Renal & Urology News March 2013 Issue by Haymarket Media

MARCH 2013

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VOLUME 12, ISSUE NUMBER 3

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www.renalandurologynews.com

Shorter Course of ADT Safe, Effective Men with high-risk PCa treated for 18 or 36 months had similar overall and cancer-specific survival Less ADT Does Not Shorten Survival New data show that reducing by half the amount of time a man with high-risk prostate cancer receives androgen deprivation therapy (ADT) has no significant effect on oncologic outcomes. Shown here are the 10-year overall and cancer-specific survival rates. ■ Overall Survival

■ Cancer-specific survival

100 80 60 40 20 0

63.2%

87.2%

63.6%

18 months

87.2% 36 months

ADT duration

BY JODY A. CHARNOW ORLANDO, Fla.—Halving the time a patient with high-risk prostate cancer (PCa) is on androgen deprivation therapy (ADT) is safe and does not compromise outcomes, researchers reported recently at the annual Genitourinary Cancers Symposium. In a randomized phase 3 study of 630 patients with node-negative highrisk PCa treated with external beam radiotherapy (EBRT) and long-term ADT, investigators found no significant differences in overall and cancerspecific survival and in the risk of biochemical and regional and distant failure among patients treated with 18 or 36 months of ADT.

BCG Works in the Immunosuppressed Donor Smoking however, and should be considered BY JODY A. CHARNOW Cuts Recipient IMMUNOSUPPRESSED patients with for early cystectomy if BCG treatment high-risk non-muscle-invasive bladder fails, researchers concluded in a report cancer (NIMBC) can be treated suc- published online ahead of print in Survival cessfully and safely with intravesical Bacillus Calmette-Guérin (BCG), new findings suggest. Transplant recipients fare worse than other immunosuppressed patients,

CME FEATURE

BJU International. Intravesical BCG is considered to be contraindicated in immunosuppressed patients with bladder cancer because continued on page 12

Earn 1 CME credit in this issue

Thyroid Functional Disease in Dialysis Patients PAGE 32

BY ROSEMARY FREI, MSc MIAMI BEACH, Fla.—Recipients of kidneys from living donors who smoke have shorter survival than recipients of kidneys from non-smoker living donors, according to a study presented at the American Society of Transplant Surgeons’ 2013 Annual State of the Art Winter Symposium. The discovery of this association suggests that it may be possible to improve survival among kidney transplant recipients by getting living donors who smoke to give up the habit, said Seth Waits, MD, of the University of Michigan Health Systems (UMHS) in Ann Arbor, who presented the results. “When we are talking about deceased donors, obviously, there was no opportunity to have them stop smoking prior to donation.” Dr. Waits, together with the rest of the research team led Michael Englesbe, MD, Associate Professor of Surgery at UMHS, reviewed information from continued on page 12

ADT consisted of bicalutamide 50 mg for one month plus goserelin 10.8 mg every three months. For the radiotherapy, the radiation dose was 44 Gy for the whole pelvis and 70 Gy for the prostate. The current recommended duration of ADT for these patients is 24-36 months, the investigators, led by Abdenour Nabid, MD, a Fellow of the Royal College of Physicians of Canada, noted. “Shorter-term hormone therapy could have a big impact on the lives of men with prostate cancer, reducing the quantity and intensity of its unpleasant side effects as well as treatment costs,” said Dr. Nabid, an associate professor continued on page 12

IN THIS ISSUE 9

Tadalafil found to improve ejaculatory dysfunction

Restless legs syndrome linked to CKD in children

The case for and against vitamin D supplementation

Why IM residents do not choose nephrology

FDA warns about tolvaptin-related liver injury

Non-aspirin NSAIDs may raise kidney cancer risk

Study identifies risk factors for ICU-managed AKI New study shows the frequency with which U.S. surgeons leave a foreign object in the patient. PAGE 30

6 Renal & Urology News

MARCH 2013

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FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD

Why Not 24/7 Dialysis Urgent Care?

lmost half a million Americans depend on chronic dialysis therapy. More than 90% of these individuals receive thrice-weekly hemodialysis treatments in an outpatient dialysis clinic. They are often sick and require frequent emergency department (ED) visits and hospital admissions, leading to the bulk of their medical care expenditures. Medicare and Medicaid cover virtually all costs related to ED care and hospitalization of these patients. Not infrequently, dialysis patients need to be admitted for an additional dialysis treatment to remove extra fluid or potassium. Dialysis patients frequently experience infectious diseases such as pneumonia and bacteremia that require antibiotic treatment or encounter vascular access problems requiring placement of a temporary central catheter for dialysis. These problems often happen afterhours or over the weekend. Our healthcare system channels these patients to the ED, leading to substantial costs, resource consumption, and patient dissatisfaction. But there may be alternatives to cut down on the number of ED visits by dialysis patients. In one of my recent overseas trips, I was fascinated by a visit to a state-ofthe-art dialysis urgent care center in Chennai, India, where walk-in dialysis patients are welcome 24/7. The building is no larger than our average dialysis centers in the U.S., but it has more to offer. In addition to 20 dialysis stations and regular dialysis shifts, it is also equipped with an X-ray area where chest X rays and KUBs can be performed. This was supported by round-the-clock radiology technicians and physician coverage. Problems such as pulmonary edema can be diagnosed and extra-dialysis sessions offered any time of the day and any day of the week. Basic blood or urine tests, including chemistry panels and CBCs, can be done within minutes so that hyperkalemia and other electrolyte abnormalities can be detected and managed immediately. Blood cultures are drawn and patients can be provided with empiric intravenous antibiotics under physician supervision. Electrocardiograph machines and pulse oximeters provide additional evaluations. The center even has a small but well-equipped procedure room, so central catheters can be placed and even thrombectomies can be performed. Fascinated by this high degree of efficiency in provision of fundamental healthcare to dialysis patients, I envied them for what they have in their fast growing and emerging economy and what we don’t have in our highly developed and regulated country. Some may say that X-ray imaging procedures are too technical for a dialysis center, but I would point out that dental offices are already equipped with them, so there is no excuse for us not to have such 24/7 walk-in dialysis urgent care that could substantially reduce costs, circumvent unnecessary ED visits and hospitalization, and provide better patient care and outcomes. Let’s hope that one day we too value efficiency and promptness in health care delivery with such innovative approaches. Kam Kalantar-Zadeh, MD, MPH, PhD Professor of Medicine and Public Health Chief, Division of Nephrology and Hypertension University of California Irvine School of Medicine Orange, Calif.

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, MBA Chief of Surgical Operations Fairview Hospital, a Cleveland Clinic hospital Professor of Surgery (Urology) Cleveland Clinic Lerner College of Medicine at Case Western Reserve University Leonard Horvitz and Samuel Miller Distinguished Chair in Urological Oncology Research Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology University of California, Irvine James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City Kenneth Pace, MD, MSc, FRCSC Assistant Professor Division of Urology St. Michael’s Hospital University of Toronto Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada

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

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

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

Renal & Urology News (ISSN 1550-9478) Volume 12, Number 3. 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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Renal & Urology News 7

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

Short Takes Hypertension in Pregnancy Increases ESRD Risk

a week. Weekly consumption of these

An analysis of data from 26,651

slightly greater risk of more aggres-

women in Taiwan with hypertensive

sive disease, researchers at the Fred

disorders in their first pregnancy

Hutchinson Cancer Research Center in

and 213,397 women without such

Seattle led by Janet L. Stanford, PhD,

products was also associated with a

disorders revealed that the incidence

reported in The Prostate. A possible

of end-stage renal disease was

reason for the increased risk is that

14-fold higher in the hypertensive

hot oil forms of potentially carcino-

cohort, with particular risk

genic compounds in the fried food,

conferred upon women who had

such as aldehydes, acrolein, hetero-

preeclampsia or eclampsia rather

cyclic amines, acrylamide, and poly-

than gestational hypertension only.

cyclic aromatic hydrocarbons.

I-Kuan Wang, MD, of the China Taichung, Taiwan, and coauthors

Bladder Cancer Outlook Poor for Heavy Smokers

also found that the incidence of

Researchers have identified a panel

chronic kidney disease was almost

of nine molecular markers that can

11-fold higher for the women with

“robustly and reproducibly” predict

hypertensive disorders, according

bladder cancer prognosis indepen-

to a report in the Canadian Medical

dent of standard clinical criteria and

Association Journal.

smoking history, according to co-

Medical University Hospital in

investigator Anirban P. Mitra, MD, PhD,

Deep-Fried Foods May Raise PCa Risk

of the Keck School of Medicine at the

Men who reported eating deep-fried

Angeles. The study results, published

foods such as French fries, fried

online ahead of print in Cancer, indi-

chicken, or doughnuts at least once

cated that bladder cancers in intense

a week had a 30% to 37% higher risk

smokers were more likely to be deadly

of prostate cancer than did men who

than those in never-smokers or less

consumed such foods less than once

heavy smokers.

University of Southern California in Los

AKI Related to NSAID Use in Children Characterized A

cute kidney injury (AKI) associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs) accounted for 2.7% of AKI found in a pediatric population, researchers reported online ahead of print in The Journal of Pediatrics. In a retrospective review of 1,015 children who had been treated for AKI from any cause, pediatric nephrology fellow Jason M. Misurac, MD, of Indiana University School of Medicine in Indianapolis, and colleagues found that 21 patients had clinical, laboratory, and radiographic studies suggesting NSAID-associated acute tubular necrosis, and another six had findings suggesting NSAID-associated acute interstitial nephritis. When excluding complex patients with multifactorial AKI, 6.6% of the children had NSAID-associated AKI. A total of 15 of the 20 patients for whom dosing data were available were found to have received NSAIDs within recommended dosing limits. The median age of children with NSAID-associated AKI was 14.7 years (range 0.5 to 17.7 years).

Low Rate of New PCa Found in REDUCE Trial Follow-up T

wo-year follow-up of 2,751 men who had participated in the four-year REDUCE (REduction by DUtasteride of prostate Cancer Events) study demonstrated a low rate of new prostate cancer (PCa) diagnoses, with no new, high-grade (Gleason score 8–10) cancers detected, a team led by Robert L. Grubb III, MD, of Washington University School of Medicine in St. Louis, reported online in The Journal of Urology. Although the 5-alpha-reductase inhibitor lowered the risk of biopsy-detectable PCa by 22.8% compared with the placebo group in the original trial, concerns remained about dutasteride’s effectiveness. During follow-up, few new PCa cases were detected in either the men who had been treated with dutasteride or those who had received placebo, and no deaths were reported. However, twice as many cancers were detected in the former dutasteride group than in the former placebo group (14 vs. 7 cases), possibly because cancers that may have been suppressed during dutasteride therapy were no longer being suppressed.

Hospital Pay for Performance In a recent online poll, Renal & Urology News asked readers, “Will Medicare’s plan to reward hospitals financially for better performance result in a higher quality of patient care?” Here are the results based on 159 respondents.

Yes 18.87%

No 72.33%

Do not know 19%

TSC Kidney Tumors Respond to Everolimus, Study Finds

he kinase inhibitor everolimus could be a potential treatment for angiomyolipomas associated with tuberous sclerosis complex (TSC), concluded John J. Bissler, MD, of Cincinnati Children’s Hospital Medical Center, and colleagues in The Lancet. The drug reduced angiomyolipoma volume with an acceptable safety profile in an international phase 3 trial. Among adults (median age 31 years) randomized to everolimus therapy or placebo, the angiomyolipoma response rate was 42% (33 of 79 patients) for everolimus and 0 (0 of 39 patients) for placebo. The most common adverse events were stomatitis in 48% of the everolimus group and 8% of the placebo group; nasopharyngitis in 24% and 31%, respectively; and acne-like skin lesions in 22% and 5%, respectively.

Contents

MARCH

2013

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VOLUME

12, ISSUE

NUMBER

Urology 9

ONLINE

this month at renalandurologynews.com

Non-Aspirin NSAIDs May Raise Kidney Cancer Risk In a large meta-analysis, use of non-aspirin non-steroidal anti-inflammatory drugs and acetaminophen was associated with a 25% and 28% increased risk of kidney cancer, respectively.

Risk Factors for ICU-Treated AKI Identified Finnish study finds link with hypovolemia, use of diuretics, and the presence of chronic kidney disease prior to admission to an intensive care unit.

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 January winner: Richard Holevas, MD

The Medical Minute

News Coverage Visit our website for coverage of the European Association of Urology annual congress in Milan, Italy (March 15-19).

CME Feature 32

Thyroid Functional Disease in Dialysis Patients Connie M. Rhee, MD, MSc, appointed to serve as faculty in the Division of Nephrology and Hypertension at University of California Irvine School of Medicine, discusses the epidemiology of thyroid functional disease, thyroid hormone metabolism, diagnosis, and management.

Restless Legs Syndrome Linked to CKD in Kids In a study, 15.3% of children with chronic kidney disease had the condition compared with only 5.9% of healthy controls. The Pros and Cons of Vitamin D Supplementation In this preview of a presentation scheduled for the 2013 Spring Clinical Meetings, Michal L. Melamed, MD, MHS, explains that vitamin D may have side effects that are as yet underappreciated. LVH Predicts Dialysis in Hypertensive Patients Left ventricular hypertrophy is associated with an increased risk of progressing to end-stage renal disease and a more advanced stage of chronic kidney disease.

“

Nephrology 13

Visit renalandurologynews.com /the-medical-minute/ to hear podcast reports on new studies. Our latest include: • High-Fiber Diet Could Improve Outcomes in Men Treated for Prostate Cancer • First-in-Class Drug Could Benefit CKD Patients

Potential MIBC Cures Underused A study found that only 52% of patients with muscle-invasive bladder cancer received aggressive therapy.

Expert Q&A Ashutosh K. Tewari, MB, BS, talks about his goals as head of the new Center for Prostate Cancer at New York-Presbyterian/Weill Cornell Medical Center in New York.

Exercise Maintains Sexual Interest During AST Exercise may enable men undergoing androgen suppression therapy for prostate cancer to maintain sexual activity.

It is clear that healthcare providers will say things or use jargon that they fully think the patients get but they don't. See our story on page 29

Departments 6

From the Medical Director The case for 24/7 dialysis urgent care

News in Brief NSAID-related AKI in children

Men’s Health Update Saw palmetto has no effect on PSA

Renal Nutrition Update Hyperuricemia and gout in CKD patients

Practice Management Improving therapeutic adherence

Malpractice News Long waits to resolve claims

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MARCH 2013

Renal & Urology News 9

Exercise Maintains Sexual Interest During AST EXERCISE MAY enable men undergoing androgen suppression therapy (AST) for prostate cancer (PCa) to maintain sexual activity, according to researchers. Prue Cormie, PhD, a senior research fellow at Edith Cowan University Health and Wellness Institute in Joondalup, Western Australia, and colleagues randomly assigned 57 PCa patients receiving AST to participate in a 12-week exercise program consisting of resistance and aerobic modes (29 subjects) or usual care (28 subjects). Prior to intervention, the two groups had no differences in sexual activity, Dr. Cormie’s group reported online ahead of print in Prostate Cancer and Prostatic

Tadalafil May Improve EjD, Data Show

Disease. After 12 weeks, patients receiving usual care had decreased sexual activity, whereas patients in the exercise program maintained their level of sexual activity. At baseline, 20.6% and 22.2% of subjects in the exercise and control groups reported a major interest in sex.

Following the intervention, the exercise group had a significantly higher proportion of subjects reporting a major interest in sex (17.2% vs. 0%). “Exercise should therefore be considered as an adjuvant therapy for prostate cancer patients on AST who are especially interested in optimizing

sexual activity,” the authors concluded. The investigators noted that previous research has demonstrated that exercise is an effective way to mitigate many adverse treatment-related effects of androgen suppression, but the potential impact of exercise on sexual activity previously had not been studied. ■

INHIBIT ANDROGEN PRODUCTION

TADALAFIL MAY improve ejaculatory or orgasmic dysfunction in men with erectile dysfunction (ED), according to an analysis of data from 3,581 men enrolled in 17 randomized, placebocontrolled trials of the drug. In a study led by Darius Paduch, MD, of New York-Presbyterian Hospital/ Weill Cornell Medical College in New York, 66% of tadalafil-treated subjects who had severe ejaculatory dysfunction (EjD) reported improved ejaculatory function compared with 36% who received placebo. In addition, 66% of tadalafil-treated patients with severe orgasmic dysfunction (OD) reported improvement compared with

BLOCK THE ANDROGEN RECEPTOR

35% of placebo recipients. Residual severe EjD or OD after treatment had negative impacts on sexual satisfaction, the researchers reported in BJU International (2013;111:334-343).

Learn more at inhibitandrogen.com/distinct

In a press release, Dr. Paduch commented that up to 18% of men have a normal erection but do not ejaculate or take a long time to do so. According to Dr. Paduch, non-erectile

*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. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN ®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 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.

sexual dysfunction is underreported and undertreated because of social stigma as well as misunderstanding about the physiology of male sexual response and OD. ■

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 10/12 K08Z12191BR1

10 Renal & Urology News

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Radiotherapy for Stage II Testis Seminoma Durable Treatment increases the risk of cardiac events, study shows Minn., found that most major cardiac events and secondary malignancy events occurred more than 20 years after radiotherapy. This finding highlights the importance of vigilant long-term follow-up, the researchers noted. In addition, the study showed that stage II testicular seminoma treated with

©PHOTO RESEARCHERS, INC. / HEALTH PROTECTION AGENCY

BY JOHN SCHIESZER BOSTON—In patients with stage II testicular seminoma treated with ra diotherapy, relapse in the irradiated site appears to be uncommon, according to a new long-term study presented at the American Society for Radiation Oncology annual meeting.

Radiotherapy for stage II testicular seminoma offers good cancer-specific survival.

