Renal & Urology News November 2014 Issue

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AVFs May Cause Cardiac Problems

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CARDIAC CHANGES AFTER AV FISTULA CREATION A pilot study using cardiovascular magnetic resonance imaging to evaluate changes in heart and vascular structures showed increases in a number of cardiac parameters, as indicated here.

Cardiac output +25%

MRI reveals ominous changes to the heart

Left ventricular end-systolic volume +21% Right ventricular end-systolic volume +18%

BY JODY A. CHARNOW ARTERIOVENOUS fistulas (AVFs) are considered the preferred form of vascular access for hemodialysis, but a new Australian pilot study using magnetic resonance imaging suggests these fistulas can result in adverse cardiovascular (CV) effects.

The study found that elective AVF creation in patients with chronic kidney disease (CKD) not yet on hemodialysis is associated with significant increases in left and right atrial and ventricular chamber volumes and left ventricular mass, as well as deteriora-

IN THIS ISSUE 8 14

Cigarette smoking found to decrease the risk of gout Elevated sclerostin levels linked to lower cardiovascular mortality

15

Increasing dietary fiber intake associated with higher GFR

20

Serious technical adverse events rare with home hemodialysis

27

Point/Counterpoint: Should metformin be used in CKD patients?

Higher dietary fiber intake is associated with better kidney function.

PAGE 15

tion in systemic endothelial function.

Such alterations in cardiovascular structure and function may contribute to the poor health outcomes seen in patients with end-stage renal disease, researchers concluded in a report in the International Journal of Nephrology and Renovascular Disease (2014;7:337–345).

A team led by Matthew I. Worthley, MBBS, PhD, of the Royal Adelaide Hospital in Adelaide, South Australia, used cardiovascular magnetic resonance imaging (MRI), which they called a “gold standard imaging modality,” to evaluate the impact of

CKD Linked to Low Levels of Magnesium LOW SERUM magnesium levels are associated with an elevated the risk of developing kidney disease, according to a new study.

Adrienne Tin, MD, of Johns Hopkins University in Baltimore, and colleagues studied 13,226 individuals aged 45–65 years participating in the Atherosclerosis Risk in Communities study. Subjects had baseline estimated glomerular filtration rates of 60 mL/min/1.73 m2 or higher in 1987–1989 and were followed through 2010. During a median follow-up of 21 years, chronic kidney disease (CKD) developed in 1,965 subjects and endstage renal disease (ESRD) developed continued on page 10

Left atrial area +11% Right atrial area +9% Left ventricular mass +12.7% 0

5

10

Percent 15

20

25

Source: Dundon BK, et al. The deleterious effects of arteriovenous fistula-creation on the cardiovascular system: a longitudinal magnetic resonance imaging study. Int J Nephrol Renovas Dis (2014;7:337-345).

AVF creation on cardiac and vascular structure and function in 24 patients with stage 5 CKD undergoing AVF creation. Patients underwent imaging at baseline and prior to and 6 months after fistula creation.

At follow-up, left ventricular ejection fraction (LVEF) remained unchanged, whereas mean cardiac output increased significantly by 25%, Dr. Worthley’s group reported. Results also showed continued on page 10

Fracture Risk Tied to eGFR MANY PATIENTS with chronic kidney disease (CKD) will suffer fractures, with the risk of fracture increasing with decline kidney function, new study findings suggest.

A Canadian team led by Amit X. Garg, MD, of the London Health Sciences Centre in London, Ontario, studied 679,114 individuals aged 40 years and older. The cohort had a mean age of 62 years. At study entry, the researchers stratified subjects according to estimated glomerular filtration rate (eGFR), gender, and age.

The primary outcome was the 3-year cumulative incidence of fracture: the proportion of subjects who fractured

their hip, forearm, pelvis, or proximal humorus at least once within 3 years of follow-up.

Results showed that the 3-year incidence of fracture among women older than 65 years was 4.3%, 5.8%, 6.5%, 7.8%, and 9.6% for those with an eGFR (in mL/min/1.73 m2) of 60 or higher, 45–59, 30–44, 15–29, and below 15, respectively, according to findings published in Kidney International (2014;86:810-818). Among men older than 65 years, the corresponding incidences were 1.6%, 2.0%, 2.7%, 3.8%, and 5.0%, respectively. According to the researchers’ estimates, 1 in 10 continued on page 10

MRA-BASED TREATMENTS FOR PATIENTS ON DIALYSIS

Murray Epstein, MD, discusses the role of mineralocorticoid receptor antagonists SEE STORY PAGE 21

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PCSM Higher After EBRT vs. Surgery

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10-YEAR PCa-RELATED DEATH RATES: EBRT

VS.

RP

EBRT-treated PCa patients have higher 10-year cancer-specific mortality rates (shown below) than those treated with RP regardless of patients’ 5-year progression-free probability calculated using treatment-specific nomograms for predicting biochemical recurrence.

30

■ External beam radiation therapy ■ Radical prostatectomy

26.6% 21.2%

EXTERNAL BEAM radiation therapy (EBRT) is associated with greater 10-year prostate cancer-specific mortality (PCSM) than radical prostatectomy across a range of nomogram-predicted risks of biochemical recurrence, according to researchers.

In a study of 13,803 men who underwent radical prostatectomy (RP), external beam radiation therapy (EBRT), or brachytherapy from 1995 to 2008, investigators led by Andrew J. Stephenson, MD, of Cleveland Clinic, calculated the 5-year progression-free probability (5YPFP) for each patient based on the treatment received using a validated treatment-specific nomogram for predicting

IN THIS ISSUE 7

Partial nephrectomy more likely if robotic systems are available

10

Premature ejaculation linked to Chlamydia in prostatitis patients

15

Hospitalization rates for prostate biopsy complications are rising

20

Higher temperatures increase kidney stone incidence

26

Smoking may raise the risk of dying from prostate cancer

Higher dietary fiber intake is associated with better kidney function.

PAGE 15

biochemical recurrence (BCR). The 10-year prostate cancer-specific mortality (PCSM) rates associated with EBRT and RP were 3% and 0.9%, respectively, among patients with a 5Y-PFP greater than 75%; 6.8% and 5.9%, respectively, for those with a 5Y-PFP of 51%75%; 12.2% and 10.6% for those with a 5Y-PFP of 26%-50%; and 26.6% and 21.2% for those with a 5Y-PFP of 25% or less, the researchers reported online ahead of print in European Urology.

After adjusting for nomogram-predicted 5Y-PFP, EBRT was associated with a significant 50% increased risk of PCSM versus RP. The investigators found no significant difference in

Bladder CA Biopsies Often Suboptimal PATIENTS WITH bladder cancer are more likely to die from the malignancy if they have suboptimal bladder biopsies, according to researchers.

A 2-year study of 335 urologists, 278 pathologists, and 1,865 patients by researchers at the University of California Los Angeles (UCLA) found that muscle tissue was reported as absent in 30.2% and was not mentioned in 17.7% of initial pathology reports. These omissions were associated with an increased mortality risk, especially among patients with highgrade disease.

The 5-year mortality rate for patients with high-grade tumors was 7.6% continued on page 10

20

12.2% 10

6.8% 5.9% 3%

0

10.6%

0.9%

>75%

51% –75% 26% –50% 5-year progression-free probability

≤ 25%

Source: Lee BH, et al. Are biochemical recurrence outcomes similar after radical prostatectomy and radiation therapy?

Analysis of prostate cancer-specific mortality by nomogram-predicted risks of biochemical recurrence. Eur Urol; published online ahead of print.

PCSM risk between brachytherapy and RP, although they acknowledged that patient selection factors and lack of statistical power limited this analysis.

“Men treated with EBRT are at higher risk of PCSM compared with RP

patients with similar nomogram-predicted risks of BCR,” the authors concluded. “This provides convincing evidence that BCR end points after RP and EBRT are not associated with similar continued on page 10

PCa Relapse, High Lipids Linked ELEVATED TRIGLYCERIDE levels are associated with an increased risk of prostate cancer (PCa) recurrence after radical prostatectomy (RP), according to a recent study.

In a retrospective study of 843 RP patients who never used statins prior to surgery, lead author Emma H. Allott, PhD, and senior author Stephen J. Freedland, MD, both of Duke University School of Medicine in Durham, N.C., and colleagues found that patients who had abnormal triglyceride levels (150 mg/dL or higher) had a significant 35% increased risk of biochemical recurrence (BCR) compared with those who had levels

below 150 mg/dL in adjusted analyses.

Additionally, results showed that each 10 mg/dL increment in serum triglycerides was associated with a significant 2% increased risk of BCR. The investigators observed no associations between biochemical recurrence risk and total cholesterol and low- and high-density lipoproteins (LDL and HDL, respectively). Among men with dyslipidemia, however, each 10 mg/ dL increase in cholesterol and HDL was associated with a significant 9% increased risk of recurrence and 39% decreased risk of recurrence, respectively, the investigators reported online continued on page 10

MRA-BASED TREATMENTS FOR PATIENTS ON DIALYSIS

Murray Epstein, MD, discusses the role of mineralocorticoid receptor antagonists SEE STORY PAGE 21

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www.renalandurologynews.com NOVEMBER 2014

Renal & Urology News 5

FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD

Offer Ebola Victims Dialysis If They Need It

E

bola hemorrhagic fever, which is accompanied by hematemesis, melena, hematuria, epistaxis, and vaginal bleeding, might remind us of a scary apocalyptic movie in which victims ooze blood from every orifice. The nature of Ebola hemorrhagic fever is such that nephrologists need to be more engaged in the management of the ensuing fluid and electrolyte disarrays that often precedes terminal acute kidney injury (AKI).

Ebola victims may need 10 to 20 liters of daily fluid replacement because of massive blood and fluid loss. Depletional hyponatremia may ensue, and thismay be difficult to manage given ongoing fluid and electrolyte losses.

Other electrolyte abnormalities, such as profound hypokalemia, hypomagnesemia, and hypophosphatemia, will often confound the condition and are major contributors to the development of dysrhythmias, cardiac arrest, and death. In my opinion, an astute nephrologist is the second most important physician next to the infectious disease specialist when it comes to the management of patients with Ebola hemorrhagic fever.

Some experts believe dialysis therapy in any form is futile, citing the irreversibility of the disease state and imminent death following development of oligoanuric AKI. Nevertheless, I believe dialysis should be offered to any Ebola patient who needs it. The terminal cases with death outcome despite dialysis referred to by some experts to substantiate their view that dialysis therapy is futile have occurred mostly in African countries. In the U.S., we apparently had two Ebola patients in whom dialysis therapy was used, including one who died and one who survived. The Liberian national who came to the U.S. to visit relatives after having contracted Ebola hemorrhagic fever in Africa died at a Dallas hospital shortly after dialysis initiation. While the use of dialysis in this case seemed to make little or no difference in the patient’s survival, nephrologists and other clinicians should not be deterred from offering all patients RRT if they need it, even if they only have a small chance of survival.

With respect to which type of RRT should be used—conventional intermittent hemodialysis (HD) or continuous RRT such as continuous venovenous hemodiafiltration (CVVHDF)—this depends on patient condition. As oligoanuric AKI occurs in terminal and the most severe stages of multiple organ failure with high likelihood of mortality independent of the underlying etiology, patients are often less stable for conventional HD. For these patients, CVVHDF may be the better option.

Notwithstanding that Ebola hemorrhagic fever—for which there is currently no approved treatment, has a high case fatality rate—most Ebola patients treated in the U.S. have survived thus far. Supportive care appears to influence the odds of survival. It is here that the expertise and training of American nephrologists, and the resources they have available, can potentially make a big difference in Ebola outcomes.

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

MH-Comm_RUN1114.indd 5

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

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

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

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

R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto Stanton Honig, MD Department of Urology Yale University School of Medicine New Haven, CT 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

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.

James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City

Rulan Parekh, MD, MS Associate Professor of Pediatrics and Medicine University of Toronto

Kenneth Pace, MD, MSc, FRCSC Assistant Professor Division of Urology St. Michael’s Hospital 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.

Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada

Lynda Anne Szczech, MD, MSCE Medical Director, Pharmacovigilence and Global Product Development, PPD, Inc. Morrisville, N.C.

Renal & Urology News Staff

Editor Jody A. Charnow Production editor Kim Daigneau Web editor

Stephan Cho

Group art director, Haymarket Medical Jennifer Dvoretz

Production manager Krassi Varbanov

Production director Kathleen Millea Grinder Circulation manager Paul Silver National accounts manager William Canning Publisher Dominic Barone Editorial director

Jeff Forster

Senior VP, medical journals & digital products

Jim Burke, RPh

Senior VP, clinical communications group

John Pal

CEO, Haymarket Media Inc.

Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 13, Number 11. 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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6 Renal & Urology News

NOVEMBER 2014

www.renalandurologynews.com

Contents

NOVEMBER 2014

■

VOLUME 13, ISSUE NUMBER 11

Nephrology 7

ONLINE

15

this month at renalandurologynews.com

Videos

Exercise May Benefit Kids with CKD A recent study suggests that acute exercise is associated with anti-inflammatory effects in children and adolescents.

Dietary Fiber, Renal Function Linked Each 10 g/day increase in dietary fiber intake was independently associated with a significant 2.6 mL/min/1.73 m2 increment in estimated glomerular filtration rate.

