Renal & Urology News June 2012 Issue by Haymarket Media

JUNE 2012

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VOLUME 11, ISSUE NUMBER 6

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www.renalandurologynews.com

RP Bests EBRT for PCa Survival BY JODY A. CHARNOW ATLANTA—Radical prostatectomy (RP) is associated with better overall and disease-specific survival compared with external beam radiation therapy (EBRT) for localized prostate cancer (PCa), according to findings presented at the American Urological Association 2012 annual meeting. In a study of 1,655 men with localized PCa—including 1,164 (70.3%) who underwent RP and 491 (29.7%) who had EBRT—researchers found that RP was associated with a 40% and 65% decreased likelihood of overall and

IN THIS ISSUE 8 12

Escherichia coli resistance to ciprofloxacin on the rise Oral calcitriol as effective as vitamin D for treating SHPT

Q&A: With ESAs, should we individualize treatment?

PD patients are at higher risk for infections

Neoadjuvant chemotherapy for small cell urothelial carcinoma

Doctors haunted by catastrophic errors in surgery PAGE 33

disease-specific mortality, respectively, compared with EBRT, after adjusting for multiple confounders. “The poorer overall survival with radiotherapy is largely due to selection bias—healthier men are more likely to get surgery,” said lead investigator Richard M. Hoffman, MD, MPH, Professor of Internal Medicine at the University of New Mexico in Albuquerque. He and his colleagues obtained information on medical conditions at the time of diagnosis based on well-accepted comorbidity scales, and they used multivariate statistical tech-

Patient selection bias could be a factor

DISEASE-SPECIFIC mortality is greater with external beam radiation than RP.

niques to adjust for comorbidity differences between treatment groups. These measures are relatively crude, however, Dr. Hoffman said. As for why radiotherapy patients had worse disease-specific survival compared with RP patients, Dr. Hoffman

observed that in the mid 1990s, radiation dosages were lower and data had yet to be published showing that men with high-risk PCa (based on high PSA levels and high Gleason scores) benefited from receiving continued on page 10

Dipstick Test for Sepsis-Related AKI Higher 25D Levels Needed NATIONAL HARBOR, Md.—New- Of these, 328 underwent dipstick testdipstick proteinuria may be a ing at admission. Serum creatinine to Lower PTH onset useful and inexpensive biomarker for increased by at least 0.3 mg/dL in BY JODY A. CHARNOW NATIONAL HARBOR, Md.—Levels of 25-hydroxyvitamin D (25D) higher than 20 ng/mL would be required to normalize intact parathyroid hormone (iPTH) levels in patients with stages 3 and 4 chronic kidney disease (CKD) as well as vitamin D insufficiency and secondary hyperparathyroidism, researchers concluded in a study presented at the National Kidney Foundation 2012 Spring Clinical Meetings. Amit Sharma, MD, Chief Medical Officer at Pacific Renal Research Institute in Meridian, Idaho, and colleagues noted that a 2010 Institute of Medicine report

predicting development of acute kidney injury (AKI) in critically ill septic patients, researchers reported at the National Kidney Foundation 2012 Spring Clinical Meetings. AKI develops in nearly 30% of patients with severe sepsis, and microalbuminuria has been described in up to 87% of septic patients, the investigators noted. Resident physician Javier Neyra, MD, and collaborators at Henry Ford Hospital in Detroit enrolled 470 patients hospitalized with severe sepsis.

CME FEATURES

continued on page 10

210 subjects (64%) within the first 72 hours of admission. In this group, the researchers observed new-onset dipstick proteinuria in 114 patients (54%), which translated into a 75% positive predictive value for AKI, and in 91 of 166 subjects (55%) with AKI by Acute Kidney Injury Network (AKIN) criteria, for a PPV of 60%. New-onset dipstick proteinuria at the time of ad-mission was independently associated with a 2.3 times increased likelihood of AKI, after adjusting for continued on page 10

Earn 2 CME credits in this issue

• Lupus: an update on management p.15 • Part III of our series on gout management p.35 PAGE 35

ADRENALS

PROSTATE TUMOR TISSUE

TESTES

Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI)—AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids, and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI.

Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Food Effect—ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC 0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

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ZYTIGA® is converted in vivo to abiraterone, an androgen biosynthesis inhibitor (ABI) that directly affects the androgen biosynthesis pathway by inhibiting CYP17 (17␣-hydroxylase/C17,20-lyase) — Consequently, androgen biosynthesis is inhibited at 3 sources of testosterone production: the testes, adrenal glands, and prostate tumor tissue Androgen biosynthesis inhibition with ZYTIGA® results in decreased levels of serum testosterone and other androgens

Proven survival benefit Results of the interim analysis of the pivotal phase 3 study*† showed a statistically significant improvement in overall survival (OS) in patients treated with ZYTIGA® plus prednisone compared with patients who received placebo plus prednisone (median OS: 14.8 months vs 10.9 months [hazard ratio (HR) = 0.646; 95% confidence interval (CI): 0.543, 0.768; P < 0.0001]) — This represents a 3.9-month difference/improvement in median OS In an updated analysis,‡ results were consistent with the interim analysis, with a 4.6-month difference/improvement in median OS with ZYTIGA® plus prednisone compared with placebo plus prednisone (median OS: 15.8 months vs 11.2 months [HR = 0.74; 95% CI: 0.638, 0.859])

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

Adverse Reactions—The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection. Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid coadministration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution. Use in Specific Populations—The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 3/12 08Z12069B

ORAL THERAPY

study in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received prior chemotherapy containing docetaxel (N = 1,195). Patients were randomized 2:1 to receive ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily (n = 797) or placebo orally once daily + prednisone 5 mg orally twice daily (n = 398). Patients were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy and were at castration levels of testosterone (serum testosterone ≤ 50 ng/dL).1 The primary efficacy endpoint was overall survival. †552 events. ‡775 events. 08Z11121R3

and

Mechanism of action

Reference: 1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

Please see adjacent pages for brief summary of full Prescribing Information.

www.zytiga.com

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castrationresistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel. CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Food Effect: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess [see Warnings and Precautions]. Adrenocortical insufficiency [see Warnings and Precautions]. Hepatotoxicity [see Warnings and Precautions]. Food effect [see Warnings and Precautions]. Clinical Trial 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 the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The median duration of treatment with ZYTIGA was 8 months. The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection. The most common adverse drug reactions that resulted in drug discontinuation were aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patients taking ZYTIGA). Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention (edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA, grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of patients [see Warnings and Precautions]. Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute increase in frequency compared to placebo, or were events of special interest (mineralocorticoid excess, cardiac adverse reactions, and liver toxicities). Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Prednisone (N=791) System/Organ Class All Grades1 Grade 3-4 Adverse reaction % % Musculoskeletal and connective tissue disorders 29.5 4.2 Joint swelling/discomfort2 26.2 3.0 Muscle discomfort3 General disorders 26.7 1.9 Edema4 Vascular disorders Hot flush 19.0 0.3 Hypertension 8.5 1.3 Gastrointestinal disorders Diarrhea 17.6 0.6 Dyspepsia 6.1 0 Infections and infestations Urinary tract infection 11.5 2.1 Upper respiratory tract infection 5.4 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 Nocturia 6.2 0 Injury, poisoning and procedural complications 5.9 1.4 Fractures5 Cardiac disorders Arrhythmia6 7.2 1.1 Chest pain or chest discomfort 7 3.8 0.5 Cardiac failure8 2.3 1.9 1 2 3

Placebo with Prednisone (N=394) All Grades Grade 3-4 % % 23.4 23.1

4.1 2.3

18.3

0.8

16.8 6.9

0.3 0.3

13.5 3.3

1.3 0

7.1 2.5

0.5 0

7.6

5.1 4.1

0.3 0

2.3

4.6 2.8 1.0

1.0 0 0.3

Adverse events graded according to CTCAE version 3.0 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness

ZYTIGA® (abiraterone acetate) Tablets 4 5 6

Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema Includes all fractures with the exception of pathological fracture Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in 1 patient on both arms. Hepatotoxicity: Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, liver function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ZYTIGA was withheld or discontinued. In two instances marked increases in liver function tests occurred [see Warnings and Precautions]. These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations. In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver function tests developing in patients participating in clinical trials were managed by treatment interruption, dose modification and/or discontinuation [see Dosage and Administration (2.2) in full Prescribing Information and Warnings and Precautions]. Patients with elevations of ALT or AST > 20X ULN were not re-treated. Other Adverse Reactions: Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 clinical trial (< 1%). Laboratory Abnormalities of Interest: Table 2 shows laboratory values of interest from the phase 3 placebocontrolled clinical trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred more frequently in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Low Potassium 28.3 5.3 19.8 1.0 Low Phosphorus 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In vitro, ZYTIGA was shown to inhibit the hepatic drug-metabolizing enzyme CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: ZYTIGA is not indicated in children. Geriatric Use: Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years and over and 28% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information]. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE: There have been no reports of overdose of ZYTIGA during clinical studies. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations]. Manufactured by: Patheon Inc. Mississauga, Canada

Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044

Issued: May 2012

08Z12155B

www.renalandurologynews.com

JUNE 2012

Renal & Urology News 5

GUEST EDITORIAL EDITORIAL ADVISORY BOARD

Put Women Back on the Research Agenda

hould a nephrologist start an osteoporotic post-menopausal transplant patient on hormone replacement therapy? What is the risk of breast cancer in a woman on chronic dialysis? Should she get a yearly mammogram? Does a 35-yearold woman with chronic kidney disease (CKD) have the same cardiovascular risk as a man? Why are women referred less frequently for fistula placement and kidney transplantation? No answers? I don’t have them either. Unfortunately, in the past few years, very few studies have looked at issues relating to gender and CKD, including response to therapy, which is of greatest concern. In almost all studies and in recommendations for care, including guidelines from the Kidney Disease: Improving Global Outcomes (KDIGO) foundation and the Kidney Disease Outcomes Quality Initiative (KDOQI), there are no specific recommendations made based on gender. At the National Kidney Foundation (NKF) Spring Clinical Meetings, Mitton et al from State University of New York Downstate Medical Center in Brooklyn and the NKF of Greater NY, reported the findings of a survey of 300 kidney disease professionals from throughout the United States, Canada, and the Caribbean, showing a universal self-perceived lack of knowledge regarding women’s health issues in CKD, including the use of hormone replacement therapy, treatment of osteoporosis and menstrual disorders, and gender disparities in care. In addition, a review of the 394 posters presented at the same meeting revealed only four (1%) addressing any issue related to gender, including the observation by Molnar et al from Harbor-UCLA Medical Center that women are referred later for initiation of dialysis after failed transplant. It is time for the NKF and the International Society of Nephrology to focus on gender difference in CKD, dialysis, and transplantation, and develop guidelines for care, following in the footsteps of the American Heart Association, that has published specific guidelines on the prevention of cardiovascular disease in women (Circulation 2011:123:1243-1262). Women make up at least half, if not more, of patients with CKD. It is time for us to put gender back on the agenda, both in research and in patient care. Mariana Markell, MD Associate Professor of Medicine State University of New York Downstate Medical Center, Brooklyn

Renal & Urology News welcomes letters to the editor. Send to: Jody A. Charnow, 114 West 26th Street, 4th Floor, New York, NY 10001 or e-mail jody.charnow@haymarketmedia.com

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 Art director Group art director, Haymarket Medical VP, audience development and operations Production manager Product manager, digital products Circulation manager National accounts manager Publisher VP medical magazines and digital products CEO, Haymarket Media Inc.

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

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

Contents

J U N E

2 0 1 2

■

V O L U M E

1 1 ,

I S S U E

N U M B E R

Urology 10

Baldness Increases PCa Risk Male pattern baldness is significantly associated with an elevated risk for prostate cancer.

Partial Nephrectomy Is An Option for Larger Tumors Partial nephrectomy can be safely performed in patients with renal tumors 7 cm or more in diameter with acceptable technical, oncologic and functional outcomes.

ONLINE

this month at renalandurologynews.com Renal & Urology News speaks with Oliver Khakmahd, MD, a member of a large nephrology practice in Oakland, Calif., about implementing an electronic health record system.

Clinical Quiz Take our latest quiz at renalandurologynews.com /clinical-quiz/. Answer correctly and you will be entered to win a $50 American Express gift card. Congratulations to our April winner: Geoffrey Lee, MD

The Medical Minute Visit renalandurologynews.com /the-medical-minute/ to hear podcast reports on new studies. Our latest include: • Metformin May Improve Prostate Cancer Surgery Outcomes • Aspirin Found to Protect Against Kidney Cancer • Stem Cells May Lower Infection Risk in Transplant Recipients

“

CME Features 15

Update on the Management of Lupus Nephritis The authors discuss the pathogenesis, disease course, and treatment.

Part 3: Clinical Challenges and Renal Considerations in Managing Gout Our ongoing series on gout management with particular emphasis on renal complications.

Perineural Invasion Predicts PSA Relapse After Brachytherapy Perineural invasion and post-treatment PSA levels at 12 months strongly predict longterm PSA relapse-free survival after definitive brachytherapy for prostate cancer.

Nephrology 13

Phosphate Binder Noncompliance Underreported Dialysis patient underreporting of noncompliance with phosphate binder therapy may contribute to poor phosphorus control. Early Dialysis Starts May Be Unwise This approach is associated with deleterious consequences, such as an increased likelihood of withdrawal from treatment.

Death Risk Is Highest With CVCs Central venous catheters are associated with the highest mortality risk among hemodialysis vascular access options.

A Down Side to Antimicrobial Locks They may result in more dangerous or harder-to-treat catheter-related bloodstream infections.

News Coverage Visit our web site for comprehensive coverage of the American Transplant Congress in Boston, June 2-6.

HIFU Focal Therapy Feasible for PCa In a small study, 90% of men had erections satisfactory for intercourse at 12 months posttreatment and all men who were pad-free at baseline were pad-free three months post-op.

“

Expert Q&A

The art of medicine is the skill of reconciling the risks and benefits of any treatment when the data are incomplete and those risks are, in part, unknown.

See our Expert Q&A on page 14

Departments 5

Guest Editorial Put women on the nephrology research agenda

News in Brief Retransplanted kidney regains function

On the Forefront Teaming up to show “meaningful use”

Renal Nutrition Update DASH-style diet may benefit CKD patients

Malpractice News Catastrophic medical errors can haunt docs

Practice Management The pros and cons of telemedicine

8 Renal & Urology News

JUNE 2012

www.renalandurologynews.com

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

Short Takes Study Demonstrates RARP Advantages

E. coli Ciprofloxacin Resistance Rising

An analysis comparing 11,889

U.S. outpatient urine samples contain-

men who underwent robot-assisted

ing Escherichia coli isolates showed

radical prostatectomy (RARP) with

that the bacterium’s resistance to cip-

7,389 open radical prostatectomy

rofloxacin rose from 3% to 17.1% and

(RP) patients demonstrated that the

its resistance to trimethoprim-sulfame-

RARP patients were 66% less likely to

thoxazole increased from 17.9% to

receive a blood transfusion, 53% and

24.2%, from 2000 to 2010, according

14% less likely to experience an intra-

to a report in Antimicrobial Agents and

operative or postoperative complica-

Chemotherapy (2012;56:2181-2183).

tion, respectively, and 72% less likely

During the same period, however,

to experience a prolonged length of

minimal change was observed in E. coli

stay compared with open RP patients.

resistance to nitrofurantoin (0.8% to

researchers reported in European

1.6%) and ceftriaxone (0.2% to 2.3%).

Urology (2012;61:679-685).

Transdermal Gel for OAB Launched

Aliskiren Warnings Being Updated

Watson Pharmaceuticals of Parsippany, N.J., and Antares Pharma.

drugs Amturnide, Tekturna, Tekturna

Inc. of Ewing, N.J., have announced

HCT, Tekamlo, and Valturna are being

the launch of Gelnique (oxybutynin),

updated to warn against the use of the

a transdermal gel for the treatment

drug with angiotensin receptor block-

of overactive bladder (OAB) with

ers (ARBs) or ACE inhibitors in patients

symptoms of urge urinary incon-

with diabetes because of a risk of renal

tinence, urgency and frequency.

impairment, hypotension, and hyper-

Gelnique is applied once-daily to

kalemia. Also being added is a warning

the thigh, abdomen, upper arm, or

to avoid the use of aliskiren with ARBs

shoulder, and delivers a consistent

or ACE inhibitors in patients with

dose of oxybutynin through the skin

moderate-to-severe renal impairment.

over a 24-hour period.

fro St m ra ig t h ht eW eb

Labels for the aliskiren-containing

The Value of Percent Free PSA 8.6%

33.7%

57.7%

A recent Renal & Urology News online poll asked urologists: “Should percent free PSA be incorporated into the decision to perform an initial prostate biopsy in men with moderately elevated PSA levels?” Here are the results based upon 175 responses.

Failing Donor Kidney Regains Function in Second Recipient A

renal allograft was removed from a 27-year-old man on posttransplant day 14 and donated to a 66-year-old man on the waiting list after the first patient suffered persistent proteinuria, worsening hypoalbuminemia, rising creatinine, and the development of intraabdominal hematoma beginning on posttransplant day 2. Both patients and the hospital ethics committee and internal review board consented to the transfer. The allograft, originally donated by the younger man’s sister, regained function immediately after retransplantation, with serum creatinine levels declining from 5.27 to 1.84 mg/dL and proteinuria falling from 25 g to 1.2 g per 24 hours, according to a report in the New England Journal of Medicine (2012;366:1648-1649). Biopsies performed on days 8 and 25 after retransplantation showed a reversal of the histopathologic lesions seen developing in the first recipient. Eight months after retransplantation, the second recipient’s glomerular filtration rate remained above 90 mL/min/1.73m2 in the setting of mild proteinuria (0.27 g per 24 hours).

Fish Oil Capsules Taken After AV Graft Creation Beneficial F

ish oil supplementation is associated with cardiovascular benefits in patients with stage 5 chronic kidney disease following creation of a synthetic arteriovenous graft for hemodialysis access, according to study findings published in the Journal of the American Medical Association (2012;307:1809-1816). In the study, 99 patients took four 1 gram capsules of fish oil and 97 took placebo on the seventh day following graft creation. After 12 months, compared with the placebo group, the fish-oil group experienced a lower rate of graft failure (3.43 vs. 5.95 per 1,000 access-days), half as many thromboses (1.71 vs. 3.41 per 1,000 access-days), fewer corrective interventions (2.89 vs. 4.92 per 1,000 access-days), improved cardiovascular-event-free survival, and lower mean systolic blood pressure. Loss of native patency did not differ significantly between the groups, however.

New Medication Approved for Erectile Dysfunction T

he FDA has approved avanafil (Stendra) for the treatment of erectile dysfunction (ED), making it the first drug to be approved for the condition in nearly 10 years. Manufactured by Vivus, of Mountain View, Calif., avanafil met all primary efficacy endpoints in more than 1,200 men with ED who participated in clinical studies, according to a press release issued by the company. Significant improvements in erectile function were observed for all doses (50 mg, 100 mg, and 200 mg) compared with placebo. “Patients and treating physicians continue to report significant dissatisfaction with current treatments of ED,” Vivus President Peter Tam said. It is recommended that avanafil be taken about 30 minutes before sexual activity. It should not be taken more than once per day.

