Renal & Urology News October 2013 Issue by Haymarket Media

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Kidney Donors Show Signs of Mild CKD Measured GFR declined by 28% at six months BY JODY A. CHARNOW Kidney donors have some of the abnormalities typically associated with mild chronic kidney disease (CKD) six months after donation, researchers concluded. These abnormalities include a decline in kidney function, increased parathyroid hormone (PTH) and uric acid levels, and lower hemoglobin levels, they stated. The prospective study compared 203 kidney donors with 201 controls, who were healthy individuals with two kidneys and who theoreti-

in this issue 9 Mortality after MI is declining in CKD patients 10 AKI outcomes linked to nephrology referrals 12 Painless MI increases CKD patient death risk

15 Ascorbic acid does not cut

risk of contrast nephropathy

18 Novel iron drug safe, effective in hemodialysis patients

A surgical complication results in a lawsuit PAGE 16

cally would have been suitable to donate a kidney. Donors and controls were comparable with respect to all parameters measured. A team led by Bertram L. Kasiske, MD, of the Hennepin County Medical Center in Minneapolis, measured glomerular filtration rate (GFR), blood pressure, and other variables at baseline (predonation) and at six months. Compared with controls, donors had a significant 28% decrease from baseline in measured GFR at six months (94.6 vs. 67.6 mL/min/1.73 m2), a significant 23% increase in PTH level

RRT Risk Higher in HIV Patients HIV patients, who are known to be at increased risk of impaired renal function, are much more likely to be placed on renal replacement therapy (RRT) than the general population, a Danish study found. In a nationwide, population-based cohort study that included 5,300 HIV patients and 53,000 population controls, Magnus G. Rasch, MD, of the University of Copenhagen, and colleagues found that HIV patients had a fourfold increased risk of any RRT (aRRT) and a threefold increased risk of chronic RRT (cRRT) compared with age- and gender-matched controls, continued on page 10

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Kidney Donor Abnormalities At Six Months Six months after donating a kidney, donors had significant changes (compared with controls) that are typically associated with chronic kidney disease:

Measured GFR

28% decrease

PTH level

23% increase

Uric acid level

8.2% increase

Hemoglobin level

3.7% decrease

Source: Kasiske BL et al. A prospective controlled study of kidney donors: Baseline and 6-month follow-up. Am J Kidney Dis (2013;62:577-586).

(42.8 vs. 52.7 pg/mL), a significant 8.2% increase in uric acid level (4.9 vs. 5.3 mg/dL), and a significant 3.7% decrease in hemoglobin level (13.6 vs. 13.1 g/dL). The study found no significant difference between donors and

controls in blood pressure, urine total protein, urine albumin, body weight, or body mass index. “The increase in PTH levels is in keeping with the correlation continued on page 10

Drug Works For Resistant CMV BY JOHN SCHIESZER DENVER—Cidofovir with or without adjunctive therapy may be an appropriate treatment option for ganciclovirresistant cytomegalovirus (CMV) infections in solid organ transplant (SOT) recipients, according to study findings reported at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy. “There is no standard of care and there has been little evidence on which agent to use in solid organ transplantation,” said study investigator Katherine Perez, PharmD, an infectious diseases clinical specialist at Houston Methodist Hospital in Texas.

cme feature

The study is the first to show the possible usefulness of cidofovir in treating ganciclovir-resistant infections among transplant recipients, and the findings could give clinicians some guidance on what to use, Dr. Perez said. Dr. Perez and her colleagues conducted a single-center analysis of all SOT recipients from 2009 through 2012. Valganciclovir universal prophylaxis was standard for the center and 1,549 patients were included in the analysis. The researchers identified CMV infection in 284 of the 1,549 patients continued on page 10

Earn 1 CME credit in this issue

Dietary Interventions for Treating Progressive CKD Page 20

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Sling Outcomes Unaffected by Age BY JILL STEIN BARCELONA—Older and younger women have similar stress urinary incontinence (SUI) outcomes after primary midurethral sling (MUS) placement, according to study findings reported at the 43rd Annual Meeting of the International Continence Society. The results, however, also show that older patients are less likely to perceive that their incontinence has improved with MUS than their younger counterparts. “We believe these results have clinical relevance as they will enable physicians

in this issue 7 Non-UTI problems common with urethral catheters 10 Ketoconazole found to improve AUR treatment 1 1

Bicycling leads all sports in genitourinary injuries

15 Metastasis-free interval affects PCa patient survival

25 Shiftworkers more likely to have elevated PSA

A surgical complication results in a lawsuit PAGE 16

to enhance age-related patient counseling, especially regarding post-intervention expectations,” said David R. Ellington, MD, Fellow/Instructor in the Division of Urogynecology and Pelvic Reconstructive Surgery at the University of Alabama School of Medicine at Birmingham. “Many women worry that they may develop new lower urinary tract symptoms after MUS placement, and our study demonstrated that new-onset UUI and resolution of symptoms of this form of incontinence are similar for both age groups.”

Younger, older women have similar success rates

a woman’s age may not matter with midurethral sling surgery.

The researchers reviewed results in 696 women who underwent primary MUS at their institution over a recent four-year period. SUI affects about one third of all women, and the likelihood of devel-

oping the condition increases with age, Dr. Ellington noted. The number of women aged 70 years and older is increasing, and thus it is thought that the number of women who seek continued on page 10

Hypogonadism PSADT Prognosis Flaws ID’d in Men Has An BY ROSEMARY FREI, MSc cal uncertainty of the PSA doubling VANCOUVER—Relying on PSA time leads to a substantial risk of Estrogen Link doubling time (PSADT) from just one patients being misclassified as having Estrogen deficiency explains, at least in part, some of the physiologic changes observed in hypogonadal men, according to a new study. While testosterone deficiency accounts for decreases in lean mass, muscle size, and strength, estrogen deficiency primarily accounts for increases in body fat. Deficiency of both hormones contributes to a decrease in sexual function. “Our findings support changes in the approach to evaluation and management of hypogonadism in men,” investigators concluded in the New England Journal of Medicine (2013;369:1011-1022). continued on page 10

year of active surveillance can result in as many as one in five prostate cancer (PCa) patients being advised to undergo curative treatment that may be unnecessary, new research has revealed. Frederik B. Thomsen, MD, from Rigshospitalet, University of Copenhagen, Denmark, and his colleagues found that using only one year of PSA testing results can lead to 10%20% of patients being misclassified as having a high risk of PCa progression. “Our study shows that the statisti-

cme feature

an aggressive tumor using the currently applied active surveillance criteria,” Dr. Thomsen said after presenting results at the 33rd Congress of the Societé Internationale d’Urologie. “Therefore, PSA doubling time should not be used as a trigger for recommending curative therapy in these patients.” He presented other results demonstrating the unreliability of PSADT earlier in the year at the 28th annual congress of the European Association of Urology. His team performed the analysis continued on page 10

Earn 1 CME credit in this issue

Dietary Interventions for Treating Progressive CKD Page 20

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From the MEDICAL DIRECTOR Editorial Advisory Board

The Future of Dialysis in the U.S.

ach year approximately 110,000 new patients start chronic dialysis treatment in the U.S. This public health metric is known as the end-stage renal disease (ESRD) incidence rate. Over the past 10 years the annual ESRD incidence rate per million U.S. population has remained stagnant or even shown sporadic downward trends. More interestingly, and probably for the first time in this country, the absolute number of new dialysis patients per year has declined despite ongoing population growth. Does this mean that the growth of the dialysis industry in the U.S. will come to a grinding halt? Additional factors may contribute to re-shaping the future of the dialysis industry, including changes in practice pattern and finances. There has been a recent trend to initiate dialysis treatment later in the course of chronic kidney disease (CKD) progression. This new approach is inspired by a number of recent studies that suggest no favorable effect or even harmful outcomes upon earlier dialysis initiation. Some data suggest that in very old CKD patients a more conservative approach without dialysis treatment may be the better approach. These new views, no matter how controversial they are, have already started impacting our practice pattern. There are additional challenges with chronic dialysis therapy in the U.S., especially if the government’s imminent plans to cut the dialysis treatment reimbursement by 9.4% are implemented in 2014. Since dialysis patient attrition is quite high given the regretfully high mortality of 20% annually in the U.S., along with high kidney transplantation rates and patient withdrawals, the decline in the ESRD incidence rate will likely mean that for the first time in our history we may see increasing numbers of vacant hemodialysis (HD) seats during our dialysis rounds. This may be a new phenomenon for American nephrologists, but Canadian and British colleagues are quite familiar with it, and this has led to trimming some HD shifts and ultimate closure of many dialysis clinics without a replacement. In the U.S., the struggle may further be intensified by recent trend to transition more patients from HD to the better incentivized peritoneal dialysis and the recent emergence of new dialysis clinics at every corner of the block in town by the competing dialysis chains. The latter observation suggests that rival dialysis companies have not yet felt the need for better coordination of plans and efforts as a unified front. Even more vulnerable may be the independent dialysis centers, although it is hard to predict which sector will be affected most. The only effective way to counter these unavoidable trends is to improve dialysis patient survival and to lower hospitalization. Kam Kalantar-Zadeh, MD, MPH, PhD Professor & Chief Division of Nephrology & Hypertension University of California Irvine School of Medicine Orange, Calif.

Medical Director, Urology

Medical Director, Nephrology

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

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

Nephrologists

Urologists Christopher S. Cooper, MD Director, Pediatric Urology Children’s Hospital of Iowa Iowa City 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 Chief of Surgical Operations Professor of Surgery CCLM Cleveland Clinic Regional Hospitals Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology University of California, Irvine James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City 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

Anthony J. Bleyer, MD, MS Professor of Internal Medicine/Nephrology Wake Forest University School of Medicine Winston-Salem, N.C. Suphamai Bunnapradist, MD Director of Research Department of Nephrology Kidney Transplant Research Center The David Geffen School of Medicine at UCLA 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 of Pediatrics and Medicine University of Toronto Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center, Detroit Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J. Lynda Anne Szczech, MD, MSCE Medical Director, Pharmacovigilence and Global Product Development, PPD, Inc. Morrisville, N.C.

Renal & Urology News Staff Editor Jody A. Charnow Executive editor Marina Galanakis Senior editor Delicia Honen Yard Web editor Stephan Cho Editorial coordinator Candy Iemma Art director Andrew Bass Group art director, Haymarket Medical Jennifer Dvoretz VP, audience development and operations John Crewe Production manager Brian Wask Production director Kathleen Millea Product manager, digital products Chris Bubeck Circulation manager Paul Silver National accounts manager William Canning Editorial director Jeff Forster Publisher Dominic Barone VP medical magazines and digital products Jim Burke CEO, Haymarket Media Inc. Lee Maniscalco Renal & Urology News (ISSN 1550-9478) Volume 12, Number 10. 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 © 2013.

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6 Renal & Urology News

october 2013 www.renalandurologynews.com

Contents

october 2 0 1 3

V olume 1 2 , issue N umber 1 0

Nephrology 9

ONLINE

this month at renalandurologynews.com Expert Q&A

Oliver Sartor, MD, of the Tulane School of Medicine in New Orleans, talks about the growing arsenal of drugs to treat mCRPC.

CME Feature

Ascorbic Acid Does Not Cut CIN Risk Ascorbic acid has no significant effect on the incidence of contrast-induced nephropathy among patients undergoing coronary angiography.

No AKI Benefit with Earlier Dialysis Earlier initiation of dialysis does not improve outcomes among patients with community-acquired acute kidney injury.

News Coverage

Visit our website for coverage of Kidney Week 2013 in Atlanta, November 5-10.

Urology 7

The Medical Minute

Visit renalandurologynews.com /the-medical-minute/ to hear podcast reports on new studies. Our latest include: • Investigational Drug May Block Advance of Type 1 Diabetes • Calcium-Based Phosphate Binders Up Death Risk • Adolescent Kidney Transplants More Likely to Fail

Study Zeroes In On Ideal BP in CKD Patients The optimal blood pressure for patients with chronic kidney disease appears to be 130159/70-89 mm Hg, researchers concluded.

Clinical Quiz

Take our latest quiz at renalandurologynews.com /clinical-quiz/. Answer correctly and you will be entered to win a $25 American Express gift card. Congratulations to our August winner: Alyssa Riley, MD

Post-MI Mortality Declining in CKD Patients From 1985-2008, the 30-day mortality risk after a myocardial infarction decreased from 11% to 6%, a study found.

Non-UTI Problems Common with Urethral Catheters Leakage/incontinence tops the list with an incidence of 11%, and spinal cord injury patients have high rates of bladder stones and gross hematuria, researchers reported.

Bicycling Leads All Sports in GU Injuries Study reveals that 43,200 such injuries occurred in the U.S. from 2002-2010.

Departments 4

From the Medical Director The future of dialysis in the U.S.

Drugs Similarly Efficacious for mRCC Pazopanib is as effective as sunitinib as first-line therapy in terms of progressionfree survival, but it is associated with fewer adverse events and better quality of life, trial data show.

News in Brief Biomarker may predict acute kidney injury

Renal Nutrition Update A high-fat, low-carb diet for CKD patients?

Legal Issues in Medicine Stone procedure injures a ureter, gets urologist sued

Expert Q&A David O. Sussman, DO: Botox for urinary incontinence

Our data support the notion that sleep or circadian

disruption is associated with elevated PSA.”

See our story on page 25

RUN1013_TOC_Nephro.indd 1

Dietary Interventions for Treating Progressive Chronic Kidney Disease Csaba P. Kovesdy, MD, Chief of Nephrology at the Memphis VA Medical Center and the Fred Hatch Professor of Medicine at the University of Tennessee Health Science Center, Memphis, discusses strategies for protein restriction and other nutritional interventions.

