Renal & Urology News November 2013 Issue

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Weekend Hospital Admissions Ominous

© SCIENCE SOURCE / MEDICIMAGE

Inpatient mortality risk among hemodialysis patients is higher compared with weekday admissions

HD PATIENTS admitted on weekends are 18% more likely to die in the first three days.

MAINTENANCE dialysis patients hospitalized over weekends have increased mortality rates and longer lengths of stay compared with those admitted during weekdays, according to researchers.

Ankit Sakhuja, MD, of Cleveland Clinic, and colleagues analyzed 3,278,572 non-elective hospital admissions of maintenance dialysis patients, of which 704,491 occurred over weekends and 2,574,081 occurred during weekdays. After adjusting for potential confounders, patients hospitalized over weekends had a 6% higher in-hospital mortality risk than those admitted on weekdays and an 18% higher mortality risk during the first three days of admission, Dr. Sakhuja’s group reported.

Reduced eGFR Ups CA Death Risk Study: CVCs DECREASED kidney function may cant 18% increase in cancer-specific Implicated in place individuals at increased risk of mortality, independent of age, smokcancer-related death, new study find- ing status, gender, blood pressure, Bacteremias ings suggest. and serum fibrinogen, and fasting In a study that included 4,077 individuals aged 49-97 years, each 10 mL/min/1.73 m2 decrease in estimated glomerular filtration rate (eGFR) was associated with a signifi-

CME FEATURE

blood glucose levels, according to findings published online ahead of print in the American Journal of Kidney Diseases. continued on page 16

Earn 1 CME credit in this issue

Bladder Cancer in the Elderly: Balancing Disease and Surgical Risk PAGE 25

BY JOHN SCHIESZER SAN FRANCISCO—Central venous catheters are significantly associated with the development of vascularaccess-related bloodstream infections (VABSI) in outpatient hemodialysis (HD) patients, according to a new study presented at IDWeek 2013.

The findings suggest that improved infection surveillance by HD providers according to vascular access type may be needed, researchers reported.

In addition, laboratories should provide ongoing notification and review of blood culture results for timely detection and response to VABSIs in HD patients.

“During the investigative period compared to the baseline period, outpatients with central venous catheters were 13 times more likely to develop VABSI than outpatients without central venous catheters,” said study investigator Kavita Trivedi, MD, who is with the Healthcare Associated Infections

Compared with patients admitted on weekdays, those admitted over a weekend were less likely to be discharged to home and more likely to be discharged to long-term skilled nursing facilities, the researchers reported. In addition, the adjusted time to death was 9% shorter and the adjusted length of hospital stay of survivors was 3% longer in patients admitted over a weekend versus those admitted on a weekday.

The phenomenon of more unfavorable outcomes associated with weekend hospital admissions has been demonstrated in other patient populations, including those with acute kidney injury (AKI), myocardial infarction, and stroke, the investigators pointed continued on page 16

IN THIS ISSUE 16 Hip fracture rate declining in hemodialysis patients

17

Kidney function deteriorates after childhood cancer

18 High BMI ups IgA nephropathy renal risk factors 1 2

Epicardial fat predicts hemodialysis patient mortality

23 Study: 24-hour urine

collections underused

24 Dyslipidemia found to increase kidney stone risk

24 High BMI predicts adverse kidney transplant outcomes Health plans with high deductibles affect men more than women PAGE 22

continued on page 16

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Optimal mCRPC Strategies Explored

© PHOTOTAKE / ISM

Study findings suggest that sipuleucel-T can be given concurrently with abiraterone plus prednisone

COMBINATION THERAPIES may help mCRPC patients with bone metastases (above).

MET Trial Proposed for Stones

BY ROSMARY FREI, MSc VANCOUVER—Urologists may want to give patients with acute renal colic a trial of medical expulsive therapy (MET) before recommending early endoscopic stone removal (EESR), a new study suggests.

Patients missed fewer days of work and were less likely to file short-term

CME FEATURE

disability claims after undergoing MET than after having early endoscopic stone removal, researchers reported in a poster presentation at the the 33rd Congress of the Societé Internationale d’Urologie.

John M. Hollingsworth, MD, MS, of the University of Michigan in Ann continued on page 16

Earn 1 CME credit in this issue

Bladder Cancer in the Elderly: Balancing Disease and Surgical Risk PAGE 25

BY JODY A. CHARNOW AMSTERDAM—Studies presented at the 2013 European Cancer Congress may provide insight into how patients with metastatic castration-resistant prostate cancer (mCRPC) respond to various sequences or combinations of recently approved therapies.

For example, researchers from the U.S. reported promising results of a phase 2 trial in which mCRPC patients were coadministered sipuleucel-T—an immunotherapy approved for use in asymptomatic or minimally symptomatic mCRPC patients—with concurrent or sequential abiraterone acetate plus prednisone. The results suggest that sipuleucel-T can be successfully manufactured during concurrent abiraterone acetate plus predni-

Post-Radiation ED Tied to Comorbidities ATLANTA—The number of comorbidities a man has prior to prostate cancer (PCa) radiotherapy influences his risk of erectile dysfunction (ED) after treatment, according to study findings reported at the American Society for Radiation Oncology's 55th annual meeting.

The study looked at the association between development of post-radiotherapy ED and the presence of hypertension, diabetes, and hyperlipidemia prior to treatment.

“Erectile dysfunction is very high in the population we studied, but we need to better understand which men have a higher risk of development of post-treatment ED,” said co-investigator Yuefeng Wang, PhD, a research scientist at Emory University in Atlanta.

“We found that if a man had no vascular comorbidities, then his increased risk for ED post radiation therapy was 40%, but if he had all three comorbidities then the risk for ED went up [by]

sone treatment without affecting product potency and immunologic prime-boost responses.

“These preliminary data are encouraging, and suggest that combining sipuleucel-T and abiraterone acetate plus prednisone is possible,” said lead investigator Eric J. Small, MD, Professor of Medicine and Chief of the Division of Hematology and Oncology at the University of California San Francisco (UCSF). “It is not known if the potential for an immunostimulatory effect from low testosterone levels achieved with abiraterone may be offset by the potentially immunosuppressive effects of prednisone.”

Dr. Small, who is Deputy Director of the UCSF Helen Diller Family continued on page 16

IN THIS ISSUE 15 Post-cystectomy morbidity risk highest in Hispanics 7 1

New device improves urine flow in benign prostatic hyperplasia

18 High-risk prostate cancer not all the same

21 Ultrasound guidance alone effective for PCNL

23 Study: 24-hour urine

collections underused

24 Coffee may lower prostate cancer recurrence risk

24

Dyslipidemia found to increase kidney stone risk Health plans with high deductibles affect men more than women PAGE 22

continued on page 16

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6 Renal & Urology News

NOVEMBER 2013 www.renalandurologynews.com

FROM THE EDITOR EDITORIAL ADVISORY BOARD

Medical Research and the Federal Shutdown

A

fter the end of 16-day federal shutdown in October, media headlines touted the financial impact on America and the cost of restarting the government. An initial analysis from Standard & Poor’s estimated that the shutdown took $24 billion out of the U.S. economy.

But the shutdown had difficult-todefine non-economic effects, such as putting a snag in medical research.

After all, the National Institutes of Health (NIH) in Bethesda, Md., the largest funder of medical research in the world (doling out nearly $31 billion annually), sent most of its employees home. This means that much of the business of medical research, such as grant submissions, reviews, and approvals, had to be put on hold.

An NIH notice issued on October 1, when the shutdown began, read: “For the duration of the funding lapse, applicants are strongly encouraged not to submit paper or electronic grant applications to NIH during the period of the lapse. Adjustments to application submission dates that occur during the funding lapse will be announced once operations resume.”

The same for peer review meetings. “For the duration of the funding lapse, the NIH will not be able to conduct initial peer review meetings—whether in-person or through teleconferences or other electronic media. Also during this time, the NIH staff will not be able to send or receive email messages, or update website information, and NIH computer systems that support review functions will not be operational. When operations resume, those meetings will be re-scheduled and the pending applications will be processed and reviewed as soon as possible.”

Visitors to the PubMed website, which is maintained by the NIH, were told that the site was being run with minimal staffing, which could mean that this essential research tool may have gotten behind in abstracting and indexing the world’s biomedical literature.

The shutdown even affected NIH at the level of patient care. NIH indicated it would not enroll new patients in ongoing studies or clinical trials at the NIH Clinical Center for the duration of the shutdown.

NIH staff will eventually clear the backlog of work that grew during the shutdown and restart the engine that drives this vital research train. It is truly unfortunate that disagreement in the House of Representatives over funding of the Affordable Care Act stopped that train. If the American people have to endure another shutdown, Republicans and Democrats should at least agree to leave medical research alone.

Sincerely, Jody A. Charnow Editor

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 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 Krassi Varbanov

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

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8 Renal & Urology News

NOVEMBER 2013 www.renalandurologynews.com

Contents

NOVEMBER 2013

n

VOLUME 12, ISSUE NUMBER 11

Nephrology

ONLINE

this month at renalandurologynews.com Expert Q&A

Juan Carlos Ayus, MD, Director of Clinical Research at Renal Consultants of Houston, reviews the causes and management of hyponatremia.

8 1

High BMI Increases IgA Nephropathy Renal Risks Patients who are overweight or obese when they are diagnosed with IgA nephropathy have more renal risk factors than normalweight patients.

23

Long-Term Belatacept Treatment Beneficial Belatacept maintains its renal function benefit and safety for at least five years in kidney transplant recipients.

24

Estrogen Affects Women’s Phosphorus Estrogen use by postmenopausal women is associated with significantly lower phosphorus levels, independent of other factors.

29

Antimicrobial Under-Dosing Common in CVVHD Antimicrobial dosing may not meet guidelines in a number of patients receiving continuous venovenous hemodialysis.

Clinical Quiz

Take our latest quiz at renalandurologynews.com /clinical-quiz/. Answer correctly and you will be entered to win a $25 American Express gift card.

Congratulations to our September winner: Brian Golden, MD

News Coverage

Visit our website for coverage of Kidney Week 2013 in Atlanta (Nov. 5-10).

8 1

UTI Risk Unaffected by Catheter Type A study of children with spina bifida shows that the risk of febrile urinary tract infection is similar with polyvinyl chloride (PVC) hydrophilic-coated single-use and PVC multi-use catheters.

23

Repeat BTXA Injections Benefit Patients with Non-Neurogenic OAB Most patients with the condition felt better after each injection of onabotulinumtoxinA.

24

25

29

Bladder Cancer in the Elderly: Balancing Disease and Surgical Risk Daniel J. Canter, MD, vice chairman of the Urologic Institute of Southeastern Pennsylvania and the Department of Urology of the Einstein Healthcare Network, Philadelphia, reviews treatment options, disease progression and survival, and the role of fraility.

Coffee May Lower PCa Recurrence Risk Drinking one cup of coffee per day was associated with a 56% decreased risk of recurrence or progression compared with drinking one cup or fewer per week.

Data Suggest Hypogonadism, Nocturia Link Desmopressin treatment appears to reduce nocturia and other lower urinary tract symptoms while also significantly increasing testosterone levels in men with late-onset hypogonadism.

On further assessment, about 35% of biopsy Gleason score 8 tumors were downgraded to Gleason score 7 or less.

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: • Study Sheds Light on Kidney Donors’ Health Risks • Novel Device Makes It Possible to Self-Test Albumin Levels • Men May Be Better at Blood Sugar Control

25

20

Departments 6

From the Editor U.S. government shutdown

17

News in Brief Device improves urine flow in BPH sufferers

20

Renal Nutrition Update The importance of vitamin D in immune function

22

Men’s Health Update Low testosterone increases risk of dementia

10/25/13 12:06 PM

1

INVOKANATM is the # branded therapy prescribed by endocrinologists when adding or switching non-insulin type 2 diabetes medications*

ENVISION NEW POSSIBILITIES *Data on file. Based on NBRx data sourced from IMS NPA Market Dynamics Database, weekly data through 9/20/13.

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.

Please see additional Important Safety Information and brief summary of full Prescribing Information on the following pages.

