Renal & Urology News April 2013 Issue by Haymarket Media

CONVENTIO N ISSUE

APRIL 2013

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VOLUME 12, ISSUE NUMBER 4

Surgery Decreases RCC Death Risk The benefit is limited to patients younger than 75

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Cancer-Specific Mortality by Management Approach New findings suggest that patients with low-risk renal tumors have better odds of cancerspecific survival if they undergo either partial nephrectomy (PN) or radical nephrectomy (RN) rather than non-surgical management (NSM). The five- and eight-year cancer-specific mortality (CSM) rates with each approach are shown here. 12 10 8 6

BY JODY A. CHARNOW MILAN—Partial or radical nephrectomy is associated with a significant cancerspecific survival advantage over the nonsurgical management (NSM) of localized kidney cancer among patients younger than 75 years, according to findings presented at the 28th annual congress of the European Association of Urology. The protective effect of immediate surgery, however, needs to be weighed against the risk of death from other causes, said Maxine Sun, PhD, of the University of Montreal Health Center, the study’s lead investigator.

IN THIS ISSUE 4

RCC prevalence higher in dialysis patients

Bladder cancer in the elderly may be undertreated

Urate-lowering in patients with hyperuricemia

Non-bone mCRPC metastases on the rise

AKI risk linked to excessive body fat in trauma patients

Leptin changes (shown here) appear to be most strongly influenced by body mass index. PAGE 17

Using data from the Surveillance, Epidemiology and End Results (SEER)– Medicare linked database, Dr. Sun and her colleagues studied an observational cohort of 10,595 patients with clinically node-negative T1 renal cell carcinoma (RCC) treated with nephrectomy or NSM from 1988 to 2005. Compared with patients treated with NSM, those treated with partial nephrectomy (PN) or radical nephrectomy (RN) had a significant 55% and 42% decreased risk of cancer-specific mortality (CSM), Dr. Sun reported. In the subset of 6,443 patients with T1a RCC, the reduction in CSM

Nondialytic ESRD Care Underused BY JOHN SCHIESZER SEATTLE—Nondialytic therapy (NDT) for selected elderly patients with end-stage renal disease (ESRD) is growing in popularity in the United Kingdom and Europe, but it is rarely used in the U.S., according to a study presented at the 33rd Annual Dialysis Conference. Investigators believe the use of NDT for elderly ESRD patients in the U.S. should be reappraised. “This study was carried out because all around the world, particularly in Europe and the United Kingdom, there has been this movement to assess patient outcomes with dialytic continued on page 5

4 2 0

NSM 10.2%

RN 6.7%

PN 3.1%

NSM 11.7%

Five-Year CSM

RN 8.8%

PN 4.9%

Eight-Year CSM

Source: Sun M, et al. Nephrectomy vs. active surveillance for small renal masses: Cancer-specific mortality and competingrisks of death. Presented at the 28th annual congress of the European Association of Urology in Milan, Italy. Poster 179.

risk was 59% and 53% for PN and RN, respectively. The five- and eight-year CSM rates for the overall cohort were 10.2% and 11.7%, respectively, for NSM, 6.7% and 8.8% for

RN, 3.1%, and 4.9% for PN. For patients with T1a RCC, the CSM rates were 7.4% and 8.5%, for NSM, 4.5% and 5.7% for RN, and 2.6% and 4.7% for PN. continued on page 5

Non-Curative Care Raises PCSM BY JODY A. CHARNOW NON-CURATIVE initial management of “low-risk” prostate cancer (PCa) in older men is associated with an increased risk of prostate cancer-specific mortality (PCSM) compared with those who undergo curative treatment, according to recently published findings. Ayal A. Aizer, MD, of the Harvard Radiation Oncology Program in Boston, and collaborators studied a cohort of 27,969 men with PSA-detected lowrisk PCa identified by the Surveillance, Epidemiology and End Results (SEER) program from 2004 to 2007. After a median follow-up of 2.75 years, 1,121 patients died, 60 (5.4%) from PCa. In

CME FEATURE

adjusted analyses, non-curative treatment was associated with a significant 3.3-fold increased risk of PCSM, Dr. Aizer’s group reported online ahead of print in BJU International. Each one-year increment in age was associated with a significant 5% increased risk of PCSM. Men older than the median age (67 years) experienced increased estimates of PCSM when treated with non-curative as opposed to curative intent; this finding was not observed in men at or below the median age. Among men older than 67, the three-year estimates of PCSM in those managed with curacontinued on page 5

Earn 1 CME credit in this issue

Adrenal Masses: Often Incidental, Not Always Insignificant PAGE 29

4 Renal & Urology News

Table 1 Incidence of Adverse Events Occurring in â&#x2030;Ľ5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Hypertension Anorexia Bone pain Upper respiratory tract infection Insomnia Musculoskeletal chest pain Cough Neck pain Weight decreased Urinary tract infection Rash Sweating Tremor

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

Grade 3-5 n (%)

45 (7.5)

14 (4.6)

22 (7.3)

37 (6.2)

22 (7.3) 23 (7.6)

34 (5.7) 34 (5.7) 33 (5.5) 31 (5.2)

17 (5.6) 14 (4.6)

*Control was non-activated autologous peripheral blood mononuclear cells.

Cerebrovascular Events. In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were reported in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group. (See Adverse Reactions [6] of full Prescribing Information.)

To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dendreon Corporation Seattle, Washington 98101

REFERENCES: 1. 3529(1*( >SDFNDJH LQVHUW@ 'HQGUHRQ &RUSRUDWLRQ -XQH 2. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med

APRIL 2013

RCC More Common In Dialysis Patients BY JOHN SCHIESZER SEATTLEâ&#x20AC;&#x201D;Patients with end-stage renal disease (ESRD) have an 0.5% prevalence of renal cell carcinoma (RCC), according to findings presented at the 33rd Annual Dialysis Conference. The findings, reported by researchers from Kaiser Permanente Northern California, emerged from a study of 6,827 ESRD patients undergoing dialysis from 1999-2008. â&#x20AC;&#x153;The prevalence of RCC in Kaiser Permanent Northern California was 0.5% during the past decade, similar to the previously reported prevalence rate for prevalent dialysis patients, but higher than the reported prevalence in the general population,â&#x20AC;? said study investigator Sijie Zheng, MD, PhD, an attending physician at The Permanente Medical Group, Kaiser Oakland Medical Center, Oakland, Calif. Study subjects were aged 18-80 years at dialysis initiation and had been on dialysis for at least six months. Investigators retrospectively followed up patients until their death or the end of the study period. Of the 6,827 patients, 163 were diagnosed with a renal mass or RCC. The majority of the RCC cases were low grade and 30% of them were detected incidentally. Patients who had a bilateral nephrectomy prior to starting dialysis were excluded, as were those diagnosed with RCC before dialysis initiation, and those who lacked a biopsy. Biopsy-proven

RCC was found in 35 patients (0.5%). The annual RCC incidence ranged from 0.3% to 0.8%. Dr. Zhengâ&#x20AC;&#x2122;s team had expected to find a higher prevalence of RCC, but noted that the 0.5% prevalence was similar to what had been reported in dialysis patients early in the last decade. Since then, few studies have re-examined the prevalence and incidence of RCC in ESRD patients.

The average time from dialysis start to RCC diagnosis was 3.4 years. Of the 35 subjects with RCC, 13 (37%) were women, 11 (31%) were black, 11 (31%) were Hispanic, nine (26%) were white, and four (11%) were Asian. The average time from dialysis start to RCC diagnosis was 3.4 years and nearly 30% of cases were detected incidentally as a result of a computed tomography scan for unrelated reasons. More than two-thirds of the patients were on hemodialysis (HD) at the time of diagnosis; the other patients utilized both peritoneal dialysis and HD as their renal replacement modality. During the study period, 12 patients died and the median duration between nephrectomy and death was eight months. â&#x2013;

Bladder Cancer May Be Undertreated, Study Finds BLADDER CANCER in elderly and female

The five-year bladder cancer mortality

patients may not be treated adequately,

rate ranged from 1% to 59% and the

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other-cause mortality rate ranged from

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6% to 90%, depending mainly on the

of the University of Sheffield in

tumor type and patient age. The oldest

Sheffield, U.K., identified 3,281 patients

patient groups had the highest cancer-

from a population-based cancer registry

specific mortality. In addition, only 12%

diagnosed with bladder cancer from

of patients older than 80 years received

1994 to 2009. The study group had a

radical treatment for invasive cancer

median follow-up of 48 months. At five

compared with 52% of those younger

years after their diagnosis, 1,246 pa-

than 60 years, a significant difference

tients (40%) had died: 617 (18.8) from

between the age groups. Female pa-

bladder cancer and 629 (19%) from

tients with high-risk non-muscle invasive

other causes, the investigators

tumors were more likely to die from the

reported online ahead of print in the

malignancy disease compared with their

British Journal of Cancer.

male counterparts. â&#x2013;

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Nondialytic ESRD care continued from page 1

therapy compared to NDT for older patients approaching ESRD, and at least some data suggest that patient outcomes with respect to quality of life was better with NDT, even though older patients on dialysis may live longer,” said study investigator Macaulay Onuigbo MD, FASN, MBA, Associate Professor of Medicine at the Mayo Clinic in Rochester, Minn., and Attending Nephrologist/Hypertension Specialist/ Transplant Nephrologist, Mayo Health Clinic System, Eau Claire, Wis. Dr. Onuigbo and his colleagues analyzed a Northwestern Wisconsin Mayo Clinic dialysis population for recent NDT activity. The analysis focused on 166 ESRD patients, of whom 82 (49%) were age 70 or older. A total 46 patients were aged 70-79 years and 36 were aged 80-89. The vast majority of these patients had extensive and significant multiple comorbidities, but NDT use was virtually nonexistent. “From anecdotal experience and evidence, we were not surprised at all by our finding of almost absence of the practice of NDT,” Dr. Onuigbo told Renal & Urology News. “The older patients tended to have a poorer quality of life with multiple procedures and multiple hospital admissions. The older patient who approaches ESRD gradually and with a significant load of medical comorbidities could indeed be very actively managed in a multidisciplinary team to take care of symptoms, anemia, volume control, hyperphosphatemia and hyperparathyroidism, hypertension, etc., adequately without the need for dialytic therapy.”

Surgery/RCC death risk continued from page 1

Among patients aged 75 years and older, CSM did not differ significantly between patients who had nephrectomy or NSM. “The current findings of this study show that it’s very important to adequately select surgical candidates, as our results show that some of these patients do not live long enough to benefit from surgery,” said Dr. Sun, who added that clinicians still face the dilemma of being unable to differentiate aggressive from nonaggressive tumors. At the recent 2013 Genitourinary Cancers Symposium, William C. Huang, MD, and colleagues reported on a study showing that surveillance for renal masses smaller than 4 cm was associated with a significant 16% decreased risk of death

Elderly patients managed with NDT have outcomes and overall survival similar to their counterparts treated with dialysis, but with a better quality of life that includes fewer hospitalizations, Dr. Onuigbo said. “Nephrology fellowship curricula have yet to address this important issue,” he said. “As a result, most nephrologists, as with most other physician groups in the U.S., have struggled with end-of-life care decisions and as a result physician counseling of patients and families on medical decision making often leaves a lot to desire.” Additionally, practices may be financially motivated to steer patients to dialysis and patients and families may have exaggerated expectations as to what dialysis can achieve for elderly ESRD patients with multiple comorbidities, Dr. Onuigbo said. He noted that the phenomenon of “technological imperative” tends to drive medicine much more in the U.S. than anywhere else in the world. NDT should be seen as another active management paradigm and an alternative to dialytic therapy in a specific group of older ESRD patients, he said. This form of conservative management should not be seen as “no dialysis” alone, but as an active medical management without dialysis. Clinicians should take into account morbidity scores, anticipated life expectancy, and functional capacity of the patient, he said. Chronological age should not be the only factor considered. “The use of therapies in a rational and appropriate fashion must be distinguished from rationing,” Dr. Onuigbo said. ■

from any cause, but that cancer-specific survival did not differ by management approach. The study also found that surveillance was associated with a significantly lower risk of cardiovascular events over time. Alexander Kutikov, MD, Associate Professor of Urologic Oncology at Temple University’s Fox Chase Cancer Center in Philadelphia, noted that “we must await publication of finalized manuscripts from each group to make meaningful comparisons between the two studies.” He warned, however, that the data from these studies “must be interpreted with extreme caution because a ‘no treatment’ group in an administrative dataset such as SEER cannot be equated to cohorts on active surveillance in modern urologic practice.” This is underscored by the fact that more than 30% of patients in each study were on so-called “active surveillance.” ■

Non-curative care/PCSM continued from page 1

tive versus non-curative approaches were 0.17% and 0.76, a significant difference between the management approaches. Among men aged 67 years or younger, the three-year estimates of CPSM in those managed with curative versus non-curative approaches, respectively, were 0.13% and 0.18%, a non-significant difference. The clinical significance of the study’s findings is that older men with “lowrisk” PCa may harbor occult high-grade disease that can be missed because of prostate biopsy sampling error despite extended biopsy, “placing them at increased risk of PCSM within a few years of the diagnosis when non-curative treatments such as active surveillance are used initially,” the researchers wrote. Additionally, the authors noted that a possible explanation for the association between increasing age and PCSM risk may be derived from the established relationship between older age and high-grade disease. PCa undergrading due to limitations in

Older men with low-risk PCa may harbor occult high-grade disease. current biopsy techniques “may, therefore, be particularly consequential in older men, in whom undergrading is known to be more common owing to increasing gland volume coupled with increasing prevalence of BPH [benign prostate hyperplasia].” The new findings contrast with those of the randomized Prostate Cancer Intervention versus Observation Trial (PIVOT), whose results were published last year in The New England Journal of Medicine (2012;367:203-213). In PIVOT, researchers compared the effectiveness of radical prostatectomy (RP) versus observation in a group of 731 men with localized PCa. During a median follow-up of 10 years, 21 of 364 (5.8%) assigned to RP and 31 of 367 (8.4%) assigned to observation died from PCa, a non-significant difference between study arms. Dr. Aizer’s group said their study, which had 27,969 patients, had greater power to detect a difference in PCSM than did PIVOT. Moreover, in PIVOT, approximately 20% of patients in the observation arm received definitive treatment, and the analysis was per-

APRIL 2013

Renal & Urology News 5

formed using intention-to-treat, Dr. Aizer and his colleagues pointed out. “Although analysis by intention-totreat is most appropriate for a randomized trial given that randomization is preserved, such an approach further compromises the power of the study to detect a difference in PCSM.” Ian M. Thompson, MD, Professor of Urology and Chairman of the Department of Urology at the University of Texas Health Science Center in San Antonio, said that although the report by Dr. Aizer and his colleagues is intriguing, “the follow-up and numbers of deaths are far too small to reach any conclusions.” “Given what we know about prostate cancer biology,” Dr. Thompson told Renal & Urology News, “what this indicates to me was that these [60] deaths were most likely due to two possibilities, occurrences that we see occasionally and rarely.” Occasionally, a man who has had an initial biopsy finding of low-grade PCa and opts for surveillance is subsequently found on follow-up biopsy to have a dramatic increase in volume or grade of disease, which sometimes is heralded by an exponential increase in PSA. Rarely, clinicians will encounter a patient who simply has a skyrocketing PSA. “Both of these events are associated with what is referred to as an ‘interval cancer,’ or development of a very rapidly-growing tumor,” said Dr. Thompson, who also is Director of the Cancer Therapy and Research Center in San Antonio. Dr. Thompson also pointed out that the new study had the limitations inherent in any retrospective study. In SEER, he said, bias almost certainly exists in how patients were treated, “and we will never know the extent of the bias.” This treatment bias may relate to the fact that low-risk disease can encompass a wide range of biopsy findings. For example, Dr. Thompson said, one low-risk patient could have had one in 12 biopsy cores positive for cancer, with less than 5% of the core involved with Gleason 3+3 cancer and a PSA of 2.5 ng/mL, whereas another low-risk patient could have had a PSA of 9.89 and five of six cores positive with 50% or more of Gleason 3+3 cancer. Another potential bias is patient age. Younger patients, who are more likely to be treated, are far less likely to die from PCa than older patients, who are at far greater risk of having high-grade disease, he noted. Dr. Thompson stressed that researchers can never eliminate the biases of retrospective studies, and such studies cannot replace appropriately-powered clinical trials. ■

