Renal & Urology News February 2012 Issue

DIFFERENCES IN the level of infl am-mation among dialysis patients may explain, in part, why African Americans have better survival than Caucasians, study fi ndings suggest.

Deidra C. Crews, MD, of Johns Hopkins University School of Medicine in Baltimore, and colleagues prospec-tively studied 816 dialysis patients—554 Caucasians and 262 African Americans—for a median of three years (range four months to 9.5 years). The mortality rate at fi ve years was 34% for Africans Americans compared with 56% for Caucasians, Dr. Crews’ team reported in the Journal of the American Society of

ESRD Survival Paradox Linked to Inflammation

RCC Tied to Lead ExposureBY JODY A. CHARNOWHIGHER BLOOD lead levels are associated with an elevated risk of renal cell carcinoma (RCC), according to a study.

The study, led by Robin Taylor Wilson, PhD, of Pennsylvania State University College of Medicine in Hershey, includ-ed 154 individuals with a new diagnosis of RCC and 308 matched controls. The subjects were male Finnish smokers participating in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The mean follow-up time was 12.1 years for cases and 18.1 years for controls.

Compared with subjects in the fi rst quartile of blood lead level (below

2.50 µg/dL), those in the fourth quartile (4.66 µg/dL and higher) had a twofold increased risk of RCC after adjusting for confounders, the research-ers reported in Cancer Epidemiology, Biomarkers & Prevention (published online ahead of print). Higher total serum calcium was associated with a signifi cantly reduced risk of RCC. Compared with subjects in the fi rst quartile of serum calcium (below 9.50 mg/dL), those in the fourth quartile (10.30 mg/dL or higher) had a 70% decreased risk.

In addition, the study showed that among cases alone, lower baseline serum

continued on page 11

CME FEATURE Earn 1 CME credit in this issue

The Management of Patients AfterRenal TransplantationPAGE 28


IN THIS ISSUE

10 Renal cell carcinoma associated with red meat intake

12 MIs are often not recognized in CKD patients

17 Bladder cancer is more likely to recur in diabetics

19 Study characterizes pediatric enterococcal UTIs

22 Renal risks lower with metformin than sulfonylureas

EHR shortcomings could raise

malpractice risk

PAGE 20

BY JODY A. CHARNOWHIGH CALCIUM and uric acid excretion are associated with vesi-coureteral refl ux (VUR) in children, and this could increase their risk for urinary stones, new fi ndings suggest. Consequently, children with VUR should be closely followed for the development of urinary stones, inves-tigators concluded.

In a study comparing 108 children with VUR (19 boys and 89 girls) and 110 healthy children (30 boys and 80 girls) with no history of refl ux or uri-nary tract infection, Iranian research-

ers found that a signifi cantly higher proportion of the VUR group had hypercalciuria and hyperuricosuria (21.3% vs. 3.6% and 18.5% vs. 1.8%, respectively). Both hypercalciuria and hyperuricosuria combined occurred in 6.5% of the VUR group but not in any of the controls.

After adjusting for age and gender, VUR was associated with a signifi cant 4.5 times and 6.9 times increased like-lihood of hypercalciuria and hyper-uricosuria, respectively. After further adjustment for independent variables and hyperuricosuria, VUR patients

had a 4.4 times increased likelihood of hypercalciuria.

Thirty-two VUR patients (29.6%) had urinary stones; of these, 15 (46.9%) had hypercalciuria and 10 (31.2%) had hyperuricosuria. No child in the control group had a urinary stone.

In a report in Pediatric Nephrology (2012;27:95-99), researchers at Tehran University of the Medical Sciences noted that the medical literature pro-vides no evidence of a genetic link between hypercalciuria and VUR, “but

New Stone Risk in VUR PatientsHypercalciuria, hyperuricosuria implicated


VESICOURETERAL REFLUX may be genetically linked to hypercalciuria.

F E B R U A R Y 2 0 1 2 ■ ■ ■ V O L U M E 1 1 , I S S U E N U M B E R 2 ■ ■ ■ www.renalandurologynews.com

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6 Renal & Urology News FEBRUARY 2012 www.renalandurologynews.com

Let Patients Sleep During Rounds

How often do you face with the unpleasant task of wak-ing a sleeping patient dur-

ing your busy rounds? It happens frequently to many clinicians during their inpatient rounds in the hospital. But it happens even more often when nephrologists go to outside dialysis clinics to round on their dialysis out-patients. Many patients sleep during their hemodialysis (HD) treatment. Not infrequently the physician feels compelled to wake the patient for a variety of important reasons, such as obtaining the most current information on the patient’s state of well-being and to fulfi ll the medicolegal requirement of a documented face-to-face visit with a real-time interview and physical examination. We tend to believe that this is practicing good medicine.

When was the last time you felt better when somebody interrupted your sleep? Would you have appreciated this if you were sick and yet people would constantly come to wake you up? In the hospital this hap-pens under different circumstances, such as checking patients’ blood pressure or measuring capillary blood sugar, pill intake calls, and blood draws early in the morning (in some hospitals as early as 5 a.m.). This ongoing sleep deprivation leads to daytime naps, which are constantly interrupted by many other activities, including doctors’ rounds.

Sleep is a fundamental requirement for health maintenance. Evidence suggests that chronic lack of sleep is linked to a predisposition to upper respiratory and viral infection, diabetes mellitus, heart disease, mental disorders, and obesity. Sleep is a quiescent period during which many organ systems, including the immune system, readjust their activities. A sick patient usually needs adequate sleep. There is virtually no disease condition where sleep deprivation or sleep interruption is considered favorable. In particular, dialysis patients are chronically ill people who would defi nitely benefi t from some more sleep, including during their three to four hours of HD treatments. How can we call ourselves the healing advocates if we practice the opposite and interrupt the sleep of our patients?

Each week, I round on 60 to 70 dialysis patients in different dialysis clinics and encounter many sleeping patients. Sometimes I round on these patients during the last 20-30 minutes of their HD treatment so that I can let them sleep longer without interruption. I instruct dialysis clinic staff to avoid doing anything that can disturb patients’ sleep, no matter which shifts they attend. There are other alternatives to meet the medico-legal requirements of the face-to-face patient encounter other than waking up a sleeping patient. Let’s adhere to our sworn principle of “fi rst do no harm,” and let patients sleep well.

Kamyar Kalantar-Zadeh, MD, MPH, PhDAssociate Professor of Medicine and Pediatrics, and Director, Dialysis Expansion & Epidemiology, Harbor-UCLA Division of Nephrology & Hypertension

Dr. Kalantar-Zadeh is Medical Director, Nephrology, for Renal & Urology News.

FROM THE MEDICAL DIRECTOR

EDITORIAL ADVISORY BOARD

Renal & Urology News (ISSN 1550-9478) Volume 11, Number 2. Published monthly by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Periodicals postage paid at New York, NY, and an additional mailing offi ce. 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 © 2012.

Renal & Urology News Staff

Editor Jody A. Charnow Executive editor Marina Galanakis Senior editor Delicia Honen Yard Web editor Stephan Cho Editorial coordinator Candy Iemma Group art director, Haymarket Medical Jennifer Dvoretz Assistant art director Natasha Marcano-Dillon VP, audience development and operations John Crewe Production manager Kathleen Millea Product manager, digital products Chris Bubeck Circulation manager Paul Silver Assistant circulation manager Monica Bond National accounts manager William Canning Editorial director Tanya Gregory Publisher Dominic Barone VP medical magazines and digital products Jim Burke CEO, Haymarket Media Inc. Lee Maniscalco

Medical Director, Urology

Robert G. Uzzo, MD, FACSG. Willing “Wing” Pepper Chair in Cancer ResearchProfessor and ChairmanDepartment of Surgery Fox Chase Cancer Center Temple University School of MedicinePhiladelphia

Urologists

Frank R. Cerniglia Jr, MDAttending Pediatric UrologistChildren’s Urology of VirginiaRichmond, Va.Christopher S. Cooper, MDDirector, Pediatric UrologyChildren’s Hospital of IowaIowa CityR. John Honey, MDHead, Division of Urology,Endourology/Kidney Stone DiseasesSt. Michael’s HospitalUniversity of TorontoStanton Honig, MDAssociate Clinical Professor of Surgery/UrologyUniversity of Connecticut School of Medicine, Urology CenterNew HavenJ. Stephen Jones, MD, FACSChairmanDepartment of Regional UrologyCleveland ClinicGlickman Urological & Kidney InstituteProfessor of SurgeryCleveland ClinicLerner College of Medicineof Case Western Reserve UniversityJames M. McKiernan, MDAssistant Professor of UrologyColumbia University Collegeof Physicians and SurgeonsNew York CityKenneth Pace, MD, MSc, FRCSCAssistant ProfessorDivision of UrologySt. Michael’s HospitalUniversity of TorontoRyan F. Paterson, MD, FRCSCAssistant ProfessorDivision of Urologic SciencesUniversity of British ColumbiaVancouver, Canada

Medical Director, Nephrology

Kamyar Kalantar-Zadeh, MD, PhD, MPHProfessor of Medicine and Pediatrics, and Director, Dialysis Expansion & Epidemiology Harbor-UCLA Division of Nephrology & Hypertension Los Angeles BioMedical Research Institute, The David Geffen School of Medicine at UCLA

Nephrologists

Anthony J. Bleyer, MD, MSProfessor of Internal Medicine/NephrologyWake Forest University School of MedicineWinston-Salem, N.C.

Suphamai Bunnapradist, MDDirector of ResearchDepartment of NephrologyKidney Transplant Research CenterThe David Geffen School of Medicine at UCLA

R. Michael Hofmann, MDAssociate Professor and Medical Director, Living Kidney Donor Program University of Wisconsin School of Medicine and Public Health, Madison

Csaba P. Kovesdy, MDAssociate Professor of Clinical Medicine University of Virginia, CharlottesvilleChief of NephrologySalem VA Medical CenterSalem, 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 Offi cer, DaVita Inc.

Rulan Parekh, MD, MSAssociate ProfessorJohns Hopkins Children’s Center, BaltimoreRobert Provenzano, MDChief, Section of NephrologySt. John Hospital and Medical Center, DetroitRobert S. Rigolosi, MDDirector, Regional Hemodialysis CenterHoly Name Hospital, Teaneck, N.J.

Lynda Anne Szczech, MD, MSCEAssociate Professor of NephrologyDuke University School of MedicineDurham, N.C.


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

Antibiotic Lock Reduces Catheter-Related Problems An antibiotic catheter lock containing gentamicin in sodium citrate can

decrease the incidence of catheter-related bloodstream infections in patients on maintenance hemodialysis (MHD), researchers reported in the American Journal of Kidney Diseases (2012;59:102-107).

In a randomized study of 303 adult MHD patients, the rate of catheter-related bloodstream infections among those who received an antibiotic lock of gentamicin 320 µg/mL in 4% sodium citrate was 0.28 episodes per 1,000 catheter-days compared with 0.91 episodes/1,000 catheter-days among patients receiving the standard catheter lock containing heparin 1,000 U/mL. The time to fi rst episode of bacteremia was signifi cantly delayed for the treatment group. The two groups had similar rates of tissue plasminogen activator use: 2.36 events/1,000 catheter days for the gentamicin/citrate patients versus 3.42 in the heparin group.

Older Age at RP Increases Urinary Incontinence Risk

A man’s age at radical prostatectomy (RP) for prostate cancer affects his risk of developing long-term urinary incontinence (UI), Swedish researchers

reported in BJU International (2011;108;1572-1577).The investigators, from the Karolinska Institutet in Stockholm, analyzed data

from questionnaires completed by 1,288 men who had undergone RP a median of 2.2 years earlier. Among the respondents, 19% of the oldest patients reported UI compared with 6% of the youngest, investigators reported.

Additionally, UI prevalence was elevated among men who had undergone salvage radiation therapy, those with respiratory disease, and subjects with lower educational level, the researchers commented. Prostate weight, body mass index, diabetes, or previous transurethral resection did not appear to affect UI prevalence. The researchers defi ned UI as the use of two or more pads per day at follow-up.

Correcting Anemia Can Protect Renal Allografts

Correcting anemia reduces progression of chronic allograft nephropathy in kidney-transplant recipients, a prospective study suggests. It also decreases

the incidence of end-stage renal disease and improves quality of life. After two years of treatment with epoetin beta to keep Hb levels in the normal range of 13.0 to 15.0 g/dL (63 kidney-transplant recipients) or at a lower concentra -tion of 10.5 to 11.5 g/dL (62 recipients), 4.8% of patients with completely cor-rected anemia developed kidney failure, compared with 21% of those with par-tially corrected anemia. Gabriel Choukroun, MD, PhD, and co-investigators also noted in Journal of the American Society of Nephrology that 94.6% of transplanted kidneys in patients with completely corrected anemia were functional, compared with 80% in the partial-correction group. The number of cardiovascular events was low and similar in both groups.

BP Drugs May Differ in Cardiovascular Benefi tsACE inhibitors and angiotensin recep-tor blockers (ARBs) confer different cardiovascular benefi ts in hemodialy-sis (HD) patients, researchers found.

In a crossover study, 15 HD patients received placebo, the ACE inhibitor ramipril 5 mg per day for seven days, and the ARB valsartan 160 mg/day for another seven days, with a washout period of three weeks between treatments. Neither ramipril nor valsartan affected blood pressure during dialysis treatment. Valsartan induced a greater anti-infl ammatory effect compared with ramipril, but ramipril appeared to prevent dialysis-induced endothelial dysfunction, T. Alp Ikizler, MD, and colleagues reported online in the Journal of the American Society of Nephrology.

Kidney Cancer Tiedto Red Meat IntakeGreater intake of red meat may increase the risk of renal cell carcino-ma (RCC), according to study fi ndings reported in The American Journal of Clinical Nutrition (2012;95:155-162). Over a mean follow-up of nine

years, 1,814 RCC cases developed among 492,186 U.S. adults aged 50 years and older. Compared with a red meat intake of 9.8 g per 1,000 kcal (median), intake of 62.7 g/1,000 kcal (median) was associated with a non-signifi cant 19% increased risk of RCC and a signifi cant twofold increased risk of papillary RCC. Intakes of the carcinogens BaP and PhiP, which are associated with grilled or barbecued meats, raised RCC risk by 20% to 30% and doubled the risk of papillary RCC.

Statins May Lower Prostate Tumor RiskA population-based investigation demonstrated that statin use was associated with substantial protec-tion against death from prostate cancer. Stephen W. Marcella, MD, MPH, of the University of Medicine and Dentistry of New Jersey in New Brunswick, and colleagues reported online in Cancer that based on the medical records of 380 men aged 55-79 years and 380 matched controls, those who died from the disease were 63% less likely to have ever taken a statin.

Short Takes

Based on the responses to a recent Renal & Urology News web poll, it appears that the vast majority of our physician readers practice defensive medicine. The poll asked, “Do you ever order diagnostic tests or scans to protect yourself from malpractice suits rather than because they are medically necessary?” Here are the results from 109 respondents.