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6 Renal & Urology News

october 2013 www.renalandurologynews.com

Contents

octo b er 2 0 1 3

V o l u me 1 2 , i ss u e N u m b er 1 0

Urology 7

ONLINE

this month at renalandurologynews.com Expert Q&A

Bicycling Leads All Sports in GU Injuries Study reveals that 43,200 such injuries occurred in the U.S. from 2002-2010.

Oliver Sartor, MD, of the Tulane School of Medicine in New Orleans, talks about the growing arsenal of drugs to treat mCRPC.

Clinical Quiz

Nephrology

The Medical Minute

Post-MI Mortality Declining in CKD Patients From 1985-2008, the 30-day mortality risk after a myocardial infarction decreased from 11% to 6%, a study found.

Study Zeroes In On Ideal BP in CKD Patients The optimal blood pressure for patients with chronic kidney disease appears to be 130159/70-89 mm Hg, researchers concluded.

News Coverage

Visit our website for coverage of Kidney Week 2013 in Atlanta, November 5-10.

CME Feature 20

Visit renalandurologynews.com /the-medical-minute/ to hear podcast reports on new studies. Our latest include: • Once-Daily ED Drug May Help Restore Normal Erectile Function • Decision Aids Fail to Change PSA Screening Rates • Appropriateness of Active Surveillance for Prostate Cancer Reaffirmed

Ascorbic Acid Does Not Cut CIN Risk Ascorbic acid has no significant effect on the incidence of contrast-induced nephropathy among patients undergoing coronary angiography. No AKI Benefit with Earlier Dialysis Earlier initiation of dialysis does not improve outcomes among patients with community-acquired acute kidney injury.

Our data support the notion that sleep or circadian

Departments 4

From the Medical Director The future of dialysis in the U.S.

News in Brief Biomarker may predict acute kidney injury

Renal Nutrition Update A high-fat, low-carb diet for CKD patients?

Legal Issues in Medicine Stone procedure injures a ureter, gets urologist sued

Expert Q&A David O. Sussman, DO: Botox for urinary incontinence

disruption is associated with elevated PSA.”

See our story on page 25

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Renal & Urology News 7

Non-UTI Problems Common with Urethral Catheters rate in outpatients and, in one study, a 70% rate of accidental removal among inpatients. The study revealed high rates of bladder stones in catheterized patients B:7.25 in ranging from with spinal cord injuries, 4% to 100%, although the studies T:7 in S:6.5 in were too heterogeneous for the team

to arrive at an overall rate. Similarly, accidental removal, blockage, leakage/ incontinence, and urethral stricture/ erosion were common. There was an overall 1% rate of bladder cancer in this population, along with a 3% rate of false passage/trauma and a 13% rate of gross hematuria. n

CLINICAL EVIDENCE INDICATES...

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EACH PLAYS AN IMPORTANT ROLE 1-3 Learn more at inhibitandrogen.com/distinct *Other treatment options may also be considered. References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Schulze H, Senge T. Influence of different types of antiandrogens on luteinizing hormone-releasing hormone analogue-induced testosterone surge in patients with metastatic carcinoma of the prostate. J Urol. 1990;144(4):934-941. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2013 3/13 K08Z12191AR2

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RUN1013_Catheters.indd 7

on urethral stricture/erosion, that the rate of this complication averaged 17% (compared with 3% in higher-quality studies). With respect to long-term catheterization, the researchers found a 52% rate of leakage, a 44% rate of blockage among inpatients, a 29% blockage

S:9.5 in

BY ROSEMARY FREI, MSc A group of researchers would like to broaden urologists’ conception of common complications from indwelling urethral catheters to include more than urinary tract infections. In a review of studies on mishaps stemming from these catheters, the team found, among an array of noninfectious complications, that leakage or incontinence occurs at a rate of 11% and that spinal cord injury patients have high rates of bladder stones and gross hematuria. The investigators believe this signals the need for much more focus on preventing these events. “Many such complications may be due to improper insertion,” said lead investigator John Hollingsworth, MD, MS, of the University of Michigan in Ann Arbor, after presenting the results at the 33rd Congress of the Societé Internationale d’Urologie. “Because 6% of all inpatient urologic consultations are for complications from catheter placement, most of which were inserted by trainees, education and skill interventions aimed at providers may be important to reduce noninfectious complications.” Dr. Hollingsworth performed the literature review and meta-analysis after a study was published showing a high rate of genitouriniary trauma associated with indwelling urethral catheter use (J Urol 2012;187:1662-1666). He and his colleagues identified all published studies that included non-infectious complications associated with indwelling urethral catheters. Their meta-analysis focused on 38 studies, including 15 studies of complications associated with catheterization lasting no longer than three weeks and 10 studies of longer-term catheterization. Sixteen of the studies included patients with spinal cord injuries. The team pooled the complication frequencies for short-term catheterization complications, although in some complication categories the studies were too heterogeneous for Dr. Hollingsworth’s group to arrive at an overall rate. Among the complications for which they could determine overall rates, leakage/incontinence topped the list at 11%. Coming in at rates of between 3% and 5% were urethral strictures, gross hematuria, and accidental removal. One study examined blockage showing a rate of 5%. The team also found, among lowerquality studies that included figures

8 Renal & Urology News

october 2013 www.renalandurologynews.com

News in Brief

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

Short Takes Exercise May Counter Diet-Related ED

occlusion had significantly smaller in-

Aerobic exercise training could be a

by ischemia. The decrease in plasma

practical means of preventing erectile

glutamate levels was associated

dysfunction (ED) brought on by a

with a significant 12.1% reduction in

Western diet, Christopher J. Wingard,

the volume of cerebral infarct, José

PhD, and colleagues at East Carolina

Sánchez-Prieto, PhD, of Universidad

University in Greenville, N.C., reported

Complutense in Madrid, and col-

online in the American Journal of Phys-

leagues reported online in The Journal

iology: Regulatory, Integrative, and

of Clinical Investigation.

creases in plasma glutamate induced

Comparative Physiology. In rats fed of saturated fat, omega-6 polyunsatu-

New Penile Cancer Guidelines Issued

rated fatty acids, and added sugar

Partial or total penectomy with a nega-

for 12 weeks, those that ran on a

tive surgical margin remains the gold

treadmill five days a week maintained

standard in managing invasive penile

erectile function, as measured by elec-

cancer, but less invasive options that

trical stimulation of the anesthetized

may improve quality of life are being

animals’ cavernosal nerve. Other rats

considered based on tumor stage

fed the same diet without exercising

and grade, according to new clinical

exhibited ED.

practice guidelines from the National

a Western diet containing high levels

Comprehensive Cancer Network and

Peritoneal Dialysis May Reduce Stroke Damage

published in the Journal of the Na-

Peritoneal dialysis (PD) may lower

(2013;11:659-662). Alternatives

glutamate levels released into the

include topical treatment with either

brain during ischemic stroke, minimiz-

imiquimod 5% or 5-fluorouracil cream,

ing tissue damage, according to study

or wide local excision with circumci-

involving rats. Rats administered PD

sion. Laser therapy and complete

2.5 hours after being subjected to

glansectomy are also appropriate in

permanent middle cerebral artery

specific circumstances.

tional Comprehensive Cancer Network

Newborn Circumcision in the U.S. Nationally, during the 32-year period from 1979 through 2010, the percentage of male newborns circumcised during their birth hospitalization decreased 10% overall. This percentage peaked in 1981 and dropped to its lowest level in 2007. 80 70 60 50 40

64.5%

64.9%

63.2%

55.4%

58.3%

1979

1981

1998

2007

2010

30 20 10 0

Source: CDC/National Center for Health Statistics, National Hospital Discharge Survey, 1979-2010.

RUN1013_NIB.indd 8

Cell Phone Allows Patients to Self-Test Albumin Level A

smartphone-based automated albumin-testing tool that weighs approximately one-third of a pound can determine urinary albumin levels and transmit results all within about five minutes. A digital sensing platform installed on the camera unit of a smartphone captures images of fluorescent assays confined within disposable test tubes, Aydogan Ozcan, PhD, and colleagues at the University of California Los Angeles explained in the Royal Society of Chemistry journal Lab on a Chip. It automatically analyzes them for sensitive and specific detection of urinary albumin using a battery-powered laser diode that probes the test-tube sample, interacts with the control tube, and collects the fluorescent emission. The phone camera captures the images of the fluorescent tubes and processes them within one second through an application running on the phone. The technology could be useful for early diagnosis of kidney disease or for monitoring chronically ill patients, particularly those with diabetes, hypertension, and/or cardiovascular diseases.

Combined High-Dosage Drugs Shown to Ease Resistant OAB E

lderly patients with overactive bladder (OAB) that does not respond sufficiently to dose-escalated antimuscarinic monotherapy may benefit from combined high-dosage antimuscarinics, researchers reported online in the UroToday International Journal. They studied 81 OAB patients older than 65 years who previously received double-dose antimuscarinic monotherapy with trospium. After at least six months of such treatment with no or short-lived symptom improvement, patients were treated with two antimuscarinics. Significant improvements were seen at a six-week follow-up, with the average number of daily incontinence events declining from six to two, average maximum bladder capacity increasing from 177 to 356 mL, average reflex volume rising from 149 to 284 mL, and average detrusor compliance improving from 16 to 37 mL/cm H 2O. Side effects were comparable to those of normal-dosed antimuscarinics.

Biomarker Found to Predict AKI in Emergency Patients A

prospective cohort study has shown plasma neutrophil gelatinase-associated lipocalin (NGAL) to be an accurate biomarker for predicting acute kidney injury (AKI) in patients admitted from the emergency department (ED). As Prasad Devarajan, MD, and colleagues described in the Clinical Journal of the American Society of Nephrology, 21% of 616 patients admitted to a hospital from the ED were classified as having AKI. Compared with other patients, this group had the highest median levels of plasma NGAL (146 to 174 ng/mL at various time points), which increased with AKI severity (207 to 244 ng/mL). The discriminative ability of plasma NGAL improved with higher grades of severity. The test distinguished AKI from normal function and transient azotemia, and could classify patients into low-, moderate-, and high-risk AKI. n

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Renal & Urology News 9

Post-MI Mortality Declining in CKD Patients Mortality after myocardial infarction (MI) has been declining among patients with chronic kidney disease (CKD), according to researchers. In a study of 12,087 patients hospitalized for MI over a 24-year period (1985-2008), the 30-day mortality risk in patients with stage 2-5 CKD decreased from 11% in 1985-1990 to 6% in 20002008. The five-year mortality rate decreased from 26% to 24%. Among patients with stage 2 CKD, those hospitalized for an MI in 20002008 had a 67% decreased 30-day mortality risk compared with those hospitalized for an MI in 1985-1990 in adjusted analyses, researchers reported in Kidney International (2013;84:353358). For patients with stage 3 and stage 4-5 CKD, the decrease in 30-day mortality risk after hospitalization for MI between the two periods was 46% and 67%, respectively. Among patients hospitalized for MI and who survived beyond 30 days, the five-year mortality risk for patients with stage 2, 3, and 4-5 CKD decreased by 20%, 4%, and 10%, respectively, from 2000-2008 compared with 1985-1990.

Compared with patients who had normal renal function, patients with stage 4 and stage 5 CKD had an 8.5-fold and 8.8-fold higher adjusted 30-day mortality risk, respectively, according to the researchers. Patients with stage 4 and stage 5 CKD had a 3.3-fold and 8.0-fold

higher mortality risk between 30 days and five years compared with patients who had normal renal function, the researchers noted. In an editorial accompanying the study, Gautam R. Shroff, MD, B:7.25 in and Charles A. Herzog, MD, of the T:7 in Hennepin County Medical Center in S:6.5 in

Minneapolis, observed that, despite the limitations of the study, “these observational data tell an informative and optimistic story of temporal reduction in 30-day mortality among patients with various degrees of renal dysfunction…in the most recent decade.” n

IN ADVANCED PROSTATE CANCER…

DO YOUR PATIENTS HAVE

MORE ANDROGEN THAN YOU CAN CATCH WITH ANDROGEN RECEPTOR BLOCKADE?

Androgen levels may impact antiandrogen therapy.1-3 Learn more at inhibitandrogen.com/excess References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical studies. Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed. Neural Endocrine Peptides and Receptors. New York, NY: Plenum Press; 1986:627-644.

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The investigators observed improved 30-day and five-year survival among MI patients without CKD. The risk of 30-day and five-year mortality decreased by 79% and 15% from 19851990 to 2000-2008. The authors noted that in recent decades, major improvements in the treatment of MI have been implemented. These improvements include thrombolytic therapy and primary percutaneous coronary intervention for ST-elevation MI. “Temporal trends in 30-day mortality reveal impressive mortality reductions during this 24-year period that were comparable for all stages of renal function and were sustained during longterm follow-up,” Sjoerd T. Nauta, MD, and colleagues at Erasmus Medical Center in Rotterdam, The Netherlands, wrote. “Although the outcome after MI improved across the whole range of renal function, we showed that renal dysfunction remains a strong risk factor for increased both short- and long-term mortality.”

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From 1985-2008, the 30-day mortality risk decreased from 11% to 6%.

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Kidney donors continued from page 1

between PTH level and kidney function reported in patients with mild CKD,” according to the researchers, who reported their findings in the American Journal of Kidney Diseases (2013;62:577-586). Additionally, the authors noted that hyperuricemia has long been suggested to cause CKD, hypertension, diabetes, and cardiovascular disease (CVD), but this has been a source of ongoing controversy because it is possible that hypertension, diabetes, and CVD directly or indirectly cause hyperuricemia. “The present study unequivocally shows that a reduction in GFR causes a significant increase in serum uric acid level, even in otherwise healthy individuals,” they wrote. “Thus, whatever other factors may be causing an association between CKD and hyperuricemia, the reduction in GFR itself may explain much or all of the observed association.” The researchers stated that they are unaware of any previous report of a significant decrease in hemoglobin in

RRT risk in HIV continued from page 1

according to findings published online ahead of print in Nephrology Dialysis Transplantation. The risk of aRRT was highest in the first year after HIV diagnosis. Among the HIV patients, intravenous drug use and hypertension were associated with a sixfold and sevenfold increased risk of aRRT, respectively. Hypertension was associated with a 19 times increased risk of cRRT. Those with an estimated glo-

donors. “Possible explanations include mild anemia due to surgical blood loss, iron deficiency, and/or reduced erythropoietin due to the reduced kidney function,” they observed. “This new knowledge of biochemical changes after donor nephrectomy is welcome,” Amit X. Garg, MD, PhD, of Western University, London, Ont., wrote in an accompanying editorial.

