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VOLUME 12, ISSUE NUMBER 2
■ ■ ■
Lower Glucose Level Reduces ESRD Risk BY JODY A. CHARNOW INTENSIVE BLOOD glucose control can improve renal outcomes in patients with type 2 diabetes, including a significant reduction in the likelihood of progressing to end-stage renal disease (ESRD), according to a large study. The prospective study included 11,140 patients with type 2 diabetes randomly assigned to follow either an intensive or standard glucose-lowering strategy. After a median follow-up of five years, the intensive group had a significant 65% decreased risk of ESRD compared with the standard group,
IN THIS ISSUE 9
GFR decline slows after the start of dialysis
Bladder cancer risk lower in parous women
Prostate cancer mortality continues to decline
Expert Q&A: an update on the implantable artificial kidney
Sedentary behavior may raise the likelihood of elevated PSA Carbohydrate control may improve TG/HDL ratio in patients with chronic kidney disease. PAGE 16
investigators led by Vlado Perkovic, MBBS, PhD, of the University of Sydney in Australia, reported online in Kidney International. The mean hemoglobin A1c (HbA1c) level was 6.5% in the intensive group compared with 7.3% in the standard group. In addition, the intensive group experienced a 30% reduction in the risk of macroalbuminuria and a 9% reduction in the risk of microalbuminuria. The progression of albuminuria was decreased significantly by 10% and its regression increased significantly by 15%. The number of subjects needed to
Tighter glycemic control benefits type 2 diabetics
INTENSIVE GLUCOSE CONTROL may slow kidney disease progression in diabetics.
treat over five years to prevent one ESRD event ranged from 410 in the overall study to 41 in those with macroalbuminuria at baseline. “These data suggest that intensive glucose lowering may be an important strategy to curb the growing number
of individuals receiving dialysis as a result of diabetic nephropathy around the world,” Dr. Perkovic’s group concluded. The target HbA1c level for patients assigned to the standard glucose-lowcontinued on page 12
Sodium Citrate Emergency Stone Visit Rate Rising Catheter Lock BY JODY A. CHARNOW primary medical care,” investigators EMERGENCY DEPARTMENT (ED) wrote in an online report in Kidney Cuts CRI Risk visit rates and the use of computed International. SODIUM CITRATE works as well as heparin as a catheter lock solution in hemodialysis patients with central venous catheters, and it is associated with significantly fewer catheter-related infections (CRIs), a new study found. Calantha K. Yon, PharmD, and Chai L. Low, PharmD, both clinical nephrology pharmacists in the Veterans Affairs San Diego Healthcare System, compared lock solutions of sodium citrate 4% and heparin 5,000 units/mL. They collected data from 360 patientmonths among 60 HD patients who used the heparin lock and 451 patientmonths among 58 HD patients who continued on page 13
tomography (CT) for urolithiasis have been increasing in the United States, new findings show. The increase in ED visits has been greater among women than men and greater among whites than nonwhites. “The increase in ED visits with urolithiasis diagnoses might result from a combination of factors including an actual change in disease incidence, improvement in diagnostic methods, and/or an increase in the number of people who use the ED for
Investigators led by Ziya Kirkali, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md., found that ED visit rates rose from 178 to 340 per 100,000 individuals from 1992 to 2009, a 91% increase. Among female patients, the ED visit rate increased from 127 to 289 per 100,000 individuals, a 128% increase. By comparison, the rate among male patients increased from 231 to 393 per 100,000, a 70% jump. Among whites, the rate rose from 191 continued on page 12
Earn 1 CME credit in this issue
Pre-treatment Percutaneous Biopsy of Small Renal Masses PAGE 30
6 Renal & Urology News
FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD
Physicians: Risk Managers
uman beings expend immense time, energy, and resources attempting to predict future events and plan accordingly. From weather modeling to vast capital and insurance market based industries—predict and control are fundamental endeavors. Importantly, those who predict accurately are often richly rewarded (bankers, insurers, hedge fund managers). The common thread is less their ability to be correct than a willingness to manage risk. Physicians are more often defined by their ability to diagnose, treat, and research a disease than their willingness to manage its spectrum of risk. Unlike our corporate counterparts, most physicians would not list “manager of risk” highly among their professional obligations. While physicians manage therapeutic risk regularly, and often well, we fall short in our understanding, communication, and willingness to trade off risks in the continuum of many diseases. Except at the extremes of age or co-morbidity, we often default to treatment without fully objectifying risk. Conspiring forces that include uncertainties, training biases, patient expectations, fragmented care, litigation, and misaligned incentives increase our inclination to treat the disease diagnosed rather than managing its risk profile. Admittedly, there are multiple variables that are difficult to fully quantify and define, including biologic risk (natural history) and patient risk (co-morbidities/ expectations); however, there are also those that are undermanaged (physician and hospital risk). To move forward in the evolving paradigm, physicians must first accept ownership of a disease’s medical risk continuum and its management as perhaps our most significant duty. Ultimately, patients come to us as much for our ability to manage their disease risk as for our ability to treat their ailment. Next, we must acknowledge that the stakes of medical risk assessment are no higher than in other professions. Pilots, police, and engineers all manage risk regularly where people’s lives are at stake by collecting and objectifying data, standardizing processes, and making/ accepting tradeoffs. Thirdly, we must better align priorities of care with patients and communicate risk more effectively using plain unbiased language and absolute risk data that highlight how treatment diminishes (or potentially increases) risk. Finally, we must use predictive tools (as imperfect as they are) and work to improve them. Accountable care will require someone to manage disease risk and reward those who do it well. Physicians can and must manage more than primarily treatment risk. As Osler said, “Medicine is a science of uncertainty and an art of probability.” 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
REFERENCE 1. Fagerlin A, Zikmund-Fisher BJ, Ubel PA, et al. Helping patients decide: ten steps to better risk communication. J Natl Cancer Inst 2011;103:1436-1443.
Medical Director, Urology
Medical Director, Nephrology
Robert G. Uzzo, MD, FACS G. Willing “Wing” Pepper Chair in Cancer Research Professor and Chairman Department of Surgery Fox Chase Cancer Center Temple University School of Medicine Philadelphia
Kamyar Kalantar-Zadeh, MD, MPH, PhD Medical Director, Nephrology Professor & Chief Division of Nephrology & Hypertension University of California, Irvine School of Medicine Orange, Calif.
Nephrologists Urologists Christopher S. Cooper, MD Director, Pediatric Urology Children’s Hospital of Iowa Iowa City R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto Stanton Honig, MD Associate Clinical Professor of Surgery/Urology University of Connecticut School of Medicine, Urology Center New Haven J. Stephen Jones, MD, FACS, MBA Chief of Surgical Operations Fairview Hospital, a Cleveland Clinic hospital Professor of Surgery (Urology) Cleveland Clinic Lerner College of Medicine at Case Western Reserve University Leonard Horvitz and Samuel Miller Distinguished Chair in Urological Oncology Research Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology University of California, Irvine James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City Kenneth Pace, MD, MSc, FRCSC Assistant Professor Division of Urology St. Michael’s Hospital University of Toronto Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada
Anthony J. Bleyer, MD, MS Professor of Internal Medicine/Nephrology Wake Forest University School of Medicine Winston-Salem, N.C. Suphamai Bunnapradist, MD Director of Research Department of Nephrology Kidney Transplant Research Center The David Geffen School of Medicine at UCLA R. Michael Hofmann, MD Associate Professor and Medical Director, Living Kidney Donor Program University of Wisconsin School of Medicine and Public Health, Madison Csaba P. Kovesdy, MD Associate Professor of Clinical Medicine University of Virginia, Charlottesville Chief of Nephrology Salem VA Medical Center Salem, Va. Edgar V. Lerma, MD, FACP, FASN, FAHA Clinical Associate Professor of Medicine Section of Nephrology Department of Medicine University of Illinois at Chicago College of Medicine, Chicago Allen Nissenson, MD Emeritus Professor of Medicine The David Geffen School of Medicine at UCLA, Chief Medical Officer, DaVita Inc. Rulan Parekh, MD, MS Associate Professor of Pediatrics and Medicine University of Toronto Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center, Detroit Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J. Lynda Anne Szczech, MD, MSCE Medical Director, Pharmacovigilence and Global Product Development, PPD, Inc. Morrisville, N.C.
Renal & Urology News Staff Editor Executive editor Senior editor Web editor Editorial coordinator Art director Group art director, Haymarket Medical VP, audience development and operations Production assistant Group production manager Product manager, digital products Circulation manager National accounts manager Editorial director Publisher VP medical magazines and digital products CEO, Haymarket Media Inc.
Jody A. Charnow Marina Galanakis Delicia Honen Yard Stephan Cho Candy Iemma Andrew Bass Jennifer Dvoretz John Crewe Brian Wask Kathleen Millea Chris Bubeck Paul Silver William Canning Jeff Forster Dominic Barone Jim Burke Lee Maniscalco
Renal & Urology News (ISSN 1550-9478) Volume 12, Number 2. Published monthly by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Periodicals postage paid at New York, NY, and an additional mailing office. The subscription rates for one year are, in the U.S., $75.00; in Canada, $85.00; all other foreign countries, $110.00. Single issues, $20.00. www.renalandurologynews.com. Postmaster: Send address changes to Renal & Urology News, c/o DMD Data Inc., 2340 River Road, Des Plaines, IL 60018. For reprints, contact Wright’s Reprints at 1.877.652.5295. Copyright: All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without the prior written permission of Haymarket Media, Inc. Copyright © 2013.
VOLUME 12, ISSUE NUMBER 2
Bladder Cancer Risk Lower in Parous Women Increasing parity and older age at first birth are associated with a decreased risk for developing bladder cancer.
Focal Therapy for Prostate Cancer Safe Focal therapy for localized prostate cancer in highly selected patients is feasible and has acceptable morbidity, a French study found.
Alpha Blockers May Improve SWL Outcomes Men taking alpha blockers for benign prostatic hyperplasia may have better outcomes from shock wave lithotripsy for kidney stones than men not taking the medications.
Better Early QOL Reported with Proton Therapy Patients undergoing treatment for prostate cancer using proton beam therapy report a higher quality of life in early follow-up compared with patients treated with other radiation modalities.
Expert Q&A Chi-Yuan Hsu, MD, and Raymond Hsu, MD, discuss their finding of a rise in the incidence of serious acute kidney injury requiring dialysis.
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 December winner: Stephen Knohl, MD
The Medical Minute Visit renalandurologynews.com /the-medical-minute/ to hear podcast reports on new studies. Our latest include: • Decreased Renal Function, Reduced Cognitive Function Linked • Prostate Cancer Death Risk Tied to Metabolic Factors • New Agent May Offer Cardiac Benefits in CKD Patients
Pre-Treatment Percutaneous Biopsy of Small Renal Masses Allison R. Polland, MD, a urology resident at the Mount Sinai School of Medicine in New York, and Jaime Landman, MD, Professor of Urology and Radiology at the University of California-Irvine, review the rationale for the procedure and give instruction on how to perform it.
Renal Impairment Hikes Enoxaparin Bleeding Risk Patients with moderate renal impairment are at increased risk of major bleeding resulting from enoxaparin treatment compared with patients who have normal kidney function.
AFib Raises ESRD Risk in CKD Patients Incident atrial fibrillation is independently associated with an increased risk of endstage renal disease in patients with chronic kidney disease.
From the Medical Director Physicians: Managers of Risk
GFRs Overestimated in ICU Patients with AKI Urine output may provide a better indication of renal function, according to researchers.
News in Brief Robotic bladder surgery’s advantages
CABG Safer than PCI for Hemodialysis Patients Coronary artery bypass grafting may be a better option than percutaneous coronary intervention for patients with end-stage renal disease requiring coronary revascularization.
Renal Nutrition Update Managing dyslipidemia can lower CV risk
Expert Q&A Shuvo Roy, PhD, discusses the artificial kidney
Legal Issues in Medicine Following a DNR gets a doctor sued
Malpractice News EHRs do not eliminate medical errors
News Coverage Visit our website for coverage of the 2013 Genitourinary Cancers Symposium in Orlando, Fla., February 14-16.
this month at renalandurologynews.com
Therapy options for patients with
organ-confined prostate cancer can be time consuming and costly with traditional radiotherapy methods. See our story on page 14
Renal & Urology News 9
Renal Impairment Hikes Enoxaparin Bleeding Risk PATIENTS WITH moderate renal impairment are at increased risk of major bleeding resulting from enoxaparin treatment compared with patients who have normal kidney function, a study found. Reliance on renal function for excretion of the anticoagulant may lead to its accumulation in patients with moderate renal impairment, but there is no dose adjustment recommended for these patients, the researchers pointed out. Douglas D. DeCarolis, PharmD, of the Minneapolis Veterans Affairs Health Care System, and colleagues studied 164 patients treated with enoxaparin 1 mg/kg every 12 hours or 1.5 mg/kg once daily. They defined moderate renal impairment as a creatinine clearance (CrCl) of 30-50 mL/min and normal renal function as CrCl greater
GFR Decline Slows After Dialysis Start
than 80 mL/min. The primary outcome was major bleeding, defined as any bleeding resulting in death, hospital admission, prolonged hospital stay, or an emergency department visit. The primary outcome occurred in six (5.7%) of the 105 patients with normal kidney function and 13 (22%)
of the 59 who had moderate renal impairment, Dr. DeCarolis’s group reported in JAMA Internal Medicine (2012;172:1713-1718). In adjusted analyses, moderate renal impairment was associated with a nearly fourfold increased risk of major bleeding. Neither group experienced recurrent
thromboembolism. “When our results are added to previous evidence and the pharmacokinetics of enoxaparin, we believe that there are ample data confirming enoxaparin accumulation and an increased risk of major bleeding in patients with moderate renal impairment,” the authors wrote. ■
INHIBIT ANDROGEN PRODUCTION
PATIENTS WITH end-stage renal disease experience a slowing in the decline in glomerular filtration rate (GFR) two to four months after the start of dialysis, according to researchers in The Netherlands. In a study involving 1,861 incident dialysis patients, GFR declined by 0.53 mL/min/1.73 m2/month in the period before dialysis initiation, but after two to four months of dialysis, the rate of decline slowed to 0.12 mL/min/1.73 m2/month, Dinanda J. de Jager, MD, Leiden University Medical Centre in Leiden, and colleagues
BLOCK THE ANDROGEN RECEPTOR
reported online in Nephrology Dialysis Transplantation. For hemodialysis patients, the GFR decline attenuated from −0.51 to −0.14. For peritoneal dialysis patients, the decline attenuated from −0.55 to −0.11. In addition, among patients who started dialysis with a GFR at or above the median GFR at dialysis start, the decline attenuated (at
Learn more at inhibitandrogen.com/distinct *Other treatment options may also be considered. References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN ®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.
three months) from −0.70 to −0.21. Among those who started dialysis with a GFR below median at dialysis start, the decline attenuated (at one month) from −0.73 to −0.04. ■
Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 10/12 K08Z12191BR1
10 Renal & Urology News
News in Brief Please visit us at www.renalandurologynews.com for the latest news updates from the fields of urology and nephrology
Short Takes ‘Smart Stethoscope’ Monitors Stone Breakup
microscopy showed that these white
A newly developed “smart stethoscope”
during disease, become agitated, and
can help clinicians determine the ef-
cause glomerular inflammation and
fectiveness of kidney stone fragmenta-
blood cells do linger in the kidney
tion achieved by shock wave lithotripsy therapy and X-ray monitoring. The
Robotic Bladder Surgery Reduces Blood Loss
device, which is placed on the patient’s
skin as he or she undergoes SWL, picks
radical cystectomy is associated with
up echoes that reverberate around the
significantly less estimated blood
body after each shock wave hits the
loss and shorter length of hospital
stone. A fragmented stone gives off a
stay compared with open radical
duller sound than does an intact stone,
cystectomy in a pilot prospective
according to findings published in the
randomized trial. Among 40 patients
Proceedings of the Royal Society A
with invasive bladder cancer random-
ized to one of these two operations,
(SWL) without unnecessary repeat
estimated blood loss was lower in the
Leukocytes Circulate in HealthY Kidneys
robotic group than in the open-surgery
Leukocytes are constantly circulating
reported in The Journal of Urology
through and patrolling blood
(2013;189:474-479). Only 65% of
vessels within healthy kidneys, as
patients in the robotic-surgery group
opposed to only arriving in the organs
stayed in the hospital for more than
during the development of disease as
five days compared with 90% of the
previously thought, Michael Hickey,
open-surgery patients. In addition,
PhD, of the Centre for Inflammatory
fewer transfusions were required by
Diseases at Monash University in
the robotic-surgery group (40% vs.
Melbourne, Australia, and colleagues
50%). The two groups were similar
reported online in Nature Medicine.
with respect to age, race, gender,
In addition, multiphoton confocal
body mass index, and comorbidities.
group (400 vs. 800 mL), researchers
Affordable Care Act: Your View In a recent online poll, Renal & Urology News asked readers the following question: Will you, as a physician, see any benefits from the Affordable Care Act? Shown here are the poll results based on 210 responses.
Do not know 14.7%
Mineral Metabolites Hold Clues to CKD Progression A
bnormalities of mineral metabolism worsen with progressive chronic kidney disease (CKD) and associate with higher risk for end-stage renal disease (ESRD) among African Americans with hypertensive nephrosclerosis, Myles Wolf, MD, of the University of Miami Miller School of Medicine, and colleagues reported online in the Journal of the American Society of Nephrology. Blood level measurements of various mineral metabolites over an average of four years in 420 CKD patients who participated in the African American Study of Kidney Disease and Hypertension revealed that fibroblast growth factor-23 (FGF-23), parathyroid hormone (PTH), and phosphate levels rose over time, with the greatest increases occurring in those with faster rates of kidney function decline. Patients with the highest baseline levels of FGF-23 had more than a twofold increased risk of kidney failure or death independent of kidney function compared with patients with the lowest levels.
Drug Ups Progression-Free Survival in Metastatic PCa C
arbozantinib, a tyrosine kinase inhibitor recently approved by the FDA as Cometriq for the treatment of metastatic medullary thyroid cancer—showed clinical activity in a study of 171 men with castration-resistant prostate cancer, accrording to the investigators. In the trial, which was supported by the drug’s maker, Exelixis, randomization was halted early based on the observed activity of the medication. As David C. Smith, MD, and collaborators reported online in the Journal of Clinical Oncology, median progression-free survival was 23.9 weeks with cabozantinib compared with 5.9 weeks among placebo recipients. The majority of patients (72%) had regression in soft-tissue lesions, and on retrospective review, bone pain improved in 67% of evaluable patients. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%).
