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VOLUME 13, ISSUE NUMBER 2

Report: New ESRD Cases Decline USRDS data show a decrease from 116,946 cases in 2010 to 115,643 cases in 2011 BY JODY A. CHARNOW THE NUMBER of new patients starting end-stage renal disease (ESRD) therapy and initiating therapy on hemodialysis (HD) declined from 2010 to 2011, the most recent year for which data are available, according to the recently released 2013 Annual Data Report from the U.S. Renal Data System (USRDS). In 2011, 115,643 patients started ESRD therapy, down from 116,946 in 2010, and 101,683 patients started HD, a decrease from 103,874 in 2010.

IN THIS ISSUE 9 ESRD ups post-operative in-hospital kidney mortality 10 Moderate hyponatremia found to increase death risk

11

Physical activity ameliorates eGFR loss

12 Racial disparity in CKD patients tied to gene varients

15 Non-medical treatments for kidney stones: a review

New tools aimed at reducing the risk of wrong site surgical mistakes PAGE 17

In addition, the population starting peritoneal dialysis (PD) grew for the third consecutive year, and now makes up 6.6% of patients with a known dialysis modality, the report stated. “The change is associated with the new bundled payment system, with its clear incentives for peritoneal dialysis,” the report said. At the end of 2011, 430,273 patients were receiving dialysis and 185,626 patients were alive with a functioning kidney transplant, a 3.2% increase from 2010, according to the report.

Exercise May Cut Kidney Stone Risk BY DELICIA HONEN YARD PHYSICAL activity may decrease the risk of kidney stones by up to nearly one-third, according to a study of 84,225 postmenopausal women. Although obesity is a strong risk factor for the development of kidney stones, the roles of physical activity and caloric intake remain poorly understood, according to researchers Mathew D. Sorensen, MD, of the University of Washington in Seattle, and colleagues. The women were participants in the Women’s Health Initiative Observational Study who had enrolled continued on page 8

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Fewer Patients Starting Renal Replacement Therapy 120000

n 2011 n 2010

100000 80000 60000 40000 20000 0

115,643

116,946

101,683

Overall

103,874

Hemodialysis

Source: U.S. Renal Data System 2010 and 2011 Annual Data Reports.

Commenting on the new report, Joseph A. Vassalotti, MD, Chief Medical Officer for the National Kidney Foundation (NKF), said he can only speculate that enhanced management of the major chronic kidney failure causes—diabetes and

hypertension—may have contributed to the decline in new ESRD cases. Encouragingly, he said, the decline in incident patients is occurring for the most part across racial groups and causes of ESRD. continued on page 8

ESRD, Resistant HTN Linked TREATMENT-resistant hypertension is associated with an increased risk for end-stage renal disease (ESRD), according to the findings of a prospective, population-based study. Researchers led by Paul Muntner, PhD, of the University of Alabama at Birmingham, identified the association when they analyzed data from 9,974 participants in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study. During a median follow-up of 6.4 years, 152 cases of ESRD developed: 110 among the 2,147 subjects with treatment-resistant hypertension and 42 cases among the 7,827 subjects without treatment-

CME FEATURE

resistant hypertension. After adjusting for multiple potential confounding factors, subjects who had treatmentresistant hypertension experienced a greater than sixfold increased risk for ESRD compared with those who did not have the condition, Dr. Muntner’s group reported online ahead of print in the American Journal of Kidney Diseases. Among the participants who developed ESRD during follow-up, 72% had treatment-resistant hypertension at baseline. “The findings of the present study emphasize the need for appropriate continued on page 8

Earn 1 CME credit in this issue

PCA3: What Is Its Role in Prostate Cancer Screening? PAGE 19

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1/23/14 11:16 AM


F E B R UA R Y 2 014

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VOLUME 13, ISSUE NUMBER 2

PCa Salvage Cryo May Be Curative Patients have superior outcomes when their ­ pre-salvage PSA levels are below 5 ng/mL BY JODY A. CHARNOW SALVAGE cryotherapy is potentially curative in patients with locally recurrent prostate cancer (PCa) after primary radiation treatment, with the best outcomes achieved when patients have a pre-salvage PSA level below 5 ng/mL, according to a new study. Philippe E. Spiess, MD, of the Moffitt Cancer Center in Tampa, Fla., and colleagues found that these patients had a three-year biochemical disease-free survival (bDFS) rate of 66.7%. They also found that early referral for salvage

IN THIS ISSUE 8

Pre-RP systemic opioids may be beneficial

9 Frailty may raise risks of minimally invasive surgery 10 Bladder cancer risk higher after uterine radiotherapy

11 Nocturia linked to low

melatonin in the elderly

14 Transperineal prostate biopsy could be a better option

New tools aimed at reducing the risk of wrong site surgical mistakes PAGE 17

treatment is associated with improved bDFS. The three-year bDFS rate was 78.3% for patients with a pre-salvage PSA level below 5 ng/mL compared with 52.9% for those who had a presalvage PSA level of 5 ng/mL or higher, Dr. Spiess’ team reported online ahead of print in the World Journal of Urology. The mean time to biochemical failure—defined as nadir PSA plus 2 ng/mL—among patients with a presalvage PSA level below 5 ng/mL (85 patients) and 5 ng/mL or more (71 patients) was 30.3 and 18.4 months,

Post-BCG Inflammation a Good Sign INFLAMMATION or granuloma in histologic samples following intravesical bacille Calmette-Guérin (BCG) treatment in patients with non-muscle-invasive bladder cancer (NMIBC) is associated with a lower risk of disease recurrence and progression, researchers reported online ahead of print in BJU International. Samer Jallad, MD, of Royal Sussex County Hospital in Brighton, U.K., and colleagues studied 215 patients who underwent BCG treatment for NMIBC. The median follow-up was 32 months. Post-treatment biopsies revealed inflammation in 125 continued on page 8

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www.renalandurologynews.com Oncologic Outcomes

A new study demonstrated that salvage cryotherapy for prostate cancer that recurs after radiotherapy offers good cancer control. Shown here are rates of biochemical disease-free survival one, two, and three years after treatment. 100

80

60

40

20

0

89% 1 year

73.7% 2 years

66.7% 3 years

Source: Spiess PE et al. Outcomes of salvage prostate cryotherapy stratified by pre-treatment PSA: update from the COLD registry. World J Urol (2013;published online ahead of print).

respectively. “The present study highlights the important role of a patient’s pre-treatment total serum PSA level prior to salvage therapy,” the authors wrote, adding that, based on their findings, it is evident that patients with a

pre-salvage PSA level below 5 ng/mL do far better than those with a PSA level of 5 ng/mL or higher. The worse outcomes observed in patients with a pre-salvage PSA level continued on page 8

ED in Diabetics Harder to Treat ERECTILE dysfunction (ED) in men with diabetes mellitus (DM) may require more aggressive treatment than ED in men without diabetes, data suggest. In a study of 136,306 men with ED, diabetic men were 55% more likely to be prescribed second-line ED treatments (penile suppositories or injectables) and 2.1 times more likely to be prescribed third-line therapies (penile prostheses) than non-diabetic men within five years of ED diagnosis, investigators reported in the International Journal of Impotence Research. The study population included 19,236 men (14%) who had diabe-

CME FEATURE

tes prior to their ED diagnosis and 117,070 men without diabetes. Results showed that 2.8% of the diabetics were prescribed second-line ED therapies compared with 1.8% of the non-diabetics. The study findings suggest that ED among diabetic men may be less responsive to first-line pharmacologic treatments, may worsen more rapidly, or both, according to the researchers. “These data are particularly important given that the incidence of diabetes is rising in the United States,” the researchers, led by Thomas J. continued on page 8

Earn 1 CME credit in this issue

PCA3: What Is Its Role in Prostate Cancer Screening? PAGE 19

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1/23/14 11:12 AM


6 Renal & Urology News 

FEBRUARY 2014 www.renalandurologynews.com

FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD

Nephrologists Underpaid in U.S vs. Canada

M

any readers may recite this title in deepest disbelief, but Canadian nephrologists collect, by far, much higher revenues than their U.S. counterparts. How on Earth is it possible that a country with socialist medicine provides higher income to its nephrologists than the capitalist U.S.? Many Canadians had a good chuckle during the debates on Obamacare, when the word “socialist” was bandied about to describe underpaid doctors and long waiting lists for surgeries. Maybe there are such health care debacles in Canada, but definitely there is no long waiting period if you need to start dialysis treatment and to find a dedicated nephrologist. Indeed, you will get more intensive care with frequent nephrology visits for transition to dialysis in this arctic place than in its Southern neighbor. This higher level of dialysis care in Canada is partly owed to substantially higher reimbursement fees for nephrologists for providing care to a Canadian dialysis patient, often resulting in at least $7,000 a year of physician fees per each dialysis patient compared to approximately $3,000 a year for providing care to a Medicare dialysis patient in the U.S. If a hardworking nephrologist provides care to 100 dialysis outpatients in Canada, he or she will collect at least $700,000 a year in addition to inpatient rounds and other outpatient clinics. This enormous dialysis fee collection may explain why a Canadian nephrologist has on average a two- to threefold greater income than their American counterparts. I asked some of my Canadian colleagues why physician reimbursement for dialysis patient care is so high in Canada. The frequent answer is that the reimbursement is not high compared with other subspecialties there. Indeed, very few medical students in Canada opt for nephrology fellowship training because they can have even higher income in other subspecialties. Some Canadian nephrologists tell me that they feel deeply sorry for their vastly underpaid American colleagues. Additionally, you may be surprised to learn that Canadian physicians are allowed to incorporate themselves so they a corporate income tax of 16% instead of personal income tax of 45%. In case you’re interested in practicing in Canada, don’t yet pack your bag for a one-way ticket to Toronto. There is practically no vacant nephrologist position in Canada, and if there were a few openings a year, only Canadian-trained nephrologists with a Canadian citizenship are qualified for such a position. Nevertheless, there are plenty of nephrology fellowship spots in Canada, with an average stipend of $80,000 to over $100,000 a year to work as a renal fellow in Toronto, Vancouver, Edmonton, and other cities. So, we have finally figured out why Canadians—or at least Canadian nephrologists—do not mind the cold climate.

Kam Kalantar-Zadeh, MD, MPH, PhD Chief, Division of Nephrology & Hypertension Professor of Medicine, Pediatrics and Public Health University of California Irvine School of Medicine

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Medical Director, Urology

Medical Director, Nephrology

Robert G. Uzzo, MD, FACS G. Willing “Wing” Pepper Chair in Cancer Research Professor and Chairman Department of Surgery Fox Chase Cancer Center Temple University School of Medicine Philadelphia

Kamyar Kalantar-Zadeh, MD, MPH, PhD Medical Director, Nephrology Professor & Chief Division of Nephrology & Hypertension University of California, Irvine School of Medicine Orange, Calif.

Nephrologists

Urologists Christopher S. Cooper, MD Director, Pediatric Urology Children’s Hospital of Iowa Iowa City R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto Stanton Honig, MD Associate Clinical Professor of Surgery/Urology University of Connecticut School of Medicine, Urology Center New Haven J. Stephen Jones, MD, FACS Chief of Surgical Operations Professor of Surgery CCLM Cleveland Clinic Regional Hospitals Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology University of California, Irvine James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City Kenneth Pace, MD, MSc, FRCSC Assistant Professor Division of Urology St. Michael’s Hospital University of Toronto Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada

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

Renal & Urology News Staff Editor Executive editor Senior editor Web editor Editorial coordinator Art director Group art director, Haymarket Medical VP, audience development and operations Production manager Production director 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 Krassi Varbanov Kathleen Millea Chris Bubeck Paul Silver William Canning Jeff Forster Dominic Barone Jim Burke Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 13, 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 © 2014.

1/23/14 11:25 AM


Contents

www.renalandurologynews.com  FEBRUARY 2014 

FEBRUARY 2014

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Renal & Urology News 7

VOLUME 13, ISSUE NUMBER 2

Nephrology 9

ONLINE

this month at renalandurologynews.com Expert Q&A

Frank Critz, MD, Medical Director of Radiotherapy Clinics of Georgia– Decatur, discusses radical prostatectomy versus radiation for localized prostate cancer.

Clinical Quiz

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

11

12 14

9

11

19

Sleep Apnea Therapy Eases Resistant Hypertension Researchers report good results with continuous positive airway pressure therapy. Sex Life Satisfactory for Most Women on Hemodialysis The majority of women on chronic hemodialysis are satisfied with their sex life.

PCA3: What Is Its Role in Prostate Cancer Screening? Reza Mehrazin, MD, and Marc C. Smaldone, MD, of Fox Chase Cancer Center in Philadelphia, discuss the potential clinical utility of PCA3 as a marker of prostate cancer.

Frailty Ups Risk of MIS Complications Preoperative frailty increases the likelihood of postoperative complications among patients undergoing minimally invasive surgery, researchers reported.

17

Departments 6

From the Medical Director Canadian nephrologists much better paid

12

NMIBC Patients May Need Longer Follow-Up In a study, bladder tumors recurred in 14.5% of patients following a five-year tumor-free period

10

News in Brief Diabetes raises prostate cancer mortality

14

More Kids Having Minimally Invasive Nephrectomy Use of minimally invasive nephrectomy is expanding in the pediatric population, new findings suggest.

13

Expert Q&A Daniel C. Cattran, MD, on membranous nephropathy

16

Renal Nutrition Update Vitamin 12 supplementation may ease inflammation

17

Malpractice News Maine ranks No. 1 in hospital safety

18

Practice Management Experts give four tips for financial solvency

Sexual inactivity is particularly common yet

does not appear to be bothersome to many women on dialysis.

See our story on page 14

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CME Feature

Nocturia Linked to Low Melatonin A study of elderly individuals shows an inverse relationship between melatonin secretion and nocturia. Increasing secretion of this hormone may prevent and treat the condition, researchers say.

News Coverage

Genitourinary Cancers Symposium, San Francisco, January 30-February 1.

High Ferritin Ups Infection Risk in Kidney Transplant Patients Elevated ferritin levels in kidney transplant recipients are associated with an increased risk of infection in the early post-transplant period.

