kidney disease and decrease morbidity from heart failure. ■ REFERENCES 1. Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med 2005;143:499-516.

2. Wu XW, Lee CC, Muzny DM, Caskey CT. Urate oxidase: primary structure and evolutionary implications. Proc Natl Acad Sci U S A 1989;86:9412-9416.

3. Scott JT. Comparison of allopurinol and probenecid.

Ann Rheum Dis 1966;25(6 Suppl):623-626.

4. Becker MA, Schumacher HR, Jr, Wortmann RL et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353:2450-2461.

5. Wu XW, Muzny DM, Lee CC, Caskey CT. Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol 1992;34:78-84.

6. Johnson RJ, Segal MS, Srinivas T, et al. Essential hypertension, progressive renal disease, and uric acid: A pathogenetic link? J Am Soc Nephrol 2005;16:1909-1919.

7. Johnson RJ, Titte S, Cade JR, et al. Uric acid, evolution and primitive cultures. Semin Nephrol 2005;25:3-8.

8. Mazzali M, Kanbay M, Segal MS, et al. Uric acid and hypertension: cause or effect? Curr Rheumatol Rep 2010;12:108-117.

9. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA 2008;300:924-932.

10. Shin HJ, Takeda M, Enomoto A, et al. Interactions of urate transporter URAT1 in human kidney with uricosuric drugs. Nephrology (Carlton) 2011;16:156-162.

11. Hamada T, Ichida K, Hosoyamada M, et al. Uricosuric action of losartan via the inhibition of urate transporter 1 (URAT 1) in hypertensive patients.

Am J Hypertens 2008;21:1157-1162.

12. Hamada T, Mizuta E, Kondo T, et al. Effects of a low-dose antihypertensive diuretic in combination with losartan, telmisartan, or candesartan on serum urate levels in hypertensive patients. Arzneimittelforschung 2010;60:71-75.

13. Mima A, Ichida K, Matsubara T, et al. Acute renal failure after exercise in a Japanese sumo wrestler with renal hypouricemia. Am J Med Sci 2008;336:512-514.

14. Ichida K, Hosoyamada M, Hisatome I, et al.

Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol 2004;15:164-173.

15. Wu AH, Ghali JK, Neuberg GW, et al. Uric acid level and allopurinol use as risk markers of mortality and morbidity in systolic heart failure. Am Heart J 2010;160:928-933.

16. Caspi D, Lubart E, Graff E, et al. The effect of mini-dose aspirin on renal function and uric acid handling in elderly patients. Arthritis Rheum 2000;43:103-108.

17. Bleyer AJ, Trachtman H, Sandhu J, et al. Renal manifestations of a mutation in the uromodulin (Tamm Horsfall protein) gene. Am J Kidney Dis 2003;42:E20-26.

18. Choi HK, Liu S, Curhan G. Intake of purine-rich foods, protein, and dairy products and relationship to serum levels of uric acid: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2005;52:283-289.

19. Choi HK, Curhan G. Alcohol and gout. Am J Med 2007;120:e5.

20. Choi HK, Curhan G. Beer, liquor, and wine consumption and serum uric acid level: the Third National Health and Nutrition Examination Survey.

Arthritis Rheum 2004;51:1023-1029.

21. Lee SJ, Terkeltaub RA, Kavanaugh A. Recent developments in diet and gout. Curr Opin Rheumatol 2006;18:193-198.

22. Clive DM. Renal transplant-associated hyperuricemia and gout. J Am Soc Nephrol 2000;11:974-979.

23. Abbott KC, Kimmel PL, Dharnidharka V, et al. New-onset gout after kidney transplantation: incidence, risk factors and implications. Transplantation 2005;80:1383-1391.

24. Perez-Ruiz F, Calabozo M, Erauskin GG, et al. Renal underexcretion of uric acid is present in patients with apparent high urinary uric acid output. Arthritis Rheum 2002;47:610-613.

25. Schlesinger N, Detry MA, Holland BK, et al. Local ice therapy during bouts of acute gouty arthritis.

J Rheumatol 2002;29:331-334.

