Renal & Urology News July 2013 Issue by Haymarket Media

july 2013

Volume 12, issue Number 7

www.renalandurologynews.com

Obesity Stops Many Kidney Donations New findings could explain, in part, why living kidney donation has stagnated in the U.S. Living Kidney Donation in Decline

2002 6,241

2004 6,647

2006 6,436

2008 5,968

2010 6,277

2012 5,622 © thinkstock

After reaching a peak in 2004, living kidney donation has been declining. Here are the numbers of living kidney donor transplants that took place in selected years:

Source: Organ Procurement and Transplantation Network, U.S. Department of Health & Human Services.

Drugs Ease CKD-Related Itching BY JILL STEIN ISTANBUL—Gabapentin and pregabalin relieve severe itching in most patients with chronic kidney disease (CKD), investigators reported at the 50th Congress of the European Renal Association-European Dialysis and Transplant Association. “Our results bolster earlier data in support of a

cme feature

role for gabapentin and pregabalin in the treatment of a problem which is much more than intermittent irritations relieved by a satisfying scratch,” said Hugh C. Rayner, MD, consultant nephrologist at Heart of England National Health Service (NHS) Foundation Trust in Birmingham, U.K. continued on page 7

Earn 1 CME credit in this issue

Update on the Medical Management of Kidney Stones Page 33

BY JODY A. CHARNOW SEATTLE—Potential living kidney donors frequently are rejected because they are obese, according to the findings of two studies presented at the 2013 American Transplant Congress suggest. Consequently, the growing prevalence of obesity in the U.S. may be contributing to a downward trend in living kidney donation. The lead investigator of one of the studies, Zoe A. Stewart, MD, PhD, of the University of Iowa Hospitals and Clinics in Iowa City, noted that 35% of adults are now considered obese, and this could impact live kidney donation. Dr. Stewart analyzed data from 450 living kidney donor candidates. Of these, 398 were rejected for donation

Longer CMV Prophylaxis May Be Better Seattle—Longer duration of prophylaxis against cytomegalovirus (CMV) is associated with a lower rate of CMV viremia in kidney transplants at high risk of CMV infection, according to new study findings reported at the 2013 American Transplant Congress. The study, by John Patrick Sia, MD, and colleagues at the University of Nebraska in Omaha, enrolled 94 CMVseronegative kidney transplant recipients who received an organ from a CMV-seropositive donor (D+/R-). Of these, 45 received a 100-day course of valganciclovir and 49 received a 200day course of the drug. The primary endpoint was the development of CMV viremia within 12 months of transplantation. The investigators found a significantly higher incidence of viremia among patients in the 100-day group (21/45, or 46.6%) compared with the 200-day group (9/49, or 18.3%) in the first year following transplanta-

and 52 were approved. Candidates who were rejected had a mean BMI of 28.9 kg/m2, which was significantly higher than the mean 25.9 kg/m2 for the approved group, Dr. Stewart reported. Of candidates approved for donation, only 11.5% were obese (BMI above 30) and 88.5% were non-obese (BMI below 30). Regardless of whether candidates were obese or not, whites were more likely to be approved for donation than non-whites (12.3% vs. 5%-6% of blacks and other race/ethnicities). Among the obese, non-whites were never approved for donation, she reported. Dr. Stewart noted that a BMI above 35 is an absolute exclusion criterion continued on page 7

in this issue 16 Low bicarbonate hikes mortality in CKD patients 17 Early readmission posttransplant raises death risk 17 Low GFR after live kidney donation not CKD

20 Expert Q&A: Kidney-saving treatments for FSGS

25 HIV drugs may raise risk of eGFR decline

27 Donor kidney size found to predict graft function

Lupus nephritis need not halt renal transplants Omega-3 fatty acids provide specific benefits for CKD and dialysis patients PAGE 18

continued on page 7

RUN0713_Cover_p00_Neph.indd 1

6/24/13 4:58 PM

july 2013

Volume 12, issue Number 7

www.renalandurologynews.com

Model Simplifies mCRPC Pt Prognoses It is based on factors associated with survival in men previously treated with abiraterone acetate Predicting Overall Survival in CRPC Patients Using a simple model they developed, researchers classified patients according to whether they had a good, intermediate, or poor prognosis, based on patients’ number of risk factors. Shown here is the mean survival, in months, for each of these groups. 25

21.3

13.9

15 10

6.1

5 0

Good

Intermediate

Poor

Prognosis Catergory

Ureteroscopy Use Increasing SAN DIEGO—Ureteroscopy use has increased and shock wave lithotripsy (SWL) use has decreased in California such that the two treatments for urinary stones are now being used at nearly equal rates, researchers reported at the American Urological Association annual meeting. Hossein S. Mirheydar, MD, and colleagues at the

cme feature

University of California San Diego, analyzed data on 113,447 outpatient stone surgeries performed in California from 2005 to 2010. Of these, 48,815 were treated with URS and 64,332 were treated with SWL. The total number of stone surgeries performed in ambulatory settings increased annually from continued on page 7

Earn 1 CME credit in this issue

Update on the Medical Management of Kidney Stones Page 33

BY JOHN SCHIESZER CHICAGO—Researchers have developed a model using readily available clinical parameters that may enable convenient prediction of overall survival (OS) among patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with abiraterone acetate. “This allows us to look at patients and to see what is really working,” said Kim N. Chi, MD, Associate Professor of Medicine at the University of British Columbia in Vancouver. “We didn’t go with a nomogram approach because we wanted a simple method for categorizing prognosis quickly.” He presented details of the model at the 2013 American Society of Clinical

Lung Cancer Linked to PCa Radiotherapy SAN DIEGO—Radiotherapy for prostate cancer (PCa) may increase patients’ risk of developing a second cancer, notably lung cancer, researchers reported at the American Urological Association annual meeting. Amanda Black, PhD, MPH, of the National Cancer Institute in Bethesda, Md., and collaborators analyzed data from 76,685 men aged 55-74 years who were randomized into the Prostate, Lung, Colorectal and Ovarian (PLCO) study from 1993-2001. The mean follow-up was six years. Of 7,479 men with PCa, 43% underwent radiotherapy, 37% underwent radical prostatectomy, 8% received primary hormone therapy, and 12% received no definitive or other treatment. Patients who received radiotherapy were slightly older than those who did not, but the researchers found no differences in smoking history, comorbidities, body mass index, or educational attainment. A total

Oncology annual meeting. Dr. Chi and his colleagues used data from a multinational, randomized, controlled, phase 3 trial comparing 797 patients treated with abiraterone acetate plus prednisone and 398 patients who received placebo plus prednisone. They analyzed data from 729 patients for whom relevant baseline data were available, and found factors associated with survival. These factors included an ECOG performance status of 2 and the presence of liver metastases, each of which was associated with a significant twofold increased risk of death. In addition, an interval of 36 months or less from the start of initial luteinizing hormone-releasing hormone agocontinued on page 7

in this issue 21 Sipuleucel-T retreatment feasible, data suggest 21 Cytokines may help predict survival in CRPC patients 24 Kidney cancer death risk lower in women

26 Black tea may lower risk of advanced prostate cancer

26 Stones linked to urinary incontinence

31 Prostatic artery embolization safe and effective for LUTS

Focal prostate laser ablation shows promise Omega-3 fatty acids provide specific benefits for CKD and dialysis patients PAGE 18

continued on page 7

RUN0713_Cover_p00_Urol.indd 1

6/24/13 4:57 PM

6 Renal & Urology News

july 2013 www.renalandurologynews.com

From the medical director Editorial Advisory Board

Self-Cannibalizing for Peritoneal Dialysis Growth?

n the nephrology community, there have been heightened discussions and apparent enthusiasm about the revival of peritoneal dialysis (PD) as the prototype for home dialysis. The proportion of PD patients to date has been approximately 7% of the entire U.S. dialysis population. This disappointingly low rate has not improved despite the federal government’s implementation of a bundled payment system in January 2011, which offers same reimbursement rates for both PD and hemodialysis (HD)–despite lower PD costs. PD patients often need to be seen only once a month in the dialysis clinic, whereas HD patients require thrice-weekly in-center treatments and other costly interventions. A dialysis clinic in the U.S. can achieve major financial gains by having more PD patients. In some countries, such as Canada and Australia, 15%-20% or more of the dialysis patient population is on PD. In the U.S., however, we have not been able to break the 10% threshold for over a decade. It is somewhat surprising that the problem has persisted some two and a half years into the new bundled payment era. So, what is going on? One of the challenges to PD growth is that it is inherently at the expense of HD growth. A dialysis clinic can maintain its census and survive only if it continues to have new dialysis patients at a rate of one-third of the entire census per year to compensate for the inevitable attrition due to patient mortality, kidney transplantation, and relocation. For instance, a dialysis clinic with 150 patients needs to have 50 new or incident end-stage renal disease (ESRD) patients each year just to maintain the 150 patient census. To grow, it needs even more new patients. The first priority for competing dialysis companies is to fill HD seats in all HD shifts, and to keep them occupied. Hence, PD growth is often out of question when the dialysis clinic still has unoccupied HD seat–even if it has the same operating costs. Moreover, data suggest that ESRD incidence has declined and dialysis patient survival has not improved significantly. Hence, the challenge of filling HD seats is going to be even tougher among competing dialysis clinics. As a result, it is highly unlikely to see a dialysis clinic self-cannibalize its own HD census to grow its PD sector. Consequently, the financial incentive created by bundling to expand the PD use is less important than the survival of the dialysis clinic. While I remain hopeful about the revival of PD, major PD growth in the current environment appears unlikely for now. Kam Kalantar-Zadeh, MD, MPH, PhD Professor & Chief Division of Nephrology & Hypertension University of California Irvine School of Medicine Orange, Calif.

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

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

Nephrologists

Urologists Christopher S. Cooper, MD Director, Pediatric Urology Children’s Hospital of Iowa Iowa City R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto Stanton Honig, MD Associate Clinical Professor of Surgery/Urology University of Connecticut School of Medicine, Urology Center New Haven J. Stephen Jones, MD, FACS, MBA Chief of Surgical Operations Fairview Hospital, a Cleveland Clinic hospital Professor of Surgery (Urology) Cleveland Clinic Lerner College of Medicine at Case Western Reserve University Leonard Horvitz and Samuel Miller Distinguished Chair in Urological Oncology Research Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology University of California, Irvine James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City Kenneth Pace, MD, MSc, FRCSC Assistant Professor Division of Urology St. Michael’s Hospital University of Toronto Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada

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

Renal & Urology News Staff Editor Jody A. Charnow Executive editor Marina Galanakis Senior editor Delicia Honen Yard Web editor Stephan Cho Editorial coordinator Candy Iemma Art director Andrew Bass Group art director, Haymarket Medical Jennifer Dvoretz VP, audience development and operations John Crewe Production manager Brian Wask Production director Kathleen Millea Product manager, digital products Chris Bubeck Circulation manager Paul Silver National accounts manager William Canning Editorial director Jeff Forster Publisher Dominic Barone VP medical magazines and digital products Jim Burke CEO, Haymarket Media Inc. Lee Maniscalco Renal & Urology News (ISSN 1550-9478) Volume 12, Number 7. Published monthly by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Periodicals postage paid at New York, NY, and an additional mailing office. The subscription rates for one year are, in the U.S., $75.00; in Canada, $85.00; all other foreign countries, $110.00. Single issues, $20.00. www.renalandurologynews.com. Postmaster: Send address changes to Renal & Urology News, c/o DMD Data Inc., 2340 River Road, Des Plaines, IL 60018. For reprints, contact Wright’s Reprints at 1.877.652.5295. Copyright: All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without the prior written permission of Haymarket Media, Inc. Copyright © 2013.

RUN0713_MastEdit.indd 6

6/20/13 12:17 PM

www.renalandurologynews.com july 2013

Obesity/kidney donation

continued from page 1

for donation at her institution. In the study, 42.5% of prescreen denials were due to a BMI above 35. Among candidates denied for medical indications, the most common reason was hypertension (10.2%), followed by BMI greater than 35 (9.6%), renal disease (6.2%), and cardiovascular disease (2.9%). “My hypothesis was that elevated BMI is a major factor for kidney donor candidate denial, and that this is one of the major reasons why we have failed to really see an increase in living kidney donors overall,” Dr. Stewart told colleagues. In fact, data from the Organ Procurement and Transplantation Network (OPTN) show that the number of living kidney donations has declined steadily from a peak of 6,647

CKD-related itching continued from page 1

His team used gabapentin and pregabalin in 71 consecutive patients with CKD stage 4 or 5, some of whom were on hemodialysis (HD) or peritoneal dialysis (PD). Uremic pruritus, also referred to as CKD-associated pruritus, is a common symptom in patients with end-stage renal disease, Dr. Rayner observed. In severe cases, the symptoms may disrupt sleep and decrease quality of life. Gabapentin and pregabalin, both of which are primarily used for the treatment of epilepsy and neuropathic pain, have been shown to control itching in small randomized controlled studies involving HD patients. Participants in the present study complained of itching that had been present for a median of six months

CMV prophylaxis continued from page 1

tion. In addition, 12 (26.6%) of the 45 patients in the 100-day group were hospitalized compared with six (12.2%) of the 49 patients in the 200day group, but the difference was not statistically significant. Significantly more patients in the 100-day than the 200-day group, however, were re-hospitalized because of CMV (six vs. 0). The study revealed no difference in the rates of acute rejection, graft loss, or mortality between the groups. The two groups were comparable

RUN0713_Cover_p00_Neph.indd 2

in 2004 to 5,622 in 2012. In the other study, Deonna Moore, MSN, and colleagues at Vanderbilt University Medical Center in Nashville, Tenn., analyzed data from 967 potential donors. Of these, 212 (22%) were ineligible to donate, and 140 of them (66%) were excluded because they had a BMI of 35 or higher. The mean BMI of excluded candidates was 39.7 kg/m2. The study found no difference in exclusion by race. The researchers presented their findings in a poster, in which they concluded: “Weight loss programs are an important potential target for intervention to increase live kidney donation.” In a separate study examining the decline in living kidney donation in the U.S., James R. Rodrigue, PhD, of The Transplant Center at Beth Israel Deaconess Medical Center in Boston, and colleagues found that the trend is most pronounced among blacks,

despite the use of simple emollients or antihistamines. Serum calcium levels were below 2.60 mmol/L in 87% of patients and serum phosphate levels were below 1.8 mmol/L in 75% of patients. Gabapentin was started at a dose of 100 mg once daily at night or after each dialysis session. Patients who were unable to tolerate gabapentin were offered pregabalin at a dose of 25 mg once daily at night or after each dialysis session. Patients rated median itch severity on a scale of 0 to 10, where 10 referred to the most severe itch imaginable. Gabapentin or pregabalin relieved itching in 60 patients (85%). Patients had a median itch severity score of 8 before treatment and 1 after treatment. Dr. Rayner cautioned that one third of patients could not tolerate gaba-

Prophylaxis duration should be decided on a case-by-case basis, findings sugest. except for immunosuppression management. The 100-day group was significantly less likely than the 200day group to receive anti-thymocyte globulin induction. Most patients received mycophenolate and tacrolimus, but more patients in the 100-day

younger and lower-income adults, siblings, and parents. The investigators concluded that “there is considerable downward pressure” on living donation rates despite novel programs to help patients find a suitable living donor, national financial programs and state tax incentives, and heightened general public awareness of living donation. The analysis by Dr. Rodrigue’s team compared two eras: 1998-2004 (Era 1) and 2005-2011 (Era 2). From Era 1 to Era 2, the proportion of living donors who were male declined from 41.9% to 39.8% and the proportion of living donors who were black declined from 13.4% to 12.2%. According to the authors, financial disincentives during an economic slump may be one contributing factor to the downward trend in living donation. Potential living donors may have greater concern about employment

Renal & Urology News 7

security or stability during a recession and less willingness to absorb lost wages, which could happen if they donate. The changing health status of the U.S. general population is another possible reason, the researchers noted. They pointed out that the proportion of adults with diabetes and adults who are obese has increased and hypertension is “alarmingly prevalent.” “Collectively,” they wrote in a poster presentation, “these risk factors increasingly are the most common reasons for [living donor] exclusion, particularly among minorities.” Another reason for the decline in living donation could be increased emphasis on transplant center performance oversight, the researchers pointed out. Such oversight might lead to more conservative policies and practices due to potential impact on center performance reports. n

pentin because of adverse effects, usually over-sedation. Many of these patients tolerated pregabalin, however. Because the study was not placebocontrolled, it is not possible to reliably

conclude that the study drugs were always responsible for the observed effects, he said. He was quick to emphasize, however, that the extent of improvement in itch severity was in line with prior placebocontrolled studies. Dr. Rayner also noted that patients described a rapid onset of effect and a clear dose-response relationship between gabapentin/pregabalin and itch severity and were able to adjust their treatment according to their response. “Nephrologists need to make a stronger effort to query their CKD patients about possible skin irritation and itch,” Dr. Rayner advised. “Patients may be reluctant to acknowledge these symptoms, which they feel suggest that they have not complied with their prescribed diet or phosphate binder therapy.” n

group were maintained on prednisone. Study findings suggest the duration of prophylaxis should be decided on a case-by-case basis, perhaps taking into account the level of immunosuppression, according to Dr. Sia, a second-year nephrology fellow. It might be appropriate, for example, to prescribe 200 days of prophylaxis for patients on more intensive immunosuppressive protocols. The study confirms the findings of the prospective, randomized, doubleblind IMPACT trial, which compared 200 days and 100 days of valganciclovir prophylaxis in a cohort of 318 D+/R- kidney transplant recipients.