002061-130903_I0062_K3_Sita_Ad_FR2.indd 1

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THIS ADVERTISEMENT PREPARED BY NeON Client: J&J Product: Invokana Job#: 5CNT_CAUS_I0062 Job Name: 10062_K3_Sita_Ad Colors: 4C Sizes: Bleed: 11” w x 15” h Sm Trim: 10.5” w x 13” h Lg Trim: 10.75” w x 14” h Live: 9.5” w x 12.5” h

Publications:

Sig

Mac Op QC Editing Copywriting Art Director Art Buying Account Traffic Production DQC

Date

Time

Time Spent

Spell Check

COVERED FOR >75% OF COMMERCIALLY INSURED PATIENTS WITHOUT PRIOR AUTHORIZATION3

INVOKANATM 300 mg demonstrated greater reductions in A1C vs sitagliptin 100 mg at 52 weeks…

...as well as greater reductions in body weight† and systolic blood pressure (SBP)†

Adjusted Mean Change in A1C From Baseline (%): INVOKANA™ 300 mg vs Sitagliptin 100 mg, Each in Combination With Metformin + a Sulfonylurea1

DIFFERENCE FROM SITAGLIPTIN

– 0.37

*

(95% CI: –0.50, –0.25); P<0.05

Change in Body Weight†

Sitagliptin 100 mg + metformin and a sulfonylurea (n=378; mean baseline A1C: 8.13%) INVOKANA™ 300 mg + metformin and a sulfonylurea (n=377; mean baseline A1C: 8.12%)

–0.66

Significant reductions in body weight at 52 weeks, each in combination with metformin + a sulfonylurea (P<0.001)1 >> Difference from sitagliptin‡: 300 mg: –2.8%

Change in SBP† Significant lowering of SBP at 52 weeks, each in combination with metformin + a sulfonylurea (P<0.001)2 >> Difference from sitagliptin‡: 300 mg: –5.9 mm Hg

References: 1. INVOKANA™ [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013. 2. Schernthaner G, Gross JL, Rosenstock J, et al.

Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care. 2013;36(9):2508-2515. 3. Data on file. Janssen Pharmaceuticals, Inc., Titusville, NJ. Data as of 9/17/13.

SGLT2 = sodium glucose co-transporter-2.

Convenient Once-Daily Oral Dosing

With metformin + a sulfonylurea over 52 weeks: INVOKANATM (canagliflozin) 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 secretagogue1

>> Recommended starting dose: INVOKANA™ 100 mg >> Dose can be increased to 300 mg in patients tolerating 100 mg who have an eGFR ≥60 mL/min/1.73 m2 and require additional glycemic control

1

*INVOKANA™ + metformin is considered noninferior to sitagliptin + metformin because the upper limit of the 95% confidence interval is less than the prespecified noninferiority margin of 0.3%.

IMPORTANT SAFETY INFORMATION (cont’d) WARNINGS and PRECAUTIONS >>Hypotension: INVOKANA™ causes intravascular volume contraction. Symptomatic hypotension can occur after 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, angiotensin-convertingenzyme [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™. 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 reninangiotensin-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.

Included 1 monotherapy and 3 add-on combination trials with metformin, metformin + a sulfonylurea, or metformin + pioglitazone.

§

†Prespecified secondary endpoint.

Incidence of Hypoglycemia

002061-130903_I0062_K3_Sita_Ad_FR2.indd 2-3

Adverse Reactions In 4 pooled placebo-controlled trials, the most common (≥5%) adverse reactions were female genital mycotic infection, urinary tract infection, and increased urination.1§

INVOKANATM is not indicated for weight loss or as antihypertensive treatment.

1.03

INVOKANATM provides SGLT2 inhibition, reducing renal glucose reabsorption and increasing urinary glucose excretion.1

‡Adjusted mean.

Learn more at INVOKANAhcp.com/journal

>>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): Dose-related 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 additional Important Safety Information and brief summary of full Prescribing Information on the following pages.

ENVISION NEW POSSIBILITIES

10/10/13 4:38 PM

COVERED FOR >75% OF COMMERCIALLY INSURED PATIENTS WITHOUT PRIOR AUTHORIZATION3

INVOKANATM 300 mg demonstrated greater reductions in A1C vs sitagliptin 100 mg at 52 weeks…

...as well as greater reductions in body weight† and systolic blood pressure (SBP)†

Adjusted Mean Change in A1C From Baseline (%): INVOKANA™ 300 mg vs Sitagliptin 100 mg, Each in Combination With Metformin + a Sulfonylurea1

DIFFERENCE FROM SITAGLIPTIN

– 0.37

*

(95% CI: –0.50, –0.25); P<0.05

Change in Body Weight†

Sitagliptin 100 mg + metformin and a sulfonylurea (n=378; mean baseline A1C: 8.13%) INVOKANA™ 300 mg + metformin and a sulfonylurea (n=377; mean baseline A1C: 8.12%)

–0.66

Significant reductions in body weight at 52 weeks, each in combination with metformin + a sulfonylurea (P<0.001)1 >> Difference from sitagliptin‡: 300 mg: –2.8%

Change in SBP† Significant lowering of SBP at 52 weeks, each in combination with metformin + a sulfonylurea (P<0.001)2 >> Difference from sitagliptin‡: 300 mg: –5.9 mm Hg

References: 1. INVOKANA™ [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013. 2. Schernthaner G, Gross JL, Rosenstock J, et al.

Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care. 2013;36(9):2508-2515. 3. Data on file. Janssen Pharmaceuticals, Inc., Titusville, NJ. Data as of 9/17/13.

SGLT2 = sodium glucose co-transporter-2.

Convenient Once-Daily Oral Dosing

With metformin + a sulfonylurea over 52 weeks: INVOKANATM (canagliflozin) 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 secretagogue1

>> Recommended starting dose: INVOKANA™ 100 mg >> Dose can be increased to 300 mg in patients tolerating 100 mg who have an eGFR ≥60 mL/min/1.73 m2 and require additional glycemic control

1

*INVOKANA™ + metformin is considered noninferior to sitagliptin + metformin because the upper limit of the 95% confidence interval is less than the prespecified noninferiority margin of 0.3%.

IMPORTANT SAFETY INFORMATION (cont’d) WARNINGS and PRECAUTIONS >>Hypotension: INVOKANA™ causes intravascular volume contraction. Symptomatic hypotension can occur after 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, angiotensin-convertingenzyme [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™. 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 reninangiotensin-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.

Included 1 monotherapy and 3 add-on combination trials with metformin, metformin + a sulfonylurea, or metformin + pioglitazone.

§

†Prespecified secondary endpoint.

Incidence of Hypoglycemia

002061-130903_I0062_K3_Sita_Ad_FR2.indd 2-3

Adverse Reactions In 4 pooled placebo-controlled trials, the most common (≥5%) adverse reactions were female genital mycotic infection, urinary tract infection, and increased urination.1§

INVOKANATM is not indicated for weight loss or as antihypertensive treatment.

1.03

INVOKANATM provides SGLT2 inhibition, reducing renal glucose reabsorption and increasing urinary glucose excretion.1

‡Adjusted mean.

Learn more at INVOKANAhcp.com/journal

>>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): Dose-related 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 additional Important Safety Information and brief summary of full Prescribing Information on the following pages.

ENVISION NEW POSSIBILITIES

10/10/13 4:38 PM

INVOKANA™

IMPORTANT SAFETY INFORMATION (cont’d)

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.

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

002061-130903_I0062_K3_Sita_Ad_FR2.indd 4-5

October 2013

002061-130903

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 pruritus, thirst, nausea, and constipation.

Please see brief summary of full Prescribing Information on the following pages.

K02CAN13149

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, 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 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.

(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

10/10/13 4:39 PM

INVOKANA™

IMPORTANT SAFETY INFORMATION (cont’d)

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.

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

002061-130903_I0062_K3_Sita_Ad_FR2.indd 4-5

October 2013

002061-130903

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 pruritus, thirst, nausea, and constipation.

Please see brief summary of full Prescribing Information on the following pages.

K02CAN13149

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, 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 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.

(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

10/10/13 4:39 PM

INVOKANA™ (canagliflozin) tablets

INVOKANA™ (canagliflozin) tablets

(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 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 dosedependent 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 depletion-related 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)

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 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

* 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 anti-microbial 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

002061-130903_I0062_K3_Sita_Ad_FR2.indd 6

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 (nonHDL-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 dilatation were

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www.renalandurologynews.com NOVEMBER 2013

INVOKANA™ (canagliflozin) tablets 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.

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

Renal & Urology News 15

Post-Cystectomy Risk Highest in Hispanics

BY ROSEMARY FREI, MSc VANCOUVER—Americans who are of Hispanic origin are more likely to develop major complications after radical cystectomy than Caucasians, according to a study presented at the 33rd Congress of the Societé Internationale d’Urologie.

Using information from a large administrative database, researchers found a 23.5% rate of major complication within 90 days of surgery among Hispanic-Americans undergoing radical cystectomy compared with a 16.0% rate among whites and a 17.0% rate among African Americans. Compared with whites, Hispanics had an 88% increased odds of major post-cystectomy complications, the researchers reported.

When the researchers analyzed data only from individuals aged 65 and older, they found that the increased major-complication risk for Hispanics remained statistically significant.

When only Medicare beneficiaries were included in analyses, however, the difference lost its statistical significance. Therefore, the team members concluded that being older than 65 and being uninsured or under-insured (that is, not covered by Medicare) may account for at least part of the racial disparity.

“One critical limitation preventing us from further interpreting the dataset is that it lacks disease-specific information such as disease stage and grade,” observed lead investigator Chenchen Feng, MD, from Brigham and Women’s

Hospital in Boston. “We definitely have to find more detailed datasets to be able to do so.”

He and his team hypothesize that barriers to accessing care for Hispanics such as lack of proficiency in English and not having full immigrant status may underlie the phenomenon they observed.

Dr. Feng and his co-investigators used information from the Prospective Rx Comparative Database. It is administered in Charlotte, N.C., and is a repository for data from more than 600 non-federal hospitals across the U.S. They gathered information from patients who had a radical cystectomy from 2003 to 2010. The cohort, in weighted numbers, included 38,903 Caucasians, 2,343 African Americans, 875 Hispanics and 8,864 people from other races.

The groups all had significantly different characteristics. These ranged from a smaller proportion of individuals aged 75 and older in the Hispanic and African-American groups compared to the “other” races; a larger proportion of females among African Americans compared with all of the other race groups; and a larger proportion of Hispanics receiving their surgery in hospitals with more than 600 beds.

A multivariate analysis looking only at patients aged 65 and older showed a significant 82% increased risk for major complications among Hispanics versus whites. n

CKD Linked to Psoriasis MODERATE or severe psoriasis is associated with an increased risk of chronic kidney disease (CKD), researchers reported online in BMJ. Joy Wan, MD, of the University of Pennsylvania in Philadelphia, and colleagues conducted a populationbased cohort study and a nested crosssectional study to examine the risk of CKD in patients with psoriasis. A total of 136,529 patients with mild psoriasis and 7,354 patients with severe psoriasis were matched to 689,702 unaffected patients in the cohort study. The nested study included 8,731 patients with psoriasis matched to 87,310 patients without psoriasis.

In the cohort study, patients with severe psoriasis were at nearly twofold increased risk for incident CKD in adjusted analyses.

Mild psoriasis or psoriasis overall was not associated with a significantly increased risk of incident CKD, the investigators added. In the severe psoriasis group, age was a significant effect modifier. Patients aged 30 years had a 3.8 times increased risk and those aged 60 years had a twofold increased risk. In the nested analysis, moderate and severe psoriasis were associated with a 36% and 58% increased risk of incident CKD, respectively. n

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NOVEMBER 2013 www.renalandurologynews.com

Weekend admissions continued from page 1

out. The potential explanations include differential staffing models with limited availability of clinician expertise, unmeasured differences in severity of illness, and decreased accessibility to diagnostic and therapeutic procedures, the authors wrote.

The potential explanations include availability of clinician expertise.

The researchers, who published their findings in the American Journal of Kidney Diseases (2013;62:763-770), classified weekend admissions as those occurring from midnight Friday to midnight Sunday, and noted that this does not take into account that healthcare services on Friday evenings, early mornings on Mondays , and holidays likely are similar to those provided

Hip Fracture Rate Down in HD Patients, Study Finds HIP FRACTURE rates over time differ markedly between Medicare patients on hemodialysis (HD) and those without end-stage renal disease (ESRD).

The study, which examined data from Medicare beneficiaries aged 66 years and older, found that hip fracture rates increased relatively rapidly among HD patients until 2004 and then decreased relatively rapidly compared with non-ESRD beneficiaries, concluded Thomas J. Arneson, MD, of the Chronic Disease Research Group, Minneapolis Medical Research Foundation, and colleagues.

The adjusted hip fracture rate among HD patients increased from 23.4 events per 1,000 person-years in 1993 to a high of 41.4 events per 1,000 person-years in 2004, and then decreased to 31.9 events per 1,000 person-years by 2010, the researchers reported in the American Journal of Kidney Diseases (2013;62:747-754).

The adjusted hip fracture rate in Medicare non-ESRD patients rose slightly from 9.6 to 10.6 events per 1,000 person-years from 1993 to 1996 and then decreased to 8.0 events per 1,000 person-years by 2010.

“The trend is different in the general non-ESRD Medicare population; it shows a small steady decrease in hip fracture rates starting in the late 1990s, suggesting that the observed trend in the hemodialysis population is due to factors specific to hemodialysis patient characteristics and clinical management,” the researchers wrote.