10 Renal & Urology News

JUNE 2012

Dipstick test for AKI continued from page 1

age, race, gender, comorbidities, and other factors. Dr. Neyra, who presented study findings, explained that sepsis results in increased urinary excretion of albumin. Evidence suggests that this could be related to decreased tubular reabsorption of albumin and upregulation of the kidney albumin gene in response to AKI. “So the appearance of proteinuria is expected in these patients,” Dr. Neyra said. Production of creatinine from muscle is reduced in septic patients, so relying on changes in serum creatinine to diagnose AKI in such settings could delay the diagnosis of AKI, Dr. Neyra and his colleagues stated. Consequently, they observed, it is important

www.renalandurologynews.com

to identify sensitive and specific biomarkers that provide timely diagnosis of AKI before substantial damage is done. The investigators concluded that new-onset dipstick proteinuria represents a simple, inexpensive biomarker in sepsis with predictive power for AKI. The study by Dr. Neyra’s group adds to a growing literature on the topic of predicting development of AKI. Last year, researchers at Mayo Clinic reported in the Clinical Journal of the American Society of Nephrology (2011;6:1744-1751) that delayed initiation of adequate antibiotic treatment and transfusion of blood products are among the risk factors associated with development AKI in patients with septic shock. Other predictors include intra-abdominal sepsis, use of an ACE inhibitor or angiotensin

receptor blocker (ARB), and body mass index (BMI). The study included 390 patients admitted to a medical intensive care unit. After adjusting for confounders, the researchers found that each hour of delay in initiation of adequate antibiotics was associated with a significant 3% increased risk of AKI. Each 1 kg/m2 increment in BMI was associated with a 2% increased risk. Use of an ACE inhibitor or ARB was associated with a significant 88% increased risk. Intraabdominal sepsis and blood product transfusion increased AKI risk twofold and fivefold, respectively. Additionally, each 1 mL/min/1.73 m2 increment in baseline GFR was associated with a 1% decreased risk of AKI. Adequate goal-directed resuscitation was associated with a 47% decreased risk. ■

Baldness Increases PCa Risk ATLANTA—Androgenic alopecia, also known as male pattern baldness, is significantly associated with an elevated risk for prostate cancer (PCa), researchers reported at the American Urological Association 2012 annual meeting. In a prospective study of 196 consecutive patients referred for prostate biopsy, Neil E. Fleshner, MD, and colleagues at the University of Toronto, and colleagues found that the more severe the pattern baldness, the greater the risk for PCa. Frontal balding was associated

PCa survival better continued from page 1

both radiation and androgen deprivation therapy. “Current radiation modalities and treatment regimens could provide better outcomes for patients,” Dr. Hoffman added. “However, another explanation could be that surgery is a better treatment.” The study, which was presented at the meeting by David F. Penson,

MD, MPH, of Vanderbilt University in Nashville, Tenn., included participants in the Prostate Cancer Outcomes Study, which enrolled subjects diagnosed with PCa between October 1994 and October 1995. Dr. Hoffman noted that no randomized controlled trials have compared survival outcomes among men with localized PCa treated with RP versus radiotherapy. The study by his group provides the first long-term survival

results comparing the two treatments for localized PCa. Previous observational studies have focused either on just one type of treatment, used surrogate endpoints such as PSA rises, or were single-center investigations. “Our results, based on a large-population-based cohort, are much more generalizable, though we recognize that patient selection and treatments have changed since we enrolled patients in the mid 1990s,” Dr. Hoffman said. ■

with a 1.3 times increased risk, whereas mild, moderate, and severe vortex balding was associated with a 1.9, 2.4, and 2.5 times increased risk. Balding remained a significant predictor even after adjusting for age, digital rectal examination (normal vs. abnormal), and PSA level. The study also looked at whether the ratio of the lengths of the index and ring fingers predicted PCa and found no association.

Higher 25D levels continued from page 1

recommended 20 ng/mL as the lower limit of the normal range for 25D for healthy individuals, but recent studies suggest that this limit may be too low for patients with stage 3 or 4 CKD and high iPTH levels. Existing therapies, he noted, such as over-the-counter vitamin D supplements, have difficulty raising 25D levels effectively or consistently. “Despite the widely held belief that a serum 25D level of 30 ng/mL is sufficient, our research suggests that we need to target much higher levels of 25D in stage 3 and 4 CKD patients, possibly as high as 60 ng/mL,” Dr. Sharma told Renal & Urology News. Dr. Sharma’s team examined the relationship between iPTH and 25D in patients with stages 3 and 4 CKD in a doubled-blind study of CTAP101 Capsules, a modified-release formulation of calcifediol, poised to enter Phase 3 development shortly. Seventy-eight patients aged 18-80

years were randomized to receive the capsules (30, 60, or 90 µg of the drug) or matching placebo for six weeks. At baseline, subjects had a mean eGFR of 39.4 mL/min/1.73 m2, iPTH of 136 pg/mL, 25D level of 22.4 ng/mL, serum calcium level, 9.3 mg/dL, and serum phosphorus level of 3.7 mg/dL.

Levels of 25D higher than 20 ng/mL needed to normalize iPTH. Throughout treatment, serum 25D values increased progressively in a dose-proportional manner up to about 100 ng/mL at the 90 µg dose, the researchers reported. After six weeks of treatment, the first iPTH lowering threshold occurred at a 25D value of about 40 ng/mL, which is substantially higher than the iPTH reduction threshold (12 ng/mL) observed in non-CKD patients.

In the active drug group, a 25D level of 84 ng/mL was associated with the upper limit of normal for iPTH (72 pg/ mL). Some patients had 25D increases exceeding 100 ng/mL, but investigators reported observing no significant change in calcium or phosphorus. Data from this clinical study suggest that stage 3 and 4 CKD patients require much higher levels of 25D to lower iPTH effectively, “certainly much higher than we can achieve through existing therapies,” Dr. Sharma said. Bone and mineral metabolism guidelines from both the Kidney Disease Outcomes Quality Initiative (K/DOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) foundation, recommend first correcting 25D levels in Stage 3 and 4 CKD patients with elevated iPTH levels. “We know from practical experience that existing therapies to correct 25D are used off-label and are ineffective for the majority of patients,” Dr. Sharma said. “A new therapy that has the ability to significantly raise 25D levels and lower iPTH in this patient population would be of significant benefit for our practice.” ■

Previous retrospective studies have suggested that a low ratio, which indicates high prenatal androgen exposure, is associated with PCa. Androgens play a role in the development of both androgenic alopecia and PCa. Previous retrospective studies have shown a relationship between male pattern baldness and PCa. For example, French researchers reported in Annals of Oncology (2011;22:1824-1827) that patients with PCa were twice as likely to have androgenic alopecia at age 20 compared with non-PCa patients. Dr. Fleshner said the findings of the new study are preliminary, so at this point they should not alter clinical decision making. “However, our next step is to test whether adding patterns of hair loss may augment current prediction models for prostate biopsies,” he said. “This should be done on a larger cohort and preferably in the primary care setting.” ■

12 Renal & Urology News

JUNE 2012

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Calcitriol is as Effective as Vitamin D Analogues NATIONAL HARBOR, Md.—Oral calcitriol is as effective as vitamin D analogues for treating secondary hyperparathyroidism (SHPT) in hemodialysis patients but is more cost effective, according to a study presented at the National Kidney Foundation 2012 Spring Clinical Meetings.

Sandeep Aggarwal, MD, and collaborators at Drexel University College of Medicine in Philadelphia retrospectively studied 52 dialysis patients with SHPT who were converted from intravenous vitamin D analogues (paricalcitol or doxercalciferol) to oral calcitriol. The researchers observed no significant

differences in calcium and phosphorus levels at three months after switching to calcitriol and at the end of the study at nine months. After switching from vitamin D analogues to calcitriol, mean intact parathyroid hormone levels increased from 360 to 418 pmol/L and mean calcium levels rose from 9.19

Brief Summary of Prescribing Information for: OMONTYS (peginesatide) Injection for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE. See full prescribing information for complete boxed warning. Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. • No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks [see Warnings and Precautions]. • Use the lowest OMONTYS dose sufficient to reduce the need for red blood cell (RBC) transfusions [see Warnings and Precautions]. INDICATIONS AND USAGE Anemia Due to Chronic Kidney Disease OMONTYS is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis. Limitations of Use OMONTYS is not indicated and is not recommended for use: • In patients with CKD not on dialysis because of safety concerns in this population [see Warnings and Precautions]. • In patients receiving treatment for cancer and whose anemia is not due to CKD, because ESAs have shown harm in some settings and the benefit-risk factors for OMONTYS in this setting have not been evaluated [see Warnings and Precautions]. • As a substitute for RBC transfusions in patients who require immediate correction of anemia. • OMONTYS has not been shown to improve symptoms, physical functioning or health-related quality of life. CONTRAINDICATIONS OMONTYS is contraindicated in patients with: • Uncontrolled hypertension [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism • In controlled clinical trials of other ESAs in patients with CKD comparing higher hemoglobin targets (13 – 14 g/dL) to lower targets (9 - 11.3 g/dL) (see Table 2), increased risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events was observed in the higher target groups. • Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Use caution in patients with coexistent cardiovascular disease and stroke. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks. • In controlled clinical trials of ESAs in patients with cancer, increased risk for death and serious adverse cardiovascular reactions was observed. These adverse reactions included myocardial infarction and stroke. • In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and deep venous thrombosis (DVT) was observed in patients undergoing orthopedic procedures. The design and overall results of 3 large trials comparing higher and lower hemoglobin targets are shown in Table 2 (Normal Hematocrit Study (NHS), Correction of Hemoglobin Outcomes in Renal Insufficiency (CHOIR) and Trial to Reduce Cardiovascular Events with Aranesp® Therapy (TREAT)).

to 9.50 mg/dL, but the increases were not statistically significant and values remained within guideline targets recommended by the Kidney Disease: Improving Global Outcomes (KDIGO) foundation. The cost per patient per week was $116.40 with vitamin D compared with $6.60 with calcitriol. ■

Table 2 Adverse Cardiovascular Outcomes in Randomized Controlled Trials Comparing Higher and Lower Hemoglobin Targets in Patients with CKD NHS (N = 1265) 1993 to 1996

CHOIR (N = 1432) Time Period of Trial 2003 to 2006 Patients with CKD Patients with CKD not on dialysis with on hemodialysis hemoglobin with coexisting CHF < 11 g/dL Population or CAD, hematocrit not previously 30 ± 3% on administered epoetin alfa epoetin alfa Hemoglobin Target; 14.0 vs. 10.0 13.5 vs. 11.3 Higher vs. Lower (g/dL) 12.6 (11.6, 13.3) 13.0 (12.2, 13.4) Median (Q1, Q3) vs. vs. Achieved Hemoglobin 10.3 (10.0, 10.7) 11.4 (11.1, 11.6) level (g/dL) Primary Endpoint

TREAT (N = 4038) 2004 to 2009 Patients with CKD not on dialysis with type II diabetes, hemoglobin ≤ 11 g/dL 13.0 vs. ≥ 9.0

12.5 (12.0, 12.8) vs. 10.6 (9.9, 11.3) All-cause mortality, All-cause mortality, All-cause mortality MI, myocardial MI, hospitalization or non-fatal MI ischemia, heart for CHF, or stroke failure, and stroke

Hazard Ratio or 1.28 (1.06 – 1.56) 1.34 (1.03 – 1.74) 1.05 (0.94 – 1.17) Relative Risk (95% CI) Adverse Outcome for All-cause mortality All-cause mortality Stroke Higher Target Group Hazard Ratio or 1.27 (1.04 – 1.54) 1.48 (0.97 – 2.27) 1.92 (1.38 – 2.68) Relative Risk (95% CI) Patients with Chronic Kidney Disease Not on Dialysis OMONTYS is not indicated and is not recommended for the treatment of anemia in patients with CKD who are not on dialysis. A higher percentage of patients (22%) who received OMONTYS experienced a composite cardiovascular safety endpoint event compared to 17% who received darbepoetin alfa in two randomized, active-controlled, open-label, multi-center trials of 983 patients with anemia due to CKD who were not on dialysis. The trials had a pre-specified, prospective analysis of a composite safety endpoint consisting of death, myocardial infarction, stroke, or serious adverse events of congestive heart failure, unstable angina or arrhythmia (hazard ratio 1.32, 95% CI: 0.97, 1.81). Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer receiving ESAs OMONTYS is not indicated and is not recommended for reduction of RBC transfusions in patients receiving treatment for cancer and whose anemia is not due to CKD because ESAs have shown harm in some settings and the benefit-risk factors for OMONTYS in this setting have not been evaluated. The safety and efficacy of OMONTYS have not been established for use in patients with anemia due to cancer chemotherapy. Results from clinical trials of ESAs in patients with anemia due to cancer therapy showed decreased locoregional control, progression-free survival and/or decreased overall survival. The findings were observed in clinical trials of other ESAs administered to patients with: breast cancer receiving chemotherapy, advanced head and neck cancer receiving radiation therapy, lymphoid malignancy, cervical cancer, non-small cell lung cancer, and with various malignancies who were not receiving chemotherapy or radiotherapy. Hypertension OMONTYS is contraindicated in patients with uncontrolled hypertension. Appropriately control hypertension prior to initiation of and during treatment with OMONTYS. Reduce or withhold OMONTYS if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions. Lack or Loss of Response to OMONTYS For lack or loss of hemoglobin response to OMONTYS, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate the patient for the presence of antibodies to peginesatide. In the absence of antibodies to peginesatide, follow dosing recommendations for management of patients with an insufficient hemoglobin response to OMONTYS therapy. Contact Affymax, Inc. (1-855-466-6689) to perform assays for binding and neutralizing antibodies. Dialysis Management Patients may require adjustments in their dialysis prescriptions after initiation of OMONTYS. Patients receiving OMONTYS may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis. Laboratory Monitoring Evaluate transferrin saturation and serum ferritin prior to and during OMONTYS treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course

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JUNE 2012

Renal & Urology News 13

Phosphate Binder Noncompliance Underreported NATIONAL HARBOR, Md.—Dialysis patient underreporting of noncompliance with phosphate binder therapy may contribute to poor phosphorus control, investigators reported at the National Kidney Foundation 2012 Spring Clinical Meetings. Nischala Dhanekula, MD, and collaborators at

Unity Health System in Rochester, N.Y., interviewed 60 adult dialysis patients with uncontrolled phosphorus levels (mean levels of 5.5 mg/dL or above) using a questionnaire. They compared these patients with a control group of 40 dialysis patients with mean phosphorus levels below 5.5 mg/dL.

of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin every 2 weeks until the hemoglobin is stable and sufficient to minimize the need for RBC transfusion. Thereafter, hemoglobin should be monitored at least monthly provided hemoglobin levels remain stable. ADVERSE REACTIONS The following serious adverse reactions observed during clinical trials with OMONTYS are discussed in greater detail in other sections of the labeling: • Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see Warnings and Precautions] • Hypertension [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of OMONTYS cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. Patients with Chronic Kidney Disease Adverse reactions were determined based on pooled data from two active controlled studies of 1066 dialysis patients treated with OMONTYS and 542 treated with epoetin, including 938 exposed for at least 6 months and 825 exposed for greater than one year to OMONTYS. The population for OMONTYS was 20 to 93 years of age, 58.5% male, and the percentages of Caucasian, Black (including African Americans), and Asian patients were 57.9%, 37.4%, and 3.1%, respectively. The median weight adjusted dose of OMONTYS was 0.07mg/kg and 113 U/week/kg of epoetin. Table 3 summarizes the most frequent adverse reactions (≥ 10%) in dialysis patients treated with OMONTYS. Table 3 Adverse Reactions Occurring in ≥10% of Dialysis Patients treated with OMONTYS Adverse Reactions

Dialysis Patients Treated with OMONTYS (N = 1066)

Gastrointestinal Disorders Diarrhea 18.4% Nausea 17.4% Vomiting 15.3% Respiratory, Thoracic and Mediastinal Disorders Dyspnea 18.4% Cough 15.9% Injury, Poisoning and Procedural Complications Arteriovenous Fistula 16.1% Site Complication Procedural Hypotension 10.9% Nervous System Disorders Headache 15.4% Musculoskeletal and Connective Tissue Disorders Muscle Spasms 15.3% Pain in Extremity 10.9% Back Pain 10.9% Arthralgia 10.7% Vascular Disorders Hypotension 14.2% Hypertension 13.2% General Disorders and Administration Site Conditions Pyrexia 12.2% Metabolism and Nutrition Disorders Hyperkalemia 11.4% Infections and Infestations Upper Respiratory Tract Infection 11.0%

Dialysis Patients Treated with Epoetin (N = 542) 15.9% 19.6% 13.3% 19.4% 16.6% 16.6% 12.5% 15.9% 17.2% 12.7% 11.3% 9.8% 14.6% 11.4%

Results showed that 25.4% of the uncontrolled patients reported that they missed taking their binders on a daily basis, which was a significantly greater percentage than the 2.5% observed in the control group. However, pharmacy records indicated that 41.7% of the uncontrolled patients were not filling

binding antibodies in patients dosed subcutaneously (1.9%) as compared to those dosed intravenously (0.7%). Peginesatide neutralizing antibodies were detected in vitro using a cell-based functional assay in 21 of these patients (0.9%). In approximately half of all antibody-positive patients, the presence of antibodies was associated with declining hemoglobin levels, the requirement for increased doses of OMONTYS to maintain hemoglobin levels, and/or transfusion for anemia of CKD. No cases of pure red cell aplasia (PRCA) developed in patients receiving OMONTYS during clinical trials. DRUG INTERACTIONS No formal drug/drug interaction studies have been performed. Peginesatide does not bind to serum albumin or lipoproteins as demonstrated in in vitro protein binding studies in rat, monkey and human sera. In vitro studies conducted with human hepatocytes or microsomes have shown no potential for peginesatide to induce or inhibit CYP450 enzymes. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Peginesatide was teratogenic and caused embryofetal lethality when administered to pregnant animals at doses and/or exposures that resulted in polycythemia. OMONTYS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of peginesatide by intravenous injection to rats and rabbits during organogenesis was associated with embryofetal toxicity and malformations. Dosing was every third day in rats for a total of 5 doses and every fifth day in rabbits for a total of 3 doses (0.01 to 50 mg/kg/dose). In rats and rabbits, adverse embryofetal effects included reduced fetal weight, increased resorption, embryofetal lethality, cleft palate (rats only), sternum anomalies, unossification of sternebrae and metatarsals, and reduced ossification of some bones. Embryofetal toxicity was evident in rats at peginesatide doses of ≥ 1 mg/kg and the malformations (cleft palate and sternoschisis, and variations in blood vessels) were mostly evident at doses of ≥ 10 mg/kg. The dose of 1 mg/kg results in exposures (AUC) comparable to those in humans after intravenous administration at a dose of 0.35 mg/kg in patients on dialysis. In a separate embryofetal developmental study in rats, reduced fetal weight and reduced ossification were seen at a lower dose of 0.25 mg/kg. Reduced fetal weight and delayed ossification in rabbits were observed at ≥ 0.5 mg/kg/dose of peginesatide. In a separate embryofetal developmental study in rabbits, adverse findings were observed at lower doses and included increased incidence of fused sternebrae at 0.25 mg/kg. The effects in rabbits were observed at doses lower (5% - 50%) than the dose of 0.35 mg/kg in patients. Nursing Mothers It is not known whether peginesatide is excreted in human milk. Because many drugs are excreted into human milk, caution should be exercised when OMONTYS is administered to a nursing woman. Pediatric Use The safety and efficacy of OMONTYS in pediatric patients have not been established. Geriatric Use Of the total number of dialysis patients in Phase 3 clinical studies of OMONTYS, 32.5% were age 65 and over, while 13% were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. OVERDOSAGE OMONTYS overdosage can elevate hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of OMONTYS dosage and/or with phlebotomy, as clinically indicated. Cases of severe hypertension have been observed following overdose with ESAs [see Warnings and Precautions]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide).