26. Terkeltaub RA, Furst DE, Bennett K, et al. High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum 2010;62:1060-1068.

27. Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum 2004;51:321-325.

28. Chohan S, Becker MA. Update on emerging urate-lowering therapies. Curr Opin Rheumatol 2009;21:143-149.

29. Gutierrez-Macias A, Lizarralde-Palacios E, MartinezOdriozola P, Miguel-de la Villa F. Fatal allopurinol hypersensitivity syndrome after treatment of asymptomatic hyperuricaemia. BMJ 2005;331:623-624.

30. Casas E, Puig JG, Mateos FA, et al. The allopurinol hypersensitivity syndrome: its relation to plasma oxypurinol levels. Adv Exp Med Biol 1989;253A:257-260.

31. Becker MA, Schumacher HR, MacDonald PA, et al.

Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout. J Rheumatol 2009;36:1273-1282.

32. Schumacher HR, Jr, Becker MA, Wortmann RL, et al.

Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum 2008;59:1540-1548.

33. Becker MA, Schumacher HR, Espinoza LR, et al.

The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther 2010;12:R63.

34. Goicoechea M, de Vinuesa SG, Verdalles U, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol 2010;5:1388-1393.

35. Siu YP, Leung KT, Tong MK, Kwan TH. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level.

Am J Kidney Dis 2006;47:51-59.

DISCLAIMER: The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Medical Education Resources or Haymarket Media, Inc. 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 Medical Education Resources, or Haymarket Media, Inc. 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.

CME Post-test Expiration Date: December 2012 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 /renalandurologynews. You must receive a score of 70% or better to receive credit.

1. The following factors lead to increased proximal tubular reabsorption of urate: a. Loop diuretics such as furosemide b. Thiazide diuretics c. Congestive heart failure d. All of the above 2. In the general population, the most common cause of hyperuricemia is: a. Decreased renal urate excretion b. Increased urate production secondary to diet c. A combination of a and b 3. According to a recent randomized trial, the superior dosage regimen for colchicine for the treatment of an acute gout attack is: a. 0.6 mg hourly until nausea and vomiting develop b. 1.2 mg orally followed by 0.6 mg one hour later c. 0.6 mg colchicine once a day 4. A kidney transplant patient receiving prednisone, azathioprine, and cyclosporine develops a gout attack. Which of the following statements is correct: a. Allopurinol would be the most appropriate therapy due to its low cost. b. Febuxostat would be the most appropriate therapy because of the interaction between allopurinol and azathioprine leading to life threatening leucopenia. c. Consideration of changing the patient from azathioprine to mycophenolate and then adding allopurinol may be indicated.

5. Which of the following would not be indicated for the management of an acute gout attack? a. Prednisone b. Indocin c. Colchicine d. Allopurinol 6. Which of the following agents is likely to decrease serum uric acid levels? a. Furosemide b. Losartan c. Irbesartan d. Hydrochlorothiazide 7. Which of the following are associated with hyperuricemia: a. Increased ethanol consumption b. Increased protein intake c. Use of diuretics d. All of the above

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Your Money W

ith investors worried about overwhelming debt burdens in the United States and Europe, the Standard & Poor’s 500 index sank 5.4% in August 2011.

But not all investments were losers.

For the month, Vanguard Consumer Staples Fund stayed in the black. The performance was not surprising. The Vanguard fund holds shares of such rock-solid consumer companies as Kraft Foods and Walgreen. People must buy food and drugs constantly—even in recessions. “Consumer companies deliver steady earnings, so they tend to hold up during economic downturns,” says Wade Stinnette, portfolio manager of FBR Balanced Fund.

Because they avoid big losses in downturns, top consumer stocks have produced strong long-term returns. During the rocky markets of the past decade, consumer funds returned 7.2% annually, outdoing the S&P 500 by more than four percentage points, according to Morningstar. At a time when the economy seems likely to remain sluggish, consumer stocks could serve as anchors for portfolios of conservative investors.