19

Urology

The Medical Minute

Visit renalandurologynews.com /the-medical-minute/ to hear podcast reports on new studies. Our latest include: • Geographic Differences for Children on Donor Waitlist • Chemical in Dialyzers May Be Toxic to Immune Cells • New Tool Predicts Prostate Cancer Overdiagnosis

ESRD Increases Post-Op In-Hospital Mortality End-stage renal disease at the time of admission to a surgical intensive care unit is independently associated with an increased risk of in-hospital death.

1/23/14 11:27 AM


Contents

www.renalandurologynews.com  FEBRUARY 2014 

FEBRUARY 2014

n

Renal & Urology News 7

VOLUME 13, ISSUE NUMBER 2

Urology 9

ONLINE

this month at renalandurologynews.com Expert Q&A

Frank Critz, MD, Medical Director of Radiotherapy Clinics of Georgia– Decatur, discusses radical prostatectomy versus radiation for localized prostate cancer.

Clinical Quiz

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

11

News Coverage

Genitourinary Cancers Symposium, San Francisco, January 30-February 1.

Nocturia Linked to Low Melatonin A study of elderly individuals shows an inverse relationship between melatonin secretion and nocturia. Increasing secretion of this hormone may prevent and treat the condition, researchers say.

12

NMIBC Patients May Need Longer Follow-Up In a study, bladder tumors recurred in 14.5% of patients following a five-year tumor-free period

14

More Kids Having Minimally Invasive Nephrectomy Use of minimally invasive nephrectomy is expanding in the pediatric population, new findings suggest.

9

CME Feature 19

PCA3: What Is Its Role in Prostate Cancer Screening? Reza Mehrazin, MD, and Marc C. Smaldone, MD, of Fox Chase Cancer Center in Philadelphia, discuss the potential clinical utility of PCA3 as a marker of prostate cancer.

11

12 14

ESRD Increases Post-Op In-Hospital Mortality End-stage renal disease at the time of admission to a surgical intensive care unit is independently associated with an increased risk of in-hospital death.

17

High Ferritin Ups Infection Risk in Kidney Transplant Patients Elevated ferritin levels in kidney transplant recipients are associated with an increased risk of infection in the early post-transplant period.

Departments 6

From the Medical Director Canadian nephrologists much better paid

Sleep Apnea Therapy Eases Resistant Hypertension Researchers report good results with continuous positive airway pressure therapy.

10

News in Brief Diabetes raises prostate cancer mortality

13

Expert Q&A Daniel C. Cattran, MD, on membranous nephropathy

16

Renal Nutrition Update Vitamin 12 supplementation may ease inflammation

17

Malpractice News Maine ranks No. 1 in hospital safety

18

Practice Management Experts give four tips for financial solvency

Sex Life Satisfactory for Most Women on Hemodialysis The majority of women on chronic hemodialysis are satisfied with their sex life.

Sexual inactivity is particularly common yet

does not appear to be bothersome to many women on dialysis.

See our story on page 14

RUN0214_TOC_Uro.indd 1

19

Nephrology

The Medical Minute

Visit renalandurologynews.com /the-medical-minute/ to hear podcast reports on new studies. Our latest include: • Geographic Differences for Children on Donor Waitlist • Chemical in Dialyzers May Be Toxic to Immune Cells • New Tool Predicts Prostate Cancer Overdiagnosis

Frailty Ups Risk of MIS Complications Preoperative frailty increases the likelihood of postoperative complications among patients undergoing minimally invasive surgery, researchers reported.

1/23/14 11:26 AM


8 Renal & Urology News 

FEBRUARY 2014 www.renalandurologynews.com

New ESRD Cases continued from page 1

Data also show than many patients starting renal replacement therapy (RRT) have never had a prior nephrology consult. In 2011, 42% of new ESRD patients had not seen a nephrologist prior to starting therapy. “That is a stunning figure, which has not changed over recent reporting years,” Dr. Vassalotti, Associate Clinical Professor of Medicine at Mount Sinai Medicine Center in New York, told Renal & Urology News. “I think low use of nephrology services is difficult to attribute entirely to lack of access to care.” Low awareness of CKD among patients and under-detection of kidney disease by practitioners are potential explanations why so many ESRD patients do not have a nephrology consultation prior to starting RRT, he said. Lastly, the use of hemodialysis (HD) catheters for incident patients is unacceptably high at nearly 80% in 2011, Dr. Vassalotti said. The duration of nephrology services prior to the onset of ESRD is clearly and consistently associated with lower catheter use at hemodialysis initiation, he said. According to the report, which was published as a supplement to the American Journal of Kidney Diseases, mortality rates in the ESRD and dialysis populations continue to decline, although they remain much higher than in the general popula-

Exercise/Kidney Stones continued from page 1

during the period 1993-1998 and were followed for a median of eight years. After adjusting for body mass index (BMI) and other nephrolithiasis risk factors, Dr. Sorensen and his team examined the independent association of physical activity (metabolic equivalents, or METs, per week), calibrated dietary energy intake, and BMI with incident kidney stone development. Results showed that, compared with the risk incurred by inactive women, the risk of incident stones decreased by 16% in women with the lowest physical activity level, the research-

ESRD, Resistant HTN continued from page 1

clinical management strategies to lower BP in individuals with treatment-resistant hypertension,” the authors wrote. The REGARDS Study enrolled a population-based sample of black

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tion. The adjusted mortality rate among ESRD patients (per 1,000 patient years at risk) decreased from 351 in 1996 to 241 in 2011, a decline of 31.3%. During that same period, the adjusted mortality rate in the dialysis population dropped from 362 to 266, a decrease of 26.5%.In 2011, among individuals aged 65 years or older, the adjusted mortality rate was 272.5 and 314.3 per 1,000 patient years at risk in the ESRD and dialysis populations, respectively, compared with 48 in the general population.The adjusted firstyear all-cause mortality rate from day 1 in 2010 was 254.4 per 1,000 patient years at risk, 268.8 for HD patients, 121.4 for PD patients, and 54.4 for kidney transplant patients (from the date of transplant). From day 90, the rate was 221.5 for HD patients and 126 for PD patients. Dialysis patients overall in 2011 had an expected 6.2 years of remaining life, whereas the general population in 2009 had an expected 22.5 years of remaining life, USRDS data show. Kidney transplant recipients fared better than dialysis patients, with 17.2 years of expected life remaining in 2011. The difference in life expectancy between dialysis patients and their non-ESRD counterparts was larger in certain age groups. For example, in the age group 50-54 years, dialysis patients had an expected 7.1 years of remaining life in 2011 compared with 27.1 years in the general population in 2009. In a preface to the report, the authors noted that rates of hospitalization for

infection in the HD population are of particular concern. These rates increased 43% from 1993 to 2011. During the same period, rates of cardiovascular and allcause hospitalization declined 7.3% and 3.0%, respectively. The adjusted infection hospital days per patient increased 19.2% for HD patients and decreased 19.4% and 25.2%, respectively, for patients on PD or with a kidney transplant. In contrast, from 1993 to 2011, the infection, cardiovascular, and all-cause hospitalization rate decreased 1.8%, 21.9%, and 14%, respectively, for PD patients and 4.6%, 39.5%, and 15.7%, respectively, for kidney transplant recipients. Regarding the increase in ESRD patient hospital admissions for infection, Dr. Vassalotti pointed out that a rise in the hospitalization rate could reflect the obvious and well-recognized problem of the use of hemodialysis catheters, particularly in the context of decreasing infectious hospitalization rates for PD and transplantation. The Fistula First Catheter Last quality improvement initiative of the Centers for Medicare and Medicaid Services is focusing on this problem through the ESRD networks. Pneumonia is another contributing factor. In 2011, pneumonia admissions for HD and PD patients were 1.9 and 1.6 times higher, respectively, than rates in 1993. Some types of pneumonia are probably beyond the scope of dialysis clinic care, Dr. Vassalotti noted. However,

pneumonia that complicates influenza infection and pneumococcal pneumonia may be prevented in the dialysis setting by the appropriate use of vaccinations. The report also summarized data for chronic kidney disease (CKD), noting that it “is important for individuals at risk for CKD be screened periodically for kidney disease.” Urine albumin and creatinine are valuable laboratory markers for detecting early signs of kidney damage, the report noted, but data show that urine albumin and creatinine testing is underused. In 2011, the probability of urine albumin and creatinine testing was 36% and 87%, respectively, among patients with diabetes but not hypertension and 5% and 88%, respectively, among patients with hypertension but not diabetes. The rates were 37% and 93%, respectively, for patients with both diabetes and hypertension. The NKF’s Kidney Disease Outcomes Quality Initiative work group led by Harold I. Feldman, MD, and Lesley A. Inker, MD, will soon publish a U.S. commentary on the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) international Clinical Practice Guideline for the Evaluation and Management of CKD, Dr. Vassalotti said. The commentary will emphasize the role of estimated GFR using the 2009 CKD-EPI creatinine equation and the urinary albumin-creatinine ratio in testing, detection, assessment of prognosis, and management. n

ers reported online ahead of print in the Journal of the American Society of Nephrology. As activity in general increased, the risk of incident stones continued to decline until leveling off at a decrease of approximately 31% for activity levels of 10 METs per week or higher. Ten METs per week is the equivalent of approximately three hours of average walking (2–3 mph), four hours of light gardening, or one hour of moderate jogging (6 mph), according to an accompanying statement from the American Society of Nephrology (ASN). Activity intensity was not associated with the development of stones, prompting Dr. Sorensen to comment

in the statement, “Even small amounts of exercise may decrease the risk of kidney stones; it does not need to be marathons, as the intensity of the exercise does not seem to matter.” Upon analyzing dietary energy intake, the researchers found that the consumption of more than 2,200 calories per day raised the risk of incident stones by up to 42%, yet the intake of fewer than 1,800 calories per day did not protect against stone formation. Higher BMI was associated with increased risk of incident stones. “In summary, physical activity may reduce the risk of incident kidney stones in postmenopausal women independent of caloric intake and [BMI],

primarily because of the amount of activity rather than exercise intensity,” the investigators wrote. “Higher caloric intake further increases the risk of incident stones.” While acknowledging in a related editorial that a recommendation for moderate physical activity might reasonably be added to dietary counseling for patients with stones, John C. Lieske, MD, of the Mayo Clinic in Rochester, Minn., pointed out that the new study would need to be replicated in populations other than postmenopausal women. Dr. Lieske also noted the possibility that women who exercise regularly could have other healthy habits that reduce nephrolithiasis risk. n

and white U.S. adults aged 45 years and older. The investigators defined treatment-resistant hypertension as uncontrolled blood pressure (BP) with concurrent use of three antihypertensive medication classes, including a diuretic, or the use of four or more antihypertensive medication classes,

including a diuretic regardless of BP level. The researchers defined uncontrolled BP as a systolic BP of 140 mm Hg or higher and/or diastolic BP of 90 mm Hg or higher, except for patients with an albumin-creatinine ratio of 30 mg/g or higher. For these

patients, the researchers defined uncontrolled BP as a systolic BP of 130 mm Hg or higher and/or diastolic BP of 80 mm Hg or higher. The investigative team identified new cases of ESRD by linkage of study participants with the U.S. Renal Data System. n

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8 Renal & Urology News 

FEBRUARY 2014 www.renalandurologynews.com

PCa Salvage Cryo continued from page 1

above 5 ng/mL “reflect that a significant proportion of such patients may harbor micrometastatic disease.” The study’s 156 patients—who are included in the COLD (cryo online data) Registry—underwent salvage radiotherapy without neoadjuvant hormone ablative therapy. Subjects had a mean follow-up of 3.8 years. Dr. Spiess and his colleagues said it is evident that patients with a presalvage PSA level below 5 ng/mL “do far better” than those with a PSA level of 5 ng/mL or higher. They noted that their results “are particularly impactful” because the two subgroups were

Post-BCG Inflammation continued from page 1

patients, granulomas in 60, and neither inflammation nor granuloma in 18 (normal histology group). Twelve patients did not have biopsies and were subsequently excluded from the study. During follow-up, 42 patients died, eight from their cancer. The recurrence rate was 17% in the granuloma group, 38% in the inflammation group, and 71% in the normal histology group. The progres-

ED in Diabetics continued from page 1

Walsh, MD, of the University of Washington in Seattle, wrote. “The increased severity of ED in men with diabetes may lead to higher healthcare utilization, and thus appropri-

matched in terms of their other clinical and pathologic characteristics, thus “minimizing any potential impact confounding variables could have had on our findings.”

