Renal & Urology News September 2013 Issue

sep t ember 2013

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Volume 12, issue Number 9

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HD Patient Outcomes, Caseload Linked Mortality rates were highest for nephrologists with the biggest caseloads, study finds Higher Caseloads=Higher Mortality Rates

86 cases*

65 cases*

103 cases*

Overall mortality 52%

Lowest mortality rate 42%

Highest mortality rate 57%

Source: Harley KT et al. Nephrologist caseload and hemodialysis patient survival in an urban cohort.

J Am Soc Nephrol 2013; published online ahead of print.

© thinkstock

*

Average Caseload Per Physician

In a study of 4,073 hemodialysis patients under the care of 41 nephrologists in Los Angeles County, the nephrologists with the highest caseload average had higher patient mortality, and the lowest mortality rate was linked to those nephrologists with the smallest average caseload.

Lifetime CKD Risk High in U.S. Moderate-to-severe chronic kidney disease (CKD) is predicted to develop in more than half of the individuals born in the United States today during their lifetime, a study found.

The study, by Morgan E. Grams, MD, MHS, and colleagues at Johns Hopkins University in Baltimore, also showed that women experienced a

cme feature

greater risk of CKD but a lower risk of end-stage renal disease (ESRD) than men.

The estimated onset of CKD was earlier in blacks than whites, according to the researchers. By age 60, 10.3% of black men and 10.4% of black women were projected to have CKD stage 3a continued on page 16

Earn 1 CME credit in this issue

OAB: Current and Emerging Therapies for Optimal Individualized Treatment Page 30

BY JODY A. CHARNOW Nephrologist caseload influences hemodialysis (HD) patient mortality rates, researchers concluded.

In a study, Kamyar Kalantar-Zadeh, MD, MPH, PhD, of the University of California Irvine, and colleagues found that nephrologists with the highest patient mortality rates had significantly higher patient caseloads, according to a report published online ahead of print in the Journal of the American Society of Nephrology. The 10 nephrologists with the lowest mortality rate (42%) had a median caseload of 65 patients, whereas the 10 nephrologists with the highest mortality rate (57%) had a median caseload of 103 patients, a significant difference between the groups.

Data May Help Clarify CRRT Role in AKI

BY JODY A. CHARNOW Findings from two recent studies may help define the role of continuous renal replacement therapy (CRRT) in treating patients with acute kidney injury (AKI).

A study by Ishir Bhan, MD, and collaborators at Massachusetts General Hospital in Boston showed that, among patients initiating CRRT for AKI, risk factors for mortality differ between patients with underlying end-stage renal disease (ESRD) or newly acquired AKI. The other study, a systemic review and meta-analysis

by Antoine G. Schneider, MD, of Austin Health in Heidelberg, Victoria, Australia, and colleagues, demonstrated that patients with severe AKI treated initially with CRRT rather than intermittent renal replacement therapy (IRRT) are less likely to become dialysis dependent.

The study by Dr. Bhan’s group, which was published online in

In adjusted analyses, each 50-patient increase in caseload was associated with a significant 2% increase in patient mortality risk. In addition, patients treated by nephrologists with the lowest patient mortality rates received higher dialysis doses, had longer sessions, and received more kidney transplants.

“Although our findings are not inconsistent with general expectations,” Dr. Kalantar-Zadeh told Renal & Urology News, “it should be noted that such findings should not be used against exceptionally efficient physicians who are known as bright and astute clinicians and who usually have a high caseload while continued on page 16

in this issue 7 Kidney transplant survival less in the severely obese 17 Uric acid unlikely to cause ischemic heart disease 18 Antibiotic regimen found to increase AKI risk

23 Researcher questions survival benefit of intensive HD

23 Lower urinary tract

symptoms linked to coffee

27 Hypogonadism increases death risk in men on hemodialysis

28

Altered taste perception common in HD patients

Twenty-four percent of all malpractice allegations were surgery-related in 2012.

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Metformin’s Effect on PCa Unclear

© Science Source / Simon Fraser

Some data show use of the diabetes drug is associated with improved outcomes, but other data do not

Metformin’s efficacy in treating PCa (shown above in red) is questionable.

.

BY JODY A. CHARNOW Recently published studies have come to different conclusions about the beneficial effect of metformin use on prostate cancer (PCa) outcomes.

A Canadian study found that increased duration of metformin use by diabetic men after a PCa diagnosis was associated with improved cancerspecific and overall survival. The finding is consistent with that of a study by researchers at Memorial-Sloan Kettering Cancer Center (MSKCC) in New York, who found that metformin use is associated with improved cancer-specific survival and other outcomes among men who underwent external beam radiotherapy for localized PCa. Investigators at Mayo Clinic

Data Show Kidney Stone-CHD Link Heavy Smoking recent study data provide evi- Ryosuke Ando, MD, of Nagoya City Raises PCa dence of a link between kidney stones University Graduate School of Medical and coronary heart disease (CHD).

Sciences in Nagoya, Japan, showed that Risk in Blacks A study by Pietro Manuel Ferraro, kidney stone-forming Japanese men MD, Columbus-Gemelli Hospital in Rome, Italy, and collaborators found that women, but not men, with a history of kidney stones are at increased risk of CHD. In another study,

cme feature

are more likely to have risk factors for CHD. Dr. Ferraro’s group analyzed data from participants in the Nurses’ Health continued on page 16

Earn 1 CME credit in this issue

OAB: Current and Emerging Therapies for Optimal Individualized Treatment Page 30

Heavy smoking is associated with increased prostate cancer (PCa) risk and higher Gleason grade among African Americans, similar to results in European Americans in other studies, according to researchers.

Among African Americans (AAs), heavy smokers (20 or more cigarettes per day) had a significant 2.6 times increased odds of a PCa diagnosis and 89% increased odds of high-grade cancer compared with never smokers or light smokers (fewer than 20 cigarettes per day), researchers reported online ahead of print in The Prostate.

Heavy smoking had no significant effect on the odds of a PCa diagnosis or high-grade cancer among European Americans (EAs). This lack of an association may be due to the smaller sample size of EAs, who made up only 20.1% of cases and 28.7% of controls, the researchers observed.

The study, by Adam B. Murphy, MD, of the Feinberg School of

in Rochester, Minn., however, found no significant reduction in the risk of biochemical recurrence, systemic progression, or all-cause mortality associated with metformin use among men who underwent radical prostatectomy (RP). A recent meta-analysis by Italian researchers revealed no association between metformin use and PCa risk.

The Canadian study, which was conducted by David Margel, MD, PhD, of the University of Toronto, and colleagues, included 3,837 diabetic men diagnosed with PCa. The men had a median age of 75 years at diagnosis. During a median follow-up of 4.6 years, 1,343 (35%) died, 291 (7.6%) from PCa. Each additional six months continued on page 16

in this issue 16 In-hospital post-cystectomy complications common 17 PSA is a marker of testosterone concentration 17 Uric acid unlikely to cause ischemic heart disease

20 Expert Q&A: Extending the

survival benefit of sipuleucel-T

22 Circumcision prevents urinary tract infections long-term

23 Lower urinary tract symptoms linked to coffee

27 ADT for prostate cancer

increases the risk of hip fracture

Twenty-four percent of all malpractice allegations were surgery-related in 2012.

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6 Renal & Urology News

september 2013 www.renalandurologynews.com

From the MEDICAL DIRECTOR Editorial Advisory Board

Genetic Risk and PCa Treatment

A

ngelina Jolie’s decision to undergo prophylactic mastectomy in the setting of an increased genetic risk of breast cancer (BRCA mutation) didn’t seem extraordinary to most oncologists. For years the relationship between genetic risk and breast cancer has led young women to preemptive surgery. Despite excellent reconstructive options, these decisions cannot be easy, yet it has become an acceptable standard for those at genetic risk.

Conversely, for men at risk of developing prostate cancer (PCa), prophylactic prostatectomy seems almost irrational for several reasons. First, PCa genetics are heterogeneous and poorly understood. Additionally, the latency period from histologic cancer to death from disease is measured over years or decades and the relationship between genetic risk and alterations in PCa biologic kinetics is unknown. Finally, the functional and resultant emotional consequences of prostatectomy in young men seem somehow, if unjustifiably, more overwhelming.

Recently, Roger Kirby, MD, Director of the Prostate Cancer Center in London, performed one of the first “prophylactic” prostatectomies in a man with a BRCA mutation as part of a clinical trial involving more than 20,000 men conducted by the Institute of Cancer Research. According to reports, the man appears to have had a biopsy consistent with low volume/ low risk cancer and made the decision based upon data suggesting he was more likely to die from the disease due on his genetics. Men with a BRCA2 mutation have an almost ninefold increased risk of developing PCa whereas those with a BRCA1 mutation have a greater than threefold increased risk.

While this case was not performed entirely for prophylactic reasons, it reflects medicine’s growing ability to link genetics to cancer risk.

Comprehensive molecular characterization of solid tumors is increasingly common (a “molecular atlas” was recently published in kidney cancer).1 When linked to clinical datasets and used in the prospective design and outcomes of clinical trials, this information will revolutionize the way patients and physicians think of cancer risk and, ultimately, how they make medical decisions. The National Cancer Institute set a target of $100,000 for sequencing a human sized genome by 2009 and $1,000 by 2014. We are getting close as several companies claim to be able to sequence 10 billion base pairs for about $5,000-$10,000. Once available, these data may not only make preemptive prostate surgery more routine, but also make current practices appear uninformed. But isn’t that always the way the future makes the past appear?

Cancer Genome Atlas Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013;499:43-49, 1

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

RUN0913_MastEdit.indd 6

Medical Director, Urology

Medical Director, Nephrology

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

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

Nephrologists

Urologists Christopher S. Cooper, MD Director, Pediatric Urology Children’s Hospital of Iowa Iowa City R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto Stanton Honig, MD Associate Clinical Professor of Surgery/Urology University of Connecticut School of Medicine, Urology Center New Haven J. Stephen Jones, MD, FACS Chief of Surgical Operations Professor of Surgery CCLM Cleveland Clinic Regional Hospitals Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology University of California, Irvine James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City Kenneth Pace, MD, MSc, FRCSC Assistant Professor Division of Urology St. Michael’s Hospital University of Toronto Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada

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

Renal & Urology News Staff Editor Jody A. Charnow Executive editor Marina Galanakis Senior editor Delicia Honen Yard

Web editor Stephan Cho Editorial coordinator Candy Iemma

Art director Andrew Bass

Group art director, Haymarket Medical Jennifer Dvoretz VP, audience development and operations John Crewe Production manager Brian Wask

Production director Kathleen Millea

Product manager, digital products Chris Bubeck

Circulation manager Paul Silver

National accounts manager William Canning Editorial director Jeff Forster Publisher Dominic Barone VP medical magazines and digital products Jim Burke

CEO, Haymarket Media Inc. Lee Maniscalco Renal & Urology News (ISSN 1550-9478) Volume 12, Number 9. Published monthly by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Periodicals postage paid at New York, NY, and an additional mailing office. The subscription rates for one year are, in the U.S., $75.00; in Canada, $85.00; all other foreign countries, $110.00. Single issues, $20.00. www.renalandurologynews.com. Postmaster: Send address changes to Renal & Urology News, c/o DMD Data Inc., 2340 River Road, Des Plaines, IL 60018. For reprints, contact Wright’s Reprints at 1.877.652.5295. Copyright: All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without the prior written permission of Haymarket Media, Inc. Copyright © 2013.

8/21/13 1:10 PM

www.renalandurologynews.com september 2013

Renal & Urology News 7

News in Brief

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

Short Takes Urine Odors May Pick Up Bladder Cancer

Washington, D.C., and co-investigators

A device containing a sensor that

cine that among 1,879 men random-

responds to chemicals in gas

ized to a print-based decision aid (628

emitted from urine can indicate

patients), a Web-based interactive deci-

in approximately 30 minutes

sion aid (625 patients), or usual care

whether cancer cells are present

(626 patients), decisional conflict was

in the bladder.

significantly lower for the intervention

reported online in JAMA Internal Medi-

Once a urine sample is inserted

groups than for the usual-care patients

into the device, called an ODOREADER,

at one and 13 months. Screening rates

a profile of the urine’s chemical

at 13 months, however, did not differ

makeup is produced, showing

significantly among groups.

whether the person has bladder the University of Liverpool,

Low IL-10 Predicts Poor Sleep in HD Patients

Liverpool, U.K., and fellow research-

Reduced circulating levels of the anti-

ers reported in PLOS ONE, the device

inflammatory cytokine interleukin-10

correctly identified 24 of 24 transi-

(IL-10) are significantly associated with

tional (urothelial) cell carcinoma cases

poor sleep quality in hemodialysis (HD)

(100%) and 70 of 74 control cases

patients, according to a study pub-

(94.6%).

lished online ahead of print in Hemodi-

cancer. Chris S. Probert, MD, of

alysis International.

PCa Decision Aids Do Not Sway Men

colleagues at Tehran University in Iran

Print- and Web-based tools presenting

studied 72 patients on maintenance

the benefits and limitations of PSA test-

HD. Of these, 54 (75%) were identified

ing served to help men resolve their

as poor sleepers and the rest were

own conflicts regarding screening, but

considered good sleepers. The poor

did not change their plans to undergo

sleepers had significantly lower levels

such testing. Kathryn L. Taylor, PhD,

of IL-10 and higher levels of serum

of Georgetown University in

triglyceride and parathyroid hormone.

Simin Dashti-Khavidaki, PharmD, and

Prescribing Medical Marijuana In a recent online poll, Renal & Urology News asked nephrologists and urologists the following question: “If the state in which you practice has legalized medicinal use of cannabis, would you prescribe it to ­eligible patients?” Here are the results based on 102 responses:

Yes: 47%

No: 41%

I do not know enough about it: 12%

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10

20

30

40

50

Testosterone Loss May Set Stage for Parkinson’s P

reservation of testosterone may be an important step in preventing development of Parkinson’s disease, suggest the findings of a mouse study published in The Journal of Biological Chemistry (2013;288:20843-20855).

Compared with normal young male mice, young male mice that had been castrated produced dramatically higher levels of inducible nitric oxide synthase (iNOS) in the nigra of the midbrain, which causes neurons to die. The study, led by biochemist Kalipada Pahan, PhD, of Rush University Medical Center in Chicago, found that subcutaneous implantation of 5α-dihywdrotestosterone pellets reversed the nigrostriatal Parkinson’s pathology in the castrated mice. The fact that castration does not cause Parkinson’s-like symptoms in male mice deficient in the iNOS gene indicates that testosterone loss causes those symptoms by means of increased nitric oxide production.

Kidney Transplant Survival Less in the Severely Obese M

ost obese patients with kidney failure experience a survival benefit from a kidney transplant, but this benefit is smaller in extremely obese patients, defined as those with a body mass index (BMI) of 40 kg/m2 or higher. At oneyear post-transplant, the risk of death was reduced by 66% or more in transplant recipients with a BMI below 40, but was reduced by only 48% in recipients with a BMI of 40 or higher, according to findings published in the American Journal of Transplantation (2013;13:2083-2090). The study, by John S. Gill, MD, MS, of the University of British Columbia in Vancouver, and colleagues also found an uncertain survival benefit in black patients with a BMI of 40 or higher. Living donor transplantation was associated with a reduced death risk of 66% or more in all BMI groups.

Walnuts Found to Prevent Prostate Tumors in Mice A

walnut-enriched diet reduced the establishment and growth of human prostate cancer in mice. In a study, prostate tumors developed in three of 16 immune-deficient mice (18%) given the walnut-enriched diet compared with 14 of 32 immune-deficient mice (44%) that were being fed a standard mouse diet. The first palpable tumors appeared three to four weeks after xenograft implantation, and were first detected in the walnut-eating mice. However, the tumors in the walnut-fed mice grew more slowly, with the final average tumor size approximately one-fourth smaller in those animals than in the controls. As Russel J. Reiter, PhD, and collaborators noted in Cancer Investigation (2013;31:365-373), previous research had shown that a standard mouse diet enriched with walnuts restrained the growth of human breast cancer cells, and dietary walnut supplementation improved biomarkers of prostate and vascular health in men aged 45 to 75 years. Walnuts have a number of compounds that could explain their ability to suppress prostate tumor growth, including omega-3 fatty acids, according to the investigators.

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8 Renal & Urology News

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Contents

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V o l ume 1 2 , issue N umber 9

Nephrology

ONLINE

7 1

High Uric Acid An Unlikely IHD Cause A recent study found no link between ischemic heart disease and a genetic marker associated with elevated uric acid.

18

Prophylaxis Regimen Ups AKI Risk Replacing cefuroxime for the prevention of wound infections after orthopedic surgery with single-dose gentamicin plus standarddose flucloxacillin appears to increase the rate of acute kidney injury.

this month at renalandurologynews.com Expert Q&A

Vikram S. Dogra, MD, of the University of Rochester, talks about a noninvasive alternative to TRUS-guided prostate biopsy he helped develop.

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 July winner: Hui Zhu, MD

28

ACEI Use Improves Post-AKI Survival Hospitalized patients with acute kidney injury experienced decreased mortality and reduced need for dialysis.

28

PD Less Expensive than HD Worldwide Peritoneal dialysis is much less expensive than hemodialysis in most places around the world, including North America, a new cost analysis has confirmed.

16

17

19

R&U University NEW

In recognition of Prostate Cancer Awareness Month, enter our contest to earn a chance to win a free iPad. RenalandUrologyNews.com/ Prostate2013

30

OAB: Current and Emerging Therapies for Optimal Individualized Treatment Michael B. Chancellor, MD, and David A Ginsberg, MD, review the different types of overactive bladder and the recommended treatments for it, including antimuscarinic agents, sacral neuromodulation, and botulinum toxins.

23

In-Hospital Complications Common After Cystectomy Certain post-operative complications occurred more frequently with some urinary diversion types than others.

PSA Levels May Predict Hypogonadism PSA is a marker of testosterone concentration and may offer a new way to confirm hypogonadism, according to Italian investigators.

Large Study Characterizes ED and Its Risk Factors Increasing age, diabetes, high body mass index, and current smoking are among the risk factors for erectile dysfunction, according to a large study of Australian men.

Coffee May Increase LUTS Risk The likelihood was increased twofold in men who drank more than two cups a day versus no coffee intake.

It’s surprising that a single dose of gentamicin

is nephrotoxic, as it is generally believed that multiple doses are required for nephrotoxicity.