20

Serious Technical Adverse Events Rare in HHD Most events were related to needle dislodgement or air embolism, according to a new study.

26

High Indoxyl Sulfate Levels Increase Heart Failure Risk High levels in hemodialysis patients increase the risk of a first heart failure event by 5-fold compared with low levels.

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 September winner: Manuel Seneriz, MD

CALENDAR

Some of our recent postings include: • Wearable Artificial Kidney: First Clinical Trial • Low Estrogen Could Mean Low Testosterone • Coffee May Cut Prostate Cancer Risk

Urology

Drug Showcase

15

PCa Biopsy Complications On the Rise Overall, the 30-day rate of hospital admission due to prostate biopsy complications is 3.7%, a British study found.

20

Ultrasonography May Suffice As Initial Test for Suspected Stones This test can be followed by computed tomography if, in a physician’s clinical judgment, it is necessary.

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

News Coverage

Visit our website for timely reports from upcoming meetings.

9

26

Genitourinary Cancers Symposium Orlando, Fla. February 26–28 European Association of Urology 30th Annual Congress Madrid March 20–24 National Kidney Foundation 2015 Spring Clinical Meetings Dallas March 25–29

Feature 27

Early Post-Op PSA Values Useful PSA levels at day 30 after radical prostatectomy predict biochemical relapse risk in men with positive surgical margins.

PCa-Related Mortality Tied to Smoking The risk of death from prostate cancer increased by a significant 20% with each 20 cigarettes smoked per day.

“The kinetics of postoperative PSA decline

may allow better stratification of patients who would benefit from immediate radiation therapy.

See our story on page 9

006_Neph_RUN1114.indd 6

Annual Dialysis Conference New Orleans January 31–February 3

POINT/COUNTERPOINT Mark E. Molitch, MD, of the Northwestern University Feinberg School of Medicine, debates the use of metformin in CKD patients with Connie Rhee, MD, MSc, and Kam Kalantar-Zadeh, MD, MPH, PhD, of the University of California Irvine.

30

Departments 5

From the Medical Director Ebola patients who need dialysis should get it.

8

News in Brief Cigarette smoking lowers gout risk.

24

Practice Management Experts offer tips for developing a workable call coverage schedule.

10/27/14 1:12 PM

6 Renal & Urology News

NOVEMBER 2014

www.renalandurologynews.com

Contents

NOVEMBER 2014

■

VOLUME 13, ISSUE NUMBER 11

Urology 9

ONLINE

15

this month at renalandurologynews.com

Videos

Some of our recent postings include: • Wearable Artificial Kidney: First Clinical Trial • Low Estrogen Could Mean Low Testosterone • Coffee May Cut Prostate Cancer Risk

Early Post-Op PSA Values Useful PSA levels at day 30 after radical prostatectomy predict biochemical relapse risk in men with positive surgical margins.

PCa Biopsy Complications On the Rise Overall, the 30-day rate of hospital admission due to prostate biopsy complications is 3.7%, a British study found.

20

Ultrasonography May Suffice As Initial Test for Suspected Stones This test can be followed by computed tomography if, in a physician’s clinical judgment, it is necessary.

26

PCa-Related Mortality Tied to Smoking The risk of death from prostate cancer increased by a significant 20% with each 20 cigarettes smoked per day.

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 September winner: Manuel Seneriz, MD

CALENDAR

Exercise May Benefit Kids with CKD A recent study suggests that acute exercise is associated with anti-inflammatory effects in children and adolescents.

15

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

Dietary Fiber, Renal Function Linked Each 10 g/day increase in dietary fiber intake was independently associated with a significant 2.6 mL/min/1.73 m2 increment in estimated glomerular filtration rate.

20

Serious Technical Adverse Events Rare in HHD Most events were related to needle dislodgement or air embolism, according to a new study.

News Coverage

26

Visit our website for timely reports from upcoming meetings.

High Indoxyl Sulfate Levels Increase Heart Failure Risk High levels in hemodialysis patients increase the risk of a first heart failure event by 5-fold compared with low levels.

“The kinetics of postoperative PSA decline

may allow better stratification of patients who would benefit from immediate radiation therapy.

See our story on page 9

006_Uro_RUN1114.indd 6

Genitourinary Cancers Symposium Orlando, Fla. February 26–28 European Association of Urology 30th Annual Congress Madrid March 20–24 National Kidney Foundation 2015 Spring Clinical Meetings Dallas March 25–29

Feature 27

Nephrology 7

Drug Showcase

Annual Dialysis Conference New Orleans January 31–February 3

POINT/COUNTERPOINT Mark E. Molitch, MD, of the Northwestern University Feinberg School of Medicine, debates the use of metformin in CKD patients with Connie Rhee, MD, MSc, and Kam Kalantar-Zadeh, MD, MPH, PhD, of the University of California Irvine.

30

Departments 5

From the Medical Director Ebola patients who need dialysis should get it.

8

News in Brief Cigarette smoking lowers gout risk.

24

Practice Management Experts offer tips for developing a workable call coverage schedule.

10/27/14 1:14 PM

www.renalandurologynews.com NOVEMBER 2014

Renal & Urology News 7

Robot Availability Increases Likelihood of PN PARTIAL NEPHRECTOMY for renal cell carcinoma (RCC) is more likely to be performed at hospitals where roboticassisted surgery is available, new findings suggest.

RCC patients also are more likely to undergo partial nephrectomy at academic medical centers and urban centers.

Using both the Nationwide Inpatient Sample and the American Hospital Association survey from 2006 to 2008, Simon P. Kim, MD, of Yale University in New Haven, Conn., and colleagues identified 4,832 patients who underwent PN and 16,347 who underwent radical nephrectomy (RN) for RCC. In multivariate analysis, patients had a significant 28% greater likelihood of undergoing PN at hospitals with robotic surgical systems compared with hospitals lacking such systems, Dr. Kim’s team reported online ahead

of print in BJU International. This relationship was apparent even after adjusting for established hospital level effects such as teaching hospitals and urban centers with high volume, “both of which are strongly associated with the use of PN,” the researchers pointed out.

Patients were 2.8 and 3.7 times more

likely to undergo PN at academic centers and urban centers, respectively, compared with non-academic and rural centers. Patients were 10% more likely to undergo PN at American College of Surgeons (ACOS)-designated cancer centers compared with non-ACOSdesignated centers.

Exercise May Benefit Kids With CKD

“Our findings supply clinical information to policy-makers and third party payers about which hospitals and surgeons are adopters of PN as a result of access to robotic-assisted surgery and better understanding of the evidence and clinical practice guidelines,” the authors wrote. n

patient: MARK SMITH PSA 6.2

ACUTE EXERCISE may benefit children and adolescents with chronic

Gleason Score

6

Oncotype DX® GPS

8

kidney disease (CKD) via antiinflammatory effects, according to

IDENTIFIED FOR

ACTIVE SURVEILLANCE

the findings of a Canadian pilot study published online ahead of print in Pediatric Nephrology.

Keith K Lau, MD, and colleagues at McMaster University in Hamilton, Ontario, studied 9 children and adolescents with CKD stages 3-5 who performed a graded exercise test to determine peak oxygen uptake (VO2 peak). Following a 10-minute break, subjects cycled for 20 minutes at 50% of VO2 peak. Investigators collected

The Oncotype DX Genomic Prostate Score (GPS) improves 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.

blood samples before and after the exercise period to determine complete blood counts, natural killer cell (NKbright and NKdim) counts, and circulating progenitor cells (CPC) counts.

Complete blood counts, NKdim

Review the development and validation data published in European Urology www.OncotypeDX.com/EUP

counts, and CPC counts remained unchanged with exercise, but NKbright cell counts increased. Results also showed a non-significant trend toward

Genomic Health and Oncotype DX are registered trademarks of Genomic Health, Inc. © 2014 Genomic Health, Inc. All rights reserved. GHI40033_0714

increased interleukin-6, decreased tumor necrosis factor-α, and an increase in the IL-6:TNF-α ratio. n GENP-13869_ProstateAd_Renal&UrologyNews_Oct2014_1-0.indd 1

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8 Renal & Urology News

NOVEMBER 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 Stone Removal by f-URS Okay for CKD Patients

tal status and 23% had severe PDD,

Flexible ureterorenoscopy (f-URS) is

“Carol Davila” University of Medicine

safe and effective for removing kidney

and Pharmacy, Bucharest, Romania

stones in patients with chronic kidney

and colleagues reported online in the

disease (CKD), researchers reported

Journal of Renal Nutrition. Results

online ahead of print in Urology.

showed that smoking and HD duration

Liliana Garneata, MD, PhD, of the

Emrah Yuruk, MD of Bagcilar Training

are the most important determinants

and Research Hospital, Istanbul, Turkey,

for PDD. Elevated C-reactive protein

and colleagues studied 149 patients

was associated with severe PDD.

who underwent f-URS for kidney stones: and 87 without CKD who served as a

ED Drug Cleared for Use 15 Minutes Before Sex

control group. The groups had similar

Avanafil, a medication approved by

peri- and postoperative complication

the FDA in 2012 for treating erectile

rates. At the third post-operative month,

dysfunction (ED), has received a new

the stone-free rate in patients with and

indication allowing the drug to be taken

without CKD was 87.1% and 86.2%,

approximately 15 minutes prior to

respectively, a non-significant difference.

sexual activity. The drug, marketed as

In 13 CKD patients, the CKD stage

Stendra by Vivus, Inc., of Mountain

shifted from stage 3 to stage 2.

View, Calif., and Auxilium Pharmaceu-

62 patients with CKD stage 3 or higher

SLE Patient Mortality Does Not Differ By Dialysis Type T

he mortality risk among patients with end-stage renal disease (ESRD) and systemic lupus erythematosus (SLE) is similar regardless of their initial dialysis modality, researchers reported online ahead of print in the Clinical Journal of the American Society of Nephrology.

Gabriel Contreras, MD, of the University of Miami Miller School of Medicine, and colleagues used propensity score matching to create 1,352 matched pairs of patients with ESRD patients and SLE who started hemodialysis (HD) or peritoneal dialysis (PD). The matched pairs were mostly women (86%) with a median age of 39 years.

The median follow-up period was 3 years. The HD and PD groups had overall mortality rates of 22.5% and 21.4%, respectively, within the first 3 years of observation, a non-significant difference between the groups. The matched pairs also had similar cardiovascular-related mortality rates (9.5% in the HD group, 10.5% in the PD group) and infection-related mortality (4.4% in the HD group and 3.0% in the PD group).

Cigarette Smoking Found To Decrease Gout Risk

ticals, Inc., of Chesterbrook, Pa., is

Periodontal Disease Common in HD Patients

approved for treating ED in men aged

Severe periodontal disease (PDD)

50, 100, and 200 mg tablets and

is present in almost one-quarter of

may be taken with or without food and

hemodialysis (HD) patients, according

moderate alcohol consumption (up to

to a new study.

3 drinks). ). In clinical studies, when

18 years and older. It is available in

compared with placebo, avanafil helped

The cross-sectional observational study of 263 HD patients revealed

more men achieve an erection in as little

that 75% of them had poor periodon-

as about 15 minutes.

Patient Access to Lab Results In a recent online poll, Renal & Urology News asked readers, “Is allowing patients direct access to lab results a good idea?” Here are the results based on 210 responses:

No: 26.67%

Do not know: 4%

NIB_RUN1114.indd 8

10

20

30

40

igarette smoking is associated with a decreased risk of incident gout, particularly among men, according to a new study published online in Rheumatology.

Weiqi Wang, PhD, and Eswar Krishnan, MD, MPH, of Stanford University School of Medicine in Palo Alto, Calif., analyzed 54-year follow-up data (19482002) for 2,279 men and 2,785 women who were gout-free at their first assessment as part of the Framingham Heart Study. The researchers identified 399 incident cases of gout (249 men and 150 women) over 151,058 person-years of observation.

In multivariable analyses, cigarette smoking was associated with a 24% decreased risk of incident gout overall, a 32% decreased risk among men, and an 8% decreased risk among women, after adjusting for age, body mass index, alcohol intake, diabetes, hypertension, kidney disease, Drs. Wang and Krishnan reported.

TUR Bladder Perforation May Worsen Outcomes B

Yes: 69.05%

0

C

50

60

70

80

ladder perforation during transurethral resection (TUR) of superficial bladder tumors is associated with worse outcomes, investigators reported in the World Journal of Urology (2014;32:1219–1223).

Evi Comploj, MD, of the Central Hospital of Bolzano, Bolzano, Italy, and colleagues studied 565 patients who underwent TUR for non-muscle-invasive bladder cancer. Of these, 37 (6.5%) experienced bladder perforation at the time of tumor resection. The investigators compared these patients (group 1) with the remaining 538 patients who did not have bladder perforation (group 2). Group 1 had a higher recurrence rate than group 2. For example, group 1 had 23 single recurrences (62.1%) and group 2 had 246 (46.6%). Results showed that group 1 had significantly earlier bladder tumor relapses and a higher risk of T-stage progression than group 2.

