Renal & Urology News February 2012 Issue

FEBRUARY 2012

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VOLUME 11, ISSUE NUMBER 2

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New Stone Risk in VUR Patients

BY JODY A. CHARNOW HIGH CALCIUM and uric acid excretion are associated with vesicoureteral reflux (VUR) in children, and this could increase their risk for urinary stones, new findings suggest.

Consequently, children with VUR should be closely followed for the development of urinary stones, investigators 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 reflux or urinary tract infection, Iranian research-

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

ers found that a significantly 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 significant 4.5 times and 6.9 times increased likelihood of hypercalciuria and hyperuricosuria, respectively. After further adjustment for independent variables and hyperuricosuria, VUR patients

ESRD Survival Paradox Linked to Inflammation DIFFERENCES IN the level of inflammation among dialysis patients may explain, in part, why African Americans have better survival than Caucasians, study findings suggest.

Deidra C. Crews, MD, of Johns Hopkins University School of Medicine in Baltimore, and colleagues prospectively 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 five years was 34% for Africans Americans compared with 56% for Caucasians, Dr. Crews’ team reported in the Journal of the American Society of continued on page 11

IMAGE COURTESY OF JOSHUA ZARITSKY, MD, PhD

Hypercalciuria, hyperuricosuria implicated

VESICOURETERAL REFLUX may be genetically linked to hypercalciuria.

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 provides no evidence of a genetic link between hypercalciuria and VUR, “but continued on page 11

RCC Tied to Lead Exposure

BY JODY A. CHARNOW HIGHER 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, included 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 first quartile of blood lead level (below

CME FEATURE

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 researchers reported in Cancer Epidemiology, Biomarkers & Prevention (published online ahead of print). Higher total serum calcium was associated with a significantly reduced risk of RCC. Compared with subjects in the first 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

Earn 1 CME credit in this issue

The Management of Patients After Renal Transplantation PAGE 28

6 Renal & Urology News

FEBRUARY 2012

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FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD

Let Patients Sleep During Rounds

H

ow often do you face with the unpleasant task of waking a sleeping patient during 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 outpatients. 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 fulfill 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 happens 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 definitely benefit 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 “first do no harm,” and let patients sleep well.

Kamyar Kalantar-Zadeh, MD, MPH, PhD Associate 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.

Medical Director, Urology

Medical Director, Nephrology

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

Kamyar Kalantar-Zadeh, MD, PhD, MPH Professor 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

Urologists

Nephrologists

Frank R. Cerniglia Jr, MD Attending Pediatric Urologist Children’s Urology of Virginia Richmond, Va.

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

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

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

R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto Stanton Honig, MD Associate Clinical Professor of Surgery/Urology University of Connecticut School of Medicine, Urology Center New Haven J. Stephen Jones, MD, FACS Chairman Department of Regional Urology Cleveland Clinic Glickman Urological & Kidney Institute Professor of Surgery Cleveland Clinic Lerner College of Medicine of Case Western Reserve University James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City Kenneth Pace, MD, MSc, FRCSC Assistant Professor Division of Urology St. Michael’s Hospital University of Toronto Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada

R. Michael Hofmann, MD Associate Professor and Medical Director, Living Kidney Donor Program University of Wisconsin School of Medicine and Public Health, Madison Csaba P. Kovesdy, MD Associate Professor of Clinical Medicine University of Virginia, Charlottesville Chief of Nephrology Salem VA Medical Center Salem, Va. Edgar V. Lerma, MD, FACP, FASN, FAHA Clinical Associate Professor of Medicine Section of Nephrology Department of Medicine University of Illinois at Chicago College of Medicine, Chicago Allen Nissenson, MD Emeritus Professor of Medicine The David Geffen School of Medicine at UCLA, Chief Medical Officer, DaVita Inc. Rulan Parekh, MD, MS Associate Professor Johns Hopkins Children’s Center, Baltimore Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center, Detroit Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J. Lynda Anne Szczech, MD, MSCE Associate Professor of Nephrology Duke University School of Medicine Durham, N.C.

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

Jody A. Charnow Marina Galanakis Delicia Honen Yard Stephan Cho Candy Iemma Jennifer Dvoretz Natasha Marcano-Dillon John Crewe Kathleen Millea Chris Bubeck Paul Silver Monica Bond William Canning Tanya Gregory Dominic Barone Jim Burke Lee Maniscalco

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 office. The subscription rates for one year are, in the U.S., $75.00; in Canada, $85.00; all other foreign countries, $110.00. Single issues, $20.00. www.renalandurologynews.com. Postmaster: Send address changes to Renal & Urology News, c/o DMD Data Inc., 2340 River Road, Des Plaines, IL 60018. For reprints, contact Wright’s Reprints at 1.877.652.5295. Copyright: All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without the prior written permission of Haymarket Media, Inc. Copyright © 2012.

10 Renal & Urology News

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

Short Takes BP Drugs May Differ in Cardiovascular Benefits

years, 1,814 RCC cases developed

ACE inhibitors and angiotensin recep-

years and older. Compared with a red

tor blockers (ARBs) confer different

meat intake of 9.8 g per 1,000 kcal

cardiovascular benefits in hemodialy-

(median), intake of 62.7 g/1,000 kcal

sis (HD) patients, researchers found.

(median) was associated with a non-

In a crossover study, 15 HD

among 492,186 U.S. adults aged 50

significant 19% increased risk of RCC

patients received placebo, the ACE

and a significant twofold increased

inhibitor ramipril 5 mg per day for

risk of papillary RCC. Intakes of the

seven days, and the ARB valsartan

carcinogens BaP and PhiP, which are

160 mg/day for another seven days,

associated with grilled or barbecued

with a washout period of three weeks

meats, raised RCC risk by 20% to

between treatments. Neither ramipril

30% and doubled the risk of papillary

nor valsartan affected blood pressure

RCC.

Antibiotic Lock Reduces Catheter-Related Problems A

n 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 catheterrelated 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 first episode of bacteremia was significantly 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.

during dialysis treatment. Valsartan effect compared with ramipril, but

Statins May Lower Prostate Tumor Risk

ramipril appeared to prevent dialysis-

A population-based investigation

induced endothelial dysfunction,

demonstrated that statin use was

T. Alp Ikizler, MD, and colleagues

associated with substantial protec-

reported online in the Journal of the

tion against death from prostate

American Society of Nephrology.

cancer. Stephen W. Marcella, MD,

induced a greater anti-inflammatory

MPH, of the University of Medicine

Kidney Cancer Tied to Red Meat Intake

and Dentistry of New Jersey in New Brunswick, and colleagues reported online in Cancer that based on the

increase the risk of renal cell carcino-

medical records of 380 men aged

ma (RCC), according to study findings

55-79 years and 380 matched

reported in The American Journal

controls, those who died from the

of Clinical Nutrition (2012;95:155-

disease were 63% less likely to have

162). Over a mean follow-up of nine

ever taken a statin.

fro St m ra ig t h ht eW eb

Greater intake of red meat may

P Practicing Defensive Medicine

Based on the resp responses to a recent Renal & Urology Newss 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.

Yes No 14.7%

85.3%

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 defined UI as the use of two or more pads per day at follow-up.