6 Renal & Urology News

APRIL 2013

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FROM THE EDITOR EDITORIAL ADVISORY BOARD

Reflections on the EAU Annual Congress

aving just returned from the always-stimulating European Association of Urology annual congress, I’d like to share a few impressions. For starters, it was interesting to see the direction in which the treatment of localized prostate cancer (PCa) surgery is likely headed. I’d like to single out a session that was devoted to focal therapy, with an emphasis on the use of magnetic resonance imaging to pinpoint the exact location of tumors and allow real-time imaging so surgeons can watch as they use various methods to destroy tumors while leaving the rest of the prostate intact. The studies presented at the session consisted of small series of patients treated with laser ablation, hemiablative brachytherapy, high-intensity focused ultrasound, cryotherapy (for salvage treatment after failed radiotherapy), and irreversible electroporation. The researchers on all of the studies reported promising results. Of course, these focal therapies need to be tested in larger numbers of patients with longer follow-ups, but I left the session with the sense that I was witnessing the beginning of what could be a fundamental shift in the surgical management of localized prostate tumors. Also evident at the meeting was the ongoing effort to fine-tune various aspects of active surveillance for low-risk PCa and small renal tumors. One study demonstrated that negative second, or confirmatory, prostate biopsies in men on active surveillance for PCa do not rule out grade progression. In a another study, British researchers found that PCa patients with a tumor visible on baseline MRI scans are more likely to experience radiologic progression while on active surveillance than those without a visible lesion. And with respect to kidney cancer, a study found that nonsurgical management of small renal tumors is associated with increased cancer-specific mortality compared with either partial or radical nephrectomy (see article on page 1). Lastly, the conference had some important new advances related to PSA screening. For example, one study demonstrated that the benefit of PSA screening in terms of PCa detection lasts for up to nine years after screening cessation. The study looked at 13,423 men in the European Randomized Study of Screening for Prostate Cancer who reached the screening upper age limit of 69 years. In 1995, 6,449 of these men had been randomized to an intervention arm (invited for biennial PSA screening) and 6,974 were in a control arm (not invited for biennial screening). (News reports on these and other studies presented at the conference are available on our website (www.renalandurologynews.com) and will appear in future issues.) All in all, it is clear from the meeting that researchers are making significant headway in the understanding of urologic diseases and their management.

Sincerely, Jody A. Charnow Editor

Medical Director, Urology

Medical Director, Nephrology

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

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

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

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

Renal & Urology News Staff Editor Executive editor Senior editor Web editor Editorial coordinator Art director Group art director, Haymarket Medical VP, audience development and operations Production assistant Group production manager Product manager, digital products Circulation manager National accounts manager Editorial director Publisher VP medical magazines and digital products CEO, Haymarket Media Inc.

Jody A. Charnow Marina Galanakis Delicia Honen Yard Stephan Cho Candy Iemma Andrew Bass Jennifer Dvoretz John Crewe Brian Wask Kathleen Millea Chris Bubeck Paul Silver William Canning Jeff Forster Dominic Barone Jim Burke Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 12, Number 4. 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.

Contents

A P R I L

2 0 1 3

■

VO L U M E

1 2 ,

I S S U E

N U M B E R

Urology 11

Prostate Cancer Risk Lower in Diabetics The protective effect of diabetes is stronger in men who do not have the metabolic syndrome.

Non-Bone PCa Metastases Increasing The trend could be related to the use of bone-targeted agents for men with metastatic castration-resistant prostate cancer.

ONLINE

Elderly Men Benefit from TRT, Study Finds Testosterone replacement therapy improved cardiovascular risk factors improved with significantly raising PSA levels in hypogonadal men aged 65 years and older.

Few Pelvic Organ Prolapse Procedures Show Edge For example, studies have not uncovered a clear advantage of anterior compartment mesh utilization over anterior repair, according to a meta-analysis.

Expert Q&A Fernando C. Fervenza, MD, PhD, of Mayo Clinic in Rochester, Minn., discusses the search for kidneysaving treatments for focal segmental glomerulosclerosis.

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 February winner: Kamyar Madani, MD

The Medical Minute Visit renalandurologynews.com /the-medical-minute/ to hear podcast reports on new studies. Our latest include: • ESRD, Atrial Fibrillation Linked in CKD Patients • ADT-Related Fracture Boosts Mortality Risk • Low Testosterone Linked to Long-Acting Opioids

News Coverage Visit our website for coverage of the National Kidney Foundation’s 2013 Spring Clinical Meetings, Orlando, Fla. (April 2-6)

“

CME Feature 29

Adrenal Masses: Often Incidental, Not Always Insignificant Alexander Kutikov, MD, Associate Professor of Urologic Oncology at Fox Chase Cancer Center, discusses adrenal imaging, tumor size and growth, adrenal biopsy, assessment of metabolic function, and adrenal mass management after initial work-up.

Nephrology 4

RCC More Common In Dialysis Patients Study of 6,827 patients reveals a 0.5% prevalence of renal cell carcinoma.

Higher Post-Nephrectomy Transfusion Rate Found Researchers report finding that 18.1% of patients undergoing nephrectomy required a perioperative blood transfusion, which is more frequent that previously appreciated in general clinical practice.

PD Exit-Site Infections Raise Peritonitis Risk Patients who experienced an exit-site infection caused by gram-positive bacteria had a significant 75% increased risk for peritonitis. Uric Acid and the Kidney – Is There a Role for Urate Lowering? Daniel E. Weiner, MD, MS, FNKF, states that hyperuricemia is a readily modifiable risk factor treatable with lifestyle changes and medications.

“

this month at renalandurologynews.com

Our findings emphasize the critical importance

of sugar metabolism to the cancer cell, providing a clinical corollary to laboratory data. See our story on page 11

Departments 6

From the Editor On the EAU congress

News in Brief Obesity ups prostate volume growth

Renal Nutrition Update BMI vs. leptin as a nutritional outcome measure

Practice Management How to improve doctor’s office productivity

Legal Issues in Medicine Urologist sued after ignoring pathologist report

Your Money Stocks will do well in the future, analysts say

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APRIL 2013

Renal & Urology News 9

Higher Post-Nephrectomy Transfusion Rate Found BLOOD TRANSFUSIONS after nephrectomy for renal masses may occur more frequently in general clinical practice than previously appreciated, according to researchers. In a population-based study of 10,902 patients, the investigators found that 18.1% of patients overall required a perioperative blood transfusion (PBT), with the rate varying by type of procedure. Older patients and those with greater comorbidities had a greater likelihood of requiring a PBT, whereas those operated on by high-volume surgeons and high-volume hospitals had a decreased likelihood of requiring a PBT, investigators led by Robert Abouassaly, MD, of University Hospitals Case Medical Center in Cleveland, reported online ahead of print in BJU International. “Patient and provider factors appear to contribute to the considerable variability that exists in the observed transfusion rate,” they concluded.

decreased likelihood of PBT, compared with ORN. Gender and year of surgery were not associated with transfusion risk. Dr. Abouassaly’s group noted that the actual transfusion rate of 28.2% for ORN patients was unexpected because

this is much higher than the rate found in previous studies. For example, in a study published by Wooju Jeong, MD, and colleagues in Urology (2011;77:819824) that compared LRN and ORN for clinical stage T2 or lower renal cell carcinoma, the reported rates of blood trans-

fusion for ORN and LRN were 4.3% and 3.6%, respectively. Dr. Abouassaly and his colleagues noted, however, that 88% of these tumors were stage pT1a or pT1b, which may have contributed to the lower rate of blood transfusion compared with their study. ■

INHIBIT ANDROGEN PRODUCTION

Transfusion risk was lower among high-volume surgeons and hospitals. They also noted: “A more detailed understanding of these factors may help with respect to preoperative patient counseling and informed consent.” The PBT rate after open radical nephrectomy (ORN), open partial nephrectomy (OPN), laparoscopic radical nephrectomy (LRN), and laparoscopic partial nephrectomy (LPN) were 28.2%, 12.7%, 9.2%, and 8.6%, respectively. The rates for patients younger than 50 years or who had a Charlson score of 0 were 11.2% and 14.5%, respectively, whereas the rates for patients aged 80 and older or who had Charlson scores of 3 or higher were 28.2% and 40.7%, respectively. After adjusting for multiple variables, patients aged 70-80, 60-69, and 50-59 had a 2.5, 2.1, and 1.5 times increased likelihood of requiring a transfusion compared with patients younger than 50 years. A Charlson score of 3 was associated with a 3.5-fold increased likelihood of PBT compared with a Charlson score of 0. PN was associated with a 46% decreased likelihood of transfusion compared with RN. LRN, OPN, and LPN were asso ciated with a 75%, 62%, and 76%

BLOCK THE ANDROGEN RECEPTOR

Learn more at inhibitandrogen.com/distinct *Other treatment options may also be considered. References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN ®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 10/12 K08Z12191BR1

10 Renal & Urology News

APRIL 2013

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

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lead to such complications as

the bone marrow avoids problems

simple lung ultrasound can detect asymptomatic pulmonary congestion in patients undergoing hemodialysis, with ultrasound B-lines score (BL-US) serving as a strong, independent predictor of death and cardiac events, according to an online report in the Journal of the American Society of Nephrology. After performing lung ultrasound in 392 dialysis patients, Carmine Zoccali, MD, of Ospedali Riuniti, Reggio Calabria, Italy, and colleagues found very severe lung congestion in 14% of the subjects and moderate-to-severe congestion in 45% (71% of the latter group was asymptomatic). Over a two-year follow-up, patients with very severe congestion had a 4.2-fold increased risk of death and a 3.2-fold increased risk of cardiac events compared with dialysis patients with mild or no congestion. Including the degree of pulmonary congestion in the model significantly improved the risk reclassification for cardiac events, by 10%.

electrolyte imbalance and bladder

Eun Bong Lee, MD, PhD, and colleagues at Seoul National Univer-

cancer, investigators reported

sity College of Medicine, enrolled 94

in the Proceedings of the

patients who experienced allopurinol-in-

National Academy of Sciences

duced AEs and 378 controls randomly

(2013;110:4003-4008).

chosen from 1,934 patients who used In multivariate analysis, colchicine

IV Hydroxyethyl Starch Increases Renal Risks

or statin use was associated with a

A meta-analysis of 31 trials comparing

threefold and twofold increased risk of

the use of intravenous hydroxyethyl

allopurinol-related AEs, respectively,

starch with other resuscitation

according to an online report in The

fluids in critically ill patients receiving

Journal of Clinical Pharmacology.

acute volume resuscitation found

allopurinol but did not experience AEs.

that hydroxyethyl starch was associ-

Bone Marrow Cells Aid Bladder Regeneration

ated with a 32% increased relative risk

Autologous bone marrow cells

and a 27% and 9% increased relative

are being used to recreate the

risk of renal failure and death, respec-

smooth muscle, vasculature, and

tively. Ryan Zarychanski, MD, MSc, of

nerve tissue of the urinary bladder

the University of Manitoba, Canada,

in end-stage neurogenic bladder

and colleagues concluded in JAMA

disease suffered by spina bifida

that due to serious safety concerns,

patients who are serving as a

use of hydroxyethyl starch for acute

proof-of-concept model. Employing

volume resuscitation is not warranted.

of requiring renal replacement therapy

In a recent online poll, Renal & Urology News asked urologists and nephrologists, “How has the HIPAA Privacy Rule affected the care you provide patients?” Here are the results based on 147 responses.

It is a major source of hassles 46.26%

It occasionally impedes care 40.14%

It has not affected care at all 19%

besity enhances prostate volume (PV) growth and attenuates PV reduction by dutasteride, according to a study. Roberto L. Muller, MD, of Duke University Medical Center in Durham, N.C., and collaegues conducted a secondary analysis of the Reduction by Dutasteride of Prostate Cancer Events trial. Of 8,122 participants, they analyzed 71.8% and 54.5% with complete two- and four-year PV data, respectively. In multivariable analysis, men on placebo with a body mass index (BMI) of 30 kg/m2 or higher versus less than 25 had enhanced PV growth from baseline (at two years: 17% vs. 10.7%; at four years: 29.4% vs. 20.1%), the researchers reported online ahead of print in European Urology. Men on dutasteride with a BMI of 30 or higher versus less than 25 had attenuated PV reduction from baseline (at two years: −14.3% vs. −18.5%; at four years: −13.2% vs. −19.3%) and a higher likelihood of having no PV reduction.

Frequent Dialysis Ups Risk For Vascular Access Events N

HIPAA and Healthcare Delivery

Obesity Enhances Prostate Volume Growth, Data Show O

ear-daily hemodialysis (HD) increases the risk of vascular access complication, concluded a research team that conducted two separate randomized trials. In the Daily Trial, 77 of 245 patients (31%) assigned to either in-center daily HD (six times per week) or conventional HD (three times per week) for 12 months experienced vascular-access repair or losses (33 repairs and 17 losses in the daily group, compared with 17 repairs, 11 losses, and 1 hospitalization in the conventional group). Overall access-event risk was 76% higher with daily HD than with conventional delivery, researchers reported in the Journal of the American Society of Nephrology (2013;24:498–505). Similar, though statistically non-significant, trends were seen among the 87 patients in the Nocturnal Trial, who had been randomized to 12 months of home nocturnal dialysis (six nights per week) or conventional HD.