“A prospective cohort design, as used in this study, is well suited to describe biochemical, GFR, and blood pressure changes after donor nephrectomy.” At the American Transplant Congress in Seattle in May, researchers from The Netherlands reported that living kidney donors should not be considered to have CKD if their renal function after nephrectomy falls to a level that usually is considered CKD. Many kidney

donors have an eGFR below 60 mL/ min/1.73 m2 early post-donation and therefore meet the criteria for CKD stage 3, according to the researchers. The prognosis of such a low GFR, however, may not be equivalent to the prognosis of the same GFR in patients with two diseased kidneys. The investigators compared 57 post-donation kidney donors and 57 CKD patients who were matched for age, gender, GFR, and duration of follow-up. GFR was determined with 125I-iothalamate clearance. In both groups, the mean age of study subjects was 48 years and the mean follow-up was 4.7 years. The donors and CKD patients had similar a GFR (67 and 70 mL/min/1.73 m 2, respectively). At the end of follow-up, donors had significantly better renal function than CKD patients, with a GFR of 73 versus 63 mL/min/1.72 m 2, respectively. Serum creatinine levels decreased by 0.03 mg/dL in the donor group but increased by 0.03 in the CKD group. Additionally, GFR improved with time in all donors and declined in all CKD patients. n

merular filtration rate (eGFR) below 60 mL/min/1.73 m2 had a nearly eightfold increased risk. Although previous studies have shown that exposure to the antiretrovirals tenofovir and atazanavir is associated with deterioration of renal function, these agents alone or in combination were not associated with aRRT or cRRT in the new study, the researchers reported. Dr. Rasch’s group noted that tenofovir was introduced in 2001 and the first case report of acute renal failure associated with exposure to the drug

was published in 2002. Studies have demonstrated an association between exposure to tenofovir and a decline in eGFR and an increased risk of chronic kidney disease. “The lack of association between tenofovir and aRRT/cRRT in the present study may be due to the fact that clinicians, knowing the nephrotoxic effects of tenofovir, discontinued the drug in patients who developed mildto-moderate impairment in renal function and thereby prevented further decrease in renal function and descent to renal failure,” the authors wrote. n

A reduction in GFR causes a significant rise in serum uric acid, study shows.

Nephrology Referrals, AKI Outcomes Linked Delayed nephrology consultation (NC)

NC and 128 (65%) had an early NC. The

compared with the early NC group, the

is associated with greater mortality and

researchers defined delayed and early

investigators reported in PLOS One

increased risk of dependence at hospi-

NC as occurring before and more than

(2013;8:e70482). Delayed NC patients

tal discharge among critically patients

48 hours after the day of AKI diagnosis,

also had significantly increased ICU

with acute kidney injury (AKI), according

respectively.

lengths of stay and significantly longer

to researchers. Veronica Torres Costa e Silva, MD,

A total of 248 patients (67.8%) died in the hospital and 115 (31.4%) required

mechanical ventilation support compared with the early NC group.

of the University of São Paulo School

dialysis at hospital discharge. The

of Medicine in São Paulo, Brazil, and

delayed NC group had a fourfold and

severity of illness compared with

colleagues studied 366 AKI patients, of

threefold increased odds of in-hospital

non-NC patients, their mortality rates

whom 196 (53.6%) had an NC. Sixty-

mortality and dialysis dependence

were similar after adjusting for propen-

eight NC patients (35%) had a delayed

at hospital discharge, respectively,

sity score. n

RUN1013_Cover_Neph.indd 2

Although NC patients had a greater

Resistant CMV continued from page 1

(18.3%) and genotypic resistance testing was obtained on 56 of the 284 patients (19.7%). Resistance mutations were identified in 20 of the 284 patients (median age 60 years), including 16 with a single UL 97 mutation, one with a UL54 mutation, and three with both mutations. The 16 patients with a single UL97 mutation included seven kidney recipients, one kidney/pancreas recipient, three heart recipients and two liver recipients. All of the UL54 mutations were found in lung recipients. Ganciclovir-resistant CMV infections developed in 16 of 20 seronegative SOT recipients of seropositive donors. Detection of these infections occurred at a median of nine months from transplantation. Cidofovir was used to treat 14 of the 20 patients with ganciclovir-resistant CMV infections. Thirteen of 14 patients treated with cidofovir achieved CMV clearance at a median time of 4.5 months; they had sustained undetectable viral loads for a median follow-up of 10 months (range one month to three years). One patient died while on therapy. Foscarnet was used to treat six of the 20 patients. Two patients died while on foscarnet, and two patients responded but relapsed once foscarnet was stopped. One of these patients maintained low level viremia until cidofovir was added to foscarnet, and one patient was still on foscarnet at the time of the analysis. No significant changes in renal function were found based on serum creatinine clearance throughout treatment with foscarnet and cidofovir. “Cidofovir and foscarnet are both two extremely nephrotoxic medications and that is one of the big reasons people shy away from using them, especially for this type of infection, because there is no real clear dosing strategy for it,” Dr. Perez told Renal & Urology News. “We actually did not see any significant changes in renal function for these patients. There was a slight increase in overall serum creatinine within the first 30 to 60 days, but it normalized.” CMV infection is among the most prevalent and serious infectious complications following SOT, ganciclovir is considered the mainstay treatment. It is now well established that that antiviral resistance in CMV is common and represents a significant therapeutic challenge, Dr. Perez said. The study included too few patients treated with foscarnet to allow a direct comparison with cidofovir, she said. n

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Sling outcomes continued from page 1

medical care for lower urinary tract conditions in this age group will also increase. Even so, limited reliable data are available about outcomes in older women undergoing MUS compared with younger women, he said. MUS is the current gold standard for SUI treatment after conservative measures have failed, with overall success rates of approximately 80% depending on the definition of success. The primary outcome of the present study was SUI symptoms defined as either “moderately” or “quite a bit” responses to at least one of the two SUI questions on the Pelvic Floor Distress Inventory (PFDI-20).

Hypogonadism continued from page 1

Joel S. Finkelstein, MD, and colleagues at Massachusetts General Hospital in Boston, studied 198 healthy men aged 20-50 years who were given goserelin acetate to suppress endogenous testosterone and estradiol (cohort 1). They randomized subjects to receive a placebo gel or 1.25, 2.5, 5, or 10 grams of testosterone gel daily for 16 weeks. Another 202 healthy men (cohort 2) received goserelin acetate, placebo gel or testosterone gel, and anastrozole (to suppress conversion of testosterone to estradiol). More than 80% of circulating estradiol in men is derived from the conversion of testosterone, the investigators noted, so decreases in serum testosterone levels are accompanied by a decline in serum estradiol levels. “Nevertheless, the consequences of male hypogonadism are routinely attributed solely to androgen deficiency; the potential role of the concomitant decline in estrogens

SUI failure rates The investigators documented SUI failure rates of 27.4% in women younger than 70 and 33.1% in women aged 70 and older. Multivariate analysis demonstrated no significant difference in SUI failure rates between the two age groups. A significantly larger proportion of older women had baseline urgency urinary incontinence (UUI) symptoms (64.1% vs. 51.4%), but the two groups did not differ in terms of rates of resolution of UUI symptoms (34.2%

and 29.6%) or de novo UUI symptoms after primary MUS (4.3% and 7.5%), according to the investigators. Only 56.6% of older women reported having the impression that their SUI improved as shown on the Patient Global Impression of Improvement (PGI-I) index after their procedure compared with 67.7% of younger women. Although the study’s retrospective design may represent a potential limitation, Dr. Ellington emphasized that the results are bolstered by the use of a large cohort of women as well as robust pre- and post-surgical data collection. He added that his group may eventually compare voiding function between older and younger patients since voiding function may have an impact on PGI-I scores. n

is typically ignored,” they observed. In the men who did not receive anastrozole (cohort 1), the percentage of body fat increased significantly in those who received placebo or 1.25 or 2.5 grams of testosterone daily compared with subjects who received 5 grams of testosterone daily. Lean mass declined significantly in men who received placebo or 1.25 grams of testosterone daily compared with men who received 2.5, 5, or 10 grams of testosterone daily. Only placebo recipients experienced a decrease in leg-press strength. In cohort 2, the percentage of body fat increased in all groups. The magnitudes of these increases were similar with placebo and 1.25, 5, and 5 grams of testosterone daily, a finding that suggests a predominantly estrogenic effect. Total-body lean mass decreased significantly in men who received placebo versus those who received 1.25, 2.5, and 10 grams of testosterone daily, “a finding that implies an independent effect of testosterone.” Subcutaneousfat area increased in all groups in

cohort 2, although only the comparison of changes between the 1.25 and 10 gram dose groups was significant. Thigh-muscle area decreased significantly in men who received placebo compared with men who received any of the four testosterone doses, Dr. Finkelstein’s group reported. Legpress strength declined significantly in men who received placebo compared with those who received the three highest testosterone doses. In cohort 1, sexual desire decreased progressively with declining testosterone doses. Erectile function worsened significantly in men who received placebo compared with men who received testosterone, and declined more in men who received 1.25 grams of testosterone daily than in those in the three highest dose groups. In cohort 2, sexual desire declined significantly in men who received placebo compared with men in the three highest dose groups, and declined more in men who received 1.25 grams of testosterone daily than in subjects in the two highest dose groups. n

The PFDI-20 is both a symptom inventory and a measure of the extent of bother and distress caused by pelvic floor symptoms and is a shortened version of the original Pelvic Floor Distress Inventory

PSADT continued from page 1

because a PSADT of less than three years is widely accepted as the cut-off for recommending definitive treatment in both clinical practice and research. They sought to demonstrate that the accuracy of the use of PSADT depends on a number of factors, including the frequency and length of PSA testing. “We chose to analyze the probability of being falsely classified as having a doubling time shorter than three years because this has obvious clinical consequences; such patients are normally recommended curative therapy,” Dr. Thomsen said. Dr. Thomsen and his colleagues modeled data from 221 patients who had at least four PSA measurements during active surveillance. The team focused on three scenarios: patients receiving PSA testing every three months for one year, PSA testing every three months for one year and subsequently every six months for two years, and testing every three months for one year and subsequently every six months for two years. Dr. Thomsen and his co-investigators calculated the PSADTs using the Memorial Sloan-Kettering Cancer Center guidelines. They found that if clinicians only use one year of PSA testing, 20% of patients with a true PSADT of five years and 10% of those with a true PSADT of nine years will be misclassified and recommended curative therapy. However, if physicians wait two years to make this determination, 5% of patients with a true PSADT of five years and 1% of those with a true PSADT of nine years will be misclassified. The probability of misclassification drops still further if clinicians used three years of PSA testing, to 2% among those with a true PSADT of five years and 0.6% of those with a true PSADT of nine years. n

Ketoconazole-Tamsulosin May Improve AUR Management Patients with acute urinary

size of 61.6 grams. Following urethral

the combined treatment group com-

All patients tolerated both medications

retention (AUR) due to benign prostatic

catheterization, the team randomized

pared with the tamsulosin group (77.3%

well and no patients discontinued treat-

obstruction can be treated safely with

participants into two equal groups.

vs. 58.9%), the researchers reported

ment, according to the researchers.

a combination of tamsulosin and keto-

One group received tamsulosin 0.4 mg

online ahead of print in Prostate Cancer

conazole to achieve a better success

once daily and ketoconazole 200 mg

and Prostatic Disease.

of a trial without catheter (TWOC).

three times a day and the other group

Among subjects who had a successful

The investigators noted that they studied the use of ketoconazole in treating AUR due to benign prostate obstruc-

received tamsulosin and placebo for

TWOC, the peak flow rate and the post-

tion because the drug can lower serum

laborators at Tanta University in Tanta,

seven days. The patients were then

void residual volume were also signifi-

testosterone to castration levels within

Egypt, studied 106 men with a mean

placed on a TWOC. The incidence of suc-

cantly better in the combined treatment

48 hours and the prostate is an andro-

age of 64 years and a mean prostate

cessful TWOC was significantly higher in

group compared with the placebo arm.

gen-dependent organ. n

Mohamed A. Elbendary, MD, and col-

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Renal & Urology News 11

Bicycling Leads All Sports in Genitourinary Injuries

RUN1013_Bikes.indd 11

were also injured in many patients, with adults being more likely than kids to have a kidney injury. The top tube was responsible for the largest portion of injuries—about 50% in both adults and children. Handle bars caused the second-largest proportion of injuries. n

In mCRPC, is it appropriate to

INHIBIT ANDROGEN PRODUCTION BEFORE BLOCKING THE ANDROGEN RECEPTOR?* THIS APPROACH IS AN OPTION FOR TREATMENT IN ADVANCED PROSTATE CANCER.1,2 Learn more at inhibitandrogen.com/sequence *Currently in the absence of published, randomized, clinical data on treatment sequencing in mCRPC posttreatment with docetaxel. mCRPC=metastatic castration-resistant prostate cancer. References: 1. Sartor AO, Tangen CM, Hussain MHA, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer. 2008; 112(11):2393-2400. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

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Collisions accounted for about 70% of the injuries. Sixty-one percent of the injured individuals were male. Furthermore, 12.1% were adult hospital inpatients and 6.6% were pediatric hospital inpatients, indicating adults were more likely to be hospitalized. Dr. Breyer calculated from these data that there were 53 and 448 bike-related GU injuries/100,000 person-years in adults and children, respectively, in 2002-2010. “I bet parents have a lower threshold to seek attention for their child, and also pediatric injuries appeared less severe, because children had fewer kidney injuries and fewer admissions,” Dr. Breyer said in explaining the disparities in rates.

football, basketball, soccer, skiing/ snowboarding, and sports involving vehicles. Children were most likely to have injuries of the female external genitalia, B:7.25 in scrotum/testes, or penis. Adults were in more likely to haveT:7injuries of the scroS:6.5 in tum/testes. The urethra and kidneys

T:10 in

Children suffer 10 times as many bike-related GU injuries as adults.

