Renal & Urology News December 2012 Issue

DECEMBER 2012

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VOLUME 11, ISSUE NUMBER 12

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www.renalandurologynews.com

© PHOTO RESEARCHERS, INC. / ZEPHYR / SCIENCE SOURCE

Drug May Benefit ADPKD Patients Tolvaptan slows kidney growth and renal decline

BY JOHN SCHIESZER SAN DIEGO—Tolvaptan, a drug approved by the FDA for treating hyponatremia, may inhibit cyst growth and slow kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD), according to a new study presented at Kidney Week 2012 and published online in the New England Journal of Medicine.

In a phase 3, double-blind, placebocontrolled study, the medication slowed the pace of kidney cyst growth over the three years of the study, but was associ-

IN THIS ISSUE 10

Cranberry juice found not to prevent UTIs

18

Metabolic syndrome raises ESRD risk in CKD patients

19

Diet has no short-term effect on renal function

25

CRP predicts RCC patient response to sunitinib

31

Anogenital distances predict prostate cancer risk Malpractice cap award upheld

by Kansas Supreme Court PAGE 30

ated with a higher discontinuation rate (23%) compared with placebo (14%) due to aquaresis-related events and liver enzyme abnormalities.

“ADPKD is the most common inherited and the fourth most common overall cause of kidney failure worldwide,” said lead investigator Vicente Torres, MD, a nephrologist at the Mayo Clinic in Rochester, Minn. “In many patients with this disease, relentless cyst growth within the kidneys destroys the tissue, causes hypertension and painful complications, and negatively impacts the quality of life. The results of this study reveal a

CKD Raises Death Risk in Pregnancy SAN DIEGO—Chronic kidney disease (CKD) independently increases pregnant women’s risk of death, researchers reported at Kidney Week 2012.

Shailendra Sharma, MD, of the University of Colorado School of Medicine in Aurora, and colleagues compared 646 pregnancies among women with chronic kidney disease (CKD) with 62,757 pregnancies among women without CKD. Compared with women who did not have CKD, those with CKD had a threefold increased risk of death, after adjusting for age, race, history of diabetes, chronic hypertension, liver disease, and connective tissue continued on page 12

IN A STUDY, a hyponatremia drug slowed the growth of ADPKD cysts (above).

potential treatment that blunts kidney growth, lessens associated symptoms, and slows kidney function decline when given over three years.”

The trial included 1,445 ADPKD patients aged 18-50 years. Each patient had a total kidney volume of 750 mL or

more and an estimated creatinine clearance of 60 mL per minute or greater.

The patients were randomized to receive tolvaptan at the highest of three twice daily split dose regimens that the patient deemed tolerable (45/15, 60/30 or 90/30 continued on page 12

Abiraterone Helps mCRPC Patients

BY JOHN SCHIESZER VIENNA—Abiraterone plus prednisone, compared to placebo plus prednisone, may help delay pain progression and functional decline in patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) patients whose disease has progressed after androgen deprivation therapy, according to new data presented at the European Society for Medical Oncology 2012 Congress.

“We now have medications where the side effect ratio is very favorable so that the therapies don’t affect quality of life,” said principal investigator Charles J. Ryan, MD, Associate

CME FEATURE

Professor of Clinical Medicine at the University of California-San Francisco Helen Diller Family Comprehensive Cancer Center. “The results were not surprising and they showed that patients not only lived longer and but had better quality of life.”

The new data were presented at the meeting by Ethan Basche, MD, of the University of North Carolina in Chapel Hill.

The investigators evaluated the impact of abiraterone on pain and functional status as part of a large phase 3 trial that included patients with asymptomatic or mildly symptomatic, progressive, continued on page 12

Earn 1 CME credit in this issue

Current Controversies Surrounding PSA Screening PAGE 35

A N E W I N D I C AT IO N

COMING SOON Please see adjacent pages for current indication, Important Safety Information, and brief summary of full Prescribing Information.

Janssen Biotech, Inc. Š Janssen Biotech, Inc. 2012 8/12 08Z12244A

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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.

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 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.

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.

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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.

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®.

www.zytiga.com Please see brief summary of full Prescribing Information on the following pages.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 8/12 08Z12244A

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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 4 26.7 1.9 Edema 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 8 Cardiac failure 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

0

5.1 4.1

0.3 0

2.3

0

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

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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

© Janssen Biotech, Inc. 2012

Revised: July 2012

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6 Renal & Urology News

DECEMBER 2012

www.renalandurologynews.com

FROM THE EDITOR EDITORIAL ADVISORY BOARD

Renal Week 2012

K

idney Week 2012, held in San Diego, is now history and as usual I like to reflect on the world’s biggest and most prestigious meeting for kidney specialists. More than 4,000 studies were presented this year. It can be a daunting task to decide which ones to report on, but Renal & Urology News writers managed to select for coverage more than three dozen studies covering a wide range of nephrology topics. All of these articles are on our website (www. renalandurologynews.com). Some appear in this issue (on the cover and on pages 18 -22), and others will appear in the January 2013 issue.

Among the articles I would like to highlight here is a report (on page 19) on a study showing that unhealthy diets are not associated with more rapid decline in renal function, at least in the short term.

The study, which had more than 5,400 participants, had a five-year follow-up for kidney parameters, which the lead investigator Julie Lin, MD, MPH, acknowledged was a study limitation. The finding contrasts with that of the Nurses’ Health Study, which had 11 years of follow-up and demonstrated that an unhealthy “Western Pattern” diet was associated with more rapid kidney function decline. With longer follow-up, Dr. Lin said, it is possible that differences in renal outcomes could become apparent.

Additionally, I would like to point out an article (on the cover) reporting on separate studies showing that chronic kidney disease increases a pregnant woman’s risk of death and women with a history of hypertensive pregnancy disorders, including pre-eclampsia, are at increased risk for renal disease later in life. Coincidentally, this issue has a Q&A interview with a nephrologist who specializes in treating pregnant CKD patients.

It is also noteworthy this year’s Renal Week had quite a few studies looking at trends in the use of erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron in dialysis patients following ESA label changes and the January 1, 2011 debut of a prospective payment system (“bundling”) for dialysis-related services. Taken together, it seems clear from these studies that ESA use has decreased and IV iron use has increased, although it remains unclear how these trends are affecting patient outcomes.

We hope you enjoy this final print issue of 2012 and that you visit our website regularly for relevant medical news that is updated daily.

Our website recently has been redesigned to make it easier to navigate and access information. If you have any comments or suggestions, we would like to hear from you.

Sincerely, Jody A. Charnow Editor

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

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

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

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

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

Renal & Urology News (ISSN 1550-9478) Volume 11, Number 12. 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.

INHIBIT ANDROGEN PRODUCTION

BLOCK THE ANDROGEN RECEPTOR

Learn more at inhibitandrogen.com/distinct *Other treatment options may also be considered.

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

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Contents

DECEMBER 2012

■

VOLUME 11, ISSUE NUMBER 12

Urology 13

ONLINE

23

this month at renalandurologynews.com RenalandUrologyNews.com has a new look! When you visit our newly redesigned website, here’s what you’ll find: Cleaner design – Easier-to-read format enables you to catch up quickly on the latest breaking news.

Easier navigation – News and clinical articles can be accessed quickly according to specific diseases and conditions.

More multimedia content – Watch medical videos or flip through physician-authored slideshows.

28

Predictors of Post-RC Bladder CA Recurrence Patients who have undergone radical cystectomy for muscle-invasive bladder cancer are at increased risk of local disease recurrence if their tumor was in an advanced pathologic stage or they had lymph node invasion.

35

CME Feature 35

Saline Lavage for Penile Implant Salvage Salvage replacement of infected penile prostheses with normal saline lavage is safe and effective in maintaining sexual function and preventing recurrence of infection.

Nephrology 14

Invasive MRSA Infections in Dialysis Patients Declining From 2005 to 2010, incidence rates of invasive methicillin-resistant Staphylococcus aureus infections decreased from 6.5 cases to 4.4 cases per 100 dialysis patients.

18

Stroke Risk Lower in PD Patients British study reveals an overall incidence of 10.6 strokes per 1,000 patient-years in peritoneal dialysis patients, which is less than the 26 strokes per 1,000 patient-years found U.S. hemodialysis patients.

19

28

Diet Has No Short-Term Effect on Renal Function To the surprise of investigators, unhealthy diets did not hasten decline in estimated glomerular filtration rate.

Pre-Eclampsia Linked to Air Pollution Modest increment in traffic-related air pollution increases third trimester risk by 30%, researchers report.

“

“

Active Surveillance Recommendations Lagging Most urologists and radiation oncologists regard active surveillance as an effective strategy for managing low-risk prostate cancer, but only a minority of them recommends it.

Physician leadership is needed to prevent these devastating infections through improved infection prevention practices.

See our story on page 14

Current Controversies Surrounding PSA Screening Gurdarshan S. Sandhu, MD, and Gerald L. Andriole, MD, of the Division of Urologic Surgery at Washington University School of Medicine in St. Louis, review the findings of major studies looking at the effect of PSA screening on prostate cancer mortality.

24

Departments 6

From the Editor Reflections on Kidney Week

10

News in Brief CKD may alter gut flora

24

Renal Nutrition Update Low testosterone in CKD patients

26

Practice Management Fees for office visit no-shows

29

On the Forefront Salvaging damaged kidneys

30

Malpractice News Award cap upheld in Kansas

10 Renal & Urology News

DECEMBER 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 New AUA Guidelines: Do More Vasectomies

some of this glycoprotein and polysac-

Vasectomy should be considered for

vessels was lost in 40 dialysis patients

permanent contraception much more

compared with 21 healthy controls.

frequently than is the current practice

The dialysis patients had high levels of

in the United States and elsewhere,

glycocalyx constituents in their blood,

according to new guidelines from the

consistent with increased shedding

American Urological Association (AUA)

of this coating. This likely contributes

on the provision of vasectomy ser-

to the aggressive vascular pathology

vices. Three other new AUA guidelines

present in patients with end-stage

published in the same journal issue

renal disease.

charide mesh that coats the blood

cover evidence-based statements management of overactive bladder;

Low Vitamin D May Endanger Bladder

urodynamic testing in common lower

Researchers observed a statistically

urinary tract symptoms; and diagno-

significant increased risk of urothelial

sis, evaluation, and follow-up of asymp-

bladder cancer (UBC) among patients

tomatic microhematuria. The guide-

presenting with the lowest concentra-

lines appear in The Journal of Urology

tions of 25-hydroxyvitamin D3 in a

(2012;188[6] Suppl 2455-2491).

study of 1,125 UBC cases and 1,028

for the diagnosis, treatment, and

control subjects in Spain. Núria Malats,

Clue Found to Dialysis Patients’ Heart Risks

MD, PhD, and colleagues at the Span-

The increased risks for cardiovascular

in Madrid found this association to be

morbidity and mortality in patients

stronger for patients with muscle-inva-

with renal failure may be attributable

sive tumors, particularly among those

to an impaired endothelial glycoca-

who were low expressers of the FGFR3

lyx barrier, suggests recent study

protein, which has a role in the devel-

findings published in the Journal of

opment of bladder cancer, according

the American Society of Nephrology

to an online report in the Journal of the

2012;23:1900-1908). In a study,

National Cancer Institute.

ish National Cancer Research Centre

Chronic Kidney Disease May Alter Gut Microbes M

icrobial DNA isolated from the stools of 24 persons with end-stage renal disease (ESRD) and 12 healthy persons revealed marked differences in the abundance of 190 bacterial operational taxonomic units (OTUs) between the two groups. The ESRD patients had markedly more OTUs from Enterobacteriaceae, Pseudomonadaceae, and seven other families. Additional studies in rates demonstrated a significant difference in the abundance of 175 bacterial OTUs between uremic and control animals, most notably as decreases in the Lactobacillaceae and Prevotellaceae families. Writing in an online report in Kidney International, Nosratola D. Vaziri, MD, and colleagues at the University of California-Irvine concluded that uremia profoundly alters the composition of the gut microbiome. Although the biological impact of this phenomenon is unknown and awaits further investigation, the profound alteration of the intestinal microbial population may contribute to the production of uremic toxins, systemic and local inflammation, and nutritional abnormalities present in persons with advanced chronic kidney disease.

Study: Cranberry Juice Does Not to Prevent UTIs A

lthough prior research demonstrated that cranberry juice might decrease the number of symptomatic urinary tract infections (UTIs) over a 12-month period, but a new Cochrane Database of Systemic Reviews analysis of up-to-date evidence suggests that cranberry juice is less effective than previously indicated.

The analysis by Ruth Jepson, PhD, of the University of Stirling in Stirling, U.K., and colleagues, which involved 4,473 participants across 24 studies, found that some small studies found a modest benefit for women with recurrent UTIs, but no statistically significant differences were observed when the results of a much larger study were included. Citing the large number of study dropouts/withdrawals, mainly attributed to the acceptability of consuming cranberry products (particularly juice) over long periods, and the low evidence of UTI prevention, the authors stated that cranberry juice cannot currently be recommended for UTI prevention.

Open Access to Visit Notes

Metabolic Factors Boost PCa Mortality, Not Risk

In a recent online poll, Renal & Urology News asked readers: Do you think giving patients open electronic access to visit notes would impede workflow or confuse or worry patients? Here are the results based on 136 responses.

A

Yes 73.53%

No 24.26%

Do Not Know 2.21%

0

10

20

30

40

50

60

70

80

large, long-term study found no evidence of an association between a high level of metabolic factors and prostate cancer (PCa) risk, but high body mass index (BMI), elevated blood pressure (BP), and a composite score of all metabolic factors were associated with an increased risk of PCa-related death. In a study by Christel Häggström, MSc, of Umeå University Hosiptal in Umeå, Sweden, and colleagues, 961 of 6,673 men diagnosed with PCa died from the disease during a mean follow-up of 12 years, according to an online report in Cancer. Men with high glucose and triglyceride levels had a decreased PCa risk, but men in the highest BMI and BP quintiles were 36% and 62%, respectively, more likely to die from PCa. Each 1-unit increment in composite score was associated with a 13% increased risk of PCa mortality.

Androgen levels may impact antiandrogen therapy.1-3 Learn more at inhibitandrogen.com/excess References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical studies.

Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed.

Neural Endocrine Peptides and Receptors. New York, NY: Plenum Press; 1986:627-644.

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12 Renal & Urology News

DECEMBER 2012

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Abiraterone helps mCRPC

Drug/ADPKD patients

Time to Pain Progression

continued from page 1

chemotherapy-naïve mCRPC. The randomized, double-blind, placebo-controlled trial included 1,088 men with mCRPC who had not received prior chemotherapy. Investigators randomized 546 subjects to receive abiraterone 1,000 mg orally once daily plus prednisone 5 mg twice daily and 542 patients to receive placebo plus prednisone 5 mg twice daily (controls).

The co-primary endpoints of the study were radiographic progressionfree survival (rPFS) and overall survival (OS). Secondary endpoints were functional status and pain progression.

The patients reported their pain and functional status at baseline and on the first day of pre-specified treatment cycles over 13.8 months and 8.3 months in the two arms, respectively.

Researchers performed these assessments using standard, validated instruments: the Brief Pain Inventory – Short Form (BPI-SF) and the Functional Assessment of Cancer Therapy – Prostate Cancer (FACT-P).

Dr. Ryan and his colleagues found that patients in the abiraterone arm reported statistically significant delays in most measures of pain progression and functional decline compared with those in the control arm, and pre-defined degrees of worsening were greater (more delayed) in the abiraterone arm compared with the control arm. Baseline scores were similar between the two arms at baseline, when the median worst pain intensity score was 1.2 and the median pain interfer-

CKD/pregnancy continued from page 1

disorders. Additionally, the women with CKD had a twofold increased risk of preterm delivery and a 38% increased risk for cesarean delivery, the researchers noted.

The women with kidney disease were more likely than those without kidney disease to have comorbid conditions, including a history of chronic hypertension and diabetes.

Madeleine V. Pahl, MD, a researcher who has studied pregnancy in CKD patients but was not involved in the latest investigation, said the new study “truly merits mention as it is the first to show in a large patient population that CKD is associated with an increased risk of death in pregnancy.”

Although the finding is new, it is not surprising, said Dr. Pahl, Professor of

continued from page 1 Abiraterone decreased measures of pain progression in men with advancing castrationresistant prostate cancer compared with placebo. Shown here are the mean times, in months, to pain progression (in red) and worst pain intensity progression (in blue).

30

26.7%

25

18.4%

20 15

10.3% 7.4%

10 5 0

Abiraterone

Placebo

Source: Basche E et al. Data presented at the European Society for Medical Oncology 2012 Congress. Abstract 8950.

ence score was 0.7 in each arm.

Abiraterone recipients had significantly delayed average pain intensity progression, pain interference progression, and degradation in FACT-P total score and all subscales except the social/family well-being subscale, where the two groups showed no statistical difference.

The mean time to pain progression was 26.7 months in the abiraterone arm compared with 18.4 months in the control group; the mean time to worst pain intensity progression was 14.8 months and 12 months, respectively.

The mean time to progression of pain interference with daily function was 10.3 and 7.4 months, respectively. The median time to opiate use for cancer pain was not reached in abiraterone arm; it was 23.7 months for the control group arm.

The median FACT-G score (general

function status) was 16.6 for the abiraterone recipients compared with 11.1 for controls. The median FACT-P total scores were 12.7 and 8, respectively.

The physical well-being instrument revealed median scores of 14.8 and 11.1, respectively. The abiraterone group also demonstrated better emotional well-being (22.1 vs. 14.2), functional well-being (13.3 vs. 8.4 months), and prostate cancer subscale score (11.1 vs. 5.8). All of the differences in scores between the two groups were statistically significant.

