Renal & Urology News - March 2015 Issue by Haymarket Media

MARCH 2015

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Study: Every Hour of CIT Matters Longer cold ischemia time means higher risks

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HOW COLD ISCHEMIA TIMES INFLUENCE GRAFT SURVIVAL According to a new study, the risk of graft failure increases as cold ischemia time (CIT) increases. Shown here are the 1- and 10-year risks of graft failure associated with varying CIT. 40

36%

35 30

25%

20%

GRAFT FAILURE and mortality risk among kidney transplant recipients increases along with cold ischemia time (CIT), according to French researchers. “Even though CIT is a well-known risk factor among the renal transplantation community, its precise etiological role on mid-term graft outcomes is still under debate as illustrated by the wide heterogeneity of results observed in the literature,” Agnes Debout, MD, of CHU Nantes, RTRS, and colleagues noted. In a study of 3,839 adult recipients of a first deceased-donor kidney, Dr. Debout’s team found that each addi-

IN THIS ISSUE 6

Kidney stone formers have worse vascular calcification

Study estimates the benefits of updated hypertension guidelines

Diagnosing and managing testosterone deficiency in CKD

Kidney disease increases the risk of pregnancy complications

Silodosin found to aid passage of distal ureteral stones

Smoking pot may cut bladder cancer risk in men. PAGE 17

tional hour of CIT was associated with a significant 1.3% increased risk of graft failure and 1.8% increased risk of death. Patients who received a kidney with a CIT of 30 hours had a significant 40% higher risk of graft failure and 53% higher risk of death than patients who received a kidney with a CIT of 6 hours, the researchers reported in Kidney International (2015;87:343-349). The risk of graft failure was 4% at 1 year and 20% at 10 years for CIT less than 16 hours and 5% and 25%, respectively, for CIT of 16 to 36 hours. When CIT was more than 36 hours,

<16 hours 16–36 hours >36 hours

15 10 5

1 year

10 years

Source: Debout A et al. Each additional hour of cold ischemia time significantly increases the risk of graft failure and mortality following renal transplantation. Kidney Int. 2015;87:343-349).

the risk of graft failure was 8% at 1 year and 36% at 10 years. “These findings are of practical clinical interest, as cold ischemia time is among one of the main modifiable pretransplantation risk factors that can be minimized by improved management

of the peri-transplantation period,” Dr. Debout and her colleagues wrote. The mean CIT for study subjects was 20.6 hours. CIT duration was 6 to 16 hours for 1,274 patients (33.2%), 16 to 24 hours for 1,531 (39.9%), 24 to 36 continued on page 9

Hypothyroidism AVF Use Increasing in the U.S. Risk Rises As ARTERIOVENOUS FISTULA (AVF) remained stable at 18%. The U.S. had has increased and catheter use has the highest proportion of HD patients eGFR Declines use decreased among hemodialysis (HD) with AVGs of all the DOPPS countries. AS KIDNEY FUNCTION decreases in patients with moderate-to-severe chronic kidney disease (CKD), the risk of hypothyroidism increases, according to a new study. In a study looking at a nationally representative cohort of 461,607 veterans with Stage 3–5 CKD, researchers found that each 10 mL/min/1.73 m2 lower estimated glomerular filtration rate (eGFR) was associated with an 18% increased risk of hypothyroidism in adjusted analyses. Hypothyroidism was determined by laboratory tests or receipt of thyroid hormone supplementation.

patients in the United States, according to a study. The use of AVFs at HD initiation remains low, however. Using data from patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) Practice Monitor, Ronald L. Pisoni, PhD, MS, of Arbor Research Collaborative for Health in Ann Arbor, Mich., and colleagues found that from August 2010 to August 2013, AVF use increased from 63% to 68% while central venous catheter (CVC) use decreased from 19% to 15% and arteriovenous graft (AVG) use

AVF use in the United States did not differ greatly across broad age groups, but AV access use differed considerably by race, the investigators reported online ahead of print in the American Journal of Kidney Diseases. AVF use was 58% among blacks compared with 74% among Hispanics and 70% among non-Hispanic whites. AVG use was 2-fold higher among blacks than non-black U.S. patients (26% vs. 13%) in 2013. CVC use was similar across the 3 racial/ethnic groups. continued on page 9