See our story on page 18

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CME Feature

Urology

The Medical Minute

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

Our latest include: • Bioengineered Blood Vessel Implanted in a Dialysis Patient • Resistant Hypertension Common in Patients with Moderate CKD • Catheters for Dialysis Place Patients At Higher Death Risk

30

24

Departments 6

From the Editorial Director Using genetic risk to guide prostate cancer treatment decisions

20

Expert Q&A Possible ways to improve the survival benefit of sipuleucel-T

22

Men’s Health Update Hypogonadism linked to anabolic steroids

24

Renal Nutrition Update Reducing fructose intake to lower uric acid

26

Malpractice News New Florida law could make it difficult to bring medical malpractice suits

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8 Renal & Urology News

september 2013 www.renalandurologynews.com

Contents

september 2 0 1 3

n

V olume 1 2 , issue N umber 9

Urology 16

ONLINE

this month at renalandurologynews.com Expert Q&A

Vikram S. Dogra, MD, of the University of Rochester, talks about a noninvasive alternative to TRUS-guided prostate biopsy he helped develop.

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 July winner: Hui Zhu, MD

17

19

23

R&U University NEW

In recognition of Prostate Cancer Awareness Month, enter our contest to earn a chance to win a free iPad. RenalandUrologyNews.com/ Prostate2013

PSA Levels May Predict Hypogonadism PSA is a marker of testosterone concentration and may offer a new way to confirm hypogonadism, according to Italian investigators.

CME Feature

Large Study Characterizes ED and Its Risk Factors Increasing age, diabetes, high body mass index, and current smoking are among the risk factors for erectile dysfunction, according to a large study of Australian men.

30

Coffee May Increase LUTS Risk The likelihood was increased twofold in men who drank more than two cups a day versus no coffee intake.

7 1

High Uric Acid An Unlikely IHD Cause A recent study found no link between ischemic heart disease and a genetic marker associated with elevated uric acid.

18

Prophylaxis Regimen Ups AKI Risk Replacing cefuroxime for the prevention of wound infections after orthopedic surgery with single-dose gentamicin plus standarddose flucloxacillin appears to increase the rate of acute kidney injury.

28

28

ACEI Use Improves Post-AKI Survival Hospitalized patients with acute kidney injury experienced decreased mortality and reduced need for dialysis.

PD Less Expensive than HD Worldwide Peritoneal dialysis is much less expensive than hemodialysis in most places around the world, including North America, a new cost analysis has confirmed.

These findings suggest a necessary refocused approach in the evaluation and treatment paradigms of young hypogonadal men.

See our story on page 22

RUN0913_TOC_Uro.indd 8

30 OAB: Current and Emerging Therapies for Optimal Individualized Treatment Michael B. Chancellor, MD, and David A Ginsberg, MD, review the different types of overactive bladder and the recommended treatments for it, including antimuscarinic agents, sacral neuromodulation, and botulinum toxins.

Nephrology

The Medical Minute

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

Our latest include: • Blacks More Likely to Harbor Aggressive Prostate Cancer • Genetic Test May Improve Metastatic Prostate Cancer Prediction

• Antibiotics Lower UTI Risk in Catheterized Patients

In-Hospital Complications Common After Cystectomy Certain post-operative complications occurred more frequently with some urinary diversion types than others.

24

Departments 6

From the Editorial Director Using genetic risk to guide prostate cancer treatment decisions

20

Expert Q&A Possible ways to improve the survival benefit of sipuleucel-T

22

Men’s Health Update Hypogonadism linked to anabolic steroids

24

Renal Nutrition Update Reducing fructose intake to lower uric acid

26

Malpractice News New Florida law could make it difficult to bring medical malpractice suits

8/21/13 12:50 PM

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Effect on Weight* Statistically significant weight reductions vs placebo at 26 weeks (P<0.001)1

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Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372-382.

Impact on Systolic Blood Pressure (SBP)* Statistically significant SBP lowering vs placebo at 26 weeks (P<0.001)2

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POSSIBILITIES Introducing INVOKANA™—the first and only treatment option approved in the United States that reduces the reabsorption of glucose in the kidneys via sodium glucose co-transporter-2 (SGLT2) inhibition1 A1C Reductions as Monotherapy INVOKANA™ monotherapy provided statistically significant A1C reductions vs placebo at 26 weeks1

Change in A1C (%) from baseline (adjusted mean)

A1C Change From Baseline With INVOKANA™ Monotherapy1

INVOKANA™ (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

INVOKANA™ is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS >>History of a serious hypersensitivity reaction to INVOKANA™. >>Severe renal impairment (eGFR <30 mL/min/1.73 m2), end stage renal disease, or patients on dialysis.

WARNINGS and PRECAUTIONS >>Hypotension: INVOKANA™ causes intravascular volume contraction. Symptomatic hypotension can occur after

I0047B_KINGsizeLaunchAd_FR.indd 2

initiating INVOKANA™, particularly in patients with impaired renal function (eGFR <60 mL/min/1.73 m2), elderly patients, and patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (eg, angiotensinconverting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA™ in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.

Please see additional Important Safety Information and Brief Summary of full Prescribing Information on the following pages.

+0.14

0.2 0

DIFFERENCE FROM PLACEBO

DIFFERENCE FROM PLACEBO

–0.4

(95% CI: –1.09, –0.73); P<0.001

(95% CI: –1.34, –0.99); P<0.001

–0.6

–0.77

–0.2

– 0.91

– 1.16

–0.8

–1.03 –1.0 –1.2

Placebo (n=192; mean baseline A1C: 7.97%)

INVOKANATM 100 mg (n=195; mean baseline A1C: 8.06%)

INVOKANATM 300 mg (n=197; mean baseline A1C: 8.01%)

A1C Reductions vs Sitagliptin INVOKANA™ 300 mg demonstrated greater A1C reductions vs sitagliptin 100 mg, in combination with metformin + a sulfonylurea, at 52 weeks (P<0.05)1 >> Difference from sitagliptin†: –0.37% Incidence of Hypoglycemia Monotherapy over 26 weeks: 100 mg: 3.6%; 300 mg: 3.0%; placebo: 2.6%1 With metformin and a sulfonylurea over 52 weeks: INVOKANATM 300 mg: 43.2%; sitagliptin 100 mg: 40.7%1 >> Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA™ can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue Convenient Once-Daily Dosing1 >> Recommended starting dose: INVOKANA™ 100 mg >> Dose can be increased to 300 mg in patients tolerating 100 mg, who have an eGFR of ≥60 mL/min/1.73 m2, and require additional glycemic control

Effect on Weight* Statistically significant weight reductions vs placebo at 26 weeks (P<0.001)1

The most common (≥5%) adverse reactions were female genital mycotic infection, urinary tract infection, and increased urination.

>> Difference from placebo†: 100 mg: –2.2%; 300 mg: –3.3%

References: 1. Invokana [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2013. 2. Stenlöf K, Cefalu WT, Kim KA, et al.

Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372-382.

Impact on Systolic Blood Pressure (SBP)* Statistically significant SBP lowering vs placebo at 26 weeks (P<0.001)2

Learn more at INVOKANAhcp.com/journal

>> Difference from placebo†: 100 mg: –3.7 mm Hg; 300 mg: –5.4 mm Hg INVOKANA™ is not indicated for weight loss or as antihypertensive treatment. *Prespecified secondary endpoint. †Adjusted mean.

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IMPORTANT SAFETY INFORMATION (continued from first page)

DRUG INTERACTIONS >> UGT Enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (eg, rifampin, phenytoin, phenobarbitol, ritonavir) must be co-administered with INVOKANA™ (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA™ 100 mg once daily, have an eGFR greater than 60mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and requiring additional glycemic control. >> Digoxin: There was an increase in the area AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA™ 300 mg. Patients taking INVOKANA™ with concomitant digoxin should be monitored appropriately.

USE IN SPECIFIC POPULATIONS >> Pregnancy Category C: There are no adequate and wellcontrolled studies of INVOKANA™ in pregnant women.

Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at ≥0.5 times clinical exposure from a 300-mg dose.

These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters.

INVOKANA™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. >> Nursing Mothers: It is not known if INVOKANA™ is excreted in human milk. INVOKANA™ is secreted in the milk of lactating rats, reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA™ showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.

Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human

kidney. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from INVOKANA™, a decision should be made whether to discontinue nursing or to discontinue INVOKANA™, taking into account the importance of the drug to the mother. >> Pediatric Use: Safety and effectiveness of INVOKANA™ in pediatric patients under 18 years of age have not been established. >> Geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA™ in nine clinical studies of INVOKANA™. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA™ (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300-mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were ≥75 years of age. Smaller reductions in HbA1C with INVOKANA™ relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA™ 100 mg and -0.74% with INVOKANA™ 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA™ 100 mg and -0.87% with INVOKANA™ 300 mg relative to placebo). >> Renal Impairment: The efficacy and safety of INVOKANA™ were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/ 1.73 m2). These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR ≥60 mL/min/1.73 m2); patients treated with INVOKANA™ 300 mg were more likely to experience increases in potassium.

The efficacy and safety of INVOKANA™ have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), with end-stage renal disease (ESRD), or receiving dialysis. INVOKANA™ is not expected to be effective in these patient populations.

>> Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment.

The use of INVOKANA™ has not been studied in patients with severe hepatic impairment and it is therefore not recommended.

OVERDOSAGE >> There were no reports of overdose during the clinical development program of INVOKANA™ (canagliflozin).

In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis.

ADVERSE REACTIONS >> The most common (≥5%) adverse reactions were female genital mycotic infections, urinary tract infections, and increased urination. Adverse reactions in ≥2% of patients were male genital mycotic infections, vulvovaginal pruritis, thirst, nausea, and constipation.

K02CAN13149

WARNINGS and PRECAUTIONS (cont’d) >> Impairment in Renal Function: INVOKANA™ (canagliflozin) increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA™. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2. >> Hyperkalemia: INVOKANA™ can lead to hyperkalemia.

Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia. Monitor serum potassium levels periodically after initiating INVOKANA™ in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions. >> Hypoglycemia With Concomitant Use With Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA™ can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA™. >> Genital Mycotic Infections: INVOKANA™ increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections. Monitor and treat appropriately. >> Hypersensitivity Reactions: Hypersensitivity reactions (eg, generalized urticaria), some serious, were reported with INVOKANA™ treatment; these reactions generally occurred within hours to days after initiating INVOKANA™.

If hypersensitivity reactions occur, discontinue use of INVOKANA™; treat per standard of care and monitor until signs and symptoms resolve. >> Increases in Low-Density Lipoprotein (LDL-C): Doserelated increases in LDL-C occur with INVOKANA™.

Monitor LDL-C and treat per standard of care after initiating INVOKANA™. >> Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA™ or any other antidiabetic drug.

Please see Brief Summary of full Prescribing Information on the following pages.

Janssen Pharmaceuticals, Inc. Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation. © Janssen Pharmaceuticals, Inc. 2013

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April 2013

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IMPORTANT SAFETY INFORMATION (continued from first page)

DRUG INTERACTIONS >> UGT Enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (eg, rifampin, phenytoin, phenobarbitol, ritonavir) must be co-administered with INVOKANA™ (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA™ 100 mg once daily, have an eGFR greater than 60mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and requiring additional glycemic control. >> Digoxin: There was an increase in the area AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA™ 300 mg. Patients taking INVOKANA™ with concomitant digoxin should be monitored appropriately.

USE IN SPECIFIC POPULATIONS >> Pregnancy Category C: There are no adequate and wellcontrolled studies of INVOKANA™ in pregnant women.

Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at ≥0.5 times clinical exposure from a 300-mg dose.

These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters.

INVOKANA™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. >> Nursing Mothers: It is not known if INVOKANA™ is excreted in human milk. INVOKANA™ is secreted in the milk of lactating rats, reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA™ showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.

Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human

kidney. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from INVOKANA™, a decision should be made whether to discontinue nursing or to discontinue INVOKANA™, taking into account the importance of the drug to the mother. >> Pediatric Use: Safety and effectiveness of INVOKANA™ in pediatric patients under 18 years of age have not been established. >> Geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA™ in nine clinical studies of INVOKANA™. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA™ (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300-mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were ≥75 years of age. Smaller reductions in HbA1C with INVOKANA™ relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA™ 100 mg and -0.74% with INVOKANA™ 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA™ 100 mg and -0.87% with INVOKANA™ 300 mg relative to placebo). >> Renal Impairment: The efficacy and safety of INVOKANA™ were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/ 1.73 m2). These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR ≥60 mL/min/1.73 m2); patients treated with INVOKANA™ 300 mg were more likely to experience increases in potassium.

The efficacy and safety of INVOKANA™ have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), with end-stage renal disease (ESRD), or receiving dialysis. INVOKANA™ is not expected to be effective in these patient populations.

>> Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment.

The use of INVOKANA™ has not been studied in patients with severe hepatic impairment and it is therefore not recommended.

OVERDOSAGE >> There were no reports of overdose during the clinical development program of INVOKANA™ (canagliflozin).

In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis.

ADVERSE REACTIONS >> The most common (≥5%) adverse reactions were female genital mycotic infections, urinary tract infections, and increased urination. Adverse reactions in ≥2% of patients were male genital mycotic infections, vulvovaginal pruritis, thirst, nausea, and constipation.

K02CAN13149

WARNINGS and PRECAUTIONS (cont’d) >> Impairment in Renal Function: INVOKANA™ (canagliflozin) increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA™. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2. >> Hyperkalemia: INVOKANA™ can lead to hyperkalemia.

Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia. Monitor serum potassium levels periodically after initiating INVOKANA™ in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions. >> Hypoglycemia With Concomitant Use With Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA™ can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA™. >> Genital Mycotic Infections: INVOKANA™ increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections. Monitor and treat appropriately. >> Hypersensitivity Reactions: Hypersensitivity reactions (eg, generalized urticaria), some serious, were reported with INVOKANA™ treatment; these reactions generally occurred within hours to days after initiating INVOKANA™.

If hypersensitivity reactions occur, discontinue use of INVOKANA™; treat per standard of care and monitor until signs and symptoms resolve. >> Increases in Low-Density Lipoprotein (LDL-C): Doserelated increases in LDL-C occur with INVOKANA™.

Monitor LDL-C and treat per standard of care after initiating INVOKANA™. >> Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA™ or any other antidiabetic drug.

Please see Brief Summary of full Prescribing Information on the following pages.

Janssen Pharmaceuticals, Inc. Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation. © Janssen Pharmaceuticals, Inc. 2013

I0047B_KINGsizeLaunchAd_FR.indd 3

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INVOKANA™

(canagliflozin) tablets, for oral use Brief Summary of Prescribing Information.

IndIcatIons and Usage INVOKANA™ (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14) in full Prescribing Information].

Limitation of Use: INVOKANA is not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. contraIndIcatIons • History of a serious hypersensitivity reaction to INVOKANA [see Warnings and Precautions].

• Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage renal disease or patients on dialysis [see Warnings and Precautions and Use in Specific Populations].

WarnIngs and PrecaUtIons Hypotension: INVOKANA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA [see Adverse Reactions] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.

Impairment in renal Function: INVOKANA increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA [see Adverse Reactions]. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2.

Hyperkalemia: INVOKANA can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia [see Adverse Reactions].

Monitor serum potassium levels periodically after initiating INVOKANA in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.

Hypoglycemia with concomitant Use with Insulin and Insulin secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA. genital Mycotic Infections: INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions]. Monitor and treat appropriately.

Hypersensitivity reactions: Hypersensitivity reactions (e.g., generalized urticaria), some serious, were reported with INVOKANA treatment; these reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat per standard of care and monitor until signs and symptoms resolve [see Contraindications and Adverse Reactions].

Increases in Low-density Lipoprotein (LdL-c): Dose-related increases in LDL-C occur with INVOKANA [see Adverse Reactions]. Monitor LDL-C and treat per standard of care after initiating INVOKANA. Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA or any other antidiabetic drug. adverse reactIons The following important adverse reactions are described below and elsewhere in the labeling: • Hypotension [see Warnings and Precautions] • Impairment in Renal Function [see Warnings and Precautions] • Hyperkalemia [see Warnings and Precautions] • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions] • Genital Mycotic Infections [see Warnings and Precautions] • Hypersensitivity Reactions [see Warnings and Precautions] • Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and Precautions] clinical studies 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 the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Pool of Placebo-Controlled Trials: The data in Table 1 is derived from four 26-week placebo-controlled trials. In one trial INVOKANA was used as monotherapy and in three trials INVOKANA was used as add-on therapy [see Clinical Studies (14) in full Prescribing Information]. These data reflect exposure of 1667 patients to INVOKANA and a mean duration of exposure to INVOKANA of 24 weeks. Patients received INVOKANA 100 mg (N=833), INVOKANA 300 mg (N=834) or placebo (N=646) once daily. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2).

Table 1 shows common adverse reactions associated with the use of INVOKANA. These adverse reactions were not present at baseline, occurred more commonly on INVOKANA than on placebo, and occurred in at least 2% of patients treated with either INVOKANA 100 mg or INVOKANA 300 mg. table 1: adverse reactions From Pool of Four 26−Week Placebo-controlled studies reported in ≥ 2% of InvoKana-treated Patients* InvoKana InvoKana 300 mg 100 mg Placebo n=834 n=833 Adverse Reaction n=646 Female genital mycotic infections† 3.2% 10.4% 11.4% Urinary tract infections‡ 4.0% 5.9% 4.3% Increased urination§ 0.8% 5.3% 4.6% Male genital mycotic infections¶ 0.6% 4.2% 3.7% Vulvovaginal pruritus 0.0% 1.6% 3.0% Thirst# 0.2% 2.8% 2.3% Constipation 0.9% 1.8% 2.3% Nausea 1.5% 2.2% 2.3% * The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin, metformin and sulfonylurea, or metformin and pioglitazone. † Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal.

Percentages calculated with the number of female subjects in each group as denominator: placebo (N=312), INVOKANA 100 mg (N=425), and INVOKANA 300 mg (N=430). ‡ Urinary tract infections includes the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. § Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. ¶ Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=334), INVOKANA 100 mg (N=408), and INVOKANA 300 mg (N=404). # Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia.

Abdominal pain was also more commonly reported in patients taking INVOKANA 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%).

Pool of Placebo- and Active-Controlled Trials: The occurrence of adverse reactions was also evaluated in a larger pool of patients participating in placebo- and active-controlled trials.

The data combined eight clinical trials [see Clinical Studies (14) in full Prescribing Information] and reflect exposure of 6177 patients to INVOKANA. The mean duration of exposure to INVOKANA was 38 weeks with 1832 individuals exposed to INVOKANA for greater than 50 weeks. Patients received INVOKANA 100 mg (N=3092), INVOKANA 300 mg (N=3085) or comparator (N=3262) once daily. The mean age of the population was 60 years and 5% were older than 75 years of age. Fifty-eight percent (58%) of the population was male and 73% were Caucasian, 16% were Asian, and 4% were Black or African American. At baseline, the

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INVOKANA™ (canagliflozin) tablets population had diabetes for an average of 11 years, had a mean HbA1C of 8.0% and 33% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 81 mL/min/1.73 m2).