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Renal & Urology News 11

Prostate Cancer Risk Lower in Diabetic Patients BY JODY A. CHARNOW DIABETES MELLITUS (DM) may decrease of developing prostate cancer (PCa) among men with coronary heart disease, according to a new study. The prospective study, led by Yaacov Richard Lawrence, MD, Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel, included 11,541 men with coronary heart disease screened to participate in a secondary cardiac prevention trial. Investigators classified subjects into one of four groups: 6,119 with neither DM nor metabolic syndrome (MS); 3,376 with MS but not diabetes; 560 with diabetes but not MS; and 1,486 with both conditions. During a median follow-up was 12.7 years (range 0-15.7 years), 459 new cases of PCa developed. In age-adjusted analyses, DM was associated with a 46% reduced risk of PCa compared with the absence of DM, researchers reported online

on prostate biopsy compared with men without DM. Dr. Lawrence’s team pointed out that, compared with previous studies, their study included men screened at a relatively older age (meant 59 years) and followed up for a relatively longer period. As the protective effect

of diabetes was observed only after more than five years of follow up, they explained, it is possible that studying a younger cohort for a shorter period will not allow full recognition of the protective effect of diabetes. “Our findings emphasize the critical importance of sugar metabolism to the

cancer cell, providing a clinical corollary to laboratory data,” Dr. Lawrence told Renal & Urology News. “Modulation of glucose pathways is an area of very active research in cancer therapeutics. Exposing prostate cancer cells to ‘a diabetic intracellular-environment’ may be a new way to fight cancer.” ■

The association is especially strong in the absence of metabolic syndrome. ahead of print in Prostate Cancer and Prostatic Disease. In multivariate analysis, diabetes continued to be associated with a decreased risk of PCa, especially in the absence of MS. Among men who did not have MS, diabetes was associated with a significant 57% decreased risk. In the presence of MS, diabetes was associated with a nonsignficant 36% decreased risk, according to the investigtors. Dr. Lawrence’s group observed that the protective effect of diabetes started after five years of follow-up. The new study confirms the findings of a number of previous investigations, which have demonstrated an inverse relationship between diabetes and PCa development. For example, a study of 4.5 million U.S. veterans published in the International Journal of Cancer (2011;128:635643) found that DM was associated with a significant 11% decreased risk of PCa. However, some studies have yielded conflicting findings. For example, a study published last year in Prostate Cancer and Prostate Disease (2012;15:70-74) demonstrated that men with DM had a 26% increased risk of having PCa found

Androgen levels may impact antiandrogen therapy.1-3 Learn more at inhibitandrogen.com/excess References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical studies. Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed. Neural Endocrine Peptides and Receptors. New York, NY: Plenum Press; 1986:627-644.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 8/12 08Z12235A

12 Renal & Urology News

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PD Exit-Site Infections Increase Peritonitis Risk PATIENTS ON peritoneal dialysis (PD) who experience an exit-site infection (ESI) are at increased risk for peritonitis, data from a Canadian study show. The study, led by Manish M. Sood, MD, of the University of Manitoba in Winnipeg, included 962 patients who started PD from January 2000 to December 2009. During the study period, 1,002 ESI and 1,228 peritonitis episodes occurred. For the study, patients with ESI were matched to those without an ESI based on PD duration. After adjusting for gender, diabetes, and Aboriginal status, patients

who experienced an ESI caused by gram-positive bacteria had a significant 75% increased risk for peritonitis compared with patients who did not have an ESI, Dr. Sood’s group reported online ahead of print in Nephrology Dialysis Transplantation. An ESI caused by coagulase-negative Staphylococcus

or Staphylococcus aureus were associated with a significant 2.2-fold and 5.8-fold increased risk, respectively. Gram negative and culture negative infections were not associated with increased peritonitis risk. The researchers noted that the increased risk in peritonitis associated with an ESI was

present despite appropriate treatment of the ESI with antibiotics. “These results suggest that, following an ESI, patients remain at high risk for the development of peritonitis, and that further interventions, above and beyond treatment of ESI may be needed,” the authors wrote. ■

Hormonal ADT Ups MI, Stroke Risk MEN RECEIVING hormonal androgen deprivation therapy (ADT) for prostate cancer (PCa) are at increased risk for myocardial infarction and stroke, new findings suggest. In a nationwide population-based study of 31,571 PCa patients in Denmark, researchers found that, in adjusted analyses, the 9,204 patients who received hormonal ADT (either antiandrogens or gonadotropin-releasing hormone agonists) had a 31% increased risk of myocardial infarction (MI) and 19% increased risk of stroke compared with patients who did not receive ADT, according to an online report in European Urology. They observed no increased risk of either MI or stroke among the 2,060 patients who underwent orchiectomy. “Decisions about ADT should weigh improvements in cancer-specific outcome against potential increased risks for cardiovascular diseases,” the authors, led by Christina G. Jespersen, MD, of Aarhus University Hospital, concluded. Dr. Jespersen and her colleagues stated that their findings are in line with the results of other recent

Learn more at inhibitandrogen.com/sequence *Currently in the absence of published, randomized, clinical data on treatment sequencing in mCRPC posttreatment with docetaxel. mCRPC=metastatic castration-resistant prostate cancer. References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

studies. The association, they noted, “appears biologically plausible due to development of metabolic syndrome, which predisposes to development of thrombosis.” ■

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Renal & Urology News 13

Calcium Used with ADT May Worsen PCa & QA

Considering that bone loss is a known side effect of androgen-deprivation therapy (ADT) for men with prostate

cancer (PCa), it might seem logical that calcium and vitamin D supplementation would help manage this consequence. Not necessarily, explains PCa epidemiologist Gary G. Schwartz, PhD, of Wake Forest Baptist Medical Center in Winston-Salem, N.C. He and co-investigator Mridul Datta uncovered data that demonstrate such supplementation can increase the risk of cardiovascular disease and, ironically, aggressive PCa (The Oncologist 2012;17:1171–1179).

What made you start suspecting that calcium and vitamin D supplementation might actually do more harm than good in men suffering ADT-related bone loss? Dr. Schwartz: Many urologists have presumed that, with respect to PCa, dietary calcium is beneficial, or is at least benign. Conversely, many epidemiologic studies have implicated dietary calcium with an increased risk of PCa. Recent prospective studies also report an increased risk of fatal PCa for men with higher levels of calcium in blood (Cancer Epidemiol Biomarkers Prev 2012;21:1768-1773). Although the mechanisms underlying the association between calcium and PCa are incompletely understood, many cancer epidemiologists regard dietary calcium as a probable prostate carcinogen.

Do you think urologists should stop prescribing such supplementation until more studies are done? Dr. Schwartz: That’s a tough question. My guess is that, like many treatment decisions in PCa, the decision whether or not to take calcium supplements may need to be individualized based on clinical judgment and patients’ wishes.

On The Web

So calcium supplements, rather than vitamin D supplementation or a combination of the two, are the main problem? Dr. Schwartz: I do think that calcium is the culprit, since vitamin D seems to have a beneficial effect on prostate cells. However, in practice, vitamin D and calcium are often taken together. The vitamin D is probably protective—there is a wealth of papers on that one (Ann Epidemiol 2009;19:96-102).

prise. However, in my experience, the urologic community is a very pragmatic one. Thus, after the initial reaction to the finding, the response quickly became, “What do we do now?”

you noted a possible link between high intestinal absorption of calcium and PCa risk. How does this influence your interpretation of your latest findings, if at all?

You also noted that no study has tested whether calcium and/or vitamin D supplementation results in higher bone mineral density (BMD) than no supplementation for men undergoing ADT. What do you think such a study would reveal? Dr. Schwartz: I imagine that BMD loss would be greater among men who are not supplemented. My belief is based on the results of the meta-analysis reported by the U.S. Preventive Services Task Force (Ann Intern Med 2011;155:827-838). That analysis showed that combined vitamin D (300–1100 IU/day) and calcium supplementation (500–1200 mg/day) can modestly reduce fracture risk.

Dr. Schwartz: Our findings that men who, genetically, are good calcium absorbers have an increased risk of PCa increases my belief in the validity of studies showing that dietary calcium increases the risk of PCa. This is because it provides a plausible mechanism whereby dietary calcium could affect PCa cells. However, those findings have had little direct influence on my interpretation of the present results. There are two steps in interpreting the results we summarized on the effect of calcium supplements on BMD. First, is there a benefit? And second, does the benefit outweigh the risks? Because there was no obvious benefit, the appreciation of the risks becomes more salient.

In two recent studies (J Bone Min Res 2012;27:187-194 and Cancer Epidemiol Biomarkers Prev; 2012; published online ahead of print),

Does dietary intake of calcium and/or vitamin D pose the same dangers as supplementation for men on ADT? Dr. Schwartz: Most epidemiologic studies show that the risks for aggressive PCa increases with both dietary calcium and calcium supplements. The data for cardiovascular disease are less clear.

Do you believe that there is probably some threshold at which calcium and/or vitamin D supplementation can help restore BMD effectively enough to balance the other risks?

If stopping supplementation is the right strategy at this time, how do you think urologists should proceed at this point in terms of prescribing such supplementation for these patients? Dr. Schwartz: Common sense suggests caution regarding calcium supplements in patients with a history of significant cardiovascular disease.

What sort of reaction has your finding evoked in the urology community? As you pointed out in your report, many professional and lay groups advocate calcium and/or vitamin D supplementation for men undergoing ADT. Dr. Schwartz: The first reaction of many urologists and oncologists was sur-

Most epidemiologic studies show a link between aggressive PCa and calcium. —Gary G. Schwartz, PhD

Dr. Schwartz: That is the key question for a future trial. The goal of maintaining BMD at older ages typically involves accumulating enough skeletal mass in youth so that age-related skeletal losses can be withstood in later life. The problem resembles saving money for retirement. Unfortunately, it is nearly impossible to save effectively for retirement if saving begins at retirement age. Thus, by analogy, it is possible that calcium and/or vitamin D supplements alone may be unable to safely restore BMD in older men undergoing accelerated bone loss caused by ADT. ■

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

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NATIONAL KIDNEY FOUNDATION 2013 SPRING CLINICAL MEETINGS

FEATURE

Uric Acid and the Kidneys: A Role for Urate Lowering? Hyperuricemia is a readily modifiable risk factor treatable with lifestyle changes and medications BY DANIEL E. WEINER, MD, MS, FNKF

Editor’s note: The author discussed the topic of this article at the National Kidney Foundation’s 2013 Spring Clinical Meetings in Orlando, Fla., April 2-6.

n a report published 115 years ago in the Journal of the American Medical Association, N. S. Davis Jr, MD, Professor of Medicine at Chicago Medical College, published a brief treatise titled “The Cardiovascular and Renal Relations and Manifestations of Gout.” In this article, he wrote: “High arterial tension in gout is due in part to uric acid or other toxic substances in the blood which increase the tonus of the arterioles.” He also observed: “The commonest and most characteristic cardiac change associated with gout is hypertrophy.” Dr. Davis concluded: “These various changes in the kidneys, arteries and heart may occur in podagra or characteristic gout, but are more frequently seen independent of it and often themselves constitute the most marked manifestations of a gouty diathesis.” Jumping forward to 2013, we have come full circle, again recognizing gout, and, more specifically, hyperuricemia, as a state that likely predisposes to cardiovascular disease (CVD) and chronic kidney disease (CKD); however, we have yet to prove Dr. Davis’ supposition that uric acid itself increases vascular risk in people.

To date, many but not all cohort studies examining the relationship between hyperuricemia and kidney disease outcomes suggest that there may be direct causality intertwined within the associations among uric acid, CKD, and CVD; however, hyperuricemia is common in individuals with other kidney disease and CVD risk factors, including the components of the metabolic syndrome and sedentary lifestyle factors. Additionally, uric acid is handled by the kidney and correlates with glomerular filtration rate (GFR), further affecting the ability to interpret cohort study data.

Evidence gleaned from experimental models and human studies To begin to answer this question—and ultimately the corollary that treatment of hyperuricemia will reduce kidney disease and CVD risk—initial lessons can be drawn from experimental models and cohort and clinical studies. Most notably, in one experimental model where rats were given a uricase inhibitor to promote mild hyperuricemia, systemic hypertension developed within three weeks and improved following administration of a xanthine oxidase inhibitor, with resultant lowering of serum uric acid. Data from this study also suggested that renal vasoconstriction, up-regulation of the renin-angiotensin-aldosterone system, and decreased nitric oxide availability may be complicit in systemic hypertension.

Daniel E. Weiner, MD, MS, FNKF

A second set of clues on whether hyperuricemia may be causal of kidney disease and CVD has emerged from studies of healthy adults. In one recent publication, Bellomo and colleagues evaluated 900 healthy adult blood donors and demonstrated that higher serum uric acid levels were associated with a modestly increased risk of estimated GFR decline, while, in a large apparently healthy Taiwanese cohort, higher uric acid levels were associated with an increased risk of CVD events. A third clue comes from the most notable clinical trial in this field to date. In this randomized, double-blind, placebo-controlled, crossover trial that included 30 adolescents, allopurinol used for lowering uric acid levels was associated with better blood pressure control. More substantial studies are ongoing although none are sufficiently

long in duration or adequately powered to determine if treatments specifically targeting uric acid lowering will result in improved kidney and CVD outcomes. Finally, several small clinical trials in at risk populations have shown a benefit on surrogate outcomes, including small differences in GFR loss associated with allopurinol use. Critically, hyperuricemia is a readily modifiable risk factor that can be treated with lifestyle changes as well as medications. Therefore, defining the relationship among uric acid, kidney disease, and CVD has significant clinical importance. Interestingly, this is one particular question where the human physiology may be best elucidated through clinical intervention trials. Unfortunately, to date, there are no adequately powered clinical trials that explore harder clinical outcomes currently underway, keeping the answer to this question elusive. Similarly, the design and implementation of this trial remains a difficult concept, as identifying the population most likely to gain significant benefit from uric acid lowering will be critical to a potential clinical trial and, ultimately, clinical successes. ■ Daniel E. Weiner, MD, MS, FNKF, is Associate Medical Director, Dialysis Clinic, Inc. Boston, and Assistant Professor of Medicine, Tufts University School of Medicine in Boston. He also is Deputy Editor of the American Journal of Kidney Diseases.

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Renal & Urology News 15

Researcher: RCC Biomarkers Remain Elusive BY NAYANAH SIVA LONDONâ&#x20AC;&#x201D;Clinicians have drugs that are effective in treating metastatic renal cell carcinoma (RCC), but they still have no biomarkers to predict therapeutic response, Rosalie Fisher, MD, Clinical Research Fellow at the Royal Marsden Hospital in London, told attendees at the Renal and Bladder Cancer 4th National Conference. Seven molecularly targeted drugs have been approved for use in metastatic RCC. The use of anti VEGF-R and anti mTOR treatments have targeted signalling pathways and â&#x20AC;&#x153;we have been able to extend overall survival, to greater than two years for the average patient,â&#x20AC;? said Dr Fisher, who added that â&#x20AC;&#x153;we have entered a new era in the management of RCC.â&#x20AC;? The problem is that these drugs have limitations and â&#x20AC;&#x153;the rather dismal bottom line ... is that in RCC there are no established predictive biomarkers of therapeutic response.â&#x20AC;? The National Institutes of Health definition of a biomarker is a characteristic that is effectively measured and evaluated as an indicator of normal

outset is really quite unpredictable,â&#x20AC;? she said. This contrasts with other solitary types of cancers such as melonama, breast cancer, colorectal cancer, and lung treatment, Dr. Fisher said. Predictive biomarkers exist for these cancers, but not for RCC. â&#x20AC;&#x153;The reality of these drugs

in the clinic is that they are toxic, so if we select at the outset those [RCC] patients who will definitely not benefit from this treatment, this would be a major advantage.â&#x20AC;? Numerous studies have attempted to find useful biomarkers in RCC since 2007, but these studies often are retro-

spective, the number of tumor samples is very small, and results are conflicting. â&#x20AC;&#x153;What is only becoming obvious now, and I think this has been grossly and persistently underestimated, is that the clinical trials that you need to do to identify biomarkers are actually complex and very difficult to do.â&#x20AC;? â&#x2013;

If itâ&#x20AC;&#x2122;s not BPH or OAB thatâ&#x20AC;&#x2122;s keeping your patients up at night, something else quite common may be causing their 1

How patients will benefit from drugs for metastatic RCC is unpredictable. biological processes, pathogenic process, or pharmacologic response to a therapeutic intervention, she noted. Dr. Fisher pointed to some well known examples routinely used in clinical medicine, such as troponins in acute coronary syndromes. Anti VEGF-R and anti mTOR treatments sometimes work well in RCC patients and they can even work well in patients with poor performance status or poor risk features, â&#x20AC;&#x153;but all patients become resistant no matter how good their initial response, and the real lesson is that despite these types of drugs being used in clinical trials since 2002, we still have no idea why they work or how they work, and why they work in some patients and not in others.â&#x20AC;? Current treatment for RCC is typically selected based on the licensed indication for drugs, which is based on the eligibility criteria used in pivotal phase 3 trials. â&#x20AC;&#x153;For an individual who starts on one of these agents, the benefit they will derive at the