PRACTICE MANAGEMENT

continued on page 9

Various options are available under ACA for providing employee health insurance What you need to know about the Affordable Care Act

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MARCH 2015

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VO L U M E 14, IS SU E N U M BE R 2

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Higher-Risk PCa Cases Increasing ORLANDO, Fla.—Intermediate- or high-risk prostate cancer (PCa) cases are increasing in the United States, according to a new study presented at the 2015 Genitourinary Cancers Symposium. Timothy E. Schultheiss, PhD, director of radiation physics at City of Hope in Duarte, Calif., and colleagues analyzed data from 87,562 men diagnosed with PCa from January 2005 to June 2013. The researchers categorized patients with localized PCa into risk groups using National Comprehensive Cancer Network (NCCN) criteria,

IN THIS ISSUE 6 15

Kidney stone formers have worse vascular calcification Silodosin found to aid passage of distal ureteral stones

Horseshoe kidney may increase UTI risk in children

Marijuana smoking decreases bladder cancer risk in men

Tramadol shows efficacy for premature ejaculation

Smoking pot may cut bladder cancer risk in men. PAGE 17

with intermediate risk defined as T2b-T2c and/or Gleason score 7 and/ or PSA 10-20 ng/mL and high risk defined as T3 or Gleason score 8-10 or PSA greater than 20 ng/mL. From 2005 to 2011, the proportion of men with PCa and PSA greater than 10 ng/mL decreased, but the proportion increased by a significant 3% per year from 2011 to 2013. From 2011 to 2013, the percentage of men aged 75 years and older presenting with PSA above 10 ng/mL increased by nearly double the rate for men of all ages. The investigators observed no significant trends

Study documents a 6% rise from 2011 to 2013

GROWTH IN HIGHER-RISK PCa cases was most pronounced among men aged 75+.

in Gleason score. Prior to 2011—when the U.S. Preventive Services Task Force (USPSTF) issued a document recommending against PSA screening regardless of a man’s age—the proportion of men with intermediate or highrisk PCa remained stable at 70%–73%.

Based on an estimated 233,000 new PCa cases in 2014, the researchers estimated that approximately 14,000 men per year will shift from a low risk into a higher-risk disease group. Due to the resulting change in prognosis with low continued on page 9

PN Found to Lower ESRD Risk Nerve Wrap May Hasten PATIENTS WITH renal cell carci- surgery and ESRD rate, but PN was asso(RCC) are at lower risk of end- ciated with a significant 52% decreased Potency Return noma stage renal disease (ESRD) requir- risk of chronic kidney disease (CKD). BY JODY A. CHARNOW WRAPPING A dehydrated human amniotic membrane allograft around the prostatic neurovascular bundle (NBV) during nerve-sparing robotassisted laparoscopic radical prostatectomy (RARP) holds promise as a way to hasten return of continence and potency after surgery, according to a new study. Vipul R. Patel, MD, of the Global Robotics Institute, Florida HospitalCelebration Health in Celebration, Fla., and colleagues studied a cohort of 58 men who were continent and potent prior to undergoing RARP and who received the allograft. The researchers

ing renal replacement therapy if they undergo partial rather than radical nephrectomy, a new study suggests. The population-based, retrospective cohort study included 11,937 RCC patients who underwent radical nephrectomy (RN) or partial nephrectomy (PN) during 1995–2010. Researchers divided subjects into an early cohort (those who had surgery from 1995–2002) and a modern cohort (those who had surgery from 2003–2010). In the full cohort, the study revealed no significant association between type of

In the modern cohort, PN recipients had a significant 56% decreased risk of ESRD requiring renal replacement therapy (RRT) compared with patients who underwent RN, after a median follow-up of 41 months, researchers led by Stanley A. Yap, MD, of the University of California Davis in Sacramento, reported online ahead of print in BJU International. In a propensity score analysis, which the investigators used to decrease bias and to control for differences between treatment groups, continued on page 9

PRACTICE MANAGEMENT

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Various options are available under ACA for providing employee health insurance What you need to know about the Affordable Care Act

PAGE 18

Contents

www.renalandurologynews.com

MARCH

2015

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VOLUME

Nephrology

ONLINE

this month at renalandurologynews.com Clinical Quiz

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

Videos

Some of our recent postings include:

• Using Biomarkers in Prostate Cancer • Implantable, Artificial Kidney • Provenge Immunotherapy for Castrate-Resistant Prostate Cancer

• Managing Hypertension in Chronic Kidney Disease

Infection Risk Higher in Diabetic CKD Patients Reduced estimated glomerular filtration rate and a history of proteinuria were found to be independent risk factors for lower respiratory tract infections, pneumonia, and sepsis. Kidney Disease Ups Pregnancy Risks Researchers found an increased risk of preterm delivery, delivery of low-birth-weight infants, and infant admission to a neonatal intensive care unit. Medicare HD Visit Policy Questioned Incentives to see providers more frequently lead to more interventions to preserve hemodialysis vascular access, but do not result in better access survival.

Study May Offer Insight into Managing AMH Cases Findings demonstrate that a positive dipstick test does not reliably predict asymptomatic microscopic hematuria, indicating that urine microscopy is a better baseline tool. Risk Factors for Late RCC Recurrence Identified These include patient age 60 years or greater and tumors that are Fuhrman grade 3 or 4 or pathologic stage pT2 or higher.

Considering the potential for adverse outcomes,

women with kidney disease who want to become pregnant should have preconception counseling. See our story on page 15

TOC_003_Neph_RUN0315.indd 3

European Association of Urology 30th Annual Congress Madrid March 20 –24 National Kidney Foundation 2015 Spring Clinical Meetings Dallas March 25 –29 American Transplant Congress Philadelphia May 2– 6 American Urological Association 110th Annual Meeting New Orleans May 15 –19 American Society of Hypertension Annual Scientific Meeting New York May 16 –19 European Renal Association-European Dialysis and Transplant Association 52nd Congress London May 28–31

Vascular Calcification Worse in Stone Formers Aortic calcification and lower bone mineral density are significantly more common among recurrent kidney stone formers than among non-stone formers.

NUMBER

American Society of Clinical Oncology Annual Meeting Chicago May 29–June 2

Prior Pelvic Surgery Need Not Contraindicate RP Robotic or open radical prostatectomy is feasible and still can achieve good overall results.

News Coverage

Visit our website for daily updates and coverage of upcoming medical conferences.

Extranasal S. aureus Common in Maintenance HD Patients In a study, 32% of patients had oropharynx and/or inguinal region colonization with the bacterium.

• Staging Chronic Kidney Disease

14, ISSUE

CALENDAR

Urology 6

Renal & Urology News 3

MARCH 2015

Departments 4

From the Medical Director Standardized care for uncomplicated UTIs

News in Brief Lycopene may reduce RCC risk in older women

Men's Health Update Pot smoking cuts bladder cancer risk in men

Practice Management Providing employee health insurance under the ACA

2/20/15 5:15 PM

MARCH

2015

■

VOLUME

Urology 6

ONLINE

this month at renalandurologynews.com 8

Clinical Quiz

Videos

Some of our recent postings include: • Using Biomarkers in Prostate Cancer • Implantable, Artificial Kidney

Extranasal S. aureus Common in Maintenance HD Patients In a study, 32% of patients had oropharynx and/or inguinal region colonization with the bacterium.

Kidney Disease Ups Pregnancy Risks Researchers found an increased risk of preterm delivery, delivery of low-birth-weight infants, and infant admission to a neonatal intensive care unit.

News Coverage

Visit our website for daily updates and coverage of upcoming medical conferences.

Prior Pelvic Surgery Need Not Contraindicate RP Robotic or open radical prostatectomy is feasible and still can achieve good overall results.

• Staging Chronic Kidney Disease • Managing Hypertension in Chronic Kidney Disease

Vascular Calcification Worse in Stone Formers Aortic calcification and lower bone mineral density are significantly more common among recurrent kidney stone formers than among non-stone formers.

• Provenge Immunotherapy for Castrate-Resistant Prostate Cancer

Medicare HD Visit Policy Questioned Incentives to see providers more frequently lead to more interventions to preserve hemodialysis vascular access, but do not result in better access survival.