Two years after transplantation, CMV disease occurred in significantly fewer patients in the 200-day group than the 100-day group (21.3% vs. 38.7%), researchers reported in Transplantation (2010;90:1427-1431). Biopsy-proven acute rejection and graft loss rates were not significantly different between the 200- and 100-day groups (11.6% and 17.2% and 1.9% and 4.3%, respectively). Seroconversion was delayed in the 200-day group, but was similar to the 100-day group by two years post-transplant (55.5% and 62.0%, respectively), according to the investigators. n

Hugh C. Rayner, MD

6/24/13 4:58 PM

www.renalandurologynews.com july 2013

Prognostic model

Brachytherapy Benefits Younger PCa Patients

continued from page 1

nist therapy to the start of abiraterone acetate treatment was associated with a significant 30% increased risk. Low albumin levels, high alkaline phosphatase, and high lactate dehydrogenase also were associated with significantly increased risk. “There is a need for a prognostic model like this. There have been so many changes in the treatment of prostate cancer that the current nomograms under-predict patient survival,” Dr. Chi said. Dr. Chi and his team divided patients into three risk-group categories based on their total number of risk factors (good prognosis [369 patients], intermediate prognosis [321 patients], and poor prognosis [107] ). The mean OS rate was 21.3 months, 13.9 months, and 6.1 months in the good, intermediate, and poor prognosis groups, respectively.

Lung cancer, PCa link continued from page 1

17,831 in 2005 to 18,933 in 2010. The URS rate increased significantly from 6,978 to 9,259 cases per year, whereas the SWL rate decreased non-significantly from 10,853 to 9,674 per year. In 2010, the number of URS procedures approached that of SWL procedures (9,259 and 9,674, respectively). In multivariate analysis, age 75 years and older and the presence of hypertension or obesity significantly decreased the likelihood of SWL. Women and Medicaid patients were significantly more likely to undergo SWL. Improved stone-free rates associated with ureteroscopy and the decreased

Ureteroscopy use up

continued from page 1

of 570 patients were diagnosed with second cancers. The rate of second cancers was 15.5/1,000 person-years in radiotherapy recipients compared with 11.4/1,000 person-years in those not treated with radiation, a difference that translated into a 25% increased risk of second cancers in radiotherapy recipients. Compared with men not treated with radiation, those who were had a 60% increased risk of lung cancer, after adjusting for age, race, education, family history of cancer, smoking, and chronic obstructive pulmonary

RUN0713_Cover_p00_Urol.indd 2

Renal & Urology News 7

By itself or combined with external beam radiation therapy, it offers excellent oncologic outcomes, researchers say Brachytherapy (BT) provides excel-

A major advantage of BT-based treat-

lent long-term outcomes for relatively

ment, Dr. Kollmeier’s team wrote, is the

young men with clinically localized pros-

ability to escalate intraprostatic doses

tate cancer (PCa), researchers reported.

above those of EBRT with minimal dose

In a study of 236 men aged 60 years or younger with clinically localized Kim N. Chi, MD

“External validation is required, but [the model] could be adopted at any institution,” Dr. Chi told Renal & Urology News. “This model can be used to stratify patients and give you a better idea of the timeline when patients are going to run into difficulties.” n

efficacy of second- and third-generation shock wave lithotripters, in part, may explain these trends, Dr. Mirheydar said. If the trends continue, he told Renal & Urology News, ureteroscopy may overtake SWL for the treatment of kidney stones. The new study echoes the findings of study presented at the Canadian Urological Association’s 2012 annual meeting. Researchers reported that URS has replaced SWL as the most common used treatment for removing ureteral stones in Canada. SWL use dropped from 68.5% of all ureteral stone procedures in 1991 to 33.7% in 2010, whereas URS use increased from 24.6% to 59.5% of procedures, the researchers noted. n

disease. According to the investigators, the increased relative risk of any second cancer and lung cancer were greater five or more years after treatment. The study also showed that the relative risk for bladder cancer and colorectal cancer was not significantly increased. The investigators noted that their study is the first to examine the risk of second cancers following PCa radiotherapy and control for potential confounders. “The increased risk of lung cancer is intriguing and warrants further investigation given the frequency and fatality of this disease,” the authors concluded in their study abstract. n

to normal surrounding tissue. “Improved dose conformality will

PCa, BT alone or in combination with

result in a reduction of normal tis-

external beam radiation therapy (EBRT)

sue radiation exposure and holds the

was associated with eight-year PSA

potential for reduced late toxicity and

relapse-free survival (RFS), cancer-

improved quality-of-life outcomes for

specific survival, and overall survival

patients,” they wrote. “Young men with

rates of 96%, 99%, and 96%, respec-

longer life expectancies, therefore, are

tively, according to findings published

the population most likely to benefit

in BJU International (2013;111:1231-

from reduced normal tissue toxicity,

1236). BT-based approaches also were

particularly erectile preservation.”

associated with a low risk of long-term

Of the 236 men in the study, 178 had

genitourinary (GI) and gastrointestinal

low-risk and 58 had high-risk disease. BT

(GI) morbidities, with erectile function

was given as monotherapy to 169 men

preserved in more than half of patients.

or with EBRT to 67 patients. The median

“Given these favorable outcomes,” the investigators concluded, “we

follow-up was 83 months. All patients had a minimum follow-up of three years.

strongly believe that young men should

For the low-risk and intermediate-

be offered BT as a treatment choice for

risk patients, the eight-year PSA RFS

clinically localized prostate cancer.”

rates were 97% and 94% respectively,

The researchers, Marisa A. Kollmeier,

a non-significant difference. The

MD, and colleagues at Memorial

study revealed no difference in PSA

Sloan-Kettering Cancer Center in New

RFS between BT alone and combined

York, noted that contemporary series

therapy. Late grade 2 or greater GU

examining radical prostatectomy, EBRT,

and GI toxicity rates were 14% and 3%,

and BT indicate excellent cancer-

respectively.

specific outcomes among younger

In addition, of 150 men who were

patients, suggesting that PCa is not

potent before treatment, 76 (51%)

necessarily more aggressive in younger

were potent at last follow-up, with

men. Despite evidence that radiation

50 (66%) of these patients not using

treatments are appropriate for young

erectile dysfunction medication. Post-

patients, clinicians still tend to favor

treatment potency rates were similar

radical surgery for this patient popula-

for the BT only and the combination

tion, they observed.

treatment groups. n

CKD Risk Higher with RN than PN New-onset chronic kidney disease (CKD) is more likely to develop in patients who undergo radical nephrectomy (RN) than partial nephrectomy (PN), according to a new study. Elin Mariusdottir, MD, and colla borators at Landspitali University Hospital in Reykjavik, Iceland, compared 44 patients with renal cell carcinoma (RCC) who underwent PN and 44 matched controls who underwent RN. Six months after surgery, eGFR

was significantly higher in the PN than RN group. RN was associated with a significant threefold increased risk of new-onset CKD compared with PN, the investigators reported online ahead of print in the Scandinavian Journal of Urology. After a median follow-up of 44 months, no patients in either group had a recurrence of RCC. The five-year overall survival was 100% and 65% in the PN and RN groups, respectively. n

6/24/13 4:57 PM

8 Renal & Urology News

july 2013 www.renalandurologynews.com

Contents

jul y

2 0 1 3

V olume

1 2 ,

i ssue

N umbe r

Nephrology 7 1

ONLINE

this month at renalandurologynews.com Expert Q&A

David O. Sussman, DO, Clinical Associate Professor of Urology at the University of Medicine and Dentistry of New Jersey, discusses the use of Botox for urinary incontinence.

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 May winner: Susan Marshall, MD

News Coverage

Visit our website for coverage of the Canadian Urological Association annual meeting in Niagara Falls, Canada (June 22-25).

Low GFR Post-Donation Not CKD Living kidney donors should not be considered to have chronic kidney disease (CKD) if their renal function after nephrectomy falls to a level that usually would be considered CKD. Kidney Disease Progression Linked to Low Bicarbonate Low serum bicarbonate is independently associated with an increased risk of kidney disease progression in patients with chronic kidney disease.

CME Feature 33

Post-Tx NODAT Linked to Low Magnesium Hypomagnesemia may confer an increased risk for new-onset diabetes after transplantation in kidney transplant recipients.

Update on the Medical Management of Kidney Stones David S. Goldfarb, MD, and Lama Nazzal, MD, New York Harbor VA Medical Center and New York University Langone Medical Center, discuss the effect of diet on stone formation, the characteristics of the various stones, and strategies to prevent stones.

Sipuleucel-T Retreatment May Benefit Patients with mCRPC Researchers demonstrate for the first time that the feasibility of retreatment with this immunotherapy following treatment for an earlier stage of prostate cancer. Cytokines May Aid CRPC Predictions High levels of macrophage colony-stimulating factor and interleukin-10 could be associated with reduced survival.

Tea May Lower Risk of Advanced PCa Highest vs. lowest intake levels of black tea consumption were associated with a 33% decreased risk of stage IV cancer.

PAE May Be Safe, Effective for LUTS A prospective study suggests that prostatic artery embolization is safe and effective for treating lower urinary tract symptoms related to benign prostatic hyperplasia.

If we can resolve itchiness for a certain

segment of these patients, we could potentially resolve other quality of life issues as well. See our story on page 25

RUN0713_TOC_neph.indd 8

Urology

The Medical Minute

Visit renalandurologynews.com /the-medical-minute/ to hear podcast reports on new studies. Our latest include: • Successful Kidney Transplantation Can Be Performed in Octogenarians • Early Flu Shots Post-Transplant Safe, Effective • Marijuana Found to Lower Blood Sugar

Early Post-Tx Readmission a Bad Sign Patients readmitted to hospitals within 30 days of receiving a kidney transplant are at 55% increased risk of death.

Departments 6

From the Medical Director Why peritoneal dialysis growth is unlikely

News in Brief PCa linked to sleep disturbances

Renal Nutrition Update The benefits of omega-3 fatty acids

Men’s Health Update Peyronie’s disease treatment promising

Malpractice News Medical errors reportedly decline in Minnesota

Practice Management Using data to improve efficiency and income

6/24/13 4:56 PM

16 Renal & Urology News

july 2013 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 Disease Does Not Hike Mortality

use of fluoroquinolones—particularly

Prevalent kidney stone disease is

associated with a twofold increased

not independently associated with

risk of AKI compared with no use.

ciprofloxacin and moxifloxacin—was

all-cause and cardiovascular (CV) mor-

In addition, concomitant use of an

tality, according to an analysis of data

oral fluoroquinolone and a renin-angio-

from 14,879 participants in the Third

tensin-system blocker increased the

National Health and Nutrition Examina-

risk of acute renal failure by 4.5-fold,

tion Survey.

according to the investigators.

In unadjusted analyses, stone formfor all-cause and CV mortality, but

No Gout Relieve From Vitamin C

the increased risk for either outcome

Patients with gout experienced no

disappeared after adjusting for age,

clinically significant urate-lowering

gender, race, and poverty, research-

effects from an 8-week course of

ers at the University of Colorado

a modest dosage of vitamin C

School of Medicine in Aurora reported

(500 mg/day), despite an increase in

in the American Journal of Nephrology

plasma ascorbate levels increased,

(2013;37:501-506).

according to study findings pub-

ers had a nearly twofold higher risk

lished in Arthritis & Rheumatism

Common Antibiotics Raise AKI Risk

(2013;65:1636-1642). The study

Oral fluoroquinolones are associated

20 were randomized to receive an

with a small but significantly increased

increased dose of allopurinol or to

risk of acute kidney injury (AKI),

start taking vitamin C, and 20 were

Steven T. Bird, PharmD, MS, of the

randomized to start treatment with

FDA, and colleagues reported online

allopurinol (100 mg/day) or vitamin C.

ahead of print in the Canadian Medical

Researchers observed no significant

Association Journal.

difference in serum urate or renal

included 40 gout patients. Of these,

function between those who received

In a study of 1,292 men with AKI

vitamin C and those who did not.

and 12,651 matched controls, current

Are Damage Caps Fair? In a recent online poll, Renal & Urology News asked readers if non- economic damage caps in medical malpractice cases are fair to plaintiffs. Here are the results based on 114 responses.

Yes: 73.68%

No: 23.68%

Don’t Know: 2.63%

RUN0713_NIB.indd 1

Prostate Cancer Associated With Sleep Disturbances C

ertain aspects of sleep disruption may confer an increased risk of prostate cancer (PCa), researchers reported in Cancer Epidemiology, Biomarkers & Prevention (2013;22:872-879). Lara G. Sigurdardottir, MD, of the University of Iceland in Reykjavik, and colleagues made the discovery when they analyzed data from 2,102 men participating in the prospective AGES-Reykjavik cohort study. The men, recruited from 2002 to 2006 and followed until the end of 2009, supplied information on their sleep-disruption patterns. During followup, 135 (6.4%) received a PCa diagnosis. Men who reported problems falling and staying asleep had a significantly greater PCa risk than did those who did not report sleep problems. The risk was increased 1.6-fold to 2.1-fold, depending on the severity of reported sleep problems. These associations were even stronger for advanced PCa compared with overall PCa, reflecting more than a threefold increase in risk for advanced PCa associated with sleep problems categorized as “very severe.”

Low Bicarbonate in CKD Patients Raises Death Risk L

ow serum bicarbonate is a strong predictor of mortality among adults with chronic kidney disease (CKD), new findings suggest. Kalani L. Raphael, MD, of the University of Utah School of Medicine in Salt Lake City, and collaborators analyzed data from 15,836 adults who participated in the National Health and Nutrition Examination Survey III. They placed subjects into one of four serum bicarbonate categories: less than 22, 22-25, 26-30, and 31 mM or greater. After adjusting for age, gender, race, estimated glomerular filtration rate, and numerous other potential confounders, subjects with CKD who had a bicarbonate level below 22 had a nearly 2.6 times increased risk of death compared with those who had a level of 26-30 (reference category), the investigators reported in Nephrology Dialysis Transplantation (2013;28:1207-1213).

Statins May Increase Odds of New-Onset Diabetes T

reatment with more potent statins may increase the risk of new-onset diabetes, according to Muhammad M. Mamdani, PharmD, MPH, of St. Michael’s Hospital and the Institute for Clinical Evaluative Sciences in Toronto, Ontario, Canada, and colleagues. In a retrospective study of individuals aged 66 years and older, the researchers found a 22% increased risk of incident diabetes associated with atorvastatin use, an 18% increased risk with rosuvastatin use, and a 10% increased risk with simvastatin use compared with pravastatin, which was the reference drug. The absolute risk for incident diabetes was approximately 31 and 34 events per 1,000 personyears for atorvastastin and rosuvastatin, respectively, the researchers reported online ahead of print in BMJ. Simvastatin use was associated with a slightly lower risk (26 events per 1,000 person-years. Researchers found no significantly increased diabetes risk among patients who received fluvastatin or lovastatin.

