Renal & Urology News May 2012 Issue

CONVENTIO N ISSUE

MAY 2012

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VOLUME 11, ISSUE NUMBER 5

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Embolization Relieves BPH Symptoms

IMAGE COURTESY OF FRANCISCO CESAR CANNEVALE, MD, PhD

Novel approach is associated with a 30% reduction in prostate size, according to researchers

FIGURE 1. Microcatheterization in the left interior vesical artery prior to embolization

RFA Treats Small Renal Tumors

BY JODY A. CHARNOW RADIOFREQUENCY ABLATION (RFA) can effectively treat small benign renal tumors in a single session, and long-term outcomes of RFA for renal tumors depend on tumor size, according to the findings of two studies.

Researchers at the University of Texas Southwestern Medical Center in Dallas

CME FEATURES

led by Jeffrey A. Cadeddu, MD, conducted both studies, which were retrospective in design. One study looked at 47 benign small (less than 3.5 cm) renal masses (SRMs) discovered incidentally in 41 patients. The tumors were determined to be benign by concurrent biopsy. The other study focused on 159 continued on page 10

Earn 2 CME credits in this issue

• Bone disease in kidney transplant patients p.17 • Part I of our series on neurogenic bladder p.40 PAGE 40

BY JOHN SCHIESZER SAN FRANCISCO—Benign prostatic hyperplasia (BPH) may be safely treated with prostatic artery embolization (PAE), according to a new study presented at the 37th Annual Scientific Meeting of the Society of Interventional Radiology (SIR).

PAE is associated with few serious adverse side effects and may reduce prostate volume by more than 30%, researchers reported.

“These new findings provide hope for those who might not be candidates for transurethral resection of the prostate and may allow them to avoid serious complications that sometime result from surgery, such as impotence, retrograde ejaculation and urinary incontinence,”

Translumbar HD Catheters Safe, Effective

BY JOHN SCHIESZER SAN FRANCISCO—Translumbar hemodialysis catheters (THCs) are safe and may offer an effective vascular access route for hemodialysis (HD) patients with limited venous access options, even in overweight patients, according to data presented at the 37th Annual Scientific Meeting of the Society of Interventional Radiology.

The new findings may be of particular interest to nephrologists because they pertain to a very challenging group of dialysis patients, said study investigator Cormac Farrelly, MD, Assistant Professor of Interventional Radiology at the University of Pennsylvania in Philadelphia. Intervention radiologists at the Hospital of the University of Pennsylvania previously published their experience with transhepatic dialysis catheters in 2003. The latest study suggests that a translumbar approach may have significant advantages over a transhepatic approach. continued on page 10

said study investigator Francisco Cesar Carnevale, MD, PhD, Professor and Chief of the Interventional Radiology Section at the Hospital das Clínicas of the Faculty of Medicine at the University of São Paulo, Brazil. “This could mean that more men have a chance at getting their lives back.”

Dr. Carnevale and his colleagues conducted a prospective, single site phase 2 study to investigate whether PAE could improve both quality of life and lower urinary tract symptoms (LUTS) in men with BPH. The study included 11 men with acute urinary retention due to BPH who had been managed with medical treatment and indwelling urethral catheters. continued on page 10

IN THIS ISSUE 4

Summer heat raises risk of acute renal failure

9

Blood pressure, uric acid linked in adolescents

11

Caution urged in use of older kidneys

15

Partial nephrectomy increasing, but disparities exist

16

U.S. kidney stone prevalence is on the rise

22

MRI scans may improve PCa detection

27

Q&A: When is brachytherapy the best choice?

A wedge-shaped hypoperfused area of the right renal parenchyma PAGE 28

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MAY 2012

Renal & Urology News 3

BP Drug May Preserve Erectile Function Post-RRP REGULAR IRBESARTAN use after nerve-sparing radical retropubic prostatectomy (RRP) could improve postoperative recovery of erectile function among patients with normal preoperative erectile function.

Investigators led by Arthur L. Burnett, MD, of Johns Hopkins Hospital

in Baltimore, studied 17 men who underwent RRP and who started daily oral irbesartan 300 mg on postoperative day 1. All were potent prior to surgery. The researchers com pared these men with a clinically matched group of 12 men who declined irbesartan use (controls).

PROVENGE® (sipuleucel-T) Suspension for Intravenous Infusion

Rx Only

BRIEF SUMMARY — See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

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Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

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

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591 (98.3)

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(Table 1 continued on next page.)

5 scores at 24 months after surgery were statistically similar between the two groups, at 12 months the IIEF-5 scores of the irbesartan group were significantly higher than those of the control arm, the investigators reported online ahead of print in BJU International. â–

4 Renal & Urology News

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Summer Heat Increases Risk of Renal Problems HIGHER SUMMER temperatures increase the likelihood of being hospitalized for acute renal failure (ARF) and other kidney related ailments, according to an analysis of data collected in New York State.

Overall, the odds of hospitalization for ARF increased 9% for each 5° F

increment in temperature based on the mean temperature a day prior to hospitalization (lag 1). The risk was greater for blacks, Hispanics, individuals aged 25-44 years, and those in the lowest income quartile, the investigators, led by Shao Lin, MD, PhD, of the New York State Department

Table 1 Incidence of Adverse Events Occurring in ≼5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Hypertension $QRUH[LD %RQH SDLQ Upper respiratory tract infection ,QVRPQLD Musculoskeletal chest pain Cough Neck pain Weight decreased Urinary tract infection Rash Sweating Tremor

Control* (N = 303)

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Grade 3-5 n (%)

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of Health’s Center for Environmental Health in Troy, reported online ahead of print in the American Journal of Epidemiology.

Hispanics had a significant 20% increased risk per 5° F increment in temperature while compared with nonHispanics (9%). Compared with whites

(8%), blacks had a 14% increased risk for each 5° F, whereas Asians had a significant 12% decreased risk.

Individuals aged 25-44 years had a significant 18% increased risk for each 5° F compared with those aged 45-64 years (9%). Individuals in the lowest income quartile ($31,406 per year or less) had a 13% increased odds of ARF hospitalization per 5° F compared with those in the highest quartile (more than $55,869 per year [7%]), the researchers noted.

The odds of an ARF hospitalization varied geographically within the state, with the largest associations observed in more urban regions.

Additionally, Dr. Lin’s group found increased odds of hospitalization for urinary tract infections, kidney stones, and other lower urinary tract disorders. “Our findings add to a growing body of work that documents the association

Each 5° F increase raises the odds of ARF admission by 9%, study finds.

(See Adverse Reactions [6] of full Prescribing Information.)

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

Dendreon Corporation Seattle, Washington 98101

References: 1. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

2. PROVENGE [package insert]. Dendreon Corporation; June 2011.

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of high temperature and morbidity, particularly hospital admissions for renal diagnoses,� the authors concluded.

The investigators noted that most previous studies considered only heat waves, but their study is one of only a few to examine the effect of all summer temperatures on renal admissions.

They noted that their findings “can be useful in developing adaptation strategies and heat-warning policies.�

Dr. Lin’s team pointed out that the biologic mechanism underlying the relationship between heat and renal disease is unclear. Previous studies have found an increased incidence of renal calculi associated with exposure to hot conditions, presumably the result of disrupted fluid balance, the researchers explained.

In a discussion of study limitations, the investigators pointed out that they relied on ecologic-level exposure data. “Exposure temperature was assigned on the basis of residential address and took no account of personal activity,â€? they wrote. “Similarly, we do not know which individuals had access to air conditioning or other mitigation resources, another source of exposure misclassification.â€? â–

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Renal & Urology News 5

FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD

PCa Screening: Can We Move Beyond PSA?

M

ore than 1 million prostate biopsies are performed annually in the United States, predominantly driven by elevations in PSA. The merits of PSA screening have been widely debated due largely to its low specificity for prostate cancer (PCa), especially for high-grade disease. Two randomized trials (PLCO/ERSCP) failed to resolve the controversy and the U.S. prostate screening task force (USPSTF) recently gave PSA screening a Grade D, recommending against it. In doing so the USPSTF failed to fully acknowledge the limitations and merits of both the PLCO and ERSCP trials and dismissed the fact that over the past 20 years of PSA-based screening, PCa-specific mortality has been reduced by close to 40%, while the risk of metastatic disease has been substantially reduced (Urol Oncol 2012;30:117-119).

Given the need to reduce overdiagnosis of low-stage/low-grade PCa while improving detection of aggressive disease, the American Urological Association, the American College of Surgeons, and National Comprehensive Cancer Network guideline committees have made recommendations for risk-adjusted PSA screening, citing data demonstrating that PSA baselining and kinetics dramatically improve screening efficiency, particularly in younger populations. Nonetheless, in the absence of widespread adoption of risk-adjusted and patient-informed screening strategies, a likelihood of over- and underdiagnosis and overand undertreatment exists.

Among the most promising new molecular tests for PCa screening is PCA-3, a non-coding, large-chain RNA over-expressed in PCa. PCA3 is detectable in urine and independent of prostate size and PSA. In a recent study led by the National Cancer Institute Early Detection Research Network and presented last month at the American Association for Cancer Research, Wei and colleagues reported on a comprehensive, prospective, independent validation of urinary PCA3 alone or in combination with common clinical factors (prior negative biopsy, PSA, race, age, abnormal DRE, and family history) for the detection of PCa at 11 U.S. sites. In nearly 1,000 men undergoing initial or repeat biopsy, these investigators found that urinary PCA3 prior to a prostate biopsy improved the prediction of PCa and high-grade disease with a high positive predictive value (90%) in the initial biopsy setting and a high negative predictive value (88%) in the repeat biopsy setting.

While widespread adoption of urinary PCA-3 has not yet been incorporated into most physician screening practices, it represents a clear positive step toward a more risk adjusted biopsy strategy, a goal on which we all can agree.

Robert G. Uzzo, MD, FACS, holds the G. Willing “Wing” Pepper Chair in Cancer Research at Fox Chase Cancer Center, where he is Chairman of the Department of Surgery. He is Professor of Surgery at Temple University School of Medicine in Philadelphia. Dr. Uzzo also serves as the Renal & Urology News Medical Director for Urology.

Medical Director, Urology

Medical Director, Nephrology

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

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

Urologists

Nephrologists

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

Anthony J. Bleyer, MD, MS Professor of Internal Medicine/Nephrology Wake Forest University School of Medicine Winston-Salem, N.C.

Christopher S. Cooper, MD Director, Pediatric Urology Children’s Hospital of Iowa Iowa City

Suphamai Bunnapradist, MD Director of Research Department of Nephrology Kidney Transplant Research Center The David Geffen School of Medicine at UCLA

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

R. Michael Hofmann, MD Associate Professor and Medical Director, Living Kidney Donor Program University of Wisconsin School of Medicine and Public Health, Madison Csaba P. Kovesdy, MD Associate Professor of Clinical Medicine University of Virginia, Charlottesville Chief of Nephrology Salem VA Medical Center Salem, Va. Edgar V. Lerma, MD, FACP, FASN, FAHA Clinical Associate Professor of Medicine Section of Nephrology Department of Medicine University of Illinois at Chicago College of Medicine, Chicago Allen Nissenson, MD Emeritus Professor of Medicine The David Geffen School of Medicine at UCLA, Chief Medical Officer, DaVita Inc. Rulan Parekh, MD, MS Associate Professor Johns Hopkins Children’s Center, Baltimore Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center, Detroit Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J. Lynda Anne Szczech, MD, MSCE Associate Professor of Nephrology Duke University School of Medicine Durham, N.C.

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

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

Renal & Urology News (ISSN 1550-9478) Volume 11, Number 5. Published monthly by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Periodicals postage paid at New York, NY, and an additional mailing office. The subscription rates for one year are, in the U.S., $75.00; in Canada, $85.00; all other foreign countries, $110.00. Single issues, $20.00. www.renalandurologynews.com. Postmaster: Send address changes to Renal & Urology News, c/o DMD Data Inc., 2340 River Road, Des Plaines, IL 60018. For reprints, contact Wright’s Reprints at 1.877.652.5295. Copyright: All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without the prior written permission of Haymarket Media, Inc. Copyright © 2012.

Contents

M A Y

2 0 1 2

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V O L U M E

1 1 ,

I S S U E

N U M B E R

5

Urology 3

ONLINE

15

this month at renalandurologynews.com

Kidney Stone Prevalence Is Increasing Study also finds that non-Hispanic blacks and Hispanics are less likely than whites to report a history of kidney stones.

22

Image-Guided Ablation Viable for Small Renal Tumors The procedure can be performed on tumors smaller than 4.8 cm with minimal morbidity and with excellent results in terms of longterm survival.

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 March Winner: Steven Rockoff, MD

17

CME Features 17

Managing Bone Disease in Renal Transplant Recipients Two experts discuss the major factors that contribute to bone disease in renal transplant patients.

40 Part 1: Diagnostic Strategies for Patients with Neurogenic Bladder This first installment highlights up-to-date assessment and management in patients with neurologic disease.

Nephrology 4

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

Our latest include: • Active Surveillance May Be Okay for Some Men with Metastatic PCa • Complete Anemia Correction Better for Renal Transplant Patients • New Oral Drug May Aid Survival in CRPC Patients

News Coverage On-site coverage of the American Urological Association annual meeting in National Harbor, Md., May 19-23

9

11

26

Summer Heat Increases Risk of Renal Problems Higher summer temperatures increase the likelihood of being hospitalized for acute renal failure and other kidneyrelated ailments.

Blood Pressure, Uric Acid Linked in Adolescents Increasing levels of uric acid are associated with elevated blood pressure among adolescents in the United States.

Caution Urged in Use of Older Kidneys Delayed graft function in kidneys from donors older than 60 increases the risk of graft loss.

Nut Consumers Have Lower Health Risks Nut consumption is associated with a decreased prevalence of certain risk factors for cardiovascular disease, type 2 diabetes, and metabolic syndrome.

“

“

Disparities Found in Partial Nephrectomy Use Partial nephrectomy rates have increased dramatically, but this surgical approach is underused in certain patient populations.

16

Expert Q&A Renal & Urology News speaks with E. David Crawford, MD, of the University of Colorado in Denver, about advances in prostate cancer drugs and how best to use them.

BP Drug May Preserve Erectile Function Post-RRP Prostate cancer patients who take irbesartan after nerve-sparing radical retropubic prostatectomy may improve postoperative recovery of erectile function.

Brachytherapy has become more sophisticated and polished in the 25 years since it was first used for prostate cancer.

See our Expert Q&A on page 27

29

Departments 5

From the Medical Director

8

News in Brief

12 Renal Nutrition Update Reducing advanced glycation end products 29 Legal Issues in Medicine Radical prostatectomy for a nonexistent prostate cancer 28 On the Forefront Page kidney resulting in new-onset hypertension 30 Malpractice News Arizona addresses wrongful birth suits 35 Your Money Investing in technology company stocks

8 Renal & Urology News

MAY 2012

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

Short Takes Circumcision May Reduce PCa Risk

A team led by Jill A. Attaman, MD,

Recent population-based study find-

the bottom third of fat intake, those

ings indicate that circumcision before

in the highest third had a 43% lower

first sexual intercourse is associated

total sperm count and 38% lower

with a reduction in the relative risk

sperm concentration. Saturated fat

of prostate cancer (PCa), perhaps

intake drove this association. Levels

by preventing sexually transmitted

of saturated fatty acids in sperm

infections. Jonathan L. Wright, MD,

were also negatively related to sperm

and coinvestigators found that among

concentration, but saturated fat intake

1,754 cases and 1,645 controls,

was unrelated to sperm levels, the

PCa was 15% less likely to develop

investigators reported.

showed that compared with men in

in men who were circumcised before cised men, according to an online

Once-Monthly Anemia Drug Is Approved

report in Cancer.

The FDA has approved peginesatide

first sexual intercourse than uncircum-

The new findings are in line with an infectious/inflammatory pathway that may be involved in PCa risk, according

(Omontys) for the treatment of anemia in adult dialysis patients.

The approval was based on the

to Dr. Wright, Assistant Professor of

results of two randomized, active-

Urology at the University of Washing-

controlled clinical trials involving a

ton School of Medicine in Seattle.

total of 1,608 patients showing that once-monthly administration of pegi-

Too Much Fat May Harm Sperm Quality

nesatide was as safe and effective

Higher total fat intake was nega-

levels with the studies’ pre-specified

tively related to total sperm count and

range of 10-12 g/dL.

concentration in an analysis of data

as epoetin in maintaining hemoglobin

The drug is not indicated for patients with chronic kidney disease not on

according to findings published online

dialysis or for patients with cancer-

ahead of print in Human Reproduction.

related anemia.

fro St m ra ig t h ht eW eb

from 99 men (mean age 36.4 years),

Bone Scans for Prostate Cancer

A recent study pub published in The Journal of U Urology (2012;187:97-102) (2012;187:97-102 showed that 45% of men with low-risk PCa received inappropriate imaging. In a recent online poll, we asked urologists the following question: Should bone scans be ordered for almost every patient newly diagnosed with prostate cancer? Here is how 176 urologists responded.

Renal Function Can Improve Despite CKD, Study Finds D

ata from 12 years of follow-up in the African American Study of Kidney Disease and Hypertension provides strong evidence that renal function can improve in some patients with hypertensive CKD. Of 949 persons with at least three follow-up estimated glomerular filtration rate (eGFR) measurements, 94 (10%) did not develop progressive kidney dysfunction, and 31 (3.3%) demonstrated clearly positive eGFR slopes. The mean slope among these patients was +1.06 (0.12) mL/min per 1.73 m2 per year, compared with -2.45 (0.07) mL/min per 1.73 m2 per year among the remaining patients. Bo Hu, PhD, and fellow researchers found that patients with low levels of proteinuria at baseline and low blood pressure (mean arterial pressure of 92 mm Hg or less) were most likely to exhibit improved eGFR, according to an online report in the Journal of the American Society of Nephrology.

Spread of Bladder Cancer To Lungs Tied to a Protein V

ersican—a protein involved in cancer cell migration—is a driver of lung metastasis in bladder cancer, Dan Theodorescu, MD, PhD, and associates reported online ahead of print in The Journal of Clinical Investigation. High levels of versican are associated with poor prognosis in patients with bladder cancer, and Dr. Theodorescu’s team found that another protein, RhoGDI2, reduced the expression of versican and suppressed lung metastasis. Further analysis indicated that RhoGDI2 suppressed metastasis by altering inflammation in the tumor microenvironment. The investigators also discovered that versican’s ability to attract the macrophages that help cancer cells to thrive and metastasis to occur relies on a third protein, CCL2. Drugs that inhibit this protein are already in clinical trials for other conditions.

RCC Subtype Is Associated With Low Recurrence Rate P

atients with papillary renal cell carcinoma (pRCC) have a low risk of tumor recurrence and cancer-related death after surgery, according to a study of 577 pRCC patients (mean age 62.4 years) across Italy. Most patients (62%) had undergone radical nephrectomy surgery for tumors ranging in size from 3-7 cm (median 4.3 cm). After a median follow-up of 39.2 months, 81% of these individuals were alive and disease-free, 14% had experienced disease progression, 11% had died from the disease, and 5% had died from other causes, researchers reported in BJU International (2012;109:11401146). The 10-year estimated recurrence-free survival (RFS) and cancer-specific survival (CSS) were 73.1% and 83.3%, respectively. Multivariate analyses revealed three independent predictors of cancer-related outcomes: Fuhrman nuclear grade, pathological lymph node stage, and presence of secondary cancer. Because pRCC only affects 10%-15% of kidney cancer patients, the small number of patients enrolled in individuals studies makes it hard to draw meaningful conclusions about how the disease will progress, said lead researcher Vincenzo Ficarra, Associate Professor of Urology at the University of Padua.

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MAY 2012

Renal & Urology News 9

Blood Pressure, Uric Acid Linked in Adolescents INCREASING LEVELS of uric acid are associated with elevated blood pressure among adolescents in the United States, according to researchers.

In a study of 6,036 individuals aged 12-17 years examined in 1999-2006 as part of the National Health and Nutrition Examination Survey (NHANES), researchers at Johns Hopkins University in Baltimore found that each 0.1 mg/dL increment in uric acid level was associated with a 38% increased odds of having elevated BP, after adjusting for age, gender, race/ethnicity, and body mass index. The researchers, led by Lauren F. Loeffler, MD, defined elevated BP as a systolic or diastolic pressure in the 95th or higher percentile for age, gender, and height.

In addition, compared with a uric acid level below 5.5 mg/dL, levels of 5.5 mg/dL or higher were associated with a twofold increased risk of elevated

Hypertension in children frequently is attributable to secondary causes, but in adolescents, primary or “essential” hypertension is the most common etiology, they explained.

Prior studies have shown that uricacid lowering therapy improves BP targets, suggesting that uric acid may be

in the causal pathway in hypertension development, the authors pointed out.

For example, in a randomized, placebo-controlled study of 30 adolescents (aged 11-17 years) with high serum uric acid levels and essential hypertension, researchers showed that allopurinol treatment resulted in a significant reduction

in BP, according to findings published in the Journal of the American Medical Association (2008;300:924-932).

Determining the role of uric acid in hypertension development is complicated by the fact that serum uric acid level and BP are associated with kidney function and other common metabolic disorders. ■

Are you leaving your patients overloaded with sodium?

Elevated BP is twice as likely when serum uric acid levels are 5 mg/dL or higher.

BP, Dr. Loeffler’s team reported online ahead of print in Hypertension.

The investigators noted that their study expands the evidence provided by a previous study showing a positive association between BP and serum uric acid, after adjusting for age, gender, race, weight, height, and sexual maturity rating.

They observed that their study cohort had normal kidney function, “making it a desirable population in which to independently assess the association of uric acid and blood pressure.” Their sample of U.S. adolescents had a high prevalence of overweight and obesity, but the association of uric acid and BP persisted after adjusting for BMI, they pointed out.

Seventeen percent of study subjects were obese; the proportion was 16% among those with normal BP and 41% among those with elevated BP. “Given the burden of chronic hypertension, cardiovascular disease, and chronic kidney disease in adulthood, identifying novel ways to intervene in the prevention and early treatment of hypertension is a priority,” the researchers concluded.

Hypertension is growing in prevalence among children and adolescents in the United States, the authors observed.

With the Phoenix® X36 Hemodialysis System you can track your patient’s sodium levels pre-treatment, during treatment and post treatment for optimal sodium and fluid management.

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10 Renal & Urology News

MAY 2012

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IMAGE COURTESY OF FRANCISCO CESAR CANNEVALE, MD, PhD

Embolization relieves BPH continued from page 1

Using a 1 mm diameter microcatheter threaded into the prostatic arteries, surgeons performed 12 PAE procedures under local anesthesia in 11 patients using resin microspheres as embolizing agents. The men ranged in age from 59 to 78 years, with a mean age of 68.5 years.

Dr. Carnevale’s team used magnetic resonance imaging (MRI) and ultrasound to analyze the prostate and fluoroscopy (digital subtraction angiogram) for the anatomy of the prostate arteries (Figure 1).

Technical success (bilateral PAE) was achieved in 75% of patients. Clinical success (catheter removal and symptom improvement) was achieved in 91%.

Patients urinated spontaneously from 4-25 days (mean 12.1 days) after catheter removal.

The most frequent symptoms related to PAE were mild pain and inflammation in the anal, urethral, and retropubic areas. The researchers observed no major complications and no instances of erectile dysfunction. They followed

Figure 2. (A) Pre-embolization MRI. Axial post-contrast T1- weighted depicting the enlarged prostate due to central gland nodules. Note the presence of the urethral catheter (white arrow). (B) 6 months post-embolization MRI. Axial post-contrast T1-weighted depicting bilateral avascular areas in the central gland (white arrows), and reduction of the prostate size. (C) 18 months post-embolization MRI. Axial post-contrast T1-weighted showing a slight reduction in size and conspicuity of bilateral avascular areas in the central gland and (white arrows), and further reduction of the prostate size.

patients for up to 45 months and found no recurrences.

At the time of treatment, the patients prostate size ranged from 30-90 grams and all patients reported acute urinary retention. Both ultrasound and MRI revealed an overall 30% volume reduction in prostate size at the final follow-up visit (Figure 2).

