Renal & Urology News January 2012 Issue by Haymarket Media

JANUARY 2012

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VOLUME 11, ISSUE NUMBER 1

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Incidental RCC Offers Better Survival

An Icelandic study shows a substantial increase in incidentally detected tumors over a 35-year period

IN A STUDY, symptomatic tumors were larger than those detected incidentally.

High Salt Intake Cuts CKD Risk BY JODY A. CHARNOW PHILADELPHIA—High dietary salt intake may decrease the risk of chronic kidney disease (CKD), whereas low dietary potassium intake may increase the risk, investigators reported at Kidney Week 2011. The findings are from two analyses of 2001-2006 data from 13,917 individu-

CME FEATURE

als aged 18 years or older (mean age 45 years) who participated in the National Health and Nutrition Examination Survey. After adjusting for age, gender, race, diabetes and hypertension status, and diuretic usage, researchers found a significant association between higher quartiles of sodium intake and continued on page 12

Earn 1 CME credit in this issue

An Update on Robotic-Assisted Partial Nephrectomy PAGE 28

BY JODY A. CHARNOW INCIDENTAL DETECTION of renal cell carcinoma (RCC) is increasing and is associated with better survival from the malignancy, according to a populationbased study conducted in Iceland. Using centralized databases, Tomas Gudbjartsson, MD, PhD, of the Landspitali University Hospital in Reykjavik, and collaborators conducted a retrospective study of all living patients diagnosed with RCC in Iceland from 1971 to 2005. In 2005, Iceland had an estimated 300,000 people. The researchers compared survival of patients with incidentally diagnosed and symptomatic RCC. Of 910 patients diagnosed with RCC during the 35-year observation period, 254 (27.9%) were diagnosed incidentally,

Small Prostate Increases Risk of PCa Upgrade SMALLER PROSTATES in men with low risk prostate cancer (PCa) may indicate a greater likelihood of harboring tumors of higher grade than indicated by prostate biopsy, according to investigators. In a study of 1,251 patients undergoing radical prostatectomy for low risk PCa, researchers found that those with smaller prostates had a higher risk of Gleason score upgrades upon examination of the surgical specimen. The implications of identifying patients at high risk for Gleason score upgrading are “profound,” the researchers reported in The Journal of Urology (2011;186:2221-2227), noting that patients, urologists, and radiation oncologists base treatment plans on patient risk strata, of which biopsy Gleason scores are an important part. “The ability to distinguish patients at high risk for upgrading may help patients and clinicians determine patient eligibility for treatment options such as continued on page 13

Dr. Gudbjartsson’s team reported in The Journal of Urology (2012;187:48-53). The incidental detection rate rose significantly from 11.1% in 1971 through 1975 to 39.2% in 2001 through 2005. The rate increased significantly among male subjects during those same intervals, but only during the last five study years among female subjects. Mortality remained unchanged for males and females. Tumors diagnosed incidentally on average were 2.6 cm smaller than symptomatic tumors, and diagnosed at lower stage and lower grade than symptomatic tumors. TNM stage was by far the strongest independent predictor of survival, the researchers found. Compared with patients with stage I continued on page 12

IN THIS ISSUE 11

Prostate cancer linked to highdose vitamin E

Denosumab found to delay CRPC bone metastases

Black donors’ kidneys may worsen transplant outcomes

Epinephrine can reduce blood loss during TURP

FDA advisory committee backs peginesatide

Electromagnetic treatment could ease BPH symptoms

Kidney paired donation boosts odds of transplantation PAGE 14

6 Renal & Urology News

JANUARY 2012

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FROM THE EDITORIAL ADVISORY BOARD EDITORIAL ADVISORY BOARD

Highlights of 2011, The Promise of 2012

he start of 2012 is a good time to look back on the previous year to see the current state of nephrology. What have been the important findings that occurred in the past year, and what do we have to look forward to in the year ahead? Our understanding of glomerular disease has increased with several ground-breaking studies. Recently, high circulating levels of soluble urokinase plasminogen activator receptor were found by Wei and colleagues to be associated with focal segmental glomerulosclerosis and its recurrence after transplantation. This protein binds to beta 3 integrin, which is highly expressed in podocytes.1 These findings were similar to studies in membranous glomerulopathy, showing that auto-antibodies to M-type phospholipase A2 receptor (PLA2R)— which is expressed in glomerular podocytes—are associated with recurrent membranous nephropathy. Additional studies this year should help us to understand the clinical impact of these findings. It would be ideal to have a way to monitor disease in both of these conditions. The clinical application of these findings appears to be the next step. More and more genetic causes of kidney disease are being identified. Mutations were identified in the gene encoding nonmuscle class 1 myosin (MYO1E) as a cause of childhood-onset, glucocorticoid resistant FSGS.2 In addition, further studies confirmed the importance of the apo-lipoprotein 1 (APOL-1) gene as a primary cause of the increased risk of kidney failure in African-Americans.3 These studies have shown that small changes in this gene helped to prevent sleeping sickness in Africans, but these changes also increase the risk of HIV nephropathy and other forms of kidney disease in African Americans. It is still unclear how we will use this information both for screening and as a stepping stone for the treatment of both trypanosomiasis and kidney disease. In dialysis, there has been a swing away from early, asymptomatic initiation of dialysis to a more conservative approach. Ironically, at the same time, there has been a push towards more frequent dialysis, though no conclusive studies have demonstrated a mortality benefit in patients on nocturnal hemodialysis (HD) or daily home HD. Unfortunately, it is unlikely that we will see any more guidance in this area in the coming year, as prospective randomized, clinical trials are very expensive and difficult to do. For all of us, each New Year gives us the opportunity to renew our commitment to improve the health and well-being of each of our patients with kidney disease. Anthony J. Bleyer, MD Professor of Internal Medicine/Nephrology Wake Forest University School of Medicine Winston-Salem, N.C. REFERENCES 1. Wei C, El HS, Li J, et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 2011;17:952-960. 2. Mele C, Iatropoulos P, Donadelli R, et al. MYO1E mutations and childhood familial focal segmental glomerulosclerosis. N Engl J Med 2011;365:295-306. 3. Genovese G, Friedman DJ, Ross MD, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 2010;329:841-845.

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, PhD, MPH Professor of Medicine and Pediatrics, and Director, Dialysis Expansion & Epidemiology Harbor-UCLA Division of Nephrology & Hypertension Los Angeles BioMedical Research Institute, The David Geffen School of Medicine at UCLA

Urologists

Nephrologists

Frank R. Cerniglia Jr, MD Attending Pediatric Urologist Children’s Urology of Virginia Richmond, Va.

Anthony J. Bleyer, MD, MS Professor of Internal Medicine/Nephrology Wake Forest University School of Medicine Winston-Salem, N.C.

Christopher S. Cooper, MD Director, Pediatric Urology Children’s Hospital of Iowa Iowa City

Suphamai Bunnapradist, MD Director of Research Department of Nephrology Kidney Transplant Research Center The David Geffen School of Medicine at UCLA

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

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 Associate Professor of Nephrology Duke University School of Medicine Durham, N.C.

Renal & Urology News Staff Editor Executive editor Senior editor Web editor Editorial coordinator Group art director, Haymarket Medical Assistant art director VP production and manufacturing Production manager Product manager, digital products Audience development director Circulation manager Assistant 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 Jennifer Dvoretz Natasha Marcano-Dillon Louise Morrin Kathleen Millea Chris Bubeck John Crewe Paul Silver Monica Bond William Canning Tanya Gregory Dominic Barone Jim Burke Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 11, Number 1. 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

JANUARY 2012

■

VOLUME 11, ISSUE NUMBER 1

Urology 11

Vitamin E May Raise PCa Risk High doses are associated with a 17% increased likelihood of the malignancy.

Hypofractionated IMRT a Viable Option Higher daily doses of radiation in fewer days is as effective as conventional radiotherapy in preventing recurrence of intermediate- or high-risk prostate cancer at five years after treatment.

ONLINE

this month at renalandurologynews.com 12

Expert Q&A David Y. T. Chen, MD, FACS, a urologic oncologist at Fox Chase Cancer Center in Philadelphia, talks about his experience so far in the use of high-intensity focused ultrasound (HIFU) for treating men with prostate cancer.

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 November winner: Ralph Hallac, MD

Vitamin D Level Has No Effect on BP Serum levels of 25-hydroxyvitamin D are not associated with blood pressure changes in postmenopausal women.

TAP Block Beneﬁts Kidney Recipients Transversus abdominis plane blocks significantly decrease nausea and opioid use in the first two days after renal transplantation.

News Coverage Visit our website for daily news reports.

“

Metastasis, Obesity Linked in PCa Patients on ADT New findings may enable risk stratification of patients based on body mass index, according to researchers.

An Update on Robotic-Assisted Partial Nephrectomy Rosalia Viterbo, MD, an Assistant Professor in the Division of Urologic Oncology at Fox Chase Cancer Center in Philadelphia, reviews the advantages and limitations of this procedure, as well as indications, preoperative evaluation, and outcomes.

Nephrology

The Medical Minute Visit renalandurologynews.com/ the-medical-minute to hear podcast reports on new studies. Our latest include: • Cranberry Capsules Less Effective for Preventing Recurrent UTIs • Diabetes Drug May Help Inhibit Atherosclerosis

Extended LND Improves Outcomes in Selected Bladder Cancer Patients Certain patients who undergo radical cystectomy experience improvements in disease recurrence and overall survival patterns.

28 CME Feature

Incidence of AKI Requiring Dialysis Is Rising Rapidly Acute kidney injury requiring dialysis has become more common than end-stage renal disease requiring renal replacement therapy. Vitamin D Treats SHPT in Tx Patients Parathyroid hormone levels in kidney transplant recipients decreased by nearly 30% after six months of treatment using cholecalciferol with or without doxercalciferol.

We tend to think of vitamins and nutritional supplements as innocuous substances, but they’re not. See our story on page 11

Departments 6

From the Editorial Advisory Board Looking forward to 2012

News in Brief Aggressive PCa linked to well-done beef

On the Forefront Kidney paired donation boosts transplants

Renal Nutrition Update Zinc deficiency in kidney disease patients

Malpractice News Health costs rise despite malpractice caps

10 Renal & Urology News

JANUARY 2012

www.renalandurologynews.com

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

Short Takes Peripheral Neuropathy Common in ED Patients

and 26% had an eGFR of 60-89 and

Peripheral neuropathy may be under-

(72%) who were arrhythymia-free over a

appreciated as a cause of erectile

one-year follow-up, eGFR increased three

dysfunction (ED), Spanish research-

months later and was maintained until

ers reported in BJU International

one year, whereas eGFR decreased over

(2011;108:1855-1859).

one year in patients with recurrences.

30-59, respectively. Of the 278 patients

In a study of 90 ED sufferers (mean those with more severe symptoms of

CV Event Risk Linked to Sodium Excretion

peripheral neuropathy have lower Inter-

Analyses of two cohorts totaling 28,880

national Index of Erectile Function (IIEF-

individuals showed that baseline urinary

5) scores and require more aggressive

sodium excretion above 7 g/day was

treatment than others. The research-

associated with an increased risk of

ers confirmed neurologic pathology in

cardiovascular (CV) events compared

68.9% of patients, peripheral neuropa-

with baseline excretion of 4-5.99 g/day.

thy in 61.1%, and myelopathy in 7.8%.

In addition, sodium excretion below 3 g/

Polyneuropathy was found in 37.8%.

day was associated with an increased

age 54 years), investigators found that

risk of CV mortality and hospitalization

Atrial Fibrillation Treatment Benefits Kidneys

for congestive heart failure. Higher esti-

In the year following successful treat-

associated with a reduced risk of stroke,

ment of atrial fibrillation (AF) by catheter

investigators reported in the Journal

ablation, kidney function improves in

of the American Medical Association

patients with mild to moderate renal

(2011;306:2229-2238).

mated urinary potassium excretion was

The authors, led by Martin J.

dysfunction, Yoshihide Takahashi, MD, and colleagues reported in Circulation

O’Donnell, MB, PhD, of McMaster Uni-

(2011;124:2380-2387). Baseline esti-

versity in Hamilton, Ontario, concluded

mated glomerular filtration rate (eGFR)

that this inverse relationship “is a po-

among 386 study subjects was 68 mL/

tential intervention that merits further

min/1.73m . Of these patients, 66%

4.7%

3.5%

2.0%

0.7%

18-44

ESRD vs. Death in Patients With Diabetic Nephropathy P

atients with type 2 diabetic nephropathy are more likely to progress to endstage renal disease (ESRD) than die, according to investigators. In a retrospective study of 3,228 adults with type 2 diabetic nephropathy, ESRD developed in 19.5% of subjects over a mean follow-up period of 2.8 years, which was 2.5 times the incidence of cardiovascular death and 1.5 times the incidence of all-cause mortality, researchers reported online in the American Journal of Kidney Diseases. A team led by Hiddo J. Labers Heerspink, PharmD, PhD, of the University Medical Center Groningen in Groningen, the Netherlands, concluded that their findings have implications for predicting future renal replacement requirements because of the rapidly increasing number of cases of type 2 diabetes worldwide. The study found that ESRD occurred more commonly than cardiovascular death in all subgroups analyzed, except for subjects with low levels of albuminuria and well-preserved levels of renal function.

How Clinicians Worldwide Manage BPH-Related AUR

The percentage of individuals aged 18 years and older in the United States who have kidney disease increases by age, according to data from the National Health Interview Survey.

study of 470 cases of aggressive prostate cancer (PCa) and 512 controls demonstrated that higher consumption of any ground beef or processed meats was associated with an increased risk of aggressive PCa, particularly when the meat was grilled or barbecued and when well-done. The study, by Sanoj Punnen, MD, of the University of California in San Francisco, and colleagues, found that high consumption of well-cooked/very-well-cooked ground beef was associated with a twofold increased risk of aggressive PCa compared with no consumption. Low consumption was associated with a 51% increased risk, according to findings published in PLoS One 2011;6:e27711). In contrast, consumption of rare or medium-cooked ground beef was not associated with aggressive PCa.

evaluation for stroke prevention.”

Kidney Disease in the U.S.

Well-Done Ground Beef May Raise Risk of Aggressive PCa A

45-64

65-74

Age Group Source: Summary Health Statistics for U.S. Adults: National Health Interview Survey, 2010.

75 and older

rethral catheterization followed by a trial without catheter (TWOC) has become a standard treatment worldwide for men with benign prostatic hyperplasia (BPH) and acute urinary retention (AUR). In addition, prescribing an alpha-1 blocker prior to TWOC approximately doubles the chance of therapeutic success, and prolonged catheterization is associated with increased morbidity. These are the conclusions of John Fitzpatrick, MD, and colleagues after they studied data from 6,074 patients and 953 urologists from public, private, and mixed healthcare practices in France, Algeria, and 13 other countries in the Middle East, Asia, and Latin America. As reported online ahead of print in BJU International, 71% of patients had spontaneous AUR and 29% had experienced AUR following a triggering event, mainly anesthesia administration or excessive alcohol intake. A urethral catheter was inserted in 89.8% of cases, usually followed by a TWOC (78%) after a median of five days. The overall TWOC success rate was 61%. Most men (86%) received an alpha-1 beta-blocker (usually alfuzosin) before catheter removal with consistently higher TWOC success rates, regardless of age and type of AUR.

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JANUARY 2012

Vitamin E May Increase PCa Risk Study reveals 17% increased likelihood of malignancy with high doses MEN WHO take vitamin E supplements may be at increased risk of prostate cancer (PCa), new findings show. Analysis of longer follow-up data from participants in the Selenium and Vitamin E Cancer Prevention Trial (SELECT)—a double-blind, placebocontrolled study that enrolled 35,533 men in the United States, Canada, and Puerto Rico—revealed that subjects who took vitamin E alone had a significant 17% increased risk of PCa compared with those who took placebo. Put another way, 76 cases of PCa were diagnosed in every 1,000 men who took vitamin E; 65 cases were diagnosed in every 1,000 who took placebo, according to lead investigator Eric A. Klein, MD, Chairman of the Glickman Urological and Kidney Institute at Cleveland Clinic. Earlier findings from SELECT showed that men who took vitamin E and selenium or both substances together experienced no significant change in their PCa risk. Previous preclinical and epidemiological studies suggested that vitamin E and selenium may decrease PCa risk, so the finding of no benefit—and even potential harm with vitamin E—was unexpected. “Almost all of the data

Eric A. Klein, MD

going into the design of SELECT suggested otherwise,” Dr. Klein said. SELECT findings could weaken enthusiasm for research into the use of antioxidants for PCa chemoprevention and prompt investigators to change course. “We need to rethink everything that we’re looking at,” Dr. Klein said. SELECT findings also should serve to educate the public. “We tend to think of vitamins and nutritional supplements as innocuous substances, but they’re not. They’re really part of our biology,

and too much of them can be harmful,” Dr. Klein said. Dr. Klein and his collaborators published their findings in the Journal of the American Medical Association (2011;306:1549-1556), where they concluded: “The lack of benefit from dietary supplementation with vitamin E or other agents with respect to preventing common health conditions and cancers or improving overall survival, and their potential harm, underscore the need for consumers to be skeptical of health claims for unregulated overthe-counter products in the absence of strong evidence of benefit demonstrated in clinical trials.” In SELECT, investigators randomly assigned men to receive selenium alone, vitamin E alone, a combination of the two supplements, or placebo. After a median 5.5 years of follow-up, researchers observed no significant reduction in PCa risk with either selenium (200 µg/ day), vitamin E (400 IU/day), or both selenium and vitamin E compared with placebo. Researchers observed the 17% increased risk after a median of seven years of follow-up. Researchers do not have a biological explanation for why vitamin E raises PCa risk, Dr. Klein said. ■

Renal & Urology News 11

Obese Black HD Patients Have the Best Survival INCREASING BODY mass index (BMI) is associated with lower mortality rates in maintenance hemodialysis (HD) patients regardless of race or ethnicity, but the survival advantage is most pronounced in blacks, data show. A study of 109,605 maintenance HD patients showed that each 1 kg/m2 increment in BMI was associated with a 2.5% lower mortality risk in blacks, a 2.0% lower risk in non-Hispanic whites, and a 1.0% lower risk in Hispanics. A possible reason for the stronger survival advantage associated with higher BMI in blacks compared with other races or ethnicities is that blacks have greater muscle mass, and more muscle mass appears to be associated with better survival, according to the researchers. The investigators, led by Kamyar Kalantar-Zadeh, MD, PhD, MPH, of the Harbor-UCLA Medical Center in Torrance, Calif., published their findings in the American Journal of Kidney Diseases (2011; 58:4:574-582). As far as they are aware, their study is the first to compare the association

Hypofractionated IMRT Is a Viable Option

between BMI and survival in blacks, non-Hispanic whites, and Hispanics in maintenance HD patients.

DELIVERING HIGHER daily doses of radiation in fewer days (hypofractionation) is as effective as conventional radiotherapy in preventing recurrence of intermediate- or high-risk prostate cancer (PCa) at five years after treatment, a study found. “Hypofractionation is rapidly gaining momentum for many types of cancers. The results presented here bring us much closer to effectively treating prostate cancer in a shorter period of time, with acceptable side effects,” said lead investigator Alan Pollack, MD, Chairman of Radiation Oncology at the University of Miami Miller School of Medicine. The strategy to compress treatment schedules using hypofractionation is based on years of studies indicating that there could be a radiobiologic advantage to this approach. Prior research has indicated that tumor cells would be killed to a greater degree with hypofrac-

tionation than the potentially damaging effects of other treatments on the surrounding normal tissues, namely the rectum, penile structures affecting erections, and bladder. Another newer approach to hypofractionation incorporated into this trial is the use of intensity modulated radiotherapy (IMRT), which further limits dose to the normal tissues. The new study involved 303 men with intermediate- or high-risk PCa randomized to receive either hypofractionated IMRT (HIMRT) or conventionally fractionated IMRT (CIMRT). High-risk patients also received androgen deprivation therapy for two years. Investigators followed patients for up to seven years. Although investigators hypothesized that HIMRT would be superior, they observed similar tumor control rates. The rate of biochemical failure at five years was 21.9% in the CIMRT group

and 21.5% in the HIMRT group using the ASTRO definition, and 14.8% and 19%, respectively, using the Phoenix definition (PSA nadir plus 2 ng/mL). For both definitions, the rates of biochemical failure were not significantly different. Thus, the hypofractionated approach achieved comparable results with two and a half fewer weeks of treatment. “This long-term study confirms that hypofractionated radiation … is a practical approach to effectively controlling prostate cancer, as compared to the more standard treatment for men with intermediate to high-risk prostate cancer,” Dr. Pollack said. He noted, however, that a followup period longer than five years is needed to have a better idea about the effects of treatment on urinary function. These effects take much longer to appear compared with GI problems, he added. ■

Previous studies have shown that black and Hispanic maintenance dialysis patients have a lower mortality rate than their non-Hispanic white counterparts, an advantage that persists even after adjusting for such important factors as comorbid diseases and laboratory result abnormalities. Obesity is associated with an increased risk of death in the general population, but in the dialysis population, obese individuals consistently have been shown to have a relatively lower death risk compared with nonobese individuals. The reasons for what researchers call the “obesity paradox” in the dialysis population remains unclear, but one possible explanation is that obese individuals have greater nutritional reserves that prevent protein-energy wasting. ■

12 Renal & Urology News

JANUARY 2012

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Extended Lymph Node Dissection Improves Outcomes observed with extended and limited LND “shows that micrometastasis outside the template of a limited LND are present only in a minority of patients. Otherwise, more substantial differences in recurrence patterns would have been expected.” They also noted that despite methodological problems in their study, a five-year recurrence-free survival of 29% in LN positive patients in the extended LND cohort shows that some LN positive patients can be cured by surgery alone. ■

extended LND and a group undergoing limited LND. Overall, the risk of any recurrence and any lymph node (LN) recurrence within 24 months did not differ significantly between the extended and limited LDN groups (27% vs. 26% and 8% vs. 6%, respectively), according to a report in the International Journal of Urology (published online ahead of print). Patients with positive lymph nodes had a significantly better prognosis after extended LND. The five-year disease-specific survival was 39% for the

extended LND cohort compared with 14% for the limited LND cohort. The five-year recurrence-free survival was 29% and 8%, respectively. Five-year overall survival was 38% and 12%. Among subjects with non-organ confined tumors, a five-year diseasespecific survival and overall survival were significantly better in the extended compared with the limited LND cohort (76% vs.62% and 71% vs. 43%, respectively). The researchers stated that the overall comparable recurrence patterns

Incidental RCC

diagnoses. The proportions were 75% and 12.5%, respectively, in 2005. The current study builds on a previous study by the same researchers, who six years earlier reported in Urology (2005;66:1186-1191) on a populationbased study of 701 RCC patients in Iceland, where incidental detection did not reach statistical significance as an independent prognostic factor of survival. Dr. Gudbjartsson’s team stated that, to their knowledge, the current study and the one published in 2005 are the only populationbased studies to have analyzed the effect of incidental detection on survival. The authors noted that their most recent results might be explained by an epidemiological variable that differs between incidentally and symptomatically diagnosed patients. For example, the two groups might interact with the health care system at different frequencies. In addition, better survival in the incidentally diagnosed group could be due to possible lead time and stage migration bias in that tumors detected sooner “may be less invasive and have lower malignancy potential, resulting in more favorable prognosis.” Biological differences between incidentally and symptomatically detected tumors are another possibility. ■

A 23% lower CKD risk was observed in the highest versus the lowest quartile of salt intake.

continued from page 1

tumors, those with stage IV tumors had a 17.7 times increased risk of diseasespecific mortality. After adjusting for age, year of diagnosis, TNM stage, and other confounders, patients with symptomatic RCC had a 40% increased risk of disease-related death than those with incidentally diagnosed RCC, but the risk was increased significantly only for patients with systemic, not local, symptoms (47% vs. 31%). The study helps to define the role of incidental detection of RCC as an independent and favorable prognostic factor, which is important because most RCC tumors are now detected incidentally, said Dr. Gudbjartsson, Professor of Surgery at the University of Iceland in Reykjavik. Investigators also observed a shift in how incidentally diagnosed tumors were detected. For the study period overall, the most common modes of detection were abdominal ultrasound (29.5%) and computerized tomography (CT, 28.3%) performed for unrelated complaints or diseases. After 2000, CT accounted for 55.4% and ultrasound accounted for 26.5% of Modes of Incidental Detection

A study conducted in Iceland showed that most incidental renal cell carcinoma tumors are found with computed tomography and ultrasound, but the proportion of tumors found with each of these modalities changed over time. 80

Computed tomography

75.0%

Ultrasound

60 55.4%

50 40 30 20

28.3%

29.5%

26.5%

10 0

12.5%

1971-2005

After 2000

2005

Source: Palsdottir HB, Hardarson S, Petursdottir V, et al. Incidental detection of renal cell carcinoma is an independent prognostic marker: Results of a long-term, whole population study. J Urol 2012;187:48-53.

EXTENDED LYMPH node dissection (LND) does not significantly change overall disease recurrence and survival patterns in patients who undergo radical cystectomy for bladder cancer compared with limited LND, but certain patient subgroups experience improvements in these outcomes, a study found. Researchers at Aarhus University Hospital in Aarhus, Denmark led by Jørgen Bjerggaard Jensen, MD, compared two different historical cohorts: a group of 265 patients undergoing

High Salt Intake continued from page 1

decreased likelihood of CKD. Compared with participants in the first quartile, those in the third and fourth quartiles had a significant 34% and 23% decreased likelihood of CKD, respectively. Low potassium levels were associated with a significant 35% increased risk of CKD compared with normal intake. High potassium intake was associated with a 22% reduced risk, but this association was of borderline significance. Individuals in the first quartile of potassium intake had a significant 55% increased risk of CKD compared with those in the fourth quartile. The investigators, Shailendra Sharma, MD, and colleagues at the University of Colorado in Denver, evaluated dietary sodium and potassium intake from 24-hour dietary recall obtained by trained interviewers. Dr. Sharma’s group classified subjects into quartiles of salt intake (2,116 mg/day or less and 2117-3,061, 3,062-4,267, and more than 4,267 mg/day) and quartiles of potassium intake (1,737 mg/day or less and 1,738-2,455, 2,456-3,341, and 3,342 or more mg/day). They also

classified subjects into low, normal, and high potassium intake (less than 2,000, 2,000-4,000, and more than 4,000 mg/day). The mean sodium intake was 3,520 mg/day and the mean potassium intake was 2,760 mg/day. The mean estimated glomerular filtration rate (eGFR) was 88 mL/min/1.73 m2. CKD, defined as an eGFR below 60 mL/min/1.73 m2, was observed in 14.2% of the study cohort. The researchers noted that experimental data suggest that salt may be directly nephrotoxic by increasing oxidative stress and indirectly nephrotoxic by raising blood pressure and attenuating the effects of antihypertensive medications. It has been unclear, however, whether dietary sodium is associated with CKD. Dr. Sharma’s team also pointed out that several studies indicate that a high dietary intake of potassium decreases blood pressure and noted that low potassium intake in the United States is considered a major contributor to the prevalence of hypertension and cardiovascular disease. The study is the first to examine the relationship between potassium intake and CKD, according to the investigators. ■

www.renalandurologynews.com

Small Prostate continued from page 1

active surveillance and brachytherapy,” the authors wrote. “Thus, the ability to predict upgrading is most relevant in patients with low risk disease.” Additionally, the findings suggest that cancers in smaller and larger prostates may be biologically different, or that PCa in men with a larger prostate gland may be detected at a more favorable time point in the disease course because of the higher PSA associated with larger prostates, the researchers concluded. Further, the higher PSA density associated with smaller prostates predicts worse disease parameters and prognosis. For the study, a team led by Daniel A. Barocas, MD, MPH of Vanderbilt University Medical Center in Nashville, Tenn., divided subjects into three groups according pathological Gleason score: no upgrade, minor upgrade (3 + 4 = 7), and major upgrade (4 + 3 = 7 or higher) from a biopsy Gleason score of 6 or less. Of the 1,251 patients, 387 (31%) were upgraded upon pathological examination of the surgical specimen, including

Vitamin D Level Has No Effect on BP SERUM LEVELS of 25-hydroxyvitamin D (25(OH)D) are not related to changes

324 (26%) with minor upgrading and 63 (5%) with major upgrading, Dr. Barocas and colleagues reported. Men who had no Gleason score upgrade had a median prostate volume of 47 cm3, which was significantly larger than the prostate volumes of patients who had minor and major upgrades (both 43 cm3). Larger prostate size was associated with a 42% and 33% decreased likelihood of any upgrade

JANUARY 2012

and major upgrade, respectively, after adjusting for age, surgery year, clinical stage, PSA level, and other potential confounders. Men with prostate volumes in the 25th percentile (36 cm3) were 50% more likely to have upgrading than men with prostate volumes in the 75th percentile (58 cm3). For the study, Dr. Barocas’ team used the weight of the surgical specimen as a

Renal & Urology News 13

surrogate for clinical prostate volume. They chose this method because many biopsies were performed by referring urologists and prostate volumes as determined by transrectal ultrasound were not universally available and biopsies were not performed according to a uniform protocol, they noted. The study population was 92% white and had a median PSA level of 5 ng/mL before surgery. ■

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 laparoscopic and robotic surgery. But our doctors also recognize when the best management is not an operation, but careful observation. We believe it is important to be well versed in all options to ensure patients receive the right treatment at the right time. Because our job is not only to save lives, but to preserve the

in blood pressure (BP) in post-

quality of life of every patient we treat. Snap the code and learn

menopausal women, according

more at UPMCPhysicianResources.com.

to researchers. In a study of 4,863 postmenopausal women recruited into the Women’s Health Initiative between 1993 and 1998, investigators led by Karen L. Margolis, MD, of HealthPartners Research Foundation in Minneapolis, observed no significant differences in the adjusted mean change in systolic or diastolic BP by quartile of 25(OH)D over seven years. In adjusted analyses, subjects in the third quartile of 25(OH)D had a significant 33% decreased risk of incident hypertension compared with those in the lowest quartile, the researchers reported (online ahead of print) in the American Journal of Epidemiology. The researchers found no significant reduction in risk among those in the second and fourth quartiles. ■

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

14 Renal & Urology News

JANUARY 2012

www.renalandurologynews.com

On the Forefront

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

Boosting Renal Transplantation with Kidney Paired Donation BY DAVID GOLDFARB, MD he fundamental problem in transplantation is a shortage of transplantable organs. More than 90,000 candidates are on the national waiting list. It is estimated that about one third of kidney transplant candidates may have a willing, medically fit living donor, but the donor is incompatible because of an unfavorable blood type or the patient has antibodies to the donor’s tissue antigens. In the past five to 10 years, researchers have developed several techniques to overcome incompatibility. One is desensitization, which involves performing extra manipulation of the immune system by removing the antibodies (plasmapheresis), blocking the antibodies (intravenous immunoglobulin), or suppressing antibody production (anti-CD20 antibodies). Desensitization does not always work, and the results achieved are not as good as with compatible donors and conventional immunosuppression. Still, it is better than waiting on the list. Another solution to incompatibility is called paired donation.

A successful paired donation Below is a case illustrating the collaborative efforts between nephrology and urology at the Glickman Urological and Kidney Institute. Cheryl, whose blood type is O, wanted to donate to her older sister, Jackie, who is on dialysis and is a blood type A patient. Cheryl

The core of a paired donation program is the computer registry of donors and willing, medically suitable but incompatible donors.

is highly motivated and is very healthy. Although she is blood type compatible with her sister, a direct transplant was not possible because Jackie had antibodies to tissue antigens on Cheryl’s kidney, a positive cross match test. At the same time in another Northeast Ohio community, Cindy wished to donate to her mother, Pat who was suffering from end-stage renal disease. Cindy was also highly motivated and healthy. Cindy is a blood type A and her mother Pat a blood type O making this combination incompatible. Both incompatible pairs enrolled in a paired donation registry jointly operated by the institute’s urologists and nephrologists. Medical information on the incompatible pairs was placed into the computer. A specialized program of the Paired Donation Network identified a match where Cindy could donate to Jackie and Cheryl could donate to Pat. Cindy’s tissue type antigens were compatible with Jackie and the two were the same blood type. Both Cheryl and Pat were blood type O with a negative cross match test, making transplantation possible. Both transplants occurred simultaneously and all are doing well.

Computer registry The core of a paired donation program is the computer registry of donors and willing, medically suitable but incompatible donors. The computer matches up donors with compatible recipients so that reciprocal pairs can swap their donor’s kidneys (Figure A). If recipient A and donor A are incompatible but recipient A is compatible with donor B and recipient B compatible with donor A, then a straight swap will get both recipients transplanted without desensitization. Both recipients are transplanted with compatible donors. For this to occur, many incompatible pairs have to enter a registry to generate sufficient matches to be successful. The straight forward swap described in Figure A requires donors to travel and for operations to occur simultaneously, which may be logistically challenging. In the case above, all participants lived close to Cleveland Clinic. To improve transplant rates, chains of non-simul-

Figure A. In paired donation, a computer matches donors with compatible recipients.

Figure B. Chains of non-simultaneous transplants have improved transplant rates.

taneous transplants are now acceptable (Figure B). Such chains have improved transplant rates compared with simple paired exchange. Furthermore, instead of donors traveling, the living donor kidney can travel much in the same way as deceased donor organs. In other words, if a recipient from Cleveland finds a donor match in Los Angeles through an incompatibility registry, the donors may donate closer to home and have the kidney travel to the recipient destination. Nephrologists and urologists at the institute recently have become involved with a paired donor registry known as the National Kidney Registry. Since 2008, this registry reports that 68% of the patients listed have been trans-

planted. This is the highest percentage of any registry in the United States today. The high transplant rates are due to a very strong computer matching program with careful oversight, the use of chain paired donation, and travel of the kidney instead of the donor. We are beginning to enter pairs in this program now and are already looking at potential transplants for our patients. We hope that this will offer an opportunity at transplantation to an otherwise underserved group of kidney disease patients with willing, medically fit but incompatible donors. ■ David Goldfarb, MD, is a urologist at the Glickman Urological and Kidney Institute at Cleveland Clinic.

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JANUARY 2012

Renal & Urology News 19

TAP Block Benefits Kidney Recipients Advantage of continuous analgesia via a catheter compared to other regional nerve blocks BY ROSEMARY FREI, MSc CHICAGO—Regional anesthesia via a transversus abdominis plane (TAP) block significantly reduces nausea and opioid use in the first two days after kidney transplantation, new findings suggest. A retrospective study presented at the American Society of Anesthesiologists’ 2011 annual meeting showed that 30 kidney recipients given a TAP block enjoyed these benefits compared with 30 individuals with intravenous, patientcontrolled analgesia. No patient received epidural anesthesia because of either reduced or dysfunctional platelets. Furthermore, the team analyzed only the first 48 post-operative hours because longer catheter use can lead to bacterial colonization and thus is not recommended. The median morphine-equivalent dose of opioids was 33.7 among people with a TAP catheter compared with 238 in the standard-care patients, a significant difference between the groups.

NKF Names New CEO THE NATIONAL KIDNEY Foundation (NKF) has announced that it has named a new Chief Executive Officer. Bruce Skyer will succeed John Davis, who served as CEO since 1982. He will continue the organization’s nationwide initiatives to provide assistance for kidney patients and professionals. Skyer first joined the NKF as Chief Operating Officer in April 2010.

Moreover, the study, led by Maged Guirguis, MD, and Ehab Farag, MD, of the Department of Anesthesiology at Cleveland Clinic, showed that the average nausea score was lower in the TAP group compared with controls (1.00 vs. 1.06) in the controls. Average pain intensity on a verbal rating scale also was lower in the TAP-catheter group, but not statistically significant (2.2 vs. 2.6). “Theoretically if your opioid requirement decreases, all the complications related to postoperative opioids usage also decrease, such as nausea, ileus, respiratory depression and the increased potential for infection,” Dr. Guirguis, MD, told Renal & Urology News. “Overall, the patient satisfaction also was high among those with TAP catheters.” Transplant surgeons at the University of Michigan Health Systems in Ann Arbor put the study findings into perspective. “There are a fair number of studies out now, in colorectal, gynecology, and other abdominal

operations, using this technique and I have not been overwhelmed by the results, though it may be an effective alternative to epidural anesthesia,” said Christopher Sonnenday, MD, MHS, Assistant Professor of

Regional analgesia using this method decreased nausea and opioid use. Surgery and Assistant Professor of Health Management & Policy. “In the kidney transplant population, incisional pain is usually not a prohibitive problem and we don’t use epidural catheters.” A colleague, Randall Sung, MD, Associate Professor of Surgery, agreed that more study is needed to show whether TAP catheters are indeed the best analgesia approach in some kidney recipients. “The major advantage presented

in the data appears to be nausea— however, resumption of oral intake isn’t a big issue in this population, so I’m not sure it’s a major improvement,” Dr. Sung said. “It would seem that TAP has advantages over epidurals, but the devil is in the details—ease of use, logistics, transition to oral pain medication, etc.” The TAP block involves delivery of local anesthetic to the region between the internal oblique muscle and the transversus abdominus muscle. It has the advantage of continuous analgesia via a catheter compared to other regional nerve blocks such as paravertebral or the combination of intercostal with ilioinguinal or iliophypogastric, Dr. Guirguis and his colleagues explained in their poster. They also state that the literature shows TAP catheters have been used successfully for pain relief after abdominal procedures such as hernia repair, hysterectomy, cesarean delivery, and suprapubic prostatectomy (Reg Anesth Pain Med 2006;31:91). ■

Renal Deterioration Reduced with PN DETERIORATION OF kidney function after renal surgery is more significant in patients who have undergone radical nephrectomy (RN) rather than partial nephrectomy (PN), according to a Polish study. In addition, the study showed that compensatory hypertrophy of the contralateral kidney seems not to be associated with hyperfunction. “The hypothesis regarding hyperfunction of the contralateral kidney should be revised because hyperfunction is not clinically or statistically signifi-

cant,” the researchers concluded in a report published online ahead of print in International Urology and Nephrology. In a study led by Slawomir Poletajew, MD, of the Medical Centre of Postgraduate Education in Warsaw, comparing 33 RN patients and 18 PN patients, RN patients had a 32% decrease in estimated glomerular filtration rate (eGFR) one year postoperatively compared with just 5% in PN patients. Postoperatively, serum creatinine had increased in both groups, but signifi-

cantly more so in the RN than the PN group. From baseline to 12 months postoperatively, serum creatinine values rose from 90.5 to 126.4 mmol/L in the RN group and from 89.4 to 95.1 in the PN group. In addition, the mean effective plasma renal flow (EPRF) in the contralateral kidney increased by 4% in the RN patients and 0.1% in the PN patients. In the RN group, the EPRF in the contralateral kidney that was operated on decreased by 24.7%. ■ ADD A LINE PLEASE

Prior to his involvement with the NKF, he was Chief Financial and Administrative Officer for the Nonprofit Finance Fund. “Skyer’s combination of experience in both the corporate and nonprofit sectors will serve NKF well,” said W. Edward Walter, chairman of the NKF Board of Directors. He said that Skyer’s business experience and interest in the community will be of great help to the NKF. ■

Program Targets Infections in Chemo Patients THE CENTERS FOR Disease Control and Prevention (CDC) has launching a new program to help prevent infections in patients receiving cancer chemotherapy. The Preventing Infections in Cancer Patients program features an interactive website called “3 Steps Toward Preventing Infections During Cancer Treatment.” (https://www.preventcancerinfections.

org/Default.aspx) Chemotherapy patients can take a short questionnaire designed to assess their risk and educate them about staying healthy. The program also includes the Basic Infection Control and Prevention Plan for Outpatient Oncology Settings (http://www.cdc.gov/hicpac/pdf/ guidelines/basic-infection-control-prevention-plan-2011.pdf), a comprehen-

sive guide to determine if an outpatient oncology facility meets minimal patient safety expectations. Attention to infection prevention varies greatly among outpatient oncology facilities, according to Alice Guh, MD, a medical officer at the CDC and co-leader of the initiative. Therefore, the CDC urges facilities to incorporate the policies and procedures in the CDC plan. ■

20 Renal & Urology News

JANUARY 2012

www.renalandurologynews.com

Metastasis, Obesity Linked in PCa Patients on ADT Risk stratification of patients based on body mass index may be possible BY JODY A. CHARNOW OBESITY IS associated with an increased risk for prostate cancer (PCa) progression among PCa patients treated with androgen deprivation therapy (ADT) after radical prostatectomy, according to a study. The retrospective study, which included 287 ADT recipients who had rising PSA after surgery but no metastases, found that men with a body mass index (BMI) of 25-29.9 and 30 kg/m 2 or higher (obesity) had a significant 3.6 times and 5.0 times increased risk of metastases compared with patients who had a BMI below 25, after adjusting for multiple variables. In addition, the higher BMI categories were associated with a nearly 3.4 and 3.9 times increased risk of progression to castration-resistant PCa, respectively, and an 8.2 and 6.6 times increased risk of PCa-specific mortality, but these increased risks did not reach statistical significance in adjusted analyses, investigators reported in BJU International (online ahead of print). The researchers, led by Christopher Keto, MD, a fellow in Urological Oncology at Duke University Medical Center in Durham, N.C., and Stephen J. Freedland, MD, Associate Professor of Surgery (Urology) and Pathology in the Duke Prostate Center, observed that their findings, if confirmed, can help guide clinicians in risk stratification of patients undergoing ADT based on BMI. Counseling of obese men considering ADT should include discussion about lifestyle changes such as weight loss, exercise, and dietary modification, according to the researchers. Although it is unknown if such measures modify the risk of PCa-specific outcomes in obese men, they are known to reduce the risk of heart disease and are unlikely to be harmful, they noted. Of the 287 patients, 67 (23%) were of normal weight, 120 (42%) were overweight, and 100 (35%) were obese. Previous research The new findings build on previous work by Dr. Freedland and colleagues as well as other research teams showing that obese men undergoing primary therapy with radical prostatectomy or

ADT Recipients by Weight Category

23% 35%

42%

Normal Weight¹ Overweight² Obese³ 1 Body Mass Index (BMI) less than 25 kg/m2 2 BMI 25-29.9 kg/m2 3 BMI 30 kg/m2 or higher Source: Keto CJ. Aronson WJ, Terris MK et al. Obesity is associated with castration-resistant disease and metastasis in men treated with androgen deprivation therapy after radical prostatectomy: results from the SEARCH database.

external beam radiation are at higher risk for biochemical recurrence after treatment compared with normalweight men. Previous research also has demonstrated that high BMI, while associated with a lower risk of a PCa diagnosis overall, is associated with an increased risk of high-grade PCa. For example, a prospective study by Cosimo De Nunzio, MD, PhD, of Ospedale Sant’Andrea, University La Sapienza, Rome, and colleagues showed that obesity with central adiposity (BMI 30 kg/m2 or greater and waist circumference of 102 cm or greater) was associated with a significant 66% increased risk of a PCa diagnosis and a 2.56 times increased risk of being diagnosed with high-grade PCa (Gleason score of 7 or higher). The study, which was published in Urologic Oncology (online ahead of print), enrolled 668 patients scheduled to undergo transrectal ultrasound-guided prostate biopsy at one of three clinics in Italy. PCa was found in 246 (38%). Each 1 kg/m2 increment in BMI and 1 cm increase in waist circumference

were associated with a significant 11% and 4% increased risk of high-grade disease, respectively. At the American Urological Association annual meeting in 2011, Dr. Freedland and his team reported on a study of 6,524 men showing that obesity was associated with a 28% increased risk of high-grade PCa, after adjusting for age and prostate volume. The men were enrolled in the four-year REDUCE (Reduction by Dutasteride of Prostate Cancer Events) study funded by GlaxoSmithKline. The study tested dutasteride 0.5 mg daily for PCa risk reduction in men with a PSA level of 2.5-10 ng/mL and negative prostate biopsy. Additionally, a study led by Dr. Freedland while he was at Johns Hopkins School of Medicine in Baltimore showed that obese men (BMI of 35 kg/m2 or greater) were significantly more likely to experience biochemical failure compared with men of normal weight (BMI below 25 kg/m2). The findings of that study were published in the Journal of Clinical Oncology (2004;22:446-453).

Study rationale For the latest study, Dr. Freedland’s group hypothesized that obese men on ADT may be at increased risk for PCa progression because prior studies have shown that obese men have lower levels of testosterone compared with normal-weight men, and thus the tumors already may be primed to grow in a low testosterone environment. Additionally, despite lower testosterone levels prior to ADT, obese men have higher levels of testosterone while receiving ADT, suggesting the amount of ADT given (i.e., the doses of the drugs used to achieve androgen deprivation) may not be enough. “These two factors plus the general link between obesity and aggressive PCa led us to this hypothesis, and indeed, the data support our hypothesis,” Dr. Keto told Renal & Urology News. “As such, we have yet another clinical scenario—this time men treated with ADT for rising PSA after radical prostatectomy— wherein obesity is linked with poor PCaspecific outcomes.” ■

Drug Delays CRPC Bone Metastases DENOSUMAB can delay bone metastases in men with castration-resistant prostate cancer (CRPC), a study found. In a phase 3 study of 1,432 men with non-metastatic CRPC randomly assigned to receive denosumab or placebo (716 patients in each group), denosumab significantly increased bone-metastasisfree survival by a median 4.2 months compared with placebo, according to an online report in The Lancet. The median survival times were 29.5 and 25.2 months, respectively. Denosumab was associated with a 15% decrease risk of bone metastasis. In addition, the drug significantly delayed the time to first bone metastasis (33.2 vs. 29.5 months). Overall survival did not differ between the denosumab and placebo arms. The treatment arms had similar rates of adverse events (AEs) and serious AEs, except for osteonecrosis of the jaw—which developed in 33 denosumab-treated patients and in none of the placebo recipients—and hypocalcemia, which developed in 12 patients who received denosumab compared with only two who received placebo. Denosumab is a fully human monoclonal antibody that specifically binds and inactivates RANKL, an essential mediator of osteoclast formation, function, and survival, according to researchers Matthew R. Smith, MD, of Massachusetts General Hospital Medical Center in Boston, and colleagues. In the bone microenvironment,

Denosumab improved bone-metastasis-free survival by a median of 4.2 months. they explained, growth factors secreted by tumor cells induce stromal cells and osteoblasts to express RANKL. “Activation of osteoclasts by RANKL results in increased bone turnover and release of growth factors from bone matrix that might promote establishment of prostate cancer in the skeleton,” they noted. “Improvement in bone-metastasisfree survival and time to first bone metastasis with denosumab treatment in our study shows that a bone-targeted agent can delay time to bone metastasis in men with prostate cancer,” the investigators wrote. ■

www.renalandurologynews.com

■ Kidney Week 2011, Philadelphia

JANUARY 2012

Renal & Urology News 21

Renal & Urology News editor Jody A. Charnow provided news coverage.

BP Rises with ESAs Not Due to Vasoconstriction NEW STUDY FINDINGS may narrow down the possible causes of increased blood pressure (BP) result from the use of erythropoiesis-stimulating agents (ESAs) to correct renal anemia, a study shows. The researchers who conducted the study noted that such BP rises occur in up to 35% of patients and it is unclear whether this is due to increased blood viscosity, increased blood volume, reduction of hypoxic vasodilation, and/ or ESA-induced vasoconstriction. In a study of 163 critically ill patients with acute kidney injury, the investigators found that using high doses of epoetin did not increase BP for up to 72 hours after administration, demonstrating that epoetin does not have an acute vasoconstrictor effect in these patients. For the study, Zoltan H. Endre, MD, of the University of Otego Christchurch, New Zealand, and colleagues randomized patients to two doses of IV epoetin 500 U/kg 24 hours apart or placebo.

Black Donors Risk Onset of Hypertension

The researchers recorded mean arterial pressure (MAP) and norepinephrine equivalent dose (NED) hourly. At baseline, MAP was 78 mm Hg in the epoetin group and 81 mm Hg in the

hypertension, researchers reported. The researchers, led by Mona D.

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placebo group, a nonsignificant difference. At four hours after the first drug dose, the investigators observed no significant difference between study arms with respect to change in MAP (6.5 vs.

8.4 mm Hg), change in norepinephrine equivalent dose (-0.8 vs. -0.1 µg/min), or in the change in MAP adjusted for change in norepinephrine equivalent dose. They also noted no differences after 24 or 72 hours, or four or 24 hours after the second dose. Hemoglobin level and hematocrit were unchanged. ■

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tions) compared with 13 non-donors (27%). Donors had a significant 2.4

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22 Renal & Urology News

JANUARY 2012

■ Kidney Week 2011, Philadelphia

www.renalandurologynews.com

Renal & Urology News editor Jody A. Charnow provided news coverage.

Black Race Worsens Renal Tx Outcomes Among patients with ESRD due to lupus nephritis or FSGS, blacks had the lowest graft survival rate BLACK RACE is associated with worse renal transplant outcomes among patients with lupus nephritis and focal segmental glomerulosclerosis (FSGS), according to two studies. In the one study, which involved a retrospective cohort of 150,118 patients who received their first kidney transplant from January 1995 to July 2006, Robert Nee, MD, and colleagues, of Walter Reed National Military Medical Center in Bethesda, Md., identified 4,214 recipients with lupus nephritis as the primary cause of their end-stage renal disease (ESRD). African-American (AA) patients had a 56% increased risk of graft loss and 48% increased risk for death compared with patients of other races, after adjusting for confounding variables. At 10 years, the

graft survival rate for AA was 42.9% compared with 58.2% for non-AA patients, and patient survival rate for AA was 72.2% compared with 77.4% for non-AA patients. “Therefore, this study demonstrated that among kidney transplant recipients with ESRD due to lupus nephritis, the AA population is at increased risk for both graft loss and death as compared to the non-AA population,” Dr. Nee told Renal & Urology News. “The underlying etiology of worse transplant outcomes among AA patients remains unclear but likely involves both immunologic and nonimmunologic risk factors to include socioeconomic status, education level, access to health care, and insurance coverage.” He also noted: “This cohort of AA patients with lupus nephritis should be

Incidence of AKI Requiring Dialysis Is Rising Rapidly ACUTE KIDNEY injury (AKI) requiring

Dialysis-requiring AKI was 8.1 times

dialysis has become more common than

more common among patients older

end-stage renal disease (ESRD) requiring

than 65 than younger patients, 1.7

renal replacement therapy (RRT), new

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whites, and 1.3 times more common

From 1998 to 2008, the U.S. incidence rate of dialysis-requiring AKI increased

among men than women. “Our study shows that the incidence

from 201 to 496 cases per million person-

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K. Hsu, MD. The population incidence rate

the study’s senior author, Chi-yuan

of dialysis-requiring AKI exceeded that of

Hsu, MD, told Renal & Urology News.

RRT-requiring ESRD since 2005. In 2008,

“Defining the true population of AKI on

the population incidence rate of dialysis-

a population level is important to inform

requiring AKI was 496 cases per million

the appropriate allocation of healthcare

person-years compared with 351 cases

resources to target disease prevention

per million person-years for RRT-requiring

and treatment appropriately.”

ESRD (defined as requiring chronic dialysis or kidney transplantation). When the investigators controlled for

In a separate study of AKI, researchers examined the intensive care unit (ICU) period prevalence of AKI at six

temporal changes in population distribu-

academic hospitals (two each in North

tion of race, age, gender and trends of

America, Europe, and Australia) and

sepsis, acute heart failure, and use of

found that the period prevalence of AKI

cardiac catheterization and mechanical

varied from 14.6% to 43.8% and hospi-

ventilation, the incidence rate decreased

tal mortality rates varied from 20.4% to

on slightly to 8% per year.

35.9% among the centers. ■

considered a high risk group and deserves close monitoring in the post-transplant period. Further progress in transplant outcomes will require a multidisciplinary and holistic approach to address modification in immunosuppression regimens and to effect socioeconomic, cultural and psychosocial factors.” In the other study, Adela D. Mattiazzi, MD, and colleagues at the University of Miami assessed 10,577 kidney transplant recipients with FSGS. The group included 6,036 Caucasian, 3,437 AA, and 1,104 Hispanic patients. Subjects were followup for a mean of 4.84 years. The rate of delayed graft function was significantly higher among AA than Hispanic and Caucasian recipients (22% vs. 13% and 14%, respectively), as was the rate of acute rejection (42% vs. 28%, and 31%,

respectively). Allograft failure occurred in 27% of AA recipients compared with 16% among Hispanics and 17% among Caucasians. Compared with Caucasians, AA patients had a significant 1.9 times increased risk of allograft failure in unadjusted analyses, but this increased risk became nonsignificant after adjusting for transplant era, sociodemographic factors, immunologic differences, and rejection. AA and Hispanic patients were younger than Caucasians (35, 33, and 41 years old, respectively) and received kidneys from younger donors (34, 33, and 37 years old, respectively). Deceased donors were the source of kidneys for 70% of AA patients compared with 53% of Hispanics and 52% of Caucasians. ■

ESA Response Could Predict ESRD Risk

of Naples in Italy, said the findings point to a potential role for persistent hypoxia in patients with more advanced renal damage. “Our results support the suggestion to consider not only achievement of Hb target, but also ESA responsiveness as a valuable tool in anemia management by extending its prognostic usefulness from cardiovascular to renal risk,” Dr. Minutolo said. The study by Dr. Minutolo’s group was among a number of studies looking at ESA responsiveness presented at Kidney Week. For example, two studies of 9,281 hemodialysis patients who underwent their first kidney transplant demonstrated that hyporesponsiveness to ESAs prior to renal transplantation is associated with a higher risk of posttransplant allograft failure and mortality. The studies, by Miklos Z. Molnar, MD, PhD, of the Harbor-UCLA Medical Center in Torrance, Calif., and colleagues, showed that patients in the second, third, and fourth quartiles of ESA responsiveness—as measured using an ESA responsiveness index calculated by dividing ESA dose by hemoglobin values—had a twofold increased risk of death-censored graft failure and a 1.7, 2.2, and 2.4 times increased risk of graftcensored death, respectively, compared with those in the first quartile, after adjusting for potential confounders. ■

PATIENTS WITH chronic kidney disease (CKD) who have a low response to erythropoiesis-stimulating agents (ESAs) are at increased risk of progressing to end-stage renal disease (ESRD), investigators reported. In a study of 194 CKD patients not on dialysis, those in the lowest tertile of ESA response had a 2.46 times increased risk of ESRD and a 2.61 times increased risk of renal death (ESRD or death) compared with those in the highest tertile, after adjusting for age, gender, body mass index, and other potential confounders. During a median follow-up of 2.9 years, ESRD developed in 99 patients and 35 died. During the initial six months, the number of months in which hemoglobin (Hb) levels were below 11 g/dL was 4.0, 1.5, and 0.8 in patients in the first, second, and third tertiles of ESA responsiveness, respectively. The mean ESA dose was 23.9, 23.5 and 17.2 µg per week, respectively. The researchers, led by Roberto Minutolo, MD, of the Second University

www.renalandurologynews.com

JANUARY 2012

Renal & Urology News 23

■ Kidney Week 2011, Philadelphia

Vitamin D Treats SHPT in Tx Patients Parathyroid hormone levels decreased by nearly 30% after six months of vitamin D therapy CHOLECALCIFEROL with or without doxercalciferol may be an appropriate treatment for secondary hyperparathyroidism (SHPT) in kidney transplant recipients, data show. The study showed that vitamin D repletion can be accomplished in six months with an accompanying decrease in PTH levels of about 30%. Mariana S. Markell, MD, and Sima Terebelo, RPAC, MPH, of the State University of New York Downstate Medical Center in Brooklyn enrolled 39 stable renal transplant recipients with SHPT and hypovitaminosis D. They randomized patients to receive cholecalciferol 1,000 U daily plus placebo or cholecalciferol 1,000 U plus 0.5 mcg doxercalciferol daily for six months. Investigators measured parathyroid hormone (PTH) levels at four weeks. Doxercalciferol (or placebo) dose was titrated up by 0.5 mcg if PTH values had not decreased. Thirty-three patients completed the study. Three from each group had

Phosphate Can Predict Death Risk BASELINE PLASMA phosphate level can predict the risk of cardiovascular events and mortality in hemodialysis (HD) patients, investigators reported. In a post-hoc analysis of data from 2,773 patients in the AURORA trial, Bengt C. Fellstrom, MD, PhD, of Uppsala University Hospital in

dropped out. No patient dropped out because of hypercalcemia. The investigators observed no difference in response to cholecalciferol or doxercalciferol with respect to PTH so they combined the groups for evaluation of treatment effect. PTH levels decreased significantly from 189.7 pg/mL at baseline to 134.7 pg/mL by six months. Levels of 25-hydroxyvitamin D increased significantly from 16.4 to 30.8 ng/mL, but levels of 1,25-dihydroxyvitamin D and fibroblast growth factor 23 did not change significantly (53.5 vs. 56.1 ng/mL and 97.9 vs. 109.9 pg/mL). Previous studies looking at vitamin D replacement in kidney transplant recipients have used supra-pharmacologic doses (100,000 U cholecalciferol), which put patients at risk for hypercalcemia and possible immunologic effects. Dr. Markell’s team was able to replace vitamin D in patients with 1000 U over six months, with a very low rate of side effects.

Mariana S. Markell, MD

“Replacement of vitamin D resulted in a significant fall in PTH levels, and we recommend this approach in transplant patients who are normocalcemic or hypocalcemic with hypovitaminosis D,” said Dr. Markell, who is Associate Professor of Medicine. She noted that she and her colleagues studied only patients with good kidney

function and who were at least one year post-transplant, so “the results may not be translatable to patients immediately post-transplant, or with poor kidney function, and these populations should be studied.” “As vitamin D deficiency has been implicated in cardiovascular as well as other disease risk, long-term replacement studies should be performed in patients with kidney transplants, the majority of whom are vitamin D deficient following years of CKD,” she said. Also at the conference, the investigators reported on a separate study showing that fibroblast growth factor 23 (FGF23) maintains an inverse relationship with 1,25-dihydroxyvitamin D in kidney transplant recipients who have vitamin D deficiency despite elevated PTH levels and abnormal kidney function. The finding suggests that FGF-23 may be more important in regulating 1,25-hydroxyvitamin D than PTH in these patients, according to the researchers. ■

Renal Decline Patterns Identified RESEARCHERS HAVE found substantial heterogeneity in trajectories of renal function during the two-year period leading up to initiation of chronic dialysis, according to a new report. Most patients (63%) had persistently low levels of estimated glomerular filtration rate (eGFR), declining from levels that already were severely reduced two years prior to dialysis initiation (group 1). Another 25% of patients had progressive loss of eGFR, declining from moderately reduced levels two years prior to initiation (group 2). Nine percent had an acceler-

ated loss of eGFR from normal levels two years before initiation (group 3). Three percent had catastrophic loss of eGFR from normal levels six months or less before initiation (group 4). The study, led by Ann M. O’Hare, MD, Associate Professor of Medicine at the University of Washington in Seattle, and supported by an inter-agency agreement between the VA Puget Sound Healthcare System and the Centers for Disease Control and Prevention, revealed that more rapid loss of eGFR was associated with an increased likelihood of hospi-

talization and inpatient acute kidney injury (AKI), and a lower likelihood of receiving outpatient nephrology care and vascular access placement during the two years before dialysis initiation. Those with more rapid loss of eGFR were more likely to initiate dialysis in the hospital at a higher level of eGFR and in the setting of AKI. Dr. O’Hare’s group also observed a correlation between renal function trajectory and survival. Median survival ranged from 3.2 years for patients in group 1 to 1.0 year for patients in group 4. ■

Uppsala, Sweden, and colleagues found that each 1 mmol/L increment in plasma phosphate at baseline is associated with a 48% increased risk of a major cardiovascular event, a 34% increased risk of death from any cause, a 53% increased risk of cardiovascular death, a 45% increased risk of an atherosclerotic event, and a 60% increased risk of nonfatal myocardial infarction. ■

Diabetics Less Likely to Receive a Transplant DIABETICS ARE less likely to be placed on a waiting list for a renal transplant and are less likely to be transplanted, new findings suggest. The reason may be that diabetics have a higher level of co-morbidities, greater body mass index (BMI), and lower rate of living donation, researchers noted.

Investigators at Beth Israel Deaconess Medical Center and Harvard Medical School in Boston led by Alexander S. Goldfarb-Rumyantzev, MD, PhD, analyzed data from 721,521 patients with end-stage renal disease (ESRD). Diabetics had a 17% decreased likelihood of being placed on a transplant

waiting list and a 26% decreased likelihood of receiving a transplant. However, after adjusting for comorbidities BMI, and donor type (living vs. deceased), diabetics had a 22% and 28% greater chance of being waitlisted and receiving a transplant, respectively, compared with non-diabetics. ■

24 Renal & Urology News

JANUARY 2012

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Renal Nutrition Update Patients with kidney disease are at risk for zinc deficiency, which could affect their inflammatory and mental status BY ALISON L. STEIBER, PhD, LD, RD

nflammation and oxidative stress are two etiologies that may contribute to poor nutritional status and ultimately increased mortality rates in patients with chronic kidney disease (CKD). Interventions that can blunt or ameliorate inflammation and oxidative stress are relevant to these patients. Nutrients with antioxidant properties may be used as such a treatment, especially if the patients are deficient in the nutrients. Zinc is an interesting trace element with antioxidant properties. Furthermore, zinc deficiency has been documented in patients with CKD. In a recent editorial, the authors reported zinc deficiency in 40%-78% of hemodialysis (HD) patients (Ren Fail 2011;33:466-467). Zinc concentrations in patients with CKD may vary between body compartments and individuals depending on diet, environment, and medications or supplements prescribed or obtained over the counter. Smythe et al (Ann

Good sources of zinc include oysters (above), red meat, poultry, and beans.

nificantly associated with carotid artery intima-media thickness: The lower the zinc concentration, the higher the carotid artery intima-media thickness (Biol Trace Elem Res 2011; published online ahead of print).

In a study of hemodialysis patients, depressed patients had significantly lower plasma zinc concentrations than non-depressed patients. Intern Med 1982;96:302-310) found no significant difference in tissue concentrations of zinc between healthy controls and patients with CKD. In contrast, McGregor et al (Kidney Int 2001;59:2267-2272) found decreased plasma zinc in CKD patients and Yilmaz et al (Am J Kidney Dis 2006;47:4250) observed a step-wise reduction in erythrocyte zinc concentrations with advancing stages of the disease. Lower concentrations of plasma zinc also may be associated with atherosclerotic status and depression in CKD patients. A 2011 study from Turkey, demonstrated that serum zinc concentrations were lower in HD patients when compared with healthy controls and serum zinc was inversely and sig-

Similarly, in a 2011 study from Iran, depressed HD patients (Beck Depression Index score higher than 14) had significantly lower plasma zinc concentrations than non-depressed patients (67.5 vs. 85.3 µg/dL) (J Renal Nutr 2011;21:184-187). Insufficient intake of dietary zinc may contribute to inadequate zinc status in CKD patients. A study in peritoneal dialysis (PD) patients showed that more than half of the patients consumed inadequate quantities of dietary zinc. This study had 73 PD patients that were assessed using the subjective global assessment, 24-hour recalls, and markers of inflammation. The patients who were malnourished had an average zinc intake of 5 mg/day

and the well-nourished patients had an average intake of 7 mg/day (Perit Dial Int 2011; published online ahead of print). Both of these intakes are below the dietary reference intake for healthy adults at 8 mg/day. Foods with higher protein content, such as beef, liver, poultry, and whole grains, tend to be richer in zinc. Patients in later stages of CKD, prior to dialysis, may be instructed on keeping to low phosphorus and protein diets, whereas patients on dialysis are instructed on low phosphorus and high protein diets. These diets may result in reduced intake of whole grain foods and possibly foods containing animal protein. Additionally, while a patient should be placed on a vitamin supplement, the supplements may not contain minerals. In a study with 211 HD patients at an inner city university hospital dialysis center, only

12.9% of the patients were prescribed oral or intravenous trace element supplementation (Nephrol Dial Transplant 2011;26:1006-1010). Zinc supplementation has been shown to be effective in increasing serum zinc concentrations, although conclusive effects on inflammation parameters have not been demonstrated. In a small clinical trial, zinc sulfate at 220 mg was given to 28 HD patients. C-reactive protein (CRP) and serum zinc were measured at days 0 and 42 and the values were compared to a control group of 27 subjects. At day 42, mean serum zinc levels significantly increased in the treatment group (from 57.4 to 88.4 µg/ dL). However, CRP levels did not significantly differ between the treatment and control groups at day 42 (J Ren Nutr 2009;19:475-478). Finally, in a small trial discussed in the 2011 editorial mentioned previously, 38 patients with serum zinc concentrations below 70 µg/dL were supplemented with zinc sulfate at a dosage of 250 mg/ day. At day 42, the serum zinc values had increased significantly and CRP had decreased significantly. In conclusion, patients with CKD are at risk for zinc deficiency that may impact their inflammatory, atherosclerotic, and mental status. Supplementation with zinc sulfate will increase serum values but whether it will improve outcomes is controversial. ■ Dr. Steiber is Coordinator of the Dietetic Internship/Master’s Degree Program at Case Western Reserve University in Cleveland.

Zinc Facts Oysters contain more zinc per serving than any other food. Most dietary zinc in the United States comes from red meat and poultry. Other food sources include beans, nuts, whole grains, pork, dairy products, crab, lobster. The recommended dietary allowance of zinc for individuals age 19 and older is 11 mg for men and 8 mg for women. Zinc deficiency can cause loss of appetite, impaired immune function, hair loss, diarrhea, delayed wound healing, and other problems. Source: Office of Dietary Supplements, National Institutes of Health

26 Renal & Urology News

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Epinephrine Can Cut TURP-Related Blood Loss EPINEPHRINE INJECTED into the prostate can be used to decrease blood loss during transurethral resection of the prostate (TURP), according to researchers. A team led by Alejandro Lira-Dale, MD, of Hospital General de Mexico in Cuauhtemoc, Mexico, divided 23 TURP patients into two groups. One

group received intraoperative intraprostatic injections of epinephrine and the other group received intraoperative intraprostatic injections of a saline solution as placebo. The mean blood loss in the epinephrine group was significantly lower than that of the placebo arm (127.48 vs. 337.63 mL), the investiga-

tors reported online ahead of print in International Urology and Nephrology. The researchers observed no significant differences in mean resection time (40.9 vs. 45.1 minutes, respectively) or mean grams of resected tissue (14 vs. 26.2). The authors noted that local epinephrine injection into tissue has been

PROVENGEÂ® (sipuleucel-T) Suspension for Intravenous Infusion

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INDICATIONS AND USAGE: PROVENGEÂ® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. DOSAGE AND ADMINISTRATION Å&#x2DC; For Autologous Use Only. Å&#x2DC; 7KH UHFRPPHQGHG FRXUVH RI WKHUDS\ IRU 3529(1*( LV FRPSOHWH GRVHV JLYHQ DW DSSUR[LPDWHO\ ZHHN LQWHUYDOV Å&#x2DC; 3UHPHGLFDWH SDWLHQWV ZLWK RUDO DFHWDPLQRSKHQ DQG DQ DQWLKLVWDPLQH VXFK DV diphenhydramine. Å&#x2DC; %HIRUH LQIXVLRQ FRQÅµUP WKDW WKH SDWLHQWÅ&#x2018;V LGHQWLW\ PDWFKHV WKH SDWLHQW LGHQWLÅµHUV RQ the infusion bag. Å&#x2DC; Do Not Initiate Infusion of Expired Product. Å&#x2DC; ,QIXVH 3529(1*( LQWUDYHQRXVO\ RYHU D SHULRG RI DSSUR[LPDWHO\ PLQXWHV Do Not Use a Cell Filter. Å&#x2DC; ,QWHUUXSW RU VORZ LQIXVLRQ DV QHFHVVDU\ IRU DFXWH LQIXVLRQ UHDFWLRQV GHSHQGLQJ RQ WKH VHYHULW\ RI WKH UHDFWLRQ (See Dosage and Administration [2] of full Prescribing Information.) CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS Å&#x2DC; PROVENGE is intended solely for autologous use. Å&#x2DC; Acute infusion reactions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ÅµUVW LQIXVLRQ DQG GHFUHDVHG WR following the third infusion. Some (1.2%) patients in the PROVENGE group were KRVSLWDOL]HG ZLWKLQ GD\ RI LQIXVLRQ IRU PDQDJHPHQW RI DFXWH LQIXVLRQ UHDFWLRQV 1R *UDGH RU DFXWH LQIXVLRQ UHDFWLRQV ZHUH UHSRUWHG LQ SDWLHQWV LQ WKH PROVENGE group. &ORVHO\ PRQLWRU SDWLHQWV ZLWK FDUGLDF RU SXOPRQDU\ FRQGLWLRQV ,Q WKH HYHQW RI DQ DFXWH LQIXVLRQ UHDFWLRQ WKH LQIXVLRQ UDWH PD\ EH GHFUHDVHG RU WKH LQIXVLRQ VWRSSHG GHSHQGLQJ RQ WKH VHYHULW\ RI WKH UHDFWLRQ $SSURSULDWH PHGLFDO WKHUDS\ VKRXOG EH administered as needed. Å&#x2DC; Handling Precautions for Control of Infectious Disease. PROVENGE is not URXWLQHO\ WHVWHG IRU WUDQVPLVVLEOH LQIHFWLRXV GLVHDVHV 7KHUHIRUH SDWLHQW leukapheresis material and PROVENGE may carry the risk of transmitting infectious GLVHDVHV WR KHDOWK FDUH SURIHVVLRQDOV KDQGOLQJ WKH SURGXFW 8QLYHUVDO SUHFDXWLRQV should be followed. Å&#x2DC; Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either FKHPRWKHUDS\ RU LPPXQRVXSSUHVVLYH DJHQWV VXFK DV V\VWHPLF FRUWLFRVWHURLGV JLYHQ FRQFXUUHQWO\ ZLWK WKH OHXNDSKHUHVLV SURFHGXUH RU 3529(1*( KDV QRW EHHQ VWXGLHG 3529(1*( LV GHVLJQHG WR VWLPXODWH WKH LPPXQH V\VWHP DQG FRQFXUUHQW XVH RI LPPXQRVXSSUHVVLYH DJHQWV PD\ DOWHU WKH HIÅµFDF\ DQG RU VDIHW\ RI 3529(1*( 7KHUHIRUH SDWLHQWV VKRXOG EH FDUHIXOO\ HYDOXDWHG WR GHWHUPLQH ZKHWKHU LW LV PHGLFDOO\ DSSURSULDWH WR UHGXFH RU GLVFRQWLQXH LPPXQRVXSSUHVVLYH DJHQWV SULRU WR WUHDWPHQW with PROVENGE. Å&#x2DC; Product Safety Testing. PROVENGE is released for infusion based on the microbial DQG VWHULOLW\ UHVXOWV IURP VHYHUDO WHVWV PLFURELDO FRQWDPLQDWLRQ GHWHUPLQDWLRQ E\ *UDP VWDLQ HQGRWR[LQ FRQWHQW DQG LQ SURFHVV VWHULOLW\ ZLWK D GD\ LQFXEDWLRQ WR GHWHUPLQH DEVHQFH RI PLFURELDO JURZWK 7KH ÅµQDO GD\ LQFXEDWLRQ VWHULOLW\ WHVW UHVXOWV DUH QRW DYDLODEOH DW WKH WLPH RI LQIXVLRQ ,I WKH VWHULOLW\ UHVXOWV EHFRPH SRVLWLYH IRU PLFURELDO FRQWDPLQDWLRQ DIWHU 3529(1*( KDV EHHQ DSSURYHG IRU LQIXVLRQ Dendreon will notify the treating physician. Dendreon will attempt to identify the PLFURRUJDQLVP SHUIRUP DQWLELRWLF VHQVLWLYLW\ WHVWLQJ RQ UHFRYHUHG PLFURRUJDQLVPV and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination. (See Warnings and Precautions [5] of full Prescribing Information.) ADVERSE REACTIONS %HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV DGYHUVH UHDFWLRQ UDWHV REVHUYHG LQ WKH FOLQLFDO WULDOV RI D GUXJ FDQQRW EH GLUHFWO\ FRPSDUHG WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHÅ¶HFW WKH UDWHV REVHUYHG LQ SUDFWLFH

used in many specialties, including orthopedic surgery (where is used introperatively in arthroplasty) and gastroenterology (where it is used in actively bleeding ulcers). The researchers noted that their study patients made up a highly selected population, which was a study limitation. â&#x2013;

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(Table 1 continued on next page.)

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â&#x2013; Kidney Week 2011, Philadelphia

JANUARY 2012

Renal & Urology News 27

Renal & Urology News editor Jody A. Charnow provided news coverage.

IV Iron Preparation Has Lower Adverse Event Rates FERUMOXYTOL HAS an efficacy comparable to iron sucrose in treating iron deficiency anemia in patients with chronic kidney disease (CKD), but it is associated with lower adverse event (AE) rates,

according to the findings a head-to-head comparison of the two formulations. In addition, ferumoxytol treatment requires fewer administrations, which could translate into a clinical resource

Table 1 Incidence of Adverse Events Occurring in â&#x2030;Ľ5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

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Dendreon Corporation Seattle, Washington 98101

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savings for patients with iron deficiency anemia requiring iron treatment, researchers stated. Ferumoxytol is an intravenous (IV) iron preparation approved in June

2009. It consists of an iron oxide with a unique carbohydrate coating designed to limit immunogenicity. Unlike other IV iron preparations, a full course of ferumoxytol (1.02 g) requires only two IV injections of 510 mg. Iron sucrose is administered IV either by slow injection or by infusion. The head-to-head comparison study enrolled 162 patients with CKD stage 1-5 and 5D, with subjects randomly assigned to receive either ferumoxytol or iron sucrose. All patients assigned to the ferumoxytol group received two IV injections of 510 mg within five days for a cumulative dose of 1.02 g. Hemodialysis patients assigned to iron sucrose received a total cumulative dose of 1.0 g administered as 100 mg doses at 10 consecutive dialysis sessions within three weeks; non-dialysis patients received a total cumulative dose of 1.0 g administered as 200 mg doses at five nonconsecutive visits within about 14 days. For the study, Iain C. Macdougall, MD, of Kingâ&#x20AC;&#x2122;s College Hospital in London, and collaborators randomized 80 patients to receive ferumoxytol and 82 to receive iron sucrose. The mean change in hemoglobin from baseline to week 5 was 0.71 g/dL for ferumoxytol and 0.61 g/dL for iron sucrose. Ferumoxytol-treated patients had a more rapid rise in the mean Hb values compared with iron sucrose recipients. Results also showed that about 50% of the ferumoxytol group experienced a 1 g/dL or greater rise in Hb at any time from baseline to week 5 compared with 42% of the iron sucrose group. The time in days to an Hb response (either a 1 g/dL or greater increase or an achieved level of 12 g/dL or greater from baseline) was on average 4.4 days earlier in the ferumoxytol recipients compared with those treated with iron sucrose (28.5 vs. 32.9 days, respectively). The ferumoxytol group had lower AE rates than the iron sucrose group (48% vs. 65%) and lower rates of AEs leading to drug discontinuation (1% vs. 5%). The observed lower rate of AEs in the ferumoxytol recipients may relate to the fewer IV iron exposures required to deliver 1 gram of iron with this drug compared with iron sucrose (two vs. four or 10 doses), according to the researchers. â&#x2013;

28 Renal & Urology News

JANUARY 2012

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CME FEATURE

An Update on Robotic-Assisted Partial Nephrectomy Short-term outcomes from early institutional experiences have confirmed the safety and feasibility of RPN, even for anatomically complex tumors.

Release Date: January 2012 Expiration Date: January 2013 Estimated time to complete the educational activity: 1 hour This activity is jointly sponsored by Medical Education Resources and Haymarket Media, Inc. TARGET AUDIENCE: This activity has been designed to meet the needs of nephrologists involved in the treatment of patients with kidney cancer. EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Discuss emerging treatment options for patients presenting with renal tumors. • Evaluate the pros and cons of the robotic platform to date. • Examine warm ischemia time and the best threshold for preservation of renal function. 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 Media, Inc. MER is accredited by the ACCME to provide continuing medical education for physicians. CREDIT DESIGNATION: Medical Education Resources designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. DISCLOSURE OF CONFLICTS OF INTEREST: Medical Education Resources ensures balance, independence, objectivity, and scientific rigor in all our educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure all scientific research referred to, reported, or used in a CME activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality CME activities that promote improvements or quality in health care and not a commercial interest. The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Faculty • Rosalia Viterbo, MD

Reported Financial Relationship No financial relationships to disclose

The content managers reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Content Manager • Jody A. Charnow, Haymarket Media, Inc. • Marina Galanakis, Haymarket Media, Inc. • Victoria C. Smith, MD, MER

BY ROSALIA VITERBO, MD

idney cancer is among the most lethal of urologic malignancies. The rising incidence of kidney cancer is attributable to greater detection of incidental small renal masses (≤4 cm) from increased use of radiographic imaging.1 The incidental detection of asymptomatic stage 1 lesions now accounts for more than half of all renal masses discovered. Decisions regarding the optimal treatment for the incidentally diagnosed small renal mass (SRM) are complex. Traditionally, clinical stage 1 renal masses have been treated with surgical excision, most commonly radical nephrectomy (RN).2 However, concern that radical nephrectomy may predispose patients to the sequelae of chronic kidney disease, including increased cardiovascular risk and shortened overall survival, has led to the increased utilization of nephron-sparing procedures with the goal of preserving long-term renal function without affecting cancer control.3 Nephron-sparing surgery (NSS) is an established treatment for patients with SRM’s, providing excellent functional and oncologic outcomes.

Since the development of open partial nephrectomy (OPN), laparoscopic partial nephrectomy (LPN) has emerged as a minimally invasive technique that maintains the functional benefits of open NSS while conferring additional advantages specific to laparoscopic surgery. Nevertheless, some urologists are deterred from employing LPN for localized renal cell carcinoma (RCC) due to the technical difficulties posed by laparoscopy. As robotic-assisted surgery becomes more prevalent within the urologic community, this modality has been increasingly applied to NSS. A prospective 2011 EORTC trial randomizing patients with tumors <5 cm to RN or partial nephrectomy (PN) provided the first level 1 evidence that oncologic efficacy is equivalent between treatment modalities (with intermediate term median follow up 9.3 years).4 Although utilization rates of NSS remain low, the AUA guidelines for the management of clinically localized renal tumors state that PN is the standard of care for cT1a lesions, and should be performed when technically feasible for T1b renal tumors.5 Although OPN remains the reference standard of care for clinically

Reported Financial Relationship No financial relationships to disclose No financial relationships to disclose No financial relationships to disclose

METHOD OF PARTICIPATION: There are no fees for participating in and receiving CME credit for this activity. During the period January 2012 through January 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/renalandurologynews, and 4) complete the evaluation form online. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better.

Rosalia Viterbo, MD, is Assistant Professor in the Division of Urologic Oncology at Fox Chase Cancer Center in Philadelphia.

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localized tumors, LPN emerged as a viable minimally invasive approach providing similar intermediate oncologic outcomes and faster postoperative recovery when compared to open techniques. 3 Initially described in 2000,6 robotic-assisted laparoscopic prostatectomy (RALP) utilizing the da Vinci® Surgical System has been rapidly embraced by the urologic community.7 Due to increased access from the dissemination of RALP into community practice and a more rapid learning curve, robotic-assisted laparoscopic partial nephrectomy (RPN) has recently emerged as an alternative to LPN. Since its introduction, multiple series have demonstrated that with short-term follow up, RPN is safe and effective with equivalent oncologic outcomes to LPN.8 As a result, performance of RPN has dramatically increased over the past five years, and in 2008 was the fastest growing robotic procedure worldwide among any surgical specialty.9

The Pros and Cons of the Robotic Platform LPN remains a technically challenging procedure requiring the surgeon to acquire advanced laparoscopic skills over a steep learning curve. Although equivalent 5- and 7-year oncologic efficacy has been reported,3 summaries of the current literature consistently demonstrate that LPN is associated with a greater warm ischemia time (WIT), increased risk of postoperative hemorrhage, and an increased risk of major urologic complications when compared with OPN.5 Limitations to LPN include two dimensional visualization, limited range of motion, and poor ergonomics due to the use of rigid instrumentation, which make tumor excision and reconstruction under minimal ischemia time challenging. While laparoscopic and robotic approaches show similar results with regard to convalescence and perioperative morbidity, advantages afforded by the robotic platform include stereoscopic visualization and enhanced dexterity (EndoWrist™; Intuitive Surgical, Inc., Sunnyvale, Calif.) facilitating the ability to perform precise reconstruction. Disadvantages to the robotic platform are primarily decreased tactile feedback, which can be overcome using learned visual cues, and prohibitive instrumentation and maintenance costs. Using cost models, Mir et al compared

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OPN, LPN, and RPN using sensitivity analyses, and reported that of the three surgical approaches, LPN was the most cost effective due to shorter length of hospital stay compared to OPN and reduced instrumentation cost compared to RPN.10

Preoperative Evaluation and Indications Conventional absolute indications for PN include bilateral tumors, renal insufficiency, or a solitary functional kidney.11 Indications for NSS have evolved to encompass the majority of tumors <4 cm in patients with a normal contralateral kidney, and in select patients with cT1b and T2 lesions.5 However, the presence of regional lymphadenopathy or systemic disease is a contraindication to PN. There are currently no absolute anatomic contraindications to a robotic-assisted approach. Although port placement and perinephric dissection can be more challenging in obese patients or following prior abdominal surgery, successful outcomes have been reported for patients with a body mass index (BMI) >30 kg/m2,12 previous intra-abdominal procedures,13 hilar lesions,14-16 tumors >4cm,17, 18 complex (endophytic) lesions,15, 19 and multifocal disease.20 Patients who have had primary ablative procedures to treat renal lesions and have recurrence may be better suited for OPN as dissection may extremely challenging owing to scarring, necrosis, and obliteration of surgical dissecting planes. Patients being considered for PN should be evaluated with a radiographic staging workup consisting of bi- or tri-phasic abdominal computed tomography (CT) scanning or contrastenhanced magnetic resonance imaging (MRI), chest non-contrast CT or radiograph, and serum chemistries including electrolytes, renal and liver function tests, and coagulation studies. Anticoagulants and anti-platelet therapies should be stopped 5 to 7 days prior to surgery and a gentle bowel preparation can be utilized in select patients the day prior to surgery.21

Robotic-Assisted LPN Technique Although RPN techniques vary, most series utilize a 4-5 port configuration with the patient in a full or modified lateral position (Figure 1). The vast

Figure 1. Port positioning for left-sided robotic assisted laparoscopic partial nephrectomy. The large black circle represents the 12mm camera port; smaller solid circles represent 8mm robotic arm ports; dotted circles represent possible locations of 12mm and 5mm assistant ports Image adapted from and with permission from Elsevier Inc. from Scoll et al. Robotic-assisted partial nephrectomy: A large single-institution experience. Urology 2010;75:1328-1334.

majority of the reported experience is transperitoneal. In our practice, the camera (12mm) port is placed off the patient’s midline at the level of the renal hilum, with two 8mm instrument ports placed in the upper and lower quadrants at a minimum of 8mm from the camera port site to avoid arm collision. Techniques using a fourth robotic instrument to minimize the need for a bedside assistant have been described. A 12mm assistant port is placed in the plane between the inferior robotic arm and the ipsilateral lower quadrant, to facilitate access to the hilum and the tumor. Occasionally, an additional 5mm assistant port is placed in the upper midline, most commonly used for rightsided tumors requiring liver retraction. For complex lesions abutting or invading the collecting system, an ipsilateral open-ended ureteral catheter under cystoscopic guidance can be used at the beginning of the procedure to facilitate identification of collecting system injuries and facilitate closure. However, it is often not required. Some initial series described laparoscopic kidney mobilization followed by robotic-assisted tumor excision and reconstruction,22 but the majority of surgeons now perform the entire procedure, including renal mobilization and hilar dissection, robotically. It is our preference to perform intra-operative ultrasound with TilePro™ (Intuitive Surgical, Inc., Sunnyvale, Calif.) projection onto the console screen to confirm tumor mar-

gins and guide scoring of the renal capsule for tumor excision in all cases. This is especially helpful for complex intrphytic tumors and lesions close or abutting the renal hilum. In the majority of cases requiring warm ischemia, bulldog clamps are used for arterial clamping while venous occlusion is performed at the surgeon’s discretion. Tumor excision is performed using round-tipped scissors to achieve a 2-3mm margin of normal renal parenchyma (Figure 2a). Collecting system defects and open arterioles/venules are closed intracorporeally using absorbable suture, and the base of the tumor bed is biopsied then coagulated using argon beam or monopolar cautery. An experienced bedside assistant is essential and performs vital tasks including application of the vascular pedicle clamp(s), retraction and suction during tumor excision, and introduction of suture and bolster material. Various techniques have been described for renal reconstruction,23 including the “sliding-clip renorrhaphy” which utilizes interrupted 2-0 polyglactin suture over rolled oxidized cellulose bolsters secured with WECK ® Hem-o-lok (Teleflex Medical, Inc., Durham, N.C.) and Lapra-Ty® (Ethicon EndoSurgery, Cinncinati, Ohio) clips,24 and two-layered closures incorporating V-Loc™ barbed suture (Covidien, Mansfield, Mass.).25 At our institution, we have recently transitioned to a singlelayer renorrhaphy using interrupted or

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CME FEATURE running V-Loc™ sutures pledgeted with surgical bolsters (Figure 2b). In all cases, sutures are cut and removed following reperfusion to minimize WIT. Closed-suction drainage is routine at our institution, but also is subject to surgeon discretion.

RPN Outcomes Initially described in 2004,26 pilot series (≤25 patients) demonstrated that a robotic approach to PN was technically feasible in select masses with acceptable peri-operative outcomes, including estimated blood loss (EBL), WIT, and hospital length of stay (HLOS).27-31 These findings have been confirmed by larger institutional series18, 32-34 and have been extended to more complex tumors.14, 16, 18, 19, 35 However, while the safety of RPN has been confirmed, relative advantages with RPN when compared to LPN are unproven,8, 22, 29, 36-41 and reported clinical outcomes are difficult to interpret in the setting of significant selection bias and lack of stratification by anatomic complexity. Several scoring systems have been described in an attempt to reproducibly stratify renal masses by anatomic characteristics and facilitate the objective comparison of varying renal lesions, and include P.A.D.U.A.,42 C-index,43 and the R.E.N.A.L. Nephrometry score (NS).44 The first such system described and the most rigorously evaluated is the R.E.N.A.L. nephrometry score, which has been utilized to predict tumor histology and grade45as well as decision making for the small renal mass.46 Categorization by nephrometric complexity has been associated with intraoperative parameters such as ischemia time, EBL, and hospital length of stay in patients undergoing LPN,47 and rates of major urologic complications stratified by Clavien classification undergoing PN.48 In a large single institution series (N=281) comparing OPN and RPN for intermediate (NS 7-9) and complex (NS 10-12) renal tumors, Simhan et al reported that for moderately complex tumors, RPN was associated with an increased operative duration (205.9 vs. 189.5 min, p=0.02), but was also associated with decreased EBL (131.3 vs. 256.5cc, p<0.01) and hospital length of stay (3.7 vs. 5.6 days, p<0.001) when compared to the OPN group.49 Similarly, comparison of highly complex lesions revealed a reduced

LOS in the RPN group (2.9 vs. 6.1 days, p<0.001).

Operative and Clinical Outcomes Across published series, mean operative time (82.7 to 279 min),27, 28 estimated blood loss (92-329 cc),22, 50 and hospital length of stay37, 41 (2.0-6.2 days) varied widely, which can be attributed to data reported at differing points on institutional learning curves. In the largest single institution series to date (100 patients, 107 lesions) Scoll et al 34 reported mean OR time, estimated EBL, and HLOS of 206 min, 127 cc, and 3.2 days respectively, which compares favorably with historic LPN series.3 Comparative data have proved to be conflicting, and to date has failed to show clear trends favoring RPN over LPN. Seven such series reported no significant differences in intra-operative variables, which may be attributable to small sample sizes.22, 27, 29, 37-39, 41 In a single institution comparative series of 102 consecutive cases undergoing LPN and RPN, Wang et al reported significant reductions in OR time (140 vs. 156 min, p=0.04) and HLOS (2.5 vs. 2.9 days, p=0.03) in the RPN group, while there was no difference in EBL (136 vs. 173 mL) between groups.36 In a large multi-institutional series comparing 118 LPN and 129 RPN patients by three experienced surgeons over a five-year period, Benway et al reported no significant difference in OR time (189 vs. 174 min) between groups, while a reduced EBL (155 vs. 196 cc, p=0.03) and shorter hospital length of stay (2.4 vs. 2.7 days, p<0.001) were noted in the RPN group.8 In the only comparison of RPN and OPN using standardized criteria, Simhan et al reported significant trends towards reduced EBL in moderately complex tumors and reduced HLOS in all patients undergoing RPN (described above).49 Again, it is important to consider that these series represent comparisons of LPN or OPN by experienced surgeons and RPN at the beginning of their respective learning curves, which likely influences these outcomes of interest. Intra-operative and peri-operative complication rates for RPN have generally been low and comparable to historical LPN series. Early series demonstrated high rates of conversion to open, laparoscopic, or hand-assisted procedures (up to 20%),27 likely reflecting surgeon experience at the begin-

Figure 2. 68-year-old female presenting with incidentally found bilateral-enhancing renal masses. As the first part of staged procedure, she underwent a successful right roboticassisted laparoscopic partial nephrectomy for a 4.5 cm (NS=2+1+3+a+2=8a) pT1b papillary type I renal cell carcinoma. The following set of images demonstrates (A) the anterior mid-pole exophytic lesion after gerota’s fascia had been removed (B) a method of renorrhaphy closure, in which the renal capsule is closed using a single layer of interrupted V-Loc™ barbed sutures anchored on surgicel®

ning of their learning curve.9 In fact, in large series the rate of conversion is roughly 1%,51 and some authors have proposed that surgeons who embark upon RPN should have the necessary skills to undock the robot and proceed laparoscopically if a device malfunction or injury occurs so that the benefits of a minimally invasive approach can be retained.22 Although these early reports are limited by lack of standardized complications nomenclature, overall complication rates in larger series of RPN range from 14%-25% 17, 18, 34-36 and are comparable with LPN in direct comparative series (8.6% vs. 10.6%).8, 39 Recent evidence has demonstrated that tumor characteristics influence complication rates following partial nephrectomy,48 and future efforts must strive to account for anatomic complexity when comparing operative outcomes.

Warm Ischemia Time and Preservation of Renal Function WIT measures the time the organ remains at body temperature after its blood supply has been cut off. The “safe” duration of warm ischemia during partial nephrectomy remains controversial. Examining WIT in five minute intervals, an estimated cut point of 25 minutes provided the best threshold for preventing negative renal function outcomes, and led to authors to conclude that “every minute counts when the hilum is clamped during PN.”52 However, in a subsequent analysis, the same authors compared 660 patients undergoing PN with warm or cold ischemia and found that when controlling for age, tumor size, pre-operative estimated glomerular filtration rate (eGFR), ischemia time, and percentage

of renal parenchyma spared, long-term renal function after PN was determined primarily by the quantity and quality of renal parenchyma preserved, not duration of ischemia.53 While these data send mixed messages, a working hypothesis may be that every effort should be made to reduce WIT during PN. A previous surgical benchmark to minimize renal injury during LPN was a WIT less than 30 minutes,54 and reported WITs in contemporary RPN series range from 18.2-35.3 minutes 39, 41 with minimal change in serum creatinine or eGFR.27, 30, 35, 51 When directly comparing RPN and LPN, a consistent finding across large series was a reduced WIT in patients undergoing RPN,8, 29, 36 which may be due to ease of reconstruction and intracorporeal suturing with the robotic platform when compared to the more technically demanding laparoscopic approach. Improving ischemia times through the RPN collective experience have been attributed to increasing surgeon experience as well as emerging techniques to reduce the time devoted to renal reconstruction, such as cutting and removing needles following hilar unclamping, pre-placement of needles,55 and the “sliding clip” renorrhaphy technique.24 Increasing surgeon experience and comfort with the robotic platform has expanded the indications for RPN to include more anatomically complex renal masses.

Oncologic Outcomes LPN has consistently demonstrated equivalent oncologic outcomes (margin status, local recurrence rates) with intermediate to long-term follow up when compared to OPN.56 Initial experience

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with RPN has demonstrated positive margin rates ranging from 1.5%-5.7% in large single institution series18, 34-36 and 3.8% in multi-institutional series,51 which is consistent with historical rates for OPN (1.3%) and LPN (2.9%) in experienced hands.3 While reported margin rates may be approximately equal between RPN and OPN, the longest duration of median follow up in the reported RPN literature is less than 24 months,17 until long-term data is available for RPN, extrapolation of long term oncologic efficacy from the durable experience with LPN will be necessary.56

single port (Triport™, Advanced Surgical Concepts, Dublin, Ireland) with an adjacent robotic port through the same incision, or a GelPort™ (Applied Medical, Ranch Santa Margarita, Calif.) as the surgical platform (R-LESS), Stein et al recently presented their initial experience with 11 R-LESS procedures which included one successful partial nephrectomy.62 Although we expect the role of R-LESS to continue to evolve and take on broader applications, until significant improvements are made in existing instrumentation and surgical platforms, these procedures will be considered experimental.

Future Considerations Conclusions Evolving techniques with RPN are primarily directed at reducing WIT, particularly in patients with complex tumors and poor baseline renal function. Novel regional ischemia techniques include use of the laparoscopic Simon clamp™ (Aesculap AG, Tuttlingen, Germany) which provides local ischemia for polar tumors without hilar clamping, and “zero ischemia” selective branch microdissection of the renal artery and vein coupled with carefully timed intraoperative reduction in blood pressure.57 In addition, “off clamp” RPN without hilar occlusion has been described in select patients, with increased EBL and decreased OR time when compared to traditional cases utilizing traditional local ischemia.58 Novel methods in the early phases of investigation to reduce time for hilar dissection, improve identification of accessory vessels poorly evident on preoperative imaging, and improve tumor identification include the use of laparoscopic doppler ultrasound59 and near infrared fluorescence imaging following injection with indocyanine green (Firefly daVinci technology).60 One of the most rapidly evolving areas in the field of minimally invasive surgery is laparoendoscopic single site (LESS) surgery, which consists of single port surgery as well as natural orifice transluminal endoscopic surgery (NOTES). Although performance of PN has been described using LESS techniques,61 challenges to its use include clashing of the laparoscope and working instruments as well as limited maneuverability with loss of instrument triangulation. Taking advantage of improved instrument articulation with the daVinci system through either a multi-channel

RPN is an emerging option for patients desiring minimally-invasive treatment for localized renal tumors. Short-term outcomes from early institutional experiences have confirmed the safety and feasibility of RPN, even for anatomically complex tumors. Although current data are limited, comparative series with LPN suggest a reduced WIT and decreased learning curve using the robotic platform, which may extend the benefits of minimally invasive nephronsparing surgery to an increasing number of urologists without significant laparoscopic experience. Although early data are encouraging, it is unclear whether RPN is equally efficacious to OPN or LPN with regard to cancer control. Efforts to further improve surgical techniques and reduce WIT are underway with intriguing results. Until more definitive prospective evidence is available, decisions regarding the optimal surgical approach for the small renal mass will be determined by individual patient and surgeon preference. ■ REFERENCES 1. Kane CJ, Mallin K, Ritchey J, et al. Renal cell cancer stage migration: analysis of the National Cancer Data Base. Cancer 2008;113:78-83. 2. Hollenbeck BK, Taub DA, Miller DC, et al. National utilization trends of partial nephrectomy for renal cell carcinoma: a case of underutilization? Urology 2006;67:254-259. 3. Gill IS, Kavoussi LR, Lane BR, et al. Comparison of 1,800 laparoscopic a nd open partial nephrectomies for single renal tumors. J Urol 2007;178:41-46. 4. Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2011;59:543-552. 5. Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical T1 renal mass. J Urol 2009;182:1271-1279. 6. Abbou CC, Hoznek A, Salomon L, et al. Remote laparoscopic radical prostatectomy carried out with a robot. Report of a case. Prog Urol 2000;10: 520-523.

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7. Badani KK, Kaul S, Menon M. Evolution of robotic radical prostatectomy: assessment after 2766 procedures. Cancer 2007;110:1951-1958. 8. Benway BM, Bhayani SB, Rogers CG, et al. Robotassisted partial nephrectomy versus laparoscopic partial nephrectomy for renal tumors: a multiinstitutional analysis of perioperative outcomes. J Urol 2009;182:866-872. 9. Gautam G, Benway BM, Bhayani SB, Zorn KC. Robotassisted partial nephrectomy: current perspectives and future prospects. Urology 2009;74:735-740. 10. Mir SA, Cadeddu JA, Sleeper JP, Lotan Y. Cost comparison of robotic, laparoscopic, and open partial nephrectomy. J Endourol 2011;25:447-453. 11. Uzzo RG, Novick AC, Nephron sparing surgery for renal tumors: indications, techniques and outcomes. J Urol 2001;166:6-18. 12. Naeem N, Petros F, Sukumar S, et al. Robot-assisted partial nephrectomy in obese patients. J Endourol 2011;25:101-105. 13. Petros FG, Patel MN, Kheterpal E, et al. Robotic partial nephrectomy in the setting of prior abdominal surgery. BJU Int 2011;108:413-419. 14. Dulabon LM, Kaouk JH, Haber GP, et al. Multiinstitutional analysis of robotic partial nephrectomy for hilar versus nonhilar lesions in 446 consecutive cases. Eur Urol 2011;59:325-330. 15. Lebed B, Jani SD, Kutikov A, et al. Renal masses herniating into the hilum: technical considerations of the “ball-valve phenomenon” during nephronsparing surgery. Urology 2010;75:707-710. 16. Rogers CG, Metwalli A, Blatt AM, et al., Robotic partial nephrectomy for renal hilar tumors: a multiinstitutional analysis. J Urol 2008;180:2353-2356. 17. Gupta GN, Boris R, Chung P, et al., Robot-assisted laparoscopic partial nephrectomy for tumors greater than 4 cm and high nephrometry score: Feasibility, renal functional, and oncological outcomes with minimum 1 year follow-up. Urol Oncol 2011. [Epub ahead of print] 18. Patel MN, Krane LS, Bhandari A, et al., Robotic partial nephrectomy for renal tumors larger than 4 cm. Eur Urol 2010;57:310-316. 19. Rogers CG, Singh A, Blatt AM, et al. Robotic partial nephrectomy for complex renal tumors: surgical technique. Eur Urol 2008;53:514-521. 20. Boris R, Proano M, Linehan WM, et al. Initial experience with robot-assisted partial nephrectomy for multiple renal masses. J Urol 2009;182:1280-1286. 21. Touijer K, Jacqmin D, Kavoussi LR, et al. The expanding role of partial nephrectomy: a critical analysis of indications, results, and complications. Eur Urol 2010;57:214-222. 22. Aron M, Koenig P, Kaouk JH, et al. Robotic and laparoscopic partial nephrectomy: a matched-pair comparison from a high-volume centre. BJU Int 2008;102:86-92. 23. Ghani KR, Anderson C. Closing the deal: renorrhaphy during laparoscopic and robotic partial nephrectomy. BJU Int 2011;108:2-4. 24. Benway BM, Wang AJ, Cabello JM, Bhayani SB. Robotic partial nephrectomy with sliding-clip renorrhaphy: technique and outcomes. Eur Urol 2009;55:592-599. 25. Sammon J, Petros F, Sukumar S, et al. Barbed suture for renorrhaphy during robot-assisted partial nephrectomy. J Endourol 2011;25:529-533. 26. Gettman MT, Blute ML, Chow GK, et al. Roboticassisted laparoscopic partial nephrectomy: technique and initial clinical experience with DaVinci robotic system. Urology 2004;64:914-918. 27. Caruso RP, Phillips CK, Kau E, et al. Robot-assisted laparoscopic partial nephrectomy: initial experience. J Urol 2006;176:36-39. 28. Ho H, Schwentner C, Neururer R, et al. Roboticassisted laparoscopic partial nephrectomy: surgical technique and clinical outcomes at 1 year. BJU Int 2009;103:663-668. 29. Kural AR, Atug F, Tufek I, Akpinar H. Robot-assisted partial nephrectomy versus laparoscopic partial nephrectomy: comparison of outcomes. J Endourol 2009;23:1491-1497. 30. Michli EE, Parra, RO, Robotic-assisted laparoscopic partial nephrectomy: initial clinical experience. Urology 2009;73:302-305. 31. Alleemudder A, Dudderidge T, Rao AR, et al. Feasibility of robotic partial nephrectomy in a UK Cancer Centre. Brit J Med Surg Urol 2011;4:78-85. 32. Mottrie A, DeNaeyer G, Schatteman P, et al. Impact of the learning curve on perioperative outcomes in patients who underwent robotic partial nephrectomy for parenchymal renal tumours. Eur Urol 2010;58:127-132. 33. Gong Y, Du C, Josephson DY, et al. Four-arm robotic partial nephrectomy for complex renal cell carcinoma. World J Urol 2010;28:111-115. 34. Scoll BJ, Uzzo RG, Chen DY, et al. Robot-assisted partial nephrectomy: a large single-institutional experience. Urology 2010;75:1328-1334. 35. White MA, Haber GP, Autorino R, et al. Outcomes of robotic partial nephrectomy for renal masses with nephrometry score of ≥7. Urology 2011;77:809-813.

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36. Wang AJ, Bhayani SB. Robotic partial nephrectomy versus laparoscopic partial nephrectomy for renal cell carcinoma: single-surgeon analysis of >100 consecutive procedures. Urology 2009;73:306-310. 37. Deane LA, Lee HJ, Box GN, et al. Robotic versus standard laparoscopic partial/wedge nephrectomy: a comparison of intraoperative and perioperative results from a single institution. J Endourol 2008;22:947-952. 38. Jeong W, Park SY, Lorenzo EI, et al. Laparoscopic partial nephrectomy versus robot-assisted laparoscopic partial nephrectomy. J Endourol 2009;23:1457-1460. 39. Haber GP, White WM, Crouzet S, et al. Robotic versus laparoscopic partial nephrectomy: singlesurgeon matched cohort study of 150 patients. Urology 2010;76:754-758. 40. DeLong JM, Shapiro O, Moinzadeh A. Comparison of laparoscopic versus robotic assisted partial nephrectomy: one surgeon’s initial experience. Can J Urol 2010;17:5207-5212. 41. Seo IY, Choi H, Boldbattr Y, et al. Operative outcomes of robotic partial nephrectomy: a comparison with conventional laparoscopic partial nephrectomy. Korean J Urol 2011;52:279-283. 42. Ficarra V, Novara G, Secco S, et al. Preoperative aspects and dimensions used for an anatomical (PADUA) classification of renal tumours in patients who are candidates for nephron-sparing surgery. Eur Urol 2009;56:786-793. 43. Simmons MN, Ching CB, Samplaski MK, et al. Kidney tumor location measurement using the C index method. J Urol 2010;183:1708-1713. 44. Kutikov A, Uzzo RG. The R.E.N.A.L. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. J Urol 2009;182:844-853. 45. Kutikov A, Smaldone MC, Egleston BL, et al. Anatomic Features of Enhancing Renal Masses Predict Malignant and High-Grade Pathology: A Preoperative Nomogram Using the RENAL Nephrometry Score. Eur Urol 2011;60:241-248. 46. Canter D, Kutikov A, Manley B, et al. Utility of the R.E.N.A.L.-nephrometry scoring system in objectifying treatment decision-making of the enhancing renal mass. Urology 2011;78:1089-1094. 47. Hayn MH, Schwaab T, Underwood W, Kim HL. RENAL nephrometry score predicts surgical outcomes of laparoscopic partial nephrectomy. BJU Int 2011;108:876-881. 48. Simhan J. Smaldone MC, Tsai KJ, et al. Objective Measures of Renal Mass Anatomic Complexity Predict Rates of Major Complications Following Partial Nephrectomy. Eur Urol 2011;60:724-730. 49. Simhan J, et al. A nephrometry based comparative analysis of robotic and open partial nephrectomy for moderate and complex renal tumors. (presented at the Society of Urologic Oncology annual meeting, Besthesda, MD), 2010. 50. Kaul S, Laungani R, Sarle R, et al. da Vinci-assisted robotic partial nephrectomy: technique and results at a mean of 15 months of follow-up. Eur Urol 2007;51:186-191. 51. Benway BM, Bhayani SB, Rogers CG, et al. Robot-assisted partial nephrectomy: an international experience. Eur Urol 2010;57:815-820. 52. Thompson RH, Lane BR, Lohse CM, et al. Every minute counts when the renal hilum is clamped during partial nephrectomy. Eur Urol 2010;58:340-345. 53. Lane BR, Russo P, Uzzo RG, et al. Comparison of cold and warm ischemia during partial nephrectomy in 660 solitary kidneys reveals predominant role of nonmodifiable factors in determining ultimate renal function. J Urol 2011;185:421-427. 54. Simmons MN, Schreiber MJ, Gill IS Surgical renal ischemia: a contemporary overview. J Urol 2008;180:19-30. 55. Abaza R, Picard J. A novel technique for laparoscopic or robotic partial nephrectomy: feasibility study. J Endourol 2008;22:1715-1719. 56. Lane BR, Gill IS. 7-year oncological outcomes after laparoscopic and open partial nephrectomy. J Urol 2010;183:473-479. 57. Gill IS, Eisenberg MS, Aron M, et al. “Zero ischemia” partial nephrectomy: novel laparoscopic and robotic technique. Eur Urol 2011;59:128-134. 58. White WM, Goel RK, Haber GP, Kaouk JH. Robotic partial nephrectomy without renal hilar occlusion. BJU Int 2010;105:1580-1584. 59. Hyams ES, Perlmutter M, Stifelman MD. A prospective evaluation of the utility of laparoscopic Doppler technology during minimally invasive partial nephrectomy. Urology 2011;77:617-620. 60. Tobis S, Knoph J, Silvers C, et al. Near infrared fluorescence imaging with robotic assisted laparoscopic partial nephrectomy: initial clinical experience for renal cortical tumors. J Urol 2011;186:47-52. 61. White WM, Haber GP, Goel RK, et al. Single-port urological surgery: single-center experience with the first 100 cases. Urology 2009;74:801-804. 62. Stein RJ, White WM, Goel RK, et al. Robotic laparoendoscopic single-site surgery using GelPort as the access platform. Eur Urol 2010;57:132-136.

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1. The treatment approach of small renal masses may include: a. Active surveillance b. Robotic surgery c. Cryoablation d. All of the above 2. Which of the following is true: a. Partial nephrectomy oncologic outcomes are equivalent to those of radical nephrectomy b. Robotic surgery offers better oncologic outcomes c. Laparoscopic surgery is superior to open surgery d. Blood loss is equivalent when comparing open to minimally invasive surgery for kidney cancer 3. Traditional absolute indications for partial nephrectomy include: a. Patients with bilateral tumors b. Renal insufficiency c. Solitary functional kidney d. All of the above 4. What is the safe duration of warm ischemia time during partial nephrectomy? a. 40 minutes b. 60 minutes c. Every minute counts d. 90 minutes 5. Warm ischemia time measures: a. The time the kidney lacks perfusion during clamping for open surgery b. The time the kidney lacks perfusion during for laparoscopic surgery c. In surgery, the time the kidney remains at body temperature after its blood supply has been reduced or cut off but before it is cooled or reconnected to a blood supply d. The time the kidney lacks perfusion during clamping for robotic surgery 6. Which outcomes compare favorably when considering robotic versus laparoscopic or open partial nephrectomy? a. Estimated blood loss b. Hospital length of stay c. Operative time d. All of the above

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Electromagnetic Therapy May Help BPH Patients RADIOFREQUENCY pulsed electromagnetic fields (EMF) may provide a non-invasive treatment for benign prostatic hyperplasia (BPH), researchers reported. Greek investigators randomly divided 20 BPH patients into two groups of 10 each. One group was treated with alfuzosin 10 mg/day for t least four weeks and the other group underwent EMF treatment, which consisted of exposure to short-duration radiofrequency pulsed EMF generated by a device called an ion magnetic inductor. Treatments lasted for 30 minutes daily for five consecutive days for each of two weeks. For the treatment, the antenna loop of the device was centered over the pubic area and under the perineum of patients at a maximum distance of 5 cm from the skin, the authors explained.

The EMF-treated patients experienced significant improvements in International Prostate Symptom Score (IPSS), from 20 before treatment to 14 afterwards, ultrasound-estimated prostate volume (from 33 to 30 cm3), mean urine flow rate (from 8 to 11 mL/sec), and ultrasound-estimated residual volume (from 100 to 70 cm3). In the alfuzosin-treated group, the only significant improvement was in IPSS (from 19 to 16). The researchers, led by Angelos M. Evangelou, MD, of the University of Ioannina in Ioannina, Greece, published their findings in International Urology and Nephrology (2011;43:955-960). They noted that EMFs are thought to induce alterations in the cell proliferation rates, changes in mRNA, and protein synthesis, as well as other effects. ■

Lab Tests Alert Workers to CKD LABORATORY TESTS performed as part of employer-sponsored health risk assessments (HRA) revealed evidence that “newly identified” at least one of three common medical conditions in more than one third of adults, a study found. The study of 52,270 subjects showed that 30.7%, 1.9%, and 5.5% had “newly identified” hyperlipidemia, diabetes, and chronic kidney disease, respectively, based on laboratory evidence, according to a report in the online medical journal PLoS ONE. The authors, all of whom work for Quest Diagnostics, a clinical laboratory testing company, said they used the term “newly identified” because “the medical risk is not ‘diagnosed’ until confirmed usually with testing on a second specimen and after excluding other causes of the laboratory finding.”

The participants were adult employees and their eligible spouses or their domestic partners. As part of the HRA survey, subjects were asked to report whether they had been informed by a physician that they had any of the medical conditions included in the study. The researchers, led by Harvey W. Kaufman, MD, concluded that their findings show that, “for a large proportion of working-age adults, healthcare access alone does not guarantee detection of risk factors for common chronic health conditions. The availability of HRA with laboratory tests serves an important role in addressing this shortcoming. By identifying such opportunities early, employer-sponsored laboratory testing may slow or prevent the progression of common medical conditions.” ■

FDA Panel Favors Peginesatide THE FDA’s Oncologic Drugs Advisory Committee, in a 15 to 1 vote, has agreed that peginesatide demonstrates a favorable benefit/risk profile for use in treatment of dialysis patients with anemia resulting from chronic kidney disease (CKD). The FDA will consider the committee’s recommendation when reviewing a New Drug Application for peginesatide submitted in May as well as a Prescription Drug User Fee Act scheduled for March 2012. If approved,

peginesatide will be the first oncemonthly treatment available in the United States for CKD anemia patients on dialysis. The phase 3 clinical program of peginesatide was the first to prospectively study the cardiovascular safety of an ESA by analyzing independently adjudicated cardiovascular events. Peginesatide is a synthetic, PEGylated peptidic compound that stimulates erythropoietin receptors. ■

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Malpractice News Report: Malpractice Caps Fail to Cut Health Costs Exorbitant pain and suffering awards in medical malpractice lawsuits, also known as non-economic damages, have been blamed for numerous evils, including high physician insurance rates in some states and increases in health care costs due to “defensive medicine” practices. But a new report from the not-for- profit watchdog group Public Citizen challenges this concept. To curtail costly malpractice suits, many states have passed laws capping damages for non-economic injury, using the rationale that caps would decrease litigation, thereby decreasing insurance rates for physicians and creating incentives for them to practice in a given state. Cap proponents also argued that health care would become less expensive and more accessible, and clinicians would order fewer unnecessary tests as legal fears diminished and they no longer felt the need to practice defensive medicine. This has not happened, however, according to Public Citizen’s new report, “A Failed Experiment,” which aimed to examine the effect of malpractice caps in Texas. The group argues that health care in Texas has worsened since 2003, when Gov. Rick Perry signed a $250,000 cap on noneconomic damages awarded in medical malpractice cases. Specifically, the report states: • Medicare spending has risen far more quickly in Texas than the national

Health care in Texas has worsened despite a damage cap.

average, debunking the theory that medical malpractice lawsuits are driving health care costs • Premiums for health insurance have also risen faster than the national average • Texas has the largest uninsured population in the United States • Clinician numbers have dwindled in Texas; the number of primary care clinicians remained flat, compared with years prior to the litigation caps • The number of rural clinicians practicing in the state has declined The two groups benefitting the most from caps seem to be medical malpractice insurance companies, who have dropped premiums by 50%, and clinicians whose malpractice payments were 64% less in 2010 than 2003, the report indicated. Yet these savings have not translated into benefits for average Texans. Damage cap proponents, including Gov. Perry, have defended the caps, arguing that premiums for employersponsored coverage have risen more slowly than the national average, and that the growth of physicians has outpaced population growth.

Settlement Reached in Case Involving Doctor’s Death A settlement has been reached in a medical malpractice case involving the 2009 death of a physician undergoing a controversial treatment for a rare disease. Kevin Parsons, MD, practiced geriatric and internal medicine until he was diagnosed with Lambert Eaton Myasthenic Syndrome (LEMS), a debilitating autoimmune disorder that affects only 300 people worldwide. Parsons spent close to 20 years immersed in LEMS research, writing newsletters on the topic and advising others who had the disease. After extensive investigation, Dr. Parsons concluded that a stem cell transplant might provide a cure and travelled to Northwestern Memorial Hospital in Chicago to undergo the procedure. In an incident unrelated to the transplant, Dr. Parsons was mistakenly given insulin by a nurse who neglected to read a doctor’s order that specifically stated no insulin be administered, according to the Parsons’ family attorney. He subsequently

Doctor death case settled for $5 million

BY ANN W. LATNER, JD

lapsed into a diabetic coma and died three weeks later. His widow and family sued the hospital, alleging malpractice. Although the case did not go to trial, it did get to the deposition stage. According to the plaintiff’s attorney, a hospital nurse testified that she had complained to the hospital administration numerous times about the fact that nurses on the floor where Dr. Parsons was located had too many patients and were overworked. The hospital allegedly rebuffed the nurse’s concerns, but the case was settled for $5 million in early October 2011.

related to the stent claims, including personal information such as patient names, addresses, dates of birth, insurance inforblemation and social security numbers during its discovery process. The information was stored on a portable hard drive and password protected. As part of its security precautions, a law firm employee would take the hard drive home nightly protect it from fire, flood, or other disasters. Unfortunately, this employee accidently left the device on the Baltimore Light Rail, and although she returned for it within a few minutes it was already gone. The law firm has since issued letters of apology to those whose records were lost and has offered these patients a one-year membership to an anti-identity theft service as a precaution. HIPAA, which mandates the protection of patient information, requires that “covered entities”—insurance companies, health care providers and

Law Firm Loses Hard Drive With Patients’ Medical Records How far does the Health Insurance Portability and Accountability Act (HIPAA) extend? That is the question facing a large medical malpractice defense law firm now that one of its employees has lost a hard drive containing detailed information for 161 patients involved in a lawsuit against a cardiologist accused of performing hundreds of unnecessary stent procedures at a Maryland medical center. The medical center took away the doctor’s privileges in 2009, and earlier this year the physician’s medical license was revoked by the Maryland Board of Physicians after it found that the physician violated the state’s Medical Practice Act. The law firm that represents the cardiologist obtained medical records

Patient data were password protected, but not encrypted.

JANUARY 2012

34 Renal & Urology News

data management companies—encrypt patient data. However, malpractice attorneys and firms are not specifically mentioned in the act. While the lost information was password protected, it was not encrypted. The law firm has now begun encrypting its data and is exploring alternate data storage methods. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.