Excessive production of urine at night is one of the leading causes of nocturia, Â&#x2122;Â&#x2039;Â&#x2013;Â&#x160; Â&#x192; Â&#x2020;Â&#x2039;Â&#x192;Â&#x2030;Â?Â&#x2018;Â&#x2022;Â&#x2039;Â&#x2022; Â&#x2026;Â&#x2018;Â?Ć¤Â&#x201D;Â?Â&#x2021;Â&#x2020; Â&#x2039;Â? Â&#x2013;Â&#x160;Â&#x2021; Â?Â&#x192;Â&#x152;Â&#x2018;Â&#x201D;Â&#x2039;Â&#x2013;Â&#x203A; Â&#x2018;Â&#x2C6; Â&#x2019;Â&#x192;Â&#x2013;Â&#x2039;Â&#x2021;Â?Â&#x2013;Â&#x2022;Ç¤1-4 Â&#x2021;Â&#x192;Â&#x201D;Â? Â?Â&#x2018;Â&#x201D;Â&#x2021; Â&#x192;Â&#x201E;Â&#x2018;Â&#x2014;Â&#x2013; Â&#x2013;Â&#x160;Â&#x2021; Â&#x2026;Â&#x192;Â&#x2014;Â&#x2022;Â&#x2021;Â&#x2022; Â&#x2018;Â&#x2C6; Â?Â&#x2018;Â&#x2026;Â&#x2013;Â&#x2014;Â&#x201D;Â&#x2039;Â&#x192;ÇĄ Â&#x192;Â?Â&#x2020; Â&#x192;Â&#x2026;Â&#x2026;Â&#x2021;Â&#x2022;Â&#x2022; Â&#x2014;Â&#x2022;Â&#x2021;Â&#x2C6;Â&#x2014;Â&#x17D; Â&#x2013;Â&#x2018;Â&#x2018;Â&#x17D;Â&#x2022; Â&#x192;Â?Â&#x2020; Â&#x201D;Â&#x2021;Â&#x2022;Â&#x2018;Â&#x2014;Â&#x201D;Â&#x2026;Â&#x2021;Â&#x2022;Ç¤ Visit NocturiaResources.comÇ¤

References: 1. Weiss JP, van Kerrebroeck PEV, Klein BM, et al. Excessive nocturnal urine production is a major contributing factor to the etiology of nocturia. J Urol. 2011;186:1358-1363. 2.Â NĂ¸rgaard JP, Hashim H, Malmberg L, et al. Antidiuresis therapy: mechanism of action and clinical implications. Neurourol Urodyn. 2007;26:1008-1013. 3. van Kerrebroeck P, Hashim H, Holm-Larsen T, et al. Thinking beyond the bladder: antidiuretic treatment of nocturia. Int J Clin Pract. 2010;64:807-816. 4. NĂ¸rgaard JP, Holm-Larsen T. Impact of nocturia on the patient and consequences for the payer. Impact dossier (publications summary). 2012:1-73. UY/374/2012/US ÂŠ2012 Ferring B.V. 11/12

16 Renal & Urology News

■ GUCS 2013

APRIL 2013

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Reports from the 2013 Genitourinary Cancers Symposium, Orlando, Fla.

Non-Bone PCa Metastases Increasing The trend could be related to the use of bone-targeted agents for men with mCRPC BY JODY A. CHARNOW NON-BONE metastases are on the rise in men with metastatic castrationresistant prostate cancer (mCRPC), according to researchers. Investigators led by William K. Oh, MD, of the Mount Sinai Icahn School of Medicine in New York, reviewed data from 127 studies of men with mCRPC that included reporting of non-osseous metastases and prior treatment. From 1990 to 2011, the rate of non-osseous metastasis increased significantly by 1.4% per year; the rate increased by 2.8% per year from 2000 to 2011. The rate for lymph node metastasis increased significantly by 2.2% per year from 1990 to 2011 and by 3.3% from 2000 to 2011. The annual rate for liver metastasis remained stable during these study periods. “It is possible that new treatments, including bone-targeted agents such as denosumab and zoledronic acid, are increasing non-bone metastases,”

said Dr. Oh, Chief of the Division of Hematology and Medical Oncology and Associate Director of Mount Sinai’s Tisch Cancer Institute. In addition, Dr. Oh observed that men with mCRPC are probably living longer, which is likely to affect their sites of metastases. He pointed out that drugs may have different effects in different sites of metastases. For example, a bone-targeting drug might elicit a dramatic PSA response and decrease in bone pain, but non-bone metastases may not respond to the same agent. Jorge A. Garcia, MD, a medical oncologist and Director of the Advanced Prostate Cancer Research Program in the Department of Solid Tumor Oncology at Cleveland Clinic, said he agrees with Dr. Oh’s speculation that the increase in non-bone metastases in mCRPC patients is probably an artifact of better treatments that have prolonged survival. With patients living longer, non-bone metastases have

Urologists a Key Factor in PCa Observation Underuse MANY OLDER men with favorable-risk prostate cancer (PCa) can be managed safely with observation. Most patients eligible for this approach choose upfront treatment, however, and the diagnosing urologist is the most important factor influencing that decision, according to a new study. Lead investigator Karen E. Hoffman, MD, MHSc, MPH, of The University of Texas M.D. Anderson Cancer Center in Houston, said she and her colleagues postulate that this may be because the diagnosing urologist has the first conversation with the patient regarding the severity of the cancer and the management options. The study examined data from 17,468 patients who received care from 2,613 urologists. Sixty-four percent of patients had T1c PCa; 85% received upfront treatment and 15% were managed with observation. Even

among men aged 80 years and older, 67% received upfront treatment. The diagnosing urologist accounted for 16% of the variance in choice of observation versus upfront treatment, the study showed. After adjusting for patient factors, office-based urologists were less likely to manage patients with observation than hospital-based urologists, and urologists trained outside the U.S. were less likely to manage patients with observation than U.S.-trained urologists. In addition, results showed that 54% of urologists had no patients being managed with observation while 12% of urologists managed more than 40% of their patients with observation. After adjusting for case mix, only 3.5% of urologists demonstrated a higher than average likelihood of managing their patients with observation; 47% of men diagnosed by these urologists were managed with observation, according to investigators. ■

More Non-Bone Metastases Emerging A review of the medical literature revealed that non-bone metastatic disease is developing in an increasing proportion of men with metastatic castration-resistant prostate cancer. Shown here are the annual rates of increase for two study periods. 3.3%

3.5

2.8%

3.0

2.2%

2.5 2.0

1.4%

1.5 1.0 0.5 0.0

1990-2011

2000 - 2011

1990 - 2011

NON-BONE METASTASES

2000 - 2011

LYMPH NODE METASTASES

Source: Oh WK et al. Evolving patterns of metastatic disease in castration-resistant prostate cancer (CRPC) reported in clinical trials from 1990 to 2011. Presented at the 2013 Genitourinary Cancers Symposium in Orlando, Fla. Abstract No. 195.

more time to develop in unusual sites, such as the lung. Dr. Garcia noted that 90% of men with mCRPC have bone metastases and 40%-45% also have lymph node metastases. Visceral metastatic disease in sites such as the lungs and liver is uncommon, so clinicians historically

have not looked for it, he said. “We only get CT [computed tomography] scans of the abdomen and pelvis and bone scans, but traditionally we never do CT scans of the chest because the likelihood of finding disease outside of the lymph nodes and bone has been low,” Dr. Garcia said. ■

ONLINE ONLY Visit renalandurologynews.com/gucs to watch videos of researchers discussing the findings of the following studies presented at the 2013 Genitourinary Cancers Symposium: Partial Nephrectomy Prolongs Survival in Younger Patients Interview with Gennady Bratslavsky, MD, SUNY Upstate Medical University, Syracuse, N.Y. Salvage Brachytherapy Results Promising Interview with Kristin Smith, a researcher in the Radiation Oncology Department at Cleveland Clinic Post-Cystectomy Chemotherapy Less Likely in Readmitted Patients Interview with Marc C. Smaldone, MD, Fox Chase Cancer Center, Philadelphia Prostate Tumor Size Predicts Salvage Radiotherapy Outcomes Interview with Skyler B. Johnson, a fourth-year medical student at the University of Michigan in East Lansing Anticoagulant Use May Improve Survival in mCRPC Patients Interview with Caroline F. Pratz, MHS, a nurse practitioner at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center,

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Renal & Urology News 17

Renal Nutrition Update L

eptin is a hormone that is released from adipose tissue and classified as an adipokine. Leptin is sometimes thought of as a “skinny” hormone in that higher levels of this hormone are associated with satiety and decreased hunger. As adipocytes become more enriched with energy stores, leptin is released to signal the brain to reduce calorie intake. Thus, body mass index (BMI) often has strong associations with leptin. In obese individuals, the effect of leptin on satiety is sometimes attenuated, and thus a proposed “leptin resistance” may exist. In diabetic patients, caloric restrictions have resulted in correlations between changes in leptin and changes in body fat, energy, and protein intake (J Ren Nutr 2010;20:255-262). Some studies have suggested that chronically elevated leptin levels may induce pancreatic β-cell apoptosis. Leptin levels have been shown to significantly increase in the presence of nephropathy. Leptin has a half-life of 25 minutes and is rapidly degraded and removed from the blood through peripheral tissues and glomerular filtration. In chronic kidney disease (CKD) populations, leptin levels are often elevated (J Ren Nutr 2011;21:316-321), and it is unclear whether this elevated value is related to a reduced ability to clear it through the kidneys or through leptin resistance. Because malnutrition and anorexia are often seen in end-stage renal disease (ESRD) populations, questions have been raised as to whether leptin has an impact on malnutrition in this population.

A better malnutrition biomarker? A recent study found that, in a group of 40 ESRD patients matched with healthy controls, serum leptin was significantly higher in the ESRD group (Indian J Nephrol 2012;22:419-423). C-reactive protein was also significantly higher in the ESRD group, but when comparing each of these parameters with BMI, only leptin was found to have a significant

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positive association. The authors indicate that this information may indicate that leptin is a better biomarker for malnutrition. Leptin concentrations, however, are often simply reflective of adipose stores in general, and thus only a secondary indication of an individual’s BMI (J Ren Nutr 2010;20;151-157). Similar results were found in a cohort of 107 CKD patients, 77 of whom were on dialysis, and 31 healthy controls (J Ren Nutr 2011;21:316-321). Leptin was significantly associated with BMI, whereas ghrelin and obestatin—two other hormonal regulators of appetite— were not significantly associated with BMI. An additional result was that leptin was significantly higher in the peritoneal dialysis group than the hemodialysis group by over sixfold, most likely due to glucose infusions.

Leptin, BMI, and dialysis duration In the previously mentioned study, BMI was inversely correlated with duration of dialysis. These associations between leptin, BMI, and changes over time have been observed in a prospective trial in dialysis patients over 24 months (Nutr J 2011;10:68). At baseline, leptin was associated with anthropometric parameters such as BMI, tricep skinfold, mid-arm circumference, and mid-arm circumference calculated, as well as bioelectrical impedance analysis (BIA) measurements such as fat mass index and fat free mass index. Although these correlations indicate that leptin is positively associated with indicators of adequate nutritional stores, leptin was not associated with intake of energy or protein after adjustments for bodyweight. After 24 months, reductions were seen in all of the anthropometric and BIA data, but these changes were not related to changes in leptin levels. Decreases in leptin levels during the study were associated with time and with FMI. After 24 months, 33 of the 101 patients died. Dividing leptin levels into tertiles, no significant difference in mortality rate was

BMI may be a more practical and reliable nutritional outcome measure in dialysis patients than leptin levels BY GRISSIM CLARK CONNERY, MS, RD, LD

Leptin (shown above) is significantly associated with body mass index.

found among the three groups, indicating that leptin’s indication of nutritional status was not indicative of survival. Results from other studies have suggested correlations between leptin levels and protein intake as estimated by nPNA. These data led investigators to conclude that higher leptin concentrations have a positive effect on appetite in dialysis populations. As noted previously, the prospective cohort study found no association between leptin and dietary intake after controlling for BMI; these results could possibly be reinterpreted to suggest that the increased BMI was a result of increased dietary intake in the first place. Many studies are analyzing leptin changes in the context of ghrelin changes. The effect of ghrelin on appetite in CKD patients will be explored further next month, but one particular study found that, in dialysis patients with protein-energy wasting (PEW), leptin levels were significantly higher as ghrelin levels decreased as opposed to patients without PEW (Kidney Int 2011;79:749-756). The results from these studies should be analyzed in the context of the “reverse epidemiology” model, whereby dialy-

sis patients exhibit improved outcomes with higher BMI. Leptin levels appear to directly correlate with BMI such that as fat mass increases and decreases, leptin changes accordingly. Reduced leptin levels thus would indicate reduced BMI and lower nutritional stores. High levels of leptin, however, trigger hormonal releases of pro-inflammatory cytokines, which also promote poor nutritional factors. At this time, leptin changes appear to be most strongly influenced by BMI and the effect of leptin levels on appetite in dialysis populations appears to minimal, if at all, present when compared with the more pronounced and classical uremic factors. Thus, using leptin as a nutritional outcome measure may be unnecessary, as BMI is measured much more easily and cost effectively. Related hormones of interest include ghrelin, adiponectin, resistin, and obestatin. Future articles will review whether these outcome measures can be of more pertinent use. ■ 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.

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SLE Flares May Occur Despite Dialysis Researchers found a higher-than-expected prevalence of lupus activity after renal failure BY JOHN SCHIESZER WASHINGTON, D.C.—Systemic lupus erythematosus (SLE) patients with renal failure often continue to experience flares, but most commonly these are serologic rather than clinical, according to study findings reported at the American College of Rheumatology annual meeting. “A definition of a real lupus flare after renal failure is controversial,” said lead investigator Cristina Gonzalez Pulido, MD, a resident in internal medicine at University Hospital Virgen del Rocio in Seville, Spain. “We found that dialysis decreased lupus activity, but careful assessment of patients for on-going activity is still important.” A 34-year follow up Dr. Gonzalez Pulido and her colleagues followed a cohort of 182 patients with lupus nephritis for (LN) for 34 years. During this study period, renal failure requiring dialysis developed in 32 patients (17.6%) and those were followup during 12 years. The majority of published studies measuring activity in patients with LN have suggested the disease is relatively quiescent after renal failure. Dr. Gonzalez Pulido’s team retrospectively

analyzed the activity index of 32 LN patients with end-renal stage disease (ESRD). They used the BILAG index, levels of complement C3 (0.9-1.8 g/L), and anti-DNA antibodies (0-50 IU/mL) to measure the lupus activity every six months at the start of dialysis or after renal transplantation finding 28 patients showed some kind of activity during the follow-up The cohort was ethnically diverse (37.5% Afrocaribbean, 25% from the Indian subcontinent, 28% Caucasian, and 9.4% others). The researchers defined inactive disease as no BILAG A/B and both C3 and DNA level within the normal range and active disease when any alteration in BILAG and/or serologic involvement was present. They defined moderate disease as at least 1 A/2 B in BILAG or serologic alterations over 20% of the normal range (C3 levels below 0.73 g/L and/or DNA levels above 149 IU/mL). Patients were considered to have severely active disease when both BILAG and serologic abnormalities were present. The researchers divided the cohort in two groups. Group 1 included 32 dialysis patients and Group 2 included 14 patients who started on dialysis but who went on to receive a renal transplant. In Group

1, 13% of the measurements showed completely inactive disease and 87% had at least mild-to-moderate activity at some time. Severe disease was present in just 18.7% of the measurements (12 patients). BILAG involvement in Group 1 was hematologic (59.4%), mucocutaneous (25%), musculoskeletal (21.9%), constitutional (18.7%), and

BILAG involvement most commonly was serologic rather than clinical, data show. cardiovascular (15.6%), the researchers reported. Eleven patients died. In Group 2, 43.3% of the measurements showed inactive disease and 56.7% had at least one flare in this period but just in 16.3% of the measurements was severe (four patients). The BILAG involvement in Group 2 was renal alteration (50%), hematologic (57.1%), mucocutaneous and musculoskeletal (35.7% each), constitutional and cardiovascular (21.4% each), and neurological and vasculitis (7.1%). Three patients died.