Success rates are similar to those of salvage radical prostatectomy. “Although the urological community continues to debate the utility of serum PSA as a screening tool for prostate cancer,” the authors observed, “the findings of the present study are quite

evident that it serves as an important prognostic marker of the therapeutic outcomes of salvage therapy.” “I think the study is helpful in providing supporting evidence for the benefit of salvage cryoablation in the treatment of locally recurrent prostate cancer following radiation treatment,” said David Y.T. Chen, MD, Director of the Urological Oncology Fellowship Program at Fox Chase Cancer Center in Philadelphia, who was not involved in the new study. Dr. Chen, who performs salvage cryotherapy for recurrent PCa, pointed out that the benchmark against which the procedure is compared—salvage radical prostatectomy—has similar rates of success and also has relatively

limited data to support its use. “While there is controversy regarding the role and effectiveness of salvage cryoablation, I think this article [by Dr. Spiess and colleagues] does support it, and the quality of the data for this study is comparatively as good if not better data than what exist supporting salvage radical prostatectomy,” Dr. Chen, Associate Professor of Surgical Oncology at Temple University School of Medicine in Philadelphia, told Renal & Urology News. He added that the data for salvage radical prostatectomy are primarily from single institution retrospective studies, whereas the study by Dr. Spiess’s group was based on pooled multicenter, prospectively collected data. n

Inflammation predicts a lower risk of bladder cancer recurrence.

sion rates were 5%, 8%, and 61%, respectively. The mean recurrence-free survival times were significantly longer in the inflammation and granuloma groups than the normal histology group (56 and 65 months, respectively, vs. 20 months). The mean progressionfree survival times were significantly higher in the inflammation and granuloma groups than the normal histology group (82 and 75 months, respectively, vs. 33 months). “In the absence of inflammation or granuloma, the risk

of recurrence and progression is significantly higher,” Dr. Jallad’s group wrote. “This necessitates a closer surveillance policy or perhaps a low threshold for alternative therapy. The practice of random biopsies after BCG

therapy could help in establishing whether inflammation or granuloma is present, which could act as a prognostic marker.” Dr. Jallad’s group noted that the mechanism by which BCG exhibits its anti-tumor effects is not fully understood. It is believed that an immune response develops in the bladder wall that ultimately clears the cancer or prolongs recurrence- or progression-free survival. “This hypothesis is supported by the findings of the present series,” they observed. n

ate resource allocation and policy regarding coverage may require reassessment.” Despite some study limitations, the investigators noted, “the novel finding of a significantly more progressive and less responsive course for ED in men with DM argues for earlier and pos-

sibly more aggressive interventions in men with DM.” For the study, Dr. Walsh’s group used insurance claim data to identify men with ED and followed claims for 48 months. “Claims-based data analysis allows us to single out men with severe ED by assessing their use of sequen-

tially more invasive therapeutic modalities,” the authors stated. “This makes it a potentially innovative tool for examining the progression of ED over time and the severity of ED in different subpopulations of men without the need for expensive urology or ED-specific longitudinal cohort studies.” n

Systemic Opioids Pre-RP May Offer Advantages SUPPLEMENTING general anesthesia with a longacting spinal or epidural painkiller during radical prostatectomy (RP) may reduce patients’ need for postoperative opioids and improve oncologic outcomes, according to a large retrospective study. Opioids are commonly given to patients during and after surgery, but because they are immunosuppressive, systemic opioids can promote tumor recurrence, Juraj Sprung, MD, PhD, of Mayo Clinic in Rochester, Minn., and colleagues explained. The investigators sought to determine whether supplementing general anesthesia with neuraxial analgesia would improve the long-term oncologic outcomes of men undergoing RP.

RUN0214_Cover_URO.indd 2

As the researchers described online ahead of print in the British Journal of Anaesthesia, they used the Mayo Clinic’s prostatectomy registry to identify 1,642 patients who had general anesthesia with neuraxial analgesia during RP, with surgery taking place from January 1991 through December 2005. These patients were then matched on a 1:1 basis with men who received general anesthesia only during the same type of surgery, with matches made according to age, surgical year, pathological stage, Gleason scores, and presence of lymph node disease. Reports of cancer recurrence, cancer metastasis, and death were confirmed with the patients’ physicians. Patients had a median follow-up of nine years.

The administration of general anesthesia alone was associated with a 2.8 times increased risk for systemic progression and a 32% increased risk of death, after adjusting for comorbidities, positive surgical margins, and adjuvant hormonal and radiation therapies within 90 postoperative days. “We found a significant association between this opioid-sparing technique, reduced progression of the prostate tumor, and overall mortality,” Dr. Sprung said in a Mayo Clinic statement. “Provided future studies confirm what we’ve found in this study, maybe down the line this would be a standard of care for pain management in persons undergoing cancer surgery.” n

1/23/14 11:12 AM


www.renalandurologynews.com  FEBRUARY 2014 

Renal & Urology News 9

ESRD Increases Post-Op In-Hospital Mortality END-STAGE renal disease (ESRD) at the time of admission to a surgical intensive care unit (ICU) is independently associated with an increased risk of inhospital death, according to researchers. That conclusion is based on retrospective analysis of prospectively gathered data from 12,938 patients admitted to a 50-bed surgical ICU from January 2004 to January 2009. Of these, 199 (1.5%) had ESRD at admission. They had higher ICU and hospital mortality rates compared with patients without ESRD (23.1% and 31.2% vs. 5.5% and 10.0%, respectively), Mareike Apel, MD, of Friedrich-Schiller-University Hospital in Jena, Germany, and colleagues reported online ahead of print in Critical Care. At ICU admission, the ESRD patients had higher disease severity scores and a higher incidence of diabetes mellitus and cirrhosis than patients without ESRD. In addition, the ESRD patients had significantly higher rates of organ failure at ICU admission and during the ICU stay. For

example, during the ICU stay, cardiovascular and hematologic failure occurred in 72.4% and 21.6% of the ESRD patients, respectively, compared with 49.2% and 4.5% of the patients without ESRD. Hepatic failure occurred in 12.1% of the ESRD patients compared with 3.0% of the patients without ESRD. The ESRD

patients also had a significantly more days in the ICU (median 2 vs. 1). In multivariable analysis, ESRD was independently associated with a nearly fourfold increased risk of in-hospital death, after adjusting for age, gender, comorbidities, and other potential confounders.

“The poor outcome in ESRD patients is probably multifactorial,” the investigators explained. “These patients most likely lack physiological reserve, as is evident from the high severity of illness and the associated comorbid conditions on admission to the ICU.” n

WE’RE

CHANGING THE WAY

PROSTATE CANCER PATIENTS ARE TREATED EVEN WHEN THEY’RE NOT BEING TREATED

Frailty Ups Risk of MIS Complications

When it comes to treating prostate cancer, we do not believe in a one-size-fits-all approach. That’s why doctors at UPMC are experts in both traditional methods of urologic surgery and in

PREOPERATIVE frailty increases the

cutting-edge robotic surgery. But our doctors also recognize

likelihood of postoperative complica-

when the best management is not an operation, but careful

tions among patients undergoing

observation. We believe it is important to be well versed in

minimally invasive surgery (MIS),

all options to ensure patients receive the right treatment at

researchers reported online ahead of

the right time. Because our job is not only to save lives, but

print in the Journal of Endourology.

to preserve the quality of life of every patient we treat. Learn

A research team studied 80 patients

more at UPMCPhysicianResources.com/ProstateCancer.

undergoing MIS. The patients had presented to urology, surgical oncology, and general surgery clinics. Of these, 13 were considered intermediately frail or frail. Thirteen patients experienced postoperative complications: five intermediately frail and frail patients (38.5%) compared with eight not frail patients (11.9%). “The advent of MIS has potentially lured surgeons into thinking older [patients] and patients with comorbidities may more easily tolerate this surgical approach compared with traditional open techniques,” the investigators concluded. “Our data suggest, however, that intermediately frail or frail patients are at increased risk of expeUPMC is affiliated with the University of Pittsburgh School of Medicine.

riencing postoperative complications compared with not frail patients.” n 2145_UPMC_Urology_7x10.indd 1

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8/21/13 11:41 AM

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10 Renal & Urology News 

FEBRUARY 2014 www.renalandurologynews.com

News in Brief

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

Short Takes Diabetes Increases PCa Mortality

which was performed by Giovanni

Men with type 2 diabetes are at

Corona, MD, of Maggiore-Bellaria

increased risk for death from

Hospital in Bologna, Italy, showed that

prostate cancer (PCa) or from any

hyponatremia was associated with a

cause, Canadian researchers reported

significant 2.6 times increased risk of

online ahead of print in Cancer Causes

death. The mean difference in serum

& Control.

sodium level between those who

The meta-analysis of 81 studies,

died and those who did not was

A team led by Laurent Azoulay, MD, of McGill University in Montreal,

4.8 mmol/L. Additional analyses re-

studied 11,920 men newly diagnosed

vealed that hyponatremia-related risk

with non-metastatic PCa. The cohort

of all-cause mortality was inversely

included 1,132 men (9.5%) with

correlated with serum sodium level.

pre-existing type 2 diabetes. 1,792 from PCa, occurred during

RCC Cryoablation Highly Efficacious

a mean 4.7 years of follow-up.

Computed tomography (CT)-guided

Compared with non-diabetics, men

percutaneous cryoablation for early-

with type 2 diabetes had a 23%

stage renal cell carcinoma (RCC) is

increased risk of PCa mortality

highly efficacious and has a favorable

and 25% increased risk of all-

safety profile, researchers reported

cause mortality, after adjusting for

online ahead of print in Cardiovascu-

potential confounders.

lar and Interventional Radiology.

Moderate Hyponatremia Increases Death Risk

with biopsy-proven RCC using CT-

Even moderate hyponatremia

tumor size was 2.8 cm. The five-year

declines are associated with an

cancer-specific and overall survival

increased risk of death, according to

was 100% and 97.8%, respectively.

a recent meta-analysis published in

No patient experienced metastatic

PLoS One (2013;8[12]:e80451).

disease during follow-up.

A total of 3,605 deaths, including

Researchers treated 134 patients guided cryotherapy. The median

Anticipated Retirement In a recent online poll, Renal & Urology News asked nephrologists and urologists, “When do you hope to retire?” Here are the results based on 330 responses:

n

Before 60

n

65

n

66-70

n

71-75

n

76+

n

I’m already retired

14.85% 23.03% 31.82% 14.55% 13.94%

RUN0214_NewsBrief.indd 10

2%

Nitrates Prior to PCI May Decrease CIN Risk N

itrate administration prior to percutaneous coronary intervention (PCI) may decrease patients’ risk of contrast-induced nephropathy (CIN), according to the findings of a retrospective single-center study. Julio G. Peguero, MD, and colleagues at the Mount Sinai Heart Institute in Miami Beach, reviewed data from 199 patients who underwent PCI. The researchers compared post-procedure renal function between 112 patients who received nitrates prior to PCI and 87 who did not. The two groups were similar with respect to baseline characteristics. The investigators defined CIN as a 25% or 0.5 mg/dL or greater increase in serum creatinine during the first 48-72 hours after contrast exposure. CIN developed in 15.2% of patients who received nitrates compared with 29.9% of those who did not, a significant difference between the groups, the investigators reported online ahead of print in the Journal of Cardiovascular Pharmacology and Therapeutics. Further analysis showed that nitrate use was independently associated with a significant 67% reduced risk of CIN.

Higher Aspirin Doses May Cut PCa Mortality M

en who take aspirin doses above 75 mg have a significantly reduced risk of death from prostate cancer (PCa) compared with men who do not take aspirin, according to a recent study. The risk is not reduced in men taking lower doses. Irish researchers led by T. Ian Barron PhD, of the University of Dublin identified 2,936 men diagnosed with localized PCa, of whom 1,131 were aspirin users. Patients were followed up for a median of 5.5 years. In adjusted analyses, aspirin use overall was associated with a non-significant 12% decreased risk of PCa-specific mortality compared with non-use, the researchers reported in the Annals of Oncology (2014;25:154-159). When stratified by dose, men taking aspirin doses greater than 75 mg had a significant 39% decreased risk of PCa-specific mortality compared with men not taking aspirin.

Uterine Radiotherapy Raises Bladder CA Risk U

se of radiation therapy for uterine cancer appears to increase a woman’s risk for later development of, and death from, bladder cancer, researchers reported online ahead of print in BJU International. In a retrospective cohort study, Janet E. Baack Kukreja, MD, of Strong Memorial Hospital, University of Rochester Medical Center in Rochester, N.Y., and colleagues analyzed data from 56,681 women diagnosed with uterine cancer as their first primary malignancy from 1980 to 2005. Follow-up for incident bladder cancer ended on December 31, 2008. Of 15,726 women who had undergone radiation therapy for uterine cancer, 146 (0.93%) subsequently were diagnosed with bladder cancer over a mean follow-up of 15 years, compared with 197 of 40,955 women (0.48%) with uterine cancer who had not received radiation therapy. Fatal bladder cancer occurred in 39 (0.25%) of the women whose uterine cancer had been managed with radiation therapy, compared with 36 (0.09%) of the women with uterine cancer who had not undergone radiation therapy.

1/23/14 11:28 AM


www.renalandurologynews.com  FEBRUARY 2014 

Renal & Urology News 11

Nocturia Linked to Low Melatonin Study of elderly individuals shows an inverse relationship between melatonin secretion and nocturia LOW melatonin levels are associated with an increased likelihood of nocturia in elderly individuals. “Enhancing endogenous melatonin levels may be a preventive and therapeutic option for nocturia,” researchers concluded. Kenji Obayashi, MD, and collaborators at Nara Medical University School of Medicine in Nara, conducted a cross-sectional study that enrolled 861 community-dwelling elderly individuals who had a mean age of 72 years. The investigators measured subjects’ nocturnal void frequency and overnight urinary 6-sulfatoxymelatonin excretion (UME), a marker for melatonin secretion. Of the 861 subjects, 261 suffered from nocturia—defined as two or more nocturnal voids—and 600 did not. After adjusting for confounding factors, Dr. Obayashi’s group found that higher UME levels were significantly associated with a decreased likelihood for nocturia. An increase in URE from 4.0 to 10.0 μg (from the 25th to 75th per-

Metformin May Benefit CRPC Patients METFORMIN MAY benefit patients with metastatic castration-resistant prostate cancer (CRPC), according to a report published online ahead of print in European Urology. In a study conducted by Christian Rothermundt, MD, Kantonsspital St. Gallen in St. Gallen, Switzerland, and colleagues, 44 men with metastatic CRPC received metformin 1,000 mg twice daily until disease progression.

centile) was associated with a 24.7% decrease in prevalent nocturia, the researchers reported online ahead of print in The Journal of Urology. In addition, in adjusted analyses, the mean volume of single voided urines increased significantly with tertiles of UME. “To the best of our knowledge, our results provide the first evidence that endogenous melatonin is significantly and inversely associated with nocturia independent of confounding factors in a general elderly population with a large sample of males and females,” the authors wrote. In analyzing their findings, the researchers adjusted for age, gender, body mass index, estimated glomerular filtration rate, benign prostatic hyperplasia, duration in bed, and other potential confounders. Secretion of melatonin, a pineal gland hormone, follows a diurnal rhythm, with almost all production at night, Dr. Obayashi’s team explained. “Endogenous melatonin has inhibitory

effects on smooth muscle contractility of the mammalian bladder. Thus, melatonin may play a key role in nocturnal regulation of voids.” Previous clinical studied have suggested that exogenous melatonin or its agonist decreases nocturia episodes. For example, a placebo-controlled study of melatonin treatment for noc-