The study revealed no statistically significant difference between the groups with respect to social/family well-being (18.4 vs. 16.6).

“This is a patient population that has not been significantly impaired by the disease yet, so the idea is to preserve quality of life and to try to keep them at a good level,” Dr. Ryan said. ■

Medicine and Director of the Fellowship Training Program in the Division of Nephrology and Hypertension at University of California, Irvine, in Orange, Calif. “CKD is associated with increased death in almost every study where it has been looked at as factor of mortality.”

a history of hypertensive pregnancy disorders (HPD), including preeclampsia, may be at increased risk for renal disease later in life.

In a population-based study of m o t h e r s i n O l m s t e d C o u n t y, Minnesota, Andrea G. Kattah, MD, of Mayo Clinic in Rochester, Minn., and colleagues found that renal disease developed in 149 (15%) of 1,023 women with diagnostic codes suggestive of HPD compared with 503 (8%) of 6,559 women without these diagnostic codes. The difference between the groups translated into a twofold increased risk of renal disease in the HPD group, the researchers stated.

“Our data suggest that the renal function of the affected women should be closely monitored after their pregnancies,” the authors concluded in their study abstract. ■

CKD also increased a woman’s risk of preterm and cesarean delivery.

It would be interesting to know if there was any effect of CKD stage on mortality and pre-term delivery, she added.

A separate study presented at the conference demonstrated that women with

mg) or placebo. The primary outcome was the yearly rate of change in total kidney volume. Secondary endpoints included a composite of time to clinical progression events: pre-specified kidney function decline, kidney pain requiring intervention, and development or progression of hypertension and albuminuria.

Over the three-year study period, the increase in total kidney volume in the tolvaptan arm was 2.8% per year compared with 5.5% per year in the placebo arm. The composite endpoint favored the medication over placebo: 44 vs. 50 events per 100 person-years of followup. The researchers observed lower rates of worsening kidney function and kidney pain events with tolvaptan. The rate of decline of kidney function was also less in the tolvaptan-treated patients.

The tolvaptan arm had fewer ADPKDrelated adverse events compared with the placebo group. The most common adverse effects in patients who received tolvaptan were anticipated and related to high urine output with more frequent voiding. Investigators observed unexpected liver test abnormalities in approximately 5% of patients and this led to the discontinuation of the study drug in 1.8% of tolvaptan-treated patients.

“The hope is that this drug can significantly delay the need for dialysis or transplantation and maybe in some cases prevent it,” Dr. Torres told Renal & Urology News. Close monitoring of liver function will be required when patients are placed on the drug. At present, tolvaptan is not approved for the treatment of ADPKD. Although the trial results are encouraging, further analyses of benefits and risks of this potential therapy need to be performed by the sponsor and regulatory agencies.

For now, patients with ADPKD should not be treated with tolvaptan outside of approved research studies.”

Commenting on the study findings, Josef Coresh, MD, PhD, a clinical epidemiologist at Johns Hopkins University in Baltimore, observed: “Polycystic kidney disease can be diagnosed early but so far rigorous evidence about treatments which slow down progression has been limited.”

The new study is important because it shows a consistent protective effect with respect to multiple outcomes, Dr. Coresh said. Still, he said, challenges remain because it is not easy to recognize when treatment should be started and it is unclear how to quantify the benefit for an individual patient. ■

www.renalandurologynews.com

DECEMBER 2012

Renal & Urology News 13

Active Surveillance Recommendations Lagging

BY JOHN SCHIESZER CHICAGO—Most urologists and radiation oncologists regard active surveillance as an effective strategy for managing low-risk prostate cancer (PCa), but only a minority of them recommend it, a survey found.

Study results, which were presented at the annual meeting of the North Central Section of the American Urological Association, showed that 47% recommended surgery, 32% recommended radiation therapy, and only 21% recommended active surveillance for low-risk PCa. Overall, physician recommendations aligned with their speciality: Most urologists recommended surgery and most radiation oncologists recommended radiation therapy. After adjusting for physician covariates, radiation oncologists were 10.7 times more likely to

360 urologists completed the survey, for a response rate of 52%. Seventytwo percent of respondents said they thought active surveillance was effective for low-risk PCa and 69% said they were comfortable routinely recommending this approach. The specialists showed some significant differences,

however. Urologists were more likely than radiation oncologists to agree that active surveillance was effective (78% vs.

65%) and more urologists than radiation oncologists were comfortable recommending it (75% vs. 62%).

“Treatment choices for low-risk prostate cancer also reflect patient prefer-

She had normal kidney function.

Urologists differ from radiation oncologists in their views. recommend radiation therapy than surgery and urologists were four times more likely to recommend surgery than radiation therapy. They also were 2.5 times more likely to recommend active surveillance.

“Our results may explain in part the relatively low use of active surveillance for low-risk prostate cancer in the United States,” said lead investigator Simon Kim, MD, MPH, a urologic oncology fellow at Mayo Clinic in Rochester, Minn.

The extent to which radiation oncologists and urologists perceive active surveillance as effective and recommend it routinely to patients has not been well studied, Dr. Kim said. He and his colleagues assessed the attitudes and treatment recommendations for low-risk PCa from a national survey of PCa specialists. For this investigation, a survey was mailed to a population-based sample of 1,494 physicians in the United States from late 2011 to early 2012. All the physicians were asked how they view active surveillance as well as what their treatment recommendations were for patients diagnosed with low-risk PCa, which was defined as a PSA level below 10 ng/dL, clinical stage T1c, and a Gleason of 6 in one of 12 cores. A total of 362 radiation oncologists and

ences, which may in part explain the higher rates of surgery and radiation therapy rather than active surveillance in the treatment recommendations for low-risk prostate cancer,” Dr. Kim told Renal & Urology News. The study was funded by the Informed Medical Decisions Foundation. ■

She became critically ill.

She was diagnosed with AKI.

She was treated differently.

AKI and ESRD patients are not the same.

For the first time ever, KDIGO has published a Clinical Practice Guideline that focuses on acute kidney injury (AKI). The Guideline is based on systematic reviews of relevant clinical studies and aims to assist practitioners caring for patients at risk for or with AKI. If you want to optimize outcomes for AKI patients—treat them differently.

Find out how by visiting crrtcounts.com/guideline or go to gambro.com/prismaflex to learn why the Prismaflex® System is the most widely used CRRT device in the world.

Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury.

Kidney International Supplements 2012; Volume 2, Issue 1: 1–126.

14 Renal & Urology News

DECEMBER 2012

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TB Therapy Effective in CKD Patients Responses are not as robust as in patients with normal renal function, but many cases can be cured

BY JOHN SCHIESZER SAN DIEGO—Anti-tuberculosis treatment (ATT) appears to be both safe and effective in patients with chronic kidney disease (CKD), data show.

In a 12-month study of 572 CKD patients, of whom 33 had tuberculosis (TB), researchers in India found that 84.8% of subjects responded to ATT, although the responses to the treatment were not as robust as seen in patients with normal kidney function. Clinicians may need to modify the dosing interval of ATT for patients with impaired kidney function, who may not achieve optimal outcomes with standard daily therapy.

The study also showed that gastritis was the most common complication from ATT in CKD patients, followed by drug-induced hepatitis. The investigators observed worsening of renal function in a minority of CKD patients.

“TB is endemic in the developing world and India has the second largest burden of disease,” said lead investigator Teny Mathew John, MD, currently a specialist in infectious diseases at Hamad General Hospital Doha Qatar.

“Chronic kidney disease is an immunosuppressed state like HIV. We had many patients with CKD presenting with unexplained fever and weight loss

and when evaluated had radiological, biochemical, or microbiological evidence of TB. Some had response to empirical anti TB treatment as well.”

Dr. John presented study findings at IDWeek, a conference sponsored by the Infectious Diseases Society of America and three other medical organizations.

TB management in CKD patients is not well defined and guidelines stop short of formulating a proper treatment plan. He and his colleagues analyzed the effectiveness of ATT overall in CKD patients as well as the effectiveness of specific dosing and duration of ATT. The prospective study, which included 33 CKD patients with TB, was conducted from August 2009 to July 2010 at Department of Nephrology/ Medicine, Government Medical College, Kottayam, Kerala,India, under the guidance of K.P.Jayakumar, MD, Professor and Head of Nephrology.

All CKD patients with a diagnosis of TB were included and each patient was started on ATT using isoniazid (5mg/ kg), rifampicin (10mg/kg), pyrazinamide (12-20 mg/kg), ethambutol (15-25mg/kg) and/or ofloxacin 400 mg. Patients were given isoniazid and rifampicin daily and given pyrazinamide

Teny Mathew John, MD

and ethambutol/ofloxacin on alternate days (thrice weekly).

Patients with severe forms of TB (central nervous system [CNS], spine, pericarditis, and disseminated) were treated longer than those with less serve forms (pleural effusion, lymphadenopathy, ascites, and abscess). Patients were excluded from the study if they were under the age of 13, were HIV infected, if they had underlying liver disease, or were renal transplant recipients.

Extra pulmonary TB was the predominant form diagnosed (84.8%) and among these patients TB pleural effusion (32.1%) was the most common followed by CNS TB (17.9%). Of the 33 TB patients, 28 (84.8%) were cured, meaning they had radiological, microbiological, or laboratory evidence of improvement.

“TB should be one of the important differential diagnoses in a CKD patient with unexplained fever and weight loss,” Dr. John told Renal & Urology News. “Genitourinary TB in CKD can present as strictures and scarring and usually the radiological findings are quite specific. The outcome of TB treatment is comparable to that of the general population although the treatment duration is prolonged, needing up to one year.”

The most common ATT-related adverse event (AE) was gastritis (36.1%), followed by drug induced hepatitis (11.1%). Other notable AEs included rash (5.6%) and isoniazidinduced psychosis (2.8%). A worsening of renal function was observed only in 2.8%. The study cohort had a 9% mortality rate. The rate was highest among those with disseminated TB and CNS TB. ■

Invasive MRSA Infections in Dialysis Pts. Declining

BY JOHN SCHIESZER SAN DIEGO—Invasive methicillinresistant Staphylococcus aureus (MRSA) infections have declined in incidence among chronic dialysis patients in the United States, according to a study.

Although the study could not ascertain the reasons for the decrease, investigator Priti Patel, MD, a medical officer with the Centers for Disease Control and Prevention (CDC in Atlanta, observed: “It is possible that the Fistula First program and other efforts to reduce central venous catheter use in outpatient hemodialysis centers have contributed to this finding. Efforts occurring within hospitals to reduce bloodstream infections and prevent MRSA transmission also could have played a role in the rate decrease.”

The researchers analyzed populationbased data from nine U.S. metropolitan areas participating in Active Bacterial

Core surveillance (ABCs). During the 2005-2010 study period, the researchers identified 6,462 cases of invasive MRSA among dialysis patients, 85.4% of them outpatient. Incidence rates decreased from 6.5 cases per 100 dialysis patients in 2005 to 4.4 cases per 100 dialysis patients in 2010. The incidence rates decreased annually by 6.5% for outpatients and 10.6% for inpatients.

The researchers identified 1,971 cases of invasive MRSA in dialysis patients from 2009-2010. Nearly 93% of these cases were bloodstream infections. The median age of these dialysis patients was 59 years (range 3-97 years). The group was 54% male and 57.4% African-American.

The dialysis modality was hemodialysis in 97.4% of patients and peritoneal dialysis in 2.6%. The study showed that 70.8% of the patients had been hospitalized in the year prior to the MRSA culture. Among the hemodialysis patients, 60.9% had a central venous catheter.

“The study was conducted to better understand the epidemiology of invasive MRSA infections among dialysis patients, including changes in infection rates over time,” Dr. Patel told Renal & Urology News. “Despite the reassuring finding of decreasing rates between 2005 and 2010, the burden of invasive MRSA infections remains extremely high in dialysis patients compared to other populations. Physician leadership is needed to prevent these devastating infections through improved infection prevention practices.”

She presented study findings at IDWeek, a joint meeting of the Infectious Diseases Society of America and three other medical organizations.

For the study, the researchers classified cases as either inpatient (culture collected beyond three days after admission) or outpatient (all others). The researchers calculated the incidence rates using

dialysis population denominators from the U.S. Renal Data System.

The mortality rate within seven days of MRSA culture was 6.1%. The investigators concluded that infection prevention measures should include “fastidious vascular access care” and efforts to decrease central venous catheter use.

“Unfortunately, the burden of invasive MRSA infections remains extremely high in the dialysis patient population, and these infections have substantial associated mortality,” Dr. Patel said. “Aggressive prevention efforts are needed that focus on improving hemodialysis catheter care, along with catheter reduction and measures to prevent AV [arteriovenous] fistularelated and graft-related infections.

Nephrologists should be aware of the CDC’s recommended list of practices for bloodstream infection prevention and the available tools to help put these into practice in dialysis centers.” ■

www.renalandurologynews.com

DECEMBER 2012

Renal & Urology News 15

Current Corticosteroid Use Hikes CVE Risk in SLE CURRENT USE of corticosteroids increases cardiovascular event (CVE) risk in patients with systemic lupus erythematosus (SLE), but past use, in the absence of current use, does not, a study found.

In a study of 1,874 SLE patients, investigators Laurence S. Magder, PhD, of the University of Maryland in Baltimore, and Michelle Petri, MD, MPH, of Johns Hopkins University in Baltimore, found that the rate of CVEs was 2.66 times higher than would be expected in the general population with similar levels of traditional risk factors, according to findings published online ahead of print in the American Journal of Epidemiology.

After adjusting for age, the excess risk was not associated with SLE duration but was

Cardiovascular event risk is found to be greater with higher daily doses. associated with current disease activity and anti-double-stranded DNA. Consistent with previous studies, the excess risk was more strongly associated with the current dose of corticosteroid than with cumulative past dose, suggesting a short-term impact of corticosteroid use on CVE risk.

Compared with patients not currently using corticosteroids, those currently taking daily doses of 10-19 mg and 20 mg or more had a significant twofold and fivefold increased risk of CVEs, respectively, after adjusting for age.

During 9,485 person-years of follow-up, the investigators observed 134 CVEs, for a rate of 14.1 per 1,000 person-years.

The researchers defined CVEs as the occurrence of myocardial infarction, clinically definite angina, thrombotic stroke, percutaneous coronary intervention, coronary artery bypass procedure, or claudication.

Drs. Magder and Petri noted that three previous studies of other large non-SLE cohorts also found that current, but not past, use of corticosteroids was associated with higher CVE rates.

These studies showed that the increased risk was highest among subjects with the higher current doses. â&#x20AC;&#x153;Our research findings, along with these previous consistent findings, suggest that there is an acute impact of corticosteroids on CVE risk,â&#x20AC;? the

authors wrote. It is also possible that current use of corticosteroids â&#x20AC;&#x153;is merely a marker for a flare of disease activity that is the real cause of the increased CVE risk,â&#x20AC;? they stated. The investigators noted, however, that in multivariable analysis, the association between current corticosteroid use

and CVE risk persisted after controlling for the disease activity level measured at the time of the corticosteroid prescription decision.

Another plausible explanation for the association is an effect of corticosteroids on traditional risk factors, such as blood pressure (BP)

Table 2: Percentages of Patients with Adverse Reactions, Derived from all Adverse Events, Reported by Greater Than 2% of Patients Treated With Myrbetriq 50 mg Once Daily in Study 4 Myrbetriq 50 mg

Active Control

(%)

(%)

Number of Patients

812

812

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or serum lipids, they observed. They pointed out, however, that the effect of corticosteroid use on CVE risk persisted after controlling for BP and serum cholesterol, suggesting that the association is independent of the effect of corticosteroids on these risk factors. â&#x2013;

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16 Renal & Urology News

DECEMBER 2012

www.renalandurologynews.com

Heart Failure-Renal Dysfunction Link Probed

BY ROSEMARY FREI, MSc TORONTOâ&#x20AC;&#x201D;Researchers have taken another step toward understanding why reduced kidney function gives patients with stable heart failure a significantly increased risk of dying. Increased cardiac filling pressure represented by right

ventricular systolic pressure (RVSP) and natriuretic peptide (NT-proBNP) is tied strongly to increased serum creatinine and reduced estimated glomerular filtration rate (eGFR).

They did not find, however, an association between left ventricular ejection

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fraction (LVEF) and kidney function, which surprised investigators because previous studies have shown that a lower LVEF is associated with reduced renal perfusion and thus leads to renal insufficiency. They hope to repeat the study with a larger number of patients

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to see if the findings change or remain the same. â&#x20AC;&#x153;At this point, we are just trying to determine whether there are relationships, and now we have to do more research to understand the details,â&#x20AC;? said Carlos Fernando, MD, who presented the results at the 2012 Canadian Cardiovascular Congress.

Dr. Fernando, who is a graduate student at the University of Toronto, worked with lead investigator Dr.Gordon Moe, a cardiologist at St. Michaelâ&#x20AC;&#x2122;s Hospital in Toronto, and other colleagues to tease out the links between renal insufficiency and heart failure. Heart failure patients with moderate to severe renal dysfunction have at least a twofold increase in relative mortality risk. A recent study published in the Journal of Cardiology (2012;60:301305) has shown that treating heart failure can improve kidney function and, in turn, lower mortality.

Canadian study findings implicate increased cardiac filling pressure.

To explore the associations between renal factors and cardiac parameters, the researchers followed 246 patients with stable chronic heart failure who were being treated at the St. Michaelâ&#x20AC;&#x2122;s Hospital heart failure program. They assessed patientsâ&#x20AC;&#x2122; LVEF and RVSP, echocardiographically; serum creatinine, eGFR and levels of the heart-failure biomarker N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP).

