Renal & Urology News January 2013 Issue

JANUARY 2013

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Nerve-Sparing RP May Predict PSM

© PHOTOTAKEUSA / BODELL COMMUNICATIONS

Positive surgical margins 50% more likely with this surgical approach, study finds

HIGHER PSM RISK with nerve-sparing may be related to lesser surgical skill.

Hyponatremia Raises Death Risk

BY JODY A. CHARNOW HYPONATREMIA IS a relatively common electrolyte abnormality in the general U.S. adult population, and it is associated with an increased risk of death, according to new data.

Using 1999-2004 data from the National Health and Nutrition Examination Survey, Sue Gu, a fourth-

CME FEATURE

year medical student, and colleagues at Columbia University Medical Center in New York looked for the presence of hyponatremia, defined as a serum sodium level below 135 mEq/L, among individuals aged 18 years and older. The overall prevalence was 3.38%, and was significantly higher among men than continued on page 13

Earn 1 CME credit in this issue

The Association Between Kidney Failure and RCC PAGE 31

BY JODY A. CHARNOW NERVE-SPARING techniques used during radical prostatectomy to preserve erectile function may increase the risk of positive surgical margins (PSM), new findings suggest.

In a prospective cohort of 1,148 men undergoing RP for localized prostate cancer, investigators at the University of Copenhagen, Denmark, led by Martin Andreas Røder, MD, found that nervesparing surgery (NSS) increased the risk of PSM by 50% compared with wide resection, according to an online report in the Scandinavian Journal of Urology and Nephrology. The overall PSM rate for the cohort was 31.4%.

Additionally, each doubling of PSA, beginning at 0.5 ng/mL, increased

Likelihood of ESRD Higher in Obese Teens OVERWEIGHT AND obese adolescents are at increased risk for end-stage renal disease (ESRD), according to Israeli researchers.

In a nationwide population-based retrospective study, Asaf Vivante, MD, of the Israeli Defense Forces Medical Corps and Sheba Medical Center, Tel Hashomer, and colleagues analyzed data from 1,194 adolescents aged 17 years who had been examined for fitness for military service between January 1, 1967 and December 31, 1997. These data were linked to the Israeli ESRD registry.

The investigators included in their analysis incident cases of treated ESRD from January 1, 1980 to May 31, 2010.

During a mean of about 25 years of follow-up, treated ESRD developed in 874 subjects (713 male and 161 female).

Compared with individuals of normal weight, overweight was associated with threefold increased risk for all-cause treated ESRD and obesity was associated with a nearly sevenfold increased continued on page 13

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PSM risk by 56% and each 10% increase in percent positive biopsies (PPBs) increased the risk by 11%. The researchers calculated PPBs from the number of positive cores divided by the total number of cores. Compared with patients who had T1 tumors, those with T3 tumors had a 2.8 times increased risk of PSM. Contrary to previous studies, biopsy Gleason score did not significantly affect PSM risk, according to the investigators.

Possible explanations for the increased risk of PSM associated with NSS include preoperative understaging, poor selection of candidates for this type of surgery, and/or improper surgical skills, the researchers noted. continued on page 12

IN THIS ISSUE 10

Male sex hormone changes may adversely affect hematocrit

11

Obesity raises risk of invasive penile cancer

13

Kidney stones tied to higher dietary zinc intake

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Once-monthly peginesatide injection cuts IV iron use

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HoLEP is an option after failed BPH surgery

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The nephrologist’s role in Fabry Disease

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Neutrophil count may predict prostate cancer on biopsy Increased stroke risk with changes in male sex hormones PAGE 22

4 Renal & Urology News

JANUARY 2013

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FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD

The Rise of the Coffee Shop Doctor

H

ow often have you met for business in a Starbucks, Coffee Bean, or any other coffee shop? Many doctors and healthcare professionals spend increasingly more time in coffee shops, and not just to fetch a cup of coffee. Meetings with drug reps and scientific liaisons of pharmaceutical companies now are often held in a coffee shop and less so in a fancy restaurant as in years past, and less often inside doctors’ offices or hospital clinics.

Coffee shops have evolved into places where, not infrequently, sensitive business meetings are held for the first time, including the interviewing and hiring of new partners for fast-growing practices.

The first meeting of many entrepreneurial healthcare and business initiatives may have started in a Starbucks. Many academic physicians spend time in coffee shops to write grants and papers or to run their periodic research meetings. I personally consider coffee shops as my second, if not my primary, office for such activities and my true operational headquarters.

What could explain the rise of the coffee shop doctor? First and foremost, a coffee shop is a neutral place where bilateral liability is at minimum, albeit not fully diminished. People may feel more comfortable and less accountable for what is said or promised in a coffee shop.

Drug reps and doctors may feel less compliance pressure if something is said in an overcrowded coffee shop while ordering and drinking iced tea. The sketches of future joint venture plans can be drafted on a napkin and then used to clean hands and thrown away, without any lawyer being able to come after you. There is free Internet access to check websites and to Google the stated numbers during a sensitive negotiation. It is a neutral zone where everybody feels safe, legally and ethically, unlike our own offices or medical center environment where we are exposed to numerous regulations and requirements just to breathe the air. I walk outside of the hospital and go into a Starbucks or Coffee Bean, am greeted by warm hellos and smiling faces, enjoy my green tea non-fat latte, check my emails, meet with a few people for business, make a few phone calls via my Blackberry, give orders over the phone or via electronic health record website, work on my papers for the next peer-review submission, email and reassure my coauthors about our next plans after a rejected paper or grant, review the profile of the next faculty candidate or fellow, conduct interviews with some of them, make small or big decisions about my life and career, and then walk out and go back safely to the hospital to continue with routine patient rounds while feeling less exhausted or even refreshed. So, I guess I am a proud to be a coffee shop doctor.

Kamyar 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, MBA Chief of Surgical Operations Fairview Hospital, a Cleveland Clinic hospital Professor of Surgery (Urology) Cleveland Clinic Lerner College of Medicine at Case Western Reserve University Leonard Horvitz and Samuel Miller Distinguished Chair in Urological Oncology Research 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 Executive editor Senior editor Web editor Editorial coordinator Art director Group art director, Haymarket Medical VP, audience development and operations Production assistant Group production manager Product manager, digital products Circulation manager National accounts manager Editorial director Publisher VP medical magazines and digital products CEO, Haymarket Media Inc.

Jody A. Charnow Marina Galanakis Delicia Honen Yard Stephan Cho Candy Iemma Andrew Bass Jennifer Dvoretz John Crewe Brian Wask Kathleen Millea Chris Bubeck Paul Silver William Canning Jeff Forster Dominic Barone Jim Burke Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 12, Number 1. 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.

Contents

JANUARY 2013

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VOLUME 12, ISSUE NUMBER 1

Urology 11

ONLINE

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this month at renalandurologynews.com Expert Q&A Shuvo Roy, PhD, of the University of California-San Francisco, talks about the progress he and his colleagues have made in developing an implantable artificial kidney.

UTI Reports to CDC May Be Misleading Researchers find discrepancies in competing definitions of catheter-related urinary tract infections.

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Drug Found to Delay PCa Progression Dutasteride prolonged PSA doubling time in men who experienced rising PSA after radical therapy.

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Visit our website for reports from the 2013 Genitourinary Cancers Symposium in Orlando, February 14-16.

“

CME Feature 31

The Association between Kidney Failure and Renal Cell Carcinoma Paul Russo, MD, of Memorial Sloan-Kettering Cancer Center in New York, reviews studies looking at the link and describes the characteristics of kidney tumors that develop in patients with end-stage renal disease.

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Abnormal SLE Serology Need Not Bar Pregnancy Abnormal serology alone should not lead clinicians to advise against pregnancy when counseling women with systemic lupus erythematosus.

Acidosis in Renal Tx Recipients Linked to Diet Researchers recommend increased consumption of fruits and vegetables and less animal protein.

Epoetin Alfa Use Down, IV Iron Use Up The trends follow the debut of prospective payment system for dialysis services and drug label changes.

Fabry Disease: The Nephrologist’s Role The complex disease requires regular follow up and assessment of the ongoing response to therapy.

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News Coverage

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Nephrology

The Medical Minute Visit renalandurologynews.com /the-medical-minute/ to hear podcast reports on new studies.

Our latest include: • A Clue to Black Lupus Patients’ Higher Risk for ESRD • Many Men Wrongly Believe Fish Oil Lowers PCa Risk • Pre-Diabetes May Not Preclude Kidney Donation

Mesh Sling Salvage Surgery Results Mixed Even if salvage operations ease complications from unsuccessful mesh sling surgery, patients often are in worse condition than before their original surgery, a urologist says.

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Clinical Quiz Take our latest quiz at renalandurologynews.com /clinical-quiz/. Answer correctly and you will be entered to win a $50 American Express gift card.

Congratulations to our newest winners: Kenneth Abreo, MD (October) Thomas Barnett, MD (November)

Obesity Increases Risk of Invasive Penile Cancer Increasing body mass index is associated with a greater likelihood of invasive penile cancer and more advanced penile cancer at presentation, data suggest.

We found in the first year after

transplantation that a majority of patients ended up getting hospitalized.

See our story on page 19

29

Departments 4

From the Medical Director Coffee shop doctors

10

News in Brief Serious acute kidney injury on the rise

16

Renal Nutrition Update Fruits, vegetables reduce dietary acid load

22

Men’s Health Update Erectile dysfunction linked to periodontitis

29

Legal Issues in Medicine When does a doctor’s obligation to a patient end?

30

Malpractice News New Hampshire confirms lawsuit screening panels

6 Renal & Urology News

JANUARY 2013

www.renalandurologynews.com

Abnormal SLE Serology Need Not Bar Pregnancy

BY JOHN SCHIESZER WASHINGTON, D.C.—Abnormal serology alone should not lead clinicians to advise against pregnancy when counseling women with systemic lupus erythematosus (SLE), even those with previous renal disease, according to a new prospective study presented at the American College of Rheumatology (ACR) annual meeting.

“Patients with past renal disease who are currently in partial or complete renal remission generally do not flare during pregnancy, even if they have persistently elevated anti-DNA and low complement levels,” said study investigator Jane Salmon, MD, Professor of Medicine at Weill Medical College of Cornell University in New York.

“This study is important because it supports the notion that if a lupus patient has never had renal disease, pregnancy, in and of itself, is not likely to increase that risk,” said coinvestigator Jill Buyon, MD, Professor of Medicine at New York University School of Medicine.

Pregnancy alone not likely to raise the risk of first-time renal disease.

Drs. Salmon and Buyon and colleagues conducted The PROMISSE Study (Predictors of pRegnancy Outcome: BioMarkers In antiphospholipid antibody Syndrome and Systemic Lupus Erythematosus), which prospectively evaluated 390 pregnant systemic lupus erythematosus patients. The investigators excluded women with multi-fetal pregnancy, taking prednisone at a dose greater than 20 mg/day, proteinuria greater than 1g/24 hr, and serum creatinine greater than 1.2 mg/dL. Overall, of the 390 patients completing pregnancy, 17% had only positive anti-dsDNA, 12% had only hypocomplementemia, 20% had both serologies, and 51% had neither serology at the time of enrollment. Of the 390 patients, 121 (31%) had preexisting renal disease as defined by ACR SLE criteria and/or a renal biopsy.

For the study, researchers defined a renal flare as an increase of at least 500 mg of protein per day with or without hematuria and/or red blood cell casts. Sixteen patients of the 120 with past renal disease experienced renal flares. All patients had

proteinuria, five (31%) had hematuria, and one (6%) had red blood cell casts.

However, the researchers found no differences among biopsy classes for patients with and without renal flares. Among 29 patients with a history of renal disease and both anti-dsDNA and hypocomplementemia, five (17%) had a renal flare.

In 44 patients with either anti-dsDNA or hypocomplementemia alone, seven (16%) had renal flares; in 47 patients with neither serology, four (9%) had renal flares. These slight trends toward a higher rate of renal flare in those patients with abnormal serologies did not reach statistical significance. In this

cohort, five patients were treated with increased doses of prednisone. Three treated patients and two untreated patients developed preeclampsia.

Rheumatologists generally advise patients to be in remission for six months prior to pregnancy, Dr. Salmon said. From a renal standpoint, this generally means

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being in a partial or complete remission (a protein/creatinine ratio less than 1).

In addition, patients on mycophenolate mofetil must be either switched to azathioprine or have immunosuppressive medications discontinued altogether. “One issue, which has been of concern for both rheumatologists and nephrolo-

gists, is whether the continued presence of serologic activity (positive anti-DNA antibodies and low complements) is a harbinger of a greater risk for renal flare,�

Dr. Salmon said. “No previous study has specifically addressed this question, although it has been reported that hypocomplementemia can predict poor fetal

JANUARY 2013

and maternal outcomes. Some physicians caution patients against contemplating pregnancy until all laboratory aspects of lupus have returned to normal.�

Adverse pregnancy outcomes included three (19%) fetal/neonatal deaths and two (13%) with SGA below the 5th percentile in the 16 patients with renal

Reducing the burden of

ESA administration Consider the first once-monthly, non-EPO ESA offering less-frequent dose administration.

INDICATION AND LIMITATIONS OF USE OMONTYSÂŽ (peginesatide) Injection is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis.

OMONTYS is not indicated and is not recommended for use in patients with CKD not on dialysis, in patients receiving treatment for cancer and whose anemia is not due to CKD, or as a substitute for red blood cell (RBC) transfusions in patients who require immediate correction of anemia. OMONTYS has not been shown to improve symptoms, physical functioning, or health-related quality of life.

IMPORTANT SAFETY INFORMATION WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE. Chronic Kidney Disease: t In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. t No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. t Use the lowest OMONTYS dose sufficient to reduce the need for RBC transfusions.

Contraindications OMONTYS is contraindicated in patients with uncontrolled hypertension and in patients who have had serious allergic reactions to OMONTYS. Warnings and Precautions Increased mortality, myocardial infarction, stroke, and thromboembolism: t Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Use caution in patients with coexistent cardiovascular disease and stroke.

Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality. A rate of hemoglobin rise of >1 g/dL over 2 weeks may contribute to these risks.

t In controlled clinical trials of ESAs in patients with cancer, increased risk for death and serious adverse cardiovascular reactions including myocardial infarction and stroke was observed. t There is increased mortality and/or increased risk of tumor progression or recurrence in patients with cancer receiving ESAs. t In controlled clinical trials of ESAs, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and deep venous thrombosis (DVT) in patients undergoing orthopedic procedures. t In 2 trials of OMONTYS, patients with CKD not on dialysis experienced increased specific cardiovascular events.

Hypertension (see Contraindications): Appropriately control hypertension prior to initiation of and during treatment with OMONTYS. Reduce or withhold OMONTYS if blood pressure becomes difficult to control.

Serious allergic reactions (see Contraindications): Serious allergic reactions have been reported with OMONTYS. Immediately and permanently discontinue OMONTYS and administer appropriate therapy if a serious allergic reaction occurs.

Lack or loss of response to OMONTYS: Initiate a search for causative factors. If typical causes of lack or loss of hemoglobin response are excluded, evaluate for antibodies to peginesatide.

Dialysis management: Patients receiving OMONTYS may require adjustments to dialysis prescriptions and/or increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.

Laboratory monitoring: Evaluate transferrin saturation and serum ferritin prior to and during OMONTYS treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. Monitor hemoglobin every 2 weeks until stable and the need for RBC transfusions is minimized. Then, monitor monthly.

Adverse reactions Most common adverse reactions in clinical studies in patients with CKD on dialysis treated with OMONTYS were dyspnea, diarrhea, nausea, cough, and arteriovenous fistula site complication.

Please see accompanying Brief Summary.

Reference 4DIJMMFS # %PTT 4 %F $PDL & %FM "HVJMB ." /JTTFOTPO "3 $PTUT PG NBOBHJOH BOFNJB XJUI FSZUISPQPJFTJT TUJNVMBUJOH BHFOUT EVSJOH IFNPEJBMZTJT B UJNF BOE NPUJPO TUVEZ Hemodial Int

# %4( ÂŞ "GGZNBY *OD BOE 5BLFEB 1IBSNBDFVUJDBMT "NFSJDB *OD "MM SJHIUT SFTFSWFE "GGZNBY UIF "GGZNBY MPHP 0.0/5:4 BOE UIF 0.0/5:4 MPHP BSF USBEFNBSLT PG "GGZNBY *OD BOE PS JUT TVCTJEJBSJFT 5BLFEB BOE UIF 5BLFEB MPHP BSF USBEFNBSLT PG 5BLFEB 1IBSNBDFVUJDBM $PNQBOZ -JNJUFE SFHJTUFSFE XJUI UIF 6 4 1BUFOU BOE 5SBEFNBSL 0GĂĽDF BOE VTFE VOEFS MJDFOTF CZ 5BLFEB 1IBSNBDFVUJDBMT "NFSJDB *OD

Renal & Urology News 7

flares. Only three renal flares occurred in the 270 patients with no history of kidney disease. Of the 50 patients with no history of renal disease and both anti-dsDNA and hypocomplementemia, two (4%) had new-onset proteinuria; preeclampsia developed in one of these patients. In 150 patients

8 Renal & Urology News

JANUARY 2013

with neither serology, only one patient had new-onset proteinuria, which was treated. She had SGA below the 5th percentile. None of the 70 patients with either serology alone had renal flares.

Although limited by small sample size, the presence of anti-dsDNA and low complement levels or an abnormality

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in either test in pregnant patients with previous nephritis and current remission, did not associate with a statistically higher risk of renal flare than those with normal analyte values.

Dr. Buyon summed up the data by noting that “this large multicenter, multiethnic prospective study provides

reassurances for physicians counseling patients with previous renal disease.

In agreement with available literature, patients in complete or partial remission have a low risk of renal flare even in the presence of abnormal serologies.

Advising against pregnancy for those with persistent serologic activity but

clinical quiescence is probably not warranted but given the trends observed may require further study.�

In this study, the good news is that increased proteinuria only occurred in 13% of patients with previous renal disease and 1% of those without a history of kidney disease, she added. â–

Table 2 Adverse Cardiovascular Outcomes in Randomized Controlled Trials Comparing Higher and Lower Hemoglobin Targets in Patients With CKD ÂŽ

Time Period of Trial

Population BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION OMONTYSŽ (peginesatide) Injection for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE. Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesisstimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. • No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks [see Warnings and Precautions]. • Use the lowest OMONTYS dose sufficient to reduce the need for red blood cell (RBC) transfusions [see Warnings and Precautions].

INDICATIONS AND USAGE Anemia Due to Chronic Kidney Disease OMONTYSÂŽ is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis.

Limitations of Use OMONTYS is not indicated and is not recommended for use: H : <-@51:@? C5@4 :;@ ;: 05-8E?5? .1/-A?1 ;2 ?-21@E /;:/1>:? 5: @45? <;<A8-@5;: [see Warnings and Precautions].

H : <-@51:@? >1/15B5:3 @>1-@91:@ 2;> /-:/1> -:0 C4;?1 -:195- 5? :;@ 0A1 @; .1/-A?1 % ? 4-B1 ?4;C: 4->9 5: ?;91 ?1@@5:3? -:0 @41 .1:125@ >5?7 2-/@;>? 2;> " "!&)% 5: @45? ?1@@5:3 4-B1 :;@ .11: 1B-8A-@10 *see Warnings and Precautions].

H ? - ?A.?@5@A@1 2;> $ @>-:?2A?5;:? 5: <-@51:@? C4; >1=A5>1 599105-@1 /;>>1/@5;: of anemia.

