Renal & Urology News July 2012 Issue

JULY 2011

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VOLUME 11, ISSUE NUMBER 7

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Preemptive Tx May Not Improve Survival Preemptive renal transplants were compared with those received within a year of starting dialysis Preemptive Transplants At a Glance

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Only a fraction of the renal transplants that occur each year are preemptive, and the proportion of patients receiving a preemptive renal transplant at the start of end-stage renal disease has increased only slightly from 1992 to 2009, according to data from the U.S. Renal Data System.

Mixed Effects of Statins in CKD

BY JILL STEIN PARIS—Statin medications appear to have different effects on patients with chronic kidney disease (CKD) depending on their disease stage, researchers reported at the 49th Congress of the European Renal Association-European Dialysis and Transplant Association.

CME FEATURE

Suetonia Palmer, MD, senior lecturer at the University of Otago in Christchurch, New Zealand, and associates elsewhere examined the benefits of statin therapy based on CKD severity.

For their study, the group conducted a meta-analysis that included 51,099 adults with CKD who were enrolled continued on page 11

Earn 1 CME credit in this issue

Part II: Treatment Options for Neurogenic Bladder Dysfunction PAGE 33

BY JODY A. CHARNOW BOSTON—Preemptive kidney transplantation may offer no survival advantage over kidney transplantation soon after dialysis initiation, according to new findings reported at the 2012 American Transplant Congress.

Morgan Grams, MD, and colleagues at Johns Hopkins University in Baltimore studied 25,420 adult first-time recipients of deceased donor kidney transplants (DDKT), of whom 10,992 received preemptive transplants and 14,428 received their organs within one year of starting dialysis. After a mean and median follow-up of 6.8 and 5.9 years, respectively, the investigators found no significant difference in mortality between these two groups,

Novel Agent Could Benefit CRPC Patients

BY JOHN SCHIESZER CHICAGO—Men with metastatic castration-resistant prostate cancer (CRPC) may benefit from treatment with OGX-427, an investigational drug that inhibits production of a protein implicated in cancer progression.

Overexpression of the protein, Heat Shock Protein 27 (Hsp27), is thought to be an important factor leading to the development of treatment resistance and is associated with negative clinical outcomes in patients with various tumor types. Hsp27 is involved in multiple cancer cell survival and growth pathways implicated in progression. In particular for prostate cancer, Hsp27 forms complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes in prostate cancer models. OGX-427 is a second generation antisense oligonucleotide that inhibits Hsp27 expression.

“No agent like this has before shown this kind of activity,” said study invescontinued on page 11

after adjusting for age, race, gender, and insurance status.

Preemptive transplant recipients were slightly older than those who received their transplants within a year of starting dialysis (53 vs. 51 years) and more likely to be female than male (44% vs. 38%), white than nonwhite (73% vs. 68%), and privately insured (58% vs. 51%).

The authors concluded that their findings raise questions about the ethics of allocating a scarce resource to patients who are not yet on dialysis.

Of the 116,395 patients who started treatment for end-stage renal disease (ESRD) in 2009, 2,759 had a preemptive renal transplant as their first ESRD treatment modality, according to the continued on page 11

IN THIS ISSUE 3

Independent risk factors for the development of RCC identified

9

Radium drug boosts survival in CRPC patients

14

More data support the use of active surveillance for PCa

16

Healthy diet may lower the risk of lower urinary tract symptoms

17

Sexual dysfunction common in women on hemodialysis

23

Expert Q&A: the growing armamentarium for advanced PCa

26

Increased prevalence of renal cysts in gout patients

The risk of complicaitons from bariatric surgery can result in reduced renal function.

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JULY 2012

Renal & Urology News 3

Study Identifies Risk Factors for Kidney Cancer ATLANTA—Researchers have identified independent risk factors for the development of renal cell carcinoma (RCC), a report presented at the American Urological Association 2012 annual meeting states. These factors include a history of kidney disease, hypertension, high body mass index (BMI), and smoking.

In a population-based cohort study of Washington State residents aged 50-76 years conducted from 2000 to 2002, investigators at the University of Washington in Seattle identified 249 incident cases of RCC. Subjects with a history of kidney disease had a 2.9 times increased risk of RCC compared with those who never

PROVENGE® (sipuleucel-T) Suspension for Intravenous Infusion

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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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had kidney disease, said researcher Liam C. Macleod, MD, MPH, who presented study findings. Hypertensive individuals were at 70% increased risk compared with those who did not have hypertension.

Compared with subjects who had a BMI below 25 kg/m2, those with a BMI of 35 or higher also had a 70% increased risk.

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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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Smokers with more than 37 pack-years of smoking had a 60% increased risk compared with nonsmokers, the study showed. Identification of modifiable risk factors offers an opportunity for targeted education and intervention in those with multiple high risk features, the investigators concluded. â–

4 Renal & Urology News

JULY 2012

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Morbid Obesity a Barrier to Living Kidney Donation NATIONAL HARBOR, Md.—Morbid obesity often is a barrier to living kidney donation, researchers reported at the National Kidney Foundation 2012 Spring Clinical Meetings.

Mala Sachdeva, MD, and colleagues at Hofstra North Shore-Long Island Jewish School of Medicine in

Great Neck, N.Y., reviewed data from 104 potential living kidney donors and stratified the donors according to body mass index (BMI).

The researchers looked at the outcomes of those with a BMI of 35 kg/m2 or higher, who are excluded from living donation accord-

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

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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.

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ing to the policy of their institution.

Of the 104 potential donors, 19 (18%) had a normal BMI (less than 25), 38 (37%) were overweight (BMI 25-29.9), 24 (23%) were obese (BMI 30-34.9), and 23 (22%) were morbidly obese (BMI 35 or greater), the study showed.

Of the 23 morbidly obese individuals, only three (13%) succeeded in losing weight and donating. Seven (30%) were unable to lose weight but were trying, six (26%) changed their minds about donating, three (13%) were lost to follow up, two (9%) were rejected because of medical reasons, one declined for social reasons, and one declined because of recipient death. “Weight loss leading to donation through diet and lifestyle modification appears to be unsuccessful, despite the fact that a considerable fraction of morbidly obese patients do report attempts at losing weight,â€? the investigators concluded. â–

Early Renal Tx Benefits PCa Patients NATIONAL HARBOR, Md.— Hemodialysis (HD) patients awaiting a kidney transplant must have a two-year cancer-free period immediately preceding transplantation.

However, study findings presented at the National Kidney Foundation 2012 Spring Clinical Meetings suggest that patients with prostate cancer (PCa) might be better served by undergoing early transplantation instead of waiting two years to be declared cancer-free.

Vivek Agarwal, MD, and colleagues at Newark Beth Israel Medical Center in Newark, N.J., analyzed data from the United Network for Organ Sharing to determine the outcome of PCa in renal transplant recipients. The study included 32 male HD patients aged 46-78 years diagnosed with PCa within six months after renal transplantation.

Within the first two years post-transplant, 13 patients were alive and cancerfree, 18 were alive with cancer, and one died from PCa. The two-year mortality rate was 3.1% (range 0.08% to 16.2%).

Even the 16.2% rate is well below the estimated 38.2% who would die while on HD, the investigators pointed out in a poster presentation. Thus, PCa patients would have a survival benefit from early renal transplantation, they concluded. â–

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Renal & Urology News 5

FROM THE EDITOR EDITORIAL ADVISORY BOARD

Outlook Brightens for CRPC Patients

I

n the past few years, urologists have seen some significant developments related to the treatment of metastatic castration-resistant prostate cancer (CRPC). Sipuleucel-T, a therapeutic cellular immunotherapy, was approved by the FDA in April 2010 after clinical trials showed that it prolonged survival by a median of four months in patients with asymptomatic and minimally symptomatic CRPC. In November 2010, the FDA approved the biologic denosumab for preventing skeletal-related events in patients with bone metastases from solid tumors. In April 2011, the FDA granted marketing clearance for abiraterone acetate in combination with prednisone as a treatment for patients with metastatic CRPC who have received prior docetaxel-based chemotherapy. In phase 3 trials, the treatment prolonged overall survival by a median of 3.6 months.

Other promising treatments for this patient population are in the pipeline, as well. At the recent annual meeting of the American Urological Association, researchers presented data showing that enzalutamide (formerly MDV3100) improved median overall survival by nearly five months.

Updated findings presented at the American Society of Clinical Oncology showed that an investigational bone-targeting agent called radium-223 prolonged median overall survival by 3.6 months with minimal toxicity. The growing list of treatments for CRPC could give researchers more to work with in designing new therapeutic paradigms for CRPC, such as using the drugs in combination or earlier in the disease process. (E. David Crawford, MD, head of urologic oncology at the University of Colorado Hospital in Aurora, discusses the possibilities in an interview on page 23.)

Although urologists will no doubt be pleased by the growing armamentarium for treating CRPC, they may be dismayed by the recently released final recommendations from the U.S. Preventive Service Task Force calling for an end to routine PSA-based mass screening for PCa (see the article on page 16). The task force concluded that the benefits of screening do not outweigh the risks. Whether the recommendations will carry any weight is questionable. Recent studies suggest that 2008 task force recommendations against PSA screening of men aged 75 and older has had little or no impact. For example, using data from the 2005 and 2010 National Health Interview Survey, investigators found that PSA tests were ordered for 40.6% of men aged 75 years and older in 2010 compared with 40.4% in 2005. So, although the task force recommendations have the potential to discourage screening, it is not a given that physicians will follow them.

Yours sincerely, Jody A. Charnow Editor

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

Medical Director, Urology

Medical Director, Nephrology

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

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

Urologists

Nephrologists

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

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

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

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

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

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

Renal & Urology News Staff Editor Executive editor Senior editor Web editor Editorial coordinator Art director Group art director, Haymarket Medical VP, audience development and operations Production manager Product manager, digital products Circulation manager National accounts manager 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 William Canning Dominic Barone Jim Burke Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 11, Number 7. 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

J U L Y

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V O L U M E

1 1 ,

I S S U E

N U M B E R

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Urology 14

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this month at renalandurologynews.com 16

Urologists Condemn Panel’s Rejection of PSA Testing In its final recommendations, the U.S. Preventive Services Task Force called for an end to routine PSA-based prostate cancer screening for men of any age.

26

Value of Preop Urodynamics for SUI Questioned Findings from a small study raise questions about the value of performing preoperative urodynamic investigations in women with stress urinary incontinence.

Expert Q&A Ralph V. Clayman, MD, dean of the University of California-Irvine School of Medicine, is one of the few urologists to hold such a post. He talks to Renal & Urology News about his experience and objectives.

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 May winner: Stanley Gahring, MD

3

9

17

News Coverage Visit our website for news reports from the Canadian Urological Association meeting in Banff Springs, Alberta, Canada.

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CME Feature Part 2: Current Treatment Options for Neurogenic Bladder Dysfunction Michael B. Chancellor, MD, Professor of Urology at Oakland University William Beaumont School of Medicine, Royal Oak, Mich., discusses the goals of treatment and the various pharmacologic and nonpharmacologic therapies.

Nephrology

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

Our latest include: • Vitamin C Could Lower Blood Pressure • New Equation is Better Predictor of Kidney Disease Risk • Antibiotics for Outpatient UTIs May Need to Change

Never Married Men Have Worse PCa Outcomes After radical prostatectomy, men who never wed are more than twice as likely to die from prostate cancer as married men.

26

Study Identifies Risk Factors for Kidney Cancer A history of kidney disease and hypertension are among the risk factors associated with an increased risk of renal cell carcinoma.

CKD Elevates Risk of Post-op Acute Kidney Injury Patients who have chronic kidney disease before undergoing surgical procedures are at increased risk of acute kidney injury after surgery.

Mortality Associated with GFR Changes, Study Shows Short-term changes in glomerular filtration rate may be linked to an increased risk of death in patients with or without chronic kidney disease.

Fibrates May Impair Renal Function A study revealed an elevated risk of serum creatinine increases in elderly patients who took the medications.

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ONLINE

Cure Possible Despite Positive Nodes Long-term PSA relapse-free survival after radical prostatectomy and pelvic lymph node dissection is possible in a subset of patients with low volume nodal metastases.

Androgen deprivation therapy has significant morbidities and therefore intermittent therapy has been proposed as an alternative regimen.

See our story on page 15

18

Departments 5

From the Editor The armamentarium for prostate cancer grows

10

News in Brief Bladder cancer linked to diabetes drug

18

Practice Management To sell or not to sell your practice

21

Renal Nutrition Update Renal function and bariatric surgery

27

Legal Issues in Medicine A urologist vs. a radiologist

28

Malpractice News Interpreters reduce medical errors

8 Renal & Urology News

JULY 2012

www.renalandurologynews.com

Outcomes Not Worse in Obese Kidney Donors BOSTON—Researchers who examined renal outcomes in obese living kidney donors observed no increased incidence of hypertension, proteinuria, or renal dysfunction compared with non-obese donors at one year after nephrectomy, according to a report presented at the 2012 American Transplant Congress.

Nidhi Aggarwal, MD, and collaborators at the University of Illinois in Chicago studied 516 living kidney donors with a mean age of 36.4 years. The racial makeup of the group was 41% African American, 24% Caucasian, and 35% Hispanic. Of the 516 donors, 119 had normal weight

(body mass index [BMI] below 25 kg/m2), 188 were overweight (BMI 25-29.9), 136 were obese (BMI 30-34.9), and 73 were morbidly obese (BMI 35 or greater).

At 12 months after donation, the proportion of patients with hypertension was 7.4%, 10.4%, 5%, and 10%

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)).

among normal weight, overweight, obese, and morbidly obese individuals, respectively. The proportion of those with proteinuria was 2.3%, 7.8%, 9.8%, and 4.8%, respectively. The mean estimated glomerular filtration rate at 12 months was 68, 66, 68, and 72 mL/min/1.73 m2, respectively. ■

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

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JULY 2012

Renal & Urology News 9

CKD Elevates Risk of Post-Op Acute Kidney Injury NATIONAL HARBOR, Md.—Patients who have chronic kidney disease (CKD) before undergoing surgical procedures are at increased risk of acute kidney injury (AKI) postoperatively, researchers reported at the National Kidney Foundation Spring Clinical Meetings.

A study of 255,188 general surgical cases revealed that the pro portion of patients who experienced AKI increased as renal function decreased. Post-operative AKI developed in 0.42% of patients with normal kidney function, 0.58% of those with reduced kidney function (estimated

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% 14.0% 11.8% 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

glomerular filtration rate [eGFR] of 60-89 mL/min/1.73 m2), 2.3% of those with CKD stage 3 (eGFR 30-59), and 9% of subjects with CKD stage 4 (eGFR 15-29).

Patients with CKD stage 4 had a 34-fold increased risk of acute renal failure (ARF) than patients with nor-

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).

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

Novel CRPC Drug Lowers Mortality CHICAGO—Treatment with the investigational drug radium-223 (Alpharadin) is associated with significantly increased overall survival in patients with castration-resistant prostate cancer (CRPC), researchers reported at the American Society of Clinical Oncology 2012 annual meeting.

In the phase 3, randomized, doubleblind, placebo-controlled Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, median overall survival among CRPC patients increased from 2.8 months at the time of a preplanned interim analysis in June 2011 to 3.6 months in an updated analysis (14.9 months for radium-223 and 11.3 months for placebo).

In addition, radium-223 was associated with a significant delay in first skeletal-related events in CRPC patients with bone metastases. Common adverse events included anemia, neutropenia, and thrombocytopenia.

The trial enrolled 921 patients in more than 100 centers in 19 coun-

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

tries. Subjects were given up to six intravenous administrations of either

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

mal kidney function, said investigator Linda W. Moore, RD, of The Methodist Hospital in Houston, who presented study findings.

