Renal & Urology News December 2013 Issue by Haymarket Media

DECEMBER 2013

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VOLUME 12, ISSUE NUMBER 12

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Fasting Phosphorus More Predictive BY JODY A. CHARNOW ATLANTA—Fasting serum phosphorus levels have a stronger association with all-cause and cardiovascular mortality than non-fasting levels, researchers reported at the American Society of Nephrology’s Kidney Week 2013. Serum phosphorus levels vary throughout the day, with a nadir occurring in the morning, a small peak in the early afternoon followed by a drop, and then a larger nocturnal peak, explained investigator Alex Chang, MD, MS, of Geisinger Health System in Danville, Pa. “Higher phosphorus

IN THIS ISSUE 13 Stone risk not higher with vitamin D supplement use 14 Neonates among the hardest hit by inpatient AKI 16 CDC releases tools to decrease hemodialysis infections

18 Patients aged 75 and older do poorly after RRT start

19 CKD risk in diabetics higher among women than men

Statin use may protect against adverse renal outcomes in ICU patients

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intake exaggerates the early afternoon rise in serum phosphorus,” Dr. Chang said. The effect of dietary phosphorus could introduce “noise” to randomly measured phosphorus and explain why some studies have not found an association between serum phosphorus and mortality, he said. “For this reason, we examined whether the association between serum phosphorus and mortality differed between those who fasted at least 12 hours and those who fasted less than 12 hours,” he told Renal & Urology News. “We found that fasting

It has a stronger association with adverse outcomes

DIETARY PHOSPHORUS can throw off serum phosphorus test results.

serum phosphorus was associated with mortality whereas non-fasting serum phosphorus was not associated with increased mortality.” In clinical practice, “we need to recognize that serum phosphorus levels are affected by time of day and dietary

phosphorus intake, Dr. Chang said. “We may want to consider basing management decisions on more than just a single, random serum phosphorus measurement. Unfortunately, it is hard to predict what will happen to serum continued on page 14

Higher Dietary ACP Rejects CKD Screening Acid Load BY DELICIA HONEN YARD trolled trials that compared the effect The American College of Physicians of systematic CKD screening versus Predicts ESRD (ACP) stands by its recommendation no CKD screening on clinical outBY JODY A. CHARNOW ATLANTA—Higher dietary acid load is associated with an increased likelihood of chronic kidney disease (CKD) progression, according to new studies presented at Kidney Week 2013. In a study of 1,486 adults with CKD who participated in the National Health and Nutrition Examination Survey III, Tanushree Banerjee, PhD, of the University of California San Francisco, and colleagues demonstated that higher dietary acid load is associated with development of end-stage renal disease (ESRD) among CKD patients. This is the first longitudinal study on the assocontinued on page 14

against routine screening for chronic kidney disease (CKD) in asymptomatic individuals with no CKD risk factors. The recommendation is part of new guidelines published October 22 in the Annals of Internal Medicine. Guideline authors Amir Qaseem, MD, PhD, MHA, and fellow members of the ACP’s Clinical Guidelines Committee did deem this recommendation to be supported by weak/lowquality evidence. The group’s research had identified no randomized, con-

CME FEATURE

comes or that evaluated the harms of such screening. A subsequent statement from the ASN confirmed that the ASN “strongly recommends” regular screening for kidney disease, regardless of an individual’s risk factors. “ASN and its nearly 15,000 members—all of whom are experts in kidney disease—are disappointed by ACP’s irresponsible recommendation,” asserted ASN Executive Director Todd Ibrahim in the statement. continued on page 14

Earn 1 CME credit in this issue

New Ablative Techniques in Urologic Oncology PAGE 25

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Urology Groups Rip IMRT Study BY JODY A. CHARNOW UROLOGY associations have condemned a new study suggesting that urology groups that have integrated intensity-modulated radiation therapy (IMRT) into their practice to make much greater use of the modality for treating prostate cancer (PCa) patients than urology groups that do not have in-office IMRT. The study, which was funded by the American Society for Radiation Oncology (ASTRO) and conducted by Jean M. Mitchell, PhD, an economist at Georgetown University in Washington, D.C., examined Medicare

IN THIS ISSUE 13 Stone risk not higher with vitamin D supplement use 14 Neonates among the hardest hit by inpatient AKI 15 Radiotherapy may benefit high-risk RCC patients

17 Comorbidities increase

post-radiotherapy ED risk

24 Obese hypogonadal men found to lose weight on testosterone

Statin use may protect against adverse renal outcomes in ICU patients

PAGE 18

claims from 2005 through 2010. The analysis revealed that the rate of IMRT use jumped by 19.2 percentage points among self-referring urologists during the study period compared with 1.3 percentage points among urologists who did not self refer. “Permitting urologists to selfrefer for IMRT may contribute to increased use of this expensive therapy,” Dr. Mitchell concluded in the The New England Journal of Medicine (2013;369:1629-1637). The study drew criticism from the Large Urology Group Practice Association (LUGPA), which in a pre-

Testosterone Therapy May Raise CV Risk BY DELICIA HONEN YARD TESTOSTERONE therapy was associated with adverse cardiovascular (CV) outcomes in a large observational study, findings that raise questions about the potential safety of testosterone use in men, according to researchers. Rebecca Vigen, MD, of the University of Texas Southwestern Medical Center in Dallas, and colleagues group assessed the association between testosterone therapy and all-cause mortality, myocardial infarction (MI), or stroke among male veterans and determined the effect of underlying corocontinued on page 14

Researcher’s methodology, conclusions criticized

SELF-REFERRAL to IMRT by urologists increases use of this treatment, a study found.

pared statement said the study was flawed and “provides no compelling reason to legislatively prohibit integrated practices from providing radiation and other treatment modalities to their patients.” LUGPA pointed out that study data show that less than one third of newly-

diagnosed PCa patients who sought treatment from an integrated urology group received IMRT in 2005-2010. “This figure is fully in line with data from academic literature that predates the development of integrated groups, continued on page 14

PCa Raises Melanoma Risk MEN WITH a history of prostate cancer (PCa) are at increased risk of melanoma, a new study suggests. Researchers came to that conclusion based on a study of 42,372 men in the Health Professionals’ Follow-Up Study (HPFS) and 18,603 men in the Physicians’ Health Study (PHS). A history of PCa was associated with an 83% increased risk of melanoma in the HPFS, a 2.2-fold increased risk in the PHS, and an 89% increased risk when the results of the two cohorts were combined. The investigators, led by Jiali Han, PhD, of Tianjin Medical University Cancer Institute and Hospital in

CME FEATURE

Tianjin, China, found no association between PCa and other non-skin cancers, “suggesting that the association between PCa and melanoma risk may not be explained by increased medical surveillance,” according to a report published online ahead of print in the Journal of Clinical Oncology. Dr. Han’s group postulated that androgens may have a role in the etiology of melanoma. “PCa develops in an androgen-dependent epithelium and is a well-recognized androgen-related cancer, although the relationships between circulating androgens and PCa risk have not been elucidated from continued on page 14

Earn 1 CME credit in this issue

New Ablative Techniques in Urologic Oncology PAGE 25

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4 Renal & Urology News

DECEMBER 2013 www.renalandurologynews.com

FROM THE EDITOR EDITORIAL ADVISORY BOARD

Placing Very Elderly Patients on RRT

s a venue for presenting important research on kidney disease to the world, Kidney Week never disappoints. In addition to the usual plethora of new studies of promising investigational therapeutics and new approaches to the care of patients with chronic kidney disease and end-stage renal disease, the conference had a number of intriguing new epidemiologic studies. One of the more eye-opening ones was a retrospective investigation that characterized what happens to the very elderly after they start renal replacement therapy (RRT) in the hospital. The statistics that emerged raise questions about the wisdom of placing these old patients on RRT. The study, led by Bjoerg Thorsteinsdottir, MD, of Mayo Clinic, Rochester, Minn., found extremely high rates of early and overall mortality (see article on page 18). The researchers reviewed the medical records of 379 patients aged 75 years and older starting any form of RRT at the Mayo Clinic Rochester Midwest dialysis network. Of the 379 patients, 286 (76%) were started on RRT in the hospital after an acute illness or surgery. A total of 173 (60%) of those began with continuous RRT in the intensive care unit (ICU). Of 254 hospitalinitiated patients admitted from independent living, only 95 (37%) were discharged home. One hundred and four patients (27%) died in less than 30 days and 140 (36%) died in less than 90 days. The six- and 12-month survival rates were 60% and 49%, respectively. Among the patients who started RRT in the hospital, 110 (43%) died during the index hospitalization. According to Dr. Thorsteinsdottir, patients frequently had no idea that their kidneys had failed and would need dialysis. In addition, many elderly patients and their families expressed regret about having started RRT. Many elderly people have strong feelings about not wanting to be dependent on others and not being able to maintain their independence, she observed. Based on the new study, she said, clinicians can inform patients that if they are sick enough to be in the ICU and needing RRT, they are unlikely to make it back home and very likely to die in the short term. Physicians and other medical professionals rightfully see it as their professional and ethical obligation to prolong life by any reasonable means possible. The sobering findings of Dr. Thorsteinsdottir’s study should remind clinicians that patients—especially very old patients— may not want life prolonged if the quality of that life will be greatly diminished. Incorporating the new study’s findings into discussions with very elderly patients before starting them on RRT would seem a prudent thing to do.

Sincerely, Jody A. Charnow Editor

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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 Chief of Nephrology Memphis VA Medical Center Fred Hatch Professor of Medicine University of Tennessee Health Science Center, Memphis 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 12. 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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6 Renal & Urology News

DECEMBER 2013 www.renalandurologynews.com

Contents

DECEMBER 2013

VOLUME 12, ISSUE NUMBER 12

Nephrology

ONLINE

this month at renalandurologynews.com Expert Q&A

Ronald K. Loo, MD, of Southern California Permanente Medical Group, talks about the Hematuria Risk Index he and his colleagues developed.

3 1

Vitamin D Supplements Do Not Raise Stone Risk A serum 25-hydroxyvitamin D level of 20 to 100 ng/mL has no significant association with kidney stone incidence.

Statins May Improve Renal Outcomes Separate studies suggest a lower risk of acute kidney injury after surgery and reduced need for dialysis among ICU patients.

Clinical Quiz

Take our latest quiz at renalandurologynews.com /clinical-quiz/. Answer correctly and you will be entered to win a $50 American Express gift card. Congratulations to our October winner: Adela Mattiazzi

Virtual Conference NEW

Sign up for the Renal & Urology News Kidney Care Congress at 6-9 p.m. EST, January 22, 2014. Go to: www.RenalandUrologyNews.com/Kidney2014

Early Dialysis May Worsen Outcomes Elderly patients who start dialysis early rather than late are at increased risk for death and hospitalization, even after adjusting for patients’ predialysis health status and healthcare use.

5 1

Radiotherapy May Benefit High-Risk RCC Patients Adjuvant radiotherapy may offer a high rate of local control with increased progressionfree survival without significantly harming quality of life in patients with high-risk stage 3 renal cell carcinoma.

Comorbidities Increase Post-Radiotherapy ED Risk The number of vascular comorbidities a man has prior to prostate cancer radiotherapy influences his risk of erectile dysfunction after treatment.

Papillary Renal Cancer Linked to Renal Cysts Papillary renal cell cancer is associated with simple renal cysts, new findings from a Finnish study suggest.

Testosterone Benefits Obese Hypogonadal Men Obese hypogonadal men who received long-term testosterone injections experience a gradual decline in weight and waist circumference.

We think this study is important because it is

the first study to demonstrate an association between sex and incident CKD in diabetes.

See our story on page 19

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CME Feature 25

Urology

The Medical Minute

Visit renalandurologynews.com /the-medical-minute/ to hear podcast reports on new studies. Our latest include: • Nocturnal Dialysis May Decrease Heart Disease Risk • Multiple-Message Campaign May Increase Kidney Donation • Scoring System Predicts Likelihood of Diabetes Remission After RYGB

Large Waists Predict Higher ESRD Risk Greater waist circumference is associated with an increased risk of end-stage renal disease after adjusting for body mass index, data show.

New Ablative Techniques in Urologic Oncology Jeffrey J. Tomaszewski, MD, and David Y.T. Chen, MD, of Fox Chase Cancer Center in Philadelphia, review innovative focal ablative therapies for kidney and prostate cancers.

Departments 4

From the Editor Placing very elderly patients on RRT

News in Brief Pre-dialysis conception improves birth rates

Practice Management Tips for complying with HIPAA

11/25/13 12:29 PM

6 Renal & Urology News

DECEMBER 2013 www.renalandurologynews.com

Contents

DECEMBER 2013

VOLUME 12, ISSUE NUMBER 12

Urology

ONLINE

this month at renalandurologynews.com Expert Q&A

Ronald K. Loo, MD, of Southern California Permanente Medical Group, talks about the Hematuria Risk Index he and his colleagues developed.

Clinical Quiz

5 1

Comorbidities Increase Post-Radiotherapy ED Risk The number of vascular comorbidities a man has prior to prostate cancer radiotherapy influences his risk of erectile dysfunction after treatment.

Papillary Renal Cancer Linked to Renal Cysts Papillary renal cell cancer is associated with simple renal cysts, new findings from a Finnish study suggest.