14.0%

Marketed by: Affymax, Inc. Palo Alto, CA 94304

11.8%

Distributed and Marketed by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015

12.4%

Seizures have occurred in patients participating in OMONTYS clinical studies. During the first several months following initiation of OMONTYS, blood pressure and the presence of premonitory neurologic symptoms should be monitored closely. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency. Allergic reactions have been reported in patients treated with OMONTYS. Discontinue OMONTYS and administer appropriate therapy if a serious allergic, anaphylactic or infusion-related reaction occurs. Immunogenicity Of the 2357 patients tested, 29 (1.2%) had detectable levels of peginesatidespecific binding antibodies. There was a higher incidence of peginesatide-specific

Renal US Use Unchanged in CKD Patients NATIONAL HARBOR, Md.—Renal ultrasound use for patients with chronic kidney disease (CKD) has not changed significantly since the release of guidelines in 2002 recommending imaging studies for patients with CKD or who are at risk for it as a result of urinary stones, infections, and other factors, according to a study of U.S. veterans presented at the National Kidney Foundation 2012 Spring Clinical Meetings. Nadia Chaudhri, MD, and Stephen Seliger, MD, of the University of Maryland Medical Center and Baltimore VA Medical Center in Baltimore, studied 127,155 active outpatients with CKD who had renal ultrasound studies performed from October 1, 2002 to September 30, 2006. This group represented 12% of veterans with CKD receiving care during that period. The researchers observed no significant change in renal ultrasound usage during the study period. Patients with an estimated glomerular filtration rate (eGFR) of 1530 mL/min/1.73 m2 had the highest

For more detailed information, see the full prescribing information for OMONTYS at www.omontys.com or contact Takeda Pharmaceuticals America, Inc. OMONTYS is a trademark of Affymax, Inc. registered in the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. All other trademarks are the property of their respective owners.

rate of renal ultrasound studies. Compared with patients who had an eGFR of 45-60, those with an eGFR of 30-45 were 41% more likely to have had a renal ultrasound. Those with an

their prescriptions regularly, “indicating that about 16% of this group underreported their noncompliance,” the researchers stated. In addition, the study showed that patient knowledge about high phosphorus diets did not differ significant between the groups. Interestingly, the investigators noted, the uncontrolled patients were better able to identify the health risks associated with high phosphorus. Dr. Dhanekula’s group concluded that drug dispensing information from pharmacies may play a role in controlling hyperphosphatemia. ■

eGFR of 15-30 and below 15 were L-DSG-0312-1

03-12-00027-A.; DSG-00057.

19% and 88% less likely to have had a renal ultrasound. ■

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With ESAs, Let the Patient Be Your Guide & QA

When using erythropoiesis-stimulating agents (ESAs) to correct anemia in patients with chronic kidney disease

(CKD), focus less on hitting a given hemoglobin target and more on improving patient-perceived quality of life (QOL) in such areas as fatigue, weakness, and shortness of breath, advises Alan S. Kliger, MD, Chief Medical Officer and Chief Quality Officer for the Saint Raphael Healthcare System in New Haven, Conn. Dr. Kliger spoke to Renal & Urology News senior editor Delicia Honen Yard on the subject.

In a recent editorial (Clin J Am Soc Nephrol 2012;7:354-357), you contend that physicians should tailor the use of ESAs within the context of the patient’s perceived quality of life. What experiences brought you to this conclusion? Dr. Kliger: Several studies of patients with CKD and those on dialysis have shown the dangers of treating anemia of CKD to goal hemoglobin (Hb) of 13 g/dL or higher. For decades, we have prescribed ESAs to achieve goal Hb levels, as if the Hb level itself is the important outcome. However, our patients tell us a different story. For some, the Hb level appears to make no difference to their health, as long as they do not have profound anemia. For others, symptoms develop and change lives at different Hb levels. Since each of our patients is different, a single goal Hb level does not work, particularly when we know that there is potential harm to set goal Hb at 13 or higher, and we do not know if that harm extends to goals below 13.

Do you endorse this QOL practice for specific subgroups—for example, in those patients who are more likely to succumb to end-stage renal disease than to the cardiovascular side effects of ESAs—or would you like to see it applied across the spectrum of all CKD patients with anemia? Dr. Kliger: I believe the practice of individualizing anemia treatment should be done for all patients. For each patient,

we must consider the balance between the benefits and the risks of ESA treatment. That balance will not be the same for all. For example, a minority of patients with ischemic heart disease develop increased angina and other symptoms when they become more anemic. For these patients, the benefits of ESAs, iron, or blood transfusions likely outweigh the risks, even if their achieved Hb levels to eliminate angina are in the range of 13 g/dL. For other patients, anemia appears to have no effect on their health, even when Hb levels are below 10 g/dL. For these patients, the risks of treating anemia outweigh the benefits, and ESAs should not be used.

or higher? We do not know. If a single goal Hb level is not appropriate for all patients, I think it is wiser to craft individualized therapy rather than seeking to find the single goal best for all. This does mean that each patient and his or her doctor must consider the relative risks and benefits of treatment to the best of their ability, and not simply depend on the FDA “black box” warning to prescribe a dose of ESA.

Another editorial in the same issue of CJASN (pp. 348-353) argued that the FDA should have been even more specific about ESA use. Instead of advising nephrologists to individualize dosing and reduce it when Hb exceeds 11 g/dL in dialysis patients and 10 g/dL in nondialysis-dependent CKD patients, should the agency have recommended targeting Hb ranges of 9 to 11 g/dL in dialysis patients and 9 to 10 g/dL in nondialysis patients. Is there any benefit to giving target ranges, or would such recommendations restrict the inclination to customize treatment? Dr. Kliger: In the absence of clear studies showing the risks of targeting Hb at 9 or 10 g/dL, I think the FDA becomes a fortune teller rather than a respon sible scientific body should

What do you think of the FDA’s modified dosing recommendation to consider starting ESA treatment when Hb level is less than 10 g/dL —without defining how far below 10 g/dL is appropriate for initiation and without recommending a goal of 10 g/dL or higher (www. fda.gov/Drugs/DrugSafety/ ucm259639.htm). Dr. Kliger: Since several studies in recent years have shown increased incidence of complications—some life-threatening—associated with using ESAs to goal Hb at 13 g/dL or higher, the FDA has responded appropriately to change the label for ESA use to reflect these dangers. The challenge is that there are no studies that show what the danger is when Hb goals are less than 13 g/dL. Is it safe to set goal Hb at 10 or 9 g/dL

We should individualize anemia treatment for all patients. — Alan S. Kliger, MD

they recommend targeting Hb levels to 9 or 10. I believe the FDA should say we have insufficient data to determine the risk of targeting Hb less than 13, and direct patients and their physicians to consider the risks and benefits as best the data allow on an individual basis.

How can nephrologists reconcile the cardiovascular risks of ESAs with following your approach if it means bringing the patient into a high hemoglobin range, perhaps above 11 g/dL or even above 13 g/dL? Dr. Kliger: The art of medicine is the skill of reconciling the risks and bene -fits of any treatment when the data are incomplete and those risks are, in part, unknown. The dilemma posed by ESA treatment urges us all to step back and examine carefully the model of care we have used. We have treated anemia to goal Hb levels, with little evidence that this model improves patients’ health. We believe that individualizing anemia care by using patient-reported outcomes, within the context of monitoring their Hb levels, may prove to be a more effective model of care.

Do you have any experiences to share about patients you have maintained at particularly high or particularly low hemoglobin levels through ESA use? Dr. Kliger: I cared for a 50-year-old man with stage IV CKD whose life was affected profoundly whenever his Hb level fell below 12 g/dL. In truth, I did not need to get a laboratory test to measure his Hb level; he came to the office and said, “I feel fine,” or at other times said, “I can’t walk up stairs,” or, “I get breathless walking more than a block, and I know my anemia needs better treatment.” At these times, his Hb level was always less than 12. When we treated his anemia based on his symptoms, he did well. I discussed with him the risks of ESA treatment to higher Hb goals, and he understood those risks, but for him the ESA treatments were life-changing. He was anxious and angry when we discussed the possibility that I might not be able to treat him with ESAs to an arbitrary Hb level. He felt it was his decision to determine the risks and receive the best treatment for him. ■

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Renal & Urology News 15

CME FEATURE

An Update on the Management of Lupus Nephritis Approximately 30%-50% of SLE patients have clinically evident renal disease at presentation, but renal involvement occurs in up to 60% of patients overall.

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

BY GERALD B. APPEL, MD, AND ALICE SUE APPEL, PHD

This activity is jointly sponsored by Medical Education Resources and Haymarket Media, Inc. STATEMENT OF NEED: Renal involvement is a frequent and potential serious manifestation of system lupus erythematosus (SLE). Studies in recent years have led to improved understanding of the pathogenesis and disease course of SLE-related lupus nephritis as well as new approaches to treating the condition. Clinicians involved in the care of patients with SLE-related lupus nephritis need to be aware of these advancements. TARGET AUDIENCE: This activity has been designed to meet the educational needs of nephrologists and others clinicians involved in the care of patients with lupus nephritis. EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Describe the clinical course of different patterns of renal involvement in patients with SLE. • Distinguish among the different lupus nephritis classes. • Choose therapies appropriate to lupus nephritis class. ACCREDITATION STATEMENT: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Medical Education Resources (MER) and Haymarket Media, Inc. MER is accredited by the ACCME to provide continuing medical education for physicians. CREDIT DESIGNATION: Medical Education Resources designates this enduring material for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. DISCLOSURE OF CONFLICTS OF INTEREST: Medical Education Resources ensures balance, independence, objectivity, and scientific rigor in all its 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 • Gerard B. Appel, MD

Reported Financial Relationship Grants/Research Support: Aspreva-Vifor, Genentech, Centacor. Consultant: Genentech, Centacor, Amgen, Pfizer Speakers’ Bureau: Genentech, Merck, Takeda, Genzyme Royalty: Up-To-Date

• Alice Sue Appel, PhD

No financial relationships to disclose

The content managers, Jody A. Charnow and Marina Galanakis, of Haymarket Media, Inc., and Victoria C. Smith, MD, of Medical Education Resources, have disclosed that they have no relevant financial relationships or conflicts of interest. METHOD OF PARTICIPATION: There are no fees for participating in and receiving CME credit for this activity. During the period June 2012 through June 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.

enal involvement is a frequent and potentially serious manifestation of systemic lupus erythematosus (SLE).1-4 It contributes to both morbidity and mortality, in part directly and in part through complications of therapy. There has been recent progress in treating patients with SLE and renal involvement. This treatment is based on the use of a uniform histologic classification system (the International Society of Nephrology [ISN] classification), better understanding of the clinical course of different patterns of renal involvement, and through the use of information obtained from large randomized trials to treat lupus nephropathy.

LN epidemiology and pathogenesis While the incidence of SLE and lupus nephritis (LN) varies considerably among studies,5 in general, females outnumber males approximately 10:1, and the peak average age is 15-45 years. Renal disease may be more severe in

children and males and affects 25%50% of SLE patients at onset and up to 60% during their disease course. LN is more common and more severe in minorities— including African Americans and Hispanic Americans— than in Caucasians, and in those with lower socioeconomic status regardless of racial background. Genetics and environmental, and hormonal factors all play a role in the predilection to lupus and perhaps to LN.3,5-7 A number of spontaneous and inducible models of SLE and LN have been well studied in mice, including the NZB B/W F1 hybrid, the BXSB/yaa, and the MRL/lpr models.3,6 Autoimmunity is important in the pathogenesis of SLE,6-9 the disease process, including a breakdown in self tolerance, polyclonal hyperactivity of B cells along with defective auto-regulation of T cells that leads to autoantibody production, and deposition of immune deposits with a subsequent inflammatory responses.3,6-9 The failure of apoptotic mechanisms to delete or silence autoreactive cells (tolerance) may allow clonal expansion of such cells later in life, leading to auto-reactive cells and auto-antibody production. The deposition of circu-

Gerald B. Appel, MD, is Professor of Clinical Medicine at Columbia University College of Physicians & Surgeons, and Director of Clinical Nephrology at the Glomerular Institute, a part of Columbia University Medical Center in New York City. Alice Sue Appel, PhD, is an Adjunct Associate Research Scientist in the Division of Nephrology at Columbia University College of Physicians & Surgeons in New York City.

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CME FEATURE

Clinical manifestations Both the course of SLE and LN is characterized by episodes of illness (flares) followed by episodes of relative quiescence (remissions). From 30%-50% of SLE patients have clinically evident renal disease at presentation,1-4 but renal involvement occurs in as many as 60% of patients during the disease course. LN is manifested by proteinuria, microhematuria with dysmorphic erythrocytes, erythrocyte casts, and hypertension. In some, development of nephritic syndrome is associated with proliferative glomerulonephritis and a decline in glomerular filtration rate (GFR). Other patients, including those with proliferative disease and some with membranous lupus nephropathy, develop the nephrotic syndrome. Clinical features generally correlate well with histologic findings on renal biopsy.

Pathology Glomerular disease in LN is a dynamic process with the potential for glomerular lesions to transform from one pattern to another. 1-4 Adjacent glomeruli may show different degrees of involvement. The widely accepted 2004 ISN/Renal Pathology Society (RPS) Classification of LN is highly reproducible, and predicts disease course and outcome.10 (Table 1). ISN

phase and a maintenance phase. The induction phase typically is used for uncontrolled, active renal disease that at times may be acutely life- or organthreatening, whereas the maintenance phase focuses on the long-term management of chronic, relatively indolent disease, where avoidance of the adverse effects of therapy and prevention of flares become very important.

Induction phase treatment of proliferative LN

COURTESY OF DR. GERALD B. APPEL

lating immune complexes, the in situ formation of others and the activation of complement are major components of glomerular involvement in LN. Although most investigators believe mesangial and subendothelial immune complex deposits are derived from deposition of circulating immune complexes while subepithelial complexes found in membranous LN are often formed in situ, many factors influence the localization of glomerular immune complexes. These include the size, charge, and avidity of the immune complexes, as well as the clearing ability by the mesangium and local hemodynamics.3,4 The glomerular localization of immune complexes activates complement-mediated damage, procoagulant factors, leukocyte chemoattraction, and release of cytokines associated with cellular proliferation and matrix formation. In some patients, vascular and tubulointerstitial damage are prominent.

Micrograph of diffuse proliferative lupus nephritis showing increased mesangial matrix and mesangeal hypercellularity.

Class I denotes normal glomeruli by light microscopy but with mesan gial immune deposits by immunofluorescence and electron microscopy. ISN CLASS II, which is mesangial proliferative LN, is characterized by mesangial hypercellularity demonstrated by LM, with greater than three mesangial cells in areas away from the vascular pole by LM as well as mesangial immune deposits. ISN CLASS III is focal LN, defined as focal segmental and/or global endocapillary and/or extracapillary glomerulonephritis affecting less than 50% of the glomeruli. ISN Class IV is diffuse LN. It is characterized by segmental and/or global endocapillary and/or extracapillary glomerulonephritis affecting more than 50% of glomeruli. Both Class III and IV have subendothelial immune deposits. LN Class IV is subdivided into diffuse segmental versus diffuse global proliferation, and both Class III and IV may have active A (proliferative), and inactive chronic C (sclerosing) lesions. ISN Class V is membranous LN defined by subepithelial immune deposits. SLE Patients may have combined lesions noted as Class III + V or IV + V. Class VI is defined as advanced sclerosing LN with more than 90% global glomerular sclerosis. In LN, IgG staining on IF is almost always present and C1q is particularly common. “Full house staining” (the

presence of IgG, IgA, IgM, and C3 and C1q – three of one kind and two of the other) is very suggestive of LN, as is IF deposition along the tubular basement membranes and the glomerular basement membranes. Likewise by EM, tubulo-reticular inclusions (TRI)—24 nm interanastomosing tubular structures in the glomerular endothelial cells—are commonly found only in biopsies of patients with LN or in those with HIV infection. With treatment or over time, serial biopsies often show transformation from one histologic class to another.4 In general, clinical renal manifestations correlate well with ISN biopsy class. Nephrotic patients with membranous lupus and lupus patients with antiphospholipid antibodies are particularly predisposed to thrombotic complications such as deep vein thrombophlebitis, renal vein thrombosis, and pulmonary emboli.20

Treatment protocol Patients with ISN Classes I and II need no attention directed at their renal lesions. Some patients with very mild class III lesions can be treated with a short course of increased corticosteroids, which typically results in a good clinical and histologic response. For most patients with active proliferative LN, Class III and IV, it is useful to divide treatment into an induction

Most clinicians initially treat active proliferative LN with high doses of corticosteroids in conjunction with other immunosuppressive medications. High dose oral regimens include starting doses of predisone or prednisolone 1 mg/kg/day or 60 mg/day and/ or “pulse” intravenous (IV) methylprednisolone infusions (0.5-1.0 g daily for one to three days followed by lower doses of oral corticosteroids. Steroid doses have usually been tapered to 0.5mg/kg/day or less by the third month of treatment to avoid such adverse effects as cosmetic alterations, gastrointestinal ulceration, hypertension, psychoses, and enhanced risk of infectious complications. Cytotoxic agents in conjunction with corticosteroids have long been a mainstay of many induction regimens for the treatment of LN.11-14 While it remains uncertain whether oral therapy or IV pulses of cyclophosphamide is more effective,15 clearly IV therapy involves a lower cumulative dose with the likelihood of fewer side effects and problems with adherence. Through a series of trials at the National Institute of Health (NIH), IV monthly pulses of cyclophosphamide ( 0.5-1 g/m2) for six consecutive months followed by pulses every third month were established as an effective therapy that is superior to corticosteroids in preventing renal failure.33 Subsequent studies have focused on achieving equal efficacy but less long-term morbidity through use of shorter or modified induction and maintenance regimens.13,14 A trial by the EuroLupus Group14 randomized 90 patients with diffuse or focal proliferative LN or membranous plus proliferative disease to receive either the standard six monthly pulses of cyclophosphamide (0.5-1 g/m2/month) followed by infusions every third month or to a shorter treatment course consist-

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Renal & Urology News 17

CME FEATURE Table 1. Classification of Glomerulonephritis in Systemic Lupus Erythematosus Class I II

Definition • Minimal mesangial LN • Normal glomeruli by LM, but mesangial immune deposits by IF • Mesangial proliferative LN • Mesangial hypercellularity with mesangial immune deposits. • Focal LN

III

• III (A): Purely active lesions: focal proliferative LN • III (A/C): Active and chronic lesions: focal proliferative and sclerosing LN • III (C): Chronic inactive with glomerular scars: focal sclerosing LN • Diffuse LN • IV-S (A) or IV-G (A): Purely active lesions: diffuse segmental (S) or global (G) proliferative LN

• IV-S (A/C) or IV-G (A/C): Active and chronic lesions: diffuse segmental or global proliferative and sclerosing LN • IV-S (C) or IV-G (C): inactive with glomerular scars: diffuse segmental or global sclerosing LN

V VI

sions at six months as well as resolution or stability of all renal and extra-renal parameters in both study arms.20 In the small subgroup of patients with initial GFR less than 30mL/min/1.73 m2, there was no indication that MMF was less effective than cyclophosphamide.21 The adverse effects of each regimen were as expected, with diarrhea the most common adverse effect with MMF and nausea/vomiting and alopecia the most common adverse effects with cyclophosphamide therapy. Mortality in both treatment arms was similar, with only 14 deaths, mostly infection-related, out of the 370 patients. With the results of these two large randomized trials , MMF has become well accepted as a first-line induction therapy for severe LN.