In a substudy of 465 colectomy cases with CKD stage 4 and matched colectomy cases without CKD, the CKD patients had a 12 times increased risk of AKI. CKD stage 4 was associated with a fivefold increase risk of 30-day mortality compared with patients who did not have CKD. Within the CKD stage 4 group, AKI increased the risk of death 3.6 times compared with no AKI. AKI did not affect the risk of death in the non-CKD group. ■

radium-223 or placebo in four-week intervals. Radium-223, which is being developed by Bayer Pharmaceuticals based in Wayne, N.J., is a first-in-class drug. It localizes specifically to bone

L-DSG-0312-1

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

metastases and emits alpha radiation, which is highly lethal. ■

10 Renal & Urology News

JULY 2012

www.renalandurologynews.com

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

Short Takes Robotic Prostate Surgery Costs More

measures compared with six weeks of

A cost analysis of 115 robotic-assisted

Pediatric Cardiology 2012;33:689-696.

placebo, according to a report in

laparoscopic radical prostatectomies pubic prostatectomies (RRPs) demon-

Obesity Raises AKI Risk in Heart Surgery

strated that the overall cost per case

Obesity independently predicts acute

for RARP exceeded the cost for RRP by

kidney injury (AKI) after cardiac

almost $5,300, mainly due to higher op-

surgery, and oxidative stress may par-

erating room supply costs (nearly seven

tially mediate this association, accord-

times greater for RARP) and indirect

ing to an online report in the Journal of

costs associated with the purchase and

the American Society of Nephrology.

maintenance of the robotic equipment.

AKI developed in 112 (25%) of 445

There was no significant difference in

heart surgery patients. Among obese

mean length of stay for RARP patients

patients (body mass index [BMI] of

(1.2 days) compared with RRP patients

30 kg/m2 or greater), AKI risk

(1.4 days), researchers reported in

increased 26.5% for every 5 kg/m2

Urology.

increase in BMI.

ED Drug Helps Kids With Cardiac Defects

Blacks Less Likely To Get a Living Donor Kidney

A six-week course of sildenafil 200 mg

African Americans are less likely to

three times daily significantly improved

receive a kidney from a living donor at

echocardiographic measures of

all 275 transplant centers in the United

ventricular performance in a study of

States, according to a study published

27 youths (mean age 14.9 years) with

in the American Journal of Kidney

single-ventricle defects. A mean 11.3

Diseases (2012;59:849-857). These

years after Fontan surgery to redirect

patients had 35% lower odds of receiv-

blood circulation, sildenafil treatment

ing such a donation at centers with the

significantly improved myocardial

least racial disparity and 76% lower

performance index and other cardiac

odds at centers with the most disparity.

fro St m ra ig t h ht eW eb

(RARPs) and 358 open radical retro-

Dutasteride for PCa Progression

In an online poll, Re Renal & Urology News as asked urologists if, in light of a recent study showing that dutasteride significantly lowered the risk of prostate cancer (PCa) progression among men on active surveillance for low-risk PCa (Lancet 2012;379:11031111), they would consider prescribing dutasteride for this purpose in the same patient population.

Here are the results from 154 respondents.

10.4%

13.6%

76%

CKD-EPI Equation Is More Accurate for Estimating GFR A

meta-analysis of data from 1.1 million adults from 25 general-population cohorts, seven high-risk cohorts (of vascular disease), and 13 CKD cohorts indicated that the Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) equation more accurately estimates GFR than does the Modification of Diet in Renal Disease (MDRD) Study equation. Compared with the MDRD Study equation, the CKD-EPI equation reclassified 24.4% of general-population participants, 15.4% of high-risk patients, and 6.6% of CKD patients to a higher eGFR category, lowering the prevalence of CKD in all cohorts except that of the elderly. Approximately 0.6% of participants were reclassified to a lower eGFR category, and the prevalence of CKD stages 3 to 5 (estimated GFR below 60 mL/min/1.73 m2) was reduced from 8.7% (MDRD) to 6.3% (CKD-EPI) in the general population and from 17.7% (MDRD) to 14.6% (CKD-EPI) in the high-risk cohorts, researchers reported in the Journal of the American Medical Association (2012;307:1941-1951).

Diabetes Drug May Raise Risk of Bladder Cancer I

n a British study of 115,727 patients with type 2 diabetes who became new users of oral hypoglycemic agents from 1988 through 2009, 470 incident cases of bladder cancer developed over 4.6 years of follow-up, according to an online report in the British Medical Journal. Subjects who had ever used pioglitazone had an 83% increased risk of bladder cancer compared with nonusers, but the absolute risk remains low. The increased risk corresponds to 74 cases per 100,000 person-years compared with 73 cases per 100,000 person-years in the general U.K. population aged 65 years and older, according to investigators. However, the risk rose to 88 cases per 100,000 person-years for patients who had taken pioglitazone for two years or more and 137 cases per 100,000 person-years for patients who had taken 28,000 mg or more. The researchers reported no increased risk with rosiglitazone.

Pediatric Donor Kidneys Suitable for Adult Recipients B

OSTONâ&#x20AC;&#x201D;Transplantation of kidneys from child donors into adult recipients can achieve good outcomes, according to researchers.

Laurence J. Belin, MD, and colleagues at New York-Presbyterian/Weill Cornell Medical Center in New York reviewed 51 cases in which adults received kidneys from donors younger than five years over a six-year period. One-year patient and graft survival were 97.8% and 94%, respectively, which was comparable to that of adult recipients of adult standard-criteria deceased donor kidneys at their institution, investigators reported at the 2012 American Transplant Congress.

The mean age of the recipients was 45.4 years and the mean donor age was 19.4 months. The mean graft size was 6.5 cm.

The investigators concluded that transplant surgeons should be encouraged to use child donor kidneys, which frequently are discarded.

www.renalandurologynews.com

Preemptive transplant continued from page 1

that previous studies have suggested,” Dr. Grams told Renal & Urology News.

2011 U.S. Renal Data System Annual Data Report.

Dr. Grams noted that her study, like previous studies of the timing of transplantation, has the limitation of being observational, with different start points between the preemptive group and the early post-dialysis initiation group and likely latent confounders for which they could not adjust.

“Our study suggests that pre-dialysis transplantation, when compared to transplantation within a year postdialysis initiation, may not offer the uniform patient survival advantage

How prior studies differ Previous studies differ from the latest investigation in the type of transplant and the period during which the transplants occurred. For example, a study by Kevin C. Mange, MD, of the University of Pennsylvania in Philadelphia, and colleagues looked at preemptive live donor transplants that took place between January 1994 and June 1997. The study, published in the New England Journal of Medicine (2001;344:726-731), found that preemptive transplantation of live donor kidneys was associated with longer allograft

survival than transplantation performed after the initiation of dialysis.

In addition, Dr. Grams noted, previous studies compared preemptive transplantation to all post-dialysis transplantation and not transplantation within a year of dialysis initiation.

“We specifically chose to study only deceased donor transplant recipients, preemptive or within a year of dialysis initiation, for two main reasons,” Dr. Grams said. “We think that the timing of transplant is a more random process within this population, and we acknowledge that longer durations of pre-transplant dialysis have been fairly consistently associated with poorer post-transplant outcomes.” ■

JULY 2012

Renal & Urology News 11

Riser BP is Common in CKD Patients NEW YORK—Patients with chronic kidney disease (CKD) and those with type 2 diabetes are more likely to have a riser blood pressure (BP) pattern than individuals without these conditions, according to findings reported at the American Society of Hypertension annual meeting.

A riser BP pattern, in which BP increases rather than dips during sleep, is associated with a very high

Novel agent for CRPC continued from page 1

tigator Kim Chi, MD, a medical oncologist at BC Cancer Agency in British Columbia.

OGX-427 has been shown to be well tolerated with single-agent activity in phase 1 studies.

In this current study, chemotherapynaïve patients with no or minimal symptoms were randomized to receive three loading doses of OGX-427 600 mg IV then 1,000 mg IV weekly with prednisone 5 mg twice a day or prednisone only. The primary endpoint was the proportion of patients who were progression free at 12 weeks (PCWG2 criteria). Secondary endpoints included PSA decline, measurable disease response, and changes in circulating tumor cell (CTC) numbers.

Sixty-four patients have been randomized and results from 42 patients in the first stage were analyzed (22 on OGX427 plus prednisone, 20 on prednisone alone). At week 12, 71% of patients in the OGX-427 plus prednisone group were progression free compared with 40% in the prednisone-only arm.

Kim Chi, MD

A 50% or greater PSA decline occurred in 50% of patients on OGX-427 plus prednisone versus 20% of patients treated with prednisone alone. The investigators observed measurable disease response in 44% of patients on OGX-427 plus prednisone, including one complete response and three partial responses, compared with none of the patients on prednisone alone. In addition, 55% of the combination arm versus 41% of the prednisone-only arm experienced

a decrease in CTCs from five or more cells per 7.5 mL to less than five cells per 7.5 mL. OGX-427 appeared to be welltolerated. “The patients get an almost flulike syndrome, but it is self-limiting,” Dr. Chi said. “It usually involves chills, diarrhea, nausea, flushing, vomiting and high fever in about 50% of patients, but 50% have had no or minimal side effects.”

Adverse events (AEs) were mainly grade 1/2 OGX-427 infusion reactions.

However, there were three grade 4 AEs: hemolytic uremic syndrome, a pulmonary embolus, and dizziness.

Mark Garzotto, MD, Associate Professor of Urology and Radiation Medicine at Oregon Health & Science University in Portland, said if studies continue to go well, OGX-427 could be an important new agent for a significant number of PCa patients.

“If these data mature, this would open up a novel approach for the treatment of a variety of cancers,” Dr. Garzotto said. “Targeting Hsp27 is an alternate and novel way of attacking the AR, which is critically important for prostate cancer recurrence and progression after castration.” ■

risk of cardiovascular disease (CVD).

In separate studies examining data from the Hygia Project conducted in northwest Spain, investigators found that a riser BP pattern was more than 2.5 times more prevalent among CKD than non-CKD patients and more than two times more prevalent among those with than without type 2 diabetes.

In one study, Alfonso Otero, MD, PhD, of Complego Hospitalario Universitario in Ourense, Spain, and colleagues analyzed data from 10,271 hypertensive patients. Of these, 3,227 had CKD, defined as an estimated glomerular filtration rate below 60 mL/min/1.73 m2, albuminuria, or both at least two times three or more months apart. The prevalence of a riser BP pattern was 17.6% in the CKD patients compared with 7.1% in the non-CKD group, a significant difference between the groups.

The other study, by Ana Moya, MD, of Gerencia de Atension Primaria de Pontevedra, Spain, and collaborators examined data from 12,765 hyper-

Mixed effects of statins continued from page 1

in 80 randomized controlled trials that compared statins with placebo or no treatment. Results showed that treatment benefits varied significantly between stages of CKD. Within stages of CKD, treatment effects were consistent. Data on all-cause mortality from the meta-analysis revealed that statins lowered the risk of premature death by 19% in patients with CKD who were not on dialysis but had little or no effect in patients on dialysis. Treatment effects in kidney transplant recipients were uncertain.

tensive patients, of whom 2,954 had

Statins reduced major cardiovascular (CV) events by 24% in CKD patients not on dialysis but had little or no effect in patients on dialysis. Again, treatment effects in kidney transplant recipients were uncertain.

“Statins don’t reduce major CV events in patients on dialysis probably because CV events in dialysis patients are more likely to be related to the thickness of the heart muscle and heart failure and not blockage of the arteries,” Dr. Palmer said.

“While statins reduce the risk of arterial blockage, arterial blockage is a much less important cause of CV death in dialysis

patients.” Statins had no significant effects on cancer, myalgia, liver function, or withdrawal from treatment.

The extent of benefit conferred by statins in CKD patients not on dialysis is on a par with that seen in the general population as well as in individuals with CV disease, she said.

“I am telling clinicians that patients not on dialysis would clearly benefit from a statin,” she added. “However, you are clearly obliged to tell patients once they reach dialysis not that they should stop statins but rather that their chances of clinical benefit are very small.” ■

type 2 diabetes. The prevalence of a riser BP pattern was significantly greater in the diabetics than nondiabetics (19.9% vs. 8.1%).

For the study, the researchers assessed circadian BP pattern using 48-hour ABPM. They defined hypertension as awake systolic/ diastolic BP mean values of 135/85 mm Hg or higher or asleep systolic/diastolic BP mean values of 120/70 mm Hg or higher, or the use of BP-lowering treatment. ■

14 Renal & Urology News

■ AUA 2012, Atlanta

JULY 2012

www.renalandurologynews.com

Renal & Urology News staff provided news coverage of the American Urological Association’s 2012 annual meeting.

Data Validate Active Surveillance Use For prostate cancer patients who eventually had RP, four-year PSA recurrence-free survival was 83% FINDINGS FROM two studies add to growing evidence supporting the use of active surveillance (AS) for selected patients with prostate cancer (PCa).

In one study, Allison S. Glass, MD, and collaborators at the University of California in San Francisco (UCSF) reviewed data from 691 PCa patients undergoing AS, 93% percent of whom were Caucasian.

On repeat biopsy, 206 (30%) had an upgrade in Gleason score and 123 (18%) were found to have increased volume to more than 33% of cores cancer positive.

After a median follow-up of 50 months, 36% of the overall cohort had delayed intervention: 22% underwent radical prostatectomy (RP), 10% had radiotherapy, and 4% received androgen deprivation therapy. Active treatment was prompted by biopsy progression (56%), PSA doubling time within 36 months (4%), or patient choice based on other clinical characteristics or per-

AKI Is Rare Following Nephrectomy ACUTE KIDNEY INJURY (AKI) rarely occurs in the immediate postoperative period following nephrectomy, according to a study.

Using the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) patient data from 2005 to 2009, Brian Le, MD, of the Northwestern University

sonal preference (40%). Treatment-free survival at five years was 62%.

For 155 men who underwent RP, four-year PSA recurrence-free survival was 83%. Five-year disease-specific survival was 100% and overall survival was 98%.

The treatment-free survival rate at five years was 62%, researchers found.

The researchers noted that their cohort’s rate of treatment intervention is similar to that found in previous studies and is most often done in response to grade migration. At intermediate follow-up, AS appears safe, they concluded.

Of the entire cohort, 64% met UCSF’s strict AS selection criteria (cT stage T2a

or less; PSA less than 10 ng/mL; diagnostic Gleason score of 6 or less without pattern 4 or 5; less than 33% cores positive; and less than 50% of a single core with cancer). Two-thirds of subjects had clinical T1 disease and the median PSA level at diagnosis was 5.3 ng/mL. The study population was 93% Caucasian.

Delayed vs. immediate RP In the other study, Raj Satkunasivam, MD, and colleagues at the University of Toronto found that RP following a period of AS for men with low-risk PCa does not result in adverse pathologic outcomes relative to patients with comparable preoperative pathology who underwent immediate RP. Compared with low-risk patients undergoing immediate RP, however, patients who undergo RP after AS are more likely to have higher-grade disease and extracapsular extension, they concluded.

Of 288 patients on AS, 42 (14.5%) underwent RP mostly because of evidence of progression. These patients were referred to as the ASRP group. These patients were compared with 132 ageand PSA-matched controls who underwent immediate RP (occurring within six months of the diagnosis of low-risk disease [Group 1]). In addition, the researchers compared 25 ASRP patients progressing to Gleason 7 disease while on active surveillance to 73 age- and PSA-matched cohort of de novo Gleason 7 disease treated with immediate RP (Group 2).

Compared with Group 1, the ASRP group had a higher proportion of patients with Gleason 7 disease (66.7% vs. 40.2%), pT3 and pT4 disease (33.3% vs. 14.7% and 7.2% vs. 0.8%, respectively), and extracapsular extension (26.2% vs. 11.4%). AS patients treated with RP after progressing to Gleason 7 disease did not differ significantly from Group 2 patients with respect to adverse pathologic outcomes. ■

Cure Possible Despite Positive Nodes LONG-TERM PSA relapse-free survival after radical prostatectomy (RP) and pelvic lymph node dissection (PLND) is possible in a subset of patients with low volume nodal metastases, according to researchers.