Virtual Conference NEW

Sign up for the Renal & Urology News Kidney Care Congress at 6-9 p.m. EST, January 22, 2014. Go to: www.RenalandUrologyNews.com/Kidney2014

Testosterone Benefits Obese Hypogonadal Men Obese hypogonadal men who received long-term testosterone injections experience a gradual decline in weight and waist circumference.

3 1

Vitamin D Supplements Do Not Raise Stone Risk A serum 25-hydroxyvitamin D level of 20 to 100 ng/mL has no significant association with kidney stone incidence.

Statins May Improve Renal Outcomes Separate studies suggest a lower risk of acute kidney injury after surgery and reduced need for dialysis among ICU patients.

Large Waists Predict Higher ESRD Risk Greater waist circumference is associated with an increased risk of end-stage renal disease after adjusting for body mass index, data show.

We think this study is important because it is

the first study to demonstrate an association between sex and incident CKD in diabetes.

See our story on page 19

RUN1213_TOC_uro.indd 6

CME Feature New Ablative Techniques in Urologic Oncology Jeffrey J. Tomaszewski, MD, and David Y.T. Chen, MD, of Fox Chase Cancer Center in Philadelphia, review innovative focal ablative therapies for kidney and prostate cancers.

Nephrology

The Medical Minute

Visit renalandurologynews.com /the-medical-minute/ to hear podcast reports on new studies. Our latest include: • Biomarker Could Identify Candidates for PCa Active Surveillance • Online Program Helps Prostate Cancer Patients Decide on Treatment • Combining Abiraterone with Prednisone Beneficial

Departments 4

From the Editor Placing very elderly patients on RRT

News in Brief Pre-dialysis conception improves birth rates

Practice Management Tips for complying with HIPAA

11/25/13 12:30 PM

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.

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INVOKANATM 300 mg demonstrated greater reductions in A1C vs Januvia® 100 mg at 52 weeks… Adjusted Mean Change in A1C From Baseline (%): INVOKANA™ 300 mg vs Januvia® 100 mg, Each in Combination With Metformin + a Sulfonylurea1

DIFFERENCE FROM JANUVIA®

– 0.37*

(95% CI: –0.50, –0.25); P<0.05

Januvia® 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

–1.03

Incidence of Hypoglycemia

Convenient Once-Daily Oral Dosing1

With metformin + a sulfonylurea over 52 weeks: INVOKANATM (canagliflozin) 300 mg: 43.2%; Januvia® 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 * INVOKANA™ + metformin is considered noninferior to Januvia® + 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.

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

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

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

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

Adverse Reactions

Change in SBP†

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

Signiﬁcant lowering of SBP at 52 weeks, each in combination with metformin + a sulfonylurea (P<0.001)2 >> Difference from Januvia®‡: 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.

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

SGLT2 = sodium glucose co-transporter-2. Included 1 monotherapy and 3 add-on combination trials with metformin, metformin + a sulfonylurea, or metformin + pioglitazone.

†Prespeciﬁed secondary endpoint. ‡Adjusted mean.

Indicated trademarks are registered trademarks of their respective owners.

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

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IMPORTANT SAFETY INFORMATION (cont’d) 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. 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

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November 2013

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INVOKANA™

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.

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K02CAN13149

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.

(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

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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

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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 DECEMBER 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

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Renal & Urology News 13

Vitamin D Supplements Do Not Raise Stone Risk DESPITE concern about an increased risk for kidney stones with vitamin D supplementation, researchers have concluded that a serum 25-hydroxyvitamin D (25[OH]D) level of 20 to 100 ng/mL has no significant association with kidney stone incidence. Among 2,012 individuals followed prospectively for a median of 19 months, 13 reported having developed a kidney stone during the study period. Although body mass index (BMI) was significantly associated with kidney stone risk (patients with a BMI of 30 or greater had a higher incidence rate of kidney stones than did others), the association between serum 25(OH)D and kidney stone development was not statistically significant. Cedric F. Garland, DrPH, of the University of California San Diego (UCSD) School of Medicine, and colleagues reported online in the American Journal of Public Health that the mean 25(OH)D serum level among the 13 patients who had kidney stones was 47 ng/mL, with a median serum level of

43 ng/mL. By comparison, the mean and median 25(OH)D serum levels among those without kidney stones were both 50 ng/mL. Eight patients with kidney stones were below the median 25(OH)D serum level of 50 ng/mL, with the levels in the five remaining participants equal to or above the median. “Mounting evidence indicates that a vitamin D serum level in the therapeutic range of 40 to 50 ng/mL is needed for substantial reduction in risk of many diseases, including breast and colorectal cancer,” Dr. Garland explained in a UCSD statement, adding that this serum level is generally only achieved with vitamin D supplementation. “Our results may lessen concerns by individuals about taking vitamin D supplements, as no link was shown between such supplementation and an increased risk for kidney stones.” Males and individuals aged 55 years and older had a higher incidence rate of kidney stones compared with other participants. n

Statement of Ownership, Management and Circulation 1. Publication Title: Renal & Urology News 2. Publication Number: 022-226 3. Filing Date: Sept. 30, 2013 4. Issue Frequency: Monthly 5. Number of Issues Published Annually: 12 6. Annual Subscription Price: U.S.: United Stated $75.00 7. Complete Mailing Address of Known Office of Publication: 114 West 26th Street, 4th Floor New York, NY 10001 8. Complete Mailing Ad0dress of Headquarters or General Business Office of Publisher: 114 West 26th Street, 4th Floor New York, NY 10001 9. Full Names and Complete Mailing Addresses of Publisher, Editor, and Managing Editor: Publisher: Dominic Barone, 114 West 26th Street, 4th Floor, New York, NY 10001; Editor: Jody Charnow 114 West 26th Street, 4th Floor, New York, NY 10001; Managing Editor: Marina Galanakis 114 West 26th Street, 4th Floor, New York, NY 10001 10. Owner: Haymarket Media Group, LTD. 174 Hammersmith Road, London, UK W6J7P 11. Known Bondholders, Mortgages, and Other Security Holders Owning or Holding 1 percent or More of Total Amount of Bonds, Mortgages, or Other Securities: None 12. Tax Status: The purpose, function, and nonprofit status of this organization and the exempt status for federal income tax purposes: Has Not Changed During Preceding 12 Months. PS Form 3526-R. August 2012 13. Publication Title: Renal & Urology News 14. Issue Date for Circulation Data Below: Sept. 2013 15. Extent and Nature of Circulation [i] Average No. Copies Each Issue During Preceding 12 Months [ii] No. Copies of Single Issue Published Nearest to Filing Date a. Total Number of Copies (Net press run) [i] 17,778 [ii] 17,773 b. Paid and/or Requested Circulation (1) Paid/Requested Outside—County Mail Subscriptions Stated on Form 3541 [i] 9,091 [ii] 8,844 (2) Paid In-County Subscriptions Stated on Form 3541 [i] 0 [ii] 0 (3) Sales Through Dealers and Carriers, Street Vendors, Counter Sales, and Other Non-USPS Paid Distribution [i] 0 [ii] 0 (4) Other Classes Mailed Through the USPS [i] 0 [ii] 0 c. Total Paid and/or Requested Circulation [i] 9,091 [ii] 8,844 d. Free Distribution by Mail (1) OutsideCounty as Stated of Form 3541 [i] 8,082 [ii] 8,480 (2) In-County as Stated on Form 3541 [i] 0 [ii] 0 (3) Nonrequested Copies Distributed Through the USPS by Other Classes of Mail [i] 0 [ii] 0 (4) Nonrequested Copies Distribution Outside the Mail [i] 25 [ii] 0 e. Total Nonrequested Distribution [i] 8,107 [ii] 8,480 f. Total Distribution [i] 17,199 [ii] 17,324 g. Copies not Distributed [i] 579 [ii] 449 h. Total [i] 17,778 [ii] 17,773 i. Percent Paid and/or Requested Circulation [i] 52.86% [ii] 51.05% 16. Total Circulation includes electronic copies: No 17. Publication of Statement of Ownership for a Requestor Publication is required and will be printed in the December 2013 issue of this publication 18. Manager or Owner: John Crewe, Chief Operations Officer 09/30/2013 I certify that all information furnished on this form is true and complete. I understand that anyone who furnishes false or misleading information on this form or who omits material or information requested on the form may be subject to criminal sanctions (including fines and imprisonment) and/or civil sanctions (including civil penalties).

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CKD screening continued from page 1

The ASN contends that because CKD is largely asymptomatic in its early stages, early detection and intervention can slow progression of the disease and help patients maintain vital kidney function and quality of life. ACP President Molly Cooke, MD, however, held firm in a comment to Renal & Urology News. “ACP’s recommendations are based on our interpretation of the available evidence,” Dr. Cooke said. “There is no evidence that obtaining a ‘baseline creatinine’ or screening for renal dysfunction in asymptomatic individuals with no risk factors for kidney disease improves outcomes for patients. Screening in low-prevalence populations results in false-positive tests and in harms, such as patient anxiety and costs associated with the evaluation of false-positive tests. Physicians should not order tests that will not change patient management.”

Proteinuria testing The ASN also disagrees with the ACP’s recommendation against testing for proteinuria in adults taking an ACE inhibitor (ACE-I) or an angiotensin II receptor blocker (ARB). Citing high blood pressure and diabetes as the two leading risk factors for the development of CKD, the ASN “emphasizes the importance” of proteinuria testing in adults being treated with antihypertensive medications. Dr. Cooke, however, supported her group’s conclusions. “The ‘treatment’ for microalbuminuria, a form of low-grade proteinuria, in patients with hypertension and/or diabetes is administration of an ACE-I or ARB,” she noted. “There is no evidence that monitoring proteinuria to assess the effect of ACE-I or ARB

administration in patients with proteinuria produces better outcomes. Therefore, once the decision has been made to initiate ACE-I or ARB treatment, there is no need to do further assessments. “As ACP states in the guideline,” she continued, ‘Many patients, regardless of CKD status, are already taking ACE inhibitors, ARBs, statins, or other drugs to treat existing comorbid conditions. Monotherapy with ACE inhibitors or ARBs statistically significantly reduced the risk for [end-stage renal disease] in patients with CKD, but benefits were limited to patients with macroalbuminuria, and most of these patients also had diabetes and hypertension.’”

NKF, RPA weigh in The National Kidney Foundation (NKF) and the Renal Physicians Association (RPA) jointly announced their agreement with the ACP’s recommendation against routine testing for kidney disease in the general population without risk conditions. Like ASN, however, the two organizations oppose the ACP advice against testing for proteinuria in individuals with or without diabetes taking an ACE-I, an ARB, or certain other antihypertensive agents. NKF and RPA recommend that proteinuria be monitored at least annually in those with major risk factors such as diabetes, even if they are taking such a medication. “If proteinuria increases, that could be a reason to intensify therapy with one of the kidney- protective blood pressure drugs, ACE inhibitors or ARBs,” NKF Chief Medical Officer Joseph Vassalotti, MD, pointed out in a statement. “In addition, if a person has hypertension, severely increased proteinuria may be a reason to consider referral to a kidney specialist for a biopsy to look for a cause of kidney disease other than high blood pressure.” n

Fasting phosphorus continued from page 1

phosphorus levels after a meal as this is probably affected by the amount of phosphorus consumed, the time of day, kidney function, and probably other factors.” Considering the variation introduced by time of day and phosphorus intake, studies examining the relationship between serum phosphorus and outcomes should standardize data collection to account for these factors to enhance their power to detect associations. More research is needed to understand the effect that different levels of phosphorus intake have on serum phosphorus levels over the course of a day in patients with CKD, he said. Dr. Chang and Morgan Grams, MD, PhD, of Johns Hopkins University in Baltimore, analyzed data from participants in the Third National Health and Nutrition Examination Survey (1988-

Dietary acid load continued from page 1

ciation of dietary acid load and progression to ESRD in a nationally representative cohort. ESRD developed in 311 participants (20.9%) during a median of 14.2 years of follow-up. Compared with subjects in the lowest tertile of net acid excretion (NAE), those in the middle and highest tertiles had a 3.8 times and 8.6 times increased risk for ESRD. The risk associated with elevated NAE increased in a graded fashion with estimated glomerular filtration rate (eGFR). Among subjects with an eGFR below 45 mL/min/1.73 m2, those in the middle and highest tertiles of NAE had a significant 9.4 and 13.8 times increased risk of ESRD compared with participants in the lowest tertile. Among participants with an eGFR of 45 and higher, those in the middle and highest tertiles of NAE had

1994). Fasting patients (those who went 12 hours or more without food or drink except for water) had significantly lower serum phosphorus levels than non-fasting participants (3.3 vs. 3.6 mg/dL). In fasting subjects, each 1 mg/dL increment in serum phosphorus was associated with a significant 48% increased adjusted risk of all-cause mortality and 67% increased adjusted risk of cardiovascular mortality. In non-fasting subjects, increases in serum phosphorus were not significantly associated with all-cause or cardiovascular mortality. The researchers pointed out that most, but not all, studies have found associations between elevated serum phosphorus levels and increased mortality. Since serum phosphorus levels may be affected by dietary phosphorus intake, they hypothesized that the association between serum phosphorus and mortality would differ by fasting status. n

a significant 5.7 and 7.6 times increased risk compared with subjects in the lowest tertile. Furthermore, among subjects with albuminuria (30 mg/g or higher), those in the middle and highest NAE tertiles had a significant 15% and 6.5 times increased risk of ESRD compared with subjects in the lowest tertile. In participants without albuminuria, NAE was not significantly associated with ESRD risk. In the other study, a Japanese team found that high net endogenous acid production (NEAP) is associated with CKD progression. The primary endpoint of the study by Eiichiro Kanda, MD, of Tokyo Kyosai Hospital, and colleagues, was a 25% decline in eGFR or initiating dialysis. In adjusted analyses, patients in the upper half of the NEAP range had a nearly twofold increased risk of CKD progression compared with those whose NEAP levels were in the lower half of the range. n

Newborns are Among the Hardest Hit by Inpatient AKI AMONG children who experience acute

Dr. Sutherland’s group reported in the

was higher among those one month older

addition, data showed that AKI was associ-

kidney injury (AKI) during hospitalization,

Clinical Journal of the American Society of

or younger (31.3% vs. 10.1) and children

ated with such procedures as intubation

mortality is highest among neonates and

Nephrology.

requiring admission to an intensive care

and mechanical ventilation, vascular

unit (ICU) or dialysis (32.8% vs. 9.4% and

catheterization, and blood transfusions.

those requiring critical care or dialysis.