He calculated that this translated into a total of more than 43,200 such injuries across the U.S. in that time period. This is significantly higher than the total for all other sports-related GU injuries combined, including swimming (the sport associated with the second-highest total of GU injuries),

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BY ROSEMARY FREI, MSc VANCOUVER—Bicycle riding accounts for more genitourinary (GU) injuries in the U.S. than any other sport, with children suffering 10 times as many bike-related GU injuries as adults, researchers reported at the 33rd Congress of the Societé Internationale d’Urologie. Those are among the findings of a review of information in the National Electronic Injury Surveillance System (NEISS) from 2002-2010. NEISS is a national probability sample of hospitals in the U.S. and its territories. NEISS is run by the U.S. Consumer Product Safety Commission and includes data from a sampling of American hospitals on every emergency department visit involving an injury associated with consumer products. Benjamin Breyer, MD, of the Department of Urology at the University of California San Francisco, dug through thousands of line items in the NEISS to find bike-related GU injuries, identifying a total of 1,627. These included any type of fall from a bike, a bike rider colliding with an object other than his/her bike or the ground, and a person striking a part of his/her bike to produce injury. Overlapping injuries could happen: That is, one incident could produce more than one type of injury.

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Underwear Alerts Incontinence Sufferers to Urinary Pad Leaks An electronic unit vibrates when wetness sensor threads detect urine overspills BY JILL STEIN BARCELONA—A product known as Smart UnderWear, which is designed to alert patients to potential urinary pad leaks, appears to perform well with good patient acceptability, according to results released at the 43rd Annual Meeting of the International Continence Society. Adele Long, Senior Researcher in Urology, and Marcus Drake, MD, Consultant Urologist with the Bristol Urological Institute in Bristol, UK, presented findings from 56 middle-aged women who routinely wore pads for urinary incontinence. The analysis showed that the Smart UnderWear was effective at signaling patients to pad leakage events 87% of the time. In addition, 85% of patients were alerted in time to change their pad before leakage to outside clothing or furnishings. In 59% of pad leaks, study participants reported that they were not otherwise aware of leakage. More than 90% of patients said that the use of the product would enhance their confidence about avoiding pad leaks that might occur when they experience urgency with incontinence and/or are unable to access a toilet or when they inadvertently displace the

pad during physical activity, the study reported. Subjects were recruited from outpatient clinics and the community via patient support networks.

Patients were cued in to pad leakage events 87% of the time, data showed. The product consists of wetness sensor threads sewn into a pair of underwear and detects overspills of urine from the pad. An electronic unit is attached to the underwear and responds to an overspill by vibrating three times when wet, thereby signaling the wearer that the pad has leaked. The system was developed by Brunel University, University of Manchester, and the Bristol Urological Institute as part of a three-year, UK-based research project called Tackling Ageing Continence Through Theory, Tools, and Technology (TACT3). Urinary incontinence pads may be highly absorbent and effective for containing urine but may leak for a range of reasons, including high-vol-

ume challenge due to uncontrolled full bladder emptying, the use of pads past their absorbency level, and movement of the pad within the fixation pant resulting in uneven absorbency, Dr. Drake explained. Study participants received five pairs of the underwear and one signaling unit during the trial. They were asked to wear the Smart UnderWear during the day for at least five days a week for two consecutive weeks and were instructed to wash the underwear as often as they wished. Dr. Drake said that “the ideal candidate for Smart UnderWear system is the patient who wears continence pads in the community, with mildto-severe incontinence, and who restricts her activity as a result of lack of confidence that the pad will control the leakage.” He also noted that the system can be used in residential care facilities. Patients who sweat excessively are not good candidates for the Smart UnderWear because the sweat can be detected by the system and set off the alert even though there has not been any urine leakage. The system might be useful for men and children but has not yet been tested in these populations, he said. n

Study Zeroes In On Ideal BP in CKD The optimal blood pressure (BP) for patients with chronic kidney disease (CKD) appears to be 130-159/70-89 mm Hg, according to researchers. In a study of 651,749 U.S. veterans with CKD, Csaba P. Kovesdy, MD, from the Memphis Veterans Affairs Medical Center, and colleagues analyzed all possible combinations of systolic BP (SBP) and diastolic BP (DBP) from lowest to highest in increments of 10 mm Hg. Compared with the reference BP value (140-149/80-89 mm Hg), BPs of 130-159/70-89 mm Hg were associated with the lowest mortality risk, which did not differ significantly from the reference value in adjusted analyses, Dr. Kovesdy’s team reported in Annals of Internal Medicine (2013;159:233-242). Below DBP of 70 mm Hg, lower SBP was associated with higher mortality rates, and SBP less than 120 mm Hg was associated with higher mortality rates regardless of the accompanying DBP, the study found. The study population consisted of 132,249 individuals with normal BP (SBP below 120 and DBP below 80 mm Hg),

PMI Increases CKD Patient Death Risk

295,937 with prehypertension

Painless myocardial infarction (PMI) is common among individuals with chronic kidney disease (CKD) and it increases their risk of death, according to researchers. James B. Wetmore, MD, MS, of the University of Kansas Medical Center in Kansas City, and collaborators studied 356 patients who underwent percutaneous coronary intervention. The researchers defined PMI as the absence of chest pain in response to balloon dilation of the affect blood vessel. PMI occurred significantly more frequently in patients with CKD than without it (43% vs. 25.4%), and the frequency of PMI increased as the level of estimated glomerular filtration rate (eGFR) decreased, Dr. Wetmore’s group reported online ahead of print in Nephron Clinical Practice. PMI was present in 20.6% of subjects with an

stage 1 hypertension (SBP 140-

RUN1013_ICS1.indd 1

eGFR of 90 mL/min/1.73 m2 or higher compared with 50%, 42%, and 28.2% of those with an eGFR below 30, 30-59, and 60-89, respectively. The study population had a mean follow-up period of 7.3 years and a maximum follow-up of 10 years, according to the investigators. During the 10-year follow-up period, 143 patients died. Overall, mortality increased as disease burden increased. Cumulative survival percentages for all-cause mortality at 10 years were 62% for subjects with neither CKD nor PMI, 45.2% for those with PMI but intact renal function, 37% for those with CKD but no PMI, and 23.7% for patients with both CKD and PMI. Compared with patients who had neither CKD nor PMI, those with CKD but no PMI and those with both CKD and PMI had a significant 64% and twofold increased risk of death.

Patients with PMI in the absence of CKD had a nonsignificant 49% increased risk of death. “In conclusion,” the investigators wrote, “this is the first long-term study demonstrating that PMI is related to the degree of CKD and that the presence of PMI in CKD confers a risk [of death] greater than that of CKD alone. Although a full understanding of the molecular mechanisms contributing to PMI remains to be elucidated, PMI may be a key process in the disproportionate incidence of death attributed to arrhythmia in patients with CKD.” Of the 356 patients in the study, 104 (29.2%) had CKD and 252 (70.8%) did not. In the CKD group, 45 patients (12.6% of the entire cohort) had PMI and 59 (16.6%) did not. In the nonCKD group, 64 patients (18%) had PMI and 188 (52.8%) did not. n

(SBP 120-139 or DBP of 80-89 mm Hg), 169,416 with 159 or DBP of 90-9 mm Hg), and 54,147 with stage 2 hypertension (SBP of 160 mm Hg or higher or DBP of 100 mm Hg or higher). In a fully adjusted model, patients who had normal BP had the highest mortality risk and those with stage 1 hypertension had the lowest mortality risk compared with patients who had prehypertension (the reference group). The authors concluded that “low BP should be regarded as potentially deleterious in this patient population, and we suggest caution in lowering BP to less than what has been demonstrated as beneficial in randomized, controlled trials.” n

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Renal Nutrition Update A high-fat, low-carbohydrate diet may be worth considering in patients with chronic kidney disease By GrissIm Clark Connery, MS, RD, LD

or years, dietary recommendations have focused on reducing saturated fat and its potential sources. This advice includes a focus to reduce red meat and other high-fat meat products because of their higher saturated fat content. Recent analyses have begun to find no significant associations between fresh meat intake and cardiovascular events. Instead, confounding factors appear to be more indicative of cardiovascular risk. The European Prospective Investigation into Cancer (EPIC) found no significant increased risk associated with unprocessed meat or poultry intake, whereas increased intake of processed meat led to a nearly 70% increase in cardiovascular disease (CVD) mortality (BMC Med 2013; published online ahead of print). A large meta-analysis in 2010 also demonstrated that risk of coronary heart disease (CHD) was not associated with unprocessed meats, but instead processed meats increased risk by 42% (Circulation 2010;121:22712283). Another meta-analysis found that saturated fat sources did not always consistently increase mortality risk; processed and unprocessed meats analyzed together increased risk while high-fat dairy products were not associated (Am J Public Health 2013;103:e31-e42). Together, these analyses beg the question of whether processed meat has been a confounding variable in the analysis of meat and saturated fat intake on CVD.

Analyzing LDLs Chronic kidney disease (CKD) populations are at increased risk for CVD mortality. Typical recommendations for reduced saturated fat intake often are derived from cholesterol-lowering strategies and the fact that saturated fat is associated with increases in total cholesterol, LDL, and HDL. LDL particle size, however, is becoming a more appreciated risk factor for CHD and mortality, more notably in CKD populations. In a

On The Web RUN1013_RenalNut.indd 1

prospective cohort of hemodialysis (HD) patients, researchers found that conventional lipid profiles did not predict mortality, whereas smaller, high-density LDL particles were associated with a 55% increase in mortality risk (Clin J Am Soc Nephrol 2011;6:2861-2870).

Carbohydrates and LDL particle size LDL particle size is influenced by carbohydrate intake. Higher carbohydrate intake increases the release of triglyceride-rich, very low density lipoproteins (VLDL) and increased serum triglycerides (Curr Opin Clin Nutr Metab Care 2012;15:381-385). Small, dense LDL particles are released in response to sequester triglycerides. These processes typically occur in the presence of insulin resistance. High insulin resistance in the form of diabetes is a known risk factor for renal impairment. Low-carbohydrate, high-protein diets have been shown to reduce triglyceride values as well as decrease LDL, HDL, insulin, free fatty acids, CRP, and glucose in obese women (Am J Clin Nutr 2005;81:1298-1306). If unprocessed meats are not associated with cardiovascular risks and highcarbohydrate diets alter LDL particles to potentially increase atherogenicity, a controlled intervention focusing on a low-carbohydrate diet and unprocessed meats may be necessary in CKD and dialysis populations. A few studies have indicated that low-carbohydrate, high-protein diets appear to be similarly effective as high-carbohydrate, low-fat diets with regard to improving estimated glomerular filtration rate (eGFR) and microalbumin-to-creatinine ratio (Diabetes Care 2013;36:2225-2232) as well as reductions in serum creatinine and creatinine clearance (Clin J Am Soc Nephrol 2012;7:1103-1111). In the latter study, the low-fat group was required to undergo caloric restriction, whereas the low-carbohydrate group ate ad libitum fat and protein

In a study, higher intake of processed meats led to a nearly 70% increase in CVD mortality.

while slowly increasing carbohydrate intake after a baseline of 20 g/day. Comparing a calorically restricted diet to an ad libitum diet, however, skews the ability to specifically compare the effects of altering macronutrient ratios. A similar issue confounds the next study. Macronutrient ratios were altered in non-diabetic obese individuals with one risk factor for metabolic syndrome (J Am Diet Assoc 2010;110:633-638). The low-carbohydrate group ate a diet consisting of 4% carbohydrate, 35% protein, and 61% fat, while the highcarbohydrate group consumed 46% carbohydrate, 24% protein, and 30% fat. Both groups also followed a caloric restriction that averaged 1,613 kcal (lowcarbohydrate group) and 1,525 (highcarbohydrate group). Weight loss was similar between groups after one year, and no significant changes were found between groups with regard to creatinine or eGFR. Of note, the average baseline eGFR of each group was 97.4 and 91.8 mL/min/1.73 m2, respectively. This study helps elucidate whether a higherprotein diet affects eGFR in patients with values greater than 60. The study’s high-carbohydrate group was actually

lower in carbohydrate percentage than many typical recommendations that promote carbohydrate intakes of 50%-60%. Some larger studies have failed to give useful insights due to minor variations in macronutrient ratios (Diabetologia 2012;55:905-914).

High protein diets and late stage CKD High-protein diets do not seem to impact renal function in patients below CKD III-V. Reduced protein intake is known to be beneficial in advanced CKD populations in reducing the effect of uremic toxins (Blood Purif 2013;35:22-25). Thus, it would beneficial to assess the effect of a low carbohydrate, moderate protein, high fat diet in stages CKD III-V. In healthy individuals without CKD, a 12-week intervention that kept carbohydrate at a static 37% but adjusted protein and fat in the groups found that no significant changes occurred with regard to blood lipids, weight loss, or glucose and insulin responses (Am J Clin Nutr 2005;81:762-772). n Mr. Connery is Research Coordinator at Case Western Reserve University in Cleveland.