Roland Seiler, MD, of the University of Bern, Switzerland, and colleagues evaluated 88 patients with positive lymph nodes and PLND after RP to determine if the patients had a chance of cure. After a median follow-up of 15.2 years, 43 patients (49%) had died from prostate cancer (PCa) and 17 (19%) had died from

other causes. Thirty-nine patients had one positive lymph node. Of these, 21 (54%) experienced symptomatic progression, including 10 who died from PCa. Nine patients (23%) showed asymptomatic PSA progression only. After 15.2 years, nine (23%) patients have remained completely disease free.

Forty-nine patients had two or more positive lymph nodes (20 had two and 29 had more than two). All of these patients experienced PSA progression; only three (6%) remained without symptomatic progression.

Of the 49 patients, 33 (67%) died from progressive disease. Of 20 patients with asymptomatic PSA progression eight years previously, five have since died from PCa. Based on study findings, Dr. Seiler stated, “PSA progression by itself does not necessarily mean cancer-related death later.”

The researchers noted that their data are from a period when the extent of PLND was more limited that it is currently. With the more extended PLND used today, outcomes may be even better. ■

Feinberg School of Medicine in Chicago, and colleagues identified 2,435 patients who underwent partial or radical nephrectomy without preoperative diagnosis of renal failure.

Only 58 patients (2.4%) had AKI within 30 days after surgery.

The investigators defined AKI as a postoperative rise in serum creatinine greater than 2 mg/dL, development of renal failure, or need for dialysis. ■

Testicular Exams Often Omitted from Physicals MORE THAN one quarter of males aged 15-45 report not having a testicular exam during a routine physical in the previous 12 months as recommended in American Cancer Society guidelines, data show.

Researchers at Northwestern University Feinberg School of Medicine in Chicago, analyzed data from 10,403 men who participated in the National Survey for

Family Growth conducted by the Centers for Disease Control and Prevention from 2006 to 2010. Of the men who had a routine physical in the previous 12 months, 27.8% reported not having a testicular exam.

The national prevalence of testicular exams varied by race, with the highest prevalence found in African Americans

(45.9%), followed by whites (37.6%), and Hispanics (29.5%). In multivariate analysis, African Americans were 26% more likely than whites to have had a testicular exam in the previous 12 months. In addIndividuals born outside the United States were 27% less likely to than those born in the United States to have had a testicular exam in the previous 12 months. ■

www.renalandurologynews.com

JULY 2012

Renal & Urology News 15

AUA 2012, Atlanta ■

Never Married Men With PCa Fare Worse After RP, they are more than twice as likely as married men to die from prostate cancer BEING MARRIED is a plus when it comes to prostate cancer (PCa) outcomes, according to the findings of two studies.

In one study, Kenneth Nepple, MD, and colleagues at Washington University School of Medicine in St. Louis showed that men who have never been married may be at increased risk of PCa-specific and all-cause mortality following radical prostatectomy (RP). That study included 3,596 PCa patients treated with RP between 1994 and 2004 and followed for a median of 10.2 years. At the time of diagnosis, 86.9% of men were married, 5.3% were divorced, 2.4% were widowed, and 5.5% were never married.

Of the 441 men who died at the end of follow-up, only 65 died from PCa. Compared with married men, nevermarried men had a 2.6 times increased

risk of PCa-related death and a 1.8 times increased risk of death from any cause, after controlling for age, PSA level, medical comorbidities, and other potential confounders. Divorced and widowed men were not at increased risk for either outcome compared with married men.

Intermittent ADT May Offer Survival Edge

The researchers defined intermittent ADT as the discontinuation of ADT for at least six months and within two years of starting it.

“Androgen deprivation therapy has significant morbidities and therefore intermittent therapy has been proposed as an alternative regimen to try to minimize some of these morbidities,” Dr. Spencer said.

Intermittent ADT has the possible advantage of delaying development of castration-resistant disease, and it is more convenient for patients and less expensive for the health care system.

Although a number of trials have shown that intermittent ADT is not inferior to continuous ADT, Dr. Spencer said, slightly longer follow up probably is necessary “to really definitively say that intermittent therapy can be considered a standard of care in this area.”

In a recently published study of 554 men with advanced PCa randomly assigned to receive intermittent or continuous ADT, Finnish researchers found that the median times from randomization to disease progression were 34.5 and 30.2 months in the intermittent and continuous ADT arms, respectively. The study, which was published in the Journal of Urology (2012;187:2074-2081), found no significant difference in PCa death rates (43% and 47%, respectively). ■

INTERMITTENT ANDROGEN deprivation therapy (ADT) for elderly patients with advanced prostate cancer (PCa) is associated with improved all-cause and PCa-specific mortality compared with continuous ADT, a study found.

Benjamin A. Spencer, MD, of Columbia University Medical Center in New York, and colleagues studied 3,073 patients with stage IV PCa treated with androgen deprivation therapy. Of these, 25% received intermittent ADT and 75% received continuous ADT. Younger age, more recent PCa diagnosis, and urban residence predicted receipt of intermittent ADT. Compared with patients aged 65-69 years, those aged 75-79, 80-84, and 85 years and older were 36%, 31%, and 54% less likely to receive intermittent ADT, respectively. In multivariate analyses, patients who received intermittent ADT had a 16% and 18% decreased risk of all-cause mortality and PCa-related mortality, respectively, compared with continuous ADT recipients.

Possible reasons include factors associated with social isolation.

“While the retrospective nature of our analysis limits the ability to draw a causal inference between marital status and survival, there are several speculative reasons why never-married men were

at higher risk for prostate cancer and overall mortality after prostatectomy,” Dr. Nepple told Renal & Urology News.

“In never-married men, factors associated with social isolation, unhealthy behaviors, follow-up medical care, or unwillingness to receive adjuvant therapy may have a detrimental effect on survival after prostatectomy.”

Single men diagnosed with PCa may benefit from increased attention to PCarelated and general medical care and the patients’ lifestyle decisions, such as alcohol use and smoking, he said.

In the other study, Mark D. Tyson, MD, and collaborators at Mayo Clinic in Phoenix, Ariz., demonstrated that unmarried men (single, divorced, separated, widowed) are at higher risk of PCaspecific mortality compared with married men of similar age, race, clinical stage,

and tumor grade, even after accounting for competing causes of death.

The investigators analyzed data from 115,922 PCa cases reported to the Surveillance, Epidemiology, and End Results (SEER) database between 1988 and 2003. Of these men, 78% were married and 22% were unmarried. Compared with married men, unmarried men had a 40% increased risk of PCa-specific mortality and a 51% increased risk in overall mortality, after controlling for age, clinical stage, tumor grade, and race. The five-year disease-specific survival for married men was 89.1% compared with 80.5% for unmarried men.

After further adjusting for competing causes of death, unmarried men had a 20% increased risk of PCa-specific mortality compared with married men. ■

Statins May Help Patients With Urologic Diseases STATIN THERAPY may slow prostate

statin users had a 5.0% decrease. Statin

growth and reduce the risk of progres-

use was not associated with PV at the

sion of localized renal cell carcinoma

four-year biopsy in either the placebo or

(RCC) after surgery, according to sepa-

dutasteride arms.

rate studies.

Researchers at the Duke Prostate Cen-

The degree of PV growth reduction found in the study is consistent

ter of Duke University Medical Center in

with prior study findings showing that

Durham, N.C., identified an association

statins reduced PSA levels by 4.1%,

between statin use and reduced prostate

suggesting that the declines in PSA may

growth after analyzing data from men

be due to PV reductions, according to

who participated in the REDUCE (Reduc-

the investigators.

tion by Dutasteride of Prostate Cancer

The other study, by Robert Hamilton,

Events) trial. The four-year randomized

MD, and colleagues at the Sidney Kim-

trial compared dutasteride and placebo

mel Center for Prostate and Urologic

for prostate cancer prevention. All men

Cancers in New York, included 1,765

underwent prostate biopsies at two and

patients who underwent surgery for

four years and had their prostate volume

localized clear cell RCC. Of these, 483

(PV) measured by transrectal ultrasound.

(27%) were on a statin at the time of

The study, which was led by Stephen

surgery. Statin use was associated with

Freedland, MD, and presented by

a significant 38% reduced risk of RCC

Roberto Muller, MD, included 6,093

progression after surgery. Statin use for

subjects, of whom 1,032 (16.9%) used

less than three years was not associated

statins at baseline. In the placebo arm,

with a reduction in progression risk, but

statin users had a 3.9% decrease in PV

statin use for three or more years was

growth compared with nonusers at the

associated with a significant 53% reduc-

two-year biopsy; in the dutasteride arm,

tion in risk. ■

16 Renal & Urology News

■ AUA 2012, Atlanta

JULY 2012

www.renalandurologynews.com

Renal & Urology News staff provided news coverage of the American Urological Association’s 2012 annual meeting.

Urologists Condemn Panel’s Rejection of PSA Testing Final task force recommendations called a “disservice to men” UROLOGISTS HAVE condemned the final recommendations from the U.S. Preventive Services Task Force (USPSTF) that call for an end to routine PSA-based prostate cancer (PCa) screening for men of any age. The task force gave PSA testing a “D” rating, meaning it believes there is “moderate or high certainty that the service has no net benefit or that the harms outweigh the benefit.”

The American Urological Association (AUA) was hosting its annual meeting in May when the task force released its final recommendations. At an AUA press conference during the meeting, John H. Lynch, MD, a member of the AUA Board of Directors and Chief of Urology at Georgetown University in Washington, D.C., asserted, “It is a disservice to men to deny them the opportunity for potential treatment and cure when necessary for a disease that affects one in six men over the course of their lifetime.”

Also at the press conference, William J. Catalona, MD, Professor of Urology at Northwestern University in Chicago and a pioneer in the development of the PSA test, stated his opposition to the task force’s position.

Early detection “The main goal of early detection and screening programs is to allow a person to avoid a particularly unpleasant death, such as a death from prostate cancer,” Dr. Catalona said. “There’s strong evidence that PSA testing substantially reduces [the risk of] prostate cancer death.”

Since the introduction of PSA screening in the United States, the PCa death rate has decreased by more than 40% and the percentage of men who have distant metastases and incurable disease at the time of diagnosis has decreased by 75%. In addition, Dr. Catalona noted that statistical teams at the National Institute of Health concluded that up to 70% of these results are attributable directly to PSA testing.

William J. Catalona, MD

PSA a powerful predictor “We think that men should be made aware and offered an opportunity to make an informed decision for themselves,” Dr. Catalona said. “The PSA test provides very powerful predictive information about a man’s risk for prostate cancer.”

David F. Penson, MD, Professor of Urologic Surgery at Vanderbilt University in Nashville, Tenn., and the incoming chair of the AUA’s Health Policy Committee, observed: “By giving the test a D rating, the USPSTF has effectively stated that primary care physicians should not have a balanced discussion with the patient.”

The task force published its final recommendations online ahead of print in the Annals of Internal Medicine, where they wrote: “The USPSTF recognizes that clinical decisions involve more considerations than evidence alone.

Clinicians should understand the evidence, but individualize decision making to the specific patient or situation.

Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.”

In an accompanying editorial, Otis W. Brawley, MD, MPH, Chief Medical Officer of the American Cancer Society, defended the task force’s position, asserting: “It is my hope that the current USPSTF recommendations ends mass screening.”

“We must heed science when making clinical and policy decisions about PSA-based screening,” he wrote. “The harms are well-proven, whereas the evidence of benefit is weak.”

Special circumstances Dr. Brawley added that the task force leaves room for mass screening within the physician-patient relationship.

“They recognized that there are men who will still want to be screened because of family history, ethnicity associated with prostate cancer risk, or a special concern.” ■

Older Men Still Screened AS UROLOGISTS voice their dissent with final recommendations from the U.S. Preventive Services Task Force advising against the use of PSA-based prostate cancer (PCa) screening, a new study suggests that a 2008 task force recommendation to stop such screening among men aged 75 years and older has had little impact on the practice.

Emil Scosyrev, PhD, and colleagues at the University of Rochester Medical Center in Rochester, N.Y., analyzed data from the Behavioral Risk Factor Surveillance System surveys completed in 2006, 2008, and 2010. The study included men aged 76 and older at the time of the survey and without a PCa diagnosis. The estimated percentages of men with a PSA test in the year before the survey were 60%, 63%, and 60% based on 9,033, 12,063, and 14,782 respondents interviewed in 2006, 2008, and 2010, respectively.

Healthy Diet May Protect Against LUTS HEALTHY EATING may lower the risk of lower urinary tract symptoms (LUTS), new findings suggest.

Investigators assessed diet quality in 1,385 men aged 40 and older using the U.S. Department of Agriculture (USDA) Health Eating Index (HEI), which grades diets by their conformance to USDA recommendations. Diets are scored from 0-100; higher scores mean more conformance. The researchers, led by Bradley A. Erickson, MD, Assistant Professor of Urology at the University of Iowa in Iowa City, compared diet quality of study participants who reported and who did not report urinary symptoms. Men with HEI scores below 50 and above 80 had poor and good diets, respectively.

The study revealed significantly higher rates of LUTS in men with poor diets than in those with good diets (25.8% vs. 17.8%). An unhealthy diet was associated with a 70% increased risk of LUTS compared with a healthy diet, after adjusting for multiple variables.

Alcohol intake has a protective effect, according to a new study.

The study also demonstrated that alcohol intake was protective, lowering the risk of LUTS by 33% compared with no alcohol consumption.

Unlike many previous studies of the relationship between diet and LUTS, the new study did not focus on a particular nutrient but rather subjects’ whole diets, which is more important, Dr. Erickson said. “Saying you [need to] have an overall healthy diet we think is more useful than saying eat less fat or eat less salt, because if you can do that, and the rest of your diet is unhealthy, I don’t think it’s going to make much of a difference for lower urinary tract symptoms,” he said.

The finding that alcohol lowers LUTS risk is not new, and Dr. Erickson observed, “Our hypothesis is that it could just have something to do with being associated with an overall healthy lifestyle.” ■

www.renalandurologynews.com

JULY 2012

Renal & Urology News 17

Jill Stein provided news coverage of the European Renal Association-European Dialysis and Transplant Association 49th Congress in Paris.

ERA-EDTA, Paris ■

Mortality Associated with GFR Changes Short-term increases or decreases of 25% or more raise death risk, researchers find SHORT-TERM changes in glomerular filtration rate (GFR) may be associated with an increased risk of death in patients with or without chronic kidney disease (CKD), British investigators reported.

“Lots of patients seen in primary care undergo repeat measurements—probably more than one or two measurements a year—of their kidney function, and primary care doctors haven’t necessarily known what the results mean,” Christopher Farmer, MD, renal consultant at East Kent University Hospitals NHS Foundation Trust, said. “What we are really saying is that individuals who have changes in their kidney function over the course of a year actually do worse and probably warrant tighter follow-up in the short-term than those who don’t have changes in their kidney function. Tighter follow-up may involve more frequent blood tests or screening patients for other possible predictors of mortality.”

Dr. Farmer and his colleagues examined the relationship between shortterm changes in kidney function and mortality in 29,156 adults who had at least two serum creatinine estimations over a 12-month period with an interval

Daily Fluid Requirement Challenged

Fluid intake was determined by a self-administered questionnaire about food frequency, and was divided into four quartiles. The lowest quartile was less than 2.1 liters per day (the equivalent of eight glasses), and the highest quartile was greater than 3.1 liters per day (the equivalent of 12.5 glasses per day).

Results from 3,858 individuals during a median follow-up of 13.1 years showed an average reported daily fluid consumption of 2.48 L/day. Overall, there were 1,047 deaths and 691 CV deaths. Compared with the lowest fluid intake, the adjusted rate for death from any cause did not differ significantly for each quartile of increasing daily fluid intake.

