Renal & Urology News May 2014 Issue by Haymarket Media

MAY 2014

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VOLUME 13, ISSUE NUMBER 5

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www.renalandurologynews.com

Stone Study: 24-Hour Urinalysis Key

IMAGE COURTESY OF DAVID S. GOLDFARB, MD

New findings demonstrate that urinary biochemical composition changes with patient age

THE URIC ACID CONTENT of kidney stones was found to increase with patient age.

BY JODY A. CHARNOW URINARY biochemical profiles change with age, and this needs to be considered in the medical management of stone disease, according to researchers. In a study of 24-hour urine collections from 1,115 patients seen in a tertiary care stone clinic, Justin I. Friedlander, MD, of the University of Texas Southwestern Medical Center in Dallas, and colleagues found that increasing age was associated with significantly decreased mean urine pH, 24-hour calcium, uric acid, ammonium, creatinine, and supersaturation (SS) of calcium oxalate and calcium phosphate on univariate analysis. Adjusted multivariate analysis showed that increasing

Combo Ups Acute Rejection Risk Higher Protein LAS VEGAS—Using ketoconazole in conazole is a potent inhibitor of Intake Hastens combination with tacrolimus in kid- cytochrome P450. Transplant proney transplant patients may increase grams frequently use ketoconazole to eGFR Decline their risk of acute rejection, according decrease tacrolimus dose requirements to findings presented at the National Kidney Foundation’s 2014 Spring Clinical Meetings. Tacrolimus is metabolized by cytochrome P450 in the liver and keto-

CME FEATURE

and financial cost. Heather LaGuardia, MD, and collaborators at Tulane University in New Orleans studied 348 adult primary continued on page 5

Earn 1 CME credit in this issue

Lesley A. Inker, MD, MS, of Tufts University School of Medicine in Boston

Kidney Function Assessment: The Need for a Confirmatory Test PAGE 14

HIGHER protein intake in middle age is associated with greater declines in kidney function over time, according to a recent study. Massimo Cirillo, MD, of the University of Salerno in Salerno, Italy, and colleagues collected data on overnight urinary urea, serum creatinine, estimated glomerular filtration rate (eGFR), and other variables in 1,522 men and women aged 45-64 years. Subjects were participants in the Gubbio study, an ongoing populationbased investigation in Gubbio, Italy. The investigators re-assessed serum creatinine, eGFR, and other variables in 1,144 of 1,425 survivors after 12 years of follow-up. At baseline, the study population had a mean eGFR of 84 mL/min/1.73 m2 as calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and protein intake of 1.34 g/day per kilogram of ideal weight as assessed by measurecontinued on page 5

age was associated with significantly increased 24-hour citrate and SS of uric acid and decreased pH, 24-hour uric acid, creatinine, and SS of calcium oxalate and calcium phosphate. “This highlights the importance of evaluating stone-forming patients of all ages with 24-hour urine collections because both the type and degree of metabolic abnormality may change with age,” the researchers concluded in a paper published online ahead of print in the Journal of Endourology. The fi ndings that urinary calcium and SS of calcium oxalate and calcium phosphate decrease with increasing age are consistent with a previous study by David S. Goldfarb, MD, and colcontinued on page 5

IN THIS ISSUE 4

Lowering uric acid levels has renal benefits

Higher BMI before kidney transplantation increases NODAT risk

Retinopathy linked to mortality in CKD patients

Predictors of AKI in lymphoma patients identified

Dialysis may trigger atrial fibrillation

‘Southern’ diet raises CKD patient death risk

Intensive dialysis recommended for pregnant ESRD patients

CKD patient mortality risk is linked to a ‘Southern’ diet PAGE 13

MAY 2014

VOLUME 13, ISSUE NUMBER 5

www.renalandurologynews.com

Prostate Cancer AS Safe Long Term Patients are more than 9 times more likely to die from causes other than PCa, a new study shows Most Patients Remain on Active Surveillance In a study of prostate cancer patients on active surveillance (AS), more than half of them remained untreated and on AS after 20 years of follow-up. 80 70 60 50 40 30 20 10 0

63.5% 10

55% 15

55% 20

Years of follow-up Source: Klotz L, et al. Long term follow-up of a large active surveillance cohort. Results presented at the European Association of Urology 29th annual congress, Stockholm. Poster 26.

Study: 24-Hour Urinalysis Key BY JODY A. CHARNOW URINARY biochemical profiles change with age, and this needs to be considered in the medical management of stone disease, according to researchers. In a study of 24-hour urine collections from 1,115 patients seen in a tertiary care stone clinic, Justin I.

CME FEATURE

Friedlander, MD, of the University of Texas Southwestern Medical Center in Dallas, and colleagues found that increasing age was significantly associated with decreased mean urine pH, 24-hour calcium, uric acid, ammonium, creatinine, and supersaturation of calcium oxalate and calcium phoscontinued on page 5

Earn 1 CME credit in this issue

Lesley A. Inker, MD, MS, of Tufts University School of Medicine in Boston

Relationships of Testosterone and Prostate Cancer PAGE 14

BY JODY A. CHARNOW STOCKHOLM—Active surveillance (AS) for patients with favorable risk prostate cancer (PCa) is safe long-term, with patients much more likely to die from causes other than PCa, according to study findings presented at the European Association of Urology 29th annual congress. The study, led by Laurence Klotz, MD, of Sunnybrook Health Sciences Centre, University of Toronto, included 993 men (median age 67.8 years) with favorable or intermediate PCa who underwent AS for a median of 8.1 years. A total of 206 men were followed for more than 10 years and 50 were followed for more than 15 years. Of the 993 men, 149 died (15%), 15

MRI Improves Higher-Risk PCa Detection BY JODY A. CHARNOW MAGNETIC resonance imaging (MRI) and MRI-guided prostate biopsy can greatly reduce the detection of low-risk prostate tumors while increasing detection of intermediateand high-risk tumors, according to the findings of a recent study. Leslie C. Thompson, MBBS, FRACS, a consultant urologist at The Wesley Hospital and Wesley Research Institute in Brisbane, Australia, and colleagues compared multiparametric MRI (mpMRI) followed by MRI-guided biopsy (MRGB) with transrectal ultrasound-guided biopsy (TRUSGB) in the detection of prostate cancer (PCa) in 223 biopsy-naïve men referred by urologists with a high or concerning PSA level. Of these, 142 (63.7%) had PCa. TRUSGB detected 126 cases of PCa in 223 men (56.5%), including 47 (37.3%) classified as low risk and 79 (62.7%) classified as intermediate or high risk. MRGB detected 99

(1.5%) from PCa. The 10- and 15-year actuarial cancer-specific survival rates were 98.1% and 94.3%, respectively. Patients were 9.2 times more likely to die from other causes than from PCa, Dr. Klotz and his colleagues reported. In addition, at 5, 10, 15, and 20 years, 75.7%, 63.5%, 55.0%, and 55.0%, respectively, remain untreated and on AS. Metastatic disease developed in an additional 7, who either died of other causes (5) or are alive with disease (2). Post-treatment failure occurred in 6.3% of the total cohort, according to the investigators. “Active surveillance for favorable risk prostate cancer is feasible and appears safe in the 15-20 year time frame,” continued on page 5

IN THIS ISSUE 4 Statins may benefit patients undergoing RCC surgery 7 Osteoporosis is often present before PCa patients start ADT 9 Radiation after radical prostatectomy improves results

9 OAB, SUI symptoms worse after vaginal birth

13 Bone turnover biomarkers may predict CRPC course

Non-Caucasian race predicts adverse BPH surgery outcomes

Researchers identify two bladder cancer subtypes

CKD patient mortality risk is linked to a ‘Southern’ diet PAGE 13

continued on page 5

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Renal & Urology News 3

FROM THE EDITOR EDITORIAL ADVISORY BOARD

Medicare Payments Exposed

or the first time, the federal Centers for Medicare and Medicaid Services (CMS) has made public a database showing what it pays out to individual physicians. In a press release, CME administrator Marilyn Tavenner stated that data transparency “is a key aspect of transformation of the health care delivery system. While there’s more work ahead, this data release will help beneficiaries and consumers better understand how care is delivered through the Medicare program.” In 2012, Medicare paid $77 billion to 880,000 providers, with nearly $1.7 billion of that going to 7,504 nephrologists (average $224,747) and $1.38 billion to 8,792 urologists (average $157,555), according to the CMS. Ninety-six nephrologists and 21 urologists received more than $1 million in payments each. Among the 96 nephrologists, total payments ranged from $1,003,835 to $2,987,182. Among the 21 urologists, payments ranged from $1,000,452 to $2,141,927. The CMS has acknowledged that the database has some limitations. For example, the database only has information for Medicare beneficiaries with Part B fee-for-service coverage, “but physicians typically treat many other patients who do not have that form of coverage.” In addition, the database excluded any aggregated records derived from 10 or fewer Medicare beneficiaries to protect beneficiary privacy. Transparency in the spending of taxpayer money generally is a good idea. It allows the press, and therefore the public, to look for wasteful spending, mismanagement, and fraud. This potentially could shape public opinion that, in theory, prompts lawmakers and policymakers to make changes to physician reimbursement. The downside, in my view, is that divulging what Medicare pays to individual doctors by name can engender misconceptions among members of the press and public, who may see a huge dollar figure and wrongly suspect that a doctor is milking or bilking the system. Millions in Medicare dollars could flow to doctors for a number of legitimate reasons, such as high costs associated with the administration of certain treatments, especially medication costs. In addition, now that Medicare payments to individual physicians are open to the public, some patients undoubtedly will look up their doctor’s Medicare income, if for no other reason than idle curiosity. They may be awestruck by the lottery-jackpot-size dollar figure they see, and gather that their doctor is rolling in dough without considering that much of this money goes to operating expenses and taxes and perhaps to paying down a huge debt burden. Despite the risk of people jumping to conclusions, greater transparency serves the greater good in terms of the big picture of government accountability, and we all might be better off in the long term. Jody A. Charnow Editor

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 Vice President Regional Medical Operations Professor & Horvitz/Miller Distinguished Chair in Urological Oncology 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 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 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 5. 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.

