Renal & Urology News September 2012 Issue by Haymarket Media

SEPTEMBER 2012

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VOLUME 11, ISSUE NUMBER 9

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Supplemental Oral Nutrition Beneficial Oral supplements taken during dialysis sessions found to improve survival, reduce hospitalizations Boosting Nutrition During Dialysis Patients who took oral nutritional supplements (ONS) versus those who did not (controls) during dialysis had significantly lower death rates in the as-treated population, as shown below. 37.3%

40 35

30.1%

30.4%

30.9%

30 25 20

15 10 5 0

Intent-to-Treat

As-Treated

Source: Lacson E Jr., et al. Outcomes associated with intradialytic oral nutritional supplements in patients undergoing maintenance hemodialysis: A quality improvement report. Am J Kidney Dis 2012; published online ahead of print.

PCa Linked to Dietary Cadmium INCREASED DIETARY intake of cadmium is associated with an elevated risk of prostate cancer (PCa), according to researchers. In a population-based prospective cohort study 41,089 Swedish men aged 45-79 years, Bettina Julin, PhD, of the Karolinska Institutet in Stockholm, and colleagues found that men in the high-

CME FEATURE

est tertile of dietary cadmium intake had a 13% increased risk of PCa compared with those in the lowest tertile. The risk for localized, advanced, and fatal PCa was increased by 29%, 5%, and 14%, respectively, the investigators reported online ahead of print in the British Journal of Cancer. continued on page 14

Earn 1 CME credit in this issue

Adrenal Hypertension: A Current Guide to Diagnosis PAGE 33

BY ROSEMARY FREI, MSc HONOLULU—Hemodialysis (HD) patients who take oral nutritional supplements (ONS) while dialyzing have improved survival and other benefits, according to findings released here at the 16th International Congress on Nutrition and Metabolism in Renal Disease. In a symposium, Raymond Hakim, MD, PhD, a consultant nephrologist at Vanderbilt University Medical Center in Nashville, Tenn., presented results indicating that providing ONS during dialysis reduces patients’ risk of death by up to 34% compared with not receiving ONS. The study was also published online ahead of print in the American Journal of Kidney Diseases (AJKD).

RCC Survival Better in Renal Tx Patients RENAL CELL CARCINOMA (RCC) that arises in the native kidneys of patients with end-stage renal disease (ESRD) exhibit more favorable features in kidney transplant recipients than in dialysis-only patients, according to a new French study. The study, led by Marc Gigante, MD, PhD, Chief of Urology and Kidney Transplantation at Félix Guyon University Hospital in Saint-Denis de la Réunion, France, examined 303 RCC cases that developed in ESRD patients. Transplanted patients accounted for 213 RCC cases (70.3%) and dialysisonly patients accounted for 90 (29.7%). RCC was diagnosed at a significantly earlier age in transplant recipients than dialysis-only patients (53 vs. 61 years). Transplant patients had a significantly smaller mean tumor size (3.4 vs. 4.2 cm) and a significantly higher frequency of pT1a stage tumors (75% vs. 60%), the investigators reported online in BJU International. Transplanted patients continued on page 14

“We think our study has been critical in showing that providing malnourish patients with ONS attenuates the deficit of amino acids that occurs during dialysis and reduces mortality,” Dr. Hakim told Renal & Urology News. “It’s important that malnourished patients receive ONS during dialysis because that’s when they do not eat or have any oral intake for at least four hours, while they lose significant amounts of amino acids along with uremic toxins in the dialysate.”

Study design Dr. Hakim, along with Eduardo Lacson Jr., MD, MPH, and others retrospectively studied 7,264 people continued on page 14

IN THIS ISSUE 8

Slower shock wave delivery to stones may be superior

Cystatin C levels predict loss of renal function

New column on Men’s Health: testosterone therapy, testicular cancer...and more

Q&A: Electronic health records

Ketoanalogues may help postpone dialysis initiation

Quality of life issues affect RCC patients’ drug preference

Long-term dialysis hikes cancer risk after renal transplantation

Treating small renal masses PAGE 16

Other pathways can contribute to prostate cancer promotion.5 References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68(15):6407-6415. 3. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66(5):2815-2825. 4. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11(13):4653-4657. 5. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12(6):1665-1671.

Janssen Biotech, Inc. ÂŠ Janssen Biotech, Inc. 2012 2/12 08ADA10012R2

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

Janssen Biotech, Inc. ÂŠ Janssen Biotech, Inc. 2012 2/12 08ADA10027CR1

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

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SEPTEMBER 2012

Renal & Urology News 5

FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD

CT and Stones: Can We Do Better with Less?

ross-sectional imaging now substitutes for physical diagnosis in most emergency rooms. It is far more sensitive and specific for identifying early structural or anatomic anomalies than even the most astute clinician. Therefore, most patients with varied non-descript abdominal symptoms make their first stop in the computed tomography (CT) scanner. Although both positive and a negative CTs are important, they come with a potential long term cost: radiation exposure. In a recently published study, Smith-Bindman et al estimated that 1 in 1,000 patients undergoing a single non-contrast CT scan incur an increased risk of a radiation induced cancer Of course, the value of a CT scan in treating an identified abnormality cannot be overstated. In the case of kidney stones, size, location, anatomy, and density are all critical components in determining proper therapy. Indeed, these are so important to the treating urologist that CT scans have become the de facto standard, particularly for patients presenting with flank pain. In a recent study using national representative data Hyams et al noted that from 2000 to 2008 there was a greater than 100% increase in the use of CT scans in the ER for the evaluation of flank pain with a simultaneous decrease in KUBs and a low but stable use of renal ultrasound. During the same time period, the proportion of patients with flank pain ultimately diagnosed with stones remained stable (20%). As physicians and health systems are increasingly required to manage risk, several investigators recently published studies showing that kidney stone characteristics (size, locations, number, density) are equally well determined using a low-dose CT protocol compared with standard protocols. Radiation dose is calculated based on body mass index, scans are performed at 2-3 mm cuts, and 3-D reconstructions are made. Average radiation doses were decreased by approximately 75% without compromising the data obtained. Equal information with less risk seems like a no brainer, but who owns the implementation of such change? Urologists? Nephrologists? Radiologists? Emergency physicians? I vote for all four. While health systems are bringing stakeholders together to develop best practices, the tempo is slow and ownership weak. Accountable care is not only about economics, it starts with physicians understanding risk, making tradeoffs, and building better care processes—something from which we can all benefit. 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 REFERENCES 1. Smith-Bindeman R, et al. Arch Intern Med 2009;169:2078-2086. 2. Hyams ES, et al. J Urol 2011;186:2270-2274. 3. Hyams ES, Shah O. Curr Urol Rep 2010;11:80-86.

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 Frank R. Cerniglia Jr, MD Attending Pediatric Urologist Children’s Urology of Virginia Richmond, Va. 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 Chairman Department of Regional Urology Cleveland Clinic Glickman Urological & Kidney Institute Professor of Surgery Cleveland Clinic Lerner College of Medicine of Case Western Reserve University James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City Kenneth Pace, MD, MSc, FRCSC Assistant Professor Division of Urology St. Michael’s Hospital University of Toronto Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada

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 Johns Hopkins Children’s Center, Baltimore Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center, Detroit Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J. Lynda Anne Szczech, MD, MSCE Medical Director, Pharmacovigilence and Global Product Development, PPD, Inc. Morrisville, N.C.

Renal & Urology News Staff Editor Executive editor Senior editor Web editor Editorial coordinator Art director Group art director, Haymarket Medical VP, audience development and operations Production 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 11, Number 9. Published monthly by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Periodicals postage paid at New York, NY, and an additional mailing office. The subscription rates for one year are, in the U.S., $75.00; in Canada, $85.00; all other foreign countries, $110.00. Single issues, $20.00. www.renalandurologynews.com. Postmaster: Send address changes to Renal & Urology News, c/o DMD Data Inc., 2340 River Road, Des Plaines, IL 60018. For reprints, contact Wright’s Reprints at 1.877.652.5295. Copyright: All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without the prior written permission of Haymarket Media, Inc. Copyright © 2012.

Contents

SEPTEMBER 2012

■

VOLUME 11, ISSUE NUMBER 9

Urology 10

PSA Screening Cuts Risk of Metastatic PCa In a large European study, screened men had a significant 42% decreased risk of developing metastatic prostate cancer.

Patient RCC Drug Preferences Revealed In a study, patients strongly preferred pazopanib over sunitinib, citing better quality of life, less fatigue.

ONLINE

Hyponatremia May Shorten RCC Survival In multivariate analysis, severe and mild hyponatremia were associated with a significant sixfold and threefold increased risk of cancer-specific mortality, respectively.

High-Risk PCa Treatable, Data Show Curative treatment for men with high-risk prostate cancer is associated with decreased cancer-specific mortality and should be considered even when serum PSA levels are higher than 20 ng/mL.

Expert Q&A Robert K. Nam, MD, MSc, of Sunnybrook Health Sciences Center in Toronto, talks about surgical correction of urinary incontinence that follows radical prostatectomy.

Clinical Quiz Take our latest quiz at renalandurologynews.com /clinical-quiz/. Answer correctly and you will be entered to win a $50 American Express gift card. Congratulations to our July winner: Andrea Brand, MD

Iron Overload Increases Post-Tx Infection Risk Kidney transplant recipients who have iron overload have a 57% increased risk for bacterial infection.

Renal Impairment Linked to Cystatin C Levels Early changes in cystatin C predicted a significant decline in renal function and development of stage 3 nephropathy.

The Medical Minute Visit renalandurologynews.com /the-medical-minute/ to hear podcast reports on new studies. Our latest include: • Blood Test May Prevent Unneeded Prostate Biopsies • Biospecimens Could Lead to Better Kidney Disease Treatment • New Genetic Cause of CKD Identified

News Coverage Visit our website for reports from the World Meeting on Sexual Medicine in Chicago, August 26-30.

“

CME Feature 33

Adrenal Hypertension: A Current Guide to Diagnosis Alexander Kutikov, MD, Assistant Professor of Urologic Oncology at Fox Chase Cancer Center in Philadelphia, reviews adrenal pathologies that can result in Cushing and Conn syndromes, and pheochromocytoma.

Nephrology

Study Links High-Grade PCa To Metabolic Syndrome Metabolic syndrome was associated with a 75% increased risk of high-grade tumors, according to Spanish investigators. Ketoanalogues May Help Delay Dialysis Initiation Supplements added to very-low-protein diets slowed eGFR decline in patients with chronic kidney disease.

“

this month at renalandurologynews.com

EHR [electronic health record] adoption

improves patient care and promises to reduce errors and improve safety over the long term. See our story on page 17

Departments 5

From the Medical Director A case for low-dose CT for stones

News in Brief Slower shock wave delivery better

Men’s Health Update (NEW) Testosterone safe for the prostate

On the Forefront Robotic NSS without ischemia

Renal Nutrition Update Proteinuria and sodium restriction

Malpractice News EHRs may avoid lawsuits

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SEPTEMBER 2012

Renal & Urology News 7

Iron Overload Increases Post-Tx Infection Risk BY ROSEMARY FREI, MSc BERLIN—Kidney transplant recipients who have iron overload are at increased risk for bacterial infection compared with those who have normal iron levels, according to preliminary results of a Spanish study. The prospective study also revealed that ferritin levels above 500 mg/dL are associated with a higher risk of death within three years compared to lower ferritin levels. “We are planning to assess the total body iron stores in kidney-transplant recipients using more accurate parameters such as serum hepcidin levels to confirm the findings that emerged from this study,” said lead investigator Mario Fernandez-Ruiz, MD, of the University Hospital, 12th of October in Madrid, after presenting the results at the 24th International Congress of The Transplantation Society. If the findings are corroborated, “monitoring of serum iron markers may have a role in predicting adverse outcomes after kidney transplantation,” Dr. Fernandez-Ruiz said.

The study reveals a 57% greater risk of bacterial infection in transplant recipients.

of any infection and a 57% increased risk of bacterial infection. Although total iron-binding capacity did not differ significantly between the patients who did and did not have any type of infection, it was significantly lower in patients with a bacterial infection compared to those without one.

The only other factor found to be significantly associated with bacterial infection was acute graft rejection, the researchers reported. Reoperation during the first post-transplant month and poorer graft function at 30 days post-transplant were significantly associated with a higher risk of any type of infection.

Post-transplant infection-free survival was significantly shorter in recipients with iron overload compared with those who did not have iron overload (134 vs. 188 days), the researchers noted. Patients with iron overload also had a significantly greater all-cause mortality rate (12.0% vs. 4.4%). ■

WE’RE

CHANGING THE WAY

PROSTATE CANCER PATIENTS ARE TREATED EVEN WHEN THEY’RE NOT BEING TREATED When it comes to treating prostate cancer, we do not believe in a one-size-ﬁts-all approach. That’s why doctors at UPMC are experts in both traditional methods of urologic surgery and in cutting-edge robotic surgery. But our doctors also recognize when the best management is not an operation, but careful

The likely link is iron’s important role in the survival and virulence of many potentially pathogenic microorganisms, he noted. Dr. Fernandez-Ruiz and his colleagues focused their analysis on 228 patients who received kidney transplants from November 2008 to February 2011. Their average age was 54.9 years, 60.5% were men and their pre-transplant conditions included glomerulonephritis, diabetic nephropathy, renal polycystosis and hypertensive nephrosclerosis. Just 10 (4.4%) received a living-donor transplant. The mean cold ischemia time was 16.8 hours. Infection occurred in 153 patients (67.1%) after transplantation. Most of the infections (117) were bacterial, but there were 73 cytomegalovirus infections and 17 fungal infections. Ninety-two subjects (40.4%) had iron overload, defined as serum ferritin levels above 500 mg/dL. They had a significantly greater incidence of bacterial infection than patients without iron overload. In adjusted analyses, iron overload was associated with a 41% increased risk

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

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

8 Renal & Urology News

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

Short Takes Rituximab Treats Kidney Disorder

cancer (PCa) specimens. Noel J.

During a median follow-up of

a report in The Prostate that although

29 months after treatment with the

the apparently ubiquitous presence of

monoclonal antibody rituximab,

these viruses in all three types of

65 of 100 consecutive patients with

tissues suggests that the viruses

idiopathic membranous nephropathy

could be harmless, HPV type 18 in

achieved complete remission (persis-

particular has high oncogenic poten-

tent proteinuria below 0.3 g/24 hours

tial and may be associated with

and a reduction in proteinuria

some PCa cases. HPV-associated

greater than 50% from baseline) or

koilocytes were identified in 24% of

partial remission (persistent protein-

the PCa specimens studied.

Whitaker, MD, and colleagues noted in

uria less than g/24 hours and a reduction in proteinuria greater than 50% from baseline). Median time to remission was 7.1

New Device Relieves Cystitis/Bladder Pain lidocaine-releasing intravesical

between patients with or without

system (LiRIS), which is folded

previous immunosuppressive therapy,

into a pretzel shape in the bladder

and the drug was well tolerated,

and releases therapeutic amounts

according to a report in the Journal of

of the drug into urine over a

the American Society of Nephrology

period of two weeks, provided

2012;23:1416-1425).

relief to 16 women with interstitial

Slower Shock Wave Delivery May Offer Superior Results S

cystitis/bladder pain syndrome.

Two Common Viruses Present in PCa

Cytoscopic examinations showed im-

Both human papillomavirus (HPV) type

com pared with day 1, with an overall

18 and Epstein-Barr virus (EBV) gene

responder rate of 64% on day 14

sequences were identified in a high

as well as two weeks later, according

and approximately equal proportion of

to a report in Science Translational

100 normal, benign, and prostate

Medicine 2012;4:143ra100).

provement on day 14 (day of removal)

Testosterone and Prostate Cancer In a recent online poll, Renal & Urology News asked urologists how concerned they are about placing hypogonadal men on testosterone replacement therapy because of the possibility of promoting the development of prostate cancer (PCa) or progression of undiagnosed PCa. Here are the results based on 130 respondents.

Very concerned 10.0%

Somewhat concerned 49.23%

Not concerned at all 40.77% 10

ilatation of renal artery stenosis (RAS) in patients with atherosclerotic renovascular disease (ARVD) has no effect on renal perfusion, according to a new study. Niina Koivuviita, MD, of Turku University Hospital in Turku, Finland, and colleagues studied 17 patients with ARVD, seven with chronic kidney disease (CKD) but no renovascular disease, and 10 healthy volunteers. All patients except one received a stent during the angioplasty procedure. The researchers measured single-kidney perfusion noninvasively with positron emission tomography and radiolabeled water. At baseline, renal perfusion correlated inversely with degree of RAS, Dr. Koivuviitaâ&#x20AC;&#x2122;s group reported online in Nephrology Dialysis Transplantation. The mean cortical renal perfusion value in ARVD patients was 1.49 mL/min/g tissue at baseline and 1.40 mL/min/g tissue after revasularization, a nonsignificant difference. The mean values for the healthy volunteers and CKD patients were 1.82 and 1.26 mL/min/g tissue, respectively. Perfusion did not correlate with estimated glomerular filtration rate in the ARVD patients.

A new device called a continuous

months. Remission rates were similar

RAS Dilatation Found Not To Improve Renal Perfusion D

lower delivery of shock waves to kidney stones results in better treatment success than faster delivery, investigators reported online in the Journal of Urology. In a study of 206 patients undergoing shock wave lithotripsy (SWL) for unilateral kidney stones, Chinese researchers found that the treatment success rate was 50.5% among patients receiving 60 shocks per minute versus 35.9% for those receiving 120 shocks per minute. The two groups had similar success rates when stones were 10 mm or less, but the patients receiving 60 shocks per minute had a significantly better success rate when stones were larger than 10 mm. Immediately following SWL, patients treated with 60 shocks per minute had significantly greater increases in renal injury markers, but the investigators said the clinical implication of this was uncertain.

Frailty at Dialysis Initiation Linked to Higher eGFR F

railty is quite common among patients starting dialysis in the United States, and it is associated with a higher estimated glomerular filtration rate (eGFR) at dialysis initiation. In a special study of the U.S. Renal Data System, 1,576 participants were enrolled in the Comprehensive Dialysis Study (CDS). The researchers identified frailty in 73% of subjects. A higher eGFR at dialysis initiation was associated with a 44% increased odds of frailty, according to findings published in Archives of Internal Medicine (2012;172:1071-1077). Frailty was independently associated with a 57% increased odds of death. Higher eGFR at dialysis initiation was significantly associated with increased mortality, but this became non-significant after accounting for frailty, the researchers said. â&#x20AC;&#x153;Recognition of signs and symptoms of frailty by clinicians may prompt earlier initiation of dialysis and may explain, at least in part, the well-described association between eGFR at dialysis initiation and mortality,â&#x20AC;? the authors concluded.