We’ve got more on our website highlighting effective diets for delaying CKD progression and helping patients manage sodium and phosphorus intake. See us at www.renalandurologynews.com/nutrition.

9/24/13 10:39 AM

www.renalandurologynews.com october 2013

Renal & Urology News 15

Metastasis-Free Interval Affects PCa Patient Survival Longer metastasis-free survival predicts better overall survival in men who experience biochemical recurrence of prostate cancer (PCa) after radical prostatectomy, according to a new study. Michael T. Schweizer, MD, and colleagues at Johns Hopkins University in Baltimore, and colleagues retrospectively studied 450 men with biochemically recurrent PCa, defined as a PSA level of 0.2 ng/mL or higher after radical prostatectomy. Metastatic disease developed in 140 of them. Androgen deprivation therapy (ADT) was deferred until after development of metastases. The cohort had a median metastasis-free survival (MFS) of 10.2 years and the median overall survival (OS) after metastasis of 6.6 years. After adjusting for other known prognostic

variables, increasing MFS was associated with a decreasing risk of death, the researchers reported online ahead of print in the Annals of Oncology. In addition, the number of metastases, the presence or absence of pain with metastases, and use or non-use of bisphosphonates predicted OS.

Patients who had three or fewer metastases had a 50% decreased risk of death compared with those who had four or more metastases. Patients who did not have pain with their metastases had a 57% decreased risk of death compared with those who did. Patients who used bisphosphonates had a 40% decreased

risk of death compared with those who did not. The study findings suggest that MFS may be a reasonable proximal endpoint when evaluating novel medications patients who experience PSA recurrence after local therapy, according to the investigators. n

WE’RE

Ascorbic Acid Does Not Cut CIN Risk

CHANGING THE WAY

PROSTATE CANCER PATIENTS ARE TREATED EVEN WHEN THEY’RE NOT BEING TREATED

Ascorbic acid has no significant effect on the incidence of contrast-

When it comes to treating prostate cancer, we do not believe

induced nephropathy (CIN) among

in a one-size-fits-all approach. That’s why doctors at UPMC are

patients undergoing coronary

experts in both traditional methods of urologic surgery and in

angiography, researchers reported

cutting-edge robotic surgery. But our doctors also recognize

in Therapeutic Apheresis and Dialysis

when the best management is not an operation, but careful

(2013;17:384-390). Benjamin

observation. We believe it is important to be well versed in

Dvoršak, MD, of the University Clinical

all options to ensure patients receive the right treatment at

Center Maribor, Maribor, Slovenia, and

the right time. Because our job is not only to save lives, but

colleagues studied 81 patients under-

to preserve the quality of life of every patient we treat. Learn

going coronary angiography, randomly

more at UPMCPhysicianResources.com/ProstateCancer.

assigning 40 to receive ascorbic acid, which has antioxidant activity, and 41 to receive placebo before the procedure. All patients also received intravenous volume expansion with normal saline before the procedure. The researchers defined CIN as a greater than 25% increase in serum creatinine level from baseline measured three to four days after the procedure. CIN occurred in two patients (3%) in the ascorbic acid group and three (7.3%) of the placebo group, a nonsignificant difference between the groups. Post-procedural rises in serum creatinine level, however, occurred significantly less frequently in the ascorbic acid than the placebo group

UPMC is affiliated with the University of Pittsburgh School of Medicine.

(12.3% vs. 23.4%). n 2145_UPMC_Urology_7x10.indd 1

RUN1013_MetaPCa.indd 15

8/21/13 11:41 AM

9/24/13 10:39 AM

16 Renal & Urology News

october 2013 www.renalandurologynews.com

Legal Issues in Medicine B

ad outcomes are not always the result of medical malpractice. Most medical procedures have known risks, and just because the outcome was not what was desired does not mean the physician or healthcare professional did anything wrong. Unfortunately, however, patients sometimes assume that if the end result is not positive, then malpractice has been committed. When you combine this with plaintiffs’ attorneys who are willing to take on any case, regardless of the facts, a lawsuit can occur even when it is unjustified. Dr. M, 49, was a urologist who shared a small practice with two other urologists. The practice was busy. Most of Dr. M’s patients were referred by primary care physicians. One such patient was Mrs. K, 56, who had been referred after complaints of difficult and painful urination. Initial tests revealed that one of Mrs. K’s ureters was being blocked by a stone. When the patient returned to the office for the results of her tests, Dr. M informed her about the stone and recommended an ureteroscopy. Mrs. K was anxious about the procedure, so the physician spent at least 15 minutes explaining it to her. When the patient asked what the risks were, Dr. M told her that there was the possibility of injury to the ureter, and that a urinary tract infection could possibly result. In addition, he outlined the potential for postsurgical bleeding and/or abdominal pain. Dr. M followed up by documenting (in the patient’s chart) that he and Mrs. K had discussed the risks associated with the procedure.

Surgical complications Mrs. K agreed to have the ureteroscopy, and it was scheduled for later that week. Dr. M performed numerous ureteroscopies a year, and did not expect this one to present any problems. However, during the dilation part of the procedure,

On The Web RUN1013_Legal.indd 1

which used a small balloon to widen the ureter, Mrs. K’s ureter split. A followup surgery was performed to repair the damage, and a ureter drain was inserted. Mrs. K was extremely distressed and expressed this to Dr. M. “It is unfortunate,” the physician said, “but having the ureter split during the dilation is a risk, and is one that I did tell you about when we discussed the procedure.” Mrs. K was dissatisfied with the physician’s explanation and several months later her son suggested that she call one of the plaintiff’s attorneys whose ads he had seen on local billboards. The patient did so, and soon was in the attorney’s office, complaining about her treatment by the urologist. “I had problems for two months after the surgery,” she told the attorney. “And frankly, I think the surgery was unnecessary to begin with! The doctor must have screwed up with that balloon thing.”

Trial motions The attorney took on the case, and Dr. M was notified. His defense attorney had the medical records looked at by an expert and agreed that Dr. M had done nothing wrong. This was simply a possible outcome when performing the procedure. The defense attorney told Dr. M that he was prepared to go to trial if necessary. The case did go to trial. At trial, the plaintiff’s attorney testified about the pain and discomfort Mrs. K experienced after the surgery, and even suggested that perhaps the surgery was unnecessary in the first place. The plaintiff’s lawyer also argued that perhaps Dr. M had not properly positioned the balloon, leading to the split ureter. The defense countered that the tests conclusively showed a stone, and defense produced independent expert testimony to verify this. Dr. M had done nothing wrong, the defense

A patient sues her urologist for malpractice after suffering a known risk of a stone procedure By Ann W. Latner, JD

A surgical complication after ureteroscopy resulted in a lawsuit.

contended, and this particular type of the damage was a known risk of the procedure. Furthermore, Mrs. K had been informed of that risk. The defense then produced the patient file detailing the discussion of the benefits and risks of ureteroscopy that ensued between Dr. M and Mrs. K. The jury returned after a brief deliberation with a verdict for the defense.

Legal background It is curious why the attorney took this case in the first place. Mrs. K suffered no permanent injury, so the damages, if any, were extremely limited. Many plaintiffs’ attorneys are paid on a contingency basis (they get a percentage of the winnings, if any), so most would not take a case that did not have at least the potential for significant damages. Protecting yourself There was little that Dr. M could do to protect himself other than what he did do. He spent time explaining the procedure to the patient. He spoke to her about the known risks. He documented their conversation.

When one of those known risks came to pass, the damage was repaired and the patient experienced no lasting harm or permanent damage. Just because an adverse event happens does not mean that someone is always at fault. Unfortunately, patients often assume that if something goes wrong, someone should be blamed. Dr. M did everything necessary to protect himself. He spent the time explaining the risks and benefits of the procedure, and most importantly, documenting everything. Careful note taking and record keeping is essential in protecting yourself from lawsuits, and while they cannot always protect you from being sued, they can help you avoid being on the losing end of a malpractice suit. n 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.

What do you think? Did the jury make the right decision in this case? We want to know your thoughts. Leave us a comment at the end of this article—or any article—at www.renalandurologynews.com/legal.

9/24/13 10:38 AM

18 Renal & Urology News

october 2013 www.renalandurologynews.com

MRI May Help Predict PCa Recurrence Positive findings are linked to a sixfold increased risk of biochemical relapse after radical surgery Multiparametric magnetic resonance imaging (MRI) may enable doctors to predict the likelihood of biochemical recurrence of prostate cancer (PCa) after radical prostatectomy, Japanese researchers reported. In a retrospective study that included 314 patients who underwent standard or laparoscopic radical prostatectomy, Seiya Hattori, MD, of the Keio University School of Medicine in Tokyo, and colleagues showed that positive findings on preoperative multiparametric MRI scans were significantly associated with a high clinical stage (cT2 or higher), a high positive biopsy core rate (greater than 0.2), a high biopsy Gleason score (8 or higher), and a high pathologic Gleason score (8 or higher). Positive findings on MRI were associated with a significant sixfold increased odds of biochemical recurrence compared with negative findings, the researchers reported online ahead of print in BJU International.

Novel Iron Drug Safe, Effective Soluble ferric pyrophosphate (SFP), an investigational parenteral iron formulation, maintains hemoglobin (Hb) levels better than placebo in hemodialysis (HD) patients, according to the results of a phase 3 study. The CRUISE-1 efficacy study included 300 HD patients randomized to receive SFP (149 patients) or placebo (151 patients). At baseline, the two groups had similar Hb levels (109.6 and 10.9.0 g/L in the SFP and placebo arms, respectively). From baseline to the end of the randomized treatment period, the SFP arm had a mean 0.6 g/L increase in Hb level and the placebo arm had a 3.0 g/L decrease, according to data reported by the drug’s developer, Rockwell Medical, of Wixom, Mich. Researchers found no significant difference in the frequency or severity of adverse events (AEs) or serious AEs between the groups. No case of anaphylaxis or hypersensitivity occurred in the SFP recipients. All FDA approved IV iron products

RUN1013_PCaMRI.indd 1

In addition, the study revealed that a pathologic Gleason score of 8 or higher was associated with a significant threefold increased odds of recurrence compared with a score of 7 or less. Positive surgical margins (PSM) were associated with a nearly fourfold increased odds of recurrence compared with negative surgical margins. “In terms of the clinical impact of the present findings,” the authors wrote, “MRI positivity is an independent, brief and non-invasive biomarker which can predict therapeutic effects preoperatively.” The investigators stated that MRI positivity “may have the potential to be an effective index for determination of a therapeutic strategy, as well as a follow-up strategy. This can be of benefit for clinicians as a strong- and easy-touse predictive factor.” The researchers used the variables significantly associated with biochemical recurrence to stratify patients into

for the treatment of iron deficiency anemia are iron-carbohydrate complexes, and it is the carbohydrate moiety that triggers the anaphylactoid or hypersensitivity reactions, explained Ajay Gupta, MD, Chief Scientific Officer for Rockwell. SFP does not contain carbohydrate, he said, pointing out that not a single anaphylactoid reaction has occurred in patients being given SFP. “This successful CRUISE-1 study data confirm our belief that SFP is an extremely safe drug that consistently maintains hemoglobin and that can effectively replace the general need for IV iron administration in dialysis patients,” Dr. Gupta said. SFP is a unique iron compound that is administered to HD patients via dialysate, replacing the 5-7 mg of iron lost during a dialysis treatment, according to Rockwell. SFP is introduced into the sodium bicarbonate concentrate that subsequently is mixed into dialysate. Once in the dialysate, SFP crosses the dialyzer membrane and enters the bloodstream where it immediately binds to transferrin and is delivered to the bone marrow, similar to the way dietary iron is processed in the human body. This is in contrast to IV iron products indicated for the treatment of iron-deficiency anemia. n

low-, intermediate-, and high-risk groups. Low-risk patients had zero or one risk factor (PSM or pathological Gleason score of 8 or higher); intermediate-risk patients had one risk factor (MRI positivity) or two risk factors

Preoperative scans potentially could aid in determining treatment strategy. (PSM or pathological Gleason score of 8 or higher); the high-risk group consisted of all other patients. The five-year biochemical recurrence-free rates were 99% in the low-risk group, 92% in the intermediate-risk group, and 72% in the high-risk group. In a separate development involving the use of multiparametric MRI for PCa, another team of Japanese

researchers demonstrated that this imaging technique can improve detection of anterior prostate tumors missed by transrectal 12-core biopsy. The study, published in The Journal of Urology (2013;190:867-873), included 324 men underwent prebiopsy multiparametric MRI and then 3D 26-core prostate biopsy, a combination of transrectal 12-core and transperineal 14-core biopsy. The overall cancer detection rate on 3-D 26-core prostate biopsy was 39%. Of these cancers, 28% were transrectal 12-core negative cancers, which the investigators defined as cancer detected by transperineal 14-core but not transrectal 12-core biopsy. Among men with and without an anterior lesion on MRI, 40% and 3.8%, respectively, had transrectal 12-core negative cancer. Prebiopsy multiparametric MRI revealed an anterior lesion in 92% of cases of significant transrectal 12-core negative cancer. n

Preop Hemoglobin, CRP Predict Bladder Cancer Survival Hemoglobin (Hb) and C-reactive

globin level below 10.5 g/L, a

protein (CRP) levels prior to radical

CRP level above 0.5 mg/dL,

cystectomy for bladder cancer inde-

and a disease stage of pT3a or

pendently predict patients’ disease-

higher each carries a value of 1.

specific survival, Japanese researchers

PSM has a value of 2. Thus, the

reported online in the International

maximum score is 5. Patients with a

Journal of Urology.

score of 0-1, 2, and 3-5 are

In an analysis of data from 249

classified as low, intermediate,

bladder cancer patients (mean age

and high risk. The four-year DSS in

71.1 years; 241 male) who underwent

patients in the low-, intermediate-,

radical cystectomy without neoadju-

and high-risk groups were 77.7%,

vant therapy, Takehiro Sejima, MD, of

23.6%, and 7.4%, respectively.