6/20/13 12:19 PM

www.renalandurologynews.com july 2013

■ ATC 2013

Renal & Urology News 17

Reports from the 2013 American Transplant Congress, Seattle

Early Post-Tx Readmission a Bad Sign Death risk increased by 55% if patients are rehospitalized within 30 days of kidney transplantation BY JODY A. CHARNOW SEATTLE—Patients readmitted to hospitals within 30 days of receiving a kidney transplant are at increased risk of death, but in most cases, such early rehospitalizations are not preventable, researchers from the University of Pennsylvania in Philadelphia reported at the 2013 American Transplant Congress. “Early rehospitalization after kidney transplantation may be a useful surrogate marker to identify uniquely vulnerable transplant recipients within an already medically complex patient population,” said lead investigator Meera Nair, MD. “These patients may benefit from more intensive follow-up or monitoring following transplantation.” Dr. Nair and her colleagues also identified factors associated with early rehospitalization after kidney transplantation, including time on a transplant waiting list, weekend discharge,

Low GFR Post-Donation Is Not CKD Living kidney donors should not be considered to have chronic kidney disease (CKD) if their renal function after nephrectomy falls to a level that usually would be considered CKD, researchers concluded. Many kidney donors have an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2 early postdonation and therefore meet the criteria for CKD stage 3, according to researchers. The prognosis of such a low GFR, however, may not be equivalent to the prognosis of the same GFR in patients with two diseased kidneys. “I think we should consider former kidney donors as healthy people and not CKD patients,” said investigator Laura V. De Vries, BSc, a PhD candidate at University Medical Center Groningen, Groningen, The Netherlands, who presented study findings. She and her colleagues compared 57 post-donation kidney donors and

RUN0713_Rehospital.indd 1

and longer hospital length of stay (LOS). The findings, which were presented at the meeting by fellow investigator Peter Reese, MD, are based on two retrospective studies of a cohort of 753 adult kidney-only transplant recipients at the University of Pennsylvania. Patients had a median age of 51 years, 34% were black, and 28% were diabetic. Of the 753 patients, 237 (32%) experienced rehospitalization within 30 days. The median time to rehospitalization was 10 days. The median duration of patient follow-up was six years. In the first study, each additional year of wait list time, weekend discharge, and a hospital LOS more than 4.5 days were associated with a significant 10%, 59%, and 42% increased likelihood of early rehospitalization, respectively. “The weekend may represent a time when processes leading to safe transitions-of-care are less robust and hospitals have alternative or lower staffing,”

57 CKD patients who were matched for age, gender, GFR, and duration of follow-up. GFR was determined with 125I-iothalamate clearance. In both groups, the mean age of study subjects was 48 years and the mean follow-up was 4.7 years. The donors and CKD patients had similar a GFR (67 and 71 mL/min/1.73 m2, respectively). At follow-up, donors had significantly better renal function than CKD patients, with a GFR of 73 versus 63 mL/min/1.72 m 2, respectively. GFR improved with time in all donors and declined in all CKD patients. Also at the congress, researchers reported study findings showing that living kidney donors in recent years have experienced greater declines in renal function in the first year following nephrectomy. In 2004, they experienced a median 23.3 mL/min/1.73 m2 decline in estimated GFR (eGFR) from before donation to one-year postnephrectomy. In 2010, the median decline was 31.9 mL/min/1.73 m2. The findings are based on a study of 31,168 living kidney donors in the Scientific Registry of Transplant Recipients by Emily Heaphy, MD, of Cleveland Clinic, and colleagues. n

Risk Factors for Early Rehospitalization A study identified longer wait list time, weekend discharge, and a longer hospital length of stay as risk factors for early rehospitalization after kidney transplantation. Shown here is the magnitude of the increased risk associated with these factors.

Each additional year on the waiting list

10% 59%

Weekend discharge Hospital length of stay more than 4.5 days

42%

Source: Nair M, et al. Early rehospitalization after kidney transplantation: Predictors and prognosis. Presented at the 2013 American Transplant Congress, Seattle. Abstract 94.

Dr. Nair told Renal & Urology News. A multivariate analysis showed that early rehospitalization was associated with a significant 55% increased risk of death. Each additional year on the waiting list and delayed graft function were also associated with a significant 21% and 59% increased risk of death, respectively.

In the other study, two physicians independently reviewed the medical records of the 237 rehospitalized patients and found that 214 (90%) of the rehospitalizations were unplanned and only 19 were considered preventable. Of the 214 unplanned hospitalizations, 201 (94%) were related to the kidney transplant. n

CMV Disease Prevention Strategies Similarly Effective Antiviral prophylaxis and preemp-

After excluding patients with missing

tive therapy are similarly effective in

serostatus information, the researchers

preventing cytomegalovirus (CMV)

found no significant difference in the

disease in solid organ transplant (SOT)

incidence of CMV disease between the

recipients, investigators reported.

patients in the prophylaxis or preemp-

Oriol Manuel, MD, of the

tive therapy groups overall or among

Transplantation Center, University

seropositive recipients (intermediate-

Hospital of Lausanne in Switzerland,

risk patients) or seronegative recipients

and colleagues enrolled 1,239 SOT

who had a seropositive donor (high-risk

recipients, of whom 466 (38%) had

patients). CMV disease was not associ-

received CMV prophylaxis and 522

ated with a lower graft failure-free

(42%) were treated preemptively. The

survival, but patients managed with

study population had 83 episodes of

preemptive therapy had a significant

CMV disease (including 13 episodes

63% increased likelihood of graft failure

of proven end-organ disease) in 75

after a median of 1.05 years of follow-

patients (6%). Study results showed

up, according to the investigators.

that CMV incidence was linked to CMV

“We found a high graft failure-free

serostatus. Seronegative recipients

survival in patients receiving antiviral

who had a seropositive donor had a

prophylaxis, most likely due to

significant fivefold increase risk of CMV

better control of early-onset viremia,”

disease compared with seropositive

the authors concluded in a poster

recipients.

presentation. n

6/20/13 12:19 PM

18 Renal & Urology News

july 2013 www.renalandurologynews.com

Renal Nutrition Update T

he benefits of omega-3 (n-3) fatty acids in renal populations were last discussed in this column in 2007. Much additional research has occurred since that time. N-3 polyunsaturated fatty acids (PUFAs) have demonstrated cardioprotective effects and reduce risks for death from cardiovascular disease (CVD) in a number of studies. The two most potent forms include docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and these fatty acids are most easily obtained through the consumption of fatty cold-water fish. They are often associated with reduced triglyceride values as well as reductions in oxidative stress. The mechanism of action often involves the regulation of pro-inflammatory eicosanoid and prostaglandin pathways, in which omega-6 (n-6) fatty acids and n-3 fats are both involved (Biomed Res Int 2013; published online ahead of print). As the ratio of n-6/n-3 tends to decrease, eicosanoid and prostaglandin metabolism begins to favor a more pro-inflammatory nature. Patients with renal disease are at increased risk for CVD-related mortality and high rates of inflammation, and thus n-3 interventions have grown in interest

Observational data Plasma adiponectin is directly associated with n-3 fatty acids and negatively associated with n-6 fatty acids (Clin Nephrol 2011;75:195-203). Long chain n-3 PUFA concentrations are low in hemodialysis (HD) populations while n-6 fats tend to predominate (Am J Nephrol 2012;36:451-458; Ren Fail 2011;33:819823). HD patients who supplement with n-3 fatty acids tend to have higher erythrocyte DHA and EPA, but the overall elevated n-6 levels result in a reduced overall ratio of n-6/n-3 compared with healthy controls (J Ren Nutr 2009;19:267274). An observational study of HD, peritoneal dialysis (PD), and kidney

On The Web RUN0713_RenalNut.indd 18

transplant recipients (KTR) assessed the blood erythrocyte fatty acid differences between groups. Although both arachidonic acid and DHA were significantly higher in the KTR group, the n-6/n-3 was reduced in the KTR group (Transplant Proc 2012;44:2932-2935. A prospective HD cohort has indicated an association between blood DHA content and a reduced risk of all-cause mortality and CVD (Am J Nephrol 2011;33:105-110; Clin Nephrol 2009;71:508-513). A six-year prospective study of n-3 versus n-6 intake in dialysis patients found that each 1-unit increment in n-6/n-3 ratio was associated with a 0.55 mg/L increase in C-reactive protein levels. In the lowest n-6/n-3 quartile, there was a 61% decrease in all-cause mortality (Am J Kidney Dis 2011;58:248-256).

Interventions In a study of PD patients, triglycerides were found to significantly decrease after supplementation with 2.4 g DHA and 1 g EPA per day for eight weeks (Ren Fail 2010;32:1031-1035). Similarly, a combination of high fish intake and n-3 supplementation was shown to significantly decrease triglyceride values in an HD population after three months (Nephrol Dial Transplant 2008;23:2918-2924). Likewise, 2.1 g of n-3 was shown to significantly decrease serum triglycerides but no other blood lipid factors (Ren Fail 2011;33:892-898). A placebo-controlled trial found that a two-month intervention with 3 g/day of n-3 found significant increases in glutathione peroxidase, superoxide dismutase, and ferric-reducing antioxidant power and reduced malondialdehyde levels (Iran J Kidney Dis 2010;4:322-326). Another study found supplementation to significantly reduce TNF-α using 3 g/day of a pharmaceutical grade n-3 supplement protocol for two months (Saudi J Kidney Dis Transpl 2012;23:500-506). Researchers found

Fish oil and omega-3 fatty acids can improve blood lipid parameters and provide other benefits for CKD and dialysis patients By GRISSIM CLARK CONNERY, MS, RD, LD

Fatty cold-water fish are a good source of omega-3 fatty acids.

no significant improvements in blood lipids with supplementation of 920 mg EPA and 760 mg DHA over four weeks (J Ren Nutr 2011;21:479-484). However, 2.4 g (1.8 g EPA, 600 mg DHA) given three times per week has been shown to improve the LDL-C/HDL-C ratio compared with controls. A four-month intervention with 2 g/day n-3 fatty acids resulted in significant decreases in blood pressure (J Nephrol 2008;21:99-105). One group of investigators found that serum DHA was negatively associated with atrial fibrillation, but supplementation with 1.7 g/day n-3 PUFA did not improve QTc interval compared with controls (Br J Nutr 2012;107:903-909). A placebo-controlled trial found that supplementation of 1 g/day of fish oil significantly decreased rates of uremic pruritis (Iran Red Crescent Med J 2012;14:515-522. A dose of 460 mg EPA and 380 mg DHA (comparable to 3 g fish oil) significantly increased 1,25 (OH) vitamin D and fetuin-A (Nutr Res 2012;32:495-502). Another study found that supplementation with n-3 resulted in increased erythrocyte DHA and

EPA and decreased oleic and saturated fatty acids (Prostaglandins Leukot Essent Fatty Acids 2012;86:29-34). Intravenous administration of 4 g n-3 PUFAs during dialysis does temporarily increase plasma content and is incorporated into platelets, but no improvements in nutritional parameters have been found at this time (J Parenter Enteral Nutr 2011;35:97-106; (J Ren Nutr 2009;19:487-493). It appears that n-3 supplementation can be used to improve blood lipid parameters, measures of oxidative stress, blood pressure, arrhythmia, and pruritus abnormalities. Dosage varies among studies, but generally 3 g/day of n-3 fatty acids is capable of achieving beneficial results. The incorporation of fatty coldwater fish may help improve n-3 fat intake as well as increase protein for improved outcomes. Due to the easy lipid peroxidation of PUFAs, lower cooking temperatures are suggested and excessive deep frying and grilling is discouraged. n Mr. Connery is Research Coordinator at Case Western Reserve University in Cleveland.

We’ve got more on our website highlighting effective diets for delaying CKD progression and helping patients manage sodium and phosphorus intake. See us at www.renalandurologynews.com/nutrition.

6/20/13 12:20 PM

20 Renal & Urology News

july 2013 www.renalandurologynews.com

FSGS: The Search for Treatments The scar tissue that forms on sections of some glomeruli in focal segmental glomerulosclerosis (FSGS) will lead to kidney failure if left untreated. Nephrologist Fernando C. Fervenza, MD, PhD, is a site principal investigator currently recruiting participants at Mayo Clinic in Rochester, Minn., for a Genzyme-sponsored phase 2 study comparing the human monoclonal antibody fresolimumab with placebo in patients with steroid-resistant primary FSGS (ClinicalTrials.gov identifier: NCT01665391). Dr. Fervenza recently discussed the challenges of FSGS management to Renal & Urology News. How common is FSGS in the United States?

Dr. Fervenza: It is a common form of glomerular disease—it is either the first- or second-leading cause of nephrotic syndrome due to a primary glomerular disease. I do not know the exact numbers, but some studies suggest that the prevalence of idiopathic FSGS in adults may be increasing: It was found in 2.5% to 4% of native renal biopsies in the 1970s, but in 12.2% to 18.7% in the 2000s, making FSGS the most common diagnosis based on native kidney biopsies. So FSGS incidence is on the rise?

Dr. Fervenza: Recent studies of renal biopsy archives in the U.S. suggest that the incidence of FSGS has increased, with the greatest incidence rates in the African-American population. But the increase in incidence has also been observed in whites and other races. What are the main drivers of this increase? Dr. Fervenza: It may be due to real increases in true FSGS incident rates, differences in reporting, changes in biopsy practice and disease classification, data base inclusion criteria, and U.S. demographics. That said, population-based studies of incident glomerular diseases are

On The Web RUN0713_QA.Fervenza.indd 1

needed before we could say for sure that incidence rate for FSGS has increased in the U.S. population. Urbanization and the progressive increase in obesity may play a role in the rising incidence of FSGS. However, obesity is unlikely to be the major factor to account for increasing incidence of FSGS, and involvement of yet-unidentified new environmental factors in causation remains an intriguing possibility.

Dr. Fervenza: The main problem is what to do with patients who fail to respond to corticosteroids or calcineurin inhibitors. Even a kidney transplant is not a solution since the disease can recur in up to 30%-40% of patients who receive a kidney transplant. Are there any misconceptions about the diagnosis, treatment, or management of FSGS that need to be corrected or updated?

Dr. Fervenza: To me, one of the main challenges is to be able to differentiate between primary and secondary forms of FSGS. This is important because primary FSGS is the one for which you would consider treatment with immunosuppressive therapy. On the other hand, you would treat secondary FSGS by maximizing conservative therapy with tight blood-pressure control using angiotensin II blockade, diet, weight and lipid control, no smoking, and so forth. How can nephrologists distinguish between primary and secondary FSGS?

Dr. Fervenza: While patients with primary FSGS characteristically have

Dr. Fervenza: No. Patients present with proteinuria and nephrotic syndrome, which could indicate FSGS, membranous nephropathy, minimal change disease, etc. Only a renal biopsy can tell the differences. What is the typical amount of time that elapses between development and diagnosis of FSGS?

Dr. Fervenza: It can vary from weeks to months. It depends on how acute the presentation is: Patients with sudden onset of massive edema are likely to seek medical attention earlier and get biopsied.

Dr. Fervenza: The most important breakthrough in recent years without a doubt is the recognition of genetic forms of FSGS and the importance of podocyte proteins in the disease process. Another major breakthrough was the finding that apolipoprotein L1 (APOL1), which is expressed in podocytes, has a high-risk alleles prevalence in patients of African descent with primary FSGS and HIVassociated nephropathy, implicating potential podocyte effects.

Dr. Fervenza: I think food additives, such as growth hormone given to animals and pesticides, may be involved. I have no proof, of course. But how can we explain the increase in numbers? What is the current gold-standard treatment for FSGS?

What is the nephrologist’s greatest challenge in identifying, treating, and/ or managing FSGS?

Are there any telltale signs or symptoms that should prompt the nephrologist to suspect FSGS?

What has been the most significant breakthrough in FSGS research in the past five years?

What environmental factors are on your list of suspects?

Dr. Fervenza: There is no gold standard. In patients with primary FSGS, highdose corticosteroids or calcineurin inhibitors can be used, but to me there is no study on which you could base a decision regarding which one to use first.

full nephrotic syndrome, those with secondary FSGS usually just have nephrotic range proteinuria—not the full syndrome. Also, electron microscopy is crucial since patients with secondary FSGS have segmental foot process effacement, while in primary FSGS effacement is usually widespread.

A major challenge is differentiating primary and secondary FSGS. —Fernando C. Fervenza, MD

What are the most critical questions that still need to be answered regarding FSGS?

Dr. Fervenza: Some of the more seminal questions that need to be addressed are why do patients develop primary FSGS? What is the mechanism(s) involved in development, and what is the best form of treatment? n

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

6/20/13 12:21 PM

www.renalandurologynews.com july 2013

Sipuleucel-T Retreatment May Benefit Patients with mCRPC Immune memory appears to be long-term, small study shows BY JOHN SCHIESZER CHICAGO—Retreatment with sipuleucel-T (Provenge), an autologous cellular immunotherapy, is safe and may benefit some patients with metastatic castrationresistant prostate cancer (mCRPC), even years after receiving the first treatment for an earlier stage of prostate cancer, according to new data presented at the 2013 American Society of Clinical Oncology annual meeting. Researchers presented data from P10-1, an open-label phase 2 study of sipuleucel-T in men with mCRPC previously treated with sipuleucel-T in the PROTECT (PROvenge Treatment and Early Cancer Treatment) trial. They evaluated antigen-presenting cell (APC) activation, a measure of product potency. The study included men who received one or more infusions of sipuleucel-T in PROTECT and progressed to mCRPC. All men in the study were retreated with three infusions of sipuleucel-T. Seven men with a median age of 70 years as of October 2012 have been enrolled in the trial. The median time from the first infusion to retreatment in the current trial was 9.2 years (range 7.8-

Tomasz Beer, MD

10.0 years). APC activation was greater at the first P10-1 treatment compared with the last retreatment. “Retreatment is feasible and it appears immune memory is long-term following treatment with this agent,” said investigator Tomasz Beer, MD, of Oregon Health & Science University Knight Cancer Institute in Portland. “More studies are needed to determine if re-treatment is something we do for patients outside of a clinical trial.”