Likewise, researchers observed no association between CV mortality and fluid intake across quartiles of daily consumption nor any evidence a dose-response relationship between increasing daily fluid consumption (in 100 mL increments) and either all-cause or CV mortality.

She added that prospective studies of fluid intake and risk of death or chronic kidney disease are now warranted.

“Patients want to be told that a certain level of fluid intake is nephroprotective but we don’t have that information yet,” she said. ■

NEW DATA from a population-based cohort study appear to challenge the belief that survival is linked to daily fluid intake. The findings showed that total daily fluid consumption had no effect on either all-cause or cardiovascular (CV) mortality.

“There was a paper a long time ago that suggested that eight glasses of water a day may improve health, and that ‘assumption’ quickly gained traction so that it is now widely believed without having been rigorously tested,” Suetonia Palmer, MD, senior lecturer at the University of Otago in Christchurch, New Zealand, said.

The eight, eight-ounce glasses of water that are routinely recommended for daily intake is the equivalent of about 1.9 liters.

Dr. Palmer and her associates used information from a population registry to examine the association between the intake of non-caffeinated fluids and risks of all-cause and CV death in adults aged 49 years or older.

The association was observed in patients with or without CKD. of at least six months between measurements. Subjects were identified from primary care databases in Kent from 2004 to 2008.

The study was undertaken to determine whether data from an earlier provincewide registry in Alberta, Canada, could be replicated in a primary care setting in

the United Kingdom. In addition to a link between short-term changes in kidney function and mortality, the Canadian analysis showed that short-term changes in kidney function predicted progression of kidney disease.

In the U.K. study, the researchers determined confirmed reductions in kidney function based on a percentage change in kidney function and change in CKD stage.

Results showed that individuals who had a 25% or greater increase or decrease in their GFR over one year with a change in CKD stage had a significant three times increased risk of dying as individuals with the same baseline CKD but no short-term changes in kidney function.

The study also found a trend towards short-term changes in kidney function and worsening kidney disease.

“The point is that wherever you are …and certainly in Europe, the States,

and in the developed world, somewhere in the region of 30% of the whole population have had tests of kidney function,” study co-investigator Paul Stevens, MD, also a renal consultant at East Kent University Hospitals NHS Foundation Trust, commented.

“And a significant portion of them will have repeated tests of kidney function which currently aren’t used to predict what will happen to them in the future as the tests may be done in order to monitor their diabetes or hypertension. Our study found that short-term changes in kidney function in either direction—either an improvement or deterioration in kidney function—are significant in terms of predicting subsequent mortality. The finding is part of our ongoing effort to better define progression of kidney disease for physicians to use in their everyday practice.” ■

Sexual Dysfunction Common in Women on Hemodialysis SEXUAL DYSFUNCTION is highly

Of 1,472 women who were contacted,

prevalent in sexually active women

659 completed the FSFI questionnaire.

with end-stage renal disease requiring

More than half of them lived with a

hemodialysis (HD), according to

partner, and slightly more than a third

new data.

described themselves as sexually ac-

Suetonia Palmer, MD, senior lec-

tive. Overall, 555 respondents, or 84%,

turer at the University of Otago in

had FSFI scores consistent with sexual

Christchurch, New Zealand, and

dysfunction.

colleagues elsewhere used the widely

When the analysis was restricted to

validated Female Sexual Function Index

the subgroup of HD patients who were

(FSFI) to screen for any form of sexual

sexually active, the prevalence of sexual

dysfunction in women with ESRD on HD.

dysfunction was 55%. Other studies

The women included in the study were

have found a prevalence rate for sexual

recruited from 27 dialysis clinics in

dysfunction of about 30% for women in

Europe and South America.

the general population.

Compared with increasing aware-

The study also found that single

ness of sexual dysfunction in men on

women who are were not waitlisted for

HD, sexual dysfunction in women with

a transplant had the highest risk for

chronic kidney disease has not been

sexual dysfunction. Given the potentially

rigorously investigated and is there-

high prevalence of sexual dysfunction

fore less well understood, Dr. Palmer

in women on dialysis, more studies are

said. Also, descriptive data for sexual

needed to examine the relevance of

dysfunction in women on HD are limited

sexual dysfunction on symptom burden

by suboptimal study design.

and quality of life in these women. ■

18 Renal & Urology News

JULY 2012

www.renalandurologynews.com

Practice Management Deciding whether or not to sell your practice involves taking a hard look at the prospective buyer and extended networks. BY TAMMY WORTH

Incentive to sell When Brian Baker, owner of Baker Healthcare Consulting Group in Nashville, Tenn., works with physician groups, one thing he notices is the decision to sell or not is made initially on the basis of emotion. Medical groups are constantly under threat of being reduced in payments or having to put up with more regulation, Baker said.

“So doctors throw up their hands and say, ‘I am tired of this, I want someone else to take on the risk.’”

Baker said he tries to get doctors to focus on the business transaction

instead. He said most practices are able to project based on the past couple of years what their business will look like in the near future. They should consider if there are new sources of business or if there is anything else they can do to enhance the practice.

Today’s sales tend to be different than those in the past. Typically, he observed, “the hospital says, ‘we are going to take you over, there is no guarantee that all employees will continue to be employed, and we are not going to pay you an exorbitant price … we’ll just buy the assets, and you’ll get a contract for X number of years with renewals.’”

Contract negotiations One major point for physicians to consider when looking at a contract isn’t the “sale price,” but the term and longevity of the relationship, Dr. Boutros said.

“Look to see if the personal compensation is in the ballpark,” he said. “They should be looking for security; that’s why they are thinking of integrating in the first place. And that comes with contract length.”

Other compensation issues to think about include whether you might be shut out of other hospitals that have given you a lot of business. Also, research whether you will potentially lose referrals from certain primary care providers that currently provide a substantive number of referrals.

Accountability concerns Nicholas Janiga, a manager at HealthCare Appraisers, Inc., in Castle Rock, Colo., said it pays to see what

Key Points When deciding whether to sell a practice to a hospital: ■ Consider the term and longevity of the relationship, and not the “sale price.”

■ Do not let emotions drive you; focus on the business transaction.

■ Think about what will happen if things don’t work out with the sale.

© THINKSTOCK / RYAN MCVAY

P

ossibly, the first thing to consider if you are thinking of selling your practice is whether or not there would be an interested buyer.

In the current climate, this is more likely for urologists than nephrologists according to Akram Boutros, MD, founder and president of BusinessFirst Healthcare Solutions, an advisory firm to hospitals, physician practices and health systems based in Great Neck, N.Y. Dr. Boutros said a trend he sees is the creation of multi-specialty practices— like a cancer center that has oncologists and urologists under one roof —where the two groups work together to increase purchasing power, but remain autonomous in ownership.

But urologists aren’t the only ones wanting to sell. Physicians of all kinds are feeling the pinch of lower Medicare reimbursements. This, along with the uncertain future posed by health reform, is a potential maelstrom many doctors don’t want to face in private practice.

If you plan to stay with the practice you are selling, ask what you will be involved with directly.

you will be incentivized to do, whether you will be held accountable for costs or paid just for productivity (the latter is rare, he said).

Contracts will also include things like inventory, tangible fixed assets, and some level of intangible value like a non-compete clause, Janiga said.

“Depending upon your required management duties there could be supplemental agreements in place if they expect you to participate in some of that,” he said.

The new span of your influence is something to understand before selling a practice.

Dr. Boutros suggests that you ask what you will be involved in directly.

Will the hospital participate in hiring and firing, creating new service offerings, practice relocation? Will your staff become hospital employees?

Thinking long-term The last financial aspect to mull over is what will happen if things don’t work out with the sale. You have to be aware of who will own the medical records, whether or not the staff can come back to work for you, and if you will be able to stay in that office.

Finally, there are a couple of considerations that are more abstract, but potentially most important. The first is the loss of autonomy inherent to becoming an employee. Most times, a doctor will still make clinical decisions, but they no longer have control over business decisions once they sell.

“Some health systems that do a good job with employed physicians keep them involved in decision making, but ultimately the owner is the decision maker,” Baker said. Physicians who choose to remain on staff have to acclimate and become accustomed to taking orders.

Most importantly, if you are going to sell your practice, it has to be to an entity for which you can work. Take the time to get to know the leadership, agenda, and structural plans of the buyer. The buyer should make you feel valued and be a group with whom you can imagine having a relationship.

“You can’t work for people you don’t trust or like,” Dr. Boutros said. “You can do it for six months or a year, but not long term.” ■ Tammy Worth is a freelance medical journalist based out of Blue Springs, MO.

www.renalandurologynews.com

JULY 2012

Renal & Urology News 19

PTH Increase in CKD Patients Greater in Blacks glomerular filtration rate (GFR) below 60 mL/min/1.73 m 2, the slope of GFR vs. PTH was significantly steeper among AA than whites, according to a report in the Journal of the American Society of Nephrology (2002;13:27622769). Dr. Ennis and her group pointed to some important limitations

of their study. For example, urine data and information on diet were unavailable, and medication information was unavailable for only 42% of cases. The researchers did not have information about socioeconomic status, body mass index, and smoking status.

Any moment is an accident waiting to happen.

TOVIAZ provides powerful efficacy.1,2 Mean UUI episodes per 24 hours at baseline

Mean UUI episodes per 24 hours at Week 12

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*

*P≤0.001 vs placebo.1

-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

Findings could have therapeutic implications for African Americans.

The mean PTH was significantly higher for AA than for non-AA in each successive stage of CKD, beginning with stage 2. Results showed that 25-D levels were significantly higher for non-AA in CKD stages 1-3. Serum calcium and phosphorus did not differ between the groups at any stage. Serum calcium, phosphorus, and 25-D were inversely correlated with PTH levels regardless of race, but all factors combined accounted for approximately 42% of the variance in PTH, Dr. Ennis’ group reported.

The new findings supplement those of previous studies. For example, in a study of 218 patients in an ethnically diverse ambulatory nephrol ogy practice at the University of California-San Francisco, Ian H. De Boer, MD, and colleagues found that the adjusted mean PTH was significantly higher among AA compared with whites (233 vs. 139 pg/mL).

Among patients with an estimated

Furthermore, they noted that because of the cross-sectional design of the study, patients may have been at various stages of treatment of CKD mineral bone disorder. “Consequently, the ability to generalize about the natural history of CKD and its implications on mineral metabolism is limited,” they wrote. ■

For your OAB patients with urge urinary incontinence

Median % reduction from baseline in UUI episodes at Week 12

PARATHYROID HORMONE (PTH) levels increase with progressive stages of chronic kidney disease (CKD) significantly more in African Americans (AA) than in patients of other races, new study findings suggest. This racial difference is apparent as early as stage 2 CKD. In addition, the study demonstrated that only a moderate component of the PTH increase in AA is explained by changes in serum calcium, phosphorus, and 25-hydroxyvitamin D (25-D), according to a report in Nephrology Dialysis Transplantation (published online ahead of print).

The findings are important “because PTH is used as a gauge of CKD mineral bone disorder, a gauge that can drive therapeutic interventions,” the researchers wrote. “Almost certainly, the weight of evidence suggests that use of this gauge must be selective in relation to AA race, an issue that has not yet been addressed in any clinical guidelines.”

Jennifer Ennis, MD, of Litholink Corp., Chicago, a subsidiary of LabCorp, and colleagues analyzed data from 2,028 CKD patients from primary care and nephrology practices across the United States.

Of the 2,028 patients, 505 were AA.

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

20 Renal & Urology News

JULY 2012

www.renalandurologynews.com

Report Suggests Ways to Expand Home Dialysis Use LEADERS IN the dialysis community have released a report that outlines key findings and recommendations for increased use of home dialysis as an alternative to in-center treatment.

The “Report of the Delegates” is a culmination of the first-ever meeting of the National Summit on Home Dialysis

Policy held in Washington, D.C., on March 29. More than 50 clinicians, patients, and policymakers attended the meeting to address the disparities of treatment modalities for dialysis patients.

“Despite the significant lifestyle, clinical and economic advantages of home

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

ALT increased

0.9

0.5

1.2

GGT increased

0.4

0.4

1.2

0.5

0.7

1.1

Investigations

Skin disorders Rash 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

dialysis, currently less than 10% of U.S. dialysis patients receive treatment at home,” summit organizers wrote in the report.

The report contains 15 specific recommendations in areas of accessibility (patient education and training), accountability (programs to support

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

home dialysis services), and aligning incentives (physician reimbursement policies). Among other recommendations, it urges federal policymakers to maintain parity between home and incenter dialysis treatment in Medicare reimbursement, encourage patientto-patient mentoring and education, and align federal and state regulatory requirements for home therapies.

Summit Director Stephanie Silverman said in a telephone press conference that some of the organizations involved in the summit are now forming an ad hoc alliance to advance their home dialysis recommendations. ■

Drug Cleared To Treat Type of Renal Tumor THE FDA has approved everolimus (Afinitor) for the treatment of renal angiomyolipomas and tuberous sclerosis complex (TSC) in adult kidney tumor patients who do not require immediate surgery.

In a double-blind, randomized, placebo-controlled Phase 3 trial, 42% of patients on everolimus experienced an angiomyolipoma response compared with 0% on placebo. It also demonstrated a 26% response rate to skin lesions, a key concern for TSC patients, compared with to 0% with a placebo.

Everolimus is manufactured by Novartis of East Hanover, N.J. While it previously received FDA approval for the treatment of subependymal giant cell astrocytoma associated with TSC, it will be the first option for the treatment of both kidney and brain tumors.

“Renal angiomyolipomas are one of the greatest causes of morbidity and mortality in adult TSC patients and can be one of the most challenging aspects of the disease to treat,” said John Bissler, MD, Clark D. West Endowed Chair of Nephrology at Cincinnati Children’s Hospital Medical Center. “Today marks an important step for the TSC community, as Afinitor is now the only approved medicine to reduce the kidney tumor burden in these patients.” ■

www.renalandurologynews.com

JULY 2012

Renal & Urology News 21

Renal Nutrition Update Declining renal function may increase the risk of complications from bariatric surgery BY GRISSIM CLARK CONNERY, MS, RD, LD

CKD patients and complication rates A recent study by Turgeon et al (J Am Soc Nephrol 2012;23:885-894) compared chronic kidney disease (CKD) stage and risk for complications from bariatric surgery. The investigators evaluated 27,736 patients who underwent bariatric surgery between 2006 and 2008. Of these, 20,806 (75%) patients had CKD stage 1, 5,011 (18.07%) had CKD stage 2, 1,734 (6.25%) had CKD stage 3, 94 (0.34%) had CKD stage 4, and 91 (0.33%) had CKD stage 5. Higher CKD stage correlated significantly with increased hospital stay and higher rate of return to the operating room. With respect to postoperative events, as CKD stage increased, so did the risk for complications. Diabetes and hypertension were the primary confounders.

Multivariate analyses that controlled

review the changes in estimated glomerular filtration rate (eGFR) before and after surgery (Int Urol Nephrol 2012; published online ahead of print). The increased body surface area (BSA) of obese individuals can confound eGFR. A total of 220 patients who underwent bariatric surgery were followed for six months. Exclusion criteria included loss to follow-up, chronic nephrotoxic medication use, and underlying chronic illness/malignancy. The following equations were used to determine eGFR: Modification of Diet in Renal Disease (MDRD) study equation, CKD-Epi, CKD-Epi with BSA-adjusted versions, Cockcroft-Gault (CG), and CockgroftGault lean body weight-adjustment formula (CG-LBW).