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4 Renal & Urology News

MAY 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 Regular Aspirin Use Lowers PCa Risk

Calif., and colleagues found that those

Regular use, and especially long-time

and achieved a serum uric acid lower

regular use, of aspirin may decrease

below 6 mg/dL had a significant 37%

the risk of prostate cancer (PCa)

decrease in the risk of renal outcomes

overall and advanced PCa, accord-

(a 30% or greater reduction in glomer-

ing to the findings of a meta-analysis

ular filtration rate [GFR] from baseline

published online ahead of print in

or progression to dialysis or a GFR of

International Urology and Nephrology.

15 mL/min/1.73 m2 or less).

treated with urate-lowering therapies

Their meta-analysis of 24 epidemiouse was associated with a 14% lower

Statins May Improve RCC Surgery Outcomes

risk of PCa overall and a 17% lower

Statin use decreases the risk of

risk of advanced PCa. Long-time

disease progression after surgery for

regular use (4 years or more) was

localized renal cell carcinoma (RCC),

associated with an 18% lower risk of

researchers reported in The Journal of

PCa overall and a 30% lower risk of

Urology (2014;191:914-919).

logic studies found that regular aspirin

advanced PCa.

Of 2,608 patients who underwent surgery for RCC from 1995-2010,

Uric Acid Lowering Has Renal Benefits

699 (27%) were statin users at the

Patients with hyperuricemia who

logic characteristics were similar

achieve a serum uric acid level below

to those of non-users. At a median

6 mg/dL using urate-lowering thera-

follow-up of 36 months, the research-

pies are less likely to experience renal

ers observed 247 progression

function decline, according to a study

events. Statin use was associated

published online ahead of print in the

with a significant 33% reduction in

Journal of Rheumatology.

progression risk, according to a re-

time of their operation. Their patho-

In a study of 16,186 patients with

search team led by Paul Russo, MD,

hyperuricemia, Gerald D. Levy, MD,

of Memorial Sloan-Kettering Cancer

of Kaiser Permanente in Downey,

Center in New York.

Balancing Work and Life In a recent online poll, Renal & Urology News asked readers, “How satisfied are you with your work-life balance?” Here are the results based on 111 responses.

Very satisfied 5.41% Generally satisfied 29.73% Somewhat dissatisfied 40.54% Very dissatisfied 24.32%

RUN0514_NewsInBrief.indd 10

Kidney Remaining After Nephrectomy Gets Larger F

ollowing nephrectomy, living kidney donors experience an immediate increment in renal parenchymal volume (RPV) in the remaining kidney, Chinese researchers reported in International Urology and Nephrology (2014;46:743-747). In a study of 45 living kidney donors, researchers used magnetic resonance imaging to measure the size of the non-transplanted kidney before surgery and 3 and 7 days post-operatively. The RPV of the remaining kidney was 118 cm3 before nephrectomy. It increased in size by 21.23% to 143.13 cm3 at 3 days and by 24.17% to 146.60 cm3 at 7 days. The RPV at 7 days was directly related to its initial preoperative size. Results also showed that kidneys with a 20% or greater increase in RPV after 7 days are more likely to show a further significant increase in glomerular filtration rate at 1 year.

Renal Mass Biopsy Seldom Used Before RCC Surgery M

ost patients diagnosed with renal cell carcinoma (RCC) from do not undergo renal mass biopsy (RMB) prior to surgery, but most who undergo ablation or systemic therapy do, researchers reported in Urology (2014;83:774-780). In a study of 24,702 patients diagnosed with RCC from 1992-2007, John T. Leppert, MD, of Stanford University School of Medicine in Palo Alto, Calif., and colleagues documented a steady and modest rise in RMB use, with the greatest use in the final study year. Among the patients who underwent radical or partial nephectomy, 17% and 20%, respectively, underwent RMB in advance of surgery. In addition, 65% of patients who underwent ablation underwent RMB before or in conjunction with the procedure. And just over half (50.4%) of those who received systemic therapy alone underwent RMB. Factors associated with RMB use included younger age, black race, Hispanic ethnicity, a tumor size smaller than 7 cm, and metastatic disease at presentation.

Higher Pre-Transplant BMI Increases NODAT Risk A

greater body mass index (BMI) prior to kidney transplantation is associated with a higher risk of developing new-onset diabetes after transplant (NODAT), a study found. Researchers at Oregon Health & Sciences University in Portland led by Diane D. Stadler, PhD, RD, LD, studied 204 adult patients who underwent a first renal transplant. The cumulative incidence of NODAT at discharge and 3, 6, and 12 months post-transplant was 14.2%, 19.4%, 20.1%, and 19.4%, respectively, the investigators reported in the Journal of Renal Nutrition (2014;24:116-122). The risk of NODAT by discharge or 3 or 6 months increased by 11%, 13%, and 15%, respectively, per 1-unit increase in BMI. The need for more aggressive diabetes treatment, suggesting a worsening diabetes status, was most usually observed between discharge and 3 months, the researchers noted. In addition, half of the patients with pre-existing diabetes required more aggressive diabetes treatment post-transplant.

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24-hour urinalysis continued from page 1

leagues published in Clinics in Geriatric Medicine (1998;14:367-381). Dr. Friedlander and his colleagues hypothesize that the decline in urinary calcium with increasing age is from age-related changes in calcium handling because of intestinal absorption, renal mechanisms, or both. The decrease in SS of calcium oxalate and calcium phosphate with increasing age is likely driven by the decline in urinary calcium because the results demonstrate that both oxalate and phosphate increase with age, they noted. “When taken in the context

Acute rejection continued from page 1

kidney transplant recipients. Of these, 199 received ketoconazole after transplant surgery and continued on it for at least 1 year or until graft failure. The remaining 149 patients did not receive ketoconazole. Patients were followed up for as long as 5 years after surgery. Results showed that 68 patients (34%) in the ketoconazole group experienced acute rejection compared with 27 (18%) in the other group, a significant difference between the groups. In multivariate analysis, ketoconazole use was associated with a significant 2.3 times increased likelihood of acute rejection compared with non-use, the investigators reported. The two study arms did not differ significantly with respect to rates of delayed graft function and overall graft loss and patient death. Other independent risk factors for

of increasing incidence of stone disease and a change in the age of peak incidence of stones, our findings give credence to the idea that lower SS values in older stone-forming patients are likely sufficient to increase the risk of stone formation, and normal ranges may need to be age-adjusted to more appropriately counsel and treat patients,” they wrote. Additionally, Dr. Friedlander’s team reviewed the composition of 436 stones and found an increasing percentage of uric acid content with increasing age. They noted that a similar trend was found in a study by Amy Krambeck, MD, and colleagues published in The Journal of Urology (2013;189:158-164).

acute rejection included black race, receipt of a deceased donor kidney, and delayed graft function. Blacks had a nearly 2.7 times increased risk of acute rejection compared with nonblacks. Patients who received a living donor kidney had a 68% decreased risk of acute rejection compared with those received a deceased donor kidney. Patients who experienced delayed graft function had a 2.1 times increased risk of acute rejection compared with those who did not. The two groups had similar demographic and clinical factors, including age, gender, race, body mass index, causes of end-stage renal disease, and the proportions of patients who received organs from deceased and living donors. Dr. LaGuardia’s team noted that the association between ketoconazole and increased risk of acute rejection could be due to various reasons, such as decreased peak tacrolimus levels. n

Study results showed that uric acid and atypical stones were significantly associated with older age, whereas calcium phosphate stones were significantly associated with younger age. Commenting on the paper by Dr. Friedlander’s team, Dr. Goldfarb, professor of medicine and physiology at the New York University (NYU) School of Medicine, told Renal & Urology News: “This interesting study confirms that age is an important variable affecting urine chemistry. We know that increasing age is associated with declines in estimated glomerular filtration rate, and this in turn is likely associated with increases in parathyroid hormone. That effect may account

Protein intake continued from page 1

ments of overnight urine excretion of urea nitrogen. Cross-sectional analyses showed that each 1 g/day increment in protein intake was associated with a 4.7 mL/min/1.73 m2 increment in eGFR. Longitudinal results demonstrated that, after 12 years of follow-up, study subjects had experienced a mean 11.6 mL/min/1.73 m 2 decline in eGFR. Each 1 g/day increment in protein intake was associated with a 4.1 mL/ min/1.73 m2 decline in eGFR and a 78% increased likelihood of having an eGFR below 60 mL/min/1.73 m2, the researchers reported. “The study reports the first evidence that, in a sample of the middle-age general population, higher protein intake is associated cross-sectionally with higher eGFR and longitudinally with greater eGFR decline over time,”