Practicing Defensive Medicine

No

Yes

85.3%

14.7%

Based on the respto a recent Renal Urology News webs

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MYOCARDIAL INFARCTION (MI) often goes unrecognized among patients with chronic kidney disease (CKD), and it is associated with a signifi cantly increased risk of death, according to researchers.

Of 18,864 participants in a popula-tion-based study who completed a base-line examination that included a 12-lead electrocardiogram (ECG), 852 (4.5%) had unrecognized MIs (UMIs) and 1,365 had recognized MIs (RMIs).

The prevalence of UMIs increased with lower levels of renal function and higher albuminuria levels. The preva-lence was 4%, 6%, 6%, and 13% for subjects with an estimated glomerular

fi ltrate rate (eGFR) of 60 or higher, 45-59.9, 30-44.9, or less than 30 mL/min/1.73 m2, respectively, investiga-tors reported online ahead of print in Nephrology Dialysis Transplantation. The prevalence was 4%, 5%, 7%, and 10% among subjects with an albumin-uria-to-creatinine ratio (ACR) of less than 10, 10-29.9, 30-299.9, and 300 or greater mg/g, respectively.

The researchers, led by Dana V. Rizk, MD, of the University of Alabama in Birmingham, defined UMIs as the presence of an MI (according to the Minnesota ECG classifi cation) in the absence of self-reported or RMI.

Among subjects with an eGFR below 60, UMI and RMI each was associated with a 65% increased risk of all-cause mortality compared with the absence of MI, after adjusting for multiple variables. UMI and RMI were associ-ated with a 49% and 88% increased risk among subjects with an ACR of 30 mg/g or higher.

Dr. Rizk’s group found that tradi-tional cardiovascular risk factors such

as age, male gender, hypertension, and smoking were associated with a greater risk for UMI. “Interestingly, however, other risk factors like diabetes and dyslipidemia were not, raising the pos-sibility that UMI may have a different mechanistic etiology than RMI,” the authors wrote.

Subjects were participants in the pop-ulation-based REGARDS (Reasons for Geographic and Racial Differences in Stroke) study.

The authors noted that study strengths included the very large number of par-ticipants from throughout the United States, with an oversampling of African Americans. “This is particularly impor-tant because African Americans rep-resent a substantial proportion of the CKD population, especially at the more advanced stages,” the research-ers observed.

In a discussion of study limitations, they noted that their categorization of UMI versus RMI was based on self-report and may be subject to recall bias. ■

COMBINED EXTERNAL BEAM radia-tion therapy (EBRT) with a brachyther-apy boost plus androgen deprivation therapy (ADT) is associated with excellent disease-free survival among men with intermediate risk prostate cancer (PCa), researchers reported. The treatment also is associated with acceptable acute and late toxicity.

That conclusion is based on a study in which 61 men with inter-mediate risk PCa received this combined treatment. After a median follow-up of 73 months, the six-year disease-free survival rate was 87%, 75%, and 85% using the study protocol defi nition, the 1997 American Society for Thera -peutic Radiation and Oncology (ASTRO) consensus defi nition, and the Phoenix defi nition, respectively. Six-year overall survival was 96%, according to study fi ndings published in Cancer (2011;117:5579-5588).

The protocol defi nition of biochemical recurrence was three consecutive rises in PSA greater than 1.0 ng/mL after 18 months from the start of treatment. The 1997 ASTRO defi nition is three consecutive PSA increases above nadir and the Phoenix defi nition is nadir plus 2 ng/mL. The protocol and subse-quently the Phoenix defi nitions were developed because of the tendency of the 1997 ASTRO defi nition to falsely indicate biochemical failure, which can occur because of PSA rises resulting from testosterone rebound after ADT cessation.

Late grade 2 and 3 toxicity, exclud-ing sexual dysfunction, occurred in 20% and 3% of patients, respectively. The investigators, led by Mark D. Hurwitz, MD, of Brigham and Women’s Hospital in Boston, noted that although treatment effi cacy is impor-tant, “the impact of any treatment on disease control or eradication has to be considered in the larger context of toxicity and quality of life.” ■

Combination Effective for Intermediate Risk PCa

REPEATED INJECTIONS of botu-linum toxin type A (BoNTA) are safe and effective for the medium-term management of refractory overactive bladder (OAB) and idiopathic detrusor overactivity (IDO), according to British investigators.

In a study of 100 patients who received 207 BoNTA injections for refractory OAB and IDO, researchers observed signifi cant decreases in urinary frequency and urgency and urge urinary inconti-nence after the fi rst BoNTA injection compared with baseline. These improve-ments were maintained after repeated injections and did not differ signifi cantly when comparing differences between injections, the authors reported online ahead of print in European Urology.

Prior to their BoNTA treatment, study patients previously had failed treatment with at least antimuscarinic drug. In the study, all 100 patients received one BoNTA injection, 53 had two injections, 20 had three, 13 had four, 10 had fi ve, fi ve had six, three had seven, one had eight, one had nine, and one had 10. Patients received onabotulinumtoxinA injections over a study period of about six years. Most were injected with 200 U.

After the fi rst and second injections, 25 (25%) and 12 (22%) patients,

respectively, did not undergo addi-tional injections, but afterwards drop-outs were rare, according to a research team led by Arun Sahai, MD, of Guy’s

Hospital in London. The most common reasons for discontinuing treatment were poor effi cacy, which was observed in 13% of patients, and issues related to clean intermittent self-catheterization (CISC), experienced by 11%. The inci-dence of CISC was 35% after the fi rst injection. Bacteriuria occurred in 21% of patients within the fi rst month. New urinary tract infections occurred in 15% of patients, which the investigators said is favorable when compared with evidence from double-blind, placebo-controlled studies showing rates of 13% to 43%.

“It is clear from all of these studies that there is a signifi cantly higher rate of UTI in patients receiving BoNTA rather than placebo, although the

exact mechanism remains unclear,” the researchers wrote. “It is possible that we are introducing bacteria deeper into the bladder during the injection procedure or that it is related to the use of CISC.”

The investigators said they observed a decrease in the interval between injec-tions over the fi rst three injections from more than 400 days to about 300 days. The authors explained that initially, “as limited information was available regarding BoNTA safety and with reports of distal muscle weakness after bladder injection, repeated injections were not performed too soon for fear of toxin accumulation.”

Consequently, willing patients were given antimuscarinics to improve symptom control, with repeated injec-tions offered when symptoms truly deteriorated to baseline levels, the authors related. “Later in our experi-ence, we offered repeated injections sooner and, in almost all cases, with-out an interval with antimuscarinics,” they stated.

To their knowledge, their study con-sisted of the largest series of patients to date treated with repeated onabot-ulinumtoxinA injections for refrac -tory IDO. ■

Repeated BoNTA Injections OkaySustained improvements in patients with refractory OAB and IDO

MIs Often Unrecognized in Patients With CKD

Poor effi cacy led to discontinuation of treatment in 13% of patients.

Ultrasound Not Inferior for Sizing Renal MassesULTRASOUND IMAGING works as well as computed tomography (CT) and magnetic resonance imaging (MRI) for evaluating renal mass size, a new study suggests.

The fi nding “might be benefi cial for long-term active surveillance protocols to contain healthcare costs and reduce radia-

tion exposure,” researchers concluded.Phillip Mucksavage, MD, of the

University of California in Irvine, and colleagues studied 116 patients who underwent ultrasound imaging prior to defi nitive therapy for a renal mass. These patients also underwent CT (66 patients) or MRI (80 patients). Thirty-three patients

underwent all three imaging modalities. The average pathologic tumor size for the entire cohort was 4.45 cm.

The renal mass size differences between CT and MRI compared with ultrasound were nonsignifi cant (less than 3.5%), Dr. Mucksavage’s team reported in Urology (2012;79:28-31).

For patients who underwent ultrasound and CT, the average tumor size was 4.73 cm and 4.57 cm, respectively. For those who underwent ultrasound and MRI, the average tumor size was 4.65 cm and 4.49 cm, respectively. For patients who underwent ultrasound, CT, and MRI, the average tumor size was 4.47 cm, 4.27 cm, and 4.29 cm, respectively.

In an accompanying editorial, Maxwell V. Meng, MD, of the University of California, San Francisco, School of Medicine, observed: “Although the urologist is traditionally most comfort-able interpreting cross-sectional images, particular CT, we must question the established paradigms and evolve to incorporate comparable modalities with less morbidity for the patient and reduced cost for the healthcare system.” ■

RFA Benefi ts Selected RCC PatientsIN APPROPRIATELY selected patients, radiofrequency ablation (RFA) is an effective minimally invasive treat-ment for cT1a renal cell carcinoma (RCC) that offers long-term oncologic outcomes comparable to nephron-sparing surgery, data show.

In a study of 74 patients with cT1a RCC—of whom 37 underwent RFA and 37 underwent partial nephrectomy (PN)—Jeffrey A. Cadeddu, MD, and colleagues at the University of Texas Southwestern Medical Center in Dallas compared fi ve-year outcomes associated with the two treatments. Five-year overall survival with RFA and PN was 97.2% and 100%, respectively, accord-ing to a report in European Urology (published online ahead of print). Cancer-specifi c survival was 97.2% and 100%, disease-free survival was 89.2% and 89.2%, local recurrence-free survival was 91.7% and 94.6%, and metastasis-free survival was 97.2% and 91.8%. None of the dif-ferences between the groups was statistically signifi cant.

The median follow-up was 6.5 years and 6.1 years for the RFA and PN groups, respectively. ■


Brief Summary: Consult package insert for complete Prescribing Information

INDICATIONS AND USAGE:Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in Full Prescribing Information).

DOSAGE AND ADMINISTRATION:Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions).

Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry.

HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva.

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS: Hypocalcemia. Xgeva can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, 2.2% of patients receiving Xgeva developed ONJ; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse Reactions). Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling:

(see Warnings and Precautions)(see Warnings and Precautions)

The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia.

Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Information) in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion.

Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46%

and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy.

Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Severity (Trials 1, 2, and 3)

a Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria:

5% greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid)

b Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL (0.71 – 0.9 mmol/L) for phosphorus]

Severe Mineral/Electrolyte Abnormalities

1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes (see Warnings and Precautions and Use in Specific Populations).

than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic acid.

Osteonecrosis of the JawIn the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic acid group (see Warnings and Precautions). When events occurring during an extended treatment phase of approximately 4 months in each trial are included, the incidence of confirmed ONJ was 2.2% in patients who received Xgeva. The median time to ONJ was 14 months (range: 4 – 25).

Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There was no evidence that various

anticancer treatments affected denosumab systemic exposure andpharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormonetherapy (see Clinical Pharmacology [12.2] in full Prescribing Information).

USE IN SPECIFIC POPULATIONS:Pregnancy: Category C. There are no adequate and well-controlled trials ofXgeva in pregnant women. Use Xgeva during pregnancy only if the potential benefit justifies the potential risk to the fetus. Encourage women who become pregnant during Xgeva treatment to enroll in Amgen’s Pregnancy SurveillanceProgram. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. In an embryofetal developmental study, cynomolgusmonkeys received subcutaneous denosumab weekly during organogenesis atdoses up to 6.5-fold higher than the recommended human dose of 120 mgevery 4 weeks, based on body weight (mg/kg). No evidence of maternal toxicity

during the first trimester, and fetal lymph nodes were not examined. Potential adverse developmental effects resulting from exposures during the second and third trimesters have not been assessed in animals (see Nonclinical Toxicology [13.2] in full Prescribing Information). In genetically engineered mice in which the gene for RANK ligand (RANKL) has been deleted (a “knockout mouse”), the absence of RANKL caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice alsoshowed altered maturation of the maternal mammary gland, leading to impaired lactation postpartum (see Use in Nursing Mothers).

Nursing Mothers. It is not known whether Xgeva is excreted into human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgevaduring pregnancy may impair mammary gland development and lactationbased on animal studies in pregnant mice lacking the RANK/RANKL signalingpathway that have shown altered maturation of the maternal mammary gland,leading to impaired lactation postpartum (see Nonclinical Toxicology [13.2] infull Prescribing Information).

Pediatric Use. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth inchildren with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL with a construct of osteoprotegerin bound toFc (OPG-Fc) at doses less than or equal to 10 mg/kg was associated withinhibition of bone growth and tooth eruption. Adolescent monkeys dosed with denosumab at 5 and 25 times (10 and 50 mg/kg dose) higher than therecommended human dose of 120 mg subcutaneously every 4 weeks (based on body weight mg/kg) had abnormal growth plates (see Nonclinical Toxicology [13.2] in full Prescribing Information).

Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacywere observed between these patients and younger patients.

Renal Impairment. In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with acreatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance of less than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology [12.3] in full Prescribing Information).

OVERDOSAGE: There is no experience with overdosage of Xgeva.

PATIENT COUNSELING INFORMATION:Advise patients to contact a healthcare professional for any of the following:

twitching, spasms, or cramps (see Warnings and Precautions and Adverse Reactions)

the jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions)

(see Warnings and Precautions)

(see Use in Specific Populations)Advise patients of the need for:

Advise patients that denosumab is also marketed as Prolia®. Patients shouldinform their healthcare provider if they are taking Prolia®.

Body SystemXgeva

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GA STROINTESTINAL Nausea Diarrhea

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Thousand Oaks, California 91320-1799©2011 Amgen Inc.

All rights reserved. Printed in USA.

©2011 Amgen Inc. All rights reserved. 63850-R1-V1 12/11 www.XGEVA.com

REFERENCES: 1. Saad F, Gleason DM, Murray R, et al, for the Zoledronic Acid Prostate Cancer Study Group. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with

metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96:879-882. 2. Ibrahim A, Scher N, Williams G, et al. Approval summary for zoledronic acid for treatment of multiple myeloma and cancer

bone metastases. Clin Cancer Res. 2003;9:2394-2399. 3. Yu EY, Nathan FE, Higano CS. Role of detection of metastatic disease as a leading cause of screening failure in an ongoing phase III trial of zibotentan

versus placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC). J Clin Oncol. 2011;29(suppl 7). Abstract 135. 4. Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical

trial end points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223-5232. 5. Tannock IF, de Wit R, Berry WR, et al, for the TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer. N Engl J Med. 2004;351:1502-1512. 6. Petrylak DP, Tangen CM, Hussain MHA, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate

cancer. N Engl J Med. 2004;351:1513-1520. 7. XGEVA® (denosumab) prescribing information, Amgen. 8. Saad F, Gleason DM, Murray R, et al, for the Zoledronic Acid Prostate Cancer Study Group. A randomized, placebo-

controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458-1468.

GREATER COMORBID illness increases the likelihood of complications after radical cystectomy for bladder cancer among patients older than 70 years, according to a study by German researchers.

In this patient age group, those with an American Society of Anesthesi-ologists (ASA) score of 3 or greater—indicating severe systemic diseases—had a signifi cantly higher rate of perioperative complications than those with an ASA score of 2 or less—indicating mild systemic diseases (37% vs. 25%), investigators reported online in the World Journal of Urology. An ASA score is a global score that assesses the physical status of patients before surgery. For the study, the researchers defi ned periop-erative complications as any adverse event within 30 days of surgery.