Increasing secretion of this hormone may prevent and treat the condition. turia in men with benign prostatic hyperplasia found that oral administration of 2 mg of controlled-release melatonin at night was associated with a significant nocturia response rate and improvement in nocturia-related bother, according to a report in The Journal of Urology (2004;171:1199-1202). The melatonin also had a good adverse

effect profile. “However, it is uncertain whether the observed changes in this study are clinically significant,” the researchers concluded. In another study, researchers at the University of the Ryukyus in Okinawa, Japan randomized 42 elderly patients with nocturia to receive either melatonin 2 mg/day (20 patients) or rilmazafone 2 mg/day (22 patients). After four weeks of treatment, the number of nocturnal urinations was significantly decreased and quality-of-life significantly improved in both groups, investigators reported in The Journal of International Medical Research (2007;35:685-691). Patient-reported effectiveness ratings did not differ significantly between treatment arms. The serum melatonin level increased significantly in the melatonin recipients, but remained unchanged in the rilmazafone-treated group, “suggesting that the decrease of nocturnal urination after treatment with rilmazafone did not depend on serum melatonin level,” the authors noted. n

Physical Activity Lessens eGFR Loss IN A recent study, patients with chronic kidney disease (CKD) who engaged in higher levels of physical activity exhibited slower declines in estimated glomerular filtration rate (eGFR). “This study demonstrated that even small amounts of physical activity, such as walking 60 minutes per week, might slow the rate of kidney disease progression,” explained study coauthor Cassianne Robinson-Cohen, PhD, of the Kidney Research Institute at the University of Washington in Seattle, in a statement from the American Society

of Nephrology that accompanied the release of the findings. “Physical inactivity is emerging as one of the few risk factors for kidney disease progression that is amenable to intervention.” Dr. Robinson-Cohen and her colleagues performed a longitudinal cohort study involving 256 participants from the Seattle Kidney Study, a clinic-based study of CKD. The researchers restricted the study population to patients who had the capacity to exercise and then adjusted for known and measured characteristics associated with eGFR decline.

During a median follow-up of 3.7 years, the mean baseline eGFR of 42 mL/ min/1.73m2 fell by 7.6% per year as determined by longitudinal measurements of serum cystatin C. Patients who reported being physically active for more than 150 minutes per week had the lowest rate of eGFR loss, with annual decreases of 6.2% per year, compared with eGFR decreases of 9.6% per year among inactive patients. In adjusted analyses, eGFR declined 0.5% more slowly with each one-hour increment in duration of weekly physical activity. n

High Ferritin Ups Infection Risk in KT Patients

The primary endpoint was the absence of disease progression at 12 weeks. Results showed that 36% of patients were progressionfree at 12 weeks and 9.1% were progression-free at 24 weeks. Research showed a 50% or greater PSA decline in two patients. n

RUN0214_Melatonin.indd 11

ELEVATED ferritin levels in kidney transplant (KT) recipients are associated with an increased risk of infection in the early post-transplant period, researchers reported in Transplant Infectious Disease (2013;15:600-611). The researchers prospectively studied 228 patients undergoing kidney transplantation and analyzed various

iron parameters within the first two weeks after transplantation and before the occurrence of the first infectious episode. Patients with ferrtin levels above 500 ng/mL had higher incidence rates of overall, bacterial, and bloodstream infection during the first posttransplant year. Multivariate analysis showed that ferritin was an indepen-

dent predictor of overall and bacterial infection. “Monitoring of serum iron parameters in the early post-transplant period may be useful in predicting the occurrence of infection in KT recipients, although further studies should be carried out to confirm this preliminary finding,” the authors concluded. n

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12 Renal & Urology News 

FEBRUARY 2014 www.renalandurologynews.com

NMIBC Pts Need Longer Follow-Up In a study, bladder tumors recurred in 14.5% of patients following a five-year tumor-free period PATIENTS with low-grade non-muscleinvasive bladder cancer (NMIBC) may require routine follow-up for as long as 10 years from the initial diagnosis, according to Japanese investigators. In a retrospective study of 190 patients (mean age 62.9 years) who underwent transurethral resection for NMIBC, 82 patients (43.2%) had tumor recurrence and 21 (11.1%) had worsening progression (WP) after a median follow-up of 101.5 months, Hiroaki Kobayashi, MD, and colleagues at Keio University School of Medicine in Tokyo reported online in BMC Urology. The average time to WP was 82.4 months. Eleven patients (14.5%) experienced late recurrence, defined as recurrence after being tumor-free for more than five years from initial transurethral resection. Of these, five (6.6%) experienced late WP. Patients experienced late recurrence and late WP after an average of 103.5 and 104.5 months, respectively, after surgery. The authors noted that about 50%-

Sleep Apnea Therapy Eases Resistant HTN INDIVIDUALS who suffer from obstructive sleep apnea and have high blood pressure (BP) that cannot be controlled with fewer than three medications may be able to address both conditions with continuous positive airway pressure (CPAP) therapy.. More than 70% of people with resistant hypertension have obstructive sleep apnea, and CPAP treatment may reduce blood pressure, but the effect of CPAP therapy on BP in patients with resistant hypertension has not been well-studied. CPAP treatment, which is commonly administered to manage obstructive sleep apnea, a machine delivers mild air pressure through a mask worn during sleep to help keep the airways open. Miguel-Angel Martinez-Garcia, MD, PhD, of the Hospital Universitario y Politecnico La Fe, in Valencia, Spain, and colleagues have found that 12 weeks of CPAP treatment reduced 24-hour mean and diastolic BP and improved the nocturnal BP pattern in patients with resistant hypertension and an apnea-hypopnea index of 15 or higher, according to

RUN0214_BladderCa.indd 12

70% of patients with NMIBC experience recurrence within five years after treatment and 5%-20% progress to invasive tumors. Solitary and multiple tumors were present in 114 and 76 patients, respectively. The five-year recurrence-free and WP-free survival rates were significantly greater for patients with solitary rather than multiple tumors (68% vs. 45.9% and 97.2% vs. 85.5%, respectively). Compared with patients who had solitary tumors, those with multiple tumors had a threefold increase risk of recurrence and a fivefold increased risk of worsening progression. In addition, the absence of intravesical instillation was associated with a threefold increased risk of recurrence. No patient died from bladder cancer during follow-up, the investigators reported. The researchers defined recurrence as the occurrence of a new tumor in the bladder and worsening progression as 1)

a report in the Journal of the American Medical Assocation. Dr. Martinez-Garcia’s team randomized 194 patients throughout 24 teaching hospitals in Spain to CPAP or no therapy. All patients continued using their usual antihypertensive medications (mean 3.8 medications). Approximately threefourths (72.4%) of the patients assigned to CPAP underwent the treatment for at least four hours per day. Baseline 24-hour mean BP was 103.4 mm Hg; systolic BP, 144.2 mm Hg; and diastolic BP, 83 mm Hg. Nearly 26% of patients displayed a dipper pattern (a decrease of at least 10% in average nighttime BP compared with the average daytime BP at baseline. The mean apneahypopnea index was 40.4. Data were collected from June 2009 to October 2011. After 12 weeks of treatment, the 98 patients in the CPAP group achieved a greater decrease in 24-hour mean BP (3.1 mm Hg) and in 24-hour diastolic BP (3.2 mm Hg), but not in systolic BP compared with the 96 patients in the control group. Also, 35.9% of the CPAP users exhibited a nocturnal BP dipper pattern at the 12-week mark compared with just 21.6% of the control group. The investigators noted significant positive correlation between hours of CPAP use and the decrease in 24-hour mean BP and systolic and diastolic BP. n

Multiple Tumors Worsen Outcomes A study of patients with non-muscle-invasive bladder cancer showed that five-year recurrencefree and worsening progression-free survival rates are lower in those with multiple rather than solitary tumors. Source: Kobayashi H et al. Long term follow-up in patients with initially diagnosed low grade Ta non-muscle invasive bladder tumors: tumor recurrence and worsening progression. BMC Urology (published online ahead of print).

n Recurrence-free survival n Worsening progression-free survival 97.2%

100

85.5%

80

68%

60

45.9%

40

20

0

Solitary tumors

confirmed high-grade Ta, all T1, or Tis/ concomitant carcinoma in situ of bladder recurrence, 2) upper urinary tract recurrence, or 3), progression to T2 disease or greater. Of the 190 patients, 71 (37.4%) and 12 (6.3%) received intravesical BCG and mitomycin C, respectively. Contrary to the findings of previ-

Multiple tumors

ous studies, the investigation by Dr. Kobayashi’s group found no association between smoking status and recurrence rate, WP rate, or late recurrence rate. One reason for their negative result, they noted, is the relatively lower percentage of smokers and lesser amount of smoking in Japanese NMIBC populations. n

Racial Disparity in CKD Linked to Gene Variants NEW RESEARCH suggests that the

CKD attributed to hypertension, and in

higher rates of end-stage renal disease

2,955 black or white CRIC participants

(ESRD) and progression of chronic

with CKD, 46% of whom had diabetes.

kidney disease (CKD) seen in black

Patients were evaluated according to

patients compared with white patients

whether they had two copies of high-

are linked to renal risk variants in

risk APOL1 variants (APOL1 high-risk

the gene encoding apolipoprotein 1

group) or zero or one copy (APOL1

(APOL1).

low-risk group).

The findings emerged from two

The primary outcome in the AASK

large National Institutes of Health-

study was a composite of ESRD or

funded study cohorts: the African

a doubling of serum creatinine level.

American Study of Kidney Disease and

This outcome occurred in 58.1% of the

Hypertension (AASK) and the Chronic

APOL1 high-risk group and in 36.6% of

Renal Insufficiency Cohort (CRIC).

the APOL1 low-risk group.

Dominic S. Raj, MD, of George

In the CRIC study, the primary out-

Washington University in Washington,

comes were the slope in the estimated

DC, and fellow investigators

glomerular filtration rate (eGFR) and the

acknowledged in their report for The

composite of ESRD or a reduction of at

New England Journal of Medicine

least 50% in the eGFR from baseline.

(2013;369:2183-2196) that among

Black patients in the APOL1 high-risk

U.S. patients with CKD, black patients

group had a faster decline in eGFR

are at higher risk for ESRD than white

and a higher risk of the composite

patients. The researchers examined

renal outcome than did white patients,

the effects of variants in APOL1 in

among those with diabetes and among

693 black AASK participants with

those without diabetes. n

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www.renalandurologynews.com  FEBRUARY 2014 

Renal & Urology News 13

Focus on Membranous Nephropathy The Membranous Nephropathy Trial of Rituximab (MENTOR) study is poised to change first-line-treatment recommendations for idiopathic membranous nephropathy. Daniel C. Cattran, MD, FRCP(C), senior scientist at Toronto General Research Institute, part of the University Health Network based in Toronto, is leading the study along with recent Renal & Urology News “Expert Q&A” ­interviewee Fernando C. Fervenza, MD, PhD. Dr. Cattran explains why MENTOR may yield significant findings. How prevalent is membranous nephropathy?

Dr. Cattran: Membranous nephropathy remains the most common cause of adult-onset nephrotic syndrome. However, it still fulfills the definition of an orphan disease, with an annual incidence of less than 5/100,000 population. Is idiopathic membranous nephropathy a difficult diagnosis to make?

Dr. Cattran: Because idiopathic membranous nephropathy means that no specific cause of the process can be determined, it is therefore considered to be a diagnosis of exclusion—i.e., you must rule out secondary causes. Since many of the known causes for the membranous pattern of injury have completely different approaches to treatment, it is essential that the practitioner make the correct diagnosis. Although the histologic diagnosis of membranous nephropathy can be made on kidney biopsy tissue alone, ruling out secondary causes requires additional thorough investigation. Some of the known secondary causes are systemic lupus erythematosus, certain drugs, and, perhaps most worrisome, malignancies. How can nephrologists recognize this condition?

Dr. Cattran: The great majority of patients present with the clinical features of the nephrotic syndrome,

On The Web RUN0214_QA.Cattan.indd 13

including edema, proteinuria, hypoalbuminemia, and hyperlipidemia. About 25% of patients present with only proteinuria and are otherwise asymptomatic. This proteinuria is often found on routine examinations of the urine done by the patient’s family doctor or for insurance purposes. The actual diagnosis of membranous nephropathy, a specific pattern of tissue injury, can only be made on examination of the renal tissue through biopsy.

and I are the two principal investigators of this trial. We are testing in an open-label, randomized controlled trial whether rituximab is non-inferior to the calcineurin inhibitor cyclosporine in inducing and maintaining a remission of the nephrotic syndrome in patients with idiopathic membranous nephropathy. What is the current gold standard for treatment and/or management?

Dr. Cattran: The KDIGO [Kidney Disease: Improving Global Outcomes] guideline in glomerulonephritis was published as a supplement in Kidney International Supplements [2012;2(2)]. The number-one recommendation for treatment of MGN in this guideline was the use of a six-month cycling routine alternating a cytotoxic drug (cyclophosphamide or chlorambucil) with corticosteroid therapy. In large part this was number one because the evidence at 10-year follow-up is better defined using this therapy than it is with the other number-one recommendation, a calcineurin inhibitor such as cyclosporine. The latter is the more

Can nephrologists avert or minimize membranous nephropathy in these patients?

Dr. Cattran: At this point there is no way to avert the condition. The natural history of the idiopathic form of MGN—membranous glomerulonephritis, which is another name for membranous nephropathy—is quite distinct. Approximately one third of patients will have a spontaneous remission, most of these occurring within the first two years after presentation. Another third of patients will have persistent low-grade proteinuria but long-term preservation of glomerular filtration function—that is, normal serum creatinine. The remaining third tends to have a higher grade of proteinuria than the other two groups and can have either slow, or rarely rapid, progression to renal failure over the course of years. What is your role in the study?