Considering the potential for adverse outcomes,

women with kidney disease who want to become pregnant should have preconception counseling. See our story on page 15

TOC_003_Uro_RUN0315.indd 3

Renal & Urology News 3

14, ISSUE

NUMBER

CALENDAR

Nephrology 5

MARCH 2015

Contents

www.renalandurologynews.com

Departments 4

From the Medical Director Standardized care for uncomplicated UTIs

News in Brief Lycopene may reduce RCC risk in older women

Men's Health Update Pot smoking cuts bladder cancer risk in men

Practice Management Providing employee health insurance under the ACA

2/20/15 5:17 PM

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In mCRPC therapy…

Is there more to the story?

mCRPC=metastatic castration-resistant prostate cancer; AST=aspartate aminotransferase; ALT=alanine aminotransferase.

Please see additional Important Safety Information on the next page. Please see brief summary of full Prescribing Information on subsequent pages.

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INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant. Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia. Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. 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. Adrenocortical Insufficiency (AI)—AI was reported 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. 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 blood pressure, hypokalemia, or 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 (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

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For men with mCRPC who progressed on ADT

In a clinical trial, patients had a median overall survival on ZYTIGA® (abiraterone acetate) of…*

More than 1,000 days. And every day tells a story. 35.3 5.2 MONTHS IMPROVEMENT IN MEDIAN OVERALL SURVIVAL

MONTHS MEDIAN OVERALL SURVIVAL FOR ZYTIGA® plus prednisone† vs 30.1 MONTHS with placebo plus prednisone (active compound).‡

compared with placebo plus prednisone.

Co-primary end point—overall survival: hazard ratio (HR)=0.792; 95% CI: 0.655, 0.956; P=0.0151; prespecified value for statistical significance not reached. Co-primary end point—radiographic progression-free survival: median not reached for ZYTIGA® plus prednisone vs a median of 8.28 months for placebo plus prednisone. HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.

*Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were overall survival (OS) and radiographic progression-free survival. ADT=androgen-deprivation therapy.

Janssen Biotech, Inc.

Please see brief summary of full Prescribing Information on subsequent pages.

Date: 01/27/15 Customer Code: 016819-140612 Group 360 Job #: 721822 File Name: 016819-140612_721822_v1 (pg 2 left hand) Brand: Zytiga Size: 7" x 10" Colors: CMYK Description: Is there more to the story? Pub: Renal & Urology News (3/1/15 Digital Issue) K

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IMPORTANT SAFETY INFORMATION (cont) Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. 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. Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). 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. 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.

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003307-130924

†At a prespecified interim analysis for OS, 37% (200/546) of patients treated with ZYTIGA® plus prednisone compared with 43% (234/542) of patients treated with placebo plus prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

Learn more today at

Every day tells a story.

www.zytigahcp.com.

Date: 01/27/15 Customer Code: 016819-140612 Group 360 Job #: 721822 File Name: 016819-140612_721822_v1 (pg 3 right hand) Brand: Zytiga Size: 7" x 10" Colors: CMYK Description: Is there more to the story? Pub: Renal & Urology News (3/1/15 Digital Issue) K

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Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate. Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. 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, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. 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. Use Z YTIGA with caution in patients with a history of cardiovascular disease. The safety of Z YTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. 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: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking Z YTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving Z YTIGA 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: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. 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 Z YTIGA 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. Increased ZYTIGA Exposures with Food: 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 Z YTIGA

ZYTIGA® (abiraterone acetate) Tablets is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 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]. ZYTIGA Exposures with Food [see Warnings and • Increased 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. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 Z YTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients. The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months. Table 1: Adverse Reactions due to Z YTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract 11.5 infection 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0

ZYTIGA® (abiraterone acetate) Tablets

Table 1: Adverse Reactions due to Z YTIGA in Study 1 (continued) ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest 7 discomfort 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 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

Table 3: A dverse Reactions in ≥5% of Patients on the Z YTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm. Table 4: L aboratory Abnormalities in >15% of Patients in the Z YTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 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 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: A dverse Reactions in ≥5% of Patients on the Z YTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2

ZYTIGA® (abiraterone acetate) Tablets

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information]. 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, Z YTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. 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, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. 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: Safety and effectiveness of ZYTIGA in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving Z YTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 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 Z YTIGA 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. In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment 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 (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). 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]. 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 Human experience of overdose with ZYTIGA is limited. There is no specific antidote. In the event of an overdose, stop Z YTIGA, 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 in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, Z YTIGA 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]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. • Patients should be informed that Z YTIGA must not be taken with food and that 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. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. • Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions. • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician. • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle Z YTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: May 2014 015924-140528