Dr. Arneson’s group noted that changes in the management of mineral bone disease in chronic kidney disease patients may partially explain the hip fracture trends in dialysis cohorts. These changes include the use of cinacalcet, a calcimimetic agent approved in March 2004, and lanthanum carbonate, a non-calcium phosphate binder approved in October 2004. “Possibly, the steep downward trend in hip fracture rates

Reduced eGFR continued from page 1

© CMSP

The highest risks of cancer death associated with reduced kidney function were in subjects with urinary tract and breast cancers, Germaine Wong, MD, PhD, of Westmead Hospital in New South Wales, Australia, and colleagues reported. Compared with subjects with an eGFR of 60 or higher,

Higher breast cancer death risk linked to low eGFR.

those with an eGFR below 60 had a 2.5 times increased risk of death from urinary tract cancers after adjusting for age, gender, and smoking status. Women with an eGFR below 60 had a twofold increased risk of death from breast cancer, after adjusting for age, smoking, and employment status.

Additionally, among subjects diagnosed with incident cancer after the

RUN1113_Cover_Neph.indd 16

over weekends. “We therefore may have underestimated the worse outcomes over weekends,” they stated.

Findings of the new study echo those of a study published in the Journal of the American Society of Nephrology (2010;21:845-851) showing that patients with AKI are more likely to die if they are admitted to a hospital on a weekend rather than a weekday.

The study, led by Glenn Chertow, MD, of Stanford University School of Medicine in Stanford, Calif., found that AKI patients admitted on weekends were 22% more likely than their weekday counterparts to die by day 3 of their stay and 7% more likely to die during their stay overall. In smaller hospitals, these percentages rose to 34% and 17%, respectively.

At the American Urological Association annual meeting in May, researchers reported study findings showing that patients with metastatic prostate cancer have a 23% increased risk of death if they visit a hospital emergency department on a weekend rather than a weekday, in adjusted analyses. n

start of the study, the overall risk of cancer death increased significantly by at least 14% for each 10 mL/min/1.73 m2 decrease in eGFR, in adjusted analyses.

In this group of cancer patients, participants with an eGFR below 45 had a 2.3-fold increased risk of cancer death than those with an eGFR of 75 or higher.

“Our observed link between reduced kidney function and cancer mortality is novel,” the authors wrote. “Although there are emerging data showing an increased risk of non-cardiovascular death in the non-dialysis-dependent population, the linear association between decreased kidney function and cancer-specific mortality reported is a new finding.”

Dr. Wong’s group observed that epidemiologic studies suggest that cancers of the urinary tract may be more resistant to treatment and prone to recurrence among those with decreased renal function.

The investigators noted that breast cancer is one of the few cancers that do not incur a heightened risk in patients with kidney disease and with kidney transplants. “The observed increased risk of death from breast cancer in women with reduced eGFR therefore is unexpected and strengthens our hypothesis that having decreased kidney function itself is a predictor for poor cancer outcomes,” they wrote.

During a median follow-up period of 12.8 years, 1,418 deaths occurred. Of these, 370 were due to cancer. n

in hemodialysis patients from 2004 to 2010 may be explained in part by the market introduction of one or both agents; however, this is speculative,” they wrote. n

CVC-related bacteremia continued from page 1

Program in the California Department of Public Health in Richmond.

She and her colleagues noted that there has been a concerted national effort to increase the use of arteriovenous fistulas (AVFs) and arteriovenous grafts (AVGs) and decrease the use of central venous catheters (CVCs). CVCs remain the most common form of access in outpatient HD centers in the U.S., however.

A Health Maintenance Organization in October 2011 noted a cluster of 11 outpatients who developed VABSIs associated with one HD provider in two counties in California during a four-month period. This prompted an investigation and the current study.

The investigators analyzed patients based on access type and blood culture data where the cluster of cases occurred. For comparison, they also looked at non-HMO patients at the same dialysis centers. The researchers compared the VABSI rates from baseline (January to June rates) to the investigative period (July to October

rates). Nine HD centers were involved in this study; infection control audits were conducted at three centers.

The VABSI rates for the HD centers overall were low compared with national rates. The study, however, revealed a rise in VABSI rates during the investigative period associated with patients who had CVCs. No CVC breaches were observed.

“These findings may be relevant to other outpatient hemodialysis settings since nine hemodialysis centers were included in the investigation,” Dr. Trivedi told Renal & Urology News. “In patients requiring chronic hemodialysis, many patients continue to have central venous catheters as their only type of vascular access, which can increase risk of developing VABSI. Nephrologists should consider establishing alternate types of vascular access more quickly. Additionally, nephrologists should assist outpatient hemodialysis centers in improving infection surveillance for timely detection and response to VABSI.” IDWeek 2013 was sponsored by the Infectious Diseases Society of America and three other professional societies. n

10/25/13 10:18 AM

16 Renal & Urology News

NOVEMBER 2013 www.renalandurologynews.com

Optimal mCRPC continued from page 1

Comprehensive Cancer Center, also noted that the study demonstrated that the co-administration of sipuleucel-T with abiraterone acetate and prednisone was generally well tolerated, and did not affect the product characteristics of sipuleucel-T or its capacity to show an immune response.

Other studies presented at the conference suggest that cabazitaxel may offer advantages over abiraterone acetate for second-line treatment in mCRPC patients whose disease has progressed while on docetaxel. In a study of 113 postdocetaxel patients, Guru Sonpavde, MD, Director of Urologic Oncology at the University of Alabama in Birmingham, and colleagues at the US Oncology Network found that cabazitaxel followed by abiraterone acetate (DCA) is associated with better outcomes than abiraterone acetate followed by cabazitaxel (DAC) even after controlling for clinical prognostic factors. The median overall survival was 18.2 months among the 77 men in the DCA group compared with 11.8 months among the 36 men in the DAC group. The median time to treatment failure (from the start of secondline therapy post-docetaxel to the end

MET trial proposed continued from page 1

Arbor, and co-investigators analyzed administrative data from MarketScan to find records of patients aged 18-64 years with renal colic.

The study, which was funded in part by U.S. Agency for Healthcare Research & Quality, excluded individuals with febrile urinary tract infections or renal failure combined with ureteral stones because they are not candidates for MET. The study also excluded patients who had been prescribed an alpha or calcium channel blocker within the 30 days before an index emergency room visit for acute renal colic. The researchers’ goal was to isolate the treatment effect of MET. The investigators focused on 257 patients who received MET. All filled a prescription for nifedipine, tamsulosin, doxazosin, terazosin, alfuzosin, or prazosin within three days of their index emergency department (ED) visit. The investigators compared these patients with a propensity-score matched group of 257 patients who underwent EESR. The MET and EESR groups had a mean age of 47.0 and 46.6 years, respectively, and similar proportions

RUN1113_Cover_Uro.indd 16

of second-line therapy) was 5.2 months in the DCA group versus 4.3 months in the DAC group. The median duration of cabazitaxel treatment was significant longer in the DCA than the DAC group (195 vs. 89), with 22% of patients in the DCA group receiving less than three months of cabazitaxel compared with 64% of those in the DAC group. The median duration of abiraterone acetate treatment was similar in both groups: 126 days in the DCA group and 123 days in the DAC group.

As for why fewer patients received cabazitaxel after abiraterone acetate rather than the reverse, Dr. Sonpavde told Renal & Urology News, “Our hypothesis is that this may be due to poorer performance status later in the disease course that render patients ineligible to receive chemotherapy or renders them suboptimal for a longer course of chemotherapy.

In contrast, abiraterone is more tolerable and may be more feasible later in the disease course even with poorer performance status.”

In light of study findings, Dr. Sonpavde said, clinicians should at least consider tailoring therapy. “Perhaps those with good performance status after docetaxel should have a discussion about cabazitaxel as well as abiraterone and make a decision after considering these data.”

In a separate study of 129 mCRPC

of patients who lived in urban areas (89.1% and 88.3%) and who were employed full time (89.8% and 93.4%).

The two groups also were similar with respect to geographic regions in which they resided (Northeast, Midwest, South, and West).

Results showed that 16.5% of the EESR group filed short-term disability claims compared with 6.0% of the MET group, which translated into a 67% decreased odds of filing a shortterm disability claim with MET versus EESR. Among those who filed a shortterm disability claim, the mean number of days missed from work was 1.8 in the surgery group compared with 0.9 in the MET group.

“An initial trial of MET is associated with significantly lower indirect costs to the patient when compared to early endoscopic stone removal,” the investigators concluded in their poster.

In an interview with Renal & Urology News, co-investigator Brent K. Hollenbeck, MD, of the University of Michigan in Ann Arbor, noted, “Future studies are needed to evaluate for potential differences in indirect costs across broader populations such as the elderly and the uninsured.” n

patients who progressed on docetaxel, Michel D. Wissing, MSc, of Leiden University Medical Center in Leiden, the Netherlands, and colleagues found that DCA was associated with an overall survival rate similar to that of DAC. The patients treated with DCA, however, had significantly better biochemical progression-free survival (9.2 vs. 7.4 months). The 129 patients included 61 patients who received DCA and 68 who received DAC. “There seems to be no advantage for giving abiraterone before cabazitaxel when giving both agents,” Wissing said.

“Overall survival did not differ significantly, time to PSA progression was better in patients receiving cabazitaxel before abiraterone than vice versa, and there was a similar trend for PFS.” If a physician plans to give a patient both cabazitaxel and abiraterone, Wissing said, he would recommend giving cabazitaxel first, based on his team’s findings. If the patient has experienced heavy toxicity from docetaxel or is in relatively poor physical condition, it may be better to start with abiraterone.

Both agents had a decreased antitumor effect as third-line treatment, but Wissing noted that “there were still some partial responses in patients, so patients should still receive such third-line therapy if they are eligible.” Some research suggests the

Post-radiation ED continued from page 1

approximately 75%.”

“This is the first study of its type,” said co-investigator Ashesh Jani, MD, Professor of Radiation Oncology at Emory in Atlanta. “Our study shows vascular morbidity has a direct consequence on the ability to preserve erections after radiation therapy.”

Vascular comorbidities are known ED risk factors, but no data were previously available on the effects of vascular comorbidities on ED incidence after PCa radiotherapy, he said.

The study cohort included 267 Caucasian and 465 African-American men who received external beam radiotherapy, brachytherapy, or both, with or without hormone therapy, from 1999 to 2010. The Caucasian and African-American groups had mean ages of 68.6 and 63.4 years, respectively.

Researchers ascertained patients' number of pre-radiation vascular comorbidities by medical history and medication list. They defined ED by use of erectile aids or by documentation of moderate or high sexual dysfunction on patient history. ED rates

presence of cross-resistance between docetaxel and abiraterone. “Our study results suggest the same may be true for cabazitaxel and abiraterone.” He added, however, that their study does not give a definite answer because other factors could have biased findings. For example, patients were probably in worse condition at this stage of their disease.

Nevertheless, another study also presented at the conference demonstrated cabazitaxel resistance in abirateroneresistant cell lines, he noted.

Also at the conference, Eleni Efstathiou, MD, of M.D. Anderson Cancer Center in Houston, and colleagues presented findings of a study demonstrating that a combination of enzalutamide and abiraterone acetate achieves steeper declines in PSA levels in men with mCRPC compared with either drug alone. Results showed that 72% of patients achieved a 50% of greater decrease in PSA, 48% achieved a 90% or greater decrease, and 10% achieved undetectable levels.

By comparison, phase 3 trial results showed that 54% of patients treated with enzalutamide (N Engl J Med 2012;367:1187-1197) and 29% of those treated with abiraterone (N Engl J Med 2011;364:1995-2005) achieved a 50% of greater decline in PSA. n

were analyzed pre-radiation therapy as well as one, two, and four years postradiation therapy.

For the overall cohort, ED incidence progressively increased from 22% prior to radiotherapy to 58% at four years post-radiation therapy. Preradiation therapy incidence rates were slightly among African Americans than Caucasians (23% vs. 20%) due to a higher incidence of vascular comorbidities in the African Americans.

Among Caucasians, the presence of zero, one, two, or three comorbidities was associated with a 40%, 55%, 60%, and 71% incidence of ED, respectively. Among African Americans, the incidences were 46%, 57%, 64%, and 76%, respectively. None of the differences between the groups were statistically significant.