Hyperphosphatemia Raises Risk of Overt Proteinuria H
yperphosphatemia and high cholesterol are associated with overt proteinuria in non-diabetic patients with late-stage chronic kidney disease (CKD), researchers have found. A team led by Yi-Chun Liu, MD, of Yuan’s General Hospital in Kaohsiung City, Taiwan, studied 418 non-diabetic patients with CKD stage 3-5. Their mean age was 66.7 years. Serum phosphorus levels of 4.3 mg/dL or higher were associated with a fourfold increased likelihood of overt proteinuria compared with levels below 3.3 mg/dL, according to an online report in International Urology and Nephrology. In addition, hypercholesterolemia (217 mg/dL or higher) was associated with a 3.6 times increased odds of overt proteinuria compared with levels of 158-184 mg/dL. “Further studies should clarify whether this relation is causal and whether serum phosphorus level should be a new therapeutic target for proteinuria reduction,” the authors concluded.
Renal & Urology News 11
Bladder Cancer Risk Lower in Parous Women INCREASING PARITY and older age at first birth are associated with a decreased risk for developing bladder cancer, according to researchers. Caroline E. Weibull, MSc, of the Karolinska Institutet in Stockholm, Sweden, and colleagues studied a cohort of more than two million Swedish women in which 2,860 new cases of bladder cancer were identified. Women who had children had a lower incidence of bladder cancer than women who did not. In addition, the incidence of bladder cancer was 15% lower in women with two children and 24% lower in women with three or
more children compared with women who had one child, Weibull’s group reported online in European Urology. The incidence of bladder cancer was lower among women who had their first child when they were 20-24 years old than women who had their first children before age 20.
The risk of bladder cancer was higher in women with low educational attainment and those with a history of chronic obstructive lung disease. The study was limited by an absence of data on menstrual history, use of exogenous hormones, and smoking, the researchers noted.
“Although smoking habits may partly explain some of the associations, our findings provide support for yet-tobe-identified protective mechanisms associated with childbearing, possibly mediated by hormonal or structural changes following pregnancy,” the authors concluded. ■
A New Clue To LUTS-PCa Connection PREVIOUSLY DESCRIBED associations between lower urinary tract symptoms (LUTS) and prostate cancer (PCa) may not be due to an underlying shared biologic etiology or causative mechanism, but rather increased diagnostic intensity among men whose LUTS comes to the attention of physicians, researchers reported online in European Urology. Christopher J. Weight, MD, of Mayo Clinic in Rochester, Minn., and colleagues followed a representative population-based cohort of 1,922 men aged 40-79 years from 1990 until 2010 with interviews, questionnaires, and abstracting of medical records for prostate outcomes. The researchers identified 168 men treated for LUTS. The median follow-up was 11.8 years. Of the eligible men, 55% enrolled in the study. Men treated for LUTS were 2.4 times more likely than those not treated for LUTS to undergo a prostate biopsy. Men younger than
Androgen levels may impact antiandrogen therapy.1-3
65 years who were treated for LUTS were 2.3 times more likely to be diagnosed with PCa, whereas those older than 65 were not. Men with self-reported LUTS were not more
Learn more at inhibitandrogen.com/excess References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical studies. Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed. Neural Endocrine Peptides and Receptors. New York, NY: Plenum Press; 1986:627-644.
likely to undergo biopsy or be diagnosed with PCa. The authors acknowledged that their study was limited by a lack of histologic or PSA data for the cohort.
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12 Renal & Urology News
Lower glucose/ESRD risk continued from page 1
ering group was defined by local guidelines. The target level for the intensive group was 6.5% or less. Patients assigned to the intensive group started on gliclazide MR (20-120 mg daily) and were required to discontinue any other sulfonylurea. The timing, selection, and dose of all other treatments used to achieve the target were at the discretion of the treating physician. Mean systolic blood pressure was 1.6 mm Hg lower on average in the intensive group compared with the standard group, and adherence to BP-lowering drugs was slightly higher (75.2% vs. 72.5%), but the investigators said “it is unlikely that these small differences accounted for the observed effects.”
“The new data presented here provide the strongest evidence yet that intensive glucose-lowering regimens may protect against the development of ESRD, one of the most devastating and expensive complications of diabetes,” the researchers noted. “The results were consistent across different levels of HbA1c, kidney function, and albuminuria.” Commenting on the new study, Barry I. Freedman, MD, Chief of the Section on Nephrology at Wake Forest School of Medicine in Winston-Salem, N.C., noted that the finding that intensive glucose lowering slows progression to ESRD is important and consistent with other studies demonstrating renoprotective effects of intensive glucose lowering. “Anything that can reduce the number of patients with diabetes who progress to dialysis is critically important
Emergency stone visits continued from page 1
to 384 per 100,000 individuals, a 101% increase; among non-whites, the rate increased from 112 to 165 per 100,000 individuals, a 47% increase. Among the various age groups examined in the study (younger than 25, 25-44, 45-64, and older than 64 years), patients aged 25-44 years had the largest increase in ED visit rates: from 258 to 599 per 100,000 individuals, a 132% increase. The proportion of urolithiasis patients imaged with CT increased from 21% in 1998-2000 to 71% in 2007-2009. “The increased use of CT for evaluation of a common clinical syndrome such as urolithiasis raises important clinical questions,” the researchers wrote. “CT clearly provides important and accurate diagnostic information for physicians caring for patients with suspected urolithiasis. However, repeated use of CT evaluations for patients with recurrent urolithiasis contributes to increased radiation exposure for patients, as well as an increase in costs.” The researchers identified these trends by analyzing data from the National Hospital Ambulatory Medical Care Survey and the National Health and Nutrition Examination Survey (NHANES). Their study also showed that medical expulsive therapy was used in 14% of emergency patients with a urolithiasis diagnosis in 2007-2009. Among NHANES participants who reported a history of kidney stones, 22.4% had passed three or more stones. The study revealed no seasonal or regional variation in ED visit rates for urolithiasis during the study period.
because diabetes is the number one cause of end-stage renal disease in the Western world,” said Dr. Freedman, who has been involved in numerous studies of chronic kidney disease in patients with diabetes but did not participate in the new study. In addition, he noted that the reduction in heavy proteinuria was quite striking, but this does not necessarily translate into preservation of renal function. “Frankly, development of end-stage renal disease is due to a reduction in kidney function. Reduction in heavy proteinuria may be a different phenomenon. Protein in the urine does not always equate with loss of kidney function.” One of the confounding issues in this study was whether the reduction in progression to dialysis or development of heavy proteinuria was strictly due to
Emergency Visits for Stones Emergency department (ED) visit rates for urinary stones increased for both men and women from 1992 to 2009, but the rise was greater for women. Shown here are the numbers of ED visits per 100,000 individuals. 1992 2009
400 350 300 250 200 150 100 50 0
Source: Fwu CW, Eggers PW, Kimmel PL, et al. Emergency department visits, use of imaging, and drugs for urolithiasis have increased in the United States. Kidney International; published online ahead of print.
The new findings are consistent with those of a study published last year in European Urology (2012;62:160-165). In an analysis of data from 12,110 participants in the 2007-2010 NHANES, researchers led by Charles D. Scales, Jr., MD, of the University of California-Los Angeles, found that 8.8% of respondents
Use of computed tomography imaging rose substantially from 1998 to 2009. reported a history of kidney stones, up from 5.2% reported by 1994 NHANES respondents. According to the investigators, “the increase is likely related to dietary and lifestyle factors.” The prevalence increased for both men and women. The 2007-2010 data revealed that 10.6% of men and 7.1% of women reported having kidney stones, up from 6.3% and 4.1%, respectively, in 1994.
Kidney stones were more common among obese individuals than among normal-weight subjects (11.3% vs. 6.1%). Compared with normal-weight individuals, obese respondents had a 55% increased risk of kidney stones. “Presuming obesity as a marker for the metabolic syndrome, which is linked epidemiologically and physiologically to risk of kidney stones, the epidemic of obesity in the United States is a likely explanation for the dramatic rise in the prevalence of stone disease,” Dr. Scales and his colleagues noted. In an interview with Renal & Urology News, Dr. Scales praised the study by Dr. Kirkali’s group as “another important contribution to our understanding of the increasing burden of kidney stone disease in the United States.” Although surgical technique has advanced rapidly over the past two decades, he added, “the tide of kidney stones has risen unabated.” Dr. Scales, who is a Robert Wood Johnson Foundation/VA Clinical Scholar at UCLA’s David Geffin School of Medicine, noted that the current
the lower blood sugars, Dr. Freedman told Renal & Urology News. In his view, the lower systolic BP achieved in the intensive group could have influenced findings, as it is well established that lowering BP slows development and progression of diabetic kidney disease. The intensive group showed greater adherence to BP-lowering drug therapy, and this could reflect greater therapeutic adherence in general, which could have had a positive effect on outcomes, he said. Furthermore, unlike previous studies that used many different medications to lower blood sugar, the new study assigned patients in the intensive group to receive one particular sulfonylurea, Dr. Freedman noted, adding that it is possible that this drug has a unique effect that benefited the intensive group. ■
treatment paradigm focuses on the acute, symptomatic kidney stone, and largely ignores the chronic underlying metabolic derangements that lead to periodic stone “attacks.” “Stone disease is now as prevalent as diabetes in the United States, and more prevalent than coronary artery disease or stroke,” he said. “A greater emphasis on the public health aspects of stone disease, and the role of primary and secondary prevention, appears indicated.” A number of intriguing findings emerge from the new study, Dr. Scales said. For example, ED visits appear to be increasing more rapidly among women than in men, although men still have more ED visits overall. “While the reasons for this difference remain unclear, the finding is consistent with several studies documenting changing differences in the gender distribution of stones,” he said. “Obesity, diabetes, and other dietary/lifestyle factors are strongly associated with the risk of stone disease, and the impact of these factors may be greater in women than men. As would be expected from the known racial/ethnic differences in risk of stone disease, white individuals had the highest rate of ED visits throughout the study period.” ■
For related articles, visit renalandurologynews.com. Scroll down to the “Nephrology & Urology News” menu and click on “Kidney Stones.”
Sodium citrate lock continued from page 1
used the sodium citrate lock. Thirtythree patients were common to both study groups. The researchers identified 20 CRI cases while the heparin solution was used and 11 while the sodium citrate solution was used, a significant difference in infection rates, Drs. Yon and Low reported in the American Journal of Health-System Pharmacy (2013;70:131-136). The number of CRIs per 1,000 catheter-days was 1.9 with the heparin solution compared with 0.81, a significant difference between the treatments. In addition, significantly more catheters were exchanged or removed when the heparin solution rather than the sodium citrate solution was used (34 vs. 18). Although more CRI-related hospitalizations occurred during heparin use than sodium citrate
use, the difference was not significant. The investigators noted that heparin is the standard lock solution in catheters, but no standard optimal dosage of heparin exists. Consequently, systemic anticoagulant effects may result from the use of heparin locks, they observed. “Studies have found an increase in activated partial thromboplastin time and bleeding risk with inadvertent systemic exposure to hepa-
rin from heparin lock solutions,” they wrote. “This is particularly concerning, since patients with renal insufficiency have an increased risk of bleeding due to platelet dysfunction secondary to uremia.” Sodium citrate 4% has been proposed as an alternative to heparin. It acts as a local anticoagulant, but it also has antimicrobial properties. For example, a previous study demonstrated that, in vitro,
Renal & Urology News 13
sodium citrate concentrations above 0.5% inhibit biofilm formation and growth of Staphylococcus aureus and Staphylococcus epidermidis. Drs. Yon and Low noted that the cost associated with one CRI episode, which includes catheter exchange or removal, hospitalization, and antibiotic treatment, “would most certainly offset the auxiliary costs associated with using sodium citrate 4% for a year.” ■
PCa Deaths Continue to Decline PROSTATE CANCER (PCa) death rates continue to decline in the United States, according to an online report in the Journal of the National Cancer Institute. The PCa death rate decreased an average of 3.2% annually from 2005 to 2009, according to the report. Data show that death rates continue to decline for all cancers combined for men and women of all major racial and ethnic groups and for most major cancer sites. The report, prepared by Ahmedin Jemal, DVM, PhD, of the American Cancer Society (ACS), noted that the death rates for men and women combined decreased by 1.6% per year from 2005 to 2009. The report is compiled by the ACS, the Centers for Disease Control and Prevention, the National Cancer Insti-
Learn more at inhibitandrogen.com/sequence
tute, and the North American Associa-
*Currently in the absence of published, randomized, clinical data on treatment sequencing in mCRPC posttreatment with docetaxel. mCRPC=metastatic castration-resistant prostate cancer.
tion of Central Cancer Registries. The death rate from urinary bladder cancer during this same period did
References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.
not change for men but decreased by 0.4% per year among women. The death rate from kidney cancer decreased 0.4% per year for men and 0.9% per year for women. ■
Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 10/12 K08Z12236AR1
14 Renal & Urology News
One Week of SBRT an Option for PCa Tumors appear to be very sensitive to high doses of targeted stereotactic body radiotherapy BY JOHN SCHIESZER BOSTON —Patients with organ-confined prostate cancer (PCa) may have a new treatment option using high doses of focused stereotactic body radiotherapy (SBRT) instead of traditional lengthy radiotherapy courses or surgery, according to new data presented at the American Society for Radiation Oncology annual meeting. “Therapy options for patients with organ-confined prostate cancer can be time consuming and costly with traditional radiotherapy methods,” said lead researcher Alan Katz, MD, JD, a radiation oncologist at Flushing Radiation Oncology in Flushing, N.Y. “We found that higher doses of stereotactic radiotherapy with fewer fractions yielded great results in terms of tumor control. Our results show that additional standard radiation treatment added to SBRT is probably unnecessary, even with high-risk patients.” Dr. Katz, who presented the study
AFib Raises ESRD Risk in CKD Patients INCIDENT ATRIAL fibrillation is independently associated with an increased risk of end-stage renal disease (ESRD) in patients with chronic kidney disease (CKD), according to a study published online ahead of print in Circulation. In the study by Nisha Bansal, MD,
findings, said this is the first long-term study of prostate SBRT with a large number of patients. The study evaluated the biochemical relapse-free survival (bRFS) rates over a five-year period for patients with organ-confined PCa. Of the 1,101 patients in the study, 92% had clinical stage T1-2a and 8% had stage T2b-3 cancer. In addition, 72% had Gleason 6, 20% had Gleason 7, and 8% had Gleason 8-10 disease. Low-, intermediate-, and high-risk patients made up 59%, 30%, and 11% of the study population, respectively. The study showed that prostate tumors appear to be very sensitive to a higher, targeted dose of radiation rather than more frequent lower doses over time, which means that patients now have a viable option of choosing a one-week course of therapy as opposed to an eight-week or nine-week course of treatment. The study evaluated low-, intermediate-, and high-risk patients. At five
years, their actuarial disease-free survival rates were 95%, 90%, and 80%, respectively. The median dose was 36.25 Gy (range 35-40 Gy) delivered in four or five fractions. This was equivalent to a range of 90-112 Gy in conventional fractionation.
The five-year rate of disease-free survival was 95% in low-risk patients. The five-year actuarial biochemical relapse-free survival rate for patients with a Gleason score of 6 or less was 95%. It was 83% and 78% for those with a Gleason score of 7 and 8-10, respectively. The actuarial five-year bRFS rates for low- and intermediate-risk cases were 97% and 89%, respectively.
For low- and intermediate-risk cases, these results compared favorably with other modalities at five years. High-risk cases also appeared to do well, although the results for this subset of patients are preliminary due to the small number of patients with five-year follow-up. The median follow-up for all cases was 36 months. Biochemical relapse, defined as a rise greater than 2 ng/mL above nadir, was determined for 49 patients, nine of whom had a resolution of the rise and showed no clinical signs of a relapse. Additionally, androgen deprivation therapy (ADT) was given to 146 patients and appeared to make no difference in biochemical relapse risk. “With these high doses, you probably don’t need ADT,” Dr. Katz told Renal & Urology News. “We found it is very safe. We aren’t losing anything in terms of the side effect profile. Basically, you see about 5%-10% of patients experiencing some late urinary irritation, urgency, frequency and burning.” ■
CV Benefits of Cinacalcet Modest CINACALCET TREATMENT is associated with a modest decrease in the risk of death or major cardiovascular (CV) events among hemodialysis (HD) patients suffering from moderate-tosevere secondary hyperparathyroidism (SHPT), according to researchers. In a study, that risk was decreased by a nonsignificant 7% in cinacalcettreated patients compared with those who received placebo in unadjusted analyses. After adjustment for baseline characteristics, cinacalcet treatment was
associated with a “nominally significant” 12% decreased risk, investigators reported in The New England Journal of Medicine (2012;367:2482-2494). In the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, Glenn M. Chertow, MD, of Stanford University School of Medicine in Palo Alto, Calif., and colleagues randomly assigned 3,883 HD patients with moderate-to-severe SHPT to receive either cinacalcet or placebo. Subjects
were followed for up to 64 months. The primary composite end point— time until death, myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event—was reached in 938 (48.2%) of the 1,948 patients in the cinacalcet arm and 952 (49.2%) of the 1,935 patients in the placebo arm. Cinacalcet recipients experienced a significantly greater frequency of hypocalcemia and gastrointestinal adverse events. ■
of the University of California-San Francisco, and colleagues, incident atrial fibrillation developed in 16,463 of 206,229 adults with CKD enrolled
Focal Therapy for Prostate Cancer Safe
in the Kaiser Permanente Northern California health care organization. The researchers defined CKD as an estimated glomerular filtration rate below 60 mL/min/1.73 m2. During a mean follow-up of 5.1 years, 345 cases of ESRD developed after atrial fibrillation. After adjusting for potential confounders, atrial
FOCAL THERAPY for localized prostate cancer in highly selected patients is feasible and has acceptable morbidity, a French study found. In a study of 106 patients who underwent focal therapy for low-risk unilateral disease, Eric Barret, MD, and collaborators at the Université Paris Descartes in Paris observed a less
than 2% rate of major complications, according to findings published online in European Urology. Of the 106 patients, 50 (47%) had cryotherapy, 23 (22%) had vasculartargeted photodynamic therapy, and 21 (20%) had high-intensity focused ultrasound. The patients had a median PSA level of 6.1 ng/mL and all had
fibrillation was associated with a 67% increased risk of ESRD. ■
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a Gleason score of 6. At 12 months post-treatment, the median PSA level was 2.7 ng/mL. Treatment-related complications occurred in 13% of patients. The researchers observed 11 minor complications (10 grade 1 and one grade 2), two grade 3 complications, and no grade 4 or higher complications. ■
Renal & Urology News 15
GFRs Overestimated in ICU Patients with AKI BY ROSEMARY FREI, MSc PUERTO RICO—Glomerular filtration rates (GFRs) of critically ill patients with acute kidney injury (AKI) are routinely overestimated, data presented at the Society for Critical Care Medicine’s 2013 annual meeting suggest. Investigators believe urine output should be used instead of creatininebased equations to assess kidney function in oligoanuric ICU patients.. “We need to develop a better realtime indication of kidney function in critically ill patients, especially those with AKI,” said lead investigator Erin Frazee, PharmD, RPh, of Hospital Pharmacy Services at Mayo Clinic in Rochester, Minn. “Because if you misinterpret GFR, you’re likely to give patients doses of medication which may be dangerously high or low, and potentially expose them to nephrotoxins which may further exacerbate the process.” She and her colleagues retrospectively studied adults treated at their center from January 2006 to June 2011. They focused on individuals who met the Acute Kidney Injury Network (AKIN) urine-output criterion for stage 3 AKI
(MDRD-4) study formula, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. Results of all six equations significantly overestimated GFR, even after the researchers adjusted for patients’ daily variation in creatinine clearance. The closest approximation of the
true GFR was given by the CG-IBW, which yielded a day-adjusted eGFR of 32 ml/min/1.73m2. The next-most accurate was the CG-ABW, with a day-adjusted eGFR of 51. The least accurate was the Jeliffe equation, with a day-adjusted eGFR or 65. Statistically and clinically significant overestimation of true GFR
persisted out to the fourth day of AKI. The findings echo those of previous studies. A multicenter observational study published in 2010 showed the CG-ABW, MDRD and Jeliffe equations overestimated urinary creatinine clearance by 80%, 33% and 10%, respectively (Nephrol Dial Transplant 2010;25:102-107). ■
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
Urine output may provide a better indication of renal function.