Dr. Cattran: Dr. Fernando Fervenza of the Mayo Clinic [Rochester, Minn.]

commonly used first-line therapy in the United States and Canada, whereas the former routine is favored in Europe. This preference in the United States and Canada is largely because of the concerns about both the short- and long-term side-effect profile of the cytotoxic agents as well as the rather high-dose steroid exposure, especially considering the increasing age of presentation of the MGN population. Why are you evaluating the effectiveness of rituximab?

Dr. Cattran: Our experience to date suggests that the initial response based on randomized controlled trials of the calcineurin inhibitors and several small but non-randomized pilot studies of rituximab have similar response rates in terms of proteinuria in MGN patients. However, there are certain advantages of rituximab in terms of adherence (given as an intravenous infusion) and side-effect profile that are distinctly different from cyclosporine. In addition, preliminary evidence suggests that the maintenance of remission might be significantly more prolonged with rituximab versus the calcineurin inhibitor, which would be a major advance in the management of these patients. So these findings could change membranous nephropathy therapy?

Rituximab may become the number one drug for this disease. ­— Daniel C. Cattran, MD

Dr. Cattran: Yes; we firmly believe that this could change the treatment landscape of idiopathic membranous nephropathy. We will be combining the therapeutic testing of these two agents with certain basic scientific studies, including serial measurement of the autoantibody. We consider that if our theory is correct, rituximab could become the number-one drug therapy for this disease process given its advantages listed above, at least in patients who are at high risk of progression to renal failure (the only ones who are eligible for our study). n [Editor’s note: Eligibility criteria and other MENTOR trial information are available at http://clinicaltrials.gov/ct2/ show/NCT01180036.]

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

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14 Renal & Urology News 

FEBRUARY 2014 www.renalandurologynews.com

Transperineal Biopsy Trumps TRUS It should be the gold standard in men with two negative TRUS-guided biopsies and rising PSA BY DELICIA HONEN YARD TRANSPERINEAL template prostate biopsy (TPTPB) identifies tumors of a smaller size and earlier stage than transrectal ultrasound (TRUS)-guided biopsy, suggesting that TPTPB may be a far more ideal diagnostic test for localized prostate cancer (PCa), researchers reported online ahead of print in the World Journal of Urology. Shady Nafie, MRCS, of the Department of Urology at Leicester (U.K.) General Hospital and colleagues. As Nafie and his team noted in their report, the possibility of PCa as a cause for steadily rising PSA levels despite previously negative TRUS-guided prostate biopsies is a major concern. The researchers reviewed the records of 122 men who had undergone 36-core TPTPB following two previous sets of negative TRUSguided biopsies despite raised PSA levels. The patients, aged 49-77 years (mean age 63 years), had a mean PSA

Sex Life Is Okay for Most Women on HD MOST women on chronic hemodialysis (HD) are satisfied with their sex life—including women who are not interested in sex. This study, led by Steven D. Weisbord, MD, MSc, of the Veterans Affairs Pittsburgh Healthcare System, involved 125 women on HD who completed a total of 1,721 assessments between 2009 and 2011 regarding their sex life. As Dr. Weisbord and colleagues explained in an online report in the Clinical Journal of the American Society of Nephrology, research has shown sexual dysfunction to be common among women undergoing chronic HD, but those studies did not differentiate between sexual dysfunction/difficulty and sexual inactivity. Dr. Weisbord’s group separated these measures to determine the prevalence of true sexual dysfunction among women receiving chronic HD. Female sexual function was prospectively assessed for six months and quarterly thereafter as part of a clinical trial of symptom management strategies in patients undergoing chronic HD.

RUN0214_pcaBiopsies.indd 14

level of 18.0 ng/mL (range 2.0-119.0 ng/ mL) at the time of TPTPB. This was higher than the mean PSA level of 14.0 ng/mL (range 1.4-122.0 ng/mL) at the time of previous TRUS-guided biopsy. An average of 24 months (range 2-228 months) had elapsed between the last TRUS-guided biopsy and the TPTPB, with mean PSA velocity of 2.3 ng/mL per year (range 0 to 33.6 ng/mL). More than half the men (71, or 58%) received a PCa diagnosis on TPTPB: • 28 (39%) had a Gleason score of 6 • 34 (48%) had a Gleason score of 7 (3 + 4) • 5 (7%) had a Gleason score of 7 (4 + 3) • 4 (6%) had a Gleason score of 9 (4 + 5). The mean number of positive cores was 7 (range 1–22), with only 15 men (21%) having three or less positive cores and a Gleason score of 6. As seen in previous studies, a high proportion of

To gather information, Dr. Weisbord and colleagues added questions to the Female Sexual Function Index that distinguished sexual dysfunction/difficulty from sexual inactivity. Beginning in month 7 and on a monthly basis thereafter, patients were asked three questions about sexual activity, difficulty, and satisfaction. Answers on 89% of the quarterly assessments were consistent with sexual dysfunction—largely due to sexual activity, which was reported on 82% of the quarterly assessments. Lack of interest in sex and lack of a partner were the most frequently described reasons for inactivity, reported in 715 (43%) and 647 (39%) of 1,663 responses. Sexual difficulty, however, was rarely reported, cited in only 36 (2%) of responses. Women were moderately to very satisfied with their sexual life in 1,020 of 1,582 assessments (64%) and in 513 of 671 (76%) assessments in which lack of interest was a reason for sexual inactivity. “Sexual inactivity is particularly common yet does not appear to be bothersome to many women on dialysis,” Dr. Weisbord pointed out in a statement from the American Society of Nephrology. “Carefully considering patients’ perspectives and preferences is essential to evaluating the presence and importance of a condition like sexual dysfunction.” n

Shady Nafie, MRCS

cancer-containing biopsies were located in the anterior zone of the prostate, with nearly 50% of cancer-containing cores found in that region. Nafie’s group pointed out that because the anterior zone of the prostate is poorly

sampled during TRUS-guided biopsy, the high proportion of anterior tumors is to be expected. However, despite the fact that TRUS-guided biopsy is able to sample posterior tumors adequately and all patients had had two previous sets of TRUS-guided biopsies, a substantial number of tumors (20%) identified on TPTPB were located in the posterior zone of the gland. Of the 51 men (42%) with a nonmalignant diagnosis on TPTPB, 11 (22%) had atypical small acinar proliferation, 10 (19%) had high-grade prostatic intraepithelial neoplasia, and 30 (59%) had benign pathology. The investigators concluded that TPTPB should be regarded as the goldstandard test in men with two sets of negative TRUS-guided biopsies and rising PSA levels, and that consideration must be given to performing TPTPB in men with one negative TRUS biopsy in whom cancer is suspected. n

More Kids Having Minimally Invasive Nephrectomy USE OF minimally invasive nephrectomy

most common in children aged 0-1 year

is expanding in the pediatric population,

(36%), and least common among those

according to investigators.

aged 6-9 years (14%). Children aged

“At the time we began our research

3-4 years underwent nephrectomy for

project, little was known about the

malignancy more often than children in

usage of laparoscopic or robotic kidney

other age groups.

removal in pediatric patients, although

Although open nephrectomy still

many studies have been done about mini-

accounts for more than 85% of pediatric

mally invasive kidney surgery in adults,”

nephrectomies, the use of minimally

noted senior study author Jack S. Elder,

invasive nephrectomy rose from 1.1% to

MD, Chief of Pediatric Urology at the

11.6% over the study period.

Vattikuti Urology Institute of the Henry

Increasing age, treatment at a

Ford Health System in Detroit, in a pre-

teaching institution, and increasing

pared statement issued by Henry Ford.

hospital volume all were associated

“As we expected, the use of [minimally

with greater use of minimally invasive

invasive nephrectomy] in children, like in

nephrectomy.

the adult population, is on the rise.”

Minimally invasive nephrectomy is argu-

Dr. Elder and colleagues evaluated

ably the current gold-standard treatment

national data on approximately 27,615

for renal tumors requiring kidney removal

children who underwent nephrectomy

in adults, but this is not the case for

between 1998 and 2010. The annual

children, according to Vattikuti’s Jesse D.

incidence of pediatric nephrectomy

Sammon, DO, lead author of the study.

was 2.90/100,000 patients per year,

Because open incisions are smaller in

and remained stable, the researchers

pediatric patients than in adult patients,

reported online ahead of print in the

children suffer less pain and blood loss

Journal of Urology. The operation was

from the open-nephrectomy approach. n

1/23/14 11:36 AM


www.renalandurologynews.com  FEBRUARY 2014 

■ NKF 2014, Las Vegas

Renal & Urology News 15

The article below is a preview of a talk scheduled for presentation at the National Kidney Foundation Spring Clinical Meetings.

Non-Medical Therapies for Stones BY SIMON L. CONTI, MD, AND BENJAMIN I. CHUNG, MD Editor’s note: Dr. Chung will be holding a workshop on this topic at the National Kidney Foundation’s 2014 Spring Clinical Meetings, April 22-26, at the MGM Grand in Las Vegas. For more information, visit www.nkfclinicalmeetings.org.

THE SURGICAL treatment of urolithiasis has undergone a marked evolution over the past 30 years Surgical treatments have evolved from maximally invasive open stone surgery to minimally invasive techniques including ureteroscopy (URS), extracorporeal shock wave lithotripsy (ESWL), and percutaneous nephrolithotomy (PCNL). As technology in fiber optics, miniaturization, and imaging has evolved alongside improvements in lithotripsy (laser, ultrasonic, and hydraulic), rendering patients stone free with minimal morbidity has become the standard of care. All are outpatient procedures except PCNL. In acute clinical situations, intervention is indicated in those patients presenting with urosepsis, renal failure, bilateral obstruction, or intractable pain. In most cases, a stent composed of a flexible polymer is placed from the kidney to the bladder within the lumen of the ureter, using cystoscopy and fluoroscopy, to bypass the obstruction. Manipulation of stones in the setting of infection is contraindicated, as high-pressure irrigation and lithotripsy will induce bacteremia and urosepsis. Therefore, infected stones are left in place and treated electively after stenting. In cases where acute intervention is indicated and infection has been excluded, URS can be performed. In non-acute clinical situations, the treatment modality is based on stone size, location, number, density, body habitus, and patient preference. Treatment goals are rendering the patient stone free with the minimum amount of morbidity. ESWL delivers a shock wave through the skin and surrounding tissues to focus on the stone and subsequently

RUN0214_NKF.KidneyStones.indd 15

fragment it. The shock wave is delivered with image guidance, either fluoroscopy or ultrasound, though most use fluoroscopic guidance, presenting a challenge for stones that are radiolucent. Classic ESWL generators use electrohydraulic energy to pulverize the stone. These machines offer the greatest efficacy but least amount of control of both pulse focus and energy delivery. More modern lithotripters use electromagnetic generators that emit cone-shaped shock waves that concentrate on the stone but spread onto a greater surface area of the skin, causing less pain. Both of these generators require general anesthesia, due to the pain with increasing shockwave energy. General anesthesia also allows for timed breathing, limiting excursion of the kidney during shock wave delivery that decreases damage

URS can be used for both ureteral and kidney stones. The ureter is accessed via a small-caliber endoscope. Distal stones can be visualized and treated with semirigid ureteroscopes, whereas stones above the distal third of the ureter are usually treated using a flexible ureteroscope. When using a flexible ureteroscope, a ureteral access sheath is usually placed so that the scope can be removed and replaced easily during treatment. Ureteroscopes have small working ports that allow for a single small Holmium laser fiber up to 200 microns for pulverization or a small wire basket used to remove stone fragments. URS complication rates are low and include ureteral stricture, ureteral perforation, ureteral avulsion, and ureteral intussusception. After URS, a ureteral stent is generally left in place for

Benjamin Chung, MD

Simon Conti, MD

to surrounding tissue and maximizes energy focused on stones. Other modern low-intensity lithotripters, such as piezoelectric lithotripters, developed for their tolerance in awake patients, have had limited efficacy. Complications of ESWL include perinephric hematomas, with an incidence of 0.6% with electrohydraulic generators and 3%-12% with electromagnetic generators.1,2 Surrounding tissue damage may also occur, but is generally self-limited. A classic complication of ESWL is known as steinstrasse (German for “stone street”) impaction of small stone fragments in the ureter created during lithotripsy causing obstruction. This can occur with any type of lithotripsy, but is most common with ESWL as the stone fragments are not removed.

varying amounts of time to avoid post procedural edema causing obstruction. PCNL is reserved for larger and more complex kidney stone burdens and has almost completely replaced open stone surgery in this indication. Access to the collecting system is obtained either by interventional radiology prior to surgery or by the urologist intraoperatively with fluoroscopic guidance through a percutaneous tract directed through the flank. This tract is then dilated and a sheath is placed to allow direct access to the collecting system with a nephroscope. The large caliber of this access sheath allows for powerful ultrasonic and hydraulic lithotripters and tools to grasp and remove large stone fragments. While still minimally invasive, this procedure does incur greater risks

than ESWL and URS, including hemorrhage and renal pelvis perforation. Multiple tracts are placed for complex collecting system anatomy. Should a postoperative scan reveal residual stone burden, the same tract can be used for a second look PCNL. Use of open stone surgery, including anatrophic nephrolithotomy, is now only reserved for patients in whom PCNL has failed or rendered impossible because of patient anatomy. Stones located in the kidney that are larger than 2 cm (cumulative stone burden) and staghorn calculi should be treated with PCNL. Lower pole kidney stones have low stone-free rates with ESWL and URS, regardless of size because fragments do not easily pass down the ureter. With URS, small stones can be moved from the lower kidney to the upper kidney, making URS the choice for small lower pole stones. Stones smaller than 1 cm not located in the lower pole can usually be treated effectively with ESWL. Stones 1-2 cm that are not in the lower pole, less than 1000 Hounsfield units (HFU) on computed tomography scans, and with a short skin to stone distance (less than 10 cm) also can be effectively treated with ESWL. Harder 1-2 cm stones (greater than 1000 HFU) can be treated with URS/laser lithotripsy. Stones in the ureter are generally treated with URS. ESWL can be used for stones at the most upper portions of the ureter. PCNL for ureteral stones is reserved for very large stones at the ureteropelvic junction or proximal ureter. While ESWL is often the treatment modality preferred by patients as it is the least invasive, ureteral stone free rates are higher with ureteroscopic lithotripsy, especially as stone density and size increases. For this reason ureteroscopy is considered the gold standard for ureteral stones. n Dr. Conti is a urology resident and Dr. Chung is Assistant Professor of ­Urology, Director of Robotic and Minimally Invasive Urologic Surgery, Stanford University School of Medicine. 1. Dhar NB, Thornton J, Karafa MT, Streem SB. A multivariate analysis of risk factors associated with subcapsular hematoma formation following electromagnetic shock wave lithotripsy. J Urol 2004;172 (6 Pt 1):2271-2274. 2. Chaussy C, Schmiedt E. Extracorporeal shock wave lithotripsy (ESWL) for kidney stones. An alternative to surgery? Urol. Radiol 1984;6:80-87.