Correcting Anemia Can Protect Renal Allografts C

orrecting 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 concentration of 10.5 to 11.5 g/dL (62 recipients), 4.8% of patients with completely corrected anemia developed kidney failure, compared with 21% of those with partially 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.

12 Renal & Urology News

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Repeated BoNTA Injections Okay Sustained improvements in patients with refractory OAB and IDO REPEATED INJECTIONS of botulinum 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 significant decreases in urinary frequency and urgency and urge urinary incontinence after the first BoNTA injection compared with baseline. These improvements were maintained after repeated injections and did not differ significantly 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 five, five 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 first and second injections, 25 (25%) and 12 (22%) patients,

respectively, did not undergo additional injections, but afterwards dropouts were rare, according to a research team led by Arun Sahai, MD, of Guy’s

Poor efficacy led to discontinuation of treatment in 13% of patients.

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

“It is clear from all of these studies that there is a significantly 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 injections over the first 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 injections offered when symptoms truly deteriorated to baseline levels, the authors related. “Later in our experience, we offered repeated injections sooner and, in almost all cases, without an interval with antimuscarinics,” they stated.

To their knowledge, their study consisted of the largest series of patients to date treated with repeated onabotulinumtoxinA injections for refractory IDO. ■

Combination Effective for Intermediate Risk PCa COMBINED EXTERNAL BEAM radiation therapy (EBRT) with a brachytherapy 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 intermediate risk PCa received this combined treatment. After a median follow-up of 73 months, the sixyear disease-free survival rate was 87%, 75%, and 85% using the study protocol definition, the 1997 American Society for Therapeutic Radiation and Oncology (ASTRO) consensus definition, and the Phoenix definition, respectively.

Six-year overall survival was 96%, according to study findings published in Cancer (2011;117:5579-5588).

The protocol definition of biochemical recurrence was three consecutive rises in PSA greater

MIs Often Unrecognized in Patients With CKD MYOCARDIAL INFARCTION (MI) often goes unrecognized among patients with chronic kidney disease (CKD), and it is associated with a significantly increased risk of death, according to researchers.

Of 18,864 participants in a population-based study who completed a baseline 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 prevalence was 4%, 6%, 6%, and 13% for subjects with an estimated glomerular

filtrate rate (eGFR) of 60 or higher, 45-59.9, 30-44.9, or less than 30 mL/ min/1.73 m2, respectively, investigators reported online ahead of print in Nephrology Dialysis Transplantation.

The prevalence was 4%, 5%, 7%, and 10% among subjects with an albuminuria-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 classification) 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 associated with a 49% and 88% increased risk among subjects with an ACR of 30 mg/g or higher.

Dr. Rizk’s group found that traditional 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 possibility that UMI may have a different mechanistic etiology than RMI,” the authors wrote.

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

The authors noted that study strengths included the very large number of participants from throughout the United States, with an oversampling of African Americans. “This is particularly important because African Americans represent a substantial proportion of the CKD population, especially at the more advanced stages,” the researchers 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. ■

than 1.0 ng/mL after 18 months from the start of treatment. The 1997 ASTRO definition is three consecutive PSA increases above nadir and the Phoenix definition is nadir plus 2 ng/mL. The protocol and subsequently the Phoenix definitions were developed because of the tendency of the 1997 ASTRO definition 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, excluding 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 efficacy is important, “the impact of any treatment on disease control or eradication has to be considered in the larger context of toxicity and quality of life.” ■

16 Renal & Urology News

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

The finding “might be beneficial for long-term active surveillance protocols to contain healthcare costs and reduce radiaBrief 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: s (YPOCALCEMIA (see Warnings and Precautions) s /STEONECROSIS OF THE *AW (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 reect 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.

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 definitive therapy for a renal mass. These patients also underwent CT (66 patients) or MRI (80 patients). Thirty-three patients 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 onstudy was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% WERE FEMALE %IGHTY lVE PERCENT WERE 7HITE (ISPANIC ,ATINO !SIAN

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

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 nonsignificant (less than 3.5%), Dr. Mucksavage’s team reported in Urology (2012;79:28-31). anticancer treatments affected denosumab systemic exposure and pharmacodynamic 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 hormone therapy (see Clinical Pharmacology [12.2] in full Prescribing Information).

USE IN SPECIFIC POPULATIONS: Pregnancy: Category C. There are no adequate and well-controlled trials of Xgeva in pregnant women. Use Xgeva during pregnancy only if the potential beneďŹ t justiďŹ es the potential risk to the fetus. Encourage women who become pregnant during Xgeva treatment to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800772-6436) to enroll. In an embryofetal developmental study, cynomolgus Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any monkeys received subcutaneous denosumab weekly during organogenesis at Severity (Trials 1, 2, and 3) doses up to 6.5-fold higher than the recommended human dose of 120 mg every 4 weeks, based on body weight (mg/kg). No evidence of maternal toxicity Xgeva Zoledronic Acid OR FETAL HARM WAS OBSERVED (OWEVER THIS STUDY ONLY ASSESSED FETAL TOXICITY Body System n = 2841 n = 2836 during the ďŹ rst 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 GASTROINTESTINAL [13.2] in full Prescribing Information). In genetically engineered mice in which Nausea 31 32 the gene for RANK ligand (RANKL) has been deleted (a “knockout mouseâ€?), the Diarrhea 20 19 absence of RANKL caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice also showed altered maturation of the maternal mammary gland, leading to GENERAL impaired lactation postpartum (see Use in Nursing Mothers).

45 46 Fatigue/ Asthenia Nursing Mothers. It is not known whether Xgeva is excreted into human milk.

INVESTIGATIONS Because many drugs are excreted in human milk and because of the potential 18 9 (YPOCALCEMIAb for serious adverse reactions in nursing infants from Xgeva, a decision should 32 20 (YPOPHOSPHATEMIAb be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva NEUROLOGICAL during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling 13 14 (EADACHE pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum (see Nonclinical Toxicology [13.2] in RESPIRATORY full Prescribing Information).

21 18 Dyspnea 15 15 Cough Pediatric Use. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in a Adverse reactions reported in at least 10% of patients receiving Xgeva in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL with a construct of osteoprotegerin bound to Trials 1, 2, and 3, and meeting one of the following criteria: Fc (OPG-Fc) at doses less than or equal to 10 mg/kg was associated with s !T LEAST GREATER INCIDENCE IN 8GEVA TREATED PATIENTS OR inhibition of bone growth and tooth eruption. Adolescent monkeys dosed with s "ETWEEN GROUP DIFFERENCE EITHER DIRECTION OF LESS THAN AND MORE THAN denosumab at 5 and 25 times (10 and 50 mg/kg dose) higher than the 5% greater incidence in patients treated with zoledronic acid compared to recommended human dose of 120 mg subcutaneously every 4 weeks (based on placebo (US Prescribing Information for zoledronic acid) body weight mg/kg) had abnormal growth plates (see Nonclinical Toxicology b Laboratory-derived and below the central laboratory lower limit of normal [8.3 – [13.2] in full Prescribing Information).

8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL (0.71 – Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 0.9 mmol/L) for phosphorus] (44%) were 65 years of age or older. No overall differences in safety or efďŹ cacy were observed between these patients and younger patients.