in a one-size-ﬁts-all approach. That’s why doctors at UPMC are experts in both traditional methods of urologic surgery and in cutting-edge robotic surgery. But our doctors also recognize when the best management is not an operation, but careful 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
after at least two days in the ICU. The investigators excluded patients who developed AKI or required dialysis within less than 48 hours of ICU admission; did not have a urinary catheter; or who had a history of end-stage renal disease or kidney transplantation. The average baseline serum creatinine level was 0.9 mg/dL, and 10% of subjects had a documented history of chronic kidney disease. On each of the first four days of AKI, patients were between 1.8 and 3.7 liters fluid positive. The researchers assumed that the patients had a true GFR of less than 15 mL/min/1.73 m2. They compared this to the patients’ estimated GFRs (eGFRs) calculated from six existing equations. The equations were the Cockcroft-Gault using actual body weight (CG-ABW), Cockcroft-Gault using ideal body weight (CG-IBW), Jeliffe, Modified Jeliffe, the four-variable Modification of Diet in Renal Disease
to preserve the quality of life of every patient we treat. Learn more at UPMCPhysicianResources.com/ProstateCancer.
UPMC is afﬁliated with the University of Pittsburgh School of Medicine.
16 Renal & Urology News
Renal Nutrition Update Managing dyslipidemia in patients with chronic kidney disease can decrease their risk of cardiovascular events BY GRISSIM CLARK CONNERY, MS, RD, LD
Lipid profiles and CKD Investigators analyzed 2007-2008 data from the Korean National Health and Nutrition Examination Survey (KNHANES) to assess associations between lipid profiles and CKD (J Korean Med Sci 2012;27:1524-1529). The population excluded individuals younger than 19 years on lipid-lowering medications and with histories of malignancy, absence of laboratory data, or who had not fasted 12 hours prior to blood draw. The researchers defined CKD stage 3 as an estimated glomerular filtration rate (eGFR) below 60 mL/ min/1.73m2. The investigators assessed
The overall CKD prevalence in this population was 6.4%. In women, the researchers found significant positive associations between all four aforementioned ratios and CKD. The strongest association was found between TG/HDL and CKD, which also was the only ratio found to be significant in men.
CKD prevalence The investigators adjusted odds ratios for CKD prevalence stratified by lipid ratios for age, systolic blood pressure, fasting plasma glucose, waist circumference, BMI, and smoking, alcohol use, and exercise status. The highest TG/HDL quartile in men was associated with a 1.82 times increased risk of CKD stage 3 compared with the lowest quartile, but the overall trend was borderline significant. In women, the highest quartiles of TC/HDL, TG/ HDL, and nHDL/HDL were associated with a 1.75, 2.45, and 1.75 times increased risk of CKD stage 3, respectively. In women, all four ratios had a significant positive trend in relation to CKD stage 3 prevalence. These results primarily indicate that the TG/HDL ratio is independently
Recent evidence suggests a strong association between the triglyceride/high-density lipoprotein ratio and CKD. total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, nonHDL cholesterol (nHDL), calculated LDL (cLDL), and triglycerides (TG), as well as four primary lipid ratios: TC/HDL, TG/HDL, cLDL/HDL, and nHDL/HDL. The results were separated into quartiles and separated by gender.
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associated with CKD status and is a stronger predictor than other lipid ratios. The stronger associations found in females in this study may be due to the use of the Modification of Diet in Renal Disease (MDRD) study equation in estimated eGFR. A recent meta-analysis of lipid-lowering medications in CKD and dialysis
yslipidemia often is a concern in patients with chronic kidney disease (CKD) because mortality in this population typically is the result of cardiovascular complications. Pharmaceutical and lifestyle modifications including diet and exercise are used to manage dyslipidemia. For CKD patients, it is important to understand which lipid profiles are most commonly associated with CKD to help understand the relationship between dyslipidemia and the progression of renal disease.
Carbohydrate control may be one dietary intervention to improve the TG/HDL ratio.
populations found that these therapies were effective in reducing likelihood of cardiac death and atherosclerosis-mediated cardiovascular events (Ann Intern Med 2012;157:251-262). However, lipid-lowering therapies had no effect on preventing kidney failure, kidney graft failure, or decline in kidney function. This analysis focused on 18 randomized controlled trials looking at statins alone or used with ezetimibe. Fibrates are primarily used to manage elevated triglyceride levels, and a separate metaanalysis of data from CKD populations found that fibrates significantly reduced the risk of cardiovascular events in CKD populations, acutely reduced eGFR, and reduced albuminuria (J Am Coll Cardiol 2012;60:2061-2071). The reduction in eGFR was attributed to a rise in creatinine and appears to be temporary and reversed when fibrate therapy is stopped. The rise in creatinine has caused concern, but studies have found that inulin clearance is not altered during fibrate use, which suggests that although eGFR declines, actual GFR may remain unchanged. Data suggest that elevated serum triglycerides influence CKD progres-
sion with some relationship to proteinuria. Further studies will be needed to assess if this relationship is strictly correlative or if any causal relationship exists. Dietary interventions to improve the TG/HDL ratio are similar to those used for diabetes and insulin resistance, namely carbohydrate portion control, increases in the ratio of unsaturated fats to saturated fat intake, and loss of excess adipose tissue through caloric restriction and increased activity.
Summary Dietitians may find this information beneficial when assessing lipid laboratory results and determining pertinent nutrition interventions in patients with progressive kidney decline. At this time, management of dyslipidemia is important for reduction of cardiovascular events, but the addition of lipid monitoring specifically for reduction of progressive renal impairment would offer another outcome variable and room for improved outcomes. ■ Mr. Connery is Research Coordinator at Case Western Reserve University in Cleveland.
We’ve got more on our website highlighting effective diets for delaying CKD progression and helping patients manage sodium and phosphorus intake. See us at www.renalandurologynews.com/nutrition.
Renal & Urology News 17
Implantable Artificial Kidney Advances & QA
With nearly 100,000 patients awaiting a kidney transplant and fewer than one-fifth likely to undergo
the procedure each year, a promising hybrid device
efficient that it will allow for filtration without the need for an electrical power supply, connections to the outside, or a battery. So just based on the blood pressure, we will be able to get therapy that’s sufficient to keep the patient alive 24/7.
that works from the inside to provide renal functions beyond dialysis 24 hours a day, seven days a week. Shuvo Roy, PhD, Associate Professor in the Department of Bioengineering and Therapeutic Sciences at the University of California-San Francisco School of Pharmacy and technical director of The Kidney Project (http://pharmacy.ucsf.edu/kidneyproject/; Facebook.com/ArtificialKidney) updates Renal & Urology News on his group’s work. How did you begin to develop the artificial kidney? Dr. Roy: In the early 2000’s, we proved that the science worked. We took offthe-shelf, bulky, large, technology that we hooked up in a circuit to mimic how our kidneys work, and my colleague at the University of Michigan, Dr. David Humes, applied this to about 60 intensive care unit (ICU) patients who were suffering from acute renal failure. About half of them survived beyond six months—longer than they would have lasted on dialysis. That clinical trial gave us a lot of confidence that this concept of a filter plus a bioreactor actually does provide a therapeutic benefit. But then the question became, “How do we take this concept from the large-scale technologies of the ICU and apply it to people who go to the dialysis center three times a week?”
And what was the answer? Dr. Roy: The medical director on our team, William Fissell, MD, who is a nephrologist [with an engineering degree from Massachusetts Institute of Technology—Eds.], said we’d have to shrink the technology into something smaller that could be implanted; that could allow patients the freedom
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of mobility and the ability to eat and drink normally; and that could operate continuously, 24/7, to provide the benefit of toxin removal as well as the biological functions of the kidney that dialysis does not provide, such as help regulate blood pressure, help produce vitamins, and help with the acid levels of the blood.
What is the status of the artificial kidney now? Dr. Roy: Over the last 10 years, we have been on a journey to miniaturize the components of our device to the size of a small to-go coffee cup using silicon nanotechnology. We enclosed the cells of the bioreactor in a container with tiny windows that allow for interaction between the body and cells but prevent the body’s immune system from getting to these cells. We showed this to work on the bench, in small animals, in sheep, and in pigs with much success; it is all working in principle. The next step, which is what we are starting now, is to integrate the filter and the bioreactor into a single compact unit and do the animal testing that will let us validate this for subsequent human study.
How temporary or permanent would the implanted artificial kidney be? Dr. Roy: It’s hard to say prospectively without doing the studies, but we hope that it will be one surgery to implant it, and that should be it. But we also recognize that you have to plan for maintenance or replacement: The filter could get clogged up, or the cells could die. So, we have thought of a strategy where the artificial kidney gets implanted right underneath the skin. That way, components can be replaced in a minimally invasive procedure, which would probably be performed by a vascular surgeon. We do not anticipate the whole device having to be removed.
Which patients would be eligible to receive the artificial kidney? Dr. Roy: Today, 95,000 people are on the wait list for kidney transplants, which are still the gold standard for treating end-stage renal disease. In this country we do about 17,000 or 18,000 transplants per year, meaning that more than 75,000 people who require transplants won’t get one this year. So, the best candidates for us are probably people who are already on that list, but are low enough that the likelihood of them getting a transplant is not that great. If they are physically able to withstand the surgery for our device, they would qualify.
How does the function of the artificial kidney differ from dialysis? Dr. Roy: The five-year survival rate for dialysis hovers around 35%, but for kidney transplantation, it is well beyond 80%. The reason for that is dialysis simply does not provide the biological functions of a healthy kidney. Our device mimics the native kidney, with a filter serving as the glomerulus. The filter is followed by a tubule—the bioreactor—which is lined with cells, to provide the full functions of a kidney. In typical dialysis you just do the filtration part; you don’t mimic the cell part at all. Our device will be connected to the blood vessels, as a kidney transplant would be. One very exciting aspect is the membrane technology we have developed for the hemofilter: It’s so
I think we will be ready to test in humans by 2017, if not before. We are collaborating closely with the FDA as part of the agency’s Innovation Pathways 2.0 program to design this research.
“I think we will be ready to test in humans by 2017, if not before.” — Shuvo Roy, PhD
How do you expect survival rates to compare? Dr. Roy: I do feel confident that our device will provide better survival than dialysis. Would it be as good as transplant? Again, prospectively it’s hard to say, but we can hope the survival rates will be closer to those seen with transplants than those seen with dialysis because our device would provide many of the functions of a transplant. ■
Continue the conversation online! We have many experts who weigh in on controversial topics important to you. Catch our discussions at www.renalandurologynews/expertqa.
18 Renal & Urology News
CABG Safer than PCI for Hemodialysis Patients CORONARY ARTERY bypass grafting (CABG) may be a better option than percutaneous coronary intervention (PCI) for patients with endstage renal disease (ESRD) requiring coronary revascularization, according to a new study. Using the U.S. Renal Data System database, Tara I. Chang, MD, of Stanford University in Palo Alto, Calif., and colleagues identified 21,981 patients on maintenance hemodialysis who received initial coronary revascularization with either CABG or PCI. The median follow-up times for the CABG and PCI groups were 1.9 years and 1.4 years, respectively.
Whole Milk May Raise PCa Death Risk GREATER INTAKE of whole milk is associated with increased risk of death from prostate cancer (PCa). Analyzing data from 21,660 male physicians in the Physician’s Health Study, Jing Ma, MD, of the Harvard School of Public Health in Boston, and colleagues investigated the association between intake of dairy products and the incidence of PCa and PCaspecific survival during 28 years of follow-up. PCa was 12% more likely to develop in men who consumed more than 2.5 servings per day of dairy products compared with those who consumed 0.5 servings per day or less, investigators reported online in The Journal of Nutrition. Skim or low-fat milk intake was positively associated with the risk of low-grade, early-stage, and screen-detected cancers, whereas whole milk intake was associated only with fatal PCa. Men who drank one serving per day or more of whole milk had a 49% increased risk of dying from PCa compared with men who rarely consumed whole milk. “Most importantly,” the authors concluded, “only whole milk was consistently associated with higher incidence of fatal PCa in the entire cohort and higher PCa-specific mortality among cases.” ■
The cohort had unadjusted five-year survival rates of 22%-25% regardless of revascularization strategy, according to the investigators. After adjusting for multiple variables, CABG was associated with a significant 13% decreased risk of death and a 12% decreased risk of a composite of death or myocardial
infarction, Dr. Chang’s group reported in the Journal of the American Society of Nephrology (2012;23:2042-2049). “In light of the absence of any randomized trials or recent nationally representative observational studies, these results help inform patients with ESRD and their physicians about the clinical
outcomes after coronary revascularization in this high-risk population,” the authors wrote. In addition, Dr. Chang’s team noted that their study “helps to fill an important gap in the currently available evidence regarding CABG compared with PCI in patients with ESRD on dialysis.” ■
Renal & Urology News 19
PN Offers Better Renal Preservation, Survival PARTIAL NEPHRECTOMY (PN) may confer a clinical benefit in terms of improved renal function and overall survival compared with radical nephrectomy (RN) after excluding the confounding effect of malignancy, according to a new study published
online in European Urology. Using the Mayo Clinic Nephrectomy Registry, Dharam Kaushik, MD, of Mayo Clinic in Rochester, Minn., and colleagues identified 442 patients with unilateral sporadic benign renal masses treated surgically with RN (206 patients) or
PN (236 patients) from 1980 to 2008. The median follow-up for patients still alive at the last follow-up was 8.3 years. The estimated overall survival rates at 10 and 15 years were 69% and 53%, respectively, for RN compared with 80% and 74%, respectively, follow-
Reducing the burden of
ESA administration Consider the first once-monthly, non-EPO ESA offering less-frequent dose administration.
INDICATION AND LIMITATIONS OF USE OMONTYSÂŽ (peginesatide) Injection is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis. OMONTYS is not indicated and is not recommended for use in patients with CKD not on dialysis, in patients receiving treatment for cancer and whose anemia is not due to CKD, or as a substitute for red blood cell (RBC) transfusions in patients who require immediate correction of anemia. OMONTYS has not been shown to improve symptoms, physical functioning, or health-related quality of life.
IMPORTANT SAFETY INFORMATION WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE. Chronic Kidney Disease: t In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. t No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. t Use the lowest OMONTYS dose sufficient to reduce the need for RBC transfusions. Contraindications OMONTYS is contraindicated in patients with uncontrolled hypertension and in patients who have had serious allergic reactions to OMONTYS. Warnings and Precautions Increased mortality, myocardial infarction, stroke, and thromboembolism: t Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Use caution in patients with coexistent cardiovascular disease and stroke. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality. A rate of hemoglobin rise of >1 g/dL over 2 weeks may contribute to these risks.
t In controlled clinical trials of ESAs in patients with cancer, increased risk for death and serious adverse cardiovascular reactions including myocardial infarction and stroke was observed. t There is increased mortality and/or increased risk of tumor progression or recurrence in patients with cancer receiving ESAs. t In controlled clinical trials of ESAs, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and deep venous thrombosis (DVT) in patients undergoing orthopedic procedures. t In 2 trials of OMONTYS, patients with CKD not on dialysis experienced increased specific cardiovascular events. Hypertension (see Contraindications): Appropriately control hypertension prior to initiation of and during treatment with OMONTYS. Reduce or withhold OMONTYS if blood pressure becomes difficult to control. Serious allergic reactions (see Contraindications): Serious allergic reactions have been reported with OMONTYS. Immediately and permanently discontinue OMONTYS and administer appropriate therapy if a serious allergic reaction occurs. Lack or loss of response to OMONTYS: Initiate a search for causative factors. If typical causes of lack or loss of hemoglobin response are excluded, evaluate for antibodies to peginesatide. Dialysis management: Patients receiving OMONTYS may require adjustments to dialysis prescriptions and/or increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis. Laboratory monitoring: Evaluate transferrin saturation and serum ferritin prior to and during OMONTYS treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. Monitor hemoglobin every 2 weeks until stable and the need for RBC transfusions is minimized. Then, monitor monthly.
Adverse reactions Most common adverse reactions in clinical studies in patients with CKD on dialysis treated with OMONTYS were dyspnea, diarrhea, nausea, cough, and arteriovenous fistula site complication.