This is the first trial to demonstrate the feasibility of sipuleucel-T retreatment following treatment for an earlier stage of prostate cancer. Sipuleucel-T is designed to stimulate humoral and cellular immune responses against prostatic antigen phosphatase, which is an antigen expressed in most prostate cancers. In the pivotal phase 3 IMPACT study, treatment with sipuleucel-T resulted in a 4.1 month improvement in median overall survival relative to control treatment in patients with asymptomatic or minimally symptomatic mCRPC. The Phase 3 PROTECT study investigated sipuleucel-T for men with rising PSA after three to four months of androgen deprivation therapy following radical prostatectomy. The primary endpoint of time to biochemical failure (PSA level 3 ng/mL or higher) was not statistically significantly different between the treatment group and the control arm (median 18.0 and 15.4 months, respectively). Men treated with sipuleucel-T, however, had a 48% increase in PSA doubling time following testosterone recovery relative to the control group (155 vs. 105 days). n

Testosterone Slow To Recover After ADT

Renal & Urology News 21

Cytokines May Aid CRPC Predictions BY JOHN SCHIESZER CHICAGO—Risk group classification based on two serum cytokines may help predict survival in men with progressive castration-resistant prostate cancer (CRPC), according to a new study presented at the 2013 American Society of Clinical Oncology annual meeting. American researchers reported that these two cytokines—macrophage colony-stimulating factor (M-CSF) and interleukin (IL)-10—may reflect the biology within the tumor microenvironment. They may also serve as biomarkers of clinical benefit. “M-CSF has previously been shown in prostate cancer to predict bone metastasis and IL-10 is known to be an immunosuppressive cytokine,” said investigator Sumit Kumar Subudhi, MD, PhD, a medical oncology fellow at Memorial Sloan-Kettering Cancer Center in New York. “So biologically this assay makes sense. If you have both high levels of both of those cytokines, you theoretically would have a higher tumor burden and theoretically you would do worse.” In a study of 75 patients with

BY JOHN SCHIESZER CHICAGO—Metastasis-free survival or overall survival may be a more reliable and meaningful clinical endpoint than PSA relapse in studies of prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT). After discontinuation of ADT, testosterone levels take a long time to recover and, consequently, PSA levels may remain low in those with androgen sensitive PCa for a prolonged period. This can be a major confounding issue for clinical trials relying on PSA based endpoints in a pre-castrate resistant population. “You need to look at testosterone recovery if you are going to follow PSA levels for study endpoints in the adjuvant setting,” said investigator Michael Schweizer, MD, a medical oncology fellow at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore. The researchers conducted a randomized

RUN0713_Asco1.indd 21

phase 3 study of 228 men who received adjuvant ADT with or without docetaxel either immediately following radical prostatectomy or deferred until the time of biochemical relapse for high-risk PCa. They analyzed testosterone recovery data from 108 men who had at least one post-ADT testosterone measurement and completed the 18 months of ADT as specified by the protocol. Median follow up time after the last dose of ADT was administered was 676 days. Testosterone recovered to more than 150 ng/dL in 90 men (83%) and to baseline in 64 men (59%). The study showed no significant differences in testosterone recovery between patients who received docetaxel and those who did not. The median time to testosterone recovery from the last day of treatment to a level greater than 150 ng/dL and to baseline was 306 days and 487 days, respectively. After a median total follow-up of 3.4 years, 39 (17%) of

the 228 patients had PSA progression and one patient experienced metastatic progression. The study indicated that recovery is prolonged after 18 months of hormone therapy, and PSA relapses occur late. Clinical trials employing PSA-derived endpoints that routinely monitor testosterone levels and their correlation to PSA relapse with progression-free and overall survival may be highly beneficial, Dr. Schweizer said. Metastasisfree survival may be a better outcome measure because it is not confounded by testosterone levels, he said, adding that recent adjuvant trials have been designed to evaluate PSA progression as the primary endpoint. Physicians should counsel their patients on prolonged courses of ADT that they should not expect their testosterone levels to recover to a meaningful level for at least a year or so, which can impact patients’ quality of life. n

progressive CRPC, Dr. Subudhi and colleagues analyzed a panel of 10 cytokines (M-CSF, interferon-gamma, tumor necrosis factor-alpha, IL-1-beta, IL-4, IL-5, IL-6, IL-10, IL-12, and IL-13) using clinically validated enzyme linked immunosorbent assays. M-CSF and IL-10 predicted survival in progressive, metastatic CRPC. The predictive value was improved by adding circulating tumor cell (CTC) enumeration. “It is fast and it something that could be as easy as a PSA [test] and that is what makes it so attractive,” Dr. Subudhi said. “The [existing] nomograms help influence our treatment decisions. However, there is a great deal of variability in survival rates. Some therapies may work for years in a subset of patients, but may only work for weeks in another.” n

6/20/13 12:22 PM

22 Renal & Urology News

july 2013 www.renalandurologynews.com

Men’s Health Update Short Takes Erectile Dysfunction Associated with Long-Term Opiate Use Long-term opiate use for back pain is associated with an increased risk of erectile dysfunction (ED), according to study findings published in Spine (2013;38:909-915). Richard A. Deyo, MD, MPH, of the Kaiser Center for Health Research in Portland, Ore., and colleagues examined electronic pharmacy and medical records for 11,327 males with back pain seen in a large group model health maintenance organization during 2004. Consideration was given to relevant prescriptions six months before and after the index visit. The 909 men who used ED drugs or testosterone replacement therapy (TRT) were significantly older than those who did not and had greater comorbidity, depression, smoking, and use of sedative-hypnotics. Long-term use of opioids was associated a 45% increased likelihood of using ED drugs or TRT compared with no opioid use.

Male LUTS Severity Linked to Constipation Lower urinary tract symptoms (LUTS) are commonly attributed to benign prostatic hyperplasia, but contemporary research suggests the cause of these symptoms are multifactorial. A new study published by Kerri L. Thurmon, MD, and colleagues in the Journal of Urology (2013;189:1409-1414) examined the association between LUTS in men older than age 40 and the presence of bowel dysfunction. More than 3,000 men were included, making this the largest of such studies in the adult population. Men reporting three or fewer bowel movements per week, hard stools, or loose stools were more likely to report more severe LUTS. These data suggest either causality or a common pathophysiology of LUTS and bowel habit abnormalities.

Cancer Mortality Higher in Men, Study Finds Non-sex specific cancers should affect men and women equally, but new data from the Surveillance, Epidemiology and End Results (SEER) program published by Bobby B. Najari, MD, and colleagues in the Journal of Urology (2013;189:14701474) shows that men develop and die more often from these types of cancers. Women continue to outlive their male counterparts by five years on average. The male-to-female relative mortality rate in 2012 was 1.060, indicating that more than 24,000 men died of cancer due to their sex. Men have a 12.6% higher death rate than women for the same cancer type. The reasons for this are likely quite

BY JAIME LANDMAN, MD and ADAM KAPLAN, MD, of the

University of California, Irvine, Department of Urology

TV Watchers Risk Low Sperm Counts S

emen quality in Western countries has been declining over the past several decades, and we are beginning to understand why. Heavy television watching has been associated with many health-related consequences because of decreased physical activity. But it can also have effects on scrotal temperature, which may be a cause of poor sperm quality. A new study in the British Journal of Sports Medicine (published online ahead of print) examined 189 men ages 18-22, evaluating their levels of physical activity, hours of TV watching, and semen quality. TV watching had an inverse relationship with sperm concentration and total sperm count. Men in the highest quartile of TV watching (more than 20 hours per week) had a 44% lower sperm concentration than men who watch no TV at all. Not surprisingly, men in the highest quartile of moderate-to-vigorous activity (more than 15 hours per week) had a 73% higher sperm concentration than men in the lowest quartile (less than 5 hours per week).

Peyronie’s Disease Treatment Promising D

ata presented at the recent annual meeting of the American Urological Association show that collagenase injections can decrease penile curvature in men with Peyronie’s disease (PD) compared with placebo, regardless of baseline severity of penile curvature. The data, reported by Larry Lipshultz, MD, of the Baylor College of Medicine in Houston, and colleagues, are from the randomized, placebo-controlled IMPRESS I and II phase 3 studies of collagenase, which enrolled 303 and 309 men with PD, respectively. Researchers examined treatment outcomes from baseline to 52 weeks. Men with baseline curvature of 30° to 60° responded as well to treatment as subjects with a curvature of 61° to 90°. In IMPRESS I, these men experienced a 39% and 31% improvement from baseline, respectively; in IMPRESS II, they experienced a 28% and 38% improvement. PD symptom bother score improved by 3.6 and 1.9 points and 2.2 and 3.0 points. All of these improvements were significantly better than those associated with placebo.

complex, and due to differences in modifiable risk factors, health care utilization,

The Future of the Condom The condom has been through many revolutions in history, but has always had the same basic design: a rubber tube with one end sealed off. The next new wave may be condoms made of silicone, which is better for blocking viruses and bacteria. It can be folded accordion-style, allowing it to be slipped on rather than rolled. Or perhaps we may see the invisible condom. A polymer gel has been designed to stick to the mucous membrane of the vagina, acting as a temporary internal condom that eventually dissolves. The condom is overdue for a makeover.

RUN0713_MensHealth.indd 1

medistat

and intrinsic biological and behavioral differences.

50 percent

The magnitude by which citrus juice consumption decreases LUTS* progression risk in men.

*Lower urinary tract symptoms Source: Maserejian NN et al. Intake of caffeinated, carbonated, or citrus beverage types and development of lower urinary tract symptoms in men and women. Am J Epidemiol. Published online ahead of print.

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

6/20/13 12:26 PM

24 Renal & Urology News

july 2013 www.renalandurologynews.com

Age Affects HIV Patients’ CKD Risk Patients aged 60 and older have a nearly eightfold increased risk compared with those aged 18-39

Women Less Likely to Die from RCC Women younger than 59 years are less likely than men to die from renal cell carcinoma (RCC), a newly published study shows. The study, led by Allan J. Pantuck, MD, Professor of Urology at the David Geffen School of Medicine at the University of California-Los Angeles, included 5,654 RCC patients—3,777 (67%) men and 1,877 (33%) women. Clear-cell RCC occurred significantly more frequently women than men (87% vs. 82%), whereas papillary RCC occurred significantly less common in women (7% vs. 12%). Overall, women had a significant 19% decreased risk of RCC-specific death compared with men, researchers reported online ahead of print in Urologic Oncology. This survival advantage was limited to women younger than 59 years and was greatest among women younger than 42 years. The five-year diseasespecific survival (DSS) rates were 84% and 70% for women and men younger than 42 years, respectively, and 73% and 66%, respectively, among patients

RUN0713_CROI.indd 1

for a shorter period. CKD also was more likely among those with AIDS.

CKD screening advised Investigators concluded that health care providers should routinely screen HIV-positive adults for CKD, particularly those over age 60. They also recommend that when CKD is detected in these patients, they should be referred early to a nephrologist and not be given nephrotoxic agents. All HIV-positive adults also should have “aggressive management of comorbid conditions such as diabetes, hypertension and obesity,” according to lead investigator Shikha Garg, MD, and her colleagues. Dr. Garg, of the Centers for Disease Control and Prevention in Atlanta, led the analysis of CKD prevalence among HIV-positive adults. They focused on the 3,814 adults in the MMP from 2009 who were both HIV-positive and had at least one recorded creatinine measurement. in the age group 42-58 years. Women presented with lower-grade and less advanced tumors than men, leading to a decreased risk of cancer-specific death compared with men. “Because this gender-based survival difference is not related to pathologic features, the role of hormonal effects on the development and progression of RCC needs to be investigated,” the authors concluded. Additionally, the study found that age is an independent predictor of DSS among women, but not men. The risk of cancer-specific death increased by about 1% with each one-year increment in age. Previous studies have shown that women have a survival advantage compared with men across many tumor types. Whether these survival differences reflect biologic or cultural factors, or both, remains controversial. If survival differences are due to biologic factors, according to the researchers, a potential mechanism to consider would be the possible protective effect of sex hormones on oncologic processes. “If a true beneficial effect of hormone status on RCC does exist,” the investigators wrote, “then the potential for therapy targeting the endocrine axis in women would also need to be investigated.” n

BY ROSEMARY FREI, MSc ATLANTA—Chronic kidney disease (CKD) is more common among older rather than younger HIV-positive individuals, researchers reported at the 20th Conference on Retroviruses and Opportunistic Infections. Compared with individuals aged 18-39 years, those aged 40-59 and 60 and older are at 2.8-fold and 7.8-fold increased risk for CKD, respectively, based on 2009 data from the Medical Monitoring Project (MMP), which involves 23 health department jurisdictions across the U.S. and focuses on clinical outcomes and behaviors of HIV-infected individuals. It is led by Jacek Skarbinski, MD, of the Centers for Disease Control and Prevention in Atlanta,GA. In adjusted analyses, CKD was 40% more likely to develop in women than men, and individuals who had HIV for 10 or more years were 40% more likely to have CKD than those who had HIV

CKD screening advised for older HIV patients.

They found 5.7% of the HIV-infected adults had stage 3 CKD, 0.6 had stage 4 CKD, and 1.3% had stage 5 CKD.

Puzzling finding Older HIV-positive adults from the MMP had a lower CKD prevalence

than similarly aged HIV-uninfected individuals from the 2001-2008 National Health and Nutritional Examination Survey (NHANES) database. Individuals aged 60 and older from the MMP were 20% less likely to have CKD compared with adults aged 60 and older from NHANES. The respective ratios for the age 18-39 and 40-59 age groups were 4.6 and 1.8. The lower CKD prevalence among HIV-infected individuals aged 60 and older in the MMP versus NHANES is puzzling, Dr. Garg said. “One potential explanation is that people with HIV infection who are sicker or have many comorbid conditions may die earlier than HIV-uninfected persons of the same age and with the same types of comorbid conditions,” Dr. Garg said. “This would result in our having compared a healthier older HIV-infected population – that is, those who did not die earlier – to a potentially sicker nonHIV-infected older population.” n

Kidney Disease Progression Linked to Low Bicarbonate Low serum bicarbonate is indepen-

studied 3,939 patients with CKD stages

dently associated with an increased

2-4 who enrolled in the Chronic Renal

risk of kidney disease progression in

Insufficiency Cohort (CRIC) study from

patients with chronic kidney disease

June 2003 to December 2008. During

(CKD), a study found.

a median follow-up of 3.9 years, 374

The association is particularly strong

subjects died, 767 had a renal outcome

in patients with preserved renal func-

(end-stage renal disease [either initia-

tion, researchers reported online ahead

tion of dialysis or kidney transplantation]

of print in the American Journal of

or a 50% reduction in eGFR), 332 had

Kidney Diseases.

an atherosclerotic event (myocardial

“In the context of the current literature, our study supports the concept of using serum bicarbonate level to

infarction, stroke, or peripheral arterial disease), and 391 had heart failure. In adjusted analyses, each 1 mEq/L

identify patients with high risk of car-

increment in serum bicarbonate level

diovascular events and kidney disease

was associated with a significant 3%

progression,” the investigators wrote.

decreased risk of a renal outcome in

“In addition, this epidemiologic associa-

the cohort overall and a significant

tion provides support to the notion

9% decreased risk among those with

that bicarbonate may be used as a

an eGFR above 45. Each 1 mEq/L

therapeutic target to slow the decrease

increment in serum bicarbonate level

in kidney function.”

above 24 mEq/L was associated with a

A team led by Mirela Dobre, MD,

significant 14% increased risk of heart

MPH, of the Division of Nephrology and

failure. Serum bicarbonate level was

Hypertension at University Hospitals

not associated with atherosclerotic

Case Medical Center in Cleveland,

events and all-cause mortality. n

6/20/13 12:27 PM

www.renalandurologynews.com july 2013

HIV Drugs May Up eGFR Decline Risk Researchers observe no association with advanced CKD or ESRD BY ROSEMARY FREI, MSc ATLANTA—Nephrologists should be vigilant for signs of a rapid decrease in estimated glomerular function rate (eGFR) in their HIV-positive patients who are taking certain antiretroviral drugs, according to new study results. In a paper published online ahead of print in the Journal of Infectious Diseases (JID) a multinational team documented that cumulative use of tenofovir and ritonavir-boosted atazanavir independently predicted progression to confirmed (more than three months apart) eGFR below 70 mL/min/1.73m2 (a threshold below which the authors speculated intervention may begin to occur) from initial normal eGFR levels (greater than 90 mL/min/1.73 m2) during a median follow-up of 4.5 years. Sustained use of ritonavir-boosted lopinavir is a predictor of both confirmed eGFR above 70 mL/min/1.73 m2 and moderate chronic kidney disease (CKD; confirmed eGFR below 60 mL/min/1.73 m2). Further, the investigators showed that individuals with a current eGFR of 60-70 discontinued tenofovir at a rate 1.72 times greater than those with current eGFRs of 90 or higher. Cumulative tenofovir use

and ritonavir-boosted atazanavir use were associated with an 18%-19% greater likelihood per additional year of use of a reduction in eGFR to confirmed 70 or below, while sustained use of ritonavir-boosted lopinavir was associated with an 11% greater likelihood of reaching this confirmed level of eGFR and a 22% increased likelihood of developing moderate CKD per additional year of use.