• Membranous LN

Other induction agents

• Advanced sclerosing LN • ≥ 90% of glomeruli globally sclerosed without residual activity

ing of 500 mg of IV cyclophosphamide every two weeks for six doses (total dose 3g) and then switching to azathioprine maintenance therapy (2mg/kg/day). Both regimens were equally effective in achieving various renal and extra-renal outcomes. The shorter regimen had less toxicity with significantly fewer severe 0and total infections. This trial was largely performed in Caucasians and may not be applicable to other populations. Reports after five and 10 years continued to find no differences in the risk of renal failure between treatment groups15 and no differences in serum creatinine values and 24-hour urinary protein excretion at 10 years. The cumulative dose of cyclophosphamide using the older NIH regimen was almost double that of the newer low-dose regimen. Although there are limitations to the Euro-Lupus data (small numbers of patients, mainly Caucasian subjects, and exclusion of patients with severe renal insufficiency), this regimen has largely replaced the older NIH regimen and is widely accepted as a first-line induction therapy for severe LN. Controlled trials, and subsequent meta-analyses, have also examined the role of mycophenolate mofetil (MMF) as a first-line induction agent for severe LN 12-14,16 One Chinese study randomized 42 patients to receive either 12 months of oral MMF (2g/d for six months followed by 1 g daily for six months) or six months of oral cyclophosphamide (2.5 mg/kg/day)

followed by oral azathioprine (1.5 mg/ kg/day) for six months,17 both along with concomitant corticosteroids. At 12 months, the number of complete or partial remissions and relapses was similar in both treatment arms, but with fewer infections and deaths in the MMF arm. Longer follow-up confirmed these benefits.18 A second Chinese trial also compared treatment with pulse IV cyclophosphamide to MMF and found that MMF -treated patients had greater reductions in proteinuria and hematuria and improved histology on repeat biopsy.1 A U.S. induction trial including 140 patients mostly with proliferative lupus nephritis compared the results of six IV cyclophosphamide monthly pulses to oral MMF up to 3 g daily with a similar tapering dose of corticosteroids.19 In both treatment arms, more than 50% of subjects were African American. At six months, complete remissions and complete and partial remission combined were significantly more common in the MMF arm. Moreover, adverse effects were less severe with MMF, with no significant differences at three years in the numbers of patients with renal failure, end-stage renal disease (ESRD), or mortality. The Aspreva Lupus Management Study (ALMS), a 370-patient international multicenter trial of induction therapy with either MMF, 3g/day, or monthly IV cyclophosphamide showed equivalent complete and partial remis-

Other agents studied as induction therapy for severe LN include azathioprine, cyclosporine, tacrolimus, plasmapheresis, IV gamma globulin, rituximab, and CTLA4IG , a co-stimulatory blocker. None has achieved the success of the EuroLupus or MMF regimens. Although a trial comparing azathioprine to cyclophosphamide found no difference in eventual outcome, there were more relapses and more doublings of serum creatinine values with azathioprine.22

Maintenance therapy for proliferative LN For most patients with active LN, six months of modern effective therapy will improve markers of disease activity, including anti-DNA antibody levels, serum complement, GFR, and degree of hematuria and proteinuria. However, some proteinuria and urinary sediment abnormalities are often still present at this time. Regimens of maintenance therapy have been devised to avoid relapses and flares of disease activity. Although low-dose daily or alternate day corticosteroids (equivalent of 5-10 mg/day prednisone) are commonly used as part of most maintenance regimens, there are no controlled studies to verify their necessity. Both controlled trials and meta-analyses clearly document the important role of continuing immunosuppressive medications during the maintenance phase of LN therapy. Although both oral and IV cyclophosphamide have been effectively used

for induction therapy of LN, their use should be limited to three to six months to avoid toxic side effects (e.g., alopecia, bladder toxicity, infertility, increased risk of long-term neoplasms). A study of 59 patients with severe LN who responded to six to eight monthly pulses of IV cyclophosphamide as induction therapy clearly showed the superiority of maintenance regimens with either oral MMF or oral azathioprine compared with IV cyclophosphamide administered every third month.13 Azathioprine and MMF both proved superior at maintaining remissions and preventing mortality or ESRD, with fewer adverse effects, including fewer days of hospitalization, fewer episodes of amenorrhea, and fewer severe infections. Two more recent trials compared these two oral agents in the maintenance phase of severe LN. The ALMS maintenance trial looked at 227 patients who had responded to a regimen of either six months of oral MMF or to IV monthly cyclophosphamide as induction therapy for severe LN.23 MMF maintenance (1g twice daily) proved superior to that with azathioprine maintenance (2 mg/kg/day). At three years, MMF proved superior to azathioprine in terms of total renal endpoints, relapse rate, doubling of serum creatinine, ESRD, and requirement for new additional immunosuppressive agents, regardless of which initial therapy the patients received, their racial background, or in what country they were treated. In the MAINTAIN Nephritis Trial, patients starting with six months of the Euro-Lupus regimen of IV cyclophosphamide and steroids were randomized to MMF or azathioprine for four years.24 Although neither drug proved statistically superior, there were fewer relapses with the MMF in this smaller, largely Caucasian population. In both studies, researchers observed excellent patient and renal survival rates, supporting the longer use of maintenance immunosuppressive drugs. There are only limited data on the use of other immunosuppressive drugs such as cyclosporine and tacrolimus as maintenance agents in LN.25,26 Likewise, repeated dosing of rituximab either every six months or when the CD19-20 B cell count rises has been used in a number of patients. A number of adjunctive agents have proved helpful in treating LN patients, including renoprotective measures such as blockade of the renin angiotensin

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CME FEATURE system in proteinuric patients, optimal blood pressure control, and the use of statins for both their lipid lowering and pleiotropic effects. Use of antimalarials may help with extrarenal symptoms, but there are only limited data on their effect in renal involvement. Measures to prevent cardiovascular disease and future coagulation events in patients who are antiphospholipid positive with a previous clotting event are also recommended. As osteoporosis and avascular necrosis of bone have become important long-term health issues for many LN patients, it is important to minimize the use of corticosteroids and encourage the use of vitamin D and calcium supplements along with other agents to reduce bone loss.

Membranous lupus nephropathy Patients with membranous lupus and subnephrotic proteinuria do extremely well regardless of treatment. There is no consensus on management with immunosuppressive agents. In membranous LN patients with nephrotic syndrome, both monthly pulse IV cyclophosphamide and oral cyclosporine have proven superior to oral prednisone therapy in inducing complete and partial remissions.26 In the two large recent trials of MMF versus IV cyclophophamide induction in LN, 84 of the 510 patients had pure membranous lupus nephropathy.27 Both drugs proved equivalent in inducing partial and complete remissions of the nephrotic syndrome. ■ REFERENCES 1. Bomback AS, Appel GB. Updates on the treatment of lupus nephritis. J Am Soc Nephrol 2010;21: 2028-2035. 2. Appel GB, Jayne D. Lupus Nephritis. In: Johnson R, Floege J, Feehaly J, eds. Comprehensive Clinical Nephrology, 4th Edition. Philadelphia, Pa. Elsevier, 2010:308-321. 3. D’Agati V, Appel GB. Lupus Nephritis: Pathology and Pathogenesis. In: Wallace DJ and Hahn BH, eds. Dubois’ Lupus Erythematosus 7th Edition. Philadelphia, Pa. Lippincott Williams & Wilkins, 2007:1094-1111. 4. Appel GB, Radhakrishnan J, D’Agati V. Secondary Glomerular Diseases. In: Taal MW, Chertow GM, Marsden PA, Skorecki K, Yu ASL, Brenner BM, eds. The Kidney. 9th Edition, Philadelphia, Pa. Elsevier, 2011:1192-1202. 5. Rus V, Maury EE, Hochberg MC. The Epidemiology of Systemic Lupus Erythematosus. In: Wallace DJ and Hahn BH, eds. Dubois’ Lupus Erythematosus

7th Edition. Philadelphia. Lippincott Williams & Wilkins, 2007:34-45. 6. Harley JB, Alarcon-Riquelme ME, Criswell LA, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet. 2008;40:204-210. 7. Appel GB. New and future therapies for lupus nephritis. Cleve Clin J Med 2012;79: 134-140. 8. Clatworthy MR, Smith KGC. Systemic lupus erythematosus: Mechanism. In Mason J, Pusey C, ed. The Kidney in Systemic Autoimmune Disease. Amsterdam, the Netherlands. Elsevier, 2008:285-309. 9. Tsokos GC. Systemic lupus erythrematosus. N Eng J Med 2011;365:2110-2121. 10. Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus nephritis revisited. Kidney Int 2004; 65:521-530. 11. Gourley MF, Austin HA 3rd, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med 1996;125:549-557. 12. Illei GG, Austin HA, Crane M, et al.: Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med 2001;135:248-257. 13. Contreras G, Pardo V, Leclercq B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004;350: 971-980. 14. Houssiau FA, Vasconcelos C, D’Cruz D, et al.: Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002;46:2121-2131. 15. Houssiau FA, Vasconcelos C, D’Cruz D et al. The 10year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose versus high-dose intravenous cyclophosphamide. Ann Rheum Dis 2010;69:61-64. 16. Walsh M, James M, Jayne D, et al. Mycophenolate mofetil for induction therapy of lupus nephritis: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2007;2:968-975. 17. Chan TM, Li FK, Tang CS, et al.: Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med 2000;343:1156-1162. 18. Chan TM, Tse KC, Tang CS, Mok MY, Li FK: Longterm study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol 2005;16:1076-1084. 19. Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 2005;353:2219-2228. 20. Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Amer Soc Nephrol 2009;20:1103-1112. 21. Walsh M, Solomons N, Jayne D. Mycophenolate mofetil in patients with lupus nephritis and poor renal function: Results from a randomized controlled trial. Data presented at Renal Week 2008. Abstract SAPO2953. 22. Grootscholten C, Ligtenberg G, Hagen EC et al. Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial. Kidney Int 2006;70:732-742. 23. Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 2011;36:1886-1895. 24. Houssiau FA, D’Cruz D Sangles S, et al. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis. Results from the MAINTAIN Nephritis Trial. Ann Rheum Dis 2010;69:2083-2089. 25. Moroni G, Doria A, Mosca M, et al. A randomized, pilot trial comparing cyclosporine and azathioprine for maintenance therapy in diffuse lupus nephritis over four years. Clin J Am Soc Nephrol 2006;1:925-932. 26. Austin H, Ilei GG, Braun MJ, Balow JE. Randomized controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy. J Am Soc Nephrol 2009;20:901-911. 27. Radhakrishnan J, Moutzouris DA, Ginzler E, et al. Mycophenolate mofetil and intravenous cyclophosphamide are similar as induction therapy for class V lupus nephritis. Kidney Int 2010;77:152-160.

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

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1. In general, the incidence of systemic lupus erythematosus (SLE) and lupus nephritis (LN) is: a. Higher in men than women b. Higher in women than men c. The same for both genders 2. What proportion of SLE patients have clinically evident renal disease at presentation: a. 10%-20% b. 20%-30% c. 30%-50% d. None of the above 3. SLE patients with LN in which ISN class(es) need attention directed at their renal lesions: a. Class I b. Class II c. Class III d. Class IV e. All of the above f. Both c and d 4. High-dose oral regimens for the initial treatment of active proliferative LN may include: a. Starting dose of prednisone or prednisolone 1 mg/kg/day b. Starting dose of prednisone or prednisolone 60 mg/day c. Both a and b d. None of the above 5. Which of the following agents have been studied as induction therapy for severe LN: a. Azathioprine b. Cyclosporine c. Tacrolimus d. Plasmapheresis e. All of the above 6. For inducing complete or partial remission in membranous LN patients with nephrotic syndrome, which of the following is true: a. Monthly pulse intravenous (IV) cyclophosphamide is superior to oral prednisone b. Oral cyclosporine is superior to oral prednisone c. Oral prednisone is superior to both IV cyclophosphamide and oral cyclospsorine d. Both a and b e. None of the above

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On the Forefront

JUNE 2012

Renal & Urology News 19

Urologists and nephrologists working together: an emerging model of patient care

Urologists and Nephrologists Team Up to Adopt EHR ‘Meaningful Use’ One major lesson learned was that physicians were slowest to adopt e-prescribing, one of the common features made available in the decade of EHR adoption. But once physicians used it for just short spans of time, few considered returning to paper prescriptions based on the efficiency, accuracy, and legibility of e-prescribing. Notably, most physicians perceived that patients would resist letting go of paper prescriptions, but fewer than 5% of patients requested written versions.

BY J. STEPHEN JONES, MD, WENDY O’CONNELL, AND COURTNEY ELLIS, RN

he federal Health Information Technology for Economic and Clinical Health Act (HITECH) is the component of health care reform that provides federal incentive payments to doctors and hospitals when they adopt electronic health records (EHRs) and demonstrate their use in ways that can improve quality, safety, and effectiveness of care. Incentive payments began in 2011 and will continue at diminishing levels for up to six years, ending once the incentive pool is depleted. After that, penalties will be assessed for non-qualification, resulting in reduced provider payments for services.

Defining ‘meaningful use’ The term “meaningful use” implies that clinicians not simply use the EHR, but that it must play a meaningful role in care delivery. The Centers for Medicare and Medicaid Services developed metrics that were designed to signify that the EHR is used to improve patient care. For year 1 (2011), qualify-

Screenshot showing the single click required to prescribe tamsulosin. Physicians determine beforehand the default settings for commonly used medications in their Preference Lists. For this test patient, the dose, number to be dispensed, and number of refills is automated, and the prescription automatically transmits as “normal”, meaning it goes directly to the patient’s personal pharmacy. All choices can be overridden, but for the overwhelming majority of medications these pre-sets save tremendous time and eliminate much of the risk for error.

decade ago both for documentation and e-billing as part of an enterprise effort. As a result of this early adoption,

Few physicians considered returning to paper prescriptions based on the efficiency, accuracy, and legibility of e-prescribing. ing clinicians had to use e-prescribing to: 1) directly deliver at least 40% of prescriptions from the EHR to the patient’s chosen pharmacy, 2) print an after visit summary (AVS) documenting the diagnosis and care plan for more than 80% of patients, and 3) maintain an active problem list that must be reviewed or updated in 80% of ambulatory visits. Despite external pressure, clinicians may delay adoption of EHRs if they perceive the meaningful use processes as contributing to decreased efficiency for most encounters. However, the Glickman Urological and Kidney Institute adopted the EHR almost a

we were prepared to combine energies towards achieving the meaningful use qualification for institute physicians.

New workflow: smart sets The first step was to identify the measures and to build them into the workflow of the Epic EHR on an institute basis. A clinical support analyst (CSA) was hired to educate, assist, and bridge the urologists and nephrologists into a combined program to have every staff member qualified within the first year. “Smart sets” were developed to facilitate documentation, diagnosis entry, and computerized physician order entry in one or two motions.

This allowed standardization where appropriate and decreased duplication of data entry. Finally, pharmacy data were entered and confirmed for each patient by the employee staff prior to all visits. The next step was to educate both nephrologists and urologists in building the three meaningful use measures (e-prescribing, AVS, and problem list maintenance) into standard workflows. Early experience was challenging, as many physicians had difficulty following all three, but starting months before the measures became official allowed us to have most physicians qualified as the program began in the fall of 2011. Monthly reports were supplied to all physicians letting them know how close they were to achieving meaningful use status. Stragglers received one-onone assistance with the CSA until all were qualified.

Lessons learned Across all three departments (Nephrology, Urology, Regional Urology), a total of 98% of physicians qualified by the first quarter of 2012.

Paid incentives and outcomes Even more remarkable was the positive impact on the organization. Providers were awarded on average $16,498, and the institute expects a slightly higher amount in 2012. This success was mirrored across Cleveland Clinic. Notably, Cleveland Clinic employs only 0.35% of all eligible providers, but 7.7% of all qualifying funds in the United States went to Cleveland Clinic, demonstrating dedication to qualification across the organization. Fully 12% of all qualifying urologists in the United States were from the Glickman Institute. The major lesson was that infrastructure was critical to this success. This took time and labor investment up front, but at this point all the steps in each encounter are quick and our prescribing process is incomparably improved, including the accuracy of medication reconciliation throughout the enterprise. As more measures are introduced, we will build on this infrastructure to further harness the evolving EHR, with the hope that it will be able to improve population outcomes as well as those for individuals. ■ The authors are affiliated with Cleveland Clinic’s Glickman Urological and Kidney Institute.