Please see accompanying Brief Summary.
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ing PN. Compared with PN-treated patients, patients who underwent RN were 75% more likely to die from any cause and more than four times more likely to develop stage IV chronic kidney disease, after adjusting for covariates. â–
20 Renal & Urology News
Low-Dose Valacyclovir CMV Prophylaxis Effective LOW-DOSE valacyclovir prophylaxis reduces the incidence of cytomegalovirus (CMV) disease in CMV-negative renal transplant recipients who receive a renal allograft from a CMV-infected donor, new findings suggest. It also results in high patient and graft survival rates.
The researchers, led by Fredrik Sund, MD, PhD, of Uppsala University in Uppsala, Sweden, noted that 8 g/day of valacyclovir has been used as prophylaxis, but neurotoxic adverse effects have limited the use of this regimen. The aim of their study was to evaluate a valacy-
clovir prophylactic regimen of 3 g/day for 90 days after transplantation in 102 CMV-negative recipients who received a kidney from a CMV-positive donor. CMV disease was diagnosed in 25% of patients, and 2% experienced tissue-invasive CMV disease, Dr. Sundâ€™s
group reported online in Nephrology Dialysis Transplantation. The rejection frequency was 22% and neurotoxic adverse effects were observed in 2% of patients. The five-year patient and graft survival rates were approximately 90% and 80%, respectively. â–
Table 2 Adverse Cardiovascular Outcomes in Randomized Controlled Trials Comparing Higher and Lower Hemoglobin Targets in Patients With CKD ÂŽ
Time Period of Trial
Population BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION OMONTYSÂŽ (peginesatide) Injection for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE. Chronic Kidney Disease: â€˘ In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesisstimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. â€˘ No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks [see Warnings and Precautions]. â€˘ Use the lowest OMONTYS dose sufficient to reduce the need for red blood cell (RBC) transfusions [see Warnings and Precautions]. INDICATIONS AND USAGE Anemia Due to Chronic Kidney Disease OMONTYSÂŽ is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis. Limitations of Use OMONTYS is not indicated and is not recommended for use: H :<-@51:@?C5@4:;@;:05-8E?5?.1/-A?1;2?-21@E/;:/1>:?5:@45?<;<A8-@5;: [see Warnings and Precautions]. H :<-@51:@?>1/15B5:3@>1-@91:@2;>/-:/1>-:0C4;?1-:195-5?:;@0A1@;.1/-A?1 %?4-B1?4;C:4->95:?;91?1@@5:3?-:firstname.lastname@example.org:125@>5?72-/@;>?2;>" "!&)%5: @45??1@@5:34-B1:;@.11:1B-8A-@10*see Warnings and Precautions]. H ?-?A.?@5@A@12;>$@>-:?2A?5;:?5:<-@51:@?C4;>1=A5>1599105-@1/;>>1/@5;: of anemia. H " "!&)%4-?:;@.11:?4;C:@;59<>;B1?E9<@;9?<4E?5/-82A:/@5;:5:3;> 41-8@4>18-@10=A-85@E;28521 CONTRAINDICATIONS " "!&)%5?/;:@>-5:05/-@105:<-@51:@?C5@4 H ':/;:@>;88104E<1>@1:?5;:*see Warnings and Precautions]. H %1>5;A?-881>35/>1-/@5;:?@;" "!&)%*see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism H :/;:@>;8810/85:5/-8@>5-8?;2;@41>%?5:<-@51:@?C5@4/;9<->5:345341> 419;38;.5:@->31@?
30see Table 2 5:/>1-?10>5?7;201-@49E;/->05-85:2->/@5;:?@>;71/;:31?@5B141->@2-58A>1 @4>;9.;?5?;2419;05-8E?5?B-?/A8->-//1??-:0;@41>@4>;9.;19.;85/1B1:@?C-? ;.?1>B105:@4145341>@->31@3>;A<? H '?5:3%?@;@->31@-419;38;.5:81B18;23>1-@1>@4-:
305:/>1-?1?@41>5?7;2 ?1>5;A?-0B1>?1/->05;B-?/A8->>1-/@5;:?-:04-?:;@.11:?4;C:@;<>;B501-005@5;:-8 .1:125@'?1/-A@5;:5:<-@51:@?C5@4/;1D5?@1:@/->05;B-?/A8->05?1-?1-:0?@>;71 #-@51:@?C5@4-:0-:5:?A225/51:@419;38;.5:>1?<;:?1@;%@41>-<E9-E.1-@ 1B1:3>1-@1>>5?72;>/->05;B-?/A8->>1-/@5;:?-:09;>@-85@E@4-:;@41><-@51:@?>-@1 ;2419;38;.5:>5?1;23>1-@1>@4-: 30;B1>C117?9-E/;:@>5.A@1@;@41?1>5?7? H :/;:@>;8810/85:5/-8@>5-8?;2%?5:<-@51:@?C5@4/-:/1>5:/>1-?10>5?72;>01-@4 -:0?1>5;A?-0B1>?1/->05;B-?/A8->>1-/@5;:?C-?;.?1>B10&41?1-0B1>?1>1-/@5;:? included myocardial infarction and stroke. H :/;:@>;8810/85:5/-8@>5-8?%?5:/>1-?10@41>5?7;201-@45:<-@51:@?A:01>3;5:3 /;>;:->E->@1>E.E<-??3>-2@?A>31>E-:0011<B1:;A?@4>;9.;?5?(&C-? ;.?1>B105:<-@51:@?A:01>3;5:3;>@4;<105/<>;/10A>1? &4101?53:-:0;B1>-88>1?A8@?;2 8->31@>5-8?/;9<->5:345341>-:08;C1>419;38;.5: @->31@?->1?4;C:5:&-.81!;>9-819-@;/>5@%@A0E!%;>>1/@5;:;219;38;.5: "A@/;91?5:$1:-8:?A225/51:/E"$-:0&>5-8@;$10A/1->05;B-?/A8->B1:@?C5@4 AranespÂŽ&41>-<E&$&
Hemoglobin Target; Higher vs. Lower (g/dL)
NHS (N = 1265)
CHOIR (N = 1432)
TREAT (N = 4038)
#-@51:@?C5@4;: #-@51:@?C5@4 #-@51:@?C5@4 :;@;:05-8E?5?C5@4 419;05-8E?5?C5@4 CKD not on dialysis /;1D5?@5:3;> 419;38;.5:
30 C5@4@E<105-.1@1? :;@<>1B5;A?8E 419-@;/>5@ 419;38;.5: administered
I ;: â‰¤
30 epoetin alfa epoetin alfa
Median (Q1, Q3) Achieved Hemoglobin level (g/dL)
88/-A?19;>@-85@E 4;?<5@-85F-@5;: 2;>;>?@>;71
88/-A?19;>@-85@E 9E;/->05-8 5?/4195-41->@ 2-58A>1-:0?@>;71
Hazard Ratio or Relative Risk (95% CI)
Adverse Outcome for Higher Target Group
Hazard Ratio or Relative Risk (95% CI)
#-@51:@?C5@44>;:5/50:1E5?1-?1!;@;:5-8E?5? OMONTYS is not indicated and is not recommended for the treatment of anemia in patients C5@4C4;->1:;@;:05-8E?5? 45341><1>/1:@-31;2<-@51:@?C4;>1/15B10" "!&)%1D<1>51:/10-/;9<;?5@1 /->05;B-?/A8->?-21@E1:0<;5:@1B1:@/;9<->10@; C4;>1/15B100->.1<;1@5:-82- 5:@C;>-:0;95F10-/@5B1/;:@>;8810;<1:8-.189A8@5/1:@1>@>5-8?;2 <-@51:@?C5@4 -:195-0A1@;C4;C1>1:;@;:05-8E?5?&41@>5-8?4-0-<>1?<1/52510<>;?<1/@5B1 -:-8E?5?;2-/;9<;?5@1?-21@E1:0<;5:@/;:?5?@5:3;201-@49E;/->05-85:2->/@5;:?@>;71 ;>?1>5;A?-0B1>?11B1:@?;2/;:31?@5B141->@2-58A>1A:?@-.81-:35:-;>->>4E@4954-F->0>-@5; Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer receiving ESAs " "!&)%5?:;@5:05/-@10-:05?:;@>1/;991:0102;>>10A/@5;:;2$@>-:?2A?5;:? 5:<-@51:@?>1/15B5:3@>1-@91:@2;>/-:/1>-:0C4;?1-:195-5?:;@0A1@;.1/-A?1 %?4-B1?4;C:4->95:?;91?1@@5:3?-:email@example.com:125@>5?72-/@;>?2;>" "!&)%5: @45??1@@5:34-B1:;@.11:1B-8A-@10 &41?-21@E-:01225/-/E;2" "!&)%4-B1:;@.11:1?@-.85?4102;>A?15:<-@51:@?C5@4 -:195-0A1@;/-:/1>/419;@41>-<E$1?A8@?2>;9/85:5/-8@>5-8?;2%?5:<-@51:@?C5@4 -:195-0A1@;/-:/1>@41>-<E?4;C1001/>1-?108;/;>135;:-8/;:@>;8<>;3>1??5;:2>11 ?A>B5B-8-:0;>01/>1-?10;B1>-88?A>B5B-8&4125:05:3?C1>1;.?1>B105:/85:5/-8@>5-8? ;2;@41>%?-095:5?@1>10@;<-@51:@?C5@4.>1-?@/-:/1>>1/15B5:3/419;@41>-<E -0B-:/1041-0-:0:1/7/-:/1>>1/15B5:3>-05-@5;:@41>-<E8E9<4;509-853:-:/E/1>B5/-8 /-:/1>:;:?9-88/1888A:3/-:/1>-:0C5@4B->5;A?9-853:-:/51?C4;C1>1:;@>1/15B5:3 chemotherapy or radiotherapy. Hypertension " "!&)%5?/;:@>-5:05/-@105:<-@51:@?C5@4A:/;:@>;88104E<1>@1:?5;: <<>;<>5-@18E/;:@>;84E<1>@1:?5;:<>5;>@;5:5@5-@5;:;2-:00A>5:3@>1-@91:@C5@4 " "!&)%$10A/1;>C5@44;80" "!&)%52.8;;0<>1??A>1.1/;91?05225/A8@@; /;:@>;80B5?1<-@51:@?;2@4159<;>@-:/1;2/;9<85-:/1C5@4-:@54E<1>@1:?5B1@41>-<E and dietary restrictions. Serious Allergic Reactions %1>5;A?-881>35/>1-/@5;:?5:/8A05:3-:-<4E8-/@5/>1-/@5;:?4E<;@1:?5;:.>;:/4;?<-?9 -:35;1019--:031:1>-85F10<>A>5@A?9-E;//A>5:<-@51:@?@>1-@10C5@4" "!&)% 99105-@18E-:0<1>9-:1:@8E05?/;:@5:A1" "!&)%-:0-095:5?@1>-<<>;<>5-@1@41>-<E 52-?1>5;A?-881>35/>1-/@5;:;//A>? Lack or Loss of Response to OMONTYS ;>8-/7;>8;??;2419;38;.5:>1?<;:?1@;" "!&)%5:5@5-@1-?1->/42;>/-A?-@5B1 2-/@;>?135>;:0125/51:/E5:21/@5;:5:28-99-@5;:.81105:32@E<5/-8/-A?1?;28-/7 ;>8;??;2419;38;.5:>1?<;:?1->11D/8A0101B-8A-@1@41<-@51:@2;>@41<>1?1:/1;2 -:@5.;051?@;<135:1?-@501:@41-.?1:/1;2-:@5.;051?@;<135:1?-@5012;88;C0;?5:3 >1/;991:0-@5;:?2;>9-:-3191:@;2<-@51:@?C5@4-:5:?A225/51:@419;38;.5:>1?<;:?1 to OMONTYS therapy. ;:@-/@22E9-D:/ @;<1>2;>9-??-E?2;>.5:05:3-:0:1A@>-85F5:3-:@5.;051? Dialysis Management #-@51:@?9-E>1=A5>1-06A?@91:@?5:@415>05-8E?5?<>1?/>5<@5;:?-2@1>5:5@5-@5;:;2" "!&)% #-@51:@?>1/15B5:3" "!&)%9-E>1=A5>15:/>1-?10-:@5/;-3A8-@5;:C5@441<->5:@;<>1B1:@ /8;@@5:3;2@411D@>-/;><;>1-8/5>/A5@0A>5:3419;05-8E?5?
Renal & Urology News 21
SBRT Found Suitable for Intermediate-Risk PCa BY JOHN SCHIESZER BOSTONâ€”Stereotactic body radiotherapy (SBRT) offers excellent cancer-free survival rates for patients with intermediate-risk, organ-confined prostate cancer (PCa) and results in few long-term rectal side effects, data reported at the American Society
for Radiation Oncology annual meeting show. â€œSBRT can complete treatment in five days instead of eight weeks and achieve what appears to be extremely high cancer-control rates with minimal reduction in long-term urinary or bowel function quality of life,â€? said lead inves-
Laboratory Monitoring Evaluate transferrin saturation and serum ferritin prior to and during OMONTYS treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin every 2 weeks until the hemoglobin is stable and sufficient to minimize the need for RBC transfusion. Thereafter, hemoglobin should be monitored at least monthly provided hemoglobin levels remain stable. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: H :/>1-?10 ;>@-85@E E;/->05-8 :2->/@5;: %@>;71 -:0 &4>;9.;19.;85?9 [see Warnings and Precautions] H E<1>@1:?5;:*see Warnings and Precautions] H %1>5;A?-881>35/>1-/@5;:?*see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of OMONTYS cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. Patients with Chronic Kidney Disease Adverse reactions were determined based on pooled data from two active controlled studies of 1066 dialysis patients treated with OMONTYS and 542 treated with epoetin, including 938 exposed for at least 6 months and 825 exposed for greater than one year to OMONTYS. The population for OMONTYS was 20 to 93 years of age, 58.5% male, and the percentages of Caucasian, Black (including African Americans), and Asian patients were 57.9%, 37.4%, and 3.1%, respectively. The median weight adjusted dose of OMONTYS was 0.07 mg/kg and 113 U/week/kg of epoetin. Table 3 summarizes the most frequent adverse reactions (â‰Ľ10%) in dialysis patients treated with OMONTYS. Table 3
Adverse Reactions Occurring in â‰Ľ10% of Dialysis Patients Treated with OMONTYS Dialysis Patients Treated with OMONTYS (N = 1066)
Dialysis Patients Treated with Epoetin (N = 542)
Adverse Reactions Gastrointestinal Disorders
Respiratory, Thoracic and Mediastinal Disorders Dyspnea
Injury, Poisoning and Procedural Complications Arteriovenous Fistula Site Complication
Nervous System Disorders 1-0-/41
Musculoskeletal and Connective Tissue Disorders
tigator Robert Meier, MD, a radiation oncologist at the Swedish Radiosurgery Center in Seattle. â€œAll the patients were treated with the CyberKnife, so it is unclear if this translates to other SBRT platforms.â€? Dr. Meier and his colleagues evaluated the toxicity and efficacy of SBRT in 129
Postmarketing Experience Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serious allergic reactions have been reported during postmarketing use of OMONTYS [see Warnings and Precautions]. Immunogenicity Of the 2357 patients tested during clinical trials, 29 (1.2%) had detectable levels of peginesatide-specific binding antibodies. There was a higher incidence of peginesatidespecific binding antibodies in patients dosed subcutaneously (1.9%) as compared to those dosed intravenously (0.7%). Peginesatide neutralizing antibodies were detected in vitroA?5:3-/188.-?102A:/@5;:-8-??-E5: ;2@41?1<-@51:@? :-<<>;D59-@18E half of all antibody-positive patients, the presence of antibodies was associated with declining hemoglobin levels, the requirement for increased doses of OMONTYS to maintain hemoglobin levels, and/or transfusion for anemia of CKD. No cases of pure red cell aplasia (PRCA) developed in patients receiving OMONTYS during clinical trials. DRUG INTERACTIONS No formal drug/drug interaction studies have been performed. Peginesatide does not bind to serum albumin or lipoproteins as demonstrated in in vitro protein binding studies in rat, monkey and human sera. In vitro studies conducted with human hepatocytes or microsomes have shown no potential for peginesatide to induce or inhibit CYP450 enzymes. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Peginesatide was teratogenic and caused embryofetal lethality when administered to pregnant animals at doses and/or exposures that resulted in polycythemia. OMONTYS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of peginesatide by intravenous injection to rats and rabbits during organogenesis was associated with embryofetal toxicity and malformations. Dosing was every third day in rats for a total of 5 doses and every fifth day in rabbits for a total of
0;?1? @; 93730;?1:>-@?-:0>-..5@?-0B1>?119.>E;21@-81221/@?5:/8A010 reduced fetal weight, increased resorption, embryofetal lethality, cleft palate (rats only), sternum anomalies, unossification of sternebrae and metatarsals, and reduced ossification of some bones. Embryofetal toxicity was evident in rats at peginesatide doses of â‰Ľ1 mg/kg and the malformations (cleft palate and sternoschisis, and variations in blood vessels) were mostly evident at doses of â‰Ľ10 mg/kg. The dose of 1 mg/kg results in exposures (AUC) comparable to those in humans after intravenous administration at a dose of 0.35 mg/kg 5:<-@51:@?;:05-8E?5?:-?1<->-@119.>E;21@-801B18;<91:@-8?@A0E5:>-@?>10A/10 fetal weight and reduced ossification were seen at a lower dose of 0.25 mg/kg. Reduced fetal weight and delayed ossification in rabbits were observed at â‰Ľ0.5 mg/kg/dose of <135:1?-@501:-?1<->-@119.>E;21@-801B18;<91:@-8?@A0E5:>-..5@?-0B1>?125:05:3? were observed at lower doses and included increased incidence of fused sternebrae at 0.25 mg/kg. The effects in rabbits were observed at doses lower (5% - 50%) than the dose of 0.35 mg/kg in patients. Nursing Mothers @5?:;@7:;C:C41@41><135:1?-@5015?1D/>1@105:4A9-:95871/-A?19-:E0>A3?->1 excreted into human milk, caution should be exercised when OMONTYS is administered to a nursing woman. Pediatric Use The safety and efficacy of OMONTYS in pediatric patients have not been established. Geriatric Use Of the total number of dialysis patients in Phase 3 clinical studies of OMONTYS, 32.5% were age 65 and over, while 13% were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. OVERDOSAGE OMONTYS overdosage can elevate hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of OMONTYS dosage and/or with phlebotomy, as clinically indicated. Cases of severe hypertension have been observed following overdose with ESAs [see Warnings and Precautions].