10/27/14 1:16 PM

www.renalandurologynews.com NOVEMBER 2014

Renal & Urology News 9

Early Post-Op PSA Values Useful PSA levels at day 30 found to predict biochemical relapse risk in men with positive surgical margins EARLY PSA measurements following radical prostatectomy (RP) may aid in risk stratification of men with positive surgical margins and perhaps spare patients who are unlikely to experience disease progression the toxicity associated with immediate adjuvant radiotherapy, according to a new study.

Stepan Vesely, MD, and colleagues at the Charles University 2nd Faculty of Medicine University Hospital in Prague, Czech Republic, studied 116 patients found to have positive surgical margins (PSM) after RP for localized prostate cancer (PCa). None of the patients received radiation or hormonal therapy. Intensive postoperative PSA monitoring with an ultrasensitive assay was begun at day 14 after surgery and then at day 30, 60, 90, and 180 days, and subsequently at 3-month intervals.

Fifty-five patients (47%) experienced biochemical failure (BCR)—defined as a PSA level of 0.2 ng/mL or higher— during a median follow-up of 31.4 months. A PSA level higher than 0.073 and 0.41 ng/mL at post-operative day 30 and day 60 predicted a significant 4.3-fold and 9.6-fold increased risk of

First Bladder CA Institute Launched JOHNS HOPKINS University in Baltimore has launched the world’s first institute devoted to bladder cancer.

The Johns Hopkins Greenberg Bladder Cancer Institute, established with a co-investment by the university and Erwin and Stephanie Greenberg, “will serve as the hub of an institutional and international community

BCR, respectively, Dr. Vesely’s group reported in BMC Urology (2014;14:79).

“Applying the PSA cut-off at day 30 as the indicator for adjuvant radiotherapy would result in the decrease of overtreatment from 61 patients (53%) to 8 patients (19%),” the researchers wrote.

Overuse of adjuvant radiation therapy could be decreased, new findings suggest.

Recent evidence from randomized trials supports the use of adjuvant radiotherapy in patients found to have PSM after surgery, the researchers noted, but not all men with PSM experience disease recurrence, and a policy of using adjuvant radiation could result in considerable overtreatment.

“The kinetics of postoperative PSA decline may allow better stratification of patients who would benefit from immediate radiation therapy,” the authors concluded.

The investigators discussed some possible explanations for why positive margins are not always associated with PCa recurrence. For example, ischemia and fibrosis resulting from the surgery may destroy small areas of residual carcinoma. Also, possible disruption of additional tissue covering cancer cells during the handling of the surgical specimen by surgeons, nurses, and pathologists “may result in inadvertent damage leading to the false impression of PSM.” Dr. Vesely and his colleagues pointed out some study limitations, including the retrospective design of the study. Another limitation was the absence of strict criteria for subjecting patients with post-operative PSM to adjuvant therapy during the whole study period. “It may be argued that by doing so some patients with PSM who received adjuvant treatment were at high risk of the recurrence and they were excluded from the analysis,” they stated. “However, the comparison of clinicopathologic characteristics did not reveal any significant difference between [the] studied group of patients and those who underwent immediate

Key Points n Researchers studied 116 prostate

cancer patients found to have positive surgical margins after radical prostatectomy. n Applying a PSA cut-off at day 30

as an indicator for adjuvant radiotherapy would have resulted in a decrease in overtreatment from 53% to 19%. n The kinetics of post-op PSA decline

may allow for better stratification of patients who would benefit from immediate radiotherapy.

secondary therapy after the surgery.”

A third limitation was the relatively short median follow-up, although some studies have found that most biochemical recurrences are detected within the first 3 years after surgery, the authors observed.

“Nevertheless, presented results should be analyzed with caution, as patients with BCR do not necessarily share the same long-term cancer outcomes.” n

Multiple Stones Predict Recurrence PATIENTS with multiple ureteral stones are more likely than those with a single ureteral stone to have hypocitraturia and to experience stone recurrence, a study found.

In a retrospective, case-controlled study, Ho Won Kang, MD, of the Department of Urology in the College of Medicine at Chungbuk National University in Cheongju, Korea, and colleagues compared 911 patients who had ureteral stones for the first time and 107 age- and sex-matched patients without stones.

Dr. Kang and colleagues classified the stone patients into 2 groups: those with a single stone (690 patients) and those with 1 or more additional stones in a ureter or kidney (212 patients).

They performed a 24-hour urinary metabolic evaluation was performed on all patients.

Compared with patients who had a single stone, those with multiple stones had a significantly higher incidence of hypocitraturia (32.1% vs. 18.6%), the investigators reported in Urology (2014;84:274-278).

For their recurrence analyses, the researchers included 240 stone patients who were followed up for more than 12 months (median 35 months). Patients with multiple stones had a 2.3 times increased risk of stone recurrence compared with patients who had a single stone.

“Patients with multiple stones, even it is their first stone episode, should undergo metabolic evaluation and possibly also potassium citrate therapy to prevent future stones,” the authors concluded. n

of researchers who share a commitment to advancing the scientific understanding of bladder cancer and improving its treatment,” according to a press release.

William B. Isaacs, MD, professor of urology and oncology at Johns Hopkins and an authority in molecular genetics of prostate cancer and other urologic diseases, will serve as the institute’s interim director. ■

NEWS_PSA-PSM_RUN1114.indd 9

Stone Treatment Success Predictors Identified HOUNSFIELD units (HU) and stone size as determined using non-contrast computed tomography (NCCT) can be used to predict the success of shock wave lithotripsy (SWL) .

Serdar Celik, MD, and colleagues at Dokuz Eylul Unversity in Izmir, Turkey, studied 254 patients: 113 with kidney

stones and 141 with ureteral stones. All had undergone NCCT prior to SWL. After serial measurements of the highest HU value (HUmax) and lowest HU value (HUmin), the researchers calculated an HU value that was the average of these 2 values (HUave), according to an online report in International Urology

and Nephrology. Patients who underwent successful SWL (the stone-free group) had significantly smaller stone diameter and lower HUmax, lower HUmin, and lower HUave values compared with patients who had residual fragments. Dr. Celik’s group also found that skin-tostone distance predicted SWL success. n

10/27/14 1:23 PM

NOVEMBER 2014 www.renalandurologynews.com

AVF cardiac effects

it remains unclear whether these observed early cardiac adaptations to increased cardiac output attenuate following initiation of hemodialysis and improved volume and blood pressure control,” Dr. Wasse told Renal & Urology News. “Overall, while it remains unclear what impact early cardiac changes have on long-term survival, these findings warrant further investigation.”

The possible adverse cardiovascular effects of AV fistula creation should not dissuade its use, she said, adding, “It is important that a nephrologist individualize vascular access, taking into account a patient’s baseline cardiovascular status, among other factors, when recommending a vascular access.”

Previous large studies consistently demonstrate that AVF use confers a significant survival benefit over catheter use on both CV and all-cause mortality, she stated.

Joseph Vassalotti, MD, Chief Medical Officer for the National Kidney Foundation in New York, noted this small pilot study had no control group, so it should be considered as hypothesis generating. The cardiac MRI findings could have resulted from AVF creation and/or the progression of kidney disease. CKD, he noted, is known to be associated with volume overload, systemic inflammation, and endothelial dysfunction with or without an AVF.

continued from page 1

significant 21% and 18% increases in left and right ventricular end-systolic volumes, respectively, significant 11% and 9% increases in left and right atrial area, respectively, and a significant 12.7% increase in left ventricular mass.

Endothelial-dependent vasodilatation had decreased significantly at followup, from 9% before fistula creation to 3% at 6 months afterwards. Fistula formation did not significantly alter aortic distensibility.

The authors wrote that “it is striking than an elective, purposeful medical intervention could cause such widespread maladaptation within the CV system of already high-risk individuals.”

The researchers explained that endothelial dysfunction is a known to be a critical precondition to the development of atherosclerosis and subsequent CV sequelae.

Commenting on the new study, Monnie Wasse, MD, Director of Interventional Nephrology at the Feinberg School of Medicine at Northwestern University in Chicago and Chair of the American Society of Nephrology’s Interventional Nephrology Advisory Group, said the study examines an important subject, given the increased prevalence of AVF use among HD patients. “Yet,

CKD-magnesium link continued from page 1

in 208. With respect to CKD, those in the 1st quartile of serum magnesium (0.25-0.70 mmol/L) had a 1.58 increased risk compared with individuals in the 4th quartile (0.90–1.15 mmol/L), in a fully adjusted model, Dr. Tin’s group reported online ahead of print in Kidney International. For ESRD, individuals in the 1st quartile had a 2.39 times increased risk compared with those in 3rd and 4th quartiles combined (0.85– 1.15 mmol/L). The researchers explained that the 3rd and 4th quartiles were combined as the reference group to ensure an adequate number of subjects in each subgroup (such as by diabetes status and diuretic use) in multivariate analysis.

“Further research is required to determine whether low total serum magnesium is itself nephrotoxic,” the authors concluded. “If so, our findings suggest that magnesium levels may be a novel therapeutic target for the prevention of CKD.” Previous studies have found associations between low magnesium and kid-

Cover_Neph_RUN1114.indd 10

ney function decline in CKD patients and diabetics, as well as decreased allograft survival in kidney transplant recipients and mortality in hemodialysis patients, the researchers noted.

For example, in a study of 455 CKD patients—including 144 with type 2 diabetic nephropathy and 311 with non-diabetic CKD—Yusuke Sakaguchi, MD, of Osaka General Medical Center in Osaka, Japan, and colleagues found that low magnesium levels (1.8 mg/dL or less) were associated with a 2-fold increased the risk of ESRD compared with high magnesium levels (greater than 1.8 mg/dL) among the patients with diabetic nephropathy, according to a report in Diabetes Care (2012;35:1591-1597). The study found no significant association between magnesium level and ESRD risk among patients with non-diabetic CKD. “We showed that hypomagnesemia independently predicts progression to ESRD in patients with advanced type 2 diabetic nephropathy,” Dr. Sakaguchi’s team concluded. “Our findings suggest that Mg supplementation may be renoprotective in this population.” n

MRI findings show that AVFs are associated with adverse cardiovascular effects.

Dr. Vassalotti said the increased cardiac output is “a concern since there are case reports and case series of high output cardiac failure associated with the AVF. How will the study findings change prospectively with the subsequent initiation of hemodialysis or kidney transplantation? For example, patients who have congestive heart failure or cardiomyopathy might not be able to tolerate an AVF. These are

Fracture risk continued from page 1

women and 1 in 20 men older than 65 with an eGFR below 15 experienced at least 1 fracture in the subsequent 3 years. Fracture was significantly more likely to occur in subjects older than 65 than in those aged 40–65 across all eGFR categories.

Fractures were more likely to occur in patients older than 65 vs. those aged 40–65.

The researchers also found that the 3-year cumulative incidence of falls with hospitalization also increased as kidney function decreased in both sexes. For example, the study showed that among women older than 65, the incidences were 3.8%, 5.9%, 7.6%, 9.1%, and 13.1% for those with an eGFR of 60 or higher, 45–59, 30–44, 15–29, and below 15.

patients who may have better outcomes with peritoneal dialysis or a kidney transplant.”

He noted that some important questions remain. For example, what are the characteristics that predict high output cardiac failure following AVF creation? Does the fixed AV graft diameter that allows for better prediction of subsequent flow provide advantages in highly selected patients who are at risk for high output cardiac failure and have no modality options other than in-center or home hemodialysis?

The questions raised by this pilot study support ongoing clinical investigation and, for routine practice, the active participation of the nephrologist in modality selection and hemodialysis dialysis access decisions, Dr. Vassalotti said.

Dr. Vassalotti pointed out that a previous study published in Nephrology Dialysis Transplantation (2011;26:32963302) came to some different conclusions.

For example, the study, which included 43 pre-dialysis patients who underwent AVF creation, showed that the fistulas resulted in a sustained decrease in arterial stiffness and an increase in LVEF. The authors of this study concluded that, overall, post-AVF adaptations “might be characterized as potentially beneficial in these patients and supports the widespread use of native vascular access, including older or cardiovascular compromised individuals.” n

Additionally, Dr. Garg’s group estimated the incidence rates of fracture per 1,000 person-years. Women older than 65 who had an eGFR of 60 or higher, 45–59, 30–44, 15–29, and less than 15 had an incidence rate of 15.0, 20.5, 24.2, 31.2, and 46.3 per 1,000 person-years, respectively. The corresponding rates for men older than 65 were 5.7, 7.3, 10.1, 15.3, and 24.3, respectively.

“The results of this study are a call to develop and test interventions to reduce the burden of fracture in this population,” the authors concluded.

The researchers commented that the higher risk of fracture observed among individuals with diminished kidney function compared with those who had normal kidney function was particularly striking. For example, among women older than 65, the rate of fracture was 3 times higher among those with an eGFR below 15 than among those with an eGFR of 60 or higher.

Among men aged 40–65, the rate was 5 times higher among those with an eGFR below 15 compared with an eGFR of 60 or higher. n

© SPL / SCIENCE SOURCE

10 Renal & Urology News

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10 Renal & Urology News

NOVEMBER 2014 www.renalandurologynews.com

A NEW STUDY by Swedish researchers provides no support for a previously suggested link between male fertility and prostate cancer (PCa) risk.