The types and frequency of common adverse reactions observed in the pool of eight clinical trials were consistent with those listed in Table 1. In this pool, INVOKANA was also associated with the adverse reactions of fatigue (1.7% with comparator, 2.2% with INVOKANA 100 mg, and 2.0% with INVOKANA 300 mg) and loss of strength or energy (i.e., asthenia) (0.6% with comparator, 0.7% with INVOKANA 100 mg and 1.1% with INVOKANA 300 mg).

In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.9, 2.7, and 0.9 per 1000 patient-years of exposure to comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.

In the pool of eight clinical trials with a longer mean duration of exposure to INVOKANA (68 weeks), the incidence rate of bone fracture was 14.2, 18.7, and 17.6 per 1000 patient years of exposure to comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Upper extremity fractures occurred more commonly on INVOKANA than comparator.

In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of patients receiving comparator, INVOKANA 100 mg and INVOKANA 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with INVOKANA, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to INVOKANA. Among these patients, 2 patients discontinued INVOKANA. One patient with urticaria had recurrence when INVOKANA was re-initiated.

Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.

Other adverse reactions occurring more frequently on INVOKANA than on comparator were: Volume Depletion-Related Adverse Reactions: INVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with INVOKANA was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletionrelated adverse reactions were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2) and age 75 years and older (Table 2) [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Use in Specific Populations]. table 2: Proportion of Patients With at Least one volume depletion-related adverse reactions (Pooled results from 8 clinical trials) InvoKana InvoKana comparator 300 mg 100 mg group* % % % Baseline characteristic Overall population 1.5% 2.3% 3.4% 75 years of age and older† 2.6% 4.9% 8.7% eGFR less than 60 mL/min/1.73 m2† 2.5% 4.7% 8.1% Use of loop diuretic† 4.7% 3.2% 8.8% * Includes placebo and active-comparator groups † Patients could have more than 1of the listed risk factors Impairment in Renal Function: INVOKANA is associated with a dose-dependent increase in serum creatinine and a concomitant fall in estimated GFR (Table 3). Patients with moderate renal impairment at baseline had larger mean changes. table 3: changes in serum creatinine and egFr associated with InvoKana in the Pool of Four Placebocontrolled trials and Moderate renal Impairment trial InvoKana InvoKana 300 mg 100 mg Placebo n=834 n=833 n=646 Creatinine (mg/dL) 0.84 0.82 0.82 Baseline eGFR (mL/min/1.73 m2) 87.0 88.3 88.8 Pool of Four Creatinine (mg/dL) 0.01 0.03 0.05 PlaceboWeek 6 Change Controlled eGFR (mL/min/1.73 m2) -1.6 -3.8 -5.0 Trials End of Treatment Creatinine (mg/dL) 0.01 0.02 0.03 Change* -1.6 -2.3 -3.4 eGFR (mL/min/1.73 m2) InvoKana InvoKana 300 mg 100 mg Placebo n=89 n=90 n=90 Creatinine (mg/dL) 1.61 1.62 1.63 Baseline eGFR (mL/min/1.73 m2) 40.1 39.7 38.5 Moderate Creatinine (mg/dL) 0.03 0.18 0.28 Renal Week 3 Change Impairment eGFR (mL/min/1.73 m2) -0.7 -4.6 -6.2 Trial End of Treatment Creatinine (mg/dL) 0.07 0.16 0.18 Change* -1.5 -3.6 -4.0 eGFR (mL/min/1.73 m2) * Week 26 in mITT LOCF population In the pool of four placebo-controlled trials where patients had normal or mildly impaired baseline renal function, the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR below 80 mL/min/1.73 m2 and 30% lower than baseline, was 2.1% with placebo, 2.0% with INVOKANA 100 mg, and 4.1% with INVOKANA 300 mg. At the end of treatment, 0.5% with placebo, 0.7% with INVOKANA 100 mg, and 1.4% with INVOKANA 300 mg had a significant renal function decline.

In a trial carried out in patients with moderate renal impairment with a baseline eGFR of 30 to less than 50 mL/min/1.73 m2 (mean baseline eGFR 39 mL/min/1.73 m2) [see Clinical Studies (14.3) in full Prescribing Information], the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR 30% lower than baseline, was 6.9% with placebo, 18% with INVOKANA 100 mg, and 22.5% with INVOKANA 300 mg. At the end of treatment, 4.6% with placebo, 3.4% with INVOKANA 100 mg, and 3.4% with INVOKANA 300 mg had a significant renal function decline.

In a pooled population of patients with moderate renal impairment (N=1085) with baseline eGFR of 30 to less than 60 mL/min/1.73 m2 (mean baseline eGFR 48 mL/min/1.73 m2), the overall incidence of these events was lower than in the dedicated trial but a dose-dependent increase in incident episodes of significant renal function decline compared to placebo was still observed.

Use of INVOKANA was associated with an increased incidence of renal-related adverse reactions (e.g., increased blood creatinine, decreased glomerular filtration rate, renal impairment, and acute renal failure), particularly in patients with moderate renal impairment.

In the pooled analysis of patients with moderate renal impairment, the incidence of renal-related adverse reactions was 3.7% with placebo, 8.9% with INVOKANA 100 mg, and 9.3% with INVOKANA 300 mg.

Discontinuations due to renal-related adverse events occurred in 1.0% with placebo, 1.2% with INVOKANA 100 mg, and 1.6% with INVOKANA 300 mg [see Warnings and Precautions].

Genital Mycotic Infections: In the pool of four placebo-controlled clinical trials, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 3.2%, 10.4%, and 11.4% of females treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on INVOKANA. Female patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrence and require treatment with oral or topical antifungal agents and antimicrobial agents [see Warnings and Precautions].

In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.6%, 4.2%, and 3.7% of males treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrent infections (22% on INVOKANA

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INVOKANA™ (canagliflozin) tablets

INVOKANA™ (canagliflozin) tablets

versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In the pooled analysis of 8 controlled trials, phimosis was reported in 0.3% of uncircumcised male patients treated with INVOKANA and 0.2% required circumcision to treat the phimosis [see Warnings and Precautions].

Hypoglycemia: In all clinical trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials [see Clinical Studies (14) in full Prescribing Information], episodes of hypoglycemia occurred at a higher rate when INVOKANA was co-administered with insulin or sulfonylureas (Table 4) [see Warnings and Precautions]. table 4: Incidence of Hypoglycemia* in controlled clinical studies

dilatation were evident at greater than or equal to 0.5 times clinical exposure from a 300 mg dose [see Nonclinical Toxicology (13.2) in full Prescribing Information].

These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. nursing Mothers: It is not known if INVOKANA is excreted in human milk. INVOKANA is secreted in the milk of lactating rats reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INVOKANA, a decision should be made whether to discontinue nursing or to discontinue INVOKANA, taking into account the importance of the drug to the mother [see Nonclinical Toxicology (13.2) in full Prescribing Information].

Pediatric Use: Safety and effectiveness of INVOKANA in pediatric patients under 18 years of age have not been established. geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA in nine clinical studies of INVOKANA [see Clinical Studies (14.3) in full Prescribing Information].

Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) in full Prescribing Information and Adverse Reactions]. Smaller reductions in HbA1C with INVOKANA relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA 100 mg and -0.74% with INVOKANA 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA 100 mg and -0.87% with INVOKANA 300 mg relative to placebo). renal Impairment: The efficacy and safety of INVOKANA were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2) [see Clinical Studies (14.3) in full Prescribing Information]. These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR greater than or equal to 60 mL/min/1.73 m2); patients treated with INVOKANA 300 mg were more likely to experience increases in potassium [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Adverse Reactions].

The efficacy and safety of INVOKANA have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), with ESRD, or receiving dialysis. INVOKANA is not expected to be effective in these patient populations [see Contraindications and Clinical Pharmacology (12.3) in full Prescribing Information].

Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and is therefore not recommended [see Clinical Pharmacology (12.3) in full Prescribing Information]. overdosage There were no reports of overdose during the clinical development program of INVOKANA (canagliflozin).

In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis.

PatIent coUnseLIng InForMatIon See FDA-approved patient labeling (Medication Guide).

Instructions: Instruct patients to read the Medication Guide before starting INVOKANA (canagliflozin) therapy and to reread it each time the prescription is renewed.

Inform patients of the potential risks and benefits of INVOKANA and of alternative modes of therapy.

Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change.

Instruct patients to take INVOKANA only as prescribed. If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of INVOKANA at the same time.

Inform patients that the most common adverse reactions associated with INVOKANA are genital mycotic infection, urinary tract infection, and increased urination.

Inform female patients of child bearing age that the use of INVOKANA during pregnancy has not been studied in humans, and that INVOKANA should only be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Instruct patients to report pregnancies to their physicians as soon as possible.

Inform nursing mothers to discontinue INVOKANA or nursing, taking into account the importance of drug to the mother.

Laboratory Tests: Due to its mechanism of action, patients taking INVOKANA will test positive for glucose in their urine.

Hypotension: Inform patients that symptomatic hypotension may occur with INVOKANA and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.

Genital Mycotic Infections in Females (e.g., Vulvovaginitis): Inform female patients that vaginal yeast infection may occur and provide them with information on the signs and symptoms of vaginal yeast infection.

Advise them of treatment options and when to seek medical advice [see Warnings and Precautions].

Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis): Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions].

Hypersensitivity Reactions: Inform patients that serious hypersensitivity reactions such as urticaria and rash have been reported with INVOKANA. Advise patients to report immediately any signs or symptoms suggesting allergic reaction or angioedema, and to take no more drug until they have consulted prescribing physicians.

Urinary Tract Infections: Inform patients of the potential for urinary tract infections. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur.

Monotherapy (26 weeks) Overall [N (%)] In combination with Metformin (26 weeks) Overall [N (%)] Severe [N (%)]† In combination with Metformin (52 weeks) Overall [N (%)] Severe [N (%)]† In combination with sulfonylurea (18 weeks) Overall [N (%)] In combination with Metformin + sulfonylurea (26 weeks) Overall [N (%)] Severe [N (%)]† In combination with Metformin + sulfonylurea (52 weeks) Overall [N (%)] Severe [N (%)]† In combination with Metformin + Pioglitazone (26 weeks) Overall [N (%)] In combination with Insulin (18 weeks) Overall [N (%)] Severe [N (%)]†

Placebo (n=192) 5 (2.6) Placebo + Metformin (n=183)

InvoKana 100 mg (n=195) 7 (3.6) InvoKana 100 mg + Metformin (n=368)

InvoKana 300 mg (n=197) 6 (3.0) InvoKana 300 mg + Metformin (n=367)

3 (1.6) 0 (0) glimepiride + Metformin (n=482) 165 (34.2) 15 (3.1) Placebo + sulfonylurea (n=69) 4 (5.8) Placebo + Metformin + sulfonylurea (n=156) 24 (15.4) 1 (0.6) sitagliptin + Metformin + sulfonylurea (n=378) 154 (40.7) 13 (3.4) Placebo + Metformin + Pioglitazone (n=115) 3 (2.6) Placebo (n=565) 208 (36.8) 14 (2.5)

16 (4.3) 1 (0.3) InvoKana 100 mg + Metformin (n=483) 27 (5.6) 2 (0.4) InvoKana 100 mg + sulfonylurea (n=74) 3 (4.1) InvoKana 100 mg + Metformin + sulfonylurea (n=157) 43 (27.4) 1 (0.6)

17 (4.6) 1 (0.3) InvoKana 300 mg + Metformin (n=485) 24 (4.9) 3 (0.6) InvoKana 300 mg + sulfonylurea (n=72) 9 (12.5) InvoKana 300 mg + Metformin + sulfonylurea (n=156) 47 (30.1) 0 InvoKana 300 mg + Metformin + sulfonylurea (n=377) 163 (43.2) 15 (4.0) InvoKana 300 mg + Metformin + Pioglitazone (n=114) 6 (5.3) InvoKana 300 mg (n=587) 285 (48.6) 16 (2.7)

InvoKana 100 mg + Metformin + Pioglitazone (n=113) 3 (2.7) InvoKana 100 mg (n=566) 279 (49.3) 10 (1.8)

* Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population † Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained) Laboratory Tests: Increases in Serum Potassium: Dose-related, transient mean increases in serum potassium were observed early after initiation of INVOKANA (i.e., within 3 weeks) in a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information]. In this trial, increases in serum potassium of greater than 5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. More severe elevations (i.e., equal or greater than 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In patients with moderate renal impairment, increases in potassium were more commonly seen in those with elevated potassium at baseline and in those using medications that reduce potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers [see Warnings and Precautions].

Increases in Serum Magnesium: Dose-related increases in serum magnesium were observed early after initiation of INVOKANA (within 6 weeks) and remained elevated throughout treatment. In the pool of four placebo-controlled trials, the mean change in serum magnesium levels was 8.1% and 9.3% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to -0.6% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], serum magnesium levels increased by 0.2%, 9.2%, and 14.8% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.

Increases in Serum Phosphate: Dose-related increases in serum phosphate levels were observed with INVOKANA. In the pool of four placebo controlled trials, the mean change in serum phosphate levels were 3.6% and 5.1% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to 1.5% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], the mean serum phosphate levels increased by 1.2%, 5.0%, and 9.3% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.

Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-Density Lipoprotein Cholesterol (non-HDL-C): In the pool of four placebo-controlled trials, dose-related increases in LDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with INVOKANA 100 mg and INVOKANA 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups [see Warnings and Precautions].

Dose-related increases in non-HDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with INVOKANA 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups.

Increases in Hemoglobin: In the pool of four placebo-controlled trials, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with INVOKANA 100 mg, and 0.51 g/dL (3.8%) with INVOKANA 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had hemoglobin above the upper limit of normal. drUg InteractIons Ugt enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with INVOKANA (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA 100 mg once daily, have an eGFR greater than 60 mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and require additional glycemic control [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. digoxin: There was an increase in the area AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA 300 mg [see Clinical Pharmacology (12.3) in full Prescribing Information]. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately.

Use In sPecIFIc PoPULatIons Pregnancy: Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies of INVOKANA in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular

I0047B_KINGsizeLaunchAd_FR.indd 5

Active ingredient made in Belgium Finished product manufactured by: Janssen Ortho, LLC Gurabo, PR 00778 Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Licensed from Mitsubishi Tanabe Pharma Corporation © 2013 Janssen Pharmaceuticals, Inc. 10282400 K02CAN13080B

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HD patient/caseload continued from page 1

their patient outcome may be superior.

There are always exceptions and more so among nephrologists.”

The study included 4,073 end-stage renal disease (ESRD) patients on HD who were under the care of 41 nephrologists in Los Angeles County. The nephrologists had caseloads ranging from 50 to 200 patients. The investigators stated that they believe their study is the first of its kind to examine the association between nephrologist caseload and mortality risk in a

New data/CRRT continued from page 1

Critical Care, looked at a prospective cohort of 823 intensive care unit (ICU) patients with either new-onset AKI or pre-existing ESRD. In-hospital mortality was 61% for the new-onset AKI patients and 54% for the ESRD group. Independent risk factors for in-hospital mortality in the AKI group included age over 60 years, serum lactate levels above 4 mmol/L, and comorbid liver disease, which were associated with a 1.9, 2.2, and 1.7 times increased odds of death, respectively. Serum creatinine levels at CRRT initiation above 3 mg/dL were associated with a 37% decreased risk of in-hospital mortality.

Lifetime CKD risk continued from page 1

or higher compared with 6.9% and 7.8% of white men and white women, respectively.

From birth, CKD stage 3a or greater—defined as an estimated glomerular filtration rate below 60 mL/min/1.73 m 2—was predicted to develop in an estimated 59% of the overall U.S. population, Dr. Grams’ group reported. The estimated overall lifetime risk of ESRD from birth was 3.6%. The estimated lifetime risk of CKD stage 3a or higher from birth for white men, white women, black men, and black women was 53.6%, 64.9%, 51.8%, and 63.6%, respectively. The predicted lifetime risk of ESRD for white men, white women, black men, and black women was 3.3%, 2.2%, 8.5%, and 7.8%, respectively.

“Thus, within each race, women had higher lifetime risks of CKD, whereas men had higher risks of ESRD,” the authors wrote.

RUN0913_Cover_Neph_alt.indd 2

large urban population setting in the United States.

“The association between nephrologist caseload and outcomes may have important policy implications given the high prevalence, costs, mortality rate, and health-care burden of ESRD,” the Dr. Kalantar-Zadeh’s team wrote.

First, the researchers noted that, “identifying mechanisms by which increased caseload confers worse outcomes “may provide an opportunity to improve the static morbidity and mortality rates of patients with ESRD.”

Second, declining interest in nephrology as a career among trainees has caused increasing concern about an impending nephrologist shortage. “If these concerns are realized, a nephrologist shortage may exacerbate the associations between high caseload and higher mortality.”

One possible reason for the association between high caseloads and worse outcomes may be the disproportionate burden of comorbid conditions and kidney disease-related complications among HD patients, who routinely undergo specialized procedures requiring complex decision-

making from a multidisciplinary team of providers.

“This population may thus require a substantial amount of individualized management and communication with multidisciplinary team members that may be more difficult to achieve among high-caseload nephrologists.”

Another reason may be that in caring for HD patients, “there may be a caseload threshold above which the benefits of acquiring greater experience and knowledge is outweighed by insufficient time and attention provided to individual patients,” the researchers observed. n

In the ESRD group, only liver disease and admission to a medical rather than surgical ICU were independently associated with increased mortality, which were associated with a 3.4 times and 2.2 times increased odds of mortality, respectively.

The researchers noted the different predictors of mortality in the AKI and ESRD patients likely reflect differences in the clinical processes that lead to CRRT initiation.

After discharge, older age predicted mortality in both groups. In the AKI and ESRD groups, patients older than 60 had a nearly twofold and fourfold increased odds of post-discharge mortality, respectively, compared with younger patients, the researchers commented.

Dr. Schneider’s group analyzed data from 23 studies of dialysis dependence among survivors of severe AKI treated with either CRRT or IRRT. The 23 studies included seven randomized controlled trials (RCTs) that included 472 patients and 16 observational studies that included 3,499 patients. Overall, initial treatment with IRRT was associated with a 1.7 times increased relative risk for dialysis dependence compared with CRRT. Pooled analyses of the RCTs demonstrated no significant difference in dialysis dependent rates between the modalities, but pooled analyses of the observational studies showed that patients who initially received IRRT had a twofold increased risk of dialysis dependence compared with

CRRT, according an online report in Intensive Care Medicine. The investigators acknowledged that the observational studies “might be associated with allocation bias and given the human and public health implications of these findings, large studies focusing on renal recovery after AKI according to choice of RRT are needed to fully understand the effects of initial modality choice on subsequent dialysis dependence.”