Renal & Urology News 5

for reductions in urine calcium excretion with age, seen in our 1998 study and in the current paper.” The finding that increasing age is associated with reductions in urinary pH and, therefore, more uric acid stones is consistent with the study by Dr. Krambeck and colleagues, said Dr. Goldfarb, who also is clinical chief of nephrology at NYU Langone Medical Center. “The study [by Dr. Friedlander’s group] also suggests that unmeasured variables, like urinary promoters and inhibitors, also contribute to the stone disease of older people, given their apparent tendency to form stones with lower supersaturations.” n

the investigators stated in a report published online ahead of print in Nephrology Dialysis Transplantation. The study’s findings agree with clinical studies demonstrating short-term GFR stimulation by protein intake and unfavorable effects of high protein diet in CKD, Dr. Cirillo’s team said. The investigators noted that the eGFR decline in their study population averaged rates much slower than observed in the CKD population. “Thus, it is uncertain if the association of protein intake with the slow eGFR decline within the general population is relevant also to the fast eGFR decline in patients with chronic kidney disease,” they wrote. In addition to the observational design, study limitations included the use of a single overnight urine collection and the lack of information about various types of dietary protein, other nutrients, other age strata, other ethnic groups, and true GFR. n

Retinopathy in CKD Patients Predicts Higher Death Risk RETINOPATHY in patients with chronic

with those who had neither condition.

researchers. Retinopathy in the absence

needed to evaluate retinopathy screen-

kidney disease (CKD) is associated with

Retinopathy in the presence of albumin-

of CKD was not associated with either

ing in CKD as a noninvasive tool for

an increased risk of death, according to

uria, but not low estimated glomerular

all-cause or cardiovascular mortality.

assessment of cardiovascular risk in this

researchers.

filtration rate (eGFR), was associated

“Mechanisms underlying these

population.” The study found that 15% of the

with a significant 4.5 times and 2.6

associations are not known,” the

in the National Health and Nutrition

times increased risk of all-cause and

authors wrote, “but potential explana-

study population had CKD—defined as

Examination Survey (1988-1994), Ana

cardiovascular mortality, respectively,

tions include microvascular damage

an eGFR below 60 mL/min/1.73 m2

C. Ricardo, MD, MPH, of the Department

the researchers reported online ahead

associated with aging, hypertension,

or albuminuria (urine protein-creatinine

of Medicine at the University of Illinois

of print in the American Journal

atherosclerosis, and other vascular and

ratio of 30 mg/g or higher)—and 4.6%

at Chicago, and colleagues found that

of Kidney Diseases.

endothelial changes that might be pres-

had retinopathy. The prevalence of

ent in the retina and other vascular beds

retinopathy among participants with

such as the heart, brain, and kidneys.”

CKD was 11%. The researchers identi-

In a study of 7,640 adult participants

individuals with both CKD and retinopa-

Patients with CKD but not retinopathy

thy had a significant 2.4 times increased

had a 52% increased risk of all-cause

risk of all-cause mortality after adjust-

mortality and 72% increased risk of car-

ing for confounders when compared

diovascular mortality, according to the

RUN0514_Cvr.Nephro.indd 5

The investigators concluded: “These findings suggest that future work is

fied 2,634 deaths during a follow-up of 14.5 years. n

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6 Renal & Urology News

MAY 2014

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Contents

M A Y

2 0 1 4

■

V O L U M E

1 3 ,

Nephrology 5

ONLINE

this month at renalandurologynews.com 13

Expert Q&A Jonathan Harper, MD, of the University of Washington in Seattle, discusses the use of ultrasonic propulsion to clear kidney stones.

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 March winner: George Nassar, MD

News Coverage Visit our website for timely reports from upcoming meetings.

N U M B E R

CALENDAR

Retinopathy in CKD Patients Predicts Higher Death Risk Study reveals a significant 2.4 times increased risk of all-cause mortality in adjusted analyses.

American Urological Association Annual Meeting Orlando, Fla. May 16-22 American Society of Hypertension Annual Meeting New York May 17-20

Predictors of AKI in Lymphoma Patients ID’d Factors include sepsis, tumor lysis syndrome, and the use of diuretics and aminoglycosides, researchers concluded.

American Society of Clinical Oncology Annual Meeting Chicago May 30-June 3

CKD Patient Death Risk Tied to Diet A diet rich in processed and fried foods is independently associated with increased mortality among patients with chronic kidney disease.

European Renal Association-European Dialysis and Transplant Association Annual Meeting Amsterdam, The Netherlands May 30-June 3

Intensive Dialysis Increases Likelihood of Live Births More frequent and longer dialysis sessions should be considered for women with endstage renal disease who are pregnant or who wish to conceive, new findings suggest.

Urology 7

Drug Showcase Read up on recently approved pharmaceuticals. Our latest include: • Adempas (riociguat), for chronic hypertension • Farxiga (dapagliflozin), for type 2 diabetes • Fortesta (testosterone gel), for hypogonadism

I S S U E

Penile Traction May Work for Peyronie’s Disease Novel treatment for the acute phase of Peyronie’s disease reduced curvature and improved erectile function and hardness. Prolapse Procedures Show Similar Efficacy Study finds no significant difference in outcomes between uterosacral ligament suspension and sacrospinous ligament fixation.

CME Feature 14

Post-RP Radiotherapy Beneficial Adjuvant radiotherapy for prostate cancer decreases the risk of biochemical progression compared with a wait-and-see approach following radical prostatectomy. Two Bladder Cancer Subtypes Identified Researchers have found evidence that two intrinsic subtypes of high-grade bladder cancer exist, and these subtypes reflect the hallmarks of breast biology.

Men with positive surgical margins are the

most likely candidates to profit from adjuvant treatment. See our story on page 9

Kidney Function Assessment: The Need for a Confirmatory Test Lesley A. Inker, MD, MS, of the Tufts University School of Medicine in Boston, discusses the circumstance when it is appropriate confirm creatinine-based eGFR using measured GFR or cystatin C.

Departments 3

From the Editor Medicare payments exposed

News in Brief Statins may improve RCC surgery outcomes

www.renalandurologynews.com MAY 2014

Renal & Urology News 7

Penile Traction May Work for Peyronie’s Disease PENILE traction therapy (PTT) is an effective treatment for the acute phase of Peyronie’s disease (PD), Spanish researchers reported in The Journal of Sexual Medicine (2014;11:506-515). Juan Martínez-Salamanca, MD, PhD, of the Department of Urology at the Autonomous University of Madrid and colleagues studied 55 patients who underwent PTT, a novel penile extender device therapy, for 6 months for acute phase (AP) of Peyronie’s disease. These patients were compared with 41 patients in the acute phase of Peyronie’s disease who received no active treatment. From baseline, mean curvature in patients treated with PTT had

decreased from 33° to 15° at 6 months and 13° at 9 months, with a decrease of 20°. Erectile function and hardness improved significantly, and the proportion of patients unable to achieve penetration decreased from 62% to 20%. The need for surgery was reduced in 40% of patients who would otherwise

have been eligible, and the complexity of surgical procedures was further simplified in 1 out of 3 patients. PTT was associated with the removal of sonographic plaques in 48% of patients treated. The non-active treatment group had a significant increase in penile defor-

mity, where function and hardness worsened and stretched flaccid penile length had decreased. “PTT seems an effective treatment for the AP of PD in terms of pain reduction, penile curvature decrease, and improvement in sexual function,” the authors concluded. n

Osteoporosis Often Present Before ADT OSTEOPOROSIS is common and underdiagnosed in Danish men prior to androgen-deprivation therapy (ADT) for prostate cancer, according to a study results published online ahead of print in the Scandinavian Journal of Urology. Vitamin D insufficiency also may be underdiagnosed in these men.

patient: MARK SMITH PSA 6.2 Gleason Score 6 Oncotype DX GPS

CAN MARK CONFIDENTLY CHOOSE

ACTIVE SURVEILLANCE ?

Mads Hvid Poulsen, MD, PhD, of the Odense University Hospital in Denmark, and colleagues researchers studied at 105 PCa patients who had a mean age of 70 years. Fifty patients (48%) had localized disease and were to be treated with external beam radiation therapy

The Oncotype DX® Genomic Prostate Score (GPS) improves

(EBRT) with 3 years of ADT and 55

risk stratification to help guide initial treatment decisions. The test is for newly diagnosed men with very low, low, and low-intermediate (low volume 3+4) risk prostate cancer.

(52%) had newly-diagnosed disseminated disease and were to be treated with lifelong ADT (52%). The median PSA level was 30.5 g/L and average Gleason score was 7.8. Osteoporosis was present in 10% of patients and osteopenia was present in 58%. Furthermore, 37% of

View Mark’s GPS report and result at www.OncotypeDX.com/GPS.

patients had vitamin D insufficiency (levels below 50 nmol/L). Smoking was the only factor significantly asso-

ciated with an increased prevalence of osteoporosis, the researchers reported. n

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Dialysis, Low Creatinine Are a Bad Combination in Patients with AKI In-hospital death risk is increased, a new study found. BY DELICIA HONEN YARD STARTING dialysis in patients with acute kidney injury (AKI) may increase their death risk if they have low creatinine concentrations, new findings suggest. Dialysis can benefit patients with AKI, such as by increasing control of volume status and possibly allowing for better nutritional supplementation. Early initiation of the treatment, however, can lead to hypotension and delayed recovery of renal function, according to a research team led by F. Perry Wilson, MD, of the Renal, Electrolyte and Hypertension Division at the University of Pennsylvania School of Medicine in Philadelphia. The decision to start dialysis in patients with AKI often is subjective, based on multiple patient factors, the investigators noted. Dr. Wilson and his colleagues evaluated adults who had been admitted to 1 of 3 acute care hospitals within the University of Pennsylvania Health System from January 2004 through August 2010, and who developed severe AKI during their stay. With baseline creatinine defined as the low-

est serum creatinine concentration within 48 hours of hospital admission, all men had a baseline creatinine level of 1.4 mg/dL or lower and all women had a baseline creatinine level of 1.2 mg/dL or lower, with these levels doubling during hospitalization. A total of 545 patients in whom dialysis was initiated were matched to 545 patients for whom dialysis was not initiated on the same day of AKI.