The study, which included 52 men, also suggests that infradiaphragmatic radiotherapy alone may be associated with a significant risk of mediastinal/supraclavicular (MSCV) failure, particularly in patients with stage IIB disease. The investigators, led by Christopher Hallemeier, MD, a resident in radiation/ oncology at Mayo Clinic in Rochester,

Key Points ■ Relapse-free survival at 10 years

was 83% and 54% for stage IIA and IIB patients, respectively. ■ The estimated cancer-specific

and overall survival at 20 years was 96% and 81%, respectively. ■ Major cardiac events occurred in

19% of patients after a median of 18 years. ■ Secondary malignancies

occurred in 10% of patients after a median of 27 years.

radiotherapy is associated with excellent cause-specific survival. “Radiation treatment is an effective treatment for patients with stage II testicular seminoma, but we did see [that] 19% of patients had a cardiac event after the radiotherapy,” Dr. Hallemeier said. “It is unclear if radiation is causative, but we do know that these patients are at a slightly higher risk for cardiac events.” Following radiotherapy, major cardiac events occurred in 10 patients (19%) at a median of 18 years and secondary malignancies occurred in five patients (10%) at a median of 27 years. The 52 patients received treatment from 1974 to 2007. Of these, 48 patients (92%) had computed tomography (CT) staging. The investigators determined overall survival (OS), relapse-free survival (RFS), and cause-specific survival (CSS). They defined major cardiac events as myocardial infarction, coronary artery bypass grafting or stenting, or valve replacement. The investigators defined a second malignancy as a

biopsy-confirmed malignancy occurring in the radiotherapy field. The median patient age at the time of diagnosis was 36 years (range 22-71 years). Twenty-four patients had stage IIA, seven had stage IIB, and 17 had IIC disease; four patients were listed as having stage II disease, but a more specific classification was not available. The median infradiaphragmatic radiotherapy dose was 30.7 Gy and 26 patients received prophylactic MSCV radiotherapy with a median dose of 20.5 Gy. Four patients with bulky nodal disease also received chemotherapy. Of these patients, one had stage IIB and three had stage IIC. “Our median follow up was 19 years,” Dr. Hallemeier told Renal & Urology News. “That is a long follow-up, and it is clinically significant in showing that the results are durable and it allowed us to look for late morbidity from the radiation. Second malignancies tended to come late after the treatment, so we think that patients who are treated with radiation and cured need to be followed long-term to monitor and detect any late complications from the radiation in treatment, such as cardiac events or secondary malignancies.” The estimated OS was 94% and 81% at 10 and 20 years, respectively, Dr. Hallemeier said. The estimated CSS was 96% and 96%. The RFS at 10 years was 83% and 54% for stage IIA and IIB patients, respectively. The RFS was 81% for patients with stage IIC and 100% for patients listed as having stage II and not otherwise specified. Ten patients (19%) experienced disease relapse. Of these, relapse occurred in the MSCV region of seven patients, the para-aortic lymph nodes in one patient, the lung in one patient, and the peritoneal cavity in one patient. Eight patients underwent successful salvage chemotherapy and/or surgery. Two died of seminoma. The patients receiving prophylactic MSCV radiotherapy had a lower relapse rate in the MSCV region (one of 26) compared with those who did not receive prophylaxis (six of 26). Dr. Hallemeier and his collaborators published their findings online ahead of print in Urologic Oncology. ■

Potential MIBC Cures Underused BY JODY A. CHARNOW POTENTIALLY CURATIVE treatments for muscle-invasive bladder cancer (MIBC) are underused in the United States, according to a recent study. Using the National Cancer Data Base, investigators Phillip J. Gray, MD, and colleagues at Massachusetts General Hospital in Boston analyzed data from 28,691 patients with MIBC (stages II–IV) treated between 2004 and 2008. The researchers excluded patients with cT4b tumors or distant metastases. Treatments included radical or partial cystectomy with or without chemotherapy (CT), chemoradiotherapy (CRT), radiation therapy (RT), or CT alone and observation following biopsy. The investigators defined aggressive therapy (AT) as radical or partial cystectomy or definitive RT/CRT (total dose 50 Gy or greater). The study showed that only 52% of patients received AT, 44.9% received surgical treatment, 7.6% received definitive CRT or RT, and 25.9% were managed by observation alone, according to an online report in European Urology. The use of AT decreased with increasing age: Compared with patients aged 50 years or younger, those aged 81-90 years were 66% less likely to receive

Aggressive therapy is given in only 52% of muscle-invasive bladder cancer cases. AT. Blacks were 26% less likely than non-blacks, uninsured patients were 27% less likely than insured patients, and Medicaid patients were 19% less likely than non-Medicaid patients to receive AT, data show. All betweengroup differences were statistically significant. Furthermore, AT use was significantly greater with increasing tumor stage: patients with T3/T4a disease were 2.2 times more likely to receive AT than patients with T2 disease. The study was limited by its retrospective design and lack of information about patient and provider motivations with respect to therapy selection, the investigators noted. ■

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Renal & Urology News 11

Sitagliptin Suitable for Diabetics on Dialysis SITAGLIPTIN AND glipizide monotherapy is safe and effective in patients with type 2 diabetes and end-stage renal disease (ESRD) requiring dialysis, according to researchers. Patients with type 2 diabetes mellitus and ESRD on dialysis therapy have limited therapeutic options to manage hyperglycemia, the researchers noted. Furthermore, few randomized controlled studies have evaluated or compared antihyperglycemic agents in this patient population. These are the findings of a 54-week, randomized, double-blind study conducted by Juan C. Arjona Ferreira, MD, of Merck Sharp & Dohme Corp., in Whitehouse Station, N.J., and colleagues. The trial included 129 patients with type 2 diabetes and ESRD requiring dialysis. At baseline, patients had a hemoglobin A 1c (HbA 1c) level of 7%-9%. Of the 129 patients, 64 were assigned to treatment with sitagliptin and 65 were assigned to treatment with glipizide.

Sitagliptin is a dipeptidyl peptidase 4 inhibitor that improves glycemic control and is associated with an incidence of hypoglycemia similar to that of placebo when used alone or with antihyperglycemic agents not associated with hypoglycemia. “Based on the pharmacokinetics of sitagliptin,

to achieve a plasma concentration of sitagliptin similar to that achieved with a once-daily 100-mg dose in patients with normal to mildly decreased kidney function, individuals with ESRD should receive one quarter of the usual clinical dose, or 25 mg daily,” the investigators noted.

The authors concluded that treatment with dose-adjusted sitagliptin provided clinically meaningful reductions from baseline in HbA1c and FPG levels similar to those observed with glipizide over 54 weeks in patients with type 2 diabetes and ESRD on dialysis. ■

Sitagliptin similar to glipizide in HbA1c and FPG lowering. For the study, patients received sitagliptin 25 mg daily or glipizide initiated with 2.5 mg daily and titrated up to a potential maximum dose of 10 mg twice daily or down to avoid hypoglycemia. After 54 weeks, mean HbA1c levels declined significantly from baseline by 0.72% and 0.87% with sitagliptin and glipizide, respectively researchers reported online ahead of print in the American Journal of Kidney Diseases. Fasting plasma glucose (FPG) levels declined significantly by 26.6 mg/dL and 31.2 mg/dL, respectively. The incidences of symptomatic hypoglycemia were 6.3% in the sitagliptin group compared with 10.8% in the glipizide group, but the between-group difference was not significant. Severe hypoglycemia occurred in 7.7% of the glipizide-treated patients but not in any of the sitagliptin recipients. The sitagliptin group had higher incidences of cellulitis and headache compared with the glipizide group. Glipizide is one of two sulfonylureas recommended for use in patients with ESRD, but they are associated with an increased risk of hypoglycemia.

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. 2012 8/12 08Z12235A

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ADT duration continued from page 1

at Centre Hospitalier Universitaire de Sherbrooke in Sherbrooke Canada. For the study, 310 patients were randomized to receive 36 months of ADT (arm 1) and 320 were randomized to receive 18 months of ADT (arm 2). At a median follow-up of 77 months, 71 patients in arm 1 (22.9%) and 76 (23.8%) in arm 2 had died. A total of 116 patients died from causes other than PCa, the researchers noted. The 10-year overall survival rates were

BCG/immunosuppressed continued from page 1

of the potential for the development of sepsis and the possibility that BCG may be ineffective in patients who cannot mount a robust immune response, according to investigators Harry W. Herr, MD, and Guido Dalbagni, MD, of Memorial Sloan-Kettering Cancer Center in New York. Drs. Herr and Dalbagni studied 45 immunosuppressed patients with NMIBC who underwent transurethral resection (TUR) of the bladder. All patients received adjuvant intravesical induction BCG treatment. Of the 45 patients, 12 were transplant recipients with a functioning organ, 23 had unrelated cancer and were undergoing systemic chemotherapy, and 10 were taking steroids for auto-immune

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63.6% and 63.2% in arm 1 and arm 2, respectively, and the 10-year cancerspecific survival rates were 87.2% and 87.2%, respectively. Commenting on the new study, Andrew J. Stephenson, MD, Director of the Center for Urologic Oncology at Cleveland Clinic’s Glickman Urological and Kidney Institute, noted the radiation doses administered to the patients were modest compared with what would be used today. In addition, noting that the current standard of care for high-risk PCa patients receiving EBRT remains adjuvant ADT for two

to three years, he said it appears that 18 months of ADT was not associated with inferior outcomes compared with 36 months. It may be reasonable to treat patients with 18 months of ADT if they experience major adverse effects while on treatment or if they have important comorbid problems that may worsen with prolonged ADT, Dr. Stephenson told Renal & Urology News.

or related diseases. Nine of the 12 transplant recipients (75%) responded completely to one or two cycles of BCG compared with 32 (99%) of the 33 other patients, according to the researchers. The investigators defined a complete response as a negative biopsy and negative urinary cytology at six months. Six (50%) of the 12 transplant patients progressed compared with five (15%) of the 33 other patients. Of the six transplant patients who progressed, metastatic disease without bladder relapse developed in two, muscle-invasive disease developed in three, and one underwent TUR plus chemotherapy, the researchers reported. Five patients died (11%), two from bladder cancer and three from unrelated causes. BCG was well tolerated. No patient experienced bacterial or BCG

sepsis. The median follow-up period was 40 months. The median follow-up time for survivors has not been reached, the researchers reported. Of the 45 patients, 34 were followed for more than three years, and 15 were followed for five years or

Serial Prostate Biopsy May Increase Inflammation SERIAL BIOPSY of the prostate may increase histologic inflammation in the gland among prostate cancer (PCa) patients being managed with active surveillance (AS), but this increase does not appear to be associated with cancer upgrading, according to a pilot study. Allison Glass, MD, and collaborators at the University of California-San Francisco (UCSF) studied 56 PCa patients being managed with AS and who underwent two or more transrectal ultrasound-guided prostate needle biopsies. In adjusted analyses, increasing numbers of biopsies were associated with small but significant increases in maximum chronic inflammation scores but were not associated with significant changes in acute inflammation, the researchers reported online ahead of print in Prostate Cancer and Prostatic Disease. Nineteen subjects (34%) experienced a Gleason score upgrade from 6 or less at diagnosis, 11 (56%) of these occurring at the second biopsy. The investigators observed no significant association between chronic inflammation and cancer upgrade. “Despite the study’s limitations and small size, we provide a relatively novel finding of a potential long-term outcome of repeated prostate needle biopsy,” the authors concluded. ■

No change to standard of care “This study does not change the standard of care; however, 18 months

No bacterial or BCG sepsis developed in any patient. more. The median recurrence-free survival time was significantly shorter for the transplant recipients than the other groups: 17 months compared with 47 months for the patients with unrelated cancers and 50 months for

Donor Smoking continued from page 1

635 consecutive living kidney donors between 2000 and 2008. Smokers were defined as individuals who actively smoked within a year before their nephrectomy. The smokers were significantly more likely to be female than male (53.7% vs. 62.9%) and were younger than nonsmokers (37.9 vs. 41.8 years). They also had lower blood urea nitrogren levels (12.2 vs. 12.8 mg/dL).Three-quarters of the recipients received kidneys from nonsmoking donors; they had a similar average age, body mass index and race (predominantly white) to those who received kidneys from smokers. Few post-operative complications occurred, and they were minor. The researchers observed a trend toward reduced death-censored kidney survival in patients who received a kidney from smokers. The risk of graft loss was 31% greater for kidneys

of therapy may be a consideration for select patients,” Dr. Stephenson commented. The study population had a median age 71 years, a median PSA level of 16 ng/mL, and a median Gleason score of 8. Most patients had T2-3 disease. The two study arms were well balanced with respect to patient characteristics, Dr. Nabid’s group noted. The symposium is sponsored by the American Society of Clinical Oncology, the Society of Urologic Oncology, and the American Society for Radiation Oncology. ■

auto-immune patients. Transplant patients had a median progressionfree survival time of 40 months. The median time to progression had not been reached in cancer or auto-immune patients. The overall BCG response rates are similar to the 80% complete responses observed in the majority of non-immune suppressed patients, the researchers stated. “Recurrence-free and progression-free survival times are inferior in transplant patients compared to immunosuppressed patients in general, indicating that early response to BCG does not translate into long-term disease-free intervals,” the authors wrote. The researchers noted that their results should be interpreted with caution because the study included only a small number of patients. ■

from smokers compared those from non-smokers, but this increased risk was not statistically significant. Donor smoking, however, was associated with a significantly adverse effect on recipient survival. Survival rates at one year post-transplant were 93.5% for recipients who received an organ from a smoker compared with 97.9% for those who did not. The rates were 85% and 90.7% at five years and 67.4% and 76.5% at 10 years, respectively. Dr. Waits noted that smoking has important effects on renal physiology. It reduces renal plasma flow, increases rates of progression of underlying renal disease, and increases the rate of renal atherosclerosis. Dr. Waits also acknowledged that he and his colleagues did not examine recipient smoking, which would likely affect outcomes, and this was an inherent bias in the study. He and his co-investigators plan to collect and analyze those data. ■

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Renal & Urology News 13

Restless Legs Syndrome Linked to CKD in Kids RESTLESS LEGS SYNDROME (RLS) is more common in children with chronic kidney disease (CKD) than in healthy children, new findings suggest. In a prospective study comparing 124 children with CKD and 85 agedmatched healthy children (controls), Sandeep K. Riar, MD, of the University of Kansas Medical Center in Kansas City, and colleagues found that RLS was present in 15.3% of the CKD patients versus 5.9% of the controls, a significant difference between the groups, according to a report published online ahead of print in Pediatric Nephrology. Previous research has shown that RLS is much more common among adults with CKD than in the general population. The new study also found that RLS was associated with a lower health-related quality of life based on parental reports, Dr. Riar’s team noted. Furthermore, among the CKD patients, those with

RLS were more likely those without RLS to rate their sleep quality as fairly bad or very bad (41.2% vs. 8.8%). RLS is a neurological disorder characterized by an irresistible urge to move the legs, with onset at night and at rest, the authors explained. For the study, the investigators used strict National

The condition is more than twice as common in children with CKD.

Institutes of Health criteria for RLS and excluded common mimics of RLS. The study, which was conducted at Emory University in Atlanta and Children’s Healthcare of Atlanta, is the first study of RLS in pediatric CKD patients to use a control group and exclude mimics. ■

ESR Predicts Post-Op RCC Survival A HIGH ERYTHROCYTE sedimentation rate (ESR) prior to nephrectomy for clear-cell renal cell carcinoma (RCC) is associated with worse survival after surgery, according to a new study. In addition, preoperative anemia is associated with an increased risk of death from other illnesses. Hyun-Moo Lee, MD, of Samsung Medical Center in Seoul, Korea, and colleagues analyzed survival outcomes among 1,307 patients with clear-cell RCC who underwent nephrectomy during 1994-2008. After a median follow-up of 43 months, patients with preoperative high levels of ESR had a twofold greater risk of dying from RCC compared with patients who had preoperative levels in the

Learn more at inhibitandrogen.com/sequence

normal range, researchers reported

*Currently in the absence of published, randomized, clinical data on treatment sequencing in mCRPC posttreatment with docetaxel. mCRPC=metastatic castration-resistant prostate cancer.

online in the British Journal of Cancer. The study also demonstrated that preoperative anemia, as assessed

References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 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.

by hemoglobin and hematocrit, had a threefold and sixfold increased risk of dying from other illnesses, respectively, compared with patients who did not have anemia. ■

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 10/12 K08Z12236AR1

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NKF PREVIEW

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FEATURE

The Pros and Cons of Vitamin D Supplementation In both nutritional and activated forms, vitamin D may have side effects that are as yet under-appreciated BY MICHAL L. MELAMED, MD, MHS

Editor’s note: The author will discuss the topic of this article at the National Kidney Foundation’s 2013 Spring Clinical Meetings in Orlando, Fla., at an April 3 session titled “Controversies in the Management of CKD— What’s Next?”

itamin D levels are almost universally low in patients with chronic kidney disease (CKD) and patients on dialysis. 1,2Low vitamin D levels have been associated with multiple poor outcomes in dialysis patients including all-cause mortality and faster progression of kidney disease.1,3-5 Low vitamin D levels, along with other metabolic abnormalities in CKD, such as hypocalcemia and hyperphosphatemia, lead to secondary hyperparathyroidism. Nephrologists prescribe activated vitamin D, calcitriol, or activated vitamin D analogs, such as paricalcitol and doxercalciferol, to patients with secondary hyperparathyroidism to lower parathyroid hormone (PTH) levels and prevent high turnover bone disease. Recently, evidence has emerged suggesting that nutritional vitamin D, in the form of cholecalciferol or ergocalciferol, may also lower PTH levels. However, there may be some detri-

mental effects of vitamin D therapy, such as an increased risk of kidney stones and vascular calcification at very high doses.

Activated vs. nutritional vitamin D There is controversy in the literature about the use of activated versus nutritional vitamin D.6,7 The use of activated vitamin D has been more widespread among nephrologists and its use has been associated with improved survival on dialysis and in pre-dialysis CKD.7 Because patients with end-stage renal disease (ESRD) do not have functioning kidneys, they do not convert 25-hydroxyvitamin D (the less active, circulating form) to 1,25-dihydroxyvitamin D as efficiently as patients with functional kidneys. Separate metaanalyses of PTH suppression with either nutritional or activated vitamin D both showed statistically significant lowering of PTH levels with the respective vitamin D compound.8,9 There have been no large random -ized clinical trials of vitamin D evaluating hard outcomes, such as mortality or progression of kidney disease.