“Clinicians can use the results of the study to provide estimates of postradiotherapy erectile dysfunction as a function of vascular comorbidities when counseling patients on treatment options for prostate cancer,” Dr. Jani told Renal & Urology News. The study also provides preliminary data for prospective trials aimed at aimed at decreasing the likelihood of this complication, he added. n

10/25/13 10:21 AM

www.renalandurologynews.com NOVEMBER 2013

Renal & Urology News 17

News in Brief

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

Short Takes CKD On the Rise in Individuals Aged 80+

device as a less invasive alternative

Efforts to address chronic kidney

option for men who cannot tolerate

disease among individuals aged 80

available drug therapies. The FDA’s

years and older may be necessary,

review of the UroLift system included

wrote the authors of a research letter

data from two clinical studies involving

in the Journal of the American Medical

a total of 274 men with BPH. The stud-

Association (2013;310:1284-1286).

ies found a 30% increase in urine flow

C Barrett Bowling, MD, of Emory

and a steady amount of residual urine in

University in Atlanta, and colleagues

the bladder.

to surgery for BPH treatment and an

found that the prevalence of estimated than 60 mL/min/1.73 m in this popu-

Citrus Component Thwarts Kidney Cysts

lation rose from 40.5% in 1988–1994

The dietary flavonoid naringenin has

to 49.9% in 1999–2004 and 51.2% in

been found to regulate the PKD2

2005–2010. The prevalence of a more

protein responsible for polycystic

severe reduction in eGFR (less than 45

kidney disease. Found in grapefruits

mL/min/1.73 m2) rose from 14.3% in

and other citrus fruits, naringenin in-

1988–1994 to 18.6% in 1999–2004

hibited the formation of cysts in vitro

and 21.7% in 2005–2010.

and in a mammalian kidney cell line.

glomerular filtration rate (eGFR) of less 2

When PKD2 levels were reduced in

New Device Improves Urine Flow in BPH

the cells, the block in cyst formation

The FDA has approved the first perma-

PhD, of Kingston University, Kingston

nent implant to relieve low or blocked

upon Thames, Surrey, U.K., and fel-

urine flow in men aged 50 years and

low researchers stated in the British

older with benign prostatic hyperplasia

Journal of Pharmacology that further

(BPH). Manufactured by NeoTract, the

studies will investigate naringenin as

UroLift System relieves urine flow by

a potential new therapeutic agent

pulling back prostate tissue pressing

in autosomal dominant polycystic

on the urethra. The FDA describes the

kidney disease.

was also reduced. Mark A. Carew,

Shortening Medical School In a recent online poll, Renal & Urology News asked readers: Can medical school training be shortened from four years to three without compromising physician competence? Here are the results based on 167 responses.

Yes: 32.34%

No: 64.07%

Do not know: 3.6%

0

RUN113_NewsinBrief.indd 1

10

20

30

40

50

60

70

80

Kidney Function Deteriorates Long After Childhood Cancer S

urvivors of childhood cancer are at risk for premature chronic renal failure as their glomerular function continues to deteriorate, according to a study of 1,122 childhood-cancer survivors aged 18 years and older.

After a median follow-up of 21 years after cancer diagnosis, glomerular function deteriorated over time in all subjects, particularly those treated with higher doses of cisplatin, researchers reported in Cancer Epidemiology, Biomarkers & Prevention (2013;22:1736-1746). Cisplatin, ifosfamide, and nephrectomy were associated with worse glomerular function that persisted during the entire follow-up period. Survivors treated with potentially nephrotoxic medications had a significantly lower glomerular filration rate and higher glomerular dysfunction probability up to 35 years after cancer diagnosis compared with survivors who did not undergo nephrotoxic therapy.

New AUA/ASTRO Guideline Addresses PCa Radiotherapy T

he American Urological Association (AUA) and the American Society for Radiation Oncology (ASTRO) have issued a joint guideline for the use of radiation therapy after radical prostatectomy (RP) for patients with and without evidence of prostate cancer recurrence, published in The Journal of Urology (2013;190:441-449) and in the International Journal of Radiation Oncology, Biology, Physics (2013;86:822828). The guideline recommends that patients with adverse pathologic findings at prostatectomy, such as seminal vesicle invasion and positive surgical margins, should be offered adjuvant radiotherapy and should be informed that compared with RP alone, adjuvant radiation therapy reduces the risk for biochemical recurrence, local recurrence, and clinical progression of cancer. Salvage radiotherapy should be offered to patients with biochemical or local recurrence after RP in whom there is no evidence of distant metastatic disease. Clinicians should define biochemical recurrence as a detectable or rising PSA value after surgery that is at least 0.2 ng/mL, with a second confirmatory level of at least 0.2 ng/mL.

Living Donor Comorbidities Are Increasing, Study Finds C

omplications and hospital lengths of stay after kidney donation declined from 10.1% and a mean 3.7 days, respectively, in 1998 to 7.6% and a mean of 2.5 days, respectively, in 2010, but presence of documented comorbid conditions has increased, a study of living kidney donors has revealed.

Jesse D. Schold, PhD, and colleagues reported in the Clinical Journal of the American Society of Nephrology that depression, hypothyroidism, hypertension, and obesity became more prevalent among donors over time, with longer lengths of stay associated with obesity, depression, hypertension, and pulmonary disorders. Men and donors with hypertension were more likely to have perioperative complications than were other donors. Complication rates and lengths of stay among kidney donors were similar to those of patients undergoing appendectomies or cholecystectomies.

10/28/13 4:35 PM

18 Renal & Urology News

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UTI Risk Unaffected by Catheter Type Risk of febrile UTI is similar with PVC hydrophilic-coated single-use and PVC multi-use catheters

BY JILL STEIN BARCELONA—A single-use hydrophilic-coated polyvinyl chloride (PVC) catheter appears to be no more effective than a PVC multi-use catheter for preventing febrile urinary tract infection (UTI) in children with spina bifida performing clean intermittent catheterization long term, Canadian investigators reported at the 43rd annual meeting of the International Continence Society.

“Although intermittent catheterization is a common procedure for patients with an incomplete bladder, UTIs are frequent and can pose a major health problem in some patients,” Katherine Moore, PhD, Professor Emeritus of Nursing at the University of Alberta in Edmonton, explained. “It has been suggested that a sterile, single-use, hydrophilic-coated catheter might reduce bacterial invasion better than a multi-use catheter washed in the standard of care manner with soap

High-Risk PCa Not All the Same

BY ROSEMARY FREI, MSc VANCOUVER—Prostate cancer (PCa) patients who have biopsy Gleason scores of 8, 9, or 10 are lumped together as having “high-risk” disease, but they represent individual subgroups with different long-term oncologic outcomes, according to a study by the European Multicenter Prostate Cancer Clinical and Translational research group. In particular, Gleason 8 tumors are associated with a substantially better prognosis after radical prostatectomy (RP) than Gleason 9 and 10 tumors.

The study, by Steven Joniau, MD, PhD, of the University Hospitals Leuven, Belgium, and colleagues included 344 men who underwent RP with pelvic lymph node dissection for Gleason 8-10 disease. The men had a minimum of 10 years of follow-up.

The researchers found that the 10-year biochemical recurrence-free survival was 42.9%, 25.1%, and 28.6% for patients who had biopsy Gleason 8, 9, and 10 tumors, respectively. The 10-year clinical progression-free survival was 70.7%, 47.2%, and 25%,

RUN1113_ICS_1.indd 1

and water, air-dried, and then re-used by the same individual. However, we found no evidence to indicate that the incidence of UTI is affected by catheter type in this population.”

Dr. Moore also pointed out that while more than 25 randomized, controlled studies have examined long-term bladder management by intermittent catheterization, prior investigations have had multiple limitations. “For example, all of them were underpowered and had attrition issues,” she said. “In addition, studies had varying definitions of UTI ranging from ‘the presence of bacteria in the urine’ to ‘the presence of symptomatic UTI.’ ” The Canadian team randomized 68 patients to 24 weeks of single-use hydrophilic or multi-use PVC catheters for clean intermittent catheterization (CIC) after which they crossed over to 24 weeks of the alternate catheter.

Study participants were children

respectively. The 10-year cancer-specific survival was 84.9%, 66.1%, and 50%. After adjusting for preoperative PSA level, clinical T stage, and age, men with a biopsy Gleason score of 9 and 10 had an approximately 2.5 and 4.0 times higher risk for clinical progression and cancer-related death compared with men who had a biopsy Gleason score of 8, according to the investigators.

In a poster presented at the 33rd Congress of the Societé Internationale d’Urologie, the researchers concluded that patients with a biopsy Gleason score of 8 “represent good candidates for RP as primary treatment.

Conversely, biopsy Gleason scores 9 and 10 define subgroups with remarkably worse clinical progression-free and cancer-specific survival thus underlining important heterogeneity within the group of high-grade PCa.” The researchers acknowledged that the small sample size of men with Gleason 10 biopsy scores (seven patients) is a study limitation.

In an interview with Renal & Urology News, Dr. Joniau said he was not surprised by these results. “On further assessment, about 35% of biopsy Gleason score 8 tumors were downgraded to Gleason score 7 or less, while in those with biopsy Gleason 9-10 this percentage was negligible.” n

with spina bifida living in the community who either self-administered CIC or received CIC consistently by the same person at least three times a day. Symptomatic UTI was defined as positive leukocytes plus at least one of several symptoms which included fever,

Study compared catheter types in children with spina bifida. flank pain, increased incontinence, malaise, and cloudy or malodorous urine requiring antibiotic treatment.

Results in 46 patients over 48 weeks showed that the mean total weeks of self-reported UTI was 3.6 weeks and 2.3 weeks in the hydrophilic single-use and multi-use PVC groups, respectively.

The difference between the two groups was not statistically significant on any variables, including symptoms besides fever, antibiotic use for any reason, and days missed for any activity including physician visits or school.

Elsewhere at the ICS, a team from St. George Hospital in Sydney, Australia, reported that the rate of bacterial cystitis and symptomatic UTI was not different between groups using noncoated multi-use or single-use catheters.

Dr. Moore cautioned that while her study was underpowered despite major attempts at recruitment, the findings are nonetheless clinically relevant. For children with limitations in manual dexterity, the PVC multi-use catheter was easier to use. Several caregivers, however, reported that they found that the hydrophilic, single-use catheter was very easy to use and also that the packaging made catheterization in a public washroom sanitary and “worry-free.” n

High BMI Increases IgA Nephropathy Renal Risks PATIENTS who are overweight or

included 102 patients with a BMI of

obese when they are diagnosed with

25-29.9 (overweight) and 34 had a BMI

IgA nephropathy (IgAN) have more

of 30 or higher (obese).

renal risk factors than normal-weight

At diagnosis, 52.9% of overweight/

patients, and these risk factors trans-

obese patients had hypertension

late into a worse prognosis, according

compared with only 24.6% of normal-

to researchers.

BMI patients, and 39.7% of overweight/

Overweight or obesity increased

obese patients had proteinuria of

hypertension frequency, proteinuria

1 g/day or more compared with 22.1%

level, and severity of some renal lesions

of normal-BMI patients. The over-

at diagnosis, which placed patients at

weight/obese group also had worse

higher risk for stage 3 or higher chronic

histopathologic lesion scores and

kidney disease (CKD) and dialysis or

worse estimated glomerular filtration

death when compared with normal-

rate (eGFR) than the normal-BMI group

weight patients, investigators reported

(69.1 vs. 80.2 mL/min/1.73 m2).

online ahead of print in Nephrology Dialysis Transplantation.

Francois Berthoux, MD, and col-

The primary composite endpoint of dialysis or death was reached by 21.3% of overweight/obese patients com-

leagues at University Hospital of

pared with only 13.9% of normal-BMI

Saint-Etienne in Saint-Etienne, France,

patients. At last follow-up, the propor-

prospectively studied data from 331

tion of patients with CKD stage 3 or

IgAN patients. At diagnosis, 195

higher was 43.4% in the overweight/

patients had a normal body mass

obese group and 21% in the normal-

index (BMI), defined as less than 25

BMI group. The final eGFR was 59.3 in

kg/m , and 136 had an elevated BMI

overweight/obese patients versus 73.4

(25 or higher). The elevated-BMI group

in normal-BMI patients. n

2

10/25/13 12:09 PM

20 Renal & Urology News

NOVEMBER 2013 www.renalandurologynews.com

Renal Nutrition Update V

itamin D is often recognized for its impact on bone metabolism, but it is also an important regulator of immune function. In patients suffering from sepsis, parathyroid hormone (PTH) typically increases while calcium levels decrease. In normal physiologic circumstances, PTH would stimulate increased conversion of the substrate 25(OH)D to the active 1,25(OH)D via the 1α-hydroxylase enzyme primarily found in renal tissues. As sepsis continues, though, PTH levels tend to decrease while calcium levels typically remain depressed. This altered relationship indicates that other factors are altering the regulation of this pathway (Endoc Metab Immune Disord Drug Targets 2013;13:135142). It is known that various other tissues also express 1α-hydroxylase activity, and the purpose primarily may be for immunologic responses (J Steroid Biochem Mol Biol 2007;103:316-321). Active 1,25 (OH)D stimulates the vitamin D nuclear receptor in neutrophils and macrophages

(serum 25(OH)D 15 ng/mL or less) and insufficiency (25(OH)D 15-30 ng/mL) have an increased risk for sepsis (Crit Care Med 2013; published online ahead of print). Those with deficiency had a 1.5 times increased risk. Each 5 ng/mL increase in 25(OH)D was associated with a 4% reduction in risk. Mortality risk after 30 days was 1.6 times greater in septic patients with deficient or insufficient vitamin D. In subanalyses of patients with more defined physiologic data for analysis of APACHE IIdefined sepsis, every 5 ng/mL increase in 25(OH)D resulted in a 19% reduced risk of sepsis or septic shock. Furthermore, an expanded data set found a 2.5 times increased risk in sepsis or septic shock between sufficient and deficient vitamin D status. Another investigation found that patients deficient in 25(OH)D had a 1.85 times increased risk of mortality 30 days after critical care initiation, and the association remained significant at 90 and 365 days after (Crit

Patients with CKD have increased risk for endothelial calcification relating to elevated calcium and phosphorus aggregating into these tissues. to upregulate the production of cathelcidin and defensin. These peptides have antimicrobial properties and improve overall immune function.