Measuring renal function Serum creatinine decreased significantly from 63 to 58 mg/dL, BMI decreased significantly from 47 to 36.12 kg/m2, and BSA decreased significantly from 2.2 to 1.8 m2. When analyzing all subjects, these changes l ed to significantly decreased eGFR as calculated using the CG, CG-LBW, adjusted CKD-Epi, and adjusted MDRD equations. Some of these equations indicated a shift from hyperfiltration to normal ranges, but there was high variability in readings. LBW appeared to

When assessing eGFR in bariatric surgery patients, equations that account for lean body weight appear to offer the most accuracy. for body mass index, anesthesiology classification, and type of procedure found that CKD stage was still an independent predictor of postoperative complications. Each increment in CKD stage was associated with a 17.8% increased risk for complications in adjusting analyses.

Another recent study took advantage of the dramatic weight changes that can accompany bariatric surgery to

be the best control when accounting for obese populations.

In a subgroup of patients who had a preoperative eGFR of 60-90, eGFR calculated using the CG-LBW equation increased significantly after surgery, whereas the eGFR calculated using the adjusted CKD-Epi equation increased significantly until corrected with BSA. Serum creatinine decreased significantly in both groups;

© CMSP / ART & SCIENCE, INC.

A

s the number of patients seeking bariatric surgery increases, it is important to assess the risks and benefits associated with these procedures. Bariatric surgery is employed to aid morbidly obese patients in obtaining a healthy body weight. Although this surgery may provide positive outcomes, many factors associated with obesity increase the risks for complications in surgery.

Bariatric surgery, such as the Roux-en-Y gastric bypass (illustrated above), may not be a prudent approach to weight loss in CKD patients with significantly impaired renal function.

this was most likely related to a reduction in LBW and a reduction in protein intake. The confounding effect of LBW may indicate that there were no permanent changes in renal function, and further follow-up would be necessary to see if this change in eGFR continued.

Assessing the risk of complications In the study by Turgeon et al, eGFR was calculated using the CKD-Epi formula. It is important to note that the data from this study still proved to be significant even with the possible confounders such as BSA and LBW. Thus, the results of this study indicate that the CKD-Epi creatinine formula can still be useful as a guide when assessing a patient’s risk of complications. CKD stage 4 only showed a 2.3% increase in risk for complications after multivariate controls were applied. These studies must be considered carefully because it has previously been shown that increased BMI offers a protective effect in the latter stages of CKD (Nephrol Dial Transplant

2009;24:2421-2428). The sample size of CKD stages 4 and 5 were much smaller than the other cohorts, and further studies would be beneficial to see if a protective effect of BMI was influencing the rate of complications in the CKD stage 4 group. The CKD stage 5 group suffered a much more dramatic increase in risk for complications. This group included those on dialysis, and thus BMI may have offered less of a protective effect.

More research needed The appropriateness of bariatric surgery in CKD populations needs further research. At this time, it appears that as eGFR declines, bariatric surgery may place patients at greater risk for complications. In addition, it is important to note that when assessing eGFR in this context, equations that account for LBW appear to offer the most accuracy. ■ Mr. Connery is Research Coordinator at Case Western Reserve University in Cleveland.

22 Renal & Urology News

JULY 2012

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BP Drugs May Promote Contrast-Induced AKI

Daily Breakfast May Prevent Development of Diabetes smoking, physical activity, diet quality, fast food visits per week, and total energy intake, study participants who ate breakfast every day were 34% less likely to develop type 2 diabetes than individuals who ate breakfast zero to three days per week over 18 years of follow-up. The investigators defined diabetes as a fasting glucose level of

© THINKSTOCK

BY JILL STEIN PHILADELPHIA—Individuals who eat breakfast on a daily basis are much less likely to develop type 2 diabetes than individuals who eat breakfast infrequently or not at all, according to results released at the 72nd Scientific Sessions of the American Diabetes Association.

Eating breakfast every day might lower a person’s risk of type 2 diabetes onset and obesity.

The data also reveal that individuals may benefit from a regular breakfast even if the overall dietary quality is less than optimal.

“Emphasizing a daily healthy breakfast is a simple public health message with potential downstream benefits,” said principal investigator Andrew Odegaard, PhD, Research Associate in the Division of Epidemiology and Community Health at the University of Minnesota in Minneapolis.

For the study, the investigators examined the relationship between the frequency of breakfast intake and the incidence of type 2 diabetes in individuals enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The CARDIA study is a population-based, prospective evaluation of cardiovascular disease risk factor evolution that enrolled 5,115 nondiabetic African-American and Caucasian women and men ranging from 18 to 30 years of age. Participants were first queried about their breakfast, snack, and other meal frequency habits at year 7.

While both the timing aspect and content of breakfast likely affect health, the role of breakfast habits in the development of type 2 diabetes has not been well studied, Dr. Odegaard observed.

After controlling for multiple variables at year 7 including age, sex, race, clinic, alcohol intake, cigarette

126 mg/dL or higher, a two-hour postchallenge glucose level of 200 mg/dL or higher, a hemoglobin A1c level of 6.5% or greater, or a prescription for an anti-diabetic medication.

Daily breakfast eaters were also 43% less likely to become obese than individuals who ate breakfast infrequently or not at all and 40% less likely to develop abdominal obesity.

Higher diet quality was inversely associated with type 2 diabetes, but breakfast frequency predicted type 2 diabetes across the entire spectrum of diet quality.

The results also indicated that individuals who ate breakfast at least four to six times a week gained less weight than those who ate breakfast zero to three times a week over 18 years.

Study strengths included the use of valid, standardized, and detailed measurements of dietary practices and clinical measures among the study participants, the examination of a wide range of breakfast intake frequency, and a heterogeneous study population, Dr. Odegaard said.

“Overall, our data suggest that breakfast intake has a strong pleiotropic influence on metabolic pathways central in the development of type 2 diabetes and we need to conduct randomized trials to better understand the potential mechanisms and causality,” he said. ■

BLOOD PRESSURE drug that block the renin-angiotensin-aldosterone system (RAAS) may increase the likelihood of contrast-induced acute kidney injury (AKI) among patients undergoing coronary angiography, a study found.

Korean investigators retrospectively studied 2,644 patients who under coronary angiography. The group included 1,322 users of RAAS blocking drugs (ACE inhibitors or angiotensin receptor blockers (ARBs) and 1,322 propensitymatched nonusers of these medications. Contrast-induced AKI occurred in 11.4% of users of the RAAS blocking drugs compared with 6.3% of nonusers, a statistically significant difference between study arms, researchers reported in the American Journal of Kidney Diseases (2012; published online ahead of print). After adjusting for multiple variables, RAAS blockade was independently associated with a significant 43% increased odds of contrast-induced AKI. Investigators led by Ji Yong Jung, MD, PhD, of Gachon University Gil Hospital in Incheon, defined AKI according to AKI Network (AKIN) criteria: an 0.3 mg/dL or greater absolute increase in serum creatinine levels or a relative 50% or greater serum creatinine rise from baseline within 48 hours after exposure to the contrast medium.

The specific pathways responsible for the pathogenesis of contrast-induced AKI have yet to be elucidated, the researchers noted, but some mechanisms have been proposed, such as direct tubular toxicity of the contrast media and endothelin- and adenosineinduced vasoconstriction.

The role of RAAS blocking agents in the pathophysiology of contrast-induced AKI is controversial because the available literature on the subject is conflicting, according to the researchers. Some reports have suggested that RAAS blocking drugs are nephrotoxic and worsen kidney failure in contrast-induced AKI, the authors noted, but other reports state that they protect the kidneys from the effects of contrast-induced AKI. Because of the greater use of RAAS in patients with chronic kidney disease or cardiovascular disease, “the potential for worsening nephrotoxicity is of increasing concern,” the authors wrote.

In their discussion of study limitations, the researchers noted that their study was observational, so random allocation to either an RAAS blockade group or untreated group was not performed. In addition, because they did not conduct an interventional trial, they were unable to evaluate whether withholding RAAS blockade prior to coronary angiography causes a withdrawal effect. ■

Hemoglobin Levels Change After Bundling Introduction NATIONAL HARBOR, Md.—Researchers have found that hemoglobin (Hb) levels

decreased from 11.4 to 10.8.

The rapid increase in the propor-

in dialysis patients have changed since

tion of patients with lower Hb is a

implementation of the bundled payment

concern because an Hb level below

system for dialysis services in January

10 is associated with a higher risk for

2011, according to a report presented

transfusion, Anjali Acharya, MD, of the

at the National Kidney Foundation 2012

NYC Health and Hospitals Corp., New

Spring Clinical Meetings.

York, and colleagues noted in a poster

Researchers who analyzed data from

presentation.

6,269 HD patients who received care

In a separate study presented at the

in hospital-based dialysis clinics found

meeting, a team led by Jay Wish, MD,

that the proportion of patients with

of Cleveland Case Medical Center,

an Hb level above 12 g/dL dropped

looked at trends in anemia manage-

from 30.4% in January 2010 to 14.4%

ment among dialysis patients and found

in December 2011 while the propor-

that average epoetin use decreased

tion of those with an Hb level below

from the first quarter of 2010 to the

10 rose from 11.9% to 19.6% during

second quarter of 2011 and average

the same period. The mean Hb level

Hb levels decreased by 0.3 g/dL. ■

www.renalandurologynews.com

JULY 2012

Renal & Urology News 23

Late-Stage PCa Treatment Advances & QA

Several new drugs have become available for treating advanced prostate cancer in the past year

and a half. E. David Crawford, MD, head of urologic oncology at University of Colorado (UC) Hospital and an investigator at the UC Cancer Center, both in Aurora, and UC colleague Thomas W. Flaig, MD, recently published a review of these agents. Dr. Crawford spoke to Renal & Urology News senior editor Delicia Honen Yard about the possible ways in which these drugs might be used.

Why did you undertake this review of new agents for the treatment of prostate cancer (Oncology 2012;26:70-77)?

Dr. Crawford: For the past few decades, there really hasn’t been a significant amount of progress in advanced prostate cancer. The last landmark discovery—the positive studies with docetaxel [Taxotere, from sanofi-aventis] in castrate-resistant prostate cancer—was almost 10 years ago.

But in the past 18 months four new drugs, all with different mechanisms of action, have been approved, and we have three more in the wings. This has created a lot of excitement in how these things are going to fall into place, how they’re going to be sequenced.

I’m on the editorial board of Oncology, and when I suggested this as a hot topic, they said, “Okay, write it!” So, Tom Flaig and I did. It was a lot of work, but a lot of it was just our opinion. Maybe other people don’t agree with our outlook for future sequencing of therapy for advanced prostate cancer.

Why did we have an 8.5-year lull after docetaxel, and then this flurry of activity in the past 18 months?

Dr. Crawford: Interest in docetaxel sparked many trials using combinations of docetaxel and novel agents. Unfortunately, none of those trials were super-winners.

Therefore, there was a hiatus for a number of years, where these doublets with

docetaxel were evaluated. Parallel to that were discoveries that this cancer is androgen-dependent. Everybody kind of thought, “Well, it’s androgen-independent or hormone-refractory.” Those two terms were replaced with “castrate-resistant,” which means that it’s resistant, but you can overcome that resistance by further lowering testosterone. That led to [the use of] ketoconazole over a decade ago, which worked a little bit.

But what really moved things forward were the studies with abiraterone [Zytiga, Janssen], an oral inhibitor of CYP17, which lowered testosterone more, and you got a response, and MDV3100 [from Medivation], which is a new-generation anti-androgen, and the immunotherapy [sipuleucel-T, or Provenge, from Dendreon]. So, the seeds were planted, and they grew and blossomed all at the same time.

It used to be that for advanced disease we had hormone therapy, and if that failed, we tried chemotherapy. [This approach] never showed anything positive. I was chairman of the genitourinary cancer committee at Southwest Oncology Group for 28 years and we studied every drug known to mankind in advanced refractory prostate cancer, and nothing really worked.

Then the big trial with docetaxel showed a modest survival benefit of two to three months. That was the first step forward, and it generated a lot of excitement and the development of other drugs.

So, what new drugs do urologic oncologists have at their disposal?

Dr. Crawford: We have sipuleucel-T, a novel immunotherapeutic agent—the only approved immunotherapeutic agent for cancer. It results in a survival benefit of four-plus months. We have a new bone agent, denosumab [Prolia and Xgeva, from Amgen], an inhibitor of the RANKL protein. We have abiraterone, which is new and has a novel mechanism of action in castrate-resistant prostate cancer. A recent study of abiraterone in the prechemotherapy setting was apparently positive. We have cabazitaxel [Jevtana, from sanofi-aventis], which is another chemotherapeutic agent.

The question is, what do we do with these drugs? So, we reviewed those agents—what the studies were—and included a figure showing where we were in 2009, where we are in 2012, and then we discussed the future.

Where do you see these new agents taking prostate cancer treatment?

Dr. Crawford: I think we’re going to see several important things happen. First, there’s going to be a shift toward using a number of these drugs earlier in the disease process, prior to chemotherapy. For example, an exciting drug waiting in the wings is radium-223, which is Alpharadin [a bone-seeking radionuclide from Algeta

We’ve got to start thinking about sequencing one drug after the other.

—E. David Crawford, MD

and Bayer]. A positive trial just surfaced, so I think we’re going to see earlier integration here.

In just about every cancer we cure, it’s not monotherapy that works; it’s multidrug therapy. I’ve been around long enough to remember when platinum came out and everybody was excited about monotherapy in testes cancer. You know what? It got responses, but it didn’t cure as many people as you cure when you start combining drug therapy.

So, now we’ve got a lot of arrows in our quiver for prostate cancer. We’ve got to start thinking about sequencing one drug after the other. I can see using abiraterone, which interferes with the production of testosterone from multiple sources, with MDV3100, which is a super anti-androgen, to super-deprive the cancer of androgen.

I can see in a few years, in patients who are progressing, that it could be a combination of, perhaps, sipuleucel-T and abiraterone, and maybe MDV3100 and chemotherapy or radium. You have to figure out if it’s better to do it that way than to sequence them. We’ll see a synergism, and we may see advanced prostate cancer turn into a chronic disease.

Prostate cancer already is often considered a chronic disease.

What would change?

Dr. Crawford: There are 240,000 men diagnosed every year, and 30,000 deaths, so more people are diagnosed than die of the disease. A lot of people have prostate cancer and they die with it, rather than of it, and that is like a chronic disease. So, what we have here is overtreatment to a degree, and that’s what all the controversy is about—early screening, diagnosis, and treatment.

But we’re talking about a subset of patients that contribute to the 30,000 men who die every year of the disease.

We’re talking about making prostate cancer a chronic disease for even the most advanced cases. We’ve got the tools now; we’ve just got to be smart enough to use them and aggressive enough to deal with this disease. ■ Editor’s note: Dr. Crawford is an advisory board member for Amgen, Dendreon, Janssen, and sanofi-aventis, as well as for Ferring Pharmaceuticals, where his wife is an employee. His coauthor on the Oncology review, Dr. Flaig, is a consultant to sanofi-aventis and has received an honorarium from Amgen.

26 Renal & Urology News

JULY 2012

www.renalandurologynews.com

Fibrates May Impair Renal Function Elevated risk of serum creatinine increases found in elderly patients who took the medications MANY ELDERLY patients who take fibrates for dyslipidemia experience a rise in serum creatinine level that in some individuals leads to hospitalization, according to Canadian researchers.

In a population-based cohort study, Amit X. Garg, MD, PhD, of the London Health Sciences Centre in London, Ontario, and colleagues studied patients aged 66 years or older who received a new prescription for either a fibrate (19,072 patients) or ezetimibe (61,831 patients). Dr. Garg’s group chose ezetimibe as a com parative drug because, like fibrates, it is considered a second-line therapy after statins for treating dyslipidemia and it has no known acute renal effects. In randomized trials, fibrates have been shown to modestly raise serum creatinine levels. Many older patients and those with pre-existing chronic kidney disease (CKD), however, were excluded from these trials.

This prompted the investigators to study fibrate use for such individuals to better understand the safety of this common medication in real practice.