“Patients with ESRD should not be inherently considered poor candidates for CRRT when compared to those with AKI,” the authors concluded. “The vast majority of patients with AKI who receive CRRT will not achieve long-term dialysisfree survival.” n

The study, published in the American Journal of Kidney Diseases (2013;62:253260), showed that CKD risk increased with age, with half the CKD stage 3a or higher cases developing after age 70.

ensure every patient with kidney disease receives optimal care.”

Dr. Grams’s group analyzed annual probabilities of death for the U.S. population by age, gender, and race using the National Vital Statistics Report.

They estimated CKD prevalence using data from the National Health and Nutrition Examination Survey (NHANES), a population-level survey of community-dwelling U.S. civilians conducted by the National Center for Health Statistics. The study population was limited to individuals aged 20 years and older who had serum creatinine, urine albumin, and urine creatinine values available.

In an editorial accompanying the new report, Raymond K. Hsu, MD, and Chi-yuan Hsu, MD, of the University of California San Francisco, pointed out that the data used by Dr. Grams and colleagues “are a decade old or older by now.” More recent NHANES data reveal no change in CKD prevalence during the past 10 years, Drs. Hsu and Hsu noted. The prevalence of CKD

stages 3-4 was 8.1% in 2001-2002, 7.7% in 2003-2004, 8.1% in 2005-2006, 8.0% in 2007-2998, and 7.8% in 2009-2010.

Additionally, they observed that the prevalence of early stage CKD has not increased in the last decade.

“It is easy to assume that as a result of CKD risk factors such as older age and diabetes mellitus becoming more common, CKD must have become more prevalent,” the editorial stated.

“However, this is not necessarily true because medical treatment also has advanced considerably in the past several decades.”

For example, large strides have been made in glycemic control, which has been shown to reduce the risk of incident CKD, according to the editorial.

Drs. Hsu and Hsu also pointed out that the U.S. Renal Data System “has consistently reported that the incidence of ESRD in the United States has reached a plateau in many groups during the past decade, in contrast to the rapid increase seen in the 1980s and 1990s.” n

CKD stage 3 or worse will develop in an estimated 59% of those born today.

Commenting on the new study, Beth Piraino, MD, President of the National Kidney Foundation, observed that the new findings “show clearly that Americans are more likely than not to develop kidney disease.”

“Importantly, if caught early, the progression of kidney disease can be slowed with lifestyle changes and medications,” Dr. Piraino said. “This underscores the importance of annual screenings, especially the at-risk population, to potentially prevent kidney disease and

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Metformin/PCa continued from page 1

of metformin use was associated with a significant 24% decreased risk for PCa-specific mortality after adjusting for potential confounders. The association with all-cause mortality also was significant, but declined over time from a 24% decreased risk in the first six months to a 7% decreased risk between 24 and 30 months.

In a discussion of the clinical implications of their findings, Dr. Margel’s group stated that, consistent with current guidelines, metformin should be considered first-line therapy for patients with PCa and diabetes, both for diabetes control and possibly to improve PCa prognosis.

The study, which was published online ahead of print in the Journal of Clinical Oncology, demonstrated no association between cumulative use of other antidiabetic drugs and either PCa-specific or all-cause mortality.

The MSKCC study, which was conducted by Daniel E. Spratt, MD, and

Heavy smoking continued from page 1

Medicine, Northwestern University, Chicago, Rick A. Kittles, PhD, of the University of Illinois at Chicago, and colleagues included 1,085 men, of whom 527 had PCa (cases) and 558 did not (controls). Heavy smoking was less prevalent among AAs than EAs (21% vs. 30.5%).

“Consistent with the smoking literature, we confirm that there is higher prevalence of smoking and lower prevalence rates of heavy smoking in AAs relative to EAs,” the authors con-

associates, included 2,901 patients who had a median follow-up of 8.7 years. The 10-year PCa-specific mortality actuarial rates were 2.7% among the 157 diabetics taking metformin compared with 21.9% and 8.2% for the 162 diabetics not taking metformin and 2,582 non-diabetic controls, respectively. Compared with the diabetic non-metformin group, the metformin users were twice as likely to be alive without PSA recurrence and 3.7 times as likely to be alive and free of distant metastases, according to a report in European Urology (2013;63:709-716).

Metformin users were 5.1 times less likely die from PCa. In addition, metformin use was independently and significantly associated with a nearly 15-fold decreased likelihood of the development of castration-resistant PCa in patients experiencing biochemical failure.

The Mayo Clinic study, which was led by R. Jeffrey Karnes, MD, included 12,052 RP patients, of whom 885 were diabetic (7.3%). Among the diabetics, 323 were taking metformin and 562 were not. After a median follow-up of 5.1 years, the researchers found no signifi-

cant association between metformin use and the risk of biochemical recurrence, systemic progression, or all-cause mortality, the researchers reported online ahead of print in Urologic Oncology. The researchers also found no significant association between metformin use and final pathologic Gleason score, disease stage, rate of positive surgical margins, or tumor volume.

“When these results are viewed in the context of the existing data on risk prevention of prostate cancer,” Dr. Karnes’ team wrote, “it appears that metformin may play a role in early stages of prostate cancer; however, our data do not shown an effect in established cases.”

The Italian meta-analysis, which was published online in PLoS One (2013;2:8:e71583), included two randomized controlled trials (RCTs) and eight observational studies that evaluated the association of metformin therapy on PCa. Both the RCTs and observational studies showed that metformin use had no effect on PCa risk. n

In-Hospital Complications Common After Cystectomy In-hospital complications are common among urinary bladder cancer (UBC) patients treated with radical cystectomy, according to a study published online in BJU International.

Mieke van Hemelrijck, PhD, of the King’s College London School of Medicine, and colleagues studied 7,608 patients who underwent radical cystectomy in Sweden from 1964 to 2008.

Urinary tract infection (UTI)/ septicemia was the most common complication with an incidence of 127.3 episodes per 1,000 person years overall. The highest incidence was among patients with an orthotopic neobladder (139.62 episodes

cluded. “Despite these differences, we find no evidence for cigarette smoking increasing the odds of being diagnosed with prostate cancer in EA men, but are associated with prostate cancer diagnosis and high-grade disease among AA men.”

Dr. Murphy pointed out some differences in smoking habits between AAs and EAs from other studies. AA men have higher plasma nicotine and metabolites than EA men even though both groups smoke the same average number of cigarettes per day, they noted. AA men have greater nicotine exposure per cigarette. This has been

attributed to differences in tobacco-use behavior, including a high prevalence of menthol cigarette use, “which may confer deeper inhalation of nicotine and tobacco toxins and be associated with increased nicotine dependence.”

Additionally, nicotine binds to melanin and can lead to prolonged clearance of nicotine in AA men.

Various pathways have been proposed for cigarette smoking to promote PCa tumorigenesis and progression, including an increase in bioavailable serum androgens and decrease in estradiol associated with cigarette smoking. n

per 1,000 person years). UTI/septicemia was 11% and 21% more likely with continent cutaneous reservoir, and orthotopic neobladder, respectively, than with ileal conduit, according to the researchers.

Kidney failure and bowel obstruction were the second and third most common complication, respectively, with an incidence of 53.15 and 50.78 episodes per 1,000 person years. Kidney failure was 19% less likely with orthotopic neobladder thanwith ileal conduit. Bowel obstruction was 36% less likely with orthotopic neobladder that with

Kidney stones-CHD continued from page 1

Study I (NHS I), which enrolled 90,235 women aged 30-55; the Nurses’ Health Study II (NHS II), which enrolled 106,122 women aged 22-42 years); and the Health Professionals Follow-up Study (HPFS), which enrolled 45,748 men aged 40-75 years.

Of a total of 242,105 subjects, 19,678 reported a history of kidney stones.

After up to 18 years of follow-up in women and 24 years in men, 16,838 CHD cases developed. Among women in NHS I, those with a history of kidney stones had a significant 18% higher risk of CHD than women without a history of kidney stones, after adjust-

RUN0913_Cover_Uro.indd 3

ing for potential confounders, the investigators reported in the Journal of the American Medical Association (2013;310:408-415). Among women in NHS II, a history of kidney stones was associated with a significant 48% increased risk of CHD. The researchers found no association between kidney stone history and CHD in men.

For the study, Dr. Ferraro’s group defined CHD as fatal or nonfatal myocardial infarction or coronary revascularization. CHD was identified by biennial questionaire and confirmed by a review of medical records.

The study by Dr. Ando’s team, which was published in The Journal of Urology (2013;189:1340-1346), included 13,418 men aged 30-69 who

voluntarily underwent medical examination from April 1995 to March 2001. The investigators divided subjects into controls and past and current kidney stone formers based on ultrasound results and medical history. Of the 13,418 men, 404 current kidney stone formers (3.0%) had kidney stones on ultrasound examination, 1,231 past kidney stone formers (9.2%) had no kidney stones on medical examination, and the remaining 11,783 (87.8%) patients had no history of kidney stones. The researchers found that body mass index, systolic and diastolic blood pressure, and serum uric acid were significantly higher in past and current stone formers than in controls. n

ileal conduit.

In addition, patients faced different complication risks depending on their diversion type. Patients treated with an ileal conduit were associated with a greater risk of bowel obstruction, but a lower risk of other complications compared to other diversions such as orthopedic neobladder.

The authors noted that their study was unique in that it looked at a patient population across 40 years of data, allowing for comparisons between different complications to be made across diversion types and creating a broader understanding of radical cystectomy complications. n

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High Uric Acid An Unlikely IHD Cause No association found between a genetic marker for elevated uric acid and ischemic heart disease Elevated uric acid levels are associated with increased risk of ischemic heart disease (IHD) and blood pressure, but appear unlikely to cause these problems, a study found.

The study, which was published online in the British Medical Journal, also demonstrated that increases in body mass index (BMI) are likely to contribute to rises in uric acid, and— given the known causal relationships between BMI and cardiovascular outcomes—to confound the relationship between uric acid and cardiovascular outcomes.

Nicholas J. Timpson, PhD, of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol in Bristol, U.K. and colleagues used measured uric acid levels and related covariables in 58,072 participants in the Copenhagen General Population Study and 10,602 in the Copenhagen City Heart Study. In these study populations,

Tadalafil Improves BPH/LUTS Tadalafil, a phosphodiesterase type 5 inhibitor approved for treated erectile dysfunction is effective for easing lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH), according to the findings of a meta-analysis published in Urologia Internationalis (2013;91:10-18).

Chinese investigators analyzed data from eight randomized controlled trials that enrolled a total of 2,913 men (1,871 tadalafiltreated patients and 1,042 placebo

the researchers identified 4,890 and 2,282 cases of IHD, respectively.

To determine whether uric acid was causally associated with IHD, Dr. Timpson’s team conducted Mendelian randomization analyses using a variation at a specific gene—the rs7442295 single nucleotide polymorphism in the SLC2A9 gene—to act as a proxy measure for this risk factor. This gene variation is known to be strongly associated with increased plasma levels of uric acid, hyperuricemia, urate excretion, and gout.

Observationally, each standard deviation increase in plasma uric acid level was associated with a 55% and 34% increased odds of IDH in the Copenhagen General Population Study, and Copenhagen City Heart Study, respectively. In a pooled analysis, the risk was increased by 49%, which was attenuated to 21% after adjusting for age, gender, smoking, educational attainment, and income. The research-

ers observed a similar pattern with hyperuricemia.

In addition, each standard deviation increase in uric acid level was associated with a 2.42 mm Hg elevation in diastolic blood pressure, according to the researchers. This was attenuated to 1.56 mm in adjusted analyses.

Subjects with hyperuricemia had an

Body mass index has a causal effect on uric acid levels, study shows. average increase of 4.61 mm Hg in diastolic pressure, which was attenuated to 2.66 mm Hg in adjusted analyses. The investigators observed a similar pattern between uric and hyperuricemia and systolic blood pressure.

Mendelian randomization revealed

no association between variation at SLC2A9 (rs7442295) and IHD or either diastolic or systolic blood pressure in either cohort. Furthermore, Mendelian randomization showed that BMI has a causal effect on uric acid level, but not the other way around. Each fourunit increment in BMI caused a 0.03 mmol/L increase in uric acid level and a 7.5% increase in the risk of hyperuricemia, the study found.

According to the investigators, their findings strongly suggest that BMI is a confounder in the observed associations between uric acid and IHD and blood pressure. The findings also suggest a role for elevated BMI or obesity in the development of uric acid-related conditions.

Dr. Timpson and his collaborators concluded that their findings “suggest that interventions to reduce body mass index could help improve management of gout and related conditions such as urolithiasis.” n

RCC Common in ADPKD Patients Patients with autosomal dominant polycystic kidney disease (ADPKD) have a “surprisingly high” prevalence of renal cell carcinoma (RCC), researchers reported online ahead of print in Nephron Clinical Practice.

Cordula Jilg, MD, of Albert Ludwigs University in Freiburg, Germany, and colleagues conducted a retrospective analysis of patients diagnosed with renal neoplasias from 1988 to 2011.

They identified 240 ADPKD patients who had undergone 301 renal surgeries at the University Medical Centre Freiburg. They found malignant or

benign lesions in 17 patients, of whom 10 had dialysis over a mean 43 months prior to surgery. Sixteen malignant renal lesions were found in 12 of these patients. Of the 12, eight had undergone dialysis prior to surgery.

The 16 malignant lesions included 10 (63%) papillary RCC, five (31%) clear cell RCC, and one (6%) papillary noninvasive urothelial cancer.

The researchers said the kidneyrelated prevalence of RCC in ADPKD kidneys was “surprisingly high.”

“Whether or not this is due to chronic dialysis or due to the underlying disease is still speculative,” they wrote.

Like other cystic renal diseases with an increased risk for RCC, the attending physician should be aware of the malignant potential of ADPKD, especially with concomitant dialysis.”

Previous studies have shown that patients on long-term dialysis experience a higher average annual incidence of RCC than the general population, Dr. Jilg’s team noted. They pointed out that 10 of the 17 patients with malignant or benign lesions had dialysis over a mean 43 months, so “the effect of chronic dialysis on increased prevalence of RCC in those kidneys is undoubtedly present in our cohort.” n

PSA Levels May Predict Hypogonadism

recipients). Compared with placebo, tadalafil was associated with significant improvements in International Prostate Symptom Score and International Index of Erectile Function score in men suffering from BPH/LUTS with and without concomitant erectile dysfunction. n

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PSA is a marker of testosterone concentration and may offer a new way to confirm hypogonadism, according to Italian investigators.

A team led by Mario Maggi, MD, of the University of Florence, studied 2,967 men attending a sexual dysfunction unit and who had PSA levels below 4 ng/mL and no history of prostate dis-

ease. Their analysis showed that PSA levels predicted severe hypogonadism (testosterone levels below 8 nmol/L), with PSA levels below 0.65 ng/mL providing the best sensitivity and specificity (65.2% and 55.5%, respectively), the researchers reported online in The Journal of Sexual Medicine. Of the entire cohort, 254 men (8.6%) had

severe hypogonadism, and 141 of them had a PSA level below 0.65 ng/mL. After adjusting for age, low PSA was associated with hypogonadism-related features, such as delayed puberty and lower testis volume, and associated conditions, such as metabolic syndrome, type 2 diabetes, and cardiovascular diseases. n

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Nephropathy Not Driven by Ethnicity In a study, South-Asian and white European diabetics showed similar declines in eGFR over five years

BY JILL STEIN ISTANBUL –Contrary to a widely held view, South-Asian and white European diabetic patients with moderately reduced kidney function have essentially the same rate of nephropathy progression, according to study findings reported at the 50th Congress of the European Renal Association-European Dialysis and Transplant Association.

“The standard wisdom based on several earlier reports is that nephropathy progresses at a faster rate in South-Asian diabetic patients than in their white European counterparts,” said Hugh C. Rayner, MD, consultant nephrologist at Heart of England National Health Service (NHS) Foundation Trust in Birmingham, U.K. The data showed that despite having worse glycemic control, South-Asian patients with diabetes and chronic kidney disease stage 3 did not differ from white European patients in the rate of decline in estimated glomerular filtra-

Prophylaxis Regimen Ups AKI Risk

BY JILL STEIN ISTANBUL—Replacing cefuroxime for the prevention of wound infections after orthopedic surgery with singledose gentamicin plus standard-dose flucloxacillin appears to increase the rate of acute kidney injury (AKI), researchers announced at the 50th Congress of the European Renal AssociationEuropean Dialysis and Transplant Association.

“It’s surprising that a single dose of gentamicin is nephrotoxic, as it is generally believed that multiple doses are required for nephrotoxicity,” said Samira Bell, MD, consultant nephrologist at Ninewells Hospital in Dundee, Scotland. Flucloxacillin can cause acute interstitial nephritis leading to AKI, but this is not commonly observed.

Dr. Bell and colleagues compared post-operative AKI rates in the two years before and the two years after her institution implemented a policy switch for antibiotic prophylaxis in patients having orthopedic implant surgery. The analysis included 7,698 patients who

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tion rate (eGFR) over a five-year followup period.

“We are trying to reduce inequalities in health between different parts of our population, and we wanted to make sure that kidney treatment was not worse for South-Asian patients than for white European patients,” Dr. Rayner commented. “From our data, it seems that we can achieve the same outcomes for the two ethnic groups, and we find that reassuring.”

The study included patients with diabetes who had attended a diabetes or renal outpatient clinic with eGFR values of 30 mL/min/1.73 m2 or higher but less than 60 mL/min/1.73 m2 from January 2001 through December 2005.

About three quarters of the 1,012 study participants were white European, and the remaining subjects were SouthAsian (from the Indian subcontinent).

The researchers observed no difference in baseline eGFR between SouthAsian and white European patients

had their surgery from October 2006 to October 2010.

Overall, post-operative AKI—as defined according to Acute Kidney Injury Network (AKIN) criteria— developed in 767 patients in their cohort. The incidence of stage 1 AKI increased from 4.3% before the antibiotic policy change to 7.6% afterwards. The incidence of stage 2 AKI increased from 0.4% to 1.1%, and the incidence of stage 3 AKI increased from 0.2% to 1%.

The significant association between the prophylactic antibiotic regimen and the subsequent development of AKI was maintained after controlling for potential confounders, including gender, age, and use of nephrotoxic drugs.