The highest incidence was observed in

Scott M. Sutherland, MD, of Stanford

children aged 15-18 years (6.6 per 1,000

27.1% vs. 14.2%, respectively). Among children older than one month,

Among those one month or younger, investigators observed a similar pattern of

University in Stanford, Calif., and col-

admissions). Although 49% of the cohort

leagues analyzed data from 2.6 million chil-

was white, AKI incidence was higher

AKI was associated with liver disease,

associations between AKI and diagnoses,

dren in the 2009 Kids Inpatient Database.

among African Americans (4.5 vs. 3.8 per

respiratory failure, and pulmonary

but AKI also was associated with circula-

AKI developed in 10,322 subjects, for an

1,000 admissions). In-hospital mortality

collapse/pulmonary inflammation, shock,

tory diseases, congenital cardiac disease,

incidence of 3.9 per 1,000 admissions,

among children with AKI was 15.3%, but it

septicemia, and coagulation disorders. In

and postoperative complications. n

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IMRT study continued from page 1

when radiation therapy was only available in hospitals and free-standing radiation centers,” LUGPA observed. Furthermore, the association noted that Dr. Mitchell’s data show that the use of active surveillance was nearly identical between integrated and referring groups (27% vs. 27.4%). “In addition, her data shows that active surveillance rates actually increased for integrated groups after they acquired IMRT technology. This demonstrates that incorporation of IMRT did not influence clinical decision-making in a manner to maximize profits.” The study also showed relatively consistent use of radical prostatectomy by integrated groups after acquisition of IMRT technology and that integrated groups’ increased use of IMRT was offset by substantial decreases in the use of brachytherapy (from 18.6% to 5.65%) and androgen deprivation therapy (from 16.5% to 8.4%). Prohibiting integrated practices from offering radiation and other treatment modalities would only undermine competition in the marketplace as well as increase up costs “as many patients resort to care in the more expensive hospital setting, and harm patient access to specialized integrated care,” according to LUGPA. The association also pointed out that Dr. Mitchell provides no rationale for her choice of control groups, which she did not match for size, patient demographics, or severity of illness. The American Urological Association (AUA) had similar criticisms, and issued a statement that read, in part, that “there are serious concerns about the author's selection of control groups that may not be representative of general practice trends.” Prior studies using the Surveillance, Epidemiology, and End Results (SEER) database have shown significant declines in the use of brachytherapy in the U.S. during the same period, “yet Dr. Mitchell's control groups fail to show any decline in brachytherapy

use. As the methods used to select the control groups are poorly described, one cannot help but wonder whether Dr. Mitchell chose the control groups to arrive at results that were acceptable to the study's sponsors,” the AUA stated. According to Dr. Mitchell's report, recent evidence suggests that the IMRT self-referral arrangement is becoming more common. By the end of 2011, she said, about 19% of urology practices had incorporated IMRT services into their practice. Dr. Mitchell constructed two study samples. One included 35 self-referring urology groups in private practice and a matched control group that included 35 non-self-referring urology groups in private practice. The other sample included non-self-referring urologists employed at 11 National Comprehensive Cancer Network (NCCN) centers matched with 11 self-referring urology groups in private practice. From 2005 through 2010, the rate of IMRT use by self-referring urologists in private practice increased significantly from 13.1% to 32.3%. By comparison, the rate of IMRT use by urologists who did not self-refer increased from 14.3% to 15.6%. The rate of IMRT use by urologists at the NCCN centers remained stable at 8.0% but rose by 33 percentage points among the 11 matched self-referring urology groups. “The findings raise concerns regarding the appropriate use of IMRT, especially among older Medicare beneficiaries, for whom the risks of undergoing intensive irradiation probably exceed the benefits,” Dr. Mitchell wrote. Self-referral is generally illegal, but the federal prohibition against it has exceptions that allow physicians to self-refer under certain conditions, she explained. “The most notable exception concerns in-office ancillary services; this provision enables individual physicians and physician groups to integrate designed health services, including radiation therapy, into their practices without violating the law.” n

PCa/melanoma risk continued from page 1

epidemiologic studies,” the authors explained. The researchers documented 539 melanomas in the HPFS and 166 in the PHS during 747,176 person-years and 251,850 person-years, respectively. “Our finding of a PCa diagnosis as a risk predictor for melanoma holds general public health significance, which may inform clinical practice to address the queries and aid the care of patients with PCa,” the researchers concluded. They noted that severe acne, a surrogate for androgen activity, was positively associated with PCa risk in a previous study by Elizabeth A. Platz, ScD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, and colleagues. That study, which was published in the International Journal

Testosterone/CV risk continued from page 1

nary artery disease (CAD) on the relationship. The researchers conducted a retrospective national cohort study of men with low testosterone levels (less than 300 ng/dL) who had undergone coronary angiography in the Veterans Affairs health system from 2005 to 2011. Average follow-up was approximately 840 days (27.5 months). Of the 8,709 study subjects with low testosterone, 1,223 (14%) started testosterone therapy after a median of 531 days following coronary angiography. Those patients tended to be younger (mean age 61 years) than the testosterone non-users (mean age 64 years) and tended to have lower rates of congestive heart failure, renal failure, and other comorbidities. Approximately one of every five men not taking testosterone died and/or had a heart attack or a stroke, compared with approximately one out of four testosterone users. Testosterone therapy was associated with a 29% greater risk of these events. The absolute rate of events among the no-testosterone group versus the testos-

of Cancer (2007;121:2688-2692), also looked at men in the HPFS. The investigators found that men with severe acne—as measured by tetracycline use for four or more years—had a significant 70% increased risk of PCa compared with men who did not have severe acne. Dr. Han and colleagues noted that acne is a chronic inflammatory disease with androgen-induced sebum production as a major contributing factor. Androgens may influence melanoma risk by suppressing host immune response, and deficiency in immune response has been implicated in prostatic tumorigenesis, the researchers observed. “Therefore, PCa and a suppressed immune system might contribute to melanoma development,” they wrote, adding that common genetic variations also have been identified for PCa and melanoma. n

terone group was 10.1% versus 11.3% at one year post-angiography, 15.4% versus 18.5% at two years, and 19.9% versus 25.7% at three years, for an absolute risk difference of 5.8% at three years after angiography, the researchers reported in the Journal of the American Medical Association (2013;310:1829-1836). Even after adjustments were made for the presence of CAD and other factors, testosterone therapy was associated with adverse outcomes—an effect that was consistent among men with and without CAD. The investigators noted some potential mechanisms through which testosterone therapy may increase CV risk. For example, other research has indicated that intramuscular testosterone can increase platelet aggregation, and that the testosterone metabolite dihydrotestosterone can promote atherosclerosis. Having pointed out potential limitations of their study, the investigators emphasized the need for more research, including randomized controlled trials, to properly characterize the risks of testosterone therapy in men with comorbidities. n

Consensus Reached on MRI Role in PCa Focal Therapy TEMPLATE-guided saturation prostate

confirmed by targeted biopsy,

researchers from Europe and

experienced radiologist. It also agreed

biopsies are no longer necessary

according to consensus panel

North America, also concluded

that state-of-the-art mpMRI is the

when high-quality state-of- the-art

findings published online ahead of

that mpMRI is the “optimum approach

technique of choice for focal ablation

multiparametric magnetic resonance

print in BJU International.

to achieve the objectives needed

follow-up, but concluded that mpMRI

for focal therapy” if made on a high-

is not accurate enough to grade tumor

quality machine and judged by an

aggressiveness consistently. n

image (mpMRI) is available, but suspicious lesions should always be

RUN1213_Cover_Uro.indd 2

The panel, which included urologic surgeons, radiologists, and basic

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Renal & Urology News 15

Radiotherapy May Benefit High-Risk RCC Patients BY JOHN SCHIESZER ATLANTA—Adjuvant radiotherapy may offer a high rate of local control with increased progression-free survival without significantly harming quality of life in patients with high-risk stage 3 renal cell carcinoma (RCC), data presented at the American Society for Radiation Oncology’s 55th annual meeting. “This is a controversial area,” said lead study investigator William Baquero, MD, an attending physician at the VIDT Centro Medico-21st Century Oncology, Buenos Aires, Argentina. “We don’t have any treatment guidelines for adjuvant radiotherapy in these renal cell carcinoma patients. I was surprised that we had such good results in terms of clinical response.” Dr. Baquero, who presented the study findings at the meeting, said the five-year overall survival (OS) rate for stage 3 RCC does not exceed 65%. In

follow-up was 71 months (range 14-91 months). Ninety percent of the patients had clear cell RCC, with infiltration of the capsule in 93% of cases. In addition, 53% had perinephric fat invasion and 20% had renal vein involvement. The median radiation dose was 55Gy (50- 59.4Gy) and the reported toxicities

included nausea (Grade 0-I) in 70% of the patients and Grade II-IV nausea in 30%. Vomiting (Grade 0-I) occurred in 80% and Grade II-IV vomiting occurred in 20%. Dr. Baquero said acute diarrhea (Grade B:7.25 in 0-I) occurred in 96.6% and GradeT:7II-IV in the remainin der (3.3%), chronic and S:6.5gastrointestinal in

hepatic toxicity were reported (Grade 0-I) 100%. The study was limited by its retrospective design, Dr. Baquero noted. Prospective trials assessing new techniques and various fraction sizes of radiotherapy in selected patients may be warranted, he added. n

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THERE ARE DISTINCT WAYS TO HELP MANAGE ADVANCED PROSTATE CANCER * INHIBIT ANDROGEN PRODUCTION

“Patients with bad prognostic factors should be offered this treatment.”

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EACH PLAYS AN IMPORTANT ROLE 1-3 Learn more at inhibitandrogen.com/distinct *Other treatment options may also be considered. References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Schulze H, Senge T. Influence of different types of antiandrogens on luteinizing hormone-releasing hormone analogue-induced testosterone surge in patients with metastatic carcinoma of the prostate. J Urol. 1990;144(4):934-941. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

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addition, he noted that in the presence of poor prognostic factors there tends to be an increased rate of local relapse affecting the quality of life in this patient population. He and his colleagues studied 30 patients with stage 3 RCC who underwent radical nephrectomy and received adjuvant radiotherapy. The five-year local control rate was 93%, and only two patients relapsed in the retroperitoneum. “Patients with bad prognostic factors should be offered this treatment,” Dr. Baquero told Renal & Urology News. “In general, these patients aren’t offered postoperative radiotherapy but they should be.” The mean time to local relapse was 67 months (range 36-91 months). The fiveyear OS rate was 80%, and the metastasis-free survival rate was 83%. Distant metastases developed in five patients (17%); the mean time to metastases was 68 months (range 9-91 months). Patients received an external beam radiotherapy dose of 45-50 Gy to the nephrectomy bed, with 10-15 Gy Boost to micro/gross disease (1,8-2 Gy/fx). The mean age of the patients was 57 years (range 36-73 years) and the mean

16 Renal & Urology News

DECEMBER 2013 www.renalandurologynews.com

News in Brief

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

Short Takes Pre-Dialysis Conception May Improve Birth Rate

the dissolution of apatite or struvite

Starting dialysis after conception, not

is no alternative product for this

before, may improve birth rates in

indication. It can also be used

women with end-stage renal disease,

as an adjunctive therapy to dissolve

Australian researchers reported online

residual apatite or struvite calculi and

ahead of print in the Clinical Journal of

fragments after surgery or to partially

the American Society of Nephrology.

dissolve kidney stones prior to

renal and vesical calculi. There

surgical removal.

Shilpa Jesudason, MBBS, PhD, of Royal Adelaide Hospital, and colleagues women conceived after starting chronic

TSPO Not Needed for Making Testosterone

dialysis and 24 conceived before start-

Long thought to be an indispensable

ing chronic dialysis. Compared with

part of steroid hormone biosynthesis,

women who conceived after starting

a protein known as the translocator

dialysis, those who conceived prior

protein (TSPO) is unnecessary for

to starting dialysis had a better live

testosterone production, findings from

birth rate (91% vs. 63%). Women who

a study of male mice suggest. Accord-

conceived after starting dialysis had

ing to study lead author Vimal Selvaraj,

a higher rate of early pregnancy loss.