All patients reported overall clinical improvement in LUTS after 12 months of follow-up and reported a high degree of satisfaction and increased quality

of life after treatment. In addition, all patients had higher urinary flow and reduced detrusor pressure and post-void residual volume compared with preembolization urodynamic studies.

“More than a quarter of a million men undergo surgery for an enlarged prostate every year, at an estimated annual costs of over $1 billion per year because current therapies, including medication, just aren’t working for them,” said Ziv Haskal, MD, Professor of Radiology and Surgery at the University

of Maryland School of Medicine in Balitmore. He was among a group of SIR members who traveled to Brazil to learn about the treatment.

“I saw first-hand how these men responded to treatment. With the possibility of faster recovery, on an outpatient basis, and with no bladder catheters, reduced symptoms, improved urination and fewer potential side effects, prostatic artery embolization could signal a bold new change in accepted prostate therapy.” ■

Translumbar catheters

continued from page 1

biopsy-confirmed benign tumors is unknown,” they wrote.

renal tumors, mostly renal cell carcinoma (RCC), in 142 patients, who received as RFA as primary treatment.

In the study of benign small SRMs, all tumors required only a single treatment session. After a mean follow-up of 45 months, no patient experienced a recurrence, defined as tumor growth and enhancement on follow-up axial imaging, the investigators reported online ahead of print in Urology. The median pre- and postoperative glomerular filtration rate was 77 and 68 mL/ min/1.73 m2, respectively. The authors noted that the study was limited by its retrospective design and small study sample.

“Long-term follow-up imaging might not be required if successful ablation is determined at the initial post-treatment cross-sectional imaging study,” Dr. Cadeddu’s group concluded. Thus, they noted, patient radiation exposure and cost can be reduced.

Intermediate- and long-term published data support the efficacy of RFA in the treatment of RCC, the researchers noted, but little or no data exist that clearly demonstrate the efficacy of RFA in ablating incidental benign tumors. “Moreover, unlike the frequent follow-up imaging required of the treated malignant tumor, the appropriate follow-up imaging protocol of these

Smaller is better In the other study, published online ahead of print in the Journal of Urology, Dr. Cadeddu and his collaborators demonstrated that long-term outcomes of RFA for renal tumors is better when the treated lesions are relatively small.

Pretreatment biopsies were performed for 150 of the 159 tumors. RCC was confirmed in 72% of these tumors.

The median tumor size was 2.4 cm and the median follow-up was 54 months (range 1.5 to 120 months). The threeand five-year disease-free survival rates were significantly better in patients with tumors smaller than 3 cm than in those with tumors 3 cm or larger (92% and 95%, respectively, vs. 79% and 79%, respectively).

The authors concluded that their findings confirm that RFA is associated with successful and durable treatment for small renal masses, especially those smaller than 3 cm. Most treatment failures are local and often can be treated successfully with a second ablative session, they observed.

“Given the increasing incidence of SRMs related to the frequent use of cross-sectional imaging, stratifying RFA success by tumor size allows the physician to best manage patient expectations and refine the treatment discussion,” they concluded. ■

“The transhepatic approach tended to have high catheter thrombosis rates,” Dr. Farrelly said.

He and his colleagues retrospectively studied 33 patients who received THCs from January 2002 to July 2011.

They had a mean age of 51.4 years and

tive therapy. There was no need for any extra procedure.”

The technical success rate was 100%.

The investigators observed only two minor complications (2.2%) and three major complications (3.3%). One minor and one major complication occurred in patients with normal BMI and one minor and two major complications occurred in overweight patients. The most common indications for exchange/ removal were catheter-related infection, catheter malfunction/occlusion, mature permanent vascular access, and conversion to peritoneal dialysis. As of March 2012, three THCs remained in use.

The mean catheter dwell time for all subjects was 86.9 days. It was 86.1 days for patients with normal BMI and 87.8 days for overweight patients. The mean cumulative access site duration was 257 days for the study population as a whole, 216.7 days for patients with a normal BMI and 309.8 days for overweight patients. The catheter-related central venous thrombosis rate was 0.01 per 100 catheter days and the catheter-associated infection rate was 0.51 per 100 catheter days.

“In our practice, experience has led us to prefer a translumbar over a transhepatic route for hemodialysis access placement. We have found no significant difference in how well these catheters function in patients with high and normal BMI’s,” Dr. Farrelly explained. ■

RFA for small renal tumors

continued from page 1

Technical success rate was 100%, with a low rate of complications.

51% were male. Of the 33 patients, 18 had a normal body mass index (BMI) and 15 had a BMI above 25 kg/m2 (overweight).

All subjects had central venous occlusion preventing catheter placement via an internal or external jugular vein.

Ninety-two THC procedures were included in the analysis (39 initial placements, 53 exchanges), with a total of 7,825 catheter days.

“To our knowledge this is the largest study to date looking at this type of catheter,” Dr. Farrelly said.

“We had very low rates of complications and we only had one episode of bleeding. This was successfully managed with blood products and conserva-

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MAY 2012

Renal & Urology News 11

Caution Urged in Use of Older Kidneys DGF in kidneys from donors older than 60 raises the risk of graft loss, according to a new study QUEBEC CITY—Surgeons should proceed with caution when deciding whether to transplant kidneys from donors older than 60 years, a new study suggests.

The retrospective review showed that, among recipients of kidneys from donors older than 60, death-censored graft loss was nearly seven times more likely with delayed graft function (DGF).

“When we think that the kidney may suffer from DGF posttransplant, and the donor is above age 60, we might be more careful of accepting the kidney,” said Sacha De Serres, MD, who presented the findings at the Canadian Society of Transplantation’s 2012 Annual Meeting. “It’s a matter of increasing the pool of kidney safely. You don’t want to discard kidneys, but at the same time you don’t want to transplant a kidney that doesn’t have a good chance of working.”

Dr. De Serres and his colleagues at the University of Laval in Quebec reviewed the relationship between DGF and long-term outcomes among 657 people who received kidneys from brain-dead donors between January 1, 1990 and July 1, 2005. The median follow-up was 106 months.

DGF occurred in 122 recipients.

Patients who received DGF kidneys had a similar average age to those with non-DGF kidneys, and most recipients were male. However, those with DGF kidneys had on average higher body mass indices (26 vs.

25 kg/m2), longer time on dialysis prior to transplantation (37 vs. 26 months), a higher rate of diabetes (21% vs. 13%), a higher rate of induction therapy (30% vs. 14%), and longer warm and cold ischemic times (37 vs. 34 minutes and 25 vs. 20 minutes, respectively), the researchers said.

Donors of DGF kidneys were significantly older than donors of non-

Radiotherapy Added to ADT Is Beneficial

Clinical progression occurred in 43 patients (33.1%) in the ADT-only group and 13 (9.8%) in the combined therapy group. The researchers stated that their data suggest that the PFS benefit is due to locoregional control. The combined therapy group had significantly lower rates of locoregional progression compared with the ADT-only arm (9.8% vs.

29.2%), as well as lower rates of metastatic progression (3% vs. 10.8%).

Overall and disease-specific survival did not differ significantly between treatment arms. Overall survival for the combined therapy and ADT-only arm was 71.4% and 71.5%, respectively, and diseasespecific survival was 93.2% and 86.2%, respectively.

With respect to safety, 10 men in the combined therapy group (8%) and three (2%) in the ADT-only group reported serious adverse events related to treatment, according to the researchers. Four of these patients—all in the combined therapy group—died, but no death was directly related to treatment, the investigators stated.

Study limitations included a relatively small study population and a short followup period, the authors noted. In addition, they acknowledged that the use of radiotherapy to treat 24 patients who progressed after ADT alone may have had an impact on the survival outcome. ■

ADDING RADIOTHERAPY to androgen deprivation therapy (ADT) improves outcomes in patients with locally advanced prostate cancer (PCa) and can be considered a standard treatment option, researchers concluded.

Nicolas Mottet, MD, of Clinique Mutualiste in St. Etienne, France, and colleagues randomized 264 PCa patients with T3-4 or pT3N0M0 disease to receive ADT alone or ADT plus radiotherapy. The primary outcome was the five-year progression-free survival (PFS) using the American Society for Therapeutic Radiology and Oncology (ASTRO) and Phoenix definitions of biochemical recurrence.

After a median follow-up of 67 months, the five-year progression-free survival (PFS) was 60.9% for the combined therapy group versus 8.5% for those who received ADT alone, according to the ASTRO definition, and 64.7% versus 15.4% using the Phoenix definition, investigators reported online ahead of print in European Urology. The differences between the groups were statistically significant.

Sacha De Serres, MD

DGF kidneys (43 vs. 37 years), had higher serum creatinine levels (84 vs.

76 µmol/L) and significantly lower esti mated glomerular filtration rates (90 vs. 104 mL/min.). The characteristics of donors over 60 years of age were similar for those whose kid-

neys did or did not experience DGF post-transplant.

Furthermore, among recipients of kidneys from donors over 60 years of age whose kidneys did or did not experience post-transplant DGF, the characteristics were similar. The only exception was that those with DGF kidneys had longer cold ischemic time (24 vs. 21 minutes), the researchers reported.

In adjusted analyses, among recipients of kidneys from donors aged 60 and older, recipients of DGF kidneys had a 2.67 times increased risk of uncensored graft loss and a 6.98 times increased risk of death-censored graft loss compared with recipients of non-DGF kidneys .

The team also examined death-censored graft loss among DGF kidneys from patients who were or were not expanded-criteria donors (ECDs).

Recipients of ECD kidneys had a 3.3 times increased risk of DGF than recipients of non-ECD kidneys. ■

Sirolimus Lowers NMSC Risk in Transplant Recipients SWITCHING FROM a calcineurin inhibitor

nificantly lower proportion of sirolimus

(CNI) to sirolimus for immunosuppression

recipients experienced new or recurrent

may decrease the risk of nonmelanoma

NMSC (56.4% vs. 80.9%), Dr. Camp-

skin cancer (NMSC) in kidney transplant

bell’s group reported in the American

recipients with a history of NMSC.

Journal of Transplantation.

In a prospective, multicenter study,

Acute rejection occurred in none of

Scott B. Campbell, MD, Consultant

the sirolimus patients and in one of the

Renal Physician at Princess Alexandra

CNI patients. The two groups had a

Hospital, and collaborators randomly

similar incidence of treatment-emergent

assigned 86 kidney transplant recipients

adverse events, but discontinuation

(at least one year post-transplant) with

rates were significantly higher in the

a history of NMSC to continue receiving

sirolimus group (46.2% vs. 0%).

CNI therapy or convert to sirolimus. The

Kidney transplant recipients have

authors noted that sirolimus is known to

greater rates of de novo and recurrent

have antineoplastic effects.

neoplasms compared with the age-

The mean length of follow-up for the

matched general population. Most of

intent-to-treat population (that is, on- and

these cancers involve the skin. NMSC

off-therapy periods) was 1.68 and 1.74

accounts for more than 90% of post-

years for the sirolimus and CNI groups,

transplant skin cancers, the investiga-

respectively. The annual NMSC rate was

tors noted. They cited previous research

significantly lower with sirolimus than

showing that among kidney transplant

with CNI (1.31 vs. 2.48 lesions/patient-

recipients, about 75% of those who

year). Squamous cell carcinoma also

had at least one skin cancer prior to

occurred at a lower rate in the sirolimus

transplantation will develop an average

group. The rate of basal cell carcinoma

of 16-20 NMSC lesions post-transplant,

was similar for both groups. A sig-

with a median of six months to onset. ■

12 Renal & Urology News

MAY 2012

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Renal Nutrition Update A

dvanced glycation end pro ducts (AGEs) are byproducts of non-enzymatic chemical reactions between sugars and amino acids, lipids, or DNA. A wide range of molecules fall into this category.

Perhaps the most familiar of these chemicals to health professionals today is hemoglobin A1c, but several others that are often studied include carboxymethyl-lysine (CML), pentosidine, pyrraline, and methylglyoxal.

These metabolites are associated with oxidative, inflammatory damage through both direct cellular damage and interaction with the receptor for AGEs (RAGE), as well as a subsequent cascade of inflammatory markers.

Because AGEs represent a wide variety of chemicals, a range of testing methods may be used. Blood tests for known AGEs and their precursors are common, but another means of assessment involves skin autofluorescence (J Ren Care 2008;34:207-212). Many of these chemicals exert fluorescent properties and can be detected non-invasively using specific devices.

Intake AGEs may be acquired both exogenously through dietary intake and endogenously. About 10% are absorbed by the gut, but only a third of the absorbed AGEs are excreted in the urine. Dietary intake of AGEs is directly associated with plasma AGE concentration. AGE content increases in foods high in protein and fat and foods treated with high heat. These factors have dramatic impacts on flavor of foods and are often a focus of food scientists due to the flavor appeal.

Risk associations AGEs are associated with a variety or chronic diseases, including end-stage

renal disease (ESRD). AGEs exert tissue damage primarily in two ways. The first involves direct crosslinking with tissues throughout the body. Examples of the results of this crosslinking include wrinkling in the skin, vascular wall stiffening, and albuminuria through interactions with the glomeruli. The second involves the interaction between AGEs and RAGE and the subsequent activation of the inflammatory cascade.

Skin autoflorescence of AGEs has been shown to correlate strongly with cardiac mortality in patients with diabetes, microalbuminuria, and neuropathy.

In addition, autofluorescence of AGEs strongly correlates with overall and cardiovascular mortality in dialysis patients (Am J Kidney Dis 2009;53:138-150).

Among peritoneal dialysis patients, high glucose loads over time tend to promote peritoneal degeneration (Adv Perit Dial 2011;27:22-26). Many studies have found that reduced glucose concentrations and glucose degradation products has increased patient survival, and this effect is attributed to a reduced impact of AGEs. Kidney transplantation is currently the only successful method to reduce AGE load in renal patients. Recent evidence suggests that ACE inhibitors, aspirin, benfotiamine, carnosine, metformin, thiamine, thiazolidinediones, curcumin, resveratrol, green tea, and pyridoxamine may be beneficial (Sell DR, Monnier VM Gerontology 2012; published online ahead of print).

Reducing AGE load in the renal population must be considered from both endogenous and exogenous sources.

Direct dietary intake of AGEs may be elevated due to high intakes of protein in patients with renal disease. Dietary restriction of AGEs reduces serum concentrations, but no health-related outcomes have been documented. A

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© ISTOCKPHOTO.COM/WILLIAM MAHAR

High protein intake may elevate levels of advanced glycation end products BY ALISON L. STEIBER, PhD, RD, LD, AND GRISSIM CLARK CONNERY, MS, RD

Foods high in protein and fat contain more advanced glycation end products.

recent study by Vlassara et al demonstrated that, in a randomized crossover study, sevelamer carbonate significantly reduced HbA1c, serum methylglyoxal, serum CML, triglycerides, 8-isoprostanes, and TNF alpha in 20 patients with CKD 2-4 compared with calcium carbonate (Clin J Am Soc Nephrol 2012; published online ahead of print). These effects were independent of phosphorus reduction.

Additional research The investigators showed in a separate in vitro experiment that sevelamer bound more than 80% of AGEs at intestinal pH, but less than 1% at stomach pH. In a separate study that also compared sevelamer and calcium carbonate in 163 patients, researchers found that pentosidine, an AGE marker, increased significantly in the calcium carbonate group, but remained unchanged in the sevelamer group.

These results indicate that another

possible target for intervention may involve competitive absorption, but this effect would only be advantageous if it is found that exogenous sources contribute to harmful outcomes. Future dietary research could focus on the role of dietary fibers and other nutrients in competitively absorbing AGEs. Additional future directions are in caloric restriction and exercise, both of which also provide possible outlets for AGE reduction. Caloric restriction has been shown to reduce AGEs, but its long-term effectiveness in healthy populations has not been proven.

Exercise has been theorized to aid in AGE reduction through increased rates of collagen turnover (Scand J Med Sci Sports 2005;15:231-240). ■ Dr. Steiber is Coordinator of the Dietetic Internship/Master’s Degree Program and Mr. Connery is Research Coordinator at Case Western Reserve University in Cleveland.

DID YOU MISS LAST MONTH’S RENAL NUTRITION UPDATE? NO PROBLEM. Now you can access all our latest articles with a simple click.

Visit us at renalandurologynews.com/nutrition

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Fewer Cystectomy Patients Have Prolonged LOS THE LIKELIHOOD OF a prolonged length of stay (LOS) in the hospital following radical cystectomy in the United States has decreased in the past decade, a study found.

The study also revealed that Medicare and Medicaid patients are more likely to have a prolonged length of stay.

Marco Bianchi, MD, of the Urologic Research Institute in Milan, and colleagues studied the discharge patterns, including rates of prolonged length of stay and transfer to a facility, for 11,876 patients from the Nationwide Inpatient Sample who underwent a radical cystectomy between 1998 and 2007.

Brief Summary of Prescribing Information for: OMONTYS (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. See full prescribing information for complete boxed warning.

Chronic Kidney Disease: • 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. • 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 OMONTYS 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: • In patients with CKD not on dialysis because of safety concerns in this population [see Warnings and Precautions].

• In patients receiving treatment for cancer and whose anemia is not due to CKD, because ESAs have shown harm in some settings and the benefit-risk factors for OMONTYS in this setting have not been evaluated [see Warnings and Precautions].

• As a substitute for 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.

CONTRAINDICATIONS OMONTYS is contraindicated in patients with: • Uncontrolled hypertension [see Warnings and Precautions].

WARNINGS AND PRECAUTIONS Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism • In controlled clinical trials of other ESAs in patients with CKD comparing higher hemoglobin targets (13 – 14 g/dL) to lower targets (9 - 11.3 g/dL) (see Table 2), increased risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events was observed in the higher target groups.

• 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 than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks.

• In controlled clinical trials of ESAs in patients with cancer, increased risk for death and serious adverse cardiovascular reactions was observed. These adverse reactions included myocardial infarction and stroke.

• In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and deep venous thrombosis (DVT) was observed in patients undergoing orthopedic procedures.

The design and overall results of 3 large trials comparing higher and lower hemoglobin targets are shown in Table 2 (Normal Hematocrit Study (NHS), Correction of Hemoglobin Outcomes in Renal Insufficiency (CHOIR) and Trial to Reduce Cardiovascular Events with Aranesp® Therapy (TREAT)).

The rates of prolonged LOS decreased from 59% in 1998-2001 to 50% in 20052007, while transfer rates remained stable at 14%, according to a report published in The Journal of Urology (2012;187:1206-1209). Prolonged LOS was 42% more likely among patients treated at hospitals with low annual

Table 2 Adverse Cardiovascular Outcomes in Randomized Controlled Trials Comparing Higher and Lower Hemoglobin Targets in Patients with CKD NHS (N = 1265) 1993 to 1996

CHOIR (N = 1432) Time Period of Trial 2003 to 2006 Patients with CKD Patients with CKD not on dialysis with on hemodialysis hemoglobin with coexisting CHF < 11 g/dL Population or CAD, hematocrit not previously 30 ± 3% on administered epoetin alfa epoetin alfa Hemoglobin Target; 14.0 vs. 10.0 13.5 vs. 11.3 Higher vs. Lower (g/dL) 12.6 (11.6, 13.3) 13.0 (12.2, 13.4) Median (Q1, Q3) vs. vs.

Achieved Hemoglobin 10.3 (10.0, 10.7) 11.4 (11.1, 11.6) level (g/dL) Primary Endpoint

TREAT (N = 4038) 2004 to 2009 Patients with CKD not on dialysis with type II diabetes, hemoglobin ≤ 11 g/dL 13.0 vs. ≥ 9.0

12.5 (12.0, 12.8) vs.

10.6 (9.9, 11.3) All-cause mortality, All-cause mortality, All-cause mortality MI, myocardial MI, hospitalization or non-fatal MI ischemia, heart for CHF, or stroke failure, and stroke

Hazard Ratio or 1.28 (1.06 – 1.56) 1.34 (1.03 – 1.74) 1.05 (0.94 – 1.17) Relative Risk (95% CI) Adverse Outcome for All-cause mortality All-cause mortality Stroke Higher Target Group Hazard Ratio or 1.27 (1.04 – 1.54) 1.48 (0.97 – 2.27) 1.92 (1.38 – 2.68) Relative Risk (95% CI) Patients with Chronic Kidney Disease Not on Dialysis OMONTYS is not indicated and is not recommended for the treatment of anemia in patients with CKD who are not on dialysis.

A higher percentage of patients (22%) who received OMONTYS experienced a composite cardiovascular safety endpoint event compared to 17% who received darbepoetin alfa in two randomized, active-controlled, open-label, multi-center trials of 983 patients with anemia due to CKD who were not on dialysis. The trials had a pre-specified, prospective analysis of a composite safety endpoint consisting of death, myocardial infarction, stroke, or serious adverse events of congestive heart failure, unstable angina or arrhythmia (hazard ratio 1.32, 95% CI: 0.97, 1.81).

Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer receiving ESAs OMONTYS is not indicated and is not recommended for reduction of RBC transfusions in patients receiving treatment for cancer and whose anemia is not due to CKD because ESAs have shown harm in some settings and the benefit-risk factors for OMONTYS in this setting have not been evaluated.

The safety and efficacy of OMONTYS have not been established for use in patients with anemia due to cancer chemotherapy. Results from clinical trials of ESAs in patients with anemia due to cancer therapy showed decreased locoregional control, progression-free survival and/or decreased overall survival. The findings were observed in clinical trials of other ESAs administered to patients with: breast cancer receiving chemotherapy, advanced head and neck cancer receiving radiation therapy, lymphoid malignancy, cervical cancer, non-small cell lung cancer, and with various malignancies who were not receiving chemotherapy or radiotherapy.

Hypertension OMONTYS is contraindicated in patients with uncontrolled hypertension.

Appropriately control hypertension prior to initiation of and during treatment with OMONTYS. Reduce or withhold OMONTYS if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions.

Lack or Loss of Response to OMONTYS For lack or loss of hemoglobin response to OMONTYS, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate the patient for the presence of antibodies to peginesatide. In the absence of antibodies to peginesatide, follow dosing recommendations for management of patients with an insufficient hemoglobin response to OMONTYS therapy.

Contact Affymax, Inc. (1-855-466-6689) to perform assays for binding and neutralizing antibodies.

Dialysis Management Patients may require adjustments in their dialysis prescriptions after initiation of OMONTYS. Patients receiving OMONTYS may require 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%. The majority of patients with CKD will require supplemental iron during the course

caseloads compared with those treated at hospitals with high annual caseloads.

Medicaid and Medicare patients were 66% and 17% more likely to experience a prolonged LOS, respectively.

Dr. Bianchi’s team defined prolonged LOS as a stay beyond the median LOS for the entire cohort. ■

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MAY 2012

Renal & Urology News 15

Disparities Found in Partial Nephrectomy Use PARIS—Partial nephrectomy (PN) rates have increased dramatically, but this surgical approach is underused in certain patient populations, according to data presented at the 27th Annual Congress of the European Association of Urology.

The data came from a study of 375,986 patients in the United States

who underwent either PN or radical nephrectomy from 1998 to 2009.

During this period, the PN rate rose from 6% to 28%, according to investigator Maxine Sun, PhD, who reported the study findings. In addition, the study showed that increasing age and multiple comorbidities were

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 observed during clinical trials with OMONTYS are discussed in greater detail in other sections of the labeling: • Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see Warnings and Precautions] • Hypertension [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 0.07mg/kg and 113 U/week/kg of epoetin.

Table 3 summarizes the most frequent adverse reactions (≥ 10%) in dialysis patients treated with OMONTYS. Table 3 Adverse Reactions Occurring in ≥10% of Dialysis Patients treated with OMONTYS Adverse Reactions

Dialysis Patients Treated with OMONTYS (N = 1066)

Gastrointestinal Disorders Diarrhea 18.4% Nausea 17.4% Vomiting 15.3% Respiratory, Thoracic and Mediastinal Disorders Dyspnea 18.4% Cough 15.9% Injury, Poisoning and Procedural Complications Arteriovenous Fistula 16.1% Site Complication Procedural Hypotension 10.9% Nervous System Disorders Headache 15.4% Musculoskeletal and Connective Tissue Disorders Muscle Spasms 15.3% Pain in Extremity 10.9% Back Pain 10.9% Arthralgia 10.7% Vascular Disorders Hypotension 14.2% Hypertension 13.2% General Disorders and Administration Site Conditions Pyrexia 12.2% Metabolism and Nutrition Disorders Hyperkalemia 11.4% Infections and Infestations Upper Respiratory Tract Infection 11.0%

Dialysis Patients Treated with Epoetin (N = 542) 15.9% 19.6% 13.3% 19.4% 16.6% 16.6% 12.5% 15.9% 17.2% 12.7% 11.3% 9.8% 14.6% 11.4%

associated with a lower rate of PN. “We also found that patients with private insurance were more likely to get partial nephrectomy relative to Medicare and Medicaid patients,” Dr. Sun said.