1/23/14 11:36 AM


16 Renal & Urology News 

FEBRUARY 2014 www.renalandurologynews.com

Renal Nutrition Update HOMOCYSTEINE (Hcy) is an intermediate metabolite in the conversion of methionine to cysteine. Elevated levels of Hcy are associated with increased levels of cardiovascular inflammation. Hcy plays a role in platelet aggregation and stroke risk (Clin Nutr 2012;31:448454). Additionally, the increase in inflammation associated with Hcy may be related to impaired glutathione production. Hcy levels correlate with increased glutathione transferase activity (Acta Diabetol 2013; published online ahead of print). Glutathione is made up of three amino acids that include cysteine. Aside from genetic mutations, low intakes of vitamin B12, B6, and folate increase risk for hyperhomocysteinemia because they are required for the metabolism of methionine to cysteine. Due to cereal fortification with folic acid, folate levels are more typically adequate, but B12 levels are often inadequate due to a lack of sensitivity in testing (CMAJ 2005;172:1569-1573) as well as reduced B12 absorption through aging (CMAJ 2004;171:251-259). Reduced B vitamin status may decrease the body’s capability to formulate glutathione adequately. This loss would reduce the ability to mitigate oxidative damage in the body. Dietary Sources of Vitamin B12 Meat Fish Clams and other mollusks Poultry Milk and milk products

Lipid peroxidation metabolites may proliferate, thereby increasing oxidative stress. Chronic renal failure (CRF) is associated with a progressive increase in inflammatory factors as the disease progresses. In a study of 154 patients with varying degrees of CRF, researchers found that Hcy increases concomitantly with other markers of inflammation in these patients (World J Nephrol 2013;2:3137). These factors include tumor necrosis factor-a, interleukin-6, interleukin-1b, and C-reactive protein. Levels of tHcy and inflammatory markers were significantly higher in hemodialysis and peritoneal dialysis patients compared with other CRF groups with better renal function. The study revealed a negative correlation between glomerular filtration rate and tHcy. Obese dialysis patients have an increased risk of atherosclerotic events in the presence of increased inflammation and Hcy (Nephrol Dial Transplant 2013;Suppl 4:iv188-iv194). Hcy and cystatin C have been shown to be sensitive biomarkers for early urine microalbumin excretion in diabetic nephropathy (ISRN Endocrinol 2013;2013:407452). Interestingly, restless legs syndrome in dialysis patients has recently been found to be associated with Hcy status (Kidney Blood Press Res 2013;37:458-463). A recent review found that supplementation with B6, B12, and folate did not reduce cardiovascular disease (CVD) risk in patients with chronic kidney disease (CKD), but it did decrease Hcy (Acta Med Indones

Recommended Dietary Allowances for Vitamin B12 Age

Male

Female

1-3 years

0.9 mcg

0.9 mcg

4-8 years

1.2 mcg

1.2 mcg

9-13 years

1.8 mcg

1.8 mcg

14 years and older

2.4 mcg

2.4 mcg

Source: Office of Dietary Supplements, National Institutes of Health

On The Web RUN0214_RenalNut.indd 16

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Vitamin B12 supplementation may help ease inflammation in CKD patients by lowering homocysteine levels BY GRISSIM CLARK CONNERY, MS, RD, LD

Liver is among the rich sources of vitamin B12.

2013;45:150-156). This effect appears to only occur as long as supplementation continues (Int J Vitam Nutr Res 2012;82:260-266). Interestingly, other B vitamin interventions have found negative effects, such as increased rates of vascular events and kidney decline (JAMA 2010;303:1603-1609). Typical B12 supplementation often uses the form of cyanocobalamin. A cyanide group is cleaved from this chemical, and the resultant cobalamin group is used to create one of two active forms. Methylcobalamin is the form needed for cysteine synthesis and glutathione production. In renal patients, the cyanide group has a higher tendency to accumulate due to the reduced glomerular filtration (Nephrol Dial Transplant 1997;12:1622-1628; Clin Chem Lab Med 2013;51:633-637). Glutathione is then required for the detoxification of cyanide. Supplementing with methylcobalamin may be more effective (Am J Kidney Dis 2010;55:1069-1078, but this supplement is more costly. Meat is among the primary food

source of B12. Adequate stomach acid is required for pancreatic proteases to cleave the B12 from the meat and for subsequent absorption via intrinsic factor. Reduced stomach acid secretion is noted in aging populations (Nutrients 2010;2:299-316). Additionally, long term use of proton pump inhibitors may be associated with reductions in B12 status, but data are still controversial (Curr Gastroenterol Rep 2010;12:448457). B12 supplements do not require stomach acid for adequate absorption, and thus in older CRF patients who may have subclinical B12 deficiency, methylcobalamin may prove to be an adequate therapy for Hcy reduction. Normal B12 ranges are typically 160600 pmol/L, but due to the fact that only 6%-20% of the body’s cobalamin is active, a serum value of 400 pmol/L must be met to ensure adequacy (Clin Chem 2009;55:2198-2206). n 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.

1/23/14 4:42 PM


www.renalandurologynews.com  FEBRUARY 2014 

Malpractice News

© THINKSTOCK

It has been estimated that wrong-site surgery—including wrong patient, wrong procedure, wrong side, or wrong site—may occur as frequently as 40 times per week in the United States. The latest, highly-publicized wrong-site surgery took place at Mt. Sinai Hospital in New York, where a surgeon mistakenly removed the wrong kidney from a 76-year-old patient. While it is unknown precisely why the error occurred, both of the patient’s kidneys were diseased and this may have led to the confusion. The surgeon was supposed to remove the more diseased kidney, but instead removed the less diseased one. The second kidney was removed once the surgeon realized his mistake. He has since been placed on leave pending an investigation. The patient survived and is living on dialysis. The hospital publicly apologized to the patient, who, according to Mt. Sinai spokeswoman Dorie Klissas, has forgiven the physician. According to Klissas, “The patient states that the surgeon in question helped him overcome bladder cancer in the past, and despite this error, says he has ‘enormous faith’ in the doctor.” In February 2012, in response to concerns about wrong-site surgery, the Joint

The “Targeted Solutions Tool” is available to diminish wrong-site surgical mistakes.

On The Web RUN0214_MalPractice.indd 17

Commission Center for Transforming Healthcare developed a tool for health care organizations to help identify, measure, and reduce risks in key processes that can contribute to wrong-site surgery. The “Targeted Solutions Tool” is available to all Joint Commissionaccredited health care organizations.

Medical Malpractice Case Ends in $5 Million Award A jury sided with the parents of an injured child in their lawsuit against two physicians and a nurse practitioner at Tufts Medical Center in Boston. The child, Edward Xu, now nine years old, was born prematurely. Xu’s family alleged that the three healthcare practitioners were negligent in their response to the infant’s symptoms of a potentially fatal condition affecting newborns. Because of this negligence, the family claimed, a portion of the baby’s intestines had to be removed and he is now unable to digest food and requires continuous overnight tube feeding. Tufts said in a statement that the physicians and nurse practitioner “performed early medical and surgical interventions to save his life, using the most advanced techniques available. Our care team is saddened that the best medicine available could not give him a better outcome.” However, the medical center added that half the infants born the same year as Xu, under similar circumstances developed medical complications and as many as 15% died. While the jury was deliberating, the attorneys for both sides reached what is known as a “high/low agreement” where the parties all agree to a maximum and a minimum award amount, depending on the jury verdict. The jury ultimately found the nurse practitioner not liable, but award approximately $30 million to the Xu family, which was reduced to $5.3 million, the agreed upon maximum. According to the plaintiff’s attorney, insurance will pay the verdict, and the Xu family may still be able to explore other ways to satisfy the jury’s judgment.

BY ANN W. LATNER, JD

Malpractice Filings Drop in Pennsylvania According to a report from the Administrative Office of Pennsylvania Courts, Pennsylvania medical malpractice filings dropped 10% in 2012. The report showed that 1,675 claims were filed in 2011 compared with 1,508 in 2012. By comparison, there was an average of 2,733 cases filed yearly between 2000 and 2003. In 2003, two significant changes to the malpractice rules in the state took effect. The first required plaintiffs in a medical malpractice case to obtain a “certificate of merit” from a medical professional, attesting that the medical care in the case fell outside of acceptable standards. The second change requires that the malpractice action be brought only in the county where the alleged malpractice took place, this change instituted to avoid what is known as “venue shopping,” when malpractice attorneys pick more favorable jurisdictions to have cases heard. A representative from the Pennsylvania Association for Justice, a trial lawyers’ group, said that the decline indicated that more drastic changes to malpractice laws – such as caps on damages – are not necessary. In Philadelphia, where the majority of malpractice suits are filed in the state, 389 cases were filed in 2012, the second lowest number in 10 years and down from 418 cases in 2011. There were 27 jury verdicts in Philadelphia in 2012 compared to an average of more than 100 between from 2000 to 2003. n

Maine Ranks No. 1 in Hospital Safety The Leapfrog Group, a national hospital watchdog organization, has just released its Hospital Safety Score ratings, and Maine is the winner. According to the ratings, 80% of Maine hospitals scored an “A.” Grades are based on 26 different measures of patient safety, ranging from bed sores and falls to treatment protocols. One

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Surgeon Removes Wrong Kidney from an Elderly Patient

Renal & Urology News 17

Maine ranks higest in hospital safety ratings, according to a watchdog group.

of the ways in which Maine strives to improve patient safety is by the yearly reporting of serious, preventable medical errors, including wrong site surgery and administration of the wrong medicine. In 2012, Maine reported 146 of these types of errors, down from 163 in 2011. Of the 146 errors, 14 included surgical objects being left in patients after surgery, and two were wrong-site surgeries. The other states scoring in the top five for patient safety after Maine were Massachusetts, Minnesota, Virginia, and Illinois. The ratings give letter grades to each hospital. Of the 2,514 general hospitals issued a Hospital Safety Score, 780 earned an “A,” 638 earned a “B,” 932 earned a “C,” 148 earned a “D” and 16 earned an “F.” The states that fared the worst in the ratings were Nevada, Kansas, Oregon, West Virginia, and New Mexico (which had the lowest percentage of hospitals earning a “A” (6.7%). According to the Leapfrog Group, the biggest change in safety measure was the Computerized Physician Order Entry, which reduces errors due to handwriting and transcription and provides error checking for incorrect doses or tests. n Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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

1/23/14 4:38 PM


18 Renal & Urology News 

FEBRUARY 2014 www.renalandurologynews.com

Practice Management P

hysicians, for the most part, live like the middle class, but for them, living within their means is dramatically different, according to financial planner Ben Utley. “Physicians make somewhere between three to 10 times as much as other middle-class people, so that shifts everything,” he said. “They tend to have bigger budgets than other middle-class families and a lot of extra money.” Physicians graduate with lots of debt, and often work long hours that can cause burnout. These are just a few of the reasons why you need to focus on finances long before you are thinking about retiring. Here are some financial considerations for all stages of your career.

Don’t live large After years of college, medical school, and residency, young doctors may be suffering from pent-up purchasing desires. They go from a low-paying residency, an old car, and an apartment to quadrupling their income literally overnight. Instead of trying to catch up all at once and spending everything you earn, you may want to still live like a resident, said Joel Greenwald of Greenwald Wealth Management in St. Louis Park, Minn. Because of all of the time in school, physicians get a later start on savings than people in many other occupations. Greenwald said he tells his clients that early in their careers, they need to make up for that by saving, not spending. “If doctors spend all of what they make when they start practicing, they aren’t going to be saving enough and they will end up being tied to the job longer than they want to be,” he said. A savings plan The first thing you need to know about savings is how much you need to save.

On The Web RUN0214_PracMan.indd 1

Utley, from Physician Family Financial Advisors in Eugene, Ore., said financial planners back into that number by understanding the sustainable withdrawal rate: 4% of the portfolio’s total. If you want to be able to take out $120,000 a year during retirement, you will need about $3 million in after-tax assets. To get to this point, he recommends saving a minimum of 15% of your income throughout your career. The secret to doing this is making savings automatic. If money comes out of your check each pay period, you never miss it. One major mistake Utley sees most people make is assuming that if they fully fund your 401k plan at work, then they will be on track for retirement. That, he says, is not the case. The most someone who is under 50 years old can put into a 401k is $50,000 a year. Over 20 years, that would only net about $1 million. He recommends putting money into IRAs and other accounts like a joint taxable account, real estate, or purchasing a medical office building.

The debt question Physicians come out of school with a lot of debt. The big debt—student loans— typically comes with competitive rates. If it doesn’t, consolidation loans with better rates are usually available once you start practicing, Utley said. It would be a mistake to pay off debts like student loans before starting to save for retirement, he said. You will have more money when you retire if you begin investing what you can while still paying off loans. Greenwald tells people to make a spreadsheet of all of their debt: credit cards, what they owe their parents, school loans, car loans, and mortgages, and so on. Put it all on one page and see what they get.

© THINKSTOCK

How to ensure financial solvency: Make a solid plan for managing your assets during productive years BY TAMMY WORTH

Rather than buying that expensive car you’ve been wanting, hold off until your debt is paid.