Tottori University Faculty of Medicine in

The researchers stated that their

Yonago, and colleagues found that low

report is the first to show the signifi-

Hb levels (less than 10.5 g/L) and high

cance of combining preoperative

CRP levels (greater than 0.5 mg/dL)

Hb with the pathology of radical cys-

independently predicted poor disease-

tectomy specimens as an independent

specific survival (DSS), as did pT3a

predictor for DSS. In addition,

or greater disease stage and positive

they noted, the study included the larg-

surgical margins (PSM).

est contemporary series to date dem-

Based on their findings Dr. Sejima’s

onstrating that two types of preopera-

group created a risk stratification

tive hematologic disorders, assessed

model to predict DSS. Each risk factor

by Hb and CRP, are independent predic-

is assigned a value, and these values

tors in bladder cancer patients treated

are added to arrive at a score. A hemo-

with radical cystectomy. n

9/24/13 10:38 AM

www.renalandurologynews.com october 2013

Renal & Urology News 19

Botox for Urinary Incontinence Since the FDA expanded the approval of onabotulinumtoxin A (Botox) in January to include adults with overactive bladder who were not helped by anticholinergic drugs, David O. Sussman, DO, has been ready to educate urology colleagues on the appropriate use of the therapy, which he believes will become a common service. As medical director of the Kennedy Continence Center in Stratford, N.J., and Clinical Associate Professor of Urology at the University of Medicine and Dentistry of New Jersey, Dr. Sussman was an investigator in the trials leading to the approval, and remains a consultant for Botox manufacturer Allergan, Inc. You recently published a study on persons given Botox for urinary incontinence (UI) due to neurogenic detrusor overactivity (Neurourology and Urodynamics. 2013;32[3]:242249). Is this condition covered by the FDA-approved indication for Botox?

Dr. Sussman: Yes. That was the first approval—for people who had detrusor overactivity from a neurogenic cause, such as multiple sclerosis (MS), or spinal cord injury. Now, it’s approved for people who have detrusor overactivity from other causes and have failed medication. Does that include people who have overactive bladder?

Dr. Sussman: Overactive bladder is kind of the catch-all symptom syndrome. It includes people with overactive bladder from a neurologic cause or a non-neurologic cause. The neurologic ones, which we studied first, have been the most difficult to treat, and usually fail medication. That’s where the Botox is so helpful, because it really improves the quality of life in people who, prior to this, often didn’t respond to oral medication or, if they did, [experienced] bothersome side effects.

On The Web RUN1013_QA.Sussman.indd 1

How do you expect this approval of Botox to change the paradigm of UI treatment?

Dr. Sussman: It’s still really for people who fail medications. I believe that’s still [stated] in the package insert, and I think that’s reasonable. Most people will still try oral therapy, and then once that fails, it is reasonable to consider Botox. Before [the recent Botox approval], we did use InterStim [an implanted electrical stimulator for urinary control.in both neurogenic and non-neurogenic populations. It was never really approved for the neurogenic population, but there wasn’t much else. But now, we reserve InterStim for more of the non-neurogenic population, and really use Botox for the neurogenic. Is Botox administered the same way to men and to women?

Dr. Sussman: Yes. We typically give anywhere between 20 and 30 injections into the bladder muscle in one visit. The procedure itself takes about 10 or 15 minutes. How often is this done?

Dr. Sussman: Studies have shown that for many people it’s every 10 months,

although that varies. But I think the average is going to be 6 to 10 months.

a noninvasive treatment called posterior tibial nerve stimulation, or PTNS.

What should urologists know to administer Botox effectively and safely?

And who should not receive Botox?

Dr. Sussman: Certainly there’s plenty out there in the literature now, but I think that attending a couple-of-hours seminar to understand the mechanism of action, the precautions and risks, the techniques of injection, and the ideal patient population, as well as the wrong patients, is necessary. None of it is difficult, but you should understand all of this. It’s important for providers identify the right candidates. Typically, patients in the neurogenic population often fail medications, so they are a little more straightforward [in terms of being suitable for Botox therapy]. I certainly think Botox, in the neurogenic population, is going to be the treatment of choice for failed medication. In the non-neurogenic population, again, there are those who either can’t tolerate medication or seek more efficacy from medication. Their options are going to be Botox, InterStim therapy, or

Dr. Sussman: People who have certain neuromuscular disorders, like myasthenia gravis or Lambert-Eaton syndrome. People who have poorly functioning bladders to begin with may not be good candidates. So there are people [in whom] we’d use a lot of caution, but the majority of patients would be candidates. Does Botox actually cure overactive bladder?

Dr. Sussman: Some patients get resolution of their urge incontinence. Others see a significant reduction. It’s a little hard to predict, and we let people know it’s not always going to be a cureall, but it may significantly improve their symptoms. What are the most likely side effects of Botox used for bladder control?

Dr. Sussman: The two biggest side effects are urinary tract infection and, for some people, difficulty emptying their bladders. So occasionally people require intermittent catheterization, but usually that’s a short-lived process, in the weeks-to-several-weeks range. It’s much more common in the neurogenic patients than in the non-neurogenic patients. Should Botox be discontinued in patients suffering those side effects?

Dr. Sussman: Sometimes it can just be modified with dose adjustments. What I’ll often do is adjust the dosage. In essence, patients requiring catheterization did have a good result because they’re holding their urine better. It’s just that they’re holding it too well.

It’s important for providers to identify the right candidates. —David O. Sussman, DO

Botox was approved as a treatment for urge incontinence; is approval for stress incontinence coming?

Dr. Sussman: This is not a medication that is currently being studied for stress incontinence because stress incontinence is a different mechanism, and Botox is not something that would really help that. n

Continue the conversation online! We have many experts who weigh in on controversial topics important to you. Catch our discussions at www.renalandurologynews/expertqa.

9/24/13 11:06 AM

20 Renal & Urology News

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CME feature

Dietary Interventions for Treating Progressive Chronic Kidney Disease The type and amount of ingested protein affects clinical outcomes such as protein-energy wasting, kidney function and even survival.

Release Date: October 2013 Expiration Date: October 2014 Estimated time to complete the educational activity: 1 hour This activity is jointly sponsored by Medical Education Resources and Haymarket Medical Education. Statement of Need: Current therapy for progressive chronic kidney disease (CKD) includes interventions such as blood pressure control, the use of ACE inhibitors and angiotensin receptor blockers, and control of diabetes mellitus. Although these interventions may slow loss of renal function, none of them are able to reliably halt it. Thus, additional complementary interventions must be explored in order to lower the high incidence and prevalence of end-stage renal disease. Target Audience: This activity has been designed to meet the needs of nephrologists and supporting clinicians who treat patients with chronic kidney disease. Educational Objectives: After completing the activity, the participant should be better able to: • Identify differing types of dietary interventions available for managing progressive CKD. • Discuss the advantages of supplemented very low protein diets in CKD patients. • Evaluate various ways of manipulating protein intake in CKD patients. Accreditation Statement: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Medical Education Resources (MER) and Haymarket Medical Education. MER is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation: Medical Education Resources designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Disclosure of Conflicts of Interest: Medical Education Resources ensures balance, independence, objectivity, and scientific rigor in all our educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure all scientific research referred to, reported, or used in a CME activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality CME activities that promote improvements or quality in health care and not a commercial interest. The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Faculty Csaba P. Kovesdy, MD

Reported Financial Relationship Grants/Research Support: Shire Royalty/Patent Holder: UpToDate Consulting Fees: Amgen

By Csaba P. Kovesdy, MD

urrent therapy for progressive chronic kidney disease (CKD) includes interventions such as blood pressure control, the use of ACE inhibitors and angiotensin receptor blockers, and control of diabetes mellitus. These interventions may slow progressive loss of kidney function, but none of them are able to reliably halt or reverse it. Therefore, it is important to explore additional interventions to complement existing ones to lower the high incidence and prevalence of end-stage renal disease (ESRD) and to potentially improve survival in patients with CKD. Dietary protein restriction has been known to have potentially beneficial effects on progressive CKD, but it has not caught on as a widely applied and routine therapeutic measure. The reasons for this are multiple, and include uncertainties about its benefits, difficulties with its implementation, convenience, and cost. There have been renewed efforts in the past decade to revitalize the field of nutritional interventions in CKD by exploring

alternative strategies addressing the various impediments towards practical implementation. These strategies need to be considered in the wider context of dietary interventions affecting nutritional status, protein-energy wasting (PEW), and, potentially, patient survival. We will hereby review the various available dietary interventions involving protein intake, and will discuss their theoretical benefits, the evidence supporting or refuting their efficacy, and practical considerations towards their use in everyday practice (Table 1).

Dietary protein restriction Reduction in dietary protein intake can have a variety of positive effects in the uremic patient, including the alleviation of uremic symptoms, control of hyperparathyroidism, hyperphosphatemia, and hyperkalemia, favorable glomerular hemodynamic effects, and a reduction of proteinuria.1 Based on these putative benefits, the Modification of Diet in Renal Disease

The content managers, Jody A. Charnow and Marina Galanakis, of Haymarket Medical Education, and Julie Johnson, PharmD, of Medical Education Resources, have disclosed that they have no relevant financial relationships or conflicts of interest. Method of Participation: There are no fees for participating in and receiving CME credit for this activity. During the period October 2013 through October 2014, 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/ renalanurologynews, 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.

Csaba P. Kovesdy, MD, is Chief of Nephrology at the Memphis VA Medical Center and the Fred Hatch Professor of Medicine at the University of Tennessee Health Science Center, Memphis.

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Renal & Urology News 21

CME feature (MDRD) study was designed to test the hypothesis that a low or very low protein diet can favorably affect the course of kidney disease in non-diabetic patients with moderate and advanced CKD. The primary results of the MDRD study showed no significant effect of the interventions on the slopes of measured GFR, although patients who received the supplemented very low protein intake had a marginally favorable outcome (p=0.07). 2 Secondary analyses indicated that the early hemodynamic effects of protein restriction may have affected the overall results because patients receiving lower protein intake had significantly more loss of kidney function in the first four months of the intervention and significantly less loss of kidney function thereafter, resulting in an aggregate null effect. This suggests that perhaps a longer follow-up would have demonstrated a beneficial effect of protein restriction.3 A subsequent meta-analysis that incorporated data from 10 randomized controlled studies in 2,000 non-diabetic patients with moderate and advanced CKD suggested that a low protein diet (defined in general as a daily protein intake of 0.6 g/kg/day) resulted in a 32% lower incidence of dialysis, death, or renal transplant. To avoid one renal death, 2 to 52 patients needed to be treated with low protein intake over one year.4 These meta-analyses suggest benefits from protein restriction in terms of slowing progression of CKD. The practical implementation of low protein diet-based strategies has been hampered by a variety of factors (Table 1). One potential reason

relates to concerns about inducing PEW and engendering increased mortality.5 While a properly implemented low protein diet is not likely to cause PEW, proper implementation of such a diet can be difficult. It requires substantial healthcare resources and significant motivation and possibly financial sacrifices on the part of patients. Insufficient energy intake is a common reason why low protein diets may lead to the development of PEW. Consumption of primarily low biological value proteins with the low protein diet (due to greater convenience or to better palatability of foods containing low quality protein) can also increase the risk of negative protein balance and consequent PEW.

Supplemented low and very low protein diets As mentioned above, restricting protein intake in a proper manner (i.e., to achieve both a pre-set low amount of high biological quality protein intake while also assuring normal energy intake) can be difficult, in part due to the complexity and individual variety of everyday diets. One way to address these difficulties is to substitute a portion of the dietary protein intake with a prescribed supplement of high quality protein or protein equivalent (such as a mixture of essential amino acids, ketoacids, or both). With such a strategy a low total protein intake (e.g., 0.6 g/kg/day) can be achieved by restricting dietary protein intake to a very low amount (e.g., 0.3 g/kg/day) and providing the difference in the form of a prescribed supplement, hence the

term “supplemented very low protein diet (SVLPD).” Such a strategy offers a number of advantages (Table 1): It allows for a more precise administration of a set amount of protein intake, it assures the intake of proper high biological value protein, it offers more flexibility and palatability in dietary choices (since there is less concern about the quality of the dietary component), it carries a low catabolic burden,6 and it is easier to assure adequate energy intake. A supplemented very low protein intake was used in Study B of the above-mentioned MDRD study. 2 While the results of the MDRD study2 and a secondary analysis7 did not suggest a benefit from this strategy, it is possible that the type of supplement used in the MDRD study was not ideal, as it contained excessive amounts of tryptophan, which could have led to production of nephrotoxic metabolites.8 Subsequently, several smaller studies have examined the effect of supplemented very low protein diets on kidney function, and found to decrease proteinuria9 and result in less severe progression of CKD.1,10,11 SVLPD is considered generally safe based on the results of observational studies or post-hoc analyses of interventional studies,12-17 but this would have to be established definitively in dedicated clinical trials before their widespread application can be advocated. The advantages of SVLPD can be conceptually extended to clinical scenarios where protein intake does not need to be restricted or where it needs to be increased (see following section). By changing the amounts of the dietary

component, the supplement component, or both, a total daily protein intake of any amount can be achieved while concomitantly maintaining control over the biological quality of the ingested proteins, the amount of daily energy intake, and minimizing the deleterious effects of excess protein intake.