Vitamin D and outcomes: albuminuria and LVH Vitamin D therapy, both in CKD and in the general population, has been hypothesized to have multiple health benefits outside of bone health including effects on albuminuria, left

ven-tricular size and function, and kidney disease progression. There are current on-going clinical trials in both CKD, ESRD, and in the general population to try to clarify whether these effects exist. A recent clinical trial (the VITAL study) showed that paricalcitol has beneficial extra-skeletal effects. This trial was a multicenter, multinational study of 281 patients with albuminuria and on an ACE inhibitor or angiotensin receptor blocker at baseline. The study revealed a significant reduction in the urinary albumin/creatinine ratio in participants on the 2 microgram dose of paricalcitol compared with placebo. This was associated with a lowering of estimated glomerular filtration rate (GFR) that was significant also at the 1 microgram dose. This was a well-designed study evaluating effects on albuminuria, but it did not examine the more important question of whether this decrease in albuminuria translates to better clinical outcomes, such as less rapid progression to dialysis. An association between low vitamin D levels and left ventricular hypertrophy (LVH) is clear in animal models, but, based on recent data, not as clear in humans. The vitamin D receptor knock-out mouse develops LVH, and 1,25-dihydroxyvitamin D has been shown to regulate myocyte proliferation.10 In humans, treatment with paricalcitol for 48 weeks in 227 patients with CKD did not change left ventricular myocardial index as

shown by the recent PRIMO study.11 In a post hoc analysis, paricalcitol treatment did decrease left atrial volume index.12 It is unclear at this point why paricalcitol did not decrease LVH in the PRIMO trial as it did in animal models.

Side effects of vitamin D therapy? Observational studies suggest that treatment with vitamin D may affect survival of dialysis patients. Several recent trials have used low-dose nutritional vitamin D in addition to an active agent (such as activated vitamin D or cinacalcet). The question then becomes, can patients with CKD or on dialysis get too much vitamin D? There is potentially an important difference in vitamin D’s action depending on the dose of a vitamin D analog. For example, in a mouse model of kidney disease, low levels of vitamin D (paricalcitol or calcitriol) were protective against vascular calcification while higher doses were associated with more calcification.13 Potentially, both lack of and too much vitamin D may lead to vascular calcification. In addition, in post-menopausal women, even a low dose of vitamin D (cholecalciferol 400 IU combined with calcium treatment) was associated with a greater risk of kidney stones compared to placebo treatment.14 Thus, vitamin D in both nutritional and activated forms may have side effects that are as yet underappreciated. More research is needed in this area. ■

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Michal L. Melamed, MD, MHS, is an associate professor in the Department of Medicine and the Department of Epidemiology and Population Health, Albert Einstein College of Medicine/ Montefiore Medical Center, Bronx, N.Y. REFERENCES 1. Wolf M, Shah A, Gutierrez O, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int 2007;72:1004-1013.

2. Bhan I, Burnett-Bowie SA, Ye J, et al. Clinical measures identify vitamin D deficiency in dialysis. Clin J Am Soc Nephrol 2010;5:460-467. 3. Ravani P, Malberti F, Tripepi G, et al. Vitamin D levels and patient outcome in chronic kidney disease. Kidney Int 2009;75:88-95. 4. Drechsler C, Pilz S, Obermayer-Pietsch B, et al. Vitamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in haemodialysis patients. Eur Heart J 2010;31:2253-2261. 5. Drechsler C, Verduijn M, Pilz S, et al. Vitamin D status and clinical outcomes in incident dialysis patients: results from the NECOSAD study. Nephrol Dial Transplant 2011;26:1024-1032. 6. Kalantar-Zadeh K, Kovesdy CP. Clinical outcomes with active versus nutritional vitamin D compounds

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in chronic kidney disease. Clin J Am Soc Nephrol 2009;4:1529-1539. 7. Melamed ML, Thadhani RI. Vitamin D therapy in chronic kidney disease and end stage renal disease. Clin J Am Soc Nephrol 2012;7: 358-365. 8. Palmer SC, McGregor DO, Macaskill P, et al. Meta-analysis: vitamin D compounds in chronic kidney disease. Ann Intern Med 2007;147: 840-853. 9. Kandula P, Dobre M, Schold JD, et al. Vitamin D supplementation in chronic kidney disease: a systematic review and meta-analysis of observational studies and randomized controlled trials. Clin J Am Soc Nephrol 2011;6:50-62. 10. Xiang W, Kong J, Chen S, et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the

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systemic and cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab 2005;288:E125-132. 11. Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA 2012;307:674-684. 12. Tamez H, Zoccali C, Packham D, et al. Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease. Am Heart J 2012;164:902-9 e2. 13. Mathew S, Lund RJ, Chaudhary LR, et al. Vitamin D receptor activators can protect against vascular calcification. J Am Soc Nephrol 2008;19: 1509-1519. 14. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-683.

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Table 2: Percentages of Patients with Adverse Reactions, Derived from all Adverse Events, Reported by Greater Than 2% of Patients Treated With Myrbetriq 50 mg Once Daily in Study 4 Myrbetriq 50 mg

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16 Renal & Urology News

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Why IM Residents Do Not Choose Nephrology MOST NON-NEPHROLOGY internal medicine subspecialty fellows—such as those in cardiology, gastroenterology, critical care, and endocrinology—never considered nephrology as a career choice, in large part because of the challenges they believed they would face, according to a survey findings

published online ahead of print in the American Journal of Kidney Diseases. Researchers led by Kenar D. Jhaveri, MD, of Hofstra North Shore-Long Island Jewish School of Medicine, N.Y reported that, of 714 non-nephrology internal medicine subspecialty fellows who responded to the survey, only 26%

had considered nephrology as a career choice. The top reason for not choosing nephrology—as indicated by 35% of respondents— was the belief that patients with end-stage renal disease are too complicated. Other reasons included the lack of a mentor during residency and medical school and

not enough procedures in the field of nephrology. In addition, about one-fourth of respondents indicated that they would have considered nephrology if the specialty had a higher income potential or the subject matter was taught well during medical school and residency training. The survey revealed that 31% of respondents indicated that nephrology was the most difficult physiology course taught in medical school. Endocrinology fellows were the most likely to have considered nephrology as a career choice at some point during their residency, Dr. Jhaveri’s group found. ■

makes all the difference

Psychological Symptoms, Low T Linked LOW ENDOGENOUS levels of testosterone may be related to an increased incidence of psychological symptoms in young men, researchers reported. In a prospective study, investigators at the Gulhane School of Medicine in Ankara, Turkey, enrolled 39 young men (mean age 21.9 years) with congenital hypogonadotropic hypogonadism (CHH) and 40 age-matched healthy males (controls). The impact of testosterone replacement therapy (TRT) on CHH patients’ anxiety and depression levels, sexual function, and quality of life were assessed before and after six month of TRT. At baseline, the treatment-naïve CHH patients had more severe symptoms of sexual

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sion, and worse QOL compared with controls. After six months of TRT, the MD, observed improvements in the above parameters.

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Writing in the Endocrine Journal (2012;59:1099-1105), the authors concluded that patients who have hypogonadism should not

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be evaluated by their metabolic and functional parameters alone, but particular attention should also be paid to signs of additional psychological problems. ■

41960ALT_ASize_v1 1

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16 Renal & Urology News

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Why IM Residents Do Not Choose Nephrology MOST NON-NEPHROLOGY internal medicine subspecialty fellowsâ&#x20AC;&#x201D;such as those in cardiology, gastroenterology, critical care, and endocrinologyâ&#x20AC;&#x201D;never considered nephrology as a career choice, in large part because of the challenges they believed they would face, according to a survey findings

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Psychological Symptoms, Low T Linked LOW ENDOGENOUS levels of testosterone may be related to an increased incidence of

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men, researchers reported.

PATIENT COUNSELING INFORMATION

Ankara, Turkey, enrolled 39 young

Cardiac Electrophysiology

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In a prospective study, investigators at the Gulhane School of Medicine in men (mean age 21.9 years) with congenital hypogonadotropic hypogonadism (CHH) and 40 age-matched healthy males (controls). The impact of testosterone replacement therapy (TRT) on CHH patientsâ&#x20AC;&#x2122; anxiety and de-

Rx Only

pression levels, sexual function, and

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Manufactured by:

and after six month of TRT. At base-

Astellas Pharma Technologies, Inc.

line, the treatment-naĂŻve CHH patients

Norman, Oklahoma 73072 Marketed and Distributed by: Astellas

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had more severe symptoms of sexual dysfunction, anxiety, and depression, and worse QOL compared with controls. After six months of TRT, the investigators, led by Umit Aydogan, MD, observed improvements in the above parameters.

012J-056-65 4

Writing in the Endocrine Journal (2012;59:1099-1105), the

authors concluded that patients who have hypogonadism should not be evaluated by their metabolic and functional parameters alone, but particular attention should also be paid to signs of additional psychological problems. â&#x2013;

www.renalandurologynews.com

MARCH 2013

Renal & Urology News 17

Device Treats Resistant Hypertension In a small study, a multi-electrode system provided a rapid and sustained treatment effect BY JILL STEIN LOS ANGELES—An investigational multi-electrode ablation catheter system is safe and effective for treating patients with resistant hypertension, according to preliminary results released at the American Heart Association Scientific Sessions 2012. “Importantly, we observed that the device has a rapid and sustained treatment effect as evidenced by office and ambulatory blood pressure measurements throughout the six-month followup period,” said Vasilios Papademetriou, MD, Professor of Medicine at Georgetown University and Director of Hypertension and Cardiovascular Research at the Veterans Affairs Medical Center in Washington D.C. In addition, there were no serious periprocedural events or changes in renal function, Dr. Papademetriou said. He presented results from the first 46 patients with resistant hypertension to be treated with the EnligHTN device (St. Jude Medical, St. Paul, Minn.). Until now, single-tip electrode radiofrequency ablation catheters have been used to achieve sympathetic fiber disruption through the renal artery wall; intentional renal fiber disruption has been found to decrease blood pressure

(BP). The multi-electrode catheter was designed to create a stable, predictable pattern of lesions circumferentially around the renal artery wall, thereby producing renal fiber disruption without scarring along with less need for contrast and a shorter procedure time. Study participants had an office systolic BP of 160 mm Hg or higher and stable use of three or more antihypertensive medications concurrently at maximally tolerated doses for a minimum of 14 days before enrollment. One of the drugs had to be a diuretic or the patient had to have previously been on a diuretic but had been documented to be diuretic-intolerant. The primary efficacy outcome was the change in office BP at six months.

A 76% treatment response Overall, 34 patients (76%) had a treatment response, defined as a 10 mm Hg decrease in systolic BP from baseline. The baseline office BP of 176/96 mm Hg decreased by a mean of 28/10 mm Hg at one month, 27/10 mm Hg at three months, and 26/10 mm Hg at six months, the researchers noted. The mean reductions in the baseline 24-hour ambulatory BP of 150/83 mm Hg were 10/5 mm Hg, 10/5 mm Hg,

dure included worsening of pre-existing proteinuria in one patient, symptomatic hypotension in one patient, and worsening of pre-existing renal artery stenosis in one patient.

Vasilios Papademetriou, MD

and 10/6 mm Hg at one, three, and six months, respectively. Two-thirds of patients had a large enough BP reduction to permit a lower stage of hypertension classification and treatment. About a third of patients were no longer considered hypertensive. Dr. Papademetriou and his colleagues observed no renal artery dissections, aneursyms, new stenoses, flow-limiting renal artery vasospasms, or major vascular access complications. Serious events related to the device or proce-

Renal function preserved The study revealed no clinically significant change in renal function as determined by a 50% or greater reduction in estimated glomerular filtration rate, a twofold increase in serum creatinine, or progression to end-stage renal disease. Dr. Papademetriou noted that the study excluded patients who had undergone a prior renal artery intervention or had evidence of renal artery disease with a diameter stenosis greater than 30%. Patients with multiple main renal arteries in either kidney or main renal arteries less than 4 mm in diameter or less than 20 mm in length also were ineligible. “I am confident that the catheter is an improvement over technologies that we have available because there was no target renal artery that we were unable to access,” he told Renal & Urology News. “Also, minimal manipulation is required to complete the procedure so I don’t have any issues with the catheter device.” ■

Study: Keep Systolic BP in Therapeutic Range BY JILL STEIN LOS ANGELES—Physicians should aim for long-term maintenance of systolic blood pressure (BP) in the therapeutic range in their hypertensive patients, investigators said here at the American Heart Association Scientific Sessions 2012. Vasilios Papademetriou, MD, Professor of Medicine at Georgetown University in Washington D.C., and colleagues examined the relationship between time in the therapeutic range and all-cause mortality over a recent 10-year period in 371,996 hypertensive patients who were treated at Veterans Administration medical centers. Their results showed that long-term maintenance of systolic BP in the therapeutic range of 120-140 mm Hg was associated with a lower risk of death than maintaining systolic BP above or below that range. “I believe that the 120-140 mm Hg [sys-

tolic] blood pressure range is the most appropriate for our patients, particularly those at high risk because of coronary disease or diabetes or other co-morbid-

Data suggest that 120-140 mm Hg offers the best survival benefit. ities,” said Dr. Papademetriou, Director of Hypertension and Cardiovascular Research at the Veterans Affairs Medical Center in Washington D.C. High BP has long been known to dramatically increase the risk of cardiovascular events and all-cause mortality, but multiple prospective studies and cohort analyses have suggested that lowering systolic BP to below 140 mm Hg improves health outcomes, he said.

The optimal systolic BP level, however, had not been identified. The analysis revealed that patients whose systolic BP was in the therapeutic range for 75% or more of the times their blood pressure was measured had a mortality rate of 6.54%. The mortality rates were 21.9% and 33%, respectively, among patients whose systolic BP was above or below the therapeutic range 75% or more of the time. Although the mortality risk was lowest in patients who maintained their systolic BP in the therapeutic range more than 75% of the time, the risk only increased slightly if the pressure was maintained in the therapeutic range 51%-75% if the time. If it remained in the therapeutic range 25% or less of the time, the mortality rate surged to 23.5%. “So it seems like we found from our retrospective, observational data in a large number of patients that a window of 120-140 mm Hg provides the

best survival benefit in hypertensive patients,” Dr. Papademetriou told Renal & Urology News. “If you are above or below this level most of the time, the mortality rate is much higher.” He also said he is not yet certain whether the findings will eventually prompt a change in current guidelines, which recommend a goal systolic BP below 140 mm Hg. “The common notion has been ‘the lower, the better.’ The thinking has been that if you could reduce it to 130 mm Hg, that was fine. But if you could decrease it to 110 mm Hg, that was even better. We now know that that’s not the case.” Dr. Papademetriou pointed out that his team obtained BP measurements from electronic medical records. Notably, patients had their BP measured, on average, 44 times throughout the entire study period. “In most studies, blood pressure is measured much less frequently,” he said. ■

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FDA Warns About Tolvaptan-Related Liver Injury THE FDA has issued a warning about the potential for significant liver injury associated with the use of tolvaptan (Samsca), a drug approved for the treatment of hyponatremia. In a double-blind, three-year, placebo-controlled trial in about 1,400 patients with autosomal dominant polycystic kidney disease and its openlabel extension trial, three patients treated with the drug experienced significant increases in serum alanine aminotransferase with concomitant, clinically significant increases in serum total bilirubin, the FDA stated on its website (www.fda.gov). In the trials, the maximum daily dose of tolvaptan administered (90 mg in the morning and 30 mg in the afternoon) was higher than the maximum 60 mg daily dose approved for the treatment of hyponatremia. Most of the liver enzyme abnormalities were observed during the first 18 months of therapy. Following dis-

continuation of treatment, all three patients improved. The FDA recommends that healthcare providers perform liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or

jaundice. If hepatic injury is suspected, tolvaptan should be promptly discontinued, appropriate treatment should be instituted, and investigations should be performed to determine probable cause, the FDA says. The drug should not be re-initiated in patients unless the cause for the observed liver injury is

definitively established to be unrelated to treatment with tolvaptan. The FDA encourages healthcare professionals and patients to report adverse events or side effects related to the use of tolvaptan to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program. ■

Too Much Caffeine Ups Mens’ UI Risk CONSUMPTION OF the amount of caffeine in two cups of coffee increases the likelihood of urinary incontinence (UI) in men, a study found. In a study of men who participated in the 2005-2006 and 2007-2008 National Health and Nutritional Examination Survey, researchers found that caffeine intake in the upper 75th

Important Safety Information

percentile (234 mg/day or more)

• COLCRYS is contraindicated in patients with renal or hepatic impairment who are currently prescribed P-gp inhibitors or strong inhibitors of CYP3A4. In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses. Dose adjustments of COLCRYS may be required when co-administered with P-gp or CYP3A4 inhibitors in patients with normal renal and hepatic function.

and 90th percentiles (392 mg/day or more) was significantly associated with a 72% and twofold increased risk of having moderate-to-severe UI, respectively, reports reported online ahead of print in The Journal of Urology. The study, led by Alayne Markland, MD, of the University of Alabama in Birmingham, looked at data from 3,960 men aged 20 years or older who had complete data. Of these, 12.9% had UI. Men with an Incontinence Severity Index score of 3 or higher were considered to have moderate-to-severe UI. ■

• Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine. Keep COLCRYS out of the reach of children. • Blood dyscrasias such as myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported in patients taking colchicine at therapeutic doses.

References: 1. COLCRYS (colchicine, USP) full prescribing information, June 2012. 2. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum. 2011;63:3136-3141.

COLCRYS is a trademark of Takeda Pharmaceuticals U.S.A., Inc., registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. ©2013 Takeda Pharmaceuticals U.S.A., Inc. 43812 03/13

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Renal & Urology News 19

LVH Predicts Dialysis in Hypertensive Patients LEFT VENTRICULAR hypertrophy (LVH) is a significant predictor of adverse renal outcomes in hypertensive patients managed in a primary care setting. Consequently, clinicians should adopt systematic screening for LVH when assessing renal risk in hypertensive patients, investigators concluded.