But once you have debt in order, you can see where your money is going and if you are paying off debt in the most effective manner. For instance, Greenwald has seen clients who take an extra $1,000 a month and spread it evenly between all of their debt. Instead of doing that, he recommends paying the whole amount to the debt with the highest interest rate and getting it paid off. When that is at zero, put the money toward the debt with the next highest rate. “If you have student loans or a mortgage that has a lower rate, you can stretch that out,” he said. Another debt rule is to pay it all off before retiring. “I haven’t let any clients retire with debt yet,” Greenwald said. “I tell them they have to keep working. It is too crazy to pay off debt and have mortgage in retirement.”

Cold, hard facts Even the best-laid plans can sometimes be derailed. For this reason, it’s best to understand your needs might change and plan for them as best you can. Take some time on occasion to sit down and

think about what money you are really going to need long before you receive the bill. Will you have a big or unexpected cash outlay at any time like helping your kids pay for college or helping your parents when they retire? You likely won’t get financial aid with a doctor’s salary, so what happens if you want your kids to go to a state school and they have their eyes on the Ivy Leagues? Or if you have three kids and the first two costs more than you anticipated? Another well-laid plan that can change is your retirement schedule. Young doctors are hungry to work and make money and usually love the pace. A few years down the road, after doctors have paid off their house, been sued once or twice, and purchased electronic medical record systems, the glory of work starts to wane. This is the time they begin thinking that early retirement looks better than it did at 30. “Young physicians often assume they will retire later than they are actually going to,” Utley said. n Tammy Worth is a freelance medical journalist based out of Blue Springs, MO.

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

1/23/14 11:38 AM


www.renalandurologynews.com  FEBRUARY 2014 

Renal & Urology News 19

CME FEATURE

PCA3: What Is Its Role in Prostate Cancer Screening? Although several biomarkers show promise, PCA3 has garnered substantial attention following FDA approval and its role in the diagnosis of PCa will grow.

Release Date: February 2014 Expiration Date: February 2015 Estimated time to complete the educational activity: 1 hour This activity is jointly sponsored by Medical Education Resources and Haymarket Medical Education. STATEMENT OF NEED: PSA tests have been used extensively worldwide for screening, diagnosis, and post-treatment surveillance of prostate cancer (PCa). The universal uptake in PSA testing has led to the overdiagnosis and treatment of indolent PCa. As a result, there is a clear need for improved diagnostic and prognostic tests to indivudualize prostate cancer management. TARGET AUDIENCE: This activity has been designed to meet the needs of urologists and primary-care providers who handle prostate cancer screening and diagnosis. EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Discuss the role of urinary biomakers for prostate cancer diagnosis. • Define how the PCA3 test is performed, calculated, and interpreted. • Review the role of the PCA3 test in relation to PSA testing, the digital rectal exam, and individual clinical judgement in an effort to reduce unnecessary biopsies. 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 Reza Mehrazin, MD

Reported Financial Relationship Consulting Fees: Fujifilm

Marc C. Smaldone, MD, MSHP

No financial relationships to disclose

BY REZA MEHRAZIN, MD, AND MARC C. SMALDONE, MD, MSHP

P

rostate cancer (PCa) is the second-leading cause of cancer death among men in the United States.1 Since its approval by the FDA in 1986,2 PSA tests have been used extensively worldwide for screening, diagnosis, and post-treatment surveillance of PCa. As a result, the universal uptake of PSA testing has led to the overdiagnosis and treatment of indolent PCa in a significant number of men, resulting in considerable morbidity, healthcare costs, and a questionable survival benefit.3 These factors contributed to the recent controversial decision by the U.S. Preventive Services Task Force (USPSTF) to recommend against routine PSA screening for PCa in asymptomatic men.4 It is important to consider that PSA was developed as a marker of PCa recurrence following prostatectomy, and not as a screening tool. Elevated levels of PSA can be detected in men with benign prostatic hyperplasia (BPH), urinary retention,5 and prostatitis.6 While performance of digital rectal exam (DRE) is thought to increase the

specificity of PCa screening, the positive predictive values (PPV) of DRE and serum PSA value below 10 ng/mL have been reported as less than 20% and 25%-30%, respectively.7,8 For these reasons, up to 70% of men presenting with elevated PSA levels between 4-7 ng/mL have false-positive PSA tests that result in negative prostate biopsy (PBx).9 Furthermore, men who have had one or more prior negative PBx and continue to have a consistently elevated or rising PSA have become increasingly challenging to manage. While repeat PBx is often recommended, the transrectal procedure is not without risk. Balancing the risk of complications with repeat procedures versus the risk from undiagnosed PCa requires diligent patient counseling and informed patient decision making. Due to the poor sensitivity and specificity of PSA as a screening tool, there has been considerable interest in identifying PCa-specific genes to guide management. Over the past decade, a number of novel PCa biomarkers have been discovered that show potential for

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 January 2014 through January 2015, participants must: 1) read the learning objectives and faculty disclosures, 2) study the educational activity, 3) complete the posttest and submit it online. Physicians may register at www.myCME.com/ renalanurologynews, and 4) complete the evaluation form online. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better.

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Reza Mehrazin, MD (left), and Marc C. Smaldone, MD, MSHP (right), are at Fox Chase Cancer Center in Philadelphia. Dr. Mehrazin is a fellow in Urologic Oncology and Dr. Smaldone is Assistant Professor of Urologic Oncology.

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20 Renal & Urology News 

FEBRUARY 2014 www.renalandurologynews.com

CME FEATURE detection and differentiation of indolent from aggressive PCa. Since using tissue as a substrate for biomarker testing is invasive and expensive, testing of biomarkers in body fluids (urine, plasma, prostate serum, and semen) is considered a promising non-invasive strategy to test for PCa. After prostate manipulation, epithelial cells are released into such biological fluids and enable detection by non-invasive methods. Additionally, because urine is readily available, its utility as a biomarker source has been well studied for a number of conditions including PCa.10

Urinary biomarkers Urine-based biomarkers rely on the presence of proteins, RNA, and DNA. Although beyond the scope of this review, the feasibility of using urine as a method of PCa cell detection has been demonstrated with mixed results.11 Prostatic ducts release prostate cells directly into the urethra.10 Considering the distance of the peripheral zone from the urethra, urine-based testing theoretically should be less sensitive for peripherally-located cancers (where 80% of PCa tumors are found). However, Nakanishi and colleagues showed no difference in the levels of the urinary prostate cancer antigen 3 gene (PCA3) between patients with peripheral versus transitional zone cancers.12 Although not shown in randomized clinical studies, the concept of prostatic manipulation or massage prior to urine sample collection for biomarker studies has been accepted as a standardized way of urine collection. To maximize yield, experts suggest collecting urine samples immediately after a firm DRE. This is done by firmly pressing down on each lobe of the prostate surface three times to compress it by approximately 1 cm, rolling the index finger from lateral to medial, and from the base to the apex of the prostate.13, 14 Over the past two decades, several PCa-specific genes or biomarkers have generated considerable interest in the scientific and urologic community. Although the role of the vast majority of these genes/biomarkers for screening purposes has not been fully determined, they have demonstrated promise in enhancing diagnostic accuracy, differentiating between low- and highrisk disease, and more appropriately selecting patients for repeat biopsy.

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Discovery of PCA3 In 1999, DD3 (differential display code 3) [now referred to as the PCA3 gene], a non-coding mRNA located on chromosome 9q21-22 with unknown function, was identified as being highly overexpressed (median 66-fold) in more than 95% of malignant prostate tissue compared with benign or normal prostatic tissue.15 Bussemakers and colleagues were first to identify PCA3 using Northern blot analysis and reverse transcriptase polymerase chain reaction (RT-PCR). They noted a 10- to 100-fold overexpression of PCA3 in 53 of 56 radical prostatectomy specimens compared with non-neoplastic prostate tissues. In 2004, Tinzl et al. described the second-generation PCA3 test known as uPM3 diagnostic test.16 They reported on the outperformance of PCA3 in comparison to PSA, with sensitivity and specificity of 82% and 76% vs. 87% and 16%, respectively. Today, the most current third-generation commercial platform is referred to as the Progensa PCA3 assay (approved in 2006),17 which is marketed by Gen-Probe.

PCA3 test Similar to other urinary markers, PCA3 is collected using a commercial kit after a firm and thorough DRE. Once the first urine catch sample (20-30 mL) is collected, the specimen is placed on ice (to maintain a target temperature between 2° to 8°C) and then shipped to the designated testing sites. The samples can be stored at this temperature for up to 14 days. The PCA3 assay is run by selecting the RNAs of interest (PCA3 and PSA) from the rest of the RNAs within the urine sample. This extraction is performed using magnetic beads coated with complementary oligonucleotide sequences. Once desired RNAs are isolated, they are amplified by PCR. Chemoluminescent-labeled probes are then used to perform the hybridization protection assay. PCA3 and PSA RNAs

Figure 1. Probability Scale for PCa Detection

Table 1: Diagnostic value of urinary PCA3 in the detection of prostate cancer following an initial negative biopsy. Reference

No. Pts

Sensitivity (%)

Specificity (%)

PPV (%) NPV (%)

Groskopf-200617

68

69

79

50

89

Marks-2007

226

58

72

-

-

PCA3 18

Haese-2008

463

47

72

39

78

Deras-200827

570

54

74

-

-

Chun -2009

809

95

92

-

-

1,026

48.4

78.6

-

-

1,913

86.5

36.6

49.6

79

108

37

93

37

94

73

52

-

-

20

34

Aubin-2010

19

Crawford-2012

28

TMPRSS2:ERG Hessels35

PCA3+TMPRSS2:ERG Hessels35

108

PPV – positive predictive value NPV – negative predictive value

are quantified in separate tubes and then PCA3 score is calculated as the PCA3/ PSA ratio. The Progensa PCA3 assay final output is the PCA3 score, calculated using the formula: PCA3 Score = (PCA3 mRNA)/(PSA mRNA) × 100026 (Figure 1). This provides a continuous value (ranging from 0-100) that correlates with probability of PCa detection on subsequent transrectal PBx.

Clinical role of PCA3 in repeat biopsy Several studies have demonstrated that PCA3 score is independent of age, PSA level, or prostate size,18-20 and may be more effective in PCa detection compared with PSA or percent-free-PSA alone.14,18-20, 22. In an early clinical study, Hessells et al investigated PCA3 measurement (using RT-PCR assay) in urine sediments of 108 men who had serum PSA value above 3 ng/mL. In 24 men who had PCa on biopsy, the assay was positive for the PCA3 gene in 67%, indicating a negative predictive value of 90% and a specificity of 83%.32 These fundamental findings led to further studies by others showing PCA3 over expression in PCa appears to be reproducible and found in up to

95% of tested samples.15,23-25 Ruiz-Aragón and Márquez-Peláez performed a meta-analysis of the published literature (2003-2009) investigating the role of PCA3 in screening for PCa.26 Fourteen studies met inclusion criteria and they included more than 3,400 men with an average age ranging between 62-65 years and mean PSA levels from 2.5 to 8.7 ng/mL. All patients underwent a PBx as a reference test to compare to the antigen determination. The overall sensitivity and specificity for PCA3 reported in this meta-analysis was 63% (range 46.8%-82.3%) and 75% (range 56.3%-89%), respectively. Due to the heterogeneity of these data, the authors concluded that PCA3 test should be used in conjunction with PSA and physician’s clinical judgment to determine which patients can be spared from repeat PBx. Several large studies have confirmed the association between PCA3 value and PCa detection. A prospective multicenter study20 evaluated the utility of the PCA3 assay in 463 European men with history of at least one prior negative PBx scheduled to undergo repeat biopsy. When comparing men with PCa to those with negative repeat biopsies, the mean PCA3 scores were significantly higher in those with detected cancers, (63.8 vs. 35.5 p <0.0001). Further, the authors reported that in patients with significant PCa (Gleason score 7 or higher on repeat biopsy), the PCA3 score was significantly higher than those in patients with indolent or less clinically significant disease (stage T1c, Gleason score less than 7, and PSA density less than 0.15), (mean 68.6

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vs. 24.5 p = 0.006). The clinical utility of the PCA3 assay in predicting repeat biopsy outcome was further validated in the placebo arm of REDUCE (Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study).19 The PCA3 assay was used in 1,140 men within the placebo arm of the study (mean PCA3 34). The probability of having a repeat biopsy was 57% in men who had PCA3 score over 100 compared to 6% among those who had PCA3 score below 5. In addition, the role of PCA3 in predicting PBx results was studied in a prospective U.S. multicenter trial in patients undergoing repeat PBx.27 The area under the curve (AUC)— whereby a predictive accuracy of 0.5 is equivalent to a coin flip and 1.0 is perfect predictive value—for PCA3 in predicting outcome on initial repeat biopsy was reported as 0.65. A community-based prospective clinical trial by Crawford et al.28 conducted at 50 urology practices within the U.S. evaluated the role of PCA3 test in 1,962 men with PSA levels above 2.5 ng/ml and/or abnormal DRE undergoing biopsy. The AUC for PSA and PCA3 alone were calculated as 0.569 and 0.706, respectively. The AUC increased to 0.720 when PCA3 was measured in conjunction with PSA. In this cohort, using a PCA3 cutoff of 35 reduced the number of false-positives from 1,089 to 249 (a 77% reduction) at the expense of missing 413 cancers. The authors concluded that increase in PCA3 score correlates with increased risk of diagnosis PCa on repeat biopsy and should be used in combination with serum PSA and other clinical information to guide PBx decisions. The clinical study leading to FDA approval of the PCA3 test in February of 2012 was a multicenter study from 14 clinical sites. The study included 466 men aged 50 years or older who had at least one negative biopsy and were offered repeat biopsy.29 Using a PCA3 score cutoff of 25 the negative PPV was 90%, 50% of repeat biopsies were avoided, and only 2% of Gleason score 7 or higher tumors were missed. This study showed that men with a PCA3 score below 25 were 4.6 times less likely to have a positive repeat biopsy than men with score of 25 or higher (P < 0.0001). Based on these findings and others,18,20,28 most experts currently advocate use PCA3 thresholds ranging

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from 25-35, which appears to achieve the optimal balance between sensitivity and specificity in guiding repeat biopsy. In early 2013, Tombal and colleagues reported the results of an interesting study assessing the value of best clinical judgment (BCJ) and the PCA3 assay in guiding the decision to perform a repeat PBx. In this case, BCJ refers to recommendations established using the RAND/UCLA Appropriateness Method for the appropriateness of repeat biopsy according to the PSA level, DRE findings, number of previous negative biopsies, prostate volume, and life expectancy, with and without consideration of PCA3. These recommendations were applied to 1,024 subjects receiving placebo in REDUCE trial,28 and three scenarios (BCJ alone, BCJ with PCA3, and the PCA3 score alone [using a threshold value of 20]) were tested for their ability to reduce the repeat biopsy rate versus missing Gleason sum 7 or higher PCa. They found that the diagnostic accuracy for Gleason sum 7 or higher PCa in the BCJ with PCA3 arm was superior to that of the other scenarios, with a NPV of 99%. In addition, 64% of repeat biopsies would have been avoided.30 These findings highlight that the simple addition of another diagnostic test does not replace the role of clinical judgment.