10 Renal & Urology News

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PSA Screening Decreases Risk of Metastatic PCa PSA SCREENING significantly decreases the risk of developing metastatic prostate cancer (PCa), according to findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC). Men randomly assigned to a group to which regular PSA screening is offered

had a 30% reduction in the relative risk of metastatic PCa compared with men assigned to a group not offered such screening (controls), investigators reported online in European Urology. The relative risk reduction was 30% in the intention-to-screen analysis and 42% among men who actually were screened.

Fritz H. Schröder, MD, of Erasmus Medical Center in Rotterdam, The Netherlands, and collaborators analyzed data from 76,813 men aged 55-69 years. Over a median follow-up of 12 years, investigators identified 666 men with metastatic PCa: 256 in the screening arm and 410 in the control arm, for

Brief Summary of Prescribing Information for: OMONTYS (peginesatide) Injection for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE. See full prescribing information for complete boxed warning. Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. • No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks [see Warnings and Precautions]. • Use the lowest OMONTYS dose sufficient to reduce the need for red blood cell (RBC) transfusions [see Warnings and Precautions]. INDICATIONS AND USAGE Anemia Due to Chronic Kidney Disease OMONTYS is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis. Limitations of Use OMONTYS is not indicated and is not recommended for use: • In patients with CKD not on dialysis because of safety concerns in this population [see Warnings and Precautions]. • In patients receiving treatment for cancer and whose anemia is not due to CKD, because ESAs have shown harm in some settings and the benefit-risk factors for OMONTYS in this setting have not been evaluated [see Warnings and Precautions]. • As a substitute for RBC transfusions in patients who require immediate correction of anemia. • OMONTYS has not been shown to improve symptoms, physical functioning or health-related quality of life. CONTRAINDICATIONS OMONTYS is contraindicated in patients with: • Uncontrolled hypertension [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism • In controlled clinical trials of other ESAs in patients with CKD comparing higher hemoglobin targets (13 – 14 g/dL) to lower targets (9 - 11.3 g/dL) (see Table 2), increased risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events was observed in the higher target groups. • Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Use caution in patients with coexistent cardiovascular disease and stroke. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks. • In controlled clinical trials of ESAs in patients with cancer, increased risk for death and serious adverse cardiovascular reactions was observed. These adverse reactions included myocardial infarction and stroke. • In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and deep venous thrombosis (DVT) was observed in patients undergoing orthopedic procedures. The design and overall results of 3 large trials comparing higher and lower hemoglobin targets are shown in Table 2 (Normal Hematocrit Study (NHS), Correction of Hemoglobin Outcomes in Renal Insufficiency (CHOIR) and Trial to Reduce Cardiovascular Events with Aranesp® Therapy (TREAT)).

a cumulative incidence of 0.67% and 0.86% per 1,000 men, respectively. The reduction in metastatic disease must be balanced against the downside of screening, primarily the rate of overdiagnosis in the screening arm, which researchers estimated to be at least 50% in the setting of the ERSPC. ■

Table 2 Adverse Cardiovascular Outcomes in Randomized Controlled Trials Comparing Higher and Lower Hemoglobin Targets in Patients with CKD NHS (N = 1265) 1993 to 1996

CHOIR (N = 1432) Time Period of Trial 2003 to 2006 Patients with CKD Patients with CKD not on dialysis with on hemodialysis hemoglobin with coexisting CHF < 11 g/dL Population or CAD, hematocrit not previously 30 ± 3% on administered epoetin alfa epoetin alfa Hemoglobin Target; Higher vs. Lower 14.0 vs. 10.0 13.5 vs. 11.3 (g/dL) Median (Q1, Q3) 12.6 (11.6, 13.3) 13.0 (12.2, 13.4) Achieved Hemoglobin vs. vs. level (g/dL) 10.3 (10.0, 10.7) 11.4 (11.1, 11.6) Primary Endpoint

TREAT (N = 4038) 2004 to 2009 Patients with CKD not on dialysis with type II diabetes, hemoglobin ≤ 11 g/dL 13.0 vs. ≥ 9.0

12.5 (12.0, 12.8) vs. 10.6 (9.9, 11.3) All-cause mortality, All-cause mortality, All-cause mortality MI, myocardial MI, hospitalization or non-fatal MI ischemia, heart for CHF, or stroke failure, and stroke

Hazard Ratio or 1.28 (1.06 – 1.56) 1.34 (1.03 – 1.74) 1.05 (0.94 – 1.17) Relative Risk (95% CI) Adverse Outcome for All-cause mortality All-cause mortality Stroke Higher Target Group Hazard Ratio or Relative Risk 1.27 (1.04 – 1.54) 1.48 (0.97 – 2.27) 1.92 (1.38 – 2.68) (95% CI) Patients with Chronic Kidney Disease Not on Dialysis OMONTYS is not indicated and is not recommended for the treatment of anemia in patients with CKD who are not on dialysis. A higher percentage of patients (22%) who received OMONTYS experienced a composite cardiovascular safety endpoint event compared to 17% who received darbepoetin alfa in two randomized, active-controlled, open-label, multi-center trials of 983 patients with anemia due to CKD who were not on dialysis. The trials had a pre-specified, prospective analysis of a composite safety endpoint consisting of death, myocardial infarction, stroke, or serious adverse events of congestive heart failure, unstable angina or arrhythmia (hazard ratio 1.32, 95% CI: 0.97, 1.81). Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer receiving ESAs OMONTYS is not indicated and is not recommended for reduction of RBC transfusions in patients receiving treatment for cancer and whose anemia is not due to CKD because ESAs have shown harm in some settings and the benefit-risk factors for OMONTYS in this setting have not been evaluated. The safety and efficacy of OMONTYS have not been established for use in patients with anemia due to cancer chemotherapy. Results from clinical trials of ESAs in patients with anemia due to cancer therapy showed decreased locoregional control, progression-free survival and/or decreased overall survival. The findings were observed in clinical trials of other ESAs administered to patients with: breast cancer receiving chemotherapy, advanced head and neck cancer receiving radiation therapy, lymphoid malignancy, cervical cancer, non-small cell lung cancer, and with various malignancies who were not receiving chemotherapy or radiotherapy. Hypertension OMONTYS is contraindicated in patients with uncontrolled hypertension. Appropriately control hypertension prior to initiation of and during treatment with OMONTYS. Reduce or withhold OMONTYS if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions. Lack or Loss of Response to OMONTYS For lack or loss of hemoglobin response to OMONTYS, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate the patient for the presence of antibodies to peginesatide. In the absence of antibodies to peginesatide, follow dosing recommendations for management of patients with an insufficient hemoglobin response to OMONTYS therapy. Contact Affymax, Inc. (1-855-466-6689) to perform assays for binding and neutralizing antibodies. Dialysis Management Patients may require adjustments in their dialysis prescriptions after initiation of OMONTYS. Patients receiving OMONTYS may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis. Laboratory Monitoring Evaluate transferrin saturation and serum ferritin prior to and during OMONTYS treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course

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SEPTEMBER 2012

Renal & Urology News 11

Renal Impairment Linked to Cystatin C Levels BY LOUISE GAGNON QUEBEC CITY—Early changes in cystatin C levels predict loss of renal function, according to new findings. Elevated serum cystatin C concentration is an emerging marker of early renal dysfunction, independent of albuminuria status, said lead investigator

Francisco J. Martinez-Martin, MD, PhD, an endocrinologist at University Hospital Dr. Negrin, Las Palmas de Gran Canaria, Spain. It is thought to be a more sensitive measure than estimated glomerular filtration rate (eGFR), which is based on creatinine.

of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin every 2 weeks until the hemoglobin is stable and sufficient to minimize the need for RBC transfusion. Thereafter, hemoglobin should be monitored at least monthly provided hemoglobin levels remain stable. ADVERSE REACTIONS The following serious adverse reactions observed during clinical trials with OMONTYS are discussed in greater detail in other sections of the labeling: • Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see Warnings and Precautions] • Hypertension [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of OMONTYS cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. Patients with Chronic Kidney Disease Adverse reactions were determined based on pooled data from two active controlled studies of 1066 dialysis patients treated with OMONTYS and 542 treated with epoetin, including 938 exposed for at least 6 months and 825 exposed for greater than one year to OMONTYS. The population for OMONTYS was 20 to 93 years of age, 58.5% male, and the percentages of Caucasian, Black (including African Americans), and Asian patients were 57.9%, 37.4%, and 3.1%, respectively. The median weight adjusted dose of OMONTYS was 0.07mg/kg and 113 U/week/kg of epoetin. Table 3 summarizes the most frequent adverse reactions (≥ 10%) in dialysis patients treated with OMONTYS. Table 3 Adverse Reactions Occurring in ≥10% of Dialysis Patients treated with OMONTYS Adverse Reactions

Dialysis Patients Treated with OMONTYS (N = 1066)

Gastrointestinal Disorders Diarrhea 18.4% Nausea 17.4% Vomiting 15.3% Respiratory, Thoracic and Mediastinal Disorders Dyspnea 18.4% Cough 15.9% Injury, Poisoning and Procedural Complications Arteriovenous Fistula 16.1% Site Complication Procedural Hypotension 10.9% Nervous System Disorders Headache 15.4% Musculoskeletal and Connective Tissue Disorders Muscle Spasms 15.3% Pain in Extremity 10.9% Back Pain 10.9% Arthralgia 10.7% Vascular Disorders Hypotension 14.2% Hypertension 13.2% General Disorders and Administration Site Conditions Pyrexia 12.2% Metabolism and Nutrition Disorders Hyperkalemia 11.4% Infections and Infestations Upper Respiratory Tract Infection 11.0%

Dialysis Patients Treated with Epoetin (N = 542) 15.9% 19.6% 13.3% 19.4% 16.6% 16.6% 12.5% 15.9% 17.2% 12.7% 11.3% 9.8% 14.6% 11.4%

Dr. Martinez-Martin and his colleagues analyzed data from 91 patients who participated in the OLAS (Olmesartan/Amlodipine vs. Olmesartan/Hydrochlorothiazide in Hypertensive Patients with Metabolic Syndrome) trial. “We wanted to see the early effect of these treatments on

binding antibodies in patients dosed subcutaneously (1.9%) as compared to those dosed intravenously (0.7%). Peginesatide neutralizing antibodies were detected in vitro using a cell-based functional assay in 21 of these patients (0.9%). In approximately half of all antibody-positive patients, the presence of antibodies was associated with declining hemoglobin levels, the requirement for increased doses of OMONTYS to maintain hemoglobin levels, and/or transfusion for anemia of CKD. No cases of pure red cell aplasia (PRCA) developed in patients receiving OMONTYS during clinical trials. DRUG INTERACTIONS No formal drug/drug interaction studies have been performed. Peginesatide does not bind to serum albumin or lipoproteins as demonstrated in in vitro protein binding studies in rat, monkey and human sera. In vitro studies conducted with human hepatocytes or microsomes have shown no potential for peginesatide to induce or inhibit CYP450 enzymes. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Peginesatide was teratogenic and caused embryofetal lethality when administered to pregnant animals at doses and/or exposures that resulted in polycythemia. OMONTYS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of peginesatide by intravenous injection to rats and rabbits during organogenesis was associated with embryofetal toxicity and malformations. Dosing was every third day in rats for a total of 5 doses and every fifth day in rabbits for a total of 3 doses (0.01 to 50 mg/kg/dose). In rats and rabbits, adverse embryofetal effects included reduced fetal weight, increased resorption, embryofetal lethality, cleft palate (rats only), sternum anomalies, unossification of sternebrae and metatarsals, and reduced ossification of some bones. Embryofetal toxicity was evident in rats at peginesatide doses of ≥ 1 mg/kg and the malformations (cleft palate and sternoschisis, and variations in blood vessels) were mostly evident at doses of ≥ 10 mg/kg. The dose of 1 mg/kg results in exposures (AUC) comparable to those in humans after intravenous administration at a dose of 0.35 mg/kg in patients on dialysis. In a separate embryofetal developmental study in rats, reduced fetal weight and reduced ossification were seen at a lower dose of 0.25 mg/kg. Reduced fetal weight and delayed ossification in rabbits were observed at ≥ 0.5 mg/kg/dose of peginesatide. In a separate embryofetal developmental study in rabbits, adverse findings were observed at lower doses and included increased incidence of fused sternebrae at 0.25 mg/kg. The effects in rabbits were observed at doses lower (5% - 50%) than the dose of 0.35 mg/kg in patients. Nursing Mothers It is not known whether peginesatide is excreted in human milk. Because many drugs are excreted into human milk, caution should be exercised when OMONTYS is administered to a nursing woman. Pediatric Use The safety and efficacy of OMONTYS in pediatric patients have not been established. Geriatric Use Of the total number of dialysis patients in Phase 3 clinical studies of OMONTYS, 32.5% were age 65 and over, while 13% were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. OVERDOSAGE OMONTYS overdosage can elevate hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of OMONTYS dosage and/or with phlebotomy, as clinically indicated. Cases of severe hypertension have been observed following overdose with ESAs [see Warnings and Precautions]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide).

14.0%

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

11.8%

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

12.4%

Seizures have occurred in patients participating in OMONTYS clinical studies. During the first several months following initiation of OMONTYS, blood pressure and the presence of premonitory neurologic symptoms should be monitored closely. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency. Allergic reactions have been reported in patients treated with OMONTYS. Discontinue OMONTYS and administer appropriate therapy if a serious allergic, anaphylactic or infusion-related reaction occurs. Immunogenicity Of the 2357 patients tested, 29 (1.2%) had detectable levels of peginesatidespecific binding antibodies. There was a higher incidence of peginesatide-specific

For more detailed information, see the full prescribing information for OMONTYS at www.omontys.com or contact Takeda Pharmaceuticals America, Inc. OMONTYS is a trademark of Affymax, Inc. registered in the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. All other trademarks are the property of their respective owners. ©2012 Takeda Pharmaceuticals America, Inc. March 2012 PEG096 R1

L-DSG-0312-1

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

cystatin C in the OLAS trial and their relationship with long-term changes in renal function,” he said. Findings were presented at the 3rd International Congress on Abdominal Obesity. In the OLAS study, non-diabetic obese, hypertensive patients who had systolic blood pressure (SBP) measurements of 140-179 mm Hg were randomized to receive olmesartan 20 mg/amlodipine 5 mg (60 patients) or olmesartan 20 mg/hydrochlorothiazide (HCTZ) 12.5mg (60 patients). Patients who did not reach the SBP target of less than 140 mm Hg received a double dose of initial therapy at 13 weeks and thereafter. Doxazosin was added at 26 weeks if necessary. At baseline, no patients had clinical renal failure or albuminuria. Dr. Martinez-Martin and colleagues measured fasting plasma cystatin C and albumin-creatinine ratio (ACR) in a morning urine specimen at baseline

Cystatin C changes predicted renal function decline, ACR did not. and weeks 13 and 26. The researchers used the Modification of Diet in Renal Disease (MDRD-4) study formula to estimate GFR at baseline and at every visit, for a total follow-up of three years. Early changes in cystatin C significantly predicted decline in renal function and development of stage 3 nephropathy, whereas changes in ACR did not. Based on study findings, Dr. MartinezMartin said he encourages the use of cystatin C as a marker of kidney function. In addition, the olmesartan/amlodipine combination offered greater renal protection than olmesartan coupled with HCTZ, he said. The olmesartan/amlodipine regimen significantly reduced serum cystatin C by 32.7% at 13 weeks and by 38.4% at 26 weeks, whereas the olmesartan/HCTZ combination reduced serum cystatin C by 3.9% at 13 weeks and 4.6% at 26 weeks. Both combinations reduced ACR in a similar fashion. In addition, the decline in eGFR was significantly slower in the olmesartan/amlodipine arm (1.4 vs. 4.7 mL/min/1.73 m2 per year). The OLAS trial was funded by Pfizer, and Dr. Martinez-Martin has received fees from Pfizer. ■

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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

Finasteride’s Sexual Side Effects May Be Long Term M

Short Takes Late Puberty Lowers Odds of Testicular Cancer LATE ONSET of puberty is associated with a decreased risk for testicular cancer, according to a recent meta-analysis. Early onset had no effect on the risk. In analyses of data from 12 case-controlled studies, Milena Maule, MD, of the University of Turin in Turin, Italy, and colleagues found that, compared with men who started shaving at the same age as their peers, those who started shaving later had a 16% decreased

likelihood of testicular cancer. When the researchers looked at selfreported onset of puberty, they found that late onset was associated with a 33% decreased risk of testicular cancer, as reported online in the International Journal of Andrology.

Psoriasis Raises Sexual Dysfunction Risk MEN WITH psoriasis have a 27% increased risk of devel-

Yi-Ju Chen, MD, PhD, of the National Yang-Ming University in Taipei, and colleagues studied 12,300 men with

oping sexual dysfunction, researchers in Taiwan reported online in the Journal of Sexual Medicine.

en who use finasteride for hair loss may experience sexual dysfunction long after discontinuing the drug, according to new data. Michael S. Irwig, MD, of the Center for Andrology and Division of Endocrinology at The George Washington University in Washington, D.C., prospectively studied 54 young men who at an initial evaluation reported sexual side effects that persisted for at least three months despite stopping finasteride use. At a reassessment 9-16 months later (mean 14 months), persistent sexual side effects continued to be present in 96% of men despite having stopped taking finasteride, Dr. Irwig reported online in the Journal of Sexual Medicine. Using the Arizona Sexual Experience Scale, the researcher found that 89% of subjects met the definition of sexual dysfunction. “It is recommended that prescribers of finasteride, as well as potential users, be aware of the potential serious long-term risks of a medication used for a cosmetic purpose,” Dr. Irwig concluded.

newly diagnosed psoriasis and 61,500 matched controls without psoriasis from Taiwan’s National Health Insurance Database. Psoriasis patients have an increased prevalence of sexual dysfunction at least in part because of physical disfigurement, coexisting atherosclerosis, and psychological problems, according to the researchers.

Big Waists Predict More Severe Urinary Symptoms MEN WITH larger waists are more likely to have urinary frequency and erectile dysfunction than men with smaller waists, data show. In a study of 409 men with moderate or severe lower urinary tract symptoms, Steven A. Kaplan, MD, of Weill Medical College in New York, and colleagues found that the proportion of men with urinary frequency (eight or more voids in 24 hours) was 39% for subjects with a waist size of 100 cm or greater, 27% for those with a waist size of 90-99 cm, and 16% for those with a waist size less than 90 cm, according to a report published online in BJU International. The proportion of men with erectile dysfunction was 74.5%, 50%, and 32%, respectively.