PhD, of Cornell University in Ithaca,

Birth weights and gestational ages were

New York, his team’s finding contradicts

similar for both groups.

a prevailing view held in the scientific

studied 77 pregnancies. Fifty-three

community for nearly 25 years that

Renacidin Irrigation Back on Market

TSPO is essential in steroid hormone biosynthesis. “This discovery rectifies a huge

After being sidelined for the past year and a half due to manufacturing issues,

misconception in the field,” Dr. Selvaraj

Renacidin Irrigation is available once

commented in a statement issued by

again. The solution, which consists of

The Endocrine Society, publisher of

citric acid, glucono-delta-lactone, and

the journal Endocrinology, in which the

magnesium carbonate, is indicated for

study findings were presented.

Retirement Age for Surgeons In a recent online poll, Renal & Urology News asked readers the following question: “Should there be a mandatory age at which surgeons must stop operating?” Here are the results based on 350 responses.

Yes: 38%

No: 55.43%

Do not know: 6.57%

RUN1213_NewsBrief.indd 1

Cystectomy Patients May Need Longer VTE Prophylaxis P

atients undergoing radical cystectomy for bladder cancer may require prolonged pharmacologic prophylaxis against venous thromboembolism (VTE), new data suggest. Amanda A. VanDlac, MD, of Oregon Health and Science University in Portland, and colleagues analyzed data from 1,307 radical cystectomy patients. Of these, VTE was diagnosed in 78 (6%), the researchers reported online ahead of print in The Journal of Urology. The mean time to diagnosis was 15.2 days after surgery; 55% of all VTE events were diagnosed after patient discharge. The 30-day mortality rate from VTE was 6.4%. In multivariate analysis, risk factors for VTE were increasing age, longer operative time, and sepsis or septic shock, according to the investigators. The authors concluded that it is reasonable to consider extended pharmacologic prophylaxis in this high-risk surgical population.

New CDC Tools Aim to Reduce Dialysis Infections T

he Centers for Disease Control and Prevention (CDC) has three new resources in the form of a video, a poster, and a pocket guide to help providers and patients prevent infectious complications in hemodialysis (HD) patients. The provider training video, Preventing Bloodstream Infections in Outpatient Hemodialysis Patients: Best Practices for Dialysis Staff, describes best practices for preventing infection in patients with catheters, fistulas, or grafts, and offers tips on hand hygiene, glove use, and dialysis-station disinfection. The provider poster, Put Together the Pieces to Prevent Infections in Dialysis Patients, is an 11×17 wall hanging that serves as a visual reminder of the measures the HD facility staff can take to reduce infection in patients. The patient pocket guide, 6 Tips to Prevent Dialysis Infections, outlines six infection-prevention tips for patients with catheters, fistulas, or grafts, with images included for each tip. More information on these dialysis safety resources is available at www.CDC.gov.

Ipecac Component Boosts Cisplatin in Bladder Cancer A

n active ingredient in ipecac syrup inhibited the proliferation of bladder tumor cells when used alone or in combination with cisplatin in a recent study. The ingredient, emetine dihydrochloride, is a natural alkaloid that had demonstrated modest anticancer efficacy in clinical trials in the 1970s, wrote Loyola University Health System researcher Kimberly E. Foreman, PhD, and colleagues in an online report in The Journal of Urology. Although these findings were not pursued at the time, emetine dihydrochloride has recently been shown to induce apoptosis (programmed cell death) in leukemia cell lines, an effect enhanced by cisplatin. Dr. Foreman’s group sought to determine the antiproliferative effects of emetine with and without cisplatin on bladder cancer cells. They found that each agent alone inhibited cancer cell proliferation, but in combination, emetine and cisplatin worked with moderate to strong synergism.

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www.renalandurologynews.com DECEMBER 2013

Renal & Urology News 17

Comorbidities Increase Post-Radiotherapy ED Risk 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 B:7.25 in the results of the study to provide estimates of postT:7 in radiotherapy erectile S:6.5 in 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

IN ADVANCED PROSTATE CANCER…

DO YOUR PATIENTS HAVE

MORE ANDROGEN THAN YOU CAN CATCH WITH ANDROGEN RECEPTOR BLOCKADE?

T:10 in

Androgen levels may impact antiandrogen therapy.1-3 Learn more at inhibitandrogen.com/excess References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical studies. Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed. Neural Endocrine Peptides and Receptors. New York, NY: Plenum Press; 1986:627-644.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2013 9/13 002097-130903

Date: 09/11/13 Customer Code: 002097-130903 File Name: 002097-130903_690755_v1a

Group 360 Job #: 690755 11/21/13 3:57 PM Brand: Zytiga

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Caucasians (23% vs. 20%) due to a higher incidence of vascular comorbidities in the African Americans, the researchers noted. Among Caucasians, the presence of zero, one, two, or three comorbidities was associated with a 40%, 55%, 60%, and 71% incidence of ED, respectively.

S:9.5 in

BY JOHN SCHIESZER ATLANTA—The number of vascular 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 [incidence] 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 approximately 75%,” Dr. Wang added. “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 AfricanAmerican 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 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. Pre-radiation therapy incidence rates were slightly higher among African Americans than

18 Renal & Urology News

■ Kidney Week 2013

DECEMBER 2013 www.renalandurologynews.com

Reports below are from the American Society of Nephrology’s Kidney Week 2013 in Atlanta

Statins May Improve Renal Outcomes STATIN use may protect against adverse renal outcomes, according to the findings of two studies. In one study, researchers found that preoperative statin use has the potential to reduce the likelihood of acute kidney injury (AKI) after cardiac surgery. Amber O. Molnar, MD, of the University of Ottawa in Canada, studied 625 adult patients undergoing elective cardiac surgery. Patients who remained on their statins had a lower risk for elevation of various AKI biomarkers than those who had their statins held in the 24 hours before surgery. These biomarkers included urine interleukin-18, urine neutrophil gelatinase-associated lipocalin (NGAL), plasma NGAL, and urine kidney injury molecule-1.Of the 625 patients, 494 (21%) had their statins held and 131 did not. AKI developed in 19 patients in the statin-held group (4%) and six in the statins-continued group (5%). AKI is defined as a doubling of serum creatinine or need for dialysis.

Dietary Acid May Raise Stone Risk HIGHER DIETARY acid load is independently associated with an increased risk of kidney stones. Ernest I. Mandel, MD, of Brigham and Women’s Hospital in Boston, and colleagues examined the association between dietary acid load and kidney stones in 44,581 men in the Health Professionals Follow-up Study (HPFS), 73,154 older women and 91,509 younger women in the Nurses’ Health Study (NHS) I and II, respectively. Subjects had 24 years, 26 years, and 16 years of follow-up, respectively. Dr. Mandel’s group analyzed dietary data obtained from a 131-item food frequency questionnaire as well as lifestyle and clinical data from biennial questionnaires. The investigators identified a total of 6,361 incident cases of kidney stones during about 4.4 million person-years of follow-up. After adjusting for potential confounders, the men, older women, and

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“Statins may prevent kidney injury after cardiac surgery as evidenced by lower levels of kidney injury biomarkers,” the authors concluded in a poster presentation. In the other study, Brazilian investigators showed that statin use prior to hospital admission is associated with a reduced likelihood of needing dialysis and a lower risk of death and sepsis among intensive care unit (ICU) patients. Isabelle Malbouisson, MD, of the Federal University of São Paulo, and colleagues studied 670 patients admitted to the ICU of an academic tertiary-care hospital. Of these, 18.2% were on statin therapy prior to hospitalization. These patients had a significant 59% decreased risk for needing dialysis therapy or death and a significant 58% decreased risk for sepsis after infection compared with patients who did not use statins prior to hospitalization. They also had a significant reduction in hospital stay (14.7 vs. 22.3 days).

younger women in the highest quintile of diet-estimated net endogenous acid production had a significant 59%, 48%, and 53% increased risk of kidney stones, respectively, compared with those in the lowest quintile. The men and younger women in the highest quintile of dietestimated potential renal acid load had a significant 54% and 30% increased risk of kidney stones compared with those in the lowest quintile. The older women had a non-significant 8% increased risk. Higher dietary acid load may reduce urinary citrate excretion, which is associated with an increased risk of kidney stone formation, researchers said. In a study published earlier this year in the Clinical Journal of the American Society of Nephrology (2013;8: 901-908), the same research team found that higher intake of nondairy animal protein, higher body mass index, and a history of nephrolithiasis, hypertension, gout, and thiazide use were independently associated with lower 24-hour urinary citrate excretion, in adjusted analyses. Higher intake of potassium, higher urinary sodium, and a history of diabetes were independently associated with higher citrate excretion. n

Data suggest a lower risk of AKI after surgery and reduced need for dialysis among ICU patients

Statins may protect ICU patients from renal failure and death.

Although these two studies demonstrated a beneficial effect of statins, other studies presented at the conference did not. In one study, researchers found that atorvastatin had no significant effect on a combined endpoint of cardiovascular death, myocardial

infarction, and stroke among diabetic patients on hemodialysis (HD). The statin also had no significant effect on fatal infection or all-cause mortality. However, researchers found a significant 17% relative risk reduction in all cardiovascular events combined. The study, by Vera Krane, MD, of the University of Würzberg in Germany, and colleagues, included 1,255 type 2 diabetes patients on HD who were randomly prescribed either 20 mg atorvastatin daily or a placebo. In addition, in a study of 503 dialysis patients, Jerome Pineault, MD, and collaborators at Maisonneuve-Rosemont Hospital in Montreal found that statin therapy did not improve erythropoietin resistance index (ERI). In fact, the study showed that patients started on statins during the study experienced an increase in ERI and those taken off statins experienced a decrease in ERI, although these findings were not significant. n

Patients Aged 75+ Have Poor Outcomes After Starting RRT EARLY AND OVERALL mortality is

living, only 95 (37%) were discharged

high among patients who start

home, the investigators reported.

renal replacement therapy (RRT)

The mean follow up was 17 months

at age 75 years and older, a study

(range 0-74).

reports. Bjoerg Thorsteinsdottir, MD, of Mayo

One hundred and four patients (27%) died in fewer than 30 days and 140 (36%)

Clinic, Rochester, Minn., and collabora-

died in fewer than 90 days. The six-

tors reviewed medical records of

and 12-month survival rates were 60%%

379 patients aged 75 years and older

and 49%, respectively. Among the

starting any form of RRT at the Mayo

patients who started RRT in the hospital,

Clinic Rochester Midwest dialysis

110 (43%) died during the

network. The group was 66% male, 93%

index hospitalization.

Caucasian. The mean age was 80.8

Dr. Thorsteinsdottir’s group observed

years. In this group, 27% had diabetes

that the “intensity of medical care

and 32% had congestive heart failure.

for the oldest old has escalated

The mean Charlson comorbidity index

beyond population growth in the past

was 7.7. Of the 379 patients, 286 (76%),

decades driven by powerful moral and

started RRT in hospital after an acute

technological imperatives to treat.”

illness or surgery. A total of 173 (60%) of

Many elderly patients and their families

those began with continuous RRT in the

feel that they have no choice but to start

intensive care unit. Of 254 hospital-initi-

RRT, some expressing regret of having

ated patients admitted from independent

initiated therapy. n

11/21/13 4:20 PM

www.renalandurologynews.com DECEMBER 2013

■ Kidney Week 2013

Renal & Urology News 19

Reports below are from the American Society of Nephrology’s Kidney Week 2013 in Atlanta

Study: CKD Risk in Diabetics Higher Among Women CHRONIC kidney disease (CKD) is more likely to develop in diabetic women than diabetic men, according to a study. The study, by Margaret K. Yu, MD, and Bessie A. Young, MD, MPH, of the University of Washington in Seattle, included 1,468 diabetic patients, of whom 766 (52.2%) were women. Women had a 36% greater risk of incident CKD at 10 years after taking into account pre-CKD death as a competing risk and after adjusting for demographics, traditional risk factors, and behavioral risk factors. “This has clinical implications because CKD is associated with functional disability and decreased quality of life,” Dr. Yu told Renal & Urology News The researchers noted that women with diabetes have a higher prevalence of CKD risk factors than men. The study found that women were more likely

than men to be unmarried, have lower education levels, and higher low-density lipoprotein levels, body mass index, and baseline estimated glomerular filtration rate (eGFR).