H " "!&)% 4-? :;@ .11: ?4;C: @; 59<>;B1 ?E9<@;9? <4E?5/-8 2A:/@5;:5:3 ;> 41-8@4 >18-@10 =A-85@E ;2 8521 CONTRAINDICATIONS " "!&)% 5? /;:@>-5:05/-@10 5: <-@51:@? C5@4 H ':/;:@>;8810 4E<1>@1:?5;: *see Warnings and Precautions].

H %1>5;A? -881>35/ >1-/@5;:? @; " "!&)% *see Warnings and Precautions].

WARNINGS AND PRECAUTIONS Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism H : /;:@>;8810 /85:5/-8 @>5-8? ;2 ;@41> % ? 5: <-@51:@? C5@4 /;9<->5:3 45341> 419;38;.5: @->31@?

3 0 @; 8;C1> @->31@?

3 0 see Table 2 5:/>1-?10 >5?7 ;2 01-@4 9E;/->05-8 5:2->/@5;: ?@>;71 /;:31?@5B1 41->@ 2-58A>1 @4>;9.;?5? ;2 419;05-8E?5? B-?/A8-> -//1?? -:0 ;@41> @4>;9.;19.;85/ 1B1:@? C-? ;.?1>B10 5: @41 45341> @->31@ 3>;A<?

H '?5:3 % ? @; @->31@ - 419;38;.5: 81B18 ;2 3>1-@1> @4-:

3 0 5:/>1-?1? @41 >5?7 ;2 ?1>5;A? -0B1>?1 /->05;B-?/A8-> >1-/@5;:? -:0 4-? :;@ .11: ?4;C: @; <>;B501 -005@5;:-8 .1:125@ '?1 /-A@5;: 5: <-@51:@? C5@4 /;1D5?@1:@ /->05;B-?/A8-> 05?1-?1 -:0 ?@>;71 #-@51:@? C5@4 -:0 -: 5:?A225/51:@ 419;38;.5: >1?<;:?1 @; % @41>-<E 9-E .1 -@ 1B1: 3>1-@1> >5?7 2;> /->05;B-?/A8-> >1-/@5;:? -:0 9;>@-85@E @4-: ;@41> <-@51:@? >-@1 ;2 419;38;.5: >5?1 ;2 3>1-@1> @4-: 3 0 ;B1> C117? 9-E /;:@>5.A@1 @; @41?1 >5?7?

H : /;:@>;8810 /85:5/-8 @>5-8? ;2 % ? 5: <-@51:@? C5@4 /-:/1> 5:/>1-?10 >5?7 2;> 01-@4 -:0 ?1>5;A? -0B1>?1 /->05;B-?/A8-> >1-/@5;:? C-? ;.?1>B10 &41?1 -0B1>?1 >1-/@5;:? included myocardial infarction and stroke.

H : /;:@>;8810 /85:5/-8 @>5-8? % ? 5:/>1-?10 @41 >5?7 ;2 01-@4 5: <-@51:@? A:01>3;5:3 /;>;:->E ->@1>E .E<-?? 3>-2@ ?A>31>E -:0 011< B1:;A? @4>;9.;?5? (& C-? ;.?1>B10 5: <-@51:@? A:01>3;5:3 ;>@4;<105/ <>;/10A>1? &41 01?53: -:0 ;B1>-88 >1?A8@? ;2 8->31 @>5-8? /;9<->5:3 45341> -:0 8;C1> 419;38;.5: @->31@? ->1 ?4;C: 5: &-.81 !;>9-8 19-@;/>5@ %@A0E ! % ;>>1/@5;: ;2 19;38;.5: "A@/;91? 5: $1:-8 :?A225/51:/E " $ -:0 &>5-8 @; $10A/1 ->05;B-?/A8-> B1:@? C5@4 AranespÂŽ &41>-<E &$ &

Hemoglobin Target; Higher vs. Lower (g/dL)

NHS (N = 1265)

CHOIR (N = 1432)

TREAT (N = 4038)

@;

@;

@;

#-@51:@? C5@4 ;: #-@51:@? C5@4 #-@51:@? C5@4 :;@ ;: 05-8E?5? C5@4 419;05-8E?5? C5@4 CKD not on dialysis /;1D5?@5:3 ;> 419;38;.5:

3 0 C5@4 @E<1 05-.1@1? :;@ <>1B5;A?8E 419-@;/>5@ 419;38;.5: administered

I ;: â&#x2030;¤

3 0 epoetin alfa epoetin alfa

B?

B?

B? â&#x2030;Ľ

Median (Q1, Q3) Achieved Hemoglobin level (g/dL)

B?

B?

B?

Primary Endpoint

88 /-A?1 9;>@-85@E ;> :;: 2-@-8

88 /-A?1 9;>@-85@E 4;?<5@-85F-@5;: 2;> ;> ?@>;71

88 /-A?1 9;>@-85@E 9E;/->05-8 5?/4195- 41->@ 2-58A>1 -:0 ?@>;71

Hazard Ratio or Relative Risk (95% CI)

G

G

G

Adverse Outcome for Higher Target Group

88 /-A?1 9;>@-85@E

88 /-A?1 9;>@-85@E

%@>;71

Hazard Ratio or Relative Risk (95% CI)

G

G

G

#-@51:@? C5@4 4>;:5/ 50:1E 5?1-?1 !;@ ;: 5-8E?5?

OMONTYS is not indicated and is not recommended for the treatment of anemia in patients C5@4 C4; ->1 :;@ ;: 05-8E?5?

45341> <1>/1:@-31 ;2 <-@51:@? C4; >1/15B10 " "!&)% 1D<1>51:/10 - /;9<;?5@1 /->05;B-?/A8-> ?-21@E 1:0<;5:@ 1B1:@ /;9<->10 @; C4; >1/15B10 0->.1<;1@5: -82- 5: @C; >-:0;95F10 -/@5B1 /;:@>;8810 ;<1: 8-.18 9A8@5 /1:@1> @>5-8? ;2 <-@51:@? C5@4 -:195- 0A1 @; C4; C1>1 :;@ ;: 05-8E?5? &41 @>5-8? 4-0 - <>1 ?<1/52510 <>;?<1/@5B1 -:-8E?5? ;2 - /;9<;?5@1 ?-21@E 1:0<;5:@ /;:?5?@5:3 ;2 01-@4 9E;/->05-8 5:2->/@5;: ?@>;71 ;> ?1>5;A? -0B1>?1 1B1:@? ;2 /;:31?@5B1 41->@ 2-58A>1 A:?@-.81 -:35:- ;> ->>4E@495 4-F->0 >-@5;

Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer receiving ESAs " "!&)% 5? :;@ 5:05/-@10 -:0 5? :;@ >1/;991:010 2;> >10A/@5;: ;2 $ @>-:?2A?5;:?

5: <-@51:@? >1/15B5:3 @>1-@91:@ 2;> /-:/1> -:0 C4;?1 -:195- 5? :;@ 0A1 @; .1/-A?1 % ? 4-B1 ?4;C: 4->9 5: ?;91 ?1@@5:3? -:0 @41 .1:125@ >5?7 2-/@;>? 2;> " "!&)% 5: @45? ?1@@5:3 4-B1 :;@ .11: 1B-8A-@10 &41 ?-21@E -:0 1225/-/E ;2 " "!&)% 4-B1 :;@ .11: 1?@-.85?410 2;> A?1 5: <-@51:@? C5@4 -:195- 0A1 @; /-:/1> /419;@41>-<E $1?A8@? 2>;9 /85:5/-8 @>5-8? ;2 % ? 5: <-@51:@? C5@4 -:195- 0A1 @; /-:/1> @41>-<E ?4;C10 01/>1-?10 8;/;>135;:-8 /;:@>;8 <>;3>1??5;: 2>11 ?A>B5B-8 -:0 ;> 01/>1-?10 ;B1>-88 ?A>B5B-8 &41 25:05:3? C1>1 ;.?1>B10 5: /85:5/-8 @>5-8? ;2 ;@41> % ? -095:5?@1>10 @; <-@51:@? C5@4 .>1-?@ /-:/1> >1/15B5:3 /419;@41>-<E -0B-:/10 41-0 -:0 :1/7 /-:/1> >1/15B5:3 >-05-@5;: @41>-<E 8E9<4;50 9-853:-:/E /1>B5/-8 /-:/1> :;: ?9-88 /188 8A:3 /-:/1> -:0 C5@4 B->5;A? 9-853:-:/51? C4; C1>1 :;@ >1/15B5:3 chemotherapy or radiotherapy.

Hypertension " "!&)% 5? /;:@>-5:05/-@10 5: <-@51:@? C5@4 A:/;:@>;8810 4E<1>@1:?5;: <<>;<>5-@18E /;:@>;8 4E<1>@1:?5;: <>5;> @; 5:5@5-@5;: ;2 -:0 0A>5:3 @>1-@91:@ C5@4 " "!&)% $10A/1 ;> C5@44;80 " "!&)% 52 .8;;0 <>1??A>1 .1/;91? 05225/A8@ @; /;:@>;8 0B5?1 <-@51:@? ;2 @41 59<;>@-:/1 ;2 /;9<85-:/1 C5@4 -:@54E<1>@1:?5B1 @41>-<E and dietary restrictions.

Serious Allergic Reactions %1>5;A? -881>35/ >1-/@5;:? 5:/8A05:3 -:-<4E8-/@5/ >1-/@5;:? 4E<;@1:?5;: .>;:/4;?<-?9 -:35;1019- -:0 31:1>-85F10 <>A>5@A? 9-E ;//A> 5: <-@51:@? @>1-@10 C5@4 " "!&)% 99105-@18E -:0 <1>9-:1:@8E 05?/;:@5:A1 " "!&)% -:0 -095:5?@1> -<<>;<>5-@1 @41>-<E 52 - ?1>5;A? -881>35/ >1-/@5;: ;//A>?

Lack or Loss of Response to OMONTYS ;> 8-/7 ;> 8;?? ;2 419;38;.5: >1?<;:?1 @; " "!&)% 5:5@5-@1 - ?1->/4 2;> /-A?-@5B1 2-/@;>? 1 3 5>;: 0125/51:/E 5:21/@5;: 5:28-99-@5;: .81105:3 2 @E<5/-8 /-A?1? ;2 8-/7 ;> 8;?? ;2 419;38;.5: >1?<;:?1 ->1 1D/8A010 1B-8A-@1 @41 <-@51:@ 2;> @41 <>1?1:/1 ;2 -:@5.;051? @; <135:1?-@501 : @41 -.?1:/1 ;2 -:@5.;051? @; <135:1?-@501 2;88;C 0;?5:3 >1/;991:0-@5;:? 2;> 9-:-3191:@ ;2 <-@51:@? C5@4 -: 5:?A225/51:@ 419;38;.5: >1?<;:?1 to OMONTYS therapy. ;:@-/@ 22E9-D :/ @; <1>2;>9 -??-E? 2;> .5:05:3 -:0 :1A@>-85F5:3 -:@5.;051?

Dialysis Management #-@51:@? 9-E >1=A5>1 -06A?@91:@? 5: @415> 05-8E?5? <>1?/>5<@5;:? -2@1> 5:5@5-@5;: ;2 " "!&)% #-@51:@? >1/15B5:3 " "!&)% 9-E >1=A5>1 5:/>1-?10 -:@5/;-3A8-@5;: C5@4 41<->5: @; <>1B1:@ /8;@@5:3 ;2 @41 1D@>-/;><;>1-8 /5>/A5@ 0A>5:3 419;05-8E?5?

www.renalandurologynews.com

JANUARY 2013

Renal & Urology News 9

Cystatin C Less Predictive than eGFR, Creatinine

BY ROSEMARY FREI, MSC TORONTOâ&#x20AC;&#x201D;Estimated glomerular filtration rate (eGFR) and serum creatinine values are more accurate than cystatin C levels in predicting acute hospitalization in patients with ambulatory heart failure, according to findings presented at the 2012 Canadian

Cardiovascular Congress. For every one-unit drop in slope of the change in eGFR over time, researchers observed a significant 1.07 increase in the number of all-cause hospitalizations.

A one-unit increase in serum creatinine was associated with a 0.56 increase in acute hospitalizations. Investigators

Laboratory Monitoring Evaluate transferrin saturation and serum ferritin prior to and during OMONTYS treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course of ESA therapy.

Following initiation of therapy and after each dose adjustment, monitor hemoglobin every 2 weeks until the hemoglobin is stable and sufficient to minimize the need for RBC transfusion. Thereafter, hemoglobin should be monitored at least monthly provided hemoglobin levels remain stable.

ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: H :/>1-?10 ;>@-85@E E;/->05-8 :2->/@5;: %@>;71 -:0 &4>;9.;19.;85?9 [see Warnings and Precautions] H E<1>@1:?5;: *see Warnings and Precautions] H %1>5;A? -881>35/ >1-/@5;:? *see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of OMONTYS cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.

Patients with Chronic Kidney Disease Adverse reactions were determined based on pooled data from two active controlled studies of 1066 dialysis patients treated with OMONTYS and 542 treated with epoetin, including 938 exposed for at least 6 months and 825 exposed for greater than one year to OMONTYS. The population for OMONTYS was 20 to 93 years of age, 58.5% male, and the percentages of Caucasian, Black (including African Americans), and Asian patients were 57.9%, 37.4%, and 3.1%, respectively. The median weight adjusted dose of OMONTYS was 0.07 mg/kg and 113 U/week/kg of epoetin.

Table 3 summarizes the most frequent adverse reactions (â&#x2030;Ľ10%) in dialysis patients treated with OMONTYS. Table 3

Adverse Reactions Occurring in â&#x2030;Ľ10% of Dialysis Patients Treated with OMONTYS Dialysis Patients Treated with OMONTYS (N = 1066)

Dialysis Patients Treated with Epoetin (N = 542)

Diarrhea

18.4%

15.9%

Nausea

17.4%

19.6%

Vomiting

15.3%

13.3%

Adverse Reactions Gastrointestinal Disorders

Respiratory, Thoracic and Mediastinal Disorders Dyspnea

18.4%

19.4%

Cough

15.9%

16.6%

Injury, Poisoning and Procedural Complications Arteriovenous Fistula Site Complication

16.1%

16.6%

#>;/10A>-8 E<;@1:?5;:

Nervous System Disorders 1-0-/41

Musculoskeletal and Connective Tissue Disorders

found no significant correlation with changes in cystatin C levels and hospitalizations in ambulatory chronic heart failure. â&#x20AC;&#x153;Cystatin C testing is more expensive and cumbersome than serum creatinine and eGFR,â&#x20AC;? said Mahwash Saeed, MD, an internal medicine resident at the

Postmarketing Experience Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serious allergic reactions have been reported during postmarketing use of OMONTYS [see Warnings and Precautions].

Immunogenicity Of the 2357 patients tested during clinical trials, 29 (1.2%) had detectable levels of peginesatide-specific binding antibodies. There was a higher incidence of peginesatidespecific binding antibodies in patients dosed subcutaneously (1.9%) as compared to those dosed intravenously (0.7%). Peginesatide neutralizing antibodies were detected in vitro A?5:3 - /188 .-?10 2A:/@5;:-8 -??-E 5: ;2 @41?1 <-@51:@? : -<<>;D59-@18E half of all antibody-positive patients, the presence of antibodies was associated with declining hemoglobin levels, the requirement for increased doses of OMONTYS to maintain hemoglobin levels, and/or transfusion for anemia of CKD. No cases of pure red cell aplasia (PRCA) developed in patients receiving OMONTYS during clinical trials.

DRUG INTERACTIONS No formal drug/drug interaction studies have been performed. Peginesatide does not bind to serum albumin or lipoproteins as demonstrated in in vitro protein binding studies in rat, monkey and human sera. In vitro studies conducted with human hepatocytes or microsomes have shown no potential for peginesatide to induce or inhibit CYP450 enzymes.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Peginesatide was teratogenic and caused embryofetal lethality when administered to pregnant animals at doses and/or exposures that resulted in polycythemia. OMONTYS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Administration of peginesatide by intravenous injection to rats and rabbits during organogenesis was associated with embryofetal toxicity and malformations. Dosing was every third day in rats for a total of 5 doses and every fifth day in rabbits for a total of

0;?1? @; 93 73 0;?1 : >-@? -:0 >-..5@? -0B1>?1 19.>E;21@-8 1221/@? 5:/8A010 reduced fetal weight, increased resorption, embryofetal lethality, cleft palate (rats only), sternum anomalies, unossification of sternebrae and metatarsals, and reduced ossification of some bones. Embryofetal toxicity was evident in rats at peginesatide doses of â&#x2030;Ľ1 mg/kg and the malformations (cleft palate and sternoschisis, and variations in blood vessels) were mostly evident at doses of â&#x2030;Ľ10 mg/kg. The dose of 1 mg/kg results in exposures (AUC) comparable to those in humans after intravenous administration at a dose of 0.35 mg/kg 5: <-@51:@? ;: 05-8E?5? : - ?1<->-@1 19.>E;21@-8 01B18;<91:@-8 ?@A0E 5: >-@? >10A/10 fetal weight and reduced ossification were seen at a lower dose of 0.25 mg/kg. Reduced fetal weight and delayed ossification in rabbits were observed at â&#x2030;Ľ0.5 mg/kg/dose of <135:1?-@501 : - ?1<->-@1 19.>E;21@-8 01B18;<91:@-8 ?@A0E 5: >-..5@? -0B1>?1 25:05:3? were observed at lower doses and included increased incidence of fused sternebrae at 0.25 mg/kg. The effects in rabbits were observed at doses lower (5% - 50%) than the dose of 0.35 mg/kg in patients.

Nursing Mothers @ 5? :;@ 7:;C: C41@41> <135:1?-@501 5? 1D/>1@10 5: 4A9-: 9587 1/-A?1 9-:E 0>A3? ->1 excreted into human milk, caution should be exercised when OMONTYS is administered to a nursing woman.

Pediatric Use The safety and efficacy of OMONTYS in pediatric patients have not been established.

Geriatric Use Of the total number of dialysis patients in Phase 3 clinical studies of OMONTYS, 32.5% were age 65 and over, while 13% were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

OVERDOSAGE OMONTYS overdosage can elevate hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of OMONTYS dosage and/or with phlebotomy, as clinically indicated. Cases of severe hypertension have been observed following overdose with ESAs [see Warnings and Precautions].

Muscle Spasms

15.3%

17.2%

Pain in Extremity

10.9%

12.7%

Back Pain

10.9%

11.3%

Arthralgia

10.7%

9.8%

E<;@1:?5;:

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Distributed and Marketed by: &-710- #4->9-/1A@5/-8? 91>5/- :/ 11>25180

12.2%

14.0%

" "!&)% 5? - @>-019->7 ;2 22E9-D :/ >135?@1>10 5: @41 ' % #-@1:@ -:0 &>-019->7 "225/1 -:0 A?10 A:01> 85/1:?1 .E &-710- #4->9-/1A@5/-8? 91>5/- :/

All other trademarks are the property of their respective owners.

11.0%

12.4%

Vascular Disorders

General Disorders and Administration Site Conditions Pyrexia Metabolism and Nutrition Disorders E<1>7-8195Infections and Infestations '<<1> $1?<5>-@;>E &>-/@ :21/@5;:

Marketed by: 22E9-D :/ Palo Alto, CA 94304

PEG096 R2_BS

Seizures have occurred in patients participating in OMONTYS clinical studies. During the first several months following initiation of OMONTYS, blood pressure and the presence of premonitory neurologic symptoms should be monitored closely.

Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency.

Allergic and infusion-related reactions have been reported in patients treated with OMONTYS.

L-DSG-1112-1

University of Manitoba in Winnipeg, who presented the results. â&#x20AC;&#x153;So there may not be a role for cystatin C in these patients.â&#x20AC;?