Monitor rapid decreases in eGFR in HIV-positive patients on antiretrovirals. The data are from the D:A:D study, a long-term prospective cohort study of 49,734 HIV-positive patients in the U.S., Europe, and Australia. However, in a poster presented here at the 20th Conference on Retroviruses and Opportunistic Infections, the same members of the D:A:D team reported that neither recent nor current use of potential nephrotoxic antiretroviral drugs (ARVs) was associated with advanced CKD (confirmed eGFR

below 30 mL/min/1.73 m 2) or endstage renal disease (ESRD; dialysis for more than three months or renal transplantation). They documented a high rate of discontinuation of some ARVs, particularly tenofovir, when patients’ eGFRs fell below 60, however. “Given the increasing awareness of the nephrotoxic potentials of especially tenofovir clinicians are prone to react to a declining eGFR in patients on this drug by either dose adjusting or switching to a more kidney-friendly treatment option if possible,” said lead author Lene Ryom, MD, and D:A:D study coordinator, from the Copenhagen HIV Programme. “We therefore believe the reason why we don’t observe a positive association between tenofovir use and advanced CKD/ESRD in our cohort is likely that patients on tenofovir switched away from the drug long before reaching severe levels of chronic kidney diseases.” The results presented in the conference poster extended the findings of the JID paper, showing that patients who had previously used tenofovir but had discontinued the drug had similar rates of advanced CKD or ESRD as patients who had never been exposed to tenofovir. n

Post-Tx NODAT Linked to Low Magnesium

Renal & Urology News 25

Pruritus Has Adverse QoL Impact BY JOHN SCHIESZER SEATTLE—Pruritus adversely affects quality of life (QoL) in a large segment of the dialysis population, according to a new study presented at the 33rd Annual Dialysis Conference. “There is a certain segment of dialysis patients who certainly are very bothered by skin itchiness both during dialysis sessions and outside of that,” said investigator Scott Sibbel, PhD, who is with DaVita Clinical Research in Minneapolis, Minn. He and his colleagues analyzed the association between itchiness scores on the Kidney Disease Quality of Life 36 instrument (KDQOL) and the component physical and mental scores reported by 71,012 dialysis patients. All the patients completed the SF-12 portion of the KDQOL. The KDQOL instrument assesses dialysis-specific, patient-reported, health-related quality of life for individuals on dialysis. The SF-12 portion looks specific at physical and mental well-being. The survey is administered every year to all dialysis patients treated at a large dialysis organization, he said. In the study, 30% of patients reported they were moderately to extremely bothered by itching, with

BY ROSEMARY FREI, MSc LAKE LOUISE, Alberta—Hypo magnesemia may confer an increased risk for new-onset diabetes after transplantation (NODAT) in kidney transplant recipients, according to a new Canadian study. The Toronto team reviewed the records of 838 patients who received kidneys at the Toronto General Hospital between 2000 and 2010. They found lower serum magnesium increases the risk of NODAT by almost 50%, although the increase is not statistically significant. “If we confirm this association in our follow-up analysis the findings may have implications for post-transplant management of serum magnesium, especially among those at increased risk of NODAT,” lead investigator S. Joseph Kim, MD, a nephrologist and Assistant Professor of Medicine at the University of Toronto, explained to Renal & Urology News after presenting the study at the

RUN0713_CROI2.indd 1

Canadian Society of Transplantation’s 2013 annual meeting. “We have deferred any changes in clinical practice locally until we have the follow-up analysis completed, hopefully the end of September.” Earlier studies suggested a relationship between hypomagnesemia and NODAT, but there is still no consensus on the existence and strength of the association. The theory is that reduced serum magnesium levels can contribute to insulin resistance, which in turn leads to type 2 diabetes. Dr. Kim and his colleagues analyzed data from adult kidney-transplant recipients in the Comprehensive Renal Transplant Research Information System between January 1, 2000 and December 31, 2010. They excluded patients who had received simultaneous or prior nonkidney transplants, had diabetes before transplantation, had primary kidney non-function after transplant, had miss-

ing lab values or were lost to follow-up. Three-quarters of the patients (628/838) had low serum magnesium levels before transplantation. The characteristics of the hypomagnesemia and non-hypomagnesemia groups were similar, except the average age of people with normal magnesium levels was a bit higher, at 46.3 versus 43.6 years. When the investigators analyzed the relationship between NODAT risk and serum magnesium levels over time, at one month post-transplant and rolling averages they found a positive association. For example, every 0.1 mmol/L increase in serum magnesium level at baseline was associated with a 48% increased likelihood of NODAT. Patients in the lowest quartile of average time-varying and rolling serum magnesium levels, 0.20-0.67 mmol/L, had a 43% increased likelihood of NODAT than those with normal levels, 0.82-1.89 mmol/L. n

60% of patients reporting at least some level of itching. In addition, the study showed a significant association between itchiness and physical and mental component scores in the SF-12 portion of the KDQOL. Overall, the study found that skin itchiness is an independent predictor of other aspects of QoL, suggesting that it is an important condition to address. In a previous study presented at the American Society of Nephrology’s 2012 Kidney Week, the same researchers reported that increasing severity of self-reported itchiness tended to occur in slightly younger patients, female patients, and those with diabetes. Patients with severe pruritus were also more likely to have CVD, chronic obstructive pulmonary disease, or liver disease. n

6/20/13 12:28 PM

26 Renal & Urology News

july 2013 www.renalandurologynews.com

Tea May Lower Advanced PCa Risk Greater consumption of black tea and other dietary sources of flavonoids may decrease the risk of advanced stage prostate cancer (PCa), according to a new study. In a study of involving 58,279 men in the Netherlands Cohort Study, men who drank five or more cups of black tea a day had a 25% decreased risk of stage III/IV PCa and a 33% decreased risk of stage IV PCa compared with those who drank one cup a day or less, after adjusting for age, researchers reported online ahead of print in the American Journal of Epidemiology.

Flavonoids Black tea is a major source of flavonoids, which are natural antioxidants. Other dietary sources include apples, cabbages, onions, leafy vegetables, legumes, and chocolate, the investigators noted. Of the 58,279 men, 3,362 PCa cases were identified from 1986 to 2003, including 1,164 advanced cancers. Dietary intake was derived from a 150-item semiquanititative food fre-

Herpes Virus Infection May Up ED Risk Herpes simplex virus (HSV) infection increases the risk of erectile dysfunction (ED). Investigators compared 1,717 male HSV-infected patients with 6,864 male controls without HSV and matched for age, time of enrollment, and comorbidities. During an average of 3.9 years of follow-up, HSV-infected subjects had a higher incidence of ED than controls (1.7% vs. 0.7%), researchers reported in Andrology (2013;1:240-

quency questionnaire filled out at baseline. The researchers divided consumption of black tea and various flavonoids into quartiles and looked at the association between quartiles and the risk of PCa and PCa subgroups. The researchers, led by Milan S. Geybels, a doctoral candidate in the Department of Epidemiology at Maastricht University in Maastricht, The Netherlands, found that patients in the highest quartile of total catechin, epicatechin, kaempferol, and myricetin had a significantly decreased risk of stage IV disease compared with those in the lowest quartile. The researchers found no association between dietary flavonoid intake and overall and non-advanced PCa risk.

Study strengths In a discussion of study strengths, Dr. Geybels’ group pointed to its prospective design, large sample size, and long and nearly complete follow-up. In addition, the range of black tea intake was side and they had data on tumor stage for most cases, which made it

Highest versus lowest consumption levels were linked to a 33% decreased risk of stage IV disease

Men who drank more than five cups of black tea per day had less risk of advanced disease.

possible to stratify by disease stage. Moreover, the study had a large number of advanced stage cancers. The study also had some limitations. For example, the researchers noted that they did not obtain information on infusion time of tea or tea strength. “Such additional information could have provided us with a more precise

estimation of daily flavonoid intake,” they wrote. In addition, misclassification could have occurred in the assignment of flavonoid levels to the foods reported. “Flavonoid concentrations are known to vary greatly by food variety, and thus, individual preferences for particular varieties of foods would lead to misclassification.” n

Stones, Urinary Incontinence Linked Urinary incontinence and chronic periodontitis are independent risk factors for upper urinary tract stones, according to separate population-based studies conducted in Taiwan. The studies examined data in Taiwan’s Longitudinal Health Insurance Database, which contains data from one million randomly selected subjects from the National health Insurance Research Database. For the urinary incontinence analysis, Hsiao-Jen Chung, MD, of Taipei Veterans General Hospital, and col-

leagues identified 1,943 subjects diagnosed with the condition from 1997 to 2001 and had no history of upper urinary stones or spinal cord injury. These subjects were matched with 9,715 age- and gender matched controls. All subjects were followed up until the end 2009, with a minimum follow-up of eight years. Upper urinary stones developed 407 (20.9%) of the study subjects compared with 1,088 (11.2%) of controls. In adjusted analyses, urinary incontinence was associated with a significant twofold

increased risk of upper urinary stones. For the chronic periodontitis study, the same team compared 16,292 individuals diagnosed with chronic periodonitis from 1997 to 2001 with 48,876 age- and gender-matched controls. The follow up was the same as in the urinary incontinence study. Upper urinary stones developed in 1,761 (10.8%) of the study subjects versus 4,775 controls (9.8%). In adjusted analyses, chronic periodontitis was associated with a significant 14% increased risk of upper urinary stones. n

RCC Prevalence High in ADPKD Patients

244). Further analyses showed that HSV infection was independently associated with a nearly threefold increased risk of ED. The researchers noted that ED and HSV infections are related to cardiovascular events. n

RUN0713_PCaTea.indd 26

Researchers found renal cancers in 5% of patients with autosomal dominant polycystic kidney disease (ADPKD), a prevalence they called “surprisingly high,” according to a report published online ahead of print in Nephron Clinical Practice. Cordula A. Jilg, MD, of the Albert Ludwigs

University of Freiburg in Freiburg, Germany, reviewed data from 240 ADPKD patients who underwent 301 renal surgeries. Sixteen malignant renal lesions were found in 12 patients (5%). Ten of the cancers (63%) were papillary renal cell carcinoma (RCC), five (31%) were clear cell RCC, and one was a

papillary noninvasive urothelial cancer. Eight of the 12 patients had undergone dialysis prior to surgery. “Like other cystic renal diseases with an increased risk for RCC, the attending physician should be aware of the malignant protential of ADPKD, especially with concomitant dialysis,” the authors concluded. n

6/20/13 12:33 PM

www.renalandurologynews.com July 2013

Renal & Urology News 27

Kidney Size Predicts Graft Function Morphomics is a new risk stratification that may enable long-term outcome prognostication BY ROSEMARY FREI, MSc MIAMI BEACH, Fla.—Abdominal computed tomography (CT) images from the work-up of kidney donors can be useful in predicting whether their recipients’ kidney function is likely to improve significantly after the transplant, according to a new study conducted by researchers at the University of Michigan Health Systems in Ann Arbor. Data presented at the 13th Annual American Society of Transplant Surgeons’ State of the Art Winter Symposium show that patients who receive kidneys from donors with relatively large kidney volumes have higher estimated glomerular filtration rates (eGFRs) up to five years posttransplant than recipients of relatively small kidneys. In addition, they have higher eGFRs when the donors have relatively large trunk muscles. Both kidney size and trunk-muscle area can be determined by examining CT images. The researchers concluded that in the future it may be valuable to include this information when assessing people who have offered to donate a kidney.

“Because of a limited donor kidney supply the criteria for donor selection has expanded. With this new cohort of patients, we need appropriate risk stratification to inform donor-recipient matching,” said Kara

Post-transplant eGFRs are higher with relatively large kidneys. Barnhart, a second-year medical student. “Morphomics represents a novel method for risk stratification and may be a tool to predict long-term donor and recipient outcomes.” Barnhart conducted the study under the supervision of Michael J. Englesbe, MD, Associate Professor of Surgery. They and five others reviewed computed tomography images and donation outcomes from 302 people who donated kidneys at the University of Michigan between 2000 and 2008. In their analyses, they divided the donors into tertiles of kidney volume and psoas major area.

The psoas major is a trunk or “core” muscle that runs from the back of the spine to the front of the pelvis. The donors’ average age was 41.8 years, their mean eGFR was 113.9 ml/ min/1.73 m 2 and their psoas major muscles’ average area was 2,609 mm2. Their average kidney volume was 198.7 cm3. Routine abdominal CT imaging also revealed that about onefifth of the donors (17.7%) had aortic calcification, and among those, the average portion of the aortic wall that was calcified was 4.5%. The recipients’ average age was 47.1 years and 40.1% were female. Furthermore, 41.1% had diabetes, 28.9% had coronary artery disease and their mean body mass index was 27.4 kg/m2. When the investigators examined death-censored graft survival, they observed that neither donor kidney volume nor donor psoas area were significant risk factors for graft loss. However, when they examined post-transplant recipient eGFR, they found that recipients of the highest-tertile kidneys had significantly higher post-transplant eGFRs than did those of the lowest-

tertile kidneys, starting at six months post-transplant and out to five years. In addition, recipients of kidneys from donors who had the largest-tertile psoas muscle area had significantly higher eGFRs from six months post-transplant onwards. Barnhart said the study has several limitations. For example, it was a single-institution, retrospective investigation and not all donor scans were suitable for analysis. In addition, not all long-term recipient follow-up data was available, she noted. “Future work will involve the analysis of additional donor morphomic measures and extending our analysis beyond five-year recipient outcomes,” Barnhart said. In a previous study of 125 living kidney donor/recipient pairs published in Transplantation (2012;94:1124-1130), researchers concluded that donor kidney volume dosing is an important determinant of recipient graft outcomes and may predict recipient kidney function. Compared with the lowest tertile of donor kidney volume to recipient weight, those in the highest tertile had a 77% reduced odds of developing an eGFR below 60. n

Lupus Nephritis Need Not Halt Renal Transplants BY ROSEMARY FREI, MSc OTTAWA—Patients with lupus nephritis can make good candidates for renal transplantation if their disease is quiescent for at least one year prior to surgery, according to new research findings presented at the 2013 annual meeting of the Canadian Rheumatology Association. Investigators reviewed outcomes from adults who had attended a lupus clinic at the Toronto Western Hospital in Toronto, Ontario, from 1970 to 2012. Among the 1,645 lupus patients treated in that interval, 25 had nephritis and underwent kidney transplantation. Most of the patients were white (40%) or African Canadian (28%). The remaining patients were Asian or members of other ethnic groups. None of them had any clinical evidence of lupus in the year before transplantation. Two of the patients had a completely non-functional kidney post-transplant. Another four had graft failure, one within five years of transplant surgery and the remaining three after a longer

RUN0713_Morphometrics.indd 1

period, with an average time to graft failure of 5.75 years. Of the 19 (76%) patients with graft survival, the graft survived at least five years in eight patients, with a mean graft survival among these eight patients of 5.7 years, according to the investigators. The four patients with graft failure and 19 with graft survival had roughly simi-

Disease should be quiescent for at least one year before surgery. lar characteristics, except that the average age in the graft-survival group was higher (40 vs. 29.8 years). Significantly more whites and African-Canadians had graft survival than graft failure, at seven and one, and six and one, respectively. In addition, the average time between lupus diagnosis and transplant was 15.5

year in the graft-survival group and 4.5 years in the graft-failure group. The respective average durations of dialysis prior to transplant were 5.8 and 3.9 years. Three of the individuals in the graftsurvival group died an average of 5.6 years post-transplant. The cause of death was not related to renal disease in two patients and unknown in the third. Another patient was lost to follow-up. In the graft-failure group, three patients died an average of six years post-transplant, and all the deaths were related to renal disease. The remaining patient is still living. One (25%) of four patients in the graft-failure group had positive lupus serology a year before transplantation compared with nine (47%) of 19 patients in the graft-survival group. At one year post-transplant, the proportion of patients with lupus serology in the graftfailure group rose to 66%, while it fell to 42% in the other group, the researchers reported.