Vitamin D and sepsis Although 1,25(OH)D is the active form of vitamin D, the body keeps this hormone more tightly regulated than its substrate, 25(OH)D. Thus, the substrate is more often used to assess vitamin D status and deficiency. Multiple studies have found increased risks of sepsis and mortality with low vitamin D status. Patients with vitamin D deficiency

On The Web RUN1113.RenalNut.indd 20

Care Med 2012;40:63-72). Of note, the investigators found that rate of sepsis did not skew the results. Another study found that patients with acute kidney injury, when compared with controls, had reduced 1,25(OH)D and vitamin D binding protein at enrollment. In these patients, 25(OH)D was significantly associated with mortality (Clin Endocrinol (Oxf.) 2013;79:491-498).

Another group of researchers focused specifically on the active 1,25(OH)D. In their cohort, all patients who entered the critical care unit were insufficient in 25(OH)D, and no significant differ-

© THINKSTOCK

Adequate vitamin D levels are important for immunologic regulation in patients with chronic kidney disease BY GRISSIM CLARK CONNERY, MS, RD, LD

Adequate vitamin D levels can be repleted by supplementation or sun exposure.

ence was found between 25(OH)D or PTH with regards to 30 day mortality.

Patients with 1,25(OH)D values less than 13.6 pg/mL had significantly reduced survival time (PLoS One 2013;8:e64348).

As PTH levels increased in this cohort, 1,25(OH)D levels tended to decrease. As stated before, increases in PTH normally stimulate increases in 1,25(OH)D, such as in response to calcium deficiency. Dysregulation of this relationship may primarily relate to immune system regulation (J Steroid Biochem Mol Biol 2007;103:316-321).

Vitamin D repletion A recent meta-analysis analyzed the effects of vitamin D supplementation in chronic kidney disease (CKD) and demonstrated that vitamin D supplementation significantly increased 25(OH)D levels and decreased PTH. Hypercalcemia and hyperphosphatemia incidence was low in the study populations (Clin J Am Soc Nephrol 2011;6:5062). Clinical outcomes such as mortality or infection were not analyzed in this dataset, but at this time, it does help support the evidence that vitamin D repletion can occur without excessive risk of

elevated blood mineral levels. Patients with CKD have increased risk for endothelial calcification related to elevated calcium and phosphorus aggregating into these tissues. Repleting vitamin D levels with supplementation carries a risk of simultaneously increasing absorption of these minerals in patients with hypercalcemia or hyperphosphatemia. CKD and dialysis patients suffer increased inflammation and immunologic stress due to disease progression and treatments. Thus, adequate vitamin D for immunologic regulation is important. The role of the dietitian is thus crucial to help ensure that vitamin D levels can be repleted by supplementation or sun exposure while decreasing oral intake of calcium and phosphorus as necessary. Phosphorus intake is particularly problematic because of phosphorus additives in various foods and greater than 90% absorption rates. Dietary education on these topics may allow for adequate vitamin D therapy without complications. 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.

10/25/13 12:10 PM

www.renalandurologynews.com NOVEMBER 2013

Renal & Urology News 21

Epicardial Fat Predicts HD Patient Mortality INCREASING epicardial adipose tissue (EAT) is associated with greater mortality risk among incident hemodialysis (HD) patients, a study suggests.

A team led by Paolo Raggi, MD, Director, Mazankowski Alberta Heart Institute and Professor of Medicine, University of Alberta Capital Health Chair in Cardiac Research, Edmonton, studied 95 incident HD patients who participated in the randomized Renagel in New Dialysis (RIND) patients study and who had available baseline EAT measurements as determined by computed tomography.

During a median follow-up period of 49.3 months, 27 patients (28.4%) died. The five-year survival rate was 44.6% for patients with EAT above the median value compared with 71,2% for those with EAT above the median,

Dr. Raggi and his colleagues reported online ahead of print in Nephrology Dialysis Transplantation. Each 10 cc increment in EAT was associated with a significant 6% increase in death risk.

Results also showed that coronary artery calcification and age were significantly associated with all-cause mortality.

Although the extent of EAT has been associated with the presence of subclinical atherosclerosis and adverse outcomes in the general population, the authors noted, their published findings are the first report on the prognostic impact of EAT in patients with stage 5 chronic kidney disease.

Due to the ease with which EAT is measured in patients, in the future it may become a useful method to assess the risk noninvasively in CKD patients, a population with extremely high rates of cardiovascular diseases, according to the investigators. n

WE’RE

CHANGING THE WAY

US Guidance Alone Okay for PCNL

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

PERFORMING percutaneous nephrolithotomy (PCNL) under

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

ultrasound (US) guidance alone

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

is safe and convenient, according

experts in both traditional methods of urologic surgery and in

to investigators in China.

cutting-edge robotic surgery. But our doctors also recognize when the best management is not an operation, but careful

A team at Sheng Jing Hospital, China Medical University,

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

Shenyang, China, led by Fei

all options to ensure patients receive the right treatment at

Xiang, MD, PhD, studied 679

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

patients who underwent PCNL

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

under US guidance alone. Of these

more at UPMCPhysicianResources.com/ProstateCancer.

patients, 26 had bilateral stones.

The overall stone-free rate at four weeks after surgery was 92.6% in patients with a single stone and 82.9% in patients with staghorn or multiple stones, the researchers reported in BJU International (2013;112:965-971).

Auxilliary treatments were performed one week after the primary procedure in 111 cases (15.7%) for residual stones larger than 4 mm.

These treatments included shockwave lithotripsy in 52 patients, rePCNL in 41, and ureteroscopy in 18.

A total of 94 grade 1 (13.3%), 17 grade 2 (2.4%), and two grade 3

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

(0.3%) complications, but no grade 4 or 5 complications, occurred. n 2145_UPMC_Urology_7x10.indd 1

8/21/13 11:41 AM

22 Renal & Urology News

NOVEMBER 2013 www.renalandurologynews.com

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

Short Takes High-Deductible Health Plans Affect Men More A new study by Katy B. Kozhimannil, PhD, of the University of Minnesota, and colleagues reveals a sex-specific response to high-deductible health plans (HDHP). The study, published in Medical Care (2013;51:639-645), followed more than 6,000 men and women before and after their employers mandated a switch from traditional HMO to an HDHP, and found a dramatic decrease in the number of emergency room (ER) visits. Men reduced ER visits at all severity levels (low, intermediate, and high) by 21.5%-34.4%, whereas women reduced only low severity visits (by 27%). Men also had a 24% decrease in hospitalizations in the first year but a 30% increase in hospitalizations between years 1 and 2. Initial across-the-board reductions in ER and hospital care followed by increased hospitalizations “imply that men may have foregone needed care following an HDHP transition,” the authors concluded.

Bariatric Surgery Does Not Improve Male Infertility The effect of obesity on male infertility has been well established. Up to 40% of men presenting to infertility clinics are overweight. Obesity causes alterations in hormone profiles, sleep apnea, diabetes and increased scrotal temperatures, all of which negatively impact semen parameters.

Bariatric surgery leads to substantial weight loss and several positive effects, including an increase in life expectancy and improvement of medical comorbidities such as hypertension and diabetes. As such, it would make sense that sperm quality would improve for infertile men undergoing bariatric surgery.

But it does not. A study published in Reproductive Sciences (2012;19:1057-1062) followed 20 morbidly obese men, 10 of whom underwent weight reduction surgery. While those who underwent surgery had increased sexual function as well as increased luteinizing hormone, follicle-stimulating hormone, and testosterone, their semen parameters went completely unchanged. New studies will need to look at birth rate as a primary endpoint.

Divorce Hits Men Hard Medically, Psychologically Divorce can have a significant impact on a man’s biological, psychological, and social health. In an article in the Journal of Men’s Health (2013;10:3-7), Daniel S. Felix, PhD, and colleagues cite mortality rates up to 250% higher for unmar-

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

University of California, Irvine, Department of Urology

Low Testosterone Found to Increase Dementia Risk L

ow levels of total and bioavailable testosterone may be associated with an increased risk of dementia in elderly men, French investigators report online ahead of print in Alzheimer’s & Dementia.

From a cohort of 3,650 men aged 65 years and older, Laure Carcaillon, MD, of Inserm in Villejuif, France, and collaborators compared 105 men with incident dementia and a random sample of 413 men without dementia. The median follow-up period was 3.1 years. Compared with the middle tertile of total testosterone (total-T) level, the lower and upper tertiles were associated with a 2.3 times and 1.9 times increased risk of dementia. Low bioavailable testosterone (bio-T) was also associated with a greater risk for dementia; the risk was greater in men aged 80 and older than in those younger than 80. In men aged 80 and older, low bio-T was associated with a significant threefold increased risk of dementia; in men younger than 80, it was associated with a nonsignificant 7% increased risk.

Erectile Dysfunction Linked to Elevated Uric Acid E

levated uric acid levels may be associated with an increased risk of erectile ­dysfunction (ED) in men with suspected coronary artery disease (CAD), researchers reported online ahead of print in the Journal of Sexual Medicine.

In a study of 312 men who underwent an exercise stress test as part of a workup of chest pain, Mehmet Kanbay, MD, of Istanbul Medeniyet University in Istanbul, Turkey, each 1 mg/dL increment in uric acid was associated with a significant 36% increased risk of ED. Compared with subjects in the first quartile of uric acid level, those in the fourth quartile had a 2.6 times increased risk of ED. In adjusted analysis, however, uric and uric acid quartiles were not independent risk factors for ED. Studies have shown that that uric acid can induce endothelial dysfunction, oxidative stress, inflammation, and microvascular disease, according to the report, and this could provide a link between uric acid and cardiovascular disease and ED, as well as other CAD risk factors.

ried men. The reasons for this are many. Never married or divorced men have

mens. The study also documented decreased levels of psychological wellbeing, happiness, and self-acceptance in divorced men. Divorce also has detrimental effects on a man’s social life, leading to lower standard of living, less wealth, and greater economic hardship.

The authors warn that these effects often go unnoticed or misattributed, and that effective treatment can be as simple as helping these men understand the effects of their life change on their biologic, emotional, and psychological well-being.

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MEDISTAT

frequent monitoring of health status, and poorer compliance with medical regi-

80.5 PERCENT The estimated prevalence of circumcision among men and boys in the U.S.

Source: Introcaso CE et al. Prevalence of circumcision among men and boys aged 14 to 59 years in the United States, National Health and Nutrition Examination Surveys 2005-2010. Sex Transm Dis 2013;40:521-525.

19.5

80.5% © THINKSTOCK

higher rates of alcohol and substance abuse, a 39% higher suicide rate, less

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Repeat BTXA Injections Benefit Patients with Non-Neurogenic OAB Most patients with the condition felt better after each injection

BY ROSEMARY FREI, MSc VANCOUVER—Repeat injections of onabotulinumtoxinA (BTXA) appear to benefit patients with non-neurogenic overactive bladder (NNOAB).

Australian researchers retrospectively reviewed the records of 52 NNOAB patients who received BTXA injections from 2004 to 2011. Among the 37 patients from whom Patient Global Impression of Improvement (PGI-I) scores were obtained, most felt better after each injection.

“The pattern of PGI-I scores among patients with two, three, four, or five or more injections indicated that higher numbers of injections appeared to be associated with a greater proportion of patients who felt either no change or a little worsening after the injections,” said lead investigator Vincent Tse, MD, of the University of Sydney. “One of the factors to explain this includes a sampling error due to a smaller number of patients having a higher number of repeat injections, so the percentages may appear more polarized. Another factor may be development of antibodies to BTXA.” “Overall, this is a very reassuring

bit of information for patients whose quality of life has been decimated by this condition,” Dr. Tse told Renal & Urology News. “We can also give confidence to our elderly population afflicted with this condition that it is safe to undergo this treatment if they wish, as the side effects are minimal.”

Dr. Tse and his co-investigators analyzed information from any patient with detrusor overactivity not attributed to a neurogenic cause at time

Side effects are minimal, so the treatment is safe for the elderly. of urodynamic diagnosis and who had not responded to at least two anticholinergic agents. All patients had responded favorably to an initial BTXA injection. The 37 women and 15 men had a mean age of 67.4 years (range 26-93 years), and 28 (54%) were aged 70 and older. Most of the patients received 100 to 200 units of BTXA cys-

toscopically. Nine of the 140 injections, however, involved doses of more than 200 units. The mean period between treatment and review of the data was 49 months (range 9-101 months).

Thirty-three patients (64%) received two injections only, 15 (29%) had three or four injections, and four (7%) had five to eight injections. The average time between injections was 9.3 months. Eight individuals started taking oral anticholinergic medications again between the BTXA injections.

“This study helps us to let our patients know that if the first injection is helpful, it is likely to predict future injections would be successful,” Dr. Tse said.

Nine patients had a urinary tract infection and three developed transient urinary retention requiring catheterization for less than two weeks.

Three died from unrelated causes.