Compared with privately insured patients, Medicare, Medicaid, and

binding antibodies in patients dosed subcutaneously (1.9%) as compared to those dosed intravenously (0.7%). Peginesatide neutralizing antibodies were detected in vitro using a cell-based functional assay in 21 of these patients (0.9%). In approximately 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 3 doses (0.01 to 50 mg/kg/dose). In rats and rabbits, adverse embryofetal effects included 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 ≥ 1 mg/kg and the malformations (cleft palate and sternoschisis, and variations in blood vessels) were mostly evident at doses of ≥ 10 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 in patients on dialysis. In a separate embryofetal developmental study in rats, reduced 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 ≥ 0.5 mg/kg/dose of peginesatide. In a separate embryofetal developmental study in rabbits, adverse findings 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 It is not known whether peginesatide is excreted in human milk. Because many drugs are 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].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide).

uninsured patients were 10%, 17%, and 21% less likely to undergo PN, the study found.

Furthermore, patients with higher income and those treated at high-volume and teaching hospitals were more likely to receive PN. Patients treated at teaching hospitals were 46% more likely to undergo PN than those treated at non-teaching hospitals. Compared with patients in the lowest quartile of income (based on zip code), those in the highest quartile were 15% more likely to undergo PN. PN rates did not differ significantly by race or gender or by urban or rural hospital location. ■

Study: PDE-5 Inhibitors May Ease LUTS PARIS—Phosphodiesterase-5 (PDE-5) inhibitors significantly improve lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) and can be considered as an alternative treatment for BPH-related LUTS in men with or without erectile dysfunction, researchers reported at the 27th Annual Congress of the European Association of Urology.

The investigstors conducted a systematic review and meta-analysis of data from 12 randomized controlled trials that included a total of 3,492 patients. Seven trials (with a total of 3,214 patients) compared PDE-5 inhibitors with placebo and five (with a total of 216 patients) comparing a combination of PDE-5 inhibitors and alpha blockers with alpha blockers alone.

Combining the results of those trials, the use of PDE-5 inhibitors alone

14.0%

Marketed by: Affymax, Inc. Palo Alto, CA 94304

was associated with a significant

11.8%

Distributed and Marketed by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015

of Erectile Function (IIEF) score and

For more detailed information, see the full prescribing information for OMONTYS at www.omontys.com or contact Takeda Pharmaceuticals America, Inc.

(IPSS), but not peak flow rate at

12.4%

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 reactions have been reported in patients treated with OMONTYS. Discontinue OMONTYS and administer appropriate therapy if a serious allergic, anaphylactic or infusion-related reaction occurs.

Immunogenicity Of the 2357 patients tested, 29 (1.2%) had detectable levels of peginesatidespecific binding antibodies. There was a higher incidence of peginesatide-specific

improvement in International Index International Prostate Symptom Score

OMONTYS is a trademark of Affymax, Inc. registered in the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. All other trademarks are the property of their respective owners. ©2012 Takeda Pharmaceuticals America, Inc. March 2012 PEG096 R1

the end of the study compared with placebo. The combination of PDE-5 inhibitors and alpha blockers improved IIEF score, IPSS, and peak flow rate

L-DSG-0312-1

03-12-00027-A.; DSG-00057.

at the end of the study compared with alpha blockers alone. ■

16 Renal & Urology News

MAY 2012

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Kidney Stone Prevalence Is Increasing Study also finds that non-Hispanic blacks and Hispanics are less likely than whites to report stones KIDNEY STONES are a growing problem in the United States, new data suggest.

Researchers who analyzed data from 12,110 participants in the 20072010 National Health and Nutrition Examination Survey (NHANES) found that 8.8% of respondents reported a history of kidney stones, up fsrom 5.2% reported by 1994 NHANES respondents, according to an online report in European Urology. According to the investigators, “the increase is likely related to dietary and lifestyle factors.”

The prevalence increased for men and women. The 2007-2010 data revealed that 10.6% of men and 7.1% of women reported having kidney stones, up from 6.3% and 4.1%, respectively, in 1994.

Kidney stones were more common among obese individuals than among normal-weight subjects (11.3% vs.

6.1%). Compared with normal-weight individuals, obese respondents had a 55% increased risk of kidney stones.

Fracture Risk Not Higher in Living Donors LIVING KIDNEY donors are at not increased fracture risk, according to a Canadian study.

Amit X. Garg, MD, PhD, of Western University in London, Ontario, and collaborators reviewed the medical charts of 2,015 living adults who donated a kidney in Ontario between 1992 and 2009. They compared this group with 20,150 matched nondonors from the healthiest portion of the general population.

“Presuming obesity as a marker for the metabolic syndrome, which is linked epidemiologically and physiologically to risk of kidney stones, the epidemic of obesity in the United States is a likely explanation for the dramatic rise in the prevalence of stone disease,” the researchers observed.

The investigators, led by Charles D. Scales Jr., MD, of the University of California-Los Angeles, also found that non-Hispanic blacks and Hispanics were 63% and 40% less likely than whites, respectively, to report a history of kidney stones.

Additionally, respondents with a history of gout had a nearly twofold increased likelihood of kidney stones.

“Given the temporary disability imposed by a symptomatic stone event, these findings have important implications for a disease that burdens a primarily working-age population,” the authors concluded. “These findings suggest that the direct and indirect costs of kidney stones will continue to rise in

Kidneys Stones on the Rise A comparison of data from the 1994 and 2007-2010 National Health and Nutrition Examination Surveys reveals a significant increase the proportion of individuals with a self-reported history of kidney stones.

1994 2007- 2010

20 15 10 5 0

Men

Women

the United States, and efforts should be directed toward ameliorating the burden of urinary stone disease.”

Dr. Scales and his colleagues observed that prospective data from the Health Professionals Follow-up Study and the Nurses’ Health Study I and II found associations between inci-

dent stone disease and weight gain, body mass index, and diabetes mellitus. For example, researchers at the Channing Laboratory of Brigham and Women’s Hospital in Boston, found that stone formation was 44% more likely in men weighing more than 220 pounds compared with those weighing less than 150 pounds, after adjusting for age, dietary factors, fluid intake, and thiazide use, according to findings published in the Journal of the American Medical Association (2005;293:455462). The risk of stone formation was 33% greater for men with a body mass index (BMI) greater than 30 kg/m2 compared with those who had a BMI of 21-22.9 kg/m2.

For older and younger women, the risk of stone formation was increased nearly twofold for those weighing more than 220 pounds compared with women weighing less than 150 pounds. The risk was increased twofold for those with a BMI above 30 compared with those with a BMI of 21.22.9. ■

Hypoxia Predicts PCa Recurrence MEN WITH intermediate-risk prostate cancer (PCa) who have low oxygen levels in their prostate tumors prior to radiation treatment are at increased risk of PCa recurrence, according to researchers.

“This is the first study to identify a relationship between pretreatment prostate hypoxia and local recurrence after radiotherapy,” the researchers noted in Clinical Cancer Research (2012;18:2108-2114).

Michael Milosevic, MD, Professor of Radiation Oncology at the University of Toronto, and his colleagues measured tumor oxygen levels in 247 men with localized intermediate-risk PCa prior

to radiation therapy. After a median follow-up of 6.6 years, the five-year biochemical relapse-free rate was 78%.

Tumor hypoxia, defined as an oxygen percentage less than 10 mm Hg, predicted early biochemical failure (PSA increase of 2 ng/mL or more above nadir) after treatment. The effect of hypoxia on biochemical failure diminished over time.

“Hypoxia often arises early in solid tumor development because of imbalances between oxygen supply and consumption and leads to a cascade of genetic and molecular signaling events that together influence biologic evolution, clinical behavior, and treatment

response,” the researchers explained.

The findings “provide a strong rationale for integrating radiotherapy with new hypoxia-targeted treatment approaches in future clinical trials,” the authors observed.

The researchers noted that a validation cohort is required to confirm their findings The patients in the study had a median age of 71 years (range 55-83 years). Of the 247 men, 71 (29%) had a Gleason score of 6, 163 (66%) had a Gleason score of 7, and 13 (5%) had a Gleason score of 8 or 9. The study population had a median PSA level of 7.8 ng/mL. ■

The rate of fragility fracture was no higher in donors compared with nondonors (16.4 vs. 18.7 events per 10,000 person-years), Dr. Garg’s group reported online ahead of print in the American Journal of Kidney Diseases. The researchers observed no significant difference in the proportion of older adults in followup who received a bisphosphonate prescription (17.1% vs. 15.2%). ■

Heart Failure Linked to Orthostatic Hypotension ORTHOSTATIC HYPOTENSION predicts incident heart failure among middle-aged adults, especially those aged 45-55 years old, researchers reported online ahead of print in Hypertension.

In a study of 12,363 participants in the Atherosclerosis Risk in Communities

study, orthostatic hypotension— defined as a decrease of 20 mm Hg in systolic pressure or a decrease of 10 mm Hg in diastolic pressure—was associated with a 54% increased risk of incident heart failure after a follow-up of 17.5 years. The risk was increased by 90% among participants aged 55

years or younger and by 37% among those younger than 55, according to the investigators .

“Orthostatic measures may enhance risk stratification for future heart development,” Christine D. Jones, MD, of the University of North Carolina in Chapel Hill, and colleagues concluded. ■

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MAY 2012

Renal & Urology News 17

CME FEATURE

Managing Bone Disease in Kidney Transplant Recipients Pre-existing renal osteodystrophy at the time of transplantation, reduced renal function, and transplantation-specific therapies are the main contributing factors.

Release Date: May 2012 Expiration Date: May 2013 Estimated time to complete the educational activity: 1 hour This activity is jointly sponsored by Medical Education Resources and Haymarket Media, Inc. STATEMENT OF NEED: Bone disease is a well-known complication in kidney transplant recipients, who experience a rapid loss of bone mass, especially during the early post-transplant period.

The management of this bone loss often is insufficient and nephrologists and other clinicians involved in the care of renal transplant recipients need to understand mineral bone disease (MBD) in these patients and be aware of the various treatment options available to prevent bone loss.

TARGET AUDIENCE: This activity has been designed to meet the educational needs of nephrologists and others clinicians involved in the care of renal transplant recipients.

EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Explain the major factors that contribute to MBD, including the effects of transplantationrelated treatments.

• Review appropriate therapeutic options to manage post-renal-transplant bone loss.

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 CreditTM. 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 its 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 • Miklos Z. Molnar, MD, PhD

Reported Financial Relationship No financial relationships to disclose • Kamyar Kalentar Zadeh, MD, Grants/Research Support: NIH, NKF, Abbott, Shire Consultant: NIH, Abbott, Amgen, DaVita, Fresenius-Kabi, MPH, PhD Genzyme, Otsuka, Shire, Vifor Speakers’ Bureau: Abbott, Amgen, Fresenius-Kabi, Otsuka, Shire The content managers, Jody A. Charnow and Marina Galanakis, of Haymarket Media, Inc., 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 May 2012 through May 2013, participants must: 1) read the learning objectives and faculty disclosures, 2) study the educational activity, 3) complete the posttest and submit it online. Physicians may register at www.myCME.com/renalandurologynews, and 4) complete the evaluation form online.

A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better.

BY MIKLOS Z. MOLNAR MD, PhD, AND KAMYAR KALANTAR-ZADEH, MD, MPH, PhD

well as treatment to prevent further bone loss is often insufficient. In this review article, we have summarized the updated information about prevalence, consequences, and therapeutic options of mineral and bone disorders (MBD) in kidney transplant recipients.

O

Prevalence of Renal Osteodystrophy by Type

rgan transplantation has become a fairly common and effective modality for the treatment of several types of end-stage conditions, including chronic kidney disease (CKD).

Advances in immunosuppressive agents and transplant techniques have led to improved long-term graft and patient survival. Successful transplantation is capable of reversing many complications of end-stage kidney disease; however, disturbances of bone and mineral metabolism may persist, while new bone disorders may also emerge as a result of transplant related medications such as corticosteroids. Particularly during the early post-transplant period, renal allograft recipients experience a rapid loss of bone mass. Although bone disease has been recognized as a common complication in kidney transplant recipients, the routine application of adequate diagnostic tools as

Renal osteodystrophy is traditionally classified into four major groups: hyperparathyroid bone disease, adynamic bone disease, mixed renal osteodystrophy, and osteomalacia.1,2 Table 1 shows the main characteristics of different types of MBD in kidney transplant recipients.

The precise histologic patterns of bone disease after transplantation are not well defined, because only in very few studies was the bone biopsy performed in kidney transplant recipients. The results of the few early reports on the bone abnormalities in patients after renal transplantation are somewhat conflicting. Heterogeneity of bone lesions has been noted in these early studies,3,4 whereas others report a high prevalence of: high bone turnover associated with persistence of secondary hyperparathyroidism;5 normal bone formation;4 or

Miklos Z. Molnar, MD, PhD is a Research Associate at Harold Simmons Center for Chronic Disease Research and Epidemiology at the Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, California.

Kamyar Kalantar-Zadeh, MD, MPH, PhD, is Professor of Medicine, Pediatrics and Epidemiology at UCLA David Geffen School of Medicine and UCLA School of Public Health, and Director of the Harold Simmons Center for Chronic Disease Research and Epidemiology.

18 Renal & Urology News

MAY 2012

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low bone turnover.6,7 Prolonged mineralization lag time without osteoid accumulation has been found in some studies,6-8 whereas frank osteomalacia has rarely been observed.3 The bone biopsy studies from the modern immunosuppressive era (21st century) suggest that the adynamic bone disorders and mixed renal osteodystrophy are the two most common abnormalities in kidney transplant recipients. In a study of 57 unselected prevalent kidney transplant patients, cancellous bone volume/tissue volume was below normal compared with 56% of age- and gender- matched control subjects.9 Bone turnover was low in 46%, normal in 28%, and elevated in 26% of patients. Mineralization was prolonged in 88% of patients, including nine with osteomalacia and 12 with focal osteomalacia.9 Similar results were found in 20 patients examined before and after kidney transplantation.10 Bone histomorphometric diagnoses at pretransplant were adynamic bone disease (12 patients); mixed bone disease (three patients); mild disease (three patients); and osteitis fibrosa (two patients). After transplantation, 11 patients had adynamic bone disease, eight with mild disease. One patient had osteomalacia.10 However, the opposite results were found in study from Germany.11 Mild osteitis fibrosa and osteitis fibrosa, the most frequent forms of renal osteodystrophy, were observed in 13 (22.8%) and 14 patients (24.6%), respectively. Mixed uremic osteodystrophy was found in seven patients (12.3%), adynamic renal bone disease in three patients (5.3%), and osteomalacia in two (3.5%).11 In 13 patients (22.8%), reduced bone mass and structural damage without typical signs of renal osteodystrophy, such as endosteal fibrosis or osteoclasia, were detected, and five patients (8.7%) showed normal histomorphometric parameters.11 Hence, in stable kidney transplant recipients low turnover bone disease (adynamic and osteomalacia) is the most common bone disorder. These patients exhibit decreased mineral apposition rate and delayed mineralization explained by the dramatic decrease in parathyroid hormone (PTH) levels in patients with relatively mild bone disease before transplantation6 and high dose of glucocorticoids.9 Moreover, a study by Velasquez-Forero et al. showed mainly alterations that were consistent with adynamic bone disease

© SPL / PHOTO RESEARCHERS, INC.

CME FEATURE

Osteomalacia, as shown here, is among the common mineral and bone disorders experienced by renal transplant recipients.

and increased deposition of iron in the mineralization front;7 other studies have shown decreased bone formation and prolonged mineralization lag time in the presence of persisting bone resorption.8 There are discrepancies among the findings described in various studies, but the main alterations in bone remodeling after renal transplantation appear to consist of a decrease in bone formation and mineralization in the face of persistent bone resorption, producing an imbalance in remodeling and favoring resorption. Likewise, the defective bone formation may be a consequence of alterations in osteoblast function, decreased osteoblastogenesis, or increased osteoblast death rate.

Consequences Bone Mineral Density Disturbances and Fractures: Loss of bone mass after kidney transplantation occurs primarily in the first 12 months, predominantly in cortical bone. The most rapid decrease in bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) occurs in the first six months post-transplant, and seems to slow thereafter, possibly reflecting a decreasing use of corticosteroids.

Rojas et al. showed that osteoid volume, osteoid thickness, osteoid resorption surface, and osteoclast surface were above the normal range before transplant and remained increased approximately 35 days after transplantation.12 However, osteoid and osteoblast surfaces, which also were increased before transplantation, significantly decreased within approximately 35 days posttransplant.12 There also was inhibition

of bone formation and mineralization and apoptosis, which was associated with dose of glucocorticoids, also appeared after transplantation.12 BMD has been reported to decrease a mean of 5.5–19.5% during the first six months,13 but only 2.6%–8.2% between months 6 and 12 after transplantation,14 and only 0.4%-4.5% thereafter.15 The overall fracture risk after renal transplantation is 3.6–3.8-fold higher than in healthy individuals,16,17 and is 30% higher during the first three years after transplantation than in patients on dialysis.16 In a retrospective study with follow-up time up to 33 years, the age and diabetic nephropathy were independent predictors of fracture risk generally, while higher activity status was protective.17 Additional risk factors for fracture that have been identified are female gender, and combined kidney–pancreas transplantation.

Similarly to the mortality risk curve of transplant patients compared with waitlisted dialysis patients, the relative risk of hip fracture associated with transplantation was 1.34-fold greater when compared with dialysis but then decreased by 1% per month until the estimated risk became equal for dialysis and transplant recipients approximately 630 days after transplantation.16 Renal transplant recipients are at particular risk of vertebral fracture; this risk is greater than their risk of lower extremity fractures.17

Contributors to MBD There are several contributing factors, but the three main factors are preexisting renal osteodystrophy at time of

renal transplantation; transplantationspecific therapies; and reduced renal function.

Pretransplant Renal Osteodystrophy: Almost all patients undergoing kidney transplantation suffer from pre-existing bone disorders caused by chronic renal insufficiency and concomitant diseases. Consequently, posttransplant renal osteopathy cannot be considered as a separate entity; rather, its course is significantly conditioned by changes in bone structure and mineral metabolism that existed before engraftment.

In the past several years, the spectrum of renal osteodystrophy in dialysis patients has changed considerably. The incidence and prevalence of low bone turnover, particularly adynamic bone disease, has increased steadily, becoming the main type of bone alteration in many centers. To help clarify the interpretation of the bone biopsy, a 2006 National Kidney Foundation (NKF) working group on renal osteodystrophy published a position paper suggesting that renal bone disease should be characterized by three key histologic descriptors: turnover, mineralization, and volume. Using this new system, a survey of 544 bone biopsy samples from patients with CKD stage 5 on dialysis, found that bone turnover was low in 52% of samples, normal in 21%, and high in 27%. Defective mineralization was found in only 3%.18 Cancellous bone volume was low in 32%, normal in 30%, and high in 38%.19 In the assessment of bone volume abnormalities, it is important to differentiate between cortical and cancellous bone.

Loss of cortical bone occurs mainly in patients with high turnover bone disease, while loss of cancellous bone is often seen in patients with low bone turnover.18 The mechanical function of bone is served mainly by cortical bone, whereas the metabolic function is primarily served by cancellous bone.

The clinical outcome of decreased bone strength is fracture, while abnormal metabolic activity results in the inability to maintain mineral homeostasis, which is associated with vascular and soft tissue calcifications.

Effect of Transplantation-Specific Therapies: Several studies suggest that post-transplantation immunosuppressive therapy constitutes a major factor in the pathogenesis of post-transplantation bone disease.20 During the first

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six months after transplantation, rapid bone loss secondary to glucocorticoidinduced acceleration in bone remodeling occurs in cancellous bone.6 A study that involved serial bone biopsies at 22 days and 160 days after transplantation reported impaired osteoblastogenesis and early osteoblast apoptosis.12 The etiology of glucocorticoid-induced bone disorder is multi-factorial. Steroids are directly toxic to osteoblasts and lead to increased osteoclast activity.21 They also have other effects that promote calcium loss and the development of osteopenia. These include decreased calcium absorption in the gut, reduced gonadal hormone production, diminished insulin-like growth factorâ&#x20AC;&#x201C;1 production, decreased sensitivity to PTH, increased in receptor activator of NF-kappa beta ligand (RANKL), and increased osteoclastogenesis.

Both cyclosporin and tacrolimus use have been linked to osteoporosis in clinical studies,22,23 but populationbased studies that have focused on fracture risk could not establish an association between use of calcineurin inhibitors and fracture risk.17,24 Although mycophenolate mofetil, sirolimus, and azathioprine did not affect bone volume in rodents, a recent in vitro study suggests sirolimus might interfere with the proliferation and differentiation of osteoblasts,25 and everolimus reduced cancellous bone loss in ovarectomized rats by decreasing osteoclastmediated bone resorption.26 Effects of Reduced Renal Function: It has been postulated that patients with post-transplantation CKD stage 3-5 are at increased risk for the persistent or de novo development of hyperparathyroidism.27 A study with more than 900 transplant patients, intact PTH showed negative correlation with estimated GFR in CKD stages 3-5 (rho = -0.289, P < 0.001).27 Additionally, high PTH values correlated with significant bone loss at the hip.28

MBD Therapy As yet, no randomized controlled trials in transplant recipients have examined bone-specific therapies on patientlevel outcomes, including mortality or fractures. Additionally, there are insufficient data to suggest any bonespecific therapies after the first year of kidney transplantation. There are several potential treatment options:

Corticosteroid Withdrawal or Avoidance: The rationale for minimizing corticosteroid exposure is compelling and provided by well-established risks of osteoporosis, avascular necrosis, and other side effects. One study found beneficial effects on BMD after early tapering of prednisolone.29 Bisphosphonates: In four studies that used multiple doses of pamidronate during the initial months after renal transplantation, prevention of bone loss occurred, even after the treatment was discontinued.30 All studies showed that the administration of pamidronate prevented bone loss in a short period after transplantation, but most of these patients already had or developed low turnover bone disease.30 Similar results were found when other bisphosphonates were administered.31-35 Compared with vitamin D sterol therapy, administration of bisphosphonates significantly improves BMD at the femoral neck and lumbar spine in kidney transplant recipients.36 Vitamin D Analogs and Vitamin D Receptor Activators: In a wellcontrolled, blinded study, Josephson et al. showed that kidney trans plant recipients who were given calcium and calcitriol had significantly less bone loss in the lumbar spine and increased BMD in the distal radius and femoral neck compared with transplant patients given calcium alone or placebo.37 The patients given calcium and calcitriol did not develop significant hypercalcemia or deterioration of kidney function during the two years of the study. Unfortunately, no studies have evaluated fracture rates. 37 Torres et al. demonstrated that therapy with low-dose calcium supplements for one year plus intermittent calcitriol for three months after transplantation is safe, decreases PTH levels rapidly, and prevents bone loss at the proximal femur.38 Compared with placebo, calcidiol and oral calcium increased BMD at the lumbar spine and femoral neck.39 Paricalcitol, a selective vitamin D receptor activator, is indicated in the prevention and treatment of secondary hyperparathyroidism.

Preliminary results of a randomized controlled trial demonstrated changes in urinary peptides due to treatment with paricalcitol,40 but no published study has assessed the association of bone fracture, BMD, or outcomes with administration of paricalcitol. Hence,

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Renal & Urology News 19

Table 1: Main characteristics of different type of mineral and bone disorders in kidney transplant recipients Type of bone disease

Main characteristics

Potential harm effects

Hyperparathyroid

Marked increase in bone turnover, irregularly shaped trabecules displaying numerous abnormal remodeling sites, and an unusually high number of bone cells with irregular arrangement and shape.