The team did not examine other parameters derived from echocardiography, such as wedge pressure. The patientsâ&#x20AC;&#x2122; median RVSP was 40.5 mm Hg, median NT-proBNP level was 1,614 pg/mL, median serum creatinine level was 104 Âľmol/L, and median eGFR was 57.5.

The median LVEF was 35%, the study showed..

Both RVSP and NT-proBNP were significantly correlated with serum creatinine and eGFR. In contrast, LVEF was not correlated with either of these kidney function measures.

Subjectsâ&#x20AC;&#x2122; mean blood pressure was 120.5 mmHg/67.4 mmHg, their average age was 69 years, and 72% were men. The majority were Caucasians, at 63.8%, while 31.3% were Asians and 4.9% were African Canadians. â&#x2013;

www.renalandurologynews.com

DECEMBER 2012

Renal & Urology News 17

The Pregnant Kidney Patient & QA

Focusing on nephrology patients who become pregnant may seem to be a niche business, but as specialist

Madeleine V. Pahl, MD, tells Renal & Urology News, this population is increasing. In an interview with senior editor Delicia Honen Yard, Dr. Pahl, who is Professor of Medicine and Director of the Fellowship Training Program in the Division of Nephrology and Hypertension at University of California-Irvine, in Orange, Calif., explains the unique considerations for nephrologists who treat pregnant dialysis or posttransplant patients.

How did you come to study the effects of pregnancy in kidney disease?

Dr. Pahl: No one has asked me that in a very long time. But years ago, when I was a fellow, I had to take care of a patient on dialysis who became pregnant, and it piqued my interest. It’s something that not too many people know about. I started to do a lot more reading and became involved in the care of those patients.

Do you have an even more specific area of interest within this?

Dr. Pahl: You might say dialysis patients who become pregnant.

What is the typical diagnosis of your patients?

Dr. Pahl: Overall, 50% of dialysis patients in the U. S. are diabetic, but not in this case. But about 40% of dialysis patients of childbearing age who do become pregnant have glomerular nephritis (GN) or lupus. Chronic GN has been reported in the literature around 29%, and lupus around 9.6%.

How big a segment of the CKD population does this group represent?

Dr. Pahl: I haven’t seen that literature, but there have been more than 1,000

On The Web

live births among kidney transplant patients reported in the literature.

That’s a lot more than in the dialysis population.

Between 1% and about 7% of dialysis patients of childbearing age have become pregnant, depending on what part of the world you’re looking at. In the U.S., the pregnancy rate among these patients used to be reported around 1.5%, but a U.S. registry was set up in 1997 or so, and they reported in 2003 that approximately 2.4% of women of childbearing age in the United States on dialysis have become pregnant. Saudi Arabia reported about 5% in the late 1990s, but I believe it has risen to 7.5%.

pregnant women, meaning many of these women should go on dialysis six days a week. That makes it a challenge for the patients and a challenge for the dialysis center to schedule them; these patients now basically take up two spots.

You have to carefully monitor the dry weight of these patients, because you have to start increasing dialysis as their pregnancy progresses and they gain weight.

Sometimes EPO [erythropoietin] management becomes a little more challenging. You have to monitor phosphorus and calcium. Nutrition is an issue. We don’t reuse the dialyzer; you don’t want to expose [the fetus] to formaldehyde.

But the biggest concern is that these women have a much higher incidence of preeclampsia, and recent literature has shown that the outcomes are much worse in pregnant women on dialysis than in pregnant women not on dialysis.

When the dialysis patient is pregnant, does the nephrologist “outrank” the obstetrician?

Dr. Pahl: If one of our nephrology patients becomes pregnant, she is immediately

What are the special concerns in treating pregnant women?

Dr. Pahl: One of the challenges to community nephrologists and to outside dialysis centers is that most experts recommend increasing the dialysis prescription for

In your experience, have these been planned pregnancies?

Dr. Pahl: No. As a rule, women who are on dialysis have classically not thought that they were going to be able to get pregnant, particularly because many had abnormalities of their menstrual periods. But as some of their gynecological issues get controlled, we are seeing pregnant people, even though they didn’t plan it.

If a nephrologist does have the opportunity to discuss pregnancy ahead of time, what points should be addressed?

What factors are driving these increases?

Dr. Pahl: I think some of the women may be receiving better care, better dialysis.

They’re more likely to have normal periods than they did before because they’re better dialyzed, and because of that they have become fertile.

referred to the high-risk obstetrician, and then we’re in constant communication with that specialist—we probably talk to each other about every two weeks.

Both our nephrologists and the obstetrician see the patient frequently in the dialysis center, and we work very closely with the obstetrician. If there are any issues, the woman is admitted to the obstetrics service.

I guess if you were going to try to set up some kind of regional management area, the obstetrician may be in charge of ensuring that the pregnancy is progressing adequately, whereas we [nephrologists] try to manage the dialysis prescription, which becomes altered in this setting.

Preeclampsia is a big concern with pregnant women on dialysis.

—Madeleine Pahl, MD

Dr. Pahl: In the past, women who had received a kidney transplant were told not to conceive for at least two years post-transplantation, until they were stable. But most recently, I think since 2005 or 2006, that has changed to one year after transplant because outcomes have been relatively good For the women with chronic kidney disease, you have to counsel them for potential for adverse risks, which may include worsening hypertension and exacerbation of their disease, such as lupus. They could have adverse obstetric outcomes much more than the general community.

Preeclampsia and preterm labor are the big issues in women transplant recipients. The big problem with newborns in the renal arena has been “small for gestational age.” ■

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

18 Renal & Urology News

■ Kidney Week 2012

DECEMBER 2012

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Reports from the American Society of Nephrology’s Kidney Week 2012 conference, San Diego

Stroke Risk Lower in PD Patients Less blood pressure flux and no routine exposure to anticoagulants may explain the finding

BY JOHN SCHIESZER SAN DIEGO—Stroke incidence rates in peritoneal dialysis (PD) patients may be lower than in hemodialysis (HD) patients, according to the largest published study of its kind.

The difference may be related to case mix, volume status, disease management, and routine exposure to anticoagulation, according to the investigators.

“We looked at a large population at three centers in London,” said lead investigator Albert Power, MD, of the Imperial College Kidney and Transplant Centre, Hammersmith Hospital, London, U.K. “It may be related to less blood pressure flux with [PD] treatment. The second reason in terms of hemorrhagic strokes would be there is no routine exposure to anticoagulants three times a week as you get with hemodialysis.”

The retrospective study included 1,511 PD patients with a mean age of 54.7 years. Of these, 7% had preexisting cerebrovascular disease. The investigators defined stroke as an acute neurologic event that is greater than 24 hours duration and confirmed on neuroimaging. The researchers excluded cases of subdural hematoma.

Over 3,672 patient-years of followup, 39 strokes occurred, for an overall incidence of 10.6 strokes per 1,000 patient-years. By comparison, during this same time period, the incidence of stroke in the U.K. general population varied from 1.0 to 1.5 per 1,000 patient-years. Eighty-two percent of the strokes were ischemic and 18% were hemorrhagic. The median PD vintage at the time of stroke was two years, the researchers stated.

The stroke rates found with PD patients in the U.K. are significant-

MetS Raises ESRD Risk in CKD Patients

bolic syndrome in patients with CKD,” Dr. Navaneethan told Renal & Urology News. “Metabolic syndrome is independently associated with end-stage renal disease. Whether interventions such as lifestyle modifications can improve the risk associated with metabolic syndrome on kidney disease progression merits further study.”

In another development related to MetS and kidney disease, investigators in Taipei, Taiwan, presented study results showing that controlling MetS can slow CKD progression. The researchers studied 323 patients with CKD and MetS who were followed for at least 12 months.

After three months of MetS treatment, the investigators divided patients into two groups: MetS controlled (group 1) and MetS not controlled (group 2).

The primary endpoint was a reduction in estimated glomerular filtration rate (eGFR) of more than 50%. Baseline eGFR (in mL/min/1.73 m2) was comparable between the two groups (27.9 for group 1 and 28.1 for group 2). After 4.5 years of follow-up, group 1 had a lower cumulative incidence of a greater than 50% reduction in eGFR than group 2.

In addition, the more MetS components controlled, the better the preservation of renal function. ■

METABOLIC SYNDROME (MetS) in patients with stage 3 and 4 chronic kidney disease (CKD) is associated with an increased risk of developing end-stage renal disease (ESRD), a new study suggests.

The study by Sankar D. Navaneethan, MD, MPH, of Cleveland Clinic, and colleagues included 25,868 patients with stage 3 and 4 CKD. Of these, 15,605 (60%) had MetS. During a mean followup of 2.3 years, 3,345 participants died before reaching ESRD and 481 reached ESRD. Overall, MetS was associated with a 30% increased risk of ESRD, but it was not associated with death.

For the individual components of metabolic syndrome, elevated triglycerides, hypertension and impaired glucose metabolism were associated with a 7%, 67%, and 83% increased risk for ESRD, respectively, compared with the absence of these components. “Our study findings reveal the higher prevalence of meta-

ly lower than strokes rates for HD patients in the United States (26 per 1,000 patient-years) for a number of reasons, Dr. Power said.

U.K. study reveals an overall incidence of 10.6 strokes per 1,000 patient-years.

“It may well be the effect of residual renal function exerting a modulatory effect on systemic inflammation that is linked to accelerated atherosclerosis, and certainly an ischemic stroke is believed to be an atherosclerotic event,” Dr. Power said.

Stephen Sozio, MD, Assistant Professor, Division of Nephrology, Johns Hopkins University, Baltimore,

said stroke is becoming a well-recognized complication of both chronic kidney disease and end stage renal disease (ESRD) that results in a lower quality of life, increased disability, and increased mortality for patients. “This study confirms the five- to 10-fold higher risk of stroke in those with ESRD seen in other studies, and adds additional insight into the risk for those on peritoneal dialysis,” Dr. Sozio said.

“Even after this study, we still do not know whether peritoneal dialysis or hemodialysis poses the lowest risk of stroke. These are important issues for our patients, and more studies such as this one need to be conducted to reduce stroke and its complications in those with ESRD.” Dr. Sozio noted that a direct comparison of stroke risk between PD patients in the U.K. and HD patients in the U.S. is difficult to interpret. ■

Intravenous Iron Has Modest Effects at Higher TSAT Levels DOSING INTRAVENOUS (IV) iron at

below 30% compared with 0.10% for

higher transferrin saturation (TSAT) lev-

those with a TSAT of 30% or higher. The

els has only a modest effect on raising

effects of IV iron on ferritin and hemo-

TSAT, ferritin, and hemoglobin in anemic

globin also were modest at a TSAT of

hemodialysis patients.

30% or higher. Each 100 mg of iron

Bruce M. Robinson, MD, MS, of

increased next month’s ferritin level by

the Arbor Research Collaborative for

17 ng/mL for patients with a TSAT

Health and the University of Michigan

below 30% compared with 7 ng/mL for

in Ann Arbor, and colleagues analyzed

patients with a TSAT of 30% or higher.

monthly data from 15,183 hemodialy-

Hemoglobin levels increased by 0.17 and

sis patients in the Dialysis Outcomes

0.004 g/dL, respectively.

and Practice Patterns Study (DOPPS).

Dr. Robinson’s group summarized

For patients prescribed IV iron, the

findings by noting that, although TSAT

investigators estimated the effects of

targets of 30% to 50% are now common

iron dose within strata of current TSAT

in the United States, IV iron dosing raises

levels on the following month’s TSAT,

TSAT and hemoglobin only modestly

ferritin, and hemoglobin values. As

when given to patients with TSAT values

expected, IV iron dose correlated with

of 30% or more. They concluded that

increases in these values the following

ongoing iron dosing when TSAT is 30%

month, but the associations were no-

or higher “provides little erythropoietic

tably weaker for current TSAT of 30%

support and may deleteriously increase

or higher. In adjusted models, each

parenchymal iron deposition. Additional

100 mg of iron increased next month’s

study is needed, and until then caution

TSAT by 0.43% for patients with TSAT

is warranted.” ■

www.renalandurologynews.com

DECEMBER 2012

Renal & Urology News 19

Kidney Week 2012 ■

Diet Has No Short-Term Effect on Renal Function

Predictors Of Early Graft Loss Confirmed

Findings from a longitudinal cohort study surprised researchers

BY JODY A. CHARNOW RESEARCHERS WHO studied pairs of renal transplant recipients who received kidneys from the same donor have confirmed previously identified recipient risk factors for early renal graft loss, according to a new report.

The report detailed a study in which investigators analyzed outcomes of donor-matched recipient pairs with discrepant graft survival: one graft surviving less than two years (early graft loss) and the other surviving at least 7.5 years (late graft loss). In this way, the researchers could determine predictors of early graft loss while controlling for donor factors. Using the United Network for Organ Sharing database, Joyce P. Samuel, MD, of the University of Texas Medical School at Houston, and colleagues identified 4,630 patients with discrepant graft survival who received a kidney from 2,315 deceased donors.

Compared with late graft loss, the risk of early graft loss was increased by 68% if the recipient was black, the study found.

The likelihood of early graft loss was 40% less likely in those recipients who had never before received a kidney transplant compared with those who had. The risk of early graft loss increased with increasing body mass index, age, and cold ischemia time. Higher antibody sensitization also predicted early graft loss. Recipient gender, dialysis prior to transplant, and time on the transplant waiting list were not associated with an increased risk of early graft loss.

The median graft survival was five months among patients with early graft loss group compared with 122 months among those with late graft loss, according to the investigators.

“This analysis utilized a unique study design to reiterate the risk for adverse graft outcome associated with various recipient characteristics,” Dr. Samuel told Renal & Urology News. “The most important implication is that certain modifiable risk factors—recipient body mass index, antibody sensitization—remain important predictors of graft outcome.” ■

to each of the four dietary patterns varied markedly by race and ethnicity.

The researchers observed no significant associations between any dietary pattern either eGFR decline or change in UACR in either unadjusted or adjusted analyses, the latter controlling for demographics, body mass index, hypertension, diabetes, lipids, and physical activity.

© THINKSTOCK

BY JODY A. CHARNOW UNHEALTHY DIETS are not associated with more rapid declines in kidney function, at least in the short term, new findings suggest.

The findings are from a longitudinal cohort study of 5,405 participants (mean age 62 years) who had baseline dietary data from a 120-item food

In a study, unhealthy eating did not hasten decline in estimated glomerular filtration rate.

frequency questionnaire and at least two measures of serum creatinine, cystatin C, or urine albumin-creatinine ratio (UACR). The researchers, led by Julie Lin, MD, MPH, of Brigham and Women’s Hospital in Boston, divided subjects into four groups based on dietary pattern: “fats and processed meats” (similar to a “Western” pattern); “beans, tomatoes, and refined grains; “vegetables and fish”; and “whole grains and fruit” (similar to a “prudent” pattern. The investigators calculated subjects’ estimated glomerular filtration rate (eGFR) using serum creatinine or cystatin C and defined rapid eGFR decline as 3 mL/min/1.73 m2 or greater per year decrease over five years of follow-up.

The racial composition of the cohort was 41% white, 25% black, 21% Hispanic, and 13% Asian. Adherence

Dr. Lin noted that she and her team sought to assess the generalizability of the previously reported associations between dietary patterns and progression of kidney function decline in the almost entirely Caucasian study population of older women in the Nurses’ Health Study (NHS). Their study included an ethnically diverse and younger population represented by the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of cardiovascular disease funded by the National Heart, Lung, and Blood Institute, National Institutes of Health. They hypothesized that less healthy eating patterns would be associated with faster decline of kidney function, whereas healthy patterns would be inversely associated. They also postulated that unhealthy dietary patterns would be associated with greater increases in

albuminuria over time, whereas healthy dietary patterns would be associated with less progression of albuminuria.

“To our surprise and disappointment,” Dr. Lin told Renal & Urology News, “we did not observe any statistically significant associations between any of the dietary patterns and either of the kidney outcomes of interest with the exception of higher adherence to the ‘vegetables and fish’ pattern being associated with an increase in albuminuria over time, which was the opposite of what we expected.”

She pointed out that the study was limited by a relatively short follow-up time of five years for the kidney parameters. In contrast, the NHS study, which reported that an unhealthy “Western Pattern” diet was associated with more rapid kidney function decline, had 11 years of follow up for changes in eGFR. Moreover, the markedly different dietary patterns in the various ethnic groups may represent an important confounding factor, she said. “It is still possible that associations between dietary patterns and kidney outcomes will become evident with longer followup time in MESA, which is an on-going cohort study that continues to collect measures of eGFR and albuminuria every few years,” Dr. Lin said.

Importantly, she added, published data from the NHS and MESA studies as well as other studies support the benefits of healthy eating patterns, such as a reduced risk of chronic medical conditions such as diabetes and cardiovascular disease (both of which are major risk factors for progressive kidney disease), even when analyses are adjusted for important confounders such as age, gender, and body mass index.

“Our experience with this study highlights the importance of longterm follow-up of several years for better assessment of progressive kidney dysfunction as well as challenges in measuring changes in albuminuria in populations where the majority [of subjects] are in the traditional ‘normal’ range,” Dr. Lin said. ■

20 Renal & Urology News

■ Kidney Week 2012

DECEMBER 2012

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Reports from the American Society of Nephrology’s Kidney Week 2012 conference, San Diego

Renal Ultrasound Unwarranted for AKI Evaluation

BY JOHN SCHIESZER ROUTINE USE of renal ultrasound may be inappropriate for evaluating hospitalized patients with acute kidney injury (AKI), and a simple electronic alerting system may provide an early warning of rising creatinine levels, according to separate studies.

Renal ultrasound frequently is used to look for obstructive uropathy, but an investigation by Dipal Patel, MD, a third-year internal medicine resident at Mount Sinai Hospital in Chicago, and colleagues showed this to be a rare cause of AKI. In addition, the study showed that renal ultrasound did not provide meaningful information that affected patient management.