A team led by Pär Stattin, MD, of Umeå University, Umeå, Sweden, performed a nationwide, populationbased, case-control study. The study included 96,301 PCa cases and 378,583 matched controls. A total of 1,112 cases and 4,538 controls had fathered dizygotic twins, a marker of high fertility.

Compared with the fathers of singletons, men who fathered dizygotic twins did not have an increased risk of PCa, the investigators reported online in PLoS One. The study also found that men with a high education level had an increased risk of PCa compared

with men who had a low educational level. Divorced, never married men, and widowers, were at decreased risk of PCa compared with married men.

Increased comorbidity was associated with a decreased risk of PCa. “The associations between educational level, marital status and comorbidity and risk of prostate cancer are likely reflections of differences in uptake of PSA testing,” the authors wrote.

Previous large population-based observational studies had found a higher risk of PCa among fathers compared with childless men, Dr. Stattin and his colleagues noted. A possible explanation for this increased risk is that androgen levels are higher in fathers than infertile men, as androgen levels could affect PCa risk.

The researchers noted that in vitro fertilization was introduced in Sweden in 1981, but twinning rates did not increase markedly until 1990. To avoid confounding, the researchers limited their analyses to men who had fathered children prior to 1991. n

Compared with the presence of muscle in a biopsy sample, the absence of muscle was associated with a 48% increased risk of death from bladder cancer. When muscle was not mentioned in the initial pathology report, patients had a nearly 2-fold increased risk.

In a UCLA press release, first author Karim Chamie, MD, assistant professor of urology and surgical director of the bladder cancer program at the university, said the findings “are very important because while patients know about the stage of their cancer, they rarely question the quality of the

biopsy. We hope these findings will help empower patients to ask about the quality of their biopsy and, if it is suboptimal, then urge their doctors to repeat the biopsy prior to deciding on what type of treatment to prescribe.”

Dr. Chamie said he believes the lack of a significant improvement in bladder cancer survival in the last 2 decades may be due in part to inadequate staging.

“Appropriately staging patients with bladder cancer is a skill set that every urologist and pathologist should have in his/her armamentarium,” Dr. Chamie said. “We believe the next step

is to change the staging system for bladder cancer to incorporate the quality of staging. Not all stage I cancers are alike.

Some patients may have stage II cancer, but because the biopsy was insufficient, these patients were inaccurately staged and may be undertreated.”

For the study, Dr. Chamie’s team reviewed the medical records of all patients diagnosed with non-invasive bladder cancer across medical institutes in Los Angeles County. The study cohort had a median age of 73 years; 76.5% of patients were male and 69.8% were white. n

clinical progression and dying from PCa. Compared with RP, they noted, the time to BCR after EBRT may be delayed 5 or more years, “with some evidence suggesting that the time from BCR to metastatic progression is shorter after EBRT compared with RP.” The researchers acknowledged some limitations to their study. For example, the study evaluated PCSM within 10 years of treatment, but previous studies suggest that patients with localized PCa appear to be at risk for PCSM for up to 20 years. In addition, EBRT recipients were older and had more adverse disease characteristics than RP patients, such as higher PSA levels, more highgrade cancer, and more advanced clinical stage, although these characteristics are taken into account in the 5Y-PFP nomogram predictions. n

PCa relapse risk

greater than 0.2 ng/mL, 2 consecutive PSA measures of 0.2 ng/mL, or secondary treatment for detectable postoperative PSA. In a previous study of 1,146 RP patients who did not take statins preoperatively, Dr. Allott, Dr. Freedland, and colleagues found that post-operative use of statins was associated with a significant 36% decreased risk of BCR, after adjusting for clinical and pathologic characteristics, according to findings published online ahead of print in BJU International. When the investigators stratified findings according to race, they found that post-operative statin use was associated with a significant 51% decreased risk of BCR among non-black patients and a nonsignificant 18% decreased risk among black patients. n

PE Linked to Chlamydia in Prostatitis Patients CHRONIC BACTERIAL prostatitis (CBP)

the PE Diagnostic Tool test (11.3 vs.

caused by Chlamydia trachomatis is

4.5) and lower scores on the Short

associated with a greater likelihood of

Form-36 tool (96.5 vs. 99.7). After

premature ejaculation (PE) than CBP

adjusting for age, smoking status, body

due to infection with other bacteria,

mass index and education level, CBP

according to a recent report.

due to C. trachomatis infection was

Tommaso Cai, MD, of Santa Chiara

associated with 3.2 times higher odds

Regional Hospital in Trento, Italy, and

of PE compared with CBP due to other

colleagues compared 317 patients diag-

bacterial infections.

nosed with C. trachomatis CBP (group

Previous research suggested that

A) with 639 patients with CBP caused

CBP is an important organic cause of

by other uropathogic bacteria (group B).

PE, given the role of the prostate in

PE was identified in 118 men in group

the ejaculation mechanism, Dr. Cai and

A (37.2%) and 73 (11.5%) in group B,

his colleagues pointed out. In addition,

a significant difference in prevalence,

they noted that C. trachomatis is not

Dr. Cai’s team reported online ahead of

frequently assessed in men with CBP,

print in The Journal of Sexual Medicine.

but it has been accepted as an etiologic

Compared with group B, group A showed significantly higher scores on

Bladder CA biopsies continued from page 1

when muscle was present, 12.1% when muscle was absent, and 18.8% when muscle was not mentioned, according to the investigators.

“Because urologists cannot reliably discern between high- and low-grade or Ta and T1 disease, we contend that patients with bladder cancer should undergo adequate muscle sampling at the time of endoscopic resection,” the authors concluded in a paper published online ahead of print in Cancer.

EBRT vs. surgery

continued from page 1

clinical consequences in terms of metastatic progression and PCSM and should be used cautiously to make comparisons between treatment modalities.”

Dr. Stephenson and his colleagues added that functional outcomes, shortand long-term complications, individual preferences, and unique practitioner and institutional expertise also should be considered when making treatment decisions.

The researchers pointed out that theoretical reasons support the concept that men treated with EBRT are significantly more advanced in the course of progressive disease when BCR is determined compared with RP patients and are thus at higher risk of experiencing

Cover_Uro_RUN1114.indd 10

PCa Risk Not Linked to Fertility

agent of CBP, and testing for this bacterium is highly recommended. n

continued from page 1

ahead of print in Cancer Epidemiology, Biomarkers & Prevention.

“These findings, coupled with evidence that statin use is associated with reduced recurrence risk, suggest that lipid levels should be explored as a modifiable risk factor for prostate cancer recurrence,” the authors concluded.

The researchers analyzed data captured in the Shared Equal Access Regional Cancer Hospital (SEARCH) database. They defined dyslipidemia using National Cholesterol Education Program guidelines. Of the 843 patients, 325 (39%) had abnormal preoperative cholesterol levels (200 mg/dL or higher) and 293 (35%) experienced BCR, defined as a single PSA value

10/27/14 1:05 PM

www.renalandurologynews.com NOVEMBER 2014

Active Surveillance for Black PCa Patients Reasonable Strategy safe despite higher risk for worse outcomes, review’s authors say 6 months, with repeat imaging and biopsy at 24 months.

“Our use of aggressive imaging, biopsy, and follow-up regimens is likely to mitigate any increased risk, which remains unclear in AA,” they concluded.

In an editorial accompanying the report by Dr. Silberstein’s group,

© THINKSTOCK

ACTIVE surveillance for low-risk prostate cancer (PCa) in African-American men is a safe and reasonable option, despite evidence suggesting they are more likely than Caucasian men to have worse pathologic and oncologic outcomes, researchers concluded in a recent literature review.

African-American prostate cancer patients need not be excluded from active surveillance.

The authors of the review, Jonathan L. Silberstein, MD, and colleagues at Tulane University School of Medicine in New Orleans, acknowledged that the available literature remains unclear regarding the risks and outcomes for African-American (AA) patients selecting active surveillance (AS), but the researchers said they are confident about using AS in AA patients “because AS patients are a heavily screened population.”

Dr. Silberstein’s team pointed out that some issues central to any consideration of AS remain unresolved, regardless of patient race, such as the criteria used to select appropriate AS candidates, how intensively patients on AS should be monitored, and defining disease progression while on AS. The authors stated that the AS protocol at their institution involves multiparametric magnetic resonance imaging within 6 months of initial diagnosis followed by directed biopsies. Repeat physical examinations and PSA measurements are obtained every

NEWS_AS-AA_WCE-ADPKD_RUN1114.indd 13

Debasish Sundi, MD, and Edward M. Schaeffer, MD, PhD, of the James Buchanan Brady Urological Institute at Johns Hopkins University in Baltimore, said it is unknown whether very lowrisk (VLR) AA men considered or enrolled in AS and who have their cancer upgraded at surgery or have treatment triggered by biopsy upgrading experience higher risks of metastases and PCSM. They pointed out, however, that the National Comprehensive Cancer network guidelines suggest that patients with adverse pathologic features or biochemical recurrence should undergo secondary radiotherapy and, in certain situations, secondary androgen deprivation therapy (ADT).

In addition, guidelines suggest that patients with high-grade cancers receiving radiotherapy should also receive combined treatment with ADT. “Therefore, PCa racial disparities among AS candidates not only affect outcomes on surveillance but also the oncologic outcomes and cancerdirected therapies on treatment,” Drs.

Sundi and Schaeffer wrote. “Most importantly, identifying the biologic basis of these disparities may shed light on the crucial distinction between indolent and aggressive PCa.” Drs. Sundi and Schaeffer, along with other researchers, recently published the findings of a study showing that AA men with very low-risk (VLR) PCa followed on AS are at higher risk for grade reclassification compared with Caucasian men.

After adjusting for PSA level, prostate size, volume of cancer on biopsy, body mass index, and treatment year, AA race independently predicted biopsy reclassification, the investigators reported online ahead of print in Urology.

The prospective study of 654 men with VLR disease (615 Caucasian and 39 AA men) demonstrated that AA men were significantly more likely than Caucasian men to experience pathologic upgrading on serial biopsy (36% vs. 16%) during AS. “Therefore, if the goal of AS is to selectively monitor men with low-grade disease, AA men may require alternate selection criteria,” the authors concluded.

Other prior studies have shown that AA patients with low-risk PCa are more likely than Caucasians to experience disease progression. Earlier this year, a team led by Ranko Miocinovic, MD, of the Detroit Medical Center, reported in Urology (2014;83:364-368) that AA men on AS for low-risk PCa have a nearly 4-fold increased risk of disease progression compared with non-AA men, and concluded that AA men may need closer follow-up than non-AA men. The study, which included 67 AA men and 72 non-AA men who had a median follow-up of 34 months and 46 months, respectively, also showed that a significantly smaller proportion of AA men than non-AA men remained on AS (66% vs. 82%) at follow-up.

In a study of 4,231 men with lowrisk PCa who were eligible for AS but underwent RP within 1 year, a team led

by Matthew R. Cooperberg, MD, of the University of California San Francisco, found that AA patients were 64% more likely than Caucasians to have positive surgical margins, according to a report published online ahead of print in European Urology. n

Renal & Urology News 13

Nephrectomy Plus Transplant May Benefit ADPKD Pts NATIVE unilateral nephrectomies in conjunction with renal transplantation in patients with autosomal dominant polycystic kidney disease (ADPKD) can improve control of hypertension, according to study findings presented at the 32nd World Congress of Endourology in Taipai, Taiwan.

A team at Indiana University School of Medicine in Indianapolis led by Chandru P. Sundaram, MD, retrospectively examined hypertension control in 143 ADPKD patients who underwent renal transplantation from 2003 to 2013. Of these, 67 underwent transplantation alone and 76 underwent transplantation with concurrent unilateral native nephrectomy.

The nephrectomy group included 40 who had a native kidney removed at the time of transplantation and 36 who had a native kidney removed in 2 stages. The staged nephrectomies were completed in a median of 9.8 months post-transplantation.

Comparing preoperative to postoperative antihypertensive medication use, patients who underwent native nephrectomy had a significantly greater decrease in the mean number of medications at 12, 24, and 36 months follow-up than those who underwent transplanta-

Novel approach can lead to improved hypertension control, a study suggests. tion alone (−1.2 vs. −0.5, 1.1 vs. 0.3, and −1.2 vs. 0.4, respectively), Dr. Sundaram and his colleagues reported in a poster.

The nephrectomy patients also experienced significantly greater decreases in defined daily dose (DDD) at 12, 24, and 36 months (−3.3 vs. −1.0, −2.9 vs. −1.0, and −2.7 vs. 0.6, respectively). Greater hypertension control was achieved in patients undergoing staged completion native nephrectomies.

DDD is a means of standardizing and analyzing drug consumption among patients, the authors explained. It is the assumed average maintenance dose per day for a medication used for its main indication in adults. n

10/27/14 2:26 PM

14 Renal & Urology News

NOVEMBER 2014

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High Sclerostin Linked to Lower CV Mortality DIALYSIS PATIENTS with high levels of circulating sclerostin may be less likely to die from cardiovascular causes.

Researchers led by Vincent M. Brandenburg, MD, of University Hospital of the RWTH Aachen, Aachen, Germany, analyzed data from 673 incident dialysis patients enrolled in a prospective cohort study in the Netherlands.