Make no mistake: Consumer stocks do not lead the markets every year. During

Mills and Kellogg, as well as soft drink giants Coca-Cola and Pepsico.

Other consumer companies make household products as well as health and beauty aids. Among the biggest are Colgate-Palmolive, the toothpaste producer, and Procter & Gamble, which makes Tide detergent and Crest toothpaste.

An especially safe choice is Coca-Cola.

The beverage company is enormously profitable, and the business grew steadily throughout the financial crisis of recent years. Growth of the soft drink business is slowing in the United States, but Coke has ceased to be primarily an American company. Most sales and earnings come from overseas, where the company is expanding steadily. Some of the most rapid growth has been reported in the booming economies of Asia and Latin America. The company recently announced that it had sold one billion cases in China during the first six months of 2011, double the figure of five years ago. “Coca-Cola has little debt and tremendous growth prospects,” Stinnette says.

Stinnette particularly likes the stock because it pays a dividend yield of 2.9%.

That is a relatively rich payout at a time when 10-year Treasury bonds yield only around 2.2%. Coca-Cola is among the

Because they avoid big losses in downturns, top consumer stocks have produced strong long-term returns. bull markets, investors often ignore consumer goods, which may seem dull compared to technology or finance. But over the long haul, consumer stocks tend to deliver competitive results.

Consumer stocks account for about 10% of the assets in the S&P 500. The group includes a range of businesses.

Prominent on the list are food and beverage producers, including ketchup maker H. J. Heinz, cereal producers General

most reliable income sources. The company has increased its dividend payment for 49 consecutive years.

Like Coca-Cola, Pepsico is a steady income producer. The stock pays a dividend yield of 3.3%, and the company has increased the dividend annually for three decades. Besides reporting strong growth of its soft drinks, Pepsico is showing gains in its other products, including Tropicana orange juice and

© ISTOCKPHOTO.COM / PENG WU

In a sluggish economy, conservative investors might do well to put money into the stocks of consumer companies BY STAN LUXENBERG

Coca-Cola sold one billion cases in China in the first six months of 2011.

Quaker oatmeal. More than one third of sales come from the emerging markets.

“Pepsico offers a relatively safe way to benefit from the growth in Asia,” says George Shipp, portfolio manager of Sterling Capital Equity Income Fund.

Another way to bet on consumer stocks is to own retailers that sell food and household goods. A solid choice is Wal-Mart Stores, the biggest retailer in the world. While the recession has slowed the growth of the chain, the company is continuing to open new outlets in the United States and expand rapidly in Latin America and other regions overseas. In the second quarter of 2011, revenues grew 5%. “Wal-Mart has exciting potential in the emerging markets,” says Jeff Auxier, portfolio manager of Auxier Focus Fund.

To own a fund that focuses on the sector, consider Rydex Consumer Products Fund, which has returned 7.7% annually during the past decade.

The fund has a big stake in Mead Johnson Nutrition, a company that is especially reliable because it sells infant formula under brand names such as Enfamil. With sales growing in emerging markets, the company has been

increasing its earnings at a 22% annual rate. Other holdings in the Rydex fund include Kimberly-Clark, the maker of Kleenex brand tissues and Estee Lauder, the cosmetics company.

For more diversification, you can try a fund that holds consumer stocks as well as holdings in other sectors. A top performer is Sterling Capital Equity Income, which has about a third of its assets in the consumer sector. During the past five years, the fund returned 3.8% annually, outdoing 99% of its competitors. Sterling often excels in downturns. When the S&P 500 lost 37.0% in 2008, the fund outperformed by 11 percentage points.

Portfolio manager George Shipp favors companies with solid balance sheets and the ability to grow consistently. He favors companies that can steadily raise their dividends. A favorite holding is hamburger giant McDonald’s, which has increased its dividend annually for more than 30 years.

Sales have been climbing briskly.

Another steady fund is Ave Maria Rising Dividend, which has 39% of its assets in consumer stocks. Many holdings in the fund are so solid that they could raise their dividends substantially during the financial crisis. ■