Cystatin C is a serine protease inhibitor that had previously been shown to be a sensitive measure of renal function. Serum creatinine and eGFR are inexpensive and relatively easy to measure, but they have some limitations, according to Dr. Saeed. For example, serum creatinine measurements may be unreliable in patients with low muscle mass and the predictive value of eGFR has not been fully validated in older individuals.

Working with Shelley Zieroth, MD, and Manish Sood, MD, Dr. Saeed studied 138 consecutive adult patients who were being treated in the ambulatory heart failure clinic at St. Boniface

Cystatin C changes not correlated with acute admissions for heart failure.

Hospital in Winnipeg. To be included in the study, subjects had to have a left ventricular ejection fraction of less than 40% within six months of recruitment.

The patients were assessed every three months and the follow-up was for up to two years (median 333 days). The patientsâ&#x20AC;&#x2122; average age at study recruitment was 62.9 years and 83.3% were male. The mean eGFR was 70.2 mL/ min/1.73 m2. Approximately one-quarter of the patients had normal kidney function and 2.3% had a creatinine clearance less than 30 mL/min.

The study cohort experienced 156 hospitalizations during the study. A total of 60.5% had at least one hospitalization, the investigators reported.

Nine patients died.

Seventy-one percent of the subjects experienced a reduction of at least 10% in eGFR and 22% had a drop in eGFR of at least 25%. Overall, eGFR fell by 0.28 mL/min/1.73 m2/ month, and creatinine was reduced by 0.62 Âľmol/L/month, the study found. â&#x20AC;&#x153;While the eGFR was not derived in chronic heart failure patients, we found that it is predictive of hospitalization in this population,â&#x20AC;? Dr. Saeed concluded. â&#x20AC;&#x153;And despite its limitations, serum creatinine also is predictive of hospitalizations in these patients.â&#x20AC;? â&#x2013;

10 Renal & Urology News

JANUARY 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 Tadalafil May Slow Muscular Dystrophy

dialysis-requiring AKI rose from 223 to

Tadalafil, an oral phosphodiesterase-5

eraging an annual increase of 10%. The

inhibitor approved for treating erec-

total number of deaths associated with

tile dysfunction, may hold promise

dialysis-requiring AKI rose from 18,000

as a treatment for Becker muscular

in 2000 to nearly 39,000 in 2009.

dystrophy in men, according to

Older age, male gender, and black race

findings published online in Science

were associated with a higher incidence

Translational Medicine. In a random-

of dialysis-requiring AKI.

533 cases per million person-years, av-

ized, placebo-controlled crossover alleviated functional muscle ischemia

New Insight into How Kidney Tumors Grow

and restored normal blood flow in

Researchers looking at multiple dif-

eight of the nine men in the trial. The

ferent levels of changes in clear cell

findings suggest that tadalafil can slow

renal cell carcinoma (RCC) have found

or prevent muscle weakening in Becker

novel tumor-related genes not previ-

muscular dystrophy if administered

ously reported in renal carcinoma.

early in the disease.

As described in Cancer Research

study, a single oral dose of the drug

(2012;72:5273-5284), George M.

Serious Acute Kidney Injury on the Rise

Yousef, MD, a laboratory pathologist at

The incidence of acute kidney injury

co-investigators used a high-resolution

(AKI) requiring dialysis in the United

microarray to identify very specific

States is now higher than the incidence

regions of the chromosomes where

of end-stage renal disease (ESRD) that

genetic alterations take place in RCC.

requires dialysis or kidney transplanta-

Combined information from chromo-

tion, Chi-yuan Hsu, MD, of the Univer-

somal changes, methylation, and gene

sity of California-San Francisco, and

expression provided a much clearer

colleagues reported online in Journal of

picture of the mechanism of kidney

the American Society of Nephrology.

cancer development, opening the door

From 2000 to 2009, the incidence of

for new treatments targets.

St. Michael’s Hospital in Toronto, and

Male UTI Treatment In a recent online poll, Renal & Urology News asked urologists, “In most cases of uncomplicated urinary tract infection in adult males, what duration of antibiotic treatment do you usually prescribe?” Here are the results based on 255 respondents:

0

10

20

30

7 days or less

74.5%

More than 7 days

25.5%

40

50

60

70

80

High-Protein Diets Increase Glomerular Filtration Rate H

igh-protein diets increase estimated glomerular filtration rate (GFR), according to findings published online in the American Journal of Kidney Diseases.

Investigators studied 164 healthy adults with prehypertension or stage 1 hypertension who consumed each of three diets for six weeks. The three diets emphasized carbohydrate, protein, or unsaturated fat. Protein accounted for 15% of energy intake in the carbohydrate and saturated fat diets and 25% of energy intake in the protein diet.

The researchers, led by Edgar R. Miller III, MD, PhD, of the Johns Hopkins Medical Institutions in Baltimore, found that the protein-rich diet imcreased eGFR by about 4 mL/min/1.73 m2 compared with the other two diets. The investigators observed no significant difference in eGFR between the carbohydrate and unsaturated fat diets. The effects of the protein diet on renal function were independent of changes in blood pressure.

Undescended Testes Raise Testicular Cancer Risk B

oys with isolated cryptorchidism are nearly three times more likely to develop testicular cancer as boys without the condition, according to a recent metaanalysis published online in Archives of Disease in Childhood.

The meta-analysis, by Robert Carachi, PhD, of the Department of Surgical Paediatrics at Royal Hospital for Sick Children, Yorkhill, Glasgow, U.K., and colleagues, included nine case-control studies involving 2,281 cases and 4,811 controls and three cohort studies that included nearly 2.2 million boys, with 345 subjects developing testicular cancer over more than 58 million personyears of follow-up.

Study limitations included possible publication bias as well as a lack of high-quality evidience focusing on the risk of malignancy in boys with isolated cryptorchidism.

Cognitive Abilities Decline Along with Kidney Function D

ecreases in estimated glomerular filtration rate (eGFR) are associated with cognitive decline, according to a five-year longitudinal study of 590 community-living individuals. The study subjects (mean age 62.1 years; mean eGFR 78.4 mL/min/1.73m2) were free of dementia, acute stroke, and end-stage renal disease (ESRD) at baseline. Changes in renal functioning over time were related to observed changes in global cognitive ability, verbal episodic memory, and abstract reasoning, a team led by Adam Davey, PhD, of Temple University’s College of Health Professions and Social Work, reported online in Nephrology Dialysis Transplantation. The relationship remained even after adjusting for demographic variables and cardiovascular disease risk factors and excluding individuals who developed dementia or experienced an acute stroke. The researchers concluded that early detection of mild to moderate kidney disease is an important publichealth concern with regard to cognitive decline.

www.renalandurologynews.com

JANUARY 2013

Renal & Urology News 11

Obesity Increases Risk of Invasive Penile Cancer INCREASING BODY mass index (BMI) is associated with a greater likelihood of invasive penile cancer and more advanced penile cancer at presentation, according to study findings published online in European Urology.

In addition, the findings showed that the odds of invasive penile can-

cer increased twofold with each 5-unit increment in BMI, and each 5-unit increase in BMI was associated with a 49% increased odds of higher cancer stage at diagnosis.

For the study, investigators at the University of Iowa in Iowa City led by Amit Gupta, MD, matched 77 penile

cancer patients with 12,420 cancer-free controls.

“The biologic mechanism for this increased risk is unknown but might be mediated by impaired genital hygiene because of obesity,” the authors wrote.

“Obesity can hamper genital selfexamination and cleansing and can

cause a buried penis with resultant smegma accumulation and functional phimosis.”

Dr. Gupta’s group also noted that obesity may impair examination by health care providers, “which may lead to delayed recognition of symptoms that leads to presentation at higher stage.” ■

We con tin to be y ue practic our al decisio clinical n su tool fo pport rt ONCOL he OGY treatm ent tea m…

ChemotherapyAdvisor.com has a new look.

We still have the same great content, only now it looks better than ever!

Fresh design Our new, clean layout enhances our best features, making it easier for you to find the information you’re looking for. And our larger photos make it easier for you to view every detail of our full-color slideshows and images.

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More interactive When you read our oncology case studies, now you can take a poll to guess the diagnosis and compare your answer with your colleagues’. New social media buttons allow you to easily share articles. Submitting your blogs and case studies is easy and convenient.

www.renalandurologynews.com

JANUARY 2013

Renal & Urology News 11

Obesity Increases Risk of Invasive Penile Cancer INCREASING BODY mass index (BMI) is associated with a greater likelihood of invasive penile cancer and more advanced penile cancer at presentation, according to study findings published online in European Urology.

In addition, the findings showed that the odds of invasive penile can-

cer increased twofold with each 5-unit increment in BMI, and each 5-unit increase in BMI was associated with a 49% increased odds of higher cancer stage at diagnosis.

For the study, investigators at the University of Iowa in Iowa City led by Amit Gupta, MD, matched 77 penile

cancer patients with 12,420 cancer-free controls. â&#x20AC;&#x153;The biologic mechanism for this increased risk is unknown but might be mediated by impaired genital hygiene because of obesity,â&#x20AC;? the authors wrote. â&#x20AC;&#x153;Obesity can hamper genital selfexamination and cleansing and can

Table 2: Percentages of Patients with Adverse Reactions, Derived from all Adverse Events, Reported by Greater Than 2% of Patients Treated With Myrbetriq 50 mg Once Daily in Study 4 Myrbetriq 50 mg

Active Control

(%)

(%)

Number of Patients

812

812

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cause a buried penis with resultant smegma accumulation and functional phimosis.â&#x20AC;?

Dr. Guptaâ&#x20AC;&#x2122;s group also noted that obesity may impair examination by health care providers, â&#x20AC;&#x153;which may lead to delayed recognition of symptoms that leads to presentation at higher stage.â&#x20AC;? â&#x2013;

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12 Renal & Urology News

JANUARY 2013

Nerve-sparing RP continued from page 1

Of the six surgeons who performed the surgeries, only two performed robotic-assisted laparoscopic prostatectomy (RALP) procedures. NSS was more frequent in RALP compared with open procedures (69.3% vs.

22.8%), the researchers reported.

The new findings contrast with those

www.renalandurologynews.com

of a recently published study in BJU International (2012;109:533-538), in which Australian investigators concluded that, with appropriate selection of patients, nerve-sparing surgery does not increase the risk of PSM, regardless of whether the cancer was organ-confined or extracapsular extension was present. The study included 945 men who underwent RP by one surgeon.

The researchers explained that nervesparing RP has been associated with an increased risk of PSM because of the close anatomical relationship of the neurovascular bundle to the posterolateral aspect of the prostatic fascia.

Commenting on the study by Dr. Røder and colleagues, Judd W. Moul, MD, Director of the Prostate Cancer Center at Duke University Medical Center in Durham, N.C.,

®

makes all the difference

observed: “This is a very interesting paper and I applaud the authors’ consecutive series and [for] presenting honest provocative data. I personally am not surprised by these results, and feel the results would be the same if this same exact analysis was done at many other U.S. and international centers.”

Dr. Moul, who also is the James H. Semans, MD, Professor of Surgery at Duke, noted that the authors did not specifically indicate that RALP was associated with higher or lower PSM and did not take into account the era of surgery. “It would have been interesting to see if there were changes over time as the surgeons gained experience,” he said.

In the mid 1990’s, Dr. Moul related, he led a multicenter study of PCa patients treated in the U.S. Military healthcare system and published a number of important papers about

Poor patient selection may be one reason for higher PSM risk.

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radical prostatectomy in the early PSA era in the United States. “These studies found very similar rates of PSM as this recent study from Denmark, where PSA screening is not practiced,” Dr. Moul said. “I will never forget receiving a letter from one of the most highly regarded American prostate cancer surgeons at the time about our work.

He basically told me in the letter that I and my military urologic surgeons did not know how to do the radical prostatectomy correctly because of our high PSM rate. However, as the Denmark authors state in their paper, it has more to do with patient selection although the surgeon does make a difference to be sure.”

Dr. Moul explained that the military studies he co-authored involved many young urologists fresh out of their training. “The PSM rate may have been somewhat lower had the cases been done at centers of excellence by high volume surgeons,” he said.

In the Denmark series, Dr. Moul pointed out, the highest volume surgeon did not have the lowest PSM rate, but he may have been taking on more difficult cases not fully reflected in the researchers’ multivariable model.

Dr. Moul noted that some patients pressure their surgeon to use a nervesparing technique despite adverse continued on page 13

41960ALT_ASize_v1 1

5/13/08 10:05:24 AM

12 Renal & Urology News

JANUARY 2013

Nerve-sparing RP continued from page 1

Of the six surgeons who performed the surgeries, only two performed robotic-assisted laparoscopic prostatectomy (RALP) procedures. NSS was more frequent in RALP compared with open procedures (69.3% vs.

22.8%), the researchers reported.

The new findings contrast with those

www.renalandurologynews.com

of a recently published study in BJU International (2012;109:533-538), in which Australian investigators concluded that, with appropriate selection of patients, nerve-sparing surgery does not increase the risk of PSM, regardless of whether the cancer was organ-confined or extracapsular extension was present. The study included 945 men who underwent RP by one surgeon.

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The researchers explained that nervesparing RP has been associated with an increased risk of PSM because of the close anatomical relationship of the neurovascular bundle to the posterolateral aspect of the prostatic fascia.

Commenting on the study by Dr. Røder and colleagues, Judd W. Moul, MD, Director of the Prostate Cancer Center at Duke University Medical Center in Durham, N.C.,

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observed: â&#x20AC;&#x153;This is a very interesting paper and I applaud the authorsâ&#x20AC;&#x2122; consecutive series and [for] presenting honest provocative data. I personally am not surprised by these results, and feel the results would be the same if this same exact analysis was done at many other U.S. and international centers.â&#x20AC;?

Dr. Moul, who also is the James H. Semans, MD, Professor of Surgery at Duke, noted that the authors did not specifically indicate that RALP was associated with higher or lower PSM and did not take into account the era of surgery. â&#x20AC;&#x153;It would have been interesting to see if there were changes over time as the surgeons gained experience,â&#x20AC;? he said.

In the mid 1990â&#x20AC;&#x2122;s, Dr. Moul related, he led a multicenter study of PCa patients treated in the U.S. Military healthcare system and published a number of important papers about

Poor patient selection may be one reason for higher PSM risk. radical prostatectomy in the early PSA era in the United States. â&#x20AC;&#x153;These studies found very similar rates of PSM as this recent study from Denmark, where PSA screening is not practiced,â&#x20AC;? Dr. Moul said. â&#x20AC;&#x153;I will never forget receiving a letter from one of the most highly regarded American prostate cancer surgeons at the time about our work.

He basically told me in the letter that I and my military urologic surgeons did not know how to do the radical prostatectomy correctly because of our high PSM rate. However, as the Denmark authors state in their paper, it has more to do with patient selection although the surgeon does make a difference to be sure.â&#x20AC;?

Dr. Moul explained that the military studies he co-authored involved many young urologists fresh out of their training. â&#x20AC;&#x153;The PSM rate may have been somewhat lower had the cases been done at centers of excellence by high volume surgeons,â&#x20AC;? he said.

In the Denmark series, Dr. Moul pointed out, the highest volume surgeon did not have the lowest PSM rate, but he may have been taking on more difficult cases not fully reflected in the researchersâ&#x20AC;&#x2122; multivariable model.

Dr. Moul noted that some patients pressure their surgeon to use a nervesparing technique despite adverse continued on page 13

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Hyponatremia/death risk

JANUARY 2013

Low Sodium in the U.S. Population

continued from page 1

women (4.32% vs. 2.37%). The prevalence increased with age. It was 2.82%, 3.32%, and 5.31% among individuals aged 18-44, 45-64, and 65 and older, the researchers found. This trend was found among men (1.75%, 2.63%, and 4.13%) and women (3.89%, 3.97%, and 6.19%). Gu’s team found that hyponatremia was associated with a significant 2.3 times increased risk of death in unadjusted analyses. The association remained significant in adjusted analyses.

“We see our results as particularly interesting, as this is the first known study to estimate the prevalence of hyponatremia in a general outpatient population,” Gu told Renal & Urology News. “While it was previously known

Obese teens/ESRD risk continued from page 1

risk, after adjusting for gender, country of origin, systolic blood pressure, and period of enrollment in the study, Dr. Vivante’s team reported in Archives of Internal Medicine (2012;172:16441650). Overweight and obesity were associated with a sixfold and 19-fold increased risk for diabetic ESRD, respectively, and a twofold and threefold increased risk for nondiabetic ESRD. The investigators considered adolescents overweight if they were in the 85th to 95th percentile of body mass index (BMI) and obese if they were in the 95th or greater percentile of BMI. Dr. Vivante’s team noted that study strengths included the use of a large nationwide cohort that included both genders and detailed clinical assessment parameters, as well as a long

The prevalence of hyponatremia in the general outpatient population increases with age in both men and women, according to a study by researchers at Columbia University Medical Center in New York.

■ Men ■ Women

8 7 6 5 4 3 2 1 0

1.75% 3.89% 18 - 44

2.63% 3.89% 45- 64

4.13%

6.19% 65+

Source: Gu S, et al. Prevalence of hyponatremia in NHANES 1999-2004 and association with mortality. Presented at Kidney Week 2012 in San Diego. Abstract TH-OR056.

that hyponatremia was associated with poor outcomes and mortality in hospitalized patients, we have found that it also portends a poor prognosis in the

ambulatory setting as well.”

In another study, researchers at the University of Texas Southwestern Medical Center in Dallas found that

follow-up period and comprehensive documentation of ESRD. With respect to study limitations, they stated that subjects’ body weight and height were measured only once. “Therefore, the effects of weight loss on risk for ESRD during the follow-up period could not

however, pointed out that CKD is rare in individuals aged 17 years.

In an accompanying editorial, Kirsten L. Johansen, MD, of the University of California-San Francisco, noted that the association of obesity with ESRD is both good and bad news. The good news is that obesity is a potentially modifiable risk factor. Control of weight and the hypertension and inactivity that often accompany excess adiposity, she wrote, could prevent or slow development of some cases of ESRD and may potentially decrease the morbidity and mortality associated with chronic kidney disease.

The bad news, she pointed out, is that it is not easy to address obesity.

In addition, Dr. Johansen observed: “The strong association between obesity at age 17 and the incidence of ESRD many years later underscores the fact that overweight adolescents generally go on to become overweight adults.” ■

Adolescent obesity increases the risk of diabetic ESRD 19-fold, data show. be determined,” they noted. In addition, subjects’ glomerular filtration rates at enrollment were unavailable.

“Consequently, some participants who subsequently developed treated ESRD may have had asymptomatic or undetected early-stage CKD.” The authors,

Renal & Urology News 13

hyponatremia is associated with an increased risk of death in an ambulatory young and ethnically diverse population. Fabrice Gankam Kengne, MD, and collaborators studied 3,551 individuals enrolled in the Dallas Heart Study. Subjects had a median age of 43 years. Hyponatremia was present in 6.9% of the cohort.

At the end of a median follow-up of 8.4 years, 202 deaths occurred, including 29 among individuals with hyponatremia (serum sodium level below 135 mEq/L).

In unadjusted analyses, hyponatremia was associated with a twofold increased risk of death. After adjusting for age, gender, ethnicity, hypertension, dyslipidemia, diabetes, smoking, alcohol use, renal function and other potential confounders, hyponatremia was associated with a significant 75% increased risk of death. ■

Zinc May Raise Kidney Stone Risk HIGHER DIETARY zinc intake is associated with an increased risk of kidney stones, according to a new study.

Researchers led by Jie Tang, MD, of the University of Colorado School of Medicine in Aurora, analyzed data from 15,444 adult participants in the Third National Health and Nutrition Examination Survey, a large U.S. population-based cross-sectional study.