Survival increased by 20% with each 1 mg/dL increment in serum creatinine. As Dr. Wilson’s group reported online ahead of print in the Clinical Journal of the American Society of Nephrology, the in-hospital mortality rate for patients in the highest tertile of serum creatinine level—higher than 4.2 mg/dL—was 47% for patients receiving dialysis compared with 57% for non-dialyzed patients. In the lowest tertile (serum creatinine lower than 2.8

mg/dL), in-hospital mortality was 78% for patients undergoing dialysis and 64% for those not receiving dialysis. Compared with patients in the lowest tertile, those in the highest tertile were younger (mean age 58 years compared with 60 years), were more often male (76% in the highest tertile vs. 43% in the lowest tertile), and were more often black (23% in the highest tertile vs. 8% in the lowest tertile). More patients in the lowest tertile were in the intensive care unit—95% compared with 82% of those in the highest tertile. The researchers calculated that the survival benefit yielded by dialysis increased by 20% for each increase of 1 mg/dL in serum creatinine concentration, even after adjustment for markers of disease severity. Dialysis was associated with more benefit than harm when initiated in patients with a creatinine concentration of 3.8 mg/dL or higher. The finding that dialysis may do more harm than good in a certain subset of patients “is analogous to chemotherapy for cancer,” Dr. Wilson commented. “If you are strong enough to cope with the adverse effects, it’s good for you, but if you’re weak, it may kill you.” n

AKI Predictors in Lymphoma Patients ID’d RESEARCHERS have identified factors that predict development of acute kidney injury (AKI) in patients with lymphoma, according to a recently published report in the International Journal of Nephrology. These factors include sepsis, tumor lysis syndrome, the use of diuretics and aminoglycosides, and the use of a chemotherapy regimen consisting of rituximab, cyclophosphamide, vincristine, and prednisolone (R-CVP). In addition, AKI stages 2 and 3 based on Acute Kidney Injury Network criteria were associated with increased mortality and prolonged hospital stay. The study, by Muhammad Abdul Mabood Khalil, MD, of Aga Khan University Hospital in Karachi, Pakistan, and colleagues, included 365 lymphoma patients, of whom 116 (31.8%) experienced AKI. “Lymphoma patients are prone to develop AKI due to acute tubular necrosis secondary to sepsis, nephrotoxic medications, and contrast studies,” the authors explained. Cancer patients may be immunocompromised as a result of multiple

Prolapse Procedures Show Similar Efficacy TWO common transvaginal surgical approaches for the treatment of pelvic organ prolapse lead to similar outcomes, according to a new study. “Two years after vaginal surgery for prolapse and stress urinary incontinence, neither ULS [uterosacral ligament suspension] nor SSLF [sacrospinous ligament fixation] was significantly superior to the other for anatomic, functional, or adverse event outcomes,” Linda Brubaker, MD, MS, dean of the Loyola University Chicago Stritch School of Medicine in Maywood, Illinois, and coauthors concluded in the Journal of the American Medical Association (2014;311:1023-1034).. As Dr. Brubaker and colleagues noted in their report, ULS and SSLF are transvaginal surgeries commonly performed to correct apical prolapse, yet little is known about how they compare with each other in terms of efficacy and safety. To learn more, the investi-

gators randomized 374 women with both apical vaginal prolapse and stress urinary incontinence to either SSLF (186 women) or ULS (188 women), performed at one of nine U.S. medical centers from 2008 to 2013. The primary outcome of surgical success was defined as no apical descent greater than one-third into the vaginal canal or the anterior or posterior vaginal wall behind the hymen (anatomic success); no bothersome vaginal bulge symptoms; and no retreatment for prolapse at the two-year mark. The two-year follow-up rate was 84.5%. At that time, surgical success rates were 60.5% for SSLF and 59.2% for ULS. Rates of serious adverse events were also very close, at 16.7% for SSLF and 16.5% for ULS. Dr. Brubaker’s group also used the study to determine whether perioperative behavioral therapy with pelvic floor muscle training (BPMT) improves out-

comes of prolapse surgery compared with usual care. For this part of the project, the participants were randomized to perioperative BPMT (186 women) or to usual care (188 women). BPMT involved one visit two to four weeks before surgery and four postoperative visits. At each visit, women in this group underwent pelvic floor muscle training, individualized progressive pelvic floor muscle exercise, and education on behavioral strategies to reduce urinary and colorectal symptoms. Usual care included routine perioperative teaching and standardized postoperative instructions. Primary outcomes for this part of the study were urinary symptom scores at six months, prolapse symptom scores at two years, and anatomic success at two years. The researchers found that perioperative BPMT did not significantly improve any of these measures compared with usual care.” n

factors, including chemotherapy, radiotherapy, impairment of normal leukocyte function, or corticosteroid use. Dysregulation of the immune system predisposes them to sepsis, which can lead to unregulated cytokine release and hemodynamic disturbances, they observed. “AKI usually ensues as a result of alterations in renal perfusion resulting from pro-inflammatory insults.” “We speculate that tumor lysis syndrome, concurrent sepsis with superimposed use of aminoglycosides, and diuretics use make lymphoma patients prone to develop AKI,” the researchers stated. “This in turn results in more mortality and morbidity. Therefore, patients with high grade lymphoma should be cautiously watched during their chemotherapy as they can potentially deteriorate by developing tumor lysis and subsequent AKI.” n

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OAB, SUI Worse After Vaginal Birth Regardless of delivery type, obesity ups the risk of more severe urinary symptoms, study shows FIVE years after delivering their first child, symptoms related to stress urinary incontinence (SUI) and overactive bladder (OAB) are more common and of greater severity after vaginal than cesarean birth, a study found. These differences, however, lessen with increasing time since childbirth. The study, by Victoria L. Handa, MD, of Johns Hopkins University in Baltimore, and colleagues, included 1,481 parous women enrolled 5-10 years after their first delivery. The women completed up to 5 annual assessments. During follow-up, the incidence of highly bothersome SUI and OAB were 2.5 per 100 womanyears and 1.7 per 100 woman-years, respectively. The estimated prevalence of leakage related to activity, coughing, or sneezing among women in the study’s reference group (5 years after delivery, 30 years old at first delivery, non-obese, and non-black) was 54%

Depression Linked to UI In Women URINARY incontinence (UI) may increase the risk for probable depression and work disability among women, according to a study published in Obstetrics & Gynecology (2014;123:822-827). Kristin J. Hung, MD, of Harvard Medical School in Boston, and colleagues studied a sample of 4,511 women enrolled in the population-based Health and Retirement Study cohort. The analysis baseline was 1996, the

among those who had at least 1 vaginal birth versus 20% among women who only had cesarean delivery, Dr. Handa’s group reported online ahead of print in Neurourology and Urodynamics. The vaginal birth group

Researchers enrolled 1,481 parous women 5-10 years after their first delivery. also had a higher estimated prevalence of leakage of “drops” (37% vs. 17%), frequent urination (27% vs. 17%), need to rush to the bathroom for urination (17% vs. 7%), and leakage related to a feeling of urgency (17% vs. 7%). The relative odds of leakage related to activity, coughing, or sneezing increased by 6% per year since first

birth in the cesarean section group, but did not change in the vaginal birth group. In both groups, the relative odds of urinary urgency (the need to rush to the bathroom for urination) increased significantly with increasing time from first birth (7% per year in the cesarean group and 6% in the vaginal birth group). “This study suggests a substantial impact of vaginal delivery on the presence and on the severity of urinary symptoms, especially 5 years from delivery,” the authors concluded. “However, over the subsequent 5 years, the odds for urinary symptoms increase annual among those who delivered by cesarean, especially for symptoms related to SUI.” The researchers also found that obesity was strongly associated with symptoms related to SUI and OAB. In the vaginal birth group, obese women had a significant 47% increased likelihood

of leakage related to activity, coughing, or sneezing and a significant 43% increased likelihood of nocturia compared with non-obese women. In the cesarean group, obese women, compared with non-obese women, had a significant 2.5 times increased likelihood of leaking related to activity, coughing, or sneezing. They also had a significant 2.9 and 2.6 times increased odds of needing to rush to the bathroom for urination and leaking related to a feeling of urgency, respectively, as well as a significant 67% increased likelihood of frequent urination and a significant 62% increased likelihood of nocturia. The authors concluded that obesity is an important risk factor for bladder symptoms “and therefore obesity control should be a primary target for reduction of incontinence and incontinence severity among parous women.” n

Post-RP Radiotherapy Beneficial ADJUVANT radiotherapy (ART) for prostate cancer (PCa) decreases the risk of biochemical progression compared with a wait-and-see approach following radical prostatectomy (RP), new findings suggest. The findings are from a study of 307 men with pT3 pN0 PCa who achieved an undetectable PSA level after RP and were randomized to wait-and-see (159 patients) or 3D conformal ART (148 patients). The median follow-up was 111 months and 113 months for the ART and wait-and-see groups, respectively.

At 10 years, the progression-free survival (PFS) rate was 56% for the ART group compared with 35% for the wait-and-see group, which translated into a significant 49% decreased risk of disease progression, the researchers reported online ahead of print in European Urology. The investigators defined disease progression as biochemical recurrence, clinical recurrence, or death. ART did not significantly improve metastasisfree or overall survival, but the study was not adequately powered for these endpoints, the authors pointed out.