Severe Mineral/Electrolyte Abnormalities s 3EVERE HYPOCALCEMIA CORRECTED SERUM CALCIUM LESS THAN MG D, OR LESS THAN Renal Impairment. In a trial of 55 patients without cancer and with varying degrees 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of of renal function who received a single dose of 60 mg denosumab, patients with a patients treated with zoledronic acid. Of patients who experienced severe creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia of severe hypocalcemia with denosumab compared to patients with normal renal and 16% experienced 3 or more episodes (see Warnings and Precautions and function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg Use in SpeciďŹ c Populations). every 4 weeks has not been evaluated in patients with a creatinine clearance of less s 3EVERE HYPOPHOSPHATEMIA SERUM PHOSPHORUS LESS THAN MG D, OR LESS than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and Reactions, and Clinical Pharmacology [12.3] in full Prescribing Information).

7.4% of patients treated with zoledronic acid.

OVERDOSAGE: There is no experience with overdosage of Xgeva.

Osteonecrosis of the Jaw PATIENT COUNSELING INFORMATION: In the primary treatment phases of Trials 1, 2, and 3, ONJ was conďŹ rmed in Advise patients to contact a healthcare professional for any of the following: 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 s 3YMPTOMS OF HYPOCALCEMIA INCLUDING PARESTHESIAS OR MUSCLE STIFFNESS

extended treatment phase of approximately 4 months in each trial are included, twitching, spasms, or cramps (see Warnings and Precautions and Adverse the incidence of conďŹ rmed ONJ was 2.2% in patients who received Xgeva. The Reactions) median time to ONJ was 14 months (range: 4 – 25). s 3YMPTOMS OF /.* INCLUDING PAIN NUMBNESS SWELLING OF OR DRAINAGE FROM the jaw, mouth, or teeth (see Warnings and Precautions and Adverse Immunogenicity. As with all therapeutic proteins, there is potential for Reactions) immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with s 0ERSISTENT PAIN OR SLOW HEALING OF THE MOUTH OR JAW AFTER DENTAL SURGERY (see denosumab doses ranging from 30 – 180 mg every 4 weeks or every 12 Warnings and Precautions) weeks for up to 3 years tested positive for binding antibodies. No patient with s 0REGNANCY OR NURSING (see Use in SpeciďŹ c Populations) positive binding antibodies tested positive for neutralizing antibodies as Advise patients of the need for: assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic proďŹ le, toxicity proďŹ le, or clinical s 0ROPER ORAL HYGIENE AND ROUTINE DENTAL CARE response associated with binding antibody development. The incidence of s )NFORMING THEIR DENTIST THAT THEY ARE RECEIVING 8GEVA antibody formation is highly dependent on the sensitivity and speciďŹ city of the s !VOIDING INVASIVE DENTAL PROCEDURES DURING TREATMENT WITH 8GEVA assay. Additionally, the observed incidence of a positive antibody (including ÂŽ . Patients should neutralizing antibody) test result may be inuenced by several factors, Advise patients that denosumab is also marketed as Prolia ÂŽ including assay methodology, sample handling, timing of sample collection, inform their healthcare provider if they are taking Prolia . concomitant medications, and underlying disease. For these reasons, Amgen Manufacturing Limited, a subsidiary of Amgen Inc. comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading.

One Amgen Center Drive 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

Thousand Oaks, California 91320-1799 Š2011 Amgen Inc. All rights reserved. Printed in USA.

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 comfortable 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.â€? â–

RFA Benefits Selected RCC Patients IN APPROPRIATELY selected patients, radiofrequency ablation (RFA) is an effective minimally invasive treatment for cT1a renal cell carcinoma (RCC) that offers long-term oncologic outcomes comparable to nephronsparing 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 five-year outcomes associated with the two treatments. Five-year overall survival with RFA and PN was 97.2% and 100%, respectively, according to a report in European Urology (published online ahead of print).

Cancer-specific survival was 97.2% and 100%, disease-free survival was 89.2% and 89.2%, local recurrence-

Š2011 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 efďŹ cacy 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: “RECISTâ€?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. XGEVAÂŽ (denosumab) prescribing information, Amgen. 8. Saad F, Gleason DM, Murray R, et al, for the Zoledronic Acid Prostate Cancer Study Group. A randomized, placebocontrolled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458-1468.

free survival was 91.7% and 94.6%, and metastasis-free survival was 97.2% and 91.8%. None of the differences between the groups was statistically significant.

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

www.renalandurologynews.com

FEBRUARY 2012

Renal & Urology News 17

Fiber Lowers Death Risk in CKD Patients Each 10 g/day increment in total dietary fiber was associated with a 19% decreased risk, study finds HIGH INTAKE of dietary fiber is associated with decreased inflammation and all-cause mortality in patients with chronic kidney disease (CKD), according to researchers.

An analysis of data from 14,533 participants in the third National Health and Nutrition Examination Survey showed that each 10 g/day increment in total fiber intake is associated with 38% and 11% decreased likelihood of having elevated C-reactive protein (CRP)—a marker of systemic inflammation—in patients with and without CKD, respectively, after adjusting for age, gender, race, and numerous comorbid conditions and laboratory measures, 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, defined CKD as an estimated glomerular filtration rate

below 60 mL/min/1.73 m 2 and an elevated CRP as a serum CRP level above 3 mg/L. In addition, each 10 g/day increment in total dietary fiber was associated with a 19% decreased risk of all-cause mortality in the CKD subpopulation. Dietary fiber was no longer associated with mor-

Bladder Ca Worse in Diabetics

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 beneficial in patients with DM, especially those with poor glycemic control.”

The mechanism by which DM contributes to bladder cancer is unclear. In a discussion of some of the possibilities, the researchers cited studies suggesting that chronic exposure to hyperinsulinemia 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 bladder 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 recurrence 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. ■

DIABETES MELLITUS (DM) appears to be an independent predictor of disease 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 (representing poor glycemic control) had a significantly greater tumor multiplicity, more high-grade tumors, and received significantly more intravesical therapy.

Survival benefit could be related to a reduction in inflammation. tality in this population after adjusting for serum CRP, suggesting that reduction in inflammation is a possible mechanism by which dietary fiber lowers mortality in CKD patients, according to researchers.

The study found no association between dietary fiber intake and all-cause mortality in the non-CKD participants.

The authors noted that various mechanisms could explain the association between high dietary fiber intake and decreased serum CRP. Dietary fiber may inhibit inflammation by lowering glycemic load of rapidly digestible and absorbable dietary carbohydrates, they pointed out. High fiber diets have been associated with higher plasma levels of adiponectin, which has antiinflammatory 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 inflammation, they stated. These substances normally would be excreted via the kidney, but they accumulate in patients with kidney disease. This could explain why the association of higher dietary fiber with lower inflammation 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 concentrations of these toxins more in the CKD population than in the non-CKD population.

The researchers pointed out that higher dietary fiber intake was associated with lower serum levels of interleukin-6 and tumor necrosis factor-alpha receptor-2 in postmenopausal women in the Women’s Health Initiative Study and that dietary fiber 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 unmeasured variables cannot be ruled out and diet was assessed using only a single 24-hour diet recall. ■

Comorbid Illnesses Worsen Post-Cystectomy Outcomes GREATER COMORBID illness increases

management,” the authors concluded.

the likelihood of complications after

“Improved attention to reasonable

radical cystectomy for bladder

perioperative processes during

cancer among patients older than

radical cystectomy can result in better

70 years, according to a study by

patient outcomes.”