A study led by Ernesto Paoletti, MD, of the IRCCS-Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy, looked at a data from 18,510 hypertensive patients for whom renal follow-up information was available. The baseline prevalence of chronic kidney disease (CKD) and LVH were 25.6% and 5.6%,

respectively. During a five-year follow-up, 1.4% of patients with LVH progressed to end-stage renal disease requiring dialysis compared with 0.5% of subjects without LVH, the researchers reported online ahead of print in the American Journal of Hypertension. In addition, 25.6% of patients with LVH progressed from each

If your patients are experiencing gout flares, consider COLCRYS (colchicine, USP) Low-dose COLCRYS is indicated to treat acute attacks of gout, a common form of arthritis.1,2

Indications COLCRYS (colchicine, USP) 0.6 mg tablets are indicated in adults for the prophylaxis of gout flares and treatment of acute gout flares when taken at the first sign of a flare. COLCRYS is not an analgesic medication and should not be used to treat pain from other causes.

• Colchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported with chronic treatment in therapeutic doses, especially when colchicine is prescribed in combination with other drugs known to cause this effect. Patients with renal dysfunction and elderly patients, even those with normal renal and hepatic function, are at increased risk. • Monitor for toxicity and if present consider temporary interruption or discontinuation of colchicine. • The most common adverse reactions in clinical trials were diarrhea (23%) and pharyngolaryngeal pain (3%). Please see brief summary of complete Prescribing Information on the following pages.

stage of CKD to a more advanced stage compared with 17% without LVH, with 0.9% of patients with LVH and 0.4% of patients without LVH reaching stage 5. LVH was associated with an 82% increased likelihood of progressing to dialysis and a 24% increased likelihood of progressing to a more advanced stage of CKD. ■

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Metabolic Syndrome Found to Increase ESRD Risk METABOLIC SYNDROME in patients with stage 3-4 chronic kidney disease (CKD) is associated with an increased risk of end-stage renal disease (ESRD) but not death, researchers concluded. A team at the Cleveland Clinic led by Sankar D. Navaneethan, MD, of the clinic’s Glickman Urological and Kidney

Institute, studied 25,868 patients with stages 3-4 CKD, of whom 15,605 (60%) had metabolic syndrome. After adjusting for multiple potential confounders, metabolic syndrome was associated with a 33% increased risk for ESRD during a 2.3-year follow-up period, according to findings published online ahead of print

in the Clinical Journal of the American Society of Nephrology. In addition, among the individual components of metabolic syndrome, impair glucose metabolism, elevated triglycerides, and hypertension were associated with an increased risk of ESRD but low high-density lipoprotein cholesterol and impaired glucose metabo-

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION COLCRYS (colchicine, USP) tablets for Oral use INDICATIONS AND USAGE Gout Flares COLCRYS (colchicine, USP) tablets are indicated in adults for prophylaxis and the treatment of acute gout flares. Prophylaxis of Gout Flares: COLCRYS is indicated for prophylaxis of gout flares. Treatment of Gout Flares: COLCRYS tablets are indicated for treatment of acute gout flares when taken at the first sign of a flare. Familial Mediterranean fever (FMF) COLCRYS (colchicine, USP) tablets are indicated in adults and children 4 years or older for treatment of familial Mediterranean fever (FMF). COLCRYS is not an analgesic medication and should not be used to treat pain from other causes. CONTRAINDICATIONS Patients with renal or hepatic impairment should not be given COLCRYS in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors, except fosamprenavir). In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses. WARNINGS AND PRECAUTIONS Fatal Overdose Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine [see OVERDOSAGE]. COLCRYS should be kept out of the reach of children. Blood Dyscrasias Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported with colchicine used in therapeutic doses. Drug Interactions Colchicine is a P-gp and CYP3A4 substrate. Life-threatening and fatal drug interactions have been reported in patients treated with colchicine given with P-gp and strong CYP3A4 inhibitors. If treatment with a P-gp or strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, the patient’s dose of colchicine may need to be reduced or interrupted [see DRUG INTERACTIONS]. Use of COLCRYS in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors, except fosamprenavir) is contraindicated in patients with renal or hepatic impairment [see CONTRAINDICATIONS]. Neuromuscular Toxicity Colchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported with chronic treatment in therapeutic doses. Patients with renal dysfunction and elderly patients, even those with normal renal and hepatic function, are at increased risk. Concomitant use of atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, gemfibrozil, fenofibrate, fenofibric acid, or benzafibrate (themselves associated with myotoxicity) or cyclosporine with COLCRYS may potentiate the development of myopathy [see DRUG INTERACTIONS]. Once colchicine is stopped, the symptoms generally resolve within 1 week to several months. ADVERSE REACTIONS Prophylaxis of Gout Flares: The most commonly reported adverse reaction in clinical trials of colchicine for the prophylaxis of gout was diarrhea. Treatment of Gout Flares: The most common adverse reactions reported in the clinical trial with COLCRYS for treatment of gout flares were diarrhea (23%) and pharyngolaryngeal pain (3%). FMF: Gastrointestinal tract adverse effects are the most frequent side effects in patients initiating COLCRYS, usually presenting within 24 hours, and occurring in up to 20% of patients given therapeutic doses. Typical symptoms include cramping, nausea, diarrhea, abdominal pain, and vomiting. These events should be viewed as dose-limiting if severe as they can herald the onset of more significant toxicity. Clinical Trials Experience in Gout Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice. In a randomized, double-blind, placebo-controlled trial in patients with a gout flare, gastrointestinal adverse reactions occurred in 26% of patients using the recommended dose (1.8 mg over 1 hour) of COLCRYS compared to 77%

lism were associated with an increased risk of death. Study findings have significant clinical importance, the authors noted, because individual components of metabolic syndrome, metabolic syndrome itself, and CKD in the U.S. population and around the world are increasing. ■

of patients taking a non-recommended high-dose (4.8 mg over 6 hours) of colchicine and 20% of patients taking placebo. Diarrhea was the most commonly reported drug-related gastrointestinal adverse event. As shown in Table 3, diarrhea is associated with COLCRYS treatment. Diarrhea was more likely to occur in patients taking the high-dose regimen than the low-dose regimen. Severe diarrhea occurred in 19% and vomiting occurred in 17% of patients taking the non-recommended high-dose colchicine regimen but did not occur in the recommended low-dose COLCRYS regimen. Table 3 Number (%) of Patients with at Least One Drug-Related Treatment Emergent Adverse Events with an Incidence of ≥ 2% of Patients in Any Treatment Group MedDRA System Organ Class COLCRYS Dose MedDRA Preferred Term High (N=52) Low (N=74) n (%) n (%)

Placebo (N=59) n (%)

Number of Patients with at Least One Drug-Related TEAE

16 (27)

Gastrointestinal Disorders

40 (77)

27 (37)

40 (77)

19 (26)

12 (20)

Diarrhea

40 (77)

17 (23)

8 (14)

Nausea

9 (17)

3 (4)

3 (5)

Vomiting

9 (17)

Abdominal Discomfort

2 (3)

1 (1)

1 (2)

2 (4)

1 (1)

1 (2)

3 (4)

2 (3)

3 (4)

1 (2)

General Disorders and 4 (8) Administration Site Conditions Fatigue Metabolic and Nutrition Disorders Gout Nervous System Disorders Headache Respiratory Thoracic Mediastinal Disorders Pharyngolaryngeal Pain

1 (2)

1 (1.4)

2 (3)

1 (2)

1 (1)

2 (3)

1 (2)

2 (3)

1 (2)

2 (3)

Postmarketing Experience Serious toxic manifestations associated with colchicine include myelosuppression, disseminated intravascular coagulation, and injury to cells in the renal, hepatic, circulatory, and central nervous systems. These most often occur with excessive accumulation or overdosage [see OVERDOSAGE]. The following adverse reactions have been reported with colchicine. These have been generally reversible upon temporarily interrupting treatment or lowering the dose of colchicine. Neurological: sensory motor neuropathy Dermatological: alopecia, maculopapular rash, purpura, rash Digestive: abdominal cramping, abdominal pain, diarrhea, lactose intolerance, nausea, vomiting Hematological: leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemia Hepatobiliary: elevated AST, elevated ALT Musculoskeletal: myopathy, elevated CPK, myotonia, muscle weakness, muscle pain, rhabdomyolysis Reproductive: azoospermia, oligospermia DRUG INTERACTIONS COLCRYS (colchicine) is a substrate of the efflux transporter P-glycoprotein (P-gp). Of the cytochrome P450 enzymes tested, CYP3A4 was mainly involved in the metabolism of colchicine. If COLCRYS is administered with drugs that inhibit P-gp, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely. Fatal drug interactions have been reported. Physicians should ensure that patients are suitable candidates for treatment with COLCRYS and remain alert for signs and symptoms of toxicities related to increased colchicine exposure as a result of a drug interaction. Signs and symptoms of COLCRYS toxicity should be evaluated promptly and, if toxicity is suspected, COLCRYS should be discontinued immediately. Table 4 provides recommendations as a result of other potentially significant drug interactions. Table 1 provides recommendations for strong and moderate CYP3A4 inhibitors and P-gp inhibitors.

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■ Kidney Week 2012

MARCH 2013

Renal & Urology News 21

Reports from the American Society of Nephrology’s Kidney Week 2012 conference, San Diego

New-Onset Diabetes Linked to Steroid Resumption KIDNEY TRANSPLANT recipients who resume steroid treatment after early withdrawal from steroids following transplant surgery are at

increased risk for new-onset diabetes (NODAT) and morbid obesity, new findings suggest. Christopher A. Carlos, MD, and col-

Table 4 Other Potentially Significant Drug Interactions Concomitant Drug Class or Food

Noted or anticipated Outcome

Clinical Comment

HMG-Co A Reductase Inhibitors: atorvastatin, ﬂuvastatin, lovastatin, pravastatin, simvastatin

Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality)

Weigh the potential beneﬁts and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.

Other Lipid Lowering Drugs: ﬁbrates, gemﬁbrozil Digitalis Glycosides: digoxin

P-gp substrate; rhabdomyolysis has been reported

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies with colchicine in pregnant women. Colchicine crosses the human placenta. While not studied in the treatment of gout flares, data from a limited number of published studies found no evidence of an increased risk of miscarriage, stillbirth, or teratogenic effects among pregnant women using colchicine to treat familial Mediterranean fever (FMF). Although animal reproductive and developmental studies were not conducted with COLCRYS, published animal reproduction and development studies indicate that colchicine causes embryofetal toxicity, teratogenicity, and altered postnatal development at exposures within or above the clinical therapeutic range. COLCRYS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery The effect of colchicine on labor and delivery is unknown. Nursing Mothers Colchicine is excreted into human milk. Limited information suggests that exclusively breast-fed infants receive less than 10 percent of the maternal weight-adjusted dose. While there are no published reports of adverse effects in breast-feeding infants of mothers taking colchicine, colchicine can affect gastrointestinal cell renewal and permeability. Caution should be exercised and breast-feeding infants should be observed for adverse effects when COLCRYS is administered to a nursing woman. Pediatric Use The safety and efficacy of colchicine in children of all ages with FMF has been evaluated in uncontrolled studies. There does not appear to be an adverse effect on growth in children with FMF treated long-term with colchicine. Gout is rare in pediatric patients, safety and effectiveness of colchicine in pediatric patients has not been established. Geriatric Use Clinical studies with colchicine for prophylaxis and treatment of gout flares and for treatment of FMF did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient with gout should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease, or other drug therapy. Renal Impairment Colchicine is significantly excreted in urine in healthy subjects. Clearance of colchicine is decreased in patients with impaired renal function. Total body clearance of colchicine was reduced by 75% in patients with end-stage renal disease undergoing dialysis. Prophylaxis of Gout Flares: For prophylaxis of gout flares in patients with mild (estimated creatinine clearance Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, the starting dose should be 0.3 mg per day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring. Treatment of Gout Flares: For treatment of gout flares in patients with mild (Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of COLCRYS. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every 2 weeks. For patients with gout flares requiring repeated courses consideration should be given to alternate therapy. For patients undergoing dialysis, the

laborators at University Hospitals Case Medical Center in Cleveland analyzed outcomes of 228 kidney transplant recipients who underwent steroid with-

total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (1 tablet). For these patients, the treatment course should not be repeated more than once every 2 weeks. FMF Although, pharmacokinetics of colchicine in patients with mild (Clcr 50 – 80 mL/min) and moderate (Clcr 30 – 50 mL/min) renal impairment is not known, these patients should be monitored closely for adverse effects of colchicine. Dose reduction may be necessary. In patients with severe renal failure (Clcr less than 30 mL/minute) and end-stage renal disease requiring dialysis, COLCRYS may be started at the dose of 0.3 mg/day. Any increase in dose should be done with adequate monitoring of the patient for adverse effects of COLCRYS. Hepatic Impairment The clearance of colchicine may be significantly reduced and plasma half-life prolonged in patients with chronic hepatic impairment, compared to healthy subjects. Prophylaxis of Gout Flares: For prophylaxis of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. Dose reduction should be considered for the prophylaxis of gout flares in patients with severe hepatic impairment. Treatment of Gout Flares: For treatment of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended COLCRYS dose is not required, but patients should be monitored closely for adverse effects of COLCRYS. However, for the treatment of gout flares in patients with severe impairment while the dose does not need to be adjusted, the treatment course should be repeated no more than once every 2 weeks. For these patients, requiring repeated courses for the treatment of gout flares, consideration should be given to alternate therapy. FMF In patients with severe hepatic disease, dose reduction should be considered with careful monitoring. OVERDOSAGE The exact dose of colchicine that produces significant toxicity is unknown. Fatalities have occurred after ingestion of a dose as low as 7 mg over a 4-day period, while other patients have survived after ingesting more than 60 mg. A review of 150 patients who overdosed on colchicine found that those who ingested less than 0.5 mg/kg survived and tended to have milder toxicities, such as gastrointestinal symptoms, whereas those who took 0.5 to 0.8 mg/kg had more severe reactions, such as myelosuppression. There was 100% mortality in those who ingested more than 0.8 mg/kg. The first stage of acute colchicine toxicity typically begins within 24 hours of ingestion and includes gastrointestinal symptoms, such as abdominal pain, nausea, vomiting, diarrhea, and significant fluid loss, leading to volume depletion. Peripheral leukocytosis may also be seen. Life-threatening complications occur during the second stage, which occurs 24 to 72 hours after drug administration, attributed to multi-organ failure and its consequences. Death is usually a result of respiratory depression and cardiovascular collapse. If the patient survives, recovery of multi-organ injury may be accompanied by rebound leukocytosis and alopecia starting about 1 week after the initial ingestion. Treatment of colchicine poisoning should begin with gastric lavage and measures to prevent shock. Otherwise, treatment is symptomatic and supportive. No specific antidote is known. Colchicine is not effectively removed by dialysis. COLCRYS is a trademark of Takeda Pharmaceuticals U.S.A., Inc., registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. All trademarks are the property of their respective owners. Distributed by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 42901-Brf. Rev 01, June 2012 For more detailed information, see the complete prescribing information for COLCRYS (colchicine, USP) tablets at Colcrys.com or contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327. L-ECH-0612-1

drawal at four days post-transplantation. Within a year of transplantation, 49 patients (21%) resumed steroid therapy. Doctors subsequently diagnosed NODAT in 29% of the steroidresumption group versus 15% of the steroid-free group, a significant difference between the groups. Dr. Carlos’ team defined NODAT as outpatient glucose levels of 126 mg/dL or higher, a random glucose measurement of 200 mg/dL or higher, or a hemoglobin A1c level of 6.5% or greater. At the time of transplantation, the rates of morbid obesity—defined as a body mass index (BMI) of 35 kg/m2 or higher—were similar for the two groups. By 24 months post-transplantation, however, the rates were significant greater for the steroid-resumption group (28% vs.15%). ■

Bolus Iron Hikes Serious Infection Risk BOLUS DOSING of intravenous (IV) iron is associated with an elevated risk of infection-related hospitalization among anemic hemodialysis (HD) patients compared with maintenance dosing, according to new findings. The investigators, led by M. Alan Brookhart, PhD, of the University of North Carolina in Chapel Hill, studied 117,050 HD patients, of whom 9,033 (16.3%) received a bolus administration, 55,457 (47.4%) received maintenance therapy, and 42,560 (36.4%) received no iron during a one-month exposure assessment period. During a three-month follow-up, patients receiving bolus iron (a large amount of iron over a short period of time) had an increased risk of infection-related hospitalization (4.3 additional hospitalizations per 100 patient-years) compared with patients receiving maintenance iron therapy (small administrations of iron designed to maintain iron repletion). ■

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

Short Takes Augmenting Antibiotics for Prostate Biopsy Found to Be Beneficial Researchers at the University of Texas Southwestern Medical Center in Dallas analyzed the effect of implementing an augmented antibiotic prophylaxis regimen in decreasing the rate of post-biopsy infections. The standard prophylactic regimen was used until December of 2010. Fluoroquinoloneresistant organisms were found in 73% or these patients, Mehrad Adibi, MD, and colleagues reported in The Journal of Urology (2013;189:535-540). Beginning January 2011, each patient received the standard regimen plus an additional intramuscular injection of gentamicin prior to the biopsy. The postbiopsy infection rate was reduced from 3.8% to 0.6%. Considering the potential devastating clinical consequences and the tremendous cost of admission of life-threatening sepsis, the use of gentamicin for PNBx appears not only indicated, but cost-effective (saving $15,000 per 100 patients).