The benefit of ART was especially pronounced in men with positive surgical margins. In this group, the 10-year PFS was 57% for ART recipients and 27% for the wait-and-see patients, according to the researchers. “Men with positive surgical margins are the most likely candidates to profit from adjuvant treatment,” the investigators concluded. In the ART group, the worst late sequelae were 1 grade 3 and 3 grade 2 cases of bladder toxicity and 2 grade 2 cases of rectum toxicity. The researchers observed no grade 4 events. n

Study: Hemodialysis May Trigger Atrial Fibrillation

year that questions about UI were added to survey instruments and at which time the women were aged 54-65 years. Participants were followed with biennial interviews until 2010-2011. At baseline, 727 women reported UI. Results showed that UI was associated with a 43% increased risk of probable depression and a 21% increased risk of work disability. n

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RESEARCHERS who studied a group of hemodialysis (HD) patients with implantable cardioverter defibrillators found that atrial fibrillation (AF) onset occurs significantly more frequently on dialysis days and specifically increases during the dialysis procedure itself, according to a study published online ahead of print in Heart. Additionally, results showed that patients with AF have a larger left atrium and a higher systolic blood pres-

AF occurs more often on a dialysis day and especially during dialysis. sure before and after HD, the investigators reported. The study, led by Lieselot van Erven, MD, of Leiden University Medical

Center in Leiden, The Netherlands, included 40 patients (80% male) with a mean age of 70 years and mean follow-up of 28 months. The researchers monitored 428 episodes of AF in 14 patients. “These findings might help to elucidate some aspects of the pathophysiology of AF in dialysis patients and could facilitate early detection of AF in these high-risk patients,” Dr. van Erven and colleagues concluded. n

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BPH Surgery Outcome Predictors ID’d Perioperative mortality risk is higher in men with low preoperative albumin levels or hematocrit ADVANCED age, non-Caucasian race, and low preoperative albumin levels and hematocrit predict adverse outcomes following surgery for benign prostatic hyperplasia (BPH), according to a study. In a study of 7,359 men who underwent BPH surgery, each 1 year increment in patient age was independently associated with a significant 3% increased risk of complications, a significant 10% increased risk of perioperative mortality, and a 1% increased likelihood of a prolonged (2 days or more) length of stay (pLOS), researchers reported online ahead of print in the Journal of Endourology. Non-Caucasian race was independently associated with a significant 55% increased risk of complications compared with Caucasian race. “In patients with these attributes, conservative treatment might be a reasonable alternative,” Naeem Bhojani, MD, and Giorgio Gandaglia, MD, of the

CKD Patient Death Risk Tied to Diet A DIET rich in processed and fried foods is independently associated with increased mortality among patients with chronic kidney disease (CKD), according to a new study. Orlando M. Gutiérrez, MD, of the University of Alabama in Birmingham, and colleagues examined the relationship between dietary patterns and allcause mortality and end-stage renal disease (ESRD) in 3,972 participants with CKD in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study, a prospective cohort study of 30,239 black and white adults aged 45 years or older. Based on information provided by participants who filled out food frequency questionnaires, the researchers arrived at five dietary patterns: the “convenience” diet (high intake of Chinese and Mexican foods, pizza, and other mixed dishes); “plant-based” (high intake of fruits and vegetables); “sweets/fats” (high intake of sugary foods); “Southern” (high intake of fried

Centre Hospitalier de l’Université de Montreal, and collaborators concluded. A preoperative albumin level greater than 3.5 g/dL was associated with a significant 59% decreased risk of complications and 87% decreased risk of perioperative mortality compared with a preoperative level below 2.5 g/dL. Compared with a preopera-

Complication risk increases by 3% with each 1-year increment in age. tive hematocrit below 30%, a level of 30%-45% and above 45% was associated with a significant 70% and 71% decreased likelihood of pLOS, respectively. A preoperative hematocrit of 30%-45% was associated with a significant 91% decreased likelihood of

foods, organ meats, sugar-sweetened beverages, and greens common found in the Southern diet); and “alcohol/salads” (high intake of alcohol, green leafy vegetables, and salad dressing). The researchers calculated dietary pattern scores based on the participants’ intake of various foods. After a mean 6.5 years of followup, 816 participants died and 141 progressed to ESRD. Results showed no significant associations between convenience, sweets/fats, or alcohol/ salads pattern scores and all-cause mortality after adjusting for multiple variables, Dr. Gutiérrez’s team reported online ahead of print in the American Journal of Kidney Diseases. Participants in the highest quartile of Southern pattern score had a 51% increased risk of all-cause mortality compared with those in the lowest quartile after adjusting for confounding factors. In contrast, participants in the highest quartile of plant-based pattern scores had a 23% decreased risk of all-cause mortality compared with those in the lowest quartile, according to the investigators. In addition, after a mean 6.4 years of follow-up, 141 participants initiated dialysis. In a fully adjusted model, none of the dietary patterns were associated with the risk of ESRD. n

a needing a blood transfusion and a significant 79% decreased risk of perioperative mortality. The investigators noted that prior studies have shown that low hematocrit is associated with chronic inflammatory disease states and infectious processes and has also been shown to increase mortality in patients undergoing hemodialysis. “Therefore, it is possible that patients with BPH and low hematocrit have a combination of chronic prostatic inflammation and lower hemoglobin, which may place them at risk of perioperative mortality,” they wrote. They concluded that “preoperative hematocrit and albumin levels represent reliable serum markers for prediction of adverse outcomes, suggesting that these markers should be evaluated before BPH surgery.” Using data from the American College of Surgeons National SurgicalQuality Improvement Program database, the researchers compared out-

comes after transurethral resection of the prostate (TURP), laser vaporization of the prostate (LVP), and laser enucleation of the prostate (LEP). The study population included 4,794, 2,439, and 126 men who underwent TURP, LVP, and LEP, respectively. The researchers found no significant difference in overall complication rates or perioperative mortality among the three surgical groups. The overall complication rates associated with TURP, LVP, and LEP were 6.5%, 6.4%, and 3.2%, respectively. Compared with TURP, LVP and LEP were associated with a significant 88% and 65% decreased likelihood of a pLOS, respectively. Patients in the TURP and LEP groups did not differ significantly in the likelihood of requiring re-intervention and blood transfusions, but LVP patients had a significant 37% and 79% decreased risk of re-intervention and blood transfusion compared with the TURP group. n

Bone Turnover Biomarkers May Predict CRPC Course ELEVATED levels of serum biomark-

Elevated baseline levels of each of

ers of bone metabolism predict poor

the bone turnover markers studied—

survival among patients with castration-

N-telopeptide and pyridinoline for bone

resistant prostate cancer (CRPC),

resorption, and C-terminal collagen pro-

according to a study. Men with the high-

peptide and bone alkaline phosphatase

est levels of these biomarkers, however,

for bone formation—were associated

appeared to have the best response

with worse survival, as were marker lev-

to the investigational drug atrasentan,

els that increased by week 9 of therapy,

which had failed in previous trials.

the researchers reported online ahead

With prior studies suggesting that

of print in the Journal of the National

elevated markers of bone turnover

Cancer Institute. Yet, approximately

are prognostic for poor survival in

6% of the patients with the highest

CRPC, Primo N. Lara, Jr., MD, of

levels of all markers showed a survival

the University of California Davis

benefit from atrasentan, despite their

Comprehensive Cancer Center, and

poor prognosis. The median survival

colleagues prospectively evaluated

for patients on atrasentan was 13

not only the prognostic role of these

months compared with 5 months for

levels, but also their predictive role

the placebo group.

relative to bone-targeted therapy. The

In a university-issued statement,

investigators analyzed bone biomark-

Dr. Lara explained: “Because certain

ers in the sera of 778 men with CRPC

drugs only succeed in a fraction of

who had participated in a phase 3 pla-

patients, drug makers need to factor

cebo-controlled trial of docetaxel with

in these bone metabolism markers in

or without atrasentan, a bone-targeted

their trial design. They need to target

endothelin-A receptor antagonist.

the patients most likely to benefit.” n

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CME FEATURE

Kidney Function Assessment: The Need for a Confirmatory Test Confirmation of creatinine-based eGFR should be performed in select circumstances using, where appropriate, either measured GFR or cystatin C

Release Date: May 2014 Expiration Date: May 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: Although adrenal masses are often discovered incidentally, only appropriate evaluation can establish these neoplasms as insignificant. Indeed, some data suggest that more than 15% of lesions may require resection. As such, modern management of so-called adrenal incidentalomas pivots on informed and individualized treatment choices. TARGET AUDIENCE: This activity has been designed to meet the needs of urologists, nephrologists, and allied healthcare clinicians who treat patients with adrenal tumors. EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • To evaluate the best way to estimated glomerular filtration rate (GFR) in the current era • To identify situations when confirmatory tests for GFR are appropriate • To define the advantages and disadvantages of all GFR estimates 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 Lesley A. Inker, MD

Grants/Research Support Pharmalink AB, Gilead Sciences, NIH, NKF

BY LESLEY A. INKER, MD, MS

linical assessment of kidney function is central to the practice of medicine. Glomerular filtration rate (GFR) is widely accepted as the best index of kidney function in health and disease and accurate values are required for optimal decision making in many clinical settings, including detection of kidney disease, understanding its severity, and for making decisions about diagnosis, prognosis and treatment1. Estimated GFR based on serum creatinine (eGFRcr) is now widely reported by clinical laboratories and is available in most clinical encounters as a “first line” test of kidney function. In other fields of medicine, first-line tests are followed by more accurate confirmatory tests when required. Classically, the confirmatory tests available for clinicians are measured GFR using urinary or plasma clearance of exogenous filtration markers at specialized centers, or measured creatinine clearance from timed urine collections. However, timed urine collections are difficult to obtain and

fraught with error. More recently, there are data that the use of estimated GFR creatinine in combination with cystatin C can also serve as a confirmatory test. I suggest that confirmation of eGFRcr should be performed in select circumstances using, where appropriate, either measured GFR or cystatin C. In this review, I will describe indications for use of a confirmatory test and then briefly review the strengths and limitations of each.