“A careful consideration of individual comorbidity is important in both preparing the patient for surgery and during the whole perioperative

management,” the authors concluded. “Improved attention to reasonable perioperative processes during radical cystectomy can result in better patient outcomes.”

Vladimir Novotny, MD, and colleagues at Technical University Dresden studied 830 patients who underwent radical cys-tectomy. Of these, 365 (44%) were aged 70 years and older (elderly) and 465 (56%) were younger than 70. The elderly cohort had a signifi cantly higher preva-lence of concomitant diseases, such as hypertension (57.3% vs. 38.5%), coro-nary heart disease (27.1% vs. 14.8%), and diabetes (25.5% vs. 14.6%), as well as a signifi cantly greater rate of periop-erative complications (31% vs. 21.5%). The elderly patients had a signifi cant 44% increased risk of perioperative complica-tions compared with younger patients.

Additionally, subjects with chronic ob-structive pulmonary disease (COPD) had a signifi cant 1.8 times increased risk of perioperative complications compared to those without COPD. ■

Fiber Lowers Death Risk in CKD PatientsEach 10 g/day increment in total dietary fi ber was associated with a 19% decreased risk, study fi nds

HIGH INTAKE of dietary fiber is associated with decreased infl amma-tion and all-cause mortality in patients with chronic kidney disease (CKD), according to researchers.

An analysis of data from 14,533 par-ticipants in the third National Health and Nutrition Examination Survey showed that each 10 g/day increment in total fi ber intake is associated with 38% and 11% decreased likelihood of having elevated C-reactive protein (CRP)—a marker of systemic infl am-mation—in patients with and without CKD, respectively, after adjusting for age, gender, race, and numerous comor-bid conditions and laboratory mea-sures, according to a report in Kidney International (published online ahead of print).

The investigators, led by Vidya M. Raj Krishnamurthy, MD, of the University of Utah School of Medicine in Salt Lake City, defi ned CKD as an estimated glomerular filtration rate

below 60 mL/min/1.73 m2 and an elevated CRP as a serum CRP level above 3 mg/L.

In addition, each 10 g/day increment in total dietary fi ber was associated with a 19% decreased risk of all-cause mortal-ity in the CKD subpopulation. Dietary fi ber was no longer associated with mor-

tality in this population after adjusting for serum CRP, suggesting that reduction in infl ammation is a possible mechanism by which dietary fi ber lowers mortality in CKD patients, according to researchers. The study found no association between dietary fi ber intake and all-cause mortality in the non-CKD participants.

The authors noted that various mech-anisms could explain the association between high dietary fi ber intake and decreased serum CRP. Dietary fi ber may inhibit infl ammation by lower-ing glycemic load of rapidly digestible and absorbable dietary carbohydrates, they pointed out. High fi ber diets have been associated with higher plasma levels of adiponectin, which has anti-infl ammatory properties.

Toxic substances such as phenols, indoles, and amines produced by colonic bacterial metabolism are other possibilties. These metabolic end products are absorbed from the gut and might have a role in systemic infl ammation, they stated. These sub-stances normally would be excreted via the kidney, but they accumulate in patients with kidney disease. This could explain why the association of higher dietary fi ber with lower infl am-mation is stronger in the CKD than non-CKD population. By altering gut

bacterial metabolism, they observed, a high-fiber diet likely decreases production and absorption of these toxins, thus decreasing systemic con-centrations of these toxins more in the CKD population than in the non-CKD population.

The researchers pointed out that high-er dietary fi ber intake was associated with lower serum levels of interleukin-6 and tumor necrosis factor-alpha recep-tor-2 in postmenopausal women in the Women’s Health Initiative Study and that dietary fi ber intake was associated with lower serum CRP in cross-sectional and longitudinal studies involving the general population.

With regard to study limitations, the authors noted that their study was observational and retrospective, which limits causal inference. In addition, residual confounding due to unmea-sured variables cannot be ruled out and diet was assessed using only a single 24-hour diet recall. ■

DIABETES MELLITUS (DM) appears to be an independent predictor of dis-ease recurrence and progression among patients who have undergone surgery for non-muscle invasive bladder cancer (NMIBC), according to investigators.

In a retrospective study of 251 patients who underwent transurethral resection (TUR) for NMIBC, the 92 patients with DM at the time of surgery had a twofold and ninefold increased risk of disease recurrence and progression, respectively, compared with non-DM patients, after adjusting for multiple possible confounders, researchers reported in the International Journal of Urology (2011;18:769-776). The DM patients were older and had a higher rate of hypertension compared with the patients without diabetes.

Additionally, compared with patients who had a hemoglobin A1c level below 7%, those with high levels (represent-ing poor glycemic control) had a signifi -cantly greater tumor multiplicity, more high-grade tumors, and received signifi -cantly more intravesical therapy.

The investigators, led by Seung Il Jung, MD, and colleagues at Chonnam National University Medical School in Gwangju, Korea, concluded that “close follow-up and intravesical therapy may be benefi cial in patients with DM, especially those with poor glycemic control.”

The mechanism by which DM con-tributes to bladder cancer is unclear. In a discussion of some of the possibilities, the researchers cited studies suggesting that chronic exposure to hyperinsuline-mia or hyperglycemia induces tumor cell proliferation and metastasis, and that increased insulin-like growth factor in diabetic patients stimulates cellular proliferation and inhibits apoptosis. Furthermore, studies have demonstrated an association between diabetes and an increased risk of urinary tract infection (UTI), which has been related to blad-der cancer risk, and UTI may affect the incidence of recurrence or progression, the authors observed.

The researchers noted that their study is limited by its retrospective design, relatively small sample size, and the low frequency of tumor recur-rence and progression. They also pointed to the fact that they did not assess the duration of DM, which may have been affected by recall bias or a period of undetected DM. ■

Bladder Ca Worse in Diabetics

Comorbid Illnesses Worsen Post-Cystectomy Outcomes

www.renalandurologynews.com FEBRUARY 2012 Renal & Urology News 17

Survival benefi t could be related to a reduction in infl ammation.


Renal Nutrition Update

Research has shown that indivi -duals who exercise have lower risk for chronic diseases than

individuals who do not exercise. Woolf et al (J Am Dietetic Assoc 2008;108:948-959) conducted a clinical trial com-paring chronic disease risk factors in healthy women by the number of steps they took. The active group, which took more than 7,500 steps as measured by a pedometer, had signifi cantly lower serum insulin and leptin concentra -tions and lower body mass index (BMI) than the group taking fewer than 7,500 steps. Additionally, when the number of steps were expressed in tertiles, and the tertiles were statistically compared, both BMI and waist circumference were signifi cantly lower in the tertile with the most steps.

CKD patient challengesPatients who have chronic kidney dis-ease (CKD) and especially those with end-stage renal disease on dialysis are quite likely to have multiple comor-bidities (such as hypertension, cardio-vascular disease, anemia of chronic disease, and diabetes) and take multiple medications (antihypertensive agents, phosphate binders, lipid and glucose lowering drugs, and others). Thus, rou-tinely engaging in physical activity is more diffi cult and may be unsafe if the activity is not carefully monitored.

A 2006 Polish study (Nephrol Dial Transplant 2006;21:1323-1327) showed that hemodialysis (HD) patients have signifi cantly lower activity, as measured by steps with a pedometer, than patients not receiving HD (6,896 vs. 14,181 steps per 48 hours, respectively). More recently, Avesani et al (Nephrol Dial Transplant 2011; published online ahead of print) determined that HD patients’ activity was comparable with a sedentary life style. This study used a multisensory device to measure steps taken, activity-related energy expenditure, and physical activ-ity level. A high BMI or diabetic status was associated with a signifi cantly lower physical activity level, and older age and diabetic status were associated with fewer steps. Additionally, all parameters were signifi cantly lower during dialysis days when compared to non-dialysis days.

Improved quality of lifeAccording to a 2011 review and meta-analysis by Heiwe and Jacobson (Cochrane Database Syst Rev 2011;[10]) in patients with CKD, physical activity signifi cantly improves quality of life (QoL), nutrition parameters (serum albumin and pre-albu-min), blood pressure and heart rate, and aerobic and walking capacity. However, even with the knowledge that patients with CKD are less active and that physical activ-ity can improve key outcome parameters in this population, many clinicians would

be unsure how to engage their patients in regular physical activity in a safe, well-monitored environment.

Two recent review articles have been published on how to initiate an exercise program in both CKD prior to dialysis (Am J Kidney Dis 2012; 59:126-134) and for patients on dialysis (Chonnam Med J 2011;47:61-65). Both reviews outline the types of exercise to consider and ways to monitor outcomes.

Exercising during dialysisA 2010 study by Chen et al (Nephrol Dial Transplant 2010;25:1936-1943) outlines a very practical intradialytic exercise program that achieved positive outcomes. In this study, the authors enrolled 50 HD patients and random-ized them to either intradialytic low intensity strength training or to stretch-ing. Patients engaged in resistance exer-cise during the second hour of dialysis, two times a week, for 48 sessions. The exercise consisted of a five-minute warm up and cool down and resistance exercise with ankle weights. The ankle weights were increased in 0.5 pound increments during the trial.

At the end of the trial, 44 patients could be analyzed for the primary out-

come, the short physical performance battery score (SPPB). The investigators evaluated both physical parameters and QoL changes. The SPPB improved sig-nifi cantly in the strength training group compared with the stretching group (21% vs. 0.2%) and the Short Form-36 physical composite score improved signifi cantly in the intervention group compared with the control group (21% vs. -0.2%). Interestingly, patient adher-ence to the exercise regime was 89%.

The Chen study shows a practical and inexpensive way to have dialysis patients exercise in the dialysis center, where they are closely monitored and the health care team can encourage and support the activity. CKD patients have many challenges that can decrease their QoL. Engaging in physical activity on a regular basis, such as while on dialysis, may promote an anabolic state to enhance body composition and nutritional status thereby resulting in reduced hospitaliza-tion, improved mortality risk, and an overall improved QoL. ■

Dr. Steiber is Coordinator of the Dietet-ic Internship/Master’s Degree Program at Case Western Reserve University in Cleveland.

Regular physical activity can help dialysis patients enhance body composition, nutritional status, and quality of life BY ALISON L. STEIBER, PhD, RD, LD

Many clinicians would be unsure how to engage CKD patients in regular physical activity in a safe, well-monitored environment.

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Exercise RecommendationsIn a recent paper published in the American Journal of Kidney Diseases (2011;59:132-140), authors Kirsten L. Johansen, MD, and Patricia Painter, PhD, noted that the optimal recommendations for exercise in CKD patients have not been determined but that it is reasonable to follow recommenda-tions contained in a 2002 report issued by an American College of Cardiol-ogy/American Heart Association task force for older adults. These recom-mendations “are explicitly intended to be relevant to younger individuals with clinically signifi cant chronic conditions and/or functional limitations, a description that applies to patients with CKD.”

The recommendations for older adults are as follows: “To promote and maintain health, older adults need moderate-intensity aerobic physical activity for a minimum of 30 minutes on fi ve days each week or vigorous intensity aerobic activity for a minimum of 20 minutes on three days each week.”

NON-MUSCLE-INVASIVE bladder tumors 15 mm or less in diameter are associat-ed with a lower risk of recurrence after surgical treatment compared with larger tumors, according to researchers.

In addition, their study of 768 patients who underwent transurethral resection for non-muscle invasive bladder cancer (Ta/T1) showed that differentiating tumors into three size categories can provide additional information in pre -dicting recurrence.

Investigators at University Hospital, Linköping, Sweden, led by Georg Jancke, MD, categorized tumors according to fi ve sizes (1-10, 11-20, 21-30, 31-40, and greater than 40 mm in diameter) or three sizes (1-15, 16-30, and greater than 30 mm in diameter).

Of the 768 patients, recurrence oc-curred in 478 (62%) and progression occurred in 71 (9%). In the fi ve-size group, tumors 21-30 mm in diameter were associated with a signifi cant 57% increased risk of recurrence compared with tumors 1-10 mm in diameter, after

adjusting for multiple variables, Dr. Jancke and colleagues reported in the Scandina-vian Journal of Urology and Nephrology (2011;45:388-392). Tumors 31-40 and greater than 40 mm were associated with a signifi cant 2.2 and 2.7 times increased risk of recurrence, respectively. In the three-size group, tumors 16-30 mm and greater than 30 mm in diameter were associated with a signifi cant 42% and 2.4 times increased risk of recurrence com-pared with tumors 1-15 mm in diameter. T1 tumor category and local recurrence were signifi cant risk factors for progres-sion, but tumor size was not.

Other factors associated with recur-rence were multiplicity, tumor category, and surgery performed by residents.

The researchers recommend the three-size over the fi ve-size model because it makes measuring easier: 15 mm and 30 mm correspond to about two and four times the diameter of the resection loop, respectively. Thus, the authors noted, it has a high reproducibility and can be easily used in clinical practice. ■

COMMUNITY-ACQUIRED urinary tract infections (UTIs) in children caused by enterococcal bacteria are associated with a high rate of underlying urinary abnormalities, a study found. As a result, renal imaging of pediatric patients with these types of UTIs is recommended, according to researchers.

In addition, in a fi ve-year prospective study of 355 children at the Schneider Children’s Medical Center of Israel in Tikva, investigators there found that enterococcal infections were not sus-ceptible to antibiotics commonly used empirically to treat UTIs.

Of the 355 children hospitalized for cultured proven UTIs, 22 (6.2%) had enterococcal bacteria as the causative pathogen, investigators reported in Pediatric Nephrology (2012;27:109-114). Underlying urinary abnormalities were identifi ed in 70% of patients with entero-coccal UTIs compared with 43.7% of those with Gram negative UTIs. Renal abnormalities in the enterococcal UTI

group included vesicoureteral refl ux (53% of patients), hydronephrosis, and extrarenal pelvis.

Antibiotic susceptibilitiesAll of the enterococcal isolates were uniformly resistant to cephalosporins, whereas Gram negative isolates had a 24%, 7%, and less than 5% rate of resistance for fi rst-, second-, and third generation cephalosporins, respectively.

Additionally, compared with Gram negative bacteria, enterococcal iso-lates were signifi cantly less commonly resistant to ampicillin (10% vs. 69%) and more common resistant to ofl oxa-cin (20% vs. 6%). All Gram negative isolates were uniformly resistant to vancomycin but all enterococcal isolates were susceptible to the drug.

Inappropriate empiric antibiotic treat-ment was given about four times more frequently to patients with enterococcal than Gram negative infections (22%

vs. 5.6%). Cefuroxime and ceftriaxone were the inappropriate antibiotics given empirically to treat enterococcal UTIs. After obtaining culture results, appro-priate antibiotics were administered to patients with enterococcal UTIs based on the known susceptibility results, the researchers stated.