Subjects had circulating sclerostin measured 3 months after the start of dialysis (baseline). After adjusting for various

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News-soo_014_RUN1114.indd 14

clinical and biochemical parameters, patients in the highest tertile of sclerostin had a significant 71% and 61% decreased risk for cardiovascular death and all-cause mortality, respectively, within 18 months compared with those in the lowest tertile, Dr. Brandenburg’s team reported online ahead of print in

Nephrology Dialysis Transplantation.

Sclerostin is a glycoprotein secreted by osteocytes that inhibits bone formation. Sclerostin levels are elevated in patients with chronic kidney disease and end-stage renal disease (ESRD).

Recent evidence suggests that sclerostin plays a role in uremic and non-uremic

cardiovascular calcification processes.

In a study published recently in Kidney & Blood Pressure Research (2014;39:230-239), researchers found that markedly elevated blood levels of sclerostin in ESRD patients decrease rapidly to normal or subnormal values after renal transplantation. ■

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Renal & Urology News 15

Dietary Fiber, Renal Function Linked Higher fiber intake is associated with increased eGFR and decreased inflammation

PCa Biopsy Complications On the Rise RESEARCHERS in England have documented an increase in the rate of hospitalizations for complications following transrectal ultrasound (TRUS)guided prostate biopsy, according to a new report.

Eleni Anastasiadis, MBChB, of the Royal College of Surgeons of England, and colleagues conducted a populationbased study of 198,361 men diagnosed with prostate cancer (PCa) from 2000 to 2008. Of these, 69% were aged 65 to 84 years. The investigators considered complications to have occurred if patients had been admitted to a hospital as a result of urologic causes, including urinary tract infection (UTI)/ sepsis, hematuria, and urinary retention within 30 days of biopsy.

Overall, the 30-day rate of complications resulting in hospital admission was 3.7% (1.1% for UTI/sepsis, 1.4% for hematuria, and 1.3% for urinary retention). The overall urologic complication rate increased over time, from 3.6% in 2000 to 3.9% in 2008.

NEWS_Fiber_Biopsy_Nocturnal_RUN1114.indd 15

intake (14.5 g/day or less), those in the highest quartile (greater than 19.2 g/ day) had a statistically significant 35% decreased odds of having elevated C-reaction protein (greater than 3 mg/L), a systemic marker of inflammation.

Higher fiber intake was associated with lower all-cause and cancer-related mortality in subjects with kidney dysfunction (eGFR below 60 mL/min/1.73 m2). In these individuals, each 10 g/ day increase in fiber intake was associated with a statistically significant 42% decreased risk of death from any cause and 75% decreased risk of cancer-related death. The researchers observed no statistically significant association between fiber intake and cardiovascular-related death.

Dr. Carrero’s group noted that potential mechanisms have been proposed linking dietary fiber and kidney function. They cited a study suggesting that dietary fiber can increase fecal bacteria mass and nitrogen excretion.

In adjusted analyses, patients undergoing TRUS-guided biopsy in 2008 had a 20% increased odds of urologic complications overall and 72% increased odds of complications due to UTI/ sepsis compared with those undergoing biopsy in 2000, Dr. Anastasiadis’ team reported online ahead of print in International Journal of Urology.

Additionally, the study showed that age and comorbid conditions are the 2 most important risk factors for post-biopsy complications. Patients aged 85 years and older had 3.8 times greater odds of complications than those younger than 55 years. Patients with 3 or more comorbidities had 3.5 times greater odds than those with no comorbidities.

The authors suggested some approaches to reduce the likelihood of complications, such as being more selective when deciding which men require a TRUS-guided biopsy.

Nomograms and predictive models, new biomarkers, PSA derivatives, and multiparametric magnetic resonance imaging can help clinicians in selecting for biopsy only patients at higher risk of PCa, they noted. Another approach might be the use of routine rectal swabs to guide prophylactic antibiotics and to characterize antimicrobial resistance rates. n

Oatmeal with pumpkin and apple is a good source of fiber.

“Consumption of fiber, which increases the energy substrate available to fecal bacteria and stimulates their proliferation, could decrease serum urea by providing a fecal route of excretion for accumulated nitrogenous wastes,” they wrote.

The new study confirms findings from an analysis of data from 14,543 participants in the National Health and Nutrition Examination Survey III (NHANES III) by Vidya M. Raj Krishnamurthy, MD, of the University of Utah School of Medicine in Salt Lake City, and colleagues. The study cohort had a 5.8% prevalence of chronic kidney disease (eGFR below 60 mL/min/1.73 m2). Each 10 g/day increase in total dietary fiber intake was associated with a 38% and 11% decrease in the odds of elevated serum CRP (above 3 mg/L) in subjects with and without CKD, respectively, after adjusting for potential confounders, Dr. Krishnamurthy’s group reported in Kidney International (2012;81:300-306). Each 10 g/day increase in total fiber intake was associated with a significant 19% decreased mortality risk in participants with CKD. The researchers found no association between total fiber intake and mortality among individuals without CKD. n

Alternate Night NHHD Found to Improve Anemia NOCTURNAL home hemodialysis

tion, 26% of the NHHD patients were

(NHHD) performed on alternate nights

able to discontinue ESA therapy com-

improves anemia and decreases the

pared with none of the CHD patients.

need for an erythropoiesis-stimulating

The NHHD group experienced greater

agent (ESA) compared with conventional

increase in standard Kt/V compared

hemodialysis, according to a new study.

with the CHD group.

Clara K. Y. Poon, MD, of Princess

“NHHD with an alternate night sched-

Margaret Hospital in Hong Kong, and col-

ule improves anemia and reduces ESA

leagues compared 23 patients receiving

requirement as a result of enhanced ure-

NHHD with 25 in-center patients receiv-

mic clearance,” the authors concluded.

ing conventional hemodialysis (CHD).

Dr. Poon’s team cited a cohort study

In the NHHD group, mean hemoglobin

in which investigators examined anemia

levels increased significantly from 9.37

parameters in patients receiving daily

g/dL at baseline to 11.34 g/dL at 24

long nocturnal hemodialysis and those

months, the investigators reported

undergoing short daily hemodialysis

online ahead of print in Hemodialysis

and CHD. The study, published in the

International. During that same period,

American Journal of Kidney Diseases

the mean weekly ESA requirement

(2003;42 (S1):S18–S23), found that all

decreased significantly from 103.4 U/

patients lost a significant amount of

kg to 47.3 U/kg. In the CHD group,

blood in hemodialysis tubing and as a

mean hemoglobin levels were 9.5 g/dL

result of laboratory testing compared

at baseline and 9.3 g/dL at 24 months,

with baseline, but the groups undergo-

a non-significant difference. The weekly

ing daily hemodialysis experienced a

ESA requirement increased significantly

significantly greater amount of blood

from 89.7 U/kg to 105.9 U/kg. In addi-

loss compared with the CHD group. n

© THINKSTOCK

HIGH INTAKE of dietary fiber is associated with better kidney function and reduced inflammation among community-dwelling elderly men, according to a Swedish study.

Researchers calculated dietary fiber intake from 7-day dietary records kept by 1,110 men aged 70–71 years who participated in the Uppsala Longitudinal Study of Adult Men. They calculated eGFR using serum cystatin C concentrations.

After adjusting for potential confounders, each 10 g/day increase in dietary fiber intake was independently associated with a statistically significant 2.6 mL/min/1.73 m2 increment in estimated glomerular filtration rate (eGFR), a team led by Juan Jesús Carrero, MD, of Karolinska University Hospital in Stockholm, reported online ahead of print in the Clinical Journal of the American Society of Nephrology.

In addition, compared with individuals in the lowest quartile of dietary fiber

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20 Renal & Urology News

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Ultrasonography May Suffice As Initial Test for Suspected Stones ULTRASONOGRAPHY as the initial diagnostic imaging test may suffice for diagnosing most cases of suspected nephrolithiasis, thus sparing many patients from having to undergo computed tomography (CT), according to a new study.

Rebecca Smith-Bindman, MD, of the University of California San Francisco, and colleagues randomly assigned 2,759 patients presenting to emergency departments with suspected nephrolithiasis to undergo initial diagnostic ultrasonography performed by an emergency physicians (point-of-care ultrasonography), ultrasonography by a radiologist (radiology ultrasonography), or abdominal CT. Of the 2,759 patients, 908 underwent point-of-care ultrasonography, 893 underwent radiology ultrasonography, and 958 underwent abdominal CT. The incidence of high-risk diagnoses with complications in the first 30 days was 0.4% and did not differ significantly by imaging method: 0.7%, 0.3%, and 0.2% in the point-of-care ultrasonography, radiology ultrasonography, and CT groups, respectively, the researchers reported in The New England Journal of Medicine (2014;371:1100-1110).

The mean 6-month cumulative radiation exposure was significantly lower in the ultrasonography groups than the CT group, the researchers noted. The proportion of patients experiencing serious adverse events did not differ significantly among the groups: 12.4%, 10.8%, and 11.2% of the point-of-care ultrasonogra-

Ultrasound imaging can be followed by CT scans based on clinical judgment. phy, radiology ultrasonography, and CT groups, respectively. Return emergency department visits, hospitalizations, and diagnostic accuracy also did not differ significantly among the groups.

“Our results do not suggest that patients should undergo only ultrasound imaging, but rather than ultrasonography should be used as the initial diagnostic imaging test, with further imaging studies performed at the discretion of the physicians on the basis of clinical judgment,” Dr. SmithBindman’s group wrote.

The new study “provides valuable information about the choice of the first imaging study for patients presenting to the emergency department with suspected nephrolithiasis,” Gary Curhan, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, wrote in an accompanying editorial (pp. 1154–1155).

Based on the study findings, he noted, “it is reasonable for a physician to use ultrasonography as the initial imaging method for a patient presenting to the emergency department with suspected nephrolithiasis, remembering that additional imaging studies should be used when clinically indicated.”

Dr. Curhan pointed out that although the sensitivity was greater with CT than ultrasonography, it did not lead to better clinical outcomes. In addition, he cautioned: “Although we want to limit radiation exposure from all sources, the decision to use ultrasonography needs to be balanced against the additional information obtained by CT, which may influence subsequent clinical decisions. For example, additional renal stones may be seen on CT but not on ultrasonography, leading to a more aggressive regimen to prevent new stone formation.” n

Stone Risk Rises With Temperature HIGHER daily mean temperatures are associated with an increased incidence of kidney stones, a new study suggests.

Gregory E. Tasian, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and colleagues estimated the relative risk of kidney stone presentation associated with mean daily temperatures using the MarketScan Commercial Claims database. The study included 60,433 patients who sought medical evaluation or treatment of kidney stones from 2005–2011 in Atlanta, Chicago, Dallas, Los Angeles, and Philadelphia.

As daily temperatures increased to more than 10° C (50° F), the risk of kidney stone presentation over the following 20 days also increased in most cities, the researchers reported in Environmental Health Perspectives (2014;122:1081-1087).

Compared with a reference daily mean temperature of 10° C, a daily mean temperature of 30° C (86° F) was associated with a 38%, 37%, 36%, 11%, and 47% increased cumu-

Serious Technical Adverse Events Rare in HHD

lative relative risk of kidney stone

SERIOUS technical adverse events rare occur among patients on home hemodialysis (HHD), investigators concluded.

Karthik K. Tennankore, of Dalhousie University/Capital Health, Halifax, Nova Scotia, Canada, and colleagues studied 202 HHD patients with a total followup of 757 patient-years. The patients underwent a median of 5 dialysis sessions per week and 8 hours per session. The researchers identified 22 first adverse events and 7 recurrent events. Adverse event (AE) rates were 0.049 per arteriovenous fistula access-year, 0.015 per arteriovenous graft access-year, and 0.022 per dialysis catheter access-year, the investigators reported online ahead of print in the American Journal of Kidney Diseases.

AE rates per 1,000 dialysis treatments were 0.208, 0.068, and 0.087 for arteriovenous fistula, arteriovenous graft, and dialysis catheter access, respectively.

Most AEs were related to needle dislodgement (18 events) or air embolism (6 events). In addition, 8 AEs resulted

respectively.

NEWS_CT-HHD-Temp_RUN1114.indd 20

in emergency department visits and 5 required hospitalization. The rate of severe AEs was 0.009 per patient-year of HHD and 0.038 per 1,000 dialysis treatments. Of the 202 patients, 30 died, with 4 deaths occurring at home.

None of the deaths was clearly related to technical errors.

Dr. Tennankore’s team concluded that their report “re-emphasizes that the overall rate of procedure-related adverse events in HHD is low, and the risk of recurrent events is even lower. A systematic approach to retraining patients after an adverse event is feasible but may not necessarily eliminate a recurrence.”

Early this year in the same journal (2014;63:251–258), Ben Wong, MD, and colleagues published the findings of a multicenter Canadian study of 190 HHD patients with about 500 patientyears of treatments showing that lifethreatening AEs occurred at a rate of 0.060 per 1,000 treatments. The study population experienced 1 death and

6 potentially fatal AEs. Of the 7 AEs, 6 involved significant blood loss and 5 involved human error with lapses in protocol adherence, according to the researchers. “Because such events are rare,” Dr. Wong’s group noted, “evaluation of specific intervention strategies will require much longer follow-up.”

Dr. Tennankore’s group acknowledged some limitations to their study.