Participants were identified through the Pathways Study, a Seattle-based prospective, observational B:7.25 in cohort of ambulatory, diabetic patients. Only patients T:7 in without baseline CKD S:6.5 inwere observed for

10-year incidence. CKD was defined as an eGFR less than 60 mL/min/1.73 m2 or microalbuminuria (urine albumin/creatinine value of 25 mg/g or more for women or 17 mg/g or more for men). n

Large Waists Predict Higher ESRD Risk end-stage renal disease (ESRD) after

T:10 in

associated with an increased risk of adjusting for body mass index (BMI), data show. The findings support the hypothesis that increased abdominal adiposity may influence kidney disease progression. The study also showed that higher

In mCRPC, is it appropriate to

INHIBIT ANDROGEN PRODUCTION BEFORE BLOCKING THE ANDROGEN RECEPTOR?*

BMI is associated with a decreased risk of ESRD after adjusting for waist circumference In a study that included 27,085 participants in the REGARDS trial, Holly J. Kramer, MD, of Loyola

THIS APPROACH IS AN OPTION FOR TREATMENT IN ADVANCED PROSTATE CANCER.1,2

University in Chicago, and colleagues found a lower prevalence of albuminuria and chronic kidney disease among subjects with a BMI of 25 kg/m2 or higher compared with those who had a lower BMI, but a higher prevalence

Learn more at inhibitandrogen.com/sequence *Currently in the absence of published, randomized, clinical data on treatment sequencing in mCRPC posttreatment with docetaxel. mCRPC=metastatic castration-resistant prostate cancer. References: 1. Sartor AO, Tangen CM, Hussain MHA, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer. 2008; 112(11):2393-2400. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

among participants with a waist circumference of 80 cm or greater (for women) and 94 cm or greater (for men) compared with those who had a

Janssen Biotech, Inc.

waist circumference less than 80 cm

and less than 94 cm, respectively. n

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Date: 09/11/13 Customer Code: K08Z12236AR2 File Name: K08Z12236AR2_690757_v1

Group 360 Job #: 690757 11/21/13 3:58 PM Brand: Zytiga

B:10.25 in

S:9.5 in

GREATER waist circumference is

20 Renal & Urology News

DECEMBER 2013 www.renalandurologynews.com

Practice Management S

hortly after the Health Insurance Portability and Accountability Act (HIPAA) was implemented, David Zetter was at a doctor’s office helping the group build a compliance plan. He was in the back of the practice training some of the staff when the receptionist walked in and handed him a piece of paper. The note was from a patient saying she could see everyone’s names and files at the front desk and she knew that was a HIPAA violation. More than a decade later, HIPAA compliance has become ingrained: Files are not left out in the open, patient information is not to be improperly disclosed, and doctors must not leave health-related messages on answering machines. It is routine to have every patient sign a HIPAA release. But compliance is not a one-and-done activity as much as an evolution of rules and procedures. Compliance gurus bet there are at least a few things physicians are not doing to comply with HIPAA.

Make a plan Practices should have a compliance plan, but many do not, said Zetter, founder of Zetter Healthcare Management Consultants. “They buy a cheap manual off of the internet and think that works,” he said. “But it cannot be implemented that way; it wasn’t set up for your practice.” Even state medical societies sell how-to manuals, but Zetter said these are only meant to guide you through creating a compliance plan, not the plan itself. Sample HIPAA compliance plans and instructions for completing one can be found online. The Massachusetts Medical Society, at www.massmed.org, provides a document with a checklist and tips to help doctors develop their own documents.

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Analyzing compliance The second thing that needs to be completed is a gap analysis. These are used to determine what the organization is doing and what they should be doing. Zetter said that an office needs to take each section of the regulation, see what is required and compare it with what is being done. Detailed information on creating a gap analysis can be found at the North Carolina Department of Health and Human Services Website at www.ncdhhs.gov Once gaps are identified, it is important to find ways to mitigate the potential problem areas. Physicians can do this by performing a risk analysis, which provides the basis for developing ways to cover themselves if an information breach should occur. Jim Hook, director of consulting services at the Fox Group, LLC, said the single largest problem he sees is with clients’ electronic health records (EHR) systems. When an office applies for meaningful use funds, they attest to the fact that their systems are HIPAA compliant because their vendor has told them it is. The problem is, only covered entities can determine if the system is HIPAA compliant––not a vendor. “When it comes to EHR, providers hear from the vendor that they are HIPAA compliant and check it off the list,” he said. “But if they haven’t done a risk assessment, they are making a false claim to the government.” Physicians need to think about issues such as how they will maintain passwords, how to back up the system, and if the system is Internet based, what information should remain on computers, Hook said. The most common error that results in breaches occurs when people transfer files containing personal health

Does your practice have a compliance plan to ensure that HIPAA r egulations are met? EHRs can be particularly tricky. BY TAMMY WORTH

Make sure that EHR vendors are protecting collected information and ensuring privacy.

information onto a laptop, which is later stolen, Hook said. This could be avoided by enacting a rule that laptops cannot be taken out of the building. Another option is encrypting files or using passwords for these files.

Stiff penalties If an organization is found to have a breach when they were willfully neglecting compliance, the penalties can be stiff. Hook said they can be as low as $100 for a first violation and much greater for successive penalties. Just last year, the Massachusetts Eye and Ear Infirmary, a hospital with only 41 inpatient beds, was fined $1.5 million after reporting the theft of a laptop that was not encrypted. “The feds have demonstrated they will fine,” Hook said. “And it can be more than a slap on the wrist.” Stay updated Two new policies include an update to the privacy practices and how it impacts business associates.

The privacy regulation now allows people to receive services without disclosing the care to their insurance company, if the patient pays in full for services. This could get tricky when someone is sent outside of the office for lab work or other services that they do not want disclosed, Hook said. The second update is clarifying that business associates like EHR vendors are responsible for protecting the security and privacy of information they receive from a provider. As of September, providers had to update their contracts to reflect this, Hook said. Many physicians just “close their eyes and hope nothing happens,” but that can be problematic. It is best to prepare in advance and not end up on the “Wall of Shame,” an online listing of organizations that have reported information breaches. To date, the site lists more than 500 breaches from private practices and hospitals alike. n Tammy Worth is a freelance medical journalist based out of Blue Springs, MO.

Want to improve your practice? Look for our tips on how to handle equipment issues, adjust to EHRs, comply with HIPAA, and more at www.renalandurologynews.com/practice.

11/21/13 3:46 PM

22 Renal & Urology News

DECEMBER 2013 www.renalandurologynews.com

Long-Term ADT Offers No Advantage Survival outcomes in intermediate-risk PCa patients not improved compared with short-term treatment BY JOHN SCHIESZER ATLANTA—Long-term androgen deprivation therapy (ADT) after radiation treatment for intermediate-risk prostate cancer (PCa) does not improve diseasespecific or overall survival, according to a new study presented at the American Society for Radiation Oncology’s 55th annual meeting. Researchers made this determination based on a secondary analysis of the RTOG 9202 trial. The trial evaluated the potential benefits of long-term adjuvant androgen deprivation (LTAD) for two years after initial androgen deprivation compared with short-term (initial) androgen deprivation (STAD) in mostly high-risk PCa patients receiving external beam radiation therapy. Because some intermediate-risk PCa patients were included in the study, the current analysis was conducted to determine if patients in the intermediate-risk subset

PAE Safe, Effective for BPH EARLY TRIAL results suggest that prostatic artery embolization (PAE) is a safe and effective treatment for benign prostatic hyperplasia (BPH), according to findings published online ahead of print in the Journal of Vascular and Interventional Radiology. The trial, by Sandeep Bagla, MD, of Inova Alexandria Hospital in Alexandria, Va., and colleagues, reported findings from 20 BPH patients who underwent PAE. Embolization was technically

experienced an additional survival benefit with LTAD. “Most clinicians have felt that ‘more was better’ when it came to blocking testosterone in prostate cancer patients; however, results for the specific endpoints we focused on, overall survival and disease-specific survival, indicate that this was clearly not the case,” said lead author Amin Mirhadi, MD, a radiation oncologist at Cedars-Sinai Medical Center in Los Angeles. “These data support administering less treatment, which will result in fewer side effects and reduce patients’ overall healthcare costs.” Dr. Mirhadi and his colleagues reviewed data from 133 men enrolled in RTOG 9202 categorized as having intermediate-risk PCa. The investigators defined this in two ways: T2 disease, a PSA level less than 10 ng/mL, and a Gleason Score of 7, or T2 disease,

a PSA level of 10-20, and a Gleason score less than 7. The LTAD group consisted of 59 patients, and the STAD group consisted of 74 patients and median follow-up was more than 11 years. The study revealed

The new findings could translate into better patient quality of life. no significant difference in overall survival, with 10-year estimates of 61% for the STAD group and 65% for the LTAD group. Disease-specific survival rates were 96% in both groups. The 10-year PSA failure rates were 53% for the STAD group and 55% for the LTAD group. “We were surprised by the findings. We thought the more hormones the bet-

ter,” Dr. Mirhadi told Renal & Urology News. “But until now no one has looked at the question is two years really that much more incrementally beneficial for intermediate-risk prostate cancer.” The results of this secondary analysis should be of particular interest to urologists, he said. Many urologists, as well as radiation oncologists, like to use long-term hormone treatment for men with intermediate-risk PCa, but the data show that four months is all that is required for intermediate-risk disease, Dr. Mirhadi said. The new findings could translate into an improved quality of life for patients with intermediate-risk PCa, he said. The adverse effects of four months of ADT are almost always reversible, but this is not the case when patients receive up to two years of ADT, he said. “It often puts men at much greater risk for bone loss, hip fracture and other complications,” he said. n

Early Dialysis May Worsen Outcomes ELDERLY PATIENTS who start dialysis early rather than late are at increased risk for death and hospitalization, even after adjusting for patients’ predialysis health status and healthcare use, according to study findings published online ahead of print in the Journal of the American Society of Nephrology. “These findings do not support the common practice of early dialysis initiation among older adults in the United States,” concluded a research team led by Deidra C. Crews, MD, of the Johns Hopkins Bayview Medical Center in Baltimore.

She and her colleagues analyzed data from 84,654 patients aged 67 years or older. Among propensity-matched patients, early dialysis initiation was associated with an 11%, 13%, and 13% increased risk of all-cause, cardiovascular, and infection-related mortality, respectively, as well as a 3% and 10% increased risk of all-cause and infectious hospitalizations, respectively. The study found no difference in cardiovascular hospitalizations. The researchers defined early initiation as starting dialysis with an estimated glomerular filtration rate (eGFR) of 10 mL/min/1.73 m2 or greater and

late initiation as starting dialysis with an eGFR below 10. Fifty-eight percent of the study population started dialysis early. The study revealed previously unreported independent risk factors for early initiation, namely congestive heart failure admissions and other hospitalizations prior to initiation. Dr. Crews’ group cited a previous study published in Archives of Internal Medicine (2011;171:1663-1669) demonstrating a trend toward initiating chronic dialysis earlier in the course of kidney disease, especially among patients aged 75 years and older. n

Papillary Renal Cancer Linked to Renal Cysts

successful in 18 (90%) and clinical success was observed in 19 (95%) at one month, with average American Urological Association symptom score improvements of 10.8 points at one month, 12.1 points at three months, and 9.8 points at six months. No minor or major complications were reported. n

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PAPILLARY RENAL CELL cancer (RCC) is associated with simple renal cysts (SRCs), new findings from a Finnish study suggest. Harri Visapää, MD, of Helsinki University Central Hospital and the University of Helsinki, and colleagues studied 482 patients who underwent partial or radical nephrectomy for kidney tumors from 2006 to 2010.

SRCs were more prevalent in patients with papillary RCC than those with other types of tumors. Of the 75 patients with papillary RCC, 55 (73%) had SRCs outside the primary tumor compared with 106 (33%) of the 319 patients with clear cell RCC and 18 (38%) of 47 with oncocytoma, the investigators reported online ahead of print in Urologia Internationalis.

In addition, male gender and increasing body mass index (BMI) and age were associated with the presence of SRCs. All obese patients (BMI of 30 kg/m 2 or greater) had SRCs, the researchers reported. The investigators acknowledged the lack of control patients without renal neoplasia was a study weakness, and that further trials are needed. n

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www.renalandurologynews.com DECEMBER 2013

Renal & Urology News 23

Update on New Therapies for mCRPC Oliver Sartor, MD, is the Laborde Professor of Cancer Research at Tulane School of Medicine in New Orleans. He was a co-principal investigator and senior author on three Phase 3 trials leading to the FDA approval of new drugs for metastatic castrationresistant prostate cancer (mCRPC). These include the randomized trial with samarium-153 EDTMP in bone-metastatic prostate cancer, the TROPIC trial, which compared cabazitaxel and mitoxantone (both in combination with prednisone), and a trial comparing radium-223 with placebo. Radium-223 was approved in May 2013 for the treatment of mCRPC with symptomatic bone metastases and no visceral disease. Describe the recent evolution of pharmacotherapy for patients with mCRPC?

Dr. Sartor: The first agent to prolong survival was docetaxel, which was used in combination with prednisone. That was FDA approved in 2004. When that happened, the world was divided into the pre-docetaxel space and postdocetaxel space, and several of the trials that were subsequently conducted were actually conducted specifically in the post-docetaxel space. The first of these post-docetaxel trials was the TROPIC trial, which compared cabazitaxel/prednisone with mitoxantrone/prednisone. The trial found that cabazitaxel was better in terms of overall survival. That established cabazitaxel as the first “secondline therapy” post-docetaxel. The next trial that was specifically performed in the post-docetaxel space was COU-AA-301. That was with abiraterone/prednisone which also had a survival advantage. That led to the approval of abiraterone in 2011. The next trial that was specifically conducted in the post-docetaxel space was the AFFIRM trial with enzalutamide,

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which was approved in 2012 (also with an overall survival benefit). One recent trial that was specifically done in the pre-docetaxel space was COU-AA-302, also with abiraterone/ prednisone. The drug was approved by the FDA for use pre-docetaxel. Now abiraterone is approved both pre- and post-docetaxel. Radium-223 was approved in May 2013 for use in patients with symptomatic bone metastases and no known visceral disease regardless of their prior exposure to docetaxel. In a trial, radium-223 was associated with prolonged survival both in patients who received prior treatment with docetaxel and those who did not. Sipuleucel-T was FDA approved in 2010 in the context of asymptomatic or minimally symptomatic patients. Who will be prescribing or administering medications to men with mCRPC?