In light of the high rates of renal abnor-malities in children with enterococcal

UTIs, “we recommend routine imaging in such cases, at least with the non-inva-sive and safe technique of ultrasonogra-phy,” the investigators noted.

The investigators, led by Gilat Livni, MD, observed that most pediat-ric UTIs are caused by Gram negative bacteria, particularly Escherichia coli. Among the Gram positive organisms, Enterococcus is the most common genus. Since Enterococcus species are almost the only species causing Gram positive UTIs in young children, “they can be detected early by using Gram stain of the urine, which we recommend performing, espe-cially in such circumstances as the presence of underlying urinary abnormalities or ineffectiveness of previous cephalosporin or other antibiotic treatment.”

They also observed, “Timely and appro-priate administration of antimicrobial therapy is essential for eliminating symp-toms, eradicating infection, reducing the likelihood of renal damage, and prevent-ing complications.” ■

Enterococcal UTIs in Kids CharacterizedThese infections may indicate urinary tract abnormalities, and empiric therapy often is inappropriate

A WIDELY USED PSA threshold for recommending prostate biopsy (4.0 ng/mL) has remained unchanged over time despite some calls to lower the threshold, according to researchers.

Steven B. Zeliadt, PhD, of the Department of Veterans Affairs Medical Center in Seattle, and col-leagues reviewed laboratory and biopsy records of 59,764 men in Group Health, a large integrated health care system in Washington State for the period 1998-2007. The study showed that 28% of tests with PSA levels of 4.0 or above were followed up with a prostate biop-sy within 12 months, the researchers reported online in the American Journal of Preventive Medicine. More than 40% of tests showing a PSA level of 4.0 or above had a urology follow up without a biopsy within 12 months, and more than 30% did not have any PSA-related follow-up within 12 months. The study also showed that 2.9% of PSA tests with levels between 2.5 and 4.0 and 0.4% of tests below 2.5 were followed with a biopsy within 12 months.

The predicted probability of biopsy for men with a PSA level of 4.0 ng/mL or higher was 33%, 29%, and 28.3% for the periods 1998-2001, 2002-2004, and 2005-2007, respectively. Further analyses indicated no signifi cant change in biopsy threshold during the study period.

The likelihood of biopsy was strong-ly associated with PSA velocity, the researchers found. Among men with PSA levels of 4.0 or higher, those with a rapidly rising PSA velocity were sig-nifi cantly more likely to undergo biopsy than those with a slow-growing velocity (36.9% vs. 21.7%).

“The present study highlights the importance of acknowledging that aggressiveness of biopsy is an impor-tant component of the PSA screening discussion, as even small changes in the PSA threshold can substantially alter the potential harms and benefits of screening,” the authors concluded.

In addition, Dr. Zeliadt’s group found that urologists were 13% more likely than primary care doctors to order a biopsy. The researchers explained in Group Health “it is likely that the majority of tests performed by urologists were diagnostic or related to other genitourinary condi-tions as men do not see urologists for routine primary care services.” Thus, the increased biopsy rate might have been due to the presence of other symptoms. ■

PSA Threshold for Biopsy Still Stable

Enterococci are a relatively uncommon cause of pediatric UTIs.

Smaller Bladder Tumors Less Likely to Recur After Surgery


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Diagnosis-Related Suits Tied to Communication Failures

Physicians who regularly order diagnos-tic tests for their patients may be at an increased risk of medical malpractice suits, according to a recent study. The risk for lawsuits comes not from the diagnostic tests, however, but rather from communication breakdowns in how the results for those tests are being conveyed.

Between 1996 and 2003, malprac-tice payments based on diagnosis rose approximately 40%. A major cause of these malpractice cases was commu-nication failures, for example, failure of physicians and patients to receive results of tests; delays in reporting fi nd-ings; and lengthy turnaround time to receiving results of diagnostic tests. Researchers at the State University of New York (SUNY) Downstate Medical Center in Brooklyn looked at the cor-relation between communication fail-ures and malpractice claims awards. The study, published in the Journal of the American College of Radiology, exam-ined data from the National Practitioner Data Bank (NPDB) from 1991 to 2010. Claims related to communication failures increased from $21.7 million in 1991 to $91 million in 2010. Analysis of the NPDB claims data from 1991 to 2009 suggested that claims payments increased at the national level by an average of $4.7 million annually. Over the same period, NPDB data showed that communication failure awards accounted for an increas-ing proportion of the total malpractice awards for all providers—the proportion increased by a factor of 1.7 from 1991

to 2009. The authors speculated that this may be because patients have an expectation of more reliable notifi cation of medical test data, or that the drastic growth in diagnostic testing has outpaced notifi cation reliability. Lead author Brian D. Gale, MD, MBA, Assistant Professor of Radiology at SUNY Downstate, and his co-authors recommend that hospitals and health care organizations need clear policies to defi ne the responsibility of reporting and following up with patients. In addition, the authors suggest that the “advent of semi-automated critical test result management systems may improve notifi cation reliability, improve workfl ow and patient safety, and, when necessary, provide legal documentation.”

National Practitioner Data Bank Closed to the Public

The Department of Health and Human Services (HHS) has shut down public access to its National Practitioner Data Bank (NPDB). The NPDB contains confi dential information on malpractice awards and disciplinary actions against physicians. This information is used by hospitals, health insurance companies, and medical boards to grant licenses and privileges. A public component of the data bank allowed the public to see a version of the information that did not contain identifying information such as names and hospitals. The public version also did not show specifi c dol-lar amounts of awards, or specifi c ages (rather, it used age ranges).

HHS decided to shut down public access to the data bank due to what it

called the media’s ability to “triangu-late” the confi dential data using court records to fi nd out classifi ed informa-tion. It has been reported that a con-tributing factor in the HHS decision was a complaint by a surgeon who was mentioned in an article in the Kansas City Star about the reluctance of state regulators to discipline doctors with his-tories of malpractice. The reporter who wrote the article used several sources to write his story—one of which was the NPDB. After this complaint, the HHS decided to remove public access. “The public use fi le for the National Practitioner Data Bank was removed because we have a responsibility to uphold the law that created the data bank, which states that information about individual practitioners must remain confi dential,” said HHS spokes-man Martin Kramer.

The move has sparked outrage among journalists and consumer advo-cacy groups such as Public Citizen, Consumers Union, the Society of Professional Journalists, the Association of Health Care Journalists, and Investigative Reporters and Editors. Senator Charles Grassley (R-Iowa) has also publicly criticized the move, writ-ing that “shutting down public access to the data bank undermines the criti-cal mission of identifying ineffi ciencies within our health care system—partic-ularly at the expense of Medicare and Medicaid benefi ciaries.”

Electronic Health Records May Increase Malpractice Risk

Electronic health records (EHRs) seem like a good idea at fi rst glance. They can provide more accurate health records, reduce errors based on handwriting, and provide all treating physicians with access to the same patient data. However, a recent report suggests that the rush to move to EHRs may result in inadequate EHR software, accord-ing to a white paper published by the AC Group, a Texas-based health information technology research and consulting fi rm. This could actually expose physicians to a greater risk of malpractice lawsuits. The paper calls on federal offi cials to slow the adop-

tion of a federal incentive program that aims to get hospitals and medical practices to use EHRs. The artifi cial-ly short deadlines for implementing the EHRs could cause vendors to cut corners and rush training and testing,the authors warn.

“As is often the case, technology is advancing more rapidly than our ability to identify and address the medicole-gal issues,” they wrote. “The result of this uneven progression is that phy-sicians and other stakeholders may be unknowingly exposed to medical liability risk.”

The authors looked at the functional-ity of 42 ambulatory EHRs and found

that almost 90% could not provide drug-lab alerts, more than 80% did not check for drug interactions during the prescription refi ll process, and 60% failed to automatically update clinical decision support to refl ect changes in recommended treatments. Most EHRs also do not account for family medical history in creating alerts and do not check drug orders against laboratory results.

Other critics of EHRs warn that they create malpractice risk as they present an overwhelming volume of informa-tion that a doctor may be unable to read completely.

The white paper recommends that EHR vendors consider external prod-uct reviews for potential malpractice concerns. ■

Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

Malpractice News BY ANN W. LATNER, JD

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Better communication could avert a lawsuit

Public access to the NPDB

denied following

a surgeon’s complaint.

Inadequate EHR software could

expose doctors to more liability.

SUBSTANTIAL PROPORTIONS of living kidney donors have diminished renal function one year following their nephrectomy, investigators reported.

In a study of 169 living kidney donors, Imran Sajjad, MD, and colleagues at Brigham and Women’s Hospital in Boston compared donors who had a 25% or greater rise in plasma creati-nine from before donation to one year after nephrectomy with those who had less than a 25% increase during that period.

At one year post-nephrectomy, 131 (78%) donors had a 25% or greater increase, 27% had a 50% or great-er increase, and 31% had a 0.4 mg/dL or greater increase in plasma creatinine compared with their pre-donation values.

In addition, the researchers found an association between mean arterial pressure (MAP) and a plasma creatinine rise of 25% or greater one year post-nephrecto-my. Each 1 mm Hg increment in MAP at the time of donation was associated with

a 6% increased risk of having a 25% or greater increase in plasma creatinine.

“There are few data addressing post-nephrectomy kidney function in con-temporary living donors,” said Julie Lin, MD, MPH, FASN, senior author of this study. “We were surprised to fi nd that relatively high proportions of donors met established clinical defi ni-tions for lower kidney function whereas the general expectation has been for higher levels of recovery at one year. Donors deserve quality information on the expected course of kidney function change after nephrectomy.”

At last year’s European Association of Urology annual congress, a British researcher presented fi ndings of a study of 3,424 individuals who underwent liv-ing donor nephrectomy (LDN) showing that a year after LDN, 53% of donors could be classifi ed as having CKD stage 3-4. Mean glomerular fi ltration rate (GFR) did not change significantly between year 1 and year 5.

Not all studies, however, have dem-onstrated a decline in renal function following LDN. In fact, a Swedish study presented last year at the XIII International Congress of The Transplantation Society showed that living kidney donors experience an increase in GFR for more than a decade after nephrectomy. ■

WORSENING OF chronic kidney disease (CKD) stage in the fi rst year following re-nal transplantation is associated with an increased risk of graft failure, research-ers reported.

The fi ndings, from a study of 77,206 adult Medicare benefi ciaries who re-ceived a kidney-only transplant, suggest that patient management strategies targeted at preserving renal function in the early post-transplant period will have a positive impact on graft survival, ac-cording to the investigators.

“Given the scarceness of donor organs, management strategies targeted at pre-serving renal function will have not only clinical implications but economic conse-quences as well,” said lead investigator William Irish, PhD, of CTI Clinical Trial and Consulting Services. “Furthermore, the results can be used to inform the design of a clinical trial where the primary objec-tive is to preserve renal function.”

The study showed, for example, that renal transplant patients who progressed from CKD stage 3 at six

months post-transplant to CKD stage 4 at 12 months had a 3.5 times increased risk of graft failure compared with pa-tients who remained in CKD stage 3 at 12 months post-transplant, and a 53% graft survival rate versus 85% at four years, respectively. Patients who pro-gressed from stage 3 to stage 5 from month 6 to month 12 had an 11.5 times increased risk of graft failure and 20% graft survival at four years compared to patients who remained in CKD stage 3 at 12 months post-transplant.

“Change in renal function in the early period post-transplantation is an impor-tant prognostic determinant of long-term graft survival,” Dr. Irish told Renal & Urology News. “These results provide further evidence that preserving renal function has a positive impact on the net benefi t of kidney transplantation.”

For the study, Dr. Irish’s team used estimated glomerular fi ltration rate thresholds established by the National Kidney Foundation defi nitions for CKD stage. ■


Renal & Urology News editor Jody A. Charnow provided news coverage. ■ Kidney Week 2011, Philadelphia

INITIATING TREATMENT of type 2 diabetes with sulfonylurea drugs is associated with an increased risk of renal function decline, end-stage renal disease (ESRD), or death compared with starting treatment on metformin, according to new study fi ndings.

Compared with patients who initiated diabetes treatment with metformin, those who started with sulfonylureas had an adjusted 20% increased risk of a primary outcome of a persistent decline in esti-mated glomerular fi ltration rate (eGFR) of 25% or more (eGFR event) or diag-nosis of ESRD. In addition, sulfonylurea use was associated with an adjusted 20% increased risk of a secondary outcome of an eGFR event, ESRD, or death com-pared with metformin use.

The researchers, led by Adriana M. Hung, MD, MPH, Assistant Professor

of Medicine at Vanderbilt University in Nashville, Tenn., and a Veterans Affairs Career Development Awardee, observed no difference in risk between metformin and rosiglitazone with respect to either the primary or secondary outcome.

The study examined a retrospective cohort of 93,577 veterans (mean age 62 years, 78% white, and 96% male) with type 2 diabetes who fi lled their fi rst prescription for an oral antidiabetic drug between October 1, 2001 and September 30, 2008, and had an eGFR of 60 mL/min/1.73 m2. The group included 61,104 patients who started on metformin, 30,550 who started on a sulfonylurea drug, and 1,923 who started on rosiglitazone.

“There are important renal benefi ts to using metformin compared to sulfony-lurea,” Dr. Hung told Renal & Urology

News. “This effect could potentially be related to the increasingly recognized anti-inflammatory and antioxidant effects of metformin.”

“The findings of this large study support the current recommenda-

tions of metformin as fi rst-line thera-py for patients with diabetes type 2,” Dr. Hung added.

Previous researchThe study is not the fi rst to show that metformin is associated with lower risks than a sulfonylurea drug. At the American Diabetes Association annual meeting in 2011, researchers reported that older patients with type 2 diabetes have a signifi cantly higher likelihood of experiencing a cardiovascular (CV) event within two years if they start treat-ment with a sulfonylurea drug than with metformin. The incidence of CV events was 14.8% among patients who started therapy with a sulfonylurea compared with 11.6% among those who started on metformin within two years of follow-up. ■

Renal Risks Lower with Metformin UseNew fi ndings support the use of the drug as fi rst-line treatment for patients with type 2 diabetes

Key Points■ Metformin less likely than sulfony-

lureas to cause 25% or greater eGFR decline or lead to ESRD

■ No increased risk observed with rosiglitazone compared with metformin

■ The lower risks with metformin could be related to its antioxidant and anti-infl ammatory effects

Worsening Post-Transplant CKD Hikes Graft Failure Risk

Living Kidney Donors Suffer Renal Decline


Extracorporeal shock wave lithotripsy (ESWL) has been the gold standard for the treatment of urinary-tract stones, but are we moving away from that approach in favor of fl exible ureteroscopy or another technique?Dr. Lingeman: Shock wave lithotripsy is still probably the most common treatment done in the U.S. for most stones. The peculiar circumstance here is that while we always assume that technology is going to improve, that hasn’t been the case with lithotripsy. And the reason is that the companies that built these machines starting back in the 1980s didn’t really understand how they worked, so it was hard for them to improve them.