“We did this study because there are not much data on this issue and whether it [renal ultrasound] is really useful or not,” Dr. Patel said. “There is a waste of money and a waste of time and it may lead to longer hospitalization. We found there was fewer than 5% who had obstructive uropathy.”

The study included 1,121 AKI patients older than 18 years. The study excluded pregnant women and patients who had a kidney transplant.

During the six-year study period, 5,010 patients underwent renal ultrasound; of these, 1,121 met study inclusion criteria. Their mean age was 62 years, 53.8% were male, and 73.5% were African American. Sixty-two patients (5.5%) had a positive renal ultrasound; of these, 43 (69%) were male and their mean age was 65 years.

Of the 62 patients, 28 (45%) presented with symptoms of urinary retention and 47 (76%) had risk factors for obstructive uropathy.

Elevated PSA levels, male gender, and medical problems known to cause obstructive uropathy were associated with a positive renal ultrasound, the researchers said.

The researchers concluded that renal ultrasound should be reserved for patients who have a higher likelihood of obstructive uropathy based on their medical history.

In a separate pilot study, British researchers demonstrated the potential benefits of using a 24-hour electronic alerting system. It could provide a simple approach to the early identification of patients experiencing a rise in creatinine following hospitalization.

The electronic notification system also

appears to provide a gateway for standardizing clinical guidance for AKI management.

“We need a new tool,” said lead investigator Edward Stern, MD, of the Royal

3744_takpeg_fa2_run_2pg.indd 1

Free Hospital Centre for Nephrology in London. “Anything that is a stimulus for a small percentage of clinicians to think about the change in a patients’ creatinine more quickly is very important. It may not

revolutionize our management, but it is a small part in this attempt to augment the physicians’ awareness of a patient’s change in creatinine and what the significance may be.”

www.renalandurologynews.com

DECEMBER 2012

Renal & Urology News 21

Kidney Week 2012 ■

He and his colleagues designed an automated rule for the hospitals’ electronic pathology systems. If the systems identified patients with a creatinine rise of 50% or more from the previous value

(within 90 days), an electronic alert was posted on the pathology report.

The report identified patients as having AKI and provided a link to the London AKI Network website, which

provided relevant clinical guidelines.

The biochemistry team used its discretion to subsequently telephone requesting clinicians. Dr. Stern and his team collected data for the first 100 adult

Reducing the burden of

ESA administration Consider the first once-monthly, non-EPO ESA offering less-frequent dose administration.

INDICATION AND LIMITATIONS OF USE OMONTYS® (peginesatide) Injection is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis.

OMONTYS is not indicated and is not recommended for use in patients with CKD D not on dialysis, in patients receiving treatment for cancer and whose anemia is not due to CKD, or as a substitute for red blood cell (RBC) transfusions in patients who require immediate correc ction of anemia. OMONTYS has not been shown to improve sympto oms, physical functioning, or health-related quality of life.

• In controlled clinical trials of ESAs in patients with cancer,

IMPORTANT SAFETY INFORMATION

Increased mortality and/or increased risk of tumor progression or recurrence in patients with cancer: The safety and efficacy of OMONTYS have not been established for use in patients with anemia due to cancer chemotherapy. OMONTYS is not indicated in patients with cancer receiving chemotherapy.

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. If typical causes of lack or loss of hemoglobin response are excluded, evaluate for antibodies to peginesatide.

Dialysis management: 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%.

WARNING: ESA As INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMB BOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR T PROGRESSION OR RECURRENCE. Chronic Kidneyy Disease: • In controlledd trials, patients experienced greater risks for death, se erious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAss) to target a hemoglobin level of greater than 11 g/dL. • No trial has iddentified a hemoglobin target level, ESA dose, or dosing stra ategy that does not increase these risks.

• Use the loweest OMONTYS dose sufficient to reduce the need for red blood cell (RBC) transfusions.

Contraindications OMONTYS is contraindicated in patients with uncontrolled hype ertension.

Warnings and Precautions Increased mortalitty, myocardial infarction, stroke, and thromboemboolism: • Using ESAs to target t a hemoglobin level of greater than 11 g/dL increases the riisk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Use caution in patie ents with coexistent cardiovascular disease and stroke. Patientss 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 hemog globin rise of >1 g/dL over 2 weeks may contribute to th hese risks

•

•

increased risk for death and serious adverse cardiovascular reactions was observed. These adverse reactions included myocardial infarction and stroke In controlled clinical trials of ESAs, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and deep venous thrombosis (DVT) in patients undergoing orthopedic procedures In 2 trials of OMONTYS, patients with CKD not on dialysis experienced increased specific cardiovascular events

Adverse reactions The most common adverse reactions in clinical studies in patients with CKD on dialysis treated with OMONTYS were dyspnea, diarrhea, nausea, cough, and arteriovenous fistula site complication.

Please see accompanying Brief Summary.

Reference: Schiller B, Doss S, De Cock E, Del Aguila MA, Nissenson AR. Costs of managing anemia with erythropoiesis-stimulating agents during hemodialysis: a time and motion study. Hemodial Int.t 2008;12(4):441-449.

03-12-00191-A.; DSG-00261. © 2012 Affymax, Inc. and Takeda Pharmaceuticals America, Inc. All rights reserved. Affymax, the Affymax logo, OMONTYS, and the OMONTYS logo are trademarks of Affymax, Inc. and/or its subsidiaries. Takeda and the Takeda logo are trademarks of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc.

9/24/12 3:23 PM

patients identified by the electronic alerting system. The group consisted of 86 inpatients, seven hospital outpatients, and seven community general continued on page 22

22 Renal & Urology News

■ Kidney Week 2012

DECEMBER 2012

www.renalandurologynews.com

Reports from the American Society of Nephrology’s Kidney Week 2012 conference, San Diego

continued from page 21

practitioner patients. The mean rise in serum creatinine was 1.27 mg/dL (130%). The median time from baseline to creatinine alert was 20 days.

The program was easy to establish and implement, Dr. Stern said. It facilitated early identification of patients with an unmet clinical need. Postoperative AKI was identified and man-

aged early and clinicians were able to identify a number of unexpected AKI cases among samples sent by community general practitioners.The system already has been extended to

five hospitals in North London. “It takes just five minutes to set up and we hope it is changing the way people think about AKI in our region,” Dr. Stern said. ■

Table 2 Adverse Cardiovascular Outcomes in Randomized Controlled Trials Comparing Higher and Lower Hemoglobin Targets in Patients with CKD ®

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]. s • Use the lowest OMONTYS dose sufficient to reduce the need for red s 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)).

3744_takpeg_fa1_run_2pg.indd 3

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; Higher vs. Lower 14.0 vs. 10.0 13.5 vs. 11.3 (g/dL) Median (Q1, Q3) 12.6 (11.6, 13.3) 13.0 (12.2, 13.4) Achieved Hemoglobin vs. vs.

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, MI, myocardial All-cause mortality MI, hospitalization or non-fatal MI ischemia, heart for CHF, or stroke failure, and stroke

Hazard Ratio or Relative Risk 1.28 (1.06 – 1.56) 1.34 (1.03 – 1.74) 1.05 (0.94 – 1.17) (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 Kidneyy Disease Not on Dialysis y 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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DECEMBER 2012

Renal & Urology News 23

Predictors of Post-RC Bladder Cancer Recurrence PATIENTS WHO have undergone radical cystectomy (RC) for muscle-invasive bladder cancer are at increased risk of local disease recurrence if their tumor was in an advanced pathologic stage or they had lymph node invasion.

Yann Neuzillet, MD, and colleagues at Hôpital Foch in Suresnes, France,

studied 903 patients treated with RC for muscle-invasive bladder cancer. Of these, 53 patients (5.9%) experienced local bladder cancer recurrence during follow-up, according to an online report in the World Journal of Urology. For all patients, clinicians diagnosed local recurrence using computed tomogra-

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 Kidneyy 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%

phy (CT). Only four patients presented with isolated pelvic pain. The mean interval from RC to local recurrence was 14.4 months.

In addition 50% of cases developed in the year following RC and 98% developed within five years. The overall median survival was nine months, with

binding antibodies in patients dosed subcutaneously (1.9%) as compared to those dosed intravenously (0.7%). Peginesatide neutralizing antibodies were detected in vitroo 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 vitroo protein binding studies in rat, monkey and human sera. In vitro o 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

46 of the 53 patients dying from bladder cancer. Thirty-one patients had a subsequent diagnosis of distant metastasis, 20 of them within the following six months. After multivariable analysis, only pathologic stage and lymph node invasion remained associated with local recurrence.

The presence of squamous cell carcinoma (which was found in six patients) at pathologic examination was associated with a poorer prognosis following local recurrence compared with pure urothelial carcinoma.

The researchers recommend the use of routine CT scans at regular intervals during postoperative follow-up. CT scans are probably useful in cases of symptoms suggesting local recurrence, mainly pain, they stated. ■

Renal Disease Complications Tied to BMI INCREASING BODY MASS index (BMI) and waist circumference are associated with elevated risks of secondary hyperparathyroidism and other complications in patients with chronic kidney disease (CKD), researchers reported in the American Journal of Nephrology (2012;36: 219-227).

In a study of 2,853 adult participants with CKD in the National Health and Nutrition Examination Surveys (1999-2006), Sankar D. Navaneethan, MD, MPH, of Cleveland Clinic, and colleagues found that a two-point increment in BMI and a 5 cm increment in waist circumference were associated with increased odds of secondary hyperparathyroidism, hypoalbuminemia, and hypertension.

Compared with subjects who had a BMI below 30 kg/m2, those with

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.

a higher BMI had increased odds of hypoalbuminemia and hypertension.

Individuals with a high waist circumference (greater than 102 cm for men

©2012 Takeda Pharmaceuticals America, Inc.

and greater than 88 cm for women)

March 2012 PEG096 R1

had higher odds of hypoalbuminemia

L-DSG-0312-4

and hypertension and lower odds of having anemia than those with a low waist circumference. ■

3744_takpeg_fa1_run_2pg.indd 4

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24 Renal & Urology News

DECEMBER 2012

www.renalandurologynews.com

Renal Nutrition Update T

estosterone deficiency is common in many patients with chronic kidney disease (CKD), but the treatment of this deficiency and associated side effects have not always received much attention. The prevalence of CKD patients with low testosterone is estimated at 50%-70%.

Testosterone has effects on hemoglobin levels as well as lean body mass accrual.

Several recent studies have elucidated more connections between testosterone and pertinent clinical parameters.

Using data from the Study of Health in Pomerania (SHIP), German investigators reviewed the overall associations between testosterone level in CKD patients and mortality risk (Am J Nephrol 2011;33:209-217). The total cohort included 1,822 men with a median age of 51 years and median estimated glomerular filtration rate (eGFR) of 83.2 mL/min/1.73 m2. Of the entire cohort, 6.4%, 19.1%, and 22.8% had kidney dysfunction, albuminuria, and CKD, respectively. Testosterone levels were significantly lower in groups with kidney dysfunction, albuminuria, and CKD. After multivariate adjustment, these three groups also exhibited sig-

increased risk, respectively. Additionally, kidney dysfunction was associated with a 2.0 and 4.3 times increased risk for cardiovascular mortality in the entire cohort and the 29-69 age group.

Excluding first-year deaths, significant associations were still seen in all-cause mortality in the albuminuria and CKD groups, whereas only cardiovascular mortality was significantly associated with kidney dysfunction. Patients with kidney dysfunction, albuminuria, or CKD had shorter survival when they also had low total testosterone. In subjects with low total testosterone, kidney dysfunction was associated with a 2.5 times increased risk of all-cause mortality in the entire cohort and a 17 times increased risk in the 29-69 age group.

Another group of investigators aimed to find associations between anemia, resistance to erythropoiesis-stimulating agents (ESAs), and testosterone levels (Nephrol Dial Transplant 2012;27:709715). The study enrolled 239 patients with a median eGFR of 48 and median age of 53. Twenty-three percent of the cohort had anemia, and these patients were significantly more likely to have a reduced eGFR and testosterone level,

Testosterone deficiency in common in CKD patients, but exercise can help dramatically improve testosterone levels. nificantly shorter survival time. Kidney dysfunction, albuminuria, and CKD were associated with a 40%, 38%, and 42% increased risk of all-cause mortality, respectively. These associations were much stronger in patients aged 29-69, in whom kidney dysfunction was associated with a twofold increased risk of all-cause mortality, and albuminuria and CKD were associated with a 62% and 66%

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have an elevated C-reactive protein (CRP) and parathyroid hormone (PTH) levels, and diabetes. In multivariate analysis controlling for age, body mass index (BMI), diabetes status, cardiovascular disease, albumin, PTH, CRP, and eGFR, the researchers found a significant association between hemoglobin and testosterone. Anemia was five times more likely to be found in

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Low testosterone increases the risk of mortality and reduced response to erythropoiesis-stimulating agents BY GRISSIM CLARK CONNERY, MS, RD, LD

Men with CKD may be able to boost testosterone levels by exercising.

testosterone-deficient patients. Of the patients taking ESAs, testosterone was negatively associated with ESA dosage in multivariate analysis. This relationship, however, did not remain significant when adjusting for hypochromic red blood cells. Of note, ESA dose was also significantly associated with BMI, but the multivariate model testing for associations between testosterone and ESA dose did not control for BMI. These studies illustrate connections between testosterone levels and several important parameters when treating CKD populations. From a nutritional standpoint, testosterone is typically not a direct factor that can be altered, but other lifestyle modifications such as exercise can help dramatically improve testosterone levels. This factor is of interest to dietitians because improving hormonal profiles can promote more appropriate metabolism of nutrients. Exercise increases the body’s ability to metabolize protein efficiently. This can benefit individuals with a protein-restricted diet.

Studies have shown that exercise is a powerful contributor in stimulating anabolic hormones, muscle mass, and

strength gains beyond that of pharmaceutical hormonal injections of anabolic agents alone, and this has been demonstrated in a cohort of CKD patients (J Am Soc Nephrol 2006;17:2307-2314).

Previous studies have also demonstrated that exercise programs in combination with low-protein diets in non-dialysis CKD patients are associated with more profound improvements in muscle mass, strength, physical function, nutritional status, and CRP and interleukin-6 levels when compared with low-protein diets alone. This is noteworthy because many clinicians still avoid protein restrictions for fear of inducing protein-energy wasting.

The addition of exercise to improve the efficacy of low-protein diets may offer a more comprehensive lifestyle modification option for CKD patients. At this time, exercise interventions in CKD populations typically improve many of the more classic outcome measures. Because dietitians are necessary in promoting more lifestyle modifications in patients, they may need to become more proactive when convincing CKD patients, especially those aged 29-69, to engage in regular exercise programs. ■

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

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DECEMBER 2012

Renal & Urology News 25

Bladder CA Linked to Diabetes Drug A recent meta-analysis reveals that pioglitazone increases the risk of bladder cancer by 22%

BY ROSEMARY FREI, MSc Researchers have confirmed a link between thiazolidinediones, particularly pioglitazone, and an elevated risk of bladder cancer in adults with type 2 diabetes. Consequently, pioglitazone should be avoided in selected highrisk patients.

Investigators led by Jeffrey A. Johnson, PhD, Professor of Public Health at the University of Alberta in Edmonton, conducted a meta-analysis to determine the risk of bladder cancer among adults with type 2 diabetes taking this class of diabetes drugs. They found a 22% higher risk of bladder cancer associated with pioglitazone in three cohort studies involving 1.7 million patients. The one large randomized, controlled trial, called PROactive (PROspective pioglitAzone Clinical Trial in macroVascular Events), suggests a substantial (236%) increased risk of bladder cancer with pioglitazone, but the low numbers of outcomes produced wide confidence intervals, which were not statistically signifi-

CRP Predicts Response To Sunitinib C-REACTIVE PROTEIN (CRP) is a significant prognostic indicator in patients with advanced renal cell carcinoma (RCC) treated with sunitinib, according to Japanese researchers.

Tetsuo Fujita, MD, and colleagues at Kitasato University School of Medicine, Sagamihara, Kanagawa, studied 41 patients with advanced clear-cell RCC

cant. Rosiglitazone was not associated with a greater risk of bladder cancer in th available studies. Dr. Johnson’s team published their findings in the Canadian Medical Association Journal (2012;184:E685-E683).

The team concluded that, despite the increased risk, pioglitazone does not have to be avoided in all patients, contrary to the sentiment among regulatory officials in France, who removed the drug from that country’s pharmacy shelves in March 2011 in light of evidence suggesting the medication significantly increases bladder cancer incidence.

Instead, the investigators concur with the warnings issued by the FDA in August 2011 not to use pioglitazone in patients with active bladder cancer and to use caution when prescribing it to those with a prior history of bladder cancer.

“The move to remove pioglitazone in France is probably an over-reaction, given that the risk is only apparent in half the population—men,” Dr.

Johnson said. “There are many risks associated with glitazones, which must be balanced with any known benefits. I think that given the considerable attention that has been raised regarding these drugs, the clinical community,

Pioglitazone only needs to be avoided in selected patients, researchers say. when aware of the risks, will use the drugs appropriately.”

The team combed the available published and unpublished literature to arrive at a set of five cohort studies, one case-control study, and four randomized controlled trials of thiazolidinediones.

They assessed the overall risk of bladder cancer with each member of this class of drugs and with the entire class collectively, taking into account the overall risk of bias in each study.

Five of the studies involving pioglitazone showed an elevated or significantly increased risk of bladder cancer with having ever taken the medication.

There was a strong trend toward a significantly increased risk of bladder cancer in the single randomized controlled trial. When the investigators pooled the results of the three cohort studies, which involved a total of 1,739,087 patients, they found a 22% increased risk of bladder cancer associated with the use of pioglitazone.