The researchers observed no change in AKI among patients with fractured neck of femur group who received prophylactic amoxicilllin/clavulanic acid throughout the study period.

Based on the results, Ninewells Hospital has discontinued the use of prophylactic gentamicin and flucloxacillin for patients undergoing orthopedic surgery in favor of amoxicillin/clavulanic acid. All hospitals in Scotland have since followed suit except for one institution, which continues to favor gentamicin/ flucolxacillin prophylaxis. n

Hugh C. Rayner, MD

(median of 49.7 and 51.7 mL/min/ 1.73 m2, respectively).

South-Asian patients were younger than white European patients (68 vs. 70 years) and had worse baseline glycemic control as indicated by lower hemoglobin (Hb) A1C level (8.0% vs. 7.6%).

After five years, eGFR was a mean of 46.8 mL/min/1.73 m2 in South-Asian patients and 45.9 mL/min/1.73 m2 in white European patients. In addition, the mean change in eGFR over the study period was -2.9 and -3.2 mL/min/1.73 m2 for the two groups, respectively.

Overall, 35 (12.4%) patients in the South-Asian group and 82 (9.2%) patients in the white European group progressed to stage 4 or 5 CKD. The data showed a trend towards higher fiveyear follow-up HbA1c levels in SouthAsian than in white European patients.

Dr. Rayner said that the findings bolster prior research showing that glycemic control is not the main determinant of the rate of progression of kidney disease in diabetic patients with moderately reduced renal function. The main reversible factor that influences the progression of diabetic nephropathy is blood pressure (BP), but the link between BP control and progression was not examined in this study. n

Renal Denervation Works Despite Multiple Arteries

BY JILL STEIN

determined to be suitable because at

ISTANBUL—The presence of multiple

least one of their renal arteries was

renal arteries probably does not justify

greater than 4 mm in diameter and

excluding patients with treatment-

greater than 20 mm in length.”

resistant hypertension from undergo-

Dr. Vink presented six-month results

ing catheter-based renal sympathetic

from 40 patients with solitary renal

denervation, Dutch investigators

arteries and 16 patients with multiple

reported at the 50th Congress of the

renal arteries who underwent renal

European Renal Association-European

denervation. Study participants had an

Dialysis and Transplant Association.

office systolic blood pressure (BP) of

“Treatment-resistant hypertensive

160 mm Hg or higher and stable use of

patients with more than one renal

three or more three antihypertensive

artery in either kidney have been

medications. In all patients, secondary

deemed ineligible for renal denerva-

forms of hypertension and white coat

tion out of concern that the procedure

hypertension had been excluded. The

might be less effective and less safe in

main outcome measure was office BP

this population,” said Eva E. Vink, MD,

at six months.

who is studying renal denervation as

At six-months, mean office BP had

part of a PhD project in the department

decreased in the entire group from

of nephrology of the University Medical

202 mm Hg at baseline to 171 mm Hg

Center in Utrecht, The Netherlands.

at six months. The mean change in

“However, we found good blood

systolic BP was similar in the two

pressure-lowering results at six months

groups (-33 mm Hg for solitary

with renal denervation in patients with

arteries and -29 mm Hg for the group

multiple renal arteries whom we had

with multiple arteries). n

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Renal & Urology News 19

Large Study Characterizes ED and Its Risk Factors Increasing AGE, diabetes, high body mass index (BMI), and current smoking are among the risk factors for erectile dysfunction (ED), according to a large study of men living in New South Wales (NSW), Australia.

The study, published in the Medical Journal of Australia (2013;199:107-111), “confirms the importance of a number of risk factors for ED that are potentially modifiable, and that may be associated with other longer lasting health benefits,” researchers concluded.

Marianne F. Weber, PhD, of Cancer Council NSW in Sydney, and colleagues studied 101,674 men aged 45 years and older who had reported no prior diagnosis of prostate cancer.

Of these, 39.3% had no ED, 25.1% had mild ED (experienced ED sometimes), 18.79% had moderate ED (usually experienced ED), and 16.8% had complete ED. After adjusting for sociodemographic characteristics, the odds of moderate/complete ED increased sig-

increased risk of moderate or complete ED than those who were not.

Moderate alcohol consumption was associated with a significantly reduced risk of ED among men aged 45-54 years, but not older men, according to the investigators. The study also found that low education and low household income was

linkd to increased odds of moderate/complete ED. Compared with men who had a university degree or higher, those who no educational qualifications had a significant 56% increased odds. Compared with men whose pretax annual household income was at least $50,000, those whose income was $20,000-$49,999

and $19,000 or less had a 39% and 85% increased odds of moderate/complete ED, respectively. “This report provides a comprehensive picture of how the prevalence of ED and its risk factors differ across men of different ages and is by far the largest analysis of ED to date,” the authors said. n

WE’RE

CHANGING THE WAY

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

Diabetes, high BMI, and smoking are associated with erectile dysfunction.

When it comes to treating prostate cancer, we do not believe in a one-size-fits-all approach. That’s why doctors at UPMC are experts in both traditional methods of urologic surgery and in cutting-edge robotic surgery. But our doctors also recognize

nificantly by 11.3% each year beginning at age 45. The prevalence of moderate/complete ED was 82% among men aged 75 and older.

In a fully adjusted model, diabetes was associated with a significant 2.4 times increased odds of moderate/ complete ED compared with the absence of diabetes.

Compared with normal-weight men (BMI of at least 18.5 but less than 25 kg/m2), obese men with a BMI of at least 35 but less than 40 and those with a BMI of 40 or higher had a 2.2 times and 3.2 times increased risk, respectively. The risk of moderate/ complete ED increased with increasing BMI for all age groups except for men aged 75 and older.

Subjects who smoked 20 or more cigarettes per day had a significant 86% increased risk of moderate/ complete ED compared with men who never smoked. Past smokers had a 26% increased risk compared with those who never smoked.

Additionally, patients treated for depression or anxiety or both in the past month had a significant twofold

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

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

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Drugs May Boost Provenge’s Benefits Sipuleucel-T (Provenge), the only FDA-approved cancer vaccine, has been shown to prolong the lives of men with asymptomatic or minimally symptomatic metastatic, hormone-resistant prostate cancer by a median of 4.1 months. Samir N. Khleif, MD, Director of the Georgia Regents University Cancer Center in Augusta, Ga., is leading a pilot study to explore ways to increase the vaccine’s survival benefit. He spoke with Renal & Urology News about the effort.

Why is your research focused on Provenge?

Dr.Khleif: It’s not the Provenge itself.

We found in the lab that if we combined therapeutic cancer vaccines with agents that enhance the immune system by inhibiting the inhibitory mechanism of the tumor, such as cyclophosphamide and the anti-PD-1 antibody CT-011, we can improve the effects of these vaccines.

Since Provenge is the only therapeutic cancer vaccine that’s approved for use by the FDA—and because of its proven efficacy in prostate cancer patients—this was the most obvious choice. In this case we’re combining standard therapy with the agents in the clinical trial.

Why are you using cyclophosphamide/ CT-011 in combination with Provenge?

Dr.Khleif: Because of what we found in preclinical experiments. Provenge is a vaccine that enhances the immune system specifically against prostate cancer.

However, cancers have developed very effective mechanisms to inhibit the immune system. What we do in our lab is to understand these mechanisms and develop strategies to break the mechanisms by which tumors inhibit the immune system, so we can make the specific immune response that is created by the vaccine work better.

The tumor expresses a molecule called PDL-1, which binds to receptors

On The Web RUN0913_QA.indd 1

on T-cells and prevents T-cells from attacking tumor cells, which is one of these mechanisms by which tumors inhibit the immune system. Anti-PD-1 (CT-011) prevents the tumor’s PDL-1 from binding to the T-cell PD-1 receptor. It is already in use in clinical trials as a single agent or in combination with other therapies.

The cyclophosphamide works on another mechanism by which tumors inhibit the immune system: It decreases suppressor T-cells, which inhibit the immune system from acting against the tumor.

So in the lab we combined therapeutic vaccines plus these two agents, and we found that they highly enhance the effect of the cancer vaccine. Based on that, we combined Provenge as the cancer vaccine, since it is approved by the FDA and works on prostate cancer, with CT-011 and cyclophosphamide, to test if we could enhance Provenge’s efficacy in patients with prostate cancer. We hope that the combination will increase the positive effect of Provenge by increasing its positive survival effect.

How many arms will the study have?

Dr.Khleif: There will be three arms: One will be Provenge alone, one will be Provenge plus the CT-011, and one will be the combination Provenge, CT-011 and cyclophosphamide. We’ll follow patients for a couple of years.

You plan on enrolling 63 men in the study. What are the eligibility criteria?

Dr.Khleif: We follow the same criteria that the FDA approved Provenge for: prostate cancer patients who have progressive, hormone-resistant disease that is minimally symptomatic.

Of course, there are other criteria, but this is the main one. As long as men are eligible to use Provenge, they can contact us about the trial.

Will you look at whether Provenge should possibly start being used earlier in the course of disease?

Dr.Khleif: That is not part of the trial.

If your trial does show an extended survival benefit beyond the already established median of 4.1 months, do you think the universe of men who use Provenge, a costly therapy, will expand?

Dr.Khleif: This is a phase 2 clinical trial.

The intention is to determine feasibility and immunologic responses.

Survival is a secondary endpoint.

Accordingly, it will not answer the question definitively but will provide

data to build on for a phase 3 study to address the survival question.

If your trial proves successful, will your findings make the decision easier?

Dr.Khleif: What we’re hoping to do with this clinical trial is to enhance the currently available standard therapy, which is the only therapeutic cancer vaccine available for patients.

And our goal is actually to see how we can enhance an available therapy for patients who otherwise don’t have many therapeutic options. This hopefully will provide prostate cancer patients with more and better options to choose from.

Would the addition of CT-011 and cyclophosphamide substantially drive up the costs of Provenge?

Dr.Khleif: I am not qualified to answer this question. Having said that, cyclophosphamide is a very inexpensive drug. It costs less than few dollars.

But in general, the cost of drugs usually decreases with time because of enhancement in technology and because more people will be using it.

Our goal as scientists is to improve therapies based on new discoveries. So, it’s very difficult to predict what might happen to the costs.

Will we start seeing more therapeutic vaccines as a result of your research?

Dr.Khleif: There are lots of therapeutic vaccines coming closer and closer to market. Our study will show that a therapeutic vaccine plus this combination [of CT-011 and cyclophosphamide] might be better than giving the vaccine as a single agent.

What role will Provenge manufacturer Dendreon have in your study?

“Our goal...is to improve therapies based on new discoveries.” ­—Samir N. Khleif, MD

Dr.Khleif: Dendreon is not sponsoring the drugs, but the company is providing a grant to conduct immunologic testing and to cover some of the costs of patient care. n For study enrollment information, call 888-658-0422, or visit www. ge o rgi a he a l th.ed u/c a n c e r/t r i a l s (Genitourinary/11-C-0231).

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

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Men’s Health Update Short Takes Circumcision Prevents UTIs Long-Term The protection offered by circumcision against urinary tract infections (UTIs) in infancy has been well documented and emphasized in the most recent recommendations for circumcision by the American Academy of Pediatrics.

A recent meta-analysis published in The Journal of Urology (2013;189:21182124) by Brian J. Morris, DSc, and Thomas E. Wiswell, MD, of the University of Sydney in Australia, showed that the protective effect of circumcision lasts throughout a lifetime. Uncircumcised infants had a nearly 10-fold increased relative risk of UTIs compared with circumcised infants. The lifetime risk of UTI was 32% in uncircumcised males and only 8.8% in circumcised males.

Considering the cost of hospitalization for UTIs and the potential for renal scarring associated with severe infections, these findings suggest that the benefits of circumcision in preventing infection are comparable the effects of other public health measures such as viral vaccines.

Infertile Men Have More Mental Health Issues Infertility has dramatic effects on the emotional well-being of many individuals and couples. Several studies have demonstrated a correlation with decreased sexual satisfaction and increased incidence of sexual dysfunction such as premature ejaculation (PE) and erectile dysfunction (ED). Additionally, men with male factor infertility have routinely scored lower on quality-of-life questionnaires.

A new study published in the Journal of Sexual Medicine (2013;10:1935-1942) is the first to systematically evaluate the association between male factor infertility and the incidence of sexual dysfunction and psychological burden in China. Anxiety and depression were more prevalent in the infertile (38% vs. 26% and 16% vs. 10%, respectively). As expected, the incidence of both PE and ED was significantly higher in the infertility group compared with the fertility group (19% vs. 10%). Additionally, both PE and ED were associated with both anxiety and depression.

Hematospermia: A Long List of Possible Causes Hematospermia, or blood in the semen, can be quite alarming to many patients. It can be caused by many conditions of the male genitourinary system, but it is most commonly benign and resolves without treatment.

The most common cause is prostate biopsy, although the list of other possible offenders is lengthy. It may be the result of benign or malignant tumors of the prostate, bladder, testes, or seminal vesicles, as well as sexually transmitted

BY JAIME LANDMAN, MD and ADAM KAPLAN, MD, of the ­

University of California Irvine, Department of Urology

Hypogonadism Linked to Anabolic Steroid Use P

rior use of anabolic androgenic steroids (AAS) is common among young men seeking treatment for symptomatic hypogonadism, according to study findings reported online in The Journal of Urology. The study also found that anabolic steroid-induced hypogonadism is the most common etiology of profound hypogonadism.

Larry Lipshultz, MD, and colleagues at the Baylor College of Medicine in Houston, reviewed data on 6,033 patients seeking treatment for hypogonadism from 2005 to 2010. They identified profound hypogonadism (testosterone level of 50 ng/dL or less) in 97 patients (1.6%).

The most common etiology was prior use of AAS, which the investigators identified in 42 (43%) patients. Dr. Lipshultz’s group conducted a follow-up anonymous survey of their current hypogonadal patient population (383 patients with a mean age of 49 years) undergoing testosterone replacement therapy. Of these patients, 80 (20.9%) had prior AAS exposure. These men had a mean age of 40 years. © thinkstock

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

Phytoestrogens Lower Hypospadias Risk H

igher intake of phytoestrogens by expectant mothers is associated with a reduced risk of delivering infants with hypospadias. In a study, mothers whose daily total phytoestrogen intake was in the 90th percentile or higher had a 30% decreased risk of having a child with hypospadias compared with mothers in the 11th to 89th percentile of total intake in adjusted analyses. High intake of some specific phytoestrogens, such as daidzein, genistein, glycetin, and secoisolariciresinol, as well as total isoflavones, and total lignans also were associated with a reduced risk of hypospadias. Lower intake of phytoestrogens, however, did not increase the risk of giving birth to a son with hypospadias. The researchers, led by Suzan Carmichael, PhD, of Stanford University in Palo Alto, Calif., reported their findings online in the American Journal of Epidemiology, where they noted that their study is the first large-scale analysis of phytoestrogen intake and hypospadias.

Hypogonadal men younger than 50 years were more than 10 times as likely as men older than 50 to have prior AAS exposure.

infections, inflammatory conditions of the prostate, epididymis, or urethra.

Hematospermia also could result from stones in the seminal vesicles or in the seminal vesicles.

The diagnostic workup most commonly includes urinalysis, cultures for sexually transmitted infection, imaging studies such as ultrasound or magnetic resonance imaging, and semen analysis in certain situations. Treatment is directed towards the underlying cause, if found. One quarter of hematospermia patients have prostatitis and they may benefit from antibiotic treatment. For most patients, however, hematospermia is not associated with any obvious cause.

No treatment is given in those cases, and it typically resolves on its own.

RUN0913_MensHealth.indd 1

medistat

prostate, urethral polyps, ejaculatory duct obstruction, or other abnormalities

26.8

The percent of adult men (aged 18 and older) who reported low back pain during the past three months

Source: National Center for Health Statistics. Health, United States, 2012.

8/21/13 12:54 PM

www.renalandurologynews.com SEPTEMBER 2013

Survival Benefit of Intensive Hemodialysis Challenged Researcher cites what he considers limitations of recent cohort studies. with just three or four nights a week of home HD. In the next study, which was published in the same journal (2012;23:895904), 1,873 short daily HD (SDHD) patients were matched 1:5 to 9,365 conventional-HD patients in the U.S. Renal Data System (USRDS) database.

Only 34% of the patients were matched on all 17 variables that were examined by the investigators, despite their hav-

© science source / life in view

BY ROSEMARY FREI, MSc A researcher has provided important perspective on the findings of three key studies purporting to show intensive hemodialysis (HD) is associated with improved survival compared with standard HD. “These high-profile studies will be much-cited but provide little true intrinsic value to addressing the mortality differences between intensive and conven-

Various studies have purported to show better survival rates with intensive HD.

tional hemodialysis,” Robert Pauly, MD, MSc, Associate Professor of Medicine at the University of Alberta in Edmonton, told attendees of the Canadian Society of Nephrology’s 2013 annual meeting, in an attempt to provoke deeper consideration into this topic.

One study analyzed data from 338 patients in the French-AmericanCanadian International Quotidian Dialysis Registry (IQRD) database and retrospective information from the Dialysis Outcomes and Practice Patterns Study (DOPPS), which was published in the Journal of the American Society of Nephrology (2012;23:696-705). The patients who underwent conventional dialysis were propensity-score-matched to patients who were prescribed nocturnal home HD. The researchers concluded that survival rates are 45% higher with intensive than conventional treatment, and the positive effect is achieved even

RUN0913_CSN2.indd 1

ing a population of more than 600,000 patients to choose from in the USRDS database. The investigators found that SDHD is associated with a 13% higher survival rate. Sensitivity and subgroup analyses did not significantly change this result.

The third study focused on 318 IQRD SDHD patients who were matched to 575 DOPPS conventionaldialysis patients. This time, SDHD appeared to be worse, yielding 1.6 times more deaths per patient-year than conventional HD, at 15.6 and 10.9, respectively, according to findings published in Kidney International (2013;83:300-307).

“Do these studies help us?” Dr. Pauly queried. “What are the concerns with these studies, and why might it be reasonable to be skeptical of all three?”

Among the major limitations, he pointed out, is the studies were not prospective, they had different defini-

tions of the variables involved, and the databases they used do not completely capture all the relevant information.

Furthermore, although DOPPS and USRDS prospectively collect data, the IQRD has many data sources and there is “unknown data integrity and internal consistency [within it],” Dr. Pauly pointed out. “[In addition,] the lack of matching on some important variables could not be performed in any of the three studies, nor is there an indication of whether the patients actually performed the dialysis they were prescribed.”