OP Tops List of Procedures for BPH DESPITE THE emergence of new surgical techniques to treat benign prostatic hyperplasia (BPH), open prostatectomy (OP) and monopolar transurethral resection of the prostate (TURP) remain the procedures used most by urologists. A recent survey, to which 600 urologists responded, found that OP and TURP are used by

The results are published in the Annals of Internal Medicine (2012;156:560569).

No mortality difference Compared with the ezetimibe patients, fibrate users were twice as likely to be hospitalized for an increase in serum creatinine levels and 30% more likely to consult a nephrologist.

The two groups showed no difference in risk for all-cause mortality or receiving dialysis for severe acute kidney injury.

In a subpopulation of 1,110 patients (220 on fibrates, 890 on ezetimibe), 9.1% of fibrate users had a rise in serum creatinine level of 50% or more compared with only 0.3% of ezetimibe users, which translated into a nearly 30-fold increased odds of a 50% or greater rise in serum creatinine level for the fibrate group.

In addition, compared with patients who did not have CKD, those with CKD were three times more likely to be hospitalized for an increase in serum creatinine level after fibrate use.

Key Points ■ Study compared the use of

fibrates and ezetimibe in a group of elderly Canadian patients.

■ Fibrate users were twice as

likely as ezetimibe users to be hospitalized for an increase in serum creatinine levels.

■ CKD patients were three times

more likely than non-CKD patients to be hospitalized for an increase in serum creatinine level after fibrate use.

“Until we have a better understanding of the underlying mechanism by which fibrates increase serum creatinine level and its long-term renal effects,” the authors concluded, “we believe that, when fibrates are prescribed to older patients, it would be prudent to start the prescription at a low dosage and arrange for close monitoring of renal function, as has been done in clinical trials. We believe

this is especially true in elderly patients with existing chronic kidney disease,” the authors added.

The researchers noted that their study was observational so their findings do not mean that the associations they detected are causal. In addition, they pointed out that fibrates and ezetimibe are not entirely comparable lipid-lowering agents. Fibrates are preferentially used to treat high glyceride levels and ezetimibe is prescribed to treat elevated low-density lipoprotein cholesterol.

In a separate study published recently in the Postgraduate Medical Journal (online ahead of print), British researchers demonstrated a significant effect of fibrate use on estimated glomerular filtration rate (eGFR) in clinical practice. The study included 132 patients started on fibrates in a lipid clinic. In the 79 patients with pre- and post-treatment eGFR values below 90 mL/min/1.73 m2, investigators observed a significant mean eGFR decrease of 8.2. Of these patients, 50% had a reduction in eGFR greater than 8, 25% demonstrated a reduction greater than 16, and 10% demonstrated a reduction greater than 21. ■

Preop Urodynamics for SUI Questioned NEW FINDINGS from a small study raise questions about the value of performing preoperative urodynamic investigations in women with stress urinary incontinence (SUI).

The findings are from the VUSIS (Value of Urodynamics prior to Stress Incojntinence Surgery) study, which included 59 women with SUI randomly assigned to a preoperative workup with urodynamics (31 patients) or without (28 patients). The primary outcome was clinical reduction in the number of complaints as measured using the Urogenital

Distress Inventory urinary incontinence subscale (UDI-UI) at 12 months after treatment.

Investigators led by Sanne van Leijsen, MD, of the Department of Obstetrics & Gynaecology at Radboud University Nijmegen Medical Centre in Nijmegen, The Netherlands, found that the mean difference in improvement on the UDIUI favored the group without urodynamic studies, confirming that the omission of urodynamics was not inferior to the use of urodynamics in the preoperative workup of women with SUI.

The mean duration of follow-up was 22 months, the researchers noted.

The two groups had similar rates of objective cure: 81% and 82% of the patients with and without urodynamics, respectively, had a negative stress test.

Moreover, the addition of urodynamics did not result in a lower occurrence of de novo overactive bladder complaints compared with a workup without urodynamics, the researchers reported online ahead of print in Neurourology and Urodynamics. ■

78% and 73% of urologists, investigators reported in the Canadian Journal of Urology (2012;19:6170-6175).

They found no differences in procedure use when results were stratified by urologist age and year of residency completion. Higher volume surgeons were more likely to perform holmium laser enucleation, diode laser vaporization, holmium laser ablation, and thulium laser ablation. ■

Renal Cysts More Common in Gout Patients GOUT PATIENTS have an increased prevalence of simple renal cysts, and these cysts are associated with a decreased likelihood of kidney stone disease, according to Brazilian investigators.

Eduardo Massato Hasegawa, MD, and colleagues at the Faculdade de

Medicina da Universidade de São Paulo, compared 146 gout sufferers with 47 gender- and age-matched healthy kidney donor (controls). The prevalence of simple renal cysts was 26% in the gout patients compared with only 10.6% in the control arm, the researchers reported online ahead of

print in Rheumatology International.

Significantly more gout patients than controls had renal stones (20.5% vs.

6.3%), but among the gout patients, renal stones were significantly less likely to found in subjects with renal cysts than in those without them (5.2% vs. 25.9%), according to the investigators. ■

www.renalandurologynews.com

JULY 2012

Renal & Urology News 27

Legal Issues in Medicine A

41-year-old man, Mr. E, was admitted to the emergency department (ED) of the local community hospital. Mr. E had been suffering from severe pain in the right flank that had persisted for more than an hour. A urinalysis revealed microscopic hematuria. An abdominal x-ray showed moderate intestinal obstruction, but overlying bowel gas made it impossible to determine if a kidney stone was present. The ED physician called the consulting urologist, Dr. R, 70, who recommended that excretory urography be performed to confirm the presence of the stone, locate the point of urinary obstruction, and evaluate the degree of dilation of the proximal ureter and renal collecting system. The ED physician conveyed the request for the urography to the radiologist, who immediately called Dr. R on the phone.

Procedural differences “It’s the policy of the radiology department to use an unenhanced CT scan of the pelvis in this sort of case rather than a urogram,” the radiologist said. “It’s preferable because CT will provide more clinical information than urography and

ceived to be an unyielding attitude on the part of Dr. R and fearing the loss of future referrals, reluctantly agreed.

The patient was taken to the radiology department where the radiologist administered an IV of the contrast solution.

Within five minutes, Mr. E went into anaphylactic shock. Attempts to revive him failed, and Mr. E was pronounced dead a half hour later. Four months later, the family of the patient filed a medical malpractice lawsuit naming as co-defendants the ED physician, the urologist, the radiologist, and the hospital. The lawsuit alleged that the defendants had acted with gross negligence.

During depositions, the plaintiff’s attorney brought in a radiologist as expert witness. He testified that unenhanced CT had completely replaced excretory urography in assessing patients with suspected urinary tract stones because of the diagnostic superiority and absence of risk of adverse reactions. The expert further testified that the use of contrast solution was associated with a small but definite risk of bodily harm and death. The expert then went on the criticize the defendant radiologist’s actions, stating that he was a board-certified professional who was

A urologist disregarded a radiologist’s caution that an unenhanced CT should replace excretory urography in assessing urinary tract stones. won’t subject the patient to the risk of a reaction from the IV contrast.”

“I’ve been ordering excretory urograms on patients with suspected stones for 40 years with satisfactory results,” Dr. R replied. “I see no need to change that practice now.”

The radiologist tried again: “The CT has really become the standard of care now,” he said. “Why subject the patient to unnecessary risk?”

“Which one of us is going to be ultimately treating this patient,” the urologist replied, “you, or me?” The radiologist, faced with what he per-

responsible for making independent judgments that would provide the best care for his patient.

The defense attorney for the radiologist on call, introduced an older, semiretired radiologist who testified that he had used excretory urography for years in similar situations without any complications.

He was, however, unable to refute the argument that unenhanced CT had essentially replaced excretory urography in most situations.

The ED physician testified that he had very limited knowledge of the various imaging modalities and would always

© ISTOCKPHOTO / THINKSTOCK.COM

A urologist and a radiologist blame each other for the death of a patient in a hospital’s emergency department BY ANN W. LATNER, JD

Had a CT scan been used instead of excretory urography, a lawsuit could have been avoided.

defer to the “superior knowledge of the radiologist.”

Dr. R testified that although he had requested that the radiologist obtain a urogram, he nonetheless would have gone along with the radiologist’s recommendations for a CT scan had the radiologist explained why it was important.

The attorney for the plaintiff was unable to provide testimony to support the charges of negligence against the ED physician or the hospital, but did call a urology expert who was critical of Dr. R, but who acknowledged that the radiologist ultimately had final say in determining which imaging tool was used was clearly .

The defense—realizing that chances of winning in court were slim—entered into settlement discussions with the plaintiff’s attorneys. The case was settled for $1 million, 90% of which was paid by the radiologist’s insurance company and 10% of which was attributed to the urologist.

Legal background The purpose of discovery, which involves deposition and the exchange of evidence such as medical records and notes, is to allow each side to assess the strength of the case and gather evidence. Quite often, this process reveals that one party isn’t likely to prevail at trial, and this spurs settlement negotiations between the parties, and often (as in this case) representatives of the malpractice liability provider.

Settlements are often worked out that take into consideration the limits of the parties’ malpractice insurance.

Protecting yourself Dr. R could have protected himself by listening to the advice of the radiologist. While Dr. R may have been older and more experienced generally, his hard line attitude about taking advice from the radiologist is what caused the death of the patient and brought him into court.

Likewise, the radiologist should have insisted that the urography decision go on record as being Dr. R’s—under strong protest from him. The radiologist should have documented all conversations with Dr. R and had a third party witness sign off on the diagnostic treatment options discussed. Furthermore, Dr. R was not completely honest under oath when he let the radiologist take the blame for his catastrophic decision. By being intractable and pulling rank, Dr. R not only destroyed a life, but he significantly damaged the radiologist’s career. ■ 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.

JULY 2012

www.renalandurologynews.com

Malpractice News

Massachusetts Hospitals Pilot Medical Liability Initiative Studies have shown that when physicians apologize to patients for errors or unfortunate results, patients are less likely to sue and are more likely to have a more positive take on the event. Now, seven healthcare systems in Massachusetts will formally pilot a project that will attempt to resolve medical liability issues without malpractice trials.

Program goals include improving patient safety, increasing transparency and trust, reducing litigation and cutting costs to healthcare systems.

One participating hospital—Baystate Medical Center—began a successful disclosure and apology initiative four years ago. The formal pilot, called “Roadmap to Reform,” will include Baystate as well as hospitals from Beth Israel Deaconess Medical Center and the Massachusetts General Hospital.

Roadmap to Reform is being led by the Massachusetts Medical Society, which received a federal grant in 2010 to create the program.

The Roadmap to Reform model consists of a policy called Disclosure, Apology and Offer (DA&O). This includes fully disclosing medical errors, detailing why and what will be done to prevent similar errors from happening in the future, issuing a sincere apology for events deemed avoidable and offering timely compensation to resolve the issue.

The process is relatively simple. Once a suspected error is reported, hospitals conduct a root cause analysis to determine who is at fault.

If fault is deemed to be on the part of a clinician or hospital policy, those responsible will be required to apologize to the injured patient. The hospital will then work with its malpractice insurance provider to determine appropriate compensation for the patient to cover injuries and/or follow-up care.

The DA&O process does not prevent patients from taking legal action, but seeks to reduce lawsuits by resolving issues in a faster and less hostile manner. Researchers from the Harvard School of Public Health will evaluate outcomes associated with the pilot program when it wraps.

Medical Malpractice Claims in Pennsylvania Level Off After a six-year decline in medical malpractice lawsuits, a new report shows that claims have leveled off in Pennsylvania. Total malpractice claim filings went from a high of 2,904 from 2000 to 2002, to a low of 1,491 in 2010.

A total of 1,528 claims were filed in the 2011 calendar year.

Although the consumer rights group Public Citizen contends that the decline reflects a nationwide reduction in malpractice lawsuits, the Pennsylvania judiciary attributes the changes to two rules implemented in 2003.

The first rule requires attorneys seeking to file malpractice cases to obtain a

certificate of merit from a health-care professional. The certificate of merit establishes that the medical treatment in the case fell short of acceptable professional standards.

The second rule mandates that medical malpractice lawsuits must only be brought in the county where the injury took place. This requirement is intended to eliminate “venue shopping”—the practice of finding a jurisdiction with more favorable laws and filing the lawsuit there. The number of filings in the state of Pennsylvania dropped significantly after the 2003 rule changes, According to the medical mal practice resource page of Pennsylvania’s Unified Judicial System, 2011 had the fewest number of jury verdicts compared with other years, and more than 70% of 2011 jury verdicts favored the defense.

For the sixth consecutive year, the number of non-jury verdicts was in the single digits. In 2011, only seven non-jury verdicts were rendered— four for the defense and three for the plaintiff. Of the verdicts that favored plaintiffs, all were for $500,000 or less.

There were a total of 110 jury verdicts in 2011—78 in favor of the defense and 32 in favor of the plaintiff. Awards for plaintiffs were as follows: nine received $500,000 or less; seven received $500,000 to $1 million; 10 received $1 million to $5 million; two received $5 million to $10 million; and four received more than $10 million.

ED Interpreters Help Reduce Number of Medical Errors

In Pennsylvania, a steep drop in malpractice lawsuits has stabilized.

© THNIKSTOCK

© THINKSTOCK

Teams now conduct a root cause analysis to stave off liability.

BY ANN W. LATNER, JD

Employing professional translators for non-English speaking patients in hospital emergency departments (EDs) reduces miscommunication and errors, study results suggest.

There were significantly fewer trans-lation mistakes that posed risks to patients when a trained interpreter (12%) was present compared with no interpreter (20%) or an amateur translator (22%), Glenn Flores, MD, of the University of Texas Medical Center in Dallas, and colleagues

Having professional translators on staff in the ED can cut down on errors

© THINKSTOCK

28 Renal & Urology News

reported in the Annals of Emergency Medicine.

Medication dosing errors were twice as likely with either no interpreter or with an amateur translator, the researchers found.

The study analyzed a total of 57 situations in the ED in which the patient and their family spoke very limited English. Twenty families had a professional interpreter, 27 had a nonprofessional translator (a relative of bilingual staff member) and 10 had no translation help.

Errors were least common when patients had an interpreter with 100 or more hours of training, the researchers determined, noting that hours of training rather than years of experience was associated with lower error rates.

A median of 12 errors occurred among translators with more than 100 training hours vs. 33 among those with fewer than 100 training hours. Only 2% of translation mistakes that occurred with translators who had more than 100 training hours had the potential for patient harm compared with 12% of those with less training.

“These findings suggest that requiring at least 100 hours of training for interpreters might have a major impact on reducing interpreter errors and their consequences in health care while improving quality and patient safety,” the researchers concluded. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

32 Renal & Urology News

JULY 2012

www.renalandurologynews.com

Chest X-Rays Unreliable for Diagnosing Pneumonia NATIONAL HARBOR, Md.â&#x20AC;&#x201D;New findings presented at the National Kidney Foundation 2012 Spring Clinical Meetings raise questions about the usefulness of the chest x-ray to diagnose pneumonia in hemodialysis (HD) patients. Chest x-rays are used routinely in clinical practice to assist 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

with the differential diagnosis of pneumonia and pulmonary edema, but their reliability has not been evaluated in this patient population, the researchers explained.

In a study involving 68 HD pa tients admitted with a diagnosis of pneumonia from the emergency departEntry 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.

ment of a large university hospital, Eric K. Judd, MD, and colleagues at the University of Alabama at Birmingham found substantial disagreement between two experienced radiologists on the radiologic diagnosis of pneumonia and pulmonary edema in HD patients. 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 Table 1. Per-patient Incidence of Selecteda 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, less than 1% (7/2758) of patients with osseous metastases treated with s 0ERSISTENT PAIN OR SLOW HEALING OF THE MOUTH OR JAW AFTER DENTAL SURGERY (see 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.