Role of PCA3 as a primary screening tool In the European Randomised Study of Screening for Prostate Cancer (ERSPC) trial, PCA3 was assessed as a first linescreening test.31 While the positive predictive values of a PCA3 score of 10 or higher and PSA value of 3 ng/mL or greater were comparable (17.1 vs. 18.8), PCA3 missed fewer cancers (32% vs. 65%), and most interestingly, detected more serious cancers (26% vs. 58%). It is important to note that these findings must be confirmed in unscreened PSA naïve patients to best assess any future role of PCA3 as a primary screening tool. In April 2013, the American Urological Association (AUA) released updated guidelines on early detection of PCa.32 The panel recognized that the PCA3 test plays a role as a secondary screening test (after PSA screening) and that the test can be used as an adjunct for informing decisions about the need for a PBx or repeat biopsy. Several recently

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PCA3 may allow clinicians to distinguish between patients with aggressive and indolent PCa.

constructed and externally validated PCA3-based biopsy nomograms (e.g., the Prostate Cancer Prevention Trial Risk Calculator) have shown that incorporation of PCA3 with other established risk factors (PSA, age, DRE, biopsy history, prostate volume) improves diagnostic accuracy and helps identify patients with clinically significant disease who may benefit from active treatment.33,34

TMPRSS2-ERG: Recently, TMPRSS2-ERG gene fusion and its role in prostate tumorogenesis has been a point of interest in PCa research. So far, research has shown that the combination of TMPRSS2ERG with PCA3 may improve overall sensitivity for PCa detection. Hessels and colleagues reported increased sensitivity from 62% (PCA3 alone) to 73% (TMPRSS2-ERG + PCA3) without compromising specificity for PCa detection.35 Salami and colleagues reported 80% sensitivity and 90% specificity to detect PCa using a combination of serum PSA, PCA3, and TMPRSS2ERG.36 At the AUA annual meeting in 2013, Jones et al. reported on the utility of PCA3 and TMPRSS2:ERG in a cohort of 638 men prior to an initial biopsy.37 When both assays were combined into risk groups, substantial differences in probability of cancer detection were observed between the low (14%) and high (84%) risk groups. Although not studied in a prospective randomized trials, these early investigations support that using a combination of PCA3 and TMPRSS2:ERG may be beneficial in not only selecting patients for repeat biopsy, but improving prediction of indolent versus clinically significant disease as well.

for active surveillance (AS) protocols. While evidence suggests that PCA3 may accurately predict low-volume, clinically insignificant cancers, a number of studies have found that PCA3 alone is not a robust predictor of locally advanced disease or aggressive tumors.23,25,27 However, Lin et al 38 recently examined the correlation of PCA3 and TMPRSS2:ERG scores with higher cancer grade and volume at the time of biopsy in a cohort of 387 men on AS. They reported a sequential increase in the scores as tumor volume increased. For a negative repeat biopsy and 1%-10% and 34% or more positive cores, the median PCA3 scores were 27, 28, and 46 (p=0.004), and median TMPRSS2:ERG scores were 3, 10, and 27 (p<0.0001), respectively. Despite these promising results, the role of PCA3 in the prediction of adverse tumor features as well as risk assessment in patients considering active surveillance requires further study.

Conclusions Biomarkers have been targeted to best achieve the elusive goal of matching intensity of treatment to individual tumor biology. Following the controversial decision by the USPSTF, there is a clear need for improved diagnostic and prognostic tests to individualize PCa management. Although several biomarkers show promise, PCA3 has garnered substantial attention following FDA approval and its role in the diagnosis of PCa will continue to grow in the future. Examining the current body of evidence suggests that PCA3 should not replace PSA for PCa screening, but may serve as a useful adjunct to PSA, DRE, and clinical judgment to help avoid unnecessary biopsies and identify patients with clinically significant disease who may benefit from active treatment. n

Use of PCA3 in active surveillance REFERENCES

As a future application, PCA3 may allow clinicians to distinguish between patients with indolent and aggressive PCa who are under consideration

1. Siegel R, Naishadham D, Jemal A. Cancer Statistics, 2013. CA Cancer J Clin 2013;63:11-30. 2. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009;360:1310-1319.

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CME FEATURE 3. Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst 2010;102:605-613. 4. Qaseem A, Barry MJ, Denberg TD, et al. Screening for prostate cancer: A guidance statement from the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med 2013;158:761-769. 5. Oesterling JE, Jacobsen SJ, Chute CG, et al., Serum prostate-specific antigen in a communitybased population of healthy men. Establishment of age-specific reference ranges. JAMA 1993;270:860-864. 6. Kawakami J, Siemens DR, Nickel JC. Prostatitis and prostate cancer: implications for prostate cancer screening. Urology 2004;64:1075-1080. 7. Carvalhal GF, Smith DS, Mager DE, et al., Digital rectal examination for detecting prostate cancer at prostate specific antigen levels of 4 ng/ml. or less. J Urol 1999;161:835-839. 8. Fowler JE Jr, Bigler SA, Farabaugh PB, Wilson SS. Prostate cancer detection in Black and White men with abnormal digital rectal examination and prostate specific antigen less then 4 ng./ml. J Urol 2000;164:1961-1963. 9. Draisma G, Etzioni R, Tsodikov A, et al. Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context. J Natl Cancer Inst 2009;101:374-383. 10. Truong M Yang B, Jarrard DF. Toward the detection of prostate cancer in urine: a critical analysis. J Urol 2013;189:422-429. 11. Killick E, Bancroft E, Kote-Jarai Z, Eeles R. Beyond prostate-specific antigen - future biomarkers for the early detection and management of prostate cancer. Clin Oncol (R Coll Radiol) 2012;24:545-555. 12. Nakanishi H, Groskopf J, Fritsche HA, et al. PCA3 molecular urine assay correlates with prostate cancer tumor volume: implication in selecting candidates for active surveillance. J Urol 2008;179:1804-1809. 13. van Gils MP, Hessels D, van Hooij O, et al. The timeresolved fluorescence-based PCA3 test on urinary sediments after digital rectal examination; a Dutch multicenter validation of the diagnostic performance. Clin Cancer Res 2007; 13:939-943. 14. Vlaeminck-Guillem V, Ruffion A, Andre J, et al. Urinary prostate cancer 3 test: toward the age of reason? Urology 2010;75:447-453. 15. Bussemakers MJ, van Bokhoven A, Verhaegh GW, et al. DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res 1999;59:5975-5979. 16. Tinzl M, Marberger M, Horvath S, et al. DD3PCA3 RNA analysis in urine--a new perspective for detecting prostate cancer. Eur Urol 2004;46:182-186. 17. Groskopf J, Aubin SM, Deras IL, et al. APTIMA PCA3 molecular urine test: development of a method to aid in the diagnosis of prostate cancer. Clin Chem 2006;52:1089-1095. 18. Marks LS, Fradet Y, Deras IL, et al. PCA3 molecular urine assay for prostate cancer in men undergoing repeat biopsy. Urology 2007;69:532-535. 19. Aubin SM, Reid J, Sarno MJ, et al. PCA3 molecular urine test for predicting repeat prostate biopsy outcome in populations at risk: validation in the placebo arm of the dutasteride REDUCE trial. J Urol 2010;184:1947-1952. 20. Haese A, de la Taille A, van Poppel H, et al. Clinical utility of the PCA3 urine assay in European men scheduled for repeat biopsy. Eur Urol 2008;54:1081-1088. 21. Ploussard G, Haese A, van Poppel H, et al. The prostate cancer gene 3 (PCA3) urine test in men with previous negative biopsies: does free-to-total

prostate-specific antigen ratio influence the performance of the PCA3 score in predicting positive biopsies? BJU Int 2010;106:1143-1147. 22. Bradley LA, Palomaki GE, Gutman S, et al. Comparative effectiveness review: prostate cancer antigen 3 testing for the diagnosis and management of prostate cancer. J Urol 2013;190:389-398. 23. Hessels D, Klein Gunnewiek JM, van Oort I, et al. DD3(PCA3)-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol 2003;44:8-15. 24. Popa I, Fradet Y, Beaudry G, et al. Identification of PCA3 (DD3) in prostatic carcinoma by in situ hybridization. Mod Pathol 2007;20:1121-1127. 25. de Kok JB, Verhaegh GW, Roelofs RW, et al. DD3(PCA3), a very sensitive and specific marker to detect prostate tumors. Cancer Res 2002;62:2695-2698. 26. Ruiz-Aragon J, Marquez-Pelaez S. [Assessment of the PCA3 test for prostate cancer diagnosis: a systematic review and meta-analysis]. Actas Urol Esp 2010; 34:346-355. 27. Deras IL, Aubin SM, Blasé A, et al. PCA3: a molecular urine assay for predicting prostate biopsy outcome. J Urol 2008;179:1587-1592. 28. Crawford ED, Rove KO, Trabulsi EJ, et al. Diagnostic performance of PCA3 to detect prostate cancer in men with increased prostate specific antigen: a prospective study of 1,962 cases. J Urol 2012;188:1726-1731. 29. Gittelman MC, Hertzman B, Bailen J, et al. PCA3 molecular urine test as a predictor of repeat prostate biopsy outcome in men with previous negative biopsies: a prospective multicenter clinical study. J Urol 2013;190:64-69. 30. Tomblad B, Andriole GL, de la Taille A, et al. Clinical judgment versus biomarker prostate cancer gene 3: which is best when determining the need for repeat prostate biopsy? Urology 2013;81:998-1004. 31. Roobol MJ, Schroder FH, van Leenders GL, et al. Performance of prostate cancer antigen 3 (PCA3) and prostate-specific antigen in prescreened men: reproducibility and detection characteristics for prostate cancer patients with high PCA3 scores (≥100). Eur Urol 2010;58:893-899. 32. Carter HB, Albersten PC, Barry MJ, et al. Early detection of prostate cancer: AUA Guideline. J Urol 2013;190:419-426. 33. Ankerst DP, Groskopf J, Day JR, et al. Predicting prostate cancer risk through incorporation of prostate cancer gene 3. J Urol 2008;180:1303-1308. 34. Chun FK, de la Taille A, van Poppel H, et al. Prostate cancer gene 3 (PCA3): development and internal validation of a novel biopsy nomogram. Eur Urol 2009;56:659-667. 35. Hessels D, Smit FP, Verhaegh GW, et al. Detection of TMPRSS2-ERG fusion transcripts and prostate cancer antigen 3 in urinary sediments may improve diagnosis of prostate cancer. Clin Cancer Res 2007;13:5103-5108. 36. Salami SS, Schmidt F, Laxman B, et al. Combining urinary detection of TMPRSS2:ERG and PCA3 with serum PSA to predict diagnosis of prostate cancer. Urol Oncol 2013;31:566-571. 37. Jones L, Day J, Meyer S, et al. Urinary PCA3 and TMPRSS2:ERG help predict biopsy outcome prior to initial prostate biopsy using a risk group analysis. American Urologic Association 2013 annual meeting, San Diego. Abstract 2129. 38. Lin DW, Newcomb LF, Brown EC, et al. Urinary TMPRSS2:ERG and PCA3 in an active surveillance cohort: results from a baseline analysis in the Canary Prostate Active Surveillance Study. Clin Cancer Res 2013;19:2442-2450.

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

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CME Post-test Expiration Date: February 2015 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 one of the following statements is TRUE: a. PCA3 is a non-coding mRNA b. PCA3 is a coding mRNA c. PCA3 is a coding DNA d. PCA3 is a non-coding DNA 2. Once the first urine catch is collected for PCA3 test, the specimen should be: a. Kept at the room temperature b. Placed on ice to maintain a target temperature between 2° to 8°C c. Placed on dry ice to maintain a target temperature between -5° to -10°C d. None of the above 3. Which statement is correct regarding AUA recommendations on PCA3: a. The AUA does not support the use of PCA3 in the diagnosis of prostate cancer b. The AUA recognizes PCA3 as a secondary screening test c. The AUA recommends PCA3 if serum PSA is less than 5 ng/mL d. The AUA recommends PCA3 if serum PSA is more than 5 ng/mL 4. Recent studies suggest that the combination of PCA3 with TMPRSS2-ERG gene fusion: a. Improves overall sensitivity for PCa detection b. Improves selection of patients for repeat biopsy c. Improves prediction of indolent versus clinically significant PCa d. All of the above 5. Which statement is most accurate?: a. PCA3 test should be obtained prior to DRE b. PSA is more specific than PCA3 c. PCA3 is more specific than PSA alone d. None of the above 6. PCA3 testing is independent of: a. Age b. PSA level c. Prostate size d. All of the above 7. Which of the following scenarios is most likely to result in a prostate cancer diagnosis for a 62-year-old man with a prior negative biopsy: a. PSA 6.4, PCA3 score 10, normal DRE b. PSA 4.8, PCA3 score 20, normal DRE c. PSA 4.0, PCA3 score 40, normal DRE d. PSA 2.5, PCA3 score 5, abnormal DRE

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