Cerebrovascular accidents occurred in two patients, Parkinson’s disease developed in two, and multiple sclerosis developed in one, but Dr. Tse noted that “there is no link between the injections and the neurological conditions.” n

Renal & Urology News 23

Long-Term Belatacept Treatment Beneficial BELATACEPT maintains its renal function benefit and safety for at least five years in kidney transplant recipients, according to study results published online ahead of print in the American Journal of Transplantation.

The findings, reported by Lionel Rostaing, MD, of University Hospital in Toulouse, France, and colleagues, are from the long-term extension phase of the BENEFIT trial, a threeyear, randomized, multicenter study that enrolled 666 adult patients who received a living donor or standard criteria deceased donor kidney.

Results at three years demonstrated comparable patient and graft survival between belatacept and cyclosporine A (CsA).

A total of 456 patients entered the extension phase at 36 months; of these, 406 completed 60 months of treatment with either belatacept or CsA. The 406 patients included 144 treated with a more intensive (MI) regimen of belatacept; 151 treated with a less intensive (LI) regimen of belatacept, and 111 treated with CsA.

Study: 24-Hour Urine Collection Underused

BY ROSEMARY FREI, MSc VANCOUVER—High-risk stone formers seldom are asked for 24-hour urine collections, according to study findings presented at the 33rd Congress of the Societé Internationale d’Urologie.

Based on an analysis of medical claims from working-age adults, 24-hour urine collections were requested for only about 8% of patients at high risk of stone.

It is common for patients who suffer their first urinary stone to experience subsequent stone episodes.

Consequently, secondary prevention has an important role, and this involves identifying and optimizing modifiable risk factors, researchers noted. The primary way to do this is with a 24-hour urine collection that is analyzed for various promoters and inhibitors of urinary stone formation.

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However, there have been no recommendations regarding 24-hour urine collections from U.S. professional organizations.

“While the prevalence of use is increasing over time, the overall rate of 24-hour urine testing is exceedingly low,” noted lead investigator John Hollingsworth, MD, MS. Dr. Hollingsworth and his colleagues at the University of Michigan in Ann Arbor have adopted a protocol for evaluating stone-recurrence risk in first-time stone formers.

“Our protocol is based on risk stratification. For those without risk factors for recurrence, we perform screening blood work, and any abnormality prompts a 24-hour urine collection,” he told Renal & Urology News. “For high-risk patients, we now routinely ask them to complete a urine collection, and we make recommendations

on diet/selective medical therapy based on the results.”

Dr. Hollingsworth’s group also found that patients who had 24-hour urine testing were more likely than those who did not have the testing to be female, salaried, and living in an urban area.

They also were more likely to have been seen by a urologist (75.3% vs. 45.9%) or a nephrologist (5.1% vs. 1.7%).

On multivariable analysis, patients seen by a urologist or nephrologist were nearly four times and three times, respectively, more likely to undergo 24-hour urine testing that those who were not.

In addition, patients aged 30 or older were 12% more likely to be tested than younger individuals. A Charlson score of zero or one was associated with an 84% and 70% increased likelihood of testing, respectively, compared with a Charlson score of 3. n

From months 36-48, one case of biopsy-confirmed acute rejection occurred in the belatacept LI group and one occurred in the CsA group, the researchers reported. No cases occurred in the belatacept MI group.

No cases of acute rejection occurred from month 48-60. Graft loss occurred in none of the belatacept recipients and in three of the CsA recipients, two from acute rejection and one from chronic allograft nephropathy. The mean calculated glomerular filtration rate (mL/ min/1.73 m2) using the Modification of Diet in Renal Disease study formula at month 60 was 74 and 76 for the belatacept MI and LI groups, respectively, compared with 53 for the CsA group.

Infection and malignancy rates were generally similar among the three treatment arms. n

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BY ROSEMARY FREI, MSc PROSTATE CANCER (PCa) patients who drink at least one cup of coffee per day may experience a significantly decreased risk of PCa recurrence or progression after treatment or while on active surveillance, researchers reported online ahead of print in Cancer Causes and Control.

In a study of 630 men aged 35-74 diagnosed with PCa from 2002 to 2005, drinking one cup of coffee per day was associated with a 56% decreased risk of recurrence or progression compared with drinking one cup or fewer per week, in adjusted analyses. Drinking four or more cups per day and two to three cups per day was associated with a 59% and 28% decreased risk, respectively.

“For men diagnosed with prostate cancer who are already consuming coffee, we would suggest that they continue to drink coffee as it may reduce their risk of recurrence/progression,” lead investigator Janet Stanford, MD, told Renal & Urology News. “For men who do not drink coffee, it is not possible to recommend that they start drinking coffee based on results from

Dyslipidemia May Raise Stone Risk DYSLIPIDEMIA is independently associated with an increased risk of kidney stones, researchers reported online ahead of print in The Journal of Urology.

Fabio Cesar Miranda Torricelli, MD, and colleagues at Cleveland Clinic retrospectively studied 2,442 patients with kidney stone disease

our observational study, especially as some of these men may have medical conditions that could be exacerbated by caffeine or coffee intake. The latter patients should consult with their physicians as to whether it would be okay for them to drink a cup of coffee a day.

This new findings appear to confirm earlier research showing a protective effect of coffee drinking in men.

Therefore, the investigators say that while the field is waiting for a randomized, controlled trial of coffee consumption, urologists can proceed on the assumption that it can be beneficial for some men.

Dr. Stanford, Co-Head of the Program in Prostate Cancer Research at the Fred Hutchinson Cancer Research Center in Seattle, and her collaborators in the U.S. and Holland reviewed data from an earlier population-based, case-control study (Am J Epid 2008;168:250-260). Of the 630 men they included in their analysis, 61% drank at least one cup of coffee a day. Twelve percent drank four or more daily. More coffee was drunk by whites, men who were former or current smokers, and those who also

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Coffee May Benefit PCa Patients

consumed alcohol. Regular exercisers and tea drinkers had lower coffee consumption.

Of 140 PCa recurrence or progression events, 25 were fatal, 77 involved secondary treatment, and 28 involved rising PSA levels alone.

The team also evaluated tea drinking and found no significant difference in risk at various levels of consumption.

However, the cohort had few regular tea drinkers, and the highest category of consumption was defined as one or

more cups per day. Earlier research had also uncovered a PCa-protective effect of coffee drinking, particularly related to the non-caffeine components of the beverage.

Although Dr. Stanford’s team did not examine dietary factors ranging from quantities of milk and sugar in the coffee to intake of fruits, vegetables, and supplements, “few such factors have consistently been associated with prostate cancer recurrence or progression.” n

Estrogen Affects Women’s Phosphorus ESTROGEN use by postmenopausal women is associated with significantly lower phosphorus levels, independent of age, race, dietary phosphorus intake, body mass index, renal function, and other factors, a new study suggests.

Among postmenopausal women, the mean serum phosphorus level was 3.83 mg/dL among those on estrogen therapy compared with 3.98 mg/dL among non-users of estrogen, investigators reported online ahead of print in the American Journal of Kidney Diseases.

“Our findings are intriguing if one considers the possibility that differences in serum phosphorus levels may contribute in part to the disproportionately higher cardiovascular morbidity and mortality in postmenopausal women,” the researchers observed.

The investigators, led by Khashayar Sakhaee, MD, of the University of Texas Southwestern Medical Center in Dallas, analyzed data from 7,005 participants aged 21 years and older (3,785 women and 3,220 men) in the National Health and

Nutrition Examination Survey (20032006).

In both men and women, serum phosphorus levels declined progressively with age. In men, the decline continues over the entire age range of 21-85 years, but the pattern is different in women.

From age 21 to 45 years, the decline in serum phosphorus levels is similar in both men and women, but after age 46 years, “contemporaneous with the onset of menopause, serum phosphorus levels are consistently higher in women than men,” the researchers wrote. n

who had a 24-hour urine analysis and lipid profile evaluation. Patients with high total cholesterol (TC) levels had significantly higher urinary potassium and calcium levels. Patients with low HDL or high triglyceride (TG) levels had significantly higher urinary sodium, oxalate, and uric acid levels, and lower urinary pH. High TC and TG levels were significantly associated with a higher uric acid stone rate. n

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High BMI Predicts Adverse Transplant Outcomes INCREASED body mass index (BMI) at kidney transplantation predicts adverse outcomes, a study found.

Simon P. Curran, MD, of the Division of Nephrology and the Kidney Transplant Program, Toronto General Hospital, University Health Network, and colleagues studied 1,151 kidney

transplant recipients. Compared with patients who had a BMI of 20-24.9 kg/m2 at transplantation, those who had a BMI of 30-34.9 had a nearly twofold increased risk of delayed graft function, the investigators reported online ahead of print in Transplantation. Patients with a BMI of 35 or higher had 4.5-fold increased

risk. In addition, a BMI of 35 or higher was associated with a 2.4-fold increased risk of biopsy-proven acute rejection, a 2.4-fold increased risk of death-censored graft failure, and a twofold increased risk of all-cause graft failure. The researchers found no significant association between BMI and death with graft function. n

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Renal & Urology News 25

CME FEATURE

Bladder Cancer in the Elderly: Balancing Disease and Surgical Risk Elderly patients face greater perioperative risks and postoperative mortality, so careful selection of surgical candidates is imperative.

Release Date: November 2013 Expiration Date: November 2014 Estimated time to complete the educational activity: 1 hour This activity is jointly sponsored by Medical Education Resources and Haymarket Medical Education.

STATEMENT OF NEED: Given the decision-making intricacies associated with radical surgery for invasive bladder cancer, there is a real need for improved risk assessment tools to objectify patients perioperative risk for adverse outcomes post-surgery versus their disease risk and likelihood of cure with invasive/maximal therapy.

TARGET AUDIENCE: This activity has been designed to meet the needs of urologists, and supporting clinicians who treat patients with bladder cancer.

EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Evaluate preoperative mechanisms for assessing surgical risk in patients with muscle-invasive bladder cancer.

• Examine existing objective criteria for making treatment decisions in this patient population.

• Relate the question of surgical frailty to stratify risk in patients with muscle-invasive bladder cancer.

ACCREDITATION STATEMENT: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Medical Education Resources (MER) and Haymarket Medical Education. MER is accredited by the ACCME to provide continuing medical education for physicians.

CREDIT DESIGNATION: Medical Education Resources designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

DISCLOSURE OF CONFLICTS OF INTEREST: Medical Education Resources ensures balance, independence, objectivity, and scientific rigor in all our educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved

by MER to ensure all scientific research referred to, reported, or used in a CME activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality CME activities that promote improvements or quality in health care and not a commercial interest.

The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Faculty Daniel J. Canter, MD

Reported Financial Relationship Consulting Fees: Olympus

BY DANIEL J. CANTER, MD

I

n 2013, more than 70,000 new cases of bladder cancer will be diagnosed and about 15,000 deaths from the malignancy will occur.1 In men, bladder cancer is the fourth most common malignancy and the most common genitourinary cancer apart from prostate cancer.1 Of all the newly diagnosed bladder cancer patients, 25%-30% of them will have muscle-invasive disease that ideally will require major surgery in the form of a radical cystectomy, bilateral pelvic lymphadenectomy, and creation of a urinary diversion as an integral part of their curative therapy.2 Although an invasive extirpative and reconstructive surgery, radical cystectomy is an effective therapy to treat bladder cancer, but it is associated with significant postoperative morbidity and mortality.

A high-risk population As with many cancers, bladder cancer is a disease of aging.1,3 Also, bladder cancer, similar to lung cancer, is strongly associated with cigarette

smoking. Thus, the combination of age and its attendant comorbidities as well as a smoking history and its associated negative health effects on a given patient’s cardiovascular and pulmonary physiology creates an inherently high-risk surgical population undergoing major non-cardiac surgery. As such, recent attention has been paid not only to standardizing but also fully compiling the true perioperative risk associated with radical cystectomy and urinary diversion. In a seminal paper from Memorial SloanKettering Cancer Center, the authors from this high-volume referral center reported their perioperative results of 1,142 patients undergoing radical cystectomy. In this series, 64% of patients experienced a postoperative complication within 90 days of surgery,4 according to a standardized complication reporting system (Clavien-Dindo classification5). Although the majority of these complications were considered minor, a still not insignificant 13% of all patients experienced a major complication, indicating the need for

The content managers, Jody A. Charnow and Marina Galanakis, of Haymarket Medical Education, and Julie Johnson, PharmD, of Medical Education Resources, have disclosed that they have no relevant financial relationships or conflicts of interest.

METHOD OF PARTICIPATION: There are no fees for participating in and receiving CME credit for this activity. During the period of November 2013 through November 2014, participants must: 1) read the learning objectives and faculty disclosures, 2) study the educational activity, 3) complete the posttest and submit it online. Physicians may register at www.myCME.com/ renalanurologynews, and 4) complete the evaluation form online. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better.

Daniel J. Canter, MD, is vice chairman of the Urologic Institute of Southeastern Pennsylvania and the Department of Urology of the Einstein Healthcare Network, Philadelphia.