Dornier built the fi rst lithotripter, and did a brilliant job. When they tried to change it and improve it, they were unable to improve it because they didn’t understand the basic physics of how it worked. In fact, it got worse, progres-sively, as they tried to change things. It changed, but not for the better.

The reason we know that [the attempt-ed improvements] were on the wrong track is that we [Dr. Lingeman and fellow researchers at Indiana University School of Medicine] have had a grant from the National Institutes of Health for about 20 years looking at the basic science of shock wave physics and how it works. And we’ve learned a lot of things that the original developers have only recently acknowledged to be correct about the way in which lithotripsy works.

Now that we’ve gained so much knowledge since the lithotripter fi rst came into use in the early 1980s, can’t we just make our own improved version?Dr. Lingeman: We actually are thinking about building our own lithotripter. There

is one very small company in Germany [trtllc.com], headed by an engineer who started with Dornier 30 years ago. He’s attended some of our research meetings and understands what we want. He has built and is marketing a machine in the United States that is, we feel, a better concept than the other machines.

What makes it better?Dr. Lingeman: The original lithotripter, which we actually still use at Methodist Hospital—we’ve tried others; they haven’t worked as well so we kept the old one—has a very wide focus so that when the shock wave is targeted on the kidney stone, there’s a large area [receiving shock waves]. That makes it relatively easy to hit the stone. Most newer machines have very small focal zones, and because patients breathe and the kidney therefore moves during treatment, it becomes quite a challenge to keep the shock wave targeted on the stone. So that’s a problem.

A second problem is that the newer lithotripters have much higher pres-sures in their focal zone, and this is damaging to renal tissue, particularly if you’re missing the stone much of the time as you do with small focal zones.

What we’ve learned from our research is you don’t need these high pressures to break up kidney stones. The Lithogold, manufactured by TRT, employs a broad focal zone but with low pressures in the focal zone. It produces minimal tissue effects on the kidney, but still breaks up stones so it’s a better balance between safety and effi cacy, in my opinion.

Where does fl exible ureteroscopy fi t into the picture?Dr. Lingeman: Ironically, in the fi eld of ureteroscopy, there have been steady advancements over the last two decades

more along the lines of what we would expect to happen with medical technol-ogy. As the endoscopes that we’ve used have gotten smaller, they’ve gotten bet-ter. We have very good lasers and other devices that we use with these, and as it turns out, you can now basically treat most stones [with fl exible ureteroscopy].

Ureteroscopy started around the same time as shock wave lithotripsy, and at that time our instruments were large and rigid—infl exible—so you couldn’t get them up into the kidney. You could only treat stones in the lower ureter. But now these instruments are fl exible and they’re small. We can run them up into the kidney. Now, any stone that you can treat with ESWL, you can treat with fl exible ureteroscopy and a laser. Ureteroscopes have become increasingly popular, and the technology is much, much less expensive than ESWL.

So why bother improving ESWL?Dr. Lingeman: For properly selected patients, ESWL is attractive because it is non-invasive. Both ESWL and uretero-scopy typically are done under anesthe-sia, so there’s not much difference there. Some people say you can do ESWL with just a sedative, but in the United States, few patients are treated that way. Almost everybody goes to sleep. This way, the doctor can control the patient’s respiration and therefore the movement of the kidney, so the stone is hit more

effectively and the results are better. A signifi cant disadvantage of fl exible ureteroscopy is that we usually have to leave a ureteral stent afterwards, because passing our telescopes through the small ureter tubes can cause swell-ing, which may result in temporary obstruction. To prevent that, we leave a stent, typically for a few days to a few weeks. Stents are irritating. Most patients dislike them, so that’s a disad-vantage of ureteroscopy.

Are any other techniques used to treat urinary tract stones?Dr. Lingeman: For most patients, the com-mon procedures are ESWL and ureteros-copy. Patients with large stones—greater than 2 cm—are treated with another mini-mally invasive procedure called percuta-neous stone removal. It goes by several different names, but that’s a good generic name for it. We make a 1 cm incision in the fl ank and insert a tube into the kidney, which allows us to insert our endoscope directly into the kidney. The advantage of that procedure is we can use larger instruments and we can remove stones much more effi ciently that way.

How popular is percutaneous stone removal?Dr. Lingeman: It actually was introduced a couple of years before ureteroscopy. It’s been around for a long time, and the techniques have been refi ned over the years. It’s increasing slowly in popularity as more physicians become more com-fortable doing it. Most urologists don’t do the procedure because it is more complicated technically. Fortunately, most kidney stones are relatively small and can be treated successfully with either ESWL or ureteroscopy. It’s a very rare patient that would need a traditional type of open surgery these days.

What about medical expulsive therapy?Dr. Lingeman: Medical expulsive therapy is the use of medications to facilitate stone passage. Most kidney stones are small and will pass on their own, albeit not without some discomfort for the patient. There is evidence to suggest that certain medications will help the stone pass more quickly if the stone is not too large. Now, understand that medical expulsive therapy is not an established indication for these medications, accord-ing to the FDA.

Better Lithotripsy On the HorizonA leading authority on kidney stone

disease, James E. Lingeman, MD, of Indiana University Health, updates

Renal & Urology News on the state of urinary stone

treatment. In a conversation with senior editor

Delicia Honen-Yard he explores the possible rebirth of

extracorporeal shock wave lithotripsy, and the

pursuit of the “holy grail” in fl exible ureteroscopy.

“The holy grail for us in urology is fi nding a stent that doesn’t hurt.”


QA&

Supplemental Vitamin D Helps Black HypertensivesBY JILL STEINORLANDO—Vitamin D supplementa-tion may reduce blood pressure (BP) in African-American patients with hypertension in a dose-dependent manner, regardless of the intensity of antihypertensive treatment, research-ers announced at the American Heart Association Scientifi c Sessions 2011.

“The fi ndings, if confi rmed in future studies, will have huge therapeutic and public health implications because vitamin D can potentially be a very useful adjunct to conventional antihy-pertensive treatment,” John Flack, MD, Chairman of the Department of Internal Medicine at Wayne State University in Detroit, told Renal & Urology News.

The investigators examined the longitu-dinal relationship between vitamin D sup-plementation and BP change, and control independent of antihypertensive drug treatment intensity in a largely African-American referral hypertensive cohort. African-Americans are known to have a high prevalence of vitamin D defi ciency and hypertension.

While vitamin D levels have repeat-edly been shown to correlate inversely with blood pressure and hyperten-sion risk both in cross-sectional and prospective epidemiological studies, previously reported vitamin D supple-

mentation studies have been “mostly but not exclusively” negative, Dr. Flack pointed out.

He was quick to emphasize, how-ever, that the earlier studies have not typically required randomized par-ticipants to have vitamin D defi -ciency (defi ned as a vitamin D level 20 ng/mL or less) or hypertension and they have also used relatively low levels of vitamin D ingestion (1000 IU/day or less).

The present study included 648 pa-tients with a mean baseline blood pres-sure of 156/92 mm Hg, and a mean baseline serum vitamin D level of 17.6 ng/mL, about two thirds of whom were women. The median follow-up was 10.6 months, or fi ve clinic visits.

Results showed that subjects who ingested 2000 IU/day or more of vitamin D had a BP reduction of 10/7 mm Hg. Subjects who took less than 2000 IU/day had a BP reduction of 4/3 mm Hg.

Overall, the BP-lowering effect was most pronounced at vitamin D doses of 2000 IU/day or higher in those with baseline serum vitamin D levels of 15 ng/mL or less.

The fi ndings are consistent with two positive randomized trials of vitamin D supplementation for BP lowering on multiple counts, Dr. Flack said. The three studies had similar pro-spective BP reductions with vitamin D supplementation. In addition, in all three studies, those individuals with the lowest baseline vitamin D

levels who received higher levels of supplementation also had the largest BP reductions. Additionally, in all three studies, vitamin D had a more marked effect on systolic than diastolic blood pressure.

“To our knowledge, ours is the largest prospective report of the blood pressure response to vitamin D sup-plementation in African Americans,” Dr. Flack said. “Though generalizability to the broader population is limited, our results are strengthened by the fact that we followed a high-risk cohort and had a relatively long period of follow-up and used relatively high daily doses of vitamin D.”

Potential limitations, he added, include the study’s non-randomized design. Further, residual confound-ing, despite the inclusion of multiple potential confounding variables, may have infl uenced the results.

Finally, he said that the fi ndings apply mostly to black hypertensives, espe-cially women, given the demographic composition of the study cohort. ■


What sort of medications would be used for this?Dr. Lingeman: Primarily alpha blockers. They are used for hypertension and for benign prostatic hyperplasia, but there’s some evidence that suggests these agents might help in passing ureteral stones.

What is your opinion?Dr. Lingeman: I use alpha blockers. Most urologists do. But there has not been a well-done study to qualify these drugs for this indication by the FDA. Most of the trials that have been published to date are small trials from Europe, and I would not classify the data as defi nitive. I would say it’s suggestive; these drugs are quite safe, so we commonly use them because if there is some evidence to sug-gest that they’re helpful, then it seems like it’s a reasonable thing to do.

Would you like to see more studies in this area, or do you think researchers’ time is better spent elsewhere?Dr. Lingeman: We do need more data—especially U.S. data. There are ongo-ing trials. I would say that most of the studies that have been published on this have been positive studies, meaning that they have found a benefi t.

How do you see stones being treated in fi ve or 10 years?Dr. Lingeman: Well, the holy grail for us in urology is fi nding a stent that doesn’t hurt. Some people tolerate the stents quite well, but many are miserable with them. It’s completely different than with vascular stents. The inside of the urinary tract is very sensitive. The stents are temporary, fortunately, but they can interfere with the patient’s ability to work and function. Companies have spent tens of millions of dollars trying to fi nd a more comfortable stent. If we could fi nd a stent that didn’t hurt, then I believe that most patients would be best managed with fl exible ureteroscopy and the holmium laser.

Why is that?Dr. Lingeman: Because the ESWL machine might come only once or twice a month to your hospital, so if you have a stone, you have to wait, whereas most hospitals have fl exible ureteroscopes; they’re continuously available. ■

Better Lithotripsy

continued from page 23

BP dropped by 10/7 mm Hg in patients taking at least 2,000 IU/day.

Fewer Prostate Cancer Patients Are Initiating ADT, Data Shows INITIATION OF androgen depriva-tion therapy (ADT) for prostate cancer (PCa) is declining and patterns of use are changing, according to recently pub-lished data from a Canadian study.

Using a population-based cohort of 26,809 patients in Ontario who started ADT from 1995 to 2005, researchers found that the rate of ADT initiation declined from 16 to 7 per 100 person-years even though PCa prevalence dou-bled during that period. The number of patients initiating ADT increased from 1995 to 2001 (2,106-2,916 patients per year) and decreased thereafter to 2,200-2,300 patients per year by 2005.

Additionally, the study revealed that pat-terns of ADT initiation varied by regimen and indication. Medical castration rose from 12% of all ADT in 1995 to 47% in 2005, whereas orchidectomy declined from 17% to 4%, Murray Krahn, MD, of Toronto General Research Institute, and colleagues reported in BJU International (2011;108:1588-1596).

ADT use for metastatic disease remained stable, but adjuvant treat-ment increased from less than 3% of all ADT in 1995 to 14% in 2005. The trends could be related to the declining

prevalence of late-stage disease, a grow-ing appreciation of the potential adverse effects of ADT, and emerging evidence supporting selected indications and regi-mens, the researchers observed.

The study cohort consisted of PCa patients in Ontario who started 90 days or more of ADT at age 66 years or older.

Dr. Krahn’s group noted that ADT was originally used for metastatic disease, but it is now used for many other indications. They also observed that there has been growing concern about the costs and adverse effects associated with wider ADT use. Documented adverse effects of ADT include hot fl ushes, sexual dysfunc-tion, loss of libido, decreased bone min-eral density, and increased fat mass.

The main strength of the study was its comprehensiveness. The study evaluated all regimens and all indications for ADT in a large population-based sample of patients with PCa over 11 years. In a discussion of limitations, they pointed out only initial ADT use and indication. Although they examined duration of ADT to determine some indications. They did not describe duration beyond 90 days or changes in regimen. ■

Remember to visit us atrenalandurologynews.com

for more interviews with thought leaders in urology

and nephrology.


ELEVATED LEVELS of serum para-thyroid hormone (PTH) and fi broblast growth factor-23 (FGF-23) are asso-ciated with an increased likelihood of progression of vascular calcifi cation (VC) in hemodialysis patients, accord-ing to French researchers.

In a study of 85 patients still alive after three years, 38 (44.7%) had expe-rienced radiographic progression of vascular calcifi cation and 47 (55.3%) did not (non-progressors).

The study, led by Guillaume Jean, MD, a nephrologist at NEPHROCARE Tassin-Charcot in Saint Foy-les-Lyon, revealed that median PTH levels and FGF-23 levels were signifi cantly higher in progressors compared with non-progressors (244.3 vs. 179.6 pg/mL and 4204 vs. 2640 RU/mL, respectively). Subjects with serum PTH values above

190 pg/mL and FGF-23 values above 3,000 RU/mL had a 5.8 times increased likelihood of vascular calcifi cation progres-sion compared with patients with lower values, according to investigators.

With regard to specifi city and sensitiv-ity in predicting CV progression, the optimal cut-off values were 191 pg/mL for PTH and 3,025 RU/mL for FGF-23. Using values above these thresholds, the

specifi city and sensitivity in predicting CV progression were 58.9% and 62%, respectively, for PTH, and 59% and 61% for FGF-23, the researchers found.

The investigators observed few hyper-phosphatemia cases (10% or less), only one case of hypercalcemia, and no severe cases of hyperparathyroidism. ■

High PTH, FGF-23 Predict Vascular Calcification

AA Kidneys May Worsen Tx OutcomesRECIPIENTS OF KIDNEYS from African Americans (AA) are at increased risk of all-cause and cardiovascular mortality compared with patients who receive kidneys from non-AA donors.

In a study of 13,692 hemodialysis patients who underwent renal trans-plantation, recipients of an AA kidney had a 39%, 80%, and 30% increased risk of all-cause mortality, cardiovas-cular mortality, and death-censored graft loss, respectively, over a six-year observation period, after adjusting for relevant clinical and transplant-related variables. Recipients were not at increased risk for delayed graft function.

Among non-AA recipients—but not AA recipients—AA donor race was associated with a signifi cant twofold higher risk of death-censored graft loss in a fully adjusted model.

The study was led by Kamyar Kalantar-Zadeh, MD, MPH, PhD and fi ndings were presented by Miklos Z. Molnar, MD, PhD. Both researchers are affi liated with the Harbor-UCLA Medical Center in Torrance, Calif. ■

Renal & Urology News editor Jody A. Charnow provided news coverage. ■ Kidney Week 2011, Philadelphia

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BY CAROLINE HELWICKSAN FRANCISCO—Prior to radical cystectomy for bladder cancer, preopera-tive neutrophil/lymphocyte ratio (NLR) can identify patients at risk for having non-organ-confi ned disease and who may benefi t from neoadjuvant chemo-therapy, University of Wisconsin investi-gators reported at the American College of Surgeons 97th Clinical Congress.