German researchers.

In this patient age group, those

Vladimir Novotny, MD, and colleagues at Technical University Dresden studied

with an American Society of Anesthesi-

830 patients who underwent radical cys-

ologists (ASA) score of 3 or greater—

tectomy. Of these, 365 (44%) were aged

indicating severe systemic diseases—

70 years and older (elderly) and 465

had a significantly higher rate of

(56%) were younger than 70. The elderly

perioperative complications than

cohort had a significantly higher preva-

those with an ASA score of 2 or

lence of concomitant diseases, such as

less—indicating mild systemic

hypertension (57.3% vs. 38.5%), coro-

diseases (37% vs. 25%), investigators

nary heart disease (27.1% vs. 14.8%),

reported online in the World Journal

and diabetes (25.5% vs. 14.6%), as well

of Urology. An ASA score is a global

as a significantly greater rate of periop-

score that assesses the physical status

erative complications (31% vs. 21.5%).

of patients before surgery. For the

The elderly patients had a significant 44%

study, the researchers defined periop-

increased risk of perioperative complica-

erative complications as any adverse

tions compared with younger patients.

event within 30 days of surgery.

“A careful consideration of individual

Additionally, subjects with chronic obstructive pulmonary disease (COPD) had

comorbidity is important in both

a significant 1.8 times increased risk of

preparing the patient for surgery

perioperative complications compared

and during the whole perioperative

to those without COPD. ■

18 Renal & Urology News

FEBRUARY 2012

www.renalandurologynews.com

Renal Nutrition Update R

esearch has shown that individuals 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 comparing 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 significantly lower serum insulin and leptin concentrations 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 significantly lower in the tertile with the most steps.

CKD patient challenges Patients who have chronic kidney disease (CKD) and especially those with end-stage renal disease on dialysis are quite likely to have multiple comorbidities (such as hypertension, cardiovascular disease, anemia of chronic disease, and diabetes) and take multiple medications (antihypertensive agents, phosphate binders, lipid and glucose lowering drugs, and others). Thus, routinely engaging in physical activity is more difficult 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 significantly 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 activity level. A high BMI or diabetic status was associated with a significantly lower physical activity level, and older age and diabetic status were associated with fewer steps. Additionally, all parameters were significantly lower during dialysis days when compared to non-dialysis days.

Improved quality of life According to a 2011 review and metaanalysis by Heiwe and Jacobson (Cochrane Database Syst Rev 2011;[10]) in patients with CKD, physical activity significantly improves quality of life (QoL), nutrition parameters (serum albumin and pre-albumin), 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 activity can improve key outcome parameters in this population, many clinicians would

Exercise Recommendations In 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 recommendations contained in a 2002 report issued by an American College of Cardiology/American Heart Association task force for older adults. These recommendations “are explicitly intended to be relevant to younger individuals with clinically significant 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 five days each week or vigorous intensity aerobic activity for a minimum of 20 minutes on three days each week.”

© ISTOCKPHOTO.COM / STEVE COLE

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. be unsure how to engage their patients in regular physical activity in a safe, wellmonitored 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 dialysis A 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 randomized them to either intradialytic low intensity strength training or to stretching. Patients engaged in resistance exercise 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 significantly in the strength training group compared with the stretching group (21% vs. 0.2%) and the Short Form-36 physical composite score improved significantly in the intervention group compared with the control group (21% vs. -0.2%). Interestingly, patient adherence 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 hospitalization, improved mortality risk, and an overall improved QoL. ■ Dr. Steiber is Coordinator of the Dietetic Internship/Master’s Degree Program at Case Western Reserve University in Cleveland.

www.renalandurologynews.com

FEBRUARY 2012

Renal & Urology News 19

Enterococcal UTIs in Kids Characterized 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 five-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 susceptible 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 identified in 70% of patients with enterococcal UTIs compared with 43.7% of those with Gram negative UTIs. Renal abnormalities in the enterococcal UTI

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

PSA Threshold for Biopsy Still Stable

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 significant change in biopsy threshold during the study period.

The likelihood of biopsy was strongly 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 significantly 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 important 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 conditions 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. ■

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 colleagues reviewed laboratory and biopsy records of 59,764 men in Group Health, a large integrated health care system in Washington State for the period 19982007. The study showed that 28% of tests with PSA levels of 4.0 or above were followed up with a prostate biopsy 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.

Antibiotic susceptibilities All 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 first-, second-, and third generation cephalosporins, respectively.

Additionally, compared with Gram negative bacteria, enterococcal isolates were significantly less commonly resistant to ampicillin (10% vs. 69%) and more common resistant to ofloxacin (20% vs. 6%). All Gram negative isolates were uniformly resistant to vancomycin but all enterococcal isolates were susceptible to the drug.

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

© CDC / JANICE HANEY CARR

These infections may indicate urinary tract abnormalities, and empiric therapy often is inappropriate

Enterococci are a relatively uncommon cause of pediatric UTIs.

vs. 5.6%). Cefuroxime and ceftriaxone were the inappropriate antibiotics given empirically to treat enterococcal UTIs. After obtaining culture results, appropriate 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 abnormalities in children with enterococcal

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

The investigators, led by Gilat Livni, MD, observed that most pediatric 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, especially in such circumstances as the presence of underlying urinary abnormalities or ineffectiveness of previous cephalosporin or other antibiotic treatment.”

They also observed, “Timely and appropriate administration of antimicrobial therapy is essential for eliminating symptoms, eradicating infection, reducing the likelihood of renal damage, and preventing complications.” ■

Smaller Bladder Tumors Less Likely to Recur After Surgery NON-MUSCLE-INVASIVE bladder tumors

adjusting for multiple variables, Dr. Jancke

15 mm or less in diameter are associat-

and colleagues reported in the Scandina-

ed with a lower risk of recurrence after

vian Journal of Urology and Nephrology

surgical treatment compared with larger

(2011;45:388-392). Tumors 31-40 and

tumors, according to researchers.

greater than 40 mm were associated with

In addition, their study of 768 patients

a significant 2.2 and 2.7 times increased

who underwent transurethral resection

risk of recurrence, respectively. In the

for non-muscle invasive bladder cancer

three-size group, tumors 16-30 mm and

(Ta/T1) showed that differentiating

greater than 30 mm in diameter were

tumors into three size categories can

associated with a significant 42% and 2.4

provide additional information in pre-

times increased risk of recurrence com-

dicting recurrence.

pared with tumors 1-15 mm in diameter.

Investigators at University Hospital,

T1 tumor category and local recurrence

Linköping, Sweden, led by Georg

were significant risk factors for progres-

Jancke, MD, categorized tumors

sion, but tumor size was not.

according to five sizes (1-10, 11-20,

Other factors associated with recur-

21-30, 31-40, and greater than 40 mm

rence were multiplicity, tumor category,

in diameter) or three sizes (1-15, 16-30,

and surgery performed by residents.

and greater than 30 mm in diameter).