The researchers observed no association between rosiglitazone and bladder cancer in the one cohort study and two randomized controlled trials that reported rates of bladder cancer among rosiglitazone users.

Overall, in four randomized controlled trials involving the use of any thiazolidinedione, the study demonstrated an elevated risk of bladder cancer but it was not statistically significant. However, the risk was significantly elevated, by 15%, in the five cohort studies. ■

Early BP Control Benefits Diabetics PATIENTS WITH diabetes who fail to control their blood pressure (BP) within the first year of hypertension onset are at increased risk of major cardiovascular events, according to researchers.

Study findings suggest that insufficient attention has been devoted to the aggressive early management of BP in diabetic patients, the researchers said.

Patrick J. O’Connor, MD, MPH, of HealthPartners Research Foundation in Minneapolis, Minn., and colleagues

studied 15,665 adult patients with diabetes and new-onset hypertension. The study population had a mean age of 51.5 years and mean BP of 136.8/80.8 mm Hg at hypertension onset. At baseline, none of the patients had a diagnosis of coronary or cerebrovascular disease.

After a mean 38-month follow-up period, subjects whose BP average was at or above 140/90 in the first year of hypertension onset had a significant 30% increased risk of major cardiovascular events (myocardial infarction [MI] or stroke) compared with

patients whose BP was below 140/90, the investigators reported online in Diabetes Care.

The increased risk was due mostly to the increased rate of MI. Patients with average BP at or above 140/90 had a significant 41% increased risk of MI and a non-significant 25% increased risk of stroke.

The study found similar reductions in cardiovascular event risk among patients controlling their BP to below 130/80 compared with 130/80 or higher. ■

treated with sunitinib. Of these, 11 (26.8%) showed a partial response to treatment and 10 (24.4%) had stable disease, according to an online report in the International Journal of Urology.

Patients with normal CRP levels (30 mg/dL or less) had a significantly higher rate of partial response and stable disease (84.6% vs. 35.7%) and significantly longer progression-free survival (median 19 vs. 6 months) than patients with elevated CRP levels. ■

RAPN Found Safe for Larger Renal Tumors ROBOT-ASSISTED partial nephrectomy (RAPN) is a possible alternative to open nephrectomy for treating patients with renal tumors larger than 4 cm, researchers say.

In a study of 49 patients who underwent RAPN for tumors of this size, the rate of positive surgical margins was not significantly different from that of

a comparison group of patients who underwent RAPN for tumors 4 cm or smaller, demonstrating that RAPN is an oncologically safe procedure for tumors larger than 4 cm, according to an online report in the World Journal of Urology.

The researchers, led by Vincenzo Ficarra, MD, of the Onze Lieve

Vrouw Clinic Aalst in Aalst, Belgium, found that the patients with the larger tumors had worse perioperative outcomes than the group with smaller tumors.

Of the 49 patients, 13 (26.5%) had postoperative complications; major complications occurred in four (8.2%), according to the researchers. ■

26 Renal & Urology News

DECEMBER 2012

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Practice Management “A

significant portion of no-show patients are habitually irresponsible people,” said Keith Borglum, a consultant with Professional Management and Marketing out of Santa Rosa, Calif.

No one is perfect. Everyone forgets a scheduled meeting now and again. But if you take a moment to look at your practice and analyze who is missing appointments, it’s likely a handful of repeat offenders.

So, what do you do about these people who are wasting the practice’s time and money? More and more, physicians are choosing to implement no-show fees.

Here’s what you should know before you implement this kind of policy.

The rationale for using fees Cancellation fees are not meant to fully recoup the missed appointment. Their goal is to change patients’ habits.

“The purpose is to have patients recognize that this time is reserved for them and there is an expense whether they show up or not,” said Deb Hill, manager at the Atlanta-based healthcare consulting firm, the Coker Group. “I think once you’ve implemented a policy like that, patients become more educated.”

Gray Tuttle, principal at Rehmann’s Healthcare Management Advisors in Lansing, Mich., said cancellation fees are justifiable. Not only is there a clear economic loss with a missed appointment, but it is a risk management issue when patients don’t review medications or get test results.

“If patients have skin in the game, they will develop better habits in the future,” he said.

There are a couple of things you might want to do before deciding whether to use cancellation fees. First, make sure your office is doing what it can to reduce the number of no-shows. There may be

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something going on internally that could be a contributing factor.

The Medical Group Management Association created a blog with 30 ways to reduce no-shows, including having staff place reminder calls before visits and providing discounts to patients who keep their appointments.

“A patient scheduled for anything other than a routine follow-up the next day gets a reminder phone call,” Borglum said.

There are several additional factors that need to be considered: • Are you sending reminder cards—especially for visits that were scheduled far in advance?

• Do physicians reschedule frequently?

• Do patients have to wait for an hour in the waiting room for visits?

“Make sure there isn’t some underlying cause,” Hill said. “If you have a large increase in no-shows, you need to get to the bottom of what is going on.”

Borglum said his preference is that offices don’t use no-show fees, but Hill has mixed feelings about them. She noted that you have to consider things like your payer mix: if the pay is predominantly Medicaid, you aren’t going to collect. Additionally, remember that most patients won’t like the fee policy. Even if they know about the charge upfront, it may alienate them.

Alternative options If you don’t want to use no-show fees, you might opt for making patients pay in advance. Particularly when visits take up a large block of time, you could have a patient remit his co-pay in advance, and then put it toward the cost of the claim.

If you want to implement a no-show policy (or you have one in place, but want to begin enforcing it) the most important thing to remember is communication.

© THINKSTOCK

Several healthcare management consultants weigh in on what you need to know about incorporating cancellation fees. BY TAMMY WORTH

Before deciding whether or not to use cancellation fees, make sure your office is doing everything it can to reduce the number of no-shows.

First, make sure patients know why you are doing it. If you are changing or implementing the practice, Ms. Hill said, you will want to send out a letter explaining the reason. She recommends telling patients that practice costs and no-shows are increasing. Explain why it is important to keep an appointment and how detrimental it is to the practice when patients don’t show.

Put your policy in writing Borglum recommends carefully articulating cancellation fees in a written policy.

Put the cancellation charge in the practice’s printed financial policy that outlines insurance details, patient payment plans. Outline how the practice deals with missed appointments. Have each patient sign and date this document. Then renew it annually or if something changes.

If someone misses an appointment, place a follow-up call and ask them why they didn’t show. Tell them about the cancellation fee and explain that it will be incorporated in the next billing cycle. You should have the policy clearly displayed

at the check-in desk and listed on your brochures, appointment cards, and billing statements.

Tuttle said a physician’s time for a typical office visit is worth about $60 to $70.

Therefore, if you are going to charge a fee, Borglum adds that it should be “significant” so patients understand their habits need to change.

Borglum recommends calling a patient on the first absence, writing a letter and charging for the second, and a dismissal from the practice after a third missed appointment.

Just remember, there is no way to tell how successful no-show fees are and you may have difficulty collecting the fees.

You also may alienate some patients from your practice.

“But we believe you can manage these issues if the cancellation fees are carefully crafted, designed, and properly communicated to your patients,” Tuttle said. ■ Tammy Worth is a freelance medical journalist based out of Blue Springs, MO.

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

28 Renal & Urology News

DECEMBER 2012

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Pre-Eclampsia Linked to Air Pollution Modest increment in traffic-related air pollution hikes third-trimester risk by 30%, study shows

Diabetes increases the risk The increased risk was more pronounced in women with pre-existing or gestational diabetes, in whom each IQR

Penile Implant Salvage Using Saline Lavage

BY JODY A. CHARNOW CHICAGO— Salvage replacement of infected penile prostheses with normal saline lavage is safe and effective in maintaining sexual function and preventing recurrence of infection, a researcher reported at the World Meeting on Sexual Medicine.

Researchers at New York Presbyterian Hospital/Weill Cornell Medical College in New York led by J. Francois Eid, MD, investigated the use of normal saline washout of the implant space during revision surgery for infected penile prostheses, followed by immediate prosthesis replacement.

From 2002 to 2011, 2,515 patients underwent insertion of a three-piece inflatable penile prosthesis. Of these patients, 27 (1.1%) presented with a prosthesis infection, and 18 underwent salvage surgery with placement of a semi-rigid implant, according to investigator Puneet Masson, MD, who presented study findings. These patients underwent a standard 10-minute skin preparation with povidone-iodine scrub followed by an alcohol solution.

increase during the third trimester was associated with a greater than threefold increased risk in pre-eclampsia risk, in adjusted analyses. For the entire pregnancy, each IQR increase was associated with a 53% increased risk.

Aboriginal women and women aged 20 or younger and 40 or older also had higher risks than the overall study population. Each IQR increase during the whole pregnancy was associated with a 35% and 34% increased risk in pre-eclampsia among the aboriginal women and those in the aforementioned age groups, respectively.

The researchers, led by Gavin Pereira, PhD, of the University of Western Australia in Perth, noted that the “biological mechanisms by which traffic-related air pollution may relate to pre-eclampsia are not yet well understood, partially because the condition is a multisystem disorder of unknown etiology. However, it is known that particulate matter air pollution is capable

They were given standard preoperative antibiotics for prosthesis surgery.

In all cases, the prosthesis, including the cylinders, scrotal pump, and reservoir, were removed. Intra-operative wound culturing, including specific culturing of the prosthesis components, was performed.

The corpora, scrotal cavity, and reservoir pockets were then copiously irrigated with 10 to 12 liters of normal saline using a Simpulse irrigator. Gloves were changed frequently. All implants were replaced with a semi-rigid implant; four penrose drains were placed. All patients were admitted for intravenous antibiotics until drains were removed, and then discharged with four to six weeks of culture-specific antibiotics. The median follow up was 12 months. No patient required reoperation for infection. All patients reported use of their replacement implant. No patient had any further complications. The researchers waited at least three months after the salvage operation before removing and replacing the semi-rigid implant.

Six (33%) patients with semi-rigid reimplants went on to have replacements with inflatable prostheses.

“These data suggest that aggressive washout rather than specificity of irrigant, along with meticulous sterile technique, may contribute to a low post-salvage infection and reoperation rate,” Dr. Masson told meeting attendees. ■

endothelial dysfunction, a precursor associated with pre-eclampsia.

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BY JODY A. CHARNOW TRAFFIC-RELATED air pollution may increase the likelihood of pre-eclampsia in pregnant women, especially in the third trimester, new findings suggest.

In Perth, Western Australia, researchers estimated residential exposure to nitrogen dioxide—a marker for traffic-related air pollution—during pregnancy among 23,452 women. Each interquartile range (IQR) increase in nitrogen dioxide during the third trimester was associated with a 30% increase in the risk of pre-eclampsia, after adjusting for other risk factors. In addition, each IQR increase during the whole pregnancy was associated with a 12% increased risk, investigators reported in the Journal of Epidemiology and Community Health (2012; published online ahead of print).

of augmenting the development and progression of atherosclerosis and may potentially contribute to hypertension.” Dr. Pereira’s team also cited research suggesting that pre-eclampsia and vascular atherosclerosis may share common pathways in relation to pollutants, and traffic-related air pollution has been directly correlated with

Pollution’s role Dr. Pereira is unable to explain why exposure to air pollution seems more relevant in late pregnancy, but noted that this is the trimester when most cases of pre-eclampsia develop. He interprets his findings to suggest that traffic-related air pollution precipitates or promotes pre-eclampsia rather than initiates it. Pre-eclampsia develops in some women independently of pollution levels and it does not develop in other women regardless of pollution levels. For some women, “air pollution could be the last straw,” he noted.

For the study, the investigators measured nitrogen dioxide levels at 22 sites across a study area of 238 km2. They selected sites to ensure representation of subregions and high, moderate, and low traffic roads. The air samplers were placed near traffic counters operated by local governments and the state. ■

High-Dose Brachytherapy Okay Despite Prior TURP HIGH-DOSE-RATE (HDR) brachytherapy

2.3 months for the HDR brachytherapy

may be a suitable option for men with

and EBRT-only groups, respectively.

localized prostate cancer who previously

After an average follow-up period of

have undergone transurethral resection

60 months, the researchers, led by

of the prostate (TURP).

Fumin Fang, MD, Director of the Depart-

Used in combination with a reduced

ment of Radiology, observed grade 3

dose of external beam radiotherapy

GU complications in 8.8% of the HDR

(EBRT), it can achieve the same onco-

brachytherapy group compared with

logic outcomes as a conventional dose

44% of the EBRT-only group, accord-

of EBRT but with a significantly lower

ing to an online report in International

incidence of major post-radiation genito-

Urology and Nephrology. The five-year

urinary (GU) complications

urinary incontinence rates were 2.9%

Investigators at Chang Gung Memo-

and 24%, respectively. The differences

rial Hospital-Kaohsiung Medical Center

between the groups were significant. In

enrolled 59 men who had a history of

multivariate analyses, patients who re-

TURP and underwent radiation therapy

ceived EBRT alone had a nearly 10-fold

for localized prostate cancer. Of these,

increased risk of grade 3 GU toxicities

34 underwent HDR brachytherapy in

compared with patients in the HDR

combination with EBRT and 25 under-

brachytherapy group. The study found

went EBRT alone. Two to three weeks

no significant difference in biochemical

after seed implantation, men in the HDR

relapse-free survival (82.4% vs. 72%).

brachytherapy group received an EBRT

Dr. Fang’s team noted that TURP has

dose of 45-57.6 Gy. The EBRT-only

been considered a contraindication for

group received a dose of 63.2-75.6 Gy.

EBRT because of the high risk of geni-

The average interval from TURP to radiation treatment was 2.7 months and

tourinary complications associated with this modality. ■

www.renalandurologynews.com

On the Forefront

DECEMBER 2012

Renal & Urology News 29

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

A Way to Reduce Discard Rates of Kidneys with Capsular Damage

BY CHARLES S. MODLIN, JR, MD, MBA, ISLAM GHONEIM, MD, AND STUART FLECHNER, MD Introduction More than 100,000 patients are on the kidney transplant waiting list and the increasing number of patients without living donor options underscores why it is importance to decrease the discard rate of deceased donor kidneys available for transplantation.1 In the March/ April 2012 issue of the Journal of the National Medical Association, kidney transplant surgeons and urologists at Cleveland Clinic described surgical techniques to reduce discard rates of kidneys from renal allografts with significant capsular defects resulting from procurement.2 CASE 1: Vicryl Mesh Repair A 49-year-old male Jehovah’s Witness who refused blood transfusions was admitted to receive a renal allograft imported to Cleveland Clinic from a transplant program in a neighboring state. The program refused to use the allograft due to multiple arteries.

Upon inspection of the allograft it was also noted that two-thirds of the renal

kidney was then successfully transplanted with no postoperative bleeding (Figure 2). More than two years later, the graft continues to function well.

CASE 2: Dexon Mesh Repair A 63-year old African-American female waiting five years for a deceased donor kidney transplant was transplanted with a kidney from a 54-year-old deceased donor. During bench preparation, a large separation of thin renal capsule on the posterior surface was noted.

Upon revascularization, persistent bleeding occurred from the shredded capsule, exposing large areas of renal parenchyma.

Several attempts to control the bleeding with electrocautery, argon beam laser, and direct pressure were unsuccessful. As a rescue attempt to salvage the allograft, the posterior renal surface was covered with Floseal (Baxter, Deerfield, Ill.) and a 6 cm sheet of Fibrillar (Ethicon, Sommerville, N.J.).

The entire kidney was wrapped with a sheet of Dexon (polyglycolic acid) Mesh (Covidien, Mansfield, Mass.), which was sutured closed at the level of the renal hilum with several 3-0 Vicryl sutures.

Significant capsular injury of renal allografts most often occurs during procurement of the deceased donor or living donor allograft. surface was devoid of capsule. The kidney capsule was repaired at Cleveland Clinic by covering the surface of the denuded renal allograft with Vicryl mesh, which acted as a capsule replacement (Figure 1). The Vicryl mesh was trimmed to match the size of the defect and the edges sutured to the capsule with 3-0 chromic catgut. Evicel, a fibrin sealant, was applied over the mesh to provide further reinforcement. The

On The Web

DISCUSSION Capsular injury Significant capsular injury of renal allografts most often occurs during procurement of the deceased donor or living donor allograft. 3-4 Capsular disruption, when significant, may lead to non-acceptance and discard of the allograft by the transplant surgeon given the potential risk of major intraoperative and/or postoperative hemor-

Figure 1 (top) shows bench allograft renal capsular reconstruction with Vicryl mesh, and Figure 2 (bottom) shows post-renal-allograft perfusion demonstrating a hemostatic repaired renal capsule.

rhage. Reinforcing the denuded capsule with Vicryl mesh with or without Evicel Fibrin sealant is a technique that can be used by the transplant surgeon to salvage the renal allograft and ultimately increase the available pool of kidney allografts for transplantation. ■ The authors are urologic surgeons at Cleveland Clinic’s Glickman Urological & Kidney Institute. Dr. Modlin is Associate Professor of Surgery and Dr. Flechner is Professor of Surgery at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve

University. Dr. Flechner also is Director of Clinical Research in the Section of Renal Transplantation.

REFERENCES 1. The 2008 annual report of the OPTN/SRTR: Kidney and Pancreas Transplantation. http://www.ustransplant.org 2. Sezhian N, Modlin CS Jr, Ghoneim I, et al.

Renal allograft capsular repair surgical technique to reduce allograft discard rates of kidneys with capsular injury. J Natl Med Assoc 2012;104:199-201.

3. Hammer C, Hawasli A, Mequid A, Oh H. Degloving of renal capsule: a rare complication of laparoscopic live donor nephrectomy. J Laparoendosc Adv Surg Tech A 2006;16:362-364.