“We found a higher prevalence of lupus activity after renal failure than expected in both groups,” Dr. Gonzalez Pulido said. “We tried to establish a higher cut-off to define a real lupus flare. When this was done we observed a decreased prevalence of lupus activity in our cohort—similar to recent published studies—and this drop in activity was more pronounced in the renal transplant group.” Decreased activity after renal transplant could be due to the immunosuppressive therapy, the researchers speculated. Most clinical flares in the two groups were not life-threatening events and mainly consisted of mildto-moderate hematologic alterations, they noted. The study demonstrated that lupus activity could be present even after more than 12 years on dialysis or after renal transplantation, suggesting that physicians should keep this in mind to avoid underdiagnosing and/ or undertreating patients, accrording to researchers. Dr. Gonzalez Pulido said it makes sense to correlate serologic findings and then combine them with a validated lupus activity index to define a real lupus flare in this patient population. ■

Proteinuria Recovery Heads Off LN Comorbidities BY JOHN SCHIESZER WASHINGTON, D.C.—Achieving partial or complete recovery from proteinuria in patients with active lupus nephritis (LN) at one year from disease onset may protect against comorbidities, including end-stage kidney disease, according to new study findings presented at the American College of Rheumatology annual meeting. “Proteinuria recovery at one year is a predictive factor for long-term outcomes—renal failure, accrual of severe damage and death—in lupus nephritis patients,” said lead investigator Zahi Touma, MD, PhD, a postdoctoral clinical research fellow of rheumatology at the University of Toronto Lupus Clinic. “Although complete recovery of proteinuria is ideal and protects against the development of long-term outcomes, even partial recovery may be protective.”

The vast majority of therapeutic trials have used complete proteinuria recovery as the primary endpoint, Dr. Touma said. It is theorized, however, achieving a 50% or greater decrease in proteinuria from baseline may improve long-term outcomes. Dr. Touma and his colleagues studied 196 active LN patients registered at a large lupus clinic. The group was 84% female. Forty-seven (24%) patients achieved partial proteinuria and 52 (26.5%) had a complete proteinuria recovery. The researchers defined complete proteinuria recovery as proteinuria less than 0.5 g/24 hours and partial response as a 50% or greater decrease in the level of proteinuria from baseline. Patients were defined as “not recovered” if they had less than 50% recovery. For this investigation, proteinuria recovery was identified if it was present on two consecutive visits within one year.

The researchers analyzed the following long-term outcomes: death, estimated glomerular filtration rate (eGFR) of 15 mL/min/1.73 m 2 or less, initiation of dialysis or receipt of a kidney transplant, Systemic Lupus International Collaborating Clinics (SLICC) Damage Index (SDI) greater than greater than 3 and atherosclerotic events. The investigators observed the following long term outcomes were observed after an approximate mean time of four years from study start: 11% of patients developed an eGFR of 15 or less and 8% started dialysis or underwent kidney transplantation; 11% of patients died, 4% developed atherosclerotic events, and 21% experienced damage (SDI greater than 3). Patients achieving a complete proteinuria response at one year had a 79% decreased likelihood of having an eGFR of 15 or less within at least six

years of follow-up, Dr. Touma reported. Patients achieving partial proteinuria recovery had a trend for being protected from developing an eGFR of 15 or less but this was not statistically significant. The complete responders also had 80% decreased likelihood of an SDI greater than 3, the study showed. No patient with complete proteinuria recovery achieved at one year went on to dialysis or renal transplantation and no atherosclerotic events have occurred within at least six years of follow-up. “Physicians should aim to achieve a complete proteinuria recovery in lupus nephritis patients. Nevertheless, complete recovery is slow,” Dr. Touma told Renal & Urology News. “Physicians should also measure partial proteinuria recovery especially since 43% of the patients with partial proteinuria recovery at one year will achieve complete recovery at two years.” ■

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Renal & Urology News 23

Practice Management Improving practice efficiency often just requires a little time and energy and begins with identifying problem areas BY TAMMY WORTH

Simple solutions The answers to a few simple questions can make a big difference. “Are patients not showing up on time? Are doctors not showing up on time? Are there blocks at the checkout counter?” If you have a flow issue, Wiggs recommends tying a string around the finger of a nurse and having her simulate where she goes while taking care of a patient. Likely, you will end up with a huge spider web. This might help you understand how to rearrange what she does so unnecessary steps can be avoided. Another option is to place a box by everyone’s desk and have them collect each piece of paper they touch. At the end of a day or week, you will see who uses what and how much overlap there is. One simple tactic is to make sure no one is doing things that can be done better by somebody else. For instance, it is important for doctors to document their work, but some of this can be done by others so physicians can spend time with patients. “There is a lot of work that physicians shouldn’t be doing but they do because it’s what they’ve always done,” she said. “You need people working at

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the highest level of their certification or training.”

Managing with electronic records A major time drain at doctors’ offices is the telephone, Wiggs said. It is almost always worth the effort to keep track of how much time people are spending on the phone and why. Many things that are done by phone can just as easily be automated. “There really isn’t an excuse not to use these systems,” she said. “My own 89-year-old father makes his own physician appointments online. Having someone fill out their information online before coming to the office can save five to seven minutes alone.” Something not done frequently enough is electronic verification of insurance benefits and eligibility, said consultant David Zetter, of Zetter Healthcare Management Consultants in Mechanicsburg, Pa. “Many patient management systems are capable of doing this, but most don’t want to spend money on having that service provided to them,” he said. “It’s kind of a throw of the dice whether they will be collecting money for services they are rendering.” The cost of using the product is well worth it if you consider staff time engaged in insurance matters, Zetter said. An even worse scenario is not verifying insurance benefits and eligibility and having to chase patients down for payments or not collecting at all. Zetter advocates using patient management systems to understand most problems in a practice (though he said you will have to have someone who really understands how to use the system to get to it). If you have a no-show issue, you can figure out when they are occurring,

aking an office more productive “isn’t sexy,” says Debra Wiggs, Vice President of Physician’s Services at St. Joseph Regional Medical Center in Lewiston, Idaho. Technology can help, but increasing productivity is often a low-tech process requiring just a little bit of dedicated time and energy. The first thing you have to do to fix your problems is know what they are. You do not need to take on the entire practice at once, Wiggs said. If you ask around, the staff will identify problem areas.

Factors that impede patient flow can be ascertained using electronic medical records.

which providers get the most no-shows, how far out visits were scheduled, who the patients are, and how the practice handles the issue. Patient flow problems can also be identified using electronic medical records. You can track a patient’s check-in time, how long they are in the waiting room (by looking at when the triage began), how long they wait for a physician, and how long the physician spends with the patient.

Proper staffing increases efficiency Some staffing practices can improve efficiency in an office. An important first step is to have a really good practice manager, Zetter said. The manager needs to be a problem solver and not someone who is just there to check in patients. He or she should be there to support the staff, make their jobs easier and ensure the practice runs smoothly. Another job is what Zetter calls a “physician handler.” A nurse or other

staff member can be assigned to providers to keep them moving along, tell them when the next patient has been triaged, and remind them someone is waiting. “Doctors need to be more customer oriented,” Zetter said. “Patients will vote with their feet if they spend too much time in a waiting room.” Plenty of tools, both simple and complex, are available that can help increase efficiency in a practice, Wiggs said. The challenge is taking advantage of them. She schedules time on her calendar each week to “sit down and breathe” and complete administrative work. “The biggest challenge of some of these is scheduling time for yourself to learn,” she said. “There is nothing magical about efficient well-run practices. It is simply a matter of choosing to stop the insanity.” ■ Tammy Worth is a freelance medical journalist based out of Blue Springs, MO.

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

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Acute Kidney Injury Risk in Trauma Patients Linked to Excessive Body Fat Researchers used CT scans to measure abdominal adiposity BY ROSEMARY FREI, MSc PUERTO RICO—Excessive body fat in trauma patients as quantified using computed tomography (CT) scans may be associated with an increased risk of acute kidney injury (AKI), data suggest. In a prospective study of 49 trauma patients presented at the Society for Critical Care Medicine’s 2013 annual meeting, researchers found that AKI risk rises rapidly in patients with large amounts of visceral or subcutaneous abdominal adiposity on CT scans. For example, trauma patients in the 75th percentile for visceral fat area have a 18% probability of developing AKI, whereas those in the 95th percentile have a 54% chance of developing AKI. For subcutaneous fat, those in the 75th percentile have an 18% risk for AKI and those in the 95th percentile have a 39% risk for AKI. The researchers noted that excess adipose tissue causes a chronic inflammatory state, and proinflammatory cytokines have been implicated in AKI pathophysiology. “The intent of the study was not to create a predictive model,” lead inves-

tigator Michael Shashaty, MD, MS, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, told Renal & Urology News. “Instead, it highlights both the potential feasibility of directly studying the amount of adipose tissue—as

The more visceral and subcutaneous fat, the higher the AKI risk, data show. opposed to the less-specific BMI [body mass index]— in the trauma population, and how probing the mechanisms underlying the obesity-AKI association may, ultimately, lead to a better understanding of AKI pathophysiology.” CT is used routinely for critically ill trauma patients and can be used to quantitate visceral and subcutaneous adipose tissue accurately, Dr. Shashaty’s group noted. Dr. Shashaty and his colleagues performed the study to build on ear-

lier research showing an association between increased AKI risk and higher BMI in critically ill patients. Using a prospective cohort of trauma patients with an Injury Severity Score of at least 16, and who had stayed in the intensive care unit for more than one day, they retrieved abdominal CT images to quantify adipose tissue. Among the 49 patients with usable abdominal CT images, those who developed AKI had a significantly higher median area of visceral adipose tissue than those who did not develop AKI (111 vs. 42 cm2). They also had significantly larger areas of subcutaneous fat (245 vs. 152 cm2). “Right now, we are focused on expanding this study to a larger sample within our trauma cohort in order to improve generalizability and to adjust the association of adipose tissue with AKI for several potential cofounders,” Dr. Shashaty said. “Depending on our findings, studies examining the potential mechanistic pathways by which adipose tissue might predispose critically ill patients to AKI may be warranted.” ■

Higher PCa Death Risk in Blacks Confirmed RESEARCHERS WHO conducted a study of prostate cancer (PCa) patients in Kentucky found that African Americans were more likely to die from the cancer than Caucasians, even after controlling for many known predictors of cancer survival. The study—led by Samuel Antwi, MPH, of the University of South Carolina in Columbia, who collaborated with researchers at the University of Kentucky in Lexington—included 17,251 Caucasian and 1,649 African American PCa patients. After adjusting for health insurance status, cancer treatment, cancer stage and PSA level at diagnosis, smoking status, and geographic location, the five- and 10-year cancer-specific mortality risk was 33% and 39% greater, respectively, among African Americans than Caucasians. Antwi’s group reported online ahead of print in the American Journal of Men’s Health. The authors noted that the causes of the survival disparity are likely multifactorial and may include differences in behavioral patterns and

Elderly Men Benefit from TRT, Study Finds

societal dynamics as well as differences in the standards of medical care received by African Americans

HYPOGONADAL MEN aged 65 years and older experience significant benefit from testosterone replacement therapy (TRT) over 12 months, similar to what is observed in younger men, new findings suggest. Using data from the Testim Registry in the U.S. (TRiUS), Rajib K. Bhattacharya, MD, of the University of Kansas Medical Center in Kansas City, and collaborators studied 845 registry participants with age information available at baseline. Of these, 133 (16%) were aged 65 and older. These men were similar to men younger than 65 years in the duration of hypogonadism prior to enrollment (a little over one year) and total testosterone (TT) and free testosterone (FT) levels at baseline. At the 12-month follow-up, mean TT levels increased significantly from baseline in patients in both age groups, according to a report in Clinical Interventions in Aging (2012;7:321-

330). The levels increased by 229.7 ng/ dL from baseline to 524 ng/dL at 12 months in the older group and by 232.9 ng/dL to 491.1 ng/dL in the younger group. The differences between the groups were not significant. Mean FT levels increased significantly by 27.7 pg/mL from baseline to 65.5 pg/mL at 12 months in the younger group, but increased nonsignificantly by 15.4 pg/ mL to 95.2 pg/mL in the older group. Notably, the researchers pointed out, the mean 12-month values did not differ significantly between the two groups. After 12 months of TRT, PSA levels did not differ significantly between the groups. In the study, most physicians prescribed either 50 mg testosterone gel (one five-gram tube) or 100 mg testosterone gel (two five-gram tubes) per day. No patient was prescribed more than 100 mg per day. Older patients were prescribed the lower dose sig-

nificantly more often than the younger patients. The study found associations between lower TT levels at baseline and the cardiovascular risk factors of greater weight, body mass index, waist and hip circumference, diastolic blood pressure, and plasma glucose levels, independent of age, according to the report. Over the 12 months of the study, the increase in TT level was associated with decreased waist circumference and plasma glucose levels, and the increase in FT level was associated with decreased total and LDL cholesterol, independent of age. Cardiovascular risk factors did not worsen during 12 months of TRT in the older patients, the authors noted. Dr. Bhattacharya’s group pointed out that TRiUS was not specifically designed to assess safety, but adverse event reporting suggests that TRT was tolerated well in both age groups. ■

and Caucasians. “For example, physicians who treat African Americans tend to have less clinical training and have reported greater difficulties in obtaining access to clinical resources for their patients compared with physicians who treat Caucasians,” the investigators noted, citing a previous study published in the New England Journal of Medicine (2004;351:575-584). “Identifying factors that do not contribute to the racial differences in PC [prostate cancer] survival helps clarify direction for future studies in this area of health disparity,” the investigators wrote. Antwi’s group noted that their study was restricted to patients in Kentucky, which limits the generalizeability of study findings. ■