On the web For more on cutting-edge models of patient care, please visit us at renalandurologynews.com/forefront

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■ CSN annual meeting, St. John’s, Newfoundland

Rosemary Frei, MSc, provided news coverage of the Canadian Society of Nephrology’s 2012 meeting

Early Dialysis Starts May Be Unwise This approach is associated with an increased likelihood of withdrawal from treatment, study finds RECENT STUDY findings add to mounting evidence of the deleterious consequences of early dialysis initiation, prompting researchers to question this approach, especially among older patients. Investigators documented a doubling of the withdrawal rate from 1.5 to 3.0 per 100 patient-years of dialysis in the Canadian Organ Replacement Registry (CORR) from 2001 and 2009. Each 10-year increase in age was associated with an 84% greater likelihood of withdrawal, and early-start dialysis is associated with a 15% greater probability of withdrawal than late starts. Meanwhile, the researchers observed a sharp rise in the proportion of deaths due to withdrawal among deceased dialysis patients, from 7.9% in 2001 to 19.5% in 2009. “More patients are starting dialysis early, especially elderly patients, with higher eGFRs [estimated glomerular filtration rates], and it is this same population that goes on to just withdraw,” said Amanda Ellwood, MD, who led the study while she was completing her nephrology fellowship at the University

of Western Ontario in London. “So the question is, should we be starting them on dialysis or should we be considering another approach, such as multidisciplinary conservative management?” Working under Louise Moist, MD, Associate Professor of Nephrology at the university, and in conjunction with other researchers, Dr. Ellwood examined CORR data from 2001-2009. They focused on patients who started dialysis in that period. For the study, the researchers defined early dialysis start as initiating dialysis at an estimated glomerular filtration (eGFR) of 10.5 mL/ min/1.73 m2 or higher and late start as an eGFR below 10.5. The 3,339 patients who withdrew from dialysis and the 42,842 who did not had divergent demographic and medical characteristics. For example, the mean age of those who stopped dialysis was 73.2 years compared with 63 years for those who remained on dialysis, with 51.5% and 26.9% of the two groups, respectively, aged 75 or older. Furthermore, 39.8% of the withdrawal subjects had early dialysis initiation com-

Dialysis Withdrawal Factors In a study, patients who started on dialysis early and those aged 75 and older had a shorter median time to dialysis withdrawal than those who started dialysis late and patients younger than 75. 15.6 months

Early dialysis start (eGFR 10.5 or higher) Late dialysis start (eGFR ⬍10.5)

20.2 months 15.9 months

Age 75 and older

21.6 months

Younger than 75 0

Median time to dialysis withdrawal in months Source: Ellwood A, et al. Data presented at the Canadian Society of Nephrology annual meeting, St. John’s, Newfoundland.

pared with 34.4% in the no-withdrawal group. The only statistically significant similarities between the two groups were their rates of hypertension and diabetes, at about 80% and 45%, respectively. Overall, the median time to withdrawal was 15.9 months and 15.6 months for patients aged 75 and older and those with early-start dialysis, respectively. The respective median times for patients with late-start dialysis and those younger than 75 years were 20.2 and 21.6 months. Dr. Ellwood’s group found that the

factors most significantly associated with withdrawal were increased age, early versus late dialysis initiation, late versus early referral to a nephrologist, initiating dialysis from 2006-2009 rather than 2001-2005, and starting dialysis in Nova Scotia (compared with Ontario, the reference province). Factors associated with not withdrawing from dialysis were being male, being black or native Indian rather than white, and starting dialysis in Alberta, British Columbia, or New Brunswick. ■

High Pre-Transplant iPTH Predicts Worse Outcomes RENAL TRANSPLANT recipients who have elevated pre-transplant levels of intact parathyroid hormone (iPTH) are at increased risk of post-transplant hypercalcemia and graft failure, according to new study findings. “The association of pre-transplant iPTH level with outcome is interesting and clearly suggests mineral metabolism is important in post-transplant outcome,” lead investigator John Gill, MD, told Renal & Urology News. “The mechanisms which underlie this association need further study.” Dr. Gill, a transplant nephrologist at St. Paul’s Hospital in Vancouver, B.C., and his co-investigators made this discovery when gathering information about the increasingly common phenomena of hyperparathyroidism and hypercalcemia in kidney transplant patients. The researchers reviewed information from 1,352 consecutive adults who received kidneys alone between January 2000 an

August 2007 in two of Canada’s largest transplant centers, St. Paul’s Hospital and the Toronto General Hospital. A “striking” 40% of the patients had at least one episode of hypercalcemia— defined as albumin-corrected serum calcium level of 2.6 mmol/L or greater—within

Study reveals increased risk of hypercalcemia and graft failure. a year of transplantation. Furthermore, 162 patients (12%) had hypercalcemia throughout the first post-transplant year. Hypercalcemia resolved within two years in 25% of patients with this condition, and it resolved within three and five years post-transplant in 36% and 54%, respectively, of the affected cohort. Twenty-one

(13%) of hypercalcemic patients required surgical parathyroidectomy. Patients with post-transplant hypercalcemia experienced an average 1.81 mL/min/1.73 m2/year drop in estimated glomerular filtration rate, compared with a 0.22 mL/min/1.73 m2/year increase among those who did not develop post-op hypercalcemia. Post-transplant hypercalcemia was significantly associated with age. Compared with individuals younger than 40 years, those aged 40-49, 50-59, and aged 60 and older had an 89%, 75%, and 114% increased risk of post-transplant hypercalcemia, respectively. A pre-transplant iPTH level of 10.653 pmol/L was associated with a fourfold higher risk of hypercalcemia compared with a level below 10.6 pmol/L, whereas an iPTH level above 53 pmol/L was associated with an 11-fold higher risk. Duration of dialysis prior to transplantation was another factor associated with

post-transplant hypercalcemia. Compared with patients who were on dialysis for less than one year prior to transplantation, those on pre-transplant dialysis for more than five years had a 2.7 times increased risk. Additionally, patients with pretransplant calcium levels greater than 2.6 mmol/L had a 5.7 times increased risk of post-transplant hypercalcemia compared with patients who had normal serum calcium levels. Post-transplant hypercalcemia was not associated with graft failure, but researchers observed an 80% higher probability of graft failure among patients with pre-transplant iPTH levels above 53 pmol/L compared with patients whose pre-transplant levels were below 10.6 pmol/L. The researchers could not determine whether post-transplant iPTH levels are associated with graft failures because these levels are not routinely measured. ■

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■ CSN annual meeting, St. John’s, Newfoundland

JUNE 2012

Rosemary Frei, MSc, provided news coverage of the Canadian Society of Nephrology’s 2012 meeting

AKI After Coronary Angiography Deters Cardiovascular Drug Use OLDER PEOPLE who have coronary angiography and then experience acute kidney injury (AKI) are significantly less likely to receive cardiovascular medications than their counterparts who do not develop AKI, a new study shows. An analysis of Alberta residents over age 65 who received coronary angiography for an acute coronary syndrome between November 1, 2002 and March 31, 2008 demonstrated that those who developed AKI during their hospitalization were 23% less likely than those without AKI to receive an ACE inhibitor or angiotensin receptor blocker (ARB). They were also 22% less likely to receive anti-platelet medication, 19% less likely to receive a statin, and 15% less likely to be prescribed a beta-blocker. The results are independent of baseline renal function and whether the patients had received the medications prior to hospitalization. “A possible explanation for this could be concern on the part of clinicians that use of the cardiovascular medications could affect renal function and worsen outcomes. So the patients

Renal & Urology News 23

Kelvin Leung, MD

were substituted to other classes of medications—but were not switched back prior to discharge,” lead investigator Kelvin Leung, MD, a nephrology fellow at the University of Calgary, told Renal & Urology News. Dr. Leung and other members of the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease and the Alberta Kidney Disease Network excluded from their database analysis individuals who were

on dialysis or who had received a kidney transplant. They included 5,991 patients who did not develop AKI and another 898 who did. The team also determined that AKI patients had a significantly lower cumulative incidence of the use of statins, beta-blockers, ACE inhibitors/ ARBs, and anti-platelet agents. An analysis of cardiovascularmedication-naïve patients who developed AKI showed that they also were significantly less likely than their medication-naïve non-AKI counterparts to receive the potentially lifesaving agents. Additionally, the investigators found that the lower rates of heart medication use among AKI patients generally was not related to the presence of diabetes, heart failure, baseline estimated glomerular filtration rate, or overall medication use. The only exception was a significantly decreased use of ACE inhibitors among patients with pre-existing heart failure who developed AKI. Dr. Leung said he and his co-investigators are “unsure if this translates into an effect on mortality.” ■

Death Risk Is Highest With CVCs CENTRAL VENOUS catheters (CVCs) are associated with the highest mortality risk among hemodialysis (HD) vascular access options, according to a systematic literature review. Arteriovenous grafts confer the second-highest risk for mortality, followed by native arteriovenous fistulas (AVFs). Although these findings are congruent with clinical practice guidelines, which tout AVFs as the preferred form of vascular access in HD patients, lead investigator Pietro Ravani, MD, told Renal & Urology News that solid evidence to back this recommendation is lacking. “The surprise is the low level of quality of the available studies and the huge variation of the point estimates from those studies,” said Dr. Ravini, of the Department of Community Health at the University of Calgary in Alberta. “Better-quality data are needed, but not from studies with the same design as those already available.” The researchers analyzed 59 studies, 68% of which were conducted in North America. The mean ages of the

Risk of Serious Infections Greater with PD PATIENTS ON peritoneal dialysis (PD) are at 51% higher risk of being hospitalized for infections than those receiving hemodialysis (HD), new findings suggest. “Higher risk of infection-related hospitalization among peritoneal dialysis patients is mostly explained by dialysis-related infections, which are for the most part peritonitis,” said primary investigator Jean-Philippe Lafrance, MD, of the University of Montreal. He and his colleagues analyzed data from the Quebec health care insurance plan, Quebec hospital discharge summary databases, and the Canadian Organ Replacement Register. They analyzed information on all adults (except those who had already had a kidney transplant or fewer than three months’ of follow-up data) with information in

all three sets of databases who initiated chronic dialysis between January 2001 and December 2007. The investigators compared the characteristics of 915 PD patients in the resultant cohort of 5,858 patients to 915 matched HD patients. Twenty-one percent of the PD patients had been hospitalized once in the previous year (not counting the hospitalization during which dialysis was initiated) compared with 16% of the matched HD patients. PD patients were also more likely than HD patients to have two or more and three or more hospitalizations (8% vs. 5% and 8% vs. 3%, respectively). Compared with HD, PD was associated with a nearly 2.9-fold higher risk of hospitalization due to dialysis-related infections and a twofold increased risk of hospitalizations due to other infections, including a 1.6-fold higher risk of

hospitalization due to abdominal infections. However, PD also was associated with 70% and 40% lower probabilities of being hospitalized for septicemia or pneumonia, respectively. In a previous retrospective cohort study of 168 patients initiating outpatient dialysis (71 on PD and 97 on HD), researchers at Sunnybrook Health Sciences Centre in Toronto found that patients who initiate outpatient PD do not have a significantly increased risk of infection-related hospitalization compared with patients who initiate outpatient HD, according to a report published in Peritoneal Dialysis International (2011;31:440-449). The study, however, showed that patients starting outpatient treatment on PD were significantly more likely than those starting on HD to be hospitalized for peritonitis. ■

combined 315,960 subjects ranged from 16-80 years. Dr. Ravani’s team found the risk of participation bias was high—that is, there was a significant likelihood that the study subjects were not representative of most hemodialysis patients—in 50 (89%) of the studies. The team identified other deficits as well. During follow-up, in 51 (86.4%) of studies, investigators did not record a switch from the initial vascular-access type to a newer one. Moreover, in only 18 (30.5%) of studies did investigators adjust the mortality risk for age, sex, and presence of diabetes and cardiovascular disease Overall, compared with patients who had AVFs, those with arteriovenous grafts had a 45% increased mortality risk. Furthermore, compared with arteriovenous grafts, CVCs conferred a 25% higher death risk. ■

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Renal Nutrition Update DASH-style diet may provide an effective way to prevent or delay progression of chronic kidney disease BY ALISON L. STEIBER, PhD, RD, LD

DASH diet The Dietary Approaches to Stop Hypertension (DASH) diet concept may be an excellent way to do this. Both the DASH and Premier studies were positive trials that demonstrated the effectiveness of dietary changes on BP control (N Engl J Med 1997;336:11171124 and JAMA 2003;289:2083-2093). The difference between the DASH and Premier trials is that DASH was a controlled feeding trial whereas Premier was a comprehensive lifestyle behavior trial. In the DASH study, Appel and colleagues executed an eight-week clinical trial in which individuals with prehypertension or stage I hypertension were placed on a diet rich in fruits, vegetables, and low-fat dairy products. This type of diet is rich in calcium, magnesium, and potassium. Meat products

sequent Premier study did show that individuals could be taught the DASH principles and experience significant reductions in blood pressure.

Potassium concerns Initially, one might be hesitant to adopt the DASH concept in individuals with CKD because a diet rich in fruits, vegetables, and dairy products would contain a lot of potassium and phosphorus. However, in the early stages of CKD, potassium content is not an issue per se, as it is not usually restricted until stages 3 and 4. It is worth noting that individuals on ACE inhibitors for hypertension should have their serum potassium monitored systematically as these drugs are potassium sparing. Furthermore, there are benefits to diets rich in fruits, vegetables, and whole grains besides BP lowering, including reduction in the albumin excretion rate (AER) and decreased risk of kidney stones. Jacobs et al. (Am J Kidney Dis 2009 53:638-646) used frozen urine from subjects who participated in the DASH diet study to determine whether AER could benefit from a DASH diet even though protein was not reduced. The study looked at three groups: the DASH diet group with 18% of energy from protein, 57% from carbohydrate, and 25% from fat; the fruit and vegetable group with 15% of energy from protein, 49%

A diet stressing fruits, vegetables, and whole grains can lower BP, decrease the albumin excretion rate, and reduce the risk of kidney stones. were also low in fat, and grains were whole wheat. Subjects in the DASH diet were provided food and thus did not have to make major behavioral changes. While this study demonstrated that the diet was effective, it did not show whether individuals who were taught the concepts could in turn be successful in lowering BP. The sub-

from carbohydrate, and 36% from fat; and the control diet with 14% of energy from protein, 51% from carbohydrate, and 36% from fat. The fruit and vegetable group was rich in fruits, vegetables, whole grains, and nuts and reduced in refined grain but otherwise similar to the control. The DASH diet was even richer in vegetables, whole grains, and nuts,

ore than 60 million Americans are in some stage of chronic kidney disease (CKD). Therefore, it makes a lot of sense to direct nutrition interventions toward prevention or delay of progression. A key modifiable characteristic that contributes to CKD is hypertension. Use of a multi-disciplinary approach, with a strong emphasis on nutrition by a registered dietitian, to reduce blood pressure (BP) could be very cost efficient for the health care system as a whole.

Increased intake of fruits and vegetables may have renal benefits in CKD patients.

had decreased meat, poultry, and fish, and eliminated whole milk and added low-fat dairy foods. After eight weeks, the researchers observed no significant changes in AER; however, a significant interaction was found in subjects with an AER of 7 mg/24 hour or greater. In subjects with the higher AER at baseline, AER at eight weeks was lower in participants eating the fruit and vegetable diet compared with those on the DASH or control diets. The results of this study may indicate that for patients further along in the progression of CKD, protein control in addition to greater intake of fruits, vegetables, and whole grains may be beneficial. Another study investigated the impact of a DASH-style diet on kidney stones. The theory was that diets high in fruits and vegetables increases urinary citrate. Citrate is an inhibitor of calcium stone formation. Furthermore, diets with moderate to high calcium content in conjunction with low animal protein and sodium can decrease the risk of calcium oxalate stone recurrence by 51% (N Engl J Med 2002; 346:77-84). However, the DASH diet is high in both vitamin C and oxalate, both of which contribute to kidney stone formation. A study by Taylor et al. (J Am Soc Nephrol

2009;20:2253-2259) demonstrated the positive benefits of the DASH-style diet by creating a DASH score. The DASH score is based on eight components (high intake of fruits, vegetables, nuts, legumes, low-fat dairy products, and whole grains, and low intake of sodium, sweetened beverages, and red and processed meats). Results of their analysis showed that people with higher DASH scores had higher intake of calcium, potassium, magnesium, oxalate, and vitamin C and lower intakes of sodium. Higher DASH scores were associated with lower risk of kidney stone development even with the higher intake of calcium and vitamin C. (See the article in the November 2009 issue or go to www .renalandurologynews/DASH.) The DASH-style diet rich in vegetables, fruit, and whole grains is a nutrition intervention shown to lower BP, reduce AER in patients with AER greater than 7 mg/24 hours, and reduce the risk of kidney stones, all important factors when trying to prevent or delay the progression of CKD in at-risk individuals. ■ Dr. Steiber is Coordinator of the Dietetic Internship/Master’s Degree Program at Case Western Reserve University in Cleveland.

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Vitamin D May Benefit Prostate Cancer Patients BY ROSEMERY FREI, MSC A NEW study suggests that vitamin D may protect against prostate cancer (PCa), but some PCa specialists remain unconvinced. The non-randomized trial was published online April 16 in The Journal of Clinical Endocrinology and Metabolism.

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in Full Prescribing Information). DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions). Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25Â°C/77Â°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 2Â°C to 8Â°C (36Â°F to 46Â°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25Â°C/77Â°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 reďŹ&#x201A;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.

Fifty-two men with an average age of 65 years took 4,000 IU/day of vitamin D3 in soft-gel capsules. Forty-four of the subjects took it for a full year and had both safety and efficacy data available for analysis. Fifty-five percent of the men had a decrease in the number of positive cores or in Gleason

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 â&#x20AC;&#x201C; 41) and median duration onstudy was 13 months (range: 0.1 â&#x20AC;&#x201C; 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 â&#x20AC;&#x201C; 93). Seventy-ďŹ ve percent of patients who received Xgeva received concomitant chemotherapy.

score at repeat biopsy, according to researchers. No significant adverse events were observed. The investigators compared with these patients with 19 control subjects with PCa who were similar to the test subjects but did not take vitamin D. Of these, 63% progressed compared with

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 Amgenâ&#x20AC;&#x2122;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 â&#x20AC;&#x153;knockout mouseâ&#x20AC;?), 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 â&#x20AC;&#x201C; [13.2] in full Prescribing Information). 8.5 mg/dL (2.075 â&#x20AC;&#x201C; 2.125 mmol/L) for calcium and 2.2 â&#x20AC;&#x201C; 2.8 mg/dL (0.71 â&#x20AC;&#x201C; 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 â&#x20AC;&#x201C; 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 â&#x20AC;&#x201C; 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 inďŹ&#x201A;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

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: â&#x20AC;&#x153;RECISTâ&#x20AC;?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.

only 34% of vitamin D supplementation group. In addition, only 21% of control subjects had improved on repeat biopsy (experienced a decrease in the number of positive cores or no increase in Gleason score at repeat biopsy). â&#x20AC;&#x153;We are now performing a randomized study, which will take another two to three years to complete, but in the meantime our open-label study showed that the supplement seems to benefit subjects,â&#x20AC;? said lead investigator Sebastiano Gattoni-Celli, MD, Professor of Radiation Oncology at the Medical University of South Carolina in Charleston. â&#x20AC;&#x153;We are not claiming this is the end of the story, but it certainly is hopeful.â&#x20AC;? However, Eric A. Klein, MD, Chairman of the Glickman Urological and Kidney Institute at Cleveland Clinic and Professor of Surgery at Cleveland Clinic Lerner College of Medicine, said the Selenium and Vitamin E Cancer

Reduced number of positive cores found on repeat prostate biopsy. Prevention Trial, which showed a significant increase in PCa incidence with vitamin E over the longer term, is a reminder of deleterious effects that can eventually be uncovered from â&#x20AC;&#x153;seemingly innocuous substances such as vitamins.â&#x20AC;? He added that the lack of placebo control group in the new trial â&#x20AC;&#x153;makes the conclusion of this study tenuous.â&#x20AC;? In addition, â&#x20AC;&#x153;fewer positive cores after a year of supplementation is not evidence of disease stabilization, regression, or lack of progression in biological aggressiveness,â&#x20AC;? Dr. Klein told Renal & Urology News. â&#x20AC;&#x153;Consumers should be wary of claims of benefits from dietary supplementation unless they are rigorously demonstrated in large-scale, placebo-controlled, randomized trials.â&#x20AC;? Eric J. Jacobs, PhD, Strategic Director, Pharmacoepidemiology, National Home Office, American Cancer Society, Inc., Atlanta, agrees. â&#x20AC;&#x153;Results of small studies such as this are interesting but preliminary, Dr. Jacobs said. There is not adequate evidence for physicians to suggest to their prostate cancer patients that vitamin D supplements may be useful in treating their disease.â&#x20AC;? â&#x2013;

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JUNE 2012

Renal & Urology News 29

■ FEATURE

Providing Renal Protection Through BP Control Innovative strategies are needed to lower blood pressure in patients with chronic kidney disease BY GEORGE L. BAKRIS, MD, AND JOSEPH A. VASSALOTTI, MD

Editor’s note: The National Kidney Foundation sponsored a session on this topic at its 2012 Spring Clinical Meetings in National Harbor, Md. The moderators were George L. Bakris, MD, Professor of Medicine and Director, ASH Comprehensive Hypertension Center, The University of Chicago Medicine, and Joseph A. Vassalotti, MD, Chief Medical Officer, NKF, and Associate Clinical Professor of Medicine, Mount Sinai School of Medicine. What follows is a summation of the presentations given during the session.

espite advances in the treatment of hypertension, the majority of patients with chronic kidney disease (CKD) remain above current blood pressure (BP) targets. Improved BP control is expected to slow progression of loss of kidney function and reduce the incidence of cardiovascular events and death. Data from NHANES 1999-2004 show adults with CKD are less likely to have control of BP than those without evidence of CKD.1 The inability to achieve goal BP despite three or more antihypertensive drugs is defined as resistant hypertension, and this is more common in CKD patients.