Of the 768 patients, recurrence oc-

The researchers recommend the threesize over the five-size model because it

curred in 478 (62%) and progression

makes measuring easier: 15 mm and

occurred in 71 (9%). In the five-size

30 mm correspond to about two and

group, tumors 21-30 mm in diameter

four times the diameter of the resection

were associated with a significant 57%

loop, respectively. Thus, the authors

increased risk of recurrence compared

noted, it has a high reproducibility and

with tumors 1-10 mm in diameter, after

can be easily used in clinical practice. ■

FEBRUARY 2012

www.renalandurologynews.com

Malpractice News

Diagnosis-Related Suits Tied to Communication Failures Physicians who regularly order diagnostic 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, malpractice payments based on diagnosis rose approximately 40%. A major cause of these malpractice cases was communication failures, for example, failure of physicians and patients to receive results of tests; delays in reporting findings; 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 correlation between communication failures and malpractice claims awards. The study, published in the Journal of the American College of Radiology, examined 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 increasing 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 notification of medical test data, or that the drastic growth in diagnostic testing has outpaced notification 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 define 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 notification reliability, improve workflow 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 confidential 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 specific dollar amounts of awards, or specific ages (rather, it used age ranges).

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

© ISTOCKPHOTO.COM / DANIEL LAFLOR

© ISTOCKPHOTO.COM / IURIISOKOLOV

Better communication could avert a lawsuit

Public access to the NPDB denied following a surgeon’s complaint.

BY ANN W. LATNER, JD

called the media’s ability to “triangulate” the confidential data using court records to find out classified information. It has been reported that a contributing 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 histories 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 file 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 confidential,” said HHS spokesman Martin Kramer.

The move has sparked outrage among journalists and consumer advocacy 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, writing that “shutting down public access to the data bank undermines the critical mission of identifying inefficiencies within our health care system—particularly at the expense of Medicare and Medicaid beneficiaries.”

Electronic Health Records May Increase Malpractice Risk Electronic health records (EHRs) seem like a good idea at first 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, according to a white paper published by the AC Group, a Texas-based health information technology research and consulting firm. This could actually expose physicians to a greater risk of malpractice lawsuits. The paper calls on federal officials to slow the adop-

tion of a federal incentive program that aims to get hospitals and medical practices to use EHRs. The artificially 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 medicolegal issues,” they wrote. “The result of this uneven progression is that physicians and other stakeholders may be unknowingly exposed to medical liability risk.”

The authors looked at the functionality of 42 ambulatory EHRs and found Inadequate EHR software could expose doctors to more liability.

© J. P. MOCZULSKI / PHOTOTAKE

20 Renal & Urology News

that almost 90% could not provide drug-lab alerts, more than 80% did not check for drug interactions during the prescription refill process, and 60% failed to automatically update clinical decision support to reflect 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 information that a doctor may be unable to read completely.

The white paper recommends that EHR vendors consider external product reviews for potential malpractice concerns. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

22 Renal & Urology News

FEBRUARY 2012

■ Kidney Week 2011, Philadelphia

www.renalandurologynews.com

Renal & Urology News editor Jody A. Charnow provided news coverage.

Renal Risks Lower with Metformin Use New findings support the use of the drug as first-line treatment for patients with type 2 diabetes 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 findings.

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 estimated glomerular filtration rate (eGFR) of 25% or more (eGFR event) or diagnosis 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 compared 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 filled their first 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 benefits to using metformin compared to sulfonylurea,” Dr. Hung told Renal & Urology

Worsening Post-Transplant CKD Hikes Graft Failure Risk WORSENING OF chronic kidney disease

months post-transplant to CKD stage 4

(CKD) stage in the first year following re-

at 12 months had a 3.5 times increased

nal transplantation is associated with an

risk of graft failure compared with pa-

increased risk of graft failure, research-

tients who remained in CKD stage 3 at

ers reported.

12 months post-transplant, and a 53%

The findings, from a study of 77,206

graft survival rate versus 85% at four

adult Medicare beneficiaries who re-

years, respectively. Patients who pro-

ceived a kidney-only transplant, suggest

gressed from stage 3 to stage 5 from

that patient management strategies

month 6 to month 12 had an 11.5 times

targeted at preserving renal function in

increased risk of graft failure and 20%

the early post-transplant period will have

graft survival at four years compared to

a positive impact on graft survival, ac-

patients who remained in CKD stage 3

cording to the investigators.

at 12 months post-transplant.

“Given the scarceness of donor organs,

“Change in renal function in the early

management strategies targeted at pre-

period post-transplantation is an impor-

serving renal function will have not only

tant prognostic determinant of long-term

clinical implications but economic conse-

graft survival,” Dr. Irish told Renal &

quences as well,” said lead investigator

Urology News. “These results provide

William Irish, PhD, of CTI Clinical Trial and

further evidence that preserving renal

Consulting Services. “Furthermore, the

function has a positive impact on the net

results can be used to inform the design

benefit of kidney transplantation.”

of a clinical trial where the primary objec-

For the study, Dr. Irish’s team

tive is to preserve renal function.”

The study showed, for example,

used estimated glomerular filtration rate thresholds established by the

that renal transplant patients who

National Kidney Foundation definitions

progressed from CKD stage 3 at six

for CKD stage. ■

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-inflammatory effects

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-

Living Kidney Donors Suffer Renal Decline 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 creatinine 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 greater increase, and 31% had a 0.4 mg/ dL or greater increase in plasma creatinine compared with their predonation 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-nephrectomy. Each 1 mm Hg increment in MAP at the time of donation was associated with

tions of metformin as first-line therapy for patients with diabetes type 2,” Dr. Hung added.

Previous research The study is not the first 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 significantly higher likelihood of experiencing a cardiovascular (CV) event within two years if they start treatment 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. ■

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

“There are few data addressing postnephrectomy kidney function in contemporary living donors,” said Julie Lin, MD, MPH, FASN, senior author of this study. “We were surprised to find that relatively high proportions of donors met established clinical definitions 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 findings of a study of 3,424 individuals who underwent living donor nephrectomy (LDN) showing that a year after LDN, 53% of donors could be classified as having CKD stage 3-4. Mean glomerular filtration rate (GFR) did not change significantly between year 1 and year 5.

Not all studies, however, have demonstrated 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. ■

www.renalandurologynews.com

FEBRUARY 2012

Renal & Urology News 23

Better Lithotripsy On the Horizon & QA

A 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 flexible ureteroscopy.

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 flexible 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 first 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, progressively, as they tried to change things. It changed, but not for the better.

The reason we know that [the attempted 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 first 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 pressures 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 efficacy, in my opinion.

Where does flexible ureteroscopy fit into the picture?

Dr. Lingeman: Ironically, in the field 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 technology. As the endoscopes that we’ve used have gotten smaller, they’ve gotten better. 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 flexible ureteroscopy].

Ureteroscopy started around the same time as shock wave lithotripsy, and at that time our instruments were large and rigid—inflexible—so you couldn’t get them up into the kidney. You could only treat stones in the lower ureter.

But now these instruments are flexible 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 flexible 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 ureteroscopy typically are done under anesthesia, 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 significant disadvantage of flexible ureteroscopy is that we usually have to leave a ureteral stent afterwards, because passing our telescopes through the small ureter tubes can cause swelling, 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 disadvantage of ureteroscopy.

Are any other techniques used to treat urinary tract stones?

Dr. Lingeman: For most patients, the common procedures are ESWL and ureteroscopy. Patients with large stones—greater than 2 cm—are treated with another minimally invasive procedure called percutaneous 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 flank 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 efficiently 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 refined over the years. It’s increasing slowly in popularity as more physicians become more comfortable 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?