Dr. Sartor: There are very few urologists in the world who will really be managing these patients all the way through. The chemotherapy agents docetaxel and cabazitaxel will be administered by medical oncologists. The oral agents

Approval Timeline form CRPC Therapies Sipuleucel-T....... April 29, 2010 Cabazitaxel....... June 17, 2010 Enzalutamide....... August 31, 2012 Abiraterone acetate....... December 10, 2012 Radium-223....... May 15, 2013

such as abiraterone and enzalutamide may well be commonly prescribed by urologists, or medical oncologists, and either can infuse sipuleucel-T, which is straightforward. Radium-223 has to be administered by somebody qualified to handle radiation, which is going to be a nuclear medicine physician or radiation oncologist. Treatment with these new agents is associated with a median survival benefit of four to five months. But do some patients live substantially longer than others?

Dr. Sartor: Yes, and this is because various parameters such as lactate dehydrogenase (LDH), alkaline

phosphatase, hemoglobin, and PSA are prognostic factors that influence survival. Pain also influences survival. If you have no pain, you live longer than if you do have pain. In addition, if you have a good performance status, you live longer than if you don’t. If you do not have visceral disease, you have a longer survival than if you do. So if we have a patient with elevated LDH, visceral disease, and poor performance status, that patient is not going to be long lived. On the other hand, if they are asymptomatic, have good performance status, and have only bone metastases, it’s clear that patient is going to be living a good while longer. What about using the drugs in sequence and in combination?

If you have good performance status, you live longer. — Oliver Sartor, MD

Dr. Sartor: We are currently in the sequencing era. But I don’t think, 10 years from now, we’re going to be in a sequencing era. We’re going to learn how to combine these agents. Right now, combination therapy with the new agents is pretty minimal. In recent studies in which abiraterone was given after enzalutamide, the responses to abiraterone postenzalutamide have been very disappointing. Studies also have looked at giving docetaxel after abiraterone, with equivocal results. One small trial shows a reasonable response rate, and another small trial shows a diminished response rate. And one trial looking at abiraterone first and then enzalutamide found diminished responses to enzalutamide. It appears that there is a fair amount of cross-resistance between abiraterone and enzalutamide. Whichever one you use first, it’s probably going to be pretty active. Whichever one you use second, it’s not going to be that active. n

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

11/21/13 4:02 PM

24 Renal & Urology News

DECEMBER 2013 www.renalandurologynews.com

Pad Test Promising for Young Women It takes about 10 minutes to administer and requires no specialized equipment or training BY JILL STEIN BARCELONA—A new urinary pad test designed to assess urine leakage in young, healthy women with stress urinary incontinence (SUI) is showing early favorable results, a team from the University of Saskatchewan reported at the at the 43rd Annual Meeting of the International Continence Society. Juliet Sarjeant, an MSc student in physical therapy, and her research supervisor Stephanie Madill, PhD, Assistant Professor of Physical Therapy, evaluated the new test in 13 nulliparous women aged 22-29 years who had a mean body mass index (BMI) of 21.69 kg/m2 whom they had recruited through advertising at a local university campus. Overall, from 7%-14% of young, healthy women have SUI, according to current reports in the literature, with the incidence increasing to 19%31% in the military population and up to 49% in college-age athletes. Pad tests described to date have only been evaluated in older, parous women. Additionally, these same investigators found that these tests are not sufficiently provocative to elicit urine loss in the young, nulliparous population with SUI.

Women who volunteered for the present study were asked to drink a liter of water and not to empty their bladder until they had completed the pad test. Afterwards, they ran up and down 40 steps twice and then performed a series of exercises followed by 10 hard coughs. The entire test took about 10 minutes to complete.

The test was able to discriminate between women with and without SUI. Study participants were instructed not to try to prevent leakage during testing by slowing down or stopping activities or squeezing their pelvic floor muscles. All women wore a pad during the test. Seven of them were continent, and six had SUI. The mean increase in pad weight following the test was 0.64 grams for the continent group and 9.92 grams for the SUI group. The finding that the increase in pad weight in the continent women did

not exceed 1 gram implies that the experimental pad test does not promote quantifiable vaginal secretions or perspiration, the researchers noted. In addition, it suggests that any gain in pad weight larger than 1 gram is evidence of incontinence. The test was not able to provoke quantifiable urine loss in two women with SUI, resulting in two false-negative results. However, the investigators emphasized that the two false-negatives do not necessarily indicate that the women had no leakage whatsoever but rather that their leakage was less than 1 gram—an amount that may nonetheless be bothersome. Accordingly, they said that more research is needed to develop methods for measuring small amounts of leakage. Further analysis showed that the pad test provoked similar amounts of urine loss on two consecutive testing days, suggesting that the test may be used to examine temporal fluctuations in SUI symptoms. As for the advantages of the pad test, the authors noted that it is quick to administer (approximately 10 minutes) and does not require any specialized equipment or training, which makes it easy to “transfer” to

The New Pad Test To administer the new pad test, young women are instructed to: • Drink a liter of water • Not empty their bladder until completion of the test • Run up and down 40 steps twice • Perform a series of exercises followed by 10 hard coughs

the clinical setting. Importantly, the researchers noted, the test was able to discriminate between the women with and without SUI. The study was limited by its small sample size, according to the investigators. In addition, although the women followed a standardized fluid consumption protocol, the researchers did not confirm that the volume of urine in women’s bladders was similar, both among the participants and between the testing days. n

Testosterone Benefits Obese Hypogonadal Men BY ROSEMARY FREI, MSc VANCOUVER—Obese hypogonadal men who received long-term testosterone injections experience a gradual decline in weight and waist circumference, according to study findings presented at the 33rd Congress of the Societé Internationale d’Urologie. This effect, researchers concluded, may be beneficial in terms of cardiometabolic and urologic outcomes. Abdulmaged Traish, MBA, PhD, professor of biochemistry and urology at Boston University School of Medicine, led the prospective, Bayer-funded registry study of 181 men who, at baseline, had a testosterone level below 12.1 nmol/L and a body mass index (BMI) of at least 30 kg/m2. Subjects’ mean age was 59.1 years (range 33-69 years). Each received one 1,000-mg testosterone undecanoate parenteral injection and, starting six weeks later, received this same dose every 12 weeks for up to five

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years. All of the men had dyslipidemia, 97% had hypertension, 39% had type 2 diabetes, 22% had coronary artery disease, and 19% had experienced a previous myocardial infarction. One patient was diagnosed with prostate cancer after 10 months of treatment.

Men had steady weight loss and decreased waist circumference. The researchers tracked subjects’ testosterone trough levels and found that, starting at 12 months of treatment and going out to 60 months, the levels were significantly higher than baseline levels. At the same time, subjects’ body weights and waist circumferences fell significantly. They lost an average of

18.83 kg from a baseline average weight of 114 kg, and 9.87 cm from an average baseline waist circumference of 111 cm. The men’s mean BMI also declined significantly, from 36.72 kg/m2 at baseline to 30.22 kg/m2 at the 60-month mark. These changes took place gradually, with the men experiencing significant year-to-year weight, waist circumference, and BMI losses each year. Ninety-nine percent of the men lost at least 5 kg over the five-year period, while 70% lost at least 15 kg and 40% lost at least 20 kg. About 3%-5% of the men gained weight, averaging 1-2 kg. Other changes the men experienced over the duration of the study included a: • gradual and steady drop in average residual bladder volume, starting at 52 mL and falling to 20.5 mL by 57 months; • gradual increase in average prostate volume, starting at 31 mL, rising to

34 mL at three years and falling again to 32 mL at 60 months; • slight but statistically significant increase in average PSA levels, starting at 1.8 ng/mL and rising to 1.95 ng/mL at the five-year mark; • steady drop in average International Prostate Symptom Score, falling from 7.8 at baseline to 3.5 at three years and 2.9 at five years;, • gradual increase in average score on the International Index of Erectile Function-Erectile Function subscale, starting at 21.1 at baseline and reaching 25.25 at the 60-month mark. Long-term testosterone treatment also produced positive effects on lipid profiles (reduction in total and LDL cholesterol, increased HDL cholesterol, and reduction in triglycerides), and decreases in fasting blood glucose, hemoglobin A1c, and inflammation. The study has been accepted for publication in the International Journal of Clinical Practice. n

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Renal & Urology News 25

CME FEATURE

New Ablative Techniques in Urologic Oncology Innovative approaches offer the potential for effective treatments to limited target areas with improved side effect profiles

Release Date: December 2013 Expiration Date: December 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: Traditional management of clinically localized renal cell carcinoma and prostate adenocarcinoma has been total organ excision. Although this is oncologically effective, standard radical surgery is associated with significant treatment-related morbidity. Innovations in tissue ablation technologies offer the potential for effective treatment to limited target areas with improved side effects. TARGET AUDIENCE: This activity has been designed to meet the needs of urologists and supporting clinicians who treat patients with kidney and prostate cancer. EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Review current ablative options for the treatment of prostate and kidney cancer. • Discuss renal ablation techniques and follow-up, as well as outcomes. • Describe complications following prostate cancer cryoablation. 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

Reported Financial Relationship

Jeffrey J. Tomaszewski, MD David Y. T. Chen, MD

No financial relationships to disclose. No financial relationships to disclose.

BY JEFFREY J. TOMASZEWSKI, MD, AND DAVID Y.T. CHEN, MD

o reduce treatment-related morbidity, ablative technologies have been applied as a treatment for a number of malignancies, including lung, hepatic, testicular, prostate, and renal cancer. Concomitantly, the widespread availability and utilization of cross-sectional imaging has led to an increase in the incidental detection of renal cancer,1 while prostate cancer screening practices have identified new opportunities for identifying smaller tumors with low probability of regional involvement and high likelihood of curability. The traditional management of clinically localized renal cell carcinoma (RCC) and prostate adenocarcinoma has been total organ excision. Although this is oncologically effective, standard radical surgery is associated with significant treatment-related morbidity, especially in patients with comorbid conditions. Innovation in tissue ablation technologies offers the potential for effective treatments to limited target areas with improved side effect profiles. Herein we review current ablative options for the treatment of prostate and kidney cancer.

Kidney cancer American Urological Association (AUA) guidelines recognize partial nephrectomy as the standard of care for managing the cT1a renal mass. Given the morbidity associated with partial nephrectomy, it may not represent the ideal treatment for all patients, especially among the elderly and infirm. Several ablative technologies have been investigated, including cryoablation (CA), radiofrequency ablation (RFA), microwave thermotherapy,2 high-intensity focused ultrasound,3 irreversible electroporation,4 and histotripsy.5 Only the first two modalities have achieved widespread use, with published reports of short to intermediate results, and these topics will be the focus of this review.

Cryoablation and radiofrequency ablation CA is a thermal ablative technique that relies on the Joule Thomson phenomenon, whereby a highly compressed liquid (argon gas) expanding through a restricted orifice rapidly changes to

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 December 2013 through December 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.

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The faculty are in the Division of Urologic Oncology at Fox Chase Cancer Center in Philadelphia, where Dr. Tomaszewski (left) is a fellow and Dr. Chen (right) is an attending surgeon.

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CME FEATURE Table 1. Summary of patient and tumor characteristics and outcomes of kidney mass ablation Study

Approach

Patients (n)

Mean Tumor Size (cm)

Mean f/u (mo)

Outcome

Complications

Hegarty et al.42

Lap CA

161

2.6

Residual tumor (1.9%)

Urine leak (0.6%) MI (0.6%) Pneumothorax (2.4%) Blood transfusion (2.4%) CHF (0.6%)

Schwartz et al.43

Lap CA

2.6

Complete lesion resolution (97.3%)

Bleeding (2.4%)

Bandi et al.