Dietary protein supplementation PEW is common, and is one of the most powerful predictors of poor outcomes in CKD and ESRD. While its etiology is complex, one of the recognized causes of PEW is a decrease in protein and energy intake.18 There is broad agreement about the need for dietary interventions in patients with CKD with protein intake <0.60.8 g/kg/day, or in patients with ESRD with protein intake <1.1-1.2 g/kg/day. Such interventions usually start with dietary counseling aimed at assuring that a proper amount and quality of proteins, energy and other nutrients is ingested (Figure 1). In cases where counseling is unsuccessful, nutritional supplementation with high biological value proteins or their equivalents in the form of essential amino acids and ketoacids can be considered. PEW can be improved by using various methods of protein supplementation.19 Whether or not there is a longer term clinical benefit of such strategies remains unproven; improvement in mortality rates can be inferred from observational studies,20 but randomized controlled trials to test this hypothesis have not yet been completed.

Table 1. Mechanisms of action, putative indications, practical advantages and disadvantages of dietary interventions affecting protein intake in CKD patients Intervention

Indication

Pros

Cons

Protein restriction (e.g. LPD)

• Progressive CKD • Metabolic complications of high protein intake

• Addresses deleterious effects of protein intake/catabolism

• Worsening PEW • Cost and inconvenience • Resource-intensive

Protein restriction + supplements (e.g. VLPD or LPD + essential amino acid or ketoanalog supplements)

• • •

• Addresses PEW and deleterious aspects of protein catabolism

• • •

Protein supplementation (e.g. oral or parenteral supplements)

• PEW or risk of PEW

• Improvement in PEW • Control over amount of intake • Ease of implementation

• Cost • Untoward consequences of increased protein load

Protein supplementation + binders (e.g. oral alimentation + K, PO4, or protein by-product binders)

• • •

• Addresses PEW and deleterious aspects of protein intake/catabolism • Ease of implementation

• • • •

Progressive CKD Metabolic complications of high protein intake Risk for PEW

PEW or risk of PEW Risk for progressive CKD Risk for metabolic complications of high protein intake

Cost Need for considerable motivation and discipline on patients’ part Resource-intensive

Cost Medication-related adverse effects Inconvenience Not all deleterious effects of high protein intake may be addressed

CKD, chronic kidney disease; PEW, protein-energy wasting; LPD, low protein diet; VLPD, very low protein diet

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CME feature Figure 1. Interventions aimed at assessing and treating protein-energy wasting by manipulating protein intake in patients with chronic kidney disease

Periodic Nutritional Assessment and Diet Counseling • Low Protein Diet (LPD) to target a DPI of ~0.6g/kg/day • Low K (<2 g/day), Na (<2 g/day), PO4 (<1 g/day), and fluid (<1 L/day) intake as needed • Assess dry weight, muscle mass, laboratory values, and nutritional scores • Assess diet adherence: 24-hour urine urea nitrogen (eDPI), creatinine, K, Na

Start Nutritional Intervention • Continue diet counseling • Correction if acidemia is present • Correction of inflammation if possible • Diet supplementation with high biological value proteins • EAA or KA to achieve (or exceed) DPI ~0.6 g/kg/day and DEI 30-35 kcal/kg/day2 • Higher alkalinized or vegetarian diet3 • Toxin absorbents in certain groups3

Indications for Nutritional Interventions • Unintentional weight loss or sarcopenia • Poor appetite or poor oral intake • Too low (<0.6 g/kg/day) or high (>0.8 g/kg/day) DPI • Disarrays in serum K, PO4 • Serum albumin level < 4.0 g/dL1 • Fast decline in renal function

Monthly-to-Quarterly Assessment • Monitor nutritional status, appetite, DPI, DEI, weight and muscle mass, and urinary and serum biomarkers

Improvement

No Improvement or Deterioration

Maintenance of Intervention • Continue dietary intervention to maintain achieved targets: DPI ~0.6-0.8 g/kg/day and DEI 30-35 kcal/kg/day

Adjunct Pharmacologics5 • Appetite stimulators • Antidepressants • Anti-inflammatory agents • Antioxidants • Anabolic agents • PO4 and K binders • Diuretics and RAAS modulators

Intensified Therapy • Increased dose of dietary supplement4 • Change supplementation method2 • If poor nutritional status continues or deteriorates, consider tube feeding or parenteral interventions • Consider initiation of dialysis

Adapted from Kovesdy CP, Kopple JD and Kalantar-Zadeh K. Am J Clin Nutr 2013;97:1163-77 Measured with bromcresol green method Head to head comparisons of the different supplementation methods for the treatment of PEW are not available. Individual patient characteristics, tolerance of, adherence to and affordability of specific supplementation methods should be considered. Efficacy and safety as treatment for PEW not proven 4 Ideal amount of daily protein intake in PEW is unclear. 5 Directed by specific clinical scenario; Efficacy and safety for treatment of PEW in NDD-CKD unproven for most. LPD, low protein diet; DPI, dietary protein intake; K, potassium; Na, sodium; PO4, phosphate; eDPI, estimated daily protein intake; CKD, chronic kidney disease; DEI, daily energy intake; RAAS, renin angiotensin aldosterone system; EAA, essential amino acids; KA, ketoacids 1 2 3

There is considerably more controversy about protein supplementation to goals above the stated 0.6-0.8 g/kg/day (or 1.1-1.2 g/kg/day in ESRD). Higher protein intake may be necessitated in acutely hypercatabolic patients (such as patients with sepsis), but the added value of increased protein intake in patients with features of PEW who are not acutely catabolic or in those at risk of PEW is much less clear. Increasing protein intake in such patients could promote anabolism and faster rebuilding of body protein and muscle stores, or it could better prevent their catabolism. However, the added anabolic value of supplemental proteins

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or protein equivalents diminishes with increasing baseline levels of intake,21 hence, it is unclear to what extent supplementation to achieve intakes above the 0.6-0.8 g/kg/day (or 1.1-1.2 g/kg/ day in ESRD) level would be useful. It is also largely unknown what total amount of daily protein intake one should aim for in such patients. Protein intake as high as 1.5 g/kg/day has been suggested in elderly patients, 22 and one of approximately 1.5-2.5 g/kg/day in patients with acute kidney injury (AKI), the actual value depending on the severity of AKI, the presence of underlying catabolic diseases, and the presence or absence of renal replacement

therapy.23 However, the amount of protein intake in CKD or ESRD patients with PEW that provides the ideal balance between improving nutrition and preventing toxic effects of excess protein remains unclear. Whatever the ideal amount of excess protein intake may be in patients with PEW, the potential toxicities associated with higher protein intake necessitate a cautious and controlled approach to these strategies, especially in patients with CKD. Glomerular filtration rate is increased by high protein intake through afferent arteriolar dilatation and through effects on the glomerular basement membrane; thus, high

protein intake can result in glomerular hyperfiltration, worsening proteinuria, and accelerated progression of CKD.24 Furthermore, the accumulation of various protein breakdown products as a result of decreasing kidney function can result in uremic toxicity, the uremic syndrome, and metabolic effects such as oxidative stress, altered endothelial function, nitric oxide production, and insulin resistance.25 As mentioned above, the deleterious effects of excess protein intake can be controlled by adding various prescription supplements containing protein equivalents such as essential amino acids or ketoacids. It is possible

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©thinkstock

CME feature

Limiting dietary protein can have positive effects in uremic patients.

that protein sources rich in branchedchain amino acids (especially leucine and isoleucine) or their keto-analogues could be more beneficial in patients with PEW by virtue of their anabolic effects. 26 However, these questions will need to be clarified in properly designed and conducted clinical trials before their mainstream application can be advocated. Until then, an individualized approach to these decisions is suggested based on a patient’s catabolic status and other clinical and financial considerations.

Novel dietary interventions Many of the deleterious effects of dietary protein are related to specific components of the diet. This has led to attempts to control such complications by selectively preventing the absorption of one or more dietary components. Theoretically, such an approach could retain the nutritional benefits of proper protein intake while avoiding its undesirable side effects (Table 1). Phosphorus Phosphorus is present in many dietary proteins. It has numerous adverse effects, including direct vascular toxicity and an association with increased mortality and progression of CKD,27 and the application of phosphorus binders in patients with non-dialysis dependent CKD has been associated with lower mortality in observational studies.28 Small clinical trials in patients with CKD29 and in laboratory

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animals30 showed an attenuation of CKD progression after dietary restriction of phosphorus. These studies would need to be corroborated by larger clinical trials before phosphorus binders can be recommended towards treatment of progressive CKD or to decrease mortality. Potassium Potassium is also introduced through intestinal absorption (albeit not necessarily with proteins), and abnormally high or low levels have been associated with increased mortality in CKD and ESRD,31,32 and hypokalemia has also been associated with significantly more severe loss of kidney function.32 Dietary interventions can thus be used to avoid both high and low serum potassium levels with a goal towards improving both renal outcomes and survival. Interventions such as dietary modifications, medical potassium supplementation or the use of potassium binders are widely applied in everyday practice due to the accepted arrhythmogenicity of both hypo- and hyperkalemia. It is thus unlikely that randomized controlled trials will ever be conducted to test the clinical utility of such interventions towards other endpoints; thus, their potential benefits in these regards will likely remain theoretical.

Metabolic acidosis Metabolic acidosis is another frequent metabolic abnormality in CKD and ESRD that can be linked to nutrition

and to the amount of protein intake. Its adverse effects are complex and include protein catabolism and PEW,33 worsening uremic bone disease,34 an association with increased mortality in patients with ESRD,35 non-dialysis dependent CKD,36 kidney damage, and increased progression of CKD.37 Bicarbonate supplementation has been shown to be renoprotective in a number of small single center randomized clinical trials,38;39 and alkali-rich diets such as vegetarian diets administered to CKD patients have been shown to decrease proteinuria40 and serum levels of phosphorus, parathyroid hormone, and fibroblast growth factor-23.41 The impact of therapies for metabolic acidosis on clinical outcomes will also have to be tested in larger clinical trials, but the ease of administration, the relative lack of side effects (provided that metabolic alkalosis is prevented), and the low cost of these interventions make it a desirable therapeutic target that can be pursued even while awaiting final evidence about its efficacy.

Other uremic toxins Indoles and phenols are other potential uremic toxins linked directly or indirectly to intestinal absorption. These are products of protein catabolism in the gut that have been shown to cause oxidative stress, inflammation, vascular and renal toxicity, and increased mortality.42 One of the most frequently studied protein catabolic by-products is indoxyl sulfate, which has also been linked to kidney damage and progression of CKD.43 Binder medications that can lower the absorption and the systemic levels of indoxyl syulfate (such as AST-120) have been shown to ameliorate renal interstitial fibrosis, glomerular sclerosis, and proteinuria43 in animal models. Human benefits have been suggested in small randomized controlled trials.44,45 Unfortunately, similar benefits were not corroborated by larger clinical trials such as the EPPIC-1 and EPPIC-2 studies (ClinicalTrial.gov study numbers: NCT00500682 and NCT00501046). Exploratory analyses indicated that certain subgroups of patients (such as those at high risk for progression and those unable to strictly adhere to the medication regimen) may derive a significant renoprotective benefit from

this intervention, but this would have to be corroborated in future studies.

Conclusions The type and amount of ingested protein affects clinical outcomes such as PEW, kidney function, and even survival, and various dietary interventions have emerged as a means to attempt improving these outcomes. Protein restriction may be effective, but its implementation on a large scale in clinical practice is difficult. Other interventions such as protein supplementation, the use of binder medications to affect intestinal absorption of phosphorus or various protein catabolic products, potassium supplementation, or correction of metabolic acidosis are all possible interventions that could be beneficial for different indications. With the exception of protein restriction (including low protein diets and supplemented very low protein diets), the clinical trial evidence for many of these interventions is sparse or nonexistent, so their wide-scale implementation in clinical practice cannot yet be recommended. n References 1. Chauveau P, Combe C, Rigalleau V, et al. Restricted protein is associated with decreased proteinuria: consequences on the progression of renal failure. J Ren Nutr 2007;17:250-257. 2. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 1994;330:877-884. 3. Levey AS, Greene T, Beck GJ, et al. Dietary protein restriction and the progression of chronic renal disease: what have all the results of the MDRD study shown. Modification of Diet in Renal Disease Study group. J Am Soc Nephrol 1999;10:2426-2439. 4. Fouque D, Laville M. Low protein diets for chronic kidney disease in non diabetic adults. Cochrane Database Syst Rev 2009; CD001892 5. Menon V, Kopple JD, Wang X, et al. Effect of a very low-protein diet on outcomes: long-term follow-up of the Modification of Diet in Renal Disease Study. Am J Kidney Dis 2009;53:208-217. 6. Gao X, Wu J, Dong Z, et al. A low-protein diet supplemented with ketoacids plays a more protective role against oxidative stress of rat kidney tissue with 5/6 nephrectomy than a low-protein diet alone. Br J Nutr 2010;103:608-616. 7. Levey AS, Adler S, Caggiula AW, et al. Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease Study. Am J Kidney Dis 1996;27:652-663. 8. Motojima M, Hosokawa A, Yamato H, et al. Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-kappaB and free radical in proximal tubular cells. Kidney Int 2003;63:1671-1680. 9. Di Iorio BR, Cucciniello E, Martino R, et al. [Acute and persistent antiproteinuric effect of a lowprotein diet in chronic kidney disease.] G Ital Nefrol 2009;26:608-615. 10. Chang JH, Kim DK, Park JT, et al. Influence of ketoanalogs supplementation on the progression of chronic kidney disease patients who had training on lowprotein diet. Nephrology (Carlton ) 2009;14:750-757.