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Renal & Urology News 25

Legal Issues in Medicine W

hen Mr. B, 60, began seeing blood in his urine, he became alarmed and immediately made an appointment with a urologist, Dr. D, 71. The physician examined the otherwise healthy patient and decided to perform a cystoscopy which revealed a tumor in the patient’s bladder. The urologist fulgurated it and obtained bladder biopsies that were sent to the lab. When the pathology report came back, it showed invasive high-grade urothelial carcinoma involving the bladder lining. In the report, the pathologist noted that he was unable to determine if the cancer had invaded the bladder muscle because the urologist failed to obtain a muscle sample in the biopsies. Dr. D barely skimmed the pathologist’s note, and simply filed the report in the patient’s file with a reminder to do a follow-up cystoscopy. Three months later, Mr. B returned for a second cystoscopy. Again, Dr. D found a tumor, fulgurated it and obtained bladder biopsies. Again, the pathology report indicated invasive urothial carcinoma. And again, the pathologist noted that because the urologist had not included a sample of muscle tissue in the biopsy specimens, he was unable to determine whether the cancer had spread to the bladder muscle. Dr. D filed this report with the other one, and told the patient that the two tumors had been destroyed, but that he’d take a “watch and wait” approach and would do additional cystoscopies to monitor the situation. The patient, who had not seen the pathology reports, agreed. Over the next two years, Mr. B had three other cystoscopies. None of the three revealed cancer, but none of the biopsies contained muscle tissue. During the fourth cystoscopy, however, Dr. D observed a large bladder tumor and took a biopsy sample that

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contained muscle. The biopsy revealed that Mr. B’s bladder cancer had in fact invaded the muscle wall and metastasized. In an attempt to prevent the cancer from spreading, Mr. B’s bladder was removed and he went through months of chemotherapy. On the advice of a friend, Mr. B sought the counsel of a plaintiff’s attorney. Mr. B wanted to know whether his cancer should have been caught earlier and if better care would have provided him with a better prognosis. The attorney ordered the medical files and had several medical experts look at them. All of the experts who were consulted told the attorney that Dr. D should have heeded the advice of the pathologist and taken a sample of the bladder muscle for biopsy purposes, and that had the cancer been diagnosed earlier, Mr. B would have had a better chance of survival. Before the attorney filed a lawsuit against Dr. D, it was discovered that Mr. B’s bladder cancer had metastasized into his bones. Mr. B passed away just as the lawsuit was filed, and his wife was named as the plaintiff. Dr. D was sued for wrongful death and negligence. The physician was assigned a defense attorney by his insurance company. The first thing the attorney did was to suggest that they get their own expert to counter the expert testimony from the plaintiff’s side. This expert produced a report stating that the standard of care did not require Dr. D to obtain any muscle in the biopsy samples because a visual inspection was sufficient. This report was submitted to the plaintiff as part of discovery. In response, the plaintiff’s expert urologist filed a supplemental report stating that the defense expert was absolutely incorrect in his claim that it was the standard of care not to obtain a muscle sample. “I have to tell you,” Dr. D’s attorney said, “I don’t think our case is that

A urologist ignores a pathologist’s recommendation related to a case of bladder cancer and ends up getting sued BY ANN W. LATNER, JD

Had a urologist biopsied bladder muscle tissue, a patient may have had better survival odds.

strong. Perhaps you should consider settling.” As the case approached trial, Dr. D considered his options and decided to settle. The case was settled out of court for $425,000.

Legal Background Expert witnesses are almost a given in medical malpractice cases. It is the experts who establish what the standard of care is, allowing jurors to decide whether the clinician has breached that standard of care. However, experts are also paid professionals, who are compensated for their testimony. It is almost always possible for an attorney to find an expert who will side with his theory, leaving the jury to decide which expert to believe. Protecting Yourself Dr. D clearly erred in not heeding the pathologist’s report and obtaining a sample of muscle tissue so that the pathologist could determine whether the cancer had invaded the bladder muscle. Had he done so after the first

report, his patient might have been treated sooner and had a better outcome. The delay in diagnosis (and hence treatment) likely contributed to Mr. B’s death, and Dr. D’s continued ignoring of the pathology reports would not be looked on favorably by a jury. If Dr. D had a concern about the pathologist’s recommendation, he should have contacted him. If the physician disagrees with the pathologist, he should have made a note in the patient’s folder to explain his decision not to follow-up on the recommendation. To simply ignore the pathologist’s note was harmful to the patient, and put Dr. D on poor footing in trying to defend his actions, or in this case, inactions. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y. Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended.

What do you think? Did the jury make the right decision in this case? We want to know your thoughts. Leave us a comment at the end of this article—or any article—at www.renalandurologynews.com/legal.

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Few Pelvic Organ Prolapse Procedures Show Edge Meta-analysis reveals downside to mesh interventions BY ROSEMARY FREI, MSc BRISBANE, AUSTRALIA—A detailed meta-analysis of the evidence related to the optimal surgical management of pelvic organ prolapse (POP) shows that only a few procedures have stood the test of time, and some have failed. According to a Cochrane review presented at the International Urogynecological Association’s 2012 annual meeting, studies have not uncovered a clear advantage of anterior compartment mesh utilization over anterior repair (colporrhaphy). Nor is transvaginal mesh better than native tissue repairs in apical or posterior compartment prolapse, and mesh also carries with it an increased risk of intervention in the short term, the team concluded. “We found a clear advantage in objective and subjective assessment of outcomes from mesh repair as compared to native tissue repairs: The downside was increased perioperative morbidity, post operative stress urinary incontinence, increased complications, primarily mesh exposure, and operations to correct this,” said senior author Christopher Maher, MD. “There is clearly a downside to mesh interventions.” Dr. Maher, of the Wesley Private Hospital and Royal Brisbane Women’s Hospital, together with three other clinician-researchers, reviewed 54 random-

ized, controlled trials involving a total of 5,775 women. Their goal was to update a review they completed in 2010 (Cochrane Database Syst Rev 2010;(4):CD004014). The new review included 15 trials that had not been published or presented when the 2010 review was conducted, as well as 10 major updates of prior studies. Prolapse of the anterior compartment has been examined in 22 clinical trials, including six that were not included in the 2010 Cochrane review. Ten of the trials compared native tissue repair (colporrhaphy) and synthetic non-absorbable mesh repair and six compared native tissue repair and biological grafts. The meta-analysis revealed that anterior colporrhaphy is associated with a 64% higher objective failure rate than any biological graft and a 291% higher rate than any graft material. It is also associated with over 300% higher rates of objective failure than polypropylene mesh anterior repair. Unfortunately, the gains in objective outcomes did not translate into improved quality of life outcomes and sexual function, which were similar in the mesh and no mesh groups. Anterior colporrhaphy, however, is associated with a nearly twofold lower total reoperation rate for POP and a 1.75-

Mesh Prolapse Procedures On the Rise, Researchers Report THE RATE OF MESH PROLAPSE procedures has been increasing, and the vast majority of these procedures are vaginal mesh surgeries, researchers reported in the American Journal of Obstetrics & Gynecology (2013;208:79.e1-e7). In an analysis of claims data from across the United States for 20052010, Michele Jonsson Funk, PhD, of the University of North Carolina in Chapel Hill, and collaborators identified 60,152 mesh prolapse procedures during 78.5 million person-years of observation, for a rate of 76 per 100,000 person-years. Overall, 74.9% of the procedures were vaginal mesh surgeries, for an overall rate of 56.9 per 100,000 person-years. Rates of abdominal sacrocolpopexy (ASC) and minimally invasive sacrocolpopexy (MISC) were 12.0 and 9.5 per 100,000 person-years, respectively. From 2005-2007, ASC was more common than MISC; since 2007, however, the rate of MISC has increased and the rate of ASC has decreased, the investigators found. Vaginal mesh procedures were considerably more common than sacrocolpopexies at all ages. ASC was more common than MISC in women older than 50 years. ■

fold lower rate of operation for de novo stress urinary incontinence compared with placement of transvaginal polypropylene mesh. These are significant advantages over mesh, the Cochrane reviewers pointed out. Native tissue repair also has the advantages of lower operating time and less intraoperative blood loss. The reviewers also assessed transvaginal mesh in the posterior and apical regions of the vagina. They found no evidence of efficacy of polypropylene mesh or smallintestine submucosa in posterior compartment repairs, stating that “posterior colporrhaphy fascial repair remains the gold standard,” including its superiority over transanal repair. Two randomized controlled trials included in the meta-analysis evaluated commercial mesh kits for conditions other than anterior compartment prolapse and showed “no advantage and plenty of downside,” Dr. Maher added. “These kits have been marketed aggressively since 2003-2004 for anterior posterior and apical prolapse—and now eight years later we have only two randomized, controlled trials and they show a definite downside to their use.” Dr. Maher pointed out that this summer Johnson & Johnson withdrew transvaginal prolapse mesh products from the market in the United States and is planning to halt their sales worldwide. This follows 2009 and 2011 FDA alerts warning of serious complications from transvaginal mesh for POP repairs. Lawsuits have been filed against most companies that market transvaginal mesh due to allegations that women have been harmed by these products. Additionally, the authors determined that for apical-compartment repairs, abdominal sacral colpopexy for apical prolapse is superior to native tissue repairs and apical transvaginal mesh. However, there is only limited evaluation of the optimal rout for performing abdominal sacral colpopexy, they found. For its part, the robotic approach “is the most expensive” option, said Dr. Maher, and the single randomized controlled trial of its kind showed robotic surgery does not have advantages over the laparoscopic approach to justify the extra cost of the robotic approach. ■

No Survival Benefit Found With Daily HD STUDIES HAVE found that daily hemodialysis (HD) is associated with improvements in some surrogate markers of survival, but a new study has found that this approach does not actually help patients live longer. Using propensity-score-based matching, Rita S. Suri, MD, of the University of Western Ontario in London, and colleagues compared 318 patients who received daily HD (more than five times per week) with 575 patients in the Dialysis Outcomes and Practice Patterns Study who received conventional HD (three times per week). During 1,382 patient-years of followup, 170 patients died. The mortality rate was 15.6 deaths per 100 patientyears in the daily HD group compared with 10.9 deaths per 100 patient-years, a difference that translated into a 60% increased risk of death associated with daily HD, the researchers reported online ahead of print in Kidney International. The mean HD frequency in the daily group was 5.8 sessions per week. The mean weekly treatment time was 15.7 hours for the daily group compared with 11.9 hours for the conventional group, according to the investigators. Dr. Suri’s team concluded that decisions to undertake daily HD should be based on quality of life improvements rather than on claims of improved survival.

Decisions to go on daily HD should be based on quality of life concerns. Previous studies have demonstrated that increasing dialysis frequency from three to six times per week improves left ventricular mass and health-related quality of life. For example, a recent study of patients in the Frequent Hemodialysis Network Daily Trial demonstrated that HD six times per week significantly improves self-reported health physical health and functioning compared with conventional HD, but had no significant effect on objective physical performance. ■

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Renal Status Influences PCI Outcomes Risk of a composite of death, shock, and heart failure increases with worsening kidney function BY JILL STEIN LOS ANGELES—Greater degrees of renal impairment at baseline are associated with increasingly adverse 90-day outcomes among patients undergoing primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI), according to findings presented at the American Heart Association Scientific Sessions 2012. John P. Vavalle, MD, MHS, an interventional cardiology fellow at Duke University Medical Center in Durham, N.C., and colleagues elsewhere examined the impact of baseline renal disease on outcomes in patients undergoing primary PCI for STEMI as part of the 4,897-patient Assessment of Pexelizumab in Acute Myocardial Infarction (APEX AMI) trial. The impact of renal disease on outcomes in STEMI patients undergoing primary PCI has not been widely studied, Dr. Vavalle noted. The new study is notable for patient population, he said. “Our analysis included patients with very advanced renal disease, including patients on dialysis, while many clinical trials similar to APEX had previously excluded these populations,” he commented. “So we have a very rich dataset.”

Dr. Vavalle’s team estimated patients’ glomerular filtration rate (GFR, mL/min/1.73m 2) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and classified patients according to stages of CKD by GFR. Results showed a stepwise significant increase in the pre-specified 90-day composite outcome of death, shock, and heart failure, which correlated directly with the degree of renal impairment The 90-day incidence of the composite outcome was 4.5%, 8.0%, 19.9%, and 30.3% among patients with a GFR above 90, 60-90, 30-60, and 30 or less, respectively. The incidence was 37.5% among patients on dialysis at baseline, according to investigators. Compared with subjects who had normal renal function, patients with a GFR below 30 had an almost eightfold increased risk of death, shock, or heart failure at 90 days. Additionally, patients with more severe CKD had significantly longer delays to PCI. The time from symptom onset to primary PCI was 4.2 hours in dialysis-dependent patients and 3.3 hours in patients with a GFR above 90, the study showed.

Adverse Effect of Renal Impairment In a study of patients undergoing percutaneous coronary intervention for acute ST-elevation myocardial infarction, the worse their renal function at baseline, the greater their 90-day incidence of a composite outcome of death, shock, and heart failure. 35 30 25 20 15 10 5 0

4.5% Over 90

8.0% 60-90

19.9% 30-60

30.3% 30 or less

Estimated glomerular filtration rate (mL/min/1.73m2) Source: Vavalle JP et al. Data presented at American Heart Association 2012 Scientific Sessions in Los Angeles. Abstract 16645.

Despite a similar distribution of pre-intervention Thrombolysis in Myocardial Infarction (TIMI) flow grades in the coronary arteries, postintervention angiographic outcomes were significantly worse with increasing degrees of renal failure. Patients with worse renal function at baseline also had significantly higher rates of atrial fibrillation, severe bleeding, infection, mechanical complications, and time spent in the intensive care unit.

“So, the take-home message is that we found worse outcomes across the board with worse baseline renal function,” Dr. Vavalle said. The analysis also revealed that the factors most likely to predict in-hospital, post-catheterization, and acute kidney injury (AKI) in STEMI patients undergoing PCI were age, female gender, presenting Killip class III or IV heart failure, and PCI duration. PCI duration was used as a surrogate for exposure to contrast media in this analysis. ■

Higher Statin Dose of Benefit in Tough HTN Cases BY JILL STEIN LOS ANGELES—Intensive lipid lowering with atorvastatin is associated with a significant decrease in cardiovascular events in patients with treatment-resistant hypertension, researchers reported at the American Heart Association Scientific Sessions 2012. Sripal Bangalore, MD, Assistant Professor of Medicine at New York University School of Medicine, and colleagues elsewhere compared intensive lipid-lowering with atorvastatin 80 mg/day to standard lipid-lowering with atorvastatin 10 mg/day in patients with treatment-resistant hypertension who were enrolled in the randomized Treating to New Targets (TNT) trial. The TNT study examined the two strategies for use as secondary prevention in 10,001 patients with stable coronary heart disease (CHD) and a low-density lipoprotein (LDL) cholesterol level below 130 mg/dL. Of the TNT cohort,

1,112 (11.1%) patients had treatmentresistant hypertension. Up to 30% of hypertensive patients have treatment-resistant hypertension, Dr. Bangalore pointed out. Treatmentresistant hypertension is defined as blood pressure (BP) that remains above

Cardiovascular outcomes superior to those achieved with standard dose. goal despite the concurrent use of three antihypertensive agents of different classes. The definition also includes individuals whose BP is controlled with four or more agents. Patients with treatment-resistant hypertension are known to have a worse prognosis; for example, such patients are 77% more

likely to have a non-fatal myocardial infarction and 41% more likely to die from any cause than patients without treatment-resistant hypertension. New therapies including catheterbased radiofrequency ablation of the renal sympathetic nerves are being tested for this condition with a specific goal of reducing BP, he said. While a focus on lowering BP is appropriate given the extremely high risk of cardiovascular events in this population, the effect of intensive lipid lowering on cardiovascular outcomes has not been known. The primary outcome of the TNT trial was the composite of death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, and fatal or nonfatal stroke. The median length of follow-up was 4.9 years. The analysis showed that intensive lipid-lowering therapy was associated with a significant 30% reduction in the risk of the primary outcome.