Practice guidelines The National Heart, Lung and Blood Institute’s Joint National Committee

(JNC) 7 2 and National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines3 currently recommend targets lower than 130/80 mm Hg in CKD patients. However, updated BP guidelines from KDIGO to be published this year suggest the level of evidence to support this target varies by the presence or absence of diabetes and the level of albuminuria in this patient population. In fact, a recent systematic review of the literature revealed only three randomized controlled trials in which patients with CKD achieved a BP lower than 130/80 mm Hg.4 None of these trials included patients with diabetes, and two of the three trials showed a benefit in terms of slowing CKD progression only in the subgroups with more than one gram of proteinuria with minor increases in both the number of anti-hypertensive drugs used and adverse effects. Data from more than 16,000 participants in the National Kidney Foundation’s Kidney Early Evaluation Program (KEEP) show associations between BP levels and end-stage renal disease (ESRD), or chronic kidney failure, in patients with stage 3 and stage 4 CKD. A higher risk for developing ESRD was observed among people with BP measurements of 140/90 or higher, but those who had BP measurements of 150/90 and above were at highest risk. Additionally, the study found that that more than 30% of people with CKD

George L. Bakris, MD

Joseph A. Vassalotti, MD

had BP measurements above 150/90. This study highlights the importance of BP control in CKD patients, suggesting that a target of 140/90 may suffice at least in terms of delaying progression to chronic kidney failure.5 Innovative strategies are needed to lower BP in patients with CKD. Novel approaches to hypertension treatment reviewed subsequently include: baroreceptor sensitization and renal nerve ablation.

therapy (BAT) on systolic blood pressure (SBP) in 265 patients with resistant hypertension.6 Subjects received either BAT (Group A) for the first six months or delayed BAT initiation following the six-month visit (Group B). The five coprimary endpoints were: • acute SBP responder rate at six months • sustained responder rate at 12 months • procedure safety • BAT safety • device safety The trial showed significant benefit for the endpoints of sustained efficacy, BAT safety, and device safety. However, it did not meet the endpoints for acute responders or procedural safety. A protocol-specified ancillary analysis showed 42% of patients in Group A achieved an SBP of 140 mm Hg or less at six months compared with 24% of Group B, a statistically significant

Baroreceptor modulation for refractory hypertension The Rheos Baroreflex Hypertension Therapy System is an implantable device that can treat patients with resistant hypertension. It activates the carotid baroreflex through electrical stimulation of the carotid sinus wall. The Rheos Pivotal Trial is a randomized, double-blind, parallel-design, phase 3 trial of baroreflex activation

continued on page 30

30 Renal & Urology News

JUNE 2012

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Partial Nephrectomy Is An Option for Larger Tumors PARTIAL NEPHRECTOMY (PN) can be safely performed in patients with renal tumors 7 cm or more in diameter with acceptable technical, oncologic and functional outcomes, according to researchers. Consequently, they concluded, PN should be a surgical option when feasible regardless of tumor size. Christopher J. Long, MD, of Fox Chase Cancer Center in Philadelphia, and colleagues used a prospectively maintained institutional kidney cancer database to identify 46 patients undergoing PN for 49 renal tumors 7 cm or more in diameter. The patient population included 33 men and 13 women. The patients had a median age of 58 years (range 21-83) and a median tumor size of 8.7 cm. Thirteen patients (25.5%) had 7.0-7.9 cm tumors, 11 (22.5%) had 8.0-8.9 cm tumors, and five (10.2%) had 9.0-9.9 cm tumors.

Twenty patients (40.8%) had tumors larger than 10 cm. Approximately 80% of tumors were malignant. The five- and 10-year overall and renal cell carcinoma-specific survivals were 94.5% and 70.9%, respectively, the researchers reported in BJU International (2012;109:1450-1456). The five- and 10-year recurrence-free survival rates were 88.7% and 66.5%, respectively. Five patients (10.9%) had an upward migration in their chronic kidney disease status after PN. Sixteen complications occurred after a median follow-up of 13.1 months (range 0.2– 170.0 months), including four (8.2%) blood transfusions and six (12.2%) urinary fistulae. The researchers noted that their results compare favorably with those of published reports of similarly stagematched tumors treated with radical nephrectomy. ■

BP control continued from page 29

overstimulated, resulting in chronically heightened sympathetic tone in hypertensive patients. Therapeutic denervation may also become an option for refractory hypertension. The “Symplicity” technique uses a catheter inserted into the renal artery via the femoral artery to deliver radiofrequency energy to ablate the renal sympathetic nerve. The Symplicity HTN-1 study included 153 patients treated with this technique at 19 cen ters in Australia, Europe, and the United States.8,9 At baseline, the study population had a mean age of 57 years; 39% of subjects were women, 31% were diabetic, and 22% had coronary artery disease. They had a mean office BP of 176/98 mm Hg and were on a mean of five antihypertensive medications. Subjects had a mean estimated glomerular filtration rate of 83 mL/min/1.73 m2. The median time from first to last radiofrequency energy ablation was 38 minutes. The procedure was without complication in 97% of patients (149 of 153). Four acute procedural complications occurred, including three groin pseudoaneurysms and one renal artery dissection, all managed without further sequelae. Automated clinic pressure with printout (the primary trial endpoint) was reduced by 20/10, 24/11, 25/11, 23/11, 26/14, and 32/14 mm Hg at 1, 3, 6, 12, 18, and 24 months, respectively. These

difference between the groups. Both groups achieved an SBP of 140 mm Hg or higher at 12 months. A non-randomized unblinded follow up of the Rheos Pivotal Trial revealed that 76% of subjects qualified as clinically significant responders, and an additional 10% were indeterminate.7 Among long-term responders receiving BAT, the mean BP drop was 35/16 mm Hg. Medication use was reduced by the end of the randomized phase and remained lower through the follow-up period. Among responders, 55% achieved goal BP (less than 140 or less than 130 mm Hg in patients with diabetes or kidney disease). BP measurements of all active patients remained stable from completion of the randomized phase through long-term follow-up. BAT substantially reduced arterial pressure for most patients participating in the Rheos Pivotal Trial, which was maintained over long-term follow-up of 22 to 53 months.

Renal denervation Nephrologists are well aware that stimulation of the renal sympathetic nerves causes increased renin release, increased sodium reabsorption, and a reduction of renal blood flow. These elements of the neural homeostatic regulation of kidney function may be

Neoadjuvant Chemo Urged For Rare Bladder Tumor NEOADJUVANT CHEMOTHERAPY for

refer patients to a medical oncologist.”

patients with small cell urothelial carci-

Dr. Siefker-Radtke and her colleagues

noma (SCUC) improves their likelihood

at M.D. Anderson Cancer Center in

of survival compared with a historical

Houston led studied 95 SCUC pa-

cohort of patients treated with initial

tients who were surgical candidates.

cystectomy, a study found.

Of these, 48 received neoadjuvant

Researchers concluded that neoadju-

chemotherapy and 47 underwent

vant chemotherapy should be con-

initial surgery. The median overall and

sidered for all patients with surgically

disease-specific survival were signifi-

resectable SCUC.

cantly greater in the adjuvant chemo-

“With neoadjuvant chemotherapy,

therapy recipients than those who had

we are now seeing a large number of

initial surgery (159.5 vs. 18.3 months

patients who are cancer-free for more

and 79% vs. 20%, respectively), ac-

than five years and are essentially

cording to a report in European Urology

cured of their small cell urothelial can-

(published online ahead of print).

cer,” lead investigator Arlene Siefker-

Adjuvant chemotherapy had no im-

Radtke, MD, told Renal & Urology

pact on overall survival among patients

News. “It is important for physicians

treated with initial cystectomy, although

to recognize the presence of this vari-

the small number of patients limits the

ant histology before cystectomy and

impact of this finding. ■

findings support the short-term safety and efficacy treatment of resistant hypertension with catheter-based renal sympathetic denervation. The Symplicity HTN-2 randomized unblinded trial of renal sympathetic denervation versus usual care for medication-resistant hyperten sion show a significant reduction in systolic and diastolic blood pressure at six months compared with age-matched, equally hypertensive controls. Although office-based BP measurements provided the sole assessment of BP as a primary endpoint, this intragroup variability of BP assessment requires further explanation, particularly because 35% of controls enjoyed a 10 mm Hg or more decrease in systolic pressure at six months. The major limitations of Symplicity HTN 1 and 2 studies are the absence of data beyond 36 months. There is speculation that functional renal sympathetic reinervation may occur, but there is no evidence of this up to three years post procedure. The Symplicity HTN-3 is a randomized blinded trial of renal sympathetic denervation versus usual care for medication-resistant hypertension. This will be the largest of the 3 trials recruiting 542 patients in the United States and recruitment is ongoing. Results from this trial should be available early next year. The overall evidence suggests that both BAT and renal denervation can

safely reduce SBP in patients with resistant hypertension. Unfortunately, most of the clinical trials with both approaches have avoided patients with Stages 3b or higher CKD. Future clinical trials will address the limitations and long-term outcomes of these therapies to further define their potential therapeutic roles. ■ REFERENCES 1. Snyder JJ, Collins AJ. KDOQI hypertension, dyslipidemia, and diabetes care guidelines and current care patterns in the United States CKD population: National Health and Nutrition Examination Survey 1999-2004. Am J Nephrol 2009;30:44-54. 2. Chobanian AV, Bakris GL, Black HR, et al, The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572. 3. National Kidney Foundation, K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis 2004;43(suppl 1):S1-S290. 4. Upadhyay A, Earley A, Haynes SM, et al. Systematic review: blood pressure target in chronic kidney disease and proteinuria as an effect modifier. Ann Intern Med 2011;154:541-548. 5. Peralta CA, Norris KC, Li S, et al. Blood pressure components and end-stage renal disease in persons with chronic kidney disease: The Kidney Early Evaluation Program (KEEP). Arch Intern Med 2012;172:41-47. 6. Bisognano JD, Bakris G, Nadim MK, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the doubleblind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol 2011;58:765-73. 7. Bakris GL, Nadim MK, Haller H, et al. Baroreflex Activation Therapy provides durable benefit in patients with resistant hypertension: results of long-term followup in the Rheos Pivotal Trial. J Am Soc Hypertens 2012 Feb 14; published online ahead of print. 8. Symplicity HTN-1 Investigators. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension 2011;57:911-917. 9. Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376:1903-1909.

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JUNE 2012

Renal & Urology News 31

HIFU Focal Therapy Feasible for PCa In a small study, 90% of men had erections satisfactory for intercourse at 12 months post-treatment FOCAL THERAPY for localized prostate cancer is associated with a low rate of erectile problems and urinary incontinence a year after treatment, according to a small prospective study. In the study, 42 men underwent focal ablation with high-intensity focused ultrasound (HIFU). Investigators used multiparametric magnetic resonance imaging (MRI) to identify cancerous areas. Almost 90% of men reported having erections satisfactory for intercourse at 12 months post-treatment. All 40 men who were pad-free at baseline were pad-free by three months and maintained pad-free continence at 12 months, according to an online report in The Lancet. In addition, investigators found no biopsy evidence of cancer in the treated regions in 30 of 39 men who were biopsied at six months; 36 of the 39 were free of clinically significant cancer. Of 31 men with good baseline function, 26 (84%) “achieved the trifecta

status” of having leak-free and padfree continence, erections sufficient for intercourse, and no evidence of clinically significant disease on multiparametric MRI at 12 months. “Focal therapy of discrete areas of cancer, whether unifocal or multifocal, is feasible, safe, and can be delivered in an ambulatory setting,” the researchers, led by Hashim U. Ahmed, MD, of University College London, noted. With HIFU, tissue destruction occurs as a result of thermal, mechanical, and cavitation effects to produce a clearly demarcated region of coagulative necrosis surrounded by normal tissue on microscopic examination, the authors explained. The researchers standardized the focal therapy process by setting three broad guidelines: a maximum of 60% of the prostate could be ablated; the edge of the ablation zone had to be at least 10 mm from a neurovascular

PCa Death Risk Low Despite PSM

cancer. Compared with patients with Gleason score 6, those with Gleason 7 or higher disease had a nearly fourfold increased risk of systemic progression and cancer-related death. Receipt of adjuvant radiotherapy (RT) was associated with a 66% decreased likelihood of receiving salvage therapy or progression. When the researchers excluded patients who received postoperative adjuvant RT from multivariate analysis, the variables of tumor volume, pathological tumor stage, and pathological Gleason score remained significantly associated with systemic progression and cancer-related death. In their discussion of study limitations, the authors noted that the study was retrospective and nonrandomized. “As such, decisions to treat with adjuvant and salvage therapies were based on patient preference and physician counseling, and were thereby subject to inherent selection bias,” they wrote. Following surgery, 439 patients (15%) received adjuvant RT, including 88 who were treated with concurrent adjuvant androgen deprivation therapy. The recipients of adjuvant RT had a significantly higher median preoperative PSA level and mean tumor volume than those who did not, the study showed. ■

PROSTATE CANCER (PCa) patients found to have a positive surgical margin (PSM) in their radical prostatectomy specimen have a low long-term risk of systemic progression and cancer-related death, data show. In a study of 2,895 PCa patients with a PSM, researchers at Mayo Clinic in Rochester, Minn., led by Stephen A. Boorjian, MD, found that the 15-year systemic- progression-free survival and cancer-specific survival was 90% and 93%, respectively, according to a report in Prostate Cancer and Prostatic Diseases (2012;15:56-62). Greater tumor volume, higher pathological Gleason score, and advanced pathological tumor stage were associated with significantly increased risks of systemic progression and death from prostate cancer, but the number and location of positive margins were not. In multivariate analysis, patients with pT3 or more advanced stage had a twofold increased risk of systemic progression and cancer-related death compared with patients who had pT2 stage

bundle (the ablation zone had to be at least 5 mm from both neurovascular bundles if disease was bilateral); and untreated areas could not have any histologic evidence of cancer. Highgrade prostate intraepithelial neoplasia and atypical small acinar proliferation were permitted.

All men who were pad-free at baseline were pad-free three months post-op. “Focal therapy could hold promise in mitigating the harms that result from current therapeutic strategies,” the authors wrote. In an accompanying editorial, Matvey Tsivian, MD, Michael R. Abern, MD, and Thomas J. Polascik, MD, of Duke University Medical Center in

Durham, N.C., noted that the new study “represents the first rigorously designed study of the early outcomes of focal therapy.” Still, they noted that the study by Dr. Ahmed and colleagues should be considered as an early report “in view of the constant development of both imaging and ablative technology.” In fact, in the new study, ablation was guided not by MRI imaging but by conventional ultrasound, they observed. Focal therapy, they added, needs standardization, definition of consensual treatment schemes and nomenclature, as well as optimization of patient selection criteria. “With these issues addressed,” they wrote, “focal therapy could potentially become a mainstream therapy for localized prostate cancer that would offer personalized treatment tailored to the patient and his disease characteristics as opposed to conventional, stereotypes, wholegland treatment.” ■

Dialysis Helps Some Patients with Treatment-Resistant CHF DIALYSIS MAY improve outcomes in pa-

investigators observed no significant

tients suffering from treatment-resistant

change in hospitalizations for all causes.

congestive heart failure (CHF) accompa-

The authors noted that “hospitaliza-

nied by severe renal insufficiency, new

tions for non-cardiovascular causes

findings suggest.

appeared to be especially pronounced

Trijntje T. Cnossen, MD, PhD, of the

in patients who were already hospital-

Maastricht University Medical Center in

ized at the start of dialysis and were in

Maastricht, The Netherlands, prospec-

general not related to complications of

tively studied 23 hypervolemic patients

the treatment.”

with CHF complicated by progressive

In addition, New York Heart Associa-

and permanent chronic renal insuffi-

tion class improved significantly from

ciency. The patients were classified as

3.8 at the start of dialysis to 2.4 after

having cardiorenal syndrome (CRS) Type

eight months. Dr. Cnossen’s team

2. All subjects had failed treatment with

observed no significant change in left

high-dose intravenous diuretics.

ventricular ejection fraction. The investi-

Twelve patients were treated with peri-

gators reported a relatively high number

toneal dialysis (PD) and 11 were treated

of technical complications associated

with intermittent hemodialysis (IHD). The

with dialysis.

median survival time after the start of

The cohort had a mean age of 66

dialysis was 16 months. Hospitalizations

years. Seventeen subjects (74%) were

for cardiovascular causes decreased

men and 12 (52%) had diabetes. The

significantly from 1.4 days/patient/

cohort’s mean glomerular filtration rate

month pre-dialysis to 0.4 days/patient/

at baseline was 14.6 mL/min/1.73 m2.

month post-dialysis, the research-

Fourteen patients had chronic kidney

ers reported online ahead of print in

disease (CKD) stage 5, seven had CKD

Nephrology Dialysis Transplantation. The

stage 4, and two had CKD stage 3. ■

32 Renal & Urology News

JUNE 2012

www.renalandurologynews.com

A Down Side to Antimicrobial Locks They may result in more dangerous or harder-to-treat catheter-related bloodstream infections ANTIMICROBIAL LOCKS (AML) decrease the incidence of catheter-related bloodstream infections in hemodialysis (HD) patients, but they may result in the emergence of problematic pathogens, data show. In a retrospective study, John J. Dixon, MD, and colleagues at St. Helier Hospital in Carshalton, Surrey, found that AML containing vancomycin and gentamicin significantly decreased the incidence of catheter-related bloodstream infections from 8.50 to 3.80/1,000 catheter-days. However, the proportion of Gram-positive bacteria, notably Staphylococcus aureus, increased significantly with AML use, although the proportion of methicillin-resistant S. aureus and vancomycin resistance did not, the researchers reported online ahead of print in Nephrology Dialysis Transplantation. Although their study demonstrates no increased risk of developing subsequent catheter-related bloodstream

infections with resistant organisms following AML treatment, the risk is not eliminated completely, the investigators observed. The most important predictor of early treatment failure of catheter-related bloodstream infections, they pointed out, appears to be the causative pathogen. The study found that AML use was lined to increased gentamicin and ciprofloxacin resistance among Enterobacter species, but not among Pseudomonas species or Escherichia coli. Dr. Dixon’s team noted that catheterrelated bloodstream infections caused by S. aureus are highly pathogenic, with studies showing that it associated with 22% in-hospital mortality, rising to 32% at 90 days. Enterobacter bacteremia has a mortality rate of 5%-20%, increasing to 44% in patients who develop endocarditis. “It seems logical that resistant Enterobacter will be harder to treat with consequent higher mortality,” the authors stated.