Increased risk of fracture Mortality and graft loss risk

Adynamic

Reduced bone volume and mineral- Increased cardiovascular ization is paralleled by a decrease risk/calcifications Increased in bone formation. It is also charac- risk of fracture terized by the presence of few osteoid seams and few osteoblasts. Osteoclast number may be low, normal, or high.

Mixed renal osteodystrophy

Primarily caused by defective mineralization with or without increased bone formation and by increased parathyroid hormone activity in bone. These features coexist to varying degrees in different patients. Bone volume is extremely variable and depends on a dominant pathogenic cause.

Other features of mixed uremic osteodystrophy include increased numbers of heterogeneous remodeling sites and, typically, an increase in osteoclast number.

Increased risk of fracture Mortality and graft loss risk

Osteomalacia

Accumulation of unmineralized matrix in which a decrease in mineralization precedes or is more pronounced than the inhibition of collagen deposition.

Increased risk of fracture

treatment with calcitriol significantly improves the BMD at the femoral neck and lumbar spine without a significantly higher risk of hypercalcemia.36 Calcimimetics: During the past few years, the calcimimetic agent cinacalcet was evaluated for the treatment of hypercalcemia in renal graft patients with ongoing secondary hyperparathyroidism. As shown in some posttransplant trials, cinacalcet successfully reduced elevated serum calcium and PTH levels with no negative effect on renal function. It also was shown to be safe in kidney transplant recipients. A favorable effect of cinacalcet on BMD in renal transplant patients was demonstrated in a few small studies.41 Other Treatments: Another therapeutic agent studied after kidney transplantation is teriparatide, recombinant human PTH. A trial from 2008 showed that teriparatide administered to kidney transplant patients for six months was safe but did not alter BMD in the lumbar spine or distal radius compared with the placebo group.42 However,

BMD at the femoral neck remained stable in those given teriparatide, compared with a decrease in the placebo group. In addition, after six months, no significant differences between the two groups were detected in fractures, bone histology, vitamin D levels, PTH levels, kidney function, or serologic bone markers. 42 Calcitonin had no effect on mortality, graft loss, and risk of fracture in patients after kidney transplantation.36

Conclusions Bone disease after kidney transplantation is characterized mainly by loss of bone volume and the presence of mineralization problems, which result in low turnover bone disease in most patients. The three main contributing factors are pre-existing renal osteodystrophy at time of renal transplantation, transplantation-specific therapies, and reduced renal function. At this time, no well-established therapeutic approaches that provide bone anabolic

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CME FEATURE effects in renal transplant recipients are available. Vitamin D and bisphosphonate can be used for treatment of mineral bone disorders after transplantation, but low turnover bone disease, especially adynamic bone disease, is the most frequent abnormality, so bone biopsy should be considered before administration of bisphosphonates. ■ REFERENCES 1. Hruska KA, Teitelbaum SL. Renal osteodystrophy.

N Engl J Med 1995;333:166-174.

2. Wang M, Hercz G, Sherrard, et al. Relationship between intact 1-84 parathyroid hormone and bone histomorphometric parameters in dialysis patients without aluminum toxicity. Am J Kidney Dis 1995;26:836-844.

3. Bonomini V, Feletti C, Di Felice A, Buscaroli A. Bone remodelling after renal transplantation (RT). Adv Exp Med Bio 1984;17:207-216.

4. Sanchez CP, Salusky IB, Kuizon BD, et al. Bone disease in children and adolescents undergoing successful renal transplantation. Kidney Int 1998;53:1358-1364.

5. Parfitt AM: Hypercalcemic hyperparathyroidism following renal transplantation: differential diagnosis, management, and implications for cell population control in the parathyroid gland. Miner Electrolyte Metab 1982;8:92-112.

6. Julian BA, Laskow DA, Dubovsky J, et al. Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med 1991;325:544-550.

7. Velasquez-Forero F, Mondragón A. Herrero B, Peña JC. Adynamic bone lesion in renal transplant recipients with normal renal function. Nephrol Dial Transplant 1996;11 Suppl 3:58-64.

8. Carlini RG, et al.: What are the bone lesions in patients with more than four years of a functioning renal transplant? Nephrol Dial Transplant 1998;13 Suppl 3:103-104.

9. Monier-Faugere MC, Mawad H, Qi Q, et al.High prevalence of low bone turnover and occurrence of osteomalacia after kidney transplantation. J Am Soc Nephrol 2000;11:1093-1099.

10. Cruz EA, Lugon JR, Jogetti V, et al. Histologic evolution of bone disease 6 months after successful kidney transplantation. Am J Kidney Dis 2004;44:747-756.

11. Lehmann G, et al.: Renal osteodystrophy after successful renal transplantation: a histomorphometric analysis in 57 patients. Transplant Proc 2007;39:3153-3158.

12. Rojas E, Carlini RG, Clesca P, et al The pathogenesis of osteodystrophy after renal transplantation as detected by early alterations in bone remodeling.

Kidney Int 2003;63:1915-1923.

13. Mikuls TR, Julian BA, Bartolucci A, Saag KG. Bone mineral density changes within six months of renal transplantation. Transplantation 2003;75:49-54.

14. Brandenburg VM, et al.: Early rapid loss followed by long-term consolidation characterizes the development of lumbar bone mineral density after kidney transplantation. Transplantation 2004;77:1566-1571.

15. Cruz DN, Wysolmerski JJ, Brickel HM, et al. Parameters of high bone-turnover predict bone loss in renal transplant patients: a longitudinal study. Transplantation 2001;72:83-88.

16. Ball AM, Gillen DL, Sherrard D, et al. Risk of hip fracture among dialysis and renal transplant recipients.

JAMA 2002;288:3014-3018.

17. Vautour LM, Melton LJ 3rd, Clarke BL, et al.

Long-term fracture risk following renal transplantation: a population-based study. Osteoporos Int 2004;15:160-167.

18. Malluche HH, Lee J, Wang G, et al. Usefulness of the new TMV classification of renal osteodystrophy. J Am Soc Nephrol 2008;19:38A. Abstract presented at Kidney Week 2008.

19. Moe S, Drüeke T, Cunningham J, et al.Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006;69:1945-1953.

20. Epstein S. Post-transplantation bone disease: the role of immunosuppressive agents and the skeleton.

J Bone Miner Res 1996;11:1-7.

21. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med 1990;112:352-364.

22. Ugur A, Guvener N, Işiklar I, et al. Osteoporosis after renal transplantation: single center experience.

Transplantation 2001;71:645-649.

23. Marcén R, Caballero C, Pascual J, et al. Lumbar bone mineral density in renal transplant patients on neoral and tacrolimus: a four-year prospective study.

Transplantation 2006;81:826-831.

24. Patel S, Kwan JT, McCloskey E, et al. Prevalence and causes of low bone density and fractures in kidney transplant patients. J Bone Miner Res 2001;16:1863-1870.

25. Singha UK, Jiang Y, Yu S, et al.Rapamycin inhibits osteoblast proliferation and differentiation in MC3T3-E1 cells and primary mouse bone marrow stromal cells.

J Cell Biochem 2008;103:434-446.

26. Kneissel M, Luong-Nguyen NH, Baptist M, et al.

Everolimus suppresses cancellous bone loss, bone resorption, and cathepsin K expression by osteoclasts. Bone 2004;35:1144-1156.

27. Ambrus C, Molnar MZ, Czira ME, et al. Calcium, phosphate and parathyroid metabolism in kidney transplanted patients. Int Urol Nephrol 2009;41:1029-1038.

28. Akaberi S, Lindergård B, Simonsen O, Myberg G. Impact of parathyroid hormone on bone density in long-term renal transplant patients with good graft function. Transplantation 2006;82:749-752.

29. van den Ham EC, Kooman JP, Christiaans ML, van Hooff JP. The influence of early steroid withdrawal on body composition and bone mineral density in renal transplantation patients. Transpl Int 2003;16:82-87.

30. Coco M, Glicklich D, Faugere MC, et al. Prevention of bone loss in renal transplant recipients: a prospective, randomized trial of intravenous pamidronate.

J Am Soc Nephrol 2003;14:2669-2676.

31. Nowacka-Cieciura E, Cieciura T, Baczkowska T, et al.

Bisphosphonates are effective prophylactic of early bone loss after renal transplantation. Transplant Proc 2006;38:165-167.

32. Grotz W, Nagel C, Poeschel D, et al. Effect of ibandronate on bone loss and renal function after kidney transplantation. J Am Soc Nephrol 2001;12:1530-1537.

33. Haas M, Leko-Mohr Z, Roschger P, et al.Zoledronic acid to prevent bone loss in the first 6 months after renal transplantation. Kidney Int 2003;63:1130-1136.

34. Torregrosa JV, Fuster D, Gentil MA, et al. Open-label trial: effect of weekly risedronate immediately after transplantation in kidney recipients. Transplantation 2010;89:1476-1481.

35. Schwarz C, Mitterbauer C, Heinze G, et al. Nonsustained effect of short-term bisphosphonate therapy on bone turnover three years after renal transplantation. Kidney Int 2004;65:304-309.

36. Palmer SC, McGregor DO, Strippoli GF. Interventions for preventing bone disease in kidney transplant recipients. Cochrane Database Syst Rev. 2007;18:CD005015.

37. Josephson MA, Schumm LP, Chiu MY, et al.

Calcium and calcitriol prophylaxis attenuates posttransplant bone loss. Transplantation 2004; 78:1233-1236.

38. Torres A, Garcia S, Gómez A, et al.Treatment with intermittent calcitriol and calcium reduces bone loss after renal transplantation. Kidney Int 2004;65:705-712.

39. De Sevaux RG, et al.: Treatment with vitamin D and calcium reduces bone loss after renal transplantation: a randomized study. J Am Soc Nephrol 2002;13:1608-1614.

40. Perez V, Sánchez A, Bayés B, et al. Effect of paricalcitol on the urinary peptidome of kidney transplant patients. Transplant Proc 2010;42:2924-2927.

41. Bergua C, Torregrosa JV, Fuster D, et al. Effect of cinacalcet on hypercalcemia and bone mineral density in renal transplanted patients with secondary hyperparathyroidism. Transplantation 2008;86: 413-417.

42. Cejka D, Benesch T, Krestan C, et al. Effect of teriparatide on early bone loss after kidney transplantation. Am J Transplant 2008;8:1864-1870.

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1. The most common type of mineral bone disorder in kidney transplant recipients is: a. High turnover bone disease b. Low turnover bone disease c. Mixed renal osteodystrophy 2. Emily receives a kidney transplant and requires corticosteroid therapy in early post-transplant period. You ordered dual-energy X-ray absorptiometry (DXA) in the 6th, 12th, and 18th months after engraftment. Which describes the best of the expected results of DXA and the type of bone loss? a. BMD decreased most rapidly in the first 6 months and loss of bone mass occurs predominantly in cancellous bone b. BMD decreased most rapidly in the 6th -12th month post-transplant and loss of bone mass occurs predominantly in cortical bone. c. BMD decreased most rapidly in the first six months and loss of bone mass occurs predominantly in cortical bone.

3. Josh received a kidney transplant recently. His estimated risk of hip fracture becomes equal to that of his dialysis-period fracture risk after approximately how many years? a. b. c. d.

0.5 years 1 year 2 years 5 years

4. All of the following components contribute to bone metabolic disturbances in patients after renal transplantation except: a. b. c. d.

Type of renal replacement therapy (hemodialysis vs. peritoneal dialysis) Pre-existing renal osteodystrophy at time of renal transplantation Immunosuppression therapies Reduced renal function

5. A type of MBD treatment is associated with better survival in kidney transplant recipients, and the treatment reduced the risk of fracture. a. b. c. d.

Both parts of the statement are true.

The first part of the statement is true, but the second is false.

Both parts of the statement are false.

The first part of the statement is false, but the second is true.

6. Which of the following is the most typical changes in markers of MBD when cinacalcet is used in kidney transplant recipients? a. Calcium decreased, PTH increased or did not change, phosphate increased b. Calcium decreased, PTH decreased, phosphate did not change c. Calcium decreased, PTH did not change or decreased, phosphate increased d. Calcium increased, PTH decreased, phosphate increased

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Renal & Urology News 21

John Schieszer provided coverage of the 37th Annual Scientific Meeting of the Society of Interventional Radiology.

RF Approach Preserves Vascular Access Radiofrequency wire technique used to re-establish patency in occluded central veins A RADIOFREQUENCY (RF) wire technique appears to be a safe alternative for managing benign chronic central venous occlusions when conventional techniques have failed, researchers reported.

“We have been the pioneers on this,” stated study investigator Marcelo Guimaraes, MD, Associate Professor of Vascular and Interventional Radiology at the Medical University of South Carolina in Charleston. “We have been doing this now for four years and probably this is the largest experience in the world with this procedure. We only treat symptomatic patients or patients who are on dialysis and the AV [arteriovenous] graft or fistula is showing malfunction.”

Dr. Guimaraes and his colleagues analyzed the outcomes of 31 patients (15 female) ranging in age from 35-78 years who were treated between June 2008 and January 2011. In these patients, previous attempts at recanalization using mechanical catheter/wire techniques had failed. The patients presented with

Marcelo Guimaraes, MD

a swollen arm and/or face secondary to benign central venous occlusions (7 subclavian veins, 19 brachiocephalic veins, and 5 superior vena cava veins) related to tunneled catheters. Simultaneous upper extremity (brachial approach) and central venograms (femoral approach) defined the central occlusion site.

The investigators used the PowerWireTM RF (Baylis Medical, Canada) wire, which was advanced within a 5-Fr KMP catheter. With this approach, a pre-stent 4 mm balloon angioplasty was followed by 9-12 mm stent placement. If the RF wire puncture was inadequate, the clinician pursued a new location. Clinical and venogram follow-ups occurred at 30 days post-treatment and again at 3, 6, and 12 months.

The RF wire technique successfully treated 29 patients. The procedure was aborted in one patient because of hemothorax that occurred before the use of RF wire. This was successfully treated with a chest tube without clinical repercussions. All of the successfully treated patients had resolution of symptoms after a mean follow-up of six months. Two of the 29 patients experienced stent occlusion within 30 days; the remaining stents were patent at nine months. The patients were asymptomatic in all 27 cases.

“We are now getting nephrologists referring patients from other parts of the country,” Dr. Guimaraes told Renal & Urology News. “The complications have been very rare and the results of this technique are impressive. Because we use RF wire recanalization only after failure of conventional endovascular techniques, the patients would have either left untreated or the alternative would be an open chest vascular by-pass surgery that typically has high morbidity and inadequate long term patency rate.”

The real key to the success with this technique is very close follow-up, Dr. Guimaraes said. “This is like when you buy a car,” he said. “We know there will be need for maintenance of the stent but, at this point, we don’t know if it will be in three months or in three years.”

Thus, he explains to patients that they need to return to the Vascular & Interventional Radiology clinic for an evaluation as soon as they experience symptoms, he said. ■

Preventing Unnecessary Nephrectomies Possible PERCUTANEOUS IMAGE-GUIDED renal mass biopsy (RMB) combined with immunohistochemical (IHC) findings can safely and accurately distinguish between benign and malignant small renal masses (less than 4 cm), a finding that could help prevent unnecessary nephrectomies or ablation, researchers reported.

“Traditionally, solid renal masses were not biopsied because most could not be reliably characterized on imaging and early biopsy results were disappointing.

These lesions were thus presumed to be cancer and removed surgically,” said study investigator Nisha Alle, BS, who is with the Department of Radiology at David Geffen School of Medicine, University of California-Los Angeles. “But we are finding that up to 30% of these small renal masses are benign on nephrectomy, so it would be helpful to have a reliable pre-procedural biopsy diagnosis of a solid renal mass to avoid any unnecessary surgical or ablative procedures.”

Alle and her colleagues retrospectively studied 173 consecutive patients who underwent percutaneous computed tomography (CT) and ultrasound (US) -guided RMB from March 2002 through January 2012. Biopsies of renal parenchyma for diagnosis of medical renal diseases were excluded. The investigators evaluated imaging variables (including size, location, and extent of disease), number of core biopsies, patient demographics (age, gender), clinical indication, final pathologic diagnosis, IHC studies, and subsequent final pathological diagnosis on nephrectomy.

Fourteen of the 173 patients (8.1%) were excluded because biopsies were performed at an outside institution, medical records were incomplete, or lesions were poorly visualized. The researchers found that three patients had two renal mass biopsies for bilateral renal cell carcinoma (RCC). Of 159 patients with 162 RMB, 114 (71.7%) were male, with a mean age of 69. Of 162 RMB, 111 were malignant (68.5%), 39 were benign

Nisha Alle

(24.1%), and 12 were non-diagnostic (7.4%). IHC was performed for 110 biopsies (67.9%) and was diagnostic in 93% of those cases; 22 patients underwent subsequent partial nephrectomy.

In all cases, RMB was concordant with nephrectomy pathology findings for malignancy. In 76% of cases, RMB

was concordant for subtype of RCC. However, in two cases, RMB diagnosis of clear cell RCC was changed to papillary type 2 on nephrectomy. In one case, RMB diagnosis of papillary type 1 RCC was changed to unclassified RCC. In addition, biopsy diagnosis of unclassified RCC was changed to clear cell RCC in one case.

In another case, the initial diagnosis of unclassified RCC on biopsy was changed to chromophobe.

Overall, the combination of RMB and IHC by subspecialized GU pathologists had a sensitivity, specificity, and positive predictive value for detecting malignancy of 100%.

“Routine H&E staining may not be able to sufficiently differentiate among different tumor subtypes, but adding immunohistochemical stains for most tumors confers high accuracy for diagnosis,” Alle said. “We only had 12 mainly self limited complications over a time period of 10 years without long-term complications.”

No cases of tumor seeding attributed to biopsy were identified. ■

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John Schieszer provided coverage of the 37th Annual Scientific Meeting of the Society of Interventional Radiology.

MRI Scans May Improve PCa Detection Fusion-targeted biopsy added to conventional random biopsy helps to zero in on suspicious lesions PROSTATE CANCER (PCa) detection rates may be markedly improved by adding magnetic resonance imaging (MRI) findings to conventional blind random biopsies, according to a new study.

“From an economic and public health perspective, early diagnosis, more sensitive screening, and more accurate characterization could have huge implications,” said principal investigator Bradford Wood, MD, Director of the Center for Interventional Oncology at the National Institutes of Health, Bethesda, Md. “Information is power, and this fusion system allows you to get and use the imaging information without needing to tie up an expensive machine during the procedure. This puts a tool in urologists’ hands that meets the clinical need, and makes an otherwise ‘blind’ biopsy smarter.

This multidisciplinary approach allows improved cancer detection and better characterization for those patients who may not need surgery or radiation.”

Prostate biopsy currently is performed blindly without focal imaging guidance other than ultrasound to aim the needle

towards the peripheral zone or a specific sextant region of the prostate. This conventional technique is both blind and random, and does not use magnetic resonance imaging (MRI) information that might localize tumors. “Up to now, physicians are often happy to just be biopsying anywhere in the gland, but they can now target the needles towards the areas suspicious for cancer,” Dr. Wood said.

The multimodality fusion navigation system for prostate biopsy developed by Dr. Wood and his colleagues allows for real-time mapping and referencing to preprocedural magnetic resonance images.

This can be helpful in the ultrasound guidance of the needle towards areas of suspicion, and also can map out areas of prior positive biopsy in select patients undergoing active surveillance.

Dr. Wood’s team assessed the clinical utility of the fusion system in a clinical trial that involved 595 prostate biopsies in 520 patients. Patients underwent multiparametric prostate MRI. The researchers then classified lesions according to suspicion level for cancer: low, moderate, or high. Patients underwent standard 12

sextant biopsies as well fusion-guided ultrasound biopsy of targets defined by pre-procedural MRI. Adding fusion-targeted prostate biopsy to conventional random biopsy in patients with suspicious targets on MRI yielded marked increase in cancer detection rates. “The detection rate was markedly improved. In fact, the detection rate was almost doubled in certain patients with high-suspicion targets on MRI,” Dr. Wood said. “It is making biopsy smarter.

The technology also lets you record the area where you are sampling so you can go back to see that area again in patients with non-aggressive cancer. This more accurate characterization of the tumor could be of tremendous value.”

He said this approach adds clinical value to standard blind prostate biopsies in the setting of previous negative biopsy and anterior, apical, or central gland lesions visible on MRI that might not otherwise be sampled by conventional ultrasound guided biopsy. In this analysis, the suspicion level on MRI correlated with Gleason scores, and prior biopsy location was used to map

subsequent biopsy location in patients with low Gleason scores undergoing surveillance biopsy.

“We are trying to define where the technology will fit in the treatment paradigm,” Dr. Wood told Renal & Urology News. “If we get a Gleason 6, then that patient may not need treatment or surgery, and may get watchful waiting. However, we don’t always know exactly what is going on at a molecular level. With this technique, we have mapped the sample, and we can not only get to the suspicious area the first time, but we can also get back to it at a later date, so we can see if the cancer has changed.”

Other key members of the multidisciplinary prostate team involved in the development of the fusion navigation system included Peter Pinto, MD, Peter Choyke, MD, Baris Turkbey, MD, and Hayet Amalou, MD. Dr. Amalou presented results of fusion-guided biopsy and ablation of a variety of tumors, including renal cell carcinoma. The study involved 10,000 tracked needles and 720 procedures. ■

Image-Guided Ablation Viable for Small Renal Tumors IMAGE-GUIDED ablation of primary renal cancers smaller than 4.8 cm may be performed with minimal morbidity and it produces excellent results in terms of long-term survival, according to a new study.

“The outcomes are comparable to partial nephrectomy,” said study investigator Roger Williams, DO, Assistant Professor of Radiology at Emory University in Atlanta. “Image-guided percutaneous cryoablation is similar to partial nephrectomy in that the ablation zone can be sculpted to cause tumor destruction, while preserving adjacent renal parenchyma and therein renal function. There is also lower morbidity.”

Dr. Williams, who presented the study findings, said percutaneous image-guided ablation is an accepted treatment for nonsurgical candidates with limited renal tumor burden and appropriate tumor location. He and his colleagues investigated four-year survival rates among

Roger Williams, DO

patients with biopsy-proven malignant renal neoplasms at their institution.

A total of 50 ablations of biopsyproven renal cell carcinoma (RCC) were performed on 43 patients from December of 2004 to July 2011. The

study included 30 males and 13 females, and the mean age was 65 years (range 47-89 years). In this group of patients, extrarenal disease was identified in 22 patients. Four patients had treated contralateral RCC and four received chemotherapy. Among the four chemotherapy patients, three received adjutant therapy and one received immunosuppression for a renal transplant.

Dr. Williams said 46 lesions (92%) were treated under moderate sedation and four (8%) under general anesthesia. Treatment modalities included radiofrequency ablation for 39 ablations and cryoablation for 11 ablations. The mean tumor diameter was 2.4 cm (range 0.9-4.8 cm).

The three- and four-year survival rates following ablation were 82% and 71%, respectively.

Survival rates did not differ by gender, treatment modality, or tumor number.

Pre-and post-ablation creatinine levels

and glomerular filtration rate also had no significant effects on survival.

For patients with stage 1 disease, the three- and four-year survival rates were both 85%. For stage 4 patients, the three- and four-year survival rates were 76% and 66%, respectively.

“These are important findings,” Dr. Williams told Renal & Urology News.

The four-year survival is above 90% for stage 1 patients, so that shows that this is a viable treatment modality. The percutaneous treatment of neoplasms has benefits for the patients. In the majority of cases there is no general anesthesia.

It is outpatient and it is important to know we can reach surgical standards using percutaneous methods.” ■ To read a recent news article on a similar topic, go to renalandurologynews.com/RFA.

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Nut Consumers Have Lower Health Risks, Data Show NUT CONSUMPTION is associated with a decreased prevalence of certain risk factors for cardiovascular disease, type 2 diabetes, and metabolic syndrome, according to a recent study.

The study, led by Carol E. Oâ&#x20AC;&#x2122;Neil, PhD, MPH, RD, of Louisiana State University in Baton Rouge, included

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in Full Prescribing Information).

DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions).

Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry.

HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat.

Avoid vigorous shaking of Xgeva.

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS: Hypocalcemia. Xgeva can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to Xgeva treatment.

Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/ min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function.

The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, 2.2% of patients receiving Xgeva developed ONJ; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse Reactions). Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling: s (YPOCALCEMIA (see Warnings and Precautions) s /STEONECROSIS OF THE *AW (see Warnings and Precautions) The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia.

Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reďŹ&#x201A;ect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Information) in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion.

Š2011 Amgen Inc. All rights reserved. 63850-R1-V1 12/11

13,292 adults participating in the 19992004 National Health and Nutrition Examination Survey. For the study, individuals who ate at least one quarter of an ounce of nuts per day were considered nut consumers. Those who ate less than this were considered nonconsumers of nuts.

Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 â&#x20AC;&#x201C; 41) and median duration onstudy was 13 months (range: 0.1 â&#x20AC;&#x201C; 41). Of patients who received Xgeva, 46% WERE FEMALE %IGHTY lVE PERCENT WERE 7HITE (ISPANIC ,ATINO !SIAN

and 3% Black. The median age was 63 years (range: 18 â&#x20AC;&#x201C; 93). Seventy-ďŹ ve percent of patients who received Xgeva received concomitant chemotherapy.

The prevalence of nut consumers was 18.6% and 21% among subjects aged 19-50 years and 51 years or older, respectively. Nut consumers had a significantly decreased mean body mass index (27.7 vs. 28.1 kg/m2), mean waist circumference (95.6 vs. 96.4 cm), and mean systolic blood pressure (121.9

anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormone therapy (see Clinical Pharmacology [12.2] in full Prescribing Information).

USE IN SPECIFIC POPULATIONS: Pregnancy: Category C. There are no adequate and well-controlled trials of Xgeva in pregnant women. Use Xgeva during pregnancy only if the potential beneďŹ t justiďŹ es the potential risk to the fetus. Encourage women who become pregnant during Xgeva treatment to enroll in Amgenâ&#x20AC;&#x2122;s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800772-6436) to enroll. In an embryofetal developmental study, cynomolgus a Table 1. Per-patient Incidence of Selected Adverse Reactions of Any monkeys received subcutaneous denosumab weekly during organogenesis at Severity (Trials 1, 2, and 3) doses up to 6.5-fold higher than the recommended human dose of 120 mg every 4 weeks, based on body weight (mg/kg). No evidence of maternal toxicity Xgeva Zoledronic Acid OR FETAL HARM WAS OBSERVED (OWEVER THIS STUDY ONLY ASSESSED FETAL TOXICITY Body System n = 2841 n = 2836 during the ďŹ rst trimester, and fetal lymph nodes were not examined. Potential % % adverse developmental effects resulting from exposures during the second and third trimesters have not been assessed in animals (see Nonclinical Toxicology GASTROINTESTINAL [13.2] in full Prescribing Information). In genetically engineered mice in which Nausea 31 32 the gene for RANK ligand (RANKL) has been deleted (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?), the Diarrhea 20 19 absence of RANKL caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice also showed altered maturation of the maternal mammary gland, leading to GENERAL impaired lactation postpartum (see Use in Nursing Mothers).

45 46 Fatigue/ Asthenia Nursing Mothers. It is not known whether Xgeva is excreted into human milk.

INVESTIGATIONS Because many drugs are excreted in human milk and because of the potential 18 9 (YPOCALCEMIAb for serious adverse reactions in nursing infants from Xgeva, a decision should 32 20 (YPOPHOSPHATEMIAb be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva NEUROLOGICAL during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling 13 14 (EADACHE pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum (see Nonclinical Toxicology [13.2] in RESPIRATORY full Prescribing Information).

21 18 Dyspnea 15 15 Cough Pediatric Use. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in a Adverse reactions reported in at least 10% of patients receiving Xgeva in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL with a construct of osteoprotegerin bound to Trials 1, 2, and 3, and meeting one of the following criteria: Fc (OPG-Fc) at doses less than or equal to 10 mg/kg was associated with s !T LEAST GREATER INCIDENCE IN 8GEVA TREATED PATIENTS OR inhibition of bone growth and tooth eruption. Adolescent monkeys dosed with s "ETWEEN GROUP DIFFERENCE EITHER DIRECTION OF LESS THAN AND MORE THAN denosumab at 5 and 25 times (10 and 50 mg/kg dose) higher than the 5% greater incidence in patients treated with zoledronic acid compared to recommended human dose of 120 mg subcutaneously every 4 weeks (based on placebo (US Prescribing Information for zoledronic acid) body weight mg/kg) had abnormal growth plates (see Nonclinical Toxicology b Laboratory-derived and below the central laboratory lower limit of normal [8.3 â&#x20AC;&#x201C; [13.2] in full Prescribing Information).

8.5 mg/dL (2.075 â&#x20AC;&#x201C; 2.125 mmol/L) for calcium and 2.2 â&#x20AC;&#x201C; 2.8 mg/dL (0.71 â&#x20AC;&#x201C; Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 0.9 mmol/L) for phosphorus] (44%) were 65 years of age or older. No overall differences in safety or efďŹ cacy were observed between these patients and younger patients.

Severe Mineral/Electrolyte Abnormalities s 3EVERE HYPOCALCEMIA CORRECTED SERUM CALCIUM LESS THAN MG D, OR LESS THAN Renal Impairment. In a trial of 55 patients without cancer and with varying degrees 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of of renal function who received a single dose of 60 mg denosumab, patients with a patients treated with zoledronic acid. Of patients who experienced severe creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia of severe hypocalcemia with denosumab compared to patients with normal renal and 16% experienced 3 or more episodes (see Warnings and Precautions and function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg Use in SpeciďŹ c Populations). every 4 weeks has not been evaluated in patients with a creatinine clearance of less s 3EVERE HYPOPHOSPHATEMIA SERUM PHOSPHORUS LESS THAN MG D, OR LESS than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and Reactions, and Clinical Pharmacology [12.3] in full Prescribing Information).

7.4% of patients treated with zoledronic acid.

OVERDOSAGE: There is no experience with overdosage of Xgeva.

Osteonecrosis of the Jaw PATIENT COUNSELING INFORMATION: In the primary treatment phases of Trials 1, 2, and 3, ONJ was conďŹ rmed in Advise patients to contact a healthcare professional for any of the following: 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic acid group (see Warnings and Precautions). When events occurring during an s 3YMPTOMS OF HYPOCALCEMIA INCLUDING PARESTHESIAS OR MUSCLE STIFFNESS

extended treatment phase of approximately 4 months in each trial are included, twitching, spasms, or cramps (see Warnings and Precautions and Adverse the incidence of conďŹ rmed ONJ was 2.2% in patients who received Xgeva. The Reactions) median time to ONJ was 14 months (range: 4 â&#x20AC;&#x201C; 25). s 3YMPTOMS OF /.* INCLUDING PAIN NUMBNESS SWELLING OF OR DRAINAGE FROM the jaw, mouth, or teeth (see Warnings and Precautions and Adverse Immunogenicity. As with all therapeutic proteins, there is potential for Reactions) immunogenicity. Using an electrochemiluminescent bridging immunoassay, s 0 ERSISTENT PAIN OR SLOW HEALING OF THE MOUTH OR JAW AFTER DENTAL SURGERY (see less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30 â&#x20AC;&#x201C; 180 mg every 4 weeks or every 12 Warnings and Precautions) weeks for up to 3 years tested positive for binding antibodies. No patient with s 0REGNANCY OR NURSING (see Use in SpeciďŹ c Populations) positive binding antibodies tested positive for neutralizing antibodies as Advise patients of the need for: assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic proďŹ le, toxicity proďŹ le, or clinical s 0ROPER ORAL HYGIENE AND ROUTINE DENTAL CARE response associated with binding antibody development. The incidence of s )NFORMING THEIR DENTIST THAT THEY ARE RECEIVING 8GEVA antibody formation is highly dependent on the sensitivity and speciďŹ city of the s !VOIDING INVASIVE DENTAL PROCEDURES DURING TREATMENT WITH 8GEVA assay. Additionally, the observed incidence of a positive antibody (including ÂŽ . Patients should neutralizing antibody) test result may be inďŹ&#x201A;uenced by several factors, Advise patients that denosumab is also marketed as Prolia ÂŽ including assay methodology, sample handling, timing of sample collection, inform their healthcare provider if they are taking Prolia . concomitant medications, and underlying disease. For these reasons, Amgen Manufacturing Limited, a subsidiary of Amgen Inc. comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading.

One Amgen Center Drive DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There was no evidence that various

Thousand Oaks, California 91320-1799 Š2011 Amgen Inc. All rights reserved. Printed in USA.

www.XGEVA.com

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

vs. 123.2 mm Hg) compared with nonconsumers, the investigators reported in the Journal of the American College of Nutrition (2011;30:502-510). In addition, nut consumers had a lower percentage of individuals with two risk factors for metabolic syndrome: hypertension (31.5% vs. 34.2%) and low HDL (29.6% vs. 34.8%).

Tree nut consumption Tree nut consumers had a signifi cantly lower mean weight than nonconsumers (78.8 vs. 80.7 kg).

They had a significantly lower prevalence of four risk factors for metabolic syndrome: abdominal obesity (43.6% vs. 49.5%), hypertension (31.4% vs. 33.9%), low HDL (27.9% vs. 34.5%), and high fasting glucose (11.4% vs. 15%). Tree nut consumers also had a signifi cantly lower prevalence of meta bolic syndrome (21.2% vs. 26.6%), the study revealed.

People who ate tree nuts had a lower prevalence of metabolic syndrome. â&#x20AC;&#x153;On a population basis, these lower risk factors could lead to better health and lower long-term health care costs,â&#x20AC;? the researchers concluded.

The investigators defined nuts as peanuts, peanut butter, tree nuts (almonds, Brazil nuts, cashews, walnuts, pecans, pistachios, macadamias, pine nuts, and hazelnuts), or tree nut butters. All nuts are low in saturated fatty acids and are rich sources of monounsaturated fatty acids, the authors observed. Nuts are high in dietary fiber, vitamin E, folate, magnesium, copper, selenium, and potassium. They also provide phytonutrients, including resveratrol, flavonoids, proanthocyanidins, and phenols.

Their study, along with the preponderance of other evidence, suggests that consumption of peanuts and tree nuts, and tree nuts alone, should be encouraged by health professionals, especially registered dietitians, the author noted. â&#x20AC;&#x153;This study also raises the possibility that future dietary recommendations should consider a separate nut category to encourage consumption,â&#x20AC;?

Dr. O'Neil said. â&#x2013;

www.renalandurologynews.com

MAY 2012

Renal & Urology News 27

Making the Case for Brachytherapy & QA

Having performed more than 1,200 brachytherapy treatments since 1996 and conducting research in this field,

urologic oncologist Michael F. Sarosdy, MD, founder of South Texas Urology & Urologic Oncology, in San Antonio, is convinced that brachytherapy is a far better choice than surgery for most men with prostate cancer, regardless of the patient’s age or tumor characteristics. Dr. Sarosdy spoke to Renal & Urology News senior editor Delicia Honen Yard on the subject.

Does brachytherapy deserve its reputation as the safest and least expensive of the three main treatments for prostate cancer (radical prostatectomy [RP] and external beam radiation therapy [EBRT])?

Dr. Sarosdy: Absolutely. Brachytherapy is very cost-effective and it has the least impact on day-to-day function in terms of treatment delivery. It’s a one-time outpatient treatment that requires about one hour in the operating room (OR), under anesthesia, to implant the seeds, which are little titanium shells that contain radioactive material. The patient can quite literally return to work the next day.

Brachytherapy has become more sophisticated and polished in the 25 years since it was first used for prostate cancer. Physics planning software, techniques, and ultrasound imaging have all improved, and we’ve learned how to operate more effectively and safely. And now, some physicians are using real-time physics, where you plan right in the operating room instead of strategizing ahead of time and then matching up the two images (the image taken in the operating room with the image done for the preplan). This does, however, lengthen the amount of time spent in the OR.

How often is brachytherapy used relative to other treatment options?

Dr. Sarosdy: Brachytherapy has a welldefined place in the treatment of prostate cancer. Over the past 10 years or so, brachytherapy has been utilized less, because while robotic surgery has

not been shown to be superior to open surgery, patients are more willing to undergo surgery using a robotic and laparoscopic technique. They feel less threatened by minimally invasive procedures, even though robotic surgery has been shown to not have a higher cure rate. In fact, urinary complications are more frequent with robotic surgery compared to open surgery.

Can you elaborate on why brachytherapy is less utilized?

Dr. Sarosdy: The other reason that we’ve seen a decrease in the number of brachytherapy cases is that physicians—both radiation oncologists and urologists—have made a shift toward IMRT [intensity-modulated radiation therapy], for no other reason than that it’s reimbursed at substantially higher rates than brachytherapy. The cost for IMRT is about three to four times higher than the cost for brachytherapy, with no improvement in outcomes. Also, IMRT treatment delivery is somewhat onerous compared to brachytherapy: The patient has to commit to a nine week treatment course, from Monday to Friday, to have the IMRT delivered, as opposed to one day for brachytherapy.

And there’s no data to support the idea that younger men should have surgery over brachytherapy or even IMRT. They have to live with the complications of surgery for much longer; they have to deal with incontinence and impotence at a younger age.

Is there a clearly defined patientcandidate for brachytherapy?

Dr. Sarosdy: No. Brachytherapy can be done in any patient with prostate

cancer. There’s no one patient that’s better treated with it than another.

It’s really suitable for any patient who desires to avoid surgery and external radiation and to undergo a relatively easy-to-deliver treatment that’s going to have less impact, both long-term and short-term, on his lifestyle.

Brachytherapy usually is not recommended for high-risk patients, but a large study

by Shen et al (International Journal of Radiation Oncology, Biology, Physics) has found that brachytherapy alone or in combination with EBRT significantly reduced prostate cancer–specific mortality compared with EBRT alone. Does this finding surprise you?

Dr. Sarosdy: Not at all! There’s more and more data coming out that brachytherapy doesn’t need to be restricted to the low-risk patients; that it’s just as effective in high-risk patients. And we presented that data to the American Urological Association ourselves in 2007.

Brachytherapy is one of your main areas of clinical investigation, and in 2007 you concluded that testosterone replacement therapy could be used with

caution and close follow-up after prostate brachytherapy. (Cancer 2007;109:536-541). What made this practice controversial?

Dr. Sarosdy: There was a bit of a hysteria about giving testosterone to men who had been treated for prostate cancer since we know that testosterone fuels prostate cancer. And there had been two very, very small reports of testosterone therapy in men who had undergone radical prostatectomy, and then my report was one of a much larger series of men who in fact still had the prostate gland in place because they had received brachytherapy. That stimulated a tremendous amount of retrospective data analysis around the country, and several additional large papers have come out now, both after surgery and after radiation, showing similar outcomes. Particularly since we have PSA as a marker, we have something that’s sensitive and accurate to utilize in following these patients that we might need to treat for hypogonadism.

When you meet with a patient, do you go in with the assumption that you’re going to recommend brachytherapy unless something specifically contraindicates that?

Dr. Sarosdy: I come from a neutral stance, but the bottom line is that any rational analysis of treatment-related side effects compared to the efficacy of different forms of treatment would lead a thinking individual away from surgery to brachytherapy or to IMRT, for that matter. There is absolutely no proven superiority of surgery over the other treatments, and in fact the side effects are greater.

Does brachytherapy have a role in treating advanced bladder cancer?

Brachytherapy has the least impact on day-today function.

—Michael F. Sarosdy, MD

Dr. Sarosdy: There was some brachytherapy done in Europe in the 1970s for bladder cancer using an open technique: They opened up the bladder and implanted seeds, and some efficacy was demonstrated. The problem with bladder cancer is that it tends to be a much faster-growing tumor than prostate, so it doesn’t lend itself as well to slow delivery of radioactivity. ■ Editor’s note: Dr. Sarosdy has no outside financial interest in any brachytherapy treatment programs, related equipment, or services.

28 Renal & Urology News

MAY 2012

www.renalandurologynews.com

On the Forefront

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

Page Kidney Resulting in New-Onset Hypertension

BY DIANA L. DEITZER, DO, AND MARC A. POHL, MD

medication that blocked the reninangiotensin-aldosterone system.

A

Discussion In 1939, Irvine Page described a cause of arterial hypertension by wrapping canine kidneys in cellophane, which induced renal ischemia. Once the cellophane was removed or the kidney was resected, BP improved.1 Page kidney has been described as arterial hypertension caused by extrinsic compression of the kidney, leading to microvascular ischemia. This model of hypertension differs from the Goldblatt model, where the major renal vessels are compressed, leading to renovascular hypertension.2 Extrinsic compression of the kidney can be the result of trauma, post-operative changes, hematomas, or mass lesions.2 More recently, Page kidney has been described in percutaneous allograft renal biopsy, in which post-biopsy complications included a rise in BP and a rise in serum creatinine accompanied by elevated resistive indices with Doppler study and ultrasound of transplanted kidneys showing large subcapsular perinephric hematoma.

Treatment included surgical intervention with evacuation of the hematoma, resulting in rapid improvement of BP and serum creatinine to baseline.3 It is important to recognize Page kidney as a cause of hyperreninemic hypertension that can be potentially reversible as compression to the kidney is alleviated. ■

55-year-old Caucasian woman initially presented to one of Cleveland Clinic’s regional outpatient urology clinics with gross hematuria and an obstructing right ureteral stone. After discussion with the patient regarding management options, including watchful waiting and lithotripsy, it was decided that the patient should undergo ureteroscopy. She was found to have a moderate-to-severely dilated right ureter up to the kidney and blood through the kidney, though there was no active bleeding noted. A 6 mm calcium oxalate stone was extracted from the right distal ureter, after which a JJ stent was placed in the right kidney.

The patient later presented on postoperative day 2 with gross hematuria and tenderness of the right flank.

On admission, she had a computed tomography (CT) scan of the abdomen and pelvis that showed significant right hydronephrosis. There was blood seen through the renal pelvis and calyces in addition to the urinary bladder. Because of anemia on admission (hemoglobin level of 6.8 g/L), she received a transfusion of two units of blood and was transferred to the Cleveland Clinic main campus for further evaluation. A repeat CT scan showed an arteriovenous malformation (AVM) in the anterior interpolar region of the right kidney that was likely congenital. Given this finding along with increasing hematuria, the patient underwent a bilateral selective renal angiogram with subselective coil embolization of the inferior anterior segmental artery and two interlobar arteries in the mid zone. This resulted in an improvement of her hematuria. Due to concern for recurrence of bleeding, the patient had a repeat CT angiogram (CTA) two weeks later for a persistent large AVM in the right kidney for which she had successful coiling and alcohol embolization. During this time, her creatinine level increased from a baseline of 0.8 mg/dL to 1.2 mg/dL. One month later, the patient was seen by her primary care physician (PCP)

Figure. The image shows a wedged-shaped hypoperfused area of the right renal parenchyma secondary to prior embolization of the right renal arteriovenous malformation.

for new onset hypertension. Her usual blood pressure measurements were 140/80 mm Hg, but her BP was higher since her procedures. At the PCP visit, BP was 183/106 mm Hg. She was started on amlodipine 5 mg; this was later increased to 10 mg as her BP remained elevated. She was then referred to the nephrology department.

Prior to her visit to the nephrology department, the patient had a CTA that showed significant improvement in the right kidney AVM. There was a new wedge-shaped hypoperfused small area in the right renal parenchyma from her second embolization (Figure). She had a small multifocal web-like stenosis in the distal right artery consistent with fibromuscular dysplasia (FMD). The patient also had a mag3 function scan showing that the left kidney contribution to total renal function was 71% and the right kidney contribution was 29%.

Her creatinine level returned to her baseline of 0.8 mg/dL. At her nephrology visit, her BPtru measurement was 127/84 mm Hg on 10 mg of amlopidine. She had elevated renin (10.8 µg/L/h) and it was unclear if the high renin was secondary to amlodipine use or from renal vascular hypertension given that she had

mild FMD on CT or activation of the renin-angiotensin-aldosterone system from renal ischemia induced from coiling of her AVMs, possibly resulting in a clinical analog of the experimental Page kidney. The patient was switched to metoprolol as she also had complaints of palpitations. In addition, 24-hour urine was collected for her ureteral stone workup.

Her 24-hour urine study revealed adequate urine volume of 2,730 cc, calcium excretion of 286.8 mg, citric acid excretion of 434 mg, sodium excretion of 159 mmol, and uric acid excretion of 488.2 mg. There was slightly increased oxalate excretion of 52 mg.

The patient was instructed to adhere to a low oxalate diet.

Six months following her initial presentation, the patient’s BP was well controlled on metoprolol 50 mg daily. Her renin levels decreased to 1.8 µg/L/hr. She has not had a recurrence of nephrolithiasis. Although the definitive diagnosis of a Page kidney would ideally demonstrate lateral ization of renin to the right kidney with bilateral renal vein renin measurements, the patient’s clinical scenario is very suggestive of a Page kidney causing hypertension because her BP improved after she was started on

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

REFERENCES 1. Page, IH. The production of persistent arterial hypertension by cellophage perinephritis. JAMA 1939;113:2046-2048.

2. Dopson, SJ, Jayakumar S. Page Kidney as a rare cause of hypertension: case report and review of the literature. Am J Kidney Dis 2009;54:334-339.

3. Posadas, MA, Muhammad BH. Acute renal failure and severe hypertension from a Page kidney post-transplant biopsy. The Scientific World Journal 2010;10:1539-1542.

CORRECTION: Ashok Agarwal, a co-author of last month’s article titled “Sperm Banking to Remote Sites,” is a PhD, not an MD.

www.renalandurologynews.com

MAY 2012

Renal & Urology News 29

Legal Issues in Medicine I

s honesty always the best policy? That is the question that a urologist had to grapple with in this month’s case.

Dr. B, 57, was a urologist with a busy private practice. One of his patients was Mr. O, 69, who had an abnormal PSA result. As he did with all patients whose PSA tests were elevated, he recommended that Mr. O have a prostate biopsy and the patient agreed. A biopsy was taken at the hospital with which Dr. B was affiliated. The next day, the pathologist sent back a report to the urologist indicating that the biopsy contained adenocarcinoma and high-grade prostatic intraepithelial neoplasia. After reviewing the report, Dr. B advised the patient that he had highly aggressive Stage II prostate cancer and needed a radical prostatectomy. The physician also recommended that Mr. O get a second opinion, which he did the next day. The second physician, based on the medical records, concurred with Dr. B’s diagnosis and also told the patient to undergo a radical prostatectomy.

A negative diagnosis, after all The following month, Dr. B performed the procedure on the patient, removing his prostate. A few days later, Dr. B received both a phone call and a report from the surgical pathologist

content of the report to the patient.

Over the course of the next five years, Dr. B treated Mr. O just as he would any other patient who had PCa and a radical prostatectomy. Mr. O came in several times a year for follow-up checks and lab work, all of which were normal.

As the years passed, Dr. B eventually forgot about the pathology report.

Five years after the surgery, however, Mr. O and his wife moved to another area and wanted the medical records so he could take them to his new urologist.

Dr. B’s office manager made a copy and sent them to the patient, who then, for the first time, saw the pathology report indicating that he had never had cancer.

The enraged patient consulted with a malpractice attorney and subsequently sued everyone involved with the situation, including Dr. B. The physician, when served with papers notifying him about the lawsuit, sought the advice of a defense attorney.

“You are being sued for a variety of reasons,” the attorney said, “including fraud. I believe we can get several of these dismissed, but there is one cause of action that I’m concerned about, and that’s informed consent. Your patient is alleging that because he didn’t know that he didn’t have cancer, he couldn’t actually consent to the five years of follow-up

A urologist kept the findings of a negative pathology report to himself and continued to provide follow-up care for five years. stating that no cancer had been found in the removed prostate. The physician was faced with a quandary—should he inform the patient that the pathology report came back negative and deal with a distraught patient who had his prostate removed for no good reason, or should he simply not tell and spare Mr. O from further distress. He decided on the latter approach, and although he put the pathologist’s report in the patient’s file, he did not mention the

treatment. Unfortunately for you, that’s a reasonable argument that could hold weight with a jury. I’ll make motions to dismiss this case, but be prepared that the informed consent claim might be hard to get rid of.”