Based on study findings, Dr. Juddâ&#x20AC;&#x2122;s group concluded that in the HD population, a chest x-ray has 50% sensitivity and 25% positive predictive value for diagnosing pneumonia. â&#x20AC;&#x153;In the hemodialysis population, it [the chest x-ray] is not a reliable or accurate tool to diagnose pneumonia, and the diagnosis of pneumonia, in general, remains a difficult diagnosis to make clinically,â&#x20AC;? Dr. Judd told Renal & Urology News. It is possible pneumonia is being overdiagnosed in HD patients, leading to excessive antibiotic exposure, he added.

For the study, two experienced radiologists blinded to patientsâ&#x20AC;&#x2122; clinical course and subsequent imaging studies independently interpreted the admission chest x-rays for the presence of pneumonia or pulmo-

It is possible pneumonia is being overdiagnosed in HD patients. nary edema. Two internal-medicine trained physicians independently determined the presence of pneu monia and pulmonary edema after reviewing patientsâ&#x20AC;&#x2122; entire hospitalization records. Dr. Juddâ&#x20AC;&#x2122;s group assessed the level of agreement among the observers.

The radiologists agreed on the diagnosis of pneumonia and pulmonary edema in 58.8% and 55.9% of cases, respectively, whereas the clinicians agreed in 60.3% and 76.5% of cases, respectively.

The investigators explained that the disagreement among radiologists perhaps reflects uncertainty about the etiology of the pulmonary infiltrate in the HD population. Clinicians more frequently agreed on the diagnosis of pulmonary edema than pneumonia, suggesting that pneumonia is more difficult to diagnose clinically, they noted. â&#x2013;

On the web For more news from the National Kidney Foundationâ&#x20AC;&#x2122;s 2012 Spring Clinical Meetings, visit renalandurologynews.com/ NKF12

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Renal & Urology News 33

CME FEATURE

Part II: Current Treatment Options for Neurogenic Bladder Dysfunction Clinicians need to keep abreast of the most current treatment options for NGB, which can result in improved patient outcomes and quality of life

BY MICHAEL B. CHANCELLOR, MD

Release Date: July 2012 Expiration Date: July 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 neurogenic bladder (NGB) dysfunction need to be knowledgeable about the various treatment options for NGB, including options for patients who fail behavioral or oral therapy, to provide optimal therapy. Since successful treatment encompasses patient satisfaction as well as meaningful improvement in symptoms, clinicians need to be aware of the impact of patient considerations and satisfaction in the management of NGB dysfunction.

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: • Evaluate management options for neurogenic bladder dysfunction, including evidence-based treatments and novel therapeutic approaches • Explain the impact of patient considerations and satisfaction in the management of neurogenic bladder dysfunction 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 1.00 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 Michael B. Chancellor, MD

Reported Financial Relationships Grants/Research Support: Allergan, Inc., Medtronic, Inc., Pfizer Inc. Consultant: Astellas, Allergan, Inc., Cook MyoSite, Inc., Lipella Pharmaceuticals, Inc., Pfizer Inc. Ownership: Lipella Pharmaceuticals, Inc. Royalty/Patent Holder: Cook MyoSite, Inc., Lipella Pharmaceuticals, Inc.

N

eurogenic lower urinary tract dysfunction—or neurogenic bladder (NGB) dysfunction—may be caused by various diseases and events affecting the nervous system controlling the lower urinary tract. The resulting dysfunction depends on location and extent of the neurologic lesion; thus, the population with NGB dysfunction is quite diverse (Table 1).1 Two common neurologic causes of neurogenic detrusor overactivity (NDO), which may cause symptoms similar to overactive bladder, are multiple sclerosis (MS) and spinal cord injury (SCI).2 Limitations imposed by the underlying disease and the broad range of symptoms encompassed by NGB dysfunction can have a significant effect on patient quality of life, necessitating both a multidisciplinary and an individualized approach to management and treatment.3

Treatment goals One proposed treatment paradigm for patients with NGB dysfunction is to

optimize oral therapy, provide local bladder treatment, and offer bladder augmentat ion a nd ur i na r y d iversion.

Considerations in managing patients with NGB include the high rates of discontinuation of antimuscarinics,4 pharmacologic safety,5,6 and surgical and emerging therapies that can maximize adherence and minimize risk of systemic effects.7 The overarching goal for the patient with NGB dysfunction—including both NDO and detrusor sphincter dyssynergia, which can cause high intravesical pressure, leading to upper urinary tract damage—is to preserve renal function, decrease potential urologic complications, and improve quality of life by relieving symptoms. Patients with SCI or MS often have NDO, which also frequently causes urinary incontinence.8 The more independent a patient can become by reducing symptoms of urgency, frequency, and incontinence, the less likely he or she will need to rely on assistance or be institutionalized.

Individualized treatment plans should take into account a patient’s history and physical examination, urodynamic findings, renal function, and personal goals and limitations, including mobility, degree of disability, hand function, cognition, willingness and/or ability to

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

METHOD OF PARTICIPATION: There are no fees for participating in and receiving CME credit for this activity. During the period July 2012 through July 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.

Michael B. Chancellor, MD, is Professor of Urology, Oakland University William Beaumont School of Medicine, and Director of the Neurourology Program in the Department of Neurology, Beaumont Hospital, Royal Oak, Michigan.

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CME FEATURE perform clean intermittent catheterization (CIC), and the need for and ability of caregivers.9 Selection of therapy should focus on minimizing risks to patients while maximizing social, emotional, and vocational acceptability, including psychological, social, occupational, physical, and intimacy domains. There are no definitive consensus guidelines, however, for how to manage NDO symptoms in patients with MS and SCI.

Treatment options Treatment for dysfunction usually includes a combination of both pharmacologic agents and nonpharmacologic approaches,10 including noninvasive, minimally invasive, and surgical options.

Schematic diagram demonstrating normal fusion and release of acetylcholine from nerve terminals via interaction of SNARE proteins.

Used with permission from Smith CP, Chancellor MB. J Urol 2004;171:2128-2137.

Noninvasive treatments Noninvasive treatment options for NGB dysfunction include intermittent catheterization, Crede and Valsalva, indwelling catheterization, lifestyle changes/ behavioral modification, and oral pharmacotherapy.

Lifestyle changes/behavioral modification. These approaches may be helpTable 1: Common Neurologic Conditions Associated with NGB Conditions affecting the brain • Cerebellar ataxia • Cerebral palsy • Dementia • Multiple system atrophy • Neoplasms • Parkinson’s disease • Stroke Conditions affecting the spinal cord • Acquired immune deficiency syndrome • Ankylosing spondylosis and disk disease • Guillain-Barré syndrome • Herpes • Lyme disease • Multiple sclerosis • Myelomeningocele • Pernicious anemia • Poliomyelitis • Spinal cord injury • Tabes dorsalis • Tethered cord syndrome and short filum terminale • Transverse myelitis • Tropical spastic paraparesis Conditions affecting the peripheral nervous system and neuromuscular junction • Diabetic neuropathy • Myasthenia gravis • Pelvic plexus injury

ful for patients with lower urinary tract rehabilitation.11 These include moderate fluid intake, reducing or eliminating caffeine, dietary changes, pelvic floor muscle exercises, biofeedback, timed voiding, toileting assistance, and bladder education/retraining.12 Clean intermittent catheterization (CIC). CIC is one of the most commonly used methods for patients with NGB that fails to empty. Adequate hand function or a caregiver willing to perform CIC is necessary for this method to be successful. Abnormal urethral anatomy, strictures, bladder capacity <200 mL, adverse reaction to catheters, or autonomic dys Table 2: Oral Pharmacologic Agents for the Treatment of NGB Drug Class Estrogen derivatives • Conjugated estrogen Anticholinergic • Propantheline bromide • Dicyclomine hydrochloride • Hyoscyamine sulfate Antispasmodic • Solifenacin succinate • Darifenacin • Oxybutynin chloride • Tolterodine L-tartrate • Trospium chloride • Fesoterodine Tricyclic antidepressants* • Imipramine hydrochloride • Amitriptyline hydrochloride *Off-label use Rackley R. Neurogenic bladder. http:// emedicine.medscape.com/article/453539overview. Accessed April 12, 2012.

reflexia with high bladder volumes may interfere with the ability to conduct CIC. Urinary tract infections, one potential side effect of CIC, may be avoided by using hydrophilic-coated catheters; for example, in patients with SCI.13 Strictures, hematuria, and bladder stones are other side effects that can occur.14 Crede and Valsalva. Third-party bladder expression (Crede) and voiding by abdominal straining (Valsalva) may be appropriate for patients with low outlet resistance. Risks include high intravesical pressures, which can lead to worsening vesicoureteral reflux or hydronephrosis; incomplete bladder emptying, leading to chronic urinary tract infections; pelvic organ prolapse; hernia; and hemorrhoids.

Indwelling and suprapubic catheterization. Considered temporary methods, these may be preferred when other approaches have failed. Complications can include bladder stones, infections, and malignancies.

Oral pharmacotherapy.Anticholinergics/antimuscarinics, the most commonly used class of agents for NGB, bind to muscarinic receptors in the detrusor muscle, reducing bladder storage pressure and increasing capacity (Table 2).15-17 They are generally used in conjunction with CIC to treat NGB dysfunction.

Perceived lack of efficacy, costs of medication, polypharmacy, dosing frequency, poor counseling, and adverse effects—including dry mouth (a wellknown effect), facial flushing, dizziness, constipation, and neurologic deficits—

can all lead to patients discontinuing treatment with anticholinergics.4 Studies have shown that among 6 therapeutic classes—angiotensin receptor blockers, bisphosphonates, oral antidiabetics, overactive bladder agents, prostaglandin analogs, and statins—medication for overactive bladder had the lowest adherence rate.18 One study found that at 1 year after initiating therapy for overactive bladder, <30% of patients are still taking antimuscarinics;19 another showed that of patients initiated on either oxybutynin and tolterodine, <14% continued for 1 year, with a median of 31 days until discontinuation.20 Individual responses to anticholinergics vary; therefore, patients may find another medication or a combination of agents can increase efficacy or reduce adverse effects.21 Other oral agents that have been used in patients with NGB include phosphodiesterase type 5 inhibitors, gonadotropin-releasing hormone antagonists, neurokinin receptor-1 antagonists, beta-3 adrenoceptor agonists,22 and desmopressin.23

Minimally invasive treatments Patients with NGB who have refractory detrusor overactivity may benefit from minimally invasive treatment. Refractory detrusor overactivity is marked by persistent urgency, frequency, and incontinence, and remains bothersome despite oral pharmacologic therapy.

Sacral neuromodulation. Although this approach is approved by the U.S. Food and Drug Administration (FDA) for the treatment of urinary retention and the symptoms of overactive bladder, its safety and efficacy have not been established for patients with neurologic disease origins. An alternative treatment option in patients with voiding dysfunction and chronic pelvic pain, it is generally performed in stages to identify responders; those who respond proceed to full implantation of pulse generator and leads.

Intravesical drug delivery. Neurogenic overactivity can be decreased for several months by intravesical instillation of agents that desensitize afferent C-fibers in the bladder. Sensation is restored when the sensory nerves regenerate.

Higher levels of anticholinergics such as oxybutynin can be increased and adverse effects decreased by avoiding hepatic first-pass metabolism.24 Vanilloid compounds, capsaicin, and resiniferatoxin have been shown to be effective

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Case Study: Managing Urinary Incontinence in Multiple Sclerosis K.A. is a 52-year-old woman with multiple sclerosis (MS) that was diagnosed at the age of 37 years. She has had to take a medical leave of absence from her job as an elementary schoolteacher because of fatigue, lack of adequate bladder control, and urinary incontinence (UI) that impaired her ability to teach. She can walk 50 feet without a cane but must watch her balance, and going up and down stairs is difficult for her. K.A. is currently on beta interferon for her MS and has not had a flare-up for more than 2 years. Her overall health is otherwise stable, with only borderline hypertension and normal lipid profiles.

Approximately 3 years ago, K.A. presented with urge UI and was prescribed extended-release oral oxybutynin 15 mg/day. At her initial follow-up, she noted a moderate degree of dry mouth but no other complications. She decided to continue with this medication, as she believed it increased her health-related quality of life by decreasing episodes of UI. One year ago, K.A. admitted she was increasingly constipated and often felt dizzy if she stood up too quickly. Her clinician determined she was having involuntary detrusor contractions starting at 79 mL and had a maximal detrusor pressure of approximately 40 cm H20. She did not have stress incontinence or pelvic prolapse on examination. Several options were suggested, including switching to a different anticholinergic agent, clean intermittent catheterization, and a suprapubic catheter, since increasing her current oxybutynin dose was not a viable alternative.

She agreed to switch to a different anticholinergic and was placed on tolterodine tartrate extended-release tablets 4 mg/day. At her 2-week follow-up, postvoid residual (PVR) was 75 mL, symptoms had improved, and incontinence was 75% better.

However, at her 10-month follow-up, K.A. asks her clinician to discuss any other options, as treatment with this anticholinergic has resulted in blurred vision and drowsiness, interfering with her ability to walk up and down stairs without fear of falling, and her UI seems to be worse. At this visit, her PVR is 35 mL, her incontinence has returned to baseline, and her urgency symptoms have returned.

Three suggested treatment modalities are neuromodulation, bladder injection of botulinum toxin, or augmentation. The efficacy and safety of each of the options are explained. K.A. opts for treatment with intradetrusor injection of onabotulinumtoxinA 200 U because she does not want to undergo a surgical procedure. She understands that the treatment with onabotulinumtoxinA will last approximately 10 months.

An initial 24-week study found that onabotulinumtoxinA 200 U and 300 U clinically significantly decreased signs and symptoms of urinary incontinence caused by NDO in 59 patients due to SCI or MS vs. placebo.31 The FDA approval was based on results of two subsequent phase 3 randomized clinical studies involving 691 patients.32,33 The studies assigned patients with NDO resulting from SCI or MS not adequately managed with anticholinergics to onabotulinumtoxinA 200 U, 300 U, or placebo. Primary end point was changed from baseline in weekly urinary incontinence episodes at week 6. Patients in the onabotulinumtoxinA 200 U and 300 U arms had significant decreases in weekly frequency of incontinence episodes vs. placebo and had similar improvements in incontinence episodes, urodynamic parameters, and health-related quality-of-life scores (Figure 1).32-34 OnabotulinumtoxinA is injected intramuscularly at multiple sites throughout the bladder,35 in an outpatient procedure. The recommended dose of onabotulinumtoxinA is 200 U per treatment and should not be exceeded. Patients may be considered for reinjection when the clinical effect of the prev ious injection diminishes (median 42-48 weeks in clinical studies) but no sooner than 12 weeks from the prior bladder injection.36

The most common adverse events associated with intravesical BoNT injection are incomplete bladder emptying and urinary tract infections.27 Contraindications to onabotulinumtoxinA are active infection and known hypersensitivity to agents; relative contraindications include preexisting neuromuscular disorders and concomitant use of agents interfering with neuromuscular transmission; pregnancy (Class C) and nursing mothers; and bladder outlet obstruction. Incidence of autonomic dysreflexia may occur in patients treated for detrusor overactivity associated with a neurologic condition that requires prompt medical therapy.36

Surgical treatments Surgical options include transurethral sphincterotomy, endourethral stents, urethral and bladder neck procedures, bladder augmentation, and urinary diversion (Table 3).