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Seizures have occurred in patients participating in OMONTYS clinical studies. During the first several months following initiation of OMONTYS, blood pressure and the presence of premonitory neurologic symptoms should be monitored closely. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency. Allergic and infusion-related reactions have been reported in patients treated with OMONTYS.
PCa patients with intermediate-risk, organ-confined disease. The median follow-up was 36 months. The four-year Kaplan-Meier progression-free survival rate was 99%. Only one patient experienced cancer recurrence. There were no reports of grade 4 to 5 toxicity. Thirty patients (23%) experienced acute grade 2 genitourinary (GU) toxicity and 11 (8.5%) experienced acute gastrointestinal (GI) toxicity with SBRT, the researchers reported. Late grade 2 GU and GI toxicities occurred in 14 patients (11%) and three patients (2%), respectively. One patient had a grade 3 bladder neck injury one year after treatment. The study included patients from 21 institutions who had a pre-treatment median PSA level of 5.9 ng/mL, which decreased to 0.8, 0.4, and 0.2 ng/mL at one, two, and three years, respectively. Patients were treated for one week with a non-isocentric robotic SBRT platform
In a study, patients had a 99% four-year progression-free survival rate. using real-time tracking of implanted fiducials. Investigators used magnetic resonance imaging to assist in target localization. SBRT was administered to patients at 40 Gy in five fractions of 8 Gy to the prostate, and 36.25 Gy was delivered to seminal vesicles. No patient received androgen deprivation therapy. Researchers assessed toxicities using common terminology criteria for adverse events. Patients with erections â€œfirm enough for intercourseâ€? were scored as potent. At baseline, 52% of patients were potent; at 24 months, this declined to 36%. â€œIn the sexual domain, there was a decrease in quality of life initially and there was a gradual reduction over the three-year study period,â€? Dr. Meier said. â€œThis is typical of radiotherapy modalities. We have 17 patients out at four years, and we have had only one biochemical failure. For intermediaterisk patients that is extremely good.â€? Dr. Meier and his team defined biochemical failure as a 2 ng/mL rise above nadir. The one case of biochemical failure, which was identified after three months of follow-up, was caused by biopsy-proven nodal metastasis. â–
22 Renal & Urology News
Male Immigrants to Sweden Have a Reduced Prostate Cancer Risk FIRST-GENERATION male immigrants to Sweden have a lower risk for all stages of prostate cancer (PCa) compared with native-born men, a study found. Researchers had speculated that lesser use of PSA testing among immigrants would result in lower rates of localized PCa and similar or higher risk of metastatic disease. Although the study revealed that immigrants were less likely than native-born men to have PCa detected by PSA testing, immigrants had a lower risk for metastatic disease, suggesting that PSA testing only partly explains their lower PCa risk, according to an online report in Cancer Causes & Control. The study, by Stacy Loeb, MD, of New York University, and colleagues, included 117,328 men with PCa diagnosed from 1991 to 2008. Of these men, 8,332 were foreign born. For each case, investigators randomly selected five cancer-free matched controls from the Swedish population registry. The control population included 505,561 Swedes and 57,083 immigrants. Compared with native-born men, Middle Eastern, Southern European,
and Asian immigrants had a 53%, 52%, and 47% decreased risk of PCa, respectively, in unadjusted analyses. These risk estimates remained virtually unchanged after adjusting for socioeconomic and marital status, educational attainment, and comorbidities, Dr. Loeb’s group reported. Additionally, the study showed that older age at immigration and short time since arriving in Sweden were significantly associated with lower PCa
Middle Eastern men had a 53% lower risk than native-born men. risk. Compared with native-born men, immigrants who were younger than 20, 20-30, 30-40, and 40 years and older when they arrived in Sweden were at 16%, 24%, 28%, and 49% decreased risk of PCa, respectively. Immigrants who had been in Sweden less than 5, 5-25, 25-50, and 50 or more years had a
53%, 50%, 27%, and 15% decreased PCa risk, respectively. Compared with native-born men, foreign-born men, including those from other Nordic countries, were significantly less likely to be diagnosed through PSA testing as part of an asymptomatic checkup, Dr. Loeb’s group found. Middle Eastern men, for example, had a 74% lower risk of diagnosis through PSA testing. Except for immigrants from North America and Northern Europe, all immigrant groups had lower risks of low-, intermediate, and high-risk disease as well as regionally metastatic and distant metastatic disease compared with native-born men. The researchers noted that their initial hypothesis was that lower use of PSA testing and subsequent lower frequency of work up among asymptomatic immigrants would result in a lower risk of localized PSA, but they pointed out that immigrants had a lower risk of advanced and metastatic disease compared with native-born men, “suggesting that disparities in screening and diagnostic testing could only partly explain the observed trends.” ■
Study: Alpha Blockers May Improve SWL Outcomes MEN TAKING alpha blockers for benign prostatic hyperplasia (BPH) have better outcomes from shock wave lithotripsy (SWL) for kidney stones than men not taking the medications, according to investigators in Turkey. A team at Baskent University in Ankara led by Umit Gul, MD, studied 248 men older than 50 years who underwent SWL for urinary stones (kidney, ureteral, or both) in 264 renal units (RUs) in 248 men. Of the 248 men, 16 had bilateral stones. Thirtyfour of the RUs were in men taking alpha blockers for BPH and 230 were in men not on the medications. SWL achieved stone-free status in 30 RUs (88.2%) in the alpha blocker group compared with 165 RUs (71.7%) in the group not taking alpha blockers, a significant difference between the groups, according to findings published online ahead of print in the Journal of Endourology. The two groups were similar with respect to stone size, number of
Elevated PSA, Sedentary Behavior Linked
SWL sessions, and number of shock waves. For the study, RUs with complete
BY JODY A. CHARNOW PSA CONCENTRATIONS are more likely to be elevated in men who engage in more sedentary behavior and lower levels of light physical activity, a study found. In an analysis of data from the 2003-2004 or 2005-2006 National Health and Nutrition Examination Survey (NHANES) cycles, researchers found that for each one-hour increase in sedentary behavior, men were 16% more likely to have an elevated PSA level, defined as a level of 4 ng/mL or higher, according to a report in Mayo Clinic Proceedings (2013;88:11-21). In addition, for each one-hour increase in light physical activity, men were 18% less likely to have an elevated PSA level. The study included 1,672 NHANES participants who were asked to wear an accelerometer—a device that measures the frequency, intensity, and duration of physical activity—on their right hip for seven days.
The investigators, Paul D. Loprinzi, PhD, of Bellarmine University in Louisville, Ky., and Manish Kohli, MD, of Mayo Clinic in Rochester, Minn., noted that there are compelling reasons to believe that physical activity may have a causative role in decreasing PSA level and possibly prostate cancer (PCa) risk. “It is hypothesized that regular participation in physical activity may reduce prostate cancer risk through a variety of biological mechanisms including changes in energy balance, immune function, inflammation, antioxidant defenses, and endogenous hormones,” they wrote. Drs. Loprinzi and Kohli noted that clinical factors already known to alter PSA measurements include inflammation or infection of the prostate or use of medications such as 5-alpha reductase inhibitors. Thus, these factors are considered when interpreting a PSA test result and before initiating a urologic workup because of an
“elevated” PSA level. Based on their results, the authors stated, evaluation of a patient’s physical activity and sedentary level before PSA testing also is important because these factors also may influence measurements and lead to a urologic diagnostic workup. The researchers cited a previous study published in Cancer Epidemiology, Biomarkers, & Prevention (2008;17:24672472) in which investigators who analyzed data from the 2001-2004 NHANES reported finding no association between self-reported physical activity and PSA level, which was consistent with other studies that used subjective measures of physical activity. “Self-reported measures of physical activity are susceptible to considerable measurement errors, such as biases associated with item interpretation, recall, and social desirability, which ultimately may attenuate the association between physical activity and PSA toward null,” Drs. Loprini and Kohli stated. ■
stone clearance or clinically insignificant residual fragments (small than 4 mm) were considered successfully treated. Previous studies have resulted in conflicting findings. A study by Bora Küpeli, MD, and colleagues at Gazi University School of Medicine in Ankara (Urology 2004;64:11111115) found that adding the alpha blocker tamsulosin to conventional treatment improved clearance of lower ureteral stones, especially when the drug was combined with SWL. However, a study by Stavros Gravas, MD, and coworkers at the University Hospital of Larissa in Larissa, Greece (Urol Res 2007;35:231-235) demonstrated no significant difference in stone clearance rates among patients with lower ureteral stones 6 mm or larger in diameter who received diclofenac without or without tamsulosin after SWL. ■
Renal & Urology News 23
Legal Issues in Medicine D
r. L, 45, a pulmonologist, was summoned to a hospital emergency department (ED) because of the severity of a particular case. The patient, Mr. Y, 78, was suffering shortness of breath. He also had a long list of serious medical conditions, including a recent intracranial hemorrhage. A computed tomography scan revealed massive blood clotting in Mr. Y’s lungs, affecting the flow of blood to his left leg. The scan also showed congestive heart failure. Dr. L determined that the only option was surgical, but the patient’s odds were poor. Mr. Y was alert, able to talk, oriented to place and time, and understood what was happening. The only option, Dr. L said, would be to surgically insert a filter in Mr. Y’s groin. He told the patient there was a good chance he would not survive the operation. Dr. L asked Mr. Y if he thought about whether he would want “heroic measures” taken if he went into cardiac arrest. The patient sat up straighter in bed, shook his head strongly, and said, “No, I don’t want that. I’ll have the operation, but if something happens, just let me go.” “Do you understand what he’s saying?” Dr. L asked the family. “Yes,” one of the children answered. The others nodded.
A critical decision Dr. L wrote the following in the patient’s chart: “Do Not Resuscitate”. I discussed with the patient whether he would want CPR, heart defibrillation, or mechanical ventilation. He was quite clear that he did not wish this. I then addressed with the family members in attendance why I did this and whether they understood, and all expressed their agreement.” The procedure itself went well, but hours later when walking to the restroom he suddenly stopped breathing and collapsed. A nurse’s aide began
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CPR and called code while the horrified family looked on. Dr. L was in the hallway when he heard the code. He rushed to Mr. Y’s room to find the aide performing CPR. “Stop!” he instructed the aide. “He has a DNR order.” The aide stopped performing CPR, and Dr. L tried to get the family out of the room. Mr. Y’s daughters were crying hysterically, but his son was shouting. “Do the CPR!” yelled the son, frantically. “Give him CPR! I’m his health care proxy! I’m telling you to do it!” Dr. L had to call several nurses to pull the son out of the room. The physician tried to speak to the son about the DNR order, but the son furiously kept insisting that his father should be resuscitated. During this time, the patient died. A few months later, the family of Mr. Y hired a plaintiff’s attorney and ultimately sued Dr. L for the wrongful death of Mr. Y. The physician met with his defense attorney who felt that the case was strong. Eventually, the case proceeded to trial.
A family’s distress At trial, Mr. Y’s family testified about the shock of witnessing their father’s death, and how they had unsuccessfully begged the nurses to continue CPR. The son testified that he was the healthcare proxy for his father, that his father had a living will that had been created two years prior, and that the living will stated that he did want CPR or other resuscitation measures in the event he needed it. Dr. L testified about his conversation with Mr. Y, and how he had clearly, and in front of his children, told them that he did not want to be resuscitated. The defense introduced medical experts who testified that Mr. Y’s prognosis was grim, and that it was very unlikely that he would have left the hospital alive, even in the best of circumstances.
© ISTOCKPHOTO / CATHERINE YEULET
A physician obeys a patient’s ‘Do Not Resuscitate’ order and winds up being sued by surviving family members BY ANN W. LATNER, JD
Patients may change their minds about what they instructed in living wills.
The jury deliberated only briefly before finding Dr. L not liable for the patient’s death.
Legal background A living will, also called an advance health care directive, is a set of written instructions by a person specifying what actions should or should not be taken if that person can no longer make healthcare decisions for themselves. Some directives set out specifically what treatments the patient wants or does not want, and what measures healthcare practitioners should take if there is an emergency. Some directives appoint a third person as the healthcare proxy, and that person is authorized to make decisions on behalf of the patient in the event that the patient becomes incapacitated. Protecting yourself Mr. Y had a living will that allowed for CPR and other measures when necessary. The document also appointed his son as his healthcare proxy in the event he could no longer make decisions. However, this document was created
two years prior to this event, and when presented with new information about the severity of his condition, Mr. Y opted to decline heroic measures. While Dr. L could not protect himself from this lawsuit, he did protect himself from being found liable by carefully documenting the conversation with both the patient and his family. In addition, it was clear to Dr. L (and noted in the file) that Mr. Y was competent to understand the situation and make a decision. The decision to have a DNR order superseded the two-year-old living will. The fact is that people change their minds. Mr. Y’s circumstances were so vastly different than they had been two years earlier, that it is understandable that with this new information, he might have a change of heart. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y. Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended.
What do you think? Did the jury make the right decision in this case? We want to know your thoughts. Leave us a comment at the end of this article—or any article—at www.renalandurologynews.com/legal.
Malpractice News Physician Sued After Having an Affair with a Patient Can an adulterous affair with a patient be considered medical malpractice? New York’s highest court has ruled that it can. The case involved a female patient who sought treatment for depression and anxiety from a licensed family physician in January 2000. The physician prescribed antidepressants, which he later switched in response to the patient’s concern that the medication was affecting her libido. The doctor recommended exercise and warm baths for stress, and referred the patient to a therapist. A year and a half later, while the patient (who was married) was still being treated by the physician, they began an affair. The first instance occurred at a gym where the physician was showing the woman
Physicians must manage “eroticized transference.”
exercises to reduce stress and anxiety. Sexual encounters continued, several times a week, for the next nine months until both parties decided to end the relationship. The woman confessed about the affair to her husband, who subsequently divorced her. The patient sued the physician for medical malpractice, testifying that she felt the affair was wrong, but was unable to stop it. Her attorney put an expert on the stand who testified that
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the patient’s romantic feelings towards her doctor were a result of “eroticized transference,” a phenomenon in which the patient experiences extreme attraction to a treating physician and that the patient is unable to resist. The woman alleged damages as a result of mental distress. The judge instructed the jury that the patient could be found partially at fault for her own injuries—a legal theory called comparative fault. The jury ultimately found the patient 25% at fault for her injuries and the physician, 75% at fault. The jury awarded the patient $154,000 for past mental distress, $50,000 for future mental distress, $134,000 for past loss of income, and $166,000 for punitive damages. These awards were reduced by the 25% that the patient was at fault. The case then went to the New York Court of Appeals, which held that the physician had a professional duty to manage the “transference” when he began treating the patient for mental health problems. The court held that “where defendant was prescribing a course of treatment for plaintiff’s mental health problems, including medication and counseling, a jury might reasonably conclude that the sexual relationship was substantially related to and, in fact, interfered with the treatment so as to constitute medical malpractice.” However, the court also decided to vacate the award for punitive damages against the physician.
Medical Errors Occur Despite Electronic Health Records Electronic health records (EHRs) have been touted as a way to address patient safety problems, but a new study shows that even with electronic records, mistakes still occur, although these mistakes tend to be “near misses” and “close calls.” The study, conducted by the Pennsylvania Patient Safety Authority, looked at EHR-related event reports from Pennsylvania hospitals to deter-
BY ANN W. LATNER, JD
mine the severity of the errors. Of the total 3,099 events, 2,763 (89%) were errors that caused no harm to patients. In addition, 320 (10%) involved unsafe conditions that did not result in harm to patients. Fifteen reports involved temporary harm to patients due to entering wrong medication data, administering the wrong medication, ignoring a documented allergy, failure to enter lab tests, and failure to document. One report of a failure to properly document an allergy resulted in significant harm to a patient. The researchers noted that dual workflow, using both paper-based and electronic records, seems to be particularly problematic and should be studied further. They also concluded that the configuration of certain EHR systems, especially those that have preset default values, seem to lead to errors in medication orders and documentation. “Further study could shed some light on best practices in the use of default values in system configuration,” the authors wrote. They suggested that additional research could “provide more insight into root causes of these errors, which may include issues in workflow design or policies and procedures, usability or functionality gaps in the design or configuration of an electronic system, or gaps in the training or understand of the user population.”
Physician Found Liable for Patient’s Suicide It is not often that a doctor is found liable for the suicide of a patient, but that is exactly what happened in a recent New York case. A jury found that the negligent treatment by a physician led a 51-year-old man commit suicide in 2009. The man’s family was awarded more than $1.5 million after two days of deliberation by a jury following a two-week trial. The physician had been prescribing the antidepressant Paxil to the patient to treat his depression, but had not
Medication errors could result from dual workflow—using paper-based and electronic records.
24 Renal & Urology News
actually seen his patient in more than 10 years. The physician was filling prescriptions over the phone without having office visits or examinations of the patient. In early 2012, the physicians was charged by the state health department with negligence for prescribing medications for patients for many years without seeing them in his office, and was placed on probation for three years. A few months later, the doctor himself was disciplined for abusing drugs and alcohol, and his probation was extended to five years. Shortly before he committed suicide, the patient began having anxiety attacks and the physician prescribed an additional antidepressant and doubled the patient’s dose of Paxil. This resulted in the patient becoming ill and going to the hospital with what he thought was a heart attack. The hospital ruled out a heart attack and lowered his dosage of Paxil. Soon afterwards, the patient had his first office visit with the doctor in over a decade and told the physician about his hospital visit. The physician allegedly became furious that his patient had gone to the hospital and revealed his treatment, and he refused to treat the patient anymore. The patient committed suicide within a few weeks. His widow said she hopes the verdict sends a message to patients to be careful about physicians overmedicating. ■
Looking for more malpractice news? Visit us at renalandurologynews.com/malpractice to see noteworthy jury verdicts, recent trends in legislation, and surprising settlements!