Current methods to estimate GFR GFR is most commonly estimated from serum creatinine using the Modification of Diet in Renal Disease (MDRD) Study equation or the Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) equation.2,3 It is estimated that serum creatinine is ordered to estimate the GFR more than 281 million times annually in the U.S., and recent reports show that more than 80% of U.S. clinical laboratories now report estimated GFR (eGFR) whenever serum creatinine

The content managers, Jody A. Charnow and Marina Galanakis, of Haymarket Medical Education, and planners from 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 May 2014 through May 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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Lesley A. Inker, MD, MS, is a nephrologist and Director of the Kidney and Blood Pressure Center and Kidney Function Evaluation Center at Tufts Medical Center in Boston, where she is Associate Professor of Medicine at the Tufts University School of Medicine.

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is ordered.4,5 An increasing number of laboratories are now beginning to use the CKD-EPI 2009 creatinine equation6,7 (personal communication Olivier Allaire and Tazeen Jafar). The CKD-EPI creatinine equation was published in 2009 and was shown in the original publication, as well as several publications since then, to be more accurate than the MDRD Study equation, particularly at higher levels of GFR.3,8,9 In addition, several publications, including a large meta-analysis, have demonstrated that the CKD-EPI equation better predicts future risk for adverse outcomes than the MDRD Study equation.10 As such, in most stable outpatients without major co-morbid conditions, the CKD-EPI equation provides GFR estimates that are sufficiently accurate for clinical decision making. However, large differences between measured and estimated GFR may be observed in some populations and clinical settings. Recognition of the strengths and limitations of any estimating equation and particular clinical settings when creatinine-based GFR estimates are likely to be inaccurate enable identification of patients in whom a kidney function confirmatory test should be considered.

Creatinine and all serum levels of endogenous filtration markers are determined by generation, renal excretion (filtration, secretion, and reabsorption), and extra-renal elimination. Estimating equations use easily measured clinical variables as surrogates for these unmeasured physiologic processes and provide more accurate estimates than the serum level alone.11 However, equations can only capture the average relationship of the surrogates to some of these physiologic processes, leading to error in some individuals (Table 1). Creatinine-based estimating equations include age, sex, race, or weight as surrogates for differences in creatinine generation from muscle mass.11 The individuals most likely to have large differences between measured and estimated GFR are those who are at the extremes of muscle mass and diet, who are malnourished or have a reduction in muscle mass from illness or amputation, who are of different races or ethnicities from individuals included in studies used to develop the equations, or who have changes in the non-GFR determinants over time.11-13 Use of a confirmatory test may be helpful in such patients or in clinical circumstances in which

decisions based on inaccurate estimates may have adverse consequences. Below is a description of clinical situations in general medicine and nephrology where use of cystatin or measurement of GFR should be considered (Table 2). Reliance on eGFRcr could lead to medical errors in these populations, such as toxicity from excess medication doses and inappropriate use of imaging tests, or inappropriate decisions regarding dialysis initiation or kidney donation.

Use of cystatin C to estimate GFR Cystatin C is a 13,347 Dalton protein consisting of 120 amino acid residues. It is expressed in all nucleated cells and is reported to be produced at a relatively constant rate.14 Circulating cystatin C levels were originally considered to have minimal non-GFR determinants, but it is now recognized that there is some variation in generation among and within people. Serum cystatin C concentrations are higher in men and in younger individuals compared with older people. Levels are increased with high-dose glucocorticoid therapy and hyperthyroidism. Higher blood cystatin C levels have also been reported in smokers and in

Renal & Urology News 15

association with high C-reactive protein levels and greater fat mass. There appears to be extra-renal elimination at lower levels of GFR. These factors may affect the accuracy of estimating equations based on cystatin C (Table 1). The CKD-EPI group developed and evaluated equations using cystatin C alone and in combination with creatinine in a diverse population.15 The CKD-EPI 2012 cystatin C equation (eGFRcys) also includes age and sex, although of smaller magnitude than for the creatinine equation, but importantly does not include a term for race. In the combined creatinine and cystatin C equation (eGFRcr-cys), the coefficients for serum creatinine and cystatin C are about half the magnitude of the coefficients in equations with the creatinine and cystatin C equations, and the age, sex, and race coefficients are intermediate between the creatinine and cystatin C equations. Evaluation in the validation populations separate from which the equations were developed showed similar accuracy of eGFRcys and eGFRcr but higher accuracy of eGFRcr-cys. There were few African Americans in the validation population, and the lack of a race term in the cystatin C estimating

Table 1: Non-GFR Determinants of Creatinine and Cystatin and their Impact on Performance of Estimating Equations Clinical State

Factor

Bias of eGFRcr relative to measured GFR

Body composition

• Muscular • Fat • Amputation

• Underestimate

Chronic illness

• Muscle wasting • Inflammation

• Overestimate

Diet

• Increase in animal protein intake • Increase in caloric and fat intake

• Underestimate

• No known effects • Underestimate

Patients with kidney transplantation may increase their overall caloric intake, leading to increased muscle and fat mass as well as protein intake

Medications

• Trimethoprim • Corticosteroids • Antibiotics

• Underestimate • Overestimate • Underestimate

• Not known effects • Underestimate • Not studied

Patients with kidney transplantation are on trimethoprim and steroids, which may affect both levels of creatinine and cystatin separately from their effect on GFR. Measured GFR may be necessary to obtain accurate level of GFR

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• Overestimate

Bias of eGFRcys relative to measured GFR • Underestimate

• Underestimate

Clinical Example Patients with high body mass index may have high levels of both muscle and fat, which would lead to underestimates of measured GFR using both markers. Measured GFR may be necessary to obtain accurate level of GFR Patients with kidney failure not on dialysis may have reduced muscle mass and inflammation. Thus, eGFRcr and eGFRcys may provide biased estimates in the opposite direction, whereas eGFRcr-cys may average these effects and provide unbiased and more precise estimates

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CME FEATURE equation will therefore require further evaluation. Performance in other subgroups showed uniform higher accuracy of eGFRcr-cys over eGFRcr and eGFRcys, with a greater accuracy of eGFRcys over eGFRcr for subgroups with lower BMI, and lesser accuracy at higher BMI.16 The lesser accuracy of eGFRcys at higher levels of BMI is thought to be secondary to the relationship of fat mass to cystatin C generation. There were small differences in accuracy in people according to diabetes status. Based on a small number of studies, the performance of the CKD-EPI cystatin C equation is better than the CKD-EPI creatinine equation in regions outside North America, Europe, and Australia, and requires less or no modification by a local coefficient.17,18 Other studies have confirmed the findings that eGFRcr-cys is more precise than eGFRcr or eGFRcys and that eGFRcys may not require a local coefficient for racial or ethnic groups.19-22 In addition, other investigations, including a large meta-analysis, have demonstrated that eGFRcys and eGFRcr-cys provide better estimates of risk than eGFRcr.23

Measured GFR The gold standard for the measurement of GFR is urinary clearance of an ideal filtration marker, defined as a substance that is freely filtered at the glomerulus, neither reabsorbed, secreted, synthesized, or metabolized by the tubules, and does not alter the function of the kidney. Inulin, a 5,200-dalton, inert, uncharged polymer of fructose, is the only known ideal filtration marker. However, inulin is difficult to handle and the procedures are invasive. Because of these disadvantages, we use alterative clearance methods and filtration markers. Below is a brief description of methods that could be used in clinical practice in the U.S. at this time. The details of the comparisons of the accuracy of these methods are beyond the scope of this article and have been reviewed elsewhere.24,25

Clearance methods Urinary clearance. Urinary clearance is the most direct method for measurement of GFR. Clearance is calculated as the urine concentration of the exogenous or endogenous filtration marker,

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multiplied by the volume of the timed urine sample, and divided by the average plasma concentration during the same time period. Measurement of creatinine or urea clearance is possible to perform in every clinical center. A long collection period, generally between 6 and 24 hours, is used to avoid the requirement for water loading. If the patient is in steady state, a single blood sample obtained either at the beginning or end of the collection period may be used to represent the average serum concentration during the urine collection. If the patient is not in steady state, use of the average of the serum concentrations at the beginning and end of the collection period should provide a better estimate of the average concentration. Timed collections are subject to errors due to inaccurate recording of time and completion of urine collection. Averaging over repeated measurements may minimize the impact of error, but is quite burdensome to the patient. It is not possible to perform urinary clearance of cystatin C as it is catabolized and then reabsorbed by the tubules. Measurements of urinary clearance of an exogenous filtration marker are only possible in centers that have been set up to perform such procedures. In general, the protocol is to administer the filtration marker, wait for equilibrium to develop, and then collect the urine over multiple (usually 2-4) 20-30 minute urine collections, with blood samples before and after each 20-30 minute period. Clearance is computed for each urine collection period, and the results are averaged. Advantages include a relatively short duration of time and comparison of the individual periods allows for an assessment of quality of test results. The marker is administered by intravenous (IV) bolus or subcutaneous bolus injection. Spontaneous voiding limits its use in populations with impaired urinary incontinence or retention, such as the elderly or children with urinary tract abnormalities. The protocol is prone to error, particularly related to complete collection of the urine and urinary retention. As such, overall reliability is highly variable across centers, thus limiting its interpretation for any one value. Plasma clearance. There is increasing interest in measuring plasma clearance to avoid inconvenience and errors from timed urine collections. In principle,

Table 2: Indications of Measured GFR Detection of CKD and AKI

CKD or AKI may be difficult to detect in circumstances where the GFR is overestimates (e.g., amputation or muscle wasting). In some circumstances, eGFRcys or eGFRcr-cys may help detect disease.