As promised, the attorney made a motion to dismiss the case against Dr. O, and was successful in getting portions of the complaint dismissed, but not the claim based on lack of informed consent.

In allowing that portion of the case to

© PUNCHSTOCK.COM/WESTEND61

After undergoing a radical prostatectomy, the patient later learns he never had prostate cancer BY ANN W. LATNER, MD

A case against a urologist hinged on his failure to obtain informed consent.

proceed, the judge wrote in his decision, “A physician violates a duty to his patient and subjects himself to liability if he withholds any facts which are necessary to form an intelligent consent by the patient to the proposed treatment.” The court ruled that the case could proceed against Dr. B based on this. After this ruling, and a discussion with his attorney, Dr. B decided to settle the case out of court with the patient for an unidentified sum.

Legal background A cause of action based on a lack of informed consent has three elements: (1) breach of the duty to inform (nondisclosure), (2) causation, and (3) injury.

In this case, it was clear that Dr. B breached his duty to inform his patient that the patient did not, in fact, have cancer. The causation element turns on whether the plaintiff would have agreed to the proposed treatment had he been adequately informed. The injury element would include pain and suffering, unnecessary lab tests, and unnecessary treatment. Given the facts of this case, it is likely that the jury would have sided with the plaintiff and agreed that he would not have consented to unnecessary follow-up treatment for cancer that he did not have.

Protecting yourself Dr B. was not being sued for performing the prostatectomy in the first place. Given the information he had at the time, including the PSA test and biopsy result, the decision to perform the surgery was sound. Where Dr. B went wrong was post-surgery, when he concealed information from the patient in a misguided attempt to spare the patient distress.

Dr. B was actually attempting to spare himself the distress of having to break bad – possibly devastating – news to a patient that his prostate had been unnecessarily removed. He probably anticipated a lawsuit if he revealed this information to the patient. However, Dr. B had an ethical responsibility, as well as a legal one, to give his patient the full facts of his situation, rather than mislead him and continue treating him as though he had cancer. ■ 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.

MAY 2012

www.renalandurologynews.com

Arizona bill would end “wrongful birth” suits

© ISTOCKPHOTO.COM / NAOMI BASSITT

Malpractice News

Arizona Senate Panel Votes to Curb ‘Wrongful Birth’ Suits An Arizona Senate panel voted in favor of overturning an Arizona Supreme Court ruling that set precedent almost 30 years ago in “wrongful birth” and “wrongful life” lawsuits. Wrongful birth lawsuits typically occur when a physician fails to properly communicate the results of prenatal screenings or fetal risk factors to prospective parents and a disabled child is born.

In many states across the country, such suits are now commonplace— particularly when the option to abort is still viable. Wrongful life suits are generally filed when an undesired pregnancy results after vasectomy or sterilization. In these cases, the current laws in Arizona allow the parents to sue for the costs of raising and caring for that child.

Precedent was set in 1983 when a lowincome Tuscon couple petitioned the court for the right to sue when the wife became pregnant after her husband’s vasectomy. As a low-income family with three children, the couple deliberately took steps to thwart any additional pregnancy. When the vasectomy failed to prevent the birth of their fourth child, a daughter, the couple won the right to sue—not just for the inadequate vasectomy—but also for the cost of raising that child. The couple argued, on religious grounds, that abortion was not an option for them. That historic

court ruling holds the potential to dramatically change the face of wrongful life suits.

In fact, that landmark case went all the way to the state’s Supreme Court.

In deliberating, the justices noted that jurors would have to offset any monetary award in “wrongful birth” cases with considerations of the value in having a relationship with a healthy child.

This particular case was settled out of court, but it laid the groundwork for future “wrongful life” cases.

Proponents of this new bill say that physicians in such cases should only be held liable for medical malpractice, that is, for breaching standards of care. Clinicians should not, they argue, additionally be forced to pay the substantial cost of living expenses for a healthy or unhealthy child. Under the bill, physicians could still be held liable for withholding prenatal information, but mere mistakes, such as failing to perform tests or detect birth defects, would not necessarily make a physician liable for the future care of that child. Proponents claim that all lives are valuable and that the bill would recognize this. Opponents of the legislation argue that the bill deprives a woman of choice and of making critical decisions about family.

If the bill passes, Arizona would be among the nine states, at present, that ban or attempt to curtail wrongful birth and wrongful life lawsuits.

BY ANN W. LATNER, JD

current malpractice system, drastically reducing unnecessary medical costs in the state. Senate Bill 1588/House Bill 1233 proposes to completely overhaul the flailing medical liability process in Florida, creating a new way for patients to gain compensation.

The new system is designed to be non-adversarial and includes patient advocates, an independent review panel (to determine whether claims have merit), a compensation department (devoted to recommending appropriate compensation), oversight by a judge, and a quality improvement counsel (to look at medical errors and then develop best practices). Proponents of this proposed bill argue that the new system is patientfocused, faster, and will avoid the high costs and complexity of the current medical liability system. Proponents also believe that the bill would reduce malpractice insurance costs for clinicians, and would curtail the need to practice defensive medicine.

The intention, ultimately, is to eliminate the practice of defensive medicine, increase the quality of healthcare across the state, protect healthcare providers from unfair litigation, and provide injured parties with fair compensation.

Most Florida healthcare practitioners are enthusiastic about the bill and the possibilities it presents. According to a statewide survey conducted by Oppenheim Research, 93% of Florida physicians support this legislation.

Patient Compensation System Considered in Florida Medical malpractice premiums in Dade County are perhaps the most expensive in the nation, forcing many clinicians to make dramatic choices when it comes to coverage.

In response, Florida legislators are thinking hard about reworking the state’s medical malpractice model and incorporating a new patient compensation schema. By using an administrative rather than judicial process for medical malpractice claims, the newly proposed system would closely model the state workers’ compensation system.

The patient compensation system, in its current outline, would replace the

Florida is mulling a non-adversarial approach to settling malpractice claims

© ISTOCKPHOTO.COM / P WEI

30 Renal & Urology News

Minnesota Medical Board Comes Under Scrutiny Minnesota’s Star Tribune newspaper recently published an investigative series profiling how the state Board of Medical Practice is mishandling complaints about physicians. The series shines new light on the board’s inability to meet its obligation to protect patients from doctors who are practicing substandard medicine.

According to the report, the state board consistently failed to discipline doctors despite numerous complaints. Of the 728 complaints received last year, the board initiated 32 disciplinary actions.

According to the watchdog group Public Citizen, this low rate of disciplinary action consistently places Minnesota near the bottom of their annual report ranking state medical boards. In the 2010 report, the board finished last— with a discipline rate of 1.29 serious actions per 1,000 cited doctors.

Robert Leach, the medical board’s executive director, told Star Tribune reporters that the Public Citizen report fails to account for the state’s non-punitive, corrective-action approach to disciplining clinicians. According to Leach, the Board doesn’t usually discipline a clinician for a single issue, but rather it looks to see if there is a pattern of practice.

However, the Star Tribune revealed that in dozens of cases the infractions were serious enough that the physician in question lost hospital privileges, yet the board took no action.

Compounding the problem is the fact that the board, unlike medical boards in 19 other states, does not allow public access to malpractice reports, revoked hospital privileges, or surgical errors.

The board also does not make it a policy to disclose prior disciplinary action taken against a clinician by a medical board in another state.

Leach says legislative approval would be necessary if the board were to make clinician information more accessible to the public. Currently, the board provides disciplinary reports and physicianreported criminal convictions, but the board does not verify this information. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

www.renalandurologynews.com

MAY 2012

Renal & Urology News 31

BPH Surgery Complication Rates Underestimated PARIS—Complication rates after surgery for benign prostatic hyperplasia (BPH) are higher in real clinical practice than in clinical trials, according to data presented at the 27th Annual Congress of the European Association of Urology.

French researchers led by Jean-Nicolas Cornu, MD, of Tenon Hospital in Paris, noted that data about BPH surgery complications are based mainly on clinical trials with stringent outcome criteria.

Based on a study of all men who had BPH surgery in France from 2004 to 2007 (262,898 patients), however, they

concluded that the rate of BPH surgery complications has been underestimated and patients should be advised that subsequent surgery after initial BPH surgical management is not rare.

After a median follow-up of 1.51 years, 4.38% of patients had undergone a new surgery for BPH. The retreat-

ment rate was higher for the 228,262 men who underwent transurethral resection of the prostate (TURP) than for the 34,635 men who had an open prostatectomy (4.77% vs. 1.92%). The study showed that 9,152 patients had a clot removal intervention (3.4% after TURP and 3.7% after open prostatec-

tomy). Over the study period, 420 men had a surgical intervention for urinary incontinence after TURP (0.18%) compared with 31 men after open prostatectomy (0.09%). In addition, 2.7% and 1.3% of TURP and open prostatectomy patients, respectively, had surgery for urethral stenosis. ■

For your OAB patients with urge urinary incontinence

Any moment is an accident waiting to happen.

TOVIAZ provides powerful efficacy.1,2

PN-Related Complications Mostly Minor

Median % reduction from baseline in UUI episodes at Week 12

Mean UUI episodes per 24 hours at baseline

PARIS—Nearly one quarter of patients undergoing partial nephrectomy (PN) experience complications, but most are minor, a researcher reported

Mean UUI episodes per 24 hours at Week 12 *P≤0.001 vs placebo.1

at the 27th Annual Congress of the European Association of Urology.

Placebo

TOVIAZ 4 mg

TOVIAZ 8 mg

(n=211)

(n=199)

(n=223)

3.7

3.8

3.7

-50% -80%* 2.5

1.8*

-88%* 1.4*

Results of a 12-week, fixed-dose, randomized, double-blind, placebo- and active-controlled international ex-US study to assess the efficacy, tolerability, and safety of TOVIAZ in adults with overactive bladder. The coprimary efficacy end points were change in micturitions per day and change in UUI episodes per day. Subjects (N=1132) were treated once daily with placebo, TOVIAZ 4 mg or 8 mg, or an active-control agent (an oral antimuscarinic).

The median percent change in micturitions at Week 12 was 19% for TOVIAZ 8 mg, 17% for TOVIAZ 4 mg, and 11% for placebo (P<0.001). The least squares (LS) mean change in micturitions at Week 12 was -1.9 episodes for TOVIAZ 8 mg, -1.8 episodes for TOVIAZ 4 mg, and -1.0 episodes for placebo (P<0.001). The median percent reduction in UUI episodes at Week 12 was 88% for TOVIAZ 8 mg, 80% for TOVIAZ 4 mg, and 50% for placebo (P≤0.001).

The LS mean change in UUI episodes at Week 12 was -2.2 episodes for TOVIAZ 8 mg, -2.0 episodes for TOVIAZ 4 mg, and -1.1 episodes for placebo (P≤0.001).1

The researcher, Hervé Baumert, MD, PhD, of Paris Saint-Joseph Hospital Trust, presented findings from a prospective study of 576 PN patients. He told congress attendees that 23.4% of subjects experienced complications. The rate of surgical complications was 13.2% and the rate of non-surgical complications was 10.2%, he noted that complication rates did not differ significantly by surgical approach. Open, laparoscopic, and robotic PN had complication rates of 13%, 12.6%, and 15.8%, respectively.

Overall, 2.3% of patients experienced urinary fistulas: 3.1% of patients who underwent open PN, 1.7% who underwent laparoscopic PN, and 0% of those who underwent robotic PN. Arteriovenous fistulas occurred in 1% of subjects: 0.8%, 0.8%, and 2.2% of patients who underwent open, laparoscopic, and robotic PN, respectively. Perioperative transfusion rates were 4.5%, 3.4%, and 5.6%, respectively. The differences in the rates of urinary fistulas and arteriovenous fistulas did not differ significantly among the three groups. ■

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

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

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

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

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

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

OAB=overactive bladder.

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

2007;52(4):1204-1212. 2. Data on file. Protocol SP583 table SCS763 13.2.1.1.1. Pfizer Inc, New York, NY.

For more information, visit www.ToviazHCP.com.

Please see brief summary of prescribing information on next page.

FSD01158C/FSD432811

© 2012 Pfizer Inc.

All rights reserved.

February 2012

32 Renal & Urology News

MAY 2012

www.renalandurologynews.com

Flexible Ureteroscopy Suitable for Obese Patients PARIS—Flexible ureteroscopy can be an effective treatment for kidney stones in obese and overweight patients, according to data presented at the 27th Annual Congress of the European Association of Urology. The procedure is associated with a low complication rate in this subpopulation.

Researchers at Goztepe Training and Research Hospital in Istanbul, Turkey, studied 112 patients who underwent flexible ureteroscopy with laser lithotripsy. They divided subjects into three groups based on their body mass index: ideal body weight (less than 25 kg/m2; group 1), overweight (25-20.9 kg/m2;

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

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

CONTRAINDICATIONS Toviaz is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Toviaz is also contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules.

WARNINGS AND PRECAUTIONS Angioedema: Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine. In some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, fesoterodine should be promptly discontinued and appropriate therapy and/or measures to ensure a patent airway should be promptly provided.

Bladder Outlet Obstruction: Toviaz should be administered with caution to patients with clinically significant bladder outlet obstruction because of the risk of urinary retention.

Decreased Gastrointestinal Motility: Toviaz, like other antimuscarinic drugs, should be used with caution in patients with decreased gastrointestinal motility, such as those with severe constipation.

Controlled Narrow-Angle Glaucoma: Toviaz should be used with caution in patients being treated for narrow-angle glaucoma, and only where the potential benefits outweigh the risks.

Hepatic Impairment: Toviaz has not been studied in patients with severe hepatic impairment and therefore is not recommended for use in this patient population.

Renal Impairment: Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment.

Concomitant Administration with CYP3A4 Inhibitors: Doses of Toviaz greater than 4 mg are not recommended in patients taking a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin).

No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (eg, erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice). While the effect of weak CYP3A4 inhibitors (eg, cimetidine) was not examined by clinical study, some pharmacokinetic interaction is expected, albeit less than that observed with moderate CYP3A4 inhibitors.

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

ADVERSE REACTIONS Clinical Trials Experience: The safety of Toviaz was evaluated in Phase 2 and 3 controlled trials in a total of 2859 patients with overactive bladder, of which 2288 were treated with fesoterodine. Of this total, 782 received Toviaz 4 mg/day, and 785 received Toviaz 8 mg/day in Phase 2 or 3 studies with treatment periods of 8 or 12 weeks. Approximately 80% of these patients had >10 weeks exposure to Toviaz in these trials.

A total of 1964 patients participated in two 12-week, Phase 3 efficacy and safety studies and subsequent open-label extension studies. In these two studies combined, 554 patients received Toviaz 4 mg/day and 566 patients received Toviaz 8 mg/day. In Phase 2 and 3 placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg were 1.9%, 3.5%, and 2.9%, respectively. All serious adverse events were judged to be not related or unlikely to be related to study medication by the investigator, except for four patients receiving Toviaz who reported one serious adverse event each: angina, chest pain, gastroenteritis, and QT prolongation on ECG. The most commonly reported adverse event in patients treated with Toviaz was dry mouth. The incidence of dry mouth was higher in those taking 8 mg/day (35%) and in those taking 4 mg/day (19%), as compared to placebo (7%). Dry mouth led to discontinuation in 0.4%, 0.4%, and 0.8% of patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg, respectively. For those patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment.

The second most commonly reported adverse event was constipation. The incidence of constipation was 2% in those taking placebo, 4% in those taking 4 mg/day, and 6% in those taking 8 mg/day.

Table 1 lists adverse events, regardless of causality, that were reported in the combined Phase 3, randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with Toviaz 4 or 8 mg once daily for up to 12 weeks.

Table 1. Adverse events with an incidence exceeding the placebo rate and reported by ≥1% of patients from double-blind, placebo-controlled Phase 3 trials of 12 weeks treatment duration Placebo N=554 %

Toviaz 4 mg/day N=554 %

Toviaz 8 mg/day N=566 %

Dry mouth

7.0

18.8

34.6

Constipation

2.0

4.2

6.0

Dyspepsia

0.5

1.6

2.3

Nausea

1.3

0.7

1.9

Abdominal pain upper

0.5

1.1

0.5

System organ class

Gastrointestinal disorders

Infections

Preferred term

Urinary tract infection

3.1

3.2

4.2

Upper respiratory tract infection

2.2

2.5

1.8

Eye disorders

Dry eyes

0

1.4

3.7

Renal and urinary disorders

Dysuria

0.7

1.3

1.6

Urinary retention

0.2

1.1

1.4

Respiratory disorders

Cough

0.5

1.6

0.9

Dry throat

0.4

0.9

2.3

General disorders

Edema peripheral

0.7

0.7

1.2

Musculoskeletal disorders

Back pain

0.4

2.0

0.9

Psychiatric disorders

Insomnia

0.5

1.3

0.4

Investigations

ALT increased

0.9

0.5

1.2

GGT increased

0.4

0.4

1.2

Rash

0.5

0.7

1.1

Skin disorders

ALT = alanine aminotransferase; GGT = gamma glutamyltransferase

Patients also received Toviaz for up to three years in open-label extension phases of one Phase 2 and two Phase 3 controlled trials. In all open-label trials combined, 857, 701, 529, and 105 patients received Toviaz for at least 6 months, 1 year, 2 years, and 3 years, respectively. The adverse events observed during long-term, open-label studies were similar to those observed in the 12-week, placebo-controlled studies, and included dry mouth, constipation, dry eyes, dyspepsia, and abdominal pain. Similar to the controlled studies, most adverse events of dry mouth and constipation were mild to moderate in intensity. Serious adverse events, judged to be at least possibly related to study medication by the investigator and reported more than once during the open-label treatment period of up to 3 years, included urinary retention (3 cases), diverticulitis (3

group 2), and obese (30 kg/m2 or greater; group 3). The three groups were similar with respect to age, gender mix, stone sizes, and stone locations. The mean number of procedures was 1.25, 1.29, and 1.33 in groups 1, 2, and 3, respectively. The overall-stone free rates were 84%, 87%, and 81%, respectively.

cases), constipation (2 cases), irritable bowel syndrome (2 cases), and electrocardiogram QT corrected interval prolongation (2 cases).

Post-marketing Experience: The following events have been reported in association with fesoterodine use in worldwide post-marketing experience: Eye disorders: Blurred vision; Cardiac disorders: Palpitations; General disorders and administrative site conditions: hypersensitivity reactions, including angioedema with airway obstruction, face edema; Skin and subcutaneous tissue disorders: Urticaria, pruritus. Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of fesoterodine in their causation cannot be reliably determined.

DRUG INTERACTIONS Antimuscarinic Drugs: Coadministration of Toviaz with other antimuscarinic agents that produce dry mouth, constipation, urinary retention, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.

CYP3A4 Inhibitors: Doses of Toviaz greater than 4 mg are not recommended in patients taking potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin. Coadministration of the potent CYP3A4 inhibitor ketoconazole with fesoterodine led to approximately a doubling of the maximum concentration (Cmax ) and area under the concentration versus time curve (AUC) of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine. Compared with CYP2D6 extensive metabolizers not taking ketoconazole, further increases in the exposure to 5-HMT were observed in subjects who were CYP2D6 poor metabolizers taking ketoconazole.

There is no clinically relevant effect of moderate CYP3A4 inhibitors on the pharmacokinetics of fesoterodine.

Following blockade of CYP3A4 by coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice a day for 2 days, the average (90% confidence interval) increase in Cmax and AUC of the active metabolite of fesoterodine was approximately 19% (11%-28%) and 27% (18%-36%) respectively. No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (eg, erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice). The effect of weak CYP3A4 inhibitors (eg, cimetidine) was not examined; it is not expected to be in excess of the effect of moderate inhibitors.

CYP3A4 Inducers: No dosing adjustments are recommended in the presence of CYP3A4 inducers, such as rifampin and carbamazepine. Following induction of CYP3A4 by coadministration of rifampin 600 mg once a day, Cmax and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of Toviaz 8 mg. The terminal half-life of the active metabolite was not changed.

CYP2D6 Inhibitors: The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, Cmax and AUC of the active metabolite are increased 1.7- and 2-fold, respectively. No dosing adjustments are recommended in the presence of CYP2D6 inhibitors.

Drugs Metabolized by Cytochrome P450: In vitro data indicate that at therapeutic concentrations, the active metabolite of fesoterodine does not have the potential to inhibit or induce Cytochrome P450 enzyme systems.

Oral Contraceptives: In the presence of fesoterodine, there are no clinically significant changes in the plasma concentrations of combined oral contraceptives containing ethinyl estradiol and levonorgestrel.

Warfarin: A clinical study has shown that fesoterodine 8 mg once daily has no significant effect on the pharmacokinetics or the anticoagulant activity (PT/INR) of warfarin 25 mg. Standard therapeutic monitoring for warfarin should be continued.

Drug-Laboratory Test Interactions: Interactions between Toviaz and laboratory tests have not been studied.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C. There are no adequate and well-controlled studies using Toviaz in pregnant women.

No dose-related teratogenicity was observed in reproduction studies performed in mice and rabbits. In mice at 6 to 27 times the expected exposure at the maximum recommended human dose (MRHD) of 8 mg based on AUC (75 mg/kg/day, oral), increased resorptions and decreased live fetuses were observed. One fetus with cleft palate was observed at each dose (15, 45, and 75 mg/kg/day), at an incidence within the background historical range. In rabbits treated at 3 to 11 times the MRHD (27 mg/kg/day, oral), incompletely ossified sternebrae (retardation of bone development) were observed in fetuses. In rabbits at 9 to 11 times the MRHD (4.5 mg/kg/day, subcutaneous), maternal toxicity and incompletely ossified sternebrae were observed in fetuses (at an incidence within the background historical range). In rabbits at 3 times the MRHD (1.5 mg/kg/ day, subcutaneous), decreased maternal food consumption in the absence of any fetal effects was observed.

Oral administration of 30 mg/kg/day fesoterodine to mice in a pre- and post-natal development study resulted in decreased body weight of the dams and delayed ear opening of the pups. No effects were noted on mating and reproduction of the F1 dams or on the F2 offspring.

Toviaz should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Nursing Mothers: It is not known whether fesoterodine is excreted in human milk. Toviaz should not be administered during nursing unless the potential benefit outweighs the potential risk to the neonate.

Pediatric Use: The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients.The safety and effectiveness of Toviaz in pediatric patients have not been established.

Geriatric Use: No dose adjustment is recommended for the elderly. The pharmacokinetics of fesoterodine are not significantly influenced by age.

Of 1567 patients who received Toviaz 4 mg/day or 8 mg/day in the Phase 2 and 3, placebo-controlled, efficacy and safety studies, 515 (33%) were 65 years of age or older, and 140 (9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies; however, the incidence of antimuscarinic adverse events, including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (at 8 mg only) and urinary tract infection, was higher in patients 75 years of age and older as compared to younger patients.

Renal Impairment: In patients with severe renal impairment (CLCR <30 mL/min), Cmax and AUC are increased 2.0- and 2.3-fold, respectively. Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment. In patients with mild or moderate renal impairment (CLCR ranging from 30-80 mL/min), Cmax and AUC of the active metabolite are increased up to 1.5- and 1.8-fold respectively, as compared to healthy subjects. No dose adjustment is recommended in patients with mild or moderate renal impairment.

Hepatic Impairment: Patients with severe hepatic impairment (Child-Pugh C) have not been studied; therefore Toviaz is not recommended for use in these patients. In patients with moderate (Child-Pugh B) hepatic impairment, Cmax and AUC of the active metabolite are increased 1.4- and 2.1-fold, respectively, as compared to healthy subjects. No dose adjustment is recommended in patients with mild or moderate hepatic impairment.

Gender: No dose adjustment is recommended based on gender. The pharmacokinetics of fesoterodine are not significantly influenced by gender.

Race: Available data indicate that there are no differences in the pharmacokinetics of fesoterodine between Caucasian and Black healthy subjects following administration of Toviaz.

OVERDOSAGE Overdosage with Toviaz can result in severe anticholinergic effects. Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended.

Manufactured by: Aesica Pharmaceuticals GmbH, Galileistraße 6, 08056 Zwickau, Germany Distributed by: Pfizer Labs, Division of Pfizer Inc, NY, NY 10017 LAB-0381-10.0 Revised November 2011 FSD01151A/FSD423505-01

© 2011 Pfizer Inc.