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

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, according to the FDA. continued on page 24

24 Renal & Urology News

FEBRUARY 2012

www.renalandurologynews.com

Supplemental Vitamin D Helps Black Hypertensives

BY JILL STEIN ORLANDO—Vitamin D supplementation may reduce blood pressure (BP) in African-American patients with hypertension in a dose-dependent manner, regardless of the intensity of antihypertensive treatment, researchers announced at the American Heart Association Scientific Sessions 2011.

“The findings, if confirmed in future studies, will have huge therapeutic and public health implications because vitamin D can potentially be a very useful adjunct to conventional antihypertensive 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 longitudinal relationship between vitamin D supplementation and BP change, and control independent of antihypertensive drug treatment intensity in a largely AfricanAmerican referral hypertensive cohort.

African-Americans are known to have a high prevalence of vitamin D deficiency and hypertension.

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

Better Lithotripsy

How do you see stones being treated in five or 10 years?

continued from page 23

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 definitive.

I would say it’s suggestive; these drugs are quite safe, so we commonly use them because if there is some evidence to suggest 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 ongoing 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 benefit.

BP dropped by 10/7 mm Hg in patients taking at least 2,000 IU/day. mentation studies have been “mostly but not exclusively” negative, Dr. Flack pointed out.

He was quick to emphasize, however, that the earlier studies have not typically required randomized participants to have vitamin D defi ciency (defined 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).

Dr. Lingeman: Well, the holy grail for us in urology is finding 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 find a more comfortable stent. If we could find a stent that didn’t hurt, then I believe that most patients would be best managed with flexible 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 flexible ureteroscopes; they’re continuously available. ■

Remember to visit us at renalandurologynews.com for more interviews with thought leaders in urology and nephrology.

The present study included 648 patients with a mean baseline blood pressure 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 five 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 findings 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 prospective 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 supplementation 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 confounding, despite the inclusion of multiple potential confounding variables, may have influenced the results.

Finally, he said that the findings apply mostly to black hypertensives, especially women, given the demographic composition of the study cohort. ■

Fewer Prostate Cancer Patients Are Initiating ADT, Data Shows INITIATION OF androgen deprivation therapy (ADT) for prostate cancer (PCa) is declining and patterns of use are changing, according to recently published 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 personyears even though PCa prevalence doubled 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 2,2002,300 patients per year by 2005.

Additionally, the study revealed that patterns 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 treatment 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 growing appreciation of the potential adverse effects of ADT, and emerging evidence supporting selected indications and regimens, 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 flushes, sexual dysfunction, loss of libido, decreased bone mineral 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. ■

www.renalandurologynews.com

■ Kidney Week 2011, Philadelphia

FEBRUARY 2012

Renal & Urology News 25

Renal & Urology News editor Jody A. Charnow provided news coverage.

High PTH, FGF-23 Predict Vascular Calcification ELEVATED LEVELS of serum parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) are associated with an increased likelihood of progression of vascular calcification (VC) in hemodialysis patients, according to French researchers.

In a study of 85 patients still alive after three years, 38 (44.7%) had experienced radiographic progression of vascular calcification 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 significantly higher in progressors compared with nonprogressors (244.3 vs. 179.6 pg/mL and 4204 vs. 2640 RU/mL, respectively).

Subjects with serum PTH values above

AA Kidneys May Worsen Tx Outcomes RECIPIENTS OF KIDNEYS from African Americans (AA) are at increased risk of

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

With regard to specificity and sensitivity 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

specificity 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 hyperphosphatemia cases (10% or less), only one case of hypercalcemia, and no severe cases of hyperparathyroidism. ■

WE’RE

CHANGING THE WAY

PROSTATE CANCER PATIENTS ARE TREATED EVEN WHEN THEY’RE NOT BEING TREATED When it comes to treating prostate cancer, we do not believe in a one-size-fits-all approach. That’s why doctors at UPMC are experts in both traditional methods of urologic surgery and in cutting-edge laparoscopic and robotic surgery. But our doctors also recognize when the best management is not an operation, but careful

all-cause and cardiovascular mortality

observation. We believe it is important to be well versed in all

compared with patients who receive

options to ensure patients receive the right treatment at the right

kidneys from non-AA donors.

In a study of 13,692 hemodialysis patients who underwent renal trans-

time. Because our job is not only to save lives, but to preserve the quality of life of every patient we treat. Snap the code and learn more at UPMCPhysicianResources.com.

plantation, recipients of an AA kidney had a 39%, 80%, and 30% increased risk of all-cause mortality, cardiovascular mortality, and death-censored graft loss, respectively, over a six-year observation period, after adjusting for relevant clinical and transplantrelated 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 significant 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 findings were presented by Miklos Z. Molnar, MD, PhD. Both researchers are affiliated with the Harbor-UCLA Medical Center in Torrance, Calif. ■

UPMC is affiliated with the University of Pittsburgh School of Medicine.

26 Renal & Urology News

FEBRUARY 2012

www.renalandurologynews.com

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

BY JOHN SCHIESZER CHICAGO—Adding abatacept to mycophenolate mofetil (MMF) may benefit nephrotic patients with lupus nephritis (LN), according to the findings of a 12-month study presented at the 2011 American College of Rheumatology annual meeting.

In these patients, researchers observed an improvement in proteinuria associated with abatacept, suggesting that additional exploration may be warranted to investigate potential biologic activity in this subset of patients.

The study, however, found that adding abatacept to MMF does not significantly 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 positive signals were seen. For example, in those patients with significant proteinuria (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-stimulation 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 efficacy endpoint was time to complete renal response (CRR) confirmed at 30 days after the first response. Secondary endpoints included 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

Abatacept did not change the time to complete renal response.

CRR did not differ between groups for abatacept 10/10 and 30/10 compared with placebo nor did time to RI. However, a subset analysis of 122 nephrotic 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 compared with placebo..

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

infections, pneumonia, herpes zoster, gastroenteritis, and urinary tract infection. Underlying disease was the cause of death for five 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 treatment,” Dr. Furie told Renal & Urology News. “Should abatacept eventually prove to be a worthwhile addition to our treatment of lupus nephritis, extension of development to other types of glomerulonephritis may be warranted.

Rheumatologists and nephrologists have been struggling with clinical trials 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 endpoint, as well as secondary endpoints, was not met. This doesn’t necessarily mean the drug doesn’t work in lupus nephritis. Entry criteria, definitions 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

BY CAROLINE HELWICK SAN FRANCISCO—Prior to radical cystectomy for bladder cancer, preoperative neutrophil/lymphocyte ratio (NLR) can identify patients at risk for having non-organ-confined disease and who may benefit from neoadjuvant chemotherapy, University of Wisconsin investigators 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 final 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 organconfined disease to non-organ-confined disease, which has a tremendous impact on prognosis and outcomes.”

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

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

Patients with non-organ-confined disease could benefit from neoadjuvant chemotherapy, which has proven overall and cancer-specific survival benefits for T3 bladder cancer. There is, therefore,

It may be possible to ID patients who may benefit from neoadjuvant chemo. great value in identifying these patients prior to surgery, he said.

“NLR has been shown to be an important 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 fight 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 patients Pathologists 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 statistically significantly 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 significant difference in NLR was observed between non-organ-confined and organ-confined groups: 4.17 versus 2.60.