For example, by relying patient reporting and subsequent documentation of non-severe adverse events, it is possible that some procedure-related AEs were missed, the authors wrote. Although this would increase the AE rate overall, it is unlikely that it would have affected the rate of severe AEs. In addition, they pointed out that the classification of severity is subjective and may not be generalizable to other cohorts. “With respect to air embolization events, none was confirmed with diagnostic imaging.

Therefore, these events may have been overestimated.” n

presentation in Atlanta, Chicago, Dallas, Los Angeles, and Philadelphia, The maximum of risk of kidney stone presentation occurs in 3 or few days following exposure to high temperature, according to the investigators.

“Our estimations suggest that there is a graded increase in the risk of patients seeking medical care for kidney stones as average daily temperatures increase and that the time between hot days and kidney stone presentation is short,” they wrote.

The link between high ambient temperature and kidney stone formation is thought to be dehydration, which results in urinary concentration and low urine volume and pH. “This increases the relative supersaturation of calcium and uric acid, which thereby promotes nucleation, growth, and aggregation of lithogenic minerals in urine,” the authors explained. n

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Renal & Urology News 21

Commentary

BY MURRAY EPSTEIN, MD, FACP, FASN

MRA-Based Treatments for ESRD Patients on Dialysis: An Emerging Role

T

he Global Burden of Disease 2010 study1 identified chronic kidney failure as one of the 3 causes of death with the greatest increase from 1990 to 2010. Cardiovascular disease (CVD) is the most common cause of mortality and morbidity in patients with chronic kidney disease (CKD). CKD patients have up to a 3.5-fold increased risk of cardiovascular (CV) events.1 Despite these sobering observations, there is a paucity of evidence-based treatments for CKD patients on hemodialysis (HD).

Recently, increasing attention has focused on the use of the mineralocorticoid receptor antagonists (MRAs)— spironolactone and eplerenone—in the treatment of CKD patients, including those on HD2-5 (Table 1). The rationale for prescribing MRAs is compelling.

The beneficial CV effects of MRAs have been attributed to several mechanisms, including their effects on CV remodeling, collagen turnover, oxidative stress and endothelial function3,4 (Table 2). As shown in Table 1, the early studies of patients undergoing dialysis were of relatively short

duration and primarily assessed changes in blood pressure and the tendency to develop hyperkalemia.

More recently, Ando et al.6 reported the results of the EVALUATE study. While the study cohort included hypertensive patients with non-diabetic CKD, and not ESRD patients on dialysis, the surrogate endpoint of a reduction in albuminuria was interpreted to suggest an improved clinical outcome. The study by Ando et al. was a prospective, double-blind, randomized, placebo-controlled trial that included 314 hypertensive patients

with albuminuria (urinary albumin-tocreatinine ratio [UACR]: 30–599 mg/g) treated with ACE inhibitors and/or angiotensin receptor blockers. Subjects were randomly assigned to either an MRA or placebo. Although this study adds to our knowledge of MRA’s role in managing hypertensive patients with albuminuria, there are limitations that confound interpretation.6,7 As I have recently proposed,7 despite differences in trial design, the abovecited results2,4,5 are sufficiently provocacontinued on page 29

Table 1. Clinical Studies assessing the use of MRAs in chronic hemodialysis patients Study

Study design

# of Pts Intervention

Gross et al Randomized 8 2005 double-blind, placebo controlled Matsumoto Prospective, open label, uncontrolled et al DOHAS 2014

SPL 50 mg × 2/d vs placebo

309 SPL 25 mg × 1/d

Length of study

Length of SPL/EPL End point

7 wks

4 wks

Change in BP

↓SBP from 142.0 ± 19.6 No effect to 131.4 ± 18.2 mm Hg (P<0.05). No change on DBP

30 wks

24 wks

Change in plasma K

↑plasma K from 4.96 ± 0.72 to 5.18 ± 0.72 mEq/L

↑from 4.96 ± 0.72 to 5.18 ± 0.72 mEq/L Marginal statistical significance. No tendency to increase with time.

24 wks

24 wks

Effect on cardiovascular function, hospitalizations, plasma K

↓LV mass, ↑ejection fraction

No effect

Results

Effect on serum K

Taheri et al 2009

16 Randomized double-blind, placebo controlled

SPL 25 mg × 3/wk added to baseline ACEi/ARB

Saudan et al 2003

Prospective, open- 14 label, controlled

8 wks SOL 12.5 mg × 3/wk for 2 weeks, then up to 25 mg × 3/wk

4 wks

Change in plasma K

Plasma K 4.9 ± 0.7 vs 4.9 ± 0.3 mEq/L

No effect

Hussain et al 2003

Prospective, open- 15 label, uncontrolled

SPL 25 × 1/d

4 wks

4 wks

Change in plasma K

Plasma K increased from 4.6 ± 0.6 mEq/L at baseline to 4.9 ± 0.9 mEq/L. One pt with K 7.6 mEq/L at day 20

No effect

Michea et al 2004

Prospective, 9 double-blind, placebo controlled

SPL 50 × 3/wk followed by placebo

6 wks

2 wks

Effect on expression of ENaC in ↑ENaC expression peripheral blood mononuclear cells

No effect

Vukusich et al 2010

Prospective, 53 double-blind, placebo controlled

SPL 50 × 3/wk vs placebo

2 yrs

2 yrs

Progression of CIMT. Change in plasma K

↓CIMT in SPL

↑K by 0.012 mEq/L per month

Shavit et al 2012

Prospective, open-label, case controlled

EPL 25 mg × 2/d

10 wks

4 wks

Change in BP

↓SBP from 166 ± 14 to 153 ± 10 mm Hg (P<0.05).

No change on DBP

No effect

Ando et al EVALUATE 2014

314 EPL Prospective 50 mg × 1/d double-blind, randomized, placebo controlled

1 yr

1 yr

↓UACr in EPL vs plaChange in urinary UACr ratio, cebo (−17.3% vs 10.3%; ­serum Cr, eGFR, urinary L-FABP p=0.222) ↓SBP ↓eGFR levels, BP, 24h urinary Na excretion, plasma & urinary aldosterone, cerebro-cardiovascular events, serum K levels & adverse events

8

↑K but measured levels not over 5.5 mmol/L in either group.

Key: SPL/EPL: spironolactone/eplerenone Cr: Creatinine UACr: Urinary albumin-creatinine eGFR: estimated glomerular filtration rate K: potassium LV: left ventricular CIMT: carotid intima media thickness

021_Commentary_RUN1114_v2.indd 21

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26 Renal & Urology News

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Stroke Ups Dialysis Patient Death Risk DIALYSIS PATIENTS are at elevated risk for death following a stroke, and the risk is similar regardless of race, according to a new study.

James B. Wetmore, MD, of Hennepin County Medical Center in Minneapolis, Minn., and colleagues analyzed a cohort of 69,371 individuals with a mean age 60.8 years. After entry into the cohort, the group experienced 21.1 ischemic strokes and 4.7 hemorrhagic strokes per 1,000 patientyears. At 30 days, mortality was 17.9% for ischemic stroke and 53.45 for hemorrhagic stroke, the investigators reported online ahead of print in the Clinical Journal of the American Society of Nephrology. In adjusted analyses, patients who had a hemorrhagic stroke at 1 year after cohort entry had a 25 times increased risk of death at 1 week and a 9.9 times, 5.9 times, and 1.8 times increased risk of death at 3, 6, and 24 months, respectively, compared with patients who did not suffer a stroke.

PCa-Related Mortality Tied to Smoking SMOKING TOBACCO modestly increases the risk of dying from prostate cancer (PCa), according to a new meta-analysis published online ahead of print in European Urology.

A team led by Stephen J. Freedland, MD, of Duke University Medical Center in Durham, N.C., analyzed 51 studies involving a total of 50,349 PCa cases, 11,823 PCa deaths, and 4.0 million cohort participants. Current cigarette smoking was associated with a significant 24% increased risk of PCa death, Dr. Freedland and colleagues reported. The risk of PCa death increased by a significant 20% with each 20 cigarettes smoked per day.

“Even if the association between smoking and PCa death is established as causal, the magnitude of association is smaller versus those reported for other smoking-related cancers including cancers of the lung and upper aerodigestive tract,” the authors wrote.

“Therefore, the proportion of the PCa deaths attributed to smoking will be

026_RUN1114.indd 26

Patients with ischemic stroke at 1 year after cohort entry had an 11.7 times, 6.6 times, and 4.7 times increased risk of death at 1 week and 3 and 6 months, respectively. Their risk of death remained significantly elevated even at 48 months, according to the investigators.

In addition, the median months of life lost were 40.7 for hemorrhagic stroke sufferers and 34.6 months for ischemic stroke sufferers. Mortality did not differ by race, regardless of stroke type.

The study demonstrated an overall stroke incidence rate of 25.8 new events per 1,000 patient-years, which the researchers observed is in the middle of the range found in other studies of dialysis patients.

The reasons why stroke may affect mortality remains uncertain, Dr. Wetmore’s group commented. “Stroke is part of an epiphenomenon involving inflammation, nutrition, and frailty,” Dr. Wetmore’s team wrote. “Individuals with

modest. However, because PCa is a common cause of cancer death, this association may have a considerable impact on cancer mortality at the population level.”

In addition, the meta-analysis showed that studies completed in 1995 or earlier—considered to be prior to the PSA screening era—found that smoking was associated with an increased incidence of PCa, whereas studies completed afterward demonstrated no or even an inverse association between smoking and PCa incidence. “This reason for this pattern is unclear,” the researchers stated. “One possible explanation is that smoking may reduce the risk of indolent nonaggressive cancers that have predominated in more recent years while promoting more aggressive cancers.”

Earlier this year, Daniel M. Moreira, MD, of the Arthur Smith Institute for Urology, North Shore Long Island Jewish Health System in New Hyde Park, N.Y., and colleagues published findings in Cancer (2014;120:197–204) showing that cigarette smoking among men undergoing radical prostatectomy (RP) for PCa did not have an increased risk of cancer-related death, but did have an increased risk of metastasis, biochemical recurrence, castration-resistant disease, and overall mortality. n

© ISTOCK

The risk of dying after suffering a hemorrhagic or ischemic stroke is greatest in the first week

A disabling stroke might adversely affect a dialysis patient’s functional status and nutrition.

a substantial inflammatory burden or a high degree of frailty are at increased risk for both stroke and death. Alternately, it is also plausible that a disabling stroke might adversely affect functional status and nutrition, leading to frailty and premature death.”

In a study published recently in the American Journal of Kidney Diseases

(2014;63:604-611), researchers in Taiwan found that the incidence of hospitalization for ischemic stroke was 102.6 and 100.1 per 10,000 personyears in patients on hemodialysis (HD) and peritoneal dialysis (PD), respectively. The incidence of hemorrhagic stroke was 74.7 and 59.4 per 10,000 person-years, respectively. n

High Indoxyl Sulfate Levels Increase Heart Failure Risk HIGH LEVELS of plasma indoxyl sulfate

increment in indoxyl sulfate was associ-

(IS), a protein-bound uremic toxin,

ated with a significant 4% increased risk

are associated with an elevated risk

of a first heart failure.

of heart failure in hemodialysis (HD) patients, according to a new study.

The authors noted that in recent years, more and more attention has been paid

A team led by Xiao-Qiang Ding, MD,

to the relationship between IS and car-

of Fudan University in Shanghai, China,

diovascular disease and chronic kidney

prospectively studied 258 patients with

disease. For example, a study of 70

a mean age of 57 years who had been

pre-dialysis patients led by Chih-Jen Wu,

on HD for more than 6 months. The

MD, PhD, of Mackay Memorial Hospital

researchers categorized patients into 2

in Taipei, Taiwan, found that serum

groups: a low-IS group (32.35 µg/mL or

IS predicted cardiovascular events,

less) and a high-IS group (greater than

according to a report in the Archives of

32.35 ug/mL) and followed them for a

Medical Research (2012;43:451- 456).

median of 48 months. During follow-

A team led by I-Ting Tsai, MD, of I-Shou

up, 68 patients experienced episodes

University, Kaohsiung, Taiwan, reported

of first heart failure. After adjusting for

in Clinical and Investigative Medicine

confounding factors, compared with

(2013;36:E42- E49) that patients with

patients in the low-indoxyl sulfate group,

significant coronary artery stenosis had

those in the high-indoxyl sulfate group

significantly higher serum IS levels than

had a significant 5.3-fold increased risk

patients with normal coronary arteries.

of a first heart failure event, Dr. Ding and

On multivariate analysis, serum IS levels

colleagues reported online ahead of print

were independently associated with

in the Clinical Journal of the American

the presence and severity of coronary

Society of Nephrology. Each 1 µg/mL

artery disease. n

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Renal & Urology News 27

Point / Counterpoint The Renal & Urology News forum for experts to debate controversial clinical questions

Metformin Use in Patients with Type 2 Diabetes and CKD

M

I

etformin remains the cornerstone of medical therapy for patients with type 2 diabetes because of its demonstrated efficacy and excellent tolerance.1,2 Because it should be made available to the widest possible range of patients, it is worth reexamining the question of safety in diabetic patients with chronic kidney disease (CKD) with respect to safety, specifically the development of metformin-associated lactic acidosis (MALA). The FDA currently recommends that