“I presume that older patients had quiescent lupus disease activity for a longer period compared to the other patients, and it is possible that the severity of lupus disease activity tends to ameliorate [or] weaken years after the diagnosis of lupus,” said lead investigator Zahi Touma, MD, PhD, from the University of Toronto Lupus Clinic at the Toronto Western Hospital, in explaining the results. In another poster presented at the rheumatology meeting, Dr. Touma and three other co-investigators analyzed the timeframe for either partial (at least 50% decrease from baseline in proteinuria) or complete, recovery from proteinuria in lupus nephritis patients. They determined that partial or complete recovery from proteinuria may be a better end point in clinical studies of this patient population because it tracks parallel to complete response but happens somewhat more quickly, which is an advantage in studies that do not last for decades. n

6/20/13 12:34 PM

july 2013 www.renalandurologynews.com

Doctors and Lawyers Support Oregon Malpractice Bill

It’s rare that both healthcare providers and trial lawyers support a medical malpractice bill, but this is exactly what has happened in Oregon. Senate Bill 438, backed by Gov. John Kitzhaber (D), suggests the state create a patient safety commission to discuss and mediate malpractice incidents. Kitzhaber, who is also a medical doctor, recently convened a bipartisan work group that assessed the state’s medical malpractice process and provided recommendations for improving it. In testimony to the Senate Judiciary Committee, Kitzhaber stated that the new bill “focuses both on improving patient safety and improving the practice environment and culture of medicine.” The new legislation proposes that all parties involved in a medical malpractice case sit down and discuss the situation openly and frankly, so an offer of compensation can be made prior to a lawsuit being filed. The legislation stipulates any discussions that take place during these conferences be confidential. However, the commission may use information that surfaces to improve safe medical practice. A professional mediator may be used to help the parties resolve their differences, it states.

Doctors and lawyers in Oregon favor creation of a malpractice mediation panel.

On The Web RUN0713_MalpNews.indd 1

The proposed program is completely voluntary—patients with malpractice cases who do not wish to participate may head straight to court. If patients choose to participate in mediation and the effort fails, the discussions that took place are not admissible in court. Both the Oregon Medical Association and the Oregon Trial Lawyers Association—two organizations that have historically been at odds over how medical liability reform should be handled— endorse the bill. Gov. Kitzhaber called the mutual endorsement “the holy grail of medical and legal politics,” and went on to say that the bill will “definitely benefit the practice of medicine.” Although the legislation aims to reduce medical malpractice claims, it does not put any restrictions on the amount of money a jury can award for medical errors, so not everyone is happy with the plan. Medical insurance companies have expressed concern that the plan does not do enough to address medical liability reform and could result in higher administrative costs for insurance companies and higher premiums for physicians.

Report: Number of Medical Errors Declines in Minnesota The number of medical errors at Minnesota hospitals fell from 2011 to 2012, data from the state’s annual adverse event report indicate. Minnesota is one of only a handful of states that issues an annual report regarding medical errors, and is currently the only state to report numbers from individual hospitals. Statewide, Minnesota hospitals reported 314 medical errors in 2012, compared with 316 in 2011. The report covers errors in six categories: surgical, environmental, patient protection, care management, products and devices, and criminal events. Data from 2012 reveal medication errors dropped by 75% since 2011, and were at the lowest level in all nine years of reporting. Other positive changes included a 16% decline in retained foreign objects during surgery, the first decline in this category in five years, and

By ANN W. LATNER, JD

Malpractice News

Medication errors dropped 75% in Minnesota from 2011 to 2012.

a 9% decline in pressure ulcer incidence, the first significant decline in this category in nine years. There was just a single report of a surgical error—an incorrect lens implant during ocular surgery that did not cause serious disability—among all 12,673 surgeries performed in Minnesota in 2012. “Any event is one event too many,” Jody Schulz, MD, Mayo Clinic Health System’s patient safety officer for southeastern Minnesota said. “Our goal is to never have any events.” Despite these improvements, there were more injuries related to patient falls and suicides in 2012 compared with 2011. Four people committed suicide in Minnesota Hospitals last year, and two others suffered serious harm from suicide attempts, prompting the Minnesota Department of Health to call for more suicide prevention training for healthcare providers.

claims against healthcare providers to a patient injury board that consists of physicians, patient advocates and attorneys, rather than filing a traditional lawsuit. If the board decides that compensation for an error is warranted, it will be paid out of a fund that all providers pay into—similar to the no-fault system covering workplace injuries. The proposed bill will simplify the system and reduce malpractice insurance premiums for physicians, as well as to reduce health insurance costs for patients. Physicians who practice “defensive medicine” to avoid lawsuits has led to skyrocketing healthcare costs in the state, according to Sen. Beach. He maintains that the new system will help patients get compensated faster and more easily. Some supporters believe that the bill would help patients get compensated for errors that are too small to provide incentive for a lawyer to take on the case. Trial lawyers, however, are not supportive of the bill, and contend that it violates the 7th amendment right to a trial by jury. n Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

Treat Malpractice Cases Like Workman’s Comp, Bill Proposes A proposed new bill in Georgia seeks to take medical malpractice cases out of the court system and treat them more like worker’s compensation cases. Introduced by Sen. Brandon Beach (R), the bill suggests that patients take

28 Renal & Urology News

A proposal in Georgia promises to simplify the handling of malpractice suits.

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

6/20/13 3:17 PM

30 Renal & Urology News

july 2013 www.renalandurologynews.com

Practice Management O

ne way physicians can be successful in today’s healthcare environment is to have a good handle on what is going on in their practice. Among the best ways to do that is through data. For starters, physicians should get patients involved in their own care, according to Todd Evenson, director of data solutions for the Medical Group Management Association-American College of Medical Practice Executives (MGMA-ACMPE). You can do this for patients with diseases such as diabetes by using your electronic medical records (EMRs) to create a patient dashboard. For example, when they visit, let them know their A1c levels and where they should be.

Patient surveys Another way to measure quality is through patient satisfaction surveys. There are a handful of benchmarks to use, like the Clinical & Groups Consumer Assessment of Healthcare Providers and Systems (CG-CAHPS). You can track survey findings over time to ascertain the “pain points” and how you compare with your peers, Evenson said. Where patient satisfaction is low or where you know you need improvement, data can help track and improve the practice. For instance, if referral patients complain about having to wait long periods before being seen, you can create metrics to find the problem. Using an Excel spread sheet, you can track when people call and when they are seen. This can be helpful in figuring out areas that might be sticking points, like getting information from a referring physician. Furthermore, knowing more about your patient referrals can also help

On The Web RUN0713_PracManage.indd 1

understand your revenue stream. “For a urologist, one of the scariest things would be to find out that all of your patients are referred from one big general practitioner’s group,” said James Gaston, senior director of clinical and business intelligence at HIMSS Analytics. “Then think about the business risk. If that big group decides to hire a urologist or if they get cut from that provider network, they would lose a huge block of income or patient volume.” Another option is tracking the origin of your income. Creating a pie chart to show where money is coming in will help you find who your payers are and who is generating the most revenue. You might see that one of your most common payers is Medicare but you net more income from a private payer like Blue Cross Blue Shield. This could allow you to focus on getting more patients whose insurers pay more.

Patients’ health coverage In this era of Accountable Care Organizations (ACOs) and bundled payments, it might be wise to know how your patients are covered. Some physicians may see all fee-for-service patients, but many are likely to begin seeing new kinds of payment types creeping into their systems. “You want to understand what type of patients fall within different types of coverage and see if that volume is growing or shrinking,” Gaston said. “It would help you monitor the fundamental shift from fee-for-service to an ACO-type of payment model.” Understanding how to use data can also help to negotiate with the different insurers who are, or will be, writing you checks. If you are going to be negotiating a fee for bundled payments, it

Patient feedback and information on referral patterns and revenue sources can help improve practice efficiency and income By Tammy Worth

Tracking revenue sources may help boost a medical practice’s bottom line.

is imperative to know how much you need for the services you provide. Your billing system can provide information related to collection for services, the amounts being charged, and how frequently you provide treatment. “Armed with data, you can work with payers and have a stronger negotiation point for what you want to be paid,” Evenson said. “Financial information is an effective vehicle to have, and you will have a different discussion than if you went in empty handed (to talk to a payer).” You can also use data that is available online showing operating expenditures and health IT costs to negotiate with vendors. Evenson said MGMA publishes data on professional liability costs that can be used to compare with peers and negotiate with insurance carriers. “Whoever owns a practice, it is in their best interest and ultimately their

responsibility to understand what the business drivers are around that practice,” Gaston said. Lisa Brooks Taylor, director of health information management practice excellence at the American Health Information Management Association, said improving quality through data will take time and effort, but the insights gained from understanding a practice are “beneficial and actionable.” She hears a lot of physicians say documenting and using EMRs interrupts their workflow. If this is the case, she recommends really pushing vendors to improve their systems and to make them more efficient. “I encourage physicians to work with their EMR vendors,” she said. “If they don’t like the way it works, they need to work with EMR vendors to get documentation that flows with their workflow process.” n

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

6/20/13 3:15 PM

www.renalandurologynews.com july 2013

Renal & Urology News 31

PCa Focal Therapy Shows Promise Laser ablation can potentially minimize or avoid the major complications of whole-gland treatments BY JOHN SCHIESZER NEW ORLEANS—Focal prostate laser ablation of prostate cancer (PCa) may be safely performed in patients undergoing active surveillance for non-aggressive tumors, according to new data presented at the Society of Interventional Radiology’s 38th Annual Scientific Meeting. The treatment is guided with magnetic resonance imaging (MRI) or realtime ultrasound fused to pre-procedural multi-parametric MRI. “This emerging technique may become an option for certain patients with low Gleason score cancer, given the early suggestion of limited side effects,” said Hayet Amalou, MD, a research fellow at the Center for Interventional Oncology at the National Institutes of Health, Bethesda, Md. “With future simplifications in technology, perhaps focal ablative therapy will become a sort of male lumpectomy for certain tumors. Also, using ultrasound fusion to guide the laser ablation allows the procedure to be performed without occupying an MRI.” Focal therapies could allow for cancer monitoring and control without the morbidity associated with whole gland therapies, Dr. Amalou said. They also

might make it possible for patients to receive repeat treatments less invasively. Dr. Amalou described an ongoing multidisciplinary clinical trial in which 14 patients underwent focal laser ablation for Gleason 6 and Gleason 7 (3+4) biopsy-proven PCa. The tumors were photogenic on MRI. “MRI provides the definition of tumor extent and allows dynamic control of energy deposition using real time MR thermometry,” Dr. Amalou told Renal & Urology News. “Laser ablation was chosen because its energy delivery system may ablate the tumor with a sharper edge or margin (transition zone) compared to cryoablation or high-intensity focused ultrasound.” The ablations may be performed safely near the capsule, urethra, nerves and rectum, with appropriate precautions, such as the use of MRI thermometry along with protective hydro-dissection of the space between the rectum and prostate, Dr. Amalou explained. It is postulated that major complications that commonly occur with whole gland therapies, including erectile dysfunction and urinary incontinence, will be less common with focal therapies. Dr. Amalou said this technique requires tight communication and

This MRI thermometry image shows the temperature of a prostate tumor as it is being ablated (light blue) and the part that has been ablated (yellow).

collaboration between urologists, diagnostic radiologists, and interventional radiologists. At the NIH, this multidisciplinary team includes Peter Pinto, MD, who is the principle investigator of the clinical trial, Peter Choyke, MD, Baris Turkbey, MD, Anthony Hoang, MD, and Bradford Wood, MD. “Although speculative, the complications and risks of whole gland treatment may be deferred, or potentially avoided

entirely, without missing the window of opportunity for early intervention,” Dr. Amalou said. “However, results are short-term thus far, and low-grade prostate cancer can be slow growing. Given our limited ability to predict cancer outcomes based solely upon pathology, morphology or Gleason score, the community should aggressively seek improved predictability based on combining imaging modalities, pathology and other independent risk factors.” n

PAE May Be Safe, Effective for LUTS, Study Finds BY JOHN SCHIESZER NEW ORLEANS—Early findings from the first prospective U.S. trial of prostatic artery embolization (PAE) suggest this approach may be safe and effective for treating lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH), researchers reported at the Society of Interventional Radiology’s 38th Annual Scientific Meeting. This minimally invasive treatment appears to have high success rates with no urologic complications, including impotence or incontinence, they found. “The results have been great so far,” said lead investigator Sandeep Bagla, MD, an interventional radiologist in the Department of Cardiovascular and Interventional Radiology at Inova Alexandria Hospital in Alexandria, Va. He also observed: “Nearly all men eventually suffer from an enlarged prostate as they age, and this treat-

RUN0713_SIR1.indd 1

ment is almost like turning back the clock and giving them the prostate of their youth. Medications are of limited benefit, and surgery, while it can correct the problem, can be risky and may cause significant side effects. PAE is a minimally invasive alter-

U.S. study yields promising findings for prostatic artery embolization. native with low risk that appears to reduce symptoms in the overwhelming majority of patients.” Virtually all men with BPH-related LUTS are looking for the least invasive treatment with the lowest risk and shy away from surgical and other transurethral procedures because they do

not want to risk urine leak, impotence or other complications that may arise from invasive procedures, Dr. Bagla said. The new clinical study confirms the results reported by interventional radiologists in Europe and South America, he added. Dr. Bagla presented early findings showing technical success in 17 of 18 men (94%) who underwent PAE and clinical success in 14 (93%) of the 17 patients. The men ranged in age from 57-81 years. None suffered any major complications, such as impotence, leaking urine, or infection, none reported post-procedural pain, and none required urinary catheterization, he said. Ninety-four percent of the patients were discharged the same day; one stayed overnight for observation. The researchers found that 47% of the treated men reported transient increased urinary frequency for 24

hours. Three of 17 patients reported post-procedural hematospermia, and one of 17 reported transient diarrhea. The researchers also observed an improvement in quality of life scores. The study population had a mean decrease in American Urological Association symptom score of 11.1 points at one month post-procedure. No non-target embolizations occurred, but more trials are warranted to show that PAE has significant benefit over other existing therapies, he said. “It is probably best that it is performed in a limited fashion now. It takes a lot of expertise.” The short- and long-term results have been promising from centers around the world, he noted. Dr. Bagla and his colleagues plan to enroll 30 men. The study, which is expected to be completed this fall, will follow up patients for two years to assess longterm results. n

6/20/13 3:38 PM

32 Renal & Urology News

july 2013 www.renalandurologynews.com

Your Money A

s the financial crisis unfolded, prices of natural gas collapsed, falling from $14 per million British thermal units to $3.10 this year. That hurt profits of gas companies and sent the stocks reeling. Now some fund managers argue that gas prices are poised to recover. The managers say that the gas stocks represent bargains for investors who have the patience to wait for a rebound. “We are at the early stages of a rally that could occur over the next several years,” says Kent Croft, portfolio manager of Croft Value Fund. Croft says that gas prices sank because of simple supply and demand. When the economy fell into recession, demand dropped as factories and power companies burned less gas. At the same time, supplies increased because of new technologies known as hydraulic fracturing. In this approach, drillers pump water and chemicals to release gas from rock formations that have never been tapped before. The technique has spread rapidly around the country, opening up huge new reserves in Pennsylvania, Texas, Wyoming, and other states.

A switch from oil to gas Now that excess supplies are helping to hold down prices, natural gas is becoming more attractive for many users. Factories that once burned oil are switching to low-cost gas. Besides being cheap, gas causes relatively little pollution. That is encouraging power companies to shut down their coal plants and shift to gas. Gas is also emerging as a cheap fuel for vehicles. Already 15% of the country’s municipal buses and garbage trucks can run on gas. Commercial trucks have been slow to shift to gas. But now several gas companies have begun investing hundreds

On The Web RUN0713_Money.indd 1

of millions of dollars to provide natural gas fuel stations at truck stops. Up till now, U.S. producers could only sell to North American users. Exports have been limited because supplies must be converted to liquefied natural gas before the product can be shipped overseas. Few LNG facilities existed because they cost billions of dollars to build. But now companies are racing to open new plants that can support exports. A new facility in Canada should begin shipping supplies to Asian customers in the next two years. Developers are currently seeking government approvals for eight projects in the U.S. All the growing demand should fatten the bottom lines of gas companies. “Over the next 10 years, demand for gas will grow, and that will push up prices,” says Tim Schwartz, portfolio manager of Schwartz Value Fund. To profit from the growing demand, investors can buy shares of gas producers. A top choice is Ultra Petroleum, which produces gas in the Marcellus Shale field of Pennsylvania. “The stock is near its lows, but the company will do well in the future because it has huge new reserves,” says Croft.