Nocturia May Portend Heart Problems The prevalence and severity of nocturia, or awakening at least once at night to urinate, tends to increase with age. Naturally, with increased awakening events

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

of California, Irvine, Department of Urology

Saw Palmetto Extract Has No Effect on PSA, Study Finds D

espite years of controversy regarding efficacy, saw palmetto remains the most common herbal treatment for men with lower urinary tract symptoms. Extracted from the fruit of the saw palmetto dwarf tree, the extract exerts effects by diminishing 5-alpha-reductase activity and binding to androgen receptors in prostatic cells. Saw palmetto reduces prostatic dihydrotestosterone by 32%. As a result of this anti-androgen effect, concerns have been raised as to whether serum PSA values should be adjusted accordingly. In a new study published in the Journal of Urology (2013;189:486-492), researchers evaluated serum PSA values in 369 patients randomized to receive saw palmetto or placebo. These men were part of the CAMUS (Complementary and Alternative Medicine for Urological Symptoms) trial, a double-blinded, randomized controlled study designed to determine whether saw palmetto extract reduced the American Urological Association symptom score compared with placebo at 72 weeks. Even with triple the recommended dose of saw palmetto, serum PSA remained unaffected compared with placebo.

come poorer sleep, a perceived poorer quality of life, and increased mortality. The deleterious effects of nocturia are likely due to an association with other comorbid systemic diseases like cardiac disease, depression, and renal disease. A recent study from the Mayo clinic found that moderate nocturia (two episodes or more per night) in men younger than 60 years portended to a higher likelihood of developing heart disease later in life, according to a report in BJU International (2012;110:848-853). The association was thought to be the result of disordered cardiovascular system hemostasis. Of note, the association of nocturia and heart disease was attenuated when adjusting for body mass index (BMI). Elevated BMI is a significant risk factor for eventual development of heart disease, making nocturia a potentially important marker.

Cycling-Related Erectile Dysfunction Can Be Prevented Among bicyclists, long-term pressure on the perineum from a narrow saddle seat can cause damage to the nerves and arteries to the penis and result in erectile dysfunction (ED). The first sign is numbness or tingling (not the good kind), but

Two Reports Summarize Smoking Cessation Benefits T

wo articles in a recent issue of The New England Journal of Medicine (2013;368:341-350; 351-364) summarize the long-term effects of smoking and smoking cessation on lung cancer, chronic obstructive pulmonary disease (COPD), and mortality. Here are the facts to encourage smoking patients to quit: • For men aged 55-74 years, the death rate from all causes combined is three times as high among current smokers as among those who have never smoked. • The rate of death from COPD continues to increase among male smokers in contrast to a significant decrease in risk among men who never smoked. This may be due to design changes in cigarettes that promote deeper inhalation of smoke, such as more porous wrapping paper and perforated filters. • Quitting smoking at any age, but especially before 40, dramatically lowers mortality from all major smoking-related diseases. • On average, male smokers lose 11 years of life compared to never smokers.

even in young men, this can progress to difficulty achieving an erection. Cyclists on the saddle more than three hours a week are at greatest risk. Studies have

the “sits bones” of the buttocks. • make sure the bicycle is the right size and that the handlebar and seat positioning are correct. Angling the seat slightly forward will help relieve perineal pressure. • change position occasionally. Standing on the pedals during long rides will allow flow back to the perineum. • check the seat itself. A “no-nose” seat may help with proper positioning and avoid pressure to the perineum.

46.4 PERCENT

The proportion of male adult users of dietary supplements who say they use them to improve overall health. Source: Bailey RL et al. Why US adults use dietary supplements. JAMA Intern Med; published online ahead of print.

• work on positioning. Body weight should be distributed to the ischial tuberosity,

MEDISTAT

shown that cyclists can decrease their ED risk by taking some simple measures:

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Renal Nutrition Update M

any articles have reported on the associations between gout and chronic kidney disease (CKD) using data gathered from different portions of the National Health and Nutrition Examination Survey (NHANES). Most recently, a group of investigators recently focused on the associations between CKD and gout using the NHANES data from 19881994 and 2007-2010 (Semin Arthritis Rheum 2013; published online ahead of print). The former cohort included a total of 15,132 subjects, while the latter was composed of 10,814 subjects. Estimated glomerular filtration rate (eGFR) was negatively associated with age, albuminuria, serum uric acid, and prevalence of diabetes mellitus, hypertension, and hyperuricemia. Diuretic and gout medication use increased with lower eGFR. The prevalence of gout in the former cohort was 2.7% while the latter was 3.7%. The relationship between eGFR and albuminuria with gout and hyperuricemia were continuous. Individuals in the lowest eGFR category had a threefold increased prevalence of gout, and every 10 mL/ min/1.73m2 increase in eGFR corre-

the SLC2A9 gene associated with the GLUT9 transporter, which not only transports urate but also glucose and fructose. Although research is still required to assess whether the relationship between hyperuricemia and gout with CKD is simply correlative or causative, dietitians working with CKD patients may often find themselves offering dietary guidance related to gout management. A range of dietary factors can promote gout. Exogenous purine intake can induce gout flares due to the metabolism of purines to uric acid (Adv Chronic Kidney Dis 2012;19:392-397). Most high-protein foods have increased levels of purines that may contribute to a gout flare. A diet extremely high in protein and fat with very little carbohydrate intake may induce ketogenesis, which is known to be an inhibitor of uric acid excretion. Another inhibitor of uric acid excretion is elevated lactate levels, which can be induced by alcohol ingestion. Refined sugar also exacerbates the issue through the increase in dietary fructose. Fructose metabolism promotes the conversion of adenine molecules found in ATP to uric acid.

Foods that may increase gout flare risk are also dietary factors that may promote further kidney decline in individuals with CKD stages 3-5. lated with a 10% reduced prevalence of gout.

Gout and kidney health Gout is linked to kidney health because urate clearance occurs through the GLUT9 transporter in the proximal renal tubule (Curr Opin Rheumatol 2012;24:127-131). Increased gout risk can occur from genetic mutations in

On The Web

Many recommendations for gout management focus primarily on the reduction of purine intake. Both animal proteins and plant proteins from beans have moderate levels of purine content; typically the highest purine content foods are derived from organ meats. Following the typical recommended dietary allowance for protein intake of 0.8 g/kg body weight will most

Assess uric acid levels in CKD patients when deciding which dietary restrictions to prioritize BY GRISSIM CLARK CONNERY, MS, RD, LD

High-protein foods have increased levels of purines that may contibute to a gout flare.

likely not provide excessive exogenous purine sources as to aggravate a gout flare. Regarding alcohol intake, beer is the most problematic for hyperuricemia because not only does the alcohol stimulate increased lactate levels, but unlike wine and spirits, beer has a significant guanosine content due to the yeast. Wine intake would be the safest form of alcohol since it does not match the purine content of beer nor the alcohol content of liquors.

The role of fructose Because most individuals consuming Western diets do not often exhibit extreme intakes of protein or alcohol that would significantly increase risk of hyperuricemia or gout, fructose intake may become a more important focus of intervention, assuming strong genetic factors have been assessed. Research has found associations between sugar-sweetened beverage intake and increased uric acid levels as well as increased uric acid levels and increased blood pressure, but the direct association

of sugar sweetened beverages to blood pressure needs more evidence at this time (J Hum Hypertens 2012; published online ahead of print). Analyzing this information in the context of CKD, a few conclusions may be deduced. Hyperuricemia has to be proven to be a causative factor in kidney decline, but the presence of hyperuricemia and gout is a risk factor for decline. The foods that may increase risks of gout flares—namely very-high-protein diets, excessive alcohol primarily from beer, and excessive fructose intake—are also dietary factors that may promote further kidney decline in individuals with CKD stages 3-5. Excessive fructose intake may aggravate blood sugar control in diabetic individuals that may further promote kidney decline. Thus, when working with CKD patients, uric acid levels should be assessed when deciding which dietary restrictions to prioritize. ■ Mr. Connery is Research Coordinator at Case Western Reserve University in Cleveland.

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

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Non-Aspirin NSAIDs May Raise Kidney Cancer Risk NON-ASPIRIN non-steroidal antiinflammatory drugs (NSAIDs) and acetaminophen are associated with a significantly increased risk of developing kidney cancer, according to a new meta-analysis. Researchers led by Eunyoung Cho, ScD, of Brigham and Womenâ&#x20AC;&#x2122;s Hospital and

Harvard Medical School in Boston, analyzed data from 20 studies that included 8,420 cases of kidney cancer. The studies included 14 with acetaminophen, 13 with aspirin, and five with other NSAIDs. In pooled analyses, use of non-aspirin NSAIDs and acetaminophen was associated with a 25% and 28% increased risk

of kidney cancer, respectively, compared with non-use, the investigators reported online ahead of print in the International Journal of Cancer. No overall increased risk with aspirin use was found. Previously, in a prospective study of 77,525 women participants in the Nursesâ&#x20AC;&#x2122; Health Study and the 49,403 men in the

Health Professionals Follow-up Study, Dr. Cho and colleagues reported finding that regular use of non-aspirin NSAIDs was associated with a 51% increased relative risk of renal cell carcinoma in a pooled analysis compared with non-regular use, according to a report in Annals of Internal Medicine (2011;171:1487-1493). â&#x2013;

(continued) Table 1. Adverse Reactions in the Randomized Trial XTANDI N = 800 Grade 1-4 Grade 3-4 (%) (%)

XTANDIÂŽ (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary: please see the package insert for full prescribing information. ------------------------------ INDICATIONS AND USAGE ----------------------------XTANDI is indicated for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel. --------------------------------- CONTRAINDICATIONS ------------------------------Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss >VHH 8VH LQ 6SHFLÂżF 3RSXODWLRQV@. -------------------------- WARNINGS AND PRECAUTIONS ------------------------Seizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures. The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. --------------------------------- ADVERSE REACTIONS ------------------------------Clinical Trial 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 WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4. 7KH PRVW FRPPRQ DGYHUVH GUXJ UHDFWLRQV Â&#x2022; UHSRUWHG LQ SDWLHQWV UHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO HGHPD PXVFXORVNHOHWDO SDLQ KHDGDFKH upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse UHDFWLRQV ZHUH UHSRUWHG DPRQJ RI ;7$1', WUHDWHG SDWLHQWV DQG RI placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the UDQGRPL]HG FOLQLFDO WULDO WKDW RFFXUUHG DW D Â&#x2022; DEVROXWH LQFUHDVH LQ IUHTXHQF\ LQ the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in the Randomized Trial XTANDI Placebo N = 800 N = 399 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 (%) (%) (%) (%) General Disorders Asthenic Conditionsa 9.0 44.4 9.3 Peripheral Edema 1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 24.3 4.0 Arthralgia 17.3 1.8 Musculoskeletal Pain 1.3 0.3 Muscular Weakness 9.8 6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

Placebo N = 399 Grade 1-4 Grade 3-4 (%) (%)

Gastrointestinal Disorders Diarrhea 21.8 1.1 0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9 0.0 Dizzinessb Spinal Cord 7.4 6.6 3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0 0.0 4.3 0.3 1.8 0.0 Mental Impairment Disordersc Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations 10.9 0.0 0.3 Upper Respiratory Tract Infectiond Lower Respiratory 2.4 4.8 1.3 Tract And Lung e Infection Psychiatric Disorders Insomnia 8.8 0.0 6.0 Anxiety 0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8 1.0 Pollakiuria 4.8 0.0 0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin 0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a Includes asthenia and fatigue. b Includes dizziness and vertigo. c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. Laboratory Abnormalities ,Q WKH UDQGRPL]HG FOLQLFDO WULDO *UDGH QHXWURSHQLD RFFXUUHG LQ RI patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both DUPV RI SDWLHQWV RQ ;7$1', DQG RQ SODFHER H[SHULHQFHG *UDGH thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on ;7$1', *UDGH DQG RI SDWLHQWV RQ SODFHER *UDGH Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo. Infections In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms. Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. Hallucinations In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioidcontaining medications at the time of the event. Hallucinations were visual, WDFWLOH RU XQGHÂżQHG

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Renal & Urology News 27

Risk Factors for ICU-Managed AKI Identified RISK FACTORS for acute kidney injury (AKI) among patients in the intensive care unit (ICU) include hypovolemia, use of diuretics, and the presence of chronic kidney disease (CKD) prior to ICU admission, according to a prospective, population-based Finnish study. The study by Sara Nisula, MD, of

Helsinki University, and colleagues included 2,901 patients in 17 ICUs. Of these, 39.3% experienced AKI, which the researchers defined first using the Acute Kidney Injury Network (AKIN) criteria supplemented with a baseline creatinine and second with the Kidney Disease: Improving Global Outcomes

----------------------------------DRUG INTERACTIONS ------------------------------Drugs that Inhibit or Induce CYP2C8 &R DGPLQLVWUDWLRQ RI D VWURQJ &<3 & LQKLELWRU JHPÂżEUR]LO LQFUHDVHG the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI >VHH 'RVDJH DQG $GPLQLVWUDWLRQ DQG &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended >VHH &OLQLFDO 3KDUPDFRORJ\@ Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers >VHH &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., ERVHQWDQ HIDYLUHQ] HWUDYLULQH PRGDÂżQLO QDIFLOOLQ DQG 6W -RKQÂśV :RUW PD\ DOVR reduce the plasma exposure of XTANDI and should be avoided if possible >VHH &OLQLFDO 3KDUPDFRORJ\ @. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring >VHH &OLQLFDO 3KDUPDFRORJ\ @. -------------------------- USE IN SPECIFIC POPULATIONS -----------------------Pregnancy- Pregnancy Category X >VHH &RQWUDLQGLFDWLRQV@ XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent ZHUH DQG RYHU ZKLOH SHUFHQW ZHUH DQG RYHU 1R RYHUDOO GLIIHUHQFHV in safety or effectiveness were observed between these patients and younger SDWLHQWV 2WKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂżHG GLIIHUHQFHV LQ responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy YROXQWHHUV QR VLJQLÂżFDQW GLIIHUHQFH LQ HQ]DOXWDPLGH FOHDUDQFH ZDV REVHUYHG LQ SDWLHQWV ZLWK SUH H[LVWLQJ PLOG WR PRGHUDWH UHQDO LPSDLUPHQW P/ PLQ Â&#x201D; FUHDWLQLQH FOHDUDQFH >&U&/@ Â&#x201D; P/ PLQ FRPSDUHG WR SDWLHQWV DQG YROXQWHHUV ZLWK EDVHOLQH QRUPDO UHQDO IXQFWLRQ &U&/ Â&#x2022; P/ PLQ 1R LQLWLDO GRVDJH adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@. Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@

(KDIGO) criteria. The populationbased incidence of ICU-treated AKI was 746 per million population per year, which is comparable to previous large multicenter ICU studies, Dr. Nisulaâ&#x20AC;&#x2122;s team reported online ahead of print in Intensive Care Medicine. Hospital mortality for AKI patients was 25.6%,

-------------------------------------- OVERDOSAGE -------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general VXSSRUWLYH PHDVXUHV WDNLQJ LQWR FRQVLGHUDWLRQ WKH KDOI OLIH RI GD\V ,Q D GRVH escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the LQ YLWUR mouse lymphoma thymidine kinase (Tk) gene mutation assay or the LQ YLYR mouse micronucleus assay. %DVHG RQ QRQFOLQLFDO ÂżQGLQJV LQ UHSHDW GRVH WR[LFRORJ\ VWXGLHV ZKLFK ZHUH consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy RI WKH SURVWDWH DQG VHPLQDO YHVLFOHV ZDV REVHUYHG DW Â&#x2022; PJ NJ GD\ HTXDO to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed DW Â&#x2022; PJ NJ GD\ WLPHV WKH KXPDQ H[SRVXUH EDVHG RQ $8& PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). Â&#x2021; ,QVWUXFW SDWLHQWV WR WDNH WKHLU GRVH DW WKH VDPH WLPH HDFK GD\ RQFH GDLO\ XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. Â&#x2021; ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV treatment during the course of treatment with XTANDI. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', KDV EHHQ DVVRFLDWHG ZLWK DQ LQFUHDVHG risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW paresthesia, hypoesthesia, and falls. Â&#x2021; ,QIRUP SDWLHQWV WKDW WKH\ VKRXOG QRW LQWHUUXSW PRGLI\ WKH GRVH RU VWRS ;7$1', ZLWKRXW ÂżUVW FRQVXOWLQJ WKHLU SK\VLFLDQ ,QIRUP SDWLHQWV WKDW if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day. Â&#x2021; $SSULVH SDWLHQWV RI WKH FRPPRQ VLGH HIIHFWV DVVRFLDWHG ZLWK ;7$1', DVWKHQLD IDWLJXH EDFN SDLQ GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ EH KDUPIXO WR D GHYHORSLQJ IHWXV Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

which is comparable to or lower than in other studies, they observed. The 90-day mortality for AKI patients was 33.7%. After adjusting for multiple variables, pre-ICU hypovolemia and CKD were independently associated with a 2.2 times and 2.6 times increased risk for AKI, according to the investigators. Pre-ICU use of diuretics and colloids were independently associated with a 68% and 35% increased risk. The investigators noted that their study is the first to evaluate the population-based incidence of ICU-treated AKI using a prospective, multicenter, nationwide study design, and with AKI defined by RIFLE, AKIN, or KDIGO criteria. In addition, no studies of 90-day mortality among ICU-treated AKI patients classified according to RIFLE or AKIN criteria exist. â&#x2013;

Priapism Risk Minimal with AndroGel 1% TESTOSTERONE replacement with 1% testosterone gel (AndroGel 1%) is rarely associated with the development of priapism, according to a study. Arthur L. Burnett, MD, of Johns Hopkins University in Baltimore, and colleagues reviewed the safety and tolerability data for AndroGel 1%, including data from three randomized controlled trials in varying populations of hypogonadal or near hypogonadal men. Of 283 men exposed to AndroGel 1% over the three trials, none reported experiencing adverse events described as priapism or related symptoms, researchers reported

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 0HGLYDWLRQ ,QF 6DQ )UDQFLVFR &$ Issued: August 2012 $ (1= %56 Rx Only ÂŠ 2012 Astellas Pharma US, Inc. XTANDIÂŽ is a registered trademark of Astellas Pharma Inc.

online ahead of print in the Journal of Sexual Medicine. The mean exposure to AndroGel 1% ranged from 84 to 149 days. The investigators also reviewed postmarketing data representing 40 million units sold and found only eight reports of cases described as priapism.