In addition, patients randomized to intensive lipid lowering had a significant 45% decreased risk of CHD-related death and a trend towards a reduction in all-cause mortality versus patients assigned to standard lipid-lowering, the study showed. Because the risk of stroke is largely dependent on BP control, intensive lipid lowering did not reduce stroke risk, Dr. Bangalore said. He cautioned that the research involved a post-hoc analysis from a CHD population not specifically enrolled for the management of BP, so the results cannot be extrapolated to other populations. “Given the exceedingly high cardiovascular morbidity and mortality in patients with treatment-resistant hypertension, intensive lipid-lowering with a statin should be considered in all such patients regardless of their blood pressure level,” he advised. ■

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CME FEATURE

Adrenal Masses: Often Incidental, Not Always Insignificant Given the frequency with which these lesions are found, urologists and nephrologists should be familiar with their evaluation

Release Date: April 2013 Expiration Date: April 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: Although adrenal masses are often discovered incidentally, only appropriate evaluation can establish these neoplasms as insignificant. Indeed, some data suggest that more than 15% of lesions may require resection. As such, modern management of so-called adrenal incidentalomas pivots on informed and individualized treatment choices. TARGET AUDIENCE: This activity has been designed to meet the needs of urologists, nephrologists, and allied healthcare clinicians who treat patients with adrenal tumors. EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Differentiate types of adrenal neoplasms—both those that are typically seen in clinical practice and lesions that manifest more rarely. • Assess imaging characteristics and protocols for managing adrenal pathology. • Review metabolic evaluation procedures that accompany adrenal tumor diagnosis. 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 Alexander Kutikov, MD

Reported Financial Relationship Grants/Research Support: Department of Defense, Physician Research Training Award Ownership Interest/Shareholder: Co-founder/Co-owner VisibleHealth, Inc.; Co-founder/Co-owner UrologyMatch LLC

BY ALEXANDER KUTIKOV, MD

drenal glands are small paired retroperitoneal organs that are essential to life. While some adrenal glands are “cappers” and are positioned over the kidney’s upper pole, others are “cradlers” that nuzzle just medial to the kidney over the renal vessels.1 Adrenal neoplasms can stem from either the adrenal cortex or medulla. In fact, adrenal mass is commonly encountered in clinical practice by both urologists and nephrologists. Approximately 5% of individuals harbor an asymptomatic adrenal lesion: 0.5% in the second and up to 7% in the seventh decade of life.2-4 Although adrenal masses are often discovered incidentally, only appropriate evaluation can establish these neoplasms as insignificant. Indeed, some data suggest that more than 15% of lesions may require resection (Table 1). As such, modern management of socalled adrenal incidentalomas pivots on informed and individualized treatment choices rooted in (1) appropriate riskassessment for the presence of malignancy and (2) thorough assessment of each mass’s metabolic activity.1

The content managers, Jody A. Charnow and Marina Galanakis, of Haymarket Medical Education, and Julie Johnson, PharmD, of Medical Education Resources, have disclosed that they have no relevant financial relationships or conflicts of interest. METHOD OF PARTICIPATION: There are no fees for participating in and receiving CME credit for this activity. During the period April 2013 through April 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.

Alexander Kutikov, MD, is Associate Professor of Urologic Oncology at Fox Chase Cancer Center in Philadelphia

Overview of adrenal neoplasia The most common adrenal neoplasm is an adenoma—an entirely benign lesion that can be metabolically active, producing excess cortisol or aldosterone in about 7% of cases. Myelolipoma is another benign adrenal tumor. Myelolipomas are oncologically indolent and are metabolically silent, yet they represent fascinating pathologic entities because their histologic structure is identical to that of bone marrow.1 Resection of these lesions, even when large, is rarely necessary. Unlike other adrenal lesions, pheochromocytomas arise from the adrenal medulla and can be malignant in the minority of cases. Malignant extra-adrenal pheochromocytomas, however, are much more common. Ganglioneuromas are exceedingly rare benign lesions that can stem from the adrenal gland and are often heralded by stippled calcifications on imaging. Meanwhile, cystic adrenal lesions are generally benign, but some authors recommend resection in young and non-comorbid individuals because up to 7% can be associated with malignancy.1 Importantly, unlike oncocytomas encountered in the kidney, malignant behavior is not uncommon

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CME FEATURE Table 1: Metabolic and oncologic attributes of incidental adrenal masses. Characteristics of Incidental Adrenal Masses as Described in a Systematic Review of Published Series of Adrenal Incidentalomas That Include ≥ 20 Patients (Total n=2005) Adrenal Lesion Metabolically active • Cortisol-producing adenoma • Aldosterone-producing adenoma • Pheochromocytoma Malignant • Adrenocortical carcinoma • Metastasis Total Potentially Surgical Lesions

Percent of Total (n=2005) 11.2% 5.3% 1.0% 5.1% 7.2% 4.7% 2.5% 18.4%

Data from Young WF Jr. Management approaches to adrenal incidentalomas. A view from Rochester, Minnesota. Endocrinol Metab ClinNorthAm 2000;29(1):159-85, x; and Young WF Jr. The incidentally discovered adrenal mass. N Engl J Med 2007;356(6);601-10. Source: Kutikov et al. Campbell-Walsh Urology. 9th Ed.

imaging methodology quantitates loss of contrast enhancement by a lesion and thus informs of lipid content in a given mass.8,11,13 As such, adenomas, including the atypical lipid-poor adenomas, demonstrate contrast washout, while adrenocortical carcinomas, pheochromocytomas, and metastases to the adrenal do not “wash out” on these studies.1,14 An online calculator also can be found at www.cancernomograms.com. CT washout studies demonstrate excellent test characteristics,11 but not all adenomas exhibit washout and rare adrenocortical carcinomas and pheochromocytomas have been known to demonstrate lipid-rich behavior.15,16 Importantly, standard post-contrast CT (generally obtained one minute following an iodinated contrast bolus), unlike noncontrast CT, does not provide meaningful information regarding the lipid content of adrenal masses.17 Furthermore, washout studies cannot be obtained with MRI because gadolinium-based contrast agents do not possess dose-dependent signal falloff properties that are seen for iodinated CT agents.18

Tumor size Figure 1. Large adrenal masses can be differentiated from large masses stemming from the upper pole of the kidney by the displacement of the renal unit that results from the former but not the latter pathologic entity.

(approximately 30%) in adrenal oncocytomas and thus these patients should be managed accordingly. Metastases to the adrenal glands have been described to stem from nearly every organ, but are most common from lung and renal malignancy. In appropriate patients, solitary adrenal metastases are resected.1 Adrenocortical carcinoma is an extremely rare malignancy with only approximately 300 cases diagnosed annually in the United States.5 Recent data reveal that despite increasing “incidental screening” of the adrenal gland with cross-sectional imaging of the chest and abdomen over the past two decades, there has yet to be any improvement in relative survival in patients diagnosed with the disease.5 Nevertheless, because surgical resection offers the only hope of cure, appropriate assessment of primary adrenal malignancy risk is mandatory in patients diagnosed with an adrenal mass.6

Imaging characteristics Ultrasound provides inadequate visualization of adrenal pathology, especially of the

left adrenal gland.7 As such, adrenals are best visualized with cross-sectional imaging studies. Whether employing magnetic resonance (MR) or computed tomography (CT), assessment of intracytoplasmic lipid content forms the basis of adrenal imaging, since high cellular lipid is pathognomonic for adrenal adenoma—the most common adrenal lesion.8 As such, low attenuation (less than 10 HU) on non-contrast CT scan is diagnostic for adrenal adenoma.9,10 Similarly, opposed phase chemical-shift MR imaging, as qualified by signal drop out, can prove the presence of intracellular lipid and thus confirm the presence of adrenal adenoma.10,11 Macroscopic lipid is diagnostic of myelolipoma.1 It is important to understand that non-contrast CT and MR imaging (MRI) are largely equally informative with regard to assessment of intracellular lipid. Nevertheless, 30% of adrenal adenomas are lipid-poor, also termed “atypical” by some authors, and cannot be differentiated from nonadenomas on non-contrast CT nor MRI.12 Instead, the vast majority of these lipidpoor adenomas can be characterized employing a CT washout study. This

On average, incidental adrenal masses are approximately 3 cm in diameter at the time of diagnosis.19 Meanwhile, adrenocortical carcinomas, present at a mean diameter of 11 cm.5 As such, in retrospective analyses of patient cohorts with adrenal incidentaloma, size has had a strong association with malignancy risk.7,19,20 Interestingly, as adrenal tumors grow large, the kidney is often displaced (Figure 1). Generally, this is in contrast to similarly sized tumors that stem from the upper pole of the kidney where the renal unit remains in its orthotopic location.1 The association of malignancy with tumor size at presentation has resulted in the proposal of size thresholds that necessitate resection. Generally, masses larger than 6 cm (that are not consistent with myelolipoma on imaging) are resected, given a greater than 30% risk of malignancy in retrospective series.6,7 Limited evidence exists regarding how to reconcile worrisome tumor size with reassuring imaging characteristics. Isolated case reports reveal that rare adrenocortical carcinomas can exhibit lipid-rich behavior, and thus the presence of washout on adrenal protocol CT does not completely rule out malignancy in large lesions.15,21 Meanwhile,

tumors smaller than 4 cm should largely be observed unless metabolically active.1,6 Controversy regarding management of 4-6 cm adrenal lesions exists, and decisions should hinge on clinical judgment as informed by age at diagnosis, patient comorbidities, and tumor growth kinetics.1,4,6,19,22,23

Tumor growth Current recommendations suggest imaging at 6, 12, and 24 months following identification of adrenal mass to establish tumor growth rates. 24 Certainly, worrisome adrenal masses should be imaged earlier, whereas small masses in elderly/comorbid patients in whom intervention is unlikely to be justified do not deserve such intense follow-up.1 Some authors have suggested that all masses that exhibit greater than 1 cm growth should be excised.6 In fact, 5%-9% of adrenal incidentalomas exhibit this behavior at two to three years of follow up, while malignancy risks are estimated to be 1 in 1,000 in such cases.7, 25 As such, patients who are taken for resection due to tumor growth must be counseled appropriately.1

Adrenal biopsy Although adrenal biopsy is associated with a low risk of complications, needletrack seeding by adrenocortical carcinoma and otherwise avoidable challenges during laparoscopic adrenalectomy following biopsy have been reported.26-28 Importantly, adrenal biopsy is unable to differentiate between adrenocortical carcinoma and benign adenoma and, as such, rarely yields clinical information that results in a change in management.27 If a biopsy is deemed necessary (e.g., in a patient with a primary malignancy where documentation of metastatic disease will alter management), metabolic work-up to exclude pheochromocytoma is obligatory.1

Assessment of metabolic function The incidentally-discovered adrenal mass larger than 1 cm requires metabolic evaluation, regardless of its size and imaging characteristics. In fact, more than 10% of these lesions can prove to be metabolically active following an appropriate endocrinologic work-up and thus generally require resection (Table 1).24,29 Testing must rule out

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Nothing to eat or drink after midnight the night prior to blood work. Blood work to be drawn before 9:30 am. ❑ Morning serum cortisol level (patient to have taken 1 mg of dexamethasone at 11 pm the night prior; patient cannot be on oral contraceptives) ❑ Morning serum aldosterone and renin level (to be drawn in sitting position) ❑ Morning plasma free metanephrines (no caffeine for 24 hours, no acetaminophen for 5 days, to be drawn with patient in supine position) ❑ 24-hour urine collection for cortisol level, creatinine level (patient must have normal renal function) ❑ 24-hour urine collection for metanephrine level, creatinine level (patient must have normal renal function) ❑ DHEA-S, 17B-OH-progesterone, Androstenedione, Testosterone, 17B-estradiol DIAGNOSIS: ADRENAL MASS Figure 2. Example of pre-printed laboratory instructions employed by the author that can be utilized in routine practice for metabolic work-up of adrenal incidentalomas. Highlighted laboratory studies can all be performed during the same morning blood-draw (after administration of 1mg of dexamethasone at 11pm the night before), thus lowering barriers for appropriate initial work-up of adrenal incidentalomas.

hypercortisolemia (Cushing syndrome), hyperaldosteronism (Conn syndrome), and excess catecholamine production (pheochromocytoma). While Cushing syndrome screening is recommended in all patients given that more than 5% of adrenal masses will hypersecrete cortisol, aldosterone-producing adenomas are exceedingly rare (approximately 1% of cases), and hyperaldosteronism testing is only necessary in patients with hypertension. When diagnosis of adenoma is certain on imaging, pheochromocytoma testing is generally still performed due to reports of isolated pheochromocytomas demonstrating lipid-rich imaging characteristics.16, 30 In all-comers with adrenal incidentaloma, pheochromocytoma is identified in more than 5% of patients; however, these lesions overwhelmingly exhibit lipid-poor imaging characteristics (i.e., greater than 10 HU on noncontrast CT, lack of signal drop-out on MRI, and absence of washout on adrenal protocol CT). While some practitioners choose to send all patients with adrenal incidentaloma for endocrinologic consultation, initial metabolic screening is not difficult. Low-dose dexamethasone suppression testing is often the test of choice for initial screening of hypercortisolemia, and this is accomplished by administering 1 mg of dexamethasone at 11 pm on the day prior to testing. A suppressed morning cortisol below 5 mcg/dL largely rules out Cushing syndrome.31 Late-night salivary cortisol testing is an alternative option to

the low dose dexamethasone test32, while 24-hour urinary cortisol is felt to not be sensitive enough by some experts.31 Plasma-free metanephrines or 24-hour urinary-fractionated metanephrines are the best initial screening studies to rule out pheochromocytoma.1 Although plasma-free metanephrines may not be as specific as 24-hour urinary testing, the test affords convenience since the same morning blood test can be used to screen for all adrenal hypermetabolic activity.33,34 Generally, plasma-free metanephrines greater than four times the normal value are definitive, whereas lower values represent equivocal results.1 As discussed above, Conn syndrome is exceedingly rare and only patients who exhibit or have a history of hypertension need to be tested. The morning plasma aldosterone level and an aldosterone to renin ratio (ARR) are the tests of choice. Morning aldosterone values greater than 15 ng/mL with a concomitant ARR greater than 30 are strongly suggestive of hyperaldosteronemia.6,24,35-37 Adrenal sex steroids testing is only necessary when adrenocortical carcinoma is strongly suspected, since hypersecretion of adrenal androgens and its derivative can then be harnessed as tumor markers following resection.6,38,39 Initial metabolic screening of adrenal incidentalomas is straightforward, but clinicians must be aware of pitfalls that may produce inaccurate results. A number of medications can interfere with adrenal metabolic interrogation1. The clinician must be attuned to the fact that low-dose

Figure 3. A computed tomography scan reveals a 2.5 cm adrenal pheochromocytoma (black arrow). The mass is located directly posterior to the vena cava (white arrow), illustrating the importance of having an adrenalectomy performed by experienced laparoscopic experts.43

dexamethasone suppression testing is affected by oral contraceptives and may yield false-positive results in up to 50% of female patients who use this form of birth control40. In these patients, latenight salivary cortisol testing or 24-hour urinary cortisol testing should be performed, understanding the limitations of the latter test. Importantly 24-hour urinary testing largely should be limited to patients with normal renal function. To avoid erroneous metanephrine testing, the patient should stop alpha-blockers and tricyclic antidepressants. Furthermore, caffeine (for 24 hours) and acetaminophen (for at least five days) should be avoided, as these agents can cause falsepositive results.41 With regard to testing for Conn syndrome, patients with hypokalemia should undergo potassium repletion, as low potassium levels can cause falsepositive results.42 Patients on potassiumsparing diuretics and/or mineralocorticoid receptor blockers must stop the medications for at least six weeks for hyperaldosteronism testing to be meaningful. Nevertheless, although a small proportion of patients on beta-blockers can exhibit false-positive results and some patients on ACE inhibitors may exhibit false-negative findings, most experts do not routinely recommend cessation of these antihypertensive agents during initial metabolic screening. Interestingly, calcium channel blockers generally do not affect the aldosteroneto-renin ratio.42