Their research, reported by Aaron Potretzke, MD, a surgical resident, earned the “Best Scientific Poster” award at the meeting.

“As urologists, we are limited in their ability to predict the fi nal pathologic stage of bladder tumors,” Dr. Potretzke said. “This is evidenced by the fact that 50% of radical cystectomy cases are upstaged, and, more importantly, 43% are upstaged from previously organ-confi ned disease to non-organ-confi ned disease, which has a tremendous impact on prognosis and outcomes.”

Good clinical predictors of upstag-ing are also lacking, despite some cor-

relation with hydronephrosis, tumor multifocality, lymphovascular invasion and carcinoma in situ.

Patients with non-organ-confined disease could benefi t from neoadjuvant chemotherapy, which has proven overall and cancer-specifi c survival benefi ts for T3 bladder cancer. There is, therefore,

great value in identifying these patients prior to surgery, he said.

“NLR has been shown to be an impor-tant predictor in gastric, colon, ovarian, pancreatic, and lymphatic cancer, so the purpose of our study was to evaluate NLR as a predictor of upstaging in bladder cancer,” Dr. Potretzke said. The NLR is an indication of the immune

system’s capacity to fi ght off malignancy and metastasis, he explained.

The study included 76 patients who underwent radical cystectomy for urothelial cell cancer and were assessed for NLR within 100 days of surgery, were clinical stage T2 or higher, and had normal white blood cell counts preoperatively. Postoperative pathology categorized patients as upstaged, no change in stage or downstaged.

Upstaging of patientsPathologists upstaged 42 patients (55.2%), downstaged 17 (22.4%), and kept the same stage in 17 (22.4%), he reported.

Patients who were upstaged had sta-tistically signifi cantly higher NLR ratios at baseline versus patients whose stage remained unchanged and those who were downstaged: 4.09, 2.78 and 2.36, respectively.

More importantly, he said, a signifi cant difference in NLR was observed between non-organ-confi ned and organ-confi ned groups: 4.17 versus 2.60.

The researchers also created a receiver operating characteristic (ROC) curve to further defi ne the utility of the NLR, com-pared with a well-validated nomogram for upstaging (Karakiewicz et al). “We found our simple assay was more predictive and useful, with an area under the curve of 0.718 versus 0.663,” he reported.

“Finally, we determined that 22 patients would have been upstaged based on their preoperative NLR,” Dr. Potretzke said. “We would have at least counseled these patients as to the benefi ts of neoadjuvant chemotherapy, which could have had a real clinical impact.”

The investigators will be implement-ing NLR in their clinic, and will further assess its utility in a clinical trial in which patients with high NLR will be randomly assigned to neoadjuvant chemotherapy or immediate cystectomy, he said.

Barbara Bass, MD, of Methodist Hospital in Houston, who moderated the Best Scientifi c Poster session, said this research “has the potential to become a clinically practice-changing.” ■

BY JOHN SCHIESZERCHICAGO—Adding abatacept to mycophenolate mofetil (MMF) may benefi t nephrotic patients with lupus nephritis (LN), according to the fi nd-ings of a 12-month study presented at the 2011 American College of Rheumatology annual meeting.

In these patients, researchers observed an improvement in pro-teinuria associated with abatacept, suggesting that additional explora-tion may be warranted to investigate potential biologic activity in this subset of patients.

The study, however, found that add-ing abatacept to MMF does not signifi -cantly improve the time to complete renal response in LN patients.

“New therapies that are safer and more effective are sorely needed for patients with lupus nephritis,” said investigator Richard Furie, MD, Chief of the Division of Rheumatology and Allergy-Clinical Immunology at the North Shore-Long Island Jewish Health System, Lake Success, N.Y. “Some posi-tive signals were seen. For example, in those patients with signifi cant protei-nuria (nephrotic syndrome), there were

greater reductions in proteinuria seen in those on abatacept than in those on placebo. Further analyses will be done and hopefully drug development with abatacept will continue in the area of lupus nephritis.”

Abatacept is a selective T-cell co-stim-ulation modulator already approved for rheumatoid arthritis. It is being evaluated as a treatment for LN. Dr. Furie and his colleagues conducted a 12-month, Phase 2/3 double-blind study in patients with active ISN/RPS Class III or IV LN. All patients received MMF (target dose 1.5–3.0 g/day depending on race) and up to 60 mg/day prednisone or equivalent (with response-guided taper after 28 days). Patients were then randomized to receive placebo or IV abatacept (either three months of abatacept 30 mg/kg followed by nine months of 10 mg/kg [30/10], or 12 months of 10 mg/kg [10/10]).

The primary effi cacy endpoint was time to complete renal response (CRR) confirmed at 30 days after the first response. Secondary endpoints includ-ed time to renal improvement (RI) and rates of CRR and RI at 12 months.

Exploratory endpoints included patient response and renal response.

A total of 298 LN patients were treated and 228 (76.5%) completed 12 months of treatment. The time to

CRR did not differ between groups for abatacept 10/10 and 30/10 com-pared with placebo nor did time to RI. However, a subset analysis of 122 neph-rotic patients (baseline urinary protein to creatinine ratio [UPCR] greater than 3.0 mg/mg) found an approximately 20%-30% greater reduction in UPCR from month 6 through month 12 in patients randomized to abatacept com-pared with placebo..

With the exception of herpes zoster occurring more frequently in abata-cept-treated patients, the safety profi le was similar in both arms. The most common adverse effects were serious

infections, pneumonia, herpes zoster, gastroenteritis, and urinary tract infec-tion. Underlying disease was the cause of death for fi ve patients, and infection was the cause of death for seven.

“As nephrologists are generally involved in the care of patients with lupus, it is important for them to keep abreast of developments in its treat-ment,” Dr. Furie told Renal & Urology News. “Should abatacept eventually prove to be a worthwhile addition to our treatment of lupus nephritis, exten-sion of development to other types of glomerulonephritis may be warranted. Rheumatologists and nephrologists have been struggling with clinical tri-als in lupus nephritis for quite a while. The question that arises when a study fails is whether the drug was at fault or whether the study design was at fault. In this particular case, the primary end-point, as well as secondary endpoints, was not met. This doesn’t necessarily mean the drug doesn’t work in lupus nephritis. Entry criteria, defi nitions of response, and rules for concomitant medications all need to be revisited as any or all of these items may have been responsible for the study’s failure.” ■

Preoperative NLR Can Predict Bladder Cancer Upstage

Abatacept May Help Some Lupus PatientsA phase 2/3 study demonstrated an improvement in proteinuria among nephrotic individuals

It may be possible to ID patients who may benefi t from neoadjuvant chemo.

Abatacept did not change the time to complete renal response.


BY JOHN SCHIESZERCHICAGO—Certain features at the time of renal biopsy are associated with a particular class of lupus nephritis (LN) and may independently predict renal out-comes, according to a new Canadian study presented at the 2011 American College of Rheumatology annual meeting.

“In our updated analysis, we found that SDI [SLICC damage index] scores of zero at the time of biopsy and lower

24-hour proteinuria were associated with complete renal remission at six months, and higher non-renal SLEDAI [SLE disease activity index] at baseline and lower chronicity index on renal biopsy were associated with complete renal remission at one year post biopsy,” said lead investigator Claire Barber, MD, a rheumatologist at the University of Calgary in Alberta, Canada.

Dr. Barber and her colleagues studied a large prospectively followed cohort of patients with systemic lupus erythema-tosus (SLE) at a single center with renal biopsy slides available and matched clinical follow-up. Investigators col-lected demographic and clinical data at time of renal biopsy. Renal biopsies were reviewed by two expert patholo-gists independently and by a third pathologist in cases of disagreement to determine a consensus score. The degree of agreement between patholo-gists on individual items of the ISN/RPS score was measured. The goal of this investigation was to examine the

clinical-pathological correlates at time of renal biopsy in LN patients accord-ing to the 2003 International Society of Nephrology and Renal Pathology Society (ISN/RPS) classifi cation.

“The ISN-RPS classifi cation of lupus nephritis was developed in 2003 and was designed to improve the prognostic signifi cance of biopsy fi ndings com-pared to the WHO classifi cation. We undertook this study as there continue

to be confl icting reports in the literature regarding the clinical correlates and long-term outcomes associated with the different classes of lupus nephritis based on the ISN/RPS classifi cation,” Dr. Barber said.

For this investigation, the researchers included only pathologic variables with at least moderate agreement between pathologists. The variables included ISN/RPS class I-VI of nephritis. For class III, the subclasses of active (A), active and chronic (A/C), and chronic (C) had poor agreement and were con-sidered as a single class. For class IV, the agreement was poor for the segmental versus global subclasses but acceptable or the active A, A/C or C lesions.

The investigators employed univariate and multivariate regression models to examine the outcomes of complete remis-sion (defi ned as serum creatinine below 1.4 mg/dL and proteinuria less than 0.33 g/day), partial remission (defi ned as a less than 25% increase in baseline serum creatinine and greater than 50% reduc-

tion in baseline proteinuria to below 1.5 g/day) and no remission at 6, 12, and 24 months post-biopsy.

A total of 127 patients had biopsy slides available for review. The average age at time of biopsy was 32.4 years. In this group of patients, 81.9% were female and 63.8% were Caucasian. The researchers found that the majority of biopsies showed class III (26.7%) or class IV nephritis (IV-A: 13.4%, IV-A/C: 24.4%, IV-C: 4.7%) and 15.7 % were pure class V. They also found that the estimated glomerular fi ltra-tion rate (eGFR) was signifi cantly dif-ferent among groups and was lowest in patients with class IV- A/C (42.8 mL/min/1.73m2) and highest in class III (91.6 mL/min/1.73m2).

The investigation showed that the non-renal SLEDAI-2K was not dif-ferent between classes. However, they discovered that the anti-dsDNA levels by Farr assay at time of biopsy were highest in class IV-A (50 U/mL)and lowest in class IV-C biopsies (5 U/mL), and C3 levels were lowest in class IV-A and IV-A/C. On multivariate analysis complete remission at six months was associated with lower baseline protei-nuria and SLICC score of zero at time of renal biopsy. Complete remission at one year was associated with higher non-renal SLEDAI at time of biopsy and lower chronicity index on the biopsy.

“Our study suggests that there may be some features at the time of renal biopsy that are associated with a particular class of lupus nephritis,” Dr. Barber told Renal & Urology News. “Although some features on renal biopsy may be associated with renal outcomes in our study, it is too early to use these features as predictors of outcome in clinical practice. We hope that our work will lead to further studies and hopefully better prediction models for assist-ing prognostication in lupus nephritis based on renal biopsy features.”

Dr. Barber said it is important for neph-rologists to be aware that the inter-rater reliability of some of the biopsy features of lupus nephritis are poor and she and her colleagues feel that further workshops or studies to clarify the defi nitions would be important to harmonize the fi ndings of future studies in this area. ■

Renal Biopsies May Indicate Class of Lupus NephritisSome pathologic features may independently predict outcomes

MYCOPHENOLATE mofetil (MMF) is more effective than azathioprine as main-tenance therapy for patients with active lupus nephritis (LN) who responded to induction therapy, researchers reported.

In a 36-month randomized, double-blind study of 227 LN patients who met response criteria during a six-month induction trial, the researchers found that MMF signifi cantly decreased the time to treatment failure, the primary outcome measure. The researchers defi ned treat-ment failure as death, end-stage renal disease, doubling of serum creatinine level, renal fl are, or rescue therapy for LN. The overall observed rates of treat-ment failure were 16.4% among the 116 patients assigned to receive oral MMF and 32.4% among the 111 patients assigned to receive oral azathioprine, according to the investigators. The difference translated into a 59% decreased risk of treatment failure for patients in the MMF group, the researchers reported in The New England Journal of Medicine (2011;365:1886-1895). During the induction trial, subjects received either oral MMF or intravenous (IV) cyclophosphamide.

In addition, compared with azathio-prine recipients, MMF-treated patients had a 50% decreased risk of renal fl are and a 61% decreased risk of requiring rescue therapy.

The rates of serious adverse events (AEs) in the MMF and azathio-prine groups were not signifi cantly dif-

ferent (23.5% vs. 33.3%, respectively), but the rate of study withdrawal related to AEs was signifi cantly higher with azathioprine than MMF (39.6% vs. 25.2%).

The authors, led by Neil Solomons, MD, of Vifor Pharma (formerly Aspreva Pharmaceuticals), which funded the study, concluded that MMF is superior to azathioprine in maintaining the renal response to treatment and in prevent-ing relapse in patients with active LN who have had a clinical response to induction therapy with either MMF or IV cyclophosphamide. ■

MMF Beats Azathioprine For LN

Mycophenolate mofetil lowered treatment failure risk by 59%.

This lupus nephritis tissue specimen shows active glomerular lesions.

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CME FEATURE


Patients who undergo renal transplantation require complex care that involves a diligent, multidisciplinary approach.

The Management of Patients After Renal Transplantation

Release Date: February 2012Expiration Date: February 2013Estimated time to complete the educational activity: 1 hour

This activity is jointly sponsored by Medical Education Resources and Haymarket Media, Inc.

TARGET AUDIENCE: This activity has been designed to meet the needs of nephrologists and primary-care physicians involved in treating renal transplant patients.

EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to:

Discuss selection criteria and pre-transplant evaluation procedures. • Summarize established protocols in post-transplant management including ancillary • evaluation, virologic monitoring, and potential medication-related complications.

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 Media, Inc. 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 CreditTM. 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 scientifi c rigor in all our educational programs. In accordance with this policy, MER identifi es confl icts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Confl icts are resolved by MER to ensure all scientifi c 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 fi nancial relationships with commercial interests whose products or services may be mentioned in this CME activity:

Name of Faculty Reported Financial Relationship• Daniel C. Brennan, MD, FACP Grants/Research Support: Pfi zer and

NIH. Consultant: Genzyme and Genentech. Speakers’ Bureau: Novartis and Genentech.

The content managers reported the following fi nancial relationships with commercial interests whose products or services may be mentioned in this CME activity:

Name of Content Manager Reported Financial Relationship• Jody A. Charnow, Haymarket Media, Inc. No fi nancial relationships to disclose• Marina Galanakis, Haymarket Media, Inc. No fi nancial relationships to disclose• Victoria C. Smith, MD, MER No fi nancial relationships to disclose

METHOD OF PARTICIPATION: There are no fees for participating in and receiving CME credit for this activity. During the period February 2012 through February 2013, 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/renalandurologynews, 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.

Daniel C. Brennan, MD, FACP, is Professor of Medicine and Director of Transplant Nephrology in the Division of

Renal Diseases at Washington University School of Medicine in St. Louis.

The management of the kidney transplant recipient requires knowledge of the patient’s history pre-, during, and

post-transplant. Typically, a team of sur-geons, nephrologists, consultants, pri-mary care physicians, and allied health professionals all work with the patient in a multidisciplinary effort to direct transplantation efforts and administer extremely detailed care.