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CME feature 11. Brunori G, Viola BF, Parrinello G, et al. Efficacy and safety of a very-low-protein diet when postponing dialysis in the elderly: a prospective randomized multicenter controlled study. Am J Kidney Dis 2007;49:569-580. 12. Chauveau P, Barthe N, Rigalleau V, et al. Outcome of nutritional status and body composition of uremic patients on a very low protein diet Am J Kidney Dis 1999;34:500-507 13. Teplan V, Schuck O, Knotek A, et al. Effects of low-protein diet supplemented with ketoacids and erythropoietin in chronic renal failure: a long-term metabolic study et al. Ann Transplant 2001;6:47-53. 14. Zakar G. Wien Klin Wochenschr The effect of a keto acid supplement on the course of chronic renal failure and nutritional parameters in predialysis patients and patients on regular hemodialysis therapy: the Hungarian Ketosteril Cohort Study. 2001;113:688-694. 15. Prakash S, Pande DP, Sharma S, et al. Randomized, double-blind, placebo-controlled trial to evaluate efficacy of ketodiet in predialytic chronic renal failure. J Ren Nutr 2004;14:89-96. 16. Aparicio M, Chauveau P, De Précigout V, et al. Nutrition and outcome on renal replacement therapy of patients with chronic renal failure treated by a supplemented very low protein diet J Am Soc Nephrol 2000;11:708-716. 17. Chauveau P, Couzi L, Vendrely B, et al. Long-term outcome on renal replacement therapy in patients who previously received a keto acid-supplemented verylow-protein diet. Am J Clin Nutr 2009;90:969-974. 18. Ikizler TA, Greene JH, Wingard RL, et al. Spontaneous dietary protein intake during progression of chronic renal failure. J Am Soc Nephrol 1995;6:1386-1391. 19. Kalantar-Zadeh K, Cano NJ, Budde K, et al. Diets and enteral supplements for improving outcomes in chronic kidney disease. Nat Rev Nephrol 2011;7:369-384. 20. Lacson E Jr, Wang W, Zebrowski B, et al. Outcomes associated with intradialytic oral nutritional supplements in patients undergoing maintenance hemodialysis: a quality improvement report. Am J Kidney Dis 2012;60:591-600. 21. Kopple JD, Jones M, Fukuda S, Swendseid ME. Amino acid and protein metabolism in renal failure. Am J Clin Nutr 1978;31:1532-1540. 22. Wolfe RR, Miller SL, Miller KB. Optimal protein intake in the elderly. Clin Nutr 2008;27:675-684. 23. Li Y, Tang X, Zhang J, Wu T. Nutritional support for acute kidney injury. Cochrane Database Syst Rev 2012;8:CD005426. 24. King AJ, Levey AS. Dietary protein and renal function. J Am Soc Nephrol 1993;3;1723-1737. 25. D’Apolito M, Du X, Zong H, et al. Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure. J Clin Invest 2010;120:203-213. 26. Mitch WE, Walser M, Sapir DG. Nitrogen sparing induced by leucine compared with that induced by its keto analogue, alpha-ketoisocaproate, in fasting obese man. J Clin Invest 1981; 67:553-562. 27. Kovesdy CP, Anderson JE, Kalantar-Zadeh K. Outcomes associated with serum phosphorus level in males with non-dialysis dependent chronic kidney disease. Clin Nephrol 2010;73:268-275. 28. Kovesdy CP, Kuchmak O, Lu JL, Kalantar-Zadeh K. Outcomes associated with phosphorus binders in men with non-dialysis-dependent CKD. Am J Kidney Dis 2010;56:842-851. 29. Barsotti G, Morelli E, Giannoni A, Guiducci A, Lupetti S, Giovannetti S. Restricted phosphorus and nitrogen intake to slow the progression of chronic

renal failure: a controlled trial. Kidney Int Suppl 1983;16:S278-S284. 30. Lumlertgul D, Burke TJ, Gillum DM, et al. Phosphate depletion arrests progression of chronic renal failure independent of protein intake. Kidney Int 1986;29:658-666. 31. Kovesdy CP, Regidor DL, Mehrotra R, et al. Serum and dialysate potassium concentrations and survival in hemodialysis patients. Clin J Am Soc Nephrol 2007;2:999-1007. 32. Hayes J, Kalantar-Zadeh K, Lu JL, et al. Association of hypo- and hyperkalemia with disease progression and mortality in males with chronic kidney disease: the role of race. Nephron Clin Pract 2012;120:c8-16. 33. Kalantar-Zadeh K, Mehrotra R, Fouque D, Kopple JD. Metabolic acidosis and malnutrition-inflammation complex syndrome in chronic renal failure. Semin Dial 2004;17:455-465. 34. Bushinsky DA, Ori Y. Effects of metabolic and respiratory acidosis on bone. Curr Opin Nephrol Hypertens 1993;2:588-596. 35. Wu DY, Shinaberger CS, Regidor DL, et al. Association between serum bicarbonate and death in hemodialysis patients: is it better to be acidotic or alkalotic? Clin J Am Soc Nephrol 2006;1:70-78. 36. Kovesdy CP, Anderson JE, Kalantar-Zadeh K. Association of serum bicarbonate levels with mortality in patients with non-dialysis-dependent CKD. Nephrol Dial Transplant 2009;24:1232-1237. 37. Raphael KL, Wei G, Baird BC, et al. Higher serum bicarbonate levels within the normal range are associated with better survival and renal outcomes in African Americans. Kidney Int 2011;79:356-362. 38. de Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM. Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol 2009;20:2075-2084. 39. Phisitkul S, Khanna A, Simoni J, et al. Amelioration of metabolic acidosis in patients with low GFR reduced kidney endothelin production and kidney injury, and better preserved GFR. Kidney Int 2010;77:617-623. 40. Azadbakht L, Esmaillzadeh A. Soy-protein consumption and kidney-related biomarkers among type 2 diabetics: a crossover, randomized clinical trial. J Ren Nutr 2009;19:479-486. 41. Moe SM, Zidehsarai MP, Chambers MA, et al. Vegetarian compared with meat dietary protein source and phosphorus homeostasis in chronic kidney disease. Clin J Am Soc Nephrol 2011;6:257-264. 42. Liabeuf S, Barreto DV, Barreto FC, et al. Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrol Dial Transplant 2010;25:1183-1191. 43. Niwa T, Ise M. Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J Lab Clin Med 1994;124:96-104. 44. Konishi K, Nakano S, Tsuda S, et al. AST-120 (Kremezin) initiated in early stage chronic kidney disease stunts the progression of renal dysfunction in type 2 diabetic subjects. Diabetes Res Clin Pract 2008;81:310-315. 45. Shoji T, Wada A, Inoue K, et al. Prospective randomized study evaluating the efficacy of the spherical adsorptive carbon AST-120 in chronic kidney disease patients with moderate decrease in renal function. Nephron Clin Pract 2007;105:c99-107.

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

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CME Post-test Expiration Date: October 2014 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. Dietary protein restriction of 0.6 g/kg/day is associated with the following benefits: a. Flatter slope of GFR over time, with benefit apparent within the first few weeks of its implementation b. Lower incidence of ESRD suggested by meta-analyses c. Significant decrease in mortality proven in randomized clinical trials d. Ease of implementation 2. Administration of dietary supplements containing essential amino acids and/or ketoacids that are specially designed for patients with CKD and ESRD, has the following effects: a. Makes implementation of protein restriction easier due to lesser restriction on dietary proteins b. Helps achieve sufficient energy intake c. Provides essential amino acids or its equivalents, with a lower catabolic burden d. a and c e. a, b and c 3. Protein supplementation in patients with CKD and ESRD and insufficient protein intake has the following effects: a. Effectively improves biochemical markers of protein-energy wasting b. Lowers all-cause mortality in CKD, but not in ESRD patients c. Has no adverse effect on progression of CKD (or on residual kidney function in ESRD) d. Increases mortality in ESRD by increasing catabolic by-products, inflammation and oxidative stress 4. Administration of AST-120 has the following effects: a. Lowers plasma levels of indoxyl sulfate b. Results in decreased incidence of ESRD based on two recent large randomized controlled studies c. Results in decreased cardiovascular event rates based on two recent large randomized controlled studies d. Results in decreased absorption of dietary phosphorus 5. Effects of supplemented very low protein diet include: a. Decrease in proteinuria b. Decreased progression of CKD in the MDRD study c. Development and significant worsening of protein energy wasting d. Decreased palatability of diet 6. The initial intervention in a patient with CKD stage 4 and a daily protein intake of 0.4 g/kg/day is: a. Initiation of CKD specific oral nutritional supplement to achieve a daily protein intake of 1.1 g/kg/day b. Dietary counseling aimed at achieving a daily protein intake of 0.6-0.8 g/kg/day c. Administration of an appetite stimulant d. No intervention needed since low protein intake has renoprotective benefits

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Drugs Similarly Efficacious for mRCC Head-to-head trial shows no difference in progression-free survival with pazopanib and sunitinib Pazopanib is as effective as sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC) in terms of progression-free survival, but it is associated with fewer adverse events and better quality of life, according to a head-to-head comparison of the two drugs. “Our analyses of health-related quality of life showed that patients who received pazopanib reported less fatigue, fewer side effects such as soreness of the hand or foot and soreness of the mouth or throat, and better satisfaction with treatment that those who received sunitinib, findings that are consistent with the safety results,” the researchers reported in the New England Journal of Medicine (2013;369:722-731). The researchers, led by Robert J. Motzer, MD, of Memorial SloanKettering Cancer Center in New York, noted that when medications with similar efficacy are options for first-line therapy, “safety profile assumes more importance in determining treatment choice.”

IBS Found To Increase ED Risk Men with irritable bowel syndrome (IBS) are at higher risk of erectile dysfunction (ED) than men without IBS, according to a study. The study compared 17,608 Taiwanese men newly diagnosed with IBS from 1997 to 2010 and 70,432 age-matched controls without IBS. The incidence of ED was 2.9 times higher in the IBS

In the trial, Dr. Motzer and colleagues randomly assigned 1,110 patients with clear-cell mRCC to receive a continuous dose of pazopanib (557 patients; 800 mg once daily) or sunitinib in six-week cycles (553 patients; 50 mg once daily for four weeks, followed by two weeks without treatment). None of the patients had previously received systemic treatment for RCC. Disease-progression events occurred in 336 patients (60%) in the pazopanib group and in 323 patients (58%) in the sunitinib group. The median progression-free survival was 8.4 months with pazopanib and 9.5 months with sunitinib. The differences in outcomes between the two groups were not statistically significant. Furthermore, compared with pazopanib recipients, patients in the sunitinib group had a higher incidence of fatigue (63% vs. 55%), hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%), according to the investigators. Pazopanib-treated

Pazopanib vs. Sunitinib Safety A head-to-head trial found that pazopanib was associated with a progression-free survival rate similar to that of sunitinib, but a more favorable overall safety profile. Sunitinib therapy was associated with higher incidences of fatigue, hand-foot syndrome, and thrombocytopenia, but a lower incidence of elevated alanine aminotransferase levels, as shown here. ■ Sunitinib ■ Pazopanib

78% 80 70 60 50 40 30 20 10 0

63%

55% 2.0 PEC

Fatigue

60%

50% 29%

Hand-foot syndrome

41%

Thrombocytopenia

43%

Elevated alanine aminotransferase

Source: Motzer RJ et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722-731.

patients had a higher incidence of increased levels of alanine aminotransferase compared with the sunitinib group (60%, vs. 43%). During the first six months, pazopanib recipients experienced significantly more improvements from baseline in 11 of 14 health-related quality-of-life domains as measured by various instruments, especially the domains related to fatigue or

soreness in the mouth, throat, hands, or feet, they noted. “The management of adverse events resulting from the use of targeted agents is known to increase medical treatment costs and medical resource utilization,” the authors wrote. “Our study showed lower monthly use of medical resources with pazopanib than with sunitinib. n

No AKI Benefit with Earlier Dialysis Earlier initiation of dialysis does not improve outcomes among patients with community-acquired acute kidney injury (AKI), and it may be associated with delayed recovery of kidney function, according to researchers. Tukaram E. Jamale, MD, of KEM Hospital in Parel, Mumbai, and colleagues prospectively studied 208 adults with AKI and progressively worsening azotemia. They were randomly assigned to receive earlier-start dialysis (102 patients) or usual-start dialysis (106 patients).

Earlier-start dialysis was initiated when serum urea nitrogen and/or creatinine levels increased to 70 and 7 mg/dL, respectively. Usual-start dialysis patients (controls) received dialysis when clinically indicated as judged by treating nephrologists. The primary outcomes were in-hospital mortality and dialysis dependence at three months. In-hospital mortality was 20.5% in the earlier-start group and 12.2% in the control arm, a non-significant difference, Dr. Jamale’s group reported

online ahead of print in the American Journal of Kidney Diseases. The study also revealed no significant difference between the groups with respect to dialysis dependence at three months (4.9% and 4.7%, respectively). Furthermore, the time to recovery of kidney function was significantly longer in the earlier-start than the usual-start group (mean 6.63 vs. 4.70 days), results showed. Uremic symptoms were the most common reason patients in the usualstart group were placed on dialysis. n

and non-IBS cohorts (29.5 vs. 10.1 per 10,000 person-years). In adjusted analyses, men with IBS had a nearly 2.6 times increased risk of ED compared with controls, researchers reported in Andrology (2013;1:793798). The risk increased with increasing age and number of comorbidities. In addition, men with depression had at higher risk of ED compared with those who did not have depression. n

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Elevated PSA More Likely in Shiftworkers Men who work night shifts or rotating shifts are more likely to have elevated PSA levels than men who do not, according to researchers. In an analysis of data from the National Health and Nutrition Examination Survey (2005-2010), Erin E. Flynn-Evans, PhD, of Brigham and Women’s Hospital in Boston, and col-

leagues found shiftworkers had a 2.6 times increased risk of an elevated PSA (4.0 ng/mL or higher) compared with non-shiftworkers, after adjusting for confounders. The researchers, who published their findings online ahead of print in the Journal of the National Cancer Institute, concluded: “Our data support the

notion that sleep or circadian disruption is associated with elevated PSA, indicating that shiftworking men likely have an increased risk of developing prostate cancer.” The study included employed men aged 40 to 65 years with no prior history of cancer, except nonmelanoma skin cancer. n

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