26 Renal & Urology News
Elevated SBP Raises Stroke Risk More in Blacks NEW FINDINGS suggest the existence of racial differences between blacks and whites in the impact of elevated systolic blood pressure (SBP) on stroke risk. In a study of 27,748 black and white subjects, George Howard, DrPH, of the University of Alabama-Birmingham, and collaborators found that increasing
SBP was associated with significantly larger increases in stroke risk in blacks compared with whites. Over 4.5 years of follow-up, 715 incident strokes occurred. A 10-mm increment in SBP was associated with a 24% increased stroke risk for blacks compared with an 8% increase among
whites, according to an online report in Archives of Internal Medicine. Among subjects aged 45-64 years, stroke risk among individuals with prehypertension and stage 1 hypertension was 38% and 2.38 times greater for blacks than whites, respectively. The researchers noted that among
individuals aged 45-65 years, incident stroke is two to three times more common in blacks than whites, a difference not explained by traditional stroke risk factors. Study subjects were participants in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) trial. â–
(continued) Table 1. Adverse Reactions in the Randomized Trial XTANDI N = 800 Grade 1-4 Grade 3-4 (%) (%)
XTANDIÂŽ (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary: please see the package insert for full prescribing information. ------------------------------ INDICATIONS AND USAGE ----------------------------XTANDI is indicated for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel. --------------------------------- CONTRAINDICATIONS ------------------------------Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss >VHH8VHLQ6SHFLÂżF3RSXODWLRQV@. -------------------------- WARNINGS AND PRECAUTIONS ------------------------Seizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures. The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. --------------------------------- ADVERSE REACTIONS ------------------------------Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared WRUDWHVLQWKHFOLQLFDOWULDOVRIDQRWKHUGUXJDQGPD\QRWUHĂ€HFWWKHUDWHVREVHUYHG in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4. 7KHPRVWFRPPRQDGYHUVHGUXJUHDFWLRQVÂ• UHSRUWHGLQSDWLHQWVUHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHDDUWKUDOJLDKRWĂ€XVKSHULSKHUDOHGHPDPXVFXORVNHOHWDOSDLQKHDGDFKH upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse UHDFWLRQVZHUHUHSRUWHGDPRQJRI;7$1',WUHDWHGSDWLHQWVDQGRI placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the UDQGRPL]HGFOLQLFDOWULDOWKDWRFFXUUHGDWDÂ•DEVROXWHLQFUHDVHLQIUHTXHQF\LQ the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in the Randomized Trial XTANDI Placebo N = 800 N = 399 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 (%) (%) (%) (%) General Disorders 9.0 44.4 9.3 Asthenic Conditionsa Peripheral Edema 1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 24.3 4.0 Arthralgia 17.3 1.8 Musculoskeletal Pain 1.3 0.3 Muscular Weakness 9.8 6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness
Placebo N = 399 Grade 1-4 Grade 3-4 (%) (%)
Gastrointestinal Disorders Diarrhea 21.8 1.1 0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9 0.0 Dizzinessb Spinal Cord 7.4 6.6 3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0 0.0 4.3 0.3 1.8 0.0 Mental Impairment Disordersc Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations 10.9 0.0 0.3 Upper Respiratory Tract Infectiond Lower Respiratory 2.4 4.8 1.3 Tract And Lung e Infection Psychiatric Disorders Insomnia 8.8 0.0 6.0 Anxiety 0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8 1.0 Pollakiuria 4.8 0.0 0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin 0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a Includes asthenia and fatigue. b Includes dizziness and vertigo. c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. Laboratory Abnormalities ,QWKHUDQGRPL]HGFOLQLFDOWULDO*UDGHQHXWURSHQLDRFFXUUHGLQRI patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both DUPVRISDWLHQWVRQ;7$1',DQGRQSODFHERH[SHULHQFHG*UDGH thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on ;7$1',*UDGH DQGRISDWLHQWVRQSODFHER*UDGH Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo. Infections In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms. Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. Hallucinations In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioidcontaining medications at the time of the event. Hallucinations were visual, WDFWLOHRUXQGHÂżQHG
Renal & Urology News 27
Better Early QOL Reported with Proton Therapy BY JOHN SCHIESZER BOSTONâ€”Patients undergoing treatment for prostate cancer (PCa) using proton beam therapy report a higher quality of life (QOL) in early follow-up compared with patients treated with other radiation modalities, according to a new study presented at the American
Society for Radiation Oncology annual meeting. The two-year non-randomized study of 370 patients evaluated the adverse effects of proton beam therapy, 3D conformal radiotherapy (3D-CRT), and intensity modulated radiotherapy (IMRT). Ninety-four patients received
----------------------------------DRUG INTERACTIONS ------------------------------Drugs that Inhibit or Induce CYP2C8 &RDGPLQLVWUDWLRQRIDVWURQJ&<3&LQKLELWRUJHPÂżEUR]LO LQFUHDVHG the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI >VHH'RVDJHDQG$GPLQLVWUDWLRQ DQG&OLQLFDO3KDUPDFRORJ\ @ The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQYLYR. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended >VHH&OLQLFDO3KDUPDFRORJ\@ Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers >VHH&OLQLFDO3KDUPDFRORJ\ @ The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQYLYR. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., ERVHQWDQHIDYLUHQ]HWUDYLULQHPRGDÂżQLOQDIFLOOLQ DQG6W-RKQÂśV:RUWPD\DOVR reduce the plasma exposure of XTANDI and should be avoided if possible >VHH&OLQLFDO3KDUPDFRORJ\@. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring >VHH&OLQLFDO3KDUPDFRORJ\@. -------------------------- USE IN SPECIFIC POPULATIONS -----------------------Pregnancy- Pregnancy Category X >VHH&RQWUDLQGLFDWLRQV@ XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent ZHUHDQGRYHUZKLOHSHUFHQWZHUHDQGRYHU1RRYHUDOOGLIIHUHQFHV in safety or effectiveness were observed between these patients and younger SDWLHQWV2WKHUUHSRUWHGFOLQLFDOH[SHULHQFHKDVQRWLGHQWLÂżHGGLIIHUHQFHVLQ responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy YROXQWHHUVQRVLJQLÂżFDQWGLIIHUHQFHLQHQ]DOXWDPLGHFOHDUDQFHZDVREVHUYHG LQSDWLHQWVZLWKSUHH[LVWLQJPLOGWRPRGHUDWHUHQDOLPSDLUPHQWP/PLQÂ” FUHDWLQLQHFOHDUDQFH>&U&/@Â”P/PLQ FRPSDUHGWRSDWLHQWVDQGYROXQWHHUV ZLWKEDVHOLQHQRUPDOUHQDOIXQFWLRQ&U&/Â•P/PLQ 1RLQLWLDOGRVDJH adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed >VHH&OLQLFDO3KDUPDFRORJ\@. Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed >VHH&OLQLFDO 3KDUPDFRORJ\@
proton beam therapy, 123 were treated with 3D-CRT, and 153 underwent IMRT. At the first follow-up visit (two to three months after the start of treatment), patients who had 3D-CRT and IMRT experienced modest yet significant problems with bowel function,
-------------------------------------- OVERDOSAGE -------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general VXSSRUWLYHPHDVXUHVWDNLQJLQWRFRQVLGHUDWLRQWKHKDOIOLIHRIGD\V,QDGRVH escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the LQYLWUR mouse lymphoma thymidine kinase (Tk) gene mutation assay or the LQYLYR mouse micronucleus assay. %DVHGRQQRQFOLQLFDOÂżQGLQJVLQUHSHDWGRVHWR[LFRORJ\VWXGLHVZKLFKZHUH consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy RIWKHSURVWDWHDQGVHPLQDOYHVLFOHVZDVREVHUYHGDWÂ•PJNJGD\HTXDO to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed DWÂ•PJNJGD\WLPHVWKHKXPDQH[SRVXUHEDVHGRQ$8& PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). Â‡ ,QVWUXFWSDWLHQWVWRWDNHWKHLUGRVHDWWKHVDPHWLPHHDFKGD\RQFHGDLO\ XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. Â‡ ,QIRUPSDWLHQWVUHFHLYLQJD*Q5+DQDORJWKDWWKH\QHHGWRPDLQWDLQWKLV treatment during the course of treatment with XTANDI. Â‡ ,QIRUPSDWLHQWVWKDW;7$1',KDVEHHQDVVRFLDWHGZLWKDQLQFUHDVHG risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Â‡ ,QIRUPSDWLHQWVWKDW;7$1',PD\FDXVHGL]]LQHVVPHQWDOLPSDLUPHQW paresthesia, hypoesthesia, and falls. Â‡ ,QIRUPSDWLHQWVWKDWWKH\VKRXOGQRWLQWHUUXSWPRGLI\WKHGRVHRUVWRS ;7$1',ZLWKRXWÂżUVWFRQVXOWLQJWKHLUSK\VLFLDQ,QIRUPSDWLHQWVWKDW if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day. Â‡ $SSULVHSDWLHQWVRIWKHFRPPRQVLGHHIIHFWVDVVRFLDWHGZLWK;7$1', DVWKHQLDIDWLJXHEDFNSDLQGLDUUKHDDUWKUDOJLDKRWĂ€XVKSHULSKHUDO edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Â‡ ,QIRUPSDWLHQWVWKDW;7$1',PD\EHKDUPIXOWRDGHYHORSLQJIHWXV Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.
Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 0HGLYDWLRQ,QF6DQ)UDQFLVFR&$ Issued: August 2012 $(1=%56 Rx Only ÂŠ 2012 Astellas Pharma US, Inc. XTANDIÂŽ is a registered trademark of Astellas Pharma Inc.
but those in the proton group had only minimal bowel problems, reported the studyâ€™s first author Phillip Gray, MD, a resident in the Harvard Radiation Oncology Program in Boston. The 3D-CRT and IMRT patients also reported modest yet significant urinary problems at first follow-up, but patients treated with proton therapy did not report similar problems until 12 months after treatment. Two years after treatment, patients undergoing all three forms of radiotherapy reported no significant problems with urination and similar problems with bowel function. Patients in all three treatment groups reported steadily worsening sexual function during the study period. The findings are important because they reflect what patients are reporting. Previous studies of the three radiotherapy modalities have been based on clinician assessments of QOL.
It causes fewer bowel and urinary problems compared with 3D-CRT, IMRT. The median patient age was 64 years for those receiving proton therapy, 70 for those receiving 3D-CRT, and 69 for those receiving IMRT. The treatment dose range was 74-82 Gy RBE for proton therapy, 66.4-79.2 Gy for 3D-CRT, and 75.6-79.2 Gy for IMRT. Lower doses given to the 3D-CRT group were thought to possibly explain some of the lower reported toxicity in that group, according to Dr. Gray. To evaluate QOL, the investigators used the Prostate Cancer Symptoms Indices (PCSI) for the proton beam and 3D-CRT patients and the Expanded Prostate Cancer Index Composite (EPIC) for the IMRT group. Baseline mean QOL scores were compared to scores at the first follow-up (two to three months after treatment) and again at 24 months post-treatment. The researchers considered QOL scores exceeding half the standard deviation of the baseline mean score to be clinically meaningful differences. â€œOur study provides a unique addition to existing research in this field and suggests that patients treated with different radiation modalities may experience distinct patterns of side effectsâ€? Dr. Gray said. â–
28 Renal & Urology News
Transplant Candidates: How Much Does Size Matter? The likelihood of an obese patient receiving a kidney transplant depends in part on how much risk a transplant center is willing to assume BY KRISTA L. LENTINE, MD, MS
Editorâ€™s note: The author will be speaking about this topic at the National Kidney Foundation 2013 Spring Clinical Meetings in Orlando, Fla.
bese individuals often are rejected as renal transplant candidates in large part because of their increased risk for surgical complications and adverse outcomes compared with normal-weight individuals. Clinicians typically determine whether patients are obese based on their body mass index (BMI), but recent studies provide evidence suggesting that high BMI alone may not be an adequate predictor of post-transplant outcomes. In addition, the current literature has not defined the limits of body composition that preclude clinical benefit from transplantation compared with longterm dialysis among patients who have passed a transplant evaluation.
BMI and delayed graft function The use of BMI as a transplant selection criterion is based on numerous studies demonstrating associations between high BMI and adverse outcomes. One such study was conducted by Molnar et al., 1 which examined data from the Scientific Registry of Transplant Recipients (SRTR) and maintenance hemodialysis (HD) records from a large
U.S. dialysis organization. The study included 11,836 HD patients dialyzed in 2001-2006 who underwent kidney transplantation by 2007. Compared with a reference BMI of 25 kg/m2, a higher pretransplant BMI was associated with progressively higher risk of delayed graft function (DGF). Those with a pretransplant BMI above 40 had a nearly threefold increased risk of DGF, after adjusting for multiple variables.
Increased risk of cardiovascular disease and graft loss Krista L. Lentine, MD, MS
Obesity also has been associated with an increased risk of graft loss. In a study of 51,927 kidney transplant recipients who had up to 10 years of follow-up, deathcensored graft loss risk was increased modestly among those with a BMI below 18, but was highest among morbidly obese patients.2 Recipients with a BMI above 36 had a 50% greater adjusted relative risk of graft loss compared with recipients who had a BMI of 24-26. Additionally, a study of 2,067 kidney transplant recipients in the Netherlands found that a BMI above 25 and above 28 were independently associated with an increased risk of graft loss and patient death compared with a BMI of 22-25.3 Furthermore, studies have demonstrated increased cardiovascular risk in obese renal transplant recipients. For example, a study of 1,107 kidney transplant recipients at a single center4 found that each 5-unit increment BMI was associated with a 19% increase in the risk of the
cardiac composite outcome of congestive heart failure, atrial fibrillation, and myocardial infarction.
BMI an unreliable predictor? Although studies have demonstrated the higher risks associated with elevated BMI, some studies have raised questions about the validity of using BMI for transplant candidate selection. Some data suggest that obese patients selected for transplantation may gain clinical benefits compared with remaining on dialysis. Contributing to some of the controversy is the concept of â€œreverse epidemiology,â€? which refers to the apparent survival benefit that high BMI confers to dialysis patients. In a historical cohort study of 151,027 patients who started renal replacement therapy in the U.S. in 1995-1997, obese patients had an unadjusted two-year
survival of 68% compared with 58% among non-obese patients.5 An analysis of the Dialysis Outcomes and Practice Patterns Study database for European HD patients in 1996-2000 found that a BMI below 20 was consistently associated with the highest relative death risk.6 Compared with dialysis patients who had a BMI of 23-24.9, those who were overweight (BMI 25-29.9), obese (BMI 30-34.9), and morbidly obese (35-39.9) had a 16%, 27%, and 24% decreased risk of death. The apparent protective effect of higher BMI in dialysis patients is explained in part by underlying comorbidities and malnutrition, both of which decrease BMI and increase mortality risk. Emerging evidence suggests that this reverse epidemiology may not be present in all subgroups. For example, a recent study that followed adult dialysis patients from the first dialysis treatment until seven years, death, for kidney transplant found that while older dialysis patients had reverse epidemiology for BMI, younger patients with a high BMI had 1.7 times the standardized mortality of younger patients with normal BMI, which reflect typical general population patterns.7
Importance of muscle mass Recent studies have suggested that BMI is an imperfect measure of adiposity. For example, Beddhu et al.8 found that the protective association of high BMI with survival on HD is limited to patients with normal or high urinary
excretion of creatinine, which is considered a marker of muscle mass. In contrast, dialysis patients with a higher BMI, low muscle mass based on urinary creatinine values, and thus inferred high body fat, had significant increased mortality compared with patients who had a normal BMI. Streja et al.9 examined associations of markers of pretransplant weight and muscle mass with mortality in transplant patients using an integration of SRTR registry data with maintenance HD records for 10,090 patients who underwent transplantation in 2001-2007. The study, which considered BMI a measure of weight and serum creatinine a measure of muscle mass, found that a BMI above 35 was associated with an increased risk of graft failure in adjusted analyses, but that this association was not significant after adjusting for multiple variables. Patients with high pretransplant serum creatinine—and thus inferred high muscle mass—had reduced risk of graft failure, whereas those with a low pretransplant serum creatinine had increased risk of graft failure. The researchers concluded that pretransplant obesity does not appear to be associated with poor post-transplant outcomes, but larger muscle mass, as reflected by higher serum creatinine, is associated with graft and patient survival advantages. A recent study of 993 kidney transplant recipients in Budapest10 also has raised doubts about the value of BMI alone for predicting post-transplant outcomes. The study found no clear association between BMI and long-term mortality, but when adjusted for waist circumference—which is a measure of abdominal fat—patients with a high BMI had lower mortality compared with patients who had normal and low BMI. Large waist circumference was
associated with increased mortality risk, an association that was more pronounced after adjusting for BMI.
Transplants benefit the obese The use of BMI as a transplant exclusion criterion is also controversial because of data suggesting that patients with a high BMI who receive a kidney transplant experience reduced long-term mortality and cardiovascular risk compared with remaining on a transplant waiting list. A recent study of 7,521 obese patients on a transplant waiting list demonstrated that those who received a transplant had a 61% reduction in the relative risk of death compared with remaining on the waiting list. In another study, researchers who used Medicare billing claims as a marker for congestive heart failure (CHF) diagnoses11 found that morbidly obese patients who underwent deceased donor transplantation had a significant 32% reduction in the adjusted relative risk of CHF.
Medicare, exclusions from private payer Center of Excellence designations, loss of Medicare participation, or program closure.12 Although SRTR equations include adjustment parameters for patients with a BMI above 25 and above 30 based on national registry data, BMI, as noted previously, is an imperfect measure of body composition, thereby limiting the benefit of this parameter for risk adjustment. Without adjustment that adequately captures the risk associated with performing renal transplants in obese patients, there will continue to be significant disincentives to offering them kidney transplants.13 In addition, transplant centers may face financial disincentives to offering transplants to obese candidates. The centers have to manage costs of care within relatively fixed reimbursement limits, and obese recipients are likely to incur higher costs per case because of longer operative times and increased rates of expensive complications, including surgical site infections and DGF.