According to Dr. Pauly, there are fundamental reasons why patients self-select to undergo home HD or are referred for intensive in-center HD, and it is difficult if not impossible to match non-intensive-dialysis patients for these characteristics. For example, patients who dialyze themselves at home are highly motivated to maintain this independence, and this critical— yet abstract—characteristic of these patients cannot be matched for. In addition, there are likely other significant residual confounders that were not taken into account, such as the severity of comorbidities. “Comorbidity does not have an on/off switch, so the degree of dysfunction may be important,” Dr. Pauly stated.

All of these factors could, in theory, explain much, if not all, of the effects found in the studies, he concluded.

What is needed to fill the void is a single-data source and a large, prospective, carefully designed study with special consideration given to transplant eligibility, vascular access, time to end-stage renal disease before dialysis initiation, and severity of comorbidities.

Although Dr. Pauly is a strong advocate for intensive home HD, he concluded by stating: “At the end of the day, survival is only one of the crucial elements to consider. Patients are more likely to consider the quality of life trade-offs with intensive dialysis, and healthcare providers must consider the costs of administering these therapies too; and, on both accounts the scales may tip in favor of intensive home hemodialysis, irrespective of what the survival studies show.” n

Renal & Urology News 23

Coffee May Increase LUTS Risk Drinking caffeinated beverages may contribute to the development of lower urinary tract symptoms (LUTS) in both men and women, according to a new report. LUTS may be less likely to develop in men who drink citrus juice.

Nancy N. Maserejian, ScD, of New England Research Institutes in Watertown, Mass., and colleagues analyzed data from 4,145 individuals who are part of the Boston Area Community Health cohort. Men who reported drinking more than two cups of coffee per day at baseline had a significant twofold increased likelihood of LUTS onset compared with those who reported drinking no coffee, Dr. Maserejian’s group reported online ahead of print in the American Journal

Orange, grapefruit juice consumption may be protective in men, study finds of Epidemiology. Men who increased their coffee intake during follow-up by two or more 8-ounce cups per day from baseline had a significant 61% increased odds of LUTS progression.

In men, consumption of orange or grapefruit juice was associated with a significant 50% decreased risk of LUTS development.

Women who increased coffee intake by at least two 8-ounce servings per day during follow-up had a significant 64% increased odds of progression of storage symptoms compared with women who had no change from baseline.

Baseline coffee consumption was not associated with LUTS among women.

Women who increased their soda intake by two or more 8-ounce servings per day had a significant 59%, 58%, and 40% increased likelihood of overall LUTS, voiding symptoms, and storage symptoms, respectively.

The researchers concluded that their findings “support recommendations to limit caffeinated beverage intake for LUTS, and in men, they suggest benefits of citrus juice consumption.”

The men in the study had a mean age of 49.9 years. The women had a mean age of 51.3 years. n

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24 Renal & Urology News

september 2013 www.renalandurologynews.com

Renal Nutrition Update High fructose intake is associated with a number of metabolic disturbances.

Elevated fructose levels cause rapid dephosphorylation of ATP in the liver, which increases levels of AMP deaminase and subsequent increases in uric acid production. Elevated uric acid levels are linked to increased risks for hypertension, gout, and renal impairment.

Although renal impairment appears to increase risk for elevated uric acid concentrations through decreased excretion, the effect of uric acid on metabolic syndrome begs the question of whether a causative effect exists between uric acid and subsequent renal impairment.

Uric acid and metabolic syndrome Recent animal models have shown that rats fed a high fructose diet and treated with allopurinol or benzbromarone did not develop hyperinsulinism, hypertension, hyperlipidemia, and excess bodyweight gain, whereas rats fed the same diet but not treated with allopurinol developed all of the aforementioned ailments (Am J Physiol Renal Physiol 2006;290:F625-631). These results indicate that elevated uric acid is a potential propagator of metabolic syndrome.

Uric acid appears to reduce nitric oxide synthesis, an important regulator

ticipants compared with controls (JAMA 2008;300:924-932). Furthermore, a twoweek intervention with a high-fructose diet led to increases in BP in 74 overweight subjects (Int J Obes 2010;34:454461). These results were reversed after uric acid reducing agents were administered.

Associations between chronic kidney disease (CKD) and elevated uric acid levels have been well established (Semin Arthritis Rheum 2013;42:551-561. As stated previously, reduced ability to excrete uric acid may be one factor. It is important to note that genetic polymorphisms in renal uric acid excretion receptors can influence uric acid levels in individuals; those with improved uric acid clearance show a reduced response to OFTT on uric acid levels (Ann Rheum Dis 2013; published online ahead of print). A recent intervention with an oral fructose load found a number of metabolic disturbances in patients with CKD (Metabolism 2013; published online ahead of print). A 70 g oral fructose tolerance test found significant increases in uric acid levels in both renal transplant recipients (RTR) and non-RTR CKD subjects. Total cholesterol, LDL, HDL, and triglyceride levels increased significantly in the

A recent intervention with an oral fructose load found a number of metabolic disturbances in patients with chronic kidney disease. of blood pressure through endothelial vasodilation (Hypertension 2001;38:11011106). In addition, there appear to be stimulatory effects of uric acid on the renin-angiotensin system. A recent study found that in hypertensive adolescents, a reduction in uric acid levels normalized blood pressure (BP) in 66% of the par-

On The Web RUN0913_RenalNut.indd 24

non-RTR CKD subjects, whereas the RTR subjects demonstrated increases in triglyceride values and decreases in total cholesterol, LDL, and HDL values. Additionally, dialysis patients have been shown to have a reduced ability to clear both uric acid and fructose metabolites. Investigators found that

© thinkstock

Curbing dietary fructose intake may be effective in decreasing elevated uric acid levels in renal disease patients By GRISSIM CLARK CONNERY, MS, RD, LD

Reducing intake of sugary soft drinks may significantly reduce dietary fructose levels.

hemodialysis patients’ uric acid levels remained elevated up to 240 minutes after ingestion of 190 mL cream and 75 g sucrose, whereas values peaked at 60 minutes in healthy controls (Scand J Clin Lab Invest 2013;73:154-160). Of note, values were measured up to 240 minutes after ingestion. They remained elevated up to that point and still had not begun to decrease at the conclusion of measurements. These studies indicate that fructose is an important target for reduction in renal patients to decrease uric acid levels.

Foods high in fructose When attempting to reduce fructose intake in the diet, the type of food and the portion must be considered. Most fructose sources generally have a varying content of fructose and glucose that approximate a 50/50 ratio and generally deviate within 10%. The most notable source of fructose in modern diets is from high fructose corn syrup and sucrose. High fructose corn syrup may range in fructose content depending on production, but generally it contains 55% fructose. Sucrose is quickly converted in

the body to its constituent sugars, thus effectively providing a 50% fructose content. Fruit sources and honey also contain a varying content of fructose and glucose that generally vary close to a 50/50 ratio with a 10% variation (assuming sucrose content is also a 50/50 ratio of glucose to fructose).

Reducing intake of added syrups and sugars in the diet is the most powerful method to reduce fructose intake.

Sweetened beverages often provide the largest fructose dose in the general population. The intakes of fruit juices or dried fruits can easily provide high sources of fructose through excessive portion intake. Focusing one’s carbohydrate intake primarily on glucose sources, namely starches, would be most beneficial in controlling fructose intake.

In renal patients without elevated potassium, tubers such as potatoes and yams are an ideal source of carbohydrates due to their low fructose content and positive effect on potential renal acid load. n .

Mr. Connery is Research Coordinator at Case Western Reserve University in Cleveland.

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

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Malpractice News

A recent study showed that 24% of all malpractice alllgations were surgery related.

Five States Responsible for Nearly Half of All 2012 Payouts Diederich Healthcare has recently released an analysis of 2012 medical malpractice payouts based on information from the National Practitioner Data Bank (NPDB). The analysis revealed that of the $3.6 billion in payouts for medical malpractice last year, 48% were attributable to five states: New York ($763,088,250), Pe n n s y l va n i a ($316 ,167, 50 0), California ($222,926,200), New Jersey ($206,668,250), and Florida ($203,671,100). Settlements were responsible for the bulk of the payouts (93%), whereas judgments were responsible for only 5% of the payouts. States with the lowest per capita payouts were Texas, North Dakota, Wisconsin, Mississippi, and Indiana.

The largest number of malpractice allegations were diagnosis related (33%), followed by surgery related (24%), treatment related (18%), and obstetrics related (11%). Diagnosisrelated allegations of malpractice accounted for a total of $1,176,345,550 in payments. Failure to diagnose accounted for 20% of all payments.

Slightly more payouts were made to women (57%) than men (43%), but the age group 40-59 years in both sexes

On The Web RUN0913_MalPract.indd 1

had the highest number of payouts by age, at 39%. A similar amount of payouts were based on inpatient (45%) and outpatient (41%) treatment, and 9% of payouts were attributable to both inpatient and outpatient treatment. In terms of severity of injury, 31% of payouts were in cases results in death, 19% were in cases of significant permanent injury, and 18% were for major permanent injury. Conversely, only 0.4 of the payouts were related to insignificant injury, 1% were based on emotional injury only and 3% were based on minor temporary injury.

In 2012, there were a total of 12,142 medical malpractice payouts in the United States—accounting for one about every 43 minutes. The positive news is that despite an increase in payouts between the years 1998 and 2001, since 2003 malpractice payouts have been steadily dropping. Payouts in 2012 were 3.4% lower than in 2011.

Florida Medical Malpractice Bill Becomes Law A new bill, which changes the rules in medical malpractice cases in Florida, has been signed into law by Gov. Rick Scott.

The Republican-supported bill, which was sponsored in the Senate

by Senate President Don Gaetz, and supported in the House by his son, Rep. Matt Gaetz, faced sharp criticism by Democrats. The bill makes Florida one of the toughest states in which to bring a medical malpractice suit.

The legislation contains two provisions.

The first is a restriction on who can testify as an expert witness. Under the new legislation, any expert witness called to testify against a defendant physician must practice the exact same type of medicine, and not just be in a similar field as was previously required. Democratic Rep. Cynthia Stafford voiced concern that this restriction would “unduly restrict the pool of experts who will be available to testify.” The second provision applies to the period of fact-finding that occurs

By ANN W. LATNER, JD

prior to when a lawsuit is actually filed.

This provision allows attorneys who are defending physicians to ask subsequent healthcare providers about the patient and the patient’s treatment.

The bill does not require the subsequent physicians to answer, but they are allowed to, and it will no longer be considered a breach of the patient’s confidentiality.

This provision only applies prior to when the lawsuit is filed. Once a lawsuit is filed, the state court rules apply as to what can and can’t be asked.

Opponents had argued that this provision tramples on the privacy of medical records and doctor/patient confidentiality.

In a prepared statement, Florida Medical Association President Vincent DeGennaro expressed his support for the legislation, saying, “For years, we have fought to correct unfair imbalances in the tort system that are hostile to doctors. Making our state a friendlier place to practice medicine attracts more doctors to Florida, which increases Florida patients’ access to care.”

On the other side, however, Florida Justice Association executive director Debra Henley had warned that the legislation “violates patient privacy, harms doctor/patient relationships and may not even be constitutional.”

based on “repeated and serious” violations of the Medical Practice Act based on the insertion of the stents.

The accusations also led to a federal investigation, and caused a loss of staff and revenue at the hospital, which was eventually sold to the University of Maryland Medical System.

Lawsuits were filed by hundreds of patients who claimed that the unnecessary stents left them with lasting medical complications. A trial brought by 21 of the plaintiffs began in Baltimore County Circuit Court, but ended prior to the defendant physician’s testimony when a settlement was reached. While the details of the settlement have not been revealed, it will resolve close to 250 of the cases against the doctor and CHI. The doctor has consistently denied any wrongdoing and continues to maintain that patients were treated appropriately. Forty-five cases are still pending against this physician and CHI. Settlement of the previous cases cannot be used as evidence in future litigation, so the settlement will likely play little role in what happens with the remaining 45 cases. n Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

Stent Lawsuit Settles on the Eve of a Doctor’s Testimony A large medical malpractice lawsuit against a doctor and Catholic Health Initiatives (CHI) owner of St. Joseph Medical Center in Maryland has settled after six weeks of trial, but prior to the defense putting on its side of the case. The doctor, an interventional cardiologist, was accused of putting hundreds of unnecessary stents in patients while working at St. Joseph between 2007 and 2009. In 2010, the medical center notified over 500 former patients that they may have been given unnecessary stents. The accused’s medical license was revoked in 2011

© thinkstock

26 Renal & Urology News

A physician is sued for allegedly placing unnecessary stents in patients.

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

8/21/13 12:53 PM

www.renalandurologynews.com september 2013

Renal & Urology News 27

ADT Often Used for Low-Risk PCa Liberal use of the treatment likely confers a hip fracture risk comparable to that of the cancer Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with an increased risk of hip fractures, according to a Finnish study published online in the Scandinavian Journal of Urology. The study found that nearly one quarter of men treated with ADT had low-risk cancer.

Antti Kaipia, MD, of Satakunta Central Hospital in Pori, Finland, and colleagues conducted a retrospective study of 1,210 men treated for proximal femoral fractures at Tampere University Hospital from 1998 to 2008. Of these men, 133 had a prior PCa diagnosis.

The researchers found that 117 of the PCa patients had been treated with ADT at some point during their course of treatment, and 113 were still undergoing ADT at the time of the fracture.

The median time between PCa diagnosis and fracture was 4.6 years. ADT and age were found to be major risk factors for fractures in all patients. In multivariate analyses, ADT use was associated

Aggressive PCa, TRT Not Linked Testosterone replacement therapy (TRT) is not associated with aggressive prostate cancer (PCa) and does not increase overall or disease-specific mortality, according to a study that also revealed that TRT use is low among men in the United States.

Alan L. Kaplan, MD, and Jim C. Hu, MD, of the University of California Los Angeles David Geffen School of Medicine, used linked Surveillance, Epidemiology, and End Results (SEER)Medicare data to identify 149,354 men diagnosed with PCa from 1992 to 2007.

The men had a median age of 73 years.

Of the total cohort, 2,237 (1.5%) underwent TRT prior to their cancer diagnosis. TRT was associated with older age at cancer diagnosis, nonwhite race, and higher comorbidity burden. TRT use increased with age. Of the TRT recipients, 47.5% were aged 75 years or older, whereas 34% were aged 70-74, and 18.5% were aged 65-69.

The median follow-up after the cancer diagnosis was five years. Compared with men who did not receive TRT,

RUN0813_HipFracture.indd 1

with a 3.0, 4.5, and 5.8 times increased risk of hip fracture among men with low-, intermediate-, and high-risk PCa, respectively.

Nearly one quarter of the fracture patients with PCa had well-differentiated T1-2 PCa, and more than 50% had low PSA values (less than 1 ng/mL) at the time of the fracture.

“These figures indicate that a large portion of these fractures might have been avoided by a more cautious attitude towards ADT and by using antiosteoporotic medication,” they wrote.

The researchers also observed: “A surprisingly large proportion of the patients suffering a fracture had been treated with primary ADT despite having a local, low-risk prostate cancer. It was thus likely that the liberal use of ADT gave these patients a risk comparable to that of the cancer itself.”

In localized PCa, the authors commented, “the use of ADT as a single treatment is questionable, since ADT

those who did were significantly more likely to be diagnosed with moderately differentiated disease (63.5% vs. 59.2%) and significantly less likely to have poorly differentiated disease (29.7% vs. 34.2%). Additionally, TRT recipients were significantly more likely to be diagnosed with clinical stage T3 (4.0% vs. 3.1%), significantly but less likely to have T4 disease (4.3% vs.

6.5%). Use of TRT was not significantly associated with differences in overall or disease-specific survival or need for salvage androgen deprivation therapy.

TRT use was low throughout the study period, peaking at 2.8% in 1998, Drs. Kaplan and Hu reported. Given the median age of their cohort, the researchers noted, they expected the prevalence of hypogonadism would be higher than that found in previous studies (2.1%-25%, depending on the strictness of diagnostic criteria).

“Despite the high prevalence of hypogonadism in older men and wellestablished health benefits of TRT,” the authors concluded, “use of TRT is markedly low. The concern of increasing prostate cancer risk or cancer severity by administering TRT has been widely disproved. . . . Our populationbased study adds to the growing body of evidence that TRT does not confer worse prostate cancer outcomes.” n

ADT and Hip Fracture Risk A Finnish study characterized the increased risk of hip fracture associated with androgen deprivation therapy for prostate cancer (PCa). The fracture risk increased along with PCa risk category, as shown here.

5.8× 6 5 4

4.5× 3.0×

3 2 1 0

Low risk

Intermediate risk

High risk

Prostate cancer risk category Source: Kaipia A et al. Androgen ablation for low-risk prostate cancer is common among male hip fracture patients. Scand J Urol 2013; published online ahead of print.

has failed to demonstrate improved survival in non-metastasized PCa. Despite this, ADT has been widely used as a treatment option, especially in elderly people and in cases unfit for curative treatment.”

Dr. Kaipia’s group cited previous research showing that decreases in bone

mineral density with ADT occur in a time-dependent manner, and long-term use may lead up to a 45% increase in the relative risk of a fracture. “The association of risk between hip fractures and ADT is of great importance because hip fractures are associated with a significant risk of death,” they wrote. n

Hypogonadism Ups Death Risk in Male HD Patients Canadian researchers found a high

led by Marcello Tonelli, MD, of the

prevalence of hypogonadism among

University of Alberta in Edmonton,

men on hemodialysis (HD), and this was

found no significant effect of testoster-

associated with an increased risk of

one level on mortality risk among men

death, according to a new report.

aged 63 years or older.

The study included 623 men on HD

Additionally, men with low testoster-

who were enrolled in the prospective

one had significant lower Health Utility

Canadian Kidney Disease Cohort Study.

Index scores than those with normal

Of these, 343 (55%) had low testoster-

testosterone levels, indicating a poorer

one (below 231 ng/dL). hypogonadism,

health-related quality of life.

defined as Compared with men who

“To our knowledge, this is the largest

had normal testosterone levels (above

study investigating the association

246 ng/dL), those who had low levels

between serum testosterone levels and

had a significant 48% increased risk of

adverse outcomes in a prospective

all-cause mortality, after adjusting for

cohort of HD patients,” the authors wrote.

potential confounders, investigators reported online ahead of print in the American Journal of Kidney Diseases.