4. Mohamed HK, Lin A, Savage SJ, et al. Parenchymal transection of the kidney inflicted by endocatch bag entrapment during a laparoscopic donor nephrectomy. Am J Transplant 2006;6:232-235.

See more of what your colleagues are doing to create cutting-edge models of patient care at www.renalandurologynews.com/forefront.

DECEMBER 2012

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© PRI / AJPHOTO / HOP AMÉRICAIN / SCIENCE SOURCE

Malpractice News

Kansas Supreme Court Upholds Medical Malpractice Award Cap The war on medical malpractice caps rages on. While several state Supreme Courts, most recently Missouri, have struck down laws that limited noneconomic damages (pain and suffering), a majority of the Kansas Supreme Court has just ruled that the law is not unconstitutional and can stand.

The case that tested this issue involved a 28-year-old patient who was having surgery to remove an ovary. The surgeon mistakenly removed the wrong ovary.

The patient then had to have a second surgery (with a different surgeon) to remove the diseased ovary, and further medical care. The original surgeon was found at fault at trial, and the patient was awarded a total of $759,679 in damages, including $575,000 for current and future noneconomic losses, plus $100,000 for future medical bills.

The judgment was then reduced to $334, 679 by the trial judge due to the state law capping non-economic damages at $250,000.

In its decision, the Kansas Supreme Court held that the law, which was enacted in 1988, is still an adequate remedy despite the fact that the sum of money is not worth as much as it

On The Web

had been close to a quarter of a century earlier. In its opinion, the court held that although the cap does restrict the common law right to compensation for damages, the legislature “has substituted an adequate statutory remedy for the modification of the individual rights at issue.”

The majority opinion in the case held that the legislature had a valid reason to enact the law. “We hold that it is “reasonably conceivable” … that imposing a limit on noneconomic damages furthers the objective of reducing and stabilizing insurance premiums by providing predictability and eliminating the possibility of large noneconomic damages awards,” the majority wrote.

Two justices disagreed, and in strongly worded dissenting opinions expressed their views that that the cap on damages meant that injured patients were getting inadequate compensation for their injuries, and were being deprived of having a jury decide the amount of their compensation.

Increased Medical Errors Linked to Chronic Conditions in Kids According to a recent study published in Pediatrics, children with chronic medical conditions are more likely to be affected by medical errors while hospitalized.

The study examined a government database of children hospitalized in 38 different states in 2006. A total of 44% of the children had at least one chronic condition such as asthma, diabetes, or cancer. The overall medical error rate was 3%. The rate was 1.3% in patients with no chronic conditions, but jumped to 5.3% in children with a chronic condition. Even when the statistics were adjusted for patient characteristics, hospital characteristics, disease severity, and length of stay, the association between chronic conditions and medical errors remained statistically significant. In addition, the likelihood of a medical error occurring increased

BY ANN W. LATNER, JD

with the number of chronic conditions from which the patient suffered.

Researchers speculated that the reason for this increase may be that children with more health issues stay in the hospital longer or require more complicated treatments. The errors were not necessarily mistakes per se, the researchers noted, but also included things like adverse reactions to medications, infections following surgery, and even bedsores.

While the study did not look at possible solutions for the problem, the researchers noted that the Agency for Healthcare Research and Quality has been funding projects to improve hospital safety and reduce common complications such as infections.

One of the researchers, Huiyun Xiang, MD, of Nationwide Children’s Hospital in Columbus, Ohio, warned parents to keep the study results in context, and noted that even the 5.3% rate of errors among children with chronic conditions was still relatively low.

nurses, and the nursing team’s commitment to safety. Survey participants were asked to agree or disagree with certain statements. Statements such as “my head nurse always practices the safety protocols he/she preaches” were designed to examine the head nurses’ behavioral integrity. Statements such as “if you make a mistake on this team, it is often held against you,” were designed to examine the psychological safety felt by staff nurses.

When nurse supervisors had spoken expectations that matched their commitment to safety, their teams had a stronger commitment to acting safely

Supervisor Support Encourages Nurses to Admit Errors Nurses are more likely to report errors when they feel safe with their supervisors, leading to a stronger commitment to safer practices and a lower error rate, according to a recent study published in the Journal of Applied Psychology.

The study looked at the relationship between what nurse supervisors say and what they do, and how that affects their staff. Researchers examined the potential conflict between enforcing strict safety protocols and the need to admit to errors. The study looked at whether the leadership actions of head nurses were aligned with the verbal expectations conveyed to their staff nurses. The investigators looked at 54 nursing teams (a head nurse and at least three staff nurses) in four hospitals in Belgium. They administered surveys to examine the behavioral integrity of head nurses, the psychological safety felt by staff

© THINKSTOCK

30 Renal & Urology News

in practice as well as a greater rate of reporting medical errors that did happen. The study authors noted that the results demonstrate “the importance of leadership in promoting a work environment in which employees feel it is safe to reveal performance errors … This benefits patients because work environments in which error is identified offer employees the opportunity to learn from those errors and, ultimately, prevent similar errors from occurring.” ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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

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DECEMBER 2012

Renal & Urology News 31

Anogenital Distance Predicts Prostate Cancer Risk A MANâ&#x20AC;&#x2122;S anogenital distance may provide a clue to his risk for prostate cancer (PCa), according to researchers.

In a study of 60 PCa patients and 52 urological controls, the distance from anus to upper penis was approximately 5 mm shorter in patients than controls, investigators reported online in BJU International. Each 5 mm increment in that distance was associated with a significant 17% decreased risk of PCa in adjusted analyses.

The study, led by Gemma CastanoVinyals, MD, of the Centre for Research in Environmental Epidemiology in Barcelona, Spain, is the first to correlate anogenital measurements in adults in relation to the risk of cancer.

In addition, the researchers looked at anogenital distance as measured from anus to scrotum, but this dis-

tance was not associated with PCa risk.

Androgens are critical for the development of the male reproductive system during gestation and they stimulate the growth of the perineal region in male offspring, the researchers observed.

They explained that anogenital distance â&#x20AC;&#x153;is a sexually dimorphic phe-

Longer distance from anus to upper penis associated with greater risk.

notype that tracks through life, with men having longer anogenital distances than women.â&#x20AC;? â&#x20AC;&#x153;The present study showed that a phenotype reflecting normal in utero sexual development in men is associated with a lower risk of prostate cancer,â&#x20AC;? the authors concluded. â&#x2013;

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

Daily HD Does Not Increase Access Risks DAILY HEMODIALYSIS (HD) is not associated with an increase in vascular access complications or failures, a study found.

In a four-year nonrandomized study, researchers led by Juan Carlos Ayus, MD, of Renal Consultants of Houston, prospectively followed 77 patients receiving either three-hour daily HD (six three-hour dialysis treatments per week; 26 patients) or conventional HD (three four-hour dialysis treatments per week; 51 patients). The incidence rate of total access procedures

Excessive production of urine at night is one of the leading causes of nocturia, Â&#x2122;Â&#x2039;Â&#x2013;Â&#x160; Â&#x192; Â&#x2020;Â&#x2039;Â&#x192;Â&#x2030;Â?Â&#x2018;Â&#x2022;Â&#x2039;Â&#x2022; Â&#x2026;Â&#x2018;Â?ƤÂ&#x201D;Â?Â&#x2021;Â&#x2020; Â&#x2039;Â? Â&#x2013;Â&#x160;Â&#x2021; Â?Â&#x192;Â&#x152;Â&#x2018;Â&#x201D;Â&#x2039;Â&#x2013;Â&#x203A; Â&#x2018;Â&#x2C6; Â&#x2019;Â&#x192;Â&#x2013;Â&#x2039;Â&#x2021;Â?Â&#x2013;Â&#x2022;Ǥ1-4 Â&#x2021;Â&#x192;Â&#x201D;Â? Â?Â&#x2018;Â&#x201D;Â&#x2021; Â&#x192;Â&#x201E;Â&#x2018;Â&#x2014;Â&#x2013; Â&#x2013;Â&#x160;Â&#x2021; Â&#x2026;Â&#x192;Â&#x2014;Â&#x2022;Â&#x2021;Â&#x2022; Â&#x2018;Â&#x2C6; Â?Â&#x2018;Â&#x2026;Â&#x2013;Â&#x2014;Â&#x201D;Â&#x2039;Â&#x192;ÇĄ Â&#x192;Â?Â&#x2020; Â&#x192;Â&#x2026;Â&#x2026;Â&#x2021;Â&#x2022;Â&#x2022; Â&#x2014;Â&#x2022;Â&#x2021;Â&#x2C6;Â&#x2014;Â&#x17D; Â&#x2013;Â&#x2018;Â&#x2018;Â&#x17D;Â&#x2022; Â&#x192;Â?Â&#x2020; Â&#x201D;Â&#x2021;Â&#x2022;Â&#x2018;Â&#x2014;Â&#x201D;Â&#x2026;Â&#x2021;Â&#x2022;Ǥ Visit NocturiaResources.comǤ

(fitulagram, thrombectomy, and access revision) was 543.2 per 1,000 person-years in the conventional HD group compared with 400.8 per 1,000 person-years in the daily HD group, according to an online report in Hemodialysis International, a nonsignificant difference between the groups after adjusting for age, gender, diabetes status, serum phosphorus and hemoglobin levels, and erythropoietin dose. The researchers also found no significant difference in time to first access

References: 1. Weiss JP, van Kerrebroeck PEV, Klein BM, et al. Excessive nocturnal urine production is a major contributing factor to the etiology of nocturia. J Urol. 2011;186:1358-1363. 2. Nørgaard JP, Hashim H, Malmberg L, et al. Antidiuresis therapy: mechanism of action and clinical implications.

Neurourol Urodyn. 2007;26:1008-1013. 3. van Kerrebroeck P, Hashim H, Holm-Larsen T, et al. Thinking beyond the bladder: antidiuretic treatment of nocturia. Int J Clin Pract. 2010;64:807-816. 4. Nørgaard JP, Holm-Larsen T. Impact of nocturia on the patient and consequences for the payer. Impact dossier (publications summary). 2012:1-73.

revision between the groups after adjusting for covariates. â&#x2013;

UY/374/2012/US Š2012 Ferring B.V. 11/12

32 Renal & Urology News

DECEMBER 2012

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Elderly Do Worse with ECD Kidneys Graft and patient survival are lower compared with receiving SCD organs ELDERLY RENAL transplant recipients have worse outcomes with an expanded-criteria donor (ECD) kidney than a standard-criteria donor (SCD) kidney, according to a new study. They also had worse outcomes than younger ECD kidney recipients.

“These findings may have implications in kidney allocation policy developments that encourage placement of ECD kidneys for older recipients,” the study investigators reported in the Clinical Journal of the American Society of Nephrology (2012;7:1163-1171).

Joshua D. Mezrich, MD, and colleagues at the University of Wisconsin School of Medicine in Madison reviewed data from all primary deceased-donor kidney transplantations performed from 2000 to 2005 at their center. The study population included 189 recipients aged 60 years and older (group 1) and 370 recipients aged 40-59 years (group 2).

In group 1, 96 patients received an ECD kidney and 93 received an SCD kidney.

In group 2, 105 received an ECD kidney and 265 received an SCD kidney.

In group 1, recipients of ECD kidneys had one-, three-, and five-year graft survival rates of 72%, 59%, and 54%, respectively, whereas the rates for recipients of SCD kidneys were 92%,

ECD vs. SCD in Elderly Recipients Among patients aged 60 years and older who receive deceased-donor kidneys, those who receive an expanded-criteria donor kidney have significantly reduced graft and patient survival compared with patients who receive a standard-criteria donor kidney.

Expanded criteria donor Standard criteria donor

IMRT Offers Small Benefit Over 3D-CRT MEN WITH higher-risk prostate cancer (PCa) are less likely to require salvage therapy if they receive primary treatment with intensity-modulated radiotherapy (IMRT) rather than three-dimensional conformal therapy

80 70

(3D-CRT), but the risk of complications

60

requiring intervention is similar for

50 40

both modalities, a new study found.

30 20

Researchers used the Surveil-

10

lance, Epidemiology, and End Results

0

54% 69% Graft survival

61% 76% Patient survival

(SEER)-Medicare database to identify 11,039 men who underwent IMRT and

Source: Mezrich JD, Pirsch JD, Fernandez LA, et al. Differential outcomes of expanded-criteria donor renal allografts according to recipient age. Clin J Am Soc Nephrol 2012;7:1163-1171.

6,976 who underwent 3D-CRT. Among higher-risk patients who did not

72%, and 69%, respectively. The rates for patient survival were 77%, 69%, and 61%, respectively, for ECD kidney recipients, compared with 95%, 79%, and 76% for SCD kidney recipients. The differences in graft and patient survival were statistically significant.

In group 2, recipients of ECD kidneys had one-, three-, and five-year graft survival rates of 88%, 73%, and 56%, respectively, and recipients of SCD kidneys had rates of 91%, 83%, and 70%, respectively. ECD kidney recipients had one-, three-, and five-year patient sur-

vival rates of 92%, 83%, and 77%, respectively, and SCD kidney recipients had rates of 95%, 89%, and 79%.

Among patients in group 1, receiving an ECD kidney was associated with a twofold increased risk of both graft loss and patient death compared with receiving an SCD kidney, after adjusting for multiple variables.

In addition, in group 1, recipients of ECD kidneys had a significantly higher proportion of acute rejection episodes than recipients of SCD kidneys (35% vs. 17%). ■

receive concurrent androgen deprivation therapy, 16% of those treated with IMRT went on to receive salvage therapy compared with 20% of patients who had 3D-CRT, investigators reported online in European Urology.

Among low-risk patients, the likelihood of salvage therapy and complications requiring an intervention were similar for IMRT and 3D-CRT. The authors, led by Bruce L. Jacobs, MD, of the University of Michigan Health System in Ann Arbor, concluded: “Findings related to the comparative effectiveness of the two

High-Grade PCa Linked to Greater %FT

approaches showed a modest benefit with IMRT: The need for salvage therapy was less for a subset of men

HIGHER LEVELS of percent-free testosterone (%FT) are associated with an increased risk of high-grade prostate cancer (PCa) being found on initial prostate biopsy, data show.

Simone Albisinni, MD, of Sant’ Andrea Hospital, Second School of Medicine, “La Sapienza” University, Rome, and colleagues analyzed data from 812 white Italian men who no history of PCa and who underwent 12-core prostate biopsies. They evaluated testosterone, free testosterone, and %FT as predictors of low-grade (Gleason score of 6 or less) or high-grade (Gleason score of 7 or higher) PCa. A greater %FT level significantly predicted high-grade but not low-grade PCa. Men in the highest tertile of %FT (above 0.23%) had a significant twofold increased risk of high-grade PCa compared with those in the first tertile (below 0.15%), Dr. Albisinni’s team reported in Urology (2012;80:162-168).

Testosterone and free testosterone levels were not significantly associated with low- or high-grade PCa. The reason a greater %FT level might predict high-grade disease is not known, the investigators stated. It is possible that in men with elevated %FT, “the hormonal milieu (elevated free testosterone and low total testosterone) might concurrently drive overexpression of the androgen receptor (as a consequence of low total testosterone) and its increased activation secondary to elevated free testosterone penetrating into the cell.”

In addition, testosterone can bind to extracellular membrane receptors and exert a pro-apoptotic effect. “Thus, although free testosterone stimulates the cell through the intracellular androgen receptor, low total testosterone might simultaneously result in reduction of this extracellular receptor-mediated apoptotic pathway, possibly leading to increased proliferation.”

In an accompanying editorial, Sandip M. Prasad, MD, of the University of Chicago, and co-authors said the “holy grail” in PCa is to differentiate potentially lethal tumors from those unlikely to metastasize or cause death. “A key success factor would be a simple, inexpensive, readily available laboratory test, such as %FT,” they wrote, adding that Dr. Albisinni and her colleagues “provide intriguing findings in this regard.”

The editorial noted that although an association between elevated %FT and high-grade PCa was identified, it is unknown whether the relationship is causal. They pointed out: “Complex intraprostatic biology that defines the interaction between free testosterone and the aggressiveness of PCa remains poorly understood and requires further study; importantly, the findings in this study might not be applicable in other racial and ethnic groups in which the disease biology might differ.” ■

with higher risk disease who did not receive concurrent ADT, whereas the risk of a complication was no different between the two modalities.

In this context, society must decide what price it is willing to pay for these benefits.”

The researchers cited a study (J Clin Oncol 2011;29:1517-1524) showing that IMRT costs approximately $11,000 more per patient than 3DCRT. The proportion of men receiving IMRT increased from 9% in 2001 to 93% in 2007, Dr. Jacobs’ group reported.

With regard to study limitations, Dr. Jacobs and his colleagues noted that their study cohort included only Medicare beneficiaries, so the findings may not be generalizable to younger patients. ■

www.renalandurologynews.com

DECEMBER 2012

Renal & Urology News 33

Program Cuts CMV-Related Admissions High-risk SOT recipients receive chemoprophylaxis initially and are screened frequently for infection

BY JOHN SCHIESZER SAN FRANCISCO—Danish researchers have developed a new program that could help dramatically lower rates of hospital admissions due to cytomegalovirus (CMV) infection among recipients of solid organ transplants (SOT).

“We were able to identify a number of processes which potentially could be optimized in a systematic way in order to diagnose the infection at an earlier stage, before it causes clinical disease and where it is easier to manage,” said lead investigator Caspar da CunhaBang, MD, an attending physician at the University of Copenhagen.

Dr. da Cunha-Bang described the program at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy.

CMV infection was growing concern athis institution because these infections were contributing to morbidity and mortality among SOT patients, he said. Many SOT recipients were presenting with severe CMV infection, so he and his colleagues developed the MATCH program, which involves a standardized prophylactic and monitoring schema according to an individual’s risk profile.