The researchers also created a receiver operating characteristic (ROC) curve to further define the utility of the NLR, compared 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 benefits of neoadjuvant chemotherapy, which could have had a real clinical impact.”

The investigators will be implementing 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 Scientific Poster session, said this research “has the potential to become a clinically practice-changing.” ■

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FEBRUARY 2012

Renal Biopsies May Indicate Class of Lupus Nephritis Some pathologic features may independently predict outcomes clinical-pathological correlates at time of renal biopsy in LN patients according to the 2003 International Society of Nephrology and Renal Pathology Society (ISN/RPS) classification.

“The ISN-RPS classification of lupus nephritis was developed in 2003 and was designed to improve the prognostic significance of biopsy findings compared to the WHO classification. We undertook this study as there continue

COURTESY OF CLEVELAND CLINIC PATHOLOGY AND LABORATORY MEDICINE INSTITUTE

BY JOHN SCHIESZER CHICAGO—Certain features at the time of renal biopsy are associated with a particular class of lupus nephritis (LN) and may independently predict renal outcomes, 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

This lupus nephritis tissue specimen shows active glomerular lesions.

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 erythematosus (SLE) at a single center with renal biopsy slides available and matched clinical follow-up. Investigators collected demographic and clinical data at time of renal biopsy. Renal biopsies were reviewed by two expert pathologists independently and by a third pathologist in cases of disagreement to determine a consensus score. The degree of agreement between pathologists on individual items of the ISN/ RPS score was measured. The goal of this investigation was to examine the

to be conflicting 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 classification,” 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 considered 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 remission (defined as serum creatinine below 1.4 mg/dL and proteinuria less than 0.33 g/day), partial remission (defined 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 filtration rate (eGFR) was significantly different 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 different 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 proteinuria 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 assisting prognostication in lupus nephritis based on renal biopsy features.”

Dr. Barber said it is important for nephrologists 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 definitions would be important to harmonize the findings of future studies in this area. ■

Renal & Urology News 27

MMF Beats Azathioprine For LN MYCOPHENOLATE mofetil (MMF) is more effective than azathioprine as maintenance therapy for patients with active lupus nephritis (LN) who responded to induction therapy, researchers reported.

In a 36-month randomized, doubleblind study of 227 LN patients who met response criteria during a six-month induction trial, the researchers found that MMF significantly decreased the time to treatment failure, the primary outcome measure. The researchers defined treatment failure as death, end-stage renal disease, doubling of serum creatinine level, renal flare, or rescue therapy for LN. The overall observed rates of treatment 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;365:18861895). During the induction trial, subjects received either oral MMF or intravenous (IV) cyclophosphamide.

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

The rates of serious adverse events (AEs) in the MMF and azathioprine groups were not significantly dif-

Mycophenolate mofetil lowered treatment failure risk by 59%. ferent (23.5% vs. 33.3%, respectively), but the rate of study withdrawal related to AEs was significantly 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 preventing relapse in patients with active LN who have had a clinical response to induction therapy with either MMF or IV cyclophosphamide. ■

28 Renal & Urology News

FEBRUARY 2012

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CME FEATURE

The Management of Patients After Renal Transplantation Patients who undergo renal transplantation require complex care that involves a diligent, multidisciplinary approach.

Release Date: February 2012 Expiration Date: February 2013 Estimated 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 Credit TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

DISCLOSURE OF CONFLICTS OF INTEREST: Medical Education Resources ensures balance, independence, objectivity, and scientific rigor in all our educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity.

Conflicts are resolved by MER to ensure all scientific research referred to, reported, or used in a CME activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality CME activities that promote improvements or quality in health care and not a commercial interest.

The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Faculty • Daniel C. Brennan, MD, FACP

Reported Financial Relationship Grants/Research Support: Pfizer and NIH. Consultant: Genzyme and Genentech.

Speakers’ Bureau: Novartis and Genentech.

BY DANIEL C. BRENNAN, MD, FACP

T

he management of the kidney transplant recipient requires knowledge of the patient’s history pre-, during, and post-transplant. Typically, a team of surgeons, nephrologists, consultants, primary 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 recipient to a transplant center. During the initial transplant evaluation, there are two essential questions that must be answered upfront. The first 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 cognizant 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 medications, laboratory evaluations, and clinic appointments—all essential for a successful transplant. It seems imprudent to allocate a donor organ if the patient history does not suggest the ability to maintain the allograft. Thus, early evaluation 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 endstage 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 transplantation are ESRD or irreversible and progressive chronic kidney disease

The content managers reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Content Manager • Jody A. Charnow, Haymarket Media, Inc. • Marina Galanakis, Haymarket Media, Inc. • Victoria C. Smith, MD, MER

Reported Financial Relationship No financial relationships to disclose No financial relationships to disclose No financial 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.

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(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 “preemptively,” 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 transplants are complex and involve multifaceted 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 five-year survival rate is greater than 50%.3 This precept was based on three important guiding principles: 1) patient autonomy (that transplantation will provide independence and freedom for individual patients), 2) utility (the capacity for productive post-transplant life), and 3) justice (equitable allocation of scant resources).

The five-year/50% life expectancy requirement seems lenient given current graft survival rates for kidney transplantation. Death with graft function (DWGF) is also the major cause of kidney transplant failure. And a primary 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 transplant 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 fiveyear/50% life expectancy requirement is waived—specifically when emotional and unquantifiable 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 physicians. Important information includes the age and gender of the patient and the cause of ESRD, which may predict the risk of disease recurrence.

Additionally, important considerations are the type of dialysis used (hemodialysis 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 information regarding co-morbidities such as diabetes, and cardiovascular, pulmonary, 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, spontaneous miscarriages, this may indicate a hypercoagulable state from antiphospholipid antibodies, factor V Leiden, prothrombin gene, methyl tetrahydrofolate reductase (MTHR) mutations, or protein C, protein S or anti-thrombin3 deficiencies 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 coccidiomycosis, which is endemic. Patients with cats may be prone to toxoplasmosis, and patients with an outdoor dog (prone to tick bites) may develop ehrlichiosis.

A second prerequisite for management is a comprehensive pre-transplant physical examination. The cardiovascular exam is especially key here. It is important to assess the patient’s carotids and femoral and peripheral pulses.

A femoral bruit from atherosclerotic disease may be mistaken for a transplant artery bruit, which is a sign of renal artery stenosis.

FEBRUARY 2012

Renal & Urology News 29

Table 1. Pre-Transplant Studies Laboratory Testing Blood Type, Tissue type-HLA Donor Specific Antibodies (monthly sample once listed) Complete blood count (CBC), comprehensive metabolic profile (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 Specific 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) • Leflunomide (Arava) • Hydroxychloroquine (Plaquenil)

30 Renal & Urology News

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CME FEATURE

The transplant procedure An understanding of the initial transplant procedure, hospitalization, and early course must be recorded in the outpatient records. Typical considerations are donor age and sex, HLA match or mismatch, the cytomegalovirus (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 problems or delayed graft function (DGF) and elevated serum creatinine on the day of discharge, the nadir serum creatinine 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 vessels. 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, entericcoated 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 discharged on post-operative day 5 with a serum creatinine of 4.52 mg/dL.