All rights reserved.

December 2011

None of the differences among the three groups was significant.

In addition, the study revealed no significant differences in mean operative time, hospital length of stay, or the rate of minor complications.

The mean operative time was 84.37, 88.58, and 92.2 minutes for groups 1, 2, and 3, respectively. The mean hospital length of stay was 1.3, 1.2, and 1.4 days, respectively. Minor complications occurred in 9%, 7.3%, and 7.4% of subjects in groups 1, 2, and 3.

The investigators observed no major complications. ■

Early Salvage Radiotherapy Recommended PARIS—Salvage radiotherapy (SRT) for recurrent prostate cancer (PCa) should be given at the earliest sign of biochemical failure, researchers reported at the 27th Annual Congress of the European Association of Urology.

The best candidates for SRT are those with positive surgical margins (PSMs) and a PSA nadir of 0.1 ng/mL or less after radical prostatectomy (RP), they concluded.

The study, led by Maria Ervandian, MD, and presented by Michael Borre, MD, both of Aarhus University Hospital in Aarhus, Denmark, included 279 patients who received SRT for recurrent PCa. Subjects had a median age of 66 years at the time of SRT and a median nine months of follow-up from SRT. At the end of follow-up, 58% of patients were without biochemical relapse after SRT. Multivariate analysis showed that PSMs, a post-RP PSA nadir of 1.0 ng/mL or less, and age of 66 years or younger independently predicted PSA recurrence.

Previously at their institution, oncologists needed histological proof of disease recurrence and higher PSA levels before recommending salvage radiotherapy, Dr. Borre noted. “Today, we are more aggressive, and we do treat as soon as the patients do fail, and the prognosis is far much better,” he said. ■

www.renalandurologynews.com

MAY 2012

Renal & Urology News 33

■ GUEST EDITORIAL

Kidney Stone Prevention: “Fact versus Fiction” With nephrolithiasis treatment and disability currently estimated to cost five billion dollars a year in the United States, minimizing risk is crucial BY MARK FINGER, MD, FACP

A

ccording to estimates, kidney stones will develop in nearly 30 million people in the United States. The prevalence is highest among those aged 30-45 years. Elevated urinary calcium can cause kidney stones in upwards of 80% of cases. The most prevalent stone composition is calcium oxalate. Once kidney stones develop, patients have a 50%-75% recurrence rate. The yearly cost of kidney stones in the United States was $2 billion (treatments, hospitalizations, lost work, etc.) in 1994 and is now estimated at $5 billion.1 Clearly, prevention is paramount.

General guidelines for prevention include protein moderation, minimal salt ingestion, and drinking enough clear liquids to generate two liters of urine per day. A low oxalate diet has proven beneficial for preventing calcium oxalate stones. Uric acid stones require purine restriction, adequate fluid intake, and manipulation of urinary pH. Cystine stones require their own preventive measures.

Which fluid to drink is controversial. While water is the mainstay, other choices exist. For example, lemon juice and lemonade increase urinary citrate that helps prevent stone formation.

Orange juice also increases urinary citrate levels, but it could raise oxalate levels. Apple and cranberry juice contain oxalates and have been associated with a higher risk of calcium oxalate stones. Likewise, grapefruit juice has been associated with increased risk of stone formation. Soft drinks, via their phosphorus content, may lead to increased risk for kidney stones.2,3 What about sugar? Analysis from the Nurses Health Study II has shown

that sugar increased kidney stone risk by more than 30%. Whether this was an independent variable was unclear but the message is that high sugar, of whatever form, is detrimental in the prevention of kidney stones.

And the calcium controversy? Excess calcium intake will increase the risk for forming kidney stones. A diet containing normal amounts of calcium will protect against stones better than a low calcium regimen. A diet too low in calcium will allow preferential absorption of oxalate in the gut and increase the risk of calcium oxalate stones.

If diet is not helpful then medications are considered. These include thiazides for hypercalciuria, citrate for hypocitraturia, cystine binding drugs (i.e., penicillamine) for hypercystinuria, as well as future options, including oxalate degrading enzymes. But these medications have side effects. Thiazides can worsen glucose tolerance, cause electrolyte imbalance, and aggravate triglyceride levels.

Besides diet and medications, there is a homeopathic approach that centers on nutraceuticals. Is this fact or fiction?

Some may argue fiction, but the literature provides fact. Citrate, while available in capsule form, is readily found in fluids such as lemonade. Citrate acts to stabilize crystal formation by binding with calcium in a soluble complex, thus reducing the amount of calcium available for binding to oxalate.4,5 Magnesium has also been shown to inhibit crystal formation thus reducing the risk for forming kidney stones.6,7 While magnesium is available in food, dietary recommendations often conflict because foods that are good sources of magnesium often are high in oxalate.

Thus, the most direct way of increasing urinary magnesium is by supplement, i.e. magnesium oxide at doses of approximately 400 mg per day.

The literature also supports the use of vitamin B6 (pyridoxine) to help reduce urinary oxalate.6,7 While most helpful in hereditary oxalate abnormalities, the benefit can also occur in those with generalized hyperoxaluria. Caution should be exercised when taking pyridoxine because very high doses can cause neurologic issues. Generally, a dose of 50 mg is used.

In my opinion, one of the most overlooked natural preventatives for calcium-based kidney stones is phytate, otherwise known as IP-6 (inositol hexaphosphate).8,9,10 IP-6 has been studied as far back as the 1950’s at Harvard where it was shown to reduce the frequency of calcium based stones.11 IP-6 acts by preventing crystallization of calcium salts whether of the oxalate or phosphate variety.12 Studies have shown reduced crystal formation in rats as well as in humans.12,13 This is a tremendous alternative to using hydrochlorothiazide and is clearly without the potential side effects.

So what would be a comprehensive recommendation to prevent kidney stones? Besides ruling out secondary causes, it would be to limit salt, drink adequate and appropriate fluids, moderate animal protein intake, minimize sugar intake, ingest adequate amounts of calcium, and strongly consider intake of high fiber plant foods containing phytate. It would also be beneficial to consider taking magnesium oxide, pyridoxine, citrate, and IP-6. Some supplements are available that combine these substances. These include

Renalstat (Rematech Nutrahealth), Kidney Support Formula (VRP), and Kidney Stone Formula (Bio Essence).

All of this taken together should help to minimize your patient’s risk of recurrent kidney stones. ■ Disclaimer: Mark Finger, MD, is Chief Executive Officer and Chief Medical Officer at Rematech Nutrahealth, makers of the Renalstat formulation.

REFERENCES 1. National Kidney and Urologic Diseases Information Clearinghouse. www.kidney.niddk.nih.gov /kudiseases/pubs/stonesadults.

2. Shuster J, Jenkins A, Logan C, et al. Soft drink consumption and urinary stone recurrence: a randomized prevention trial. J Clin Epidemiol 1992;45:911-916.

3. Curham GC, Willett WC, Rimm EB, et al.

Prospective Study of beverage use and the risk of kidney stones. Am J Epidemiol 1996;143 240-247.

4. Pak CY, Fuller C, Sakhaee K, et al. Long-term treatment of calcium nephrolithiasis with potassium citrate. J Urol 1985;134:11-19.

5. Lee YH, Huang WC. The efficacy of potassium citrate based medical prophylaxis for preventing upper urinary tract calculi; a midterm follow up study. J Urol 1999; 161:1453-1457.

6. Gershoff SN, Prien EL. Effect of daily MgOx and vitamin B6 administration to patients with recurring calcium oxalate stones. Am J Cl in Nutr 1967;20(5):393-399.

7. Prien EL, Gershoff SF. Magnesium oxide-pyridoxine therapy for recurrent calcium oxalate calculi. J Urol 1974; 112:509-512.

8. Ohkawa, T. Rice bran treatment for patients with hypercalciuric stones: experimental and clinical studies. J Urol 1984;132:1140-1145.

9. Shah PJ, Williams, G, Green NA. Idiopathic hypercalciuria: Its control with unprocessed bran. Br J Urol 1980;52: 426-429.

10. Ebisuno S, Morimoto S, Yoshida T, et al.

Rice bran treatment for calcium stone formers with idiopathic hypercalciuria. Br J Urol 1986;58:592-595.

11. Hennerman PH, Benedict PH, Forbes AP, Dudley HR. Idiopathic Hypercalciuria. N Engl J Med 1958;17:802-807.

12. Grases F, Costa-Bauzá A. Phytate (IP-6) is a powerful agent for preventing calcifications in biological fluids: Usefulness in renal lithiasis treatment.

Anticancer Res 1999; 19(5A):3717-22.

13. Curhan GC, Willett WC, Knight EL, Stampfer MJ. Dietary factors and the risk of incident kidney stones in younger women: Nurses’ Health Study II. Arch Intern Med 2004;164:885-891.

34 Renal & Urology News

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■ 2012 Genitourinary Cancer Symposium, San Francisco

Previous Sunitinib Duration Matters Long time on the drug prolongs PFS of patients with metastatic RCC receiving second-line therapy

Rye Bread Protective Against PCa? GREATER RYE BREAD consumption in adolescence may be associated with a decreased risk of prostate cancer (PCa), especially advanced disease, data show.

Nutritionist Johanna E. Torfadottir, a PhD student at the University of Iceland in Reykjavik, and colleagues studied 2,268 men aged 67 to 96 years who had reported their dietary habits in the AGES-Reykjavik cohort study.

A total of 347 subjects had or were diagnosed with prostate cancer during follow-up, 63 with advanced disease.

Daily rye bread consumption in adolescence (age 14-19 years), compared with less than daily consumption, was associated with a 22% decreased PCa risk and a 47% decreased risk of advanced PCa, after adjusting for numerous potential confounders, including fish, fish liver oil, meat, and milk intake, Torfadottir reported. High

Prolonged PFS Patients receiving second-line treatment for metastatic renal cell carcinoma who previously were treated with sunitinib for nine months or more had prolonged progression-free survival (PFS). The median PFS rates by study arm are shown here.

Source: Rini BI, et al. Phase III AXIS trial for second-line metastatic renal cell carcinoma (mRCC): Effect of prior first-line treatment duration and axitinib dose titration on axitinib efficacy.

Presented at the 2012 Genitourinary Cancers Symposium in San Francisco. Abstract 354.

8

Axitinib

7 6

Months

BY JOHN SCHIESZER PRIOR SUNITINIB treatment for nine months or longer is associated with longer progression-free survival (PFS) in patients receiving either axitinib or sorafenib as second-line treatment for metastatic renal cell carcinoma (RCC).

Brian Rini, MD, Associate Professor of Medicine at Cleveland Clinic, and his colleagues evaluated the effect of prior sunitinib treatment duration and axitinib dose titration on subsequent axitinib efficacy. Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3.

The FDA recently approved axitinib (Inlyta) to treat patients with advanced RCC who have not responded to another RCC drug. In the phase 3 AXIS trial of axitinib versus sorafenib for second-line mRCC, axitinib significantly prolonged median PFS (6.7 vs 4.7 months).

In the current trial, eligible patients had clear-cell mRCC with measurable RECIST-

Sorafenib

6.3

5

4.6

4

4.5

3

2.9

2 1 0

Nine months or more

defined progressive disease after one prior first-line systemic therapy. Investigators randomized patients to either axitinib at a starting dose of 5 mg twice daily or sorafenib 400 mg twice a day.

Patients without toxicities greater than grade 2 and blood pressure less than 150/90 mm Hg and who were without antihypertensive medication for more than two weeks were eligible to have their

intake of oatmeal in adolescence (five or more times vs. four or fewer times per week) was not significantly associated with the risk of any PCa or advanced PCa. Midlife consumption of rye or oatmeal was not associated with cancer risk, she said.

Of the 2,268 men in the study, 1,046 reported at least daily consumption of rye bread in adolescence and 1,212 reported less than daily consumption.

Torfadottir said it is thought rye bread may contain phytoestrogens that could have a protective effect against PCa. The study by her and her colleagues is the first to demonstrate that greater rye bread consumption early in life is associated with a decreased PCa risk.

A recently published prospective study of 26,691 Danish men aged 50-64 years with a median follow-up period of 12.4 years showed no association between PCa risk and total intake of whole-grain products or intake of specific whole-grain products—including whole-grain rye bread, whole-grain bread, and oatmeal. The study was published in Cancer Causes and Control (2011;1133-1139). ■

Less than nine months

Prior sunitinib duration

axitinib dose increased to 7 mg twice a day and then to 10 mg twice a day.

The median PFS was 6.6 months for 132 patients receiving at least one total daily axitinib dose greater than 10 mg (dose-titrated group) and 8.3 months for 227 patients receiving an axitinib dose of 10 mg or less. A total of 194 patients (53.7%) in the axitinib arm and 195 (53.9%) in the sorafenib arm

had prior sunitinib treatment.

The median PFS for duration of prior sunitinib treatment for nine months or more and less than nine months was 6.3 months and 4.5 months, respectively, for axitinib patients. The median PFS for duration of prior sunitinib treatment of nine months or more and less than nine months was 4.6 months and 2.9 months, respectively, for sorafenib patients.

The investigators concluded that duration of prior sunitinib treatment for nine months or more may be associated with a longer PFS on second-line VEGFR tyrosine kinase inhibitors.

The study also showed that both axitinib dose-increased and non-increased patients had longer PFS compared with the sorafenib arm.

“If people are at subtherapeutic levels they are very unlikely to respond to it,” Dr. Rini told Renal & Urology News.

“We need to optimize drug levels. Dose titration allows people to meet the minimum requirements.” ■

Drug Combo May Improve Survival in RCC Patients

BY JOHN SCHIESZER

in Group 2). The groups were balanced in

COMBINING A bisphosphonate with

terms of known prognostic factors. The

sunitinib may improve progression-free

patients were also balanced with regard

survival (PFS) and overall survival (OS)

to past cytokines/targeted treatments,

in patients with bone metastases from

and mean sunitinib dose/cycle.

renal cell carcinoma (RCC), according to a multicenter, retrospective study.

Bisphosphonates can prevent skeletal

The investigators observed disease progression in five members (14%) of Group 1 compared with 12 members

events related to bone metastases, but

(29%) of Group 2. The median PFS was

the findings from this study suggest

15 months for Group 1 compared with

bisphosphonates also may have anti-

five months for Group 2. Overall survival

tumor effects in this patient population,

was 21 months for Group 1 versus 13

said lead investigator Daniel Keizman,

months for Group 2.

MD, an attending physician at Meir Medical Center in Tel Aviv, Israel..

For this investigation, patients were

In multivariate analysis, PFS was twice as likely among bisphosphonate users compared with nonusers and 62% less

divided into bisphosphonate users (Group

likely among those with a pre-treatment

1) and non-users (Group 2).

neutrophil to lymphocyte ratio greater than

From 2004-2011, 209 patients with

3. OS was nearly threefold more likely

metastatic RCC were treated with suni-

in bisphosphonate users than nonusers

tinib. Of these, 76 patients had bone me-

and 72% less likely in subjects with an

tastases (35 patients in Group 1 and 41

elevated alkaline phosphatase level. ■

www.renalandurologynews.com

MAY 2012

Renal & Urology News 35

Your Money I

n recent months, investors have been eagerly pursuing shares of Facebook, Groupon, and other hot technology companies. That has led some Wall Street analysts to worry that the stocks in the sector could be overheated and poised to sink. But the outlook remains solid for makers of computers, software, and mobile devices. Earnings are growing, and the stocks of many companies appear to be priced at bargain levels. “Some of the stocks are the cheapest that they have been in years,” says Ian Warmerdam, portfolio manager of Henderson Global Technology Fund.

Prices of many technology stocks last hit a peak in 2000, Warmerdam says.

At the time, consumers and investors were embracing all kinds of technology companies. Convinced technology products could work miracles, corporations bought more computers and software than they actually needed. Investors raced to buy shares of technology powerhouses such as software giant Microsoft and Apple. Internet stocks with little or no earnings were also soaring. Then the bubble burst. Corporate customers cut their purchases, and dozens of Internet companies went out of businesses.

During the three years ending in 2002, technology funds lost 74.6%, according to fund tracker Morningstar.

At the height of the bull market, technology stocks sold for 45 times their annual earnings. Then for much of the next decade, the multiple fluctuated between 15 and 20 times earnings. In the last several years, earnings have been increasing, but the share prices have rallied only sluggishly. The stocks currently sell for 12 times earnings. Investors have been reluctant to buy some of the stocks because they fear another technology downturn could be on the horizon.

Many of the biggest companies appear especially cheap. Consider Apple, which sells for a price-earnings multiple of 14—about the same as the figure for the average stock in the S&P 500. While

Apple sells for an average price, the company is hardly an average business.

Apple’s sales jumped 73% in the most recent quarter, a huge growth spurt for a large company. Sales of the company’s iPhones and iPad tablets are booming as customers around the globe race to grab the latest Apple products.

So why is the stock so cheap? Investors figure that Apple cannot possibly keep growing so fast, Warmerdam says. All too often consumer electronics companies have become hot and then faded quickly.

Warmerdam concedes that Apple’s growth could slow down, but he argues that the stock is a good value because the company will continue growing. “Apple has extremely loyal customers who will continue using the products,” he says.

Besides reporting strong earnings, most technology companies also have rock-solid balance sheets. After so many Internet companies vanished a decade ago, the surviving technology companies resolved to hold plenty of cash so that they could stay in business during downturns. Since then many blue-chip companies have been hoarding their cash. Now Apple has $30 billion in cash, while Microsoft holds $50 billion. The cash guarantees that the companies have the ability to stay

© ISTOCKPHOTO.COM/HOCUS -FOCUS

Makers of computers, software, and mobile devices have a solid outlook, with the stocks of many companies seemingly available at bargain prices

The stocks of many technology companies appear to be priced at bargain levels.

and many products are becoming obsolete, says James Swanson, chief investment strategist for MFS Investment Management. Corporate customers have begun buying in recent months.

“To remain competitive, corporate customers are beginning to play catch-up,” Swanson says.

To find bargains, consider stocks of companies that provide equipment for making computers, says Mark Oelschlager, portfolio manager of Red Oak Technology Fund. Sales of the equipment makers are highly cyclical, falling steeply when the economy slows

Besides reporting strong earnings, most technology companies also have rock-solid balance sheets. afloat and invest in expansion.

Sales for many of the companies are growing nicely. Much of the new demand comes from China and other emerging markets. But there is also strong demand in the United States.

During the financial crisis that began in 2007, many companies postponed making new purchases. Now the average age of installed software is 5.5 years,

and rising when a boom appears. These days the companies are recovering from the slowdown and moving into a period of solid growth. Oelschlager likes Applied Materials, which makes equipment used to make semiconductors, vital components of many technology products. The company has $6 billion in cash and only sells for 8 times earnings. “Demand for semiconductors is

going to get greater and greater as the economy picks up,” Oelschlager says.

Growth should be particularly strong for search giant Google and other companies that benefit from online advertising. Google stands to continue expanding as more advertising moves from print publications to the Internet, says Kevin Landis, portfolio manager of Firsthand Technology Opportunities.

“Most of the world’s advertising has not moved online yet,” Landis says.

Warmerdam likes Baidu, which is the Google of China. While most Americans have access to the Internet, only about one third of Chinese consumers currently have access. But China is racing to ensure that more of its citizens can get online. That is producing rapid sales gains for Baidu. The company accounts for more than 80% of all the searches done in China. In contrast, Google, handles about 65% of search traffic in the United States.

Warmerdam also likes Priceline.com, the online travel service. The company is expanding in Europe where online booking is still in its early stages of development. In the United States, half of all hotel rooms are booked online. But the figure for Europe is only 15%. “The online travel market in Europe could expand to the point where it matches the U.S.,” Warmerdam says. ■

40 Renal & Urology News

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CME FEATURE

Part I: Assessment and Diagnostic Strategies for Neurogenic Bladder Diagnostics and treatment options for NGB are continually advancing, and clinicians need to remain up-to-date to accurately assess and optimally manage patients

Release Date: May 2012 Expiration Date: May 2013 Estimated time to complete the educational activity: 1 hour This activity is jointly sponsored by Medical Education Resources and Haymarket Medical Education and is supported by an educational grant from Allergan, Inc. STATEMENT OF NEED: Urologists and other healthcare professionals caring for patients with bladder dysfunction should be knowledgeable about the symptoms of neurogenic bladder (NGB) and integrate assessment and diagnostic approaches that may facilitate identification of patients for earlier treatment. Providers should also be knowledgeable about the various treatment options for NGB, including options for patients who fail behavioral or oral therapy.

TARGET AUDIENCE: This activity has been designed to meet the educational needs of urologists and other clinicians involved in the treatment of patients with bladder dysfunction.

EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Identify patients for individualized treatment earlier using diagnostic strategies.

• Describe management options for neurogenic bladder, including evidence-based treatments and novel therapeutic approaches.

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 its 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 • David A. Ginsberg, MD

Reported Financial Relationship Grants/Research Support: Allergan, Inc., Medtronic, Inc. Consultant: Allergan, Inc., American Medical Systems, Inc. Speakers’ Bureau: Allergan, Inc., Pfizer, Inc.

BY DAVID A. GINSBERG, MD

NGB can lead to a higher risk for renal complications.

N

Pathophysiology and etiology

eurogenic bladder (NGB) affects many adults in the United States and is commonly caused by multiple sclerosis (MS), spinal cord injury (SCI), cerebral vascular accident, and Parkinson’s disease. Many of these patients have bothersome urinary symptoms, including urinary incontinence (UI), urinary frequency, and urgency.

The primary urodynamic finding for most patients with NGB is an uninhibited bladder contraction, or neurogenic detrusor overactivity (NDO).

Bladder disorders have been reported in 40% to 90% of patients with MS and in 37% to 72% of patients with Parkinson’s disease, with a higher rate of UI in patients with cerebral vascular accident and Parkinson’s disease than in the general population.1 In addition to their physical burden, urinary symptoms such as incontinence can significantly impair quality of life.2 The occurrence of urinary tract infections (UTIs) in the NDO population is common.3 UI also increases the risk for skin irritation and breakdown as well as depression.4,5 In some cases,

The content managers, Roxanne Nelson, RN, Mary Jo Krey, Lori Marrese, Jody A. Charnow, and Marina Galanakis of Haymarket Medical Education, and Victoria C. Smith, MD, of Medical Education Resources, have disclosed that they have no relevant financial relationships or conflicts of interest.

METHOD OF PARTICIPATION: There are no fees for participating in and receiving CME credit for this activity. During the period May 2012 through May 2013, participants must: 1) read the learning objectives and faculty disclosures, 2) study the educational activity, 3) complete the posttest and submit it online. Physicians may register at www.myCME.com/renalandurologynews, and 4) complete the evaluation form online.

A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better.

David A. Ginsberg, MD, is Associate Professor of Clinical Urology at the Keck School of Medicine at the University of Southern California in Los Angeles.

The two main functions of the bladder are storage and voiding, and a normal cycle depends on coordination between the bladder and the urethral sphincter.6 Normal micturition involves autonomic and somatic pathways from the lumbosacral spine to the urethral outlet, bladder neck, and detrusor muscle—and a change in any of these can produce symptoms of NGB.7 Furthermore, an alteration in bladder wall innervation, or of the pelvic floor and urethra, can trigger overactivity.

Neurologic disorders often damage and disrupt the central or peripheral pathways involved in the central control of the lower urinary tract.8 Damage to areas of the nervous system may result in detrusor overactivity, with or without detrusor-sphincter dyssynergia, detrusor underactivity, detrusor areflexia, and impaired contractility.

The causes of neurologic conditions leading to NGB include supraspinal, spinal, peripheral, or mixed.8 Supraspinal disorders involve central nervous system lesions that occur above the pontine micturition center. They

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MAY 2012

Renal & Urology News 41

CME FEATURE include conditions such as Parkinson’s disease, Shy-Drager Syndrome, cerebral palsy, frontal lobe lesions, stroke, cerebral trauma,8 and MS. Bladder dysfunction at this level usually presents as neurogenic detrusor overactivity combined with synergistic activity between the bladder and sphincter (i.e., when the bladder contracts, the sphincter appropriately relaxes).