Transplant center considerations Conclusion The likelihood of an obese patient receiving a kidney transplant depends in part on how much risk a transplant center is willing to assume. Transplant centers are graded on patient and graft survival rates. Centers may suffer serious consequences if they receive a citation for recipient death and/or graft loss rates that exceed expected rates as determined by the United Network for Organ Sharing Membership and Professional Standards Committee, the Centers for Medicare and Medicaid Services, or private insurance networks. In addition to regulatory penalties, citations may have significant financial impact, including costly Systems Improvement Agreements with
Markers of increased adiposity, including BMI and waist circumference, appear to be associated with worse post-transplant outcomes, such as DGF, graft failure, cardiac disease, and higher costs compared with ideal body composition. Still, exclusion from transplantation solely on the basis of BMI alone may not be appropriate from the viewpoint of individual candidates. Determining whether a patient is a suitable transplant candidate involves a balance between optimizing post-transplant outcomes and a patient-centered approach that takes into account the outcomes of transplantation compared with remaining on dialysis. As for how
Renal & Urology News 29
much size should matter, pending more data, including much needed studies of the impact of intentional weight loss, it appears to depend on the experience and risk tolerance of individual transplant centers. ■ Krista L. Lentine, MD, MS, is Associate Professor of Medicine at the Saint Louis University Center for Outcomes Research in St. Louis, Mo. REFERENCES 1. Molnar MZ, Kovesdy CP, Musci I, et al. Higher recipient body mass index is associated with posttransplant delayed kidney graft function. Kidney Int 2011;80:218-224. 2. Meier-Kriesche HU, Arndorfer JA, Kaplan B. The impact of body mass index on renal transplant outcomes: a significant independent risk factor for graft failure and patient death. Transplantation 2002;73:70-74. 3. Aalten J, Christiaans MH, de Fijter H, et al. The influence of obesity on short- and long-term graft and patient survival after renal transplantation. Transplant Int 2006;19:901-907. 4. Lentine KL, Rocca-Rey LA, Bacchi G, et al. Obesity and cardiac risk after kidney transplantation: experience at one center and comprehensive literature review. Transplantation 2008;86:303-312. 5. Glanton CW, Hypolite IO, Hshieh PB et al. Factors associated with improved short term survival in obese end stage renal disease patients. Ann Epidemiol 2003;13:136-143. 6. Leavey SF, McCullough K, Hecking E, et al. Body mass index and mortality in ‘healthier’ haemodialysis patients: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 2001;16:2386-2394. 7. Hoogeveen EK, Halbesma N, Rothman KJ, et al. Obesity and mortality risk among younger dialysis patients. Clin J Am Soc Nephrol 2012;7:280-288. 8. Beddhu S. Pappas LM, Ramkumar N, Samore M. Effects of body size and body composition on survival in hemodialysis patients. J Am Soc Nephrol 2003;14:2366-2372. 9. Streja E, Molnar MZ, Kovesdy CP, et al. Associations of pre-transplant weight and muscle mass with mortality in renal transplant recipients. Clin J Am Soc Nephrol. 2011;6:1463-1473. 10. Kovesdy CP, Czira ME, Rudas A, et al. Body mass index, waist circumference and mortality in kidney transplant recipients. Am J Transplant 2010;10:2644-2651. 11. Lentine KL, Xiao H, Brennan DC, et al. The impact of kidney transplantation on heart failure risk varies with candidate body mass index. Am Heart J 2009;158:972-982. 12. Sullivan B. Beyond CMS certification: mitigating factors application and systems improvement agreements. 20th Annual UNOS Transplant Management Forum. http://www.regonline.com/builder/site/tab3. aspx?EventID=1030813 (accessed September 3, 2012). 13. Schold JD. Unintended consequences of PSRs. Consensus Conference on Transplant Program Quality and Surveillance. http://www.srtr.org/cctpqs/ Default.asp (accessed September 25, 2012).
Diabetes Ups Post-RP Metastasis Risk in Obese Men BY JODY A. CHARNOW DIABETES IN obese men with prostate cancer (PCa) increases their risk of metastasis after radical prostatectomy (RP), according to researchers. A team led by Chenwei Wu, MD, and Stephen J. Freedland, MD, of the Duke Prostate Center at Duke University Medical Center in Durham, N.C., and the Durham VA Hospital, studied 2,058 U.S. veterans with PCa who were enrolled in the Shared Equal-Access Regional Cancer Hospital (SEARCH) database and underwent RP. For the cohort as a whole, diabetes at the time
of RP was not associated with metastasis risk after adjusting for multiple variables, Drs. Wu and Freedland and colleagues reported online in BJU International. When the researchers divided men into obese and non-obese groups, however, they found that diabetes in obese patients was associated with a significant fourfold increased risk of metastasis, whereas diabetes in non-obese patients was not significantly associated with metastasis risk, according to the investigators. Among obese men, diabetes was associated with a nonsignificant 39%
increased likelihood of receiving aggressive secondary treatment (radiation or androgen deprivation therapy [ADT]). After excluding men who received adjuvant radiation or ADT, diabetes was associated with a significant 61% increased likelihood of receiving aggressive secondary treatment among obese men, suggesting that less aggressive secondary treatments could not explain the higher metastases risk. Among the diabetics, longer diabetes duration was associated with higher metastasis risk. If this finding is confirmed in future studies, the research-
ers stated, “the clinical implication is that men with long-standing diabetes who develop PCa may harbor a more aggressive variant, and this possibility should be kept in mind when determining treatment.” The study found that race had no significant effect on the association between diabetes and metastasis risk. “Our findings add to the limited research on diabetes, obesity, and PCa progression, suggesting men with diabetes and obesity together might harbor particularly aggressive disease,” the authors concluded. ■
30 Renal & Urology News
Pre-treatment Percutaneous Biopsy of Small Renal Masses Urologists typically treat a renal cortical mass without biopsy, but this should be re-evaluated in the era of the incidental small renal cortical neoplasm.
Release Date: February 2013 Expiration Date: February 2014 Estimated time to complete the educational activity: 1 hour
BY ALLISON R. POLLAND, MD, AND JAIME LANDMAN, MD
This activity is jointly sponsored by Medical Education Resources and Haymarket Medical Education. STATEMENT OF NEED: The urologic community to date has been reticent to rely on renal biopsy in the treatment of renal cortical masses. The historically common presentation of renal tumors—a classic triad of pain, a flank mass, and hematuria—almost always resulted in the discovery of a large renal tumor. These tumors were mostly malignant, and, by definition, symptomatic. As such, the use of renal biospy was not warranted. In addition, the presence of small incidental renal cortical neoplasms was quite rare in the past, and biopsy even rarer. This algorithm must be re-evaluated, as incidental small renal cortical neoplasms are more frequently seen today. TARGET AUDIENCE: This activity has been designed to meet the educational needs of urologists and allied healthcare clinicians who treat patients with nephrotic amd acute nephritic syndromes, and associated cancer. EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Review the epidemiology of small renal cortical neoplasm. • Discuss renal biopsy techniques, image guidance, and type of biopsy. • Underline complications associated with a biopsy of the kidney. ACCREDITATION STATEMENT: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Medical Education Resources (MER) and Haymarket Medical Education. MER is accredited by the ACCME to provide continuing medical education for physicians. CREDIT DESIGNATION: Medical Education Resources designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. DISCLOSURE OF CONFLICTS OF INTEREST: Medical Education Resources ensures balance, independence, objectivity, and scientific rigor in all our educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure all scientific research referred to, reported, or used in a CME activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality CME activities that promote improvements or quality in health care and not a commercial interest. The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Faculty Allison R. Polland, MD Jaime Landman, MD
Reported Financial Relationship No financial relationships to disclose Research Support: Hitachi Aloka
ephrologists routinely use biopsy of the kidney for making diagnoses such as nephrotic and acute nephritic syndromes. In contrast, urologists have largely ignored renal biopsy in the diagnosis and management of small renal cortical neoplasms. Thoughtful consideration of the risks and benefits of pre-treatment biopsy for the small renal cortical neoplasm will often lead the reasonable clinician towards the routine application of biopsy in this setting. The current urologic reticence in using pre-treatment biopsy of renal cortical neoplasms clearly stems from the historically common presentation of renal tumors. The classic triad including pain, a flank mass, and hematuria almost always resulted in the discovery of a large renal tumor. These tumors were mostly malignant, and, by definition, symptomatic. As such, the use of renal biopsy in this setting was not warranted.1 In the past, the pres-
The content managers, Jody A. Charnow and Marina Galanakis, of Haymarket Medical Education, and Julie Johnson, PharmD, of Medical Education Resources, have disclosed that they have no relevant financial relationships or conflicts of interest. METHOD OF PARTICIPATION: There are no fees for participating in and receiving CME credit for this activity. During the period February 2013 through February 2014, participants must: 1) read the learning objectives and faculty disclosures, 2) study the educational activity, 3) complete the posttest and submit it online. Physicians may register at www.myCME.com/renalanurologynews, and 4) complete the evaluation form online. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better.
Allison R. Polland, MD, (at left) is a urology resident at the Mount Sinai School of Medicine in New York. Jaime Landman, MD, (at right) is Professor of Urology and Radiology at the University of California-Irvine, where he is the Chairman of the Department of Urology.
ence of small incidental renal cortical neoplasms was quite rare, and biopsy even rarer. Indeed, biopsies were typically being performed only when the origin of the tumor was in question, as may be the case in patients with a known extra-renal primary tumor or when the tumor has the atypical appearance of an infi ltrating process, which might suggest a lymphoma or infectious etiology. For these reasons, the urologic community developed a culture of renal cortical mass treatment without biopsy. This culture must be re-evaluated in the era of the incidental small renal cortical neoplasm. Not only will biopsy help avoid surgery for some patients with benign renal tumors, but identification of more indolent renal cell carcinoma (RCC) subtypes will help the urologist select appropriate minimally invasive treatment options for less aggressive cancers.
Biology and epidemiology of the small renal cortical neoplasm The increased use of imaging has dramatically increased the number of renal cortical neoplasms identified. Additionally, advances in imaging, specifically multi-detector computer-
Renal & Urology News 31
CME FEATURE alone. Benign primary renal masses include simple renal cyst, psuedotumors, angiomyolipoma, oncocytoma, juxtaglomerular tumor, multilocular cystic nephroma, mesoblastic nephroma, and papillary adenoma. In a recent surgical series of 482 patients who underwent partial or radical nephrectomy, of the 228 lesions ≤4 cm, 26.3% were benign.8 The relatively high fraction of benign renal cortical neoplasms that undergo surgery highlights the importance of biopsy to avoid overtreatment. Even among malignancies, biopsy findings can aid in making decisions about the management of these masses, whether extirpative (partial or radical nephrectomy), ablative, or nonsurgical (surveillance). More indolent malignancies, such as chromophobe RCC, may be well served with renal sparing options or even surveillance in the appropriate patient. A recent review of the SEER database found histology to be significantly associated with disease-specific and overall survival.9 Sarcomatoid elements may be associated with any subtype of RCC and portend a worse prognosis, even when presenting with low-stage disease. The same is true of collecting duct carcinoma. In a recent review of nonmetastatic renal cortical tumors treated with partial or radical nephrectomy, controlling for size and stage, chromophobe RCC, as compared to papillary, was a significant variable for disease progression.10 Still, chromophobe RCC is very indolent and may often be managed conservatively. Much recent focus has been placed on differentiation between chromophobe RCC and oncocytoma, as both may contain oncocytic cells. However, this differentiation may be causeless as even the diagnosis of an “oncocytic neoplasm” can be very helpful in the management of many patients. In considering biopsy, the urologist is no longer looking only for a binary answer: malignant or benign. Rather, consideration of RCC subtype is important, as indolent RCC histopathology may lead the decisionmaking process towards a less invasive modality even in younger and healthier patients.
Needle biopsy technique: image guidance and type of biopsy The two principle variables of renal mass biopsy are image-guidance modal-
Figure 1. Age-Adjusted Rates by Data Type Kidney and Renal Pelvis, All Ages, All Races, Both Sexes 1975-2009
Rate per 100,000
ized tomography (CT) and magnetic resonance imaging (MRI) technology, which have less partial volume averaging effects, have allowed radiologists to identify progressively smaller renal masses. In fact, in contemporary practice, up to 90% of kidney tumors are discovered before symptoms arise.2 In current practice, the majority of tumors are treated. As such, the mean size of tumors that undergo active treatment has progressively decreased over the course of the last decade.3 Despite the vastly increased number of incidental small renal cortical neoplasms, the age-adjusted U.S. mortality for renal carcinoma has remained fairly steady.4 (Figure 1). The increased incidence and stable mortality is strong evidence of over-treatment using our current management algorithm. Additionally, surgical treatment for renal masses carries a morbidity ranging from approximately 15% in the general population to 38.8% in octogenarians.5,6 Furthermore, both nephron-sparing surgery and radical nephrectomy can diminish renal function, although postoperative creatinine is lower after partial as compared with radical nephrectomy, and radical nephrectomy carries a higher risk of chronic renal insufficiency. A recent multicenter prospective phase 2 clinical trial was conducted examining the treatment algorithm of active surveillance of 209 small renal masses in 178 elderly and/or infirm patients with treatment delayed until progression.7 Tumor diameters increased by an average of 0.13 cm/year and local progression occurred in 25 patients (12%). Needle core biopsy in 101 of these masses demonstrated that the presence of RCC did not significantly change growth rate. RCC is the most common malignant primary renal mass in adults. There are distinct subtypes, and the biological aggressiveness and the prognosis of these subtypes has been documented. Clear-cell RCC is the most common RCC subtype followed by papillary RCC, chromophobe RCC, and unclassified RCC. Collecting duct carcinoma is a rare and highly malignant type of RCC. Although most enhancing renal masses in adults are RCC, a significant percentage are benign, commonly oncocytoma, and these benign tumors cannot be distinguished from malignant tumors based on imaging
Year or Diagnosis/Death SEER Incidence
Cancer sites include invasive cases only unless otherwise noted. Mortality source: US Mortality Files, National Center for Health Statistics, CDC. INcidence source: SEER 9 areas (San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexico, Seattle, Utah, and Atlanta). Rates are per 100,000 and are age-adjusted to the 2000 US Std Population (19 age groups - Census P25-1130). Regression lines are calculated using the Joinpoint Regression Program Version 3.5, April 2011, National Cancer Institute.
ity and needle type and size. In addition, there are many factors that affect efficacy and safety, including patientrelated variables such as body habitus and cooperativeness, tumor-related variables such as size, location, and vascularity, and operator-related variables such as technical expertise with renal biopsy, the availability of technology, and relationships with other sub-specialties. Ultrasound (US) and CT are the most commonly used image-guidance techniques. MRI is rarely used. Although the different imaging modalities have not been compared head-to-head, the risk of complications and reported failed biopsy rates are similar. Unfortunately, the literature is often imprecise with respect to definition of failed biopsy, making it difficult to evaluate studies comparatively. Failed biopsy—an absence
of tumor cells—is usually due to erroneous sampling of normal kidney, fibrosis, fat, inflammation, necrosis, or blood. This must be differentiated from indeterminate biopsy, in which tumor tissue is present but it is impossible to differentiate benign from malignant cells due to insufficient cells, morphological overlap, or cellular heterogeneity. Each imaging technique has its own benefits and limitations. US is the least expensive modality and can be used at the bedside by the urologist. Additionally, US provides multi-planar imaging without ionizing radiation. Limitations of US include its inability to visualize bowel and pleural space and the needle tip. US is also of limited value in obese patients and those with renal masses that are isoechoic to surrounding renal parenchyma. CT, with the use of intravenous contrast
32 Renal & Urology News
as necessary, can visualize almost all renal masses, as well as bowel, pleural space, and needle tip. CT may also demonstrate intra-tumoral changes such as hemorrhagic zones, allowing the operator to avoid these and thus increase biopsy yield. The greatest drawback to CT is the risk of ionizing radiation. MRI is valuable for biopsy of masses that are not well-visualized on US or CT, or when MRI-guided treatment is planned. The use of MRI is limited by availability and expense, as it requires use of costly MRI technology and specialized nonferromagnetic needles.11 Biopsy needles vary in size, and authors typically divide these into two classes: fine (19-gauge or thinner) or large (20-gauge or larger). Fine needles are typically used for fine-needle aspiration (FNA) in which the sample is examined cytologically rather than histopathologically. These samples may also be examined using immunohistochemistry (IHC), flow cytometry, fluorescent in situ hybridization (FISH), apoptosis assays, and picrosirius red F3BA staining.11 Large needles are typically used for core biopsies, which are examined histologically and using IHC. In general, core biopsy offers greater sensitivity. Larger caliber needles, as one might guess, will likely increase accuracy and decrease failure rate.12 Silverman and colleagues13 recommend beginning with a fine needle and asking an on-site cytologist to examine specimens intra-procedurally. If the specimen is adequate, the procedure can be completed with fine needle alone. If not, then a large needle should be used. Others have suggested performing both types of biopsy during the same procedure.14 In this case, FNA should be performed first to reduce the amount of blood in the cytological specimen.11 The authors prefer core needle biopsy alone as we firmly believe that there is indeed a superior ability to gain an accurate diagnosis with this practice. With respect to the number of biopsies performed, the literature advises at least two core biopsies.11,12 For FNA, as many passes as necessary should be performed to ensure a diagnostic smear. Techniques for image-guided renal mass biopsy have been described in detail.15 In short, once the patient is positioned properly and the mass visualized, a guiding cannula is advanced on to the tumor surface and the needle
Figure 2. An office-based renal biopsy under local anesthesia with a needle passed through a probe to target renal cortical neoplasm
is passed through the cannula into the tumor. Use of the cannula avoids direct contact between the tumor tissue and the retroperitoneal tissue through which the needle passes during percutaneous biopsy, theoretically decreasing the risk of tract seeding.
Office-based renal biopsy technique The authors have recently been performing office-based renal biopsy under local anesthetic. Office-based renal biopsy has allowed for improved coordination and ease of scheduling, leading to more expeditious and precise management of small renal cortical neoplasms. Once biopsy is deemed indicated, and the patient agrees after a discussion of the risks and benefits, a limited retroperitoneal US examination is performed to determine if a biopsy is feasible. The skin is then marked over the area where the biopsy will be performed. If the patient needs to return on another day for the biopsy, he or she is asked to keep the area marked with a pen after each bathing. On the day of the biopsy, the patient places EMLA cream on the marked area and takes a low dose of diazepam two hours prior to the procedure. Positioning is typically flank or prone. The Hitachi Aloka Preirus US system is used to target the lesion. The system projects a dotted target line through the exact needle path and an 18G needle is deployed through the hole in the transducer (Figure 2). This is familiar to the urologist as it mimics needle biopsy of the prostate. Performing the biopsy under local anesthesia
only has tremendous advantages as the patient can participate in the procedure as an “assistant.” The conscious and alert patient can respond to surgeon requests for deep or shallow inspiration, and can there -fore help to move the kidney (and therefore the tumor) down (via inspiration) to a location where it can be accessed below or between ribs. The patient can also be asked to hold breathing to facilitate a precise needle deployment in an immobile kidney. Immobilizing the kidney at the precise time of biopsy may help minimize the risk of bleeding. In our experience to date, patients typically experience little to no pain. After the procedure, the patient is observed for one to two hours and repeat US is performed in the office to confirm that there is no peri-renal hematoma.