Selection criteria for kidney transplantation

Transplant management actually begins with the referral of the potential recipi-ent to a transplant center. During the initial transplant evaluation, there are two essential questions that must be answered upfront. The fi rst is to the potential recipient: Why does he/she want a transplant? The second to the referring physician: Is this patient an appropriate transplant candidate? Crucial to all discussions is the fact that transplantation is a treatment not a cure and requires expensive, life-long immunosuppression with multiple side effects, frequent blood draws, and long-

term clinical management. The patient and referring physician need to be cog-nizant of this and realize the trade-offs, which for the vast majority of patients are worth it.

An equally important consideration in the early evaluation is a patient’s prior adherence to their medical and dialysis regimens. Also, clinicians must assess whether the prospective recipient will be able to afford expensive medica-tions, laboratory evaluations, and clinic appointments—all essential for a suc-cessful transplant. It seems imprudent to allocate a donor organ if the patient history does not suggest the ability to maintain the allograft. Thus, early evalua-tion by the transplant team encompasses a comprehensive look at patient records, the full history, a thorough physical exam, and pertinent laboratory evaluations. With end-stage renal disease (ESRD)as opposed to other solid organ end-stage disease, we are fortunate in the U.S., to have the option of dialysis, as an alternative to transplantation—a funded alternative.

The inclusion criteria for kidney trans-plantation are ESRD or irreversible and progressive chronic kidney disease

BY DANIEL C. BRENNAN, MD, FACP


(CKD) with an estimated glomerular filtration rate (eGFR) of <20 mL/min/1.73 m2. Patients with progressive kidney disease should be referred for transplant evaluation when the eGFR is <30 mL/min/1.73 m2 and before ESRD for several reasons. First, there is a graft and patient survival advantage to receiving a kidney transplant “pre-emptively,” that is, before initiation of dialysis.1 Second, time on the wait list is the major determinant for receiving a kidney transplant, and especially in determining the allocation of a deceased donor kidney (which can take several years). Third, dialysis is associated with progressive complications that may lead to the exclusion of consideration for kidney transplantation.

Exclusion criteria for renal trans-plants are complex and involve mul-tifaceted medical, social, and ethical considerations. The current half-life of a deceased donor kidney transplant is approximately nine years, and for a living donor transplant, it is roughly 12 years.2 The World Health Organization Ethics Statement on Transplantation, which was accepted by the United Network of Organ Sharing (UNOS), recommends that a potential recipient should not be considered for organ transplantation unless the fi ve-year sur-vival rate is greater than 50%.3 This precept was based on three important guiding principles: 1) patient autono-my (that transplantation will provide independence and freedom for indi-vidual patients), 2) utility (the capacity for productive post-transplant life), and 3) justice (equitable allocation of scant resources).

The fi ve-year/50% life expectancy requirement seems lenient given cur-rent graft survival rates for kidney trans-plantation. Death with graft function (DWGF) is also the major cause of kidney transplant failure. And a pri-mary cause of DWGF is cardiovascular disease (CVD). Among diabetic kidney transplant recipients, CVD accounts for DWGF in 81% of patients. But DWGF occurs in only 26% of trans-plant patients without diabetes, with the other major causes of DWGF being infection and malignancy.4 It should be noted that when there is a possibility of living donor transplant, the fi ve-year/50% life expectancy requirement is waived—specifi cally when emotional and unquantifi able considerations may supersede biologic considerations.

Pre-transplant evaluation

The pre-transplant evaluation begins with a careful review of the patient’s past medical history, which is solicited from the patient as well as the primary nephrologist and primary care physi-cians. Important information includes the age and gender of the patient and the cause of ESRD, which may pre-dict the risk of disease recurrence. Additionally, important considerations are the type of dialysis used (hemodialy-sis versus peritoneal) and whether the patient has received a previous kidney or other organ transplant. Whether the patient makes urine or has proteinuria or hematuria may impact interpretation post-transplant. In general, proteinuria and hematuria resolve by one month after transplantation. The persistence or recurrence of hematuria after this time period should lead to investigation for such diseases as focal segmental glomerulosclerosis (FSGS) or recurrent IgA nephropathy.5

The history should provide informa-tion regarding co-morbidities such as diabetes, and cardiovascular, pulmo-nary, or atherosclerotic disease, which are major factors impacting both patient and graft survival. If the patient has frequent episodes of thrombosis in the dialysis access port, a history of deep venous thromboses, or early, spontane-ous miscarriages, this may indicate a hypercoagulable state from antiphos-pholipid antibodies, factor V Leiden, prothrombin gene, methyl tetrahydro-folate reductase (MTHR) mutations, or protein C, protein S or anti-thrombin3 defi ciencies that would put the graft at risk for early thrombosis.

Endemic, occupational, or social infection risks are also important. Patients in the southwestern United States may be predisposed to coccidi-omycosis, which is endemic. Patients with cats may be prone to toxoplas-mosis, and patients with an outdoor dog (prone to tick bites) may develop ehrlichiosis.

A second prerequisite for manage-ment is a comprehensive pre-transplant physical examination. The cardiovas-cular exam is especially key here. It is important to assess the patient’s carot-ids and femoral and peripheral pulses. A femoral bruit from atherosclerotic disease may be mistaken for a trans-plant artery bruit, which is a sign of renal artery stenosis.

Table 1. Pre-Transplant Studies

Laboratory Testing

Blood Type, Tissue type-HLA

Donor Specifi c Antibodies (monthly sample once listed)

Complete blood count (CBC), comprehensive metabolic profi le (CMP), phosphorous, uric acid, lipid panel, hemoglobin A1c (HbA1c ), intact parathyroid hormone (iPTH)

Infection studies-CMV, EBV, HSV, HIV, VZV, Hepatitis serology, RPR

Immunizations-hepatitis B, VZV is seronegative, pneumococcal

Annual testing while listed (selected studies)

Adjunctive Testing

Dental: Panorex to rule out abscesses

Cardiac: EKG, echocardiogram, stress test ± cardiac catheterization, 6 minute walk

Vascular: Carotid Doppler, CT abdomen and pelvis to assess iliac atherosclerosis

Pulmonary: Chest x-ray , pulmonary function tests

Screening: PAP smear, mammogram over 40, PSA over 40, colonoscopy over 50

Table 2. Post-Transplant Studies

Laboratory Testing

Complete blood count (CBC) with differential and renal panel weekly � 16 weeks, then every two weeks to one year, then monthly

Substitute a comprehensive metabolic panel( CMP) for the renal panel quarterly, on the quarter: January, April, July, October

Fasting lipid panel, uric acid, magnesium, and creatinine kinase quarterly on the quarter

Urine random protein/creatine ratio weekly � 4 in patients at risk for recurrent FSGS then quarterly on the quarter, and quarterly for patients with proteinuria

BK-PCR monthly 1-6, then months 9, 12 and for cause.

CMV-PCR

• For cause in those who received prophylaxis

• Weekly � 12 weeks for those using a preemptive strategy

Urinalysis at all clinic visits.

Donor Specifi c Antibodies (for cause only)

Table 3. Post-Transplant Maintenance Immunosuppression

Immunophillin binding

Calcineurin inhibitors

• Cyclosporine (Neoral, GenGraf)

• Tacrolimus (Prograf)

Non-Calcineurin

• Rapamycin (Rapamune)

• Everolimus (Zortress, Certican)

Corticosteroids

• Prednisone

Anti-metabolites

• Azathioprine (Imuran)

• Mycophenolate (CellCept, myFortic)

• Cyclophosphamide (Cytoxan)

• Lefl unomide (Arava)

• Hydroxychloroquine (Plaquenil)


CME FEATURE

Much of what is used to direct our evaluation and management comes from the laboratory assessment. It is unusual to have symptoms or signs of renal disease until there is anemia, impaired metabolic homeostasis such as hyperkalemia, metabolic acidosis, hyperphosphatemia, and elevated parathyroid levels until the GFR is <40 mL/min/1.73 m2. Therefore, a comprehensive laboratory evaluation is important pre- and post-transplant (Table 1 and 2).

The transplant procedure

An understanding of the initial trans-plant procedure, hospitalization, and early course must be recorded in the outpatient records. Typical consider-ations are donor age and sex, HLA match or mismatch, the cytomegalo-virus (CMV) and Epstein-Barr virus (EBV) serostatus of the donor and recipient, induction agent and dose, surgeon, placement of a urinary stent, whether there were any technical prob-lems or delayed graft function (DGF) and elevated serum creatinine on the day of discharge, the nadir serum creati-nine and the baseline serum creatinine. Below is an example of a patient record which can be used as a starting point when being queried by the fellows or coordinators for follow up.

Mr. W is a 60-year-old black man with ESRD from FSGS and who was on hemodialysis for four years using a left forearm arteriovenous fistula. Mr. W was under the care of Dr. S prior to receiving an expanded criteria donor kidney from a 65-year-old black man in February of 2010. This was an “import” kidney and the cold ischemia time was 16 hours. During surgery, the artery and vein were anastomosed end-to-side to the common iliacs because of recipient atherosclerosis of the external iliac ves-sels. The ureter was anastomosed to the native ureter because the bladder was small and contracted. A ureteral stent was placed and subsequently removed. The HLA mismatch was a 2A, 2B, 1 DR mismatch and the CMV serostatus was D+/R+ and the EBV status D+/R+. The patient received induction therapy with thymoglobulin 5 mg/kg over three days (100 mg/200 mg/200 mg). Maintenance therapy was with tacrolimus, enteric-coated mycophenolic acid (MPA), and a steroid taper to 5 mg by one month. The patient received 1 g of intravenous

(IV) iron dextran prior to discharge. The course was complicated by slow graft function and the patient was dis-charged on post-operative day 5 with a serum creatinine of 4.52 mg/dL.

Post-transplant maintenance immunosuppression

Typical maintenance immunosuppres-sion is shown in Table 3. It is beyond the scope of this review to go into detail and the readers are referred to UpToDate (www.uptodate.com) for a current discussion of maintenance immunosuppression and some of the controversies such as calcineurin inhibi-tor (CNI) or steroid withdrawal or avoidance, or the use of mammalian targets of rapamycin (mTORs).

The typical immunosuppressive regi-men at our center is induction with thy-moglobulin 5mg/kg total body weight intravenously with the fi rst dose 1 mg/kg begun intraoperatively followed by 2 mg/kg/d for two days. The dose is rounded to the nearest 25 mg and not adjusted for ideal body weight and there is no maximum dose. Tacrolimus is usually begun on post-operative day 1 or 2 even when DGF is present because delayed introduction and fail-ure to obtain a therapeutic calcineurin inhibitor (CNI) level by post-operative day 7 is associated with more rejection and no decrease in the incidence or duration of DGF.6, 7 For tacrolimus, we target trough levels at 7-10 ng/mL for the fi rst month and then 3-7 ng/mL thereafter. For cyclosporine, we pre-fer to monitor peak (usually 90 minute levels), although the concentration at two hours post-dosing (C2) levels have been investigated and are interpretable. Because the “peak” might be missed, we rely on the trend of cyclosporine levels to inform us “how high can the patient get.” Our peak level targets are 800-1200 ng/mL for the first month and then 400-600 ng/mL thereafter. These targets were chosen based on literature showing that a level of 1000 ng/mL provides 90% cal-cineurin inhibition of lymphocytes and C2 levels of 400 prevent rejection and are associated with less nephrotoxicity in cardiac transplant recipients.8-10

Our team initiates enteric-coated mycophenolic acid (MPA) at 760 mg bid but decrease to 360 mg bid by post-operative day 5. We prefer MPA over MMF because the absorption of MMF requires hydrolysis of the mofetil

ester, which requires an acid environ-ment that is blocked by proton-pump inhibitors, medications commonly used for gastrointestinal prophylaxis.6,11 This “reduced dose” of MPA is used because the pivotal trials leading to the approval of MMF and MPA were performed with cyclosporine, which inhibits the absorp-tion of MMF and MPA by 30%-50%.12 We prefer enteric coated mycophenolic acid (MPA) to MMF because we use proton pump inhibitors (PPIs) to con-trol gastrointestinal symptoms. These agents reduce the exposure of MMF but not MPA.13 Methylprednisolone 7 mg/kg is used intraoperatively and then prednisone 1 mg/kg is administered to a maximum of 80 mg prior to administra-tion of rATG on post operative days 1 and 2. Prednisone is then administered at 20 mg per day during the fi rst week and tapered by 5 mg/week to 5 mg/day by week 4-5 where it is maintained.

The ELITE-Symphony trial, which compared cyclosporine, tacrolimus, and rapamycin showed that the best overall maintenance regimen is one using rela-tive low-dose tacrolimus, mycopheno-late, and low-dose steroids.14 We have a low threshold to replace mycophenolate with azathioprine for any indication based on the MYSS and MYSS follow-up trials, which showed that there was no difference in rejection or patient or graft survival, but GFR was better long term with azathioprine compared

with MMF even if steroids were with-drawn.15,16 The current literature and available immunosuppression regimens do not support steroid avoidance. In a randomized, double-blind, placebo-controlled trial with fi ve year follow up of early corticosteroid withdrawal compared with low-dose continua-tion there were no major differences in corticosteroid- related side effects but an almost doubling of the acute and chronic rejection rates in the group with early corticosteroid withdrawal.17

Post-transplant clinic visits

Post-transplant monitoring visits are not routine. Routine visits or laboratory work ups are not billable. Thus, we typically state in the chief complaint, “The patient returned today for continued care of his renal transplant (diagnostic code V42.0), immunosuppressive management (diag-nostic codes V58.69 and V58.44), and related medical problems.” The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines do not specify how often kidney transplant recipients should be seen by a physician.18 Historically, patients were seen after discharge twice a week for the fi rst month, monthly for six months, and then every three to four months thereafter. This is no longer nec-essary or feasible. With the widespread use of induction agents, particularly anti-lymphocyte depleting therapy, and

Deceased donor and living donor transplants have a half-life of about nine and 12 years, respectively, according to a recent report (Am J Transplant 2011;11:450-462).

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improved maintenance immunosup-pression, acute rejection rates in the fi rst three months are relatively uncommon and the incidence of acute rejection is 5%-15% nationally in the fi rst year. Kidney volumes and improved success have led to overcrowded clinics and overworked staff.

At our center, patients see the sur-geons at two weeks after transplant and the transplant nephrologists at two to four weeks post-transplant and then at six weeks and every three months thereafter up to one year. Then we see patients every three months for the next two years. Patients are asked to coordinate visits with their primary nephrologist and primary care physi-cian so that they are seen every three to six months.

Regular clinic visits give clinicians the opportunity to assess signs and symptoms that may dictate a change in immunosuppressive management beyond what might have been suggested from laboratory monitoring. Such signs and symptoms may be uncontrolled hypertension, insomnia and tremors (tacrolimus), rage disorder or warts (prednisone), or gastrointestinal com-plications (MMF, MPA, tacrolimus). The yearly clinic visit to the transplant cen-ter provides an opportunity to update patients on developments in transplanta-tion and to verify data to satisfy UNOS requirements for reporting.