BY MARK E. metformin should not be used with serum creatiMOLITCH, MD nine levels 1.5 mg/dL or higher in men and 1.4 mg/ dL or higher in women to reduce the risk of MALA. Metformin is filtered at the glomerulus and secreted in the proximal tubule with a high clearance of 505 ± 129 mL/min in normal subjects.3 The clearance decreases by about 75% when the GFR is below 60 mL/min/1.73m2 without further change when the GFR declines to 30 mL/min/1.73m2.4 Median serum concentrations (ranges) of metformin are 4.5 (range 0.1– 20.7), 7.71 (range 0.12–15.5) and 8.88 (range 5.99–18.6) μmo/L (1 μg/mL = 7.8 μmol/L) at GFR levels below 60, 30–60, and below 30 mL/min/1.73m2, respectively.5 In patients presenting with MALA, metformin levels are 5–15 fold higher than this, however, and serum creatinine levels generally are over 3 mg/dL.6 The overall incidence of lactic acidosis with metformin use is very low. A Cochrane database review of 347 prospective trials and observational cohort studies showed no cases of fatal or nonfatal lactic acidosis in 70,490 patientyears of metformin use or in 55,451 patient-years of users of other anti-hyperglycemic agents.7 In a nested case-control analysis of 50,048 patients in the U.K. General Practice Research Database, only 6 cases of lactic acidosis were found, giving incidence rates of 3.3 cases per 100,000 person-years among metformin users and 4.8 cases per 100,000 person-years among users of sulfonylureas.8 In the Swedish National Diabetes Register of 51,675 patients, compared with other diabetes treatments, there were significantly reduced risks for any acidosis/serious infection for metformin use in patients with eGFR greater than 60 (n=41,048) and 45–60 (n=6,960) and an insignificantly reduced risk in those with eGFR’s 30–45 mL/min/1.73m2 (n=2,044).9 No cases of lactic acidosis were observed in a 4-year prospective study of 393 patients with serum creatinine levels of 1.48 to 2.5 mg/dL who were randomized to stopping or continuing to receive metformin.10 Despite the low numbers in these studies, MALA certainly does occur but it is rare. In retrospective series evaluating MALA, in most cases hypotension, sepsis, hypoxia and, in particular, acute kidney injury (AKI) related

n the absence of contraindications, metformin is recommended as the first-line oral agent for the treatment of type 2 diabetes.1,2 In addition to its favorable effects on glucose by decreasing hepatic gluconeogenesis, improving insulin sensitivity, and increasing peripheral glucose uptake, metformin has been shown to reduce body fat and weight, lower lipids, and diminish cardiovascular morbidity and mortality.3 Despite its irrefutable benefits, almost equivaCONNIE M. lent attention has been placed upon metformin’s RHEE, MD, MSc potential adverse effects, namely, lactic acidosis.

In the 1960’s and 1970’s, other drugs in the biguanide class, phenformin and buformin, were removed due to their high incidence of fatal lactic acidosis.4 Approved by the FDA in 1995,3 metformin bears a lower risk of lactic acidosis compared with phenformin (1 to 16 vs. 40 to 64 cases per 100,000 patient-years, respectively5-7). However, there has been intense debate with regard to the KAM KALANTARZADEH, MD, MPH, differential safety and effectiveness of metformin in chronic kidney disease (CKD) patients verPhD sus their non-CKD counterparts. Metformin is renally eliminated in unchanged form by glomerular filtration and active tubular secretion, and its clearance may be reduced by 75% in those with an estimated glomerular filtration rate (eGFR) below 60mL/min/1.73m2.8 Clinical practice guidelines, mostly opinion based, have proposed various kidney function cut-offs and metrics (serum creatinine vs. eGFR) for defining metformin’s safety threshold in CKD, which remains uncertain.

According to the FDA mandatory black-box warning label on metformin and National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) recommendations, metformin is contraindicated at a serum creatinine level of 1.4 mg/dL or higher and 1.5 mg/dL or higher in women and men, respectively8; these cut-offs are conservative estimates of the threshold at which 3 grams of metformin can be removed at steady state levels in 24 to 48 hours.9 A consensus statement proposed by the American Diabetes Association and European Association for the Study of Diabetes advise that metformin may be safe above an eGFR threshold of 30 mL/min/1.73m2.1 The Kidney Disease Improving Global Outcomes (KDIGO) group has proposed comparatively more stringent guidelines, advising that metformin use be reviewed in those with an eGFR 30–44 mL/min/1.73m2 (but continued if eGFR is ≥45mL/min/1.73m2), discon-

continued on page 28

continued on page 28

POINT

A Cochran database review of 347 prospective trials and observational cohort studies showed no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use.

Pt-CPt_RUN1114.indd 27

COUNTERPOINT

Metformin use should be reviewed in those with an eGFR below 60, withheld in those with an eGFR below 45, and avoided in those with an eGFR below 30 mL/min/1.73 m2.

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28 Renal & Urology News

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Point

continued from page 27

to abrupt volume loss seemed to be the driving cause of lactic acidosis in addition to metformin.6,11-15 High levels of metformin, either from an overdose or from accumulation due to AKI, can cause lactic acidosis through multiple mechanisms, including inhibition of mitochondrial electron transport, acceleration of glycolysis and activation of anaerobic metabolism of glucose in the intestine.6,16 Overall, it appears that metformin use is quite safe in patients with mild-tomoderate CKD and that MALA is very rare. As Herrington and Levy point out, metformin use is much safer that insulin and sulfonylurea use, citing the incidence of MALA as 6.3 per 100,000 patient-years, with a 50% mortality, yielding a predicted number of deaths of 3 per 100,000 patient-years in contrast to incidences of hypoglycemia of 1,000 for sulfonylureas and 18,000 for insulin per 100,000 patient-years with a 4.3% mortality, yielding predicted numbers of deaths of 43 for sulfonylureas and 77 for insulin per 100,00 patient-years.17 I agree with the suggestions of others:17,18 (1) if the eGFR is 45–59 mL/ min/1.73m2, metformin can be used but caution is needed with dosing

Overall, it appears that metformin use is quite safe in patients with mild-to-moderate CKD and that metformin-associated lactic acidosis is very rare. and renal function should be followed closely, e.g., every 3–6 months; (2) if the eGFR is 30–44 mL/min/1.73m2, the dose should be limited to a maximum of 1,000 mg daily or reduced by 50%, renal function should be monitored every 3 months, and initiation of metformin should be avoided; and (3), if the eGFR is less than 30 mL/ min/1.73m2, metformin use should be avoided.

In addition, metformin should be stopped in the presence of situations that are associated with hypoxia or an acute decline in kidney function such as sepsis/shock, hypotension, acute myocardial infarction, and use of radiographic contrast or other nephrotoxic agents.21,22 Since many patients

Pt-CPt_RUN1114.indd 28

admitted to the hospital experience 1 or more of these events, we routinely stop metformin on admission to the hospital regardless of their eGFR on admission.19 Patients with eGFR’s below 60 mL/min/1.73m2 should be instructed to withhold metformin and contact their healthcare providers if they experience intercurrent illness (e.g., vomiting and/or diarrhea) that could lead to rapid volume depletion. Given these cautions, I feel that metformin use can be extended to many patients with moderate CKD, i.e., those with eGFR’s of 30–60 mL/min/1.73m2. n Dr. Molitch is the Martha Leland Sherwin Professor of Endocrinology at Northwestern University Feinberg School of Medicine in Chicago.

REFERENCES 1. Inzucchi SE, Nauck M, Bergenstal RM et al.

Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).

Diabetes Care. 2012;35:1-16.

2. Hirst JA, Farmer AJ, Ali R, et al. Quantifying the effect of metformin treatment and dose on glycemic control. Diabetes Care. 2012;35:446-454.

3. Graham GG, Punt J, Arora M et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet.

2011;50:81-98.

4. Sambol NC, Chiang J, Lin ET, et al.: Kidney function and age are both predictors of pharmacokinetics of metformin. J Clin Pharmacol. 1995;35:1094-1102.

5. Frid A, Sterner GN, Londahl M, et al. Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function: clinical recommendations. Diabetes Care. 2010;33:1291-1293.

6. Duong JK, Furlong TJ, Roberts DM, et al. The role of metformin in metformin-associated lactic acidosis (MALA): case series and formulation of a model of pathogenesis. Drug Saf. 2013;36;733-746.

7. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010(4):CD002967.

8. Bodmer M, Jick SS, Meier C, et al. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia. A nested case-control analysis. Diabetes Care. 2008;31; 2086-2091.

9. Ekström N, Schiöler L, Svensson AM, et al. Effectiveness and safety of metformin in 51675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open. 2012;2:e001076.

10. Rachmani R, Slavachevski I, Levi Z, et al. Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Intern Med. 2002;13:428-433.

11. Lalau JD, Lacroix C, Compagnon P, et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care. 1995;18:779-784.

12. Runge S, Mayerle J, Warnke C, et al. Metforminassociated lactic acidosis in patients with renal impairment solely due to drug accumulation? Diabetes Obes Metab. 2008;10:91-93.

13. Seidowsky A, Nseir S, Houdret N, Fourrier F. Metformin-associated lactic acidosis: a prognostic and therapeutic study. Crit Care Med. 2009;37: 2191-2196.

14. Friesecke S, Abel P, Roser M et al. Outcome of severe lactic acidosis associated with metformin accumulation. Crit Care. 2010;14:R226 15. Renda F, Mura P, Finco G, et al. Metforminassociated lactic acidosis requiring hospitalization.

A national 10-6314 survey and a systematic literature review. Eur Rev Med Pharmacol Sci. 2013;17(Suppl 1):45-49.

16. Lalau JD, Arnouts P, Sharif A, DeBroe ME. Metformin and other antidiabetic agents in renal failure patients.

Kidney Int. 2014 doi:10.1038/ki.2014.19.

17. Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency.

Diabetes Care. 2011;34:1431-1437.

18. Herrington WG, Levy JB. Metformin: effective and safe in renal disease? Int Urol Nephrol.

2008;40:411-417.

19. Hahr AJ, Molitch ME. Glucose control in diabetes mellitus and kidney disease. In Handbook of Chronic Kidney Disease Management, JT Daugirdas (ed.). Lippincott Williams & Wilkins. Philadelphia.

2011;207-223.

Counterpoint continued from page 27

tinued in those with eGFR <30mL/ min/1.73m 2, and temporarily held in those with eGFR below 60 mL/ min/1.73m2 with a concurrent serious illness increasing their risk of acute kidney injury (AKI).10 The principle risk of metformin toxicity is nonhypoxic (type B) lactic acidosis.11 In contrast to the classic or hypoxemic (type A) lactic acidosis that occurs in settings of impaired tissue perfusion (e.g., cardiogenic and septic shock),11 metformin toxicity results in: (1) increased conversion of glucose to lactate in the small intestine, and impaired mitochondrial function leading to (2) accelerated glycolysis, and (3) reduced gluconeogenesis from lactate, pyruvate, and alanine, increasing lactate and lactate substrate. Lactic acidosis may subsequently lead to gastrointestinal symptoms (nausea, vomiting, diarrhea), and if profound may cause altered mental status, including coma; hypotension, systolic heart failure, and arrhythmia; respiratory abnormalities (tachypnea, pulmonary edema); and hypothermia.11 Treatment options for metforminassociated lactic acidosis (MALA) are limited and largely supportive, which include: (1) gastrointestinal decontamination with activated charcoal; (2) hemodialysis in those with a) severe acidemia, b) impaired kidney function, or c) failure to improve with supportive care; and (3) continuous venovenous hemofiltration or continuous venovenous hemodialysis in those who are hemodynamically unstable, albeit less preferred to hemodialysis due to lower clearance of metformin. Sodium bicarbonate in the management of MALA remains controversial due its potential adverse effects, including rebound metabolic alkalosis, increased carbon dioxide production, and electrolyte derangements.12 More recently, the low incidence of MALA observed in clinical studies has called into question whether or not current guidelines restricting the use of metformin should be modified or even removed. Several points should be considered prior to relaxing the restrictions centered around metformin and CKD: (1) The fatality case rate of MALA is high, (2) The real-life incidence of MALA may be underestimated, (3) CKD patients with an eGFR below 45 mL/min/1.73m2 (stage 3B) have a lower reserve for kidney function decline, further increasing their risk of MALA, and (4) CKD patients may have

multiple concomitant MALA risk factors given their advanced age and high comorbidity burden.

In addition to the aforementioned safety concerns, it remains uncertain as to whether metformin may yield the same multi-organ benefits in patients with advanced CKD or other contraindications. To date, no randomized controlled trials have specifically evaluated the potential benefits and risks of metformin in patients with CKD.9 Given the high fatality rate of MALA, such a study may not be feasible. At this time, we recommend a conservative approach in the use of metformin of CKD based upon, but not limited to, KDIGO’s guidelines combined with other evidence, such that metformin use be reviewed in those with an eGFR below 60 mL/min/1.73m 2; withheld in those with an eGFR less than 45 mL/min/1.73m 2 for further risk-benefit evaluation, especially in those with a concurrent serious illness heightening their risk of superimposed AKI;10 and permanently discontinued and avoided in those with an eGFR less than 30 mL/min/1.73m2. n Dr. Rhee and Dr. Kalantar-Zadeh are affiliated with the Harold Simmons Center for Chronic Disease Research and Epidemiology, Division of Nephrology and Hypertension, University of California Irvine School of Medicine, Irvine.