ONCOLOGY

The researchers concluded from their findings that AndroGel 1% use is associated with a minimal risk of inducing priapism. â&#x2013;

28 Renal & Urology News

MARCH 2013

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MMF Response Not Linked to Genotype Drug’s effect on lupus nephritis unrelated to certain genetic variations, preliminary data show BY JOHN SCHIESZER WASHINGTON, D.C.—The genotypes of patients with lupus nephritis (LN) may not predict response to mycophenolate mofetil (MMF), according to a new study presented at the American College of Rheumatology annual meeting. “Mycophenolate mofetil is one of the first-line treatments of lupus nephritis,” said Noa Schwartz, MD, who was part of the New York University team that conducted the study under lead investigator Robert Clancy, MD. “However, not all patients respond similarly to this treatment, and as of yet, there are no known reliable response-prediction factors. Genetics is thought to play a major role in patients’ propensity to respond to MMF, and several singlenucleotide polymorphisms (SNPs) in the drug’s target enzyme, inosine monophosphate dehydrogenase (IMPDH), have been implicated in the renal transplant literature as affecting response to MMF therapy.” Dr. Schwartz, who is now an intern in internal medicine at Montefiore Medical Center in New York, presented the study data. She said the Aspreva Lupus Management Study (ALMS) has previously shown that MMF is

effective for both induction and maintenance in LN patients. These patients, however, demonstrate a wide range of responses to MMF. The team studied two SNPs with reported opposite effects: rs2278294 makes the disease more susceptible to MMF (patients with this variation respond better to MMF), while rs11706052 diminishes the effects of MMF. Individuals carrying variant forms of IMPDH are also thought to have an attenuated ability to produce pathogenic nitric oxide (NO). The study included 66 patients from the ALMS patients who had been randomized to MMF in induction and/ or maintenance. The researchers obtained DNA and blood samples to evaluate genetic variation and serum NO levels. The allele calling rate of 66 DNA samples was 98% for rs2278294 and 100% for rs11706052. Assignments were verified by PCR amplification and direct sequencing, and both rs11706052 (IMPDH2) and rs2278294 (IMPDH1) were tested by the researchers for departure from Hardy-Weinberg equilibrium (HWE) expectations. Representation of the two candidate SNPs had no HWE deviation and the

Noa Schwartz, MD

relatively frequent minor alleles were comparable to those in the dbSNP database and in agreement with allelic discrimination and direct sequencing. The researchers divided the patients into two groups. Group 1 included responders to MMF at induction and non-treatment failures at maintenance. Group 2 included non-responders at induction and treatment failures at maintenance. For the IMPDH2 variant rs11706052, the distribution of variant alleles was similar for subjects in both groups

(7.8% for Group 1 vs. 7.1% MAF for Group 2). In addition, the results were similar when the analysis was restricted to Hispanics, which was the largest ethnic group. For the IMPDH1 variant rs2278294, the investigators found no association between groups (45.0% for Group 1 vs. 46.4% MAF for Group 2). The researchers observed no association between genotypes at rs2278294 and NO levels (14.5% vs. 20.4%). “The ALMS database provided an opportunity for us to investigate whether these previously identified SNP’s also confer a particular MMF response profile in lupus nephritis, as such a finding could have major implications on disease management decisions. Our results are preliminary, but do not demonstrate an association between lupus nephritis response to MMF and genetic variation in these previously identified SNPs,” Dr. Schwartz told Renal & Urology News. “Currently, more and more efforts are placed on identifying specific genetic profiles, and attributing much of interpatient variation in disease and therapy to the genome. Within this context, our study makes an important point in that it demonstrates that perhaps other variables should be taken into account, beyond the patients’ genetic makeup.” ■

CAD Raises Death Risk in Renal Failure Patients BY ROSEMARY FREI, MSc TORONTO—Coronary artery disease (CAD) is associated with a significantly increased risk of death among people with chronic renal failure. Moreover, the prognosis is not completely benign when renal failure patients have nonobstructive CAD, a large international study has shown. Investigators performed coronary computed tomography angiography (CCTA) on 5,572 patients and found those with either non-obstructive or obstructive CAD had a significantly shorter average survival than patients without CAD. Every 10-unit decrease in estimated glomerular filtration rate (eGFR) was associated with a 23% increased risk of death. The researchers, who presented the results in poster form at the 2012 Canadian Cardiovascular Congress, are urging nephrologists to consult with a cardiologist or radiologist regarding patients at risk for atherosclerosis.

“The take-home message from this [study] is that cardiac CT can be used to detect CAD and cardiac risk stratification in chronic renal failure patients,” said the study’s first author, Girish Dwivedi, MD, PhD, a cardiac-imaging fellow at the Ottawa Heart Institute.

Death risk increased by 23% with each 10-unit decrease in eGFR, data show. “Cardiac CT can be safely performed in patients with moderate renal failure and also in severe renal failure if the latter are on hemodialysis.” Dr. Dwivedi advised that only the lowest possible contrast dose should be used for the imaging study in such patients. Patients should be kept well-hydrated

and that nephrotoxic drugs such as metformin should be stopped before the CCTA and should be re-introduced usually 48 hours after the test when the renal function returns to the pretest level. This is one of the many analyses of data from the CONFIRM (COroNary Computed Tomography Angiography Evaluation for Clinical Outcomes: An InteRnational Multicenter Registry) study, which was led by Benjamin Chow, MD, of the University of Ottawa Heart Institute. Researchers from six countries, including the United States, Canada and Europe, screened 27,125 consecutive patients undergoing CCTA from February 2003 and December 2009. The present study included only those patients who had serum creatinine, and left ventricular ejection fraction (LVEF) assessments, as well as those for whom follow-up data were available.

The researchers excluded those with a history of coronary revascularization, congenital heart disease, or cardiac transplantation. Dr. Dwivedi’s group confirmed that cardiac CT provides incremental information over and above the other well established clinical variables for mortality prediction in such patients. After controlling for confounding factors, impaired renal function was associated with a 2.3-fold increased mortality risk. CAD severity and LVEF less than 50% were also highly significantly associated with mortality. Although the use of only clinical variables with eGFR and CAD severity was associated with a much more accurate prediction of survival than clinical variables alone, overall the most accurate prediction of mortality was obtained by the combination of clinical variables, eGFR, CAD severity, and abnormal LVEF data. ■

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Renal & Urology News 29

Practice Management Therapeutic nonadherence is a clinical challenge, but there are strategies you can use to get patients to take their medicines BY TAMMY WORTH

Why patients do not comply Burkholder’s group has been studying nonadherence for its campaign Script Your Future. They are working to educate consumers, their families and providers about the importance of taking prescribed medication. She said there is no single specific reason people fail to follow their doctor’s orders, but a handful of reasons rose to the top of the list. First, patients are often unconvinced that they need the medication. Second, they don’t think it will work, particularly if they do not actually see or feel the results. Others fear adverse effects

On The Web

or experience effects that are unpleasant. Some cannot afford medication, and others simply forget to take it as prescribed. “There is nothing more important than that five-minute conversation a physician has with a patient to make sure they understand their treatment,” Burkholder said. “Patients know it is important to talk to their physician about it, but it is not always happening.”

Knowledge is power Leslie Martin, a health psychologist and professor in the department of psychology at La Sierra University in Riverside Calif., said patients have to understand their treatment to follow it. “It is clear that healthcare providers will say things or use jargon that they fully think the patients get but they don’t,” she said. “And patients aren’t on average good at ferreting out information that they don’t have.” What do you need to know as a provider? First, aim low. Do not assume your patient has any knowledge. If you start at a high level, they likely won’t request that you dumb things down. If you get a sense their knowledge is greater, you can always adjust your communication. Second, patients will often nod their heads like they understand directions, even when they do not, she said. To avoid this, ask questions that do not allow them to parrot back your instructions. Try, “What will this look like for you tomorrow?” or “How will you manage doing XYZ?” Burkholder provides a note card of questions that patients should ask in order to fully understand their medication. Beat patients to the punch by asking the following:

ot taking medication or following a treatment regimen may not seem like a big deal to your patients. But nonadherence not only costs the health system dearly, it could be the difference between life and death. For about half of the 3.2 billion prescriptions written each year in the United States, the drugs are not taken as prescribed, according to a report prepared by researchers at Duke University in Durham, N.C., and the National Consumers League (NCL). The total cost for nonadherence is estimated to be up to $300 billion and account for approximately 125,000 deaths each year. “We view this as a public health problem,” said Rebecca Burkholder, vice president of health policy for the NCL. “It really takes a whole health care team working with the patient to solve this.” Various strategies are available to help solve the problem: listening to patients, providing comprehensive information, and helping remove barriers to their treatment.

Patients have to want to take their medication or see a treatment regimen through.

• What is the medicine called and what does it do? • How and when should you take it, and for how long? • What if you miss a dose? • What should you do if you have a side effect? Physicians should educate patients about whether it is safe to take a certain drug with other medicines or vitamins and mention and whether they can stop taking the drug if they feel better.

What makes them tick Patients have to want to take medication or see a treatment regimen through. There are ways you can encourage this. The challenge is that people are motivated by different things. As a physician, you have to find out what moves your patients. “Take some time, ask questions and allow patients to answer them,” she said. “Patients often get interrupted

really early in the dialogue … make sure you let them finish; it indicates you want to listen and you will get better information.” If you have electronic medical records, Martin recommends keeping good notes about what you know about your patient. And make it a point for the whole staff to do so when they have patient contact. “Keep track of what motivates patients and keep effective notes on what their personal priorities are, what their struggles are and what can be reiterated and talked about that can be useful,” she said. A strong motivator for patients (and for most of us in general) is consequences. Burkholder adds that it is important to make sure patients understand not only their condition, but what the consequences are if they don’t take their medication—especially for people with chronic diseases. ■

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.

MARCH 2013

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Malpractice News

U.S. surgeons leave a foreign object behind an estimated 39 times in a week.

Surgical ‘Never Events’ Occur At Least 4,000 Times Annually Surgical “never events”—or occurrences that should never happen, such as operations on the wrong part of the body, or foreign objects left in the body after surgery—are happening at least 4,000 times per year, according to a new study. The study, conducted by Martin Makary, MD, MPH, and colleagues at Johns Hopkins University in Baltimore, revealed some startling results. The investigators estimate that surgeons in the United States leave a foreign object (for example, a sponge or towel) inside a patient’s body after an operation 39 times a week. In addition, the study found that surgeons perform the wrong procedure on a patient 20 times a week, and operate on the wrong part of the body 20 times a week. For the study, researchers looked at records in the National Practitioner Data Bank (NPDB), a national repository of medical malpractice claims. The researchers examined judgments and settlements related to foreign objects left in patients after surgery, wrong site, wrong patient, and wrong procedure surgeries. By law, hospitals are required to report to the NPDB all never events that lead to a settlement or judgment, but researchers believe

On The Web

that the number may appear lower than they really are because not all items left behind in surgery are discovered. The researchers looked at data from 1990 to 2010, and estimate that a total of 80,000 never events took place, but again, suggest that these estimates may be on the low side. The researchers identified 9,744 malpractice judgments and paid claims over this 20-year period relating to such events, with payments totaling $1.3 billion. Mortality resulting from these never events occurred in 6.6% of patients, permanent injury occurred in 39.2%, and temporary injury in 59.2 percent of patients. While Dr. Makary’s team noted that patient safety procedures are in place in many medical centers—such as counting sponges and towels before and after surgery, marking the surgery site with indelible ink before the procedure, and making sure that surgery plans and medical records match the patient— these efforts are not foolproof. Some hospitals are moving towards electronic bar codes on materials and instruments to prevent error. “There are mistakes in healthcare that are not preventable,” Dr. Makary, Associate Professor of Surgery, said in a news release. “Infection rates will likely never get down to zero even if everyone does everything right, for example. But the events we’ve estimated are totally preventable. This study highlights that we are nowhere near where we should be and there’s a lot of work to be done.”

BY ANN W. LATNER, JD

several unnecessary endoscopic procedures that destabilized his injured back and significantly damaged his earnings potential as a professional wrestler. The lawsuit alleges a loss of past and future earnings in excess of $50 million. According to the lawsuit, traditional spinal surgery had been recommended to Hogan by several prominent spine surgeons to enable him to continue his athletic career. Hogan alleges that he was repeatedly told by the institute’s physicians that the traditional spinal surgery he was scheduled for would in fact end his career, and that their “minimally invasive” alternatives to traditional surgery would enable him to continue. Hogan maintains that he underwent six procedures in 19 months, and only experienced short-term relief for two to three weeks following each procedure. He alleges that the temporary relief was caused by the surgery center’s physicians using a laser to burn nerves, which eventually regenerated, causing pain again. According to the lawsuit, Hogan first became aware that he may have been a victim of medically unnecessary surgery after reading a Bloomberg News article detailing complaints about the surgery center, including that the treatments are expensive and ineffective. Following his failed procedures at the surgery center, Hogan had traditional spine Hulk Hogan alleges unnecessary spinal surgery was performed.

Wrestler Hulk Hogan Files Medical Malpractice Suit Wrestling star Terry G. Bollea, better known by his stage name Hulk Hogan, has filed a medical malpractice action seeking damages against a Floridabased spine institute, a high-volume surgery center, and several of its owner physicians. Hogan alleges that between February 2009 and August 2010, he underwent

30 Renal & Urology News

fusion surgery, and was able to return to his professional career three months after the surgery.

Study Underscores Long Waits To Resolve Malpractice Claims A new study has shed light on the exceedingly long period it takes to resolve medical malpractice cases. The study, published in Health Affairs, analyzed data from more than 40,000 physicians and found that, on average, a physician will spend over 50 months (or over 10% of an assumed 40-year career) with an open, unresolved malpractice claim. The study also found that the bulk of that time was spent on claims that were later dropped or dismissed, and never resulted in payment. Physicians in high-risk fields, such as neurosurgeons, spent even longer waiting for malpractice cases to be resolved: an average of 10 years. Psychiatrists spent the least amount of time fighting malpractice claims: an average of just 16 months. The investigators suggested that efforts to improve the medical malpractice system need to focus on not just capping damage awards, but reducing the time needed to resolve malpractice claims. Even lawsuits that are dismissed prior to trial can take about two years, the authors noted, and cases that settle out of court typically take between two and three years. Cases that actually go to a jury trial can take five years to be resolved. The researchers agreed that a well functioning medical malpractice system should compensate patients who have suffered harm both fairly and quickly, and that a five-year wait is too long for both parties. They recommended shifting to an alternative dispute resolution process, which proactively looks for errors, discloses them to patients, and uses a central review committee to resolve disputes and recommend compensation when there is fault. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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

CURVED ERECTION DIFFICULT for your patients to talk about

FOR PATIENTS WITH PEYRONIE’S DISEASE, THE IMPACT GOES BEYOND THE PHYSICAL AND MAY INCLUDE SEXUAL, PSYCHOLOGICAL, AND SOCIAL EFFECTS1 Yet patients with curvature deformity find it hard to talk about it with their physicians and may be reluctant to seek help.1-3 As a physician, you play a key role. Learn how to have more productive conversations at WWW.ASKABOUTTHECURVE.COM or call 1-855-LETS-ASK to order program materials. © 2013 Auxilium Pharmaceuticals, Inc. All rights reserved.

DAPD-00069

References: 1. Bella AJ, Perelman MA, Brant WO, Lue TF. Peyronie’s disease (CME). J Sex Med. 2007;4(6):1527-1538. 2. Moreira ED, Brock G, Glasser DB, et al; GSSAB Investigators’ Group. Help-seeking behaviour for sexual problems: the Global Study of Sexual Attitudes and Behaviors. Int J Clin Pract. 2005;59(1):6-16. 3. Levine LA, ed. Understanding Peyronies Disease: A Treatment Guide for Curvature of the Penis. Omaha, NE: Addicus Books; 2007.

AUXXIA13SIRADSZE AskJournalAd Renal_Urology News_2.indd 1

2/11/13 10:39 AM

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CME FEATURE

Thyroid Functional Disease in Dialysis Patients Emerging data suggest that thyroid hormone deficiency may be associated with greater cardiovascular morbidity and mortality in this population.

Release Date: March 2013 Expiration Date: March 2014 Estimated time to complete the educational activity: 1 hour

BY CONNIE M. RHEE, MD, MSc

This activity is jointly sponsored by Medical Education Resources and Haymarket Medical Education. STATEMENT OF NEED: There is a disproportionately higher prevalence of hypothyroidism as well as thyroid hormone metabolic derangements in dialysis patients, and emerging data suggest that thyroid hormone deficiency may be associated with greater cardiovascular morbidity and mortality in this population. Further study is needed to determine the mechanistic links between hypothyroidism and kidney disease, as well as the optimal methods of thyroid functional assessment, prognostic implications, and the potential risks and benefits of exogenous thyroid hormone treatment in the dialysis population. TARGET AUDIENCE: This activity has been designed to meet the needs of nephrologists and allied healthcare clinicians who treat patients with kidney disease who also suffer from thyroid dysfunction. EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Analyze what is known about the mechanistic links and association between thyroid dysfunction and kidney disease. • Assess thyroid hormone metabolism and diagnostic considerations for patients on dialysis. 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 Connie M. Rhee, MD, MSc

Reported Financial Relationship No financial relationships to disclose

ypothyroidism is a common endocrine disorder (estimated prevalence 5%-10% in U.S. cohorts1,2) characterized by an elevated serum thyrotropin (TSH) level and a reduced (i.e., severe or “overt” hypothyroidism) or normal (i.e., mild or “subclinical” hypothyroidism) thyroxine (T4) level.3 Epidemiologic studies suggest that there is a disproportionately higher prevalence of hypothyroidism in patients with kidney disease.4-9 Despite these data, the mechanistic link between thyroid functional disorders and kidney disease remains unclear, and there is likely under-recognition of hypothyroidism given symptom overlap with uremia. Kidney disease patients may also manifest various thyroid metabolic derangements in the context of euthyroidism, making the accurate assessment of thyroid functional disease challenging.5 In this review, the diagnostic considerations, prognostic implications, and management of hypothyroidism in dialysis patients will be discussed.

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 March 2013 through March 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.