Of these participants, 710 reported a history of kidney stones.

Compared with subjects who had the lowest dietary zinc intake (less than 7 mg/day), those with the highest intake (more than 15 mg/day) had

Nerve-sparing RP continued from page 16

pathology that might generally preclude this. “Certainly, giving in to patient pressure in this regard will increase PSM’s,” Dr. Moul said. “We do not know if this occurred in Denmark in this series.”

Karim A. Touijer, MD, a urologic surgeon at Memorial Sloan-Kettering Cancer Center in New York, said the findings by Dr. Røder’s group are difficult to generalize. “The algorithm used by the authors to decide whether to perform nerve-sparing surgery or not is specific to their practice and not widely recognized,” Dr. Touijer said. In particular, the investigators

reported that the majority (71%) of their patients received wide nerve resection and only 9.9% received bilateral nerve sparing.

In modern RP series, Dr. Touijer observed, the majority of patients— about 80%—receive bilateral nerve sparing and the overall PSM rate is 10% to 13%, whereas the study by Dr. Røder and colleagues demonstrated an overall PSM rate of 31.4% and a rate of 29.8%, 27.2%, and 32.5% for unilateral and bilateral nerve sparing and wide resection, respectively.

As with many previous series, Dr. Touijer said, the series reported

by Dr. Røder and colleagues demonstrated wide variability among surgeons,

“which again confirms the impact of the surgeon on outcomes and highlights the fact that while the goal of radical prostatectomy is complete excision of cancer with preservation of quality of life to the greatest extent possible, avoiding a PSM starts before the operating room with surgical planning.”

Unlike other PCa prognostic factors, he added, PSM status is the only one impacted by the surgeon and surgical technique, particularly in organconfined disease, he said. Dr. Touijer and collaborators have demonstrated that quality assurance efforts through pathologic and intraoperative video documentation review can help decrease PSM rates. ■

a significant 70% increased risk of kidney stones, the investigators reported in the American Journal of Nephrology (2012;36:549-553).

“Future prospective studies are needed to clarify the causal relationship between zinc intake and kidney stone formation,” the authors noted.

The investigators stated that their findings are consistent with those of a previous study (Br J Urol 1991;67:230-236) which demonstrated that urinary zinc excretion was significantly higher in calcium stone formers than nonstone-forming controls. ■

14 Renal & Urology News

JANUARY 2013

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Stereotactic Radiosurgery Safe for RCC Small study demonstrated that treatment was associated with a very low rate of adverse effects

BY JOHN SCHIESZER BOSTON—Researchers have reported promising results from the first safety trial of stereotactic radiosurgery for patients with localized primary renal cell carcinoma (RCC) who are considered poor surgical candidates and who do not have a prior history of pelvic or abdominal radiation.

Huge first step “This is a huge first step to show this is safe,” said investigator Rodney Ellis, MD, Clinical Director and Vice Chair for Clinical Affairs in the Department of Radiation Oncology at University Hospitals Case Medical Center Seidman Cancer Center in Cleveland. “We are very pleased with the findings, and I think this is good news for urologists and their patients because it may give them another option that is non-invasive.”

Dr. Ellis, who also is an associate professor of radiation oncology and urology at Case Western Reserve University School of Medicine in Cleveland, presented the data on behalf of Lee Ponsky MD, Associate Professor of Urology and principal investigator for this trial.

Dr. Ellis presented results from 20 patients at the American Society for Radiation Oncology annual meeting.

The response rate suggests that patients reacted well and had acceptable levels of treatment-related toxicity following treatment. There were no reports of gastrointestinal or small bowel toxicity, or RCC-related deaths. For patients who underwent a post-treatment biopsy, incomplete or refractory treatment was found in 91%.

“We still don’t know yet the optimal doses to achieve comparable efficacy to surgery or cryotherapy,” Dr. Ellis said.

The 15 men and five women ranged from 58 to 92 years old (mean 80).

The 20 patients received initial doses of 600 cGy per fraction for four fractions, followed by increments of 200 cGy per fraction to total doses of 24, 32, and 48 Gy in groups of four to six patients per dose level. Doses were escalated after patients showed nonprohibitive levels of toxicity within 180 days from the date of treatment. Limiting levels of toxicity were defined as any Grade 3 or higher gastrointestinal/genitourinary acute radiation toxicity, accord-

ing to the National Cancer Institute common toxicity criteria. Imaging and post-treatment biopsy results were evaluated for tumor response and treatment efficacy.

Toxicities The Acute toxicity was limited to Grade 1 fatigue in two patients in the highest-dose treatment group, which was relieved by rest. Late toxicity occurred in two patients who experienced Grade 2 chronic renal insufficiency as demonstrated by elevated creatinine values (range 2-4 mg/dL), the researchers stated.

“What was remarkably surprising was that we had very few, if any, side effects in these patients,” Dr. Ellis said.

All of the patients had biopsy or radiologically determined diagnosis of localized primary renal cancer and were considered poor surgical candidates. They were divided into four treatment groups (24, 32, 40, and 48 Gy). None of the patients had prior pelvic or abdominal radiation.

The tumor response rate was 94% across all treatment groups (all four patients in the 24 Gy group, all six

Key Points ■ Acute toxicity was limited to

Grade 1 fatigue in patients in the highest-dose treatment group.

■ The tumor response rate was

94% across all four treatment groups.

■ The treatment may provide

urologists with a another non-invasive option.

in the 32 Gy group, two of three in the 40 Gy group, and all five in the 48 Gy group). The investigators defined tumor response rate as stable or reduced tumor volume on posttreatment imaging.

“The trial is ongoing and has been expanded to treat 12 additional patients in groups of four at 48, 54, and 20 Gy in three fractions, and we anticipate improved pathologic response rates at these doses to be higher. A multi-center trial would then be needed to confirm the findings,” Dr. Ellis said. ■

Mesh Sling Salvage Surgery Results Mixed

BY ROSEMARY FREI, MSc BEIJING—Even if salvage operations ease complications from unsuccessful mesh sling surgery, patients often are in worse condition than before their original surgery, according to a urologist.

Jerry Blaivas, MD, of the Weill Cornell Medical Center in New York, who reviewed 47 cases in which he performed corrective surgery after at least one prior surgical attempt to correct mesh sling complications. The cases were from 1998 to 2011. The majority of the operations were successful, Dr. Blaivas noted, but the outcomes were frequently suboptimal, even in cases of success and with careful technique such as removing as much of the mesh as possible and repairing the anatomic defect.

“The ‘successes’ were only relative for many patients—that is, they were better than were before their salvage surgery, but most were much worse than before their original sling surgery,” Dr. Blaivas

told Renal & Urology News. “It was a shortcoming of our study to not ask the patients how their final status compared to how they were originally.”

Dr. Blaivas presented the case series at the International Continence Society’s 2012 annual meeting to highlight the difficulties urologists can expect when

Even if operations are successful, outcomes often are suboptimal. performing such salvage operations.

The women’s mean age was 60 years (range 35-83 years) and the average time from sling surgery to diagnosis of a complication was about two years (range one month-eight years). They had a mean of 1.9 prior surgeries to correct the sling complication. In 76.5% of cases the original sling was

an Amid type 1 (monofilament and macroporous) and 87% were placed in the retropubic position.

The women presented to him with conditions ranging from urethra-vaginal fistulas and erosions into the bladder or urethra to overactive bladder, stress incontinence, pelvic pain/dysuria and vaginal extrusion. He proceeded with sling excision with or without urethrolysis in 16 cases, sling excision with urethral reconstruction with or without autologous fascial sling and Martius flap in 14, sling incision in 10, and uretero-neocystotomy or cystotomy with or without partial cystectomy in the remaining seven cases.

Outcomes The mean follow-up time after salvage surgery was 3.3 years. Thirty-four of the salvage surgeries (72.4%) were a success. Four were outright failures.

The remaining patients had a successful second operation: three had augmentation cystoplasty, one had an autologous

sling, and one had a continent urinary diversion with cystectomy.

Even in “successful” post-salvage surgery, however, many women retained their presenting symptoms. For example, both women presenting with ureteral injury still had their presenting pain symptoms at follow-up; in fact, only 50% of patients with pain were improved after surgery. A successful outcome, however, was achieved in 93% of those with a pre-operative fistula, 91% of those with bladder or urethral erosion, 100% of those with voiding dysfunction, and 86%% presenting with discharge or hematuria.

“Nevertheless, the failure rate is still too high,” Dr. Blaivas concluded.

Besides striving to remove as much of the mesh as possible and repairing the anatomic defect, he advised meeting attendees to use biologic tissue rather than another synthetic if another sling is needed, and place a Martius flap between the reconstructed urethra and the new sling. ■

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JANUARY 2013

Renal & Urology News 15

Acidosis in Renal Tx Recipients Linked to Diet DIET MAY contribute to metabolic acidosis in renal transplant recipients (RTRs), according to investigators.

In a study of 707 RTRs, Else van den Berg, MD, of University Medical Center Groningen in Groningen, the Netherlands, and colleagues found that patients with high intake of animal protein, such as from meat, fish, and fish, and low intake of fruits and vegetables had significantly lower serum bicarbonate and serum pH. Dr. van den Berg and her colleagues explained that many RTRs have metabolic acidosis, which may adversely impact cardiometabolic processes, such as blood pressure (BP) and insulin resistance, and interfere with the proper functioning of multiple tissues.

The kidney is important in maintaining acid-base homeostasis because it excretes excess acids taken in with diet, the researchers explained. In RTRs, however, the capacity to excrete acid

ally because it provides important information on acid-base status relatively easily, they noted. “If acidosis is confirmed, attention should be paid not only to known risk factors such as graft function but also to dietary habits,” they stated.

On the basis of their results, the investigators reported, daily enrichment

of the diet with 100 grams of vegetables and 100 grams of fruits and elimination of 50 grams of meat and 20 grams of cheese would decrease NAE by 15 mEq/day and serum bicarbonate levels would rise by about 0.5 mmol/L. Study strengths included a large sample size and the use of 24-hour urine

samples, which allowed direct measurement of NAE as a marker of metabolic acid load as well as estimation of dietary acid load based on dietary recall, the researchers noted. Study limitations included its observational and crosssection design, which does not allow for proving causality. ■

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More fruits and vegetables, less animal protein recommended. is decreased because of impaired renal function, they noted.

“Modification of the diet by increasing fruit and vegetable intake and decreasing intake of animal protein might improve acid-base balances in RTRs,” the authors concluded in an online report in the Clinical Journal of the American Society of Nephrology.

The researchers assessed metabolic acid load by measuring 24-hour urinary net acid excretion (NAE). They defined acidosis as a serum bicarbonate level below 24 mmol/L. Overall, acidosis was present in 31% of subjects.

After adjusting for age, gender, body surface area, medication use, estimated glomerular filtration rate, time since transplantation, and smoking behavior, NAE was inversely associated with serum bicarbonate and serum pH. NAE was positively associated with acidosis, but was not associated with insulin resistance and high BP. The researchers observed that their findings, if confirmed by prospective and interventional studies, might have implications for clinical practice.

Acidosis is highly prevalent among RTRs, they noted, so venous blood gas analysis should be performed occasion-

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© 2012 National Kidney Foundation, Inc. All rights reserved. 02-77-5053_KBC

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Renal Nutrition Update A

ge and physical activity have profound effects on the accrual and retention of lean body tissues, but a range of nutritional factors can influence this process. One factor that appears to be a significant contributor is the acidotic and alkaline effects of foods.

It has been well documented that renal populations with acidosis suffer increased catabolism of muscle stores, and this acidosis can be influenced by a diet that contains a higher potential renal acid load (PRAL). The PRAL is a calculation that takes into account the intake of protein, phosphorus, potassium, calcium, and magnesium and estimates the mEq acid load that the body incurs. Protein increases the PRAL primarily through the acidogenic effect induced by the metabolism of sulfurcontaining amino acids. Phosphorus also contributes to an increased PRAL. The potassium, calcium, and magnesium cations are often bound to alkalineinducing anions such as citrate and bicarbonate, which decrease the PRAL. Fruits and vegetables are the richest sources of these cations, whereas animal products and cereals contribute to the acidogenic factors.

position. PRAL was estimated based on the results of the food frequency questionnaire. The population ranged in age from 18-79 years and 50% of the subjects were older than 50. The groups were stratified into PRAL quartiles.

As expected, higher protein intakes correlated with increased PRAL and increased potassium and magnesium intakes correlated with a lower PRAL. Meat, fish, and cereals were significantly associated with an increased PRAL, while fruits and vegetables were associated with a reduced PRAL. When analyzing potassium specifically, the primary food contributions included fruits and vegetables, dairy products, and potatoes.

In addition, fat free mass (FFM) was significantly greater in those consuming a lower PRAL after adjusting for age, physical activity, smoking, fat mass, and energy intake to estimated energy expenditure ratio. This association continued after adjusting for protein intake as a percentage of total calories consumed. Similar results were found for FFM% and fat free mass index (FFMI). This translated into a 1.3% and 1.9% difference in FFM% and FFMI, respectively, when comparing

Protein increases the potential renal acid load mainly through the acidogenic effect induced by the metabolism of sulfur-containing amino acids.

A recent study by Welch AA et al reviewed data from 2,689 female twins from the UK Adults Twins Registry (Osteoporos Int 2012; published online ahead of print), including information obtained via food frequency questionnaires, physical activity levels, smoking status, and dual-energy X-ray absorptiometry scans analyzing body com-

On The Web

the lowest PRAL quartile to the highest.

Percentage protein intake was negatively associated with FFM%. Notably, the average protein intake of the cohort was 1.26 g/kg/day compared with the recommended dietary allowance (RDA) recommendations of 0.8 g/kg/day. This intake may suggest that an elevated intake of protein without metabolic

© THINKSTOCK

Increased intake of fruits and vegetables lowers dietary acid load and promotes a more favorable body composition BY GRISSIM CLARK CONNERY, MS, RD, LD

Plant-based diets offer a number of health benefits beyond calorie density alone.

need may induce reduction in FFM through increased PRAL. It would appear from these data that, although stronger factors such as physical activity, smoking, and age exist, increased fruits and vegetables can not only promote a more favorable body composition, but also an overall greater content of lean body mass. The mean protein intake was noticeably higher than the RDA, but this intake is typical in Western nations. Protein is generally regarded as crucial in helping to increase lean body mass, but this factor may only be true until nitrogen requirements have been met. The study may suggest that once general nitrogen needs have been met, endogenous acid production begins to outweigh the benefit unless it can be neutralized with increased fruits and vegetables.

A team of investigators recently used data from 145 participants in the DONALD Study to analyze associations between PRAL and non-alcoholic fatty liver disease (J Nutr 2012;142:313319). The DONALD Study is a prospective cohort study that has been gathering dietary and other data from patients beginning in infancy starting in

1985. Among the female subjects, PRAL was significantly associated with alanine-aminotransferase (ALT), hepatic steatosis index (HSI), and fatty liver index (FLI) in multivariate regression models. Subjects with an adolescent PRAL in the highest tertile had 3.5, 4.4, and 4.5 higher values of ALT, HSI, and FLI, respectively, as adults compared with those who had the lowest PRAL. These same associations were not found in men.

The results of these studies indicate that excessive endogenous acid production and subsequent metabolic effects may be related to negative effects on liver health and fat free mass. In each study, the correlations were still found to be significant even when adjusting for BMI, waist circumference, energy intake, and other factors that would suggest general excessive energy intake was to blame. These results further promote the concept that plant-based diets offer a multitude of health benefits beyond caloric density alone. ■ 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.

18 Renal & Urology News

JANUARY 2013

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Penises Shorter After Prostate Cancer Surgery PATIENTS WHO undergo radical prostatectomy (RP) for localized prostate cancer can expect to have penises nearly 1 cm shorter than before surgery, but the original length is completely restored by 48 months postoperatively, according to researchers. Eloisio Alexsandro da Silva,

MD, and colleagues at Pedro Emesto Memorial Hospital in Rio de Janeiro, Brazil, prospectively evaluated penile length of 105 men after open RP. Stretched-penis measurements were obtained preoperatively and at 3, 6, 12, 24, 36, 48, and 60 months after RP. To measure penile length, the

investigators used the stretched length of the flaccid penis, from the pubopenile skin angle to the end of the glans after the prepubic fat was depressed under maximum manual traction.

The mean stretched penile length three months post-operatively decreased significantly by an average of 1 cm

from baseline, the researchers reported in Urology (2012;80:1293-1297).

This difference persisted until 24 months. At 36 months, the length differed by 0.6 cm. At 48 and 60 months, the mean differences in penile length before and after surgery were not significant. â&#x2013;

(continued) Table 1. Adverse Reactions in the Randomized Trial XTANDI N = 800 Grade 1-4 Grade 3-4 (%) (%)

XTANDIÂŽ (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary: please see the package insert for full prescribing information.

------------------------------ INDICATIONS AND USAGE ----------------------------XTANDI is indicated for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel.

--------------------------------- CONTRAINDICATIONS ------------------------------Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss >VHH 8VH LQ 6SHFLÂżF 3RSXODWLRQV@.

-------------------------- WARNINGS AND PRECAUTIONS ------------------------Seizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures.

The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

--------------------------------- ADVERSE REACTIONS ------------------------------Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG in practice.

In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo.

All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4.

7KH PRVW FRPPRQ DGYHUVH GUXJ UHDFWLRQV Â&#x2022; UHSRUWHG LQ SDWLHQWV UHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO HGHPD PXVFXORVNHOHWDO SDLQ KHDGDFKH upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse UHDFWLRQV ZHUH UHSRUWHG DPRQJ RI ;7$1', WUHDWHG SDWLHQWV DQG RI placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the UDQGRPL]HG FOLQLFDO WULDO WKDW RFFXUUHG DW D Â&#x2022; DEVROXWH LQFUHDVH LQ IUHTXHQF\ LQ the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in the Randomized Trial XTANDI Placebo N = 800 N = 399 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 (%) (%) (%) (%) General Disorders Asthenic Conditionsa

9.0 44.4 9.3 Peripheral Edema

1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4

24.3 4.0 Arthralgia

17.3 1.8 Musculoskeletal Pain

1.3

0.3 Muscular Weakness 9.8

6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

Placebo N = 399 Grade 1-4 Grade 3-4 (%) (%)

Gastrointestinal Disorders Diarrhea 21.8 1.1

0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9

0.0

Dizzinessb Spinal Cord 7.4 6.6

3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0

0.0 4.3 0.3 1.8 0.0 Mental Impairment Disordersc Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations 10.9 0.0

0.3 Upper Respiratory Tract Infectiond Lower Respiratory

2.4 4.8 1.3 Tract And Lung e Infection Psychiatric Disorders Insomnia 8.8 0.0 6.0

Anxiety

0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8

1.0 Pollakiuria 4.8 0.0

0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin

0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a Includes asthenia and fatigue. b Includes dizziness and vertigo. c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities ,Q WKH UDQGRPL]HG FOLQLFDO WULDO *UDGH QHXWURSHQLD RFFXUUHG LQ RI patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both DUPV RI SDWLHQWV RQ ;7$1', DQG RQ SODFHER H[SHULHQFHG *UDGH thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on ;7$1', *UDGH DQG RI SDWLHQWV RQ SODFHER *UDGH

Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo.

Infections In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms.

Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.

Hallucinations In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioidcontaining medications at the time of the event. Hallucinations were visual, WDFWLOH RU XQGHÂżQHG

www.renalandurologynews.com

JANUARY 2013

Renal & Urology News 19

Infection-Related Admissions Common Post-Tx

BY JOHN SCHIESZER SAN DIEGOâ&#x20AC;&#x201D;Most renal transplant recipients require at least one hospitalization after transplantation surgery, and infections are among the most common reasons, new findings suggest.