Post-transplant maintenance immunosuppression Typical maintenance immunosuppression 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 inhibitor (CNI) or steroid withdrawal or avoidance, or the use of mammalian targets of rapamycin (mTORs).

The typical immunosuppressive regimen at our center is induction with thymoglobulin 5mg/kg total body weight intravenously with the first 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 failure 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 first month and then 3-7 ng/mL thereafter. For cyclosporine, we prefer 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 8001200 ng/mL for the first month and then 400600 ng/mL thereafter. These targets were chosen based on literature showing that a level of 1000 ng/mL provides 90% calcineurin 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

© ZEPHYR / PHOTO RESEARCHERS, INC.

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).

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).

ester, which requires an acid environment 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 absorption 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 control 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 administration of rATG on post operative days 1 and 2. Prednisone is then administered at 20 mg per day during the first 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 relative low-dose tacrolimus, mycophenolate, and low-dose steroids.14 We have a low threshold to replace mycophenolate with azathioprine for any indication based on the MYSS and MYSS followup 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 withdrawn.15,16 The current literature and available immunosuppression regimens do not support steroid avoidance. In a randomized, double-blind, placebocontrolled trial with five year follow up of early corticosteroid withdrawal compared with low-dose continuation 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 (diagnostic 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 first month, monthly for six months, and then every three to four months thereafter. This is no longer necessary or feasible. With the widespread use of induction agents, particularly anti-lymphocyte depleting therapy, and

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improved maintenance immunosuppression, acute rejection rates in the first three months are relatively uncommon and the incidence of acute rejection is 5%-15% nationally in the first year.

Kidney volumes and improved success have led to overcrowded clinics and overworked staff.

At our center, patients see the surgeons 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 physician 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 complications (MMF, MPA, tacrolimus). The yearly clinic visit to the transplant center provides an opportunity to update patients on developments in transplantation and to verify data to satisfy UNOS requirements for reporting.

Because of this infrequent face-to-face contact, our team is unable to accommodate patients adequately. Therefore, we rely on care from informed primary nephrologists and primary care physicians. 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.

FEBRUARY 2012

Our team obtains a complete blood count (CBC), renal panelâ&#x20AC;&#x201D;which includes phosphorus, calcium, and albumin levels, in contrast to a basic metabolic panel (BMP)â&#x20AC;&#x201D;and CNI and/or mammalian target of rapamycin (mTOR) inhibitor levels weekly for the first 16 weeks and then every other week up to one year, and then monthly. This is less frequently than suggested by KDIGO early after transplantation and more frequently later. This reflects 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 associated with CNI use and may be associated 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-tocreatinine 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 quarterly. 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, proteinuria after six weeks is probably coming from the transplanted kidney.

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 specificity 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

Virologic monitoring

Anemia. Nearly every CKD or ESRD patient is anemic and most are iron deficient or functionally iron deficient. 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 approximately 250 mg of iron. Additionally, the estimated blood loss over the first three months is 750 mL.24 Thus, most patients at our center receive iron dextran 1 g IV prior to discharge. Reactions are uncommon, perhaps because of concomitant steroid use. We do not use oral iron as it may bind to mycophenolate and other drugs,

Cytomegalovirus. Monitoring for cytomegalovirus (CMV) is unnecessary 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 first 12 weeks is recommended.

This is because CMV most commonly reactivates in the first 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

Renal & Urology News 31

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

Hypertension. The first-line antihypertensive at our center is the calcium

Cytomegalovirus monitoring in renal transplant recipients is unnecessary during the period of prophylaxis with valgancyclovir. 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 first six months, at months 9 and 12, and then for cause.

This is a modification of the consensus guidelines and reflects 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

channel blocker amlodipine. It is a longacting agent that has only minimal interference with cytochrome P-450 system, particularly (CYP3A4), and thus, does not affect CNI or mTOR levels dramatically. 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 metoprolol or nebivolol or a combination alpha and beta blocker such as carvedilol. Nebivolol increases nitric oxide, which is vasodilatory and may be particularly 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 experience hyperkalemia or an elevated serum creatinine with introduction of an ACEI or ARB. Dyslipidemia. Many patients will have dyslipidemia with either high total or lowdensity lipoprotein (LDL) cholesterol or low high-density lipoprotein (HDL) and high triglyceride levels. The use of the statin, fluvastatin, a relatively week statin was shown to be associated with less Major Adverse Cardiac Events (MACE) after five years.25 We usually use atorvastatin because it is commonly effective at lowering LDL to goal with the initial starting

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CME FEATURE 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 potencies 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 continuing therapy.

Fever. Fever is a common complication 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 culture includes obtaining a CMV-PCR and BK-PCR, although BK uncommonly is associated with fever. Many bacterial infections can be identified and treated according to sensitivities. We commonly use ciprofloxacin or azithromycin for outpatient treatment. Although azithromycin 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 infections, 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 immunosuppression. 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 modifiable 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, Griffin MD, et al. Patient survival and cardiovascular risk after kidney transplantation: 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 following 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, multicenter study. Am J Transplant 2006;6:1042-1048.

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

8. Kung L, Batiuk TD, Palomo-Pinon S, et al. Tissue distribution 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 leukocytes in vivo is rapidly reversible. J Clin Invest 1995;96:1254-1260.

10. Cantarovich M, Elstein E, de Varennes B, et al.

Clinical benefit 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 first 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 pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro findings. Transpl Immunol 1997;5:225-232.

13. Kofler 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 randomised trial. Lancet 2004;364:503-512.

16. Remuzzi G, Cravedi P, Costantini M, et al. Mycophenolate 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 multicenter 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 management of cytomegalovirus infection in adult renal transplant recipients. Am J Transplant 2006;6:21342143.

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;2:946954.

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 deficiency 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 fluvastatin: the ALERT extension study. Am J Transplant 2005;5:2929-2936.

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

27. Schnitzler MA, Lowell JA, Hmiel SP, et al. Cytomegalovirus 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.

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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 glomerulofiltration (eGFR) rate is below: a. 10 mL/min/1.73 m2 b. 20 mL/min/1.73 m2 c. 30 mL/min/1.73 m2, but with progressive renal disease such as polycystic kidney disease or lupus nephritis d. 40 mL/min/1.73 m2, 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? a. Living in the southwestern United States and coccidiomycosis b. Living with an outdoor cat and toxoplasmosis c. Turkey hunting with an outdoor dog and erhlichiosis d. Raising chickens and chicken pox (varicella) 3. A femoral bruit in association with hypertension is a reliable sign of transplant renal artery stenosis. a. True b. False 4. Proton pump inhibitors are most likely to interfere with the absorption of which immunosuppressive agent? a. Azathioprine c. Enteric mycophenolic acid (MPA) b. Mycophenolate mofetil (MMF) d. Tacrolimus 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? a. Use azithromycin and make no change to the tacrolimus dose b. Use clarithromycin, but decrease the tacrolimus dose by twofold c. Use either azithromycin or clarithromycin, but decrease the tacrolimus dose by twofold d. Tacrolimus has to be stopped as it is contraindicated with a macrolide 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 significantly? a. Diltiazem c. Lisinopril b. Carvedilol d. Amlodipine 7. The most common cause of death in a diabetic transplant recipient is: a. Cardiovascular disease c. Infection b. Malignancy d. Trauma

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