In summary, testing for hypercortisolemia, hyperaldosteronism, and pheochromocytoma can all be accomplished with the same blood draw. Figure 2 depicts an example of a preprinted prescription that can be used in clinical practice to streamline adrenal incidentaloma testing. The described testing represents preliminary screening for each condition and a referral to an endocrinologist is advised if this testing is positive, since confirmatory studies can be quite nuanced. Notably, all patients with hyperaldosteronism require adrenal venous sampling prior to adrenalectomy.1

Adrenal mass management following initial work-up As discussed above, re-imaging of adrenal masses is recommended at 6, 12, and 24 months following diagnosis.24 The general recommendation is to repeat metabolic work-up every year for three to four years24; however, only 2% of metabolically silent adrenal lesions will exhibit abnormal endocrinologic activity upon further testing.7 Adrenalectomy is only required in select cases, and should be performed by experienced urologic or general surgical specialists. Resection of even small adrenal masses can be challenging due to the adrenal’s perilous anatomic location. In fact, recent data suggest centra lization of adrenalectomy to highvolume hospitals has occurred over the recent years with perioperative outcomes being superior at these centers.43

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CME FEATURE Summary Adrenal masses are often incidental, but not always insignificant. Comprehensive evaluation pivots on appropriate radiologic and metabolic interrogation. Given the frequency with which adrenal lesions are encountered in clinical practice and the intimate anatomic/physiologic relationship of the adrenal gland to the kidney, both urologists and nephrologists should be familiar with evaluation of adrenal neoplasia. ■ REFERENCES 1. Kutikov A, Crispen PL, Uzzo RG. Pathophysiology, Evaluation, and Medical Management of Adrenal Disorders. In: Wein AJ, Kavoussi LR, Partin AW, Peters CA, eds. Campbell-Walsh Urology. 10th ed. Philadelphia: Elsevier; 2011:1685-1736. 2. Song JH, Chaudhry FS, Mayo-Smith WW. The incidental adrenal mass on CT: prevalence of adrenal disease in 1,049 consecutive adrenal masses in patients with no known malignancy. AJR Am J Roentgenol 2008;190:1163-1168. 3. Russell RP, Masi AT, Richter ED. Adrenal cortical adenomas and hypertension. A clinical pathologic analysis of 690 cases with matched controls and a review of the literature. Medicine (Baltimore) 1972;51:211-225. 4. Young W. Management approaches to adrenal incidentalomas: A view from Rochester, Minnesota. Endocrinol Metab Clin North Am 2000;29:159-185. 5. Kutikov A, Mallin K, Canter D, et al. Effects of increased cross-sectional imaging on the diagnosis and prognosis of adrenocortical carcinoma: analysis of the National Cancer Database. J Urol 2011;186:805-810. 6. Young WF, Jr. The Incidentally Discovered Adrenal Mass. N Engl J Med. 2007;356:601-610. 7. Barzon L, Sonino N, Fallo F, et al. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol 2003;149:273-285. 8. Boland GW. Adrenal imaging: why, when, what, and how? Part 3. The algorithmic approach to definitive characterization of the adrenal incidentaloma? AJR Am J Roentgenol 2011;196:W109-111. 9. Lee MJ, Hahn PF, Papanicolaou N, et al. Benign and malignant adrenal masses: CT distinction with attenuation coefficients, size, and observer analysis. Radiology 1991;179:415-418. 10. Korobkin M, Brodeur F, Yutzy G, et al. Differentiation of adrenal adenomas from nonadenomas using CT attenuation values. Am. J. Roentgenol 1996;166:531-536. 11. Boland GW, Blake MA, Hahn PF, Mayo-Smith WW. Incidental adrenal lesions: principles, techniques, and algorithms for imaging characterization. Radiology 2008;249:756-775. 12. Boland G, Lee M, Gazelle G, et al. Characterization of adrenal masses using unenhanced CT: an analysis of the CT literature. Am. J. Roentgenol 1998;171:201-204. 13. Pena CS, Boland GWL, Hahn PF, et al. Characterization of indeterminate (lipid-poor) adrenal masses: use of washout characteristics at contrast-enhanced CT. Radiology 2000;217:798-802. 14. Bhargav P, Mishra A, Agarwal G, et al. Adrenal incidentalomas: experience in a developing country. World J Surg 2008;32:1802-1808. 15. Simhan J, Canter D, Teper E, et al. Adrenocortical carcinoma masquerading as a benign adenoma on computed tomography washout study. Urology 2012;79:e19-20. 16. Blake MA, Kalra MK, Sweeney AT, et al. Distinguishing benign from malignant adrenal masses: multi-detector row CT protocol with 10-minute delay. Radiology. 2006;238:578-585. 17. Szolar DH, Kammerhuber FH. Adrenal adenomas and nonadenomas: assessment of washout at delayed contrast-enhanced CT. Radiology 1998;207:369-375.

18. Hussain HK, Korobkin M. MR imaging of the adrenal glands. Magn Reson Imaging Clin N Am 2004;12:515-544. 19. Mantero F, Terzolo M, Arnaldi G, et al. A survey on adrenal incidentaloma in Italy. J Clin Endocrinol Metab 2000;85:637-644. 20. Angeli A, Osella G, Ali A, Terzolo M. Adrenal incidentaloma: An overview of clinical and epidemiological data from the National Italian Study Group. Horm Res 1997;47:279-283. 21. Caoili EM, Korobkin M, Francis IR, et al. Adrenal masses: characterization with combined unenhanced and delayed enhanced CT. Radiology 2002;222:629-633. 22. Barry MK, van Heerden JA, Farley DR, Grant CS, Thompson GB, Ilstrup M.S DM. Can adrenal incidentalomas be safely observed? World J Surg 1998;22:599-603. 23. Thompson GB, Young WF Jr. Adrenal incidentaloma. Curr Opin Oncol 2003;15:84-90. 24. Grumbach MM, Biller BMK, Braunstein GD, et al. Management of the clinically inapparent adrenal mass (“incidentaloma”). Ann Intern Med 2003;138:424-429. 25. Libe R, Dall’Asta C, Barbetta L, et al. Long-term follow-up study of patients with adrenal incidentalomas. Eur J Endocrinol 2002;147:489-494. 26. Welch TJ, Sheedy PF, 2nd, Stephens DH, Johnson CM, Swensen SJ. Percutaneous adrenal biopsy: review of a 10-year experience. Radiology 1994;193:341-344. 27. Quayle FJ, Spitler JA, Pierce RA, et al. Needle biopsy of incidentally discovered adrenal masses is rarely informative and potentially hazardous. Surgery 2007;142:497-504. 28. Silverman SG, Mueller PR, Pinkney LP, et al. Predictive value of image-guided adrenal biopsy: analysis of results of 101 biopsies. Radiology 1993;187:715-718. 29. Young WF, Jr. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med 2007;356:601-610. 30. Blake MA, Krishnamoorthy SK, Boland GW, et al. Low-density pheochromocytoma on CT: a mimicker of adrenal adenoma. Am J Roentgenol 2003;181:1663-1668. 31. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526-1540. 32. Findling JW, Raff H. Cushing’s Syndrome: important issues in diagnosis and management. J Clin Endocrinol Metab 2006;91:3746-3753. 33. Grossman A, Pacak K, Sawka A, et al. Biochemical diagnosis and localization of pheochromocytoma: can we reach a consensus? Ann N Y Acad Sci 2006;1073:332-347. 34. Eisenhofer G, Siegert G, Kotzerke J, et al. Current progress and future challenges in the biochemical diagnosis and treatment of pheochromocytomas and paragangliomas. Horm Metab Res 2008; 40:329-337. 35. Montori VM, Young WF, Jr. Use of plasma aldosterone concentration-to-plasma renin activity ratio as a screening test for primary aldosteronism. A systematic review of the literature. Endocrinol Metab Clin North Am 2002;31:619-632. 36. Mulatero P, Morello F, Veglio F. Genetics of primary aldosteronism. J Hypertens 2004;22:663-670. 37. Vierhapper H. Determination of the aldosterone/renin ratio in 269 patients with adrenal incidentaloma. Exp Clin Endocrinol Diabetes 2007;115:518-521. 38. Cordera F, Grant C, van Heerden J, et al. Androgen-secreting adrenal tumors. Surgery 2003;134:874-880. 39. Moreno S, Montoya G, Armstrong J, et al. Profile and outcome of pure androgen-secreting adrenal tumors in women: experience of 21 cases. Surgery 2004;136:1192-1198. 40. Nickelsen T, Lissner W, Schoffling K. The dexamethasone suppression test and long-term contraceptive treatment: measurement of ACTH or salivary cortisol does not improve the reliability of the test. Exp Clin Endocrinol 1989;94:275-280. 41. Eisenhofer G. Editorial: biochemical diagnosis of pheochromocytoma-is it time to switch to plasma-free metanephrines? J Clin Endocrinol Metab 2003;88:550-552. 42. Young WF. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol 2007;66:607-618. 43. Simhan J, Smaldone MC, Canter DJ, et al. Trends in regionalization of adrenalectomy to higher volume surgical centers. J Urol 2012;188:377-382.

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.

CME Post-test Expiration Date: April 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. An adrenal incidentaloma that stems from the adrenal medulla: a. Can be differentiated from a cortical lesion on cross-sectional imaging b. Must be biopsied c. Secretes cortisol or aldosterone d. Demonstrates lipid-poor characteristics on imaging 2. Metabolic work-up of adrenal lesions can be omitted when: a. The patient does not have Cushinoid features b. The patient is normotensive c. Resection is already planned d. None of the above 3. Adrenal protocol computed tomography (CT) washout study: a. Is superior in characterizing lipid-poor adenomas than magnetic resonance imaging (MRI) b. Is the study of choice for lesions shown to be lipid poor on non-con CT or MRI c. Consists of a non-contrast, 1-minute post-contrast, and 15-minute post-contrast phases d. All of the above 4. Which of the following is FALSE regarding adrenal lesions that exhibit macroscopic lipid content: a. Resection is nearly uniformly unnecessary b. These lesions are pathologically identical to angiomyolipomas found in the kidney c. Hematopoietic elements are present in these lesions d. These lesions are never malignant 5. The following is TRUE regarding an adrenal mass larger than 6 cm: a. Similarly to a large upper pole renal mass, usually leaves the ipsilateral renal unit in its orthotopic location b. Usually presents with severe back pain c. Uniformly demonstrate greater than 60% washout on 15-minute CT washout studies d. Are associated with malignancy in some 30% of cases 6. The two most common malignancies associated with solitary metastases to the adrenal gland include: a. Lung and kidney cancer b. Lung and colon cancer c. Kidney and colon cancer d. Colon cancer and melanoma 7. Which of the following is TRUE about metabolic testing of adrenal incidentalomas: a. Adrenal sex steroids should be tested in all patients b. Vanillylmandelic acid levels should be tested in all patients c. Renin to aldosterone ratio should be tested in all patients d. Low dose dexamethasone suppression test entails checking a cortisol level morning after late night dexamethasone administration

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APRIL 2013

Renal & Urology News 33

Your Money S

ince the financial crisis began, investors have been dumping stocks and shifting to bonds. In the past year alone, shareholders have pulled $120 billion out of stock mutual funds and deposited $235 billion into bond funds, according to Morningstar. So far, however, it appears that investors who abandoned stocks have made a mistake. During the past three years, the Standard & Poor’s 500-stock index has returned 10.2% annually, while the Barclays Capital Aggregate bond index only returned 5.7%. Can stocks continue delivering decent long-term returns? Many analysts argue that the markets can produce at least single-digit results in the coming years. So investors should continue holding stocks. The exodus from stocks was triggered by the turmoil of the financial crisis. With the financial system about to collapse, stocks around the world fell sharply.

Irrational conclusions While they may have had cause to be wary, many investors have panicked and drawn irrational conclusions about how bad the downturns were. Consider a recent study of investor perceptions done by Franklin Templeton, a mutual fund company. The study found that investors had an unduly negative view of the market returns. In 2009, the S&P 500 returned 26.5%, but 66% of investors in the survey thought that the market had lost money that year. In 2010, the S&P gained 15.1%, but 49% of those in the survey believed that stocks declined. Figuring that stocks have returned nothing in recent years, many investors now talk about a “lost decade.” In fact, there was a brief time at the trough of the downturn when the 10-year returns

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were close to zero. Since then, the picture has improved. During the past decade, the S&P stocks returned 6.7% annually. During the past 15 years, the returns were 4.5%. Now many analysts argue that stocks will do as well in the future as they have done in recent past. One of the foremost bulls is John Bogle, founder of Vanguard Group. Bogle relies on a simple system for his predictions. He starts by looking at the dividend yield of the S&P 500. The current figure is 2%. So that is the return that investors will receive if they just collect dividends and don’t benefit from any share price appreciation. Bogle also considers the average historical growth in corporate earnings, which is about 5% to 6% annually. Stock prices tend to rise along with earnings gains, he says. Adding dividends and earnings growth, he predicts that stocks will return 7% to 8% annually over the next 10 years. Cynics may scoff at Bogle’s simple method, but his forecasts have proved remarkably accurate over the decades. In the 1990s, Bogle predicted that markets would deliver double-digit returns—a forecast that proved accurate. In 2000, he correctly warned investors to expect modest results.

Inflation erodes bond results Investors who are clinging to bonds should note Bogle’s prediction that Treasury bonds will return 2% to 3% annually in the next 10 years. According to his thinking, the return of bonds is equal to the interest that they pay. In today’s market, 10-year Treasuries yield 1.6%, while 30-year issues yield 2.7%. Bond results will be especially unsatisfying because inflation erodes the purchasing power of interest payments. Inflation is currently running at an annual rate

Most investors should hold sizable stakes in stocks to take advantage of positive economic developments BY STAN LUXENBERG

The S&P stock index has returned 10.2% annually for the past three years.

of 2%. If that continues for the next decade, bond investors would see no after-inflation gain in their assets. Another analyst who favors stocks is Michael Roberge, president of MFS Investment Management, a mutual fund company. Roberge says that investors have been frightened by reports about a variety of problems, including the European financial crisis and troubled U.S. housing markets. He concedes that these concerns could explode and take down the markets. But he argues that the odds are good that the backdrop for the markets will improve markedly in the next decade. For starters, the housing market is poised to recover. After several years when few people bought houses, there is a huge amount of pent-up demand. Now that the economy is stabilizing, sales of houses are climbing. That trend is likely to continue since prices have dropped to the point where many buy-

ers can afford to make the purchases that had been postponed.

Outlook improving in Europe The outlook in Europe is also improving. In recent years, debt problems in Greece and other countries pushed Europe into recession. That hurt export sales of U.S. goods. Now Germany and other countries have begun stepping forward to prevent a collapse and enable Europe to begin growing again within the next year. The improvements in Europe should help to prop up U.S. stocks during the next decade. To take advantage of the positive economic developments, most investors should hold sizable stakes in stocks. If you do not need to tap holdings for 10 years or longer, consider putting at least 50% of your assets in stocks. To avoid disappointment, stick with rock-solid companies or funds that hold blue chips. ■

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.

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