Perc/Lap CA

2.6

OS (88.5%) CSS (100%) RFS (98.7%)

Perinephric bleeding (2.8%) Bowel injury (1.3%) Persistent dz (5.1%)

Desai et al.45

Lap CA

2.1

24.6

Complete lesion resolution (97%)

Pulmonary (5.1%) Bleeding (1.3%) Biopsy-proven recurrence (3%)

Matsumoto et al.46

Perc/Lap RFA

109

2.4

19.4

Residual tumor (2.8%)

Major (2.8%) Minor (9%)

Psutka et al.47

Perc RFA

185

3.0

Residual disease (13%) 5-yr CSS (99.4%) 5-yr disease free survival (87.6%) 5-yr OS (73.3%)

Hiraoka et al.48

Perc RFA

2.4

Residual tumor (15%)

Major (0%) Minor (3.9%; hematuria, perinephric hematoma)

Levinson et al.49

Perc/Lap RFA

2.0

60.5

Residual tumor (9.7%)

Overall (20.6%) Mortality (3.2%) Perirenal hematoma (12.9%)

CSS = cancer-specific survival OS = overall survival RFS = recurrence-free survival

a gaseous state and creates extreme cooling.6 When the extracellular fluid freezes, the osmotic pressure increases in the extracellular compartment; the resulting fluid shift causes cellular dehydration, accumulation of toxins within the cells, change in pH, and protein denaturation.6 Ice ball formation produces mechanical disruption of cellular membranes and blood vessel walls,7 leading to crystallization of the intracellular fluid. Endothelial damage indirectly triggers ischemia, thrombosis, and coagulative necrosis. All these effects synergize to result in cell death.6 Modern probes are capable of creating ice balls of widely varied sizes (3.1 × 3.6 cm to 4.5 × 6.4 cm), but the -40°C isotherm, the zone of lethal treatment, is generally smaller.7 Therefore, in clinical practice, the ice ball is usually extended 5 to 10 mm beyond the tumor edge to ensure sufficient coverage of the target area. A double freeze-thaw cycle is associated with greater clinical efficacy compared with a single cycle,8 and renal CA is typically performed either laparoscopically or percutaneously. Like CA, RFA can be performed percutaneously or laparoscopically, and the ideal approach depends on the condition of the patient, tumor location, and provider preference.9 Currently, there is insufficient evidence for what

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constitutes the ideal delivery method. RFA uses high-frequency monopolar alternating current delivered directly to the target tissue to generate thermal damage by converting radiofrequency waves into heat.10 When tissue reaches temperatures higher than 60°C, thermal dessication and coagulative necrosis lead to cell death through irreversible protein denaturation and cross-linking.10 The effectiveness of RFA depends on both the temperature and duration of treatment.7 A wide variety of RFA probes are available, with single-needle probes for small lesions, multiprobe array electrodes for larger areas (3-5 cm), and internally cooled electrodes to target the largest ablation volumes.11

Renal ablation follow-up Although no specific post-CA protocol has been widely implemented, computed tomography (CT) and magnetic resonance imaging (MRI) are commonly used for follow-up imaging. Initially, tumor size may increase due to peritumoral hemorrhage, but tumor periphery can be hard to differentiate from surrounding fibrosis and stranding.6 Post-CA, any enhancement greater than 10 HU or an interval increase in tumor size is suspicious for inadequate tumor ablation or recurrence. On T1-weighted

MRI, 61% of adequately treated tumors are isointense to renal parenchyma, whereas 95% are hypointense on T2.6,12 Radiologic absence of disease may not serve as a surrogate for clinical cure; 3.6% of post-RFA biopsies are positive six months following treatment.13 Post-RFA, imaging plays an important role in tumor localization, real-time monitoring of the ablation zone, and follow-up. RFA is typically monitored with ultrasound, and ablation zones are seen as hyperechogenic areas created by vaporization of interstitital fluid. A follow-up contrast enhanced CT or MRI is typically used to ensure a lack of enhancement within treated tissue, and a thin enhancing rim representing either inflammation or hemorrhagic granulation tissue may be seen in early followup.14 Given the difficulty in determining the extent of the coagulation zone, the goal of RFA is to ablate a 1 cm margin of normal tissue surrounding the tumor on all sides; however, preservation of normal surrounding renal parenchyma limits margin size.9

Renal ablation outcomes While some have suggested followup for CA series is too limited to draw meaningful conclusions about oncologic efficacy,15 intermediate oncologic outcomes with follow-up ranging from

9 to 36 months suggest excellent local control (95%-100%) and cancerspecific survival (95%-100%) in patients with single sporadic renal masses.16-18 Following RFA, short- and intermediate-term oncologic outcomes reveal recurrence-free rates of 90%-96.8 % in patients with mean tumor volumes of 2.0-3.2 cm.15 In the 2009 AUA guideline for the management of clinically localized stage I RCC, a meta-analysis revealed total recurrence-free survival of 87.6% and 85.2% for CA and RFA with a mean follow-up of 26.2 months and 39.3 months, respectively.15 A recent meta-analysis of 20 studies with a total of 457 cases revealed a pooled proportion of clinical efficacy of 89% (95% CI 0.83–0.94) for CA and 90% (95% CI 0.86–0.93) for RFA.15 In review of 2,104 tumors, the reported overall complication rates ranged from 0.9%-16.2%,6 with hemorrhage (1.1%16.2%), perinephric hematoma (1.6%4.4%), and urine leak (1.2%-7.1%) most commonly reported. Increasing anatomic tumor complexity and “nearness” to the renal hilum as objectified by R.E.N.A.L. nephrometry score is associated with an increased risk of complications following CA.19 Following RFA, the most common minor complication is pain and paresthesias at the probe insertion site, while most major

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complications are secondary to thermal injury to the renal collecting system (UPJ obstruction, urine leak). A metaanalysis of 11 studies revealed a complication rate of 19.0%,15 while renal function following RFA is typically preserved.20

Local recurrence-free rates similar Unfortunately, no prospective comparative trial exists to determine the ideal treatment modality when considering RFA and CA.21 As opposed to RFA, CA has also been shown to be effective in the treatment of tumors larger than 3 cm in greatest dimension.22 RFA is limited in the treatment of central renal masses, given thermal sink effects originating in the highly vascular renal hilum.23 Conductive relative cooling at the central ablation margin results in local failures in up to a third of such masses.24 A recent large series clearly demonstrates no differences between the technologies with regard to complication and local recurrence-free rates.15, 23 The debate about which technology is more effective is essentially over, with RFA and CA demonstrating equal efficacy and morbidity.25 Long-term data on oncologic efficacy and more rigorous head-to-head trials are needed to determine the role of CA

and RFA in the management of small renal tumors.

Prostate Cancer PSA screening has led to increased detection of less aggressive and potentially clinically insignificant prostate tumors, and many patients show similar outcomes whether they elect active surveillance or radical whole gland therapy. There is little to no difference in overall and prostate cancer (PCa)-specific survival after a median of 10 years of followup.26 However, the recognized urinary, bowel, and sexual function adverse effects commonly resulting from radical treatment27 have driven interest in ablative therapies aimed at reducing morbidity while maintaining oncologic efficacy.28 Furthermore, as 20%-30% of PCa patients recur after standard treatment, ablative therapy for local retreatment, such as salvage cryoablation (SCA) may be as effective as traditional options but with less toxicity.29 A number of investigational approaches exist for targeted prostate ablation: in-bore laser ablation 30 and photodynamic therapy, 31 but only CA and highintensity focused ultrasound (HIFU) have more substantial data and will be the primary modalities reviewed.

Cryoablation Over the past decade, prostate CA has been increasingly used for primary, salvage, and focal therapy of PCa. Current cryotherapy systems represent third generation cryotechnology that achieve tissue destruction via direct cellular and vascular injury, apoptosis induction, and immune mediated cytotoxicity (as described above).32 A trans-rectal ultrasound probe and perineal template are used to define the anatomical configuration of the prostate and facilitate localization of the cryoprobes into appropriate distribution for sufficient gland coverage.32 Thermosensors can be applied to monitor the treatment and temperature at surrounding margins, such as the external sphincter and Denonvilliers fascia. A warm saline urethral irrigation is used to prevent urethral damage and minimizes post-treatment urinary morbidity.32 CA is started at the anterior region and progresses posteriorly, and commonly an additional 2-4 mm zone of freezing into the periprostatic tissues is obtained, to achieve a wider margin of treatment.32 A recognized limitation of prostate CA is defining success of treatment. There is no accepted standard for determining efficacy. As prostate CA by design leaves the periurethral region untreated,

Renal & Urology News 27

residual benign prostate in that location can produce PSA, and so undetectable PSA levels are uncommonly seen after prostate CA. In a series of 590 patients with a mean follow-up of 5.4 years treated for primary prostate CA, using a PSA nadir of 0.5 ng/mL as a threshold for recurrence, the biochemical diseasefree survival (BDFS) rate was 61%, 68%, and 61% for D’Amico low-, intermediate-, and high-risk groups, respectively, with an overall BDFS of 62% at seven years.32, 33 However, using the ASTRO definition, BDFS dramatically improved to 92%, 89%, and 89%, respectively, with a combined seven-year BDFS rate of 89.5%.32, 33 Similarly, examination of PSA nadir levels among 2,427 patients following whole gland prostate CA revealed that a PSA nadir of 0.6 ng/ml or greater was associated with significant risks of biochemical failure (29.5%, 46%, and 54% in low-, intermediate-, and high-risk groups, respectively) within the first two years.34 Following primary prostate CA, 10-year BDFS rates (median followup 12.5 years) of 80.6%, 74.2%, and 45.5% for low-, intermediate-, and high-risk patients, respectively, have been reported, and the overall negative biopsy rate at 10 years was 76.96%.35

Table 2. Summary of outcomes and complications following primary prostate whole-gland cryoablation Reference

Cryotechnology

Patients (n)

Median f/u (mo)

Levy et al.34

2nd & 3rd generation

2,427

Cryton et al.50

3rd generation

Han et al.

Cohen et al.52

Outcome

Complications

60-mo PSA nadir of 0.1 was 91.8%, 76%, and 71% (low-, inter-, and high-risk)

PSA < 1 ng/ml: 68% and <0.5 ng/ml: 81%

3rd generation

122

PSA < 0.4 ng/ml: 75%

2nd generation

239

PSA < 1 ng/ml: 69–77% and <0.4 ng/ml: 40–60%; positive biopsies: 31%

Bahn et al.53

2nd & 3rd generation

590

BDFS 92%, 89%, and 89% (low-, inter-, and high-risk; ASTRO criteria)

Permanent incontinence (4.3%) New-onset impotence (94.9%) Fistula (<0.1%) TURP (5.5%) Sloughing (3.9%)

Prepelica et al.54

3rd generation

65 (high-risk)

Projected 6-yr data: ASTRO: 81.7% PSA < 4 ng/ml: 50% and <1 ng/ml: 35%

Aus et al.55

2nd generation

58.5

5-yr actuarial BDFS 38.9%

Penile numbness (15%) TURP (15%) Stricture (17%) Impotence (90.7%) Incontinence (18.5%)

Long et al.37

2nd generation

975

5-yr BDFS (PSA < 1 ng/ml): 76%, 71%, and 61% (low-,inter-, and high-risk, respectively)

Incontinence (7.5%) Impotence (93%) TURP (13%) Fistula (0.5%)

Jones et al.38

2nd & 3rd generation

1,198

5-yr BDFS 77.1% (ASTRO) and 84.7% (Phoenix)

Fistula (0.4%) Incontinence (4.8%) Impotence (91.2%)

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CME FEATURE

Standard radical surgery for RCC and prostate adenocarcinoma is associated with significant treatment-related morbidity.

Complications Complications following prostate CA include urinary incontinence, erectile dysfunction, voiding dysfunction, and fistula formation. Rates of clinically significant incontinence range from 4.8%-7.5%,36, 37 with the highest rates reported among patients with apical disease or those undergoing SCA (7.9%-10.2%).38 ED rates are high, with 72%-93% of men reporting worsening function after therapy.37 Following SCA, ED occurs in 72%86%,39 and while these rates are partly contributable to preexisting ED from primary treatment, the introduction of third-generation technology has not significantly improved the rates of ED.32 Voiding dysfunction (3%4%) is largely attributable to urethral sloughing, which is dramatically minimized with the use of urethral warming catheters.36 Rates of prostatorectal fistulae have fallen secondary to use of the urethral warmer and in contemporary series range from 0%-0.5%.36

High-intensity focused ultrasound With HIFU, high-energy ultrasonic beams are delivered into the prostate via a transrectal approach. The acoustic energy is converted into thermal energy, causing coagulative necrosis.7 While prostate HIFU is approved and widely available in Europe, Japan, and other countries worldwide, it has not gained FDA approval and is currently only available in the U.S. within clinical trials. Similar to prostate CA, the best means to assess the efficacy of prostate HIFU remains undefined. Among

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1,002 patients treated with HIFU for localized PCa, eight-year biochemicalfree survival rates (by Phoenix definition) were 76%, 63%, and 57% for low-, intermediate-, and high-risk patients, respectively (p < 0.001).40 At 10 years, the PCa-specific survival rate and metastasis-free survival rate (MFSR) were 97% and 94%, respectively.40 Severe incontinence and bladder outlet obstruction were initially significant but have improved with refinement in the technology and experience, from 6.4% and 34.9% originally to 3.1% and 5.9%, respectively. Other groups have reported urethral stricture, impotence, epididymitis, and urinary incontinence in 16%, 14%, 4%, and 0.8%, respectively.7

Salvage treatment Prostate salvage HIFU shows promise, but current follow-up is limited, ranging from 3 to 39 months, and with reported DFS rates of between 25% to 54%.41 Morbidity following salvage HIFU is higher compared with primary HIFU treatment, including urinary incontinence (49.5%), rectourethral fistula (3%-12.5%), bladder neck contracture or urethral stricture (10%-20%), UTI (1%-6%), and prolonged urinary retention (6%).41 Salvage HIFU remains a promising treatment alternative in patients who have localized failure after radiation therapy. Given the high risk of complications associated with salvage therapy, careful selection of patients is imperative. Long term follow-up and prospective multicenter randomized controlled trials are required to assess whether these encouraging results are truly equivalent to those observed after other salvage treatments such as radical prostatectomy, brachytherapy and CA. Although extirpative surgery remains the standard of care for most urologic malignancies, some patients may benefit from the reduced morbidity of minimally invasive ablative therapies that are quickly establishing themselves as viable primary treatment options. n REFERENCES 1. Hollingsworth JM, Miller DC, Daignault S, Hollenbeck BK. Rising incidence of small renal masses: a need to reassess treatment effect. J Natl Cancer Inst 2006;98:1331-1334. 2. Yoshimura, K., Okubo, K., Ichioka, K. et al.: Laparoscopic partial nephrectomy with a microwave tissue coagulator for small renal tumor. J Urol 2001;165 (6 Pt 1):1893-1896.