Drug dosage adjustment

The kidneys excrete many drugs, and some medicinals have a narrow therapeutic window. Confirmation of eGFRcr should be considered prior to initiation of prolonged and potentially toxic therapy, such as cancer chemotherapy. Possibly, toxicities of some therapeutic agents could be reduced, and therapeutic efficacy improved, if more accurate GFR values were used to determine dosage. Use of cystatin C for drug dosing has not been studied and important to test whether the medication has an effect on nonGFR determinants of cystatin C.

Imaging tests

Contrast agents containing iodine and gadolinium have heightened toxicity at low GFR, requiring individual decision making regarding risks and benefits of imaging tests.

Monitoring impact or toxicity of treatments

Nephrotoxicity is a major concern in the use of drugs. However, drugs may also affect non-GFR determinants of serum creatinine or cystatin C by decreasing generation or inhibiting tubular secretion or extra-renal elimination. In addition, drugs may affect overall health status, leading to changes in creatinine generation from diet or muscle mass, or in cystatin C from fat mass. In these circumstances, measured GFR may be necessary to distinguish drug effects on serum creatinine or cystatin C due to GFR versus non-GFR determinants.

Decision for kidney donation

If the estimated GFR is low in an otherwise healthy potential kidney donor, measured GFR should be considered so as to not exclude an otherwise eligible kidney donor.

Decision of initiation of RRT

Timing of access placement, preemptive transplantation, and initiation of dialysis are generally determined based on an estimated GFR and patient symptoms. Symptoms of uremia are non-specific and inaccurate eGFR could lead to inappropriate initiation or delays in start of dialysis.

Evaluation and management of kidney transplant recipients

Interpretation of changes in eGFR following kidney transplantation can be challenging. There are multiple factors that affect non-GFR determinants of serum creatinine and cystatin C, such as liberalization of diet and use of trimethoprim and corticosteroids. Measured GFR may be necessary in complex cases in which it is suspected that both GFR and GFR determinants of serum creatinine and cystatin C are changing.

plasma clearance should be unbiased and more precise compared with urinary clearance except for markers that undergo extra-renal elimination. GFR is calculated from plasma clearance following a bolus IV injection of an exogenous filtration marker, with clearance computed from the amount of the marker administered using the area under the curve of plasma concentration over time. The decline in serum levels is secondary to the immediate disappearance of the marker from the plasma into its volume of distribution (fast component) and to renal excretion (slow component). This is best estimated using a two-compartment model that requires blood sampling early (usually 2-3 time points until 60 minutes) and late (1-3 time points from 120 minutes forward), but equations

have been developed to use only the late time points.26,27 The major disadvantage of plasma clearance is the length of time required (~4 hours at high levels of GFR and 8-24 hours at low levels of GFR). 28 Shorter time periods may lead to overestimation of GFR.29 Second, a large volume of distribution, such as edematous conditions, prolongs the initial component leading to an overestimation of GFR.30

Exogenous filtration markers Iothalamate. Iothalmate is commonly administered as a radioactive iodine label for ease of assay after small doses, but can also be administered in its non-radioactive form and measured using high performance liquid

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chromotography (HPLC) without impact on its filtration properties. In the radioactive form, it is most commonly administered using bolus subcutaneous injection. To block thyroidal uptake, cold iodine is administered at the time of 1,25 I-iothalmate administration, thus precluding its use in people with known allergies to iodine, such as iodine in shellfish or iodinated contrast media. Iohexol. Concern about radiation led to the use of a non-radioactive radiographic contrast agent, iohexol. Iohexol is administered most often using bolus IV injection for plasma clearance, but could be used for urinary clearance, as well. Other advantages include low expense, wide availability, stability in biologic fluids, and rare adverse reactions when given as a small dose (5 mL 300 mg/mL iodine when assayed with a sensitive HPLC assay). Major limitations are the complexity and expense of the HPLC assay. Diethethylenetriaminopenta-acetic acid (DTPA). DTPA is usually labeled with 99mTc. Advantages include a short half-life (6 hours) that minimizes radiation exposure, high counting efficiency of 99mTc, and is commonly used in most nuclear medicine departments. Its major limitation is the potential for dissociation of 99mTc from DTPA and binding to plasma proteins. The extent of dissociation is not predictable, leading to imprecision as well as bias. In addition, chelating kits and technetium generators are not standardized in the U.S., making comparisons of measured GFR among different institutions difficult.

Clinical recommendations There are a variety of differences among markers and clearance methods for GFR measurement compared with the classic method of inulin clearance. However, the bias appears relatively small, and imprecision can be reduced by adhering to standardized protocols, providing accuracy substantially greater than estimated GFR. Based on advantages and disadvantages described above, plasma clearance of non-radioactive exogenous markers is likely the most simple to implement by clinical laboratories not already performing GFR measurements. However, one should consider the laboratory in which the exogenous

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marker will be assayed, as these methods are highly sensitive to error.

When to use confirmatory tests for eGFR from creatinine The KDIGO [Kidney Disease: Improving Global Outcomes] 2012 update to the clinical practice guidelines for evaluation and management of chronic kidney disease included several recommendations for the evaluation of GFR. The guidelines recommended using eGFRcr for initial assessment and eGFR cys or eGFRcr-cys or a measured GFR for confirmatory testing in specific circumstances when eGFRcr is less accurate (Table 2). The KDIGO guideline also recommends that for adults with eGFRcr 45-59 mL/ min/1.73m2 without markers of kidney damage, clinicians should measure cystatin C if confirmation of CKD is required. If eGFRcr-cys is also below 60 mL/min/1.73m2, the diagnosis of CKD is confirmed. If eGFRcr-cys is 60 mL/min/1.73m2 or above, the diagnosis of CKD is not confirmed. This recommendation is based on reclassification analyses based on data from the National Health and Nutrition Examination Survey (NHANES).15 The KDIGO guidelines do not make other specific recommendations as to other circumstances under which cystatin C-based estimates should be used as the confirmatory test or when one should move directly to measured GFR. The advantage of the eGFRcr-cys equation is that each filtration marker provides approximately 50% of the information, and as such lessens the impact of the non-GFR determinants of each marker. As described above, data has shown that eGFRcr-cys provides more accurate estimates than either marker alone across a range of subgroups. Use of the combined creatinine and cystatin C equation is likely to provide the best estimate in most circumstances. In circumstances of uncertainty, where there is large discordance between eGFRcr and eGFRcys, and particularly where accurate levels of GFR are required, measurement of GFR should be considered.

Conclusions GFR estimation is essential to the assessment of kidney disease. GFR

estimating equations provide more accurate estimates from serum markers than serum markers alone, and can be used in most clinical encounters, but have serious limitations in some circumstances. Measured GFR and estimated GFR based on cystatin C in combination with creatinine are two confirmatory tests that can be used to enhance clinical decision making. New data on eGFRcr-cys suggests that it is more accurate than either eGFRcr or eGFRcys. Protocols for GFR measurement have been widely tested and are accurate and safe. Nephrologists should provide leadership in changing the paradigm of a single test to assess GFR to the use of initial tests followed by confirmatory tests where applicable, and in collaboration with clinical laboratories or nuclear medicine departments, in the implementation of GFR measurement protocols in their local institutions. Further research is necessary to determine specific circumstances when confirmatory tests should be implemented but in the meantime, the above suggestions are a start. n REFERENCES 1. Levey AS, Inker LA, Coresh J. GFR Estimation: From Physiology to Public Health. Am J Kidney Dis. Jan 28 2014. 2. Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. Aug 15 2006;145(4):247-254. 3. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. May 5 2009;150(9):604-612. 4. Stevens LA, Schmid CH, Greene T, et al. Comparative performance of the CKD Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) Study equations for estimating GFR levels above 60 mL/min/1.73 m2. Am J Kidney Dis. Sep 2010;56(3):486-495. 5. College of American Pathologists. Current Status Of Reporting Estimated Glomerular Filtration Rate (eGFR). 2011; http://www.cap.org/apps/cap. portal?_nfpb=true&cntvwrPtlt_actionOverride=% 2Fportlets%2FcontentViewer%2Fshow&_windowL abel=cntvwrPtlt&cntvwrPtlt%7BactionForm.cont entReference%7D=committees%2Fchemistry%2F chemistry_resources.html&_state=maximized&_ pageLabel=cntvwr. Accessed December 5, 2011. 6. LabCorp. Lab Horizons. [web]. 2011; https://www. labcorp.com/wps/wcm/connect/97cc568048949 9ed88f4ef1d8cc08f20/LabHorizons+Vol+11+No+ 10+(Sept+2011)--FINAL.pdf?MOD=AJPERES&CAC HEID=97cc5680489499ed88f4ef1d8cc08f20&CA CHEID=6400b30048921344ab8ffb30c787aa90. Accessed October 25, 2011. 7. Quest Diagnostics. Estimating Glomerular Filtration Rate Equation Update. 2001; http://www.wpakidneysupport.org/documents/Quest%20Estimated%20 Glomerular%20Filtration%20Rate.pdf. Accessed August 1, 2012.