The adjusted risk of all-cause mortal-

The finding that low testosterone may contribute to excess all-cause mortality and low quality of life in men on HD “raises the hypothesis that hypogonad-

ity varied by age, the study showed.

ism may be a novel and modifiable risk

Among men younger than 63 years,

factor for adverse clinical outcomes

those with low testosterone had a

and poor quality of life in this patient

significant 2.9 times increased risk

group—a hypothesis that should be

compared with men who had normal

tested in randomize clinical trials,” the

testosterone levels. The researchers,

authors wrote. n

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28 Renal & Urology News

september 2013 www.renalandurologynews.com

ACEI Use Improves Post-AKI Survival In a study, patients had a 65% lower risk of 90-day mortality

BY ROSEMARY FREI, MSc HONG KONG—Use of ACE inhibitors (ACEIs) is associated with decreased mortality and the need for dialysis among hospitalized patients with acute kidney injury (AKI), according to new study findings presented at the 2013 World Congress of Nephrology.

In a secondary analysis of data from patients in the RENAL (Randomized Evaluation of Normal vs. Augmented Level) renal replacement therapy (RRT) study, Australian researchers found a 65% higher survival rate at 90 days after randomization and significantly fewer days on dialysis with use of ACEIs. Lead analyst Amanda Wang, a PhD student at the George Institute for Global Health in Camperdown, New South Wales, cautioned, however, that “the possibility of unmeasured residual confounders remains, and they could impact the results.”

The RENAL study involved 1,508 patients with AKI who were randomized to either low-intensity (25 mL/ kg/h) or high-intensity (40 mL/kg/h) continuous RRT. It was conducted at 35 ICUs in Australia and New Zealand from 2006-2008.

Dr. Wang and senior author Martin Gallagher, PhD, of the Sydney Medical School, and others performed a posthoc analysis of the data, focusing on the effect of ACEIs. They analyzed information from the 142 individuals on ACEIs and the 1,321 who were not, all of whom had complete information ranging from days on mechanical ventilation to baseline estimated glomerular

ACE inhibitors have certain positive effects that could explain the finding. filtration rate.

Overall, patients taking ACEIs had better baseline health parameters and outcomes, with a few exceptions.

Significantly fewer had severe sepsis at baseline (34.5% vs. 50.9%), they had lower APACHE III scores (97.9 vs. 102.9), and more intensive care unit (ICU)-free days (60.7 vs. 47.5), hospitalfree days (40.4 vs. 31.4) and RRT-free days (20.7 vs. 17.0). On average, however, patients taking ACEIs had more days on mechanical ventilation (11.1

vs. 6.9) and higher Sequential Organ Failure Assessment-Cardiovascular (SOFA CV) scores (3.2 vs. 2.8).

“The division into participants receiving ACEIs and those not receiving ACEIs for this study was done post-randomization so there are notable differences between the groups,” Dr. Wang said. “The likely reason for this was the very high mortality in the early phase of the RENAL study, with the patients who survived this phase having more opportunity for exposure to ACEIs.” Additional analyses showed that ACEI use was associated with a 65% decreased risk of 90-day mortality and a 69% decreased risk of 28-day mortality.

In addition, they selected a group of patients who had survived for five or more days in the ICU and found that ACEI use was still associated with a survival benefit and less dialysis requirement, although not less hospital or ICU bed-day use.

The beneficial effects of ACEIs are likely due to their anti-inflammatory effects, positive impacts on cardiac function, and anti-fibrotic properties that may help prevent scarring in patients with kidney injury, Dr. Wang noted. n

Impaired Taste in HD Patients Common Altered taste perception is common among hemodialysis (HD) patients, and it is independently associated with poorer markers of nutritional status and increased risk of death, according to a new study.

Steven M. Brunelli, MD, of Brigham and Women’s Hospital in Boston, and colleagues analyzed data from 1,745 participants in the Hemodialysis Study. In that study, investigators assessed taste perception at baseline and then annually. Patients with end-stage renal disease (ESRD) are at increased risk for taste perception impairment.

Although the mechanism for this impairment is not well understood, it is thought to be a consequence of uremia, the authors noted. Another possibility is zinc deficiency, which is common because of high dialytic removal.

At baseline, 34.6% of patients reported altered taste perception, and this was associated with poorer baseline nutritional status, according to a report published in the Journal of Renal Nutrition (2013;23:288-

PD Less Expensive than HD Worldwide

295). Compared with patients who

BY ROSEMARY FREI, MSc HONG KONG—Peritoneal dialysis (PD) is much less expensive than hemodialysis (HD) in most places around the world, including North America, a new cost analysis has confirmed. Therefore, since the two modalities are clinically equivalent, PD should be used more, according to investigators.

Their study—which they published online in Nephrology Dialysis Transplantation and presented at the 2013 World Congress of Nephrology— showed the cost of HD is between 1.25 and 2.35 time higher than that of PD in five developing and 17 developed countries. In the U.S., for example, the HD:PD cost ratio is 1.29:1 and in Canada it is 1.9:1.

“While I understand that it is rather difficult in the U.S.to have a PD-first policy or a target percentage of PD use, it is clear that something could be done to improve PD education

lower serum albumin, lower serum

RUN0913_WCN1.indd 1

and awareness among doctors,” lead investigator Aakash Nayak Karopadi, BE, MSc, from the International Renal Research Institute Vicenza, San Bortolo Hospital, Vicenza, Italy, told Renal & Urology News.

Only 7% of dialysis in the U.S. is done with PD, Karopadi said. If this percentage was at the world average of 12%, an additional 18,000 patients would be on PD, and this would have led to an annual savings of nearly $ 360 million to the American economy.

Karopadi and his co-investigators in Italy searched the published literature for studies on the cost and use of PD and HD, and mailed questionnaires to senior nephrologists in countries from which no published data were available.

PD:HD cost ratios range from 2.35 in Hong Kong, where there is a PD-first policy, to 0.22 in Egypt. Furthermore, the rates of PD per million people vary

from 0.06 in Nigeria to 488.5 in Hong Kong. The rates of HD per million people run from 0.2 in Ghana to 2,107 in Japan and Taiwan.

In the U.S. the rate of PD per million people is 87 and that for HD is 1,157 (the HD rate is third-highest after Japan and Taiwan). The U.S. Renal Data System 2012 Annual Report states that the annual per-patient HD cost is approximately $87,500 while for PD it is $66,750.

The investigators also performed analyses that indicate countries with a higher Human Development Index score—a composite of life expectancy, educational level, and income—have higher costs of HD relative to PD, as do countries with a higher prevalence of PD per million population. Conversely, the HD:PD cost ratio decreases with increased percentage of private health care in countries’ total health care expenditures. n

had normal taste perception, those with altered taste perception had creatinine, lower normalized protein catabolic rate, lower reported protein intake, lower reported sodium intake, lower parathyroid hormone levels, and smaller mid-arm muscle circumference.

After a median two years of followup, 739 patients died. In adjusted analysis, altered taste perception was associated with a significant 17% increased risk of all-cause mortality compared with the normal taste perception.

Dr. Brunelli’s team explained that nutritional decline is common among HD patients, and their findings suggest that altered taste perception may be one pathway through which HD patients become malnourished. n

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30 Renal & Urology News

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CME feature

OAB: Current and Emerging Therapies for Optimal Individualized Treatment Keeping abreast of the most current treatments for idiopathic OAB can lead to improved outcomes and quality of life Release Date: September 2013 Expiration Date: September 2014 Estimated time to complete the educational activity: 1 hour This activity is jointly sponsored by Boston University School of Medicine and Haymarket Medical Education.

This activity is supported by an educational grant from Allergan, Inc. Statement of Need: The prevalence of overactive bladder (OAB) suggests that clinicians do not succeed in identifying patients early for optimal individualized treatment. Many patients fail to achieve adequate relief of idiopathic OAB symptoms with current treatments, indicating that physicians frequently may not select therapy tailored to the individual patient to achieve optimal outcomes.

Target Audience: This activity has been designed to meet the educational needs of urologists, urogynecologists, and other health care providers who treat patients with bladder dysfunction.

Educational Objectives: After completing the activity, the participant should be better able to: • Apply diagnostic and assessment strategies to identify patients with OAB earlier for optimal individualized treatment • Evaluate current evidence-based treatments and emerging therapies to better select individualized therapy for OAB 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 Boston University School of Medicine (BUSM) and Haymarket Medical Education. Boston University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: Boston University School of Medicine designates this enduring activity for a maximum of 1.0 AMA PRA Category 1 Credit TM. Physicians should claim only credit commensurate with the extent of their participation in the activity.

Disclosure of Conflicts of Interest: Boston University School of Medicine asks all individuals involved in the development and presentation of Continuing Medical Education (CME) activities to disclose all relationships with commercial interests. This information is disclosed to CME activity participants. Boston University School of Medicine has procedures to resolve any apparent conflicts of interest. In addition, faculty members are asked to disclose when any unapproved use of pharmaceuticals and devices is being discussed.

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 Relationship Grants/Research Support: Allergan, Inc., Astellas Pharma US, Inc., Medtronic, Merck & Co., and Pfizer Inc. Consultant: Allergan, Inc., Cook Medical, Lipella Pharmaceuticals Inc., Merck & Co., and Pfizer Inc. Stockholder: Cook Medical, Lipella Pharmaceuticals Inc.

David A. Ginsberg, MD

Grant/Research Support: Allergan, Inc. and Medtronic Consultant: Allergan, Inc., Medtronic, and Pfizer Inc. Speakers’ Bureau: Allergan, Inc.

The content managers, Debra A. Hughes, MS, Mary Jo Krey, Lori Marrese, Jody A. Charnow, and Marina Galanakis of Haymarket Medical Education, and Linda Ng, MD, of Boston University School of Medicine, 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 September 2013 through September 2014, participants must: 1) read the learning objectives and faculty disclosures, 2) study the educational activity, 3) complete the post-test 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.

RUN0913_CME.Chancellor_v2.indd 30

By Michael B. Chancellor, MD David A. Ginsberg, MD

T

he International Continence Society (ICS) consensus definition of overactive bladder (OAB) is based on symptoms of urgency, with or without urgency ("urge") incontinence, usually with frequency and nocturia, in the absence of pathologic or metabolic conditions that might explain these symptoms (Table 1).1 Patients who present with OAB describe a frequent urge to void, getting up at night to urinate, and inability to get to the bathroom in time, and may leak large volumes of urine.

In the United States, more than 20 million people have incontinence and OAB, with 57% reporting urgency incontinence episodes and 16.6% symptoms of OAB. This accounts for 40% to 70% of all cases of incontinence diagnosed. Prevalence increases with age. The prevalence of OAB is similar in men (~16%) and women (~17%); however, women are more likely to experience urgency urinary incontinence and may be more bothered by symptoms. Many who suffer with symptoms do not seek treatment.2

OAB has a medical, economic, and social impact on patients, including diminished quality of life (QoL).2 The medical consequences of OAB include pressure ulcers, perineal rashes, urosepsis, falls, fractures, and urinary tract infections (UTIs). OAB particularly predisposes the elderly to all of these adverse effects.3 The social consequences of OAB include fear of odor and embarrassment; disruption of domestic and social life; social isolation, low selfesteem, and depression; limitation of day-to-day activities; risk of job loss; and risk of institutionalization.4,5 The impact of urinary incontinence on QoL can be psychological, social, domestic, occupational, sexual, and/ or physical.

Differentiating Urinary Incontinence Urinary incontinence may be defined as urgency, stress, overflow, functional, or mixed (defined as a combination of urgency and stress urinary incontinence). Urgency incontinence associated with OAB is usually of idiopathic etiology; if there is a neurologic cause

Michael B. Chancellor, MD, (left) 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 David A. Ginsberg, MD, (right) is the Associate Professor of Clinical Urology, Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, California, and Chief of Urology, Rancho Los Amigos National Rehabilitation Center, Downey, California

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www.renalandurologynews.com SEPTEMBER 2013

Table 1. Current ICS Terminology for OAB Symptom

Description

Urgency

• Sudden, difficult-to-defer, compelling desire to pass urine •M ust differentiate from normal “urge” or desire to urinate that can be deferred with certain strategies

Urgency ("urge") incontinence

• I nvoluntary leakage accompanied, or immediately preceded, by urgency

Frequency/nocturia

• Subjective complaint that individual considers he/she voids too often during the day (>8/day) or at night (≥1/night)

Source: Abrams P, et al. Urology. 2003;61(1):37-49.

Table 2. Differentiating Between OAB and Stress Incontinence Symptoms

OAB

Stress Incontinence No

Urgency (strong, sudden desire to void)

Yes

Frequency with urgency (>8 times/24 h)

Yes

No

Leak with physical activity

No

Yes

Large

Small

Ability to reach the toilet in time following an urge to void

Seldom

Yes

Waking to pass urine at night

Usually

Seldom

Amount of urinary leakage (if present)

Source: Abrams P, Wein AJ. The Overactive Bladder — A Widespread and Treatable Condition. Stockholm, Sweden: Erik-Sparre Medical AB; 1998.

leading to urgency incontinence, the patient has a neurogenic bladder. Stress urinary incontinence is due to poor outlet resistance (eg, urethra or bladder neck sphincter problem). Possible risk factors leading to stress incontinence include increased parity and/or changes related to the pelvic floor, and fascial, muscular, neurologic, or hormonal factors. About 38% of patients with OAB have mixed incontinence, often with one symptom complex predominating—ie, either urgency or stress; therefore, it is important to determine a patient’s primary symptom.6 The diagnosis of OAB involves differentiating stress and mixed incontinence from OAB (Table 2).

Identifying Neurogenic OAB Neurogenic OAB is caused by an underlying neurologic condition and often affects those with multiple sclerosis, spinal cord injury, cerebrovascular accident, and Parkinson’s disease.7 It can also occur in patients with diabetic neuropathy.8 Neurogenic OAB is sometimes initially misdiagnosed.9 Many patients with neurogenic OAB are in wheelchairs, incontinent, and wet, and must self-catheterize along with their other OAB treatments. Urodynamic studies can help determine the underlying neurologic problem, categorize the

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vesicourethral dysfunction,7 and provide a basis for appropriate treatment.

Among the goals of management are to maintain low bladder pressures, prevent UTIs, and preserve upper urinary tract function.10,11 Management of neurogenic detrusor overactivity is often similar to that for OAB except that some patients may require intermittent catheterization—to allow for adequate bladder emptying and a reduced risk for infection and longterm complications.7

Diagnosing Urinary Incontinence The American Urological Association (AUA) and the Society for Uro­ dynamics, Female Pelvic Medicine & Urogenital Reconstruction (SUFU) Adult Urodynamic Guidelines offer a diagnosis and treatment algorithm for OAB, urgency urinary incontinence, and mixed urinary incontinence.12 These guidelines recommend documenting signs and symptoms that characterize OAB so that other disorders can be excluded. This includes, at a minimum, a thorough history, physical examination, and a urinalysis.

A history should include questions regarding the length of time a patient has had incontinence and the age at which it started. Details that should be recorded include the volume of urine,

degree of bother, and characteristics of leakage, such as whether it is activity related or suggests bladder overactivity (“day and night, wet pads at night”).

Fluid intake, UTIs, pain, hematuria, lower extremity swelling, and prolapse should be investigated.

Other causes of symptoms of urinary incontinence include local pathology (infection, bladder stones, bladder tumor, interstitial cystitis, outlet obstruction), metabolic conditions (diabetes, polydipsia), medications (diuretics, antidepressants, antihypertensives, hypnotics and sedatives, and analgesics and narcotics), and other factors (pregnancy, psychological, or estrogen deficiency). Alcohol, caffeine, and other agents may also influence— and worsen—existing symptoms of OAB (Table 3).

A physical examination should include checking the abdomen for palpable bladder masses; the pelvis/ perineum for atrophic vaginitis, prolapse (which is associated with 50% of patients with stress urinary incontinence), and loss of urine with cough; the rectum for tone, masses and bulbocavernosus reflex coordination; and the prostate. During the rectal exam, the Kegel technique can be taught to strengthen pelvic floor muscles. A neurologic assessment of the lower extremities tests sensory neuron and motor responses, including reflexes.

Additional Diagnostic Measures In some patients, additional procedures and measures may be necessary to validate a diagnosis of OAB and to inform the treatment plans. This includes obtaining a urinalysis (eg, for hematuria,

Renal & Urology News 31

pyuria, proteinuria, glycosuria), checking a postvoid residual, and having patients complete bladder diaries and/or symptom questionnaires. Prostatespecific antigen (PSA), renal function, and serum glucose laboratory testing may be needed, as well as urodynamic studies (UDS) or voiding cystourethrogram. However, urodynamics, cystoscopy, and renal and bladder ultrasound should not be used in the initial workup of the uncomplicated patient.13 Use of a bladder record or diary (Figure 1)14 is extremely helpful in diagnosing OAB as well as other types of incontinence. Over a 3-, 5-, or 7-day period, a patient is asked to record both continent times and incontinence episodes. A review of these data can assist the physician in making a correct diagnosis and prescribing proper treatment.

The treatment goal should also be discussed with the patient. Reviewing the bladder diary will help identify urgency episodes, daytime frequency, nocturia, and the incontinence/dry rate to detect whether treatment is improving these symptoms.

Patients seek treatment for OAB due to poor QoL, and perceived improvement from medical therapy is multifactorial. Many believe that the efficacy and success of medical therapy for OAB should be linked to patient expectation and improvement in QoL, not to improvements in 1 or 2 end points.

Ideally, once patient-centered goals are defined, outcomes should be correlated with relief of symptom(s), patient satisfaction, and goal attainment expectations as a result of treatment.15 It is important to keep in mind that OAB is a symptom complex, not a disease. After assessment has been

Table 3. Effect of Agents on Existing Symptoms of OAB Agent

Effect on Symptoms of OAB

Sedatives

Confusion, secondary incontinence

Alcohol, caffeine

Diuresis1

Anticholinergics other than antimuscarinics2 • Impair detrusor contractility • Voiding difficulty3 • Overflow incontinence4 α-Agonists3

Increase outlet resistance, voiding difficulty

β-Blockers

• Decrease urethral closure • Stress incontinence3

Calcium channel blockers4

Reduce bladder smooth muscle contractility

ACE inhibitors4

Induce cough, stress urinary incontinence

ACE=angiotensin-converting enzyme.

1. Crespi-Lofton J. J Am Pharm Assoc. 2001;41:S3-S17. 2. Gill SS, et al. Arch Intern Med. 2005;165(7):808-813. 3. Lavelle JP, et al. Am J Med. 2006;119(3 suppl 1):37-40. 4. DuBeau CE. J Urol. 2006;175(3 pt 2):S11-S15.