Testosterone Replacement Therapy Safe for the Prostate W

ith proper clinical monitoring, testosterone therapy is safe for the prostate, British researchers concluded. In an online report in the Journal of Sexual Medicine, Mark R. Feneley, MD, of University College Hospital London, and Malcolm Carruthers, MD, of the Center for Men’s Health in London, wrote that the main concern limiting the introduction of testosterone replacement therapy (TRT) in men relates to the progression of undiagnosed PCa or its development with advancing age. Drs. Feneley and Carruthers studied 1,365 men aged 28-87 years with symptomatic androgen deficiency and receiving testosterone replacement therapy (TRT). Over a 20-year period, 14 new PCa cases were diagnosed after 2,966 man-years of treatment (one case per 212 years). The incidence of PCa was equivalent to that expected in the general population, they reported. “Testosterone treatment with regular monitoring of the prostate may be safer for the individual than any alternative without surveillance,” the authors wrote.

Erectile Dysfunction Linked to Hemorrhoids Hemorrhoids may increase the risk of erectile dysfunction (ED), according to Lin, MD, of Taipei Medical University, studied 6,310 men with ED and compared them with 31,550 randomly selected controls. A total of 1,572 (24.9%) ED patients and 4,491 (14.2%) controls had a history of hemorrhoids. Compared with controls, ED patients were nearly twice as likely to have a history of hemorrhoids after adjusting for hypertension, diabetes, coronary heart disease, and other potential confounders, researchers reported online in the International Journal of Andrology. ED patients younger than 30 years were 3.7 times as likely to have had hemorrhoids.

MEDISTAT

researchers in Taiwan. The investigators, Joseph J. Keller, MD, and Herng-Ching

76.2

is the average life expectancy from birth (in years) for a man in the U.S. in 2010, according to the latest federal statistics. For women, it is 81.1 years.

Source: National Center for Health Statistics

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Oral nutrition beneficial continued from page 1

who received ONS during HD (case patients) at Fresenius Medical Care North America (FMCNA) facilities and had at least one albumin level of 3.5 g/dL or less. They compared their outcomes to those from another 21,347 patients who also had at least one albumin level of 3.5 g/dL or less but did not receive ONS (controls). None of the subjects was receiving ONS outside of the HD center. The patients receiving ONS could choose among four products: NeproCarb Steady, ProStat RC, ZonePerfect, and VitalProteinRX. The study included an intent-totreat (ITT) population consisting of 5,227 case patients propensity-score matched with 5,227 controls. From the same patient population, they created an as-treated cohort consisting of 4,289 case patients propensity-score matched with 4,289 controls. The characteristics of the matched pairs in both the ITT and as-treated analyses were similar, researchers noted, including mean baseline albumin levels of 3.3 g/dL in all groups. However, the as-treated ONS patients had been on dialysis slightly longer than the as-treated control patients, with a mean of 3.89 vs. 3.60 years.

Improved survival The crude death rates in the ITT cohort were 30.1% for the ONS group and

RCC in transplant patients continued from page 1

also had a significantly higher rate of a papillary RCC (44% vs. 22%) and a significantly lower rate of clear cell RCC (50% vs. 77%). Nodal and distant metastasis rates were significantly higher in dialysis-only patients.

The survival benefit may be due to earlier cancer diagnosis. In addition, the five-year cancerspecific survival rates were 97% and 77% for transplanted and dialysis-only patients, respectively. The five-year progression-free survival rates were 88% and 52%, respectively. After controlling for multiple variables, only T stage remained an independent predictor of cancer-related death.

Nutritional Supplement Use in CKD T. Alp Ikizler, MD, a leading authority on the use of diets and supplements to improve outcomes patients with chronic kidney disease (CKD), has proposed an algorithm for the assessment, treatment, and monitoring of nutritional and metabolic derangements in this population. In the algorithm, the indications for nutritional intervention are: • Poor appetite and/or poor oral intake; • Unintentional loss of weight and development of sarcopenia; • Albumin less than 40 g/L* or pre-albumin less than 300 mg/L; • Malnutrition-inflammation score of 5 or higher or subjective global assessment in malnourished range; • Dietary protein intake less than 1.0 g/kg/day (CKD stage 5) or less than 0.5 g/kg/day (CKD stages 1-4). One to two servings/day of CKD-specific oral nutritional supplements (ONS) should be started at: • CKD stages 1-4 and renal-transplant recipient; dietary protein intake target of approximately 0.6 g/kg/day (possibly including amino acids and/or ketoanalogues); • CKD stage 5D; dietary protein intake target of greater than 1.2 g/kg/day using ONS at home and in-center meals and ONS during dialysis treatment. If monthly assessment shows improvement and albumin reaches 40 g/L, the in-center meals and ONS should be continued to maintain dietary protein intake of 1.2 g/kg or more (CKD stage 5) or approximately 0.6 g/kg/day (CKD stages 1-4) and dietary energy intake 30-35 kcal/kg/day; liquid oral supplement with pill intake should also be considered. Patients for whom monthly assessment indicates no improvement or deterioration should receive larger quantities of oral therapy, tube feeding and parenteral interventions such as intradialytic parenteral nutrition, particularly if enteral feeding is not possible. *Government regulations in the U.S. allow ONS only to dialysis patients with albumin levels of 3.5 g/dL or below

30.4% for the controls, while they were 30.9% and 37.3%, respectively, in the as-treated cohort. These extremely high death rates reflect that hypoalbuminemic patients belonged to the worst risk group in the maintenance HD population because they are severely malnourished, the investigators explained in the AJKD paper.

Overall, ONS patients had 9% increased survival than controls in the ITT analysis and 34% increased survival in the as-treated analysis. The difference in outcomes between the two models is because in the ITT analyses, 40% of the patients in the control group did receive some ONS during the followup period. Additional analyses showed

that the greatest effect of supplements on the death rate was among those with baseline albumin levels of 3.2 g/ dL or less. In other words, the worse the malnutrition, the more effective is ONS. The observed difference in survival represents a major finding that sup-

Earlier diagnosis of RCC in transplant recipients is the main hypothesis that explains their findings, researchers said. “Transplanted patients were likely to have their native kidneys monitored by a surgeon more frequently than dialysis-only patients,” the researchers stated. In French centers, they noted, urologists perform surgical monitoring of renal transplant patients and nephrologists follow dialysis patients. However, that transplanted and dialysis-only patients differed in their RCC pathologic subtypes, suggesting differences in the tumorigenesis process. In a study published last year in European Urology (2011;60:366-373), another French team reported on a retrospective study showing that RCC arising in native kidneys of ESRD patients appears to exhibit many favorable clinical, pathologic, and outcome features compared with RCC diagnosed in patients in the general population. The study included 1,250 RCC patients (303 with ESRD and 947 from the general population). ■

PCa linked to cadmium

Their study is the first prospec tive investigation examining the relationship between dietary cadmium exposure and PCa risk, according to the researchers. Earlier epidemiological studies have found an association between occupational exposure to cadmium and PCa. In a previous case-control study of the relationship between toenail cadmium and PCa risk in Italy, investigators found a 4.7 times increased risk of PCa in men in the highest quartile of toenail cadmium concentration compared with those in the lowest quartile, according to a report in Science of the Total Environment (2007;373:77-81). Men in the third quartile had a 30% increased risk. However, a case-control study conducted in the United States found that median toenail cadmium concentrations did not differ significantly between PCa cases and controls, and PCa risk did not rise with increasing concentrations of cadmium, researchers reported in Prostate (2002;52:288-296). ■

continued from page 1

Experimental data suggest that cadmium, a toxic metal, is a prostate carcinogen that is widely dispersed in the environment, Dr. Julin’s team noted. Farmland has become contaminated with the metal, so food constitutes the main source of exposure in the nonsmoking population, they stated. Lung cancer has been linked to occupational exposure to cadmium. For the study, men were followed from 1998 through 2009. The mean follow-up period was 10.8 years, during which 3,085 PCa cases were diagnosed (894 localized, 794 advanced, and 326 fatal). The researchers estimated dietary cadmium exposure using food frequency questionnaires that subjects filled out at baseline in 1998. Data on the cadmium contents of foods were provided mainly by the Swedish national Food Agency. Bread, potatoes, and root vegetables were among the main contributors of dietary cadmium.

continued on page 15

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Oral nutrition beneficial continued from page 14

ports what has long been proposed: that increasing protein and caloric intake during thrice-weekly HD treatments may facilitate achieving sufficient nutritional support and improve physiologic processes enough to reduce their high risk of mortality,” Dr. Hakim and his colleagues stated in their paper. They strongly recommended “that int-

was significantly longer in intradialytic ONS patients compared with controls. The average hospitalization rates were 2.5 and 2.7 episodes/patient-year in the two groups, respectively. In addition, the ONS and controls group had 19.2 and 20.4 hospitalization days/patientyear, respectively, and 29.4% and 36.6% mortality rates, respectively. Also at the symposium, T. Alp Ikizler, MD, also of Vanderbilt, stressed the

SEPTEMBER 2012

importance of boosting nutrition among patients with chronic kidney disease (CKD) when indicated, an approach used widely around the world but not in North America. Although eating meals during dialysis potentially could be associated with a small risk of hypotension and some inconvenience for dialysis center staff, it can counteract HD-related protein catabolism, improve patients’ nutri-

Renal & Urology News 15

tional status, increases their dialysis adherence, and enhance phosphate and fluid removal, Dr. Ikizler said. He discussed these points in detail in a recent review article, which also included a proposed algorithm for nutritional support in CKD patients (Nature Rev Nephrol 2011;7:369-384). He also discussed the algorithm in detail at the congress (see related article on page 14). ■

Intradialytic ONS patients had a longer time to first hospitalization. radialytic oral nutrition be offered as a treatment option to eligible hypoalbuminemic maintenance-hemodialysis patients.” In a separate presentation at the meeting, Dr. Lacson, using the same study population, showed that intradialytic ONS reduces the risk of hospitalization and the length of hospital stay compared to not receiving intradialytic ONS. The time to first hospitalization

Study Links High-Grade PCa to MS

It’s time to turn OAB on its head.

OAB remains a problem for many patients As the number of patients diagnosed with overactive bladder (OAB) continues to grow, so does the need for improved prevention, diagnosis, and management.1 For many Americans now living with OAB, the disease can have a signiﬁcant negative impact on their quality of life. 2,3 Current OAB treatments may work well for some, but they are not for everyone.4

METABOLIC SYNDROME (MS) is associated with an increased risk of more aggressive prostate cancer (PCa), according to researchers in Spain. In a study of 2,408 men who underwent prostatic biopsies, Juan Morote, MD, of Vall d’Hebron Hospital and Research Institute, and his coinvestigators observed no significant

Why are many patients suffering despite current therapeutic options? One potential reason is lack of persistence with OAB therapy.5 While discontinuation of therapy is a signiﬁcant issue among patients with chronic conditions, OAB therapy has demonstrated a higher rate of discontinuation compared with other drug classes.5 In a 2008 study investigating discontinuation rates of OAB therapy in the UK,* the median time to discontinuation was 4.76 months, with 77% of patients discontinuing their OAB treatment by 1 year.6

difference in the detection rate of PCa overall between men with MS and those without it (34.5% and 36.4%, respectively), according to a online report in BJU International. They did find, however, that patients with MS had a significantly higher rate of highgrade PCa (Gleason score 8-10) than those without MS (35.9% vs. 23.9%). Multivariate analyses confirmed that

*A national health record database of women under the care of general practitioners in the UK (National Health Service).6 References: 1. Irwin DE, Kopp ZS, Agatep B, Milsom I, Abrams P. Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. BJU Int. 2011;108:1132-1138. 2. Coyne KS, Sexton CC, Irwin DE, Kopp ZS, Kelleher CJ, Milsom I. The impact of overactive bladder, incontinence and other lower urinary tract symptoms on quality of life, work productivity, sexuality and emotional well-being in men and women: results from the EPIC study. BJU Int. 2008;101:1388-1395. 3. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20:327-336. 4. Benner JS, Nichol MB, Rovner ES, et al. Patient-reported reasons for discontinuing overactive bladder medication. BJU Int. 2009;105:1276-1282. 5. Yeaw J, Benner JS, Walt JG, Sian S, Smith DB. Comparing adherence and persistence across 6 chronic medication classes. J Manag Care Pharm. 2009;15:728-740. 6. Gopal M, Haynes K, Bellamy SL, Arya LA. Discontinuation rates of anticholinergic medications used for the treatment of lower urinary tract symptoms. Obstet Gynecol. 2008;112:1311-1318.

MS was not associated with the risk of PCa, but was associated with a significant 75% increased risk of highgrade tumors. ■

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On the Forefront

Urologists and nephrologists working together: an emerging model of patient care

Robotic NSS without Ischemia for Exophytic Small Renal Masses BY ANTHONY N. AVALLONE, MD

leveland Clinic’s Glickman Urological & Kidney Institute has pioneered a practice model that lends itself to close cooperation between nephrology and urological surgery. This pairing of the medical and surgical teams has improved our ability to treat renal cell carcinoma (RCC) while minimizing subsequent development of chronic kidney disease

increasing emphasis has been placed on reducing surgical morbidity. The 3D vision and wristed instruments of robotic technology have allowed many surgeons to master minimally-invasive partial nephrectomy for tumor removal and renal reconstruction compared to conventional laparoscopic partial nephrectomy. Nevertheless, robotic partial nephrectomy requires a period of warm ischemia time (WIT.) Warm ischemia, compared to cold ischemia, is more likely to have

Figure 1. Small exophytic renal mass has been isolated.

(CKD.) To treat selected small renal masses and decrease the incidence of developing CKD, we have begun to employ non-ischemic nephron-sparing surgery (NSS) during robotic partial nephrectomy. The ability to treat RCC with nephronsparing surgery has seen a significant decrease in the development of chronic kidney disease (CKD) compared to the era when radical nephrectomy was routinely employed. As nephron-sparing surgery has become widely accepted,

Contemporary studies now suggest the amount of renal parenchyma remaining after partial nephrectomy is the main determinant of subsequent renal function. This, however, is a non-modifiable factor. Decreasing or eliminating WIT, however, is a modifiable factor that can improve functional nephrologic outcomes. Techniques that require isolating and controlling segmental renal vessels are technically complicated, making widespread adoption difficult.

Figure 2. Renorrhapy sutures are being placed with tumor in situ.

a negative impact on subsequent renal function. WIT can result in the development of acute kidney injury (AKI), CKD, and even permanent dialysis. Furthermore, many incidental renal masses are discovered in elderly patients and those with diabetes and hypertension. The incidence of CKD in these patients is 38%, 35%, and 29%, respectively. As CKD predisposes to AKI, any attempt to minimize or eliminate WIT during robotic partial nephrectomy could potentially decrease or avoid renal injury.

gist, the surgeon secures the exposed renal parenchyma with several running sutures and then tightly secures the renorrhapy sutures. Rolled hemostatic fabric and other agents are often used to obtain optimal hemostasis. The pressure of the pneumoperitoneum is then reduced to assess for bleeding. Although renorrhapy sutures are widely use for renal reconstruction after tumor removal during robotic partial nephrectomy, our novel approach of

Figure 3. The tumor is being excised without hilar clamping.

Our procedure, though, is easily transferable as it uses techniques familiar to most surgeons performing robotic renal procedures. The technique we have begun to use in selected patients with solitary or multiple small exophytic renal tumors uses pre-placement of renorrhapy sutures prior to tumor removal (Figures 1 and 2). These are partially tightened, affording a relatively bloodless field. After tumor removal, while awaiting frozen section results from the patholo-

placing them prior to tumor excision (Figure 3) without cross-clamping the renal hilum avoids subjecting the kidney to any renal ischemia. This lack of WIT minimizes the potential for renal damage. Furthermore this approach to NSS uses familiar techniques and is easily mastered by robotic surgeons currently performing renal surgery. ■ Anthony N. Avallone, MD, is a urologist at the Cleveland Clinic’s Glickman Urological & Kidney Institute.

Cleveland Clinic No. 1 for Urology, Nephrology lence in patient care, as well as our

GLICKMAN AT A GLANCE

and urology programs, which are

by this recognition, which acknowledges

commitment to expanding diagnostic

Founded: 2008

housed at the Glickman Urological &

the talent and dedication of the

and treatment options for our patients

Number of nephrologists: 24

Kidney Institute, are each ranked

entire institute team at all levels in

through innovation and research.”

Number of urologists: 59

no. 1 in the nation, according to U.S.

both urology and nephrology,” said

U.S. News & World Reports evaluated

News & World Report’s “Best Hospitals

Glickman Institute Chairman Eric A.

nearly 5,000 hospitals, with fewer than

more than 12,000

2013. The clinic also ranked no. 1 in

Klein, MD. “It’s a reflection of our

150 scoring high enough to be ranked

Number of outpatient

cardiology/heart surgery.

dedicated teamwork focusing on excel-

in even one category. ■

visits in 2011: approximately 75,000

CLEVELAND CLINIC’S nephrology

“We are delighted and humbled

Number of cases in 2011:

www.renalandurologynews.com

SEPTEMBER 2012

Renal & Urology News 17

Electronic Health Records Are For You & QA

Nobody had to ask Oliver Khakmahd, MD, twice to implement an electronic health record (EHR) system in his large,

busy nephrology practice. He was ahead of the game by developing his own computerized program at the East Bay Nephrology Medical Group (Oakland, Calif.) and Oakland’s Dialysis Access Center, where he is the medical director. For physicians less enthusiastic or simply overwhelmed by the prospect of converting to EHRs, Dr. Khakmahd outlines why their practices need to go electronic and how to make that happen. How big is your practice? Dr. Khakmahd: We have 18 nephrologists, two nurse practitioners, and two physician assistants throughout the four offices in our practice, which covers a 35-mile range in the East Bay area of San Francisco. We have more than 900 dialysis patients, 14 dialysis units, two access centers, and five hospitals to cover.

When did you start implementing an EHR system? Dr. Khakmahd: I have a bioengineering background, so back in 2005 I had developed a chronic kidney disease database that we used to track the patients. And four of our doctors had jumped into that implementation. Then, when the government started having these regulations about adopting electronic medical record [EMR] systems, we thought about certifying my database by one of the government certifying agencies, but since I was just a one-man operation in terms of developing the software and expanding on it, we decided to go with a proprietary software that I don’t have to keep up with. So in early 2011, to maximize our government incentives, we sent requests for proposals for a certified EMR system that is useful and practical in a nephrology practice.