Hypertension Risk Tied to Remoteness

into account, Tsuyoshi Hamano, MA, an Associate Professor at Shimane University in Izumo, and colleagues reported online ahead of print in the American Journal of Hypertension. For the study, the researchers estimated distance from subjects’ actual home addresses to the population center based on road network data and did not use straight-line distance. “This is because a road network is more complicated in a mountainous region compared with an urban region; therefore, the straight-line distance might be less effective in this kind of research design,” the authors noted. The researchers noted that they used self-reported hypertension to define the presence of the condition because a BP measurement taken at a public center might increase bias towards a higher BP. As for why remoteness from a population center might increase hypertension risk, the authors noted that Japanese living in rural areas might consume more traditional Japanese food, which has a higher salt content than the food of people living in urban areas. In discussing study limitations, the authors noted that their data did not allow for the assessment of other important risk factors for hypertension, such as diet, education, income, and family history. ■

HYPERTENSION RISK among individuals living in rural areas may depend on the distance of their residence from population centers, according to a study conducted in Japan. The study included 1,348 individuals in a rural mountainous region in the eastern part of Shimane prefecture who were interviewed face to face by trained staff and had sitting blood pressure measurements taken at a public center. Individuals who lived a moderate and far distance from a population center (Matsue city) had a significant 44% and 78% increased risk of self-reported hypertension (patients reporting that they were taking antihypertensive medication or were under treatment for hypertension without medication) compared with those who lived close to the population center, after adjusting for potential confounders. However, the association between distance and hypertension risk became nonsignificant when hypertension defined by BP measurement (140/90 mm Hg or higher) was taken

“Given the prevalence of S. aureus and resistant Enterobacter, there is a need for a trial directly comparing the effectiveness of AML with non-antibiotic locks (e.g. citrate) in reducing CR-BSI,” they wrote. Non-antibiotic locks do not promote antimicrobial resistance and may be more cost-effective, they noted.

Researchers observe a greater likelihood of Staphylococcus aureus infections. The study included 927 HD patients, of whom 662 received vancomycin and gentamicin systemically as well as in an AML. The other 265 patients received only systemic vancomycin and gentamicin and served as a control group. The proportion of S. aureus cultures was 37.7% in the AML group com-

pared with only 28.6% of the control arm. In the AML group, 29.4% of Enterobacter isolates were resistant to gentamicin, 23.5% were resistant to ciprofloxacin, and 15.7% were resistant to both drugs. In the control group, none of the Enterobacter isolates were resistant to gentamicin and 2.9% were resistant to ciprofloxacin. None of the isolates was resistant to both drugs. In addition, the researchers calculated that three patients needed to be treated with AML to prevent one catheterrelated bloodstream infection. The proportion of patients with acute kidney injury who developed catheterrelated bloodstream infections in tunneled hemodialysis catheters was lower than expected in both study arms. Although the retrospective design of the study was its major limitation, the authors pointed out that the data collection method and contemporary analysis were robust enough to have not missed any data. ■

Perineural Invasion Shows PSA Relapse Post-Brachytherapy Perineural invasion (PNI) and post-treat-

mL at 12 months was 98.5%, 85.7%,

ment PSA levels at 12 months strongly

61.5%, and 22.2%, respectively, the in-

predict long-term PSA relapse-free surviv-

vestigators reported in the International

al (PRFS) after definitive brachytherapy

Journal of Radiology, Biology, Physics

seed implantation for prostate cancer

(published online ahead of print). The

(PCa), according to a study.

10-year PRFS for patients with PSA

William Ding, MD, of California Pacific

levels of 1.00 or less and 1.01-2.00

Medical Center in San Francisco, and

at 12 months was 90.5% and 85.7%,

colleaguges studied 204 patients with

respectively.

localized PCa not previously treated

In multivariate analyses, patients with

with hormonal therapy. Of these pa-

a PSA level of 1.01-2.00, 2.01-3.00,

tients, 60%, 35%, and 2% had low-,

and greater than 3.00 at 12 months

intermediate-, and high-risk disease

had a 4.96, 27.57, and 65 times

according to the National Comprehen-

increased likelihood of long-term PSA

sive Cancer Network risk classification

relapse compared with men whose

system. Subjects had a median age

12-month post-treatment PSA level was

of 69 years. They underwent I-125 or

1.00 or less. PNI was present in 5%

Pd-103 brachytherapy seed implanta-

of patients and it was associated with

tion. The primary clinical outcome

a 6.1 times increased risk of long-

measure was PSA relapse according to

term PSA relapse compared with the

the Phoenix definition (PSA nadir plus 2

absence of PNI.

ng/mL). The median follow-up was 80 months. The five-year PRFS for patients with

Dr. Ding and his colleagues propose that in addition to traditional high-risk features, “the presence of positive

PSA levels of 1 or less, 1.01-2.00,

PNI may play an important role in the

2.01-3.00, and greater than 3.00 ng/

standard risk assessment.” ■

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Many physicians consider a career change after a surgical catastrophe.

Anesthesiologists Surveyed About Catastrophic Errors Results of a recent survey indicate that catastrophic medical errors can haunt practitioners for years. The study, published in the journal Anesthesia & Analgesia, looked at the results of surveys sent to 1,200 randomly selected members of the American Society of Anesthesiologists to determine how physicians handle the emotional impact of surgical catastrophes. A total of 659 physicians (56%) completed the survey. Results indicated that most respondents (84%) had been involved in at least one unanticipated death or serious patient injury during surgery. Alarmingly, although 67% of responding physicians reported that their ability to provide patient care was impaired in the first four hours following the event, and only 7% were given time off. Results also showed that 12% of respondents considered a career change after a surgical catastrophe. The authors concluded that surgical catastrophes can have a profound and lasting emotional impact on anesthesiologists and may affect a physician’s ability to provide patient care following such an incident.

Six State Alone Payout Over 50% of Malpractice Claims Diederich Healthcare, a medical malpractice insurance company, recently released an analysis of medical malpractice payments made in 2011, as recorded by the National Practitioner

Data Bank. By far, the state with the highest malpractice payout was New York, at $677,866,050, followed by Pennsylvania ($319,710,250), Illinois ($242,108,800), New Jersey ($221,170,750), Florida ($218,123,050) and California ($215,519,200). These six states together represent 51.4% of total payouts for 2011. States with the lowest payouts included South Dakota ($3,033,750), Vermont ($3,938,250), Wyoming ($4,235,000), North Dakota ($4,852,500), and Alaska ($6,347,500). The majority of payments were made for patients between the ages of 40 and 59 ($1,351,743,100) followed by those between the ages of 20 and 30 ($786,317,650). Fifty-eight percent of the total payouts were for female patients. In more positive news, medical malpractice payouts have been dropping since they reached a high of $4,822,485,800 in 2003. The numbers for 2011 were slightly less than those in 2010.

Former Airman Sues U.S. for Medical Malpractice In the most recent challenge to the Feres Doctrine, a former airman who lost his legs due to a botched gallbladder surgery is suing the U.S. government, the Air Force, and the David Grant Medical Center for medical malpractice. The Feres Doctrine, based on a 1950 case, Feres v. United States, states that the federal government cannot be held liable for injuries arising from activities incident to military service. Basically, the doctrine is an extension of the common law concept of sovereign immunity. Numerous challenges have tried to overturn the Feres precedent, but the Supreme Court has yet to overrule the verdict. A 23-year-old airman who went in for a routine laparoscopic cholecystectomy just prior to being deployed overseas is bringing suit. He was treated at a local air force base medical center. During surgery, one of the operating physicians lacerated the airman’s aorta, which caused a massive bleed in the retroperitoneal area. The surgical team did not initially realize that

Renal & Urology News 33

BY ANN W. LATNER, JD

the patient’s aorta had been lacerated. Later in the operation as the airman’s blood pressure dropped precipitously, the operating team opened up the airman’s abdomen to ascertain if there was an internal bleed. At that point, the doctors’ tried to repair the aortic tear with sutures, but by then more than two-thirds of the airman’s blood supply was gone. After surgery, the airman was remanded to the intensive care unit. After several hours, the ischemia in both his legs was apparent—they were cold, pale, and mottled. The airman was then transferred to the University of California-Davis Medical Center. A vascular surgeon at the hospital determined that the aorta supplying blood to his legs had been blocked for too long and that necrosis had set in. The airman’s legs were subsequently amputated. The airman and his wife are suing for at least $34.3 million in damages for pain, loss-of-earning capacity, physical impairment, mental anguish, and disfigurement. The suit also seeks an

Malpractice News

JUNE 2012

A mistake made during routine surgery led to this officer losing both his legs.

additional $20.5 million for the airman’s wife for loss of consortium and capacity to enjoy life.

Indemnity Payments Jack Up Malpractice Defense Costs Defense costs for malpractice cases range widely among specialties, but invariably are higher for claims resulting in indemnity payments, a recently published letter in The New England Journal of Medicine states.

Researchers at leading academic and medical institutions, and the RAND Corporation analyzed the defense costs associated with 26,853 malpractice claims closed between 1995 and 2005. Each claim contained information on whether or not a payment was made to a patient, the specialty of the physician involved, and the defense costs associated with the claim. The defense costs analyzed included only items directly associated with the defense of the individual claim—expert-witness fees and filing costs. The mean defense cost was about $23,000. However, claims where an indemnity payment was made were associated with higher mean defense costs than those where no payment was made ($45,070 vs. $17,130). Mean defense costs varied widely among specialties, the researchers found. Cardiologists had the highest defense costs: claims against cardiologists that resulted in an indemnity payment had a mean defense cost of $83,056. Oncologists had the second highest defense costs on record, with a mean of $78,890 for cases involving indemnity payments. Neurology, family general practice, psychiatry, obstetrics, internal medicine, and pediatrics were other specialties typically associated with higher than average defense costs. The specialties with the lowest defense costs were gynecology ($25,073), dermatology ($24,007), and ophthalmology ($23,780). To see the full report on mean defense costs for paid and unpaid claims, according to physician specialty, go to www.nejm.org/ doi/full/10.1056/NEJMc1114805 Accessed May 10, 2012). The authors of the study are careful to point out that though there is a substantive variation in costs among specialties, this variation is not necessarily the same as the difference in the frequency or size of claims. They conclude that “lowering the costs of dispute resolution could lead to considerable savings for physicians and insurers, particularly in specialties with high mean defense costs.” ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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Practice Management T

elemedicine, the use of electronic communication to provide health care, has been relatively slow to catch on in some places, but many physicians who have incorporated telemedicine into their practice believe it can be advantageous. It helps provide regular care to patients in remote areas, saves time for patients and providers, and increases efficiency. In interviews with Renal & Urology News, Larry Greenbaum, MD, PhD, Chief of Pediatric Nephrology at Children’s Healthcare in Atlanta, and Tejas Desai, MD, Assistant Program Director of the Internal Medicine Residency Program at the Brody School of Medicine at East Carolina University in Greenville share their experiences with telemedicine.

Extended reach Children’s Healthcare of Atlanta (CHOA) has had enough success using telemedicine that it is continuously expanding the service, Dr. Greenbaum said. The hospital has an internal “hub” that connects to a network of sites funded and equipped by the Georgia Partnership of Telehealth. These sites are set up in rural areas, allowing patients to connect with distant doctors. Nephrologists affiliated with CHOA use the technology for outpatients. At each remote site, there is a “presenter,” which might be a nurse or physician assistant, who performs a routine physical exam that the physician can see and hear with specially equipped

stethoscopes, otoscopes, and ophthalmoscopes. The only part of the physical exam that cannot be easily transmitted is palpation of the abdomen. Dr. Greenbaum said the technology provides access for families that might not be able to travel to Atlanta. Patients and parents do not need to miss a full day of school and work, respectively. It also allows them to monitor rural patients more frequently. “We can communicate by phone, but it’s just not the same as this kind of interaction,” he said. Accessing a doctor when there is not one on hand is the main reason the Brody School of Medicine at East Carolina University in Greenville uses the technology said Dr. Desai. It allows doctors to be “in different places at the same time.” Physicians, pharmacists, and residents all have either iPhones or iPads with cameras. If clinicians are with a patient and they need to connect with Dr. Desai or another senior-level physician, they log into the program FaceTime, which connects the two parties via video. “We don’t use it as a way to eliminate us from the room. We use it so when someone junior is there, he can talk with me,” he said. “We can see more people in a faster amount of time and give them the feeling they have been taken care of.” He uses it for talking with patients in a dialysis unit, lab follow ups, seeing a patient prior to discharge, summarizing information for family members, and to see a patient who cannot easily be moved.

Resources for Telehealth The Telehealth Resources Center provides a wealth of information on everything from training to staffing and legal issues to reimbursement information on its site at www.telehealthresourcecenter.org/operations-tools. A Medicare reimbursement checklist for telehealth professional fees can be found online at www.nrtrc.org/wp-content/uploads/CMSTelehealth ProfessionalFees2011.pdf. The document highlights requirements for Medicare reimbursement, the services that are covered and their codes.

Telemedicine can offer a number of distinct advantages, but its use is not appropriate in certain circumstances BY TAMMY WORTH

Telemedicine allows doctors to consult with other experts across a wide geographic area.

He also communicates with patients via e-mail so they use an office visit for things like lab results. Reimbursement is one of the biggest challenges of telemedicine. A handful of states including California, Louisiana, Texas, Oklahoma, and Kentucky mandate reimbursement by private insurance for telehealth services. The reimbursement rates may vary and aren’t always equivalent to an in-person meeting. Medicaid reimburses for telemedicine in many states. Medicare reimburses for services such as outpatient visits, nutritional counseling, kidney disease education, medication management and end-stage renal disease-related services—but only for rural patients. Another disadvantage, according to Dr. Greenbaum, is the imperfect physical exam. If clinicians suspect problems, they have to make sure the patient gets a hands-on exam by another physician. Telemedicine should be avoided when patients have emergency needs, Dr. Desai said. It also should not be used for “really bad news” or as a replacement for a daily face-to-face visit with hospitalized patients.

Telemedicine tips Speak with someone experienced in using telemedicine prior to implementing

a program, said Dr. Desai, who offers the following advice: • Document all e-mails in a patient’s health record. Video conferences can also be recorded, saved, and uploaded into their record. • Only allow video conferencing from 9 a.m. to 5 p.m. • Require patients to initiate communication and agree to check it afterward for his response. Patients should be informed that serious issues should be handled by telephone and if their e-mail will not be answered weekends. Drs. Desai and Greenbaum do not recommend using programs like Skype for patient visits. The image quality isn’t exactly great, and there is no reimbursement for a consult here (because there is no physical exam), Dr. Greenbaum said. Dr. Greenbaum noted that he and his colleagues are fortunate to have the infrastructure they do. “I think it obviously makes sense with what I’m doing—outpatient visits with patients coming from a significant distance,” he said. “For people who have a practice that has a wide geographic coverage area it works really nicely.” ■ Tammy Worth is a freelance medical journalist based out of Blue Springs, Mo.

www.renalandurologynews.com

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Renal & Urology News 35

CME FEATURE

Part III: Clinical Challenges and Renal Considerations in Managing Gout A case study involving a 58-year-old man with acute gout attacks and multiple comorbidities, including hypertension and hypercholesterolemia

Release Date: June 2012 Expiration Date: June 2013 Estimated time to complete the educational activity: 1 hour This activity is jointly sponsored by Medical Education Resources and Haymarket Medical Education and is supported by an educational grant from Savient Pharmaceuticals. STATEMENT OF NEED: Clinicians today face an increasing number of patients with gout. Nephrologists in particular must contend with complex cases in patients with varying degrees and stages of renal dysfunction in addition to other comorbidities and individual characteristics that affect treatment decisions and, ultimately, treatment success. As gout occurs in tandem with renal disorders, nephrologists must be able to appropriately identify and treat these patients. TARGET AUDIENCE: This activity has been designed to meet the educational needs of nephrologists and other clinicians involved in the treatment of patients with gout. EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Describe how renal function affects the management of gout. • Evaluate current and emerging options for urate-lowering therapy with regard to their benefits and limitations in patients with varying degrees of renal impairment. • Discuss ways to motivate patient adherence to a long-term treatment plan that incorporates lifestyle considerations and pharmacotherapy. ACCREDITATION STATEMENT: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Medical Education Resources (MER) and Haymarket Medical Education. MER is accredited by the ACCME to provide continuing medical education for physicians. CREDIT DESIGNATION: Medical Education Resources designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. DISCLOSURE OF CONFLICTS OF INTEREST: Medical Education Resources ensures balance, independence, objectivity, and scientific rigor in all our educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure all scientific research referred to, reported, or used in a CME activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality CME activities that promote improvements or quality in health care and not a commercial interest. The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Faculty

Reported Financial Relationship

• Anthony J. Bleyer, MD

Consultant: Takeda Pharmaceuticals, Savient Pharmaceuticals

BY ANTHONY J. BLEYER, MD This is the third part of an ongoing series profiling case-based challenges in gout management with particular emphasis on renal considerations therein. To see parts I and II, please visit us online at www.mycme.com/marchgout and www.mycme.com/aprilgout or look at our March and April 2012 issues.

CASE INTRODUCTION: hypertension, high blood cholesterol, and gout Mr. F, a 58-year-old man, presents for evaluation of gout. The patient first developed gout attacks approximately 10 years ago. Mr. F has a history of hypertension and hypercholesterolemia treated with atorvastatin. He also has a history of calcium oxalate renal calculi. Physical examination shows the patient is obese (body mass index, 33.5 kg/m2). His blood pressure is 130/85 mm Hg. Mr. F’s pulmonary and cardiac examinations are normal. He has no edema. He has tophi, approximately 0.5 cm in diameter, on several fingers, and a 2 cm tophus on both the right and left elbows. Mr. F has seen several physicians over the years who told him that he “just had to live with” his condition, and that his unhealthy diet was contributing to his gout.

The content managers, Krista Sierra, Susan Basilico, Jody A. Charnow, and Marina Galanakis of Haymarket Medical Education, and Victoria C. Smith, MD, of Medical Education Resources, have disclosed that they have no relevant financial relationships or conflicts of interest. METHOD OF PARTICIPATION: There are no fees for participating in and receiving CME credit for this activity. During the period June 2012 through June 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/junegout (June 2012), 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.

Anthony J. Bleyer, MD is Professor of Medicine in the Section of Nephrology at Wake Forest University School of Medicine in Winston-Salem, N.C. Dr. Bleyer’s clinical interests include the management of gout in patients with CKD.

For the past 3 years, the gout attacks had become more frequent and the patient had developed worsening tophi that occasionally drain. Mr. F has been treated with colchicine and frequent courses of prednisone. He would like to stay on prednisone long-term for his condition. He says he was on allopurinol in the past, but cannot remember why it was stopped.

Discussion: addressing lifestyle and medical issues Gout is often perceived as a lifestyle disease, primarily the result of overeating purine-rich foods. While the clinician needs to evaluate dietary factors, it is also important to look at both lifestyle and medical issues that contribute to the disorder. The clinician should view gout as an opportunity to influence lifestyle choices and also to uncover any hidden medical conditions that may contribute to hyperuricemia.