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another procedure, unplanned ICU admission, or death.4 Other studies using either institutional,6,7populationbased,8 or administrative datasets9 have confirmed a similar perioperative complication rate. Furthermore, a recent study from the Mayo Clinic detailed just over a 60% incidence of long-term complications related to a patient’s urinary diversion, indicating the potential chronic morbidity associated with this surgery.10

Robotic vs. open radical cystectomy Finally, it is worth noting that despite the perception that robotic surgery in general is better tolerated with fewer complications than traditional open surgery for bladder cancer, recently published data from a large robotic consortium appears to contradict this assumption. In this series of 939 patients from multiple centers, the median hospital stay was eight days, and 448 (48%) patients experienced a complication.11 Furthermore, there was a 20% 90-day readmission rate and a 30- and 90-day post-operative mortality rates of 1.3% and 4.2%, respectively.11 The perioperative morbidity and mortality rates reported in this robotic study are very similar to the reported rates in patients undergoing open radical cystectomy. Importantly, as this study highlights, many patients will incur a complication after the traditional 30-day postoperative time point, and the risk of 90-day mortality after radical cystectomy is strongly associated with increasing age. For example, in one population-based study, patients younger than 70 years and aged 70-79 years experienced a 2.0% and 5.4% rate of 90-day perioperative mortality after radical cystectomy.12 Furthermore, for octogenarians, the risk of perioperative mortality after radical cystectomy ranged from 9.2%-20% in both population-based and institutional studies.12,13

Disease progression and survival As with any intervention, the goal is to maximize disease cure while minimizing harm from treatment. For bladder cancer, this maxim seems especially relevant. Adding greater complexity to the treatment decision-making analysis is the reality that many patients after appropriate treatment (chemotherapy

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and surgery)14 for invasive bladder cancer will experience a disease recurrence and ultimately will die of bladder cancer. Although variable and, as expected, related to final pathologic staging, single institutional and multiinstitutional studies have reported rates of recurrent bladder cancer after surgery ranging from 21.6%-50%.15-17 Additionally, overall survival during follow-up for these patients similarly ranges from 36%-50%. For example, Shariat et al reported the experience of three high-volume radical cystectomy centers and demonstrated varying survivals stratified by pathologic stage. In this large cohort of 888 patients, the overall five-year progression-free survival (PFS) and bladder-cancer specific (BCS) survival rates were 58.3% and 65.7%, respectively.18 However, PFS and BCS survival rates were 88.8%, 75.3%, 80.8%, 71.6%, 44.2%, and 28.4% and 93.9%, 87.2%, 85.9%, 78.9%, 47.7%, and 31.0% for pTa, pTis, pT1, pT2, pT3, and pT4 bladder cancer, respectively.18 Similarly, patients with lymph node positive disease at the time of radical cystectomy had three-year PFS and BCS of 29.1% and 37.5%.

Thus, although radical cystectomy is an effective treatment for bladder cancer, it is associated with significant perioperative risk, and its efficacy in producing a long-term cure in certain subsets of patients (those with greater than pT3 disease and positive lymph nodes) is less than 50%, creating a therapeutic “Catch-22” for the urologic oncologist.

Recent competing risks models for renal cell carcinoma (RCC) have elegantly quantified the risk of death from kidney cancer versus the risk of death from a patient’s associated medical problems.19,20 For these risk assessments, the time frame associated with these calculations is five years. Unlike RCC, where a large group of patients can defer treatment for up to five years or perhaps even longer,21 bladder cancer patients do not have this luxury.

In fact, if left untreated, patients with muscle-invasive bladder cancer (MIBC) will die of their disease within 18-24 months.3 It is a rare patient with MIBC who will present with medical comorbidities so severe that their risk of death not due to bladder cancer outweighs their risk of death due to bladder cancer, making a competing-risks analysis somewhat inapplicable in this clinical scenario. Therefore, given all

© THINKSTOCK

CME FEATURE

Figure 1. Preoperative assessment of weakness includes measuring hand grip strength.

the decision-making intricacies associated with radical surgery for invasive bladder cancer, there is a real need for improved risk assessment tools to objectify a patient’s perioperative risk for adverse outcomes after surgery versus their disease risk and likelihood of cure with invasive/maximal therapy.

Few objective criteria for making treatment decisions Unfortunately, the ability to accurately predict a patient’s pathologic stage with bladder cancer is poor,22 thus leaving much of the modifiable risk assessment to preoperative evaluation of a patient’s physiologic state. In general, however, available preoperative risk assessment tools to objectively predict a patient’s surgical risk are either lacking or too time-consuming. As such, surgical decision-making is overly subjective and full of physician and patient biases that unduly guide treatment decisions.

Due to this lack of objective data, many important treatment decisions are made on incomplete data or instinct.

In fact, it has been shown by behavioral economists that people will make decisions based on the perception of potential gain or loss. Interestingly, people tend to make decisions that are more risk-taking when they are presented with a scenario that is framed as a loss.23 Despite these flaws, the physician is faced with a population that is living longer, and once patients reach a certain age, their likelihood of still having a significant life expectancy is high.

Thus, the decision to operate/treat must account for a patient’s life span versus the natural history and severity of a given disease. Furthermore, the treatment decision-making process must somehow be able to adequately quantitate a patient’s ability to survive and recover from a given surgery with an acceptable rate of morbidity and/or mortality. Finding or developing tools to fill this void are clearly needed.

This clinical challenge is no more apparent than in the elderly bladder cancer patient. To date, one of the only pieces of objective data that reliably correlate with adverse perioperative outcomes is increasing patient age. As already mentioned, in patients with invasive bladder cancer who require radical cystectomy, population-based and institutional datasets show a clear increasing risk of 90-day postoperative mortality with increasing age.12,13 Furthermore, this relationship is similarly also present in the elderly undergoing pancreatic and esophageal surgeries (15%-20%). 24 Although these surgeries carry a significantly increased risk of perioperative death when compared with other surgeries, it is worth highlighting that this percentage is still a minority. Unfortunately, what is lacking is the ability to definitively and objectively identify the vast majority of patients who will recover well from this surgery while sparing the remaining subset of patients from an adverse outcome.

It is important to note that this relationship between perioperative

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outcomes and age exists in other surgical populations that are not undergoing as extensive a surgical procedure.

Polanczyk et al examined the relationship among age, length of stay, and complications in patients undergoing non-cardiac surgery. In this large study, the authors found a statistically significant relationship between increasing age and major or fatal perioperative complications.25 Patients aged 80 years or older were 3.5 times more likely to die during their hospitalization compared with patients younger than 80 years.25 Similarly, Hamel et al. assessed the relationship between surgical risk and age. The findings of this analysis were very similar to that of Polanczyk et al, demonstrating a significantly higher rate of complications (p < 0.001) and mortality (p < 0.001) for patients older than 80 years as compared to patients younger than 80 years. 26 Specifically, for every year above the age of 80, a patient had a 5% increase in post-operative mortality.26

The concept of surgical frailty Although age by itself is certainly a predictive factor for adverse surgical outcomes, it is not absolute. There are many elderly patients who undergo surgical interventions and recover without incident. Yet, there is no denying that within this group, there are more patients who are potentially more at risk and thus being able to better objectify and identify this subset of patients is imperative. Simply deferring or denying care based on age alone—a practice known as ageism—would unnecessarily prevent a majority of patients from receiving appropriate and life-saving surgery.

Frailty is a relatively new concept that encompasses not only a patient’s chronologic age, but also a patient’s ability to withstand physiologic stressors. Fried et al initially introduced this concept and described frailty “as a biologic syndrome of decreased reserve and resistance to stressors, resulting from cumulative declines across multiple physiologic systems, and causing vulnerability to adverse outcomes.”27 In their initial study, Fried and colleagues operationalized the measurement of frailty focusing on the following domains: shrinking (weight loss or sarcopenia), weakness, slowness, poor endurance/exhaustion, and low activity

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(Table 1). Shrinking is measured by simply asking the patient if he/she has had recent unintentional weight loss of greater than 10 pounds; weakness (Figure 1) and slowness are quick physical tests that can be performed in the office or during the preoperative anesthesia visit; and, poor endurance/ exhaustion and low activity are questionnaires that the patient fills out and is scored by an independent observer.27 Each component of frailty is scored individually on a binary scale.

In Fried’s original study, patients were considered frail if they tested positive for ≥4 criteria, with patients positive for 2-3 criteria considered intermediately frail. Not surprisingly, in their large cohort of patients, there was an increased incidence of frailty with increasing age. For example, only 3.2% of patients aged 65-70 years were frail whereas 16.3% and 25.7% of patients aged 80-84 years and 85-89 years, respectively, were considered frail.27 Patients who were deemed frail had a statistically significant higher incidence of death, first hospitalization, first fall, worsening ADL disability, and worsening mobility (all p-values < 0.0001). 27 Expanding on Fried’s work, Makary and colleagues established the importance of the relationship between frailty and surgical outcomes. In the study by Makary et al study, the authors reported complication rates of 11.4% and 43.5%, respectively, in frail patients undergoing minor and major procedures.28 On multivariate analysis, frailty remained an independent predictor of surgical complications with intermediately frail and frail patients having a nearly 2.0 and 2.5 times higher risk of complications, respectively, compared with nonfrail patients. Furthermore, frailty was an independent predictor of increasing length of stay and discharge to a skilled or assisted-care facility. Although not studied by Makary et al, discharge to a skilled nursing facility has been shown to be a risk factor for 90-day mortality after radical cystectomy.29 The initial results found by Makary have been validated in other surgical populations. For example, in patients undergoing elective laparoscopic cholecystectomy, frailty was associated with an increased incidence of postoperative complications (p = 0.022), longer length of hospital stay (p=0.023), and higher pain scales (p = 0.04).30

Similarly, in a study of patients undergoing colorectal surgery for cancer, frail patients were 4.0 and 3.5 times more likely to experience a major complication or a surgical/medical complication.31 Finally, in a study of women with a gynecologic malignancy undergoing resection, 27% and 16% of the patients were either intermediately frail or frail. The presence of any degree of frailty was a statistically significant predictor of a 30 day post-operative complication (p = 0.04).32 These studies highlight that the traditional preoperative evaluation of elderly patients is lacking. Although the number of studies is not large and the ones to date have included a small number of patients, our present methods of understanding patients’ (especially elderly patients’) ability to withstand the intended physiologic stress of surgery is most likely unsophisticated. From the studies to date, it is evident that not all elderly surgical patients are created equal, and further refinement is needed. Even in younger patients, detecting frailty may be useful in identifying patients who require preoperative intervention/ optimization or, perhaps, intensive post-operative care to help forestall adverse post-operative outcomes.

Due to the relative sparseness of measuring frailty in the present surgical literature, we have just completed an initial study and have started a second validation study measuring

Renal & Urology News 27

frailty in a multidisciplinary surgical setting (urology, general surgery, and surgical oncology). We have initially begun with Fried’s criteria as a template and have supplemented those measurements with an assessment of other questionnaires and biochemical variables (e.g., albumin, serum creatinine, estimated glomerular filtration rate, etc.). The goal of these studies is to potentially create a more precise and potentially concise method to assess patients for preoperative frailty. Although still early, our initial experience has shown us that measuring frailty is quick and inexpensive and can be performed by clinic support staff with minimal disruption to the normal clinic flow. Furthermore, our initial experience has shown that identifying patients who are either intermediately frail or frail is better at discriminating/predicting adverse postoperative outcomes than existing tools (data in press). If further validated, the routine preoperative measurement of frailty may serve to improve patient risk stratification.

Summary In general, there is an increasing number of elderly patients that will require surgical procedures for their given medical condition, especially bladder cancer patients. Accurate preoperative assessment of the elderly surgical patient is paramount to identify those

Table 1: Fried frailty criteria collected Shrinking

Self-reported unintentional weight loss > 10 lbs in the last year

Weakness

Measured by having the patient squeeze a hand-held JAMAR dynamometer. Three serial tests of maximum grip strength with the dominant hand were performed, and the mean was adjusted by gender and BMI

Exhaustion

Measured by responses to two statements about effort and motivation from the Center for Epidemiological StudiesDepression scale. Possible responses were 0 = rarely or none of the time (< 1 day); 1 = some or little of the time (1-2 days); 2 = a moderate amount of the time (3-4 days); and 3 = most of the time. Subjects answering either statement with a response of 2 or 3 met the criteria for exhaustion

Low activity

Ascertained by inquiring about physical activities for the previous 2 weeks using the short version of the Minnesota Leisure Time Activities Questionnaire. Tasks were converted to equivalent kilocalories, and individuals were considered to have low activity if weekly kilocalorie expenditure was below < 383 kcal/week for men and < 270 kcal/week for women

Slowed walking speed

Measured by the speed at which a patient walks 15 feet at usual pace. Final time represents an average of 3 trials.

Times were compared to standards based on gender and height, and walk speed greater than reference value indicated slowness

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28 Renal & Urology News

NOVEMBER 2013 www.renalandurologynews.com

CME FEATURE who will tolerate the insults of surgery. Current preoperative assessment tools are inadequate to discriminate between fit and unfit surgical candidates. Failure to do so may either wrongly deny patients the standard of care treatment or put them at a greater, unnecessary risk for adverse perioperative outcomes. As such, the relatively new concept of surgical frailty may better assess functional reserve and thus the ability of an elderly patient to avoid an untoward outcome after surgery. n REFERENCES 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11-30.

2. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001;19:666-675.

3. Clark PE, Agarwal N, Biagioli MC, et al. Bladder cancer. J Natl Compr Canc Netw 2013;11:446-475.

4. Shabsigh A, Korets R, Vora KC, et al. Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol 2009;55:164-174.

5. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205-213.

6. Stimson CJ, Chang SS, Barocas DA, et al. Early and late perioperative outcomes following radical cystectomy: 90-day readmissions, morbidity and mortality in a contemporary series. J Urol 2010;184:1296-1300.

7. Gregg JR, Cookson MS, Phillips S, et al. Effect of preoperative nutritional deficiency on mortality after radical cystectomy for bladder cancer. J Urol 2011;185:90-96.

8. Konety BR, Allareddy V, Herr H. Complications after radical cystectomy: analysis of population-based data. Urology 2006;68:58-64.

9. Kim SP, Boorjian SA, Shah ND, et al. Contemporary trends of in-hospital complications and mortality for radical cystectomy. BJU Int 2012;110:1163-1168.

10. Shimko MS, Tollefson MK, Umbreit EC, et al. Longterm complications of conduit urinary diversion.

J Urol 2011;185:562-567.

11. Johar RS, Hayn MH, Stegemann AP, et al.

Complications after robot-assisted radical cystectomy: Results from the International Robotic Cystectomy Consortium. Eur Urol 2013;64:52-57.

12. Liberman D, Lughezzani G, Sun M, et al.

Perioperative mortality is significantly greater in septuagenarian and octogenarian patients treated with radical cystectomy for urothelial carcinoma of the bladder. Urology 2011;77:660-666.

13. Morgan TM, Keegan KA, Barocas DA, et al.

Predicting the probability of 90-day survival of elderly patients with bladder cancer treated with radical cystectomy. J Urol 2011;186:829-834.

14. Grossman HB, Natale RB, Tangen CM, et al.

Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced

bladder cancer. N Engl J Med 2003;349:859-866.

15. Hassan JM, Cookson MS, Smith JA, Jr., Chang SS. Patterns of initial transitional cell recurrence in patients after cystectomy. J Urol 2006;175:2054-2057.

16. Rink M, Ehdaie B, Cha EK, et al. Stage-specific impact of tumor location on oncologic outcomes in patients with upper and lower tract urothelial carcinoma following radical surgery. Eur Urol 2012;62:677-684.

17. Gakis G, Efstathiou J, Lerner SP, et al. ICUD-EAU International Consultation on Bladder Cancer 2012: radical cystectomy and bladder preservation for muscle-invasive urothelial carcinoma of the bladder.

Eur Urol 2013;63:45-57.

18. Shariat SF, Karakiewicz PI, Palapattu GS, et al.

Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium. J Urol 2006;176 (6 Pt 1):2414-2422; discussion 2422.

19. Kutikov A, Egleston BL, Wong YN, Uzzo RG. Evaluating overall survival and competing risks of death in patients with localized renal cell carcinoma using a comprehensive nomogram. J Clin Oncol 2010;28:311-317.

20. Kutikov A, Egleston BL, Canter D, et al. Competing risks of death in patients with localized renal cell carcinoma: a comorbidity based model. J Urol 2012;188:2077-2083.

21. Smaldone MC, Kutikov A, Egleston BL, et al. Small renal masses progressing to metastases under active surveillance: a systematic review and pooled analysis. Cancer 2012;118:997-1006.

22. Guzzo TJ, Magheli A, Bivalacqua TJ, et al.

Pathological upstaging during radical cystectomy is associated with worse recurrence-free survival in patients with bacillus Calmette-Guerin-refractory bladder cancer. Urology 2009;74:1276-1280.

23. Tversky A, Kahneman D. The framing of decisions and the psychology of choice. Science 1981;211:453-458.

24. Finlayson E, Fan Z, Birkmeyer JD. Outcomes in octogenarians undergoing high-risk cancer operation: a national study. J Am Coll Surg 2007;205:729-734.

25. Polanczyk CA, Marcantonio E, Goldman L, et al.

Impact of age on perioperative complications and length of stay in patients undergoing noncardiac surgery. Ann Intern Med 2001;134:637-643.

26. Hamel MB, Henderson WG, Khuri SF, Daley J. Surgical outcomes for patients aged 80 and older: morbidity and mortality from major noncardiac surgery. J Am Geriatr Soc 2005;53:424-429.

27. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56:M146-156.

28. Makary MA, Segev DL, Pronovost PJ, et al. Frailty as a predictor of surgical outcomes in older patients.

J Am Coll Surg 2010;210:901-908.

29. Aghazadeh MA, Barocas DA, Salem S, et al.

Determining factors for hospital discharge status after radical cystectomy in a large contemporary cohort. J Urol 2011;185:85-89.

30. Lasithiotakis K, Petrakis J, Venianaki M, et al.

Frailty predicts outcome of elective laparoscopic cholecystectomy in geriatric patients. Surg Endosc 2013;27:1144-1150.

31. Tan KY, Kawamura YJ, Tokomitsu A, Tang T. Assessment for frailty is useful for predicting morbidity in elderly patients undergoing colorectal cancer resection whose comorbidities are already optimized. Am J Surg 2012;204:139-143.

32. Courtney-Brooks M, Tellawi AR, Scalici J, et al.

Frailty: an outcome predictor for elderly gynecologic oncology patients. Gynecol Oncol 2012;126:20-24.

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1. Smoking is NOT a risk factor for the development of bladder cancer. a. True b. False 2. If left untreated, what is the life expectancy of a patient with muscleinvasive bladder cancer? a. One month b. Six to nine months c. 12 months d. 18-24 months e. Five years 3. Post-surgical complications are common after radical cystectomy for the treatment of invasive bladder cancer. a. True b. False 4. According to Fried’s criteria, how many components are there in the definition of “frailty”? a. Two b. Five c. 10 d. 50 5. Which of the following components is NOT part of Fried’s frailty criteria? a. Solid grip b. Weight loss c. Weakness d. Low Activity e. Slowness 6. Increasing age is NOT associated with an increasing incidence of frailty. a. True b. False 7. How many of Fried’s criteria need be present to deem a patient frail? a. None b. One c. Two d. Three e. Four

10/25/13 12:13 PM

www.renalandurologynews.com NOVEMBER 2013

Renal & Urology News 29

Urinary ATP Nixed for Assessing UTI The neurotransmitter alone does not improve on current diagnostic markers of urinary tract infection

BY JILL STEIN BARCELONA—Urinary adenosine5’ triphosphate (ATP) offers no advantage as a clinical test and surrogate marker of urinary tract infection (UTI) in patients with lower urinary tract symptoms (LUTS), according to data reported by a British group at the 43rd Annual Meeting of the International Continence Society.

“We found that urinary ATP disappoints as a potential surrogate, clinical diagnostic marker of urinary infection in patients with LUTS,” James Malone-Lee, MD, Professor of Medicine at University College London Medical School, and associates said in a poster presentation. “In fact, urinary ATP, when used alone, does not improve on current diagnostic markers of urinary tract infection such as urine microscopy.”

Their study examined the effects of age, gender, symptoms, pyuria, and midstream urine culture on urinary ATP.

Data Suggest Hypogonadism, Nocturia Link

BY ROSEMARY FREI, MSc VANCOUVER—Desmopressin treatment appears to reduce nocturia and other lower urinary tract symptoms while also significantly increasing testosterone levels in men with late-onset hypogonadism. These new results from a 62-patient prospective trial suggest that nocturia may be related to hypogonadism in this population.

The study, by Jong Wook Kim, MD, PhD, of the Korea University Guro Hospital, Seoul, South Korea, and colleagues, analyzed the parameters of men treated with demopressin in an open-label trial that ran from April 2011 to November 2012. The men were older than 40 years, had at least two nocturia episodes per night, and serum total testosterone levels below 3.5 ng/mL or a positive score on the Androgen Deficiency in Aging Men scale. The investigators excluded individuals with cardiovascular disease, hyponatremia, primary hypogonadism, hypogoandotropic hypogonadism, or who were using hypnotics or desmo-

RUN1113_ICS3.indd 1

Exclusion of UTI is a “mandatory first step” in patients with LUTS, the authors said. In individuals who present with the classic symptoms of acute frequency and dysuria, the diagnosis of UTI is not difficult to establish. In those with LUTS, however, clinicians rely on dipstick tests and midstream urine culture to rule out possible infection.

Despite their widespread use, the midstream urine culture and urinary dipstick test are inadequate for excluding UTI in patients with LUTS symptoms but without acute frequency and dysuria, they added. The best marker currently available for UTI is microscopy of a fresh, unspun urine sample, which reportedly has a nearly 70% sensitivity rate. Patient clinics, however, often do not have the means to analyze urine samples promptly, and delayed analysis of a urine sample may produce a false-negative result. Thus, there is a need to identify other surrogate urinary markers that can be used

pressin for treatment of other diseases such as diabetes. The subjects received desmopressin 0.1 mg once daily.

The study population had an average age of 68.4 years and average body mass index of 24 kg/m2. Their mean total testosterone at baseline was 4.28 ng/mL, their mean free testosterone was 5.47 pg/mL, and their mean PSA level was 1.4 ng/mL. The total and free testosterone levels increased significantly in men with baseline total testosterone levels below 3.5 ng/mL, researchers reported at the 33rd Congress of the Societé Internationale d’Urologie. Their mean total testosterone levels increased from 2.85 to 3.97 ng/mL and their mean free testosterone levels increased from 3.84 to 4.86 pg/mL. In addition, the patients’ average scores on the overall International Prostate Symptom Score (IPSS) scale dropped significantly, as did their scores on question 7 of the IPSS (which probes nocturia), the IPSS subscores of voiding and storage symptoms, and the IPSS quality of life question. The patients’ nocturnal urine volume levels also fell significantly, as did their nocturnal polyuria index scores, their actual number of nightly voids, the nocturia index scores and their nocturnal bladder capacity index scores. n

clinically, Dr. Malone-Lee and his colleagues said.

ATP is a neurotransmitter and inflammatory cytokine implicated in the pathophysiology of lower urinary tract disease. It is used in the food,

It ‘disappoints’ as a potential marker of urinary infection in LUTS sufferers. water hygiene, and sanitation industry as a marker of bacterial contamination. Urinary ATP has been proposed as a clinical test and surrogate marker of UTI. For the study, 340 patients presenting with LUTS were recruited over a two-month period from incontinence clinics, and clean-catch midstream urine samples were obtained. Seventy-

five healthy control volunteers were recruited from hospital staff.

Urinary ATP was assayed by the conventional luciferin-luciferase method, and pyuria was counted by microscopy of fresh, spun urine. Symptoms were assessed using validated scales.

The study included 100 LUTS patients who were classified as being without pyuria, 120 LUTS patients with pyuria, 120 LUTS patients with pyuria, and 75 controls.

The statistical analysis showed that the urinary ATP was very unlikely to explain any more of the disease activity than that achieved by current tests.

This was confirmed by analysis of the sensitivity and specificity in relation to current accepted gold-standards.

The investigators said that their results underscore the need for additional research to find other surrogate markers of urinary infection in order to exclude UTI in patients who present with LUTS. n

Antimicrobial Under-Dosing Common in CVVHD

BY JOHN SCHIESZER

and intravenous antimicrobial therapy

DENVER—Antimicrobial dosing may

during a two-month period. Subjects

not meet guideline recommendations

had a mean age of 58.4 years and

in a significant number of patients

47.6% were male. The objective was

receiving continuous venovenous

to analyze the number of study days

hemodialysis (CVVHD), new findings

the antimicrobial doses were in accord

presented at the 53rd Interscience

with institutional guidelines. The most

Conference on Antimicrobial Agents

frequently prescribed antimicrobials

and Chemotherapy suggest.

were piperacillin/tazobactam and

“We found that 22% of patients didn’t

meropenem.

have the right dose for the entire time

Antimicrobial therapy dosing met

they were on continuous venovenous

guideline recommendations for only

hemodialysis, which means they are not

163 (78%) of the 209 study days, and

getting enough antibiotic and it means

all non-concordant doses were below

we are not controlling the infection,”

guideline recommendations. “We think

said investigator Marianna Fedorenko,

this is a problem across the U.S.,” said

PharmD, an infectious disease phar-

Dr. Fedorenko, who noted that CVVHD

macy resident at Barnes-Jewish

alters antimicrobial pharmacokinetics.

Hospital in St. Louis, Mo. “I think this is

Based on survival analyses, the

something that nephrologists should be

median time to recommended dose

looking at as part of their assessment

was 20 hours after CVVHD initiation.

of the patients.”

In cases where antimicrobial therapies

Dr. Fedorenko and her colleagues

were initiated when patients were

at Cleveland Clinic retrospectively

already on CVVHD, 74% of the initial

evaluated 42 patients receiving CVVHD

doses met guideline criteria. n

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