Most of these hospitalizations occur within six months after transplantation,

indicating the need for close follow-up during this time period, said lead investigator Elena Beam, MD, an internal medicine resident at Mayo Clinic in Rochester, Minn. â&#x20AC;&#x153;We found in the first year after transplantation that a majority of patients ended up getting hospitalized and the usual stay was three days,â&#x20AC;?

----------------------------------DRUG INTERACTIONS ------------------------------Drugs that Inhibit or Induce CYP2C8 &R DGPLQLVWUDWLRQ RI D VWURQJ &<3 & LQKLELWRU JHPÂżEUR]LO LQFUHDVHG the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers.

Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI >VHH 'RVDJH DQG $GPLQLVWUDWLRQ

DQG &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended >VHH &OLQLFDO 3KDUPDFRORJ\@ Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers >VHH &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., ERVHQWDQ HIDYLUHQ] HWUDYLULQH PRGDÂżQLO QDIFLOOLQ DQG 6W -RKQÂśV :RUW PD\ DOVR reduce the plasma exposure of XTANDI and should be avoided if possible >VHH &OLQLFDO 3KDUPDFRORJ\ @.

Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring >VHH &OLQLFDO 3KDUPDFRORJ\ @.

-------------------------- USE IN SPECIFIC POPULATIONS -----------------------Pregnancy- Pregnancy Category X >VHH &RQWUDLQGLFDWLRQV@ XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established.

Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent ZHUH DQG RYHU ZKLOH SHUFHQW ZHUH DQG RYHU 1R RYHUDOO GLIIHUHQFHV in safety or effectiveness were observed between these patients and younger SDWLHQWV 2WKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂżHG GLIIHUHQFHV LQ responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy YROXQWHHUV QR VLJQLÂżFDQW GLIIHUHQFH LQ HQ]DOXWDPLGH FOHDUDQFH ZDV REVHUYHG LQ SDWLHQWV ZLWK SUH H[LVWLQJ PLOG WR PRGHUDWH UHQDO LPSDLUPHQW P/ PLQ Â&#x201D; FUHDWLQLQH FOHDUDQFH >&U&/@ Â&#x201D; P/ PLQ FRPSDUHG WR SDWLHQWV DQG YROXQWHHUV ZLWK EDVHOLQH QRUPDO UHQDO IXQFWLRQ &U&/ Â&#x2022; P/ PLQ 1R LQLWLDO GRVDJH adjustment is necessary for patients with mild to moderate renal impairment.

Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@.

Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@

Dr. Beam said. â&#x20AC;&#x153;This is something that increases cost of care.â&#x20AC;?

Dr. Beam presented study findings at IDWeek, a joint meeting of the Infectious Diseases Society of America and three other organizations.

The study showed that infections were the cause of 60% of hospitaliza-

-------------------------------------- OVERDOSAGE -------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general VXSSRUWLYH PHDVXUHV WDNLQJ LQWR FRQVLGHUDWLRQ WKH KDOI OLIH RI GD\V ,Q D GRVH escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose.

Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the LQ YLWUR mouse lymphoma thymidine kinase (Tk) gene mutation assay or the LQ YLYR mouse micronucleus assay. %DVHG RQ QRQFOLQLFDO ÂżQGLQJV LQ UHSHDW GRVH WR[LFRORJ\ VWXGLHV ZKLFK ZHUH consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy RI WKH SURVWDWH DQG VHPLQDO YHVLFOHV ZDV REVHUYHG DW Â&#x2022; PJ NJ GD\ HTXDO to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed DW Â&#x2022; PJ NJ GD\ WLPHV WKH KXPDQ H[SRVXUH EDVHG RQ $8&

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). Â&#x2021; ,QVWUXFW SDWLHQWV WR WDNH WKHLU GRVH DW WKH VDPH WLPH HDFK GD\ RQFH GDLO\

XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. Â&#x2021; ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV treatment during the course of treatment with XTANDI. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', KDV EHHQ DVVRFLDWHG ZLWK DQ LQFUHDVHG risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW paresthesia, hypoesthesia, and falls. Â&#x2021; ,QIRUP SDWLHQWV WKDW WKH\ VKRXOG QRW LQWHUUXSW PRGLI\ WKH GRVH RU VWRS ;7$1', ZLWKRXW ÂżUVW FRQVXOWLQJ WKHLU SK\VLFLDQ ,QIRUP SDWLHQWV WKDW if they miss a dose, then they should take it as soon as they remember.

If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day. Â&#x2021; $SSULVH SDWLHQWV RI WKH FRPPRQ VLGH HIIHFWV DVVRFLDWHG ZLWK ;7$1', DVWKHQLD IDWLJXH EDFN SDLQ GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ EH KDUPIXO WR D GHYHORSLQJ IHWXV Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 0HGLYDWLRQ ,QF 6DQ )UDQFLVFR &$ Issued: August 2012 $ (1= %56 Rx Only Š 2012 Astellas Pharma US, Inc. XTANDIŽ is a registered trademark of Astellas Pharma Inc.

ONCOLOGY

tions within one year of surgery. Renal complications were a factor in 48% of hospitalizations and post-surgical wound complications accounted for 19%.

Risk factors The presence of diabetes mellitus before transplantation and allograft rejection were the major risk factors associated with hospitalization secondary to an infectious cause.

Dr. Beam and her colleagues analyzed data from 285 kidney transplant recipients with a median age of 57 years. They collected data on each hospitalization due to infectious complications. They looked at indications for hospitalizations, duration of stay, and time from transplantation. The study cohort was 59% male and 84% of patients received the kidney allograft from living donors.

43% hospitalized at one year At one month after transplantation, 22% of patients were hospitalized; 43% were hospitalized at one year. During the entire follow up period, 51% of the cohort experienced at least one hospitalization. Ninety-six hospitalizations were related to infections, which accounted for 31% of all indications for hospitalization. Urinary tract and skin and soft tissue infections were the most common indications for infectionrelated hospitalization.

A pre-transplant diagnosis of diabetes mellitus and diabetic nephropathy as the underlying cause for renal transplant were associated with a significant twofold increased the risk for infection-related hospitalization. Urologic abnormalities increased the risk for hospitalization by a significant 86%.

Allograft rejection increased the risk for hospitalization twofold.

The study could lead to new ways of decreasing hospitalizations among renal transplant recipients and the morbidity and mortality associated with each hospitalization, Dr. Beam said. â&#x20AC;&#x153;By knowing the patients who are at highest risk, we can keep a closer eye on them and we can also counsel patients that they need to look out for infections and what the signs of infection may be,â&#x20AC;? Dr. Beam told Renal & Urology News. â&#x20AC;&#x153;In addition, clinicians can use this information to identify the patients at highest risk of hospitalization following kidney transplantation and institute close outpatient follow-up and higher vigilance for complications in this population.â&#x20AC;? â&#x2013;

20 Renal & Urology News

■ Kidney Week 2012

JANUARY 2013

www.renalandurologynews.com

Reports from the American Society of Nephrology’s Kidney Week 2012 conference, San Diego

Epoetin Alfa Use Down, IV Iron Use Up Trends follow debut of “bundling,” drug label changes

BY JODY A. CHARNOW CLINICIANS ARE prescribing less epoetin alfa and more intravenous iron for anemic hemodialysis patients, according to study findings. The trends follow the introduction of Medicare’s prospective payment system (PPS) for dialysis services (“bundling”) and changes to drug labels for erythropoiesis-stimulating agents (ESAs).

In addition, data point to a trend of declining hemoglobin (Hb) levels in dialysis patients.

Under the PPS, which debuted January 1, 2011, Medicare reimburses dialysis providers with a single payment for dialysis-related services and medications that used to be paid for on a free-for-service basis.

In one study, T. Christopher Bond, PhD, and colleagues at DaVita Clinical Research in Minneapolis, Minn., found that from January 1, 2009 to April 30, 2012, the proportion of patients receiving epoetin alfa (EPO) decreased from

95% to 85%, which, according to the researchers, suggests an increase in dose holds.

Mean EPO doses declined by more than 30,000 units per month, they reported. The average dose of intravenous (IV) iron decreased over the study period from 291 to 241 mg per month, but the proportion of patients receiving any IV iron increased from 10% to 14% and the frequency of iron dosing increased from 2.54 doses per patientmonth in April 2009 to 2.95 doses per patient-month in April 2012. During the three years of the study, mean Hb levels decreased from 11.6 to 10.8 g/dL. The investigators noted that the effects of the dosing trends are unknown.

Separately, a study led by Richard A. Hirth, PhD, of the University of Michigan School of Public Health in Ann Arbor, demonstrated a substantial decline in ESA use in the months immediately before and after the debut of the PPS, whereas the use of iron prepara-

Researchers: Consider Dual Kidney Transplants DUAL KIDNEY transplants (DKT), in which transplant patients receive both of a donor’s kidneys, have outcomes similar to those of recipients of expanded criteria donor (ECD) kidneys, researchers reported.

In a poster presentation, investigators at Columbia University Medical Center in New York observed that DKT is not a consideration in the current allocation algorithm in the United States.

Many kidneys used for DKT otherwise would have been discarded because of their high-risk characteristics, they noted. These characteristics include a donor age older than 60 years, a terminal creatinine level higher than 2.5 mg/ dL, an estimated glomerular filtration rate below 65 mL/min/1.73 m2, donor diabetes or hypertension, and moderate glomerulosclerosis.

Using data from the United Network for Organ Sharing database, Sowmini Medavaram, MD, and colleagues identified 1,601 DKT patients and 23,457

ECD transplant patients. Donors of the dual kidney transplant patients were aged 50 years and older. The DKT group had a significantly greater proportion of diabetics than the ECD group (16.8% vs. 11.7%).

The DKT and ECD transplant patients had an acute rejection rate of 14.8% and 13.4%, respectively, and a chronic rejection rate of 35% and 38.4%, respectively. Graft thrombosis occurred in 6.5% and 5.1% of patients. Death with a functioning kidney occurred in 6.7% and 4.3%, respectively. The 90-day post-transplant mortality rate was 3.9% and 3.1%. The five-year death-censored graft survival rate was 51% in both groups. None of the outcome differences between the groups was statistically significant.

Dr. Medavaram’s group concluded that DKT needs to be optimized by offering them as part of an ECD algorithm and should be considered prior to discarding available kidneys. ■

EPO and Iron Use Trends The proportion of patients receiving epoetin alfa decreased from January 1, 2009 to April 30, 2012, whereas the proportion of patients receiving any IV iron increased.

100

■ January 1, 2009 ■ April 30, 2012

80 60 40 20 0

95%

85%

10% 14% IV iron dose

EPO

Source: Bond TC et al. Changing hemoglobin targets: Effects on epoetin alfa, intravenous iron, and iron storage measures from 2009-2012. Data presented at Kidney Week 2012, San Diego. Abstract TH-PO822.

tions, which frequently are substituted for ESAs, increased.

Dr. Hirth and his colleagues used Medicare claims data to assess monthly trends during January 2010 to June 2011 for key injectable drugs that were previously bill separately. For 2010, the investigators assessed actual spending; for 2011, they projected spending based on reported utilization.

For ESAs and vitamin D analogues, the biggest changes occurred during the last quarter of 2010, with less expensive vitamin D analogues substituted for more expensive versions, the researchers reported. Drug spending fell by $14 per session, nearly three times the mandated reduction in the base payment rate of $5, the researchers found. ■

ONLINE ONLY Visit renalandurologynews.com/kw12podcasts to watch videos of researchers discussing the findings of the following studies presented at Kidney Week 2012: Study Highlights Need for Earlier AKI Diagnosis Interview with Brittany E. Yee, a medical student at the University of California-San Diego Carbon Drug Found Not to Slow CKD Advance Interview with Gerald Schulman, MD, Professor of Medicine at Vanderbilt University in Nashville, Tenn.

Hematocrit Decreases as eGFR Declines Interview with Theresa K. Chen, MD, MHS, of Johns Hopkins University in Baltimore Side Effects Cited for Many Binder Discontinuations Interview with Thomas Alfieri, PhD, of DaVita, Inc., in Denver PPI Use with MMF May Increase Acute Rejection Risk Interview with Pankaj Jawa, MD, transplant nephrology fellow at Einstein Medical Center in Philadelphia

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JANUARY 2013

Renal & Urology News 21

Kidney Week 2012 ■

Most Living Donors Would Do It Again, Study Finds

BY JOHN SCHIESZER A GERMAN STUDY found that living kidney donation is safe and most donors report that they would donate again. Still, a small percentage of living kidney donors may experience physical or mental discomforts following donation.

Researchers studied 128 living kidney donors and found that fewer than 10% of them reported impaired quality of life directly related to kidney donation.

“Currently in Germany there is a discussion about chronic fatigue syndrome after living kidney donation,” said investigator Ralf Dikow, MD, a nephrologist at the Renal Transplant Center of University Hospital of Heidelberg.

“There are a few patients who are very politically active going about saying that nephrologists do a bad job and we are harming people. So we said ‘okay, let’s have a look at our patients.’”

Only 10% reported problems, which included sleepiness and back pain.

ly about sleepiness, back pain, lack of concentration and also abdominal pain and gastrointestinal problems.”

In a separate study presented at the

conference, researchers led by Shiv Kapoor, PhD, of the University of Pennsylvania in Philadelphia, found that nephrectomies performed on living

donors are associated with significant changes in endothelial function, bone metabolism, and cytokines that could influence future health outcomes. ■

WE’RE

CHANGING THE WAY

PROSTATE CANCER PATIENTS ARE TREATED EVEN WHEN THEY’RE NOT BEING TREATED When it comes to treating prostate cancer, we do not believe in a one-size-fits-all approach. That’s why doctors at UPMC are experts in both traditional methods of urologic surgery and in cutting-edge robotic surgery. But our doctors also recognize when the best management is not an operation, but careful

Living donors are involved in 28% of renal transplants in Germany and 40% of renal transplants in Dr. Dikow’s institution.

In a prospective, observational study, Dr. Dikow and his colleagues used standardized questionnaires (ZERSSEN Symptom Score, SF-12) and additional questions specifically related to living donation. Of the 128 kidney donors, 46 were male. The mean age was 52.7 years and the mean time after transplantation was 3.7 years.

None of the donors had serious posttransplant complications and all had stable renal function, according to Dr. Dikow. The vast majority reported that they were satisfied with their present health; only 18 donors reported they were dissatisfied. Thirteen donors reported a quality of life that was worse than before donation, and 13 reported that their discomforts were caused by kidney donation.

“We found that 98% [of donors] said that they would donate again,” Dr. Dikow said. “Only 10% reported problems and the problems were main-

observation. We believe it is important to be well versed in all options to ensure patients receive the right treatment at the right time. Because our job is not only to save lives, but to preserve the quality of life of every patient we treat. Learn more at UPMCPhysicianResources.com/ProstateCancer.

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

22 Renal & Urology News

JANUARY 2013

www.renalandurologynews.com

Men’s Health Update Please visit us at www.renalandurologynews.com for the latest news updates from the fields of urology and nephrology

Gum Disease, Erectile Dysfunction Linked Men with erectile dysfunction (ED) are more likely to have chronic periodontitis than those without ED, researchers in Turkey reported. The study, by Faith Og˘ uz, MD, of Inonu University in Malatya, and colleagues, enrolled 162 men aged 30-40 years. Of these, 80 had ED and 82 did not (controls). Results showed that 42 patients (53%) in the ED group had severe chronic periodontitis compared with 19 (23%) in the control group, according to findings published online in The Journal of Sexual Medicine. After adjusting for potential confounders, the men with ED were 3.29 times more likely than controls to have chronic periodontitis.

Sildenafil’s Effect Not Enhanced with Testosterone Adding testosterone therapy to sildenafil is not more effective in treating erectile dysfunction (ED) than sildenafil alone, data show. In a double-blind study that included 140 men prescribed sildenafil for ED, Matthew Spitzer, MD, of Boston University, and collaborators randomly assigned 70 subjects to 14 weeks of daily transdermal testosterone gel and 70 to receive placebo. At baseline, the two study arms had similar scores on the erectile function domain (EFD) of the International Index of Erectile Function. Sildenafil alone was associated with a substantial increase in EFD score, but change in EFD score after randomization

Male Sex Hormone Changes May Increase Stroke Risk C

hanges in sex hormone levels in men may adversely affect hematocrit.

In a study of 1,273 men, Adrian S. Dobs, MD, of the Johns Hopkins University School of Medicine in Baltimore, and colleagues found that men with low free testosterone levels had a significantly lower hematocrit than those with normal free testosterone levels. The study, which was published in the Journal of Andrology (2012;33:1332-1341), found no association between total testosterone and hematocrit. Among men aged 20 and older, both low and high levels of sex hormone-binding globulin (SHBG) were associated with lower hematocrit. Among men aged 50 and older, only high SHBG levels were associated with lower hematocrit. In addition, high total and free estradiol levels were associated with higher hematocrit.

Dr. Dobs’ team pointed out that both low and high hematocrit levels are associated with increased morbidity and mortality, mediated via anemia and thromboembolic effects, respectively. © CMSP

Short Takes

did not differ between the groups, the investigators reported in Annals of Internal Medicine (2012;157:681-691).

Data Cast Doubt on Resveratrol Benefits In a small study, high-dose resveratrol supplementation had no effect on insulin sensitivity and certain other metabolic parameters in obese men, despite promising findings from some animal studies, researchers reported online in Diabetes. Morten Poulsen, MD, of Aarhus University Hospital in Denmark, and colleagues randomized 24 obese but otherwise healthy men to receive four weeks of resveratrol—a potent antioxidant found in the skins of grapes and in red wine—or placebo. Insulin sensitivity deteriorated insignificantly in both groups. Endogenous glucose production and the turnover and oxidation rates of glucose remained unchanged. Resveratrol also had no effect on inflammatory and metabolic biomarkers, blood pressure, lipid oxidation rates, resting energy expenditure, and ectopic or visceral fat content.

PCa Aggressiveness Linked to Dietary Fiber Dietary fiber intake is inversely associated with prostate cancer (PCa) aggressiveness in both African-American and European-American men, a study found.

Longer Rx Does Not Reduce Male UTI Recurrence Risk L

onger-duration antibiotic treatment for urinary tract infections (UTIs) in men does not decrease their risk of early or late recurrence, data show.

Dimitri M. Drekonja, MD, MS, of the Minneapolis Veterans Affairs Health Care System in Minneapolis, and colleagues identified 39,149 UTI episodes in 33,336 unique patients among 4,854,765 male outpatients in the Veterans Affairs system.

Longer-duration treatment—defined as more than seven days of antibiotics—was not associated with a reduction in early or late recurrence compared with shorter-duration treatment (seven days or fewer), according to findings published online ahead of print in Archives of Internal Medicine. Longer-duration treatment was associated, however, with a significantly increased rate of late recurrence (10.8% vs. 8.4%), which in multivariate analysis translated into a 20% increased risk of late recurrence.

The researchers defined early and late recurrence as UTIs that returned in 30 days or less and more than 30 days, respectively.

The study, by Fred Tabung, MD, of the University of South Carolina in Columbia, and colleagues included 1,923 PCa patients—930 African Americans and 993

compared with men in the lowest tertile of total fiber intake, those in the second and third tertiles had a 30% and 39% decreased likelihood of having high aggressive PCa, the investigators reported online in Prostate Cancer. When stratified by race, the study showed that, among European Americans, patients in the third tertile of total fiber intake had a 56% decreased likelihood of having high aggressive PCa compared with subjects in the lowest tertile. Among African Americans, men in the second tertile had a 43% decreased likelihood of having high aggressive PCa.