Stick with low-cost producers Now Schwartz says that it is important to stick with low-cost producers. Because of the current level of low prices, many high-cost companies are barely profitable. But efficient producers can stay afloat in hard times—and deliver outsized earnings when gas prices rally in the future. Besides producers, Croft also likes pipeline companies. These charge producers fees for transporting gas. Revenue for the pipeline companies can be particularly reliable because

Gas stocks represent bargains for investors who have the patience to wait for a rebound By STAN LUXENBERG

Utility funds for natural gas are poised to grow if investors commit for the long term.

the businesses are virtual monopolies. Once a pipeline is built, competitors have trouble winning permits to build facilities in the same areas. When gas prices rise, pipeline companies cannot charge more. But their fee income rises as more volume flows through the pipes. So as demand grows, pipeline companies should report more revenues. The pipeline fees are limited by federal regulators. But regulators permit companies to increase fees along with the rate of inflation. A stock that Croft likes is Williams, which operates gas pipelines that serve New York City and other areas. The company has healthy profit margins and pays a dividend of 3.9%. A cautious way to bet on a gas rebound is Hennessy Gas Utility Index Fund. The fund holds mostly regulated utilities that deliver gas to customers. Holdings include Spectra Energy and TransCanada. Most of

the stocks pay reliable dividends. The fund has a dividend yield of 2.7%. Portfolio manager Skip Aylesworth argues that increasing demand for gas should enable the utility industry to grow and support rising dividends. Aylesworth says that the staid utilities can generate solid single-digit returns over long periods. “This is an industry that should grow 6% or 7% annually for years to come,” he says. Some funds specialize in master limited partnerships (MLPs), which own pipelines. Many of the MLPs yield more than 5%. The yields are so rich partly because of the special tax status of the partnerships. To encourage construction of energy infrastructure, Congress granted tax benefits to MLPs. Under the rules, MLPs do not pay income tax as other corporations do. Instead, the income is passed along to shareholders who pay income taxes on their dividends. n

Where’s the best investment? Check out what our financial columnist has to say about how to invest your money. We’ve got lots more online at www.renalandurologynews.com/money.

6/20/13 12:37 PM

www.renalandurologynews.com july 2013

Renal & Urology News 33

CME feature

Update on the Medical Management of Kidney Stones The first step in prevention is adequate and quantitative counseling regarding fluid intake, which is effective and inexpensive.

Release Date: July 2013 Expiration Date: July 2014 Estimated time to complete the educational activity: 1 hour This activity is jointly sponsored by Medical Education Resources and Haymarket Medical Education. Statement of Need: Kidney stone prevention is often neglected, and deserves more attention by nephrologists and urologists. Adequate and quantitative counseling regarding fluid intake is the first step and is effective and inexpensive. Appropriate dietary manipulations can be prescribed based on 24-hour urine collections. While dietary adherence may be difficult for many patients to achieve, at present, medical therapies are effective and underutilized. Target Audience: This activity has been designed to meet the needs of nephrologists and urologists who treat patients with nephrolithiasis. Educational Objectives: After completing the activity, the participant should be better able to: • Assess dietary effects on calcium stone formation. • Discuss pharmacologic options for treating hypercalciuria. • Discuss the etiology and appropriate management for differing types of calculi. Accreditation Statement: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Medical Education Resources (MER) and Haymarket Medical Education. MER is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation: Medical Education Resources designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Disclosure of Conflicts of Interest: Medical Education Resources ensures balance, independence, objectivity, and scientific rigor in all our educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure all scientific research referred to, reported, or used in a CME activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality CME activities that promote improvements or quality in health care and not a commercial interest. The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Faculty David S. Goldfarb, MD

Lama Nazzal, MD

Reported Financial Relationship Consultant: Takeda, Keryx Grants: NIDDK, ORDR Lecture Honoraria: Quintiles, Mission Ownership Interest: Ravine Group No financial relationships to disclose

By David S. Goldfarb, MD, and Lama Nazzal, MD

idney stones are common, painful, costly, and preventable. Our experience suggests that only a small proportion of stone formers are counseled by a knowledgeable professional about prevention, resulting in the ample recurrence of stones. Perhaps not completely congruent with what physicians believe, patients consistently state that they are interested and motivated to prevent stones. Recent links between kidney stones and diabetes, hypertension, coronary artery disease, and chronic kidney disease indicate that nephrolithiasis is far from a merely inconvenient disorder.1 While the causal basis and directions for these associations have not been confidently established, stone formers should have their diet, activity, body mass index (BMI), and comorbidities assessed, and have appropriate individualized preventive regimens prescribed. In addition to preventive efforts, patients with renal and ureteral calculi should have their risk for other associated conditions addressed.

In this update, we focus on some recent developments regarding calcium and uric acid stones, rather than offer a comprehensive survey. The recent review by the Agency for Healthcare Research & Quality (AHRQ) is an important resource, although its conclusions are limited by its attention only to data produced by high quality randomized clinical trials (RCT).2 Given the surprising paucity of such trials, clinicians must also rely on observational studies, as well as our knowledge of the factors that influence urine chemistry, recognizing the limitations of our attempts to extrapolate from non-interventional studies to clinical outcomes. Elsewhere we have reviewed developments in cystinuria.3

Dietary effects on calcium stone formation The influence of diet on urine chemistry has been repeatedly demonstrated, and subsequently there is little mystery about how dietary modifications change urine profiles to prevent

The content managers, Jody A. Charnow and Marina Galanakis, of Haymarket Medical Education, and the content manager at Medical Education Resources, have disclosed that they have no relevant financial relationships or conflicts of interest. Method of Participation: There are no fees for participating in and receiving CME credit for this activity. During the period July 2013 through July 2014, participants must: 1) read the learning objectives and faculty disclosures, 2) study the educational activity, 3) complete the posttest and submit it online. Physicians may register at www.myCME.com/ renalanurologynews, and 4) complete the evaluation form online. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better.

David S. Goldfarb, MD (left), and Lama Nazzal, MD (right), are affiliated with New York Harbor VA Medical Center and New York University Langone Medical Center, where Dr. Goldfarb is Professor and Clinical Chief of Nephrology and Dr. Nazzal is a third-year fellow in the Nephrology Division.

RUN0713_CME.Goldfarb_alt.indd 33

6/24/13 4:54 PM

34 Renal & Urology News

july 2013 www.renalandurologynews.com

CME feature

RUN0713_CME.Goldfarb_alt.indd 34

cost factor averted—by getting patients to drink more than 2L of water per day—were recently quantitated.10

Management with thiazides Prevention of stones in patients with hypercalciuria has not significantly advanced in recent years. RCTs have consistently shown that thiazides prevent recurrent stones.11 The AHRQ review stated that treatment with thiazides did not necessarily require the presence of hypercalciuria, as some studies had not indicated specific lev-

chlorthalidone has not been associated with the same cardiovascular benefits. In addition, when HCTZ has been successful in reducing hypertension-associated outcomes, it was with a twice-aday dosage. Similarly, the doses used to manage hypercalciuria have also decreased despite a lack of supportive evidence. Studies showing efficacy of thiazides to reduce stone recurrence have used either chlorthalidone or indapamide, or HCTZ twice a day. One survey of prescriptions demonstrated that HCTZ once a day was prescribed most commonly, often at doses

200

164 Fall in urine CA (mg/d)

kidney stones. We recently reviewed the data regarding diet and stones.4 There is only one RCT that demonstrated a beneficial effect of diet on stone recurrence.5 In that study, men with hypercalciuria were randomized to either a diet with a restricted intake of animal protein, sodium, and oxalate, but up to 1,200 mg of calcium per day, or a diet of 400 mg of calcium and restricted oxalate intake. The highercalcium diet was associated with roughly 50% less stone recurrence at three years. That is currently the diet that we most frequently recommend to patients, though we concentrate on discussing the components most relevant to stone formers based on their individual 24-hour urine collections. For the study, researchers did not measure bone mineral density (BMD), but we speculate that the participants in the higher-calcium intake group would have had better BMD at the end of the study. Increased dietary calcium intake is associated with a lower incidence of kidney stones, and this has been known for 20 years.6 The leading hypothesis about this effect has been the ability of ingested calcium to bind oxalate in the intestinal lumen and diminish its absorption by the intestine, and thereby its excretion by the kidney. The possibility that some other property of dairy foods besides calcium content is responsible for this inhibitory effect has also been suggested. Recent data have demonstrated that non-dairy calcium is also associated with reduced stone formation, supporting the role of calcium itself in stone prevention.7 Weight gain has been consistently associated with an increased risk for recurrent stones.8 Given the associated risk of the metabolic syndrome and hypertension, it is reasonable to prescribe weight loss to appropriate patients. However, no studies to date have addressed whether weight loss actually leads to fewer stones. It is also important to stress that both RCTs and studies of urine chemistry demonstrate that increasing fluid intake to 3L per day to achieve urine volumes of greater than 2L per day should be emphasized.9 Patients should learn to be quantitative about fluid intake and not be told simply to drink “a lot.” The substantial numbers of stones prevented and the sizable

144

150

84.7

100

CTD 25 mg

HCTZ 25 mg

HCTZ 50 mg

* P< 0.01 compared to CTD

Figure 1. Hypocalciuric Activity of Chlorthalidone vs. Hydrochlorothiazide

els of calcium excretion as an inclusion criterion and because successful studies did not demonstrate that efficacy was clearly associated with the expected reduction in urinary calcium excretion.2 This is consistent with the idea that there is no clear demarcation useful in defining hypercalciuria. Observational studies indicate no clear threshold at which higher calcium excretion suddenly becomes associated with higher relative risk for stones.12 The use of thiazides may, therefore, be appropriate when fluid and diet therapy (particularly reduction of dietary sodium intake) is not sufficient, regardless of whether urinary calcium excretion meets the traditional definition of hypercalciuria. Thiazides are commonly used in the management of hypertension, where they are considered a first-line agent. However, the trend toward using lower doses has recently been criticized as not being evidence based.13 The use of the shorter-acting hydrochlorothiazide (HCTZ) rather than the longer-acting

that would not be expected to provide satisfactory reductions in urinary calcium excretion.14 A retrospective study (Figure 1) showed that patients with hypercalciuria treated with 25 mg chlorthalidone had a greater reduction in urinary calcium excretion (164 mg, 41 %) than those on HCTZ (85 mg, 21 %).15 When given at 12.5 mg once a day, neither drug significantly lowered urinary calcium excretion. The significant benefit of thiazides to increase BMD is, perhaps, not sufficiently heralded.16 Hypercalciuria has consistently been associated with reductions in BMD and increased rates of osteoporotic fractures in both men and women.17 In fact, some studies have suggested that hypercalciuria represents the result of a primary disorder of bone turnover.18 As the result of the reduction in urine calcium, or perhaps due to a direct effect on bone turnover, thiazides lead to improvements in BMD. No RCTs have been performed, but the actions of the drug support the observational studies that demonstrate

reduced fractures. Measuring BMD may often be appropriate in patients with hypercalciuria, especially in older patients. Describing the association of lower BMD and stones may be helpful in motivating even younger patients to reduce dietary sodium intake. (See the section on bisphosphonates below.) A note of caution must be put forth about the use of thiazides. While this class of drugs, when prescribed at appropriate doses, has clear cardiovascular benefits for hypertensives, that effect has not been demonstrated in stone formers, who are often younger and normotensive.19 Available data have not provided sufficient monitoring of long-term adverse effects in stone formers. Supplementation of potassium is always appropriate, as it avoids the hypocitraturia that occurs with potassium depletion (even without hypokalemia) and probably prevents reduced glucose tolerance as well. Triamterene should be avoided because it is poorly soluble and may promote calcium stone formation. Amiloride or spironolactone are acceptable alternatives as “K-sparing” diuretics.

Bisphosphonate use Given the association of hypercalciuria with low BMD, interest in the use of bisphosphonates for treatment of idiopathic hypercalciuria has grown. No RCT has been performed to demonstrate reduction of stone recurrence, but with bisphosphonate use urinary calcium excretion falls and BMD increases. This drug class is effective in genetic hypercalciuric stoneforming rats; alendronate reduced urinary calcium excretion and urinary calcium oxalate and brushite supersaturation.20 Similar data have been acquired in an RCT with humans.21 Post-menopausal osteoporotic female patients with idiopathic hypercalciuria were randomly assigned to receive either 70 mg alendronate once weekly, 2.5 mg indapamide daily, or a combination of alendronate plus indapamide at the same doses. After 12 months of therapy, there was no significant change in BMD from baseline in the indapamide group, but BMD was significantly increased in the alendronate and combination groups. All treatment groups experienced a reduction in urinary calcium excretion, with the greatest effect for both endpoints observed

6/24/13 4:54 PM

www.renalandurologynews.com july 2013

in the combination arm. Whether the findings can be generalized to hypercalciuric men is not known. In another study that included men, the combination of 50 mg HCTZ daily and 70 mg alendronate each week was more effective than alendronate alone in reducing urine calcium excretion and increasing BMD in hypercalciuric stone-formers with osteopenia or osteoporosis. 22 From these data, one can conclude that bisphosphonates are likely beneficial in hypercalciuric patients with maximal benefit when used in combination with thiazides. These data are particularly important given that the Women’s Health Initiative demonstrated a small absolute increased risk of kidney stones without significant increases in BMD as the result of calcium and vitamin D supplementation.23

Hyperuricosuria and calculi formation Hyperuricosuria has long been thought to be a risk factor promoting calcium stone formation. While the original hypothesis was that monosodium urate crystals served as a nucleus for calcium oxalate crystal formation, the rarity of urate crystals in urine and the failure to identify them in calcium oxalate stones led to the current hypothesis that uric acid instead “salts out,” or reduces the solubility of, calcium oxalate.15 Whatever the chemical interaction, the association was supported by an RCT in which 100 mg allopurinol three times a day reduced stone recurrence at three years compared with placebo.16 Participants were calcium stone formers with 24-hour uric acid excretion of 800 mg/day in men and 750 mg/day in women; patients with hypercalciuria were excluded. The epidemiologic data have not been entirely supportive of the effect. In the Nurses’ Health Study (NHS) 1 and 2, and the Health Professionals Follow-Up Study (HPFS), higher 24-hour uric acid excretion was not associated with a greater risk for stone formation. In fact, the relative risk for stones was inversely associated with 24-hour uric acid in HPFS.17 Earlier smaller studies that first suggested that uricosuria was a risk factor for calcium stones were not prospective. It has been suggested that allopurinol’s ability to prevent calcium stones could be related to some other effect

RUN0713_CME.Goldfarb_alt.indd 35

not directly related to the lowering of uric acid excretion.17 For instance, allopurinol has antioxidant properties and promotes endothelial function.18 Despite the uncertainty about how, or if, uric acid promotes calcium stones, there is a further need for studies, and we designed a trial of febuxostat, analogous to the earlier study of allopurinol.24 Febuxostat is a non-purine analog that also inhibits xanthine oxidoreductase and predominantly undergoes hepatic metabolism. In recurrent stone formers with hyperuricosuria (>700 mg/day) and a radio-opaque stone seen on computed tomography scans, we randomized patients to 300 mg allopurinol once a day, 80 mg febuxostat once a day, or placebo. Patients with hypercalciuria were not excluded. The primary outcome is reduction in 24-hour urinary uric acid excretion after six months of therapy. The duration of follow up will be too short to demonstrate an effect of the drugs on stone growth or recurrence. Although higher doses of allopurinol would probably further reduce 24-hour uric acid excretion, we used the dose previously shown to be effective and the one most commonly prescribed for stones or gout. We hope to replicate this study design for a longer duration to test for effects on stone recurrence.

Calcium phosphate stones While kidney stones composed predominantly of calcium phosphate are less than 10 % of total stones, the importance of this compound arises from the recent findings that calcium phosphate appears to be an initiator of calcium oxalate stones.25 Randall plaque is an amorphous apatite that ruptures from its site of growth in the papillary interstitium through the papillary urothelium into the urinary space.25 Calcium oxalate then nucleates around the ruptured plaque and grows into a kidney stone. Most calcium phosphate stones are reported by labs as hydroxyapatite, the same crystal phase seen in bone. Many of these stones probably start as brushite, a relatively unstable phase of calcium phosphate that may convert in vivo to hydroxyapatite. Urinary conditions that favor the formation of calcium phosphate stones are the combination of hypercalciuria and

hypocitraturia in alkaline urine. At a higher pH, monobasic phosphate gives up a proton and becomes dibasic phosphate, which is more prone to combine with the divalent cation calcium and precipitate. Patients with calcium phosphate stones should be evaluated for hyperparathyroidism and distal renal tubular acidosis (RTA). While incomplete RTA may also be a risk factor for calcium phosphate stones, testing for it has not been shown to lead to better results than if hypocitraturia is treated with citrate supplementation, regardless of the results of urine pH responses to acid loads.26 If the stone is composed of the calcium phosphate crystal phases carbonate apatite or struvite, urinary tract infection should be ruled out. High quality clinical trials to address the prevention of calcium phosphate stones are lacking. Clinicians usually apply a similar preventive approach to treat calcium phosphate stones and calcium oxalate stones. The approach includes increased water intake to 3L per day, dietary changes and pharmacologic agents (Table 1). The recent finding that urinary calcium is highest after dinner and urine volume lowest during sleep (combining to yield significant nocturnal supersaturation) emphasizes the need for fluid intake at bedtime.27 This suggestion is not specific to stone composition. The optimal diet for the prevention of calcium phosphate stones has not been established. Each patient should have 24-hour urinary collections with subsequent dietary modification targeted to specific issues. Perhaps most important for calcium phosphate

Renal & Urology News 35

stones, a decrease in dietary sodium intake is associated with reduction of urinary calcium excretion. Decreased animal protein consumption leads to increased urinary citrate. Adherents of the DASH (Dietary Approaches to Stop Hypertension) diet have fewer stones and the effect might apply to calcium phosphate stones, though the diet has never been assigned to test its efficacy for that purpose.28 Higher calcium diets have not been studied for calcium phosphate stones specifically. Therefore, patients who form calcium phosphate stones are recommended a low salt, moderate animal-protein diet. Pharmacologic therapy should be guided by the findings of the 24-hour urine collection. Controversy arises regarding citrate supplementation.29 Citrate is an inhibitor of calcium stone formation, whether oxalate or phosphate, but its metabolism causes consumption of a proton and alkalinization of the urine. The increased urine pH increases the supersaturation of calcium phosphate and potentially promotes calcium phosphate stones. However, it is not inevitable stones will recur if patients increase their fluid intake, experience a small decrease in urinary calcium due to the effects of alkali on bones and renal calcium transport, and have increased urinary citrate excretion. The net effect of citrate supplementation in calcium phosphate stone formers has not been studied, although non-randomized studies claim benefit in patients with RTA.30 Potassium citrate is preferred over sodium citrate to decrease the effect of sodium on calcium excretion. The role of thiazides in calcium

Hyperuricosuria is thought to be a risk factor promoting calcium oxalate stone formation (magnification 5X).