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CME feature Antimuscarinic Agents Antimuscarinic agents are the mainstay of treatment and the pharmacotherapy that should be selected first-line to control symptoms.16 Comparative trials have generally demonstrated similar efficacy among antimuscarinic agents.13 Most patients discontinue antimuscarinic agents after a few weeks or months,13 and approximately 80% to 90% of patients reportedly discontinue antimuscarinics in the first year of therapy.17,18 Factors related to discontinuation include patient perception of lack of benefit or efficacy and adverse events, including dry mouth, constipation, blurred vision, tachycardia, somnolence, and impaired cognitive function.13,18,19 The tricyclic antidepressants imipramine and doxepin, which decrease bladder contractility, have also been used to treat OAB; however, they are not indicated for the first-line treatment of OAB.

Mirabegron

Use this sheet as a master for making copies that you can use as a bladder diary for as many days as you need. http://kidney.niddk.nih.gov/kudiseases/pubs/diary/diary_508.pdf Figure 1. Sample Bladder Diary

performed to exclude conditions requiring treatment and counseling, no treatment is an acceptable choice made by some patients and caregivers.

Recommended Treatments for OAB The AUA/SUFU guideline recommends first-, second-, and third-line treatment for OAB. First-line treatment includes behavioral therapies that may be combined with antimuscarinics. Second-line treatments include the antimuscarinics darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium, with extended-release formu lations preferred; and transdermal oxybutynin (patch or gel). Third-line treatments are sacral neuromodulation, peripheral tibial nerve stimulation, and intradetrusor onabotulinumtoxinA (onaBoNTA), with surgery considered for severe refractory OAB in rare cases.13

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Advantages of behavioral therapy are that it is safe and effective, with patients generally expressing satisfaction. Such therapies include bladder education/ retraining, bladder diaries, fluid intake management (including caffeine reduction), timed voiding, pelvic floor exercises, and delayed voiding. Limitations include patient adherence/motivation, cognitive status, the need for a skilled “continence nurse,” the ability to identify and contract pelvic muscles, the amount of time involved, and the need for physician support.13 Other devices used for treatment of OAB include absorbent products (eg, pads, shields, guards, undergarments), penile compression devices, pelvic organ support devices (pessaries), intravaginal support devices, extraurethral occlusive devices, and intraurethral devices, such as intermittent or indwelling catheters; however, indwelling catheters are not recommended except as a last resort in selected patients.13

Mirabegron is a once-daily beta 3adrenergic agonist that stimulates beta3-receptors of the bladder detrusor muscle, leading to relaxation with minimal intrinsic activity on beta1 and beta 2. Three 12-week, randomized, double-blind, placebo-controlled, multicenter clinical trials evaluated mirabegron at doses of 25 mg, 50 mg, and 100 mg in patients with OAB and symptoms of urgency urinary incontinence, urgency, and urinary frequency.

The 25 mg dose effectively treated

OAB symptoms within 8 weeks, and the 50 mg dose, within 4 weeks.

Efficacy of mirabegron 25 mg and 50 mg was maintained throughout the 12-week treatment period with respect to the number of incontinence episodes, micturitions per 24 hours, and volume voided per micturition.

Patients prescribed mirabegron who are taking concomitant CYP2D6 agents should be monitored and, if digoxin is required, it should be initiated cautiously and titrated.

Mirabegron, a pregnancy category C agent, may elevate blood pressure and should be used cautiously in those with bladder outlet obstruction or taking antimuscarinics.20

Defining Refractory OAB Refractory OAB is defined as persistent urgency, frequency, and incontinence that remains bothersome despite oral pharmacologic therapy.18 Approximately 25% to 40% of patients fail to achieve adequate symptom relief of incontinence with antimuscarinic agents.21 In patients with general OAB who combine behavioral therapy with pharmacologic therapy, there may be a lack of improvement in at least 20% of cases.22 When treatment fails or patients generally are dissatisfied with the adverse effects of oral therapy, available options include sacral neuromodulation, percutaneous tibial nerve stimulation (PTNS), botulinum toxin A, and augmentation cystoplasty.

Figure 2. Botulinum toxin acts by binding presynaptically to sites on parasympathetic nerve terminals and decreasing the release of acetylcholine, causing a neuromuscular blocking effect. (Used with permission from Smith CP, Chancellor MB. J Urol. 2004;171:2128-2137.)

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Renal & Urology News 33

Case Study: A 55-Year-Old Woman With Urinary Incontinence M.B. is a 55-year-old woman who works in sales. She has a 9-year history of urge incontinence. Her health is stable, except for borderline hypertension. Her lipids are normal. Approximately 4 years ago, she was put on oral oxybutynin extended-release 15 mg/day and continued despite reporting dry mouth. Six months ago, she reported being increasingly constipated and feeling dizzy if she stood up too quickly.

She has 12 to 15 voids per 24 hours. Urge urinary incontinence is 3 to 6 episodes per day. She has no symptoms of stress urinary incontinence and no other genitourinary complaints.

Urodynamic studies reveal postvoid residual (PVR) volume 40 mL, multiple involuntary detrusor contractions, and detrusor pressure (Pdet) max 40 cm H20.

Recommended treatment for M.B. includes behavioral therapy—bladder diary, diet modification, and pelvic floor rehabilitation—and a trial of several anticholinergics.

However, she reports only a 50% improvement in symptoms at tolerable doses and still has bothersome urgency and frequency, with 2 to 4 episodes of urge urinary incontinence per day.

M.B. and the urologist agree that the initial conservative therapy was inadequate, and she remains dissatisfied. What are her other options? One is, she will have to live with her condition. Others include pads/diapers or an indwelling catheter. Additional treatment options include mirabegron, an anticholinergic plus mirabegron, sacral neuromodulation, botulinum toxin injection, or augmentation. Bladder augmentation is not an option, as M.B. considers this too invasive at her age.

M.B. seems to be an appropriate patient for botulinum toxin injections, as she has had inadequate efficacy from anticholinergic therapy, is dissatisfied with her current therapy, and wants better control. The urologist discusses the efficacy and safety of onabotulinumtoxinA, checks for willingness and ability to perform clean intermittent catheterization, and asks M.B. if she is receiving botulinum toxin for any other indication.

M.B. agrees to undergo injection with onabotulinumtoxinA 100 U at multiple sites in the bladder in an outpatient procedure.

Sacral Neuromodulation Sacral neuromodulation is generally performed in stages, with a test phase to identify responders. Those who respond proceed to full implantation of a pulse generator and leads.23,24 The technique, believed to work via stimulation through sacral afferents, requires the device to be programmed.24,25 A long-term study showed an 87% efficacy rate at 1 month and 62% at 5 years, defined as ≤50% daily incontinence episodes or pads used.26

Botulinum Toxins Botulinum toxin acts by binding presynaptically to sites on parasympathetic nerve terminals and decreasing the release of acetylcholine, causing a neuromuscular blocking effect (Figure 2).

Several botulinum toxin formulations are available for use in the United States; however, each has a different dose, efficacy, and safety profile, and they should not be considered equivalent in regard to effect or dosing (Table 4).

OnabotulinumtoxinA. In 2 doubleblind, placebo-controlled, randomized, multicenter studies of onabotulinumtoxinA (onaBoNTA) 100 U vs placebo in 1105 patients with OAB who had inadequate response to or were intolerant of an anticholinergic, significant improvement in mean change in daily episodes of urinary incontinence was observed. In Study 1, mean change was *Unlabeled/investigational use.

RUN0913_CME.Chancellor_v2.indd 33

-2.5 vs -0.9 for placebo (baseline 5.5 vs 5.1; P<0.001) and, in Study 2, -3.0 vs -1.1 (baseline 5.5 vs 5.7; P<0.001). Urinary retention at week 12 was 6% (n=31) vs 0% (n=2), and clean intermittent catheterization at any time during the complete treatment cycle was 6.5% (n=36) vs 0.4% (n=2). 27,28 Adverse events (≥2%) at week 12 in patients treated with onaBoNTA and more frequent than in those in the placebo arm were UTI, dysuria, bacteriuria, urinary retention, and elevated residual urine volume.

OnaBoNTA has a boxed warning: its effects may spread from the area of injection to produce symptoms consistent with those of botulism, including swallowing and breathing difficulties that may be life-threatening. Symptoms have been reported hours to weeks after injection, and deaths have been reported.28 Contraindications include hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation; infection at the proposed injection site; and, for intradetrusor injections, acute UTI or acute urinary retention.

OnaBoNTA is also indicated for the treatment of neurogenic lower urinary tract dysfunction, or neurogenic bladder. Autonomic dysreflexia associated with intradetrusor injections of onaBoNTA could occur in patients treated for detrusor overactivity associated with a neurologic condition and may require prompt medical therapy.28

RimabotulinumtoxinB*. A randomized, double-blind, placebo-controlled study of the effects of rimabotulinum­toxinB (rimaBoNTB) 5000 U or placebo injected through a cystoscope on refractory detrusor overactivity found that changes in average voided volume and incontinence frequency over 12 weeks were significantly better in the rimaBoNTB arm. The majority of the 17 patients had idiopathic detrusor overactivity; 3 patients had neurogenic detrusor overactivity. Treatment was generally well tolerated; 2 patients had urinary retention, 1 of whom also had constipation, and 1 patient had constipation and dry mouth.29

Surgical Options Augmentation cystoplasty has a significant risk profile, including bladder stones, mucus, small-bowel obstruction, surgical complications, and

perforation, and is generally reserved for patients refractory to conservative therapy.13,30,31 Other surgical options include continent augmentation cystoplasty, ileal conduit urinary diversion, and intermittent and indwelling catheterization.

Assessing Patient Satisfaction Validated questionnaires can assist in determining the level of satisfaction patients have with treatment. These include the Incontinence Quality of Life Questionnaire (I-QoL), a diseasespecific, 22-item survey to measure the impact of urinary incontinence on patients’ lives, including avoidance and limiting behavior, psychosocial impact, and social embarrassment;32 and the Modified OAB-Patient Satisfaction with Treatment Questionnaire (OABSAT-q), a 16-item survey to assess the

Table 4. Botulinum Toxins Available for Clinical Use Serotype A A A

B

Generic Name

OnabotulinumtoxinA (OnaBoNTA)*

AbobotulinumtoxinA (AboBoNTA)

IncobotulinumtoxinA (IncoBoNTA)

RimabotulinumtoxinB (RimaBoNTB)

Brand Name

Botox

Dysport

Xeomin

Myobloc/ NeuroBloc†

Packaging, U/vial

100

500

100

2500, 5000, 10,000

Specific activity, U/ng

20

40

167

75-125

*Only botulinum toxin approved for OAB in the US. The brand name is Myobloc in the US, Canada, and Korea; and NeuroBloc in the European Union, Iceland, and Norway.

†

Adapted from Albanese A. JAMA. 2011;305(1):89-90.

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CME feature impact of medication on symptoms of OAB and incontinence and on the ability to interact more freely in various situations; questions also focus on cost and treatment satisfaction.33

Conclusion Diagnosis of OAB includes, at a minimum, a thorough history, physical examination, and a urinalysis. Selecting a particular treatment for OAB is based on the severity of symptoms and the extent that these symptoms interfere with the patient’s lifestyle. Therapeutic decisions should weigh the potential benefits of treatment against the risk of treatmentrelated adverse events. Optimal management can lead to improved patient outcomes and quality of life. n

References 1. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology in lower urinary tract function: report of the standardisation sub-committee of the International Continence Society. Urology.

2003;61(1):37-49.

2. Stewart WF, Van Rooyen JB, Cundiff GW, et al.

Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20(6):327-336.

3. Resnick NM. Geriatric incontinence. Urol Clin North Am. 1996;23:55-74.

4. Crespi-Lofton J. Managing adult bladder control problems. J Am Pharm Assoc. 2001;41:S3-S17.

5. Brown JS, Subak LL, Gras J, et al. Urge incontinence: the patient’s perspective. J Women Health.

1998;7(10):1263-1269.

6. Luber KM, Boero S, Choe JY. The demographics of pelvic floor disorders: current observations and future projections. Am J Obstet Gynecol.

2001;184(7):1496-1501; discussion 1501-1503.

7. Ginsberg DA. Part I: Neurogenic bladder: assessment and diagnostic strategies. Renal & Urology News. 2012;11(5):40-44.

8. Pannek J, Stöhrer M, Block B, et al. Guidelines on neurogenic lower urinary tract dysfunction.

European Association of Urology (EAU); 2011 Mar. http://www.uroweb.org/gls/pdf/19_Neurogenic_ LR%20II.pdf. Accessed May 28, 2013.

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

10. Chancellor MB, Anderson RU, Boone TB. Pharmacotherapy for neurogenic detrusor overactivity. Am J Phys Med Rehabil. 2006;85(6):536-545.

11. Gormley EA. Urologic complications of the neurogenic bladder. Urol Clin North Am. 2010;37(4):601-607.

12. Winters JC, Dmochowski RR, Goldman HB, et al.

Urodynamic studies in adults: AUA/SUFU guideline.

J Urol. 2012;188(6 suppl):2464-2472.

13. Gormley EA, Lightner DJ, Burgio KL, et al. Diagnosis and treatment of overactive bladder (nonneurogenic) in adults: AUA/SUFU guideline. J Urol.

2012;188(suppl 6):2455-2463. http://www.auanet. org/common/pdf/education/clinical-guidance/ Overactive-Bladder.pdf. Accessed May 28, 2013.

14. National Institute of Diabetes and Digestive and Kidney Diseases. Daily Bladder Diary. http://kidney. niddk.nih.gov/kudiseases/pubs/diary/diary_508. pdf. Accessed May 28, 2013.

15. Sagar S, Nitti VW. Defining efficacy in the treatment of overactive bladder syndrome. Rev Urol.

2009;11(4):196-202.

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

17. Schabert VF, Bavendam T, Goldberg EL, et al.

Challenges for managing overactive bladder and guidance for patient support. Am J Manag Care.

2009;15:S118-S122.

18. D’Souza AO, Smith MJ, Miller LA, et al. Persistence, adherence, and switch rates among extendedrelease and immediate-release overactive bladder medications in a regional managed care plan.

J Manag Care Pharm. 2008;14(3):291-301.

19. Benner JS, Nichol MB, Rovner ES, et al. Patientreported reasons for discontinuing overactive bladder medication. BJU Int. 2010;105:1276-1282.

20. Mirabegron. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202611Orig1s000TOC. cfm. Accessed May 28, 2013.

21. Wein AJ. Diagnosis and treatment of overactive bladder. Urology. 2003;62(5 suppl 2):20-27.

22. Ellsworth P. Overactive Bladder. Medscape Reference. Updated August 25, 2011. http://emedicine.medscape.com/article/ 459502-overview. Accessed May 28, 2013.

23. Siegel SW, Catanzaro F, Dijkema HE, et al.

Long-term results of a multicenter study on sacral nerve stimulation for treatment of urinary urge incontinence, urgency-frequency, and retention.

Urology. 2000;56(6 suppl 1):87-91.

24. Leong RK, De Wachter SG, van Kerrebroeck PE. Current information on sacral neuromodulation and botulinum toxin treatment for refractory idiopathic overactive bladder syndrome: a review. Urol Int. 2010;84(3):245-253.

25. Medtronic Interstim® Therapy Implant Manual 2006.

26. Groen J, Blok BF, Bosch JL. Sacral neuromodulation as treatment for refractory idiopathic urge urinary incontinence: 5-year results of a longitudinal study in 60 women. J Urol. 2011;186(3):954-959.

27. Nitti VW, Dmochowski R, Herschorn S; EMBARK Study Group. OnabotulinumtoxinA for the treatment of patients with overactive bladder and urinary incontinence: results of a phase 3 randomized placebocontrolled trial. J Urol. 2013;189(6):2186-2193.

28. OnabotulinumtoxinA. http://www.accessdata.fda. gov/drugsatfda_docs/label/2013/103000s5251lbl. pdf. Accessed May 28, 2013.

29. Ghei M, Maraj BH, Miller R, et al. Effects of botulinum toxin B on refractory detrusor overactivity: a randomized, double-blind, placebo controlled, crossover trial. J Urol. 2005;174(5):1873-1877; discussion 1877.

30. Campbell JD, Gries KS, Watanabe JH, et al.

Treatment success for overactive bladder with urinary urge incontinence refractory to oral antimuscarinics: a review of published evidence.

BMC Urol. 2009;9:18-29.

31. Rao PK. Augmentation cystoplasty. http://emedicine.medscape.com/article/ 443916-overview. Accessed May 28, 2013.

32. Wagner TH, Patrick DL, Bavendam TG, et al. Quality of life of persons with urinary incontinence: development of a new measure. Urology. 1996;47:67-71.

33. Margolis MK, Fox KM, Cerulli A, et al. Psychometric validation of the Overactive Bladder Satisfaction with Treatment Questionnaire (OAB-SAT-q).

Neurourol Urodyn. 2009;28(5):416-422.

Disclaimer: The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Boston University School of Medicine or Haymarket Medical Education. The authors have disclosed if there is any discussion of published and/or investigational uses of agents that are not indicated by the FDA in their presentations.

The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of Boston University School of Medicine or Haymarket Medical Education. Before prescribing any medicine, primary references and full prescribing information should be consulted. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. The information presented in this activity is not meant to serve as a guideline for patient management.

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CME Post-test Expiration Date: September 2014 Boston University School of Medicine 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. Which one of the following statements is true about antimuscarinic agents? a. Great variability with regard to adverse events b. Comparative trials have generally demonstrated similar efficacy c. Most effective for mixed incontinence d. 50% of patients discontinue in first year of therapy 2. What are the options for OAB when treatment fails? a. Cystoscopy b. Botulinum toxin A c. Sacral neuromodulation d. All of the above 3. What adverse event is a potential concern with administration of onabotulinumtoxinA? a. Increased postvoid residual volume b. Constipation c. QT prolongation d. Delayed gastric emptying 4. Which of the following statements about OAB is true? a. OAB cannot be diagnosed at the same time as stress urinary incontinence b. OAB is similarly prevalent among men and women c. Women with OAB are less likely to be incontinent compared with men d. Prevalence of OAB is not affected by age 5. Which one of the following best describes stress incontinence compared with OAB? a. Urgency b. Frequency c. Leak with physical activity d. Wake to pass urine at night 6. The subjective complaint of “frequency” indicates an individual voids how many times per day? a. >4/day b. >5/day c. >8/day d. >11/day 7. Which one of the following is NOT a useful tool for managing the majority of patients with initial OAB presentation before a pharmacotherapy trial? a. Bladder diary b. Incontinence Quality of Life Questionnaire c. Modified OAB-Patient Satisfaction with Treatment Questionnaire d. Urodynamic studies 8. What pharmacotherapy should be selected first-line to control symptoms of OAB? a. Antimuscarinic agents b. OnabotulinumtoxinA c. RimabotulinumtoxinB d. None of the above

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