REFERENCES 1. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care.

2009;32:193-203.

2. Rodbard HW, Jellinger PS, Davidson JA, et al.

Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract.

2009;15:540-559.

3. Rocha A, Almeida M, Santos J, Carvalho A. Metformin in patients with chronic kidney disease: strengths and weaknesses. J Nephrol. 2013;26: 55-60.

4. Fantus IG. Metformin’s contraindications: needed for now. CMAJ. 2005;173:505-507.

5. Brown JB, Pedula K, Barzilay J, et al. Lactic acidosis rates in type 2 diabetes. Diabetes Care.

1998;21:1659-1663.

6. Stang M, Wysowski DK, Butler-Jones D. Incidence of lactic acidosis in metformin users. Diabetes Care.

1999;22:925-927.

7. Tahrani AA, Varughese GI, Scarpello JH, Hanna FW. Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated? BMJ. 2007;335(7618):508-512.

8. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update. Am J Kidney Dis. 2012;60: 850-886.

9. Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency.

Diabetes Care. 2011;34:1431-1437.

10. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.

Kidney Int Suppl. 2013;3:1-163.

11. Kalantar-Zadeh K, Uppot RN, Lewandrowski KB. Case records of the Massachusetts General Hospital.

Case 23-2013. A 54-year-old woman with abdominal pain, vomiting, and confusion. N Engl J Med. 2013;369:374-382.

12. Heaney D, Majid A, Junor B. Bicarbonate haemodialysis as a treatment of metformin overdose. Nephrol Dial Transplant. 1997;12:1046-1047.

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www.renalandurologynews.com NOVEMBER 2014

Table 2. Potential mechanisms whereby aldosterone mediates fibrosis and collagen formation* Upregulation of angiotensin II receptors Potentiation of the pressor responses of angiotensin II Increases in sodium influx in vascular smooth muscle cells Inhibition of norepinephrine uptake in vascular smooth muscle cells and myocardial cells Participation in vascular smooth muscle cell hypertrophy Modulation of the effect of angiotensin II on plasminogen activator inhibitor-1 expression Promoting proinflammatory effects that appear to be MR-mediated Stimulation of transforming growth factor beta-1-synthesis Generation of reactive oxygen species Promotion of endothelial dysfunction *Modified and adapted from an earlier article by the author (ref. 4)

Commentary continued from page 21

tive to encourage additional large-scale, multicenter, randomized, double-blind, placebo-controlled trials necessary to provide a definitive answer as to the role of MRAs in patients with ESRD on HD. One such trial, ALCHEMIST (ALdosterone Antagonist Chronic HEModialysis Interventional Survival Trial; NCT01848639),8 is ongoing with plans to recruit 825 patients. The primary endpoint is time to onset of the first incident (nonfatal myocardial infarction or hospitalization for heart failure or nonfatal stroke or CV death).

Conceivably, ALCHEMIST and additional studies with finerenone (BAY 94-8862)9 will demonstrate a reduction in CV events in patients with ESRD on HD. The therapeutic role of MRA in the management of CKD and ESRD may be further amplified by the introduction of newer, chemically dissimilar MRAs.10

There are clear cut concerns regarding hyperkalemia.11 First, one must realize that the diagnosis of hyperkalemia should not be established by occasional or solitary determination of serum potassium. Repetitive serial determinations are necessary to ascertain if the hyperkalemia is sustained, or at times merely constitutes a transient and evanescent event. Indeed, in the ALCHEMIST clinical trial,8 the recognition of fluctuations in potassium has necessitated the development of a telemonitoring loop, including the development of a point of care (measuring potassium, creatinine, plasma volume variations), to facilitate dynamically managing dose titration of the renin-angiotensin-aldosterone system (RAAS) inhibition regimen.

Most clinicians are reluctant to use MRAs in patients with CKD and ESRD patients on HD because of the risk of hyperkalemia. Hyperkalemia often constitutes a constraint to prescribing MRAs. These agents are currently contraindicated

in patients with an estimated glomerular filtration rate (GFR) below 30 mL/ min/1.73 m2, including patients on HD. Although sodium polystyrene sulfonate is a common treatment for hyperkalemia, there is no convincing evidence that it increases fecal losses of potassium in animal or human studies. 12 If approved, the potential availability of 2 new, nonsystemic oral agents (patiromer and ZS-9) that sequester potassium in the gastrointestinal (GI) tract may obviate our current concerns regarding hyperkalemia,7,13,14 thereby facilitating maintaining patients on optimal therapeutic doses of RAAS inhibitors and MRAs. Hopefully, this will facilitate a further reduction in cardiovascular events.

In summary, the recent initiation of additional clinical trials of regimens comprising an RAAS inhibitor with add-on of an MRA in CKD /ESRD patients and the future availability of newer MRAs should further delineate the role of MRAbased treatment regimes in reducing CV events. The potential availability of new oral agents to control RAAS and MRAengendered hyperkalemia, by sequestering potassium in the GI tract, may facilitate MRA treatment in CKD patients despite reduced GFR. Collectively, these classes of drugs may comprise a novel treatment paradigm potentially promoting cardiovascular benefits and hopefully enhance quality of life in these very high-risk patients with CKD and ESRD on dialysis. n Murray Epstein, MD, FACP, FASN, is professor of medicine in the division of nephrology and hypertension at the University of Miami’s Leonard M. Miller School of Medicine.

Renal & Urology News 29

Disclosures Dr. Epstein is a consultant and on an advisory board or panel for Relypsa, Inc, Redwood City, CA and OPKO Health, Miami.

REFERENCES 1. Ortiz A, Covic A, Fliser D, et al. Epidemiology, contributors to, and clinical trials of mortality risk in chronic kidney failure. Lancet. 2014;383:1831-1843 2. Shavit L, Lifschitz MD, Epstein M. Aldosterone blockade and the mineralocorticoid receptor in the management of chronic kidney disease: current concepts and emerging treatment paradigms. Kidney Int. 2012;81:955-968.

3. Brown NJ. Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nat Rev Nephrol. 2013;9:459-469.

4. Epstein M. Aldosterone as a determinant of cardiovascular and renal dysfunction. J R Soc Med. 2001;94: 378-383.

5. Matsumoto Y, Mori Y, Kageyama S, et al. Spironolactone reduces cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients.

J Am Coll Cardiol. 2014;63:528-536.

6. Ando K, Ohtsu H, Uchida S, et al. Anti-albuminuric Effect of an aldosterone blocker in non-diabetic hypertensive patients with albuminuria: A double-blind, randomized, placebo-controlled trial. The EVALUATE Study Group.

Lancet Diabetes Endocrinol. (published online Oct 28. http://dx.doi.org/10.1016/S2213-8587(14)70194 -9).

7. Epstein M. Mineralocorticoid receptor antagonists: part of an emerging treatment paradigm for chronic kidney disease. Lancet Diabetes Endocrinol. (published online Oct 28. http://dx.doi.org/10.1016/ S2213-8587(14)70216-5).

8. ClinicalTrials.gov-NCT01848639. ALCHEMIST (ALdosterone Antagonist Chronic HEModialysis Interventional Survival Trial).

9. ClinicalTrials.gov-NCT01874431. A randomized, double-blind, placebo-controlled, multi-center study to assess the safety and efficacy of different oral doses of bay94–8862 in subjects with type 2 diabetes mellitus and the clinical diagnosis of diabetic nephropathy. 2013.

10. Kolkhof P, Delbeck M, Kretschmer A, et al. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury.

J Cardiovasc Pharmacol. 2014;64:69-78.

11. Epstein M. Hyperkalemia as a constraint to therapy with combination renin-angiotensin system blockade: the elephant in the room. J Clin Hypertens. 2009;11:55-60.

12. Sterns RH, Rojas M, Bernstein P, Chennupati S. Ion-exchange resins for the treatment of hyperkalemia: are they safe and effective? J Am Soc Nephrol 2010;21:733 -735.

13. Weir M, Bakris G, Mayo M, et al. A two-part trial of patiromer for the treatment of hyperkalemia in chronic kidney disease subjects on renin angiotensin aldosterone system inhibition. J Am Soc Nephrol.

2013;Abstract SA-PO1085.

14. Singh B, Ash SR, Lavin P, et al. Effect of ZS-9, a novel selective cation trap, on urinary potassium and sodium excretion when used for the treatment of hyperkalemia in patients with chronic kidney disease. J Am Soc Hypertens. 2014;8 (Suppl):e15 (Abstract FP-4).

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30 Renal & Urology News

NOVEMBER 2014 www.renalandurologynews.com

Practice Management J

udy Bee, a management consultant with Practice Performance Group, equates call coverage with the “hideous schedules in residency”: It doesn’t have to be as bad as it is, but it’s become a tradition. Particularly in a time when younger doctors are coming out of school seeking some semblance of work-life balance, call coverage can be the kind of issue that can break up a practice. But it doesn’t have to be.

“You can use call coverage to your advantage … or it can be a huge disadvantage,” said Bee, who has seen doctors kicked out of a group over the issue.

Here are some tips from the experts on how to manage call to make everyone as happy as possible.

Early and often Practices should look at their employment agreement once a year and find out whether or not it addresses maternity or paternity leave, phasing into retirement, and potential unplanned issues that can impact call coverage.

“The time to start negotiating is not when you need to make a decision,” Bee said. “Every year it should be on the calendar to review and see if it still makes sense as you grow older and the dynamics of the community and healthcare change.”

Planning for the unknown There are a host of reasons why call coverage in a practice might be changing. Whether it’s a pregnancy, illness, retirement, or physician burnout, each should be dealt with in an agreed-upon method by a practice.

If a group lands on a predictable schedule that works for doctors most of the time, then legitimate reasons for change should be defined and ways to deal with them should be determined. For instance, a practice partner may want time off after the birth of a child and 2 months is the agreed-upon leave. If a problem occurs and the partner needs to stay away for a longer period, the doctors should decide in advance how the physician can make up for that extension.

One often-used option is the buyout.

Bee said she has had practices call her wanting to know how much to charge for covering call and her answer is always the same: whatever it’s worth.

Call is essentially worth whatever a partner will take to cover it. She recommends splitting the work of the practice into categories, whether it is just taking calls from patients or performing surgery, and determining what they are worth.

Senior partners are often able to work with younger partners (who Dr. Provenzano said have more energy, are

If a group lands on a predictable schedule that works for doctors most of the time, then legitimate reasons for change should be defined.

The first thing doctors considering joining a practice ask is how much vacation they will get and how often they will take call, said Robert Provenzano, MD, Vice President of Medical Affairs at DaVita Healthcare Partners. A 1-in-4 is the most traditional schedule: 1 weekend a month or once every fourth night is usually considered “tolerable.”

But practices change and evolve and it’s best to have some sort of plan set up before they occur, not after.

PM_RUN1114.indd 30

trying to get their name known, and who need extra money) if call is valued fairly. He said many practices don’t allow senior partners to completely exit from being on call, but they can sell it.

Another option is to cut back on call coverage but reduce vacation time.

Outside the box Aside from selling call, there are a few options that can solve the call problem in a practice.

© THINKSTOCK

Call coverage may be less problematic if groups can focus on what is best for the practice as a whole, not for each individual BY TAMMY WORTH

Hiring a nephrohospitalist is among the newer options for dealing with call coverage.

Many practices have a large number of patient calls that don’t necessarily require admissions. These calls that are a “bloody nuisance” can sometimes be handled by mid-level providers, Bee said.

A nurse practitioner could manage most of those calls and only refer ones that they can’t handle to the on-call physician.

“Using a mid-level on a rotation is viable and worthwhile, especially if there aren’t a lot of you to share the load,” Bee said.

Another option is to work with other, similar groups in your area. People get particularly fixated with weekend call because of the disruption it can cause to a family. A small group may want to handle their own calls during the week, but have a call group with 2 other practices so they may only have to take call once every 3 months.

A final solution is a newer option that is not yet widely employed: hiring nephrohospitalists. Dr. Provenzano said this position is often a young partner who would have no responsibility outside of the hospital. They would round in the hospital every day and take a disproportionate share of call.

This job can be very demanding, and he said it usually only works for a couple of years before the physician will

evolve into a more normal practice pattern. This position can either lighten or eliminate the need for call, depending upon the group. It can be a good way for a group to transition when someone is retiring or there is high burnout.

A nephrohospitalist’s salary is usually 10% to 20% higher than a traditional position because they generate money from their first day on the job.

In the end, Kenneth Hertz, principal with the Medical Group Management Association’s Health Care Consulting Group, said wrangling with the issue of call coverage is really about problem solving. A practice that has a good method for decision making and knows what its core values are will likely have an easier time working out this issue.

If a group can focus on what is best for the whole instead of what is best for each individual doctor, it will have fewer battles with call coverage. Instead of having everyone give input, he recommends choosing just a few doctors who can create a study group to come up with a couple of recommendations for the whole group to decide upon. n Tammy Worth is a freelance medical journalist based out of Blue Springs, MO.

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