36 Renal & Urology News

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CME FEATURE

While asking patients about their habits, particular attention should be paid to alcohol intake. Consumption of alcohol, especially beer, may be excessive and the patient may require counseling in this regard.

CASE: assessing dietary factors Mr. F drinks four to five beers per week. He eats out frequently at fast-food restaurants and does enjoy beef and seafood. However, he states that avoiding these foods in the past failed to decrease the frequency of his gout attacks.

Discussion: purine-rich foods and metabolism Beer has a high content of guanosine, a purine that is converted to uric acid. In addition, alcohol increases the degradation of adenosine triphosphate (ATP) to adenosine monophosphate (AMP), resulting in increased uric acid production.1 Thus, beer is associated with a much higher incidence of hyperuricemia; liquor has only a modest effect, and wine is neutral. It would seem prudent to probe into the individual’s history and risk for alcoholism rather than suggesting a change from beer to hard liquor or wine. All forms of meat—especially beef and organ meats—are high in purine content and can contribute to gout. Sandwich meat and hot dogs also have a high purine content. Men who are in the highest quintile of meat intake have a 41% increased chance of developing gout.2 Seafood—especially shellfish—also has a high purine content. Vegetables with a high purine content—for example, spinach, mushrooms, and peas—do not increase the risk of gout for reasons that are not clearly understood. The dietary history may uncover causes of overproduction of uric acid; however, the medical and family histories are more likely to identify reasons for underexcretion of uric acid. Underexcretion of uric acid, as defined by a low fractional excretion, is present in most individuals with gout. Urate is freely filtered at the glomerulus. Urate reabsorption occurs in the proximal tubule. A number of organic anion transporters participate in proximal tubular urate reabsorption. How these transporters function together is not completely understood, but there are several aspects of proximal urate transport that are known and of importance to clinical nephrologists.

The x-ray above shows pronounced tophi (in red) affecting several proximal- and distalinterphalangeal joints in each hand.

One important consideration is that there are slight variations at the DNA level in the genes for urate transporters in the population. For example, large population studies have identified polymorphisms in the gene ABCG2 as a cause of hyperuricemia.3 The function of this gene had previously been unidentified, but this study led to further investigations identifying ABCG2 as a high efflux urate transporter. Polymorphisms in this gene may be responsible for up to 10% of gout cases.3 These small changes can affect the ability of the urate transporters to reabsorb urate. Such genetic differences between individuals are likely to explain why some individuals are underexcreters of urate vs. other individuals with normal urate excretion. Another important clinical aspect of urate tubular transport is that urate reabsorption is tightly linked to sodium reabsorption. Factors that increase sodium reabsorption will increase urate reabsorption. These factors include volume depletion, the use of diuretics, and congestive heart failure. Similarly, patients with decreased proximal tubular absorption of sodium will have low serum uric acid levels. For example, in hyponatremia due to volume depletion, the serum urate level will tend to be high. In patients with hyponatremia due to the syndrome of inappropriate antidiuretic hormone excess, patients are mildly volume-expanded, with decreased proximal sodium reabsorption resulting in lower serum urate levels.

CASE: patient history Mr. F has a 5-year history of hypertension, for which he has been receiving hydro-

chlorothiazide. He was on a low-sodium diet. He has also suffered from nephrolithiasis with several calcium oxalate renal calculi in the last five years. Mr. F has no history of kidney disease. His father and two uncles also suffered from gout but they did not have kidney disease.

Discussion: comorbidities affecting hyperuricemia The medical history has revealed several conditions associated with gout. An association between hypertension and gout has long been documented. The use of hydrochlorothiazide increases distal tubular sodium excretion, which leads to a secondary increase in proximal tubular sodium reabsorption. The increased proximal tubular sodium reabsorption secondarily leads to increased urate reabsorption and hyperuricemia.4 Nephrolithiasis is also highly associated with gout. Patients who experience urate overproduction excrete increased levels of urate in the urine. While a high urinary urate excretion is a risk factor for uric acid calculi, an even more important determinant is urinary pH owing to the solubility of urate vs. uric acid and the pKA of uric acid. There is a significant difference in the solubility of urate vs uric acid, with urate having a solubility of 158 mg/dL, and uric acid having a solubility of only 8 mg/dL. The pKA of uric acid is 5.7. This means that at a pH of 7, 95% is present as urate (very soluble), and at a pH of 5, about 80% is present as uric acid (very insoluble). Shifting pH can change uric acid solubility by almost a factor of 20.5 Dietary factors such as excess meat in the diet will not only increase uric acid produc-

tion but will also decrease urinary pH, resulting in an increased potential for uric acid calculi.5,6 In addition, there is an increased risk of calcium oxalate calculi in patients with hyperuricosuria, as uric acid acts as a promoter for calcium oxalate stone formation, with approximately 20% of patients with calcium oxalate nephrolithiasis having urinary urate excretions of >800 mg/d (men) and >750 mg/d (women).5 Excess consumption of meat causes increased uric acid production as well as increased urinary acidity, thereby increasing the risk of calcium oxalate calculi. In a double-blind randomized study,6 60 patients suffering from recurrent calcium oxalate calculi, hyperuricosuria, and normocalciuria were randomized to allopurinol (300 mg/d) vs. placebo. In this study, the mean rate of subsequent calculous events was 0.26 per patientyear in the placebo group and 0.12 in the allopurinol group (P<0.02). While allopurinol is currently only indicated in the treatment of symptomatic gout, one needs to consider this possible benefit in patients with the disease. While 24-hour urine collections are not necessary in the management of most patients with gout, in difficult cases such as this, it is important to understand the pathophysiology of urate excretion. Random spot urine uric acid:creatinine ratios have been found to be unreliable in predicting 24-hour urinary uric acid excretion due to diurnal variation. For this reason, one must consider obtaining a 24-hour collection for uric acid and creatinine with a simultaneous measurement of uric acid excretion. A 24-hour excretion of greater than 700 mg of uric acid is the diagnostic threshold for urate overproduction.7

CASE: identifying urate overproduction In 24 hours, the patient produces one liter of urine containing 800 mg of uric acid and 1500 mg of creatinine. The serum uric acid level is 9.5 mg/dL, and the serum creatinine is 0.9 mg/dL.

Discussion: understanding high serum urate levels The results indicate that the patient has a high daily uric acid excretion of 800 mg. As he is in a relatively steady state, the amount produced will be equal to the amount excreted. The fractional excretion of uric acid in this patient is

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Renal & Urology News 37

CME FEATURE (800/9.5) / (1500/0.9) = 0.05%, which is low. Thus, there are two factors that are contributing to the high serum uric acid levels observed in this patient. He produces excessive uric acid (800 mg/dL; at the same time, he reabsorbs more uric acid than normal, leading to a low fractional excretion of urate. Uric acid excretion is very high in infancy and about 8% to 20% during childhood. With puberty, there is a decline in the fractional excretion of uric acid in men, but not in women, resulting in an increase in serum uric acid relative to women. After menopause, the fractional excretion of uric acid is similar between men and women. The low fractional excretion of uric acid, in addition to the relative increased dietary protein intake in men, results in an increased incidence of gout in men vs. women. In an observational study of 100 patients with gout vs. 72 controls,7 the mean fractional excretion of urate was 4.6 ± 1.2 mg/dL in gout patients and 7.6 ± 1.9% in controls. For unclear reasons, patients with increased urinary uric acid excretion frequently have low fractional excretions of uric acid as well.7 An interesting note in this patient is the low urinary output. This low urinary excretion places the patient at increased risk of kidney stones, as decreased urinary output has consistently been associated with an increased risk of renal calculi. In addition, increased water intake has been associated with a decreased risk of development of gouty attacks. There are two important condi tions that the nephrologist should consider in patients with chronic kidney disease, hyperuricemia, and decreased fractional excretion of uric acid. First, lead poisoning has been well associated with both gout and chronic kidney disease. Lead poisoning can be due to lead exposure to paint that was produced many years ago or from occupational exposure. This is less common today. Another important consideration is mutation in the UMOD gene encoding uromodulin (Tamm-Horsfall protein) as a cause of gout and chronic kidney disease.8 In this condition, production of abnormal uromodulin in the thick ascending limb results in defective function of the thick ascending limb and impaired sodium reabsorption. The

because it is inexpensive and has been used for many years. Dosage usually starts at 100 mg/d and is titrated up to 300 mg/d. The initial lowering of serum urate levels that accompanies the administration of allopurinol and febuxostat has been associated with the development of acute gout attacks. Patients are at risk for these attacks after allopurinol or febuxostat initiation for up to 6 months. Educating the patient about the potential for acute attacks and the prescribing of a glucocorticoid dose pack may be indicated. Prophylaxis with colchicine or nonsteroidal agents may also be considered, though these agents may not be appropriate in patients with a decreased

impaired sodium reabsorption leads to increased proximal tubular sodium (and secondarily urate) reabsorption. Patients usually present with gout in the teenage years, but attacks can begin at any age. Chronic kidney disease with a bland urinary sediment and absence of proteinuria occurs during the third through seventh decades of life. Clues to the diagnosis include a very strong family history of gout and kidney disease. Mutational analysis is available in many clinical genetics laboratories. At this point, the clinician had a good understanding of the pathophysiology of the patient’s gout and initiated prolonged discussion with the patient about potential treatments.

In this patient with severe tophaceous gout, it is likely that the uric acid burden will increase over time and that attacks will become more frequent. Prevention with attempts to significantly lower serum urate levels are required in this case, since an increased body burden of uric acid will result in an increased risk of gout in the future. Mr. F has been treated chronically with colchicine and prednisone. These two medications decrease inflammation and prevent gout attacks; in the meantime, however, the body’s uric acid burden will increase, and tophi can increase in size. Prednisone is an unacceptable agent for long-term gout management,

CASE: chronic debility

Indications for the treatment of chronic gout are based on the frequency and severity of flare-ups, uric acid burden, and prognosis.

Mr. F stated that he had suffered from gout for about 10 years. Over the last five years, he has become increasingly debilitated with the development of tophi on the feet and both hands. Mr. F, an accountant, has acknowledged that the pain from the tophi now substantially hinders his job performance. The patient was tearful in his discussion about how the progressive gout has not only affected his professional life but decreased his ability to do many things outside of the home.

Discussion: indications and options for treatment Indications for the treatment of chronic gout are based on attack frequency and severity, uric acid burden, and prognosis. Gout attacks occurring less than once per year may respond well to symptomatic care. Many patients would opt for symptomatic treatment of acute events together with lifestyle modification rather than chronic medication. On the other hand, individuals who are very active may find even infrequent gout attacks a burden and desire preventive treatment. Patients with more frequent attacks are more likely to favor preventive care; the decision is a personal one that must be discussed between the patient and clinician. The risk of developing another gout attack is also associated with higher serum urate levels; this should be taken into account when discussing therapy. For a patient with mild gout and a mildly elevated serum urate level, preventive therapy may not be required.

because of the potential for toxicities over time. Colchicine, which is no longer generic, is now quite expensive, and chronic therapy with this agent may result in myopathy and other adverse effects. For this reason, treatment should focus on decreasing the body’s burden of urate. In patients whose hyperuricemia is solely due to underexcretion of urate, probenecid is a possible alternative to lower serum urate levels. This agent is not used as frequently in the United States as in other countries. A 24-hour urine collection should be obtained prior to usage to rule out uric acid overproduction. Urine output must remain high, and urine pH should be monitored to prevent the development of uric acid stones. For this patient, probenecid would not be a good choice because he is overproducing uric acid, has renal calculi, and produces low urinary volume. There are three agents that are of potential benefit in the treatment of this patient’s gout: allopurinol, febuxostat, and pegloticase. Allopurinol and febuxostat are both xanthine oxidase inhibitors. They prevent hypoxanthine and xanthine metabolism to uric acid, and as such function to decrease serum uric acid levels. Allopurinol should be given primary consideration in the treatment of gout

glomerular filtration rate. Prophylaxis with prednisone is not recommended but in an extreme case such as this patient’s, it may be considered for a short period of time. At usual doses, allopurinol does not lower serum uric acid levels as much as febuxostat. Some physicians, especially rheumatologists, are more comfortable prescribing doses of allopurinol up to 800 mg/d in individuals with “normal” kidney function.9 It is unclear if this places patients at increased risk of toxicity or the severe allergic reactions that have been documented with allopurinol. Febuxostat appears to be more potent and at routine doses has been found to be more effective than allopurinol. Febuxostat is not a purine analogue; as such, patients may not be at risk of developing the severe hypersensitivity reactions that have been seen with allopurinol. In a study of 762 hyperuricemic patients10 assigned to febuxostat (80 mg or 120 mg) or allopurinol (300 mg) daily for one year, the primary end point of a serum urate level less than 6 mg/dL was reached in 53% of patients receiving 80 mg of febuxostat, 62% of patients receiving 120 mg of febuxostat, and in 21% of individuals receiving 300 mg of allopurinol (P<.001). Pegloticase is a pegylated uric acidspecific enzyme that is indicated for chronic gout in adult patients who are

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CME FEATURE refractory to conventional therapy. Most animal species have the enzyme uricase, which converts uric acid to allantoin, which is benign and soluble. Humans do not produce this enzyme.11 Administering uricase to humans is immunogenic and results in the rapid production of antibody. Therefore, investigators developed a porcine uricase enzyme that was surrounded by methoxy polyethylene-glycol. Due to the need for intravenous administration every two weeks and the rate of anaphylactic reactions, pegloticase is reserved for more severe, refractory cases of gout or in individuals who cannot tolerate other treatments. When antibodies do not render pegloticase inactive, it dramatically lowers serum urate levels and is extremely effective in tophaceous gout in patients in whom allopurinol or febuxostat cannot be given.12 Two replicated randomized prospective studies have been done with pegloticase.13 These studies enrolled 225 patients with serum urate levels ≥8 mg/dL with chronic gout refractory to other medications. Patients were randomized to placebo, a pegloticase dose of 8 mg every two weeks, or a pegloticase dose of 8 mg every four weeks. All patients received colchicine or nonsteroidal prophylaxis and received fexofenadine on the night prior and the morning of infusion, as well as 200 mg of hydrocortisone immediately before treatment. Serum uric acid levels fell to less than 6 mg/dL in 42%, 35%, and 0% of individuals in the two-week, monthly, and placebo groups. Serum uric acid levels fell precipitously within 24 hours of the first infusion. Resolution of at least one tophus occurred in 40% of those receiving pegloticase every two weeks. Unfortunately, antibodies developed in nearly 90% of those receiving active drug, and 41% developed an inability to respond to pegloticase. The patients who sustained a loss of the urate-lowering effect of pegloticase were especially at high risk of developing infusion reactions. The loss of response to pegloticase usually occurred within the first four months of therapy. Thus, pegloticase represents a new therapeutic agent that can be dramati-

cally effective in reducing tophus size and treating gout; however, development of antibodies may reduce its efficacy in a substantial proportion of patients. Instead of prescribing this medication infrequently, it is probably better to refer patients to a physician with expertise in its use.

CASE: patient summary As Mr. F had previously been on allopurinol and developed a questionable rash, he opted to receive febuxostat. In conjunction, he is changing his diet and has been placed on losartan (which decreases proximal tubular reabsorption of urate) instead of hydrochlorothiazide for gout. He is considering starting pegloticase if he does not notice a decrease in the size of his tophi. Due to the severe nature of his gout and the risk of future gout attacks, Mr. F was also referred to a rheumatologist for help in management of his arthritis and the potential use of pegloticase. ■ REFERENCES 1. Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med 2005;143:499-516. 2. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med 2004;350:1093-1103. 3. Woodward OM, Kottgen A, Coresh J, Boerwinkle E, Guggino WB, Kottgen M. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc Natl Acad Sci U S A 2009;106:10338-10342. 4. Iwaki K, Yonetani Y. Decreased renal excretion of uric acid following diuretic administration in rats. Jpn J Pharmacol 1984;34:389-396. 5. Coe FL, Parks JH. Nephrolithiasis: Pathogenesis and Treatment. 2nd ed. Chicago: Yearbook Medical Publishers; 1988. 6. Ettinger B, Tang A, Citron JT, Livermore B, Williams T. Randomized trial of allopurinol in the prevention of calcium oxalate calculi. N Engl J Med 1986;315:1386-1389. 7. Perez-Ruiz F, Calabozo M, Erauskin GG, Ruibal A, Herrero-Beites AM. Renal underexcretion of uric acid is present in patients with apparent high urinary uric acid output. Arthritis Rheum 2002;47:610-613. 8. Hart TC, Gorry MC, Hart PS, et al. Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet 2002;39:882-892. 9. Neogi T. Gout. N Engl J Med 2011;364:443-452. 10. Becker MA, Schumacher HR, Jr., Wortmann RL et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353:2450-2461. 11. Johnson RJ, Titte S, Cade JR, Rideout BA, Oliver WJ. Uric acid, evolution and primitive cultures. Semin Nephrol 2005;25:3-8. 12. Sundy JS, Baraf HS, Yood RA, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials JAMA 2011;306:711-720.

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

CME Post-test Expiration Date: June 2013 Medical Education Resources designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Participants should claim only the credit commensurate with the extent of their participation in the activity. Physician post-tests must be completed and submitted online. Physicians may register at no charge at www.myCME.com/junegout. You must receive a score of 70% or better to receive credit.

1. Pegloticase: a. Is a form of uricase used to treat tumor lysis syndrome b. Is an oral medication that rapidly decreases serum urate levels c. Is an intravenous formulation that rapidly decreases serum urate levels d. Has the same mechanism of action as allopurinol 2. The primary cause of gout in the general population is: a. Consumption of high-purine-content foods b. Underexcretion of uric acid c. Overproduction of uric acid d. Both under-excretion and over-production of uric acid 3. In a patient with renal calculi containing calcium oxalate: a. Increased consumption of meat increases urinary acid secretion, increasing the risk of calculi. b. In one study, treatment with allopurinol decreased hyperuricosuria and decreased stone formation in calcium oxalate stone formers with hyperuricosuria. c. Increased fluid intake will decrease the risk of stone formation. d. All of the above 4. In individuals receiving pegloticase infusions: a. Decreased efficacy of pegloticase in lowering serum uric acid levels is associated with the development of allergic reactions with infusion. b. Allergic reactions usually develop only after many months of therapy. c. It usually takes 4 to 6 weeks to see a decline in serum urate levels. d. As uric acid levels drop so quickly, an exacerbation of gout flares does not occur. 5. Which of the following is the best dietary recommendation to lower serum urate levels? a. Stop drinking liquor and switch to red wine b. Stop drinking beer and switch to milk c. Stop eating hamburgers and switch to seafood and shellfish d. Decrease sodium in the diet 6. Patients with a mutation in the gene encoding uromodulin: a. Often develop gout in middle age and kidney failure in their 80s b. Often develop gout in their teenage years and 20s and proceed to dialysis in their 40s c. Do not have gout, but develop kidney failure in their 40s d. Develop both gout and kidney failure in childhood 7. Which of the following conditions does NOT result in hyperuricemia? a. Congestive heart failure b. Volume depletion c. Lead poisoning d. Syndrome of inappropriate antidiuretic hormone excess

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