249,136,000 The number of physician office visits in the United States by men aged 45 years and older in 2009.

Source: National Ambulatory Medical Care Survey: 2009

© THINKSTOCK

intermediate, or low based on Gleason grade, PSA level, and clinical stage. Overall,

MEDISTAT

European Americans. The aggressiveness of their cancers were classified as high,

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JANUARY 2013

Renal & Urology News 23

Reports from the American Society of Nephrology’s Kidney Week 2012 conference, San Diego

Kidney Week 2012 ■

Study: IV Iron Use Less with Once-Monthly ESA ONCE-MONTHLY injections of peginesatide are as effective as one to three injections per week of epoetin in maintaining hemoglobin levels in anemic hemodialysis patients, but peginesatide treatment is associated with significantly decreased use of intravenous iron, according to post-hoc analyses of data from two large trials comparing the erythropoiesis-stimulating agents.

The analyses, by Robert Provenzano, MD, of St. John Hospital & Medical Center in Detroit, and collaborators, examined pooled data from U.S. patients enrolled in the EMERALD 1 and 2 studies and included two analysis populations: a full analysis group (randomized patients who received at least one study dose); and completers (those who had at least 60 weeks of drug exposure and serum ferritin and

recipients (148.8 vs. 168.5 mg/month for the full analysis group and 152.9 vs. 171.8 mg/month for completers, respectively). In both study popula-

tions, the peginesatide and epoetin arms had similar serum ferritin levels, but peginesatide recipients had higher TSAT levels.

The FDA last March approved peginesatide, which is marketed under the name Omontys, for the treatment of anemia in adult dialysis patients. ■

INHIBIT ANDROGEN PRODUCTION

Analyses show reduced iron need with peginesatide versus epoetin. transferrin saturation [TSAT] measured at the same visit). Serum ferritin and TSAT were measured every 12 weeks for up to 60 weeks. The full analysis group included 853 peginesatide recipients and 436 epoetin recipients. The completers included 604 peginesatide recipients and 336 epoetin recipients.

The peginesatide- and epoetin-treated patients had mean Hb levels of 11.3 and 11.3 g/dL, respectively, at baseline.

In addition 52% of the peginesatide arm and 55% of the epoetin group were receiving IV iron; median IV iron use was 33.7 and 36.2 mg/month, respectively.

Among the completers, the peginesatide and epoetin groups had mean Hb levels of 11.3 and 11.3 g/dL, respectively, at baseline; 51% and 56% of these groups, respectively, were receiving IV iron, and their median IV iron use was 18.1 and 40.7 mg/month.

In both the full analysis group and completers, Hb levels at four-week intervals were similar among peginesatide and epoetin recipients, according to investigators. Study results showed that median IV iron use was significantly less in the peginesatide than epoetin

BLOCK THE ANDROGEN RECEPTOR

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. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN ®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 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. 2012 10/12 K08Z12191BR1

24 Renal & Urology News

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UTI Reports to CDC May Be Misleading Discrepancies found in competing definitions of catheter-related urinary tract infections

BY JOHN SCHIESZER SAN DIEGO—What physicians report to the Centers for Disease Control and Prevention (CDC) about catheter-associated urinary tract infections (CAUTIs) may differ from they are treating, according to a new study.

In the United States, all hospitals are required to report CAUTIs using the CDC definition. A definition proposed

by Infectious Diseases Society of America (IDSA), however, may be more clinically relevant, according to the researchers.

“People in our hospital and in the ICU [intensive care unit] were not feeling that the numbers being reported were nearly as high as what was being treated,” said investigator Paul Pottinger, MD, Associate Professor of Infectious Diseases at the University of Washington School of Medicine in Seattle. “We report according to strict criteria by the CDC, but it is possible that the CDC definition of CAUTIs is too strict or not reflective of the clinical management that physicians are seeing in the ward. We wanted to look at real life experience and see what categories they would fall in.”

Dr. Pottinger, who presented the study findings at the meeting, said CAUTIs are

the most common hospital-acquired infection in the United States, but controversy exists over how to define these infections.

He and his colleagues examined the differences between the definitions in the same cohort of patients. Of 2,460 cultures ordered, only 163 (6.6%) met either the CDC or IDSA criteria for CAUTIs. Dr. Pottinger told Renal & Urology News that this finding was unexpected and suggests that clinicians may be ordering too many cultures.

The two definitions overlapped in only 46% of cases. The major sources of discordance were the CDC’s limitation to two or fewer cultures and the absence of such a limit in IDSA’s definition. If yeast is the only pathogen that can be cultured, then it is excluded under the IDSA’s definition. The IDSA definition resulted in 45% more cases of CAUTIs compared with CDC’s definition.

The study suggests that the IDSA definition may be perceived by physicians to be more clinically relevant than the CDC definition, Dr. Pottinger said. The CDC definition is used strictly as a reporting definition, thus what physicians treat may be significantly different from what is reported.

CAUTI Facts According to the Centers for Disease Control and Prevention’s “Guideline for Prevention of Catheter-Associated Urinary Tract Infections 2009”: • Mean pooled CAUTI rates ranged from 3.1-7.5 infections per 1,000 catheter-days, based on data from National Healthcare Safety Network acute care hospitals in 2006.

• Highest rates were in burn intensive care units (ICUs), followed by inpatient medical wards, and neurosurgical ICUs. • An estimated 17%-69% of CAUTIs may be preventable with recommended infection control measures.

“Why is what we track not what we treat?” Dr. Pottinger asked. “Each definition has its flaws and each definition has its strengths. We need to sit down and come to a consensus. There needs to be agreement on one definition for the sake of research purposes and for public reporting.”

For this study, a novel CAUTIs surveillance tool was developed. It collected electronic medical record data from February 2010 through July 2011, including demographics, diagnoses, catheterization history, body temperature,

urinalysis, and urine and blood cultures.

The tool was able to capture subjective symptoms found in notes via natural language processing.

The researchers identified 2,460 candidate cases among 1,519 patient admissions. In all of these cases, urine cultures were ordered while the patient was catheterized. The controls for this study were candidate cases with negative urine cultures. Patients meeting both the CDC’s and IDSA’s definitions of CAUTIs had a hospital and ICU length of stay and mortality rate comparable to controls. ■

NOACs Pose Risk in Patients with Renal Disease

BY ROSEMARY FREI, MSc TORONTO—Nephrologists should determine the estimated glomerular filtration rate (eGFR) at least twice a year for patients who have severely impaired renal function and who are prescribed one of the novel oral anticoagulants (NOACs) for a comorbid condition, a cardiologist advised.

Speaking at the Canadian Cardiovascular Congress, Jean Grégoire, MD, told listeners that NOACs are potentially dangerous in patients with renal failure because the medications are predominantly renally excreted and thus could accumulate and cause catastrophic bleeding.

Dr. Grégoire stressed the importance of this during a presentation of the results of a survey of 62 clinicians suggesting that some patients with an eGFR of below 30 mL/min/1.73 m2 are being prescribed NOACs. “We have to emphasize the need to follow patients on NOACs more than patients on other medications, in order

to avoid deleterious consequences,” said Dr. Grégoire, who was the principal investigator and practices at the Montreal Cardiology Institute. “We have to be sure that the kidney function is stable and that other medications are not introduced that can reduce the renal function further.”

The medications are excreted predominantly by the kidneys.

The FDA announced in December 2011 that its officials are evaluating reports of serious bleeding events in patients taking the NOAC dabigatran, some of whom had compromised renal function. The agency, however, has not yet followed the lead of Health Canada, which in March 2012 changed its recommendations to stipulate that

renal function should be assessed in all patients prior to being given dabigatran, and that the medication should not be given to those with a creatinine clearance below 30 mL/min.

Dr. Grégoire and his colleagues conducted the survey (the Physician Practice Assessment—Stroke Prevention & Atrial Fibrillation Evaluation) because they suspected many physicians are not aware of, or are not compliant with, these new recommendations.

Furthermore, many physicians rely on serum creatinine rather than eGFR to assess kidney function, despite eGFR being a better overall index of renal function, Dr. Grégoire noted.

The researchers administered the survey to 42 family physicians and 20 specialists including cardiologists, internists, and neurologists between May and August 2011. The survey questionnaire asked about their perceptions about their current management of atrial fibrillation and stroke risk. Each physician also answered questions after

completing visits with approximately 15 atrial fibrillation patients. In total, the investigators gathered data from 663 patient visits.

The patients’ mean age was 74 years and 52.9% were male. In all, 75.6% had hypertension, 54.4% had dyslipidemia, 37.3% had coronary artery disease, and 31.7% had diabetes. In addition, 53% had an eGFR of above 60; 41% of patients over age 80 years had an eGFR of 30-60, according to the investigators.

Older patients were less likely to be taking anticoagulant medication, with 18% of those aged 65 years or under taking no anticoagulants compared with 24% of patients aged 66-80 years and 44% of those 80 years of age or older.

Dr. Grégoires team reported.

Some patients with compromised renal function were taking anticoagulants. Fifty of those with an eGFR of 60 or lower were taking dabigatran and approximately twice as many were taking warfarin. ■

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Renal & Urology News 25

HoLEP An Option After Failed Prior BPH Surgery

BY JOHN SCHIESZER CHICAGO—Holmium laser enucleation of the prostate (HoLEP) surgery may be safe and effective at relieving persistent lower urinary tract symptoms after previous unsuccessful surgery for benign prostatic hyperplasia (BPH), according to a new study presented at the North Central Section of the American Urological Association’s annual meeting.

The study compared surgical and postsurgical outcomes among patients who had a previous unsuccessful surgery for enlarged prostate and a group with no previous surgery.

No difference in outcomes “Other than a clinically and statistically insignificant slower morcellation rate … and a mean urine flow rate for patients who had a previous surgery, the study found no difference in outcomes between the groups,” said senior study author Amy Krambeck, MD, Associate Professor of Urology at the Mayo Clinic, Rochester, Minn.

Dr. Krambeck and her colleagues compared perioperative and postoperative outcomes in patients who under underwent holmium laser enucleation of the prostate between 2009 and 2012.

In this retrospective review, patients were grouped according to their history of prior prostate surgery. One group included those with prior BPH surgery and the other group included those patients who had no previous BPH surgery. A total of 37 patients with prior BPH surgery (mean age 71 years) were matched to 36 individuals without prior surgery (mean age 69 years) based on preoperative characteristics.

The researchers observed no significant difference in operative or postoperative complications, but the morcellation rate appeared to be slower in the prior surgery group (4.1 vs. 5.0 g/min); however, this was not statistically significant. The study found no significant differences in length of catheterization between the prior surgery group and the group without prior surgery (1.3 vs. 1.1 days) and showed that all patients were urinating at last follow-up.

Findings not surprising “We were not surprised by the findings,” Dr. Krambeck told Renal & Urology News. “I personally think if we could get more centers to adopt this technique we could have better outcomes for our patients. Even though the patient has failed a prior BPH

surgery, the risk of bleeding, incontinence, or overall complications are not increased if they have a holmium laser enucleation surgery.”

The postoperative peak flow (23.4 vs.

26.9 mL/sec) and post void residual (51 vs. 50 mL) were not significantly different between groups. The average

flow was slightly slower in the group with prior surgery (12.7 vs. 15.9 mL/ sec); however, this was not statistically significant. Postoperative American Urology Association symptom scores were not significantly different (6.5 vs.

5.7). She and her colleagues concluded that this laser procedure is safe and

effective at relieving LUTS after failed previous BPH surgery.

“The holmium laser has been around since the late 1990s, but it is only used at a few institutions around the country,” Dr. Krambeck said. “I think part of the problem is that the learning curve is steep for this technique.” ■

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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■ FEATURE

Fabry Disease: The Nephrologist’s Role The complex disease requires regular follow up and assessment of the ongoing response to therapy BY DAVID G. WARNOCK, MD

A

Understanding Fabry disease Found in approximately 1 out of 117,000 people1, “classical” Fabry disease is an inherited disorder caused by the deficiency of an enzyme called alphagalactosidase A or alpha-GAL. The gene locus is on the X chromosome, so

Complications

IMAGE COURTESY OF GENZYME

s a nephrologist, I have treated several Fabry disease patients over the years.

Invariably, by the time I see these patients their situation is chronic, and they already have organ damage.

This is fairly common because many patients and clinicians don’t recognize the earlier and often less severe symptoms of Fabry disease. As a result, in many patients, symptoms progress until cardiac hypertrophy develops, and patients experience strokes and transient ischemic attacks, and/or kidney problems (proteinuria and decreased filtration).

When Fabry disease is not diagnosed and treated, complications such as arrhythmias, strokes, and gastrointestinal problems can occur, resulting in patients being referred to different medical specialists. The onset of nephropathy typically results in a referral to a nephrologist. But even at that stage, it can take several weeks or even months for some Fabry patients to receive a confirmed diagnosis. It is essential for nephrologists to be informed about the clinical presentation and pathophysiology of Fabry disease so they can better manage the ailment.

Figure 1. In Fabry disease, GL-3 builds up in renal capillary endothelial cells (see arrows).

Fabry disease is a sex-linked disorder.

Decreased alpha-GAL activity causes a buildup of a globotriacylceramide known as GL-3 in cells (Figure 1) throughout the body, which can affect the heart, kidneys, skin, brain and gastrointestinal system.

Symptoms of Fabry disease usually begin in childhood, especially in males, but early symptoms often lead to an inaccurate diagnosis of rheumatoid or juvenile arthritis, rheumatic fever, erythromelalgia, multiple sclerosis, lupus, neurosis, Raynaud’s syndrome, acute appendicitis, petechiae, or collagen vascular disease. To ensure that Fabry disease is accurately diagnosed, nephrologists and other clinicians should make note of key signs, including pain (typically in the hands and feet), clusters

of small, dark red spots on the skin, decreased ability to sweat, chronic fatigue, heat intolerance, depression, anxiety, corneal whirl (cloudiness of the front part of the eye), gastrointestinal problems, ringing in the ears, and hearing loss.

Genetic testing can confirm a diagnosis of Fabry disease and also determine whether a female who is asymptomatic has a mutation in the alpha-GAL gene.

Upon confirmation of Fabry through genetic testing, other members of a patient’s family can then readily be tested. Serum or whole blood alpha-GAL enzyme levels are easily measured but may be in the normal range in female patients who in fact have Fabry disease, emphasizing the importance of genetic testing and confirmation.

If Fabry disease is not diagnosed early, nephropathy can progress and patients can develop significant proteinuria and a progressive loss of kidney function leading to end-stage renal disease.1 The current experience is that the renal outcome is worse without early diagnosis and intervention.

Although genetic testing is mandatory for a confirmed diagnosis, routine clinical tests may fail to detect early changes in kidney function. In addition, physicians may also ignore “normal” serum creatinine levels or “minimal” proteinuria and fail to assess the severity of kidney involvement. In the hands of an experienced nephrologist, the renal biopsy can yield important information about the kidney status, even in patients who are already diagnosed with Fabry disease or in those who have minimal proteinuria or “normal” kidney function. Evidence of scarring (fibrosis and sclerosis) of the glomeruli and/or interstitial tissue and intracellular GL-3 deposits are important signs of serious kidney involvement.

In addition, my colleagues and I have discovered several new families with Fabry disease after the initial family member underwent a kidney biopsy for proteinuria and decreased filtration rate, and the pathology report revealed that Fabry disease was the cause of the nephropathy. Finally, it may be important to rule out the presence of another, more common kidney disease in patients with Fabry disease.

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In contrast to most forms of chronic kidney disease (CKD) that are associated with elevated blood pressure (BP), Fabry disease may well present with “normal” BP measurements. This can be problematic because many Fabry patients do not receive ACE inhibitors or angiotensin receptor blockers (ARBs) to control their proteinuria because their BP is “normal.”

Controlling proteinuria with ACE inhibitors or ARBs is important for patients with Fabry nephropathy, but can be difficult because many patients with Fabry-related nephropathy have relatively low-normal BP. Nephrologists and other clinicians should employ careful dose titration of ACE inhibitors and ARBs to a target of 500 mg/day to control proteinuria without adversely affecting BP. Beta blockers and diuretics are typically poorly tolerated in these patients and can complicate the use of ACE inhibitors or ARBs to control proteinuria.

As a multi-system disease, treatment regimens for Fabry should incorporate ACE inhibitors or ARBs to help stabilize kidney function. Cholesterol control, smoking cessation, and a prudent diet are additional approaches that are commonly used to control all forms of CKD. With these options and strategies available, efforts to expand awareness of Fabry disease in the nephrology community can support more effective treatments that can improve quality of life for many patients affected by the disease.

focuses on inherited disorders of renal function, with an emphasis on the renal manifestations of Fabry disease.

Dr. Warnock is a consultant on Fabry disease for Genzyme Corporation, and has received grant support, and travel expenses from Genzyme Corporation.

JANUARY 2013

nephropathy of Fabry disease. Biologics: Targets and Therapy 2008;2:1-22.

ADDITIONAL RESOURCES: Banikazemi M, Bultas J, Waldek S, et al. Agalsidasebeta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med 2007;146:77-86 Tahir H, Jackson LL, Warnock DG. Antiproteinuric therapy and Fabry nephropathy: Sustained reduction in proteinuria in patients receiving enzyme replacement therapy with agalsidase-beta. J Am Soc Nephrol 2007;18:2609-2617.

REFERENCES 1. Fervenza FC, Torra R and Warnock DG. Safety and efficacy of enzyme replacement therapy in the

Ortiz A, Oliveira JP, Waldek S, et al. Nephropathy in males and females with Fabry disease: crosssectional description of patients before treatment with

Renal & Urology News 27

enzyme replacement therapy. Nephrol Dial Transplant 2008;23:1600-1607.

Fogo AB, Bostad L, Svarstad E, et al. Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN). Nephrol Dial Transplant 2010;25:2168-2177.

Ortiz A, Cianciaruso B, Cizmarik M, et al. End-stage renal disease in patients with Fabry disease: natural history data from the Fabry Registry. Nephrol Dial Transplant 2010;25:769-775.

Wanner C, Oliveira JP, Ortiz A, et al. Prognostic indicators of renal disease progression in adults with Fabry disease: natural history data from the Fabry registry. Clin J Am Soc Nephrol 2010;5:2220-2228.

Conclusion Nephrologists are well versed in managing patients with complex multi-system diseases like diabetes, so they are especially well positioned to manage the multi-faceted presentations of Fabry disease in male and female patients.

Diagnosis of Fabry disease is straightforward once the possibility is considered. What has to be emphasized is the complex nature of the disease, which requires regular follow up and assessment of the ongoing response to therapy, including repeated measures of serum creatinine, glomerular filtration rate, and urinary protein excretion with ongoing titration of ACE inhibitor ARB dosing. ■ David G. Warnock, MD, is the Hilda B. Anderson Endowed Professor in Nephrology at the University of Alabama at Birmingham and a leading nephrologist. Dr. Warnock’s work focuses on genetic and environmental factors that contribute to hypertension and chronic kidney disease. He also

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. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 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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Drug Found to Delay PCa Progression Dutasteride prolonged PSA doubling time in men who experienced rising PSA after radical therapy

BY JODY A. CHARNOW DUTASTERIDE TAKEN for two years may prevent progression of prostate cancer (PCa) in men who experience PSA failure after radical therapy, according to a study.

In a two-year double-blind trial, Fritz H. Schröder, MD, of Erasmus Medical Center in Rotterdam, The Netherlands, and colleagues randomly assigned 294 PCa patients who had PSA failure after radical therapy to receive dutasteride, which is a 5␣-reductase inhibitor, or placebo (147 participants in each study arm). A total of 187 patients (64%) completed 24 months of dutasteride or placebo treatment and 107 discontinued treatment prematurely: 71 (48%) in the placebo group, 36 (24%) in the dutasteride group.