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FROM THE MEDICAL DIRECTOR

Uncomplicated UTIs: A Case for Standardization

oogle “curse” or “expletive” and you’ll find variably vulgar words. From 4-letter profanities to 12+ letter obscenities, these terms assert strongly negative or even hostile emotions. What won’t appear on such lists are words like “guidelines,” “standards,” or “checklists,” even though they can be equally dispiriting to many well-intentioned, hard-working clinicians who equate such terms with excessive oversight or “cookbook medicine.” Physicians recognize the need for standards and process improvement in medicine. Yet the complexities of individual patient care seem far removed from manufacturing and other industries necessitating rigorously controlled standards. Indeed, standardization implies loss of control. Most providers understand that the benefits of variations in care are best measured only after appropriate and rational standards are put in place, particularly for the treatment of common ailments. Outpatient treatment of uncomplicated urinary tract infections (UTIs)* is common. They account for more than 8 million visits to doctors’ offices, emergency departments, and urgent care facilities annually. Practicing physicians recognize that evaluation, antibiotic choice, duration of therapy, and follow-up of UTIs vary significantly. In a recently published review of 27 randomized controlled trials, 6 systematic reviews, and 11 observational studies involving more than 250,000 patients, Grigoryan and colleagues outline common sense processes and standards for management for uncomplicated UTIs.1 Strong data support that women with at least 2 symptoms of UTI (dysuria, urgency, or frequency) and no vaginal discharge have a 90% or greater chance of having a bacterial UTI. Given the high pre-test probability, additional testing (urine dipstick and culture) appear to provide no additional benefit. Thus, an office visit without culture, telephone management, or patient-initiated therapy is acceptable for uncomplicated UTIs in women. Treatment with single dose fosfomycin (3 g), nitrofurantoin (100 mg po bid × 5 days) or trimethoprim-sulfamethoxazole (1 DS bid × 3 days) is equivalent to alternative and overused therapies (e.g., ciprofloxacin 250 mg bid × 3 d) and better than a beta-lactam antibiotic (e.g., amoxicillin-clavulanate). Algorithmic care can be easily and broadly applied to most practices. Health system, data-driven, community-centric, physician-led standardized approaches to common ailments represent the lowest-hanging fruit toward delivering better care. Standardizing when it’s easy allows you to standardize when it’s hard. Building a provider culture around simple standards is anything but profane. 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 *Not pregnant and no fever above 100 .5° F/flank pain/retention or voiding dysfunction/immunosuppression/suspicion for STD/recurrent UTIs or vaginal symptoms 1 Grigoryan L et al. Diagnosis and management of urinary tract infections. JAMA. 2014;312:1677-1684.

MH-Editorial_004_RUN0315.indd 4

EDITORIAL ADVISORY BOARD 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

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

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

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

R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto Stanton Honig, MD Department of Urology Yale University School of Medicine New Haven, CT J. Stephen Jones, MD, FACS Vice President Regional Medical Operations Professor & Horvitz/Miller Distinguished Chair in Urological Oncology Cleveland Clinic Regional Hospitals Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology University of California Irvine

Csaba P. Kovesdy, MD Chief of Nephrology Memphis VA Medical Center Fred Hatch Professor of Medicine University of Tennessee Health Science Center, Memphis 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.

James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City

Rulan Parekh, MD, MS Associate Professor of Pediatrics and Medicine University of Toronto

Kenneth Pace, MD, MSc, FRCSC Assistant Professor Division of Urology St. Michael’s Hospital University of Toronto

Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center, Detroit Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J.

Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada

Lynda Anne Szczech, MD, MSCE Medical Director, Pharmacovigilence and Global Product Development, PPD, Inc. Morrisville, N.C.

Renal & Urology News Staff

Editor Jody A. Charnow Web editor

Natasha Persaud

Production editor Kim Daigneau

Group art director, Haymarket Medical Jennifer Dvoretz

Production manager Krassi Varbanov

Production director Kathleen Millea Grinder Circulation manager Paul Silver National accounts manager William Canning Publisher Dominic Barone Editorial director

Jeff Forster

Senior VP, medical journals & digital products

Jim Burke, RPh

Senior VP, clinical communications group