How did you choose your vendor? Dr. Khakmahd: We pursued certified technology that is nephrology-practicefriendly and we wanted a superb support team. After multiple demos from different vendors, we decided on Falcon EHR. You need a vendor with a strong

backbone and with a support team that does not rest until all the problems are resolved, understands nephrology workflows, and is always available.

How did you prepare in-house? Dr. Khakmahd: We created a committee of four physicians who were interested in EHR implementation, and we got input from those people, because in a large practice, when you have 18 strong ideas, things may go in the wrong direction and not be productive. The committee members were not all particularly computer-savvy, but they were from all different areas of our practice and represented different age groups. With that input, we developed a clear-cut project plan with reasonable, measurable goals.

We went live on September 12, 2011. We didn’t have much time to meet the [Centers for Medicare & Medicaid Services, or CMS] Meaningful Use requirements that way, but we had set our goals to meet the requirements in 2011. I was the physician champion on the team, so I sent weekly reminders and newsletters to keep the users informed about what was happening, and we had adequate support from Falcon, and everybody was engaged in the implementation process.

What unique characteristics of a nephrology practice make EHR adoption particularly challenging? Dr. Khakmahd: As nephrologists we go to the dialysis units, we go to the office, we go to the hospital, and we go to some community clinics and access centers, so we are all over the place. We wanted something that would be available online and available everywhere we go, so everybody could do their documentation in one place, from wherever they are. Patients also move from place to place—they come to the office, they get hospitalized and they go to the dialysis unit, and they go to the access center, and they go back to dialysis. Having all the documentation and charting in

one readily available place leads to better patient care.

Does EHR adoption make sense for small nephrology practices and solo practitioners? Dr. Khakmahd: We deal with complex patients on lots of medications and a lot of lab work. Having those lab interfaces and being able to analyze the reports in one place and being able to track and reconcile medications for the patient is a big advantage, whether you’re one physician or one of 18 physicians. EHR adoption improves patient care and promises to reduce errors and improve safety over the long term. CMS and the government have a lot of new regulations nowadays, and if you’re in an era of accountable care, you need an infrastructure that supports those mandates. It is crucial for all practices to look at their infrastructure, and having an electronic medical record system is one part of that infrastructure. The government incentives are a good reason for everybody to try to convert to an electronic record system. CMS has already warned all of us that reimbursements will be reduced if we don’t adopt electronic records by 2015, but has also promised some incentives for early adoption. So each practice has a choice of adopting early and getting the incentives that can help pay for the electronic medical records system, or procrastinating and paying out of pocket and facing cuts in reimbursements. It’s better to do it now.

What did following the project plan entail?

What advice can you give the nephrologist who doesn’t know where to begin?

Dr. Khakmahd: We started this project in March 2011, and we spent most of our summer reviewing our workflows and our practice processes, redesigning our exam rooms so that the computers could easily fit in and not interfere with patient interaction, and creating the templates for different clinics that we offer. For example, we have erythropoietin, CKD, and transplant clinics, so we designed the templates for the medical records to meet the needs of each. With the help of Falcon EHR support team, we also spent some time converting some of our old system data and demographics into formats compatible with the new system, so we had a ready-to-go system.

Dr. Khakmahd: As with any type of adoption, at the beginning everything is scary. Start with a project plan in place, look at your workflows in advance, and engage everyone in your office, including the office staff and support services. Everybody in the office needs to be on the same page in order to move forward successfully. You need to have meetings with your staff and your vendor so you can find the problems and solutions to the problems. If you want to have a successful implementation, everybody on the team must be involved and those falling behind should be encouraged. The CMS EHR incentive website has a lot of good resources and education material. ■

You need a vendor with a strong backbone and with a superb support team. — Oliver Khakmahd, MD

SEPTEMBER 2012

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7.2 Cyclosporine (CYP3A4/P-gp inhibitor and CYP3A4 substrate) The steady-state Cmax and AUC estimates of everolimus were significantly increased by co-administration of single dose cyclosporine. [See Clinical Pharmacology (12.3) in the full prescribing information] Dose adjustment of everolimus might be needed if the cyclosporine dose is altered. [See Dosage and Administration (2.3) in the full prescribing information] Everolimus had a clinically minor influence on cyclosporine pharmacokinetics in transplant patients receiving cyclosporine (Neoral). 7.3 Ketoconazole (Strong CYP3A4 Inhibitor) Multiple-dose ketoconazole administration to healthy volunteers significantly increased single dose estimates of everolimus Cmax, AUC, and half-life. It is recommended that strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) not be co-administered with everolimus. [See Warnings and Precautions (5.11), and Clinical Pharmacology (12.3) in the full prescribing information] 7.4 Erythromycin (Moderate CYP3A4 Inhibitor) Multiple-dose erythromycin administration to healthy volunteers significantly increased single dose estimates of everolimus Cmax, AUC, and half-life. If erythromycin is co-administered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary. [See Clinical Pharmacology (12.3) in the full prescribing information] 7.5 Verapamil (CYP3A4 and P-gp Substrate) Multiple-dose verapamil administration to healthy volunteers significantly increased single dose estimates of everolimus Cmax and AUC. Everolimus half-life was not changed. If verapamil is co-administered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary. [See Clinical Pharmacology (12.3) in the full prescribing information] 7.6 Atorvastatin (CYP3A4 substrate) and Pravastatin (P-gp substrate) Single-dose administration of everolimus with either atorvastatin or pravastatin to healthy subjects did not influence the pharmacokinetics of atorvastatin, pravastatin and everolimus, as well as total HMG-CoA reductase bioreactivity in plasma to a clinically relevant extent. However, these results cannot be extrapolated to other HMG-CoA reductase inhibitors. Patients should be monitored for the development of rhabdomyolysis and other adverse events as described in the respective labeling for these products. 7.7 Simvastatin and Lovastatin Due to an interaction with cyclosporine, clinical studies of everolimus with cyclosporine conducted in kidney transplant patients strongly discouraged patients with receiving HMG-CoA reductase inhibitors such as simvastatin and lovastatin. [See Warnings and Precautions (5.12)] 7.8 Rifampin (Strong CYP3A4) Inducers Pre-treatment of healthy subjects with multiple-dose rifampin followed by a single dose of everolimus increased everolimus clearance and decreased the everolimus Cmax and AUC estimates. Combination with rifampin is not recommended. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) in the full prescribing information] 7.9 Other Possible Interactions Moderate inhibitors of CYP3A4 and P-gp may increase everolimus blood concentrations (e.g., fluconazole; macrolide antibiotics; nicardipine, diltiazem; nelfinavir, indinavir, amprenavir). Inducers of CYP3A4 may increase the metabolism of everolimus and decrease everolimus blood concentrations (e.g., St. John’s Wort [Hypericum perforatum]; anticonvulsants: carbamazepine, phenobarbital, phenytoin; efavirenz, nevirapine). 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of everolimus in pregnant women. In rats and rabbits, everolimus crossed the placenta and was toxic to the conceptus. The potential risk for humans is unknown. Everolimus should be given to pregnant women only if the potential benefit to the mother justifies the potential risk to the fetus. Women of childbearing potential should be advised to use effective contraception methods while they are receiving everolimus and up to 8 weeks after treatment has been stopped. Everolimus administered daily to pregnant rats by oral gavage at 0.1 mg/kg from before mating through organogenesis resulted in increased preimplantation loss and early resorptions of fetal implants. AUCs in rats at this dose were approximately one-third those in humans administered the starting dose (0.75 mg twice daily). Everolimus administered daily by oral gavage at 0.8 mg/kg to pregnant rabbits during organogenesis resulted in increased late resorptions of fetal implants. At this dose, AUCs in rabbits were slightly less than the AUCs in humans administered the starting clinical dose. 8.3 Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites readily transferred into milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, women should avoid breast-feeding during treatment with Zortress. 8.4 Pediatric Use The safe and effective use of Zortress in kidney transplant patients younger than 18 years of age has not been established. [See Clinical Pharmacology (12.4) in the full prescribing information] 8.5 Geriatric Use There is limited clinical experience on the use of Zortress in patients of age 65 or older. There is no evidence to suggest that elderly patients will require a different dosage recommendation from younger adult patients. [See Clinical Pharmacology (12.4) in the full prescribing information] 8.6 Hepatic Impairment No dosage adjustment is needed for patients with mild hepatic impairment (Child-Pugh Class A). In patients with moderate hepatic impairment (Child-Pugh Class B), the daily dose needs to be reduced by one-half recommended initial daily dose. There is no information on the effects of severe hepatic impairment (Child-Pugh Class C) on everolimus pharmacokinetics. [See Clinical Pharmacology (12.3) in the full prescribing information] 8.7 Renal Impairment No dose adjustment is needed in patients with renal impairment. [See Clinical Pharmacology (12.3) in the full prescribing information] 10 OVERDOSAGE Reported experience with overdose in humans is very limited. There is a single case of an accidental ingestion of 1.5 mg everolimus in a two-year-old child where no adverse reactions were observed. Single doses up to 25 mg have been administered to transplant patients with acceptable acute tolerability. Single doses up to 70 mg (without cyclosporine) have been given with acceptable acute tolerability. General supportive measures should be followed in all cases of overdose. Everolimus is not considered dialyzable to any relevant degree (<10% of everolimus removed within 6 hours of hemodialysis). In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed after single oral doses of 2000 mg/kg (limit test) in either mice or rats. Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2012-110 April 2012

Ketoanalogues May Help Delay Dialysis Initiation BY ROSEMARY FREI, MSc HONOLULU—Adding ketoanalogues to very low-protein diets for patients with chronic kidney disease (CKD) could significantly delay dialysis initiation, according to new data presented at the XVI International Congress on Nutrition and Metabolism in Renal Disease. A recent Romanian study indicated that patients on a ketoanalogue-supplemented very-low-protein diet (sVLPD) had a slower decline in renal function than patients on a conventional low-protein diet (LPD). To evaluate the effectiveness of sVLPD as compared to the conventional LPD, Liliana Garneata, MD, PhD, Assistant Professor of Nephrology, Gabriel Mircescu, MD, PhD, Professor of Nephrology, and colleagues at the “Dr Carol Davila” Teaching Hospital of Nephrology in Bucharest, performed a randomized trial at their institution that included 207 adult patients with an eGFR of less than 30 mL/min/1.73 m2 without uremic complications, feeding inability, or relevant comorbid conditions. Diabetic patients were not considered for enrollment because of the difficulty to achieve the recommended energy intake while restricting both proteins and carbohydrates in the diet. The sVLPD consisted of 0.3 g of vegetable proteins/kg/day plus one capsule of Ketosteril/5 kg/day, while the LPD comprised 0.6 mixed proteins/kg/day. The overall energy intake of each diet was approximately 30 kcal/kg/day. Optimum blood pressure control was achieved and maintained during the study, with similar proportions in both groups taking antihypertensive medications, and, specifically, ACE inhibitors. Only 11% of the patients on sVLPD patients required dialysis during the 48 weeks of follow-up compared with 30% of the LPD subjects, a difference that was statistically significant. Furthermore, the time to end-stage renal disease was significantly longer with sVLPD (33 vs. 19 weeks), and the decline in eGFR was slower with sVLPD than LPD (2.1 vs. 4.9 mL/min/1.73 m2). “This represents a 57% slower decline in their renal function, which translates into a gain of almost one year without the need for dialysis,” Dr. Garneata explained. “These patients were safely managed by nutritional intervention and monitoring for almost one year, rather than having to go on dialysis immediately.” These

data, she noted, are consistent with those of similar studies published previously by Walser M et al (J Am Soc Nephrol 1999;10:110-116) and Brunori G et al (Am J Kidney Dis 2007;49:569-580), as well as to those of a recent meta-analysis by Fouque D et al (Cochrane Database Syst Rev 2009;3:CD001892). The researchers also observed an amelioration of certain metabolic disturbances of advanced CKD with sVLPD (lower serum urea levels and better control of acidbase balance and calcium-phosphorus

22 Renal & Urology News

Supplements added to very-low-protein diets slowed eGFR decline, data show. metabolism abnormalities), which allowed postponement of dialysis initiation. A delay in dialysis start also translates into cost-savings, as the same group led by Dr. Garneata and Dr. Mircescu found in an earlier study (J Ren Nutr 2009;19[Suppl 5]:S19-S21). The authors determined that use of sVLPD in stage 4/5 CKD patients and the resultant delay of dialysis would result in a 10% reduction in costs. Nutritional status was well preserved in both groups throughout the study, thus showing that sVLPD does not lead to malnutrition, Dr. Garneata noted. In daily practice, Dr. Garneata and Dr. Mircescu consider VLPD in selected patients with stages 4/5 CKD who adhere closely to a conventional diet, have a good nutritional status, are decidedly motivated to postpone dialysis, and have enough social and family support to allow them to follow the special diet. ■

www.renalandurologynews.com

SEPTEMBER 2012

Renal & Urology News 23

Renal Nutrition Update P

rioritizing dietary interventions in patients with renal disease can be difficult because of the multitude of associated complications. Thus, it is important to choose the most appropriate intervention at a given time. Sodium restriction is beneficial for reducing blood pressure (BP), and chronic kidney disease (CKD) frequently is associated with hypertension (Lancet 2002;23;359:1004-1010). Controlling high BP can aid in slowing CKD progression, but the appropriate level of treatment is of concern in the wake of several studies showing that more conservative BP goals did not confer benefits in terms of cardiovascular outcomes and CKD progression.

Role of albuminuria A recent study published online ahead of print by Yan et al (PLoS One 2012;7:e37837) aimed to evaluate new data suggesting that individuals with higher levels of proteinuria may be better targets for intensive BP control. The study used data collected by the National Health and Nutrition Examination Survey (NHANES) from 1999-2006. The study included 12,440 adults without diagnosed kidney disease, diabetes, or cardiovascular disease. Researchers categorized subjects into four BP groups: normotension, prehypertension, undiagnosed hypertension, and diagnosed hypertension. Factors

nicity, non-smoker status, non-drinker status, energy intake, and albumin/ creatinine ratio below 30. Stratifying the groups by estimated glomerular filration rate (eGFR), an overall eGFR below 60 mL/min/1.73m2 (specifically eGFR ranges of 45-59 and 30-44) was significantly and positively associated with hypertension status. Among subjects with an albumin/creatinine ratio of 30 or higher, the association between eGFR below 60 and hypertension status was much stronger. In other words, those with renal impairment appear to be much more likely of having hypertension if albuminuria is present. This factor is important because it may offer new assessment criteria when considering whether intensive BP control regimens are necessary. The limitation of these data is that no factor can be clearly deemed causative. Consequently, it is uncertain if the hypertension is inducing the renal impairment and albuminuria, if the renal impairment and albuminuria are inducing the hypertension, or whether the entire relationship is correlative in general.

Systematic review The results from this study add to a growing pool of evidence that patients with early proteinuria may be good targets for intense BP control. A systematic review by Upadhyay et al (Ann Intern Med 2011;154:541-548) reviewed three

Data from various studies suggest that more conservative blood pressure goals confer benefits in the presence of proteinuria. significantly and positively associated with hypertension included less than a high school education, an annual household income below $25,000, sedentary lifestyle, body mass index less than 30 kg/m2, and albumin-creatinine ratio of 30 mg/g or greater. Factors significantly and negatively associated with hypertension included Mexican-American eth-

trials and their data regarding BP control, kidney disease, and proteinuria. These studies include the Modification of Diet in Renal Disease (MDRD) study, the African American Study of Kidney Disease and Hypertension (AASK), and the Ramipril Efficacy in Nephropathy 2 (REIN-2) trial. The MDRD study followed 585 patients with an eGFR of

ÂŠ THINKSTOCK

Proteinuria in patients with kidney disease may indicate a need for intensive sodium restriction BY GRISSIM CLARK CONNERY, MS, RD, LD

Patients should be cautioned to avoid smoked and cured meats with high sodium content.

25-55 and 255 patients with an eGFR of 13-24. These patients were randomized to a usual or high protein diet and to one of two BP targets: 140/90 or 130/80 mm Hg. ACE inhibitors were favored, followed by calcium channel blockers. In the AASK trial, patients were stratified into one of three medication regimens and were stratified into either a normal or low BP target group. The REIN-2 trial included individuals with proteinuria of 1,000-3,000 mg/day and creatinine clearance less than 45 mL/ min and those with proteinuria above 3,000 mg/day and creatinine clearance below 70. Individuals were stratified into either a normal or low BP group and treated with felodipine in addition to their other medications. None of the trials demonstrated a direct benefit of a low BP goal in reducing complications during the trials. With respect to proteinuria, AASK trial results demonstrated that subjects with low BP targets who had a protein/creatinine ratio above 0.22 g/g (approximately more than 300 mg proteinuria/day) had significantly improved outcomes during the trial and follow up. The MDRD study demonstrated a benefit in low BP targets for patients with greater than 1000 mg proteinuria/day in trial A and more than 3,000 mg proteinuria/ day in trial B.

Adverse drug effects The primary concern with intensive BP control regimens is the potential adverse complications from the medications themselves. Each trial showed an increase in adverse events in the low BP groups that were attributed to higher doses of medication. Overall, though, the data from these studies indicate that more conservative BP goals do confer benefits in the presence of proteinuria. Therefore, more rigorous sodium restrictions may be of benefit when trying to reach these goals by helping reduce the necessary dosages. Current guidelines from the Kidney Disease Outcomes Quality Initiative (KDOQI) recommend a sodium restriction of 2,000 mg/day. Meanwhile, the 2010 Dietary Guidelines for Americans recommends a reduction of sodium to 1,500 mg/day for at-risk individuals, including those with hypertension. These guidelines are often tough for new patients without adequate dietary education, but evidence supports the need for a stronger nutritional intervention in controlling BP, especially for patients with elevated proteinuria. In addition, these data may offer potential as a screening tool for gauging appropriate dietary interventions. â&#x2013; Mr. Connery is Research Coordinator at Case Western Reserve University in Cleveland.

SEPTEMBER 2012

www.renalandurologynews.com

Bold Malpractice Reform Enacted in New Hampshire In a bold move, the New Hampshire Legislature has overridden a veto by Gov. John Lynch and enacted a new, first-of-a-kind “early offer” program for dealing with medical malpractice claims. The new law incentivizes defendants to make settlement offers early in the litigation process. Settlement offers would cover the plaintiff’s economic losses, such as medical bills and lost employment, as well as modest compensation for pain and suffering. If the early offer is accepted, then the plaintiff can get the settlement money within a few months without the time and expense (and uncertainty) of a trial. However, if the plaintiff chooses not to accept the offer and instead wishes to proceed to trial, the bill makes the loser liable for the attorney and court fees. Specifically, the bill states that “a claimant who rejects an early offer and who does not prevail in an action for medical injury against the medical care provider by being awarded at least 125 percent of the early offer amount, shall be responsible for paying the medical care provider’s reasonable attorney’s fees and costs.” Proponents of the bill believe that the early offer system will lower the cost of malpractice insurance, speed up the slow tort system, and offer injured patients a way to get settlements quickly and more easily. Opponents, including Lynch, believe that it puts injured patients at a disadvantage. Lynch also took issue

On The Web

with another provision of the bill requiring the injured patient to post a bond before entering the court system. In his veto message, Lynch stated that he felt that the bill “lacks certain fundamental safeguards that are necessary to protect injured patients.” Despite his veto, the bill was passed by the state legislature, making New Hampshire the first state in the country to enact an early offer system.

Consumer Reports Issues Hospital Safety Ratings For the first time ever, Consumer Reports magazine has rated hospitals for safety, and the results are somewhat alarming. Over 1,100 hospitals, in 44 states, were rated on a scale of 1 (the worst) to 100 (the best). The ratings focused on six categories: infections, readmissions, communication, CT scanning, complications, and mortality. The hospital that fared the worst in the rankings was Sacred Heart Hospital in Chicago, which earned a mere 16 points out of 100. Sacred Heart had a reported rate of bloodstream infections that was over twice the national average. Sadly, the highest-rated hospital, Billings Clinic in Montana, only scored 72 out of 100.

More needs to be done to enhance patient safety in hospitals.

A new law encourages defendants to make early settlement offers.

Malpractice News

According to Consumer Reports, even well known hospitals did not fare well in the ratings. For example, Massachusetts General Hospital in Boston scored 45, Ronald Reagan UCLA Medical Center in Los Angeles scored 43, Cleveland Clinic scored 39, New York Presbyterian

BY ANN W. LATNER, JD

scored 32, and Mount Sinai Medical Center in New York scored only a 30. The ratings were hindered by certain factors: data on patient harm is not fully (or consistently) reported nationwide, and sometimes only on a voluntary basis. The ratings only included 18% of the country’s hospitals, and information on every category wasn’t available for all hospitals. In an accompanying article, Consumer Reports expanded on some of the categories used to rate the hospitals. Infections were studied since about one in 20 hospitalized patients will develop one. Hospitals were rated on surgicalsite infections and central-line catheter infections. Johns Hopkins Hospital in Baltimore had less than half the infections as compared to the national benchmark, but the hospital could not be given a safety rating because other data was lacking. Readmissions rates were based on data from the Centers for Medicare and Medicaid services, which tracks patients hospitalized for heart attack, heart failure, and pneumonia, who are readmitted to a hospital within 30 days of being discharged. Researchers found almost 500 hospitals were lacking when it came to internal communications—specifically information about medications and discharge plans were unclear. Computed tomography scans were analyzed based on whether or not scans had to be ordered twice for the same patient, with contrast and without. Double scanning increases radiation exposure and possible cancer risk, yet only 28% of the hospitals rated had double scan rates of 5% or less. The article stated that more needed to be done to enhance patient safety in hospitals. It recommended that a national system be instituted to track— and publicly report—medical errors, and that hospital administrators and regulators listen more to the patients.

Lower Lawsuit Rate Linked To Electronic Health Records A Massachusetts study, published online in the Archives of Internal Medicine, suggests

EHR users had a sixfold reduction in malpractice claims.

24 Renal & Urology News

that electronic health records (EHRs) may be linked to a lower rate of malpractice claims. Researchers Mariah A. Quinn, MD, MPH, and colleagues noted that while EHRs “enhance documentation, make visits more efficient, reduce medication errors, and allow providers to track and manage their entire patient population, some physicians harbor reservations about potential unintended consequences of EHRs, including a possible increased risk of adverse events.” To assess the effect of EHRs on malpractice claims, the researchers merged closed-claim data from a major malpractice insurer in the state of Massachusetts with data from two surveys sent to a random sample of physicians in state. When the data were calculated, the researchers discovered that the rate of malpractice claims when EHRs were used was one-sixth the rate when EHRs were not used. “This study adds to the literature suggesting that EHRs have the potential to improve patient safety and supports the conclusions of our prior work, which showed a lower risk of paid claims among physicians using EHRs,” the researchers concluded. The sixfold reduction in claims shown in the study among physicians who adopted the used of EHRs “lends support for widespread implementation of health information technology.” ■ 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 and recent trends in legistation.

www.renalandurologynews.com

SEPTEMBER 2012

Renal & Urology News 29

Patient RCC Drug Preferences Revealed In a study, patients strongly preferred pazopanib over sunitinib, citing better QOL, less fatigue BY JOHN SCHIESZER CHICAGO—Patients with metastatic renal cell carcinoma (mRCC) prefer pazopanib over sunitinib largely because the former has less adverse effects on quality of life (QOL), according to study findings presented at the American Society for Clinical Oncology 2012 annual meeting. In a double-blind, randomized crossover study, 168 mRCC patients were randomized to pazopanib for 10 weeks followed by a two-week break and then sunitinib for 10 weeks, or vice versa. In a primary analysis of 114 patients, 70% preferred pazopanib, 22% preferred sunitinib, and 8% had no preference. The differences were statistically significant. The most common reasons that patients gave for preferring pazopanib were better quality of life (QOL) and less fatigue. In addition, patients on pazopanib had fewer dose reductions than those taking sunitinib (13% vs. 20%) as well as fewer treatment interruptions (6% vs. 12%). Physician

preference was not as strong as patient preference: 60% preferred pazopanib, 21% preferred sunitinib, and 21% had no preference. GlaxoSmithKline, the maker of pazopanib, funded the study, which involved several cancer centers worldwide. “While we expected patients would prefer one drug over the other due to the known toxicity profiles, we didn’t expect this great a preference,” said lead investigator Bernard J. Escudier, MD, of the Institut Gustave Roussy, Villejuif, France. Study findings provide “an important reminder that low-grade toxicities patients experience may not seem bad, but if you are experiencing the toxicity over a long time, it has an effect on your quality of life.” How patients feel when they take a drug over many months is not reflected in traditional adverse event reporting, he said. Patient-reported outcomes like these, however, are being added to traditional efficacy outcomes to better understand

Herbal Drug May Reduce Proteinuria

In addition, urinary levels of the inflammatory marker tumor necrosis factor (TNF)-alpha and urinary and serum levels of malondialdehyde (an oxidative stress marker) decreased significantly in the silymarin group compared with the placebo arm. The possible mechanisms underlying the observed efficacy of silymarin may be inhibition of inflammatory mediators such as TNF-alpha and attenuation of oxidative stress. Except for gastrointestinal disturbances and headache in a few patients, the authors stated, silymarin was safe and without major adverse effects. Silymarin is a lipophilic extract of the milk thistle that has potent antioxidant, anti-inflammatory, and antifibrotic properties, the researchers noted. RAS activation has a major role in the pathogenesis of diabetic nephropathy, and RAS inhibition with ACE inhibitors or angiotensin receptor blockers is the mainstay of diabetic nephropathy management. Despite RAS inhibition, however, diabetic nephropathy progresses to endstage renal disease in a large proportion of patients, the investigators observed. “This shows that in addition to the RAS, other pathways are involved in the pathogenesis of diabetic nephropathy, and suggests that finding ways to block these pathways could lead to new treatments.” ■

ADDING THE herbal preparation silymarin to a renin-angiotensin system (RAS) inhibitor may decrease proteinuria in patients with diabetic nephropathy. Researchers studied 60 patients with type 2 diabetes and macroalbuminuria (urinary albumin excretion greater than 300 mg/24 hours) despite treatment with the maximum dose of an RAS inhibitor for more than six months. All subjects had an estimated glomerular filtration rate above 30 mL/min/1.73 m2. The researchers, led by Mohammad Kazem Fallahzadeh, MD, of Shiraz University of Medical Sciences in Shiraz, Iran, randomly allocated patients to receive three 140 mg tablets of silymarin or three tables of placebo daily for three months. Compared with patients in the placebo arm, silymarin recipients experienced a significantly greater decrease in the urinary albumin-creatinine ratio (UACR) from baseline to the end of the treatment period, according to an online report in the American Journal of Kidney Diseases. The UACR decreased by a mean of 566 mg/g in the silymarin recipients versus 219 mg/g in the placebo group.

Pazopanib vs. Sunitinib In a study, patients with metastatic renal cell carcinoma said they preferred pazopanib over sunitinib, with better quality of life and less fatigue the most commonly cited reasons. 80 70

The percentages refer to the proportion of patients that preferred each drug.

60 50 40 30 20 10 0

70% Pazopanib

22% Sunitinib

8% No preference

Source: Escudier BJ, Porta C, Bono P et al. Patient preferences between panopanib (Paz) and sunitinib (Sun): Results of a randomized double-blind, placebo-controlled, cross-over study in patients with metastatic renal cell carcinomia (mRCC)— PISCES study, NCT 01064310. Presented at the ASCO 2012 annual meeting. J Clin Oncol 30, 2012 (suppl; abstr CRA4502).

the clinical relevance of differences in toxicity between therapies. QOL differences between two therapies with relatively similar safety profiles may appear relatively modest to physicians, but can be perceived quite differently by patients who may have to take therapies for many months or years, he said. Urologist Robert G. Uzzo, MD, FACS, Chairman of the Department of Surgery

at Fox Chase Cancer Center in Philadelphia, said the study findings are novel. As mRCC becomes more of a chronic condition instead of a terminal illness, patient preferences will become a bigger concern for physicians, Dr. Uzzo said. “This is an interesting study because adverse events impair quality of life for patients on these drugs,” he said. ■

Blunted Morning BP Surges Raise Cardiovascular Risks BLUNTED MORNING blood pressure (BP)

noted that none of the studies looking at

surges, not excessive surges as previous

morning BP surge were conducted in

research has suggested, predict an

large cohorts of hypertensive patients who

increased risk of cardiovascular (CV)

were untreated at the time of 24-hour

events among hypertensive patients.

ambulatory BP monitoring. Contrary to

Italian investigators who studied 3,102

their expectations, the magnitude of the

initially untreated subjects with essential

early morning BP surge did not contribute

hypertension found that those with a

to improvement in cardiovascular risk

pre-awakening systolic BP surge in the

stratification, the researchers said. With

first quartile (below 9.5 mm Hg) had a

respect to study limitations, the investiga-

71% increased risk of major CV events

tion was conducted in a white population,

compared with subjects in the highest

so results should not be extended to differ-

quartile (greater than 27.5 mm Hg), after

ent ethnic groups.

adjusting for numerous variables, including

For the study, pre-awakening morning

left ventricular hypertrophy and estimated

BP surge was determined by the differ-

glomerular filtration rate. In addition,

ence between the average BP during

subjects in the bottom quartile of sleep-

the two hours after awakening and the

trough systolic BP surge (19.5 mm Hg or

average BP during the two hours before

less) had a 66% increased risk of events

awakening. Sleep-trough BP surge is the

compared with those in the top quartile

difference between the average BP during

(greater than 36.0 mm Hg).

the two hours after awakening and the

A blunted day-night BP dip was associ-

lowest nighttime BP. They considered

ated with a blunted morning BP surge and

major CV events to be a composite of

vice versa.

cardiovascular death, nonfatal myocardial

The researchers, who reported their findings in Hypertension (2012;60:34-42),

infarction, nonfatal stroke, and heart failure requiring hospitalization. ■

30 Renal & Urology News

SEPTEMBER 2012

www.renalandurologynews.com

Practice Management How useful are patient surveys? We asked a healthcare research firm to weigh in on what works and what doesn’t BY TAMMY WORTH

Patient comfort A patient’s comfort with his or her physician can affect the clinical aspect of care, however. According to PRC surveys, the better the patient’s experience, the more likely they are to comply with clinical instructions, Binder said. Data from a nationwide 2009 consumer loyalty study of 1,000 adults found that patients don’t

perceive the care delivered by their physicians as excellent,” Binder said. “It’s the excellent physicians who have a higher percentage following their instructions … something that a patient satisfaction survey would report.” Patient surveys are now required to be performed by nursing homes and hospitals to receive payments from Medicare. They aren’t mandatory for other providers, but experts say they may be within the next couple of years. Even if they aren’t compulsory, patient surveys may provide useful information that can improve your practice.

What’s available Surveys can be administered through an organization like Binder’s, but they can also be found online at no cost. The one used by the Centers for Medicare and Medicaid Services is called the Consumer Assessment of Healthcare Providers and Systems, (CG CAHPS for physician groups) and can be found, along with instructions for operation, at http://www.ahrq.gov/ cahps/clinician_group/. Patient satisfaction surveys can be administered by handing them out, e-mail, regular mail, or by phone. Alan

The percentage [of patients] that followed instructions are more likely to perceive the care delivered by their physicians as excellent. follow their doctors’ orders because the instructions weren’t easy to follow, medications had adverse effects, or the patients just chose not to. “The percentage that followed all instructions are much more likely to

On The Web

Jackson, president and CEO of The Jackson Group Inc. in Hickory, N.C., said phone surveys provide the “best, most comprehensive data” because they are more likely to get a larger representation of your population.

o you know that the top three things that are important to patients in urology practices are a doctor’s courtesy and friendliness, how well a physician explains someone’s medical condition, and whether or not a doctor involves a patient in decisionmaking? These are the findings of a recent survey of urologists by PRC, a healthcare research firm in Omaha, Neb. Janna Binder, PRC’s Director of Marketing and Public Relations, noted that survey findings are not hard clinical data, but they can be useful to a practice. “It is a little more warm and fuzzy type of stuff,” she said. “Patients can’t really evaluate clinical skills; they assume overall that their doctor is good clinically. What they do know is how they are treated as people. That’s really what these surveys go into.”

When asked to respond to a survey in the office, patients may not answer honestly.

However, they are more expensive to administer. If you decide to distribute surveys yourself, you should avoid handing out questionaires during a visit. Binder said a patient will feel that it is not anonymous and won’t want to answer honestly. If they take it with them, they probably won’t remember to mail it back in. Jackson recommends mailing or e-mailing them to patients instead, with the knowledge that e-mail surveys probably won’t reach older patients.

Getting the most from surveys The questions on a CAHPS or other survey are a great start, but you might want also to add queries that are more specific to your office. Pediatric urology patients may have different needs than adults, for instance. The CAHPS survey asks about demographics—age, education, overall health, and so on. If you are using a survey other than the CAHPS, you should ask about age and gender. This will help you break down the data to see if there are subsets

of patients that you aren’t serving as well as others. The effort also has to be from the top down. Binder recommends having a practice manager as well as one physician champion the effort, maybe even by showing the staff his or her scores to get the ball rolling. “If top management and physicians embrace it, it will be accepted, everyone will use it,” Binder said. “If they say it’s the next fly-by-night thing, it is just a waste of money.” Finally, don’t be discouraged by low marks. If you can benchmark against other providers (the CAHPS site has a database of information for comparison) you can identify where scores tend to dip. Some areas, like cost, are always rated low. “There’s about 5% to 10% of the population that are just not happy,” Binder said. “But in general, patients do love their doctors and their staff. [Physicians] will probably be pleasantly surprised.” ■ Tammy Worth is a freelance medical journalist based out of Blue Springs, MO.

For more innovative ways to manage your practice, please visit us at renalandurologynews.com/practice.

www.renalandurologynews.com

SEPTEMBER 2012

Renal & Urology News 31

Long-Term Dialysis Boosts Cancer Risk Post-Tx BY ROSEMARY FREI, MSc BERLIN—Patients on long-term dialysis prior to receiving a donor kidney are at increased risk for cancer following transplantation, according to findings presented at the 24th International Congress of The Transplantation Society. In a study of 5,417 patients, researchers led by Germaine Wong, MBBS, PhD, a nephrologist and Early Career Research Fellow at the University of Sydney’s School of Public Health in Australia, found that patients on dialysis for more than 4.5 years had a greater than threefold increased risk for lung cancer compared

and colorectal cancer each were higher with longer dialysis. Overall, the adjusted probability of having any cancer by 12 years after transplantation was 15% among patients dialyzed for less than 1.5 years, 18% among those dialyzed 1.5-2.5 years, 21% for 2.5-4.5 years of dialysis, and 23%

for more than 4.5 years of dialysis. The respective probabilities for urinary tract cancer at 12 years were 2.1%, 2.7%, 2%, and 5.1%. The results fit with the researchers’ initial hypothesis that immunosuppression is not the only risk factor for cancer after transplantation, but long-term

On the web For more on dialysis-related news, please visit us at renalandurologynews.com

For your OAB patients with urge urinary incontinence

Any moment is an accident waiting to happen. TOVIAZ provides powerful efﬁcacy.1,2

Lung, urinary, and colorectal cancers are more likely to occur, study finds.

Mean UUI episodes per 24 hours at baseline Median % reduction from baseline in UUI episodes at Week 12

with those who had dialyzed for fewer than 1.5 years. They also had a 2.5 times increased risk for urinary tract cancer. Furthermore, patients on dialysis for 2.5-4.5 years had a 2.5 times increased risk for colorectal cancer compared with those on dialysis for fewer than 1.5 years. “Increased duration on dialysis raises the risk of acquired cystic disease, which is a risk factor for renal cancer, but we cannot explain the increased risk for the other cancers,” Dr. Wong told Renal & Urology News. Dr. Wong’s team analyzed data from the Australian and New Zealand Dialysis and Transplantation Registry. They focused on patients who received a living- or deceased-donor kidney transplant from January 1997 to December 2009. The investigators excluded patients who had multiple organ grafts, preemptive transplants, had primary renal disease caused by cancers such as multiple myeloma and renal cancers, or a history of cancer prior to starting dialysis. Cancer developed in 454 patients who met these criteria. The investigators compared them to another 5,963 patients in whom cancer did not develop. The two groups had different average ages, races, smoking status, and prevalence of peripheral vascular disease but a similar ratio of men to women (about 60% of each group were men). Longer time on dialysis prior to transplantation was associated with a higher incidence of cancer. The adjusted risk for urinary tract cancer, lung cancer,

uremia, for which dialysis is also a surrogate indicator. ■

Mean UUI episodes per 24 hours at Week 12 *P≤0.001 vs placebo.1

Placebo

TOVIAZ 4 mg

TOVIAZ 8 mg

(n=211)

(n=199)

(n=223)

3.7

3.8

3.7

-50% -80%* 2.5

1.8*

-88%* 1.4*

Results of a 12-week, fixed-dose, randomized, double-blind, placebo- and active-controlled international ex-US study to assess the efficacy, tolerability, and safety of TOVIAZ in adults with overactive bladder. The coprimary efficacy end points were change in micturitions per day and change in UUI episodes per day. Subjects (N=1132) were treated once daily with placebo, TOVIAZ 4 mg or 8 mg, or an active-control agent (an oral antimuscarinic). The median percent change in micturitions at Week 12 was 19% for TOVIAZ 8 mg, 17% for TOVIAZ 4 mg, and 11% for placebo (P<0.001). The least squares (LS) mean change in micturitions at Week 12 was -1.9 episodes for TOVIAZ 8 mg, -1.8 episodes for TOVIAZ 4 mg, and -1.0 episodes for placebo (P<0.001). The median percent reduction in UUI episodes at Week 12 was 88% for TOVIAZ 8 mg, 80% for TOVIAZ 4 mg, and 50% for placebo (P≤0.001). The LS mean change in UUI episodes at Week 12 was -2.2 episodes for TOVIAZ 8 mg, -2.0 episodes for TOVIAZ 4 mg, and -1.1 episodes for placebo (P≤0.001).1

TOVIAZ is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. Important Safety Information TOVIAZ is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma, and in patients with known hypersensitivity to the drug or its ingredients or to DETROL® (tolterodine tartrate) tablets or DETROL® LA (tolterodine tartrate extended release capsules). Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine, in some cases after the first dose. Patients should be advised to promptly discontinue fesoterodine therapy and seek immediate medical attention if they experience edema of the tongue, laryngopharynx, or difficult breathing. TOVIAZ tablets should be used with caution in patients with clinically significant bladder outlet obstruction, decreased gastrointestinal motility, controlled narrow-angle glaucoma, or myasthenia gravis. The recommended starting dose of TOVIAZ is 4 mg once daily swallowed whole. Based upon individual response and tolerability, the dose may be increased to 8 mg once daily. Doses greater than 4 mg are not recommended in patients with severe renal insufficiency (CLCR <30 mL/min), or in patients taking a potent CYP3A4 inhibitor. TOVIAZ is not recommended for use in patients with severe hepatic impairment (Child-Pugh C). The most frequently reported adverse events (≥4%) for TOVIAZ were: dry mouth (placebo, 7%; TOVIAZ 4 mg, 19%; TOVIAZ 8 mg, 35%) and constipation (placebo, 2%; TOVIAZ 4 mg, 4%; TOVIAZ 8 mg, 6%). OAB=overactive bladder. References: 1. Chapple C, Van Kerrebroeck P, Tubaro A, et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol. 2007;52(4):1204-1212. 2. Data on file. Protocol SP583 table SCS763 13.2.1.1.1. Pfizer Inc, New York, NY.

For more information, visit www.ToviazHCP.com. Please see brief summary of prescribing information on next page. FSD01158C/FSD432811

February 2012

32 Renal & Urology News

SEPTEMBER 2012

www.renalandurologynews.com

Cell-Free DNA Predicts Mortality in HD Patients ELEVATED LEVELS of circulating cell-free DNA (CFD) in hemodialysis (HD) patients independently predict an increased risk of death, new findings suggest. CFD appears following cell damage and DNA release, and increases in HD patients, especially following dialysis.

In a prospective study, David Tovbin, MD, and colleagues at Ben-Gurion University in Beer-Sheva, Israel, measured CFD levels in 31 chronic HD patients without acute disease before and after they dialyzed. To obtain the measurements, Dr. Tovbin’s group used a rapid, non-cumbersome, inex-

TOVIAZ® (fesoterodine fumarate) extended release tablets Rx only BRIEF SUMMARY OF PRESCRIBING INFORMATION. The following is a brief summary only; see full Prescribing Information for complete product information. INDICATIONS AND USAGE Toviaz is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. CONTRAINDICATIONS Toviaz is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Toviaz is also contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules. WARNINGS AND PRECAUTIONS Angioedema: Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine. In some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, fesoterodine should be promptly discontinued and appropriate therapy and/or measures to ensure a patent airway should be promptly provided. Bladder Outlet Obstruction: Toviaz should be administered with caution to patients with clinically significant bladder outlet obstruction because of the risk of urinary retention. Decreased Gastrointestinal Motility: Toviaz, like other antimuscarinic drugs, should be used with caution in patients with decreased gastrointestinal motility, such as those with severe constipation. Controlled Narrow-Angle Glaucoma: Toviaz should be used with caution in patients being treated for narrow-angle glaucoma, and only where the potential benefits outweigh the risks. Hepatic Impairment: Toviaz has not been studied in patients with severe hepatic impairment and therefore is not recommended for use in this patient population. Renal Impairment: Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment. Concomitant Administration with CYP3A4 Inhibitors: Doses of Toviaz greater than 4 mg are not recommended in patients taking a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin). No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (eg, erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice). While the effect of weak CYP3A4 inhibitors (eg, cimetidine) was not examined by clinical study, some pharmacokinetic interaction is expected, albeit less than that observed with moderate CYP3A4 inhibitors. Myasthenia Gravis: Toviaz should be used with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction. ADVERSE REACTIONS Clinical Trials Experience: The safety of Toviaz was evaluated in Phase 2 and 3 controlled trials in a total of 2859 patients with overactive bladder, of which 2288 were treated with fesoterodine. Of this total, 782 received Toviaz 4 mg/day, and 785 received Toviaz 8 mg/day in Phase 2 or 3 studies with treatment periods of 8 or 12 weeks. Approximately 80% of these patients had >10 weeks exposure to Toviaz in these trials. A total of 1964 patients participated in two 12-week, Phase 3 efficacy and safety studies and subsequent open-label extension studies. In these two studies combined, 554 patients received Toviaz 4 mg/day and 566 patients received Toviaz 8 mg/day. In Phase 2 and 3 placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg were 1.9%, 3.5%, and 2.9%, respectively. All serious adverse events were judged to be not related or unlikely to be related to study medication by the investigator, except for four patients receiving Toviaz who reported one serious adverse event each: angina, chest pain, gastroenteritis, and QT prolongation on ECG. The most commonly reported adverse event in patients treated with Toviaz was dry mouth. The incidence of dry mouth was higher in those taking 8 mg/day (35%) and in those taking 4 mg/day (19%), as compared to placebo (7%). Dry mouth led to discontinuation in 0.4%, 0.4%, and 0.8% of patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg, respectively. For those patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment. The second most commonly reported adverse event was constipation. The incidence of constipation was 2% in those taking placebo, 4% in those taking 4 mg/day, and 6% in those taking 8 mg/day. Table 1 lists adverse events, regardless of causality, that were reported in the combined Phase 3, randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with Toviaz 4 or 8 mg once daily for up to 12 weeks. Table 1. Adverse events with an incidence exceeding the placebo rate and reported by ≥1% of patients from double-blind, placebo-controlled Phase 3 trials of 12 weeks treatment duration System organ class

Gastrointestinal disorders

Infections

Preferred term

Placebo N=554 %

Toviaz 4 mg/day N=554 %

Toviaz 8 mg/day N=566 %

Dry mouth

7.0

18.8

34.6

Constipation

2.0

4.2

6.0

Dyspepsia

0.5

1.6

2.3

Nausea

1.3

0.7

1.9

Abdominal pain upper

0.5

1.1

0.5

Urinary tract infection

3.1

3.2

4.2

Upper respiratory tract infection

2.2

2.5

1.8

Eye disorders

Dry eyes

1.4

3.7

Renal and urinary disorders

Dysuria

0.7

1.3

1.6

Urinary retention

0.2

1.1

1.4

Respiratory disorders

Cough

0.5

1.6

0.9

Dry throat

0.4

0.9

2.3

General disorders

Edema peripheral

0.7

1.2

Musculoskeletal disorders

Back pain

0.4

2.0

0.9

Psychiatric disorders

Insomnia

0.5

1.3

0.4

Investigations

ALT increased

0.9

0.5

1.2

GGT increased

0.4

1.2

Rash

0.5

0.7

1.1

Skin disorders

ALT = alanine aminotransferase; GGT = gamma glutamyltransferase

Patients also received Toviaz for up to three years in open-label extension phases of one Phase 2 and two Phase 3 controlled trials. In all open-label trials combined, 857, 701, 529, and 105 patients received Toviaz for at least 6 months, 1 year, 2 years, and 3 years, respectively. The adverse events observed during long-term, open-label studies were similar to those observed in the 12-week, placebo-controlled studies, and included dry mouth, constipation, dry eyes, dyspepsia, and abdominal pain. Similar to the controlled studies, most adverse events of dry mouth and constipation were mild to moderate in intensity. Serious adverse events, judged to be at least possibly related to study medication by the investigator and reported more than once during the open-label treatment period of up to 3 years, included urinary retention (3 cases), diverticulitis (3

pensive fluorometric assay that they developed. During 42 months of follow-up, 13 subjects (41.9%) died. The decedents were older than survivors (69.9 vs. 61.5 years), but the two groups did not differ significantly in duration of end-stage renal disease (ESRD), gender, albumin, hemo-

cases), constipation (2 cases), irritable bowel syndrome (2 cases), and electrocardiogram QT corrected interval prolongation (2 cases). Post-marketing Experience: The following events have been reported in association with fesoterodine use in worldwide post-marketing experience: Eye disorders: Blurred vision; Cardiac disorders: Palpitations; General disorders and administrative site conditions: hypersensitivity reactions, including angioedema with airway obstruction, face edema; Skin and subcutaneous tissue disorders: Urticaria, pruritus. Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of fesoterodine in their causation cannot be reliably determined. DRUG INTERACTIONS Antimuscarinic Drugs: Coadministration of Toviaz with other antimuscarinic agents that produce dry mouth, constipation, urinary retention, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. CYP3A4 Inhibitors: Doses of Toviaz greater than 4 mg are not recommended in patients taking potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin. Coadministration of the potent CYP3A4 inhibitor ketoconazole with fesoterodine led to approximately a doubling of the maximum concentration (Cmax ) and area under the concentration versus time curve (AUC) of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine. Compared with CYP2D6 extensive metabolizers not taking ketoconazole, further increases in the exposure to 5-HMT were observed in subjects who were CYP2D6 poor metabolizers taking ketoconazole. There is no clinically relevant effect of moderate CYP3A4 inhibitors on the pharmacokinetics of fesoterodine. Following blockade of CYP3A4 by coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice a day for 2 days, the average (90% confidence interval) increase in Cmax and AUC of the active metabolite of fesoterodine was approximately 19% (11%-28%) and 27% (18%-36%) respectively. No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (eg, erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice). The effect of weak CYP3A4 inhibitors (eg, cimetidine) was not examined; it is not expected to be in excess of the effect of moderate inhibitors. CYP3A4 Inducers: No dosing adjustments are recommended in the presence of CYP3A4 inducers, such as rifampin and carbamazepine. Following induction of CYP3A4 by coadministration of rifampin 600 mg once a day, Cmax and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of Toviaz 8 mg. The terminal half-life of the active metabolite was not changed. CYP2D6 Inhibitors: The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, Cmax and AUC of the active metabolite are increased 1.7- and 2-fold, respectively. No dosing adjustments are recommended in the presence of CYP2D6 inhibitors. Drugs Metabolized by Cytochrome P450: In vitro data indicate that at therapeutic concentrations, the active metabolite of fesoterodine does not have the potential to inhibit or induce Cytochrome P450 enzyme systems. Oral Contraceptives: In the presence of fesoterodine, there are no clinically significant changes in the plasma concentrations of combined oral contraceptives containing ethinyl estradiol and levonorgestrel. Warfarin: A clinical study has shown that fesoterodine 8 mg once daily has no significant effect on the pharmacokinetics or the anticoagulant activity (PT/INR) of warfarin 25 mg. Standard therapeutic monitoring for warfarin should be continued. Drug-Laboratory Test Interactions: Interactions between Toviaz and laboratory tests have not been studied. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C. There are no adequate and well-controlled studies using Toviaz in pregnant women. No dose-related teratogenicity was observed in reproduction studies performed in mice and rabbits. In mice at 6 to 27 times the expected exposure at the maximum recommended human dose (MRHD) of 8 mg based on AUC (75 mg/kg/day, oral), increased resorptions and decreased live fetuses were observed. One fetus with cleft palate was observed at each dose (15, 45, and 75 mg/kg/day), at an incidence within the background historical range. In rabbits treated at 3 to 11 times the MRHD (27 mg/kg/day, oral), incompletely ossified sternebrae (retardation of bone development) were observed in fetuses. In rabbits at 9 to 11 times the MRHD (4.5 mg/kg/day, subcutaneous), maternal toxicity and incompletely ossified sternebrae were observed in fetuses (at an incidence within the background historical range). In rabbits at 3 times the MRHD (1.5 mg/kg/ day, subcutaneous), decreased maternal food consumption in the absence of any fetal effects was observed. Oral administration of 30 mg/kg/day fesoterodine to mice in a pre- and post-natal development study resulted in decreased body weight of the dams and delayed ear opening of the pups. No effects were noted on mating and reproduction of the F1 dams or on the F2 offspring. Toviaz should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. Nursing Mothers: It is not known whether fesoterodine is excreted in human milk. Toviaz should not be administered during nursing unless the potential benefit outweighs the potential risk to the neonate. Pediatric Use: The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients.The safety and effectiveness of Toviaz in pediatric patients have not been established. Geriatric Use: No dose adjustment is recommended for the elderly. The pharmacokinetics of fesoterodine are not significantly influenced by age. Of 1567 patients who received Toviaz 4 mg/day or 8 mg/day in the Phase 2 and 3, placebo-controlled, efficacy and safety studies, 515 (33%) were 65 years of age or older, and 140 (9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies; however, the incidence of antimuscarinic adverse events, including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (at 8 mg only) and urinary tract infection, was higher in patients 75 years of age and older as compared to younger patients. Renal Impairment: In patients with severe renal impairment (CLCR <30 mL/min), Cmax and AUC are increased 2.0- and 2.3-fold, respectively. Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment. In patients with mild or moderate renal impairment (CLCR ranging from 30-80 mL/min), Cmax and AUC of the active metabolite are increased up to 1.5- and 1.8-fold respectively, as compared to healthy subjects. No dose adjustment is recommended in patients with mild or moderate renal impairment. Hepatic Impairment: Patients with severe hepatic impairment (Child-Pugh C) have not been studied; therefore Toviaz is not recommended for use in these patients. In patients with moderate (Child-Pugh B) hepatic impairment, Cmax and AUC of the active metabolite are increased 1.4- and 2.1-fold, respectively, as compared to healthy subjects. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Gender: No dose adjustment is recommended based on gender. The pharmacokinetics of fesoterodine are not significantly influenced by gender. Race: Available data indicate that there are no differences in the pharmacokinetics of fesoterodine between Caucasian and Black healthy subjects following administration of Toviaz. OVERDOSAGE Overdosage with Toviaz can result in severe anticholinergic effects. Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended. Manufactured by: Aesica Pharmaceuticals GmbH, Galileistraße 6, 08056 Zwickau, Germany Distributed by: Pfizer Labs, Division of Pfizer Inc, NY, NY 10017 LAB-0381-10.0 Revised November 2011 FSD01151A/FSD423505-01

December 2011

globin, diabetes mellitus, and weight. Post-dialysis CFD levels were significantly lower in survivors (median 688 vs. 880 ng/mL). The sensitivity and specificity of CFD levels of 850 ng/mL to predict mortality at 42 months were 73% and 75%, respectively, the investigators reported online in Nephrology Dialysis Transplantation. A CFD value above 850 ng/mL was associated with a significant eightfold increased risk of all-cause mortality, after adjusting for age, ESRD duration, weight, and creatinine levels. The researchers noted that their hypothesis-generating study “has shown that post-HD levels of CFD are reliable and independent predictors of all-cause mortality.” They concluded that “postdialysis CFD is an inexpensive and easy to perform assay that could be used as an integrative parameter to follow in populations of patients undergoing HD.” ■

Hyponatremia May Shorten RCC Survival Hyponatremia is associated with shorter cancer-specific survival in patients with metastatic renal cell carcinoma (RCC) treated with molecular targeted therapy, Japanese researchers reported online in the International Journal of Urology. In a retrospective study of 87 patients with metastatic RCC treated with sorafenib or sunitinib as first-line treatment, Atsunari Kawashima, MD, of Osaka University Graduate School of Medicine, and colleagues found that median cancer-specific survival times were 8.8 months for patients with severe and mild hyponatremia compared with 32.6 months for patients with normal natremia. In multivariate analysis, severe and mild hyponatremia were associated with a significant sixfold and threefold increased risk of cancer-specific mortality, respectively. Severe hyponatremia was defined as a serum sodium concentration of 134 mEq/L or less, mild hyponatremia as a concentration of 135-137 mEq/L, and normal natremia as a concentration of 138 mEq/L or higher. ■

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Renal & Urology News 33

CME FEATURE

Adrenal Hypertension: A Current Guide to Diagnosis Given the intimate anatomical and physiological relationship of the adrenals to the kidney, an understanding of adrenal disease is imperative for urologists and nephrologists alike.

Release Date: September 2012 Expiration Date: September 2013 Estimated time to complete the educational activity: 1 hour This activity is jointly sponsored by Medical Education Resources and Haymarket Medical Education. STATEMENT OF NEED: Urologists, nephrologists and allied healthcare professionals caring for patients with adrenal hypertension need to have a clear understanding of adrenal pathophysiology and varying etiologies of the condition. TARGET AUDIENCE: This activity has been designed to meet the educational needs of urologists, nephrologists, and other clinicians involved in the treatment of patients with adrenal hypertension. EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Review the pathophysiology of adrenal hypertension. • Discuss the etiology of adrenal hypertension: Cushing syndrome, pheochromocytoma, and primary hyperaldosteronism • Discuss the metabolic work-up of adrenal incidentalomas. 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 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. DISCLOSURE OF CONFLICTS OF INTEREST: Medical Education Resources ensures balance, independence, objectivity, and scientific rigor in all its educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure all scientific research referred to, reported, or used in a CME activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality CME activities that promote improvements or quality in health care and not a commercial interest. The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Faculty • Alexander Kutikov, MD

Reported Financial Relationship Grants/Research Support: Department of Defense, Physician Research Training Award

Ownership Interest/Shareholder: Co-founder/Co-owner VisibleHealth, Inc; Co-founder/Co-owner UrologyMatch LLC

BY ALEXANDER KUTIKOV, MD

ocated in the seclusion of the retroperitoneum, the small triangular shaped adrenal glands are critical to metabolic homeostasis. Hypertension secondary to adrenal dysfunction is rare; however, it carries deleterious long-term effects and is often correctible. As such, it is essential to diagnose and treat.

Adrenal anatomy and physiology Weighing approximately 5 grams, the adrenal glands may either “cap” the kidney by sitting above its upper pole or “cradle” the renal unit by being located medially and just above the renal vessels.1-4 Embryologically and physiologically, the adrenal gland is two distinct organs—the cortex and the medulla. The cortex stems from the intermediate mesoderm, as do the kidneys, while the medulla originates from the neural crest cells of the sympathetic ganglia.2, 5, 6 It is important to note that despite anatomic proximity, adrenal and renal development are distinct embryologic processes and in cases of renal agenesis or malposition the

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 September 2012 through September 2013, participants must: 1) read the learning objectives and faculty disclosures, 2) study the educational activity, 3) complete the posttest and submit it online. Physicians may register at www.myCME.com/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.

Alexander Kutikov, MD, is Assistant Professor of Urologic Oncology at Fox Chase Cancer Center in Philadelphia.

adrenal glands are nearly always found in their usual orthotopic location.2 The adrenal cortex is stratified into three distinct layers: zona glomerulosa, zona fasiculata, and the zona reticularis. The endocrine function of each zone pivots on the ratios of its enzymes, which convert cholesterol to corresponding steroid hormone derivatives.7, 8. Zona glomerulosa, the outermost layer, primarily produces mineralocorticoid aldosterone (100-150 mcg/day), while zona fasiculata—the middle cortical layer—is responsible for production of the glucocorticoid cortisol (10-20 mg/day). The innermost layer of the cortex, the zona reticularis, synthesizes adrenal androgens in excess of >20 mg/day.7 While corticosteroid and adrenal androgen production are under control of the hypothalamicpituitary-adrenal (HPA) axis,9 secretion of aldosterone by the zona glomerulosa is under tight regulation of the reninangiotensin-aldosterone-system.10 The adrenal medulla lies in the adrenal center and accounts for approximately 10% of the gland’s total mass. As a critical part of the autonomic nervous system, the medulla’s chromaffin cells are innervated by T-11 through L-2 sympathetic fibers. As such, the medulla secretes the catecholamines

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CME FEATURE epinephrine (80%), norepinephrine (19%), and dopamine (1%).11, 12 Glucocorticoid, mineralocorticoid or catecholamine hypersecretion may result in significant physiologic perturbations, which often include hypertension. Etiology for such adrenal hypermetabolic activity are multifactorial and complex (Figure 1).

Figure 1 summarizes etiologies of Cushing syndrome. Exogenous Cushing syndrome, which results from iatrogenic glucocorticoid intake is the most common cause of Cushinoid symptomatology and is important to rule out when obtaining the patientâ&#x20AC;&#x2122;s history. Endogenous Cushing syndrome is divided into ACTH-dependent and ACTH-independent disease.

Cushing syndrome Cushing syndrome is defined as hypersecretion of cortisol by the adrenal cortex and causes hypertension in 70 to 90% of patients who are diagnosed with the condition.13 14 Although the disease is rare, affecting approximately 3 of every million individuals per year, understanding of its multifactorial etiology and having a high index of suspicion for its presence are critical for urologists and nephrologists alike, given its deleterious short and long-term conseuquences.15, 16

ACTH-dependent Cushing syndrome ACTH-dependent overproduction of cortisol by the adrenal is the most common cause of endogenous Cushing syndrome, accounting for up to 85% of cases.17. The vast majority (80%) of ACTH-dependent disease is due to hypersecretion of ACTH by the pituitary. Described by the early twentieth century neurosurgeon, Harvey Cushing, the condition stems largely from ACTHsecreting pituitary microadenomas and rarely from macroadenomas (1 cm or

greater in size). If fact, Cushing syndrome that results from pituitary pathology is known as Cushing disease,18, 19 and females are diagnosed two times more frequently than males.20 ACTH-dependent Cushing syndrome can also be a result of ectopic production of corticotropin by non-pituitary tumors. Known as Ectopic ACTH Syndrome, and accounting for ~10% of endogenous hypercortisolemia, the condition can be caused by a number of malignancies with lung cancers being the primary culprits.18

ACTH-independent Cushing syndrome ACTH independent secretion of excess cortisol by the adrenal glands accounts for approximately 10% of Cushing syndrome. Benign adenomas are the most common offenders; however, multifocal bilateral adrenal hyperplasia, adrenal carcinomas, ACTHindependent macronodular adrenal

Figure 1: Summary of causes for adrenal hypertension Conn syndrome (hyperaldosteronism)

Bilateral Hyperplasia 60%

Adenoma

Unilateral adrenal hyperplasia 2%

35%

Carcinoma <1%

Ectopic aldosteroneproducing tumor <1%

Familial hyperaldosteronism <1%

Increased aldosterone production

Cortisol hypersecretion

Catecholamine hypersecretion

Pheochromocytoma

Cushing syndrome (hypercortisolemia) Exogenous*

Adrenal 75-90%

Endogenous

ACTH independent

ACTH dependent

Iatrogenic steriods

Pituitary ACTH ~70%

Ectopic ACTH ~10 -15%

ÂŠ PHOTO RESEARCHERS, INC. / BSIP

Aldosterone hypersecretion

Increased CRH <1%

Extra-adrenal 10-25%

Increased Catecholamine Production

Primary adrenal ~10%

Increased cortisol production *most common

Source: Adapted from Kutikov 2011

hyperplasia (AIMAH), and primary pigmented nodular adrenocortical disease (PPNAD) also account for rare cases of the condition.17, 21, 22

Diagnosis of Cushing syndrome Clinical presentation of Cushing syndrome is varied. In fact, in addition to hypertension, classic features such as central obesity, moon faces, buffalo hump, muscle wasting, and truncal striae can be subtle or entirely abscent.1,16 Furthermore, presentation can often mimic classic signs of the ever-prevalent metabolic syndrome.13,23 Nevertheless, urologists should appreciate that hypogonadal hypogonadism is not uncommon in patients with Cushing,13,16 while both urologists and nephrologists must be aware that nearly half of patients with Cushing syndrome develop urolithiasis.24 While diagnosis of hypercortisolemia is relatively straightforward, identification of its etiology can be one of the most complex tasks faced by modern endocrinologists. Briefly, an overnight low-dose dexamethasone suppression test, late night salivary cortisol, or 24-hour urinary free cortisol can serve as screening modalities to identify pathologic glucocorticoid elevations.25 The former strategy involves administration of 1 mg of dexamethasone at 11pm prior to a morning lab draw, and assessing if am cortisol is suppressed below a generally agreed upon cutoff of 5 mcg/dL.16 It is important to note that urinary free cortisol levels may not be sufficiently sensitive to screen patients with adrenal incidentalomas, 25 while late night salivary cortisol is a newer test with acceptable test characteristics that is gaining clinical traction.16, 26 Once hypercortisolemia is identified, its etiology must be established. Because of the complexity of this undertaking, some experts believe that endocrinologists at tertiary centers should be charged with the task.19 In short, ACTH levels are determined to separate patients with ACTH-dependent from those with ACTH-independent causes. In the latter group, adrenal imaging is obtained. The greatest diagnostic challenge lies in differentiating patients with Cushing disease from those with ectopic ACTH syndrome, since non-functional microadenomas of the pituitary are common and up to 50% of functional microadenomas are difficult to identify on imaging.17, 27 As such, petrosal sinus sampling for measurement of ACTH concentrations

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following CRH stimulation has largely become the test of choice.17, 28.

Treatment of Cushing syndrome Cushing disease is treated with surgical resection or radiation of the pituitary lesion.17, 29 Bilateral adrenalectomy is usually reserved for when at least one attempt to treat pituitary pathology has failed.30-32 In these instances, the patient must be counseled regarding life-long mineralocorticoid/glucocorticoid supplementation and NelsonSalassa syndrome (occurring in 8-30% of patients), where bilateral adrenalectomy results in accelerated growth of the pituitary lesion, producing complications such as compression of the ocular chiasm and elevation in intracranial pressure.17, 33 For patients with ectopic ACTH syndrome, identification and resection of the primary malignancy is often therapeutic. Nevertheless, bilateral adrenalectomy remains an option for those with unresectable disease and acceptable life-expectancy.17, 34 ACTH independent disease stemming from an adrenal mass is treated with total or partial adrenalectomy.35

Conn syndrome Primary hyperaldosteronism, described by Jerome Conn in mid-20th century, nearly always results from disregulated production of aldosterone by the adrenal gland(s) outside of control of the reninangiotensin-aldosterone system (RAAS) (Figure 1). As such, diagnosis is made by documenting an elevated serum aldosterone level in the setting of a reduced renin level. 36-38 An aldosterone (ng/dL) to renin (ng/mL/hr) ratio of ≥20 (some suggest ≥30) in the setting of an aldosterone concentrations above ≥15 ng/mL are strongly suggestive of Conn syndrome, and confirmatory testing is initiated at this point.39-42 Hyperaldosteronism nearly uniformly results in hypertension, and the condition is present in 5% of hypertensive patients.40, 43 Hypokalemia, albeit classically associated with Conn syndrome, is present in only a minority of contemporary patients and, thus, normal potassium levels should not rule out diagnosis of hyperaldosteronism.36 Due to a rise of blood pressure with elevated aldosterone levels in nearly all patients, normotensive individuals with adrenal adenomas who are not taking antihypertensive medica-

tions do not require an evaluation for primary aldosteronism. In fact, only 1% of adrenal adenomas exhibit excess aldosterone production.44 Once the diagnosis of hyperaldosteronism is made, identification of its exact etiology is critical in those patients who are surgical candidates (Figure 1). By far the most common causes of Conn syndrome are bilateral adrenal hyperplasia (also known as idiopathic hyperplasia) and aldosterone-secreting adrenal adenoma, accounting for 60% and 35% of the condition, respectively.36 Because adrenalectomy is therapeutic only when unilateral adrenal hypersecretion is established, bilateral adrenal hypersecretion must be ruled out even if adrenal imaging documents a unilateral adrenal mass. As such, findings on CT or MRI cannot completely dictate management for the following reasons: (1) some 20% of aldosteroneproducing adenomas measure <1cm and may not be detectable on imaging (2) non-functional adrenal incidentalomas may be present in patients with bilateral adrenal hyperplasia in some 25% of cases.45 Thus, many experts recommend routine adrenal vein sampling for all patients with Conn Syndrome who are otherwise appropriate candidates for adrenalectomy. Through femoral vein access, blood from the vena cava, right adrenal vein, and left adrenal vein are tested for cortisol and aldosterone concentrations. Cortisol concentrations serve as a quality metric of appropriate adrenal vein canulation, since cortisol levels in the adrenal vein are higher than that in the inferior vena cava. Also, cortisol concentrations are used for normalization of aldosterone levels. As such, lateralization of aldosterone is determined by the following formula: (Aldosteronedominant/ Cortisoldominant)/(Aldosteronenon-dominant/ Cortisolnon-dominant).1, 46 If normalized aldosterone levels are >2x higher from one adrenal vein than from its contralateral counterpart, adrenalectomy of the hypersecreting adrenal gland should be considered.45 In patients in whom aldosterone hypersecretion does not lateralize or those who are not surgical candidates, aldosterone receptor blockers such as spironolactone and eplerenone are employed.38 Some rare forms of familial hyperaldosteronism can be corrected with glucocorticoid supplementation, as in these patients mineralocorticoid secretion is modulated by ACTH.47

SEPTEMBER 2012

Pheochromocytoma Another potential cause of hypertension stemming from adrenal pathology is hypersecretion of the catecholamines by pheochromocytoma. Approximately 1-2 per 100,000 individuals are diagnosed with pheochromocytomas each year, and less than 1% of hypertension cases are due to this condition.48, 49 It is important to mention that up to a quarter of all sporadic pheochromocytoma cases are proven hereditary upon genetic evaluation.50 Pheochromocytoma accounts for approximately 5% of adrenal incidentalomas, and unlike aldosterone or cortisol-secreting adenomas, these tumors are lipid-poor on cross sectional imaging. As such, pheochromocytomas measure >10HU in attenuation on non-contrast CT scan, fail to washout contrast on CT-washout studies, and do not exhibit signal dropout on in and out of phase magnetic resonance imaging.1, 51, 52 The classic triad of headache, paroxysmal perspiration, and tachycardia is not reported by all patients, and up to 20% of individuals are entirely asymptomatic.53 Although pheochromocytoma classically is known as the “10% tumor,” some aspects of this rule no longer apply. As mentioned, up to 30% of cases are familial,54 as many as 25% are extra-adrenal,55 and only ~5% of adrenal pheochromocytomas are malignant (while as many as 30% of extraadrenal pheochromocytomas, known as paragangliomas, demonstrate metastatic potential).49 Nevertheless, it is generally accepted that 10% of pheochromocytoma’s are bilateral and approximately 10% are found in children.55 Modern metabolic diagnosis of pheochromocytoma focuses on testing of catecholamine metabolites. Measurement of metanephrines—a collective term for metabolite of epinephrine (metanephrine) and metabolite of norepinephrine (normetanephrine)—in the serum or urine constitutes the most reliable method of biochemical diagnosis of pheochromocytoma. Because this conversion of catecholamines to metanephrines occurs in the adrenal medulla, elevation of metanephrine levels is a much more reliable metabolic perturbation than the short-lived paroxysmal rise in catecholamine levels themselves.56, 57 As such, measurement of plasma free metanephrines or total urinary metanephrines is mandatory in patients in whom diagnosis of pheochromocytoma must be ruled out.

Renal & Urology News 35

Treatment of pheochromocytoma is largely surgical. Adrenalectomy should be performed by experienced practitioners who understand the nuances of peri-operative management and catecholamine blockade.49, 58, 59. Importantly, recurrent pheochromocytoma has been documented up to 15 years following initial adrenalectomy and because of this, patients require life-long metabolic follow-up.49, 60-62

Metabolic evaluation of adrenal incidentalomas All adrenal masses require metabolic testing, as some 10% of these will prove to be either: cortisol, aldosterone, or catecholamine-producing lesions.41 As stated, Conn syndrome work-up is only necessary for those with hypertension, while hypercortisolemia and pheochromocytoma work-up is recommended for all patients. Although only 2% of patients with small adrenal lesions are destined to develop metabolic activity following an initial negative work-up,64 guidelines indicate the metabolic evaluation should be repeated annually for 3 to 4 years.41

Conclusions Diagnosing adrenal causes of hypertension requires a high level of clinical suspicion and a working knowledge of adrenal pathophysiology. Given the intimate anatomical and physiological relationship of the adrenals to the kidney, an understanding of adrenal disease is imperative for urologists and nephrologists alike. ■ REFERENCES 1. Kutikov A, Crispen PL, Uzzo RG. Pathophysiology, Evaluation, and Medical Management of Adrenal Disorders. In: Wein AJ, Kavoussi LR, Partin AW, et al, ed; Campbell-Walsh Urology, 10th ed. Philadelphia: Elsevier; 2011:1685-1736. 2. Mitty HA. Embryology, anatomy, and anomalies of the adrenal gland. Semin Roentgenol 1988;23:271-279. 3. Avisse C, Marcus C, Patey M, et al. Surgical anatomy and embryology of the adrenal glands. Surg Clin North Am 2000;80: 403-415. 4. Silverman ML, Lee AK. Anatomy and pathology of the adrenal glands. Urol Clin North Am 1989;16:417-432. 5. Barwick TD, Malhotra A, Webb JA, et al. Embryology of the adrenal glands and its relevance to diagnostic imaging. Clin Radiol 2005;60:953-959. 6. Kempná P, Flück CE. Adrenal gland development and defects. Best Pract Res Clin Endocrinol Metab 2008;22:77-93. 7. Arlt W, Stewart PM. Adrenal corticosteroid biosynthesis, metabolism, and action. Endocrinol Metab Clin North Am 2005;34:293-313. 8. Rainey WE. Adrenal zonation: clues from 11beta-hydroxylase and aldosterone synthase. Mol Cell Endocrinol 1999;151:151-160. 9. Jacobson L. Hypothalamic-pituitary-adrenocortical axis regulation. Endocrinol Metab Clin North Am 2005;34:271-292. 10. Gibbons GH, Dzau VJ, Farhi ER, Barger AC. Interaction of signals influencing renin release. Annu Rev Physiol 1984;46:291-308.

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CME FEATURE 11. de Diego AM, Gandia L, Garcia AG. A physiological view of the central and peripheral mechanisms that regulate the release of catecholamines at the adrenal medulla. Acta Physiol (Oxf) 2008;192:287-301. 12. Robertson D. The Adrenal Medulla and Adrenomedullary Hormones. In: Scott WH, ed; Surgery of the adrenal glands. Philadelphia: JB Lippincott;1990:55-68. 13. Pivonello R, De Martino MC, De Leo M, et al. Cushing’s Syndrome. Endocrinol Metab Clin North Am 2008;37:135-149. 14. Orth DN, Liddle GW. Results of treatment in 108 patients with Cushing’s syndrome. N Engl J Med 1971;285:243-247. 15. Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late prognosis of Cushing’s syndrome: a population-based study. J Clin Endocrinol Metab 2001;86:117-123. 16. Findling JW, Raff H. Screening and diagnosis of Cushing’s syndrome. Endocrinol Metab Clin North Am 2005;34:385-402. 17. Porterfield JR, Thompson GB, Young WF Jr, et al. Surgery for Cushing’s syndrome: an historical review and recent ten-year experience. World J Surg 2008;32:659-677. 18. Orth DN. Cushing’s Syndrome. N Engl J Med 1995;332:791-803. 19. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet 2006;367:1605-1617. 20. Scott WH, Orth DN. Hypercortisolism (Cushing’s Syndrome). In: Scott WH, ed; Surgery of the Adrenal Glands. Philadelphia: JB Lippincott;1990;115-151. 21. Young WF Jr, du Plessis H, Thompson GB, et al. The clinical conundrum of corticotropin-independent autonomous cortisol secretion in patients with bilateral adrenal masses. World J Surg 2008;32:856-862. 22. Lacroix A, Bourdeau I. Bilateral adrenal Cushing’s syndrome: macronodular adrenal hyperplasia and primary pigmented nodular adrenocortical disease. Endocrinol Metab Clin North Am 2005;34:441-458. 23. Pivonello R, Faggiano A, Lombardi G, Colao A. The metabolic syndrome and cardiovascular risk in Cushing’s syndrome. Endocrinol Metab Clin North Am 2005;34:327-339. 24. Faggiano A, Pivonello R, Melis D, et al. Nephrolithiasis in Cushing’s disease: prevalence, etiopathogenesis, and modification after disease cure. J Clin Endocrinol Metab 2003;88:2076-2080. 25. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526-1540. 26. Raff H, Findling JW. A physiologic approach to diagnosis of the Cushing syndrome. Ann Intern Med 2003;138:980-991. 27. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2003;88:5593-5602. 28. Findling JW, Raff H. Cushing’s syndrome: important issues in diagnosis and management. J Clin Endocrinol Metab 2006;91:3746-3753. 29. Utz AL, Swearingen B, Biller BM. Pituitary surgery and postoperative management in Cushing’s disease. Endocrinol Metab Clin North Am 2005;34:459-478. 30. Chow JT, Thompson GB, Grant CS, et al. Bilateral laparoscopic adrenalectomy for corticotrophindependent Cushing’s syndrome: a review of the Mayo Clinic experience. Clin Endocrinol (Oxf) 2008;68:513-519. 31. Vella A, Thompson GB, Grant CS, et al. Laparoscopic adrenalectomy for adrenocorticotropin-dependent Cushing’s syndrome. J Clin Endocrinol Metab, 2001;86:1596-1599. 32. Lacroix A. Evaluation of bilateral laparoscopic adrenalectomy in adrenocorticotropic hormonedependent Cushing’s syndrome. Nat Clin Pract Endocrinol Metab 2008;4:310-311. 33. Assié G, Bahurel H, Coste J, et al. Corticotroph tumor progression after adrenalectomy in Cushing’s disease: a reappraisal of Nelson’s syndrome. J Clin Endocrinol Metab 2007;92:172-179. 34. Aniszewski JP, Young WF Jr, Thompson GB, et al. Cushing syndrome due to ectopic adrenocorticotropic hormone secretion. World J Surg 2001;25:934-940. 35. Walz MK. Extent of adrenalectomy for adrenal neoplasm: cortical sparing (subtotal) versus total adrenalectomy. Surg Clin North Am 2004;84:743-753. 36. Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 2004;89:1045-1050.

37. Rossi GP, Bernini G, Caliumi C, et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol 2006;48:2293-2300. 38. Young WF. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol (Oxf) 2007;66:607-618. 39. Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 2004;89:1045-1050. 40. Young WF Jr. The incidentally discovered adrenal mass. N Engl J Med 2007;356: 601-610. 41. Grumbach MM, Biller BM, Braunstein GD, et al. Management of the clinically inapparent adrenal mass (“incidentaloma”). Ann Intern Med 2003;138:424-429. 42. Vierhapper H. Determination of the aldosterone/renin ratio in 269 patients with adrenal incidentaloma. Exp Clin Endocrinol Diabetes 2007;115:518-521. 43. Adler JT, Mack E, Chen H. Isolated adrenal mass in patients with a history of cancer: remember pheochromocytoma. Ann Surg Oncol 2007;14:2358-2362, 44. Young WF Jr. Management approaches to adrenal incidentalomas. A view from Rochester, Minnesota. Endocrinol Metab Clin North Am 2000;29:159-185. 45. Young WF, Stanson AW, Thompson GB, et al. Role for adrenal venous sampling in primary aldosteronism. Surgery 2004;136:1227-1235. 46. Young WF, Stanson AW. What are the keys to successful adrenal venous sampling (AVS) in patients with primary aldosteronism? Clin Endocrinol (Oxf) 2009;70:14-17. 47. Lifton RP, Dluhy RG, Powers M, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992;355:262-265. 48. Bravo EL, Tagle R. Pheochromocytoma: state-of-the-art and future prospects. Endocr Rev 2003;24:539-553. 49. Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet 2005;366:665-675. 50. Neumann HP, Bausch B, McWhinney SR, et al. Germline mutations in nonsyndromic pheochromocytoma. New Engl J Med 2002;346:1459-1466. 51. Boland GW. Adrenal imaging: why, when, what, and how? Part 1. Why and when to image? AJR Am J Roentgenol 2010;195:W377-W381. 52. Boland GW, Blake MA, Hahn PF, Mayo-Smith WW. Incidental adrenal lesions: principles, techniques, and algorithms for imaging characterization. Radiology 2008;249:756-775. 53. Adler JT, Meyer-Rochow GY, Chen H, et al. Pheochromocytoma: current approaches and future directions. Oncologist 2008;13:779-793. 54. Benn DE, Robinson BG. Genetic basis of phaeochromocytoma and paraganglioma. Best Pract Res Clin Endocrinol Metab 2006;20:435-450. 55. Ilias I, Pacak K. Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab 2004;89:479-491. 56. Eisenhofer G, Goldstein DS, Kopin IJ, Crout JR. Pheochromocytoma: rediscovery as a catecholamine-metabolizing tumor. Endocr Pathol 2003;14:193-212. 57. Eisenhofer G, Goldstein DS, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. J Clin Endocrinol Metab 2003;88:2656-2666. 58. Pacak K. Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab. 2007;92:4069-4079. 59. Pacak K, Linehan W, Eisenhofer G, et al. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 2001;134:315-329. 60. Plouin PF, Gimenez-Roqueplo AP. Initial work-up and long-term follow-up in patients with phaeochromocytomas and paragangliomas. Best Pract Res Clin Endocrinol Metab 2006;20:421-434. 61. Amar L, Servais A, Gimenez-Roqueplo AP, et al. Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 2005;90:2110-2116. 62. Pacak K, Eisenhofer G, Ahlman H, et al. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab 2007;3:92-102. 63. Dluhy RG. Pheochromocytoma--death of an axiom. N Engl J Med 2002;346: 1486-1488. 64. Barzon L, Sonino N, Fallo F, et al. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol 2003;149:273-285.

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1. In patients with pelvic kidney the adrenal gland is found: a. Capping the kidney b. Cradling the kidney c. Just above the renal vessels d. In its usual location high in the retroperitoneum 2. Adrenal cells that produce aldosterone: a. Are innervated by T-11 through L-2 sympathetic fibers b. Are located in the Zona Reticularis c. Are located in the Zona Fasiculata d. Are largely ACTH independent 3. All of the following is true regarding Cushing disease except: a. Is a subtype of ACTH dependent Cushing syndrome b. Is a type of Cushing syndrome that stems from pituitary pathology c. Results in hypercortisolemia stemming from ectopic ACTH production d. Was described by a neurosurgeon 4. Conn syndrome a. Is most commonly associated with bilateral adrenal hyperplasia b. Is present in over 5% of patients with adrenal incidentalomas c. Is nearly always associated with hypokalemia d. Should uniformly be treated with adrenalectomy 5. Pheochromocytomas a. Measure <10 HU on non-contrast CT imaging b. Exhibit signal dropout on in and out of phase MR c. Demonstrate >60% washout on 15 minute CT washout studies d. Appear to be familial in up to 30% of cases 6. Metabolic evaluation of adrenal incidentalomas a. Involves bilateral adrenal vein sampling in all patients with hypertension b. Requires uniform testing for Conn syndrome, Cushing syndrome, and pheochromoctyoma c. Can be performed without testing for hyperaldosteronism in patients without hypertension d. Should be repeated Q3 months for the first 5 years following diagnosis of adrenal incidentaloma.

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SEPTEMBER 2012

Renal & Urology News 37

Vegan Diet Benefits Type 2 Diabetics BY JILL STEIN PHILADELPHIA—A low-fat vegan diet made available on the job decreases body weight and cardiovascular risk in adults who are overweight and/or have type 2 diabetes compared with the standard American diet, investigators reported at the 72nd Scientific Sessions of the American Diabetes Association. Suruchi Mishra, PhD, Clinical Research Coordinator at the Washington Center for Clinical Research, a subsidiary of the Physicians Committee for Responsible Medicine in Washington D.C., and colleagues randomized individuals at 10 worksites to a vegan or control group. The vegan group was asked to follow a diet consisting of whole grains, vegetables, legumes, and fruits, and also to avoid animal products and minimize added oils. They also were encouraged to select foods with a low glycemic index. In addition, they were advised to take a daily B-12 supplement. Controls were given no dietary advice.

Study participants were recruited from a major U.S. insurance company. Results from 212 individuals who completed anthropometric and laboratory assessments at the end of the 18-week study showed that the intervention group had lost a mean of 2.9 kg while the control group had gained 0.06 kg. Total cholesterol decreased by 8.0 mg/dL in the intervention group compared with only 0.01 mg/dL in the control group; low-density lipoprotein (LDL)-cholesterol decreased by 8.1 and 0.9 mg/dL in the two groups, respectively. High-density lipoprotein (HDL)-cholesterol decreased by 1.8 mg/dL in the intervention group and increased by 0.9 mg/dL in the control group. There was a 9.9 mg/dL increase in triglyceride levels in the intervention arm and a decrease of 1.4 mg/dL in the control arm. In diabetic patients, hemoglobin A1c levels fell by 0.6 percentage points in the intervention group and 0.08 percentage points in the control

High-Risk PCa Treatable, Data Show

curative treatment, according to the investigators. For subjects with PSA levels of 51-100 ng/mL, the 10-year PCa-specific mortality was 55% and 20%, respectively. Among patients with PSA levels of 20-50 ng/mL at diagnosis, those treated with curative intent had a 77% decreased risk of PCa-related mortality compared with patients who received palliative care, after adjusting for age, comorbidities, disease stage, PSA level, and Gleason score. Among patients with PSA levels of 51-100 ng/mL, patients who had curative treatment had a 78% decreased risk. The researchers noted that androgen deprivation therapy (ADT) frequently is the first line of treatment for men with PSA levels above 20 ng/mL, but their results show that ADT is not sufficient for these patients. “Either RP or RT in combination with ADT should therefore be considered for men without evidence of distant metastases, even with PSA levels close to 100 ng/mL,” they wrote. Dr. Ladjevardi’s group said they believe their study is the second largest to analyze cancer-specific mortality among men with high-risk PCa. They pointed out that the risk of selection bias when assessing outcomes after treatment is well known and should not be neglected. ■

CURATIVE TREATMENT for men with high-risk prostate cancer (PCa) is associated with decreased cancer-specific mortality and should be considered even when serum PSA levels are higher than 20 ng/mL, researchers concluded. Treatment of men with high-risk PCa is controversial, they noted in an online report in BJU International, because of a lack of conclusive well-controlled or randomized studies comparing outcomes with palliative treatment, radiotherapy (RT), and radical prostatectomy (RP). A team led by Sam Ladjevardi, MD, PhD, of University Hospital, Uppsala, Sweden, analyzed data from 11,380 men diagnosed with high-risk PCa who had PSA levels of 20-100 ng/mL and no evidence of distant metastases. A total of 7,476 patients received palliative treatment and 3,904 had curative treatment, most commonly RP and external beam RT. The 10-year PCaspecific mortality for patients with a PSA level of 20-50 ng/mL was 36% for patients who received palliative care compared with 13% for those who had

Researchers observe significant weight loss and a decline in total and LDL cholesterol levels

Diets without animal fat reduce disease risk.

group. The differences between the intervention and control groups were significant for all measures. “About two thirds of Americans are overweight, and about half of overweight individuals are obese,” Dr. Mishra said. “Nutritional intervention

programs are needed at the worksite for both medical and financial reasons.” She also noted that weight reduction with a vegan diet is probably due to early satiety resulting from increased fiber intake, which produces a decrease in energy intake and a slight increase in postprandial energy expenditure from increased insulin sensitivity. The decreases in total and LDL cholesterol that occur with vegan diets are the result of a lack of animal fat and cholesterol in such diets coupled with the lipid-lowering effect of certain plant-based foods that are typical of a vegan diet. Dr. Mishra cited as study strengths the inclusion of a geographically diverse population, the use of a simple intervention that can used at other corporate sites, and adequate statistical power to show significant changes. She was quick to add, however, that the study was only 18 weeks and that men were underrepresented. ■

Untreated Renal Failure More Likely Among Elderly Patients RESEARCHERS IN Alberta, Canada,

eGFR below 15 without renal replace-

have found that untreated renal failure

ment therapy.

is significantly more common in older

The researchers, led by Brenda R.

than younger individuals, according

Hemmelgarn, MD, PhD, of Foothills

to a report published in the Journal

Medical Centre in Calgary, observed that

of the American Medical Association

their results “suggest that the incidence

(2012;307:2507-2015).

of advanced kidney disease in the

In a study that included more than

elderly may be substantially underesti-

1.8 million adults, the adjusted rates of

mated by rates of treated kidney failure

untreated kidney failure cases among

alone and that untreated kidney failure

individuals in the lowest stratum of esti-

may be more common than initiation of

mated glomerular filtration rate ([eGFR]

renal replacement at older ages.”

15-29 mL/min/1.73 m ) were 3.53

In an accompanying editorial (pp.

per 1,000 person-years for those aged

2545-2546), Manjula Kurella Tamura,

18-44 years versus 19.95, 13.25, and

MD, MPH, and Wolfgang C. Winkelmay-

8.54 per 1,000 person-years for those

er, MD, MPH, ScD, both of the Stanford

aged 85 years and older, 75-84 years,

University School of Medicine in Palo

and 65-74 years, respectively.

Alto, Calif., noted that the magnitude

Untreated kidney failure among

of untreated kidney failure among

patients aged 75 years or older with

older adults does not necessarily imply

a baseline eGFR of 15-29 was about

inappropriate withholding of treatment.

2- to 10-fold more common than kidney

“It is possible that older patients may

failure treated by dialysis, according to

have decided, after a shared decision-

the report.

making process with their medical

The investigators defined untreated kidney failure as progression to an

team and family, to forego dialysis and to opt for supportive care.” ■

38 Renal & Urology News

SEPTEMBER 2012

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Your Money A shifting economic environment has prompted financial advisors to rethink the old wisdom about diversification BY STAN LUXENBERG

Where to place your assets Faced with a shifting environment, financial advisors have been rethinking their strategies. A growing minority is urging clients to take new defensive measures. Some advisors are telling clients to hold big stakes in Treasury bonds. Another defensive approach is to use stock mutual funds that shift to cash when markets look expensive. “People thought that corporate bonds or foreign stocks would protect them, but that kind of diversification didn’t help,” says David Darst, chief investment strategist of Morgan Stanley Smith Barney.

yield. In addition, the principal value of the inflation securities rises along with the consumer price index. Say you invest $1,000 into TIPS, and inflation rises 3%. By the end of the first year, your principal value will have climbed to $1,030. Because they provide inflation protection, TIPS tend to be resilient, sometimes rising when stocks are declining.

Shifting between bonds and stocks Some financial advisors recommend funds that have the ability to shift between bonds and stocks. When markets look risky, the funds sell their stocks and invest in fixed income. Managers of the funds concede that they sometimes make mistakes, selling stocks when markets are still rising. But by holding cash and bonds in downturns, the funds often limit losses. Among the most notable performers in recent downturns has been Columbia Thermostat, which returned 3.8% annually during the past five years and outdid the S&P 500 by 5 percentage points, according to Morningstar. The fund follows a mechanical formula that aims to buy stocks when they are cheap and sell when they become dear. When the S&P 500 is under 1000, Thermostat

Defensive strategies include holding big stakes in Treasury bonds and investing in mutual funds that shift to cash when markets look expensive. In the past, Darst urged some clients to keep most of their assets in stocks. But these days he is recommending bigger doses of government bonds. For moderate-risk clients, he suggests keeping only 33% of assets in stocks. He puts 10% in government bonds and 7% in cash. Darst is keen on Treasury Inflation-Protected Securities (TIPS). Like other bonds, TIPS pay a fixed

keeps 90% of assets in stocks and 10% in cash and bonds. As the market rises, the fund sells stocks and shifts to fixed income. When the index tops 1750, the fund will only hold 10% in equities. With the S&P recently at 1315, the fund had 60% in equities and 40% in fixed income. Portfolio manager Charles McQuaid says that the fund doesn’t always get it right. “We make a judgment

or years, many financial advisors gave clients standard advice: Buy a diversified portfolio of stocks and bonds and hold it through up and down markets. Portfolios should include foreign and domestic stocks as well as corporate and government bonds, advisors said. If one investment sank, others were bound to stay afloat and enable investors to avoid big losses. But when markets crashed in 2008, the old advice about diversification failed to provide much protection. The problem was that most kinds of investments fell at once. In the depths of the financial crisis, only Treasury bonds and cash held their values.

In the depths of the financial crisis in 2008, only Treasury bonds and cash held their value.

call about when stocks look cheap, and the best we can do is predict in a rough range,” he says. The Columbia managers designed the fund after studying market history and noticing that stocks often move in patterns. For periods of about two decades, markets tend to rise. Then there are long periods when stocks go nowhere. One of the greatest rallies of all time occurred from 1982 to 2000. The rally ended when the Internet bubble burst. Studying the losses, the Columbia managers figured that markets were due for a long period of churning up and down. The Thermostat fund aimed to produce profits in the frustrating times.

Funds that are succeeding Since it was started in 2002, the fund has mostly succeeded, outdoing both stocks and bonds. But Thermostat does not excel every year. The fund trailed the S&P 500 from 2003 through 2006. During that time, stocks mostly rose. As the S&P 500 climbed, Thermostat gradually sold shares. The low stock allocation hurt the fund in the boom times. But when the financial crisis unfolded, Thermostat had big fixed-income holdings that provided protection.

Another fund that protected shareholders during the downturn is Stadion Managed Portfolio. In 2008, the fund lost 5.8%. The result may look uninspiring, but Stadion outpaced the S&P 500, which lost 37%. The fund follows trends, loading up on stocks when they are rising and selling when markets hit the skids. Stadion began shedding stocks in October 2007 when prices starting turning down. By late 2008, the portfolio was 100% in fixed income. Because Stadion waits to buy stocks until a rally has started, the fund often misses part of the gains that occur in bull markets. That does not trouble portfolio manager Brad Thompson. “If we can limit losses in downturns, then we will do quite well over the long term,” he says. Stadion began 2012 with big stock holdings. Then in April the market began weakening, and he shifted to all cash. At first the move seemed premature. Then investors began worrying that trouble in Spain and Greece could spread to global markets. That pushed down stocks. During the May downturn, Stadion outdid 99% of its peers. Financial advisors who recommended the fund could feel satisfied that they protected clients from a period of rough markets. ■

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