Long-term follow-up of patients with NDO must be conducted, as changes in detrusor compliance and urodynamic patterns may occur over time.37

Barriers to care Barriers to care include patient embarrassment about their condition, lack of awareness that serious complications can result from mismanagement of inconti-

Figure 1. Change from Baseline in Incontinence Quality-of-Life Total Score with OnabotulinumtoxinA 200 U or Placebo 30

Placebo

OnaBoNTA 25.1*

24.4*

25

Change From Baseline

in refractory urge incontinence in adults with SCI and MS. Further studies are needed to determine long-term efficacy and safety.25 Advances in development of intravesical drug delivery, including the use of liposomal nanoparticles, will help improve management of symptoms of the lower urinary tract.26 Botulinum neurotoxin (BoNT) injection. Cystoscopic injections of BoNT modulate acetylcholine and other biochemical messengers at presynaptic nerve terminals and noncholinergic mechanisms in the detrusor smooth muscle,27 preventing detrusor contraction and leading to transient smooth muscle paralysis and symptom alleviation. A broader mechanism of action has been proposed that suggests BoNT blocks release of acetylcholine, ATP, and substance P, leading to central desensitization and effectiveness in detrusor overactivity.28 In August 2011, the FDA approved the use of onabotulinumtoxinA (Botox) injection to treat urinary incontinence in patients with NDO who have failed or cannot tolerate the adverse effects of anticholinergic therapy.29 Although three other BoNT serotype preparations are availableâ&#x20AC;&#x201D;abobotulinumtoxinA (Dysport), incobotulinumtoxinA (Xeomin), and rimabotulinumtoxinB (Myobloc)â&#x20AC;&#x201D;they are not approved to treat NDO and cannot be used interchangeably.30

20 15 11.7 10

8.6

5 0

6 Weeks

*P<0.001 vs. placebo Adapted from Cruz F, et al. Eur Urol 2011;60(4):742-750.

12 Weeks

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CME FEATURE nence, the perception that bladder issues are not life-threatening, fear of needing invasive surgical intervention, a lack of awareness that effective treatment options are available, and a lack of access to treatment options covered under insuranceplan benefits. Patients and clinicians need to be aware of the potentially detrimental effects of poorly managed or unmanaged NDO on disease outcomes.

Patient satisfaction with treatment Patient perceptions, expectations, and satisfaction with treatment can affect

adherence,38 as can costs7,10 and reimbursement issues. To ensure treatment adherence and a successful outcome, patients and clinicians need to be informed of available options and any training as well as the day-to-day requirements and long-term expectations for treatment. Ideally, bladder management strategy should be adapted to the underlying disease.

Patient satisfaction with treatment in the NGB population has been inadequately studied, using tools developed for idiopathic overactive bladder.39,40 The Actionable MS Urinary Function

Table 3: Types of Surgical Treatments for the Patient with NGB Surgery

Patient Selection

Transurethral • Detrusor external sphincter sphincterotomy dyssynergia

Screening Tool is a new measurement instrument developed to assess the impact of NGB dysfunction on quality of life in patients with MS.41 Until study results are available, clinicians cannot accurately assess patient satisfaction with treatment.

Conclusion Successful treatment of the patient with NGB dysfunction encompasses satisfaction with therapy as well as meaningful improvement in symptoms. Optimal management can result in improved patient outcomes, and a consistent effect on bladder control can result in sustained improvement in quality of life. ■

Advantages/Disadvantages • May need to be repeated • Minimal comorbidities

Endourethral stents

• Patients with detrusor sphincter • Beneficial in long-term management in patients dyssynergia who desire reflex with SCI voiding and have difficulty catheterizing, or with repeated • P otentially reversible procedure autonomic dysreflexia • Reduced hospital stay • Second stent can be deployed after first stent is epithelialized

Urethral and bladder neck procedures

• Bladder neck incision indicated in secondary changes of the bladder neck caused by scarring and fibrosis • Autologous fascial slings effective in increasing the Valsalva or stress leak point pressures without increasing leak point pressures

Bladder augmentation

• Generally reserved for patients • Complications include refractory to more conservative bacteriuria, metabolic disortherapy ders, absorption disorders, stones, risk of malignancy, and long recovery period • Excellent continence rates with high patient satisfaction

Other options

• Simple procedure, relatively • Detrusor myectomy (auto-auglow adverse-effect profile mentation) in selected patients is an extraperitoneal procedure wherein the detrusor muscle over the dome of the bladder is removed and the compliance and capacity of the bladder can be increased much like a diverticulum

Urinary diversion

• Patients with indwelling urinary catheters when the urethra is destroyed and capacity is lost • Patients with urethrocutaneous fistulas, perineal pressure ulcers, hydronephrosis and vesicoureteral reflux, or a thickened noncompliant detrusor muscle • Incontinent diversion with a urine collecting device • Can be combined with a bladder neck reconstruction to limit incontinence from the urethra

• Upper tracts not endangered

• Potential complications include intestinal or urinary leak, stomal stricture or hernia, urinary tract infection, and stone disease • Umbilical access can increase risks for strictures • Incontinent urinary diversions can be converted to continent ones • Improved quality of life, selfimage, and sexual satisfaction in women

REFERENCES 1. Stohrer M, Goepel M, Kondo A, et al. The standardization of terminology in neurogenic lower urinary tract dysfunction: with suggestions for diagnostic procedures. International Continence Society Standardization Committee. Neurourol Urodyn 1999;18:139.

2. Abrams P, Cardozo L, Fall M, et al; Standardisation Sub-committee of the International Continence Society. The standardization of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21(2):167-178.

3. Ku JH. The management of neurogenic bladder and quality of life in spinal cord injury. BJU Int 2006;98(4):739-745.

4. Rosenblum N. Will the evolution of overactive bladder delivery systems increase patient compliance? Rev Urol 2009;11(2):45-51.

5. Kay GG, Ebinger U. Preserving cognitive function for patients with overactive bladder: evidence for a differential effect with darifenacin. Int J Clin Pract 2008;62(11):1792-1800.

6. Sand PK, Rovner ES, Watanabe JH, Oefelein MG. Once-daily trospium chloride 60 mg extended release in subjects with overactive bladder syndrome who use multiple concomitant medications: post hoc analysis of pooled data from two randomized, placebocontrolled trials. Drugs Aging 2011;28(2):151-160.

7. Watanabe JH, Campbell JD, Ravelo A, et al. Cost analysis of interventions for antimuscarinic refractory patients with overactive bladder. Urology 2010;76(4):835-840.

8. Hicken BL, Putzke JD, Richards JS. Bladder management and quality of life after spinal cord injury. Am J Phys Med Rehabil. 2001;80(12):916-922.

9. 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.

10. Sussman DO. Overactive bladder: treatment options in primary care medicine. J Am Osteopath Assoc 2007;107(9):379-385.

11. Stohrer M, Blok B, Castro-Diaz D, et al. EAU guidelines on neurogenic lower urinary tract dysfunction. Eur Urol 2009;56:81.

12. Yamaguchi O, Nishizawa O, Takeda M, et al.

Clinical guidelines for overactive bladder. Int J Urol 2009;16(2):126-142.

13. De Ridder DJ, Everaert K, Fernandez LG, et al.

Intermittent catheterisation with hydrophilic-coated catheters (SpeediCath) reduces the risk of clinical urinary tract infection in spinal cord injured patients: a prospective randomised parallel comparative trial. Eur Urol 2005;48(6):991-995.

14. Lisenmeyer 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.

15. Andersson KE, Yoshida M. Antimuscarinics and the overactive detrusor—which is the main mechanism of action? Eur Urol 2003;43(1):1-5.

16. Cameron AP. Pharmacologic therapy for the neurogenic bladder. Urol Clin North Am 2010;37(4):495-506.

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

18. Yeaw J, Benner JS, Walt JG, et al. Comparing

adherence and persistence across 6 chronic medication classes. J Manag Care Pharm 2009;15(9):728-740.

19. Haab F, Castro-Diaz D. Persistence with antimuscarinic therapy in patients with overactive bladder. Int J Clin Pract 2005;59(8):931-937.

20. D’Souza AO, Smith MJ, Miller LA, et al. Persistence, adherence, and switch rates among extended-release and immediate-release overactive bladder medications in a regional managed care plan. J Manag Care Pharm 2008;14(3):291-301.

21. Yamanishi T, Yasuda K, Kamai T, et al. Combination of a cholinergic drug and an alpha-blocker is more effective than monotherapy for the treatment of voiding difficulty in patients with underactive detrusor. Int J Urol 2004;11:88.

22. Andersson KE, Chapple CR, Cardozo L, et al. Pharmacological treatment of overactive bladder: report from the International Consultation on Incontinence. Curr Opin Urol 2009;19(4):380-394.

23. Chancellor MB, Rivas DA, Staas WE. DDAVP in the urological management of the difficult neurogenic bladder in spinal cord injury: preliminary report. J Am Paraplegia Soc 1994;17(4):165-167.

24. Buyse G, Waldeck K, Verpoorten C, et al. Intravesical oxybutynin for neurogenic bladder dysfunction: less systemic side effects due to reduced first pass metabolism. J Urol 1998;160(3 pt 1):892-896.

25. MacDonald R, Monga M, Fink HA, Wilt TJ. Neurotoxin treatments for urinary incontinence in subjects with spinal cord injury or multiple sclerosis: a systematic review of effectiveness and adverse effects. J Spinal Cord Med 2008;31(2):157-165.

26. Kaufman J, Tyagi V, Anthony M, et al. State of the art in intravesical therapy for lower urinary tract symptoms. Rev Urol 2010;12(4):e181-e189.

27. Yokoyama T, Chancellor MB, Oguma K, et al. Botulinum toxin type A for the treatment of lower urinary tract disorders. Int J Urol 2012;19:202-215.

28. Apostolidis A, Dasgupta P, Fowler CJ. Proposed mechanism for the efficacy of injected botulinum toxin in the treatment of human detrusor overactivity. Eur Urol 2006;49(4):644-650.

29. US Food and Drug Administration. FDA approves Botox to treat specific form of urinary incontinence. http:// www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269509.htm. Accessed April 25, 2012.

30. Albanese A. Terminology for preparations of botulinum neurotoxins. JAMA 2011;305(1):89-90.

31. Schurch B, de Sèze M, Denys P, et al; for the Botox Detrusor Hyperreflexia Study Team. 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(1):196-200.

32. 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(4):742-750.

33. Ginsberg D, Gousse A, Keppenne V, et al. Phase 3 efficacy and safety study of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity. 2011 American Urological Association Annual Meeting. May 2011, Abstract 1515.

34. Chancellor MB, Patel V, Leng W, et al. OnabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: effects on health related quality of life. American Urological Association Annual Meeting. May 2011, Abstract 1518.

35. Apostolidis A, Dasgupta P, Denys P, et al. Recommendations on the use of botulinum toxin in the treatment of lower urinary tract disorders and pelvic floor dysfunctions: a European consensus report. Eur Urol 2009;55(1):100-119.

36. OnabotulinumtoxinA (Botox) [prescribing information].

Physicians’ Desk Reference. 65th ed. Montvale, NJ: PDR.net; 2011.

37. Ellsworth PI, Coyle PK, Esquenazi A, et al. UroToday Int J. 2012;5(suppl 1):art 96. http://dx.doi. org/10.3834/uij.1944-5784.2012.03.01.

38. Benner JS, Nichol MB, Rovner ES, et al. Patient-reported reasons for discontinuing overactive bladder medication. BJU Int 2010;105(9):1276-1282.

39. O’Leary M, et al. Improvement in health-related quality of life following treatment with onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity. Poster presented at the Society of Urologic Nurses and Associates, 42nd Annual Conference, October 28-31, 2011, San Antonio, TX. 40. Schurch B, Denys P, Kozma CM, et al. Reliability and validity of the Incontinence Quality of Life questionnaire in patients with neurogenic urinary incontinence. Arch Phys Med Rehabil 2007;88:646-652.

41. Chancellor M, Burks J, Signori M, et al. Development and validation of the urinary incontinence in multiple sclerosis screening tool. International Continence Society Annual Meeting, Glasgow, UK. 2011. http:// www.icsoffice.org/Abstracts/Publish/106/000553_ poster.pdf.

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CME Post-test Expiration Date: July 2013 Medical Education Resources designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Participants should claim only the credit commensurate with the extent of their participation in the activity. Physician post-tests must be completed and submitted online. Physicians may register at no charge at www.myCME.com/ renalandurologynews. You must receive a score of 70% or better to receive credit.

1. What is considered to be first-line treatment for patients with neurogenic bladder dysfunction?

5. One of the most common adverse events of intravesical injection of BoNT is:

a. Bladder augmentation

a. Urinary tract infection

b. Intravesical instillation

b. Stones

c. Antimuscarinic agents

c. Autonomic dysreflexia

d. Indwelling catheter

d. Urinary leak

2. The most commonly used class of agents for neurogenic bladder dysfunction is:

a. Patients with spinal cord injury can have long-term benefit

b. Anticholinergics

b. Hospital stay can be reduced

c. Capsaicin

c. Procedure is generally irreversible

3. Patients may discontinue oral pharmacotherapy primarily due to what well-known adverse effect? a. Facial flushing b. Dizziness c. Hypotension d. Dry mouth

Renal & Urology News 37

FREE Look no further than Renal & Urology News to earn 1 credit hour CREDIT of continuing medical education (CME) in nephrology and urology for free.

CME

In addition to the CME articles in this issue, you can earn 1 credit hour of CME credit by accessing past CME articles online at www.renalandurologynews.com/CME. Recent topics include:

6. Which of the following statements about endourethral stents is false?

a. Tricyclic antidepressant

d. Botulinum toxin

JULY 2012

d. Patients who have difficulty catheterizing can benefit 7. Which of the following is among the most commonly used methods for patients with normal hand function and neurogenic bladder that fails to empty?

The Management of Patients After Renal Transplantation

An Update on Robotic-Assisted Partial Nephrectomy

BY DANIEL C. BRENNAN, MD, FACP,

BY ROSALIA VITERBO, MD,

Professor of Medicine

Assistant Professor of in the Division

at Washington University School

of Urologic Oncology at Fox Chase

of Medicine in St. Louis

Cancer Center in Philadelphia

A Nephrologic Perspective on the Management of Gout

BY ANTHONY J. BLEYER, MD,

Examining the Pharmacoeconomics of Advanced Prostate Cancer

Professor of Medicine at

BY DANIEL P. PETRYLAK, MD,

Wake Forest University School

Professor of Medicine, Columbia

of Medicine in Winston-Salem, N.C.

University Medical Center in New York

a. Crede b. Valsalva

4. Which of the following statements is true regarding various botulinum toxin serotypes? a. They are interchangeable b. The dosing units are not equivalent c. All have the same generic name d. They are all approved to treat neurogenic detrusor overactivity

c. Indwelling catheter d. Clean intermittent catheterization 8. A surgical treatment with excellent continence rates and high patient satisfaction is: a. Bladder augmentation b. Transurethral sphincterotomy c. Detrusor myectomy d. Urinary diversion

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Other pathways can contribute to prostate cancer promotion.5 References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer.

Cancer Res. 2008;68(15):6407-6415. 3. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66(5):2815-2825. 4. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11(13):4653-4657. 5. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12(6):1665-1671.

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References: 1. Gregory CW, Johnson RT Jr, Mohler JL, French FS, Wilson EM. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res. 2001;61(7):2892-2898. 2. Holzbeierlein J, Lal P, LaTulippe E, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgenresponsive genes and mechanisms of therapy resistance. Am J Pathol. 2004;164(1):217-227. 3. Yu S-Q, Lai K-P, Xia S-J, Chang H-C, Chang C, Yeh S. The diverse and contrasting effects of using human prostate cancer cell lines to study androgen receptor roles in prostate cancer. Asian J Androl. 2009;11(1):39-48. 4. Corey E, Quinn JE, Buhler KR, et al. LuCaP 35: a new model of prostate cancer progression to androgen independence. Prostate. 2003;55(4):239-246. 5. Loberg RD, St. John LN, Day LL, Neeley CK, Pienta KJ. Development of the VCaP androgen-independent model of prostate cancer. Urol Oncol. 2006;24(2):161-168.

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References: 1. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12(6):1665-1671. 2. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 3. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10(1):33-39.

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