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8. Earley A, Miskulin D, Lamb EJ, et al. Estimating equations for glomerular filtration rate in the era of creatinine standardization: a systematic review. Ann Intern Med. Jun 5 2012;156(11):785-795. 9. Inker LA, Levey AS. Pro: Estimating GFR using the chronic kidney disease epidemiology collaboration (CKD-EPI) 2009 creatinine equation: the time for change is now. Nephrol Dial Transplant. Jun 2013;28(6):1390-1396. 10. Matsushita K, Mahmoodi BK, Woodward M, et al. Comparison of risk prediction using the CKDEPI equation and the MDRD study equation for estimated glomerular filtration rate. JAMA. May 9 2012;307(18):1941-1951. 11. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function--measured and estimated glomerular filtration rate. N Engl J Med. Jun 8 2006;354(23):2473-2483. 12. Ma YC, Zuo L, Chen JH, et al. Modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney disease. J Am Soc Nephrol. Oct 2006;17(10):2937-2944. 13. Imai E, Horio M, Nitta K, et al. Modification of the Modification of Diet in Renal Disease (MDRD) Study equation for Japan. Am J Kidney Dis. Dec 2007;50(6):927-937. 14. Inker LA, Okparavero A. Cystatin C as a marker of glomerular filtration rate: prospects and limitations. Curr Opin Nephrol Hypertens. 2011;20(6):631-639. 15. Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367(1):20-29. 16. Fan L, Inker LA, Rossert J, et al. GFR Estimation Using Cystatin C Alone or Combined with Creatinine as a Confirmatory Test. Nephrol Dial Transplant. (In Press). 17. Horio M, Imai E, Yasuda Y, et al. GFR estimation using standardized serum cystatin C in Japan. Am J Kidney Dis. Feb 2013;61(2):197-203. 18. van Deventer HE, Paiker JE, Katz IJ, George JA. A comparison of cystatin C- and creatinine-based prediction equations for the estimation of glomerular filtration rate in black South Africans. Nephrol Dial Transplant. May 2011;26(5):1553-1558. 19. Rule AD, Bergstralh EJ, Slezak JM, et al. Glomerular filtration rate estimated by cystatin C among different clinical presentations. Kidney Int. Jan 2006;69(2):399-405. 20. Ma YC, Zuo L, Chen JH, et al. Improved GFR estimation by combined creatinine and cystatin C measurements. Kidney Int. Dec 2007;72(12):1535-1542. 21. Schaeffner ES, Ebert N, Delanaye P, et al. Two novel equations to estimate kidney function in persons aged 70 years or older. Ann Intern Med. Oct 2 2012;157(7):471-481. 22. Teo BW, Xu H, Koh YY, et al. Estimating kidney function in a multiethnic Asian population with multiple filtration markers. Am J Kidney Dis. Sep 2012;60(3):500-502. 23. Shlipak MG, Matsushita K, Arnlov J, et al. Cystatin C versus creatinine in determining risk based on kidney function. N Engl J Med. 2013;369(10):932-943. 24. Stevens LA, Levey AS. Measured GFR as a confirmatory test for estimated GFR. J Am Soc Nephrol. Nov 2009;20(11):2305-2313. 25. Inker LA, Levey AS. Assessment of glomerular filtration rate in acute and chronic settings In: Gilbert SJ, Weiner DE, eds. Primer on Kidney Diseases. 6th ed. Philadelphia, PA: Elsevier Saunders 2013:26-32. 26. Brochner-Mortensen J. Routine methods and their reliability for assessment of glomerular filtration rate in adults, with special reference to total [51Cr]EDTA plasma clearance. Dan Med Bull. Oct 1978;25(5):181-202. 27. Schwartz GJ, Furth S, Cole SR, et al. Glomerular filtration rate via plasma iohexol disappearance: pilot study for chronic kidney disease in children. Kidney Int. Jun 2006;69(11):2070-2077. 28. Gaspari F, Perico N, Ruggenenti P, et al. Plasma clearance of nonradioactive iohexol as a measure of glomerular filtration rate. J Am Soc Nephrol. Aug 1995;6(2):257-263. 29. Agarwal R, Bills JE, Yigazu PM, et al. Assessment of Iothalamate Plasma Clearance: Duration of Study Affects Quality of GFR. Clin J Am Soc Nephrol. 2009;4:77-85. 30. Skluzacek P, Szewc R, Nolan C, Riley D, Lee S, Pergola P. Prediction of GFR in liver transplant candidates. Am J Kidney Dis. 2003;42(6):1169-1176.

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 Media, Inc. 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 Media, Inc. 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 FEATURE CME Post-test Expiration Date: April 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. What is a determinant of any endogenous filtration marker? a. Muscle mass b. Dietary protein intake c. Renal excretion (filtration, secretion, and reabsorption) d. Inflammation 2. The CKD-EPI equation differs from the MDRD Study equation in which of the following ways: a. It includes a term for diabetes b. It better estimates measured GFR c. It better predicts future risk for adverse events d. All of the above e. Both b and c 3. Which of the following are advantages of eGFRcr-cys over eGFRcr a. It is less biased b. It is more precise c. It provides better estimates of risk d. Each filtration marker provides approximately 50% of the information, and as such lessens the impact of the non-GFR determinants of each marker e. All of the above f. b, c, and d 4. Which of the following did KDIGO recommended for evaluating GFR? a. Use eGFRcr for initial assessment and eGFR cys or eGFRcr-cys or a measured GFR for confirmatory testing in specific circumstances when eGFRcr is less accurate b. Use eGFRcr-cys in all circumstances to replace eGFRcr c. Use eGFRcys in all circumstances to replace eGFRcr 5. How is urinary clearance calculated? a. Urine concentration of the exogenous or endogenous filtration marker, multiplied by the volume of the timed urine sample, and divided by the average plasma concentration during the same time period. b. Urine concentration of the exogenous or endogenous filtration marker, divided by the average plasma concentration during the same time period. c. Urine concentration of the exogenous or endogenous filtration marker, multiplied by the volume of the timed urine sample d. Clearance computed from the amount of the marker administered using the area under the curve of plasma concentration over time 6. What are advantages of plasma clearance methods to measure GFR? a. Avoids inconvenience and errors from timed urine collections leading to more precision of the measured GFR value b. Avoids inconvenience and errors from timed urine collections leading to less bias c. Shorter test than urinary clearance d. More accurate measures in patients with extensive third spacing (e.g., cirrhosis)

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Intensive Dialysis Increases Likelihood of Live Births MORE frequent and longer dialysis sessions should be considered for women with end-stage renal disease (ESRD) who are pregnant or who wish to conceive, according to the findings of a recent study. Pregnancy is rare in women with ESRD and is often accompanied by significant maternal and fetal morbidity and even mortality, Michelle A. Hladunewich, MD, of Sunnybrook Health Sciences Centre in Toronto, and fellow researchers noted in the Journal of the American Society of Nephrology. After preliminary data from the Toronto Nocturnal Hemodialysis Program suggested that increased clearance of uremic toxins by intensified hemodialysis (HD) improves pregnancy outcomes, Dr. Hladunewich and associates explored the matter further. The investigators compared the outcomes of 22 pregnancies in the Toronto Pregnancy and Kidney Disease Clinic and Registry (2000– 2013), 18 of which occurred after dialysis had been initiated, with the outcomes of 70 pregnancies in the American Registry for Pregnancy in Dialysis Patients (1990-2011), four of which occurred after the start of dialysis. In Toronto, young women undergo a mean 43 hours of dialysis per week, compared with a mean 17 hours per week for young women in the U.S.

The live birth rate was significantly higher in the Canadian cohort than in the American cohort (86.4% vs. 61.4%). In women with established kidney failure at conception, live birth rates were 83% for the Toronto patients, compared with just 53% in the American group. Dr. Hladunewich’s team also found the following: • Among women with established ESRD, median duration of pregnancy in the more intensively dialyzed Toronto cohort was 36 weeks compared with 27 weeks for the American women. • A dose response between dialysis intensity and pregnancy outcomes emerged: Live birth rates were 48% among women who had been dialyzed for at least 20 hours per week and 85% among women who underwent dialysis for more than 36 hours per week. • Babies born to women who underwent dialysis for more than 20 hours per week had healthier birth weights than did babies born to women who had been dialyzed for 20 hours a week or less. “We propose that intensive hemodialysis should be considered as a viable and feasible option for dialysis patients of childbearing age who want to become pregnant or who are pregnant,” the authors wrote. n

Two Bladder CA Subtypes ID’d RESEARCHERS have found evidence that two intrinsic subtypes of high-grade bladder cancer exist, and these subtypes reflect the hallmarks of breast biology. Upon analyzing 262 bladder tumors, William Y. Kim, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center, and colleagues discovered that invasive bladder cancer can be divided into at least two molecularly and clinically distinct genetic subtypes: basal-like and luminal. These subtypes, which have characteristics of different stages of urothelial differentiation, reflect the luminal and basal-like molecular subtypes

of breast cancer and have clinically meaningful differences in outcome, the investigators wrote in a paper published online ahead of print in the Proceedings of the National Academy of Sciences. “It will be particularly interesting to see whether the bladder subtypes, like the breast subtypes, are useful in stratification for therapy,” Dr. Kim commented in a university statement describing his team’s findings. The research by Dr. Kim and his collaborators also revealed that women had a significantly higher incidence of basal-like tumors, which are more deadly than the luminal subtype. n

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