Suprasacral spinal neurologic conditions include SCI, spinal stenosis, spinal cord infarction, MS, transverse myelitis, cervical spondylosis, and intervertebral disk disease.8 Patients with complete cord transections above the level of the sacrum generally present with NDO and striated sphincter dyssynergia (i.e., when the bladder contracts, the external sphincter inappropriately contracts at the same time).6 Detrusor external sphincter dyssynergia (DESD) is associated with a high risk for other urologic complications such as hydronephrosis, vesicourethral reflux, urosepsis, and urolithiasis.8 In addition, patients with lesions at T6 and higher are also at risk for symptoms of autonomic dysreflexia.

Lesions in the sacral spinal cord, including those in patients with spina bifida, diabetes mellitus, herpes zoster, and herniated lumbar disk disease, often lead to an acontractile detrusor.8 In addition, poor bladder compliance can be seen, which places the patients at risk for upper urinary tract damage if bladder storage pressures are too high. These patients are at risk for poor sphincteric activity as well. Among patients with peripheral nerve lesions caused by diabetes mellitus, herpes zoster, and herniated lumbar disk disease, bladder dysfunction generally manifests as detrusor areflexia.6 It is important to realize that there are a great many exceptions to these general patient categorizations. Neurologic lesions can often be incomplete or span multiple levels; thus, each patient benefits from a complete and thorough neurourologic evaluation.

©1995 -2012 Healthwise, Incorporated. www.healthwise.org. Reprinted with permission.

This information does not replace the advice of a doctor. Healthwise disclaims any warranty or liability for your use of this information.

Intermittent catheterization is the preferred method of catheterization for patients with NGB.

ultrasound (as indicated), endoscopic examination (as indicated), and urodynamic studies (Table 1).8 Presenting symptoms can be roughly divided into failure to empty or failure to store. Typical symptoms of disrupted bladder emptying include feelings of fullness and difficulty emptying the bladder, such as a slow stream while straining to void. Other patients report hesitancy, an interrupted or diminished stream, a sensation of incomplete emptying, lower abdominal discomfort, nocturia, and recurrent UTIs.7 Failure to store usually presents as frequency, urgency, and UI. Depending on the level and severity of the neurologic

lesion, patients may not have any bladder sensation; symptoms therefore may not be a reliable indicator of significant NGB dysfunction in certain patients.

Issues related to NGB include childhood urologic history, prior surgical procedures, and other medical conditions. Current medication use should be evaluated, as certain drugs can impact bladder function. In addition, issues related to bowel and sexual function are commonly seen in patients with NGB and may have to be addressed.

Loss of genitourinary and gastrointestinal function are important sequelae of SCI.10 Constipation can affect voiding function, leading to incontinence or

Table 1. Initial Evaluation History and physical examination • Urologic • Neurologic: S2-4; bulbocavernosus reflex • Bowel function • Autonomic dysreflexia • Erectile dysfunction Neurologic examination Urinalysis with or without urine culture Renal function study (serum creatinine)

Diagnosis and assessment of NGB Appropriate management relies on an accurate diagnosis. In some patients with NGB, the original cause of their symptoms may be misdiagnosed, resulting in failure of initial therapy.9 Assessment includes a comprehensive medical and voiding history, a physical examination, laboratory tests, computed tomography urogram or renal

Computed tomography urogram or renal ultrasound (as indicated) Endoscopic examination (as indicated) Urodynamic testing • Uroflow • Postvoid residual volume • Cystometrogram with or without electromyogram • Pressure-flow (micturition) study • Videourodynamic study (multichannel with fluoroscopy) Adapted from: Kennelly MJ, DeVoe WB. Rev Urol 2008;10(3):182-191.

retention. When taking a history, it is important to realize that some patients may have coexisting problems such as stress UI or benign prostatic hyperplasia, in addition to lower urinary tract dysfunction from NGB. Physical examination should include a focused neurourologic evaluation. In addition to standard evaluation of the abdomen, back, rectum, pelvis, and genitalia, clinicians need to evaluate the sacral dermatomes, including perianal sensation and anal sphincter tone. The neurologic evaluation should be primarily focused at the sacral 2-4 level and assess the bulbocavernosus reflex, voluntary external sphincter control, and reflexes in the sacral dermatome levels. Deep tendon reflexes in the lower extremities, clonus, and plantar responses should be included.7,8 A urinalysis, with or without a urine culture,8 should be done to rule out UTI, glucosuria indicative of diabetes, and blood or protein in the urine that might indicate renal disease. If the results suggest an associated condition, the patient may need further diagnostic testing.

Urodynamic assessment can help determine the underlying neurologic issue, categorize the vesicourethral dysfunction, and provide a basis for appropriate therapy. In fact, clinical evaluation is often unable to identify the type of bladder dysfunction; therefore, optimal therapy is dependent on an appropriate urodynamic evaluation, as follows:6,11 • Uroflow rate—the volume of urine voided per unit of time. It is primarily used to screen for bladder outlet obstruction.

• Postvoid residual volume —considered part of the basic evaluation for UI. A high rate suggests acontractile bladder or bladder outlet obstruction.

• Cystometrogram (with or without electromyogram)—a filling cystometrogram evaluates bladder capacity, compliance, and the presence of detrusor overactivity, while a voiding test records voiding detrusor pressure along with the rate of urinary flow.

• Electromyography—can help determine the presence of coordinated or uncoordinated voiding, and allows for an accurate diagnosis of detrusor sphincter dyssynergia that is common in suprasacral SCIs. • Videourodynamic study (multichannel with fluoroscopy)—combines

42 Renal & Urology News

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CME FEATURE Case Study: Managing Neurogenic Bladder Mr. J. is a 25-year-old male graduate student. Two years ago, he suffered a complete SCI at T4 as a result of a motor vehicle accident. Although confined to a wheelchair, he has recovered sufficiently to return to graduate school to complete his degree and obtain a job as an educator.

He has good health overall, with strong upper body function, and lives independently. He has continuing UI, managed with anticholinergic medication and CIC, which his schedule, hand function, and mobility permit.

Mr. J has tried 3 anticholinergic drugs and formulations without success. He has a moderate degree of dry mouth and a worsening of baseline constipation. He also has occasional symptoms of autonomic dysreflexia and 2 to 3 UTIs per year, treated easily with no complications. He fears a higher dose will lead to worse adverse effects and asks about alternative options.

His clinician evaluates Mr. J. Urodynamics reveal detrusor overactivity and DESD with a detrusor pressure of 60 cm H2O at 165 mL. This and the fact that he continues to leak urine between catheterizations suggest that he has failed therapy with CIC and anticholinergics. Since Mr. J prefers to continue CIC, alternatives such as an indwelling catheter or reflex voiding to a condom catheter are not options. To continue with CIC and maintain low intravesical storage pressures urodynamically and continence clinically, his only choices are intradetrusor injection of botulinum toxin A (onaBoNTA) or surgery.

OnaBoNTA, FDA-approved for neurogenic detrusor overactivity for patients with NGB who failed or cannot tolerate therapy with anticholinergics, reduces incontinence episodes and can significantly improve urodynamic parameters. Mr. J decides to pursue this option instead of a more invasive procedure such as bladder augmentation.

the radiographic findings of voiding cystourethrogram with multichannel urodynamics.

Evaluating current treatment options: an overview Treatment includes nonpharmacologic and pharmacologic interventions, bladder injection, surgery, and urinary diversion using catheters (Table 2).

The primary goals of treatment include preserving the upper urinary tract, maintaining adequate bladder capacity, promoting low-pressure micturition, and avoiding bladder overdistention.8 Another key objective is to prevent UTIs and minimize the use of indwelling catheters. The patient as a whole needs to be considered, and

therapy should minimize risk while maximizing social, emotional, and vocational acceptability. The ability/ willingness of the patient to perform clean intermittent catheterization (CIC) also must be considered.

In patients with elevated bladder storage pressures or vesicoureteral reflux at higher risk for renal complications, the primary goal is to protect kidney function and prevent further complications.

Conversely, in patients not at high risk for kidney damage, quality-of-life issues such as UI may be of greatest concern.

Clinicians need to consider the patient’s degree of disability, mobility, hand function, cognitive status, general condition, likelihood of progression of the neurologic disease, goals and concerns, and available resources.12

Table 2. Treatment for Neurogenic Bladder Failure to Empty • Behavioral modification, i.e., pelvic floor exercises • Intermittent catheterization • Botulinum toxin A injection into the sphincter • Suprapubic catheter • Indwelling catheter • Sphincterotomy • Urethral stent • Urinary diversion Failure to Store • Lifestyle modifications, i.e., diet and fluid intake, timed voiding • Antimuscarinics • Botulinum toxin A injections into the detrusor • Indwelling catheter • Reconstruction

Behavioral/nonpharmacologic interventions Behavioral/nonpharmacologic interventions include lifestyle interventions, the use of external appliances such as pads and/or portable urinals, and the use of CIC, or condom or indwelling catheters for patients with incomplete bladder emptying.13-15 These conservative approaches are often used in combination with medications.13 Lifestyle intervention includes timed voiding, fluid alterations, pelvic floor muscle exercises, biofeedback, toileting assistance, and bladder education/ retraining.16 These interventions, primarily applicable to patients with idiopathic overactive bladder (OAB), may not be helpful for all patients with NGB. Urinary diversion via catheterization is a mainstay of anti-incontinence therapy.

Intermittent catheterization Intermittent catheterization is the preferred method for patients with NGB who cannot adequately void volitionally.

CIC decreases the risk of infection17 and lowers the risk for long-term complications such as hydronephrosis, bladder and renal calculi, and autonomic dysreflexia.18 However, for patients with poor hand function or who lack a caregiver, CIC is not an option. It also may be less than optimal in patients with bladder capacity <200 mL, abnormal urethral anatomy such as bladder neck obstruction and strictures, poor cognition, or who cannot adhere to

a catheterization schedule.18 Using a hydrophilic-coated catheter reduces and delays the onset of symptomatic UTIs and can also decrease the risk of complications related to UTIs.19 CIC can be more challenging for obese patients and those with higher-level injuries, and for the female confined to a wheelchair because of difficulty accessing the urethra.

Women with NGB may more often use a chronic indwelling catheter (or wear a diaper).20,21 However, for most patients with adequate upper-extremity function and hand function, CIC works well over the long term without complications.22

Indwelling catheterization Indwelling catheters, often considered a last resort, may still be the best option for certain patients. Remaining on anticholinergics may be preferable for bladder health with an indwelling catheter. It may be used in patients with acute central nervous system trauma who require precise monitoring of urinary output, those with no available alternatives, and those unable, or lacking a caregiver, to perform CIC or reflex voiding.6,18 Long-term indwelling catheters cause UTIs and may lead to reduced compliance and a thickened bladder.

Over time, patients may develop vesicoureteral reflux that leads to bladder stones, a higher risk for kidney stones, and renal damage. A suprapubic catheter is less traumatic to the urethra and more hygienic.18

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CME FEATURE Pharmacologic treatment options Anticholinergic/antimuscarinic agents, the standard therapy for patients with neurogenic detrusor overactivity,15 are often used in conjunction with CIC to allow for optimal storage and emptying.

However, most are not registered for this indication, and data are limited.

Medications with proven efficacy for NGB include oxybutynin, trospium, tolterodine, and propiverine.23 Adverse effects, such as dry mouth, often limit patient adherence. Constipation may be an issue, as many of these patients also have concomitant neurogenic bowel and may already be using laxatives, suppositories, and manual defecation.24-26 Combination therapy with two or three drugs may lead to significant urodynamic and clinical improvements for patients with NGB.27 A meta-analysis showed that longer-acting formulations were more effective and had a lower rate of adverse effects.28

Imipramine Tricyclic antidepressants suppress OAB via various mechanisms. Imipramine has improved incontinence in adults with NGB.29 Alpha-blockers/muscle relaxants Alpha-blockers can treat DESD, lower bladder pressure during voiding, and reduce outlet resistance at the external sphincter.18 Muscle relaxants such as baclofen, benzodiazepines, and dantrolene have been used to treat outlet obstruction at the level of the striated sphincter due to DESD. Efficacy is not optimal in alleviating skeletal muscle spasticity, however, and adverse effects minimize their overall usefulness.30 Botulinum toxin injection: an emerging therapy Botulinum toxin A (BoNTA) is an alternative for patients who fail or cannot tolerate the adverse effects of anticholinergic therapy. Detrusor injections of BoNTA are considered second-line treatment for neurogenic detrusor overactivity, and the US Food and Drug Administration (FDA) approved onabotulinumtoxinA (onaBoNTA; Botox®) for this indication in 2011. Two other BoNTA preparations are available, abobotulinumtoxin A (Dysport®) and incobotulinumtoxin A (Xeomin®), and a botulinum toxin B

(rimabotulinumtoxinB; Myobloc™).

None have FDA approval for the treatment of neurogenic detrusor overactivity. These preparations cannot be used interchangeably.

BoNTA is usually administered in the office setting, with a local anesthetic.

Patients should be closely monitored for autonomic dysreflexia.

The use of BoNTA to treat NDO was first published in 2000 by Schurch et al with 300 U of onaBoNTA injected into the detrusor muscle.31 The toxin inhibits acetylcholine release at the neuromuscular junction and prevents peripheral neurotransmitter release at presynaptic cholinergic nerve terminals.

The neuromuscular contraction is then blocked and relaxes muscles that may be overactive or spastic.18,32 Many nonrandomized, single-dose studies have validated the use of 300 U of onaBoNTA in this patient population. Further investigation by Cruz et al was done in a multicenter, randomized controlled trial, including 275 patients with NGB.33 Patients with NGB secondary to MS or SCI were randomized to placebo and two doses of onaBoNTA (200 and 300 U). Significant clinical and urodynamic improvements were seen in both onaBoNTA arms vs placebo, and the 300 U dose was not superior to 200 U. Baseline UI decreased by 21.8 episodes per week in the 200 U arm from a baseline of 33.5, and median time to request retreatment was 42.1 weeks. This study was one of two trials whose findings ultimately led to the FDA approving this drug for the indication of NDO at the dose of 200 U. BoNTA appears to last 6 to 9 months in most patients. Reinjections do not appear to diminish efficacy34 or decrease bladder compliance and can improve quality of life.35 The most common adverse events are urinary retention and UTI.33 The risk for UTI may be decreased with BoNTA injection.35

More invasive procedures An intraurethral stent may be an option for the long-term management of detrusor-sphincter dyssynergia in patients with SCIs.36 Potentially reversible, it can circumvent urethral obstruction while avoiding surgery.18 A transurethral resection of the external urinary sphincter converts the bladder into an open draining conduit.18

Considered irreversible, it reduces the intravesical voiding pressure mediated by bladder contractions against a contracted external urethral sphincter from DESD. Bladder augmentation uses an intestinal segment (usually ileum) to enlarge the bladder and increase bladder capacity. The aim is to restore continence and preserve upper urinary tracts by lowering intravesical storage pressures and minimizing the risk of reflux and hydronephrosis.18 Ileovesicostomy uses a section of ileum to create a channel leading from the urinary bladder upward to the abdominal wall. It provides for a low-pressure conduit for urinary drainage and decreases detrusor leak point pressures.37

Conclusion NGB is common in patients with neurologic disorders and requires thorough assessment to select appropriate management. Diagnostics and treatment options are continually advancing, and clinicians need to remain up-to-date to accurately assess and optimally manage patients with this condition. ■

Part II of our series, coming in the July issue, will focus on evaluating treatment options for neurogenic bladder dysfunction.

REFERENCES 1. Linsenmeyer TA, Culkin D. APS recommendations for the urological evaluation of patients with spinal cord injury. J Spinal Cord Med 1999;22(2):139-142.

2. Hicken BL, Putzke JD, Richards JS. Bladder management and quality of life after spinal cord injury. Am J Phys Med Rehabil 2001;80: 916-922.

3. Sauerwein D. Urinary tract infection in patients with neurogenic bladder dysfunction. Int J Antimicrob Agents 2002;19:592-597.

4. Zorn BH, Montgomery H, Pieper K, et al.

Urinary incontinence and depression. J Urol 1999; 162:82-84.

5. Hu TW, Wagner TH, Bentkover JD, et al. Costs of urinary incontinence and overactive bladder in the United States: a comparative study. Urology 2004;63:461-465.

6. Rackley R, Vasavada S, Firoozi F, et al. Neurogenic bladder. Medscape Reference. Updated November 23, 2011. http://emedicine.medscape.com/ article/453539-overview#a1. Accessed March 7, 2012.

7. Semins MJ, Chancellor MB. Diagnosis and management of patients with overactive bladder syndrome and abnormal detrusor activity. Nat Clin Pract Urol 2004;1(2):78-84.

8. Kennelly MJ, DeVoe WB. Overactive bladder: pharmacologic treatments in the neurogenic population. Rev Urol 2008;10(3):182-191.

9. Kershen RT. Algorithms for the management of overactive bladder. Curr Urol Rep 2009;10(5):352-361.

10. Benevento BT, Sipski ML. Neurogenic bladder, neurogenic bowel, and sexual dysfunction in people with spinal cord injury. Phys Ther 2002 Jun;82(6):601-612.

11. Weld KJ, Dmochowski RR. Association of level of injury and bladder behavior in patients with post-traumatic spinal cord injury. Urology 2000;55(4):490-494.

12. Wyndaele JJ, Kovindha A, Madersbacher H, et al; Committee 10 on Neurogenic Bladder and Bowel of

the International Consultation on Incontinence 20082009. Neurologic urinary incontinence. Neurourol Urodyn 2010;29(1):159-164.

13. Abrams P, Andersson KE, Birder L, et al. Fourth International Consultation on Incontinence Recommendations of the International Scientific Committee: Evaluation and treatment of urinary incontinence, pelvic organ prolapse, and fecal incontinence.

Neurourol Urodyn 2010;29:213-240.

14. Smith JH, Berghmans B, Burgio K, et al. Committee 12. Adult conservative management. In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence: 4th International Consultation on Incontinence. Paris, France: Health Publication Ltd; 2009:1025-1120.

15. Wyndaele JJ, Kovindhaa A, Madersbacher H, et al.

Committee 10. Neurologic urinary and faecal incontinence. In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence: 4th International Consultation on Incontinence. Paris, France: Health Publication Ltd; 2009:793-960.

16. Yamaguchi O, Nishizawa O, Takeda M, et al; Neurogenic Bladder Society. Clinical guidelines for overactive bladder. Int J Urol 2009;16(2):126-142.

17. Newman DK, Willson MM. Review of intermittent catheterization and current best practices. Urol Nurs 2011;31:12-28.

18. Linsenmeyer TA, Bodner DR, Creasey GH, et al. Bladder management for adults with spinal cord injury. A clinical practice guideline for health-care providers. J Spinal Cord Med 2006;29(5):527-573.

19. Cardenas DD, Moore KN, Dannels-McClure A, et al. Intermittent catheterization with a hydrophiliccoated catheter delays urinary tract infections in acute spinal cord injury: a prospective, randomized, multicenter trial. PM R 2011;3(5):408-417.

20. Singh G, Thomas DG. The female tetraplegic: an admission of urological failure. Br J Urol 1997;79:708-712.

21. Song GW, Fam BA, Lee IY, et al. Management of neurogenic bladder in female spinal cord injury patients.

J Am Paraplegia Soc 1984;7(1):4-7.

22. Ginsberg DA. Management of the neurogenic bladder in the female patient. Curr Urol Rep 2006;7(5):423-428.

23. Stöhrer M, Blok B, Castro-Diaz D, et al. EAU guidelines on neurogenic lower urinary tract dysfunction.

Eur Urol 2009;56:81-88.

24. Stöhrer M, Mürtz G, Kramer G, et al. Propiverine compared to oxybutynin in neurogenic detrusor overactivity—results of a randomized, double-blind, multicenter clinical study. Eur Urol 2007;51(1):235242.

25. Horstmann M, Schaefer T, Aguilar Y, et al. Neurogenic bladder treatment by doubling the recommended antimuscarinic dosage. Neurourol Urodyn 2006;25(5):441-445.

26. Van Kerrebroeck PE, Amarenco G, Thüroff JW, et al. Dose-ranging study of tolterodine in patients with detrusor hyperreflexia. Neurourol Urodyn 1998;17(5):499-512.

27. Cameron AP, Clemens JQ, Latini JM, McGuire EJ. Combination drug therapy improves compliance of the neurogenic bladder. J Urol 2009;182(3):1062-1067.

28. Novara G, Galfano A, Secco S, et al. A systematic review and meta-analysis of randomized controlled trials with antimuscarinic drugs for overactive bladder.

Eur Urol 2008;54(4):740-763.

29. Cole AT, Fried FA. Favorable experiences with imipramine in the treatment of neurogenic bladder. J Urol 1972;107(1):44-45.

30. Mohfouz W, Corcos J. Management of detrusor external sphincter dyssynergia in neurogenic bladder.

Eur J Phys Rehabil Med 2011;67:639-650.

31. Schurch B, Stöhrer M, Kramer G, et al.

Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results. J Urol 2000;164:692-697.

32. Schurch B, de Seze M, Denys P, et al. Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study. J Urol 2005;174:196-200.

33. Cruz F, Herschorn S, Aliotta P, et al. Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial.

Eur Urol 2011;60:742-750.

34. Karsenty G, Reitz A, Lindemann G, et al. Persistence of therapeutic effect after repeated injections of botulinum toxin type A to treat incontinence due to neurogenic detrusor overactivity. Urology 2006;68(6):1193-1197.

35. Gamé X, Khan S, Panicker JN, et al. Comparison of the impact on health-related quality of life of repeated detrusor injections of botulinum toxin in patients with idiopathic or neurogenic detrusor overactivity. BJU Int 2011;107:1786-1792.

36. Seoane-Rodríguez S, Sánchez R-Losada J, MontotoMarqués A, et al. Long-term follow-up study of intraurethral stents in spinal cord injured patients with detrusor-sphincter dyssynergia. Spinal Cord 2007;45:621-626.

37. Tan HJ, Stoffel J, Daignault S, et al. Ileovesicostomy for adults with neurogenic bladders: complications and potential risk factors for adverse outcomes.

Neurourol Urodyn 2008;27:238-243.

44 Renal & Urology News

MAY 2012

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1. The primary urodynamic finding for most patients with neurogenic bladder (NGB) is: a. Abnormal micturition b. Neurogenic detrusor overactivity c. Vesicoureteral reflux d. Autonomic dysreflexia

5. The preferred method for patients with NGB who cannot adequately void volitionally is: a. Indwelling catheterization b. Intermittent catheterization c. Condom catheterization d. Suprapubic catheterization

2. Supraspinal disorders leading to NGB include conditions such as: a. Parkinson’s disease and Shy-Drager Syndrome b. Cerebral palsy and frontal lobe lesions c. Stroke, cerebral trauma, and multiple sclerosis d. All of the above

6. Which of the following statements is true? a. Anticholinergic/antimuscarinic agents are often used in conjunction with CIC to allow for optimal storage and emptying b. Alpha-blockers diminish total bladder capacity c. Muscle relaxants are the standard therapy for patients with neurogenic detrusor overactivity d. Imipramine has improved urinary urgency in adults with NGB

3. Appropriate urodynamic evaluation: a. Can help determine the underlying neurologic issue, categorize the vesicourethral dysfunction, and provide a basis for therapy b. Always includes uroflow rate, postvoid residual volume, and electromyogram c. Should be done to rule out urinary tract infection, glucosuria indicative of diabetes, and blood or protein in the urine d. Is not needed to determine optimal therapy 4. In patients with elevated bladder storage pressures or vesicoureteral reflux, the primary goal of treatment is: a. To improve quality of life b. To preserve the upper urinary tract, maintaining adequate bladder capacity c. To protect kidney function and prevent further complications d. To prevent urinary tract infections and minimize the use of indwelling catheters

7. Second-line treatment for neurogenic detrusor overactivity that is an alternative for patients who fail or cannot tolerate the adverse effects of anticholinergic therapy is: a. Bladder augmentation b. Reflex voiding to a condom catheter c. Intradetrusor injection of botulinum toxin A d. Ileovesicostomy 8. A potentially reversible option for the long-term management of detrusor-sphincter dyssynergia in patients with SCIs that circumvents urethral obstruction while avoiding surgery is: a. A transurethral resection of the external urinary sphincter b. An indwelling catheter c. Endoscopic sphincterotomy d. An intraurethral stent

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