3. Watkin NA, Morris SB, Rivens IH, et al.: Highintensity focused ultrasound ablation of the kidney in a large animal model. J Endourol 1997;11:191-196. 4. Olweny EO, Kapur P, Tan YK, et al.: Irreversible electroporation: evaluation of nonthermal and thermal ablative capabilities in the porcine kidney. Urology 2013;81:679-684. 5. Winterroth F, Xu Z, Wang TY, et al.: Examining and analyzing subcellular morphology of renal tissue treated by histotripsy. Ultrasound Med Biol 2011;37:78-86. 6. Kapoor A, Touma NJ, Dib RE. Review of the efficacy and safety of cryoablation for the treatment of small renal masses. Can Urol Assoc J 2013;7:E38-E44. 7. Vricella GJ, Ponsky LE, Cadeddu JA. Ablative technologies for urologic cancers. Urol Clin North Am 2009;36:163-178. 8. Woolley ML, Schulsinger DA, Durand DB, et al. Effect of freezing parameters (freeze cycle and thaw process) on tissue destruction following renal cryoablation. J Endourol 2002;16:519-522. 9. Friedman M, Mikityansky I, Kam A, et al.: Radiofrequency ablation of cancer. Cardiovasc Intervent Radiol 2004;27:427-434. 10. Corwin TS, Lindberg G, Traxer O, et al.: Laparoscopic radiofrequency thermal ablation of renal tissue with and without hilar occlusion. J Urol 2001;166: 281-284. 11. Shah DR, Green S, Elliot A, et al. Current oncologic applications of radiofrequency ablation therapies. World J Gastrointest Oncol 2013;5:71-80. 12. Remer EM, Weinberg EJ, Oto A, et al. MR imaging of the kidneys after laparoscopic cryoablation. AJR Am J Roentgenol 2000;174:635-640. 13. Atwell TD, Farrell MA, Leibovich BC, et al. Percutaneous renal cryoablation: experience treating 115 tumors. J Urol 2008;179:2136-2140. 14. Mirza AN, Fornage BD, Sneige N, et al. Radiofrequency ablation of solid tumors. Cancer J 2001;7:95-102. 15. El Dib R, Touma NJ, Kapoor A. Cryoablation vs radiofrequency ablation for the treatment of renal cell carcinoma: a meta-analysis of case series studies. BJU Int 2012;110:510-516. 16. Lehman DS, Hruby GW, Phillips CK, et al.: First Prize (tie): Laparoscopic renal cryoablation: efficacy and complications for larger renal masses. J Endourol 2008;22:1123-1127. 17. Johnson DB, Solomon SB, Su LM, et al. Defining the complications of cryoablation and radio frequency ablation of small renal tumors: a multi-institutional review. J Urol 2004;172:874-877. 18. Finley DS, Beck S, Box G, et al.: Percutaneous and laparoscopic cryoablation of small renal masses. J Urol 2008;180:492-498. 19. Sisul DM, Liss MA, Palazzi KL, et al. RENAL nephrometry score is associated with complications after renal cryoablation: a multicenter analysis. Urology 2013;81:775-780. 20. Lucas SM, Stern JM, Adibi M, et al. Renal function outcomes in patients treated for renal masses smaller than 4 cm by ablative and extirpative techniques. J Urol 2008;179:75-79. 21. Meng MV. Commentary on “Radiofrequency ablation of incidental benign small renal mass: outcomes and follow-up protocol.” Tan YK, Best SL, Olweny E, Park S, Trimmer C, Cadeddu JA, Department of Urology, University of Texas Southwestern Medical School, Dallas, Texas, TX. Urol Oncol 2013;31:132-133. 22. Atwell TD, Farrell MA, Callstrom MR, et al. Percutaneous cryoablation of large renal masses: technical feasibility and short-term outcome. AJR Am J Roentgenol 2007;188:1195-1200. 23. Atwell TD, Schmit GD, Boorjian SA, et al. Percutaneous ablation of renal masses measuring 3.0 cm and smaller: comparative local control and complications after radiofrequency ablation and cryoablation. AJR Am J Roentgenol 2013;200:461-466. 24. Gervais DA, McGovern FJ, Arellano RS, et al. Radiofrequency ablation of renal cell carcinoma: part 1, Indications, results, and role in patient management over a 6-year period and ablation of 100 tumors. AJR Am J Roentgenol 2005;185:64-71. 25. Cadeddu JA. Re: Percutaneous Ablation of Renal Masses Measuring 3.0 cm and Smaller: Comparative Local Control and Complications After Radiofrequency Ablation and Cryoablation. J Urol. 2013;190:63. 26. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012;367:203-213. 27. Resnick MJ, Koyama T, Fan KH, et al. Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med 2013;368:436-445. 28. Eggener S, Salomon G, Scardino PT, et al. Focal therapy for prostate cancer: possibilities and limitations. Eur Urol 2010;58:57-64. 29. Punnen S, Cooperberg MR, D’Amico AV, et al. Management of biochemical recurrence after primary treatment of prostate cancer: A systematic review of the literature. Eur Urol 2013 (Epub ahead of print).

30. Raz O, Haider MA, Davidson SR, et al. Real-time magnetic resonance imaging-guided focal laser therapy in patients with low-risk prostate cancer. Eur Urol 2010;58:173-177. 31. Bozzini G, Colin P, Betrouni N, et al. Photodynamic therapy in urology: what can we do now and where are we heading? Photodiagnosis Photodyn Ther 2012;9:261-273. 32. Mohammed A, Miller S, Douglas-Moore J, et al.: Cryotherapy and its applications in the management of urologic malignancies: A review of its use in prostate and renal cancers. Urol Oncol 2013 (Epub ahead of print). 33. Bahn DK, Lee F, Badalament R, et al. Targeted cryoablation of the prostate: 7-year outcomes in the primary treatment of prostate cancer. Urology 2002;60:3-11. 34. Levy DA, Pisters LL, Jones JS. Primary cryoablation nadir prostate specific antigen and biochemical failure. J Urol 2009;182:931-937. 35. Cohen JK, Miller RJ Jr., Ahmed S, et al. Ten-year biochemical disease control for patients with prostate cancer treated with cryosurgery as primary therapy. Urology 2008;71:515-518. 36. Jones JS, Rewcastle JC, Donnelly BJ, et al. Whole gland primary prostate cryoablation: initial results from the cryo on-line data registry. J Urol 2008;180:554-558. 37. Long JP, Bahn D, Lee F, et al. Five-year retrospective, multi-institutional pooled analysis of cancerrelated outcomes after cryosurgical ablation of the prostate. Urology 2001;57:518-523. 38. Pisters LL, Rewcastle JC, Donnelly BJ, et al. Salvage prostate cryoablation: initial results from the cryo on-line data registry. J Urol 2008;180:559-563. 39. Ismail M, Ahmed S, Kastner C, et al. Salvage cryotherapy for recurrent prostate cancer after radiation failure: a prospective case series of the first 100 patients. BJU Int 2007;100:760-764. 40. Crouzet S, Chapelon JY, Rouviere O, et al. Wholegland ablation of localized prostate cancer with high-intensity focused ultrasound: Oncologic outcomes and morbidity in 1002 patients. Eur Urol 2013 (Epub ahead of print). 41. Autran-Gomez AM, Scarpa RM, Chin J. High-intensity focused ultrasound and cryotherapy as salvage treatment in local radio-recurrent prostate cancer. Urol Int 2012;89:373-379. 42. Hegarty NJ, Gill IS, Desai MM, et al. Probeablative nephron-sparing surgery: cryoablation versus radiofrequency ablation. Urology 2006;68 (1 Suppl):7-13. 43. Schwartz BF, Rewcastle JC, Powell T, et al. Cryoablation of small peripheral renal masses: a retrospective analysis. Urology 2006;68(1 Suppl):14-18. 44. Bandi G, Wen CC, Hedican SP, et al. Cryoablation of small renal masses: assessment of the outcome at one institution. BJU Int 2007;100:798-801. 45. Desai MM, Aron M, Gill IS. Laparoscopic partial nephrectomy versus laparoscopic cryoablation for the small renal tumor. Urology 2005;66 (5 Suppl):23-28. 46. Matsumoto ED, Johnson DB, Ogan K, et al. Short-term efficacy of temperature-based radiofrequency ablation of small renal tumors. Urology 2005;65:877-881. 47. Psutka SP, Feldman AS, McDougal WS, et al. Longterm oncologic outcomes after radiofrequency ablation for T1 renal cell carcinoma. Eur Urol 2013;63:486-492. 48. Hiraoka K, Kawauchi A, Nakamura T, et al. Radiofrequency ablation for renal tumors: our experience. Int J Urol 2009;16:869-873. 49. Levinson AW, Su LM, Agarwal D, et al. Long-term oncological and overall outcomes of percutaneous radio frequency ablation in high risk surgical patients with a solitary small renal mass. J Urol 2008;180:499-504. 50. Cytron S, Paz A, Kravchick S, et al. Active rectal wall protection using direct transperineal cryo-needles for histologically proven prostate adenocarcinomas. Eur Urol 2003;44:315-320. 51. Han KR, Cohen JK, Miller RJ, et al. Treatment of organ confined prostate cancer with third generation cryosurgery: preliminary multicenter experience. J Urol 2003;170 (4 Pt 1):1126-1130. 52. Cohen JK, Miller RJ, Rooker GM, et al. Cryosurgical ablation of the prostate: two-year prostate-specific antigen and biopsy results. Urology 1996;47:395-401. 53. Bahn D, de Castro Abreu AL, Gill IS, et al. Focal cryotherapy for clinically unilateral, lowintermediate risk prostate cancer in 73 men with a median follow-up of 3.7 years. Eur Urol 2012;62:55-63. 54. Prepelica KL, Okeke Z, Murphy A, et al. Cryosurgical ablation of the prostate: high risk patient outcomes. Cancer 2005;103:1625-1630. 55. Aus G, Pileblad E, Hugosson J. Cryosurgical ablation of the prostate: 5-year follow-up of a prospective study. Eur Urol 2002;42:133-138.

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Renal & Urology News 29

CME Post-test Expiration Date: December 2014 Medical Education Resources designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Participants should claim only the credit commensurate with the extent of their participation in the activity. Physician post-tests must be completed and submitted online. Physicians may register at no charge at www.myCME.com /renalandurologynews. You must receive a score of 70% or better to receive credit. 1. The mechanism of cell death following cryoablation (CA) includes all of the following except: a. Extracellular fluid shift causing cellular dehydration. b. Accumulation of intracellular toxins. c. Mechanical shearing associated with ice crystallization. d. Changes in pH. e. Denaturation of proteins. 2. Following renal mass CA, all of the following are true except: a. Any enhancement >10 HU is suspicious for tumor recurrence or persistence. b. On MRI, adequately treated tumors are hyperintense on T2-weighted images. c. On MRI, adequately treated tumors are isointense to renal parenchyma on T1-weighted images. d. On MRI, adequately treated tumors are hypointense on T2-weighted images. e. Radiologic absence of disease recurrence does not serve as a surrogate for clinical freedom from disease. 3. As compared to CA, radiofrequency ablation (RFA) is ideally suited for ablation of renal masses with which of the following characteristics: a. Exophytic tumors b. Large tumors (>3cm) c. Central tumors d. Small tumors (<3cm) e. a and c f. b and d g. a and d

4. With regard to the treatment of small renal masses, RFA and CA have equivalent efficacy and morbidity. a. True b. False 5. Following whole-gland ablation of localized prostate cancer with high-intensity focused ultrasound (HIFU): a. A nadir PSA >0.6ng/mL was associated with an increased risk of BCR. b. The eight-year biochemical-free survival rates (Phoenix definition) were 76%, 63%, and 57% for low-, intermediate-, and highrisk patients. c. At 10 years, the PCa-specific survival rate and metastasisfree survival rate were 97% and 94%, respectively. d. Rates of severe incontinence and bladder outlet obstruction have decreased with technological improvements in cryotechnology. e. All of the above. 6. HIFU can be characterized as: a. In a defined biological environment, the size of the thermal lesion cannot be controlled by the power and duration of the US pulse. b. Causing tissue damage by acoustic cavitation. c. Resulting in tissue coagulative necrosis via induced hypothermia. d. None of the above. e. All of the above.

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