6/24/13 4:54 PM

36 Renal & Urology News

july 2013 www.renalandurologynews.com

CME feature Table 1. Prevention of Calcium Phosphate Stones 29 Implement 1, 2 and 3 either sequentially or simultaneously, depending on patient preferences 1. Increase total fluid intake to 3L to increase urine output to 2.5L per day 2. Modify diet: • Prescribe diet based on 24-hour urine chemistry • Limit sodium intake to 100 meq (about 2g) per day to reduce urinary calcium excretion • Limit oxalate intake if calcium oxalate is a stone component –– Refer patients to https://regepi.bwh.harvard.edu/health/Oxalate/files • Moderate protein intake to 1.2 g/kg per day • Moderate dairy intake, especially for calcium oxalate component • Consider DASH diet –– Refer patients to http://www.nhlbi.nih.gov/health/public/heart/hbp/ dash/new_dash.pdf 3. Pharmacologic therapy (prescribe and judge efficacy based on 24-hour urine response): • Thiazides; even if only moderate calcium excretion –– Chlorthalidone 25-50 mg per day –– Indapamide 2.5-5.0 mg per day –– Hydrochlorothiazide 25-50 mg twice a day • Amiloride 5-10 mg twice a day or potassium chloride 20-40 meq to accompany thiazides and avoid K depletion and hypocitraturia • Or potassium citrate 20-60 meq in divided doses especially if hypocitraturia is present

oxalate stones has been well established, but none of the studies specifically examined calcium phosphate stone formers. Nonetheless, treating calcium phosphate stone formers with thiazides makes sense and may allay worries about citrate use, especially if urine calcium falls in response to the effects of alkali on bone turnover and renal calcium reabsorption.

Uric acid stones The most prevalent urinary abnormality causing uric acid stones is low urine pH.31 Uric acid is a weak organic acid with pKa 5.35 at 370C. In acidic urine, its solubility decreases dramatically. The urine then becomes supersaturated with uric acid and stones result. At urine pH 5.3, uric acid solubility is 200 mg/L; at a pH of 6.5 more than 1,200 mg/L of uric acid can be present without reaching supersaturation. The majority of patients with idiopathic uric acid stones have normal uric acid excretion with low urine pH. The etiology of “unduly acidic urine” is not completely understood. Recent epidemiologic, metabolic, and physiologic studies have linked insulin resistance to low urinary pH. Urine pH is inversely correlated with BMI and insulin resistance.32,33 Insulin stimulates ammoniagenesis in renal tubular cells and sodium/hydrogen exchange in the

RUN0713_CME.Goldfarb_alt.indd 36

proximal tubule. The insulin resistance then impairs ammoniagenesis resulting in excessive unbuffered protons in the distal tubule and a low urine pH. There is also evidence that patients with metabolic syndrome have increased net acid excretion, further contributing to a more acidic urine.34 Urinary alkalinization is the mainstay of treatment for patients with uric acid stones with or without hyperuricosuria. There are no RCTs evaluating the efficacy of treatment, but the effects are so obvious in practice that RCTs seem superfluous. Urinary alkalinization with potassium citrate is usually used as first-line treatment of uric acid stones. The xanthine oxidoreductase inhibitors allopurinol and febuxostat are unlikely to offer benefit if urine pH is not increased and are reserved for patients who have stones despite adequate alkalinization or are difficult to alkalinize such as those with bowel disease. The starting dose of potassium citrate is from 20-40 meq per day in divided doses. The goal is to keep urine pH greater than 6.0. Urine pH testing can be useful; we ask patients to measure urine pH once a day at varying times. Inexpensive pH testing paper can be obtained from Microessential Laboratory (Available at https://www .microessentiallab.com, item #067). In case of reduced glomerular filtration

rate or hyperkalemia, sodium citrate or bicarbonate are reasonable alternatives. After stones are removed or dissolved, either of these compounds taken once daily, usually after dinner or at bedtime, may suffice for uric acid stone prevention.35 There are no data regarding the optimal dosing and frequency of alkali administration.

Summary Kidney stone prevention is often neglected, and deserves more attention by nephrologists and urologists. Adequate and quantitative counseling regarding fluid intake is the first step and is effective and inexpensive. Appropriate dietary manipulations can be prescribed based on 24-hour urine collections. While dietary adherence may be difficult for many patients to achieve, medical therapies are effective and underutilized. n References 1. Obligado SH, Goldfarb DS. The association of nephrolithiasis with hypertension and obesity: A review. Am J Hypertens 2008;21:257-264. 2. Fink HA, Wilt TJ, Eidman KE, et al. Medical management to prevent recurrent nephrolithiasis in adults: A systematic review for an American College of Physicians clinical guideline. Ann Intern Med 2013;158:535-543. 3. Sumorok N, Goldfarb DS. Update on cystinuria. Curr Opin Nephrol Hypertens 2013;22:427-431. 4. Heilberg IP, Goldfarb DS. Optimum nutrition for kidney stone disease. Adv Chronic Kidney Dis 2013;20:165-174. 5. Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med 2002;346:77-84. 6. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med 1993;328:833-838. 7. Taylor EN, Curhan GC. Dietary calcium from dairy and non-dairy sources and risk of symptomatic kidney stones. J Urol 2013 Published online ahead of print). 8. Taylor EN, Stampfer MJ, Curhan GC. Obesity, weight gain, and the risk of kidney stones. JAMA 2005;293:455-462. 9. Borghi L, Meschi T, Amato F, et al. Urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: A 5-year randomized prospective study. J Urol 1996;155:839-843. 10. Lotan Y, Buendia Jimenez I, Lenoir-Wijnkoop I, et al. Increased water intake as a prevention strategy for recurrent urolithiasis: Major impact of compliance on cost-effectiveness. J Urol 2013;189:935-939. 11. Pearle MS, Roehrborn CG, Pak CY. Meta-analysis of randomized trials for medical prevention of calcium oxalate nephrolithiasis. J Endourol 1999;13:679-685. 12. Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Twenty-four-hour urine chemistries and the risk of kidney stones among women and men. Kidney Int 2001;59:2290-2298.

13. Messerli FH, Bangalore S. Half a century of hydrochlorothiazide: Facts, fads, fiction, and follies. Am J Med 2011;124:896-899. 14. Reilly RF, Peixoto AJ, Desir GV. The evidence-based use of thiazide diuretics in hypertension and nephrolithiasis. Clin J Am Soc Nephrol 2010;5:1893-1903. 15. Wolfgram DF, Gundu V, Astor BC, Jhagroo RA. Hydrochlorothiazide compared to chlorthalidone in reduction of urinary calcium in patients with kidney stones. Urolithiasis 2013; Published online ahead of print. 16. Adams JS, Song CF, Kantorovich V. Rapid recovery of bone mass in hypercalciuric, osteoporotic men treated with hydrochlorothiazide. Ann Intern Med 1999;130:658-660. 17. Asplin JR, Bauer KA, Kinder J, et al. Bone mineral density and urine calcium excretion among subjects with and without nephrolithiasis. Kidney Int 2003;63:662-669. 18. Heilberg IP, Weisinger JR. Bone disease in idiopathic hypercalciuria. Curr Opin Nephrol Hypertens 2006;15:394-402. 19. Huen SC, Goldfarb DS. Adverse metabolic side effects of thiazides: Implications for patients with calcium nephrolithiasis. J Urol 2007;177:1238-1243. 20. Bushinsky DA, Neumann KJ, Asplin J, Krieger NS. Alendronate decreases urine calcium and supersaturation in genetic hypercalciuric rats. Kidney Int 1999;55:234-243. 21. Giusti A, Barone A, Pioli G, et al. Alendronate and indapamide alone or in combination in the management of hypercalciuria associated with osteoporosis: A randomized controlled trial of two drugs and three treatments. Nephrol Dial Transplant 2009;24:1472-1477. 22. Arrabal-Polo MA, Arias-Santiago S, de Haro-Munoz T, et al. Effects of aminobisphosphonates and thiazides in patients with osteopenia/osteoporosis, hypercalciuria, and recurring renal calcium lithiasis. Urology 2013;81:731-737. 23. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-683. 24. Goldfarb DS. Potential pharmacologic treatments for cystinuria and for calcium stones associated with hyperuricosuria. Clin J Am Soc Nephrol 2011;6:2093-2097. 25. Coe FL, Evan AP, Worcester EM, Lingeman JE. Three pathways for human kidney stone formation. Urol Res 2010;38:147-160. 26. Arampatzis S, Ropke-Rieben B, Lippuner K, Hess B. Prevalence and densitometric characteristics of incomplete distal renal tubular acidosis in men with recurrent calcium nephrolithiasis. Urol Res 2012;40:53-59. 27. Bergsland KJ, Coe FL, Gillen DL, Worcester EM. A test of the hypothesis that the collecting duct calcium-sensing receptor limits rise of urine calcium molarity in hypercalciuric calcium kidney stone formers. Am Journal Physiol Renal Physiol 2009;297:F1017-1023. 28. Taylor EN, Fung TT, Curhan GC. DASH-style diet associates with reduced risk for kidney stones. J Am Soc Nephrol 2009;20:2253-2259. 29. Goldfarb DS. A woman with recurrent calcium phosphate kidney stones. Clin J Am Soc Nephrol 2012;7:1172-1178. 30. Preminger GM, Sakhaee K, Skurla C, Pak CY. Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis. J Urol 1985;134:20-23. 31. Maalouf NM, Cameron MA, Moe OW, Sakhaee K. Novel insights into the pathogenesis of uric acid nephrolithiasis. Curr Opin Nephrol Hypertens 2004;13:181-189. 32. Maalouf NM, Sakhaee K, Parks JH, et al. Association of urinary pH with body weight in nephrolithiasis. Kidney Int 2004;65:1422-1425. 33. Maalouf NM, Cameron MA, Moe OW, et al. Low urine pH: A novel feature of the metabolic syndrome. Clin J Am Soc Nephrol 2007;2:883-888. 34. Cameron M, Maalouf NM, Poindexter J, et al. The diurnal variation in urine acidification differs between normal individuals and uric acid stone formers. Kidney Int 2012;81:1123-1130. 35. Rodman JS. Intermittent versus continuous alkaline therapy for uric acid stones and ureteral stones of uncertain composition. Urology 2002;60:378-382.

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

6/24/13 4:54 PM

www.renalandurologynews.com july 2013

CME Post-test Expiration Date: July 2014 Medical Education Resources designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Participants should claim only the credit commensurate with the extent of their participation in the activity. Physician post-tests must be completed and submitted online. Physicians may register at no charge at www.mycme.com /renalandurologynews. You must receive a score of 70% or better to receive credit. 1. Increased amounts of dietary calcium may be protective against kidney stones because: a. Dietary calcium is accompanied by dietary base loads increasing citrate excretion. b. Dietary calcium binds intestinal oxalate and reduces its absorption and urinary excretion. c. Dairy is low in purines and therefore reduces urinary uric acid excretion. d. Repletion of vitamin D suppresses PTH and reduces calcium release by bone. 2. Hyperuricosuria promotes calcium stone formation by: a. Promoting uric acid crystals that serve as a nidus for calcium stone formation. b. Adding protons to urine to lower pH and precipitate uric acid. c. Forming monosodium urate crystals that promote nucleation of calcium oxalate crystals. d. Reducing the solubility of calcium salts. 3. The only dietary intervention that, in a randomized controlled trial, reduced stone incidence was: a. Higher calcium, less oxalate, sodium, animal protein. b. 2 liters per day of lemonade. c. Greater intake of foods high in pyridoxine. d. Reduced dairy intake. 4. The effect of thiazides on bone mineral density is to: a. Increase it due to stimulation of intestinal calcium absorption. b. Reduce it due to increase in urinary sodium and calcium excretion. c. Reduce it due to increased urine sodium excretion. d. Increase it due to reduced urinary calcium excretion. 5. Bisphosphonates could be useful for stone formers because they: a. Reduce release of calcium from bone. b. Inhibit effects of vitamin D on bone turnover. c. Increase calcium in the intestinal lumen to reduce oxalate absorption. d. Reduce release of calcium from bone. 6. Calcium phosphate stones are prevented by: a. Reducing dietary phosphate ingestion b. Parathyroidectomy c. Cinacalcet d. Thiazides and potassium citrate 7. Increases in uric acid stone prevalence occur in patients with: a. Pyrazinamide use b. Furosemide use c. Diabetes d. Chronic kidney disease 8. Prevention of uric acid stones is best accomplished by: a. Urinary alkalinization b. Increasing dietary fiber c. Allopurinol or febuxostat d. Restriction of organ meat ingestion

RUN0713_CME.Goldfarb_alt.indd 37

Renal & Urology News 37

Researcher: Turn Off Cell Phones at BP Visits Blood pressure increased in hypertensive patients who took calls prior to measurement. BY JOHN SCHIESZER SAN FRANCISCO—Hypertensive patients who take cell phone calls during blood pressure (BP) check-ups in the doctor’s office may experience significant rises in BP, according to Italian investigators. Systolic and diastolic readings may rise by 7.1 and 4.7 mm Hg, respectively, the researchers reported at the American Society of Hypertension’s 28th Annual Scientific Meeting. “The blood pressure increase we detected is not negligible from the clinical point of view,” said researcher Giuseppe Crippa, MD, a staff physician the Bravi of Guglielmo da Saliceto Hospital, Piacenza, Italy. “Large surveys have shown that a blood pressure reduction of 2 mm Hg is highly significant for the risk stratification and the prognosis of the patients. Dr. Crippa and his colleagues conducted a study with 94 mild-tomoderate hypertensive patients. The mean age of the patients was 53 years, and 49 (52%) of 94 patients were female. All the patients were taking antihypertensive medications. At the start of the study, investigators asked subjects about their habitual use of cell phones. They recorded the mean number of daily calls made, and patients’ attitudes about turning off their phones. The phone numbers of all the subjects were recorded and during one of the two consecutive visits the patient’s mobile phone number was dialed three times by one of the investigators. The phone showed that the person calling was unknown. This part of the test was considered complete if the subject answered and spoke on at least one of the three phone calls made by the investigator. Dr. Crippa said all the subjects were randomly assigned to receive phone calls during the first or the second series of automated measurements. In each of these series of automated measurements, an initial BP reading

was recorded. The subjects would remain alone and seated in a comfortable armchair in the consulting room. The investigators then obtained the mean systolic and diastolic pressure readings and heart rate with and without phone calls. The study showed that the systolic pressure rise was less drastic in patients who were used to participating in more than 30 phone calls per day. There may be two possible reasons for this, he said. First, the patients who were more accustomed to cell phone use were younger, and younger people may be less prone to be disturbed by telephone intrusions. Second, it is possible that people who make more than 30 calls per day may feel more reassured if the mobile phone is activated. An optimal BP reading is below 120/80 mm Hg, so it is possible that a temporary increase of 7/5 mm Hg is not harmful for normotensive subjects, he said. “Conversely, an even mild increase in blood pressure in patients with blood pressure levels above 140/90 mm Hg should be considered a negative,” he said. The use of mobile phones has grown exponentially, and the devices are fast becoming an indispensable communication tool for business and social relations, he said. However, the study suggests that turning cell phones off at a doctor’s visit may be advisable because taking cell phone calls shortly before having a BP reading may lead to less-than-optimal measurements. “This phenomenon might lead to misinterpretation and overestimation of the patients’ real blood pressure s tatus,” Dr. Crippa told Renal & Urology News. “The great majority of the patients recruited for the study was not used to turning off the mobile phone during a medical examination and easily answered the calls. We believe that it is important to advise all patients to turn off their phone before entering the doctor’s office.” n

6/24/13 4:55 PM