Compared with placebo, dutasteride significantly decreased the risk of PSA doubling by 66% for the overall study period, the researchers reported online in European Urology. The drug also sig-

ESAs Boost Stroke Risk, Not Mortality IN PATIENTS with chronic kidney disease (CKD) and anemia, using erythropoiesis-stimulating agents (ESAs) to achieve higher hemoglobin (Hb) targets increases the risk of cardiovascular events, according to a recent meta-analysis published online in Nephron Clinical Practice.

The meta-analysis by Jose M. Vinhas, MD, and colleagues at Centro Hospitalar de Setubal in Setubal,

nificantly delayed disease progression (which included PSA-related and nonPSA-related outcomes) compared with placebo, for an overall risk reduction of 59% in favor of dutasteride.

Additionally, among subjects with a baseline PSADT less than 12 months, the incidence of PSA doubling was 34% in the dutasteride arm compared with 62% among the placebo recipients.

The tolerability and safety of dutasteride generally were consistent with prior experience, the researchers noted.

The study arms had a similar incidence of adverse events (AEs), serious AEs, and AEs leading to study withdrawal.

Investigators were not blinded to PSA levels, which they noted is a study limitation. “Knowledge of PSA level could potentially unblind the study and influence investigators’ decisions such as time of rescue therapy,” Dr. Schröder’s team wrote. “Revealing PSA values was necessary, however, for investigators to manage their patients

and also to explore the impact of the disease and treatment on patientreported health outcomes.”

Additionally, the researchers pointed out that the median follow-up was significantly longer for the dutasteride than the placebo group (722 vs. 456 days).

Risk of disease progression was reduced by 59%, study shows.

“This is most likely due to the higher withdrawal rate in the placebo group than in the dutasteride group, which, in turn, was driven by withdrawal due to disease progression and investigator/ patient decision to withdraw.”

The authors noted that the selection of a PSA-related endpoint is clinically less meaningful than harder endpoints

such as biopsy-confirmed progression in clinical stage or metastases confirmed with bone scan. It also may have resulted in inherent bias in favor of dutasteride given the effect of treatment on PSA levels.

A previous study published last year in The Lancet (2012;379:1103-1111) demonstrated that dutasteride can delay the time to disease progression in PCa patients on active surveillance for low-risk tumors. In the study, Neil E. Fleshner, MD, MPH, of the University of Toronto, and colleagues randomly allocated patients to receive once-daily dutasteride (144 patients) or matching placebo (145 men).

By three years, significantly fewer men in the dutasteride group (38%) had pathologic or therapeutic PCa progression compared with those in the control group (48%), which translated into a 38% decreased risk of progression in the dutasteride recipients, the researchers reported. ■

Neutrophil Count May Predict PCa A LOW NEUTROPHIL count in men with an elevated PSA level may indicate a greater likelihood that a prostate biopsy will detect cancer, according to Japanese researchers.

Investigators at Osaka General Medical Center reviewed the medical records of 323 men who underwent transrectal ultrasound-guided 12-core needle prostate biopsy because of an elevated PSA level or abnormal findings on digital rectal examination. Of the 323 patients, 203 (62.8%) had a positive biopsy and 120 (37.2%) did not. The positive biopsy group had a significantly higher median age than the negative biopsy group (73 vs. 68 years)

and a significantly higher median PSA level (12.4 vs. 7.84 ng/mL).

The neutrophil count was significantly higher in the negative biopsy group than the positive biopsy group (3.58 vs. 3.32 × 103 µL-1).

In a subgroup analysis of 159 men with a PSA level below 10 ng/mL, 77 (48.1%) had a positive biopsy and 82 (51.9%) had a negative biopsy. The neutrophil count was significantly higher in those with a negative rather than a positive biopsy (3.54 vs. 2.97 × 103 µL-1). Among 104 men with a neutrophil count below 2,900 µL-1, 78 (75%) had a positive prostate biopsy compared with 125 (57%) of 219

men with count above that neutrophil count, the researchers reported in Prostate Cancer and Prostatic Diseases (2012;15:386-390).

“The neutrophil count, which is a routine test and easily performed, may be a good indicator of the result of prostate biopsy, although this remains to be confirmed in a larger study,” the authors concluded. “Men with a low neutrophil count and increased serum PSA level should be strongly considered for prostate biopsy.”

The researchers pointed out that all men in the study were Japanese, so the results may not be extended to other races. ■

Portugal included five randomized, controlled trials that allocated patients to different ESA doses. The five trials included a total of 7,902 subjects. The mean or median duration of follow-up ranged from 14 to 36 months.

A higher Hb target was associated with a significant 34% increased risk of vascular access thrombosis and a 73% increased risk of stroke, but had no effect on end-stage renal disease risk or overall mortality. ■

NAC May Improve Residual Renal Function TREATMENT WITH N-acetylcysteine (NAC) may improve residual renal function (RRF) in hemodialysis (HD) patients, the results from a small pilot study suggest.

Investigators in Israel enrolled 20 hemodialysis patients with a residual urine output of at least 100 mL/24 hours. The patients took 1,200 mg oral NAC twice daily for two weeks. All

patients served as their own control.

Urine volume increased from 320 mL/24 hours at baseline to 430 mL/24 hours at the end of the study, Leonid Feldman, MD, of Assaf Harofeh Medical Center in Zerifin, and colleagues reported online ahead of print in Hemodialysis International.

Residual Kt/V increased from 0.19 to 0.29 and residual glomerular filtration

rate increased from 1.6 to 2.4 mL/ min/1.73 m2 , according to the investigators . All increases were statistically significant.

Previously, in a small pilot study published in Peritoneal Dialysis International (2011;31:545-550), Dr. Feldman and collaborators showed that NAC improved RRF in peritoneal dialysis patients. ■

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JANUARY 2013

Renal & Urology News 29

Legal Issues in Medicine D

r. P was a 50-year-old urologist with a solo practice. Most of his patients were referrals from other physicians, although occasionally new patients would make appointments on their own without a referral from a primary care physician. One such patient was Mr. C, 58.

Mr. C told the urologist that nearly a year ago, he had begun experiencing urinary problems. He went to his family physician, who did not order a PSA test and did not believe Mr. C’s problems were due to cancer. The family physician did not order any other diagnostic testing, such as a biopsy, and did not refer Mr. C to a urologist. About 10 months after his visit to his family physician, Mr. C made an appointment with Dr. P. Dr. P took blood and ordered a PSA test, and then conducted a physical examination. The urologist suspected cancer and noted in the patient’s chart that a biopsy should be conducted once the blood tests were back.

“Okay Mr. C,” the urologist said, “I’m sending your blood out to the lab for testing and we’ll schedule another appointment for a week or so, once the results are in.”

The patient agreed and left. A few days later, Dr. P’s office manager came in to speak with him.

Not covered by insurance “Do you remember Mr. C, who was in a few days ago?” she asked. Dr. P nodded. “He called yesterday to cancel his next appointment,” the office manager said. “He realized that we weren’t in his insurance network and he didn’t want to pay out of pocket, so he was going to find another urologist who is on his plan.”

He filed the patient’s chart away, and when the blood work came back a few days later the results were simply stuck in the patient’s closed file.

Unknown to Dr. P, the patient did indeed go to a second urologist who

On The Web

was covered under his insurance plan.

The second urologist, based on a manual examination of the patient’s prostate, concluded that the prostate was normal and that there was no evidence of cancer.

It would be another two years after this before Mr. C’s cancer, which Dr. P had suspected, was diagnosed. By this time it had metastasized and Mr. C was given five years or less to live.

Mr. C consulted with a plaintiff’s attorney who immediately obtained copies of Mr. C’s medical records, including those from Dr. P. In his file from Dr. P were the results of the PSA test, showing an elevated PSA. In addition, there was a note in the file mentioning Dr. P’s suspicion of cancer and his thought that a biopsy should be conducted. The attorney took the case, and sued all three physicians, including Dr. P. Although shocked at hearing about the lawsuit, Dr. P did not believe he had any culpability until he met with the defense attorney provided by his malpractice insurance.

“You suspected cancer?” the attorney asked.

“Yes,” the physician replied.

“And the PSA results came back out of range?” the attorney asked.

“Yes, I know that now, but I didn’t look at them at that point,” the physician replied. “I assumed the patient had gone to a new doctor who was running his own tests.”

“What about the patient’s family physician. Did you have his name?” the attorney asked. “You could have contacted him with your concerns.”

Dr. P hesitated. “It just didn’t occur to me,” he said. “I assumed the next urologist would have the same concerns.”

During discovery, it was revealed that had Mr. C been diagnosed by his family physician, by Dr. P, or by the second urologist when he first saw him, he would have had a 97% chance of sur-

© PHOTO RESEARCHERS, INC. / PHANIE / SCIENCE SOURCE

A urologist learns the hard way that he has certain obligations to a former patient who was later diagnosed with prostate cancer BY ANN W. LATNER, JD

A patient’s lawsuit hinged in large part on a urologist’s communication failure.

viving the cancer. As it stood now, however, the cancer was too advanced.

After many hours of discussions, the three physicians ultimately decided it was in their best interest to settle the case. The case was settled for a total of $2.5 million.

Legal background Medical malpractice or negligence can be either an act (for example, operating on the wrong body part) or an omission (failing to do something). In this case, two types of omissions occurred.

One was the failure of the primary care physician and the second urologist to follow the proper screening guidelines, which would have called for a PSA test.

The second failure was that of Dr. P. It was the failure to notify either the patient (even though he was no longer a patient) or the patient’s primary care physician about the blood test results and Dr. P’s suspicion of cancer.

Protecting yourself Dr. P’s error was largely one of communication. Dr. P failed to communicate

his findings, suspicions and recommendations to Mr. C’s general practitioner or his second urologist, or even Mr. C himself. While there is no way to know whether either of the other physicians would have followed up on the results of the PSA test or on Dr. P’s recommendation that a biopsy be conducted, at least they would have had information and a perspective that they were missing. Conveying this information would have protected Dr. P from being part of this lawsuit.

Whether a patient is in your insurance network or not, once they have seen you and you have ordered lab tests and have concerns, it is essential to convey this information to the patient, his general practitioner, or his next physician. ■ 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 defendants 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.

30 Renal & Urology News

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Malpractice News

Medical screening panels are constitutional, a New Hampshire court rules.

© THINKSTOCK

In 2007, New Hampshire established an expert-panel system for use in medical malpractice lawsuits in order to cut back on frivolous suits and speed up resolution of cases. This system was recently challenged as unconstitutional, but the New Hampshire Supreme Court just handed down a decision upholding the use of such panels.

The case involved a woman who went to a New Hampshire emergency department complaining of back pain. The patient was then admitted to hospital with a diagnosis of intractable back pain. A neurosurgeon was called to review the case several hours later. The neurosurgeon initiated a lumbar puncture, indicating meningitis. The patient was taken to the intensive care unit, but her condition quickly deteriorated and she died. Her family proceeded to sue the hospital, claiming that there were clear signs of neurologic illness and that a specialist should have been consulted sooner.

A pretrial medical screening panel, comprised of a retired judge, an attorney, and two physicians unanimously found that the hospital was not negligent. The patient’s family took the case to trial nonetheless, and filed a motion asking that the panel’s findings not be presented, arguing that the panel is an

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unconstitutional alternative to a jury trial. The court granted the motion, but the hospital appealed.

The resulting legal decision left the panel process largely intact, and the New Hampshire Supreme Court ruled that the panel process is constitutional. However, the court noted that it is the purview of the trial judges to decide how much information about the panel will be presented to juries.

There has been concern that information about the panel’s decision could exert too much influence on a jury, but the Supreme Court decision largely dismissed these concerns.

Medical malpractice screening panels are used in some form or another in 16 states, and largely operate with much less stringent rules of discovery and witness testimony, and far shorter schedules than trials. In New Hampshire, the panel must consist of a retired judge, an attorney and one or two physicians.

Even if the panel makes a unanimous decision that there is no liability, the case may still go to trial, however, the jury is told of the panel’s findings. The state Supreme Court has now left it up to Superior Court judges to decide on an individual basis precisely how much information about the panel process the jury should be allowed to hear.

‘Pay for Performance’ Reduces Hospital Mortality in U.K. The idea of giving financial rewards to health care providers in order to improve quality of care for patients is increasingly being adopted internationally. However, little evaluation has taken place in order to determine whether these programs have any actual effect. Only three hospital pay-for-performance programs have been evaluated, and good evidence was available for only one—the Hospital Quality Incentive Demonstration (HQID) adopted by the Centers for Medicare and Medicaid Services in 2003.

Results were, at best, modest, and there was no improvement in mortality seen in the HQID program.

Pay for performance incentives appear to work in England.

© THINKSTOCK

New Hampshire Affirms Malpractice Screening Panels

BY ANN W. LATNER, JD

However, in 2008, a program called Advancing Quality, very similar to the HQID program, was introduced in all 24 National Health Service hospitals in northwestern England. The program financially rewarded only the top performing hospitals, and a total of $5 million in bonuses was paid to hospitals at the end of the first year. Researchers examined the results of this program to determine whether paying for performance could reduce mortality rates in hospitals. The results of this study were recently published in the New England Journal of Medicine (2012;367:1821-1828). Data was collected from the hospitals for 18 months prior to the start of the program and 18 months after it’s initiation.

Researchers focused on deaths that occurred within 30 days of admission for three specific conditions: pneumonia, acute myocardial infarction, and heart failure. Mortality was compared among 134,435 patients in the Advancing Quality program, compared with 722,139 patients admitted for the same three conditions to the 132 other hospitals in England. According to the researchers, riskadjusted absolute mortality for the three conditions in the Advancing Quality group decreased significantly, with a reduction of 1.3 percentage points, and a relative reduction of 6%, equivalent to 890 fewer deaths during the 18-month period after the program onset. The most significant reduction in mortality was for patients

with pneumonia. The study authors were unsure about why the reductions in England were significant, while reductions in a similar program in the U.S. were not, but they speculated that this might be due to the fact that the U.K. program had larger bonuses and a greater investment by hospitals in quality improvement activities. The researchers concluded that, “details of the implementation of incentive programs and the context in which they are introduced may have an important bearing on their outcome.”

Wyoming Safety Program Substantially Cuts Error Rate In 2009, Wyoming Medical Center in Casper, instituted a safety program designed to reduce errors causing serious harm to patients. Prior to the development of the program, hospital administrators studied two years’ worth of data and safety reports, and found that the medical center was rating average in terms of patient safety.

To improve safety and reduce serious errors, the medical center held focus groups among staff to discuss safety improvements and created a hotline where physicians could report concerns. To reduce medication errors, nurses began wearing red badges while administering medication to indicate that they should not be disturbed.

Protocols were put into place to allow staff to raise concerns and ask questions in a cooperative environment without feeling threatened.

Speaking at the Wyoming Patient Safety Summit in Casper, risk manager Shawna Willcox described the improvements seen with the program. Over the past three years the medical center has seen a 70% reduction in errors+ that cause serious harm to patients, and, according to Willcox, the hospital has now gone six months without a serious incident. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

Looking for more malpractice news? Visit us at renalandurologynews.com/malpractice to see noteworthy jury verdicts, recent trends in legislation, and surprising settlements!

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JANUARY 2013

Renal & Urology News 31

CME FEATURE

The Association between Kidney Failure and Renal Cell Carcinoma Scientific speculation suggests that uremic toxins, viral mediators, and immune inhibition could play a role in malignant transformation.

Release Date: January 2013 Expiration Date: January 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: In the vast majority of patients with renal cell carcinoma (RCC), extensive nephropathological findings are observed in the non-neoplastic kidney at the time of nephrectomy. At present, it is unknown if these nephropathological changes somehow induce renal neoplasia or are simply the result of medical comorbidities that are prevalent in kidney tumor patients. Thus, a working knowledge of the relationship between chronic kidney disease and RCC is now essential for all urologic oncologists.

TARGET AUDIENCE: This activity has been designed to meet the educational needs of urologists, urologic oncologists, and allied healthcare clinicians who treat patients for chronic kidney disease, particularly end-stage renal disease, and associated cancer.

EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: â&#x20AC;˘ Review recent literature that identifies the association between end-stage renal disease and malignancy. â&#x20AC;˘ Discuss kidney cancer-associated nephropathology and the surgical management of renal tumors.

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 Paul Russo, MD

Reported Financial Relationship Consulting Fees: Wilex AG

BY PAUL RUSSO, MD

E

nd-stage renal disease (ESRD) patients requiring renal replacement therapy, either by dialysis or transplantation, are at increased risk for developing cancer and at four- to five-fold increased risk of developing renal cancer in their native kidneys.1-3 ESRD-associated renal cell carcinoma (RCC) and competing medical comorbidities, principally cardiovascular (CV), are a source of morbidity and mortality. New evidence also implicates chronic kidney disease (CKD) as placing patients at greater risk for developing cancer compared with the general population, and at a greater risk for developing RCC in particular.

Nephropathological changes are commonly observed in the non-neoplastic kidney at the time of nephrectomy for RCC, and correlate with a higher incidence of CKD in RCC patients than in the general population. It is unknown whether these changes are carcinogenic or if renal dysfunction increases circulating serum carcinogens or causes immune inhibition leading to RCC. An estimated 60,920 new cases and 13,120 deaths from RCC occurred in

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 January 2013 through January 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.

Paul Russo, MD, is in the Department of Surgery in the Urology Service at Memorial Sloan-Kettering Cancer Center in New York. Dr. Russo is also a Professor of Urology at Weill Medical College of Cornell University.

the U.S. in 2011. RCC is increasing at a rate of approximately 3% per year.

Compared with 1971, this represents a fivefold increase in incidence and twofold increase in mortality. Associated risk factors include hypertension, smoking, obesity, and diabetes, all of which can affect kidney function alone or in combination. Epidemiologic evidence suggests an increase in all stages of RCC.4,5 Approximately 30% to 40% of RCC patients will either present with or later develop metastatic disease.

The problem of kidney cancer The widespread use of the modern abdominal imaging (CT, MRI, and ultrasound) over the last 20 years, usually ordered to evaluate nonspecific abdominal and musculoskeletal complaints or during unrelated cancer care, has changed the profile of the typical RCC patient from one with a massive, symptomatic tumor at presentation to one with a small, asymptomatic, renal mass (< 4 cm) incidentally discovered in 70% of the cases.6 A documented increase in incidence in African Americans without an increase in RCC-specific mortality has raised the possibility that RCC may be less aggressive in this population.7

32 Renal & Urology News

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CME FEATURE

Figure 1. A 64-year-old woman on dialysis for 10 years; solitary left kidney with ACD and a 3 cm renal tumor present.

RCC-specific survival rates have not significantly improved over the last 15 years. The aggressive treatment of smaller tumors appears insufficient to offset increasingly virulent tumors presenting as localized or metastatic disease.8 A survival rate of 90% or greater, depending on the tumor histology, is expected for small tumors whether partial nephrectomy (PN) or radical nephrectomy (RN) is performed.9,10 Renal cortical tumors are members of a complex family with unique histopathology, cytogenetics, familial and hereditary syndromes, and variable metastatic potentials. Approximately 20% of surgically resected renal masses are benign lesions (i.e., angiomyolipoma, oncocytoma, metanephric adenoma, or hemorrhagic cyst), 25% are indolent tumors (papillary, chromophobe carcinoma) with limited metastatic potential, and 54% are the potentially malignant conventional clear-cell carcinoma that accounts for 90% of the metastatic renal tumors.11,12

ESRD and associated malignancy A definite association between malignancy and ESRD has been reported.13,14 Stewart et al evaluated 28,855 patients who required renal replacement therapy and reported a fourfold increased incidence of cancer (Figure 1).