“The principle we have established is to use chemoprophylaxis initially for

the high-risk patients and once discontinued to consistently and frequently screen for emerging CMV infection,” Dr. da Cunha-Bang explained. “The database has direct and real-time links to the databases where medicine is prescribed and results of blood tests

Researchers identify a way to diagnose CMV infection at an earlier stage. are downloaded directly from the viral laboratories.”

If chemoprophylaxis is not prescribed and/or planned blood tests not performed according to the initial plan generated as part of the program, an alert is generated and corrective action is taken.

The researchers compared the outcomes of recipients transplanted prior to (2007-2008) with the outcomes of recipients after the program was started (2009-2010) and those who received transplants in 2011.

The investigators analyzed the incidence of CMV infection among recipi-

ents transplanted in each of the three different calendar periods. They also assessed severity of infection (mild/ moderate/severe) and rate of admission at time of diagnosis.

The study included 809 SOT recipients (48% kidney, 24% lung, 20% liver, 8% heart), including 279 in 20072008, 337 in 2009-2010, and 193 in 2011. CMV infection developed in 148 patients (18%); the incidence did not vary over time.

At diagnosis, the prevalence of moderate-to-severe CMV infection decreased from 49%in 2007-2008 to 41% in 2009-201 and 10% in 2011.

In addition, the rate of CMV-related admission decreased from 44%to 52% and 10%.

“An approach similar to the MATCH program has not previously been described in the literature, Dr. da Cunha-Bang said. “It is challenging to restructure the approach to prevent severe CMV and other infectious complications in a large transplant hospital, and our projection was that although the MATCH program would be expected to be beneficial in terms of reduced rate of severe CMV infection and be cost effective, we had not expected that these benefits would be

so marked and could be achieved so shortly after its introduction.”

The researchers concluded that the clinical prognosis of CMV infection radically improved through the systematic and rational screening for emerging infection introduced by this rather simple program. In addition, the researchers say this is a program can be implemented at any transplant unit.

“The results of our study show that implementation of this optimized approach indeed resulted in markedly lower risk of clinical disease caused by the CMV infection,” Dr. da Cunha-Bang told Renal & Urology News.

Additionally, the cost in handling this frequent infectious complication after transplantation was reduced in patients who that followed the MATCH Program relative to the cost prior to the introduction of the program. As such, these findings are clinically relevant and can be applied also by other transplant hospitals with similar problems.”

After he and his colleagues publish their findings in a peer-reviewed journal, they plan to provide other transplant units with the technical details required to use the MATCH program. ■

Tailored UTI Prevention Strategies Proposed

BY JOHN SCHIESZER SAN FRANCISCO—Prevention strategies for recurrent urinary tract infections (rUTIs) should be based on patients’ individual characteristics, and should include consideration of non-antibiotic approaches, according to researchers.

Vaginal application of estrogens can be recommended for postmenopausal women with at least three UTIs per year, according to Suzanne Geerlings, MD, of the Academic Medical Center in Amsterdam. The disappearance of vaginal lactobacilli in postmenopausal women increases the likelihood of colonization with Enterobacteriaceae, which is associated with the occurrence of UTIs. In addition, she said, in an earlier study performed by other investigators, oral administration of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 has been shown to restore the vaginal lactobacilli flora and to reduce colonization by potentially pathogenic bacteria.

At the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy, Dr. Geerlings presented the findings of two UTI prevention trials conducted in The Netherlands. One trial included 252 postmenopausal women with rUTIs. In this trial, 127 women received trimethoprim-sulfamethoxazole (TMP/SMX) 480 mg once daily and 125 received capsules of lactobacilli (L. rhamnosus GR-1 and L. reuteri RC-14) twice daily as prophylaxis for 12 months.

The mean cumulative number of symptomatic UTIs after 12 months was 2.9 for TMP/SMX recipients and 3.3 for the lactobacilli recipients. The percentage of patients with at least one symptomatic UTI at 12 months and the median time to first recurrence also favored TMP/SMX. The researchers concluded that TMP/SMX was more effective for preventing rUTIs. Development of antibiotic resistance among the normal bacterial flora was considerably less in the women

receiving lactobacilli, so the researchers concluded that lactobacilli may be an acceptable alternative for UTI prevention, especially in women who are against taking antibiotics.

In the other study, 221 premenopausal women with rUTIs were randomized to receive 12-months of prophylaxis with TMP/SMX 480 mg once-daily (110 subjects) or cranberry capsules 500 mg twice-daily (111 subjects). Cranberries contain fructose and proanthocyanidins, which can inhibit adherence of Escherichia coli to the uroepithelial cell receptors, Dr. Geerlings said.

After 12 months, the mean number and the proportion of patients with at least one symptomatic UTI were higher in the cranberry than in the TMP/SMX group (4.0 or 78% vs. 1.8 or 71%). The median times to the first symptomatic UTI were four months for the cranberry group and eight months for the TMP/SMX group.

Within four weeks, however, the research-

ers observed increased resistance rates for trimethoprim, TMP/SMX, amoxicillin, and ciprofloxacin among E. coli isolates of the normal flora.

After discontinuing TMP/SMX, resistance reached baseline levels after three months. As expected, antibiotic resistance did not increase in subjects taking cranberries. Both the cranberry preparation and TMP/SMX were equally well tolerated. The researchers concluded that TMP/SMX regimen was more effective than the cranberry regimen for preventing rUTIs. They cautioned that the greater efficacy of TMP/SMX should be weighed against the increased likelihood of antibiotic resistance.

Although cranberries were not as effective as TMP/SMX, Dr. Geerlings pointed out that a previous meta-analysis showed that in women with rUTIs, cranberry products reduced the incidence of recurrences at 12 months by 35% compared with placebo or control interventions. ■

34 Renal & Urology News

DECEMBER 2012

www.renalandurologynews.com

Higher Rate of Post-Tx Nephrectomy Found

BY JILL STEIN ATLANTA—The rate of perioperative blood transfusion after nephrectomy appears to be higher in general practice than the rates commonly cited in published urologic reports, researchers reported at the American Urological Association annual scientific meeting.

The results are drawn from a large population-based, retrospective study of patients who underwent nephrectomy for a renal mass. Overall, 18.2% of patients required a transfusion perioperatively, which is about three times the rate reported thus far in the literature.

Gino Vricella, MD, chief resident in urology at Case Western Reserve University in Cleveland, and colleagues determined the rates of blood transfusion as well as patient, surgeon, and hospital risk factors for transfusion in 10,902 patients who underwent a laparoscopic or open partial or radical nephrectomy for a renal mass over a recent five-year period. The procedures were performed at facilities in seven Canadian provinces, and information on patient demographics and treatment approach were obtained from a nationwide database.

“There are reports in the contemporary medical literature stating that patients who receive transfusions for

whatever reasons have worse outcomes,” Dr. Vricella said. “However, most outcomes data in urologic oncology are reported by higher volume surgeons and institutions, and the paucity of population-based analyses means that our current understanding of expected outcomes after surgery for kidney cancer is susceptible to publication and reporting bias. This is especially true for highly technical procedures such as laparoscopic partial nephrectomy.”

Study looks at ‘all comers’ The study was undertaken to determine the transfusion rate for “all comers” and to identify specific factors that predict which patients will require a transfusion, he said.

Overall, 28.2% of patients undergoing open radical nephrectomy required at least one transfusion perioperatively compared with 12.7%, 9.2%, and 8.6% of patients who underwent open partial nephrectomy, laparoscopic radical nephrectomy, and laparoscopic partial nephrectomy, respectively.

The transfusion rate was strongly associated with patient factors such as age and comorbidity. Transfusion rates were 11.2% and 14.5%, respectively, in patients under 50 years of age and patients with a Charlson co-morbidity score of 0 compared with 28.2% and

Transfusion Rate by Nephrectomy Type A study found that the rate of post-nephrectomy blood transfusions varied by surgical approach, as shown here.

30 25 20 15 10 5 0

28.2% Open radical

12.7% Open partial

40.7% in patients 80 years of age or older and patients with a Charlson score of 3 or higher.

Other factors shown on multivariable analysis to be strongly associated with the need for transfusion were provider variables such as procedure type, surgeon and hospital volume. Year of surgery, gender, and income quintile had no impact on the transfusion rate.

Better informed consent “Our findings allow us to better counsel patients preoperatively, which, in turn, makes them more knowledgeable when providing informed consent,” Dr. Vricella said. “Before our study, we might have told patients that it was

9.2% Laparoscopic radical

8.6% Laparoscopic partial

highly unlikely that they would need a blood transfusion given the 5% transfusion rate published in the literature.

With our population-based data, we would now tell patients that their risk of requiring a transfusion is around 20%, so that if a patient does not want a transfusion for whatever reason— religious or otherwise—he or she is better informed about that risk before providing informed consent.”

He cautioned that a possible study limitation is the lack of pathology data. “For example, we don’t know if the patient’s renal mass was large or small because the information was not included in the data set we looked at,” he said. ■

Losartan May Protect Renal Allografts The drug was associated with a trend towards less interstitial fibrosis, according to a study

BY ROSEMARY FREI, MSc BERLIN—Treatment with an angiotensin receptor blocker (ARB) may slow the rate at which fibrosis of transplanted kidneys develops, according to a study presented at the 24th International Congress of The Transplantation Society.

Hassan Ibrahim, MD, MSc, Professor of Medicine at the University of Minnesota in Minneapolis, showed in his five-year, randomized, doubleblind, placebo-controlled trial that, compared with placebo, losartan (Cozaar, Merck) had a statistically modest benefit for a significant reduction in rate of doubling of the interstitium or end-stage renal disease (ESRD) from interstitial fibrosis or tubular atrophy (IF/TA), but its use slows the rate of expansion of the renal interstitium.

With losartan, a 10% increase in the volume fraction of the interstitial tissue per glomerular cortex (Vvint/c) was associated with a loss of GFR of 3 mL/ min./1.73 m2 over a five-year period.

With placebo, the GFR loss was 18 mL/min./1.73 m2. “This difference is clinically relevant. It conveys a strong signal for this therapy being important,” Dr. Ibrahim told Renal & Urology News. “Only 20% of transplant recipients in the U.S. receive this therapy by six months post-transplant. These results should ease some of the concerns about using this drug in transplant patients.”

“At the end of the study the event rate was much lower than we expected, and that limits the conclusions of the study,” Dr. Ibrahim said.

“However, I would argue that in a lowpower situation we were able to show

some benefit, although it’s far from definitive.”

Dr. Ibrahim was the principal investigator in this $5 million study, which was largely funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Merck provided $150,000 as well as the losartan and placebo tablets.

The researcher randomized 77 adult kidney recipients to 100 mg/day losartan and another 76 to placebo.

The patients were non-pregnant recipients of a first or second renal transplant. They were not recipients of a kidney from an HLA-identical sibling and did not require ACE inhibitors or ARBs for a cardiovascular condition.

Forty-seven recipients in the losartan group and 44 taking placebo had both baseline and exit biopsies or ESRD

from IF/TA. The investigators also ascertained the baseline and exit biopsy information from patients in the two groups who developed ESRD or have died before the end of the study.

The primary endpoint was a reduction of the combined outcomes of the doubling of Vvint/c and graft loss from IF/TA over the five years of the trial. A total of only 16 graft losses occurred, 12 from IF/TA and four from other causes. Losartan did not significantly reduce the rate of the primary endpoint, possibly because of the low number of events or the lack of true benefit, Dr. Ibrahim said. Likewise, losartan did not show a statistically significant effect on death, ESRD, or doubling of interstitium volume. A significant effect of losartan was the reduction in the rate of decline of GFR concomitant with slowing interstitial expansion. ■

www.renalandurologynews.com

DECEMBER 2012

Renal & Urology News 35

CME FEATURE

Current Controversies Surrounding PSA Screening It is hoped that selective screening, selective biopsy, and selective therapy will further decrease the morbidity associated with screening.

Release Date: December 2012 Expiration Date: December 2013 Estimated time to complete the educational activity: xx hour This activity is jointly sponsored by Medical Education Resources and Haymarket Medical Education.

STATEMENT OF NEED: Moving forward with PSA screening mandates careful selection of those men most likely ot derive benefit. It is hoped that selective screening, selective biopsy, and selective therapy will further decrease the morbidity associated with screening.

TARGET AUDIENCE: This activity has been designed to meet the educational needs of urologists and allied healthcare clinicians involved in screening patients for prostate cancer.

EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Review recent randomized trials and assess the benefits of PSA screening.

• Evaluate additional advantages and disadvantages of PSA screening.

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 • Gurdarshan S. Sandhu, MD) • Gerald L. Andriole, MD

Reported Financial Relationship No financial relationships to disclose Grants/Research Support: NIH, NIDDK, Johnson & Johnson, Medivation, Wilex.

Consulting Fees: Amarex LLC, Amgen, Augmenix, Bayer, Bristol Myers Squibb, Cambridge Endosciences, Caris, GlaxoSmithKline, Janssen Biotech, Myriad Genetics, Steba Biotech, Ortho-Clinical Diagnostics, Viking Medical.

Ownership Interest/Shareholder: Envisioneering Medical.

BY GURDARSHAN S. SANDHU, MD, AND GERALD L. ANDRIOLE, MD

P

rostate cancer (PCa) is the most common cancer diagnosed in males with an estimated 241,740 new cases in 2012, accounting for 29% of all malignancies. It is also estimated to account for 28,170 deaths in 2012, making it the second most common cause of cancer-related death in males.1 This high incidence to mortality ratio is strongly linked to the introduction of prostate-specific antigen (PSA) as a screening test in the 1980’s,2 which facilitated detection of PCa over preexisting methods.3 PSA screening has been widely promoted in the U.S. as a public health initiative and was fairly rapidly adopted without evidence of improved mortality.

4 Several large, randomized trials, such as the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC), that evaluated mortality outcomes of PSA screening sparked further debate

about the benefits of PSA screening.5, 6 Recently the U.S. Preventive Services Task Force (USPSTF) concluded that screening was associated with a small or no reduction in PCa-specific mortality, and was also associated with significant harms. The USPSTF gave it a Grade D recommendation.7 This review highlights some of the controversies currently surrounding PCa screening.

Randomized trials and benefits of screening Mass screening refers to the application of diagnostic tests or procedures to an asymptomatic population in order to divide that population into two groups: those with a condition that benefits from early diagnosis and intervention and those that do not have such a condition,4 with the ultimate goal being an improvement in morbidity and mortality. To evaluate these goals and determine the utility of PCa screening, the USPSTF reviewed six randomized studies;5, 6, 8-11 the results of which are summarized below.

Quebec trial In Quebec, 46,486 men aged 45-80 were randomized to screening or no

The content managers, Jody A. Charnow and Marina Galanakis, of Haymarket Medical Education, and Julie Johnson, PharmD, of Medical Education Resources, have disclosed that they have no relevant financial relationships or conflicts of interest.

METHOD OF PARTICIPATION: There are no fees for participating in and receiving CME credit for this activity. During the period December 2012 through December 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/renalanurologynews, and 4) complete the evaluation form online. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better.

Gurdarshan S. Sandhu, MD, (at left), and Gerald L. Andriole, MD, (at right) are in the Division of Urologic Surgery at Washington University School of Medicine in St. Louis.

Dr. Sandhu is urologic oncology fellow and Dr. Andriole is the Robert Killian Royce Distinguished Professor and Chief of the Division.

36 Renal & Urology News

DECEMBER 2012

www.renalandurologynews.com

CME FEATURE screening in 1988.8 Screening in this study included serum PSA (with 3.0 ng/mL being the upper limit of normal) and digital rectal examination (DRE) at the first visit, with PSA only on subsequent visits. In the group invited for screening, 23.6% of men were screened compared with 7.3% of controls who received screening.

No difference in PCa mortality was observed after a median follow-up of 7.93 years, based on an intention-toscreen analysis (risk ratio [RR], 1.085, 95% CI [0.822-1.29]). However, based on a per protocol analysis, there was a significant 62% decrease in PCa mortality (RR 0.385, 95% CI [0.207-0.714], p=0.0025).8

Stockholm Trial The Stockholm trial9 randomly invited 2400 men aged 55-70 years to a onetime screening for PCa in 1988. These men were subsequently followed for 15 years and outcomes were compared to the remaining “source” population of 24,804 men, who were not invited for screening. Seventy-four percent of men who had been invited attended screening.

Participants were screened with a serum PSA, DRE, and transrectal ultrasound (TRUS) with biopsies performed for abnormal findings on DRE or TRUS. If the PSA level was greater than 7 ng/mL, repeat TRUS was performed and if greater than 10 ng/mL, biopsies were performed.

On an intention-to-screen analysis, no difference was observed in PCa mortality (RR 0.98, 95% CI [0.92-1.05]) or overall mortality (RR 1.10, 95% CI [0.83-1.46]). However, improved overall survival was noted when comparing those men who had actually undergone screening with the “source” population (RR 0.82, 95% CI [0.76-0.90]).9 Nörrkoping Trial Sandblom et al reported on the 20year follow-up of their screening trial in Nörrkoping, Sweden.11 In 1987, all men aged 50-69 were identified and every sixth man was randomized to screening. There were 1,449 men in the screening group and 7,532 men in the control group. The screening interval was every three years from 1987 to 1996. The screening regimen included DRE for the first two occasions and DRE with a PSA (cutoff 4 ng/mL) for the last two. Depending on the screening

occasion, 70%-78% of the invited men were compliant with screening.

After a median follow-up of 75 months, no significant difference was observed in PCa mortality between the screened group and controls (RR 1.16, 95% CI [0.78-1.73]).

The above three trials were considered to be of poor-quality based on a high risk of bias by the USPSTF. Accordingly, the primary focus of the USPSTF report7 was on the PLCO and ERSPC trials.