Because of this infrequent face-to-face contact, our team is unable to accom-modate patients adequately. Therefore, we rely on care from informed primary nephrologists and primary care physi-cians. We ask that the patient be the intermediary and inform the transplant center if there has been any addition, deletion, or change in any medication so that we can check for interactions and side effects. We also rely on frequent post-transplant monitoring labs.

Post-transplant monitoring and ancillary evaluation

General laboratory evaluation. Typical post-transplant monitoring labs are shown in Table 2. KDIGO suggests (with low evidence of support) that labs be obtained two to three times per week for weeks 2-4 and then weekly for months 2 and 3, every two weeks for months 4-6, monthly for months 7-12, and then every two to three months thereafter.

Our team obtains a complete blood count (CBC), renal panel—which includes phosphorus, calcium, and albumin levels, in contrast to a basic metabolic panel (BMP)—and CNI and/or mammalian target of rapamycin (mTOR) inhibitor levels weekly for the fi rst 16 weeks and then every other week up to one year, and then monthly. This is less frequently than suggested by KDIGO early after trans-plantation and more frequently later. This refl ects our appreciation for the decreased incidence of early events and a need for monitoring long term when we are not able to see patients in the clinic.

At our center, a complete metabolic panel is substituted for the renal panel to assess liver function tests quarterly. We also assess uric acid quarterly because asymptomatic hyperuricemia is associ-ated with CNI use and may be associ-ated with cardiovascular complications, necessitating the use of allopurinol. We obtain a serum magnesium level quarterly because the CNIs and mTORs cause magnesium wasting. We obtain a fasting lipid panel and creatine kinase because most of our patients are dyslipidemic and on a statin (See below).

Proteinuria. For patients with FSGS, we obtain a random urine protein-to- creatinine ratio prior to discharge after transplantation, four times weekly and then quarterly. We obtain a dipstick urinalysis at each clinic visit. For those with new onset proteinuria we obtain a random urine protein-to-creatinine ratio and follow these at least quar-terly. It is important to realize that most native residual kidney function, and thus native kidney proteinuria, ceases by about four to six weeks.5 Thus, pro-teinuria after six weeks is probably coming from the transplanted kidney.

Virologic monitoring

Cytomegalovirus. Monitoring for cytomegalovirus (CMV) is unneces-sary during the period of prophylaxis with valganciclovir. However, some patients cannot afford valganciclovir and a preemptive approach is used. For these patients, weekly CMV-PCRs for the fi rst 12 weeks is recommended. This is because CMV most commonly reactivates in the fi rst three months after transplantation and a diligent preemptive approach has been shown to be as cost-effective as prophylaxis in preventing symptomatic disease.19

However, CMV prophylaxis is easier

and in some studies, prophylaxis has been associated with less acute rejection and better long-term outcomes than preemptive therapy.20, 21

Epstein-Barr virus. We do not usually monitor EBV since interpretation is complicated and the sensitivity and spec-ifi city are poor for either post-transplant lymphoproliferative disease (PTLD) or EBV-associated disease. We are required to obtain special approval from our laboratory medicine colleagues to order

an EBV-PCR in the hospital. However, among patients suspected of having PTLD, or among EBV-seronegative patients such as diabetics or children, prospective EBV monitoring may allow earlier recognition of a predisposition to PTLD that may be prevented with immunosuppressive reduction.22

BK virus. We monitor BK-PCRs in the blood monthly for the fi rst six months, at months 9 and 12, and then for cause. This is a modifi cation of the consensus guidelines and refl ects studies that show that BK viruria is uncommon in the absence of BK viremia, which seldom occurs before month 1 post-transplant. The incidence rapidly increases by three months and plateaus by six months. Sustained viremia may be a precursor to BK-virus nephropathy.23

Post-transplant medications and complications

Anemia. Nearly every CKD or ESRD patient is anemic and most are iron defi -cient or functionally iron defi cient. Even if a patient has a hemoglobin level of 11 mg/dL and adequate iron stores (with a normal hemoglobin being 15 mg/dL) the patient is still 1 g iron depleted. Each unit of blood should raise the hemoglobin by 1 mg/dL and each unit contains approxi-mately 250 mg of iron. Additionally, the estimated blood loss over the fi rst three months is 750 mL.24 Thus, most patients at our center receive iron dextran 1 g IV prior to discharge. Reactions are uncom-mon, perhaps because of concomitant ste-roid use. We do not use oral iron as it may bind to mycophenolate and other drugs,

is not very effective, and is associated with gastrointestinal side effects. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are useful for treating post-transplant eryth-rocytosis, which usually does not occur in the fi rst three months. However, their introduction early after transplant may perpetuate anemia, cause hyperkalemia and raise the serum creatinine.

Hypertension. The fi rst-line antihy-pertensive at our center is the calcium

channel blocker amlodipine. It is a long-acting agent that has only minimal inter-ference with cytochrome P-450 system, particularly (CYP3A4), and thus, does not affect CNI or mTOR levels dra-matically. Its vasodilatory properties may counteract some of the vasoconstriction caused by CNIs and mTORs. We avoid using diltiazem or verapamil because they are potent inhibitors of CYP3A4 and raise CNI and mTOR levels.

Most patients have CVD and will require a beta blocker such as meto-prolol or nebivolol or a combination alpha and beta blocker such as carve-dilol. Nebivolol increases nitric oxide, which is vasodilatory and may be par-ticularly useful for patients on a CNI. Most patients will have left ventricular hypertrophy or a history of coronary artery disease for which an ACEI or ARB are indicated. We prefer to delay introduction of these agents until after three months, when much of the anemia should have resolved and the patient is relatively stable and on lower CNI doses. The patient is less likely to expe-rience hyperkalemia or an elevated serum creatinine with introduction of an ACEI or ARB.

Dyslipidemia. Many patients will have dyslipidemia with either high total or low-density lipoprotein (LDL) cholesterol or low high-density lipoprotein (HDL) and high triglyceride levels. The use of the sta-tin, fl uvastatin, a relatively week statin was shown to be associated with less Major Adverse Cardiac Events (MACE) after fi ve years.25 We usually use atorvastatin because it is commonly effective at lower-ing LDL to goal with the initial starting

Cytomegalovirus monitoring in renal transplant recipients is unnecessary during the period of prophylaxis with valgancyclovir.

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1. An individual may be placed on the United Network of Organ Sharing transplant waiting list and made active when the estimated glomerulofi ltration (eGFR) rate is below:

10 mL/min/1.73 ma. 2

20 mL/min/1.73 mb. 2

30 mL/min/1.73 mc. 2, but with progressive renal disease such as polycystic kidney disease or lupus nephritis40 mL/min/1.73 md. 2, but with evidence of anemia, metabolic acidosis, and hyperparathyroidism from renal disease

2. Which pair has not been shown to be an increased endemic risk for infectious complications post-transplant?

Living in the southwestern United States and coccidiomycosisa. Living with an outdoor cat and toxoplasmosisb. Turkey hunting with an outdoor dog and erhlichiosisc. Raising chickens and chicken pox (varicella)d.

3. A femoral bruit in association with hypertension is a reliable sign of transplant renal artery stenosis.

True b. Falsea.

4. Proton pump inhibitors are most likely to interfere with the absorption of which immunosuppressive agent?

Azathioprine c. Enteric mycophenolic acid (MPA)a. Mycophenolate mofetil (MMF) d. Tacrolimusb.

5. Your patient was just diagnosed with H Pylori. It is recommended that you use a macrolide antibiotic as part of the treatment. Which is the best approach?

Use azithromycin and make no change to the tacrolimus dosea. Use clarithromycin, but decrease the tacrolimus dose by twofoldb. Use either azithromycin or clarithromycin, but decrease the tacrolimus dose c. by twofoldTacrolimus has to be stopped as it is contraindicated with a macrolide d.

6. John receives a kidney transplant and requires antihypertensive therapy after transplant. Which of his pre-transplant antihypertensive medications would be expected to increase tacrolimus levels signifi cantly?

Diltiazem c. Lisinoprila. Carvedilol d. Amlodipineb.

7. The most common cause of death in a diabetic transplant recipient is:Cardiovascular disease c. Infectiona. Malignancy d. Traumab.

dose. We have not found pravastatin to be effective, and the FDA has recently issued a warning contraindicating the use of simvastatin with concomitant use of cyclosporine but not tacrolimus and not to exceed 20 mg with concomitant amlodipine.26 The FDA drug safety page also has a table of the relative poten-cies of the various statins.26 If patients are at goal and asymptomatic with any agent and any dose, we have not felt obliged to change therapy but put a note in the medical record of our awareness of the FDA warning and why we are con-tinuing therapy.

Fever. Fever is a common complica-tion after transplant. The most common causes are bacterial infections and most commonly urinary tract infections and less commonly pneumonia and sepsis. We routinely admit patients with a fever greater than 102°F, pan culture them, and begin empiric antibiotics. Pan cul-ture includes obtaining a CMV-PCR and BK-PCR, although BK uncommonly is associated with fever. Many bacterial infections can be identifi ed and treated according to sensitivities. We commonly use ciprofl oxacin or azithromycin for outpatient treatment. Although azithro-mycin is a macrolide antibiotic similar to erythromycin or clarithromycin, it does not interfere with the CYP 3A4 system and does not interfere with CNIs or mTOR inhibitors. For bacterial infec-tions, we do not routinely decrease immunosuppression unless they are recurrent or life threatening. However, we do routinely stop the antimetabolite for CMV or BK infections because we recognize these viral infections as an in vivo biomarker of excessive immuno-suppression. This approach seems to be successful and does not increase the rates of rejection or graft loss.27, 28

Conclusion

Transplant management is complex and requires diligence and communication among the patient, the transplant center, and other treating physicians and allied health care personnel. It is hard work that is necessary but rewarding. ■

REFERENCES

1. Meier-Kriesche HU, Kaplan B. Waiting time on dialysis as the strongest modifi able risk factor for renal transplant outcomes: a paired donor kidney analysis. Transplantation 2002;74:1377-1381.

2. Lamb KE, Lodhi S, Meier-Kriesche HU. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant 2011;11:450-462.

3. General principles for allocating human organs and tissues. Transplant Proc 1992;24:2227-2235.

4. Cosio FG, Hickson LJ, Griffi n MD, et al. Patient sur-vival and cardiovascular risk after kidney transplanta-tion: the challenge of diabetes. Am J Transplant 2008;8:593-599.

5. D’Cunha PT, Parasuraman R, Venkat KK. Rapid resolution of proteinuria of native kidney origin follow-ing live donor renal transplantation. Am J Transplant 2005;5:351-355.

6. Kamar N, Garrigue V, Karras A, et al. Impact of early or delayed cyclosporine on delayed graft function in renal transplant recipients: a randomized, multi-center study. Am J Transplant 2006;6:1042-1048.

7. Andres A, Budde K, Clavien PA, et al. A random-ized trial comparing renal function in older kidney transplant patients following delayed versus im-mediate tacrolimus administration. Transplantation 2009;88:1101-1108.

8. Kung L, Batiuk TD, Palomo-Pinon S, et al. Tissue dis-tribution of calcineurin and its sensitivity to inhibition by cyclosporine. Am J Transplant 2001;1:325-333.

9. Batiuk TD, Pazderka F, Enns J, et al. Cyclosporine inhibition of calcineurin activity in human leuko-cytes in vivo is rapidly reversible. J Clin Invest 1995;96:1254-1260.

10. Cantarovich M, Elstein E, de Varennes B, et al. Clinical benefi t of neoral dose monitoring with cyclosporine 2-hr post-dose levels compared with trough levels in stable heart transplant patients. Transplantation 1999;68:1839-1842.

11. Borobia AM, Romero I, Jimenez C, et al. Trough tacrolimus concentrations in the fi rst week after kidney transplantation are related to acute rejection. Ther Drug Monit 2009;31:436-442.

12. Zucker K, Rosen A, Tsaroucha A, et al. Unexpected augmentation of mycophenolic acid pharmacokinet-ics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro fi ndings. Transpl Immunol 1997;5:225-232.

13. Kofl er S, Shvets N, Bigdeli AK, et al. Proton pump inhibitors reduce mycophenolate exposure in heart transplant recipients-a prospective case-controlled study. Am J Transplant 2009;9:1650-1656.

14. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007;357:2562-2575.

15. Remuzzi G, Lesti M, Gotti E, et al. Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a ran-domised trial. Lancet 2004;364:503-512.

16. Remuzzi G, Cravedi P, Costantini M, et al. Mycophe-nolate mofetil versus azathioprine for prevention of chronic allograft dysfunction in renal transplantation: the MYSS follow-up randomized, controlled clinical trial. J Am Soc Nephrol 2007;18:1973-1985.

17. Woodle ES, First MR, Pirsch J, et al. A prospective, randomized, double-blind, placebo-controlled multi-center trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg 2008;248:564-577.

18. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9:S1-15

19. Khoury JA, Storch GA, Bohl DL, et al. Prophylactic versus preemptive oral valganciclovir for the manage-ment of cytomegalovirus infection in adult renal transplant recipients. Am J Transplant 2006;6:2134-2143.

20. Spinner ML, Saab G, Casabar E, et al. Impact of prophylactic versus preemptive valganciclovir on long-term renal allograft outcomes. Transplantation 2010;90:412-418.

21. Kliem V, Fricke L, Wollbrink T, et al. Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: results of a randomized clinical trial. Am J Transplant 2008;8:975-983.

22. Tsai DE, Nearey M, Hardy CL, et al. Use of EBV PCR for the diagnosis and monitoring of post-transplant lymphoproliferative disorder in adult solid organ transplant patients. Am J Transplant 2002;2:946-954.

23. Bohl DL, Brennan DC. BK virus nephropathy and kidney transplantation. Clin J Am Soc Nephrol 2007;2:S36-46.

24. Zheng S, Coyne DW, Joist H, et al. Iron defi ciency anemia and iron losses after renal transplantation. Transpl Int 2009;22:434-440.

25. Holdaas H, Fellstrom B, Cole E, et al. Long-term cardiac outcomes in renal transplant recipients receiving fl uvastatin: the ALERT extension study. Am J Transplant 2005;5:2929-2936.

26. FDA drug safety page. U.S. Food and Drug Admin-istration website. Available at www.fda.gov/Drugs/DrugSafety/ucm256581.htm.

27. Schnitzler MA, Lowell JA, Hmiel SP, et al. Cytomega-lovirus disease after prophylaxis with oral ganciclovir in renal transplantation: the importance of HLA-DR matching. J Am Soc Nephrol 2003;14:780-785.

28. Hardinger KL, Koch MJ, Bohl DJ, et al. BK-virus and the impact of pre-emptive immunosuppression reduction: 5-year results. Am J Transplant 2010;10:407-415.

Renal & Urology News February 2012 Issue

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