Immunodeficiency-related cancers were increased from one and a half fold while on dialysis to fivefold after transplantation, and the initiation of anti-rejection medication leads to speculation that this increase is virally mediated.15 Liang et al matched 21,817 ESRD patients in Taiwan to patients from the general population and found the risk of developing cancer was 64% higher in the ESRD

Figure 2. Gross appearance of ACD-associated RCC arising in the kidney with multiple cysts.

patients.16 Lee evaluated 4,582 patients with ESRD and found 106 patients that developed cancer. The most common cancers were in the GI tract (51%), urinary tract (20%) and lung (8%).

In this subgroup of patients, 69% of the mortality was due to cancer.17 Mosconi et al evaluated 1,184 Italian patients with ESRD awaiting kidney transplantation and found cancers in 2.2% of patients, most of which were nonmetastatic, arising most commonly from the kidney and thyroid.18 Tickoo and colleagues reported a spectrum of renal neoplasms in kidneys of ESRD patients and stressed the association of acquired cystic disease and associated renal cell carcinoma (ACDassociated RCC) (Figure 2). The tumors often appear as nodules arising in cyst walls, occasionally completely filling the cysts, or can appear as solid tumors distinct from the cysts and can have both solid and papillary architecture.

Multifocality and bilaterality are seen in 50% and 20% of the cases, respectively.19 ESRD patients have a higher prevalence of RCC than the general populations20 and have distinct clinical and pathological features. Neuzillet et al compared the pathologic features of 303 RCC patients with ESRD to 947 sporadic kidney cancer patients and found that the mean age at diagnosis was younger (55 vs. 62), the mean tumor size was smaller (3.7 vs. 7.3 cm), more were asymptomatic (87% vs. 44%), less were high stage (10% vs. 42%), less had nodal metastasis (3% vs. 12%) and less had distant metastasis (2% vs. 15%). After a median follow up of 33 months, 13 ESRD (4.3%) patients had died of RCC vs. 261 (27.6%) from the sporadic tumor population. The authors concluded that

Figure 3. A 53-year-old woman with ADPKD and CKD with an eGFR of 36 mL/min/1.73m2 , and 5 cm RCC present in the left renal hilum.

RCC arising in the native kidneys of ESRD patients may be more indolent.21 Hora et al described pathologic characteristics of renal cortical tumors in 19 ESRD kidneys and reported 13 with multiple tumors. Papillary and clear cell tumors alone or in combination were reported.22 Hajj et al reported 89 nephrectomies (including 10 bilateral) from 79 patients with autosomal dominant polycystic disease (ADPKD), 50 of who had ESRD (Figure 3). In 11 of the 89 kidneys, RCC was found including one bilateral and three multifocal tumor. Of these, 58.3% were clear cell and 41.7% tubulopapillary carcinomas. The authors calculated that the prevalence of renal cancer in the combination of ADPKD and ESRD was two to three times more than in ESRD patientâ&#x20AC;&#x2122;s alone.23 Nouth et al reported a wide spectrum of tumor histology distinct from sporadic RCC in 34 ESRD patients.

Pathologic subtypes included ACDassociated RCC, mucinous tubular, spindle cell, and Xp11.2 translocation RCC. In nine of 15 patients with a duration of dialysis less than 10 years, conventional clear cell was the predominant histology whereas ACD-associated RCC was predominant (seven of 12) in those with dialysis of greater than 10 years.24 Suson et al reported 15 posttransplant patients who underwent RN for renal masses in their native kidney.

A total of 22 renal units were removed with a total of 18 cancers, 10 of which were P1, resected. There were 11 papillary, four clear cell, and three chromophobe cancers. Only one patient developed metastatic disease.25 These reports, when taken together, describe a propensity for the development of a wide range of RCC in patients with

ESRD whose renal tumors may have less metastatic potential than their sporadic counterparts.

CKD and links to cancer CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73m2, is increasingly viewed as a major public health problem in the U.S. and, since 2003, is considered an independent CV risk factor.26-30 The prevalence of CKD in the general population is 4% but may be as high as 30% in the elderly population.

An estimated 19 million adults in the U.S. have CKD and by the year 2030, two million of these will progress to ESRD and be in need of chronic dialysis or renal transplantation.31 Worldwide epidemics of CV disease, obesity, hypertension and diabetes, all of which can have adverse effects on the kidney, have gained increasing attention but their contribution to the development of CKD has gone relatively unnoticed among clinicians and patients alike.

The adverse impact of CKD on CV disease is significant as CKD progresses to ESRD.32 As CKD stages progress there are increased rates of hospitalization, CV events, and death, which occur before overt ESRD requiring dialysis or renal transplantation.33 In addition, as patients drift deeper into the stages of CKD, CV risk factors and requisite medical interventions also increase. The low prevalence of patients with stage 4 or 5 CKD is attributable to a five-year survival rate of only 30%.34 The metabolic consequence of CKD, including anemia, hypocalcemia, hyperphosphatemia, and hyperparathyroidism are particularly marked in

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patients over 65 years of age.35 This high prevalence of CKD in the aging and elderly is superimposed upon the very patient population most at risk for the development of cancer.

As with ESRD, there are now reports indicating that patients with CKD are at higher risk for the development of cancer in addition to CV disease. Weng et al evaluated 123,717 adults in Taiwan in 1998 and calculated their eGFR. After a median of over seven years, mortality was ascertained by computer linkage to their national death registry. The investigators found a higher overall cancer mortality in CKD patients vs. non-CKD patients. CKD was associated with an adjusted hazard ratio of 1.74, 3.3, and 7.3 for liver, kidney, and urothelial cancers respectively.36 Wong et al evaluated 3,654 patients in Australia aged 49-97 and followed them for a mean 10.1 years. Cancer developed in 711 patients (19.5%). Men with CKD stage 3 were at increased risk for the development of cancer starting at an eGFR of 55 (HR 1.39). For every 10 mL/min decline in eGFR, the risk of cancer rose 29% and was greatest for an eGFR of 40 (HR 3.01) with lung and urinary tract the most likely.37 Cancer patients appear to have a higher rate of CKD than the general population.

Launay-Vacher and colleagues evaluated 4,684 patients with cancer, median age 58, and reported that 12% and 20% had an eGFR less than 60 mL/min/ 1.73 m2 by the MDRD study and Cockcroft Gault equations, respectively.38 Canter et al reported the prevalence of baseline CKD in 1,114 patients presenting with solid renal tumors. Twenty-two percent had stage 3 CKD or greater despite 88% having a serum creatinine within normal limits (<1.4 mg/dl). In a subgroup of 282 patients 70 years or older, 113 (40%) had CKD stage 3.39 These results are similar to those first reported by Memorial Sloan-Kettering Cancer Center investigators, which demonstrated a 26% rate of CKD in 662 patients with small renal tumors and a serum creatinine within normal limits.40

Kidney cancer-associated nephropathology The extent to which ESRD- or CKDassociated nephropathological changes are simply associated with RCC or cause RCC is unknown. In patients with ESRD, numerous renal cysts develop and persistently grow in native kidneys even after

transplantation. Goh et al reported 10 asymptomatic transplant recipients who developed RCC in native kidneys at a median of 5.8 years, while their grafts were functioning at a greater than 90% rate. The patients at greatest risk for developing RCC were those with preexisting renal cysts and those on dialysis the longest.41 In patients without ESRD/ CKD and renal cancer, many nephropathological changes are observed. Bijol et al examined the nontumor-bearing normal appearing kidney in 110 nephrectomy specimens resected for RCC. Extensive and unsuspected underlying renal disease (including vascular sclerosis, diabetic nephropathy, glomerular hypertrophy, mesangial expansion, and diffuse glomerulosclerosis) was reported. Only 10% of patients had completely normal renal tissue adjacent to the tumor.42 Henriksen and colleagues confirmed a wide range of kidney abnormalities in the non-neoplastic kidney, including mesangial sclerosis or hypercellularity, segmental sclerosis, crescent formation, glomerulitis, and glomerular basement membrane disease.43 Pathologists are now being urged to routinely report these findings in tumor nephrectomy specimens.44 The precise mechanism by which the uremic state, dialysis, and transplantation can cause malignant transformation in the kidney is unknown. Cancer-induced paraneoplastic nephropathy, exposure to toxins, viral-mediated carcinogenesis, immune inhibition, and circulating toxins have all been implicated.45 Retention of uremic toxins, such as p-cresol, could also promote malignant transformation by their inhibitory effect on the immune system and transendothelial leukocyte migration.46,47 In the last decade, the surgical management of renal tumors has shifted from the historical RN for all tumors of all sizes48,49 to PN whenever possible. Unlike the carefully screened kidney transplantation donors, RCC patients were older, often had common medical comorbidities such as hypertension, diabetes and vascular disease,50-52 and experienced an agerelated decline in baseline GFR. 53 In addition, the oncologic results of RN and PN were equivalent for small renal masses but RN patients experienced rising creatinine, albuminuria, and a greater likelihood of new-onset CKD as determined by eGFR.40,54,55 Other studies indicated that the RN

JANUARY 2013

patients had worse overall survival and a greater likelihood of a CV event.56-58 A recent pooled analysis of 51 studies involving 31,728 patients from the world’s literature was published by Kim and colleagues. The authors reported that PN was associated with a 19% risk reduction in all-cause mortality, a 29% risk reduction in cancer-specific mortality, and a 61% risk reduction in severe CKD. Despite these findings, the authors pointed out that the data obtained were observational and subject to selection biases and statistical heterogeneity.59 Similar results were reported in patients undergoing laparoscopic RN and PN.60 The effect of these reports has made urologists increasingly aware that pre-existing CKD can be significantly worsened by the liberal use of RN for the treatment of the small renal mass.61 Short-term endpoints, including length of hospital stay, analgesic requirements, and cosmetic elements, viewed by many as the reason to elect laparoscopic RN over the more challenging PN, must now be tempered by these new concerns regarding CKD and overall survival.

The most recent American Urological Association guidelines for the management of the small renal tumor emphasize these points and strongly support the use of PN whenever technically feasible.62 Despite this information, evidence of overutilization of RN exists when databases such as the National Inpatient Sample.63 SEER,64 and SEER linked to Medicare57,58 are analyzed with an approximately 70% RN rate even for tumors of 4 cm or less. For uncertain reasons, women and elderly patients are more likely to be treated with RN.65

Conclusions Renal insufficiency, ESRD, and CKD are associated with the development of RCC. Unlike healthy kidney donors used for transplantation, kidney tumor patients are older, have common medical comorbidities that can affect the kidneys and CV system, and have a higher rate of baseline CKD (up to 40%) than the general patient population. In the nonneoplastic kidney at the time of nephrectomy, extensive nephropathologic findings are observed in the vast majority of patients with RCC. It is unknown if these changes somehow induce renal neoplasia or are simply a result of medical comorbidities that are prevalent in the

Renal & Urology News 33

kidney tumor patients. The precise mechanism by which the uremic state causes malignant transformation is unknown but it is speculated that uremic toxins, viral mediators, and immune inhibition could play a role. For surgeons operating on small renal tumors, it is now clear that PN provides equivalent oncologic results to RN while at the same time maximally preserving renal function and preventing or delaying the onset of CKD and its late CV morbidity and mortality. Despite a decade of clinical evidence in support of PN, RN remains overutilized in the United States and abroad. Formal support for PN in the management of small renal masses has been made by major urological surgical organizations. A working knowledge of the relationship of CKD/ ESRD and RCC is now essential for all urological oncologists. ■

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2. Buell JF, Gross TG, Woodle ES. Malignancy after transplantation. Transplantation 2005;80: S254-S264.

3. Birkelan SA, Løkkegaard H, Storm HH: Cancer risk in patients on dialysis and after renal transplantation.

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4. McLaughlin JK, Lipworth L. Epidemiologic aspects of renal cell cancer. Semin Oncol 2000;27:115-123.

5. Ljungberg B, Campbell SC, Cho HY, et al. The epidemiology of renal cell carcinoma. Eur Urol 2011;60:615-621.

6. Russo P. Renal cell carcinoma: Presentation, staging, and surgical treatment. Semin Oncol 2000;27:160-176.

7. Lipworth L, McLaughlin JK, Tarone RE, Blot WJ. Renal cancer paradox: higher incidence but not higher mortality among African-Americans. Eur J Cancer Prev 2011;20:331-333.

8. Russo P, Jang T, Eggener S, et al. Survival rates after resection for localized kidney cancer 1989-2004.

Cancer 2008;113(1):84-96.

9. Kattan MW, Reuter V, Motzer RJ, Katz J, Russo P. A postoperative prognostic nomogram for renal cell.

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10. Russo P. Partial nephrectomy for renal cancer: Part 1.

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11. Teloken PE, Thompson RH, Tickoo SK, et al. Prognostic impact of histological subtype in patients with surgically treated localized renal cell carcinoma.

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12. Algaba F, Akaza H, López-Beltrán A, et al. Current pathology keys of renal cell carcinoma. Eur Urol 2011;60:634-643.

13. Matas AJ, Simmons RL, Kjellstrand CM, et al. Increased incidence of malignancy during chronic renal failure. Lancet 1975;1:883-886.

14. Cengiz, K. Increased incidence of neoplasia in chronic renal failure (20-year experience). Int Urol Nephrol 2002;33:121-126.

15. Stewart JH, Vajdoc CM, van Leeuwen MT, et al. The pattern of excess cancer in dialysis and transplantation. Nephrol Dial Transplant 2009;10:3225-3231.

16. Liang JA, Sun LM, Yeh JJ, et al. The association between malignancy and end stage renal disease in Taiwan. Jpn J Clin Oncol 2011;41:752-757.

17. Lee JE, Han SH, Cho BC, et al. Cancer in patients on chronic dialysis. J Korean Med Sci 2009;41:S95-S101.

18. Mosconi G, Stalterii L, Centofanti F, et al. Incidence of cancer in kidney transplantation waiting list patients: a single center experience. Transplant Proc 2011;43:1003-1005.

19. Tickoo SK, DePerolta-Venturia MN, Harik LR. Worcester neoplasms in end stage renal disease: An experience from 66 tumor-bearing kidneys with emphasis on histological patterns distinct from those in sporadic adult renal neoplasms. Am J Surg Path 2006;30:141-153.

20. Ishikawa I, Kovacs G. High incidence of papillary renal cell tumors in patients on chronic haemodialysis. Histopathology 1993;22:135-139.

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CME FEATURE 21. Neuzillett Y, Mathieu R, Long JA, et al. Renal cell carcinoma (RCC) in patients with end stage renal disease exhibits many favorourable clinical, pathologic, and outcome features compared with RCC in the general population. Eur Urol 2011;60:366-373.

22. Hora M, Hes O, Reischig T, et al. Tumours in endstage kidney. Transplant Proc 2008;10:3354-3358.

23. Hajj P, Ferlicot S, Massoud W, et al. Prevalence of renal cell carcinoma in patients with autosomal dominant polycystic kidney disease and chronic renal failure. Urology 2009;74:631-634.

24. Nouth MA, Kuroda N, Yamashita M, et al. Renal cell carcinoma in patients with end stage renal disease: relationship between histological type and duration of dialysis. BJU Int 2010;105:620-627.

25. Suson KD, Sausville JE, Sener A, Phelan MW. Native nephrectomy for renal cell carcinoma in transplant recipients. Transplantation 2011;91:1376-1379.

26. Sarnak M, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for the development of cardiovascular disease: a statement from the American Heart Association Council on Kidney in Cardiovascular Disease. High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.

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27. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on TN Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572-2589.

28. Levey AS, Coresh J, Bolton K, et al. Kidney Disease Outcome Quality Initiative. K/DOQI clinical guideline for chronic kidney disease evaluation, classification, stratification. Am. J. Kidney Dis 2002;40:E19-E22.

29. Ritz E, McClellan WW. Overview: increased cardiovascular risk in patients with minor renal dysfunction: an emerging issue with far-reaching consequences.

J Am Soc Nephrol 2004;15:513-516.

30. Shlipak MG, Fried LF, Cushman M, et al. Cardiovascular mortality risk in chronic kidney disease. JAMA 2005;293:1737-1745.

31. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA 2007;298:2038-2047.

32. Stenvinkel P. Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease. J Intern Med 2010;268:456-467.

33. Go AS, Chertow GM, Fan D, et al: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;35:112-196.

34. Foley RN, Wang C, Collins AJ. Cardiovascular risk factor profiles and kidney function stage in the US general population: the NHANES 3 study. Mayo Clin Proc 2005;80:1270-1277.

35. Stevens LA, Li S, Wang C, et al. Prevalence of CKD and comorbid illness in elderly patients in the United State: results from the Kidney Early Evaluation Program (KEEP). Am J Kidney Dis 2010;55:S23-S33.

36. Weng PH, Hung KY, Huang HL, et al. Cancer-specific mortality in chronic kidney disease: longitudinal follow up of a large cohort. Clin J Am Soc Nephrol 2011;6:1121-1128.

37. Wong G, Hayen A, Chapman JR, et al. Association of CKD and cancer risk in older people. J Am Soc Nephrol 2009;20:1341-1350.

38. Launay-Vacker V, Oudard S, Janus N, et al. Prevalence of renal insufficiency in cancer patients and implications for anti cancer drug management. The renal insufficiency and anticancer medications study (IRMA). Cancer 2007;110:1376-1384.

39. Canter D, Kutikov A, Sirohi M, et al. Prevalence of baseline CKD in patients presenting with solid renal tumors. Urology 2011; 77:781-785.

40. Huang WC, Levey AS, Serio AM, et al. Chronic kidney disease after nephrectomy in patients with renal cortical tumors: a retrospective cohort study. Lancet Oncol 2006;7:735-740.

41 Goh A, Vathsala A. Re: native renal cysts and dialysis duration are risk factors for renal cell carcinoma in renal transplant recipients. Am J Transplant 2011;11:86-92.

42. Bijol V, Mendez GP, Huwitz S, et al. Evaluation of the nonneoplastic pathology in tumor nephrectomy specimens. Am J Surg Pathol 2006;30:575-584.

43. Henriksen KJ, Meehan SM, Chang A. Nonneoplastic kidney diseases in adult tumor nephrectomy and nephroureterectomy specimens: common, harmful, yet underappreciated. Arch Pathol Lab Med 2009;133:1012-1025.

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1. The risk for developing kidney cancer in the native kidney in a patient with ESRD is: a. No greater than the patient without ESRD b. Four to five times greater than the patient without ESRD c. Less than the patient without ESRD d. The same as a patient without ESRD 2. The typical patient with a kidney tumor today is diagnosed following the evaluation of signs or symptoms unrelated the urinary system. a. True b. False 3. The incidence of and mortality from kidney cancer have decreased in the last 15 years. a. True b. False 4. For renal cell carcinoma of 4 cm or less partial nephrectomy and radical nephrectomy provide equivalent oncological tumor control. a. True b. False 5. ESRD is associated with: a. Greater incidence of malignancy b. ACD of the kidneys c. ACD-associated renal cell carcinoma d. All of the above 6. The prevalence of CKD in the general population is 4% but may be as high as 30% in the elderly population. a. True b. False 7. It is rare to see nephropathological changes in the normal kidney tissue adjacent to a resected renal cell carcinoma. a. True b. False 8. When comparing patients with a small renal mass treated with radical or partial nephrectomy, post-operatively the radical nephrectomy patients are more likely to: a. Develop albuminuria b. Develop a rising creatinine and CKD c. Experience an adverse CV event d. Have worse overall survival e. All of the above