PLCO Cancer Screening Trial In the PLCO trial, 576,685 men were randomized to screening or usual medical care. The screening regimen consisted of an annual PSA for six years and an annual DRE for four years. All screened men and their caregivers received PSA results; initially a PSA above 4 ng/mL was considered suspicious and these men were advised to seek further diagnostic evaluation. Patients were recruited across 10 U.S. centers.

After 13 years of follow-up, no difference in PCa mortality (RR 1.09, 95% CI [0.87-1.36]) was observed between the groups.5 There was a large degree of prescreening among men enrolled in both arms and contamination of up to 52% of men in the usual care group undergoing a PSA test at some point during the

interaction between screening effect and comorbidity was later found to be sensitive to the comorbidity definition used by PLCO investigators.5 These benefits in a population with minimal or no comorbidity are important to consider given the protracted natural history of screen-detected PCa, which can predate a clinical diagnosis by 6-14 years.14 The majority of these patients have organ confined and potentially indolent disease.15 Of the men treated with curative intent, up to one third can be expected to recur;16 however, even following such a recurrence there can be a prolonged survival before death from PCa.17, 18 In light of the well-documented competing mortality risks in men diagnosed with PCa,19, 20 the men expected to benefit the most from a diagnosis and subsequent treatment of PCa would be those who are young with minimal comorbidities.

ERSPC The ERSPC trial randomized 182,160 men to a screening arm or control group across seven European countries. The screening regimen was dependent on center and year with most centers using a PSA cutoff of 3 ng/mL for biopsy.

For the entire group there was no mortality benefit to screening; however, in a

Moving forward with PSA screening mandates careful selection of those most likely to derive benefit, such as younger patients with a long life expectancy. study. This and the fact that 85% of men in the screened arm underwent testing may have affected the power of the trial, resulting in a decreased ability to detect a beneficial effect from screening.12 A subsequent post-hoc analysis examined PCa-specific mortality in young men with no or minimal comorbidity in the PLCO trial. After a median followup of seven years, in men with minimal or no comorbidity, there was a significant 44% reduction in the risk of PCa mortality in the screening arm (hazard ratio [HR], 0.56, 95% CI [0.33-0.95], p=0.03). Moreover, the number needed to treat (NNT) to prevent one PCa death in this subgroup was five.13 Importantly, in this analysis,13 an expanded comorbidity definition was used and the

pre-defined “core group” consisting only of men aged 55-69 years (n=162,243), after a median follow-up of 11 years, a 21% reduction in PCa-specific mortality was seen in the screened group (RR 0.79, 95% CI [0.68-0.91]). This corresponded to an absolute mortality risk reduction of 1.07 deaths per 1,000 men. Researchers concluded that 1,055 men would need to be invited for screening and 37 cases of PCa would need to be detected in order to prevent one PCa death, which has furthered concerns about overdiagnosis of this disease. No difference in overall mortality was noted (RR 0.99, 95% CI [0.97-1.01]).6 Significant reductions in PCa mortality were seen in only two of the centers (Sweden and Netherlands), and removal of both of these centers

would result in no mortality benefit for the entire remaining group.

The PCa-specific mortality in the ERSPC was also affected by noncompliance in the intervention arm as well as contamination in the control group.

To adjust for these effects, Roobol et al extrapolated the contamination seen in the Rotterdam arm (15.2% true contamination) to the entire ERSPC cohort.21 After adjusting only for noncompliance, PCa mortality risk reduction further increased to 27% (RR 0.73, 95% CI [0.58-0.93]). With adjustment for both noncompliance and contamination, the PCa mortality risk reduction increased to 29-31% (RR 0.69, 95% CI [0.51-0.92] and RR 0.71, 95% CI [0.55-0.93]),21 which also approached the 44% relative risk reduction seen in the Göteborg trial.10 One concern about ERSPC relates to difference in treatment for men in the screened and control arms. Generally, men in the screened arm were treated at large university centers while control patients were treated in the community.

Data have shown statistically significant treatment differences between these groups, even after adjusting for stage differences at the time of diagnosis.22 For example, men in the screened arm with high-risk localized disease were almost twice as likely to undergo radical prostatectomy and half as likely to receive hormonal therapy as men in the control group. Moreover, it is also possible that treatment such as radical prostatectomy (RP) and radiation therapy are better when administered at high-volume (e.g., university) centers as was more common in the screened arm rather than community settings, which predominated in the control arm. These differences may explain some of the mortality difference between the two arms of this study.

Göteborg Trial In 1994, 19,904 men aged 50-64 in Göteborg, Sweden, were randomized to screening or a control group. Screening was performed with a PSA every two years, with additional evaluation performed for an elevated PSA consisting of DRE and biopsy. The PSA cutoff was noted to have changed over the course of the study. A total of 76% of men in the intervention group attended screening at least once.

After a median follow-up of 14 years, a significant 44% decrease in PCa mor-

tality was noted in the screened group (RR 0.56, 95% CI [0.39-0.82]), with a 56% risk reduction noted in the group of men actually screened (RR 0.44, 95% CI [0.28-0.68]). Based on the risk reduction observed, in order to prevent one PCa death, the NNS was 293 and the NNT was 12.10 Also, it is worth noting that in this very positive trial for screening, it has been estimated that 1,000 men would need to be screened for 14 years to avert five PCa deaths and with that screening about 120 men would have been diagnosed and potentially treated.23 An additional important observation stemming from this trial was that this improvement in mortality was seen in a population where about 30% of men in each arm diagnosed with PCa were managed with active surveillance at last follow-up, suggesting that the risks of overtreatment can be minimized by good clinical management.10

widely practiced, modern forms of radiation therapy had been introduced and more men were receiving hormonal therapy. Since then there have been annual PCa mortality decreases of 4.1% from 1994-2005 and 2.6% from 2005-2007.31 Age-adjusted PCa mortality was also seen to decrease more rapidly (1990-2005) in the U.S., where screening was more prevalent, than in the U.K.32 Similarly, greater improvements in PCa mortality were noted with initiation of populationbased screening and treatment in Tyrol, Austria, compared to other regions of Austria without screening.33 Although modeling has attributed 45%-70% of this observed PCa mortality reduction to PSA screening,34 other groups have cautioned that this improvement may result from many additional factors35 such as the contribution of improved treatments36, 37 or attribution bias.38

Additional advantages of screening The potential harms in screening Certain advantages of screening, which are not addressed by the aforementioned randomized trials, are reviewed below.

Stage migration Prior to the PSA screening era, a majority of men diagnosed with PCa had advanced or metastatic disease.24 With the introduction of screening, a marked increase in the diagnosis of asymptomatic, clinically localized disease has been observed.15, 25, 26 Catalona et al reported locally advanced tumors in 57% of a comparison group to 29% in a group undergoing serial PSA screening.25 The Cancer of the Prostate Strategic Urological Research Endeavor (CaPSURE) revealed an increase in clinical T1 disease from 23% in 19935 to 50% in 2002,27 and SEER data from 2004-5 showed that 94% of newly diagnosed men have localized disease (T1 or T2).15 A decrease in distant or metastatic disease was seen following the introduction of screening,28, 29 with a 40% reduction noted in the screening group in the ERSPC.30 Mortality benefit from epidemiologic studies A sustained decrease in PCa mortality has been noted since the early 1990s.

This decline began as PSA testing was beginning to become widespread.

In the prior decade, RP had become

Explicit in the concerns regarding screening are the concerns related to biopsy and to overdiagnosis and overtreatment.

About 15% of men in screening programs have false positive tests and undergo unnecessary biopsy, which has a 0.5%-1.0% serious complication rate.

Moreover, many more men will be diagnosed with PCa (at least one in six) than will die of the disease (approximately one in 36), as death from PCa has been shown to be an infrequent occurrence in men with low risk, screen-detected disease.19, 20 It has been estimated that 25%-84% of screen detected PCa is overdiagnosed,14 with over 1.3 million such cancers diagnosed from 1986-2005.39 The detection of these tumors in USA frequently results in treatment: 91% of men in PLCO5 and 92.5% of men in CaPSURE40 were treated. Radical treatment is unlikely to yield a survival benefit in those with indolent disease41 or in those men older than 65 years,42 but can result in a significant decrease in quality of life as a result of potentially persistent urinary, sexual and bowel dysfunction.43 The PIVOT trial of radical prostatectomy versus observation for men with screen detected cancer showed no improvement in survival.44 Fortunately, the overtreatment of patients with low-risk disease appears to be improving with time.40 The false positives associated with PCa screening have also been found

DECEMBER 2012

Renal & Urology News 37

© PHOTO RESEARCHERS, INC. / DR. GOPAL MURTI / SCIENCE SOURCE

www.renalandurologynews.com

The high incidence of prostate cancer (SEM of prostate cancer cells shown above) is strongly linked to the introduction of PSA screening in the 1980’s.

to have a detrimental effect on mental health. Further, a population-based analysis revealed that a diagnosis of PCa was associated with a significant increase in cardiovascular events (RR 1.3, 95% CI [1.3-1.3]) and suicide (RR 2.6, 95% CI [2.1-3.0]) within the first year following diagnosis, with an even more pronounced effect noted in the first week after diagnosis.45 Economic concerns are also an important consideration with PCa screening.

Using mathematical models, researchers concluded that the introduction of screening had resulted in an increase of costs for PCa by 100%, 39% of which was related to overdiagnosis.

Screening costs were only a small part of the expenses related to PCa diagnosis, evaluation and treatment.46

Future directions Moving forward with PSA screening at this point mandates careful selection of those men most likely to derive benefit.

This population includes patients with a long life expectancy due to young age and minimal or no comorbidity13 given the indolent nature of most screendetected PCa.15 Other populations that are likely to benefit from screening include patients at risk for aggressive disease, who are more likely to experience PCa mortality. However, in the absence of specific markers for such disease, the identification of such patients remains challenging. Clinical variables may be evaluated in a variety of nomo-

grams, models and on-line tools but their applicability to a specific patient is unclear. Progress is being made with molecular tests47 on biopsy specimens that should assist with better risk prognostication and thus selection of more appropriate risk-based therapies for patients, such as active surveillance. It is hoped that selective screening, selective biopsy, and selective therapy will further decrease the NNT and morbidity associated with screening. ■ REFERENCES 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10-29.

2. Stamey TA, Yang N, Hay AR, et al. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987;317:909-16.

3. Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 1991;324:1156-61.

4. Gates TJ. Screening for cancer: evaluating the evidence. Am Fam Physician 2001;63:513-22.

5. Andriole GL, Crawford ED, Grubb RL, 3rd, et al.

Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up.

J Natl Cancer Inst 2012;104:125-32.

6. Schroder FH, Hugosson J, Roobol MJ, et al.

Prostate-cancer mortality at 11 years of follow-up.

N Engl J Med 2012;366:981-90.

7. Moyer VA. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012;157:120-34.

8. Labrie F, Candas B, Cusan L, et al. Screening decreases prostate cancer mortality: 11-year followup of the 1988 Quebec prospective randomized controlled trial. Prostate 2004;59:311-8.

9. Kjellman A, Akre O, Norming U, et al. 15-year followup of a population based prostate cancer screening study. J Urol 2009;181:1615-21; discussion 21.

10. Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Goteborg randomised populationbased prostate-cancer screening trial. Lancet Oncol 2010;11:725-32.

11. Sandblom G, Varenhorst E, Rosell J, et al. Randomised prostate cancer screening trial: 20 year follow-up. BMJ 2011;342:d1539.

12. Cuzick J, Edwards R, Segnan N. Adjusting for noncompliance and contamination in randomized clinical trials. Stat Med 1997;16:1017-29.

38 Renal & Urology News

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CME FEATURE CME Post-test Expiration Date: December 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 /renalandurologynews. You must receive a score of 70% or better to receive credit.

1. Which of the following randomized trials of PSA screening have shown a significant reduction in PCa mortality in the entire study population? a. PLCO b. ERSPC c. Stockholm Trial d. Göteborg Trial 2. Post hoc analyses of the PLCO trial have demonstrated significantly reduced PCa mortality in which of the following subgroups? a. African Americans b. Caucasians c. Young men with minimal or no comorbidity d. Elderly men with minimal or no comorbidity 3. Which subgroup of men in ERSPC had a significantly reduced prostate cancer-specific mortality? a. Men aged 55-69 years b. Men aged 55-74 years c. Men treated at university centers d. Men treated at community centers 4. Purported benefits of screening include: a. Improved overall survival b. Patient reassurance c. Stage migration of disease to more localized disease d. None of the above 5. Adverse effects on mental health related to a PCa diagnosis include: a. Increased risk of suicide b. Increased cardiovascular risk c. Patient anxiety d. All of the above 6. The ratio of PCa incidence to PCa mortality is: a. 10:1 b. 2:1 c. 1:1 d. 6:1 7. Prospects to reduce overdiagnosis and overtreatment of screendetected PCa include all but: a. Selective screening of individuals with a long life expectancy b. Limit screening to patients with minimal or no comorbidity c. Selective screening of patients at “high risk” for aggressive PCa d. Limit screening to elderly patients 8. The observed PCa mortality decline seen in epidemiologic studies since the early 1990s has been attributed to: a. PSA screening b. Attribution bias c. Improved therapeutic options d. All of the above

13. Crawford ED, Grubb R, 3rd, Black A, et al. Comorbidity and mortality results from a randomized prostate cancer screening trial. J Clin Oncol 2011;29:355-61.

14. Draisma G, Etzioni R, Tsodikov A, et al. Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context.

J Natl Cancer Inst 2009;101:374-83.

15. Shao YH, Demissie K, Shih W, et al. Contemporary risk profile of prostate cancer in the United States.

J Natl Cancer Inst 2009;101:1280-3.

16. D’Amico AV, Chen MH, Roehl KA, et al. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 2004;351:125-35.

17. Freedland SJ, Humphreys EB, Mangold LA, et al.

Death in patients with recurrent prostate cancer after radical prostatectomy: prostate-specific antigen doubling time subgroups and their associated contributions to all-cause mortality. J Clin Oncol 2007;25:1765-71.

18. Stephenson AJ, Kattan MW, Eastham JA, et al.

Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostatespecific antigen era. J Clin Oncol 2009;27:4300-5.

19. Albertsen PC, Hanley JA, Fine J. 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 2005;293:2095-101.

20. Lu-Yao GL, Albertsen PC, Moore DF, et al. Outcomes of localized prostate cancer following conservative management. JAMA 2009;302:1202-9.

21. Roobol MJ, Kerkhof M, Schroder FH, et al. Prostate cancer mortality reduction by prostate-specific antigen-based screening adjusted for nonattendance and contamination in the European Randomised Study of Screening for Prostate Cancer (ERSPC).

Eur Urol 2009;56:584-91.

22. Wolters T, Roobol MJ, Steyerberg EW, et al. The effect of study arm on prostate cancer treatment in the large screening trial ERSPC. Int J Cancer 2010;126:2387-93.

23. Carroll PR, Whitson JM, Cooperberg MR. Serum prostate-specific antigen for the early detection of prostate cancer: always, never, or only sometimes?

J Clin Oncol 2011;29:345-7.

24. Farkas A, Schneider D, Perrotti M, et al. National trends in the epidemiology of prostate cancer, 1973 to 1994: evidence for the effectiveness of prostatespecific antigen screening. Urology 1998;52:444448; discussion 8-9.

25. Catalona WJ, Smith DS, Ratliff TL, et al. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993;270:948-54.

26. Howlader NA, Krapcho M, Neyman N, et al (eds).

SEER Cancer Statistics Review, 1975-2008.

Bethesda, MD: National Cancer Institute; 2011.

27. Cooperberg MR, Lubeck DP, Mehta SS, et al. Time trends in clinical risk stratification for prostate cancer: implications for outcomes (data from CaPSURE).

J Urol 2003;170:S21-S25; discussion S6-S7.

28. Kopec JA, Goel V, Bunting PS, et al. Screening with prostate specific antigen and metastatic prostate cancer risk: a population based case-control study.

J Urol 2005;174:495-9; discussion 9.

29. Etzioni R, Gulati R, Falcon S, et al. Impact of PSA screening on the incidence of advanced stage prostate cancer in the United States: a surveillance modeling approach. Med Decis Making 2008;28:323-31.

30. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009;360:1320-8.

31. Siegel R, Ward E, Brawley O, et al. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61:212-36.

32. Collin SM, Martin RM, Metcalfe C, et al. Prostatecancer mortality in the USA and UK in 1975-2004: an ecological study. Lancet Oncol 2008;9:445-52.

33. Bartsch G, Horninger W, Klocker H, et al. Tyrol Prostate Cancer Demonstration Project: early detection, treatment, outcome, incidence and mortality. BJU Int 2008;101:809-16.

34. Etzioni R, Tsodikov A, Mariotto A, et al. Quantifying the role of PSA screening in the US prostate cancer mortality decline. Cancer Causes Control 2008;19:175-81.

35. Etzioni R, Feuer E. Studies of prostate-cancer mortality: caution advised. Lancet Oncol 2008;9:407-9.

36. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002;360:103-6.

37. Cooperberg MR, Grossfeld GD, Lubeck DP, et al. National practice patterns and time trends in androgen ablation for localized prostate cancer. J Natl Cancer Inst 2003;95:981-9.

38. Lu-Yao G, Stukel TA, Yao SL. Changing patterns in competing causes of death in men with prostate cancer: a population based study. J Urol 2004;171:2285-90.

39. Welch HG, Albertsen PC. Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening: 1986-2005. J Natl Cancer Inst 2009;101:1325-9.

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

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Learn more at inhibitandrogen.com/sequence *Currently in the absence of published, randomized, clinical data on treatment sequencing in mCRPC posttreatment with docetaxel. mCRPC=metastatic castration-resistant prostate cancer.

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

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