Connie M. Rhee, MD, MSc, has trained at the Brigham and Women’s Hospital/Massachusetts General Hospital Joint Nephrology Fellowship Program, and is appointed to serve as faculty in the Division of Nephrology and Hypertension at the University of California Irvine, School of Medicine.

Prevalence of hypothyroidism Epidemiologic studies have shown that there is an increasing prevalence of hypothyroidism with incrementally impaired renal function.4,9 Data from 14,623 participants in the Third National Health and Nutrition Examination Survey (NHANES III) demonstrated that the prevalence of hypothyroidism was 5.4%, 10.9%, 20.4%, 23.0%, and 23.1% among those with estimated glomerular filtration rates (eGFRs) of >90, 60-89, 45-59, 30-44, and <30 mL/ min/1.73 m2, respectively.9 Even after accounting for differences in age, sex, and race/ethnicity using multivariable logistic regression models, there was a two-fold higher risk of hypothyroidism among those with eGFRs of <30 vs. ≥90 mL/min/1.73 m2. These data complement descriptive studies from the 1980’s demonstrating a high prevalence of thyroid functional disease in dialysis patients.5,6 There has been comparatively less examination of hypothyroidism’s prevalence in contemporary, large-scale dialysis cohorts, but recent data from single and dual-center studies show that about 15%-25% of hemodialysis (HD) and peritoneal dialysis (PD) patients have elevated TSH levels.7,8

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Dysfunction in the thyroid gland (shown above) may cause CV complications in ESRD patients.

deficiency have also been described. Greater than 99% of thyroid hormone is protein-bound (mostly to thyroxinebinding globulin, followed by transthyretin, albumin, and lipoproteins),30,31 and urinary protein losses have been associated with serum T4/T3 reductions proportional to the degree of hypoalbuminemia and proteinuria.32 However, most nephrotic patients remain euthyroid, as serum levels of free T4 (FT4) and TSH typically remain normal despite urinary thyroid hormone losses.

Mechanistic links Kidney disease leading to hypothyroidism The mechanistic link and directionality of association between hypothyroidism and kidney disease has not been fully elucidated. It has been hypothesized that kidney disease may lead to thyroid hormone derangements owing to non-thyroidal illness, decreased thyroid hormone-protein binding due to low-protein states and uremic toxins, malnutrition, inflammation, mineral deficiencies (e.g., selenium), and medications.5,23,24 Impaired iodine clearance (resulting in hypothyroidism via the Wolff-Chaikoff effect) and metabolic acidosis have also been implicated as potential risk factors. In terms of the former, anecdotal data have suggested that iodine excess from dietary sources and povidine-iodine agents may be associated with reversible hypothyroidism in dialysis patients.25-27 In terms of the latter, induction of metabolic acidosis was shown to give rise to higher TSH and lower T4 and triiodothyronine (T3) levels in healthy adults,28 and correction of acidosis with oral sodium citrate normalized low T3 levels in HD patients.29 Variable associations between nephrotic syndrome and thyroid hormone

Renal & Urology News 33

may also alter hypothalamic-pituitarythyroid axis activity.5 Thus, accurate assessment of thyroid functional status may be challenging in the context of uremia-associated thyroid metabolic derangements. © SCIENCE SOURCE / ANATOMICAL TRAVELOGUE

Subclinical disease accounts for a large proportion of hypothyroidism in both non-uremic and kidney disease populations.1,2,9 In this milder form of hypothyroidism, the TSH level may be high in the context of a normal T4 level (as an individual’s T4 set-point is narrower than the laboratory reference range),3 and approximately 5%-18% of cases progress to overt (“severe”) disease in the general population.10 Approximately half of the aforementioned NHANES III cases had subclinical disease, and data suggest that the prevalence of subclinical hypothyroidism may be as high as 10%16%, 16%, and 25% in pre-dialysis, PD, and HD cohorts, respectively.4,9,11-14 Previously thought to represent a biochemical derangement only, studies in the general population suggest that subclinical hypothyroidism is associated with increased cardiovascular (CV) morbidity (i.e., heart failure, endothelial dysfunction, atherosclerosis15-17), and some1821 but not all22 studies suggest greater mortality risk. Given their exceedingly high underlying CV risk, dialysis patients may be particularly vulnerable to the CV sequelae of mild hypothyroidism.

MARCH 2013

Hypothyroidism leading to reduced kidney function Thyroid hormone influences kidney development23 and may contribute to functional and structural derangements of the kidney because of altered cardiac output and intra-renal hemodynamics, and possibly via changes in glomerular architecture.33,34 Case series have shown that glomerular filtration reductions measured by renal isotopic scans in overt hypothyroidism were reversed with thyroid hormone replacement.35,36 In a recent cohort study of chronic kidney disease (CKD) patients with subclinical hypothyroidism, exogenous thyroid hormone replacement was associated with greater preservation of renal function compared with non-treatment.37 In contrast to the general population, it has been postulated that the majority of hypothyroid cases in kidney disease may not be explained by an autoimmune etiology.33 Although there have been anecdotal reports of an association between glomerulonephritis (i.e., membranous, membranoproliferative, and minimal change disease) and autoimmune thyroid disease,38,39 two studies have shown that, compared to hypothyroid patients with preserved

kidney function, those with reduced function had a lower prevalence of thyroid auto-antibodies.9,12 Dialysis effects on thyroid hormone metabolism Dialysis therapy does not appear to normalize thyroid function5 and may in fact contribute to alterations in thyroid hormone metabolism. Increased dialysis vintage has been associated with greater risk of hypothyroidism, corroborating the hypothesis that uremic toxins and iodine retention may be predisposing factors.12 Varying dialysis modalities may also have differential effects on thyroid hormone metabolism. For example, in PD patients, two studies have shown that 10%-30% of the daily production of T4 may be lost in peritoneal dialysate in both free and protein-bound forms;40,41 however, others have contended that peritoneal thyroid hormone losses are trivial.42,43 With regard to HD patients, one study examining thyroid functional tests pre- and post-dialysis demonstrated a significant rise in T3 and T4 levels post-dialysis (speculated to be related to medication effects44 and extravascular shifts in thyroid hormone45), whereas TSH levels remained stable.46

Thyroid hormone metabolism and diagnostic considerations Thyroid hormone production is regulated by TSH secreted from the pituitary gland. In turn, TSH secretion is inhibited by small increases in circulating T3 and T4, and is increased by thyrotropin-releasing hormone (TRH).23 The kidney plays a key role in the metabolism, degradation, and excretion of thyroid hormone, and uremic toxins

Triiodothyronine levels Low levels of T3, the more biologically active form of thyroid hormone, are the most frequently observed thyroid biochemical aberration observed in uremia (up to 78% of patients with eGFRs <15 mL/min/1.73 m2 in one study).47,48 Whereas T4 is solely produced by the thyroid gland, 80% of T3 is generated by 5’-deiodination of T4 to T3 in peripheral organs that include the kidney. Deiodination activity is reduced with uremia, mild illness, decreased caloric intake, and with elevations in cytokines, cortisol, and free fatty acids.23,49 Several cross-sectional studies have demonstrated an inverse association between T3 levels and IL-6, IL-10, CRP, and serum albumin in dialysis patients,50,51 suggesting that low T3 levels may be a marker of inflammation and malnutrition in dialysis patients. Reverse triiodothyronine levels In contrast to the low T3 levels of nonthyroidal illness in which there is greater conversion of T4 to inactive reverse T3 (rT3), rT3 levels are typically normal in dialysis patients, and may distinguish between low T3 levels observed in nonrenal non-thyroidal illness and hypothyroidism (rT3 levels high and low, respectively).5 Total and free thyroxine levels TT4 and FT4 levels may also be low in euthyroid dialysis patients due to low protein states, as well as uremic toxins (i.e., urea, creatinine, indoles, phenols) and medications interfering with thyroid hormone protein binding and with FT4 assay measurements.5 Although most FT4 assays have excellent sensitivity for hypothyroidism in symptomatic patients, certain methods of FT4 assessment in uremia and other non-thyroidal illnesses may result in spuriously low results.3 Assays that are minimally dependent on protein binding (i.e., ultrafiltration, direct equilibrium dialysis) may more accurately reflect circulating FT4 levels, but are not routinely available for clinical use.

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CME FEATURE Table 1. Studies Examining Thyroid Functional Disease and Cardiovascular Surrogates in Dialysis Patients Study Jaroszynski59 (2005)

Zoccali58 (2006)

Dialysis Modality (n) HD (52)

HD and PD (234)

Definition of hypothyroidism or subclinical hypothyroidism

Outcome

Low FT3

Delayed ventricular depolarization measured by signal-averaged EKG

Low FT3

Decreased left ventricular systolic function and increased left ventricular mass; estimates attenuated to null with adjustment for IL-6 and serum albumin

Kang70 (2008)

PD (51)

Baseline TSH >5 mIU/L & normal FT4

Decreased left ventricular ejection fraction

Tatar60 (2011)

HD (137)

Low FT3

Carotid artery atherosclerosis and abnormal pulse wave velocity

Tatar61 (2011)

PD (57)

Low FT3

Increased arterial stiffness

Saito62 (2012)

HD (52)

Low FT3

Increased interstitial edema

Abbrevations: HD, hemodialysis; PD, peritoneal dialysis; FT3, free triiodothyronine; TSH, thyrotropin; FT4, free thyroxine; EKG, electrocardiogram

Table 2. Studies Examining Thyroid Functional Disease and Mortality in Dialysis Patients Study

Dialysis Modality (n)

Definition of hypothyroidism or subclinical hypothyroidism

Outcome

Zoccali69 (2006)

HD (200)

Low FT3

Increased all-cause mortality

Enia63 (2007)

PD (41)

Low FT3

Increased all-cause mortality

Low FT3 and TT3

Increased all-cause and cardiovascular mortality with low TT3 but not FT3

Carrero54 (2007)

Dialysis (187)

Fernandez-Reyes64 (2010)

HD (89)

Low FT3

No association with all-cause mortality

Ozen68 (2011)

HD (669)

Low FT3

Increased all-cause mortality; estimates attenuated to null with concurrent adjustment for serum albumin and CRP

Horacek65 (2012)

HD (167)

Low FT3

Increased all-cause mortality

Lin66 (2012)

PD (46)

Subclinical hypothyroidism (TSH >4 mIU/L and normal FT4, or low FT4 and normal TSH) OR low TT3 or low TT4

Increased all-cause mortality

Meuwese 67 (2012)

HD (210)

Low TT3 and T4 (Baseline and repeated measurements)

Low TT3 and T4 (basal and persistently low) associated with increased all-cause and cardiovascular mortality

High TSH

Increased all-cause mortality

Rhee11 (2013)

HD and PD (2715)

Abbrevations: HD, hemodialysis; PD, peritoneal dialysis; FT3, free triiodothyronine; TT3, total triiodothyroxnine; TSH, thyrotropin; FT4, free thyroxine; TT4, total thyroxine; CRP, C-reactive protein

Thyrotropin levels In the general population, TSH is considered to be the most sensitive and specific marker of thyroid function and

is typically used to monitor treatment of primary hypothyroidism.3,52 In dialysis patients, various TSH alterations may be observed, such as altered clearance,

blunted response to TRH, decreased pulsatility, impaired glycosylation, and increased half-life.5,47 However, most patients with kidney disease retain nor-

mal TSH levels,23,47 and TSH has been shown to be a more reliable indicator of thyroid function vs. T3 in dialysis patients based on metabolic testing.53

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Hazard ratio (95% CI)

1.27 (1.06-1.52)

1.35 (1.15-1.58)

1.5

MARCH 2013

ment for CV risk factors, suggesting that CV pathways may mediate the hypothyroidism-mortality association.11 However, the observational nature of these studies precludes conclusions regarding causality, and further mechanistic studies are needed to understand these relationships.

Exogenous thyroid hormone treatment 1 (ref) 1

Euthyroid

Hypothyroid (Lagged)

Hypothyroid (Non-Lagged)

Figure 1. Association between hypothyroidism (thyrotropin [TSH] greater than assay upper limit normal) vs. euthyroidism (referent group; TSH within reference range) and mortality in dialysis patients in lagged and non-lagged analyses, start of at-risk time began 30 days and 1 day, respectively, after TSH measurement. Figure 1 is adapted from Rhee CM, Alexander EK, Bhan I, Brunelli SM. Hypothyroidism and Mortality Among Dialysis Patients. Clin J Am Soc Nephrol 2012; published online ahead of print.

Additionally, exogenous thyroid hormone has been shown to suppress TSH levels, and thyroidectomies have been shown to result in appropriate rises of TSH in uremia, suggesting an intact thyroid-pituitary feedback loop.54 Some experts have advised that elevated TSH in conjunction with low FT4 levels may be used to identify hypothyroidism in uremic patients.55 Further study is needed define the optimal approach to thyroid functional assessment in dialysis patients in order to prevent misdiagnosis and unwarranted treatment.

Prognostic implications of hypothyroidism In the general population, hypothyroidism has been associated with a broad range of CV complications, including congestive heart failure, electrophysiologic conduction abnormalities, altered endothelial function, and accelerated atherosclerosis.15,56,57 Exogenous thyroid hormone treatment in mild hypothyroidism has also been shown to reverse impaired cardiac contractility and vascular disease, supporting causal associations.16,17 These studies have led to the examination of hypothyroidism as a predictor of morbidity and mortality in dialysis patients. (Tables 1 and 2) Early studies suggested that hypothyroidism may be a protective mechanism to preserve energy and protein stores in dialysis patients, who are prone to

hypercatabolism, malnutrition, and protein losses via dialytic procedures.42 However, an increasing body of literature has shown that baseline low levels of thyroid hormone may be associated with impaired systolic function;58 conduction abnormalities predisposing to ventricular arrhythmias;59 atherosclerosis; endothelial dysfunction;60,61 interstitial edema;62 and greater CV and all-cause mortality.54,63-69 In one study of dialysis patients employing repeated measurements, persistently low levels of thyroid hormone were associated with a 2.7 and 4.0-fold higher risk of all-cause and CV mortality, respectively.67 However, these studies may provide limited evidence due to utilization of T3 and T4 levels, which are confounded by malnutrition/inflammation and may be spuriously low in the context of uremia.5,49 To date, few studies have examined the prognostic implications of hypothyroidism as defined by TSH levels in uremic patients. In a cross-sectional analysis of PD patients, subclinical hypothyroidism defined by TSH and FT4 levels was associated with decreased systolic function compared to euthyroidism.70 In another study of HD and PD patients, hypothyroidism defined by baseline TSH levels was associated with greater all-cause mortality compared to euthyroidism (Figure 1); sensitivity analyses demonstrated an attenuation of estimates with adjust-

Levothyroxine is the 3rd and 11th most commonly prescribed medication in CKD and end-stage renal disease Medicare Part D enrollees, respectively,71 but the therapeutic benefits of treatment in these populations remains uncertain. To date, there has been limited study of the impact of thyroid hormone replacement therapy on surrogate or hard outcomes among hypothyroid dialysis patients. In HD patients with low T3 levels, exogenous T3 administered at slightly higher than physiologic doses resulted in increased markers of protein degradation, suggesting that thyroid hormone treatment may worsen protein malnutrition.42 In another study of euthyroid HD patients, exogenous T4 was shown to reduce LDL cholesterol and lipoprotein(a) levels without subsequent clinical thyrotoxicosis.72 In a more recent study of HD and PD patients, those receiving exogenous thyroid hormone with normal TSH levels (i.e., presumed to be hypothyroid patients treated to target) had similar mortality risk compared with spontaneously euthyroid patients, whereas hypothyroid patients had greater mortality risk.11 Given the CV implications of thyroid hormone deficiency, the high burden of CV disease and hypothyroidism in uremia, and the potential risks and benefits of exogenous thyroid hormone, further study is needed to examine the impact of treatment in dialysis patients.

Conclusion In summary, there is a disproportionately higher prevalence of hypothyroidism as well as thyroid hormone metabolic derangements in dialysis patients, and emerging data suggest that thyroid hormone deficiency may be associated with greater CV morbidity and mortality

Renal & Urology News 35

in this population. At this time, further study is needed to determine the mechanistic links between hypothyroidism and kidney disease, as well as the optimal methods of thyroid functional assessment, prognostic implications, and the potential risks and benefits of exogenous thyroid hormone treatment in the dialysis population. ■ REFERENCES 1. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160:526-534. 2. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489-499. 3. Ladenson PW: Diagnosis of Hypothyroidism. In: Werner and Ingbar’s The Thyroid, 10th ed., edited by Braverman LE, Cooper DS, Philadelphia, PA: Lippincott Williams and Wilkins, pp 606-611, 2013. 4. Chonchol M, Lippi G, Salvagno G, et al. Prevalence of subclinical hypothyroidism in patients with chronic kidney disease. Clin J Am Soc Nephrol 2008;3:1296-1300. 5. Kaptein EM. Thyroid hormone metabolism and thyroid diseases in chronic renal failure. Endocr Rev 1996;17:45-63. 6. Kaptein EM, Quion-Verde H, Chooljian CJ, et al. The thyroid in end-stage renal disease. Medicine (Baltimore) 1988;67:187-197. 7. Kutlay S, Atli T, Koseogullari O, et al. Thyroid disorders in hemodialysis patients in an iodine-deficient community. Artif Organs 2005;29:329-232. 8. Lin CC, Chen TW, Ng YY, et al. Thyroid dysfunction and nodular goiter in hemodialysis and peritoneal dialysis patients. Perit Dial Int 1998;18:516-521. 9. Lo JC, Chertow GM, Go AS, Hsu CY. Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease. Kidney Int 2005;67:1047-1052. 10. McDermott MT: Overview of the Clinical Manifestations of Hypothyroidism. In: Werner and Ingbar’s The Thyroid, 10th ed., edited by Braverman LE, Cooper DS, Philadelphia, PA: Lippincott Williams and Wilkins, pp 569-575, 2013. 11. Rhee CM, Alexander EK, Bhan I, Brunelli SM. Hypothyroidism and mortality among dialysis patients. Clin J Am Soc Nephrol (Epub ahead of print). 12. Ng YY, Wu SC, Lin HD, et al. Prevalence of clinical and subclinical thyroid disease in a peritoneal dialysis population. Perit Dial Int 2012;32:86-93. 13. Shantha GP, Kumar AA, Bhise V, et al. Prevalence of subclinical hypothyroidism in patients with end-stage renal disease and the role of serum albumin: A cross-sectional study from South India. Cardiorenal Med 2011;1:255-260. 14. Targher G, Chonchol M, Zoppini G, et al. Prevalence of thyroid autoimmunity and subclinical hypothyroidism in persons with chronic kidney disease not requiring chronic dialysis. Clin Chem Lab Med 2009;47:1367-1371. 15. Gencer B, Collet TH, Virgini V, et al. Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts. Circulation 2012;126:1040-1049. 16. Monzani F, Caraccio N, Kozakowa M, et al. Effect of levothyroxine replacement on lipid profile and intima-media thickness in subclinical hypothyroidism: a double-blind, placebo- controlled study. J Clin Endocrinol Metab 2004;89:2099-2106. 17. Monzani F, Di Bello V, Caraccio N, et al. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J Clin Endocrinol Metab 2001;86:1110-1115. 18. Imaizumi M, Akahoshi M, Ichimaru S, et al. Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab 2004;89:3365-3370. 19. McQuade C, Skugor M, Brennan DM, et al. Hypothyroidism and moderate subclinical hypothyroidism are associated with increased all-cause mortality independent of coronary heart disease risk factors: a PreCIS database study. Thyroid 2011;21:837-843. 20. Razvi S, Weaver JU, Vanderpump MP, Pearce SH. The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism: reanalysis of the Whickham Survey cohort. J Clin Endocrinol Metab 2010;95:1734-1740. 21. Rodondi N, den Elzen WP, Bauer DC, et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 2010;304:1365-1374. 22. Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA 2006;295:1033-1041.

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CME FEATURE 23. Mariani LH, Berns JS. The renal manifestations of thyroid disease. J Am Soc Nephrol 2012;23:22-26. 24. Schomburg L. Selenium, selenoproteins and the thyroid gland: interactions in health and disease. Nat Rev Endocrinol 2011;8:160-171. 25. Brough R, Jones C. Iatrogenic iodine as a cause of hypothyroidism in infants with end-stage renal failure. Pediatr Nephrol 2006;21:400-402. 26. Sanai T, Inoue T, Okamura K, et al. Reversible primary hypothyroidism in Japanese patients undergoing maintenance hemodialysis. Clin Nephrol 2008;69:107-113. 27. Takeda S, Michigishi T, Takazakura E. Iodine-induced hypothyroidism in patients on regular dialysis treatment. Nephron 1993;65:51-55. 28. Brungger M, Hulter HN, Krapf R. Effect of chronic metabolic acidosis on thyroid hormone homeostasis in humans. Am J Physiol 1997;272:F648-F653. 29. Wiederkehr MR, Kalogiros J, Krapf R. Correction of metabolic acidosis improves thyroid and growth hormone axes in haemodialysis patients. Nephrol Dial Transplant 2004;19:1190-1197. 30. Benvenga S: Thyroid Hormone Transport Proteins and the Physiology of Hormone Binding. In: Werner and Ingbar’s The Thyroid, 10th ed., edited by Braverman LE, Cooper DS, Philadelphia, PA: Lippincott Williams and Wilkins, pp 93-103, 2013. 31. Bartalena L. Recent achievements in studies on thyroid hormone-binding proteins. Endocr Rev 1990;11:47-64. 32. Feinstein EI, Kaptein EM, Nicoloff JT, Massry SG. Thyroid function in patients with nephrotic syndrome and normal renal function. Am J Nephrol 1982;2:70-76. 33. Iglesias P, Diez JJ. Thyroid dysfunction and kidney disease. Eur J Endocrinol 2009;160:503-515. 34. van Hoek I, Daminet S. Interactions between thyroid and kidney function in pathological conditions of these organ systems: a review. Gen Comp Endocrinol 2009;160:205-215. 35. Karanikas G, Schutz M, Szabo M, et al. Isotopic renal function studies in severe hypothyroidism and after thyroid hormone replacement therapy. Am J Nephrol 2004;24:41-45. 36. Kreisman SH, Hennessey JV. Consistent reversible elevations of serum creatinine levels in severe hypothyroidism. Arch Intern Med 1999;159:79-82. 37. Shin DH, Lee MJ, Kim SJ, et al. Preservation of renal function by thyroid hormone replacement therapy in chronic kidney disease patients with subclinical hypothyroidism. J Clin Endocrinol Metab 2012;97:2732-2740. 38. Saha A, Bagri N, Mehera N, Dubey NK, Batra V. Membranoproliferative glomerulonephritis associated with autoimmune thyroiditis. J Pediatr Endocrinol Metab 2011;24:789-792. 39. Shima Y, Nakanishi K, Togawa H, et al. Membranous nephropathy associated with thyroid-peroxidase antigen. Pediatr Nephrol 2009;24:605-608. 40. Gavin LA, Eitan NF, Cavalieri RR, Schmidt WR. Hypothyroidism induced by continuous ambulatory peritoneal dialysis. West J Med 1983;138:562-565. 41. Kerr DJ, Singh VK, Tsakiris D, McConnell KN, Junor BJ, Alexander WD. Serum and peritoneal dialysate thyroid hormone levels in patients on continuous ambulatory peritoneal dialysis. Nephron 1986;43:164-168. 42. Lim VS. Thyroid function in patients with chronic renal failure. Am J Kidney Dis 2001;38:S80-S84. 43. Robey C, Shreedhar K, Batuman V. Effects of chronic peritoneal dialysis on thyroid function tests. Am J Kidney Dis 1989;13:99-103. 44. Nishikawa M, Ogawa Y, Yoshikawa N, et al. Plasma free thyroxine (FT4) concentrations during hemodialysis in patients with chronic renal failure: effects of plasma non-esterified fatty acids on FT4 measurement. Endocr J 1996;43:487-493. 45. van Leusen R, Meinders AE. Cyclical changes in serum thyroid hormone concentrations related to hemodialysis: movement of hormone into and out of the extravascular space as a possible mechanism. Clin Nephrol 1982;18:193-199. 46. Alsaran K, Sabry A, Alshahhat H, et al. Free thyroxine, free triiodothyronine and thyroid-stimulating hormone before and after hemodialysis in Saudi patients with end-stage renal disease: is there any difference? Saudi J Kidney Dis Transpl 2011;22:917-921. 47. Carrero JJ. SP, Lindholm B.: Endocrine Aspects of Chronic Kidney Disease. In: Taal: Brenner and Rector’s The Kidney, 9th ed., edited by Taal M.W., Chertow G.M., Marsden P.A., Skorecki K., Yu A.S., Brenner B.M., Philadelphia, Elsevier Saunders, 2012, 2122-2137. 48. Song SH, Kwak IS, Lee DW, et al. The prevalence of low triiodothyronine according to the stage of chronic kidney disease in subjects with a normal

thyroid-stimulating hormone. Nephrol Dial Transplant 2009;24:1534-1538. 49. Wiersinga WM, van den Berghe G: Nonthyroidal Illness. In: Werner and Ingbar’s The Thyroid, 10th ed., edited by Braverman LE, Cooper DS, Philadelphia, PA: Lippincott Williams and Wilkins, pp 203-217, 2013. 50. Zeraati AA, Layegh P, Famili Y, et al. Serum triiodothyronine level as an indicator of inflammation in patients undergoing dialysis. Iranian J Kidney Dis 2011;5:38-44. 51. Zoccali C, Tripepi G, Cutrupi S, et al. Low triiodothyronine: a new facet of inflammation in end-stage renal disease. J Am Soc Nephrol 2005;16:2789-2795. 52. Jonklaas J: Treatment of Hypothyroidism. In: Werner and Ingbar’s The Thyroid, 10th ed., edited by Braverman LE, Cooper DS, Philadelphia, PA: Lippincott Williams and Wilkins, pp 611-628, 2013. 53. Spector DA, Davis PJ, Helderman JH, et al. Thyroid function and metabolic state in chronic renal failure. Ann Intern Med 1976;85:724-730. 54. Carrero JJ, Qureshi AR, Axelsson J, et al. Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med 2007;262:690-701. 55. Tang WW, Kaptein EM, Massry SG. Diagnosis of hypothyroidism in patients with end-stage renal disease. Am J Nephrol 1987;7:192-197. 56. Cini G, Carpi A, Mechanick J, et al. Thyroid hormones and the cardiovascular system: pathophysiology and interventions. Biomed Pharmacother 2009;63:742-753. 57. Iervasi G, Molinaro S, Landi P, et al. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med 2007;167:1526-1532. 58. Zoccali C, Benedetto F, Mallamaci F, et al. Low triiodothyronine and cardiomyopathy in patients with end-stage renal disease. J Hypertens 2006;24:2039-2046. 59. Jaroszynski AJ, Glowniak A, Chrapko B, et al. Low-T3 syndrome and signal-averaged ECG in haemodialysed patients. Physiol Res 2005;54:521-526. 60. Tatar E, Kircelli F, Asci G, et al. Associations of triiodothyronine levels with carotid atherosclerosis and arterial stiffness in hemodialysis patients. Clin J Am Soc Nephrol 2011;6:2240-2246. 61. Tatar E, Sezis Demirci M, Kircelli F, et al. The association between thyroid hormones and arterial stiffness in peritoneal dialysis patients. Int Urol Nephrol 2012;44:601-606. 62. Saito O, Saito T, Ueno K, et al. Comparison between serum free triiodothyronine levels and body fluid distribution in hemodialysis patients. Clin Exp Nephrol 2012;16:952-958. 63. Enia G, Panuccio V, Cutrupi S, et al. Subclinical hypothyroidism is linked to micro-inflammation and predicts death in continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 2007;22:538-544. 64. Fernandez-Reyes MJ, Diez JJ, Collado A, et al. Are low concentrations of serum triiodothyronine a good marker for long-term mortality in hemodialysis patients? Clin Nephrol 2010;73:238-240. 65. Horác ˘ek J, Dusilová Sulková S, Kubišová M, et al. Thyroid hormone abnormalities in haemodialyzed patients: low triiodothyronine as well as high reverse triiodothyronine are associated with increased mortality. Physiol Res 2012;14:495-501. 66. Lin YC, Chen TW, Yang WC, Lin CC. Abnormal thyroid function predicts mortality in patients receiving long-term peritoneal dialysis: a case-controlled longitudinal study. J Chin Med Assoc 2012;75:54-59. 67. Meuwese CL, Dekker FW, Lindholm B, et al. Baseline levels and trimestral variation of triiodothyronine and thyroxine and their association with mortality in maintenance hemodialysis patients. Clin J Am Soc Nephrol 2012;7:131-138. 68. Ozen KP, Asci G, Gungor O, et al. Nutritional state alters the association between free triiodothyronine levels and mortality in hemodialysis patients. Am J Nephrol 2011;33:305-312. 69. Zoccali C, Mallamaci F, Tripepi G, Cutrupi S, Pizzini P. Low triiodothyronine and survival in end-stage renal disease. Kidney Int 2006;70:523-528. 70. Kang EW, Nam JY, Yoo TH, et al. Clinical implications of subclinical hypothyroidism in continuous ambulatory peritoneal dialysis patients. Am J Nephrol 2008;28:908-913. 71. U.S. Renal Data System, USRDS 2011 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2011. 72. Bommer C, Werle E, Walter-Sack I, et al. D-thyroxine reduces lipoprotein(a) serum concentration in dialysis patients. J Am Soc Nephrol 1998;9:90-96.

DISCLAIMER: The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Medical Education Resources or Haymarket Medical Education. The authors have disclosed if there is any discussion of published and/or investigational uses of agents that are not indicated by the FDA in their presentations. The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of Medical Education Resources or Haymarket Medical Education. Before prescribing any medicine, primary references and full prescribing information should be consulted. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. The information presented in this activity is not meant to serve as a guideline for patient management.

CME Post-test Expiration Date: March 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) Subclinical and overt hypothyroidism are typically characterized by: a. Normal TSH levels in subclinical hypothyroidism, and elevated TSH levels in overt hypothyroidism (both with normal T4 levels) b. Reduced T4 levels in subclinical hypothyroidism, and normal T4 levels in overt hypothyroidism (both with elevated TSH levels) c. Normal T4 levels in subclinical hypothyroidism, and reduced T4 levels in overt hypothyroidism (both with elevated TSH levels) d. Normal T4 levels in subclinical hypothyroidism, and reduced T4 levels in overt hypothyroidism (both with normal TSH levels) 2) The most common serum protein to which thyroid hormone is bound is: a. Transthyretin b. Lipoprotein c. Thyroxine binding globulin d. Albumin 3) The most frequently observed thyroid hormone metabolic abnormality in dialysis patients is: a. Elevated TSH levels b. Elevated reverse T3 levels c. Reduced T4 levels d. Reduced T3 levels e. Elevated thyroid auto-antibodies 4) In contrast to patients with low T3 levels due to non-thyroidal illness, reverse T3 levels in dialysis patients are typically: a. Elevated b. Normal c. Low

5) Which of the following statements regarding thyroid hormone metabolism and assessment is correct: a. Deiodination of T4 to T3 is increased by malnutrition, inflammation, and increased cortisol and free fatty acid levels b. Deiodination of T4 to T3 is reduced by malnutrition, inflammation, and increased cortisol and free fatty acid levels c. All FT4 assays routinely used in clinical practice are minimally dependent on thyroid hormone protein binding 6) According to observational data in dialysis patients, low levels of thyroid hormone have been associated with all of the following cardiovascular surrogates, except for: a. Increased cardiac output b. Increased carotid artery atherosclerosis c. Increased interstitial edema d. Delayed ventricular depolarization as a risk factor for malignant ventricular arrhythmias e. Increased arterial stiffness 7) It is hypothesized that decreased renal iodine clearance in dialysis patients may result in: a. Hypothyroidism via the Jod Basedow phenomenon b. Hyperthyroidism via the Jod Basedow phenomenon c. Hypothyroidism via the Wolff-Chaikoff effect d. Hyperthyroidism via the Wolff-Chaikoff effect

Erratum In our February CME installment, post-test question number two was in err. The question should have read as follows, “Which of the following is not an indication for renal mass biopsy.” We apologize for the error.

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POINT/ COUNTERPOINT

MARCH 2013

Renal & Urology News 37

EARLY VS. LATE DIALYSIS INITIATION

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38 Renal & Urology News

MARCH 2013

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Urologist: Perform More Renal Tumor Biopsies BY NAYANAH SIVA LONDONâ&#x20AC;&#x201D;With a growing number of small renal masses being detected, renal tumor biopsies should be performed more frequently, a urologist skilled in the technique told attendees at the Renal and Bladder Cancer 4th National Conference. Neil Barber, FRCS, Consultant Urological Surgeon at Frimley Park Hospital, Surrey, U.K., spoke about his experience of the role of renal tumor biopsies. â&#x20AC;&#x153;Of course the concept of taking a biopsy is not a new thing, we have been doing this for many years,â&#x20AC;? he said. Biopsy already has an established role for an inoperable mass, a lymphoma, an abscess or an infective lesion. â&#x20AC;&#x153;The traditional approach to a renal mass is to chop it out, which is quite an unusual approach as you wouldnâ&#x20AC;&#x2122;t think about doing that with prostate cancer,â&#x20AC;? Dr. Barber said. â&#x20AC;&#x153;With small renal masses we typically use CT [computed tomography] scan, MRI [magnetic resonance imaging] scan, and contrast-enhanced ultrasound to decide what we are going to do.â&#x20AC;? These approaches, however, provide insufficient information. â&#x20AC;&#x153;Surely, when dealing with a tumor it would be good to know if it is benign or malignant, what the grade might be, and what the histological subtype might be. These things might influence how a mass might behave and that may influence what treatment options we may offer the patient: surveillance, ablation or partial nephrectomy.â&#x20AC;? Previous studies have consistently found that 25%-30% of small renal masses are benign and 65% are lowgrade tumors. High-grade tumors are quite rare. â&#x20AC;&#x153;What is really changing everything is the arrival of the small renal mass. I donâ&#x20AC;&#x2122;t think seven or eight years ago we could really see the tsunami of small renal masses that have come our way; it has gone from being a minor part of what we might to do,

to a predominant part of what we do.â&#x20AC;? Dr. Barber addressed the typical concerns with biopsy: safety, accuracy, and complications of bleeding and seeding. â&#x20AC;&#x153;From a safety point of view, [and with regards to bleeding] biopsy needles have changed and there is much more confidence on that front,â&#x20AC;? he explained. â&#x20AC;&#x153;With regards to accuracy, we now have specialist interventional radiologists who are increasing our confidence in the procedure. We also now have specialist pathologists who are getting more accurate and reliable answers to what the mass might be, and this is all leading to the urologist who is dealing with the patient being more confident about the intervention they decide on.â&#x20AC;? Dr. Barber questioned whether the accuracy of biopsy diagnosis really matters. Knowing whether the tumor is grade 1, 2, 3, or 4 is not that important, he said. Knowing whether it is low grade or high grade is more important in managing the patient. Seeding has always been a concern, but Dr. Barber pointed out that since 2001 there have only ever been six cases of reported seeding and no more cases since then. â&#x20AC;&#x153;So we can really put that one to bed.â&#x20AC;? So, what are the predictive factors for which tumors are good for biopsy. â&#x20AC;&#x153;One thing is size. The bigger the tumor, the greater the accuracy,â&#x20AC;? he said, â&#x20AC;&#x153;the smaller the tumor the greater the chance there may be some error on that biopsy.â&#x20AC;? With regard to solid tumors versus cystic tumors, studies favor solid tumors for biopsy. Tumor location is also a factor. â&#x20AC;&#x153;The anterior upper pole lesions are more difficult to biopsy than lower pole posterior lesions,â&#x20AC;? he stated. As for patient characteristics, patients should be able to lie still long enough to obtain a CT scan. Obesity also is a concern because it could hinder access to the tumor. â&#x2013;

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