Sensitivity and specificity of biopsy Several studies have evaluated sensitivity, specificity, and accuracy of renal mass biopsy in diagnosing malignancy; however, their results vary considerably by patient population, biopsy guidance-modality, needle size, and tumor type. A recent meta-analysis among studies published after 2001 found that accuracy was 96%, rate of false negatives was 0.6%, and rate of false positives was 0%.12 The sensitivity of biopsy for small masses (≤3 cm) is lower than for large masses.15 Sensitivity is limited by false-negative results, which are due to failure to properly target a small mass or sampling of a necrotic center in a large tumor.15
Biopsy is not only useful in de termining malignancy versus benignity, but also in diagnosing histology and grade, as these may affect prognosis and management, especially in patients being considered for nephron-sparing surgery or percutaneous ablation. Advances in pathology, including immunohistochemistry and cytogenetic techniques, have improved the accuracy of subtype determination in renal mass biopsy. Overall accuracy in subtype identification has been reported to be as high as 94%.12 FISH and polymerase chain reaction (PCR) can be used to aid in differentiation between subtypes of RCC. This is especially useful in differentiation between oncocytoma and chromophobe RCC, as they may coexist as a hybrid tumor. Hale’s colloidal iron stain can also be helpful in this setting. The immunocytochemical and cytogenetic profiles of the various subtypes of RCC are increasingly better described. DNA microarrays have been used to measure the expression levels of large numbers of genes simultaneously and can be used to differentiate subtypes of RCC based on mRNA expression. For example, high CA9 expression is seen in clear-cell RCC, AMACR in papillary RCC, and CLCNKB in chromophobe RCC and oncocytoma.16 Further research using this technology will improve our algorithm for subtype determination. Higher grade portends worse prognosis. Chromophobe, collecting duct, renal medullary, and unclassified RCC are designated as high or low grade. Fuhrman nuclear grading is used for clear cell and papillary RCC. It is based on nuclear characteristics, including size, contour, and nucleoli without consideration for mitotic activity. Renal tumors are commonly hetero geneous, so there is concern that Fuhrman nuclear grade identification based on a small sampling may be misleading. In two large series, nuclear grade was determined correctly at biopsy in 70% (17) and 84% (18) of cases. Grade accuracy can be improved by grouping tumors into “low grade” (Fuhrman I–II) and “high grade” (Fuhrman III–IV).
Renal & Urology News 33
CME FEATURE Specific indications for biopsy The rise in incidental detection of small (cT1a) renal masses has brought new attention to the debate about renal mass biopsy. Radiologically, it is difficult to distinguish between benign and malignant small renal cortical neoplasms. When stratified by size there is a direct correlation between benignity and size of the mass,8 with a high percentage of small renal cortical neoplasms being benign. Among those that are malignant, a significant number are low grade and likely indolent.15 This is why biopsy before jumping to treatment, especially in older patients with comorbidities, is so important. Unfortunately, the sensitivity of biopsy of small renal masses has been found to be lower than that of biopsy of 4-6 cm renal masses, 84% vs. 97%,19 although more recent papers looking only at small renal masses have found higher sensitivity. Subtype determination is also less accurate in small as compared with larger masses;12 however, with the use of IHC, accuracy of subtype determination has been reported as high as 93%.20
Pre- and post-ablative biopsy With the increasing use of ablative technologies for renal masses, tissue sampling prior to percutaneous or laparoscopic ablation has emerged as an indication for renal mass biopsy. Ablative technologies such as cryotherapy, radiofrequency ablation, and more recently, microwave ablation and extracorporeal high-intensity focused ultrasound ablation, are being used on small solid renal tumors. Pre-ablation biopsy in combination with imaging findings is the only way to determine if these small masses are benign or malignant. In two recent meta-analyses, biopsy of the masses occurred in only 62.2% to 88% of ablations.21,22 Thus a number of patients, some of whom likely have benign lesions, are being empirically treated based on imaging without tissue evidence. A benign diagnosis can avoid subjecting patients to the risks of an ablative procedure and prevents years of unnecessary imaging and follow-up visits as well as the patient anxiety associated with a cancer diagnosis. From a societal perspective, benign determinations on biopsy can avoid the healthcare costs of unnecessarily treating incidentally discovered small renal masses. From a research
perspective, without tissue diagnosis of malignancy, treatment efficacy of ablation may be overestimated if benign lesions are included in the data. Biopsy may also be used to assess the success of ablation. Although typically this is done with contrast-enhanced CT with lack of enhancement indicating the absence of tumor recurrence, lack of enhancement does not completely rule out the presence of viable tumor cells, particularly with radiofrequency ablation technologies.23 Oxidative stress stains may be a valuable addition in assessing biopsy results after ablation.24
Biopsy of indeterminate cystic renal masses A number of landmark reviews have described the radiological features of benign and malignant cystic masses.1,25 The Bosniak classification is based on imaging and used to guide the clinical management of renal cysts. Bosniak type I are simple cysts; type II are minimally complex with thin septations and fine calcifications or uniformly high attenuation cysts <3cm. Type IIF cysts are minimally complex but require follow up because of an increased number of septations or thicker calcifications. This
may also be seen making it impossible to rule out RCC. Aspiration of cyst fluid may be helpful. Clear fluid is generally assumed to be benign and hemorrhagic fluid malignant. There are, however, reports of RCC from which clear fluid was aspirated27 and only 15%â€“20% of bloody cysts are malignant at resection.28 In spite of its limitations, percutaneous biopsy has been used to aid in management of indeterminate cystic masses with those determined to be malignant undergoing definitive treatment and those determined to be benign being observed. Those that are observed are typically considered to be benign if they demonstrate no growth at one year,16,27 although it is important to recognize that some cancers may be extremely slow growing and no interval of time can be used to definitively diagnose a mass as benign.
Repeat biopsy A recent study retrospectively analyzed the pathology and outcomes of small renal mass biopsy, with special attention paid to those patients who underwent repeat biopsy for nondiagnostic results.29 Of the 345 biopsies performed initially, 67 (19.4%) were nondiagnos-
months after biopsy. Concern for bleeding is greatest with angiomyolipomas because of their hypervascularity and potential to bleed spontaneously. Pneumothorax may occur in 14%-29% of cases, although it is often clinically insignificant.13,30 The risk is greatest when biopsy is performed from the posterior approach and may be lessened by performing the puncture during expiration with needle positioned subcostally. Tumor seeding is an often reported objection to percutaneous biopsy, but the overall estimated risk is less than 0.01%. There have only been six reported cases from 1977 to 1999 and no cases reported in over a decade.13 There is a greater risk of seeding with transitional cell carcinomas than with RCC, so it is recommended that percutaneous biopsy be avoided when there is any concern that the tumor might be transitional cell carcinoma and not a renal cortical neoplasm.30 In patients who are planned to undergo ablation, tumor biopsies may be taken immediately after ablation to minimize risk of seeding as well as bleeding. RCC can be identified by the pathologist based on its architecture after either RFA or cryoablation and post-ablation biopsy does not decrease diagnostic yield.31
With increasing use of ablative technologies for small renal masses, biopsy may take on a larger role in diagnosis prior to ablation. category also includes hyperdense cysts >3cm in diameter. Indeterminate cystic renal masses (Bosniak type III) have thick or irregular septa and a thickened or irregular cyst wall. Bosniak type IV cysts contain enhancing solid tissue components adjacent to but independent of the cyst wall or septa. Type III and IV cysts are typically managed surgically, as they cannot be classified on the basis of imaging findings alone and can only be categorized after surgical removal and complete pathologic assessment. At the time of resection, however, the prevalence of benign masses among type III cysts has been reported to be as high as 41%.26 Benign indeterminate cystic renal masses are usually complicated cysts with inflammatory changes, and biopsy shows inflammatory cells, renal epithelial cells, and fibrous tissue. Atypical cells
tic. Repeat biopsy was performed in 12 of the 67 nondiagnostic cases, leading to diagnosis in 10 (83.3%), with two of those masses being benign.29
Complications Renal mass biopsy is generally safe. Minor complications occur in approximately 5% of all biopsies and major complications are rare.12 The most common complication is bleeding, which is often subclinical and self-limited. Microscopic hematuria is frequently seen but gross hematuria is rare and suggests inadvertent biopsy of normal renal parenchyma. Arteriovenous fistula, though rare, should be considered in cases of persistent bleeding. Pseudoaneurysm formation is also rare and may not manifest for several
From a financial perspective, a recent study found biopsy of small renal cortical neoplasms to be a cost-effective addition to the treatment algorithm.32 Pandharipande and colleagues used a decision-analytic Markov model to estimate life expectancy and lifetime costs for patients with small renal tumors less than or equal to 4 cm looking at initial biopsy to direct therapy to surgery or imaging surveillance versus empiric surgery. Using renal mass biopsy to direct therapy resulted in a clinically insignificant difference in quality-adjusted life expectancy (four days), but a lifetime cost saving of $3,466. Their model incorporated biopsy performance, the probability of track seeding with malignant cells, the prevalence and growth of benign and malignant tumors, treatment effectiveness and costs, and patient outcomes.
Conclusions While the traditional algorithm of renal mass management has not included biopsy, current advances in imaging
34 Renal & Urology News
CME FEATURE have resulted in increased detection of small renal masses and led to increased treatment and possibly over-treatment. This carries not only financial burden for society but also significant risk for patients. Biopsy of renal masses, which is commonly performed using CT or US guidance, can be used to determine if a mass is malignant or benign and thereby avoid over-treatment. Biopsy can be performed easily in the office by the urologist. Renal mass biopsy can be both specific and sensitive, although sensitivity is lower for small renal masses. Accuracy in determination of nuclear grade and subtype of biopsy specimens from malignant masses can be improved with PCR and FISH. With increasing use of ablative technologies for small renal masses, biopsy may take on a larger role in diagnosis prior to ablation and assessment of treatment success after ablation. The risk of complications is low and most are minor. Major complication such as clinically significant pneumothorax and tumor seeding are rare. With improvements in imaging and development of new immunohistochemical markers, renal mass biopsy is sure to be used more frequently in the diagnostic and treatment algorithms of renal masses. ■ REFERENCES 1. Bosniak MA. The small (less than or equal to 3.0 cm) renal parenchymal tumor: detection, diagnosis, and controversies. Radiology 1991;179:307–317. 2. Rodriguez-Rubio FI, Diez-Caballero F, Martin-Marquina A, et al. Incidentally detected renal cell carcinoma. Br J Urol 1996;78:29-32. 3. Kummerlin IP, ten Kate FJ, Wijkstra H, et al. Changes in the stage and surgical management of renal tumours during 1995–2005: an analysis of the Dutch national histopathology registry. BJU Int 2008;102:946-951. 4. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) 5. Mullins J, Feng T, Pierorazio P, et al. Comparative analysis of minimally invasive partial nephrectomy techniques in the treatment of localized renal tumors. Urology 2012;80:316-321. 6. Berger J, Fardoun T, Brassart E, et al. Detailed analysis of morbidity following nephrectomy for renal cell carcinoma in octogenarians. J Urol 2012;188:736-740. 7. Jewett MA, Mattar K, Basiuk J, et al. Active surveillance of small renal masses: progression patterns of early stage kidney cancer. Eur Urol 2011;60:39-44. 8. Schachter L, Cookson M, Chang S, et al. Frequency of benign renal cortical tumors and histologic subtypes based on size in a contemporary series: What to tell our patients. J Endourol 2007;21:819-823.
9. Keegan KA, Schupp CW, Chamie K, et al. Histopathology of surgically treated renal cell carcinoma: survival differences by subtype and stage. J Urol 2012;188:391-397. 10. Beck S, Patel M, Snyder M, et al. Effect of papillary and chromophobe cell type on disease-free survival after nephrectomy for renal cell carcinoma. Ann Surg Oncol 2004;11:71-77. 11. Volpe A, Jewett MA. Current role, techniques and outcomes of percutaneous biopsy of renal tumors. Expert Rev Anticancer Ther 2009;9:773-783. 12. Lane BR, Samplaski MK, Herts BR, et al. Renal mass biopsy–a renaissance? J Urol 2008;179:20-27. 13. Silverman SG, Gan YU, Mortele KJ, et al. Renal masses in the adult patient: the role of percutaneous biopsy. Radiology 2006;240:6-22. 14. Smith, Arthur D. Smith’s Textbook of Endourology. Chichester, West Sussex: Wiley, 2012. 15. Herts, BR. Imaging guided biopsies of renal masses. Curr Opin Urol 2000;10:105-109. 16. Chen YT, Tu JJ, Kao J, et al. Messenger RNA expression ratios among four genes predict subtypes of renal cell carcinoma and distinguish oncocytoma from carcinoma. Clin Cancer Res 2005;11:6558–6566. 17. Neuzillet Y, Lechevallier E, Andre M, et al. Accuracy and clinical role of fine needle percutaneous biopsy with computerized tomography guidance of small (less than 4.0 cm) renal masses. J Urol 2004; 171:1802-1805. 18. Wunderlich H, Hindermann W, Al Mustafa AM, et al. The accuracy of 250 fine needle biopsies of renal tumors. J Urol 2005;174:44-46. 19. Rybicki FJ, Shu KM, Cibas ES, et al. Percutaneous biopsy of renal masses: sensitivity and negative predictive value stratified by clinical setting and size of masses. AJR Am J Roentgenol 2003;180:12811287. 20. Volpe A, Mattar K, Finelli A, et al. Contemporary results of percutaneous biopsy of 100 small renal masses: a single center experience. J Urol 2008; 180:2333-2337. 21. Kunkle DA, Uzzo RG. Cryoablation or radiofrequency ablation of the small renal mass: a meta-analysis. Cancer 2008;113:2671-2680. 22. Hui GC, Tuncali K, Tatli S, et al. Comparison of percutaneous and surgical approaches to renal tumor ablation: metaanalysis of effectiveness and complication rates. J Vasc Interv Radiol 2008;19:1311-1320. 23. Weight CJ, Kaouk JH, Hegarty NJ, et al. Correlation of radiographic imaging and histopathology following cryoablation and radio frequency ablation for renal tumors. J Urol 2008;179:1277-1281. 24. Raman JD, Hall DW, Cadeddu JA. Renal ablative therapy: radiofrequency ablation and cryoablation. J Surg Oncol 2009;100:639-644. 25. Bosniak MA. The current radiological approach to renal cysts. Radiology 1986; 158:1-10. 26. Curry NS, Cochran ST, Bissada NK. Cystic renal masses: accurate Bosniak classification requires adequate renal CT. AJR Am J Roentgenol 2000;175:339-342. 27. Harisinghani MG, Maher MM, Gervais DA, et al. Incidence of malignancy in complex cystic renal masses (Bosniak category III): should imaging-guided biopsy precede surgery? AJR Am J Roentgenol 2003;180:755-758. 28. Renshaw AA, Granter SR, Cibas ES. Fine-needle aspiration of the adult kidney. Cancer 1997;81:71-88. 29. Leveridge M, Finelli A, Kachura J, et al. Outcomes of small renal mass needle core biopsy, nondiagnostic percutaneous biopsy, and the role of repeat biopsy. Eur Urol 2011; 60:578-584. 30. Hopper KD, Yakes WF. The posterior intercostal approach for percutaneous renal procedures: risk of puncturing the lung, spleen, and liver as determined by CT. AJR Am J Roentgenol 1990;154:115-117. 31. Beemster PW, Trias I, ten Kate FJ, et al. The diagnostic yield of immediate postcryoablation biopsies of small renal masses. J Endourol 2009;23:1203–1207. 32. Pandharipande PV, Gervais DA, Hartman RI, et al. Renal mass biopsy to guide treatment decisions for small incidental renal tumors: a cost-effectiveness analysis. Radiology 2010;256:836-846.
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CME Post-test Expiration Date: February 2014 Medical Education Resources designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Participants should claim only the credit commensurate with the extent of their participation in the activity. Physician post-tests must be completed and submitted online. Physicians may register at no charge at www.myCME.com /renalandurologynews. You must receive a score of 70% or better to receive credit. 1. Which of the following is not true with regard to surgical management of renal masses? a. Surgical treatment carries a morbidity ranging from about 15% in the general population to 38.8% in octogenarians. b. Both nephron-sparing surgery and radical nephrectomy can diminish renal function. c. There is an inordinately high risk of tumor seeding during surgery. d. Postoperative creatinine is lower after partial as compared with radical nephrectomy. e. Radical nephrectomy carries a higher risk of chronic renal insufficiency than partial nephrectomy. 2. Which of the following is an indication for renal mass biopsy: a. When the origin of the tumor is in question. b. When the tumor has the atypical appearance of an infiltrating process. c. When an infectious origin is high on the differential. d. Pre- and post-ablation of renal masses. e. When transitional cell carcinoma is highest on the differential. 3. In which of the following patients would you not consider surveillance? a. A young man with sarcomatoid elements seen on biopsy. b. An elderly gentleman with poorly-controlled diabetes, CHF and chromophobe RCC on biopsy. c. An elderly woman with oncocytoma on biopsy. d. A dialysis patient with simple renal cyst. e. A patient with tuberous sclerosis and suggestion of fat containing tumor on imaging. 4. Office-based renal biopsy offers all of the following benefits except: a. Improved coordination and ease of scheduling leading to more expeditious and precise management of small renal cortical neoplasms. b. It is somewhat familiar to the urologist as it mimics needle biopsy of the prostate. c. It can be performed under local anesthesia, allowing for patient cooperation with inspiration and facilitating kidney visualization and biopsy. d. It offers same-day histologic diagnosis. e. Patients typically experience little to no pain. 5. Which of the following stains is useful in differentiation between oncocytoma and chromophobe? a. Hale’s colloidal iron stain b. CA9 c. AMACR d. CLCNKB e. HER2 6. Complications of renal mass biopsy include all of the following except: a. Thrombocytopenia b. Extremely rare tumor seeding c. Hematuria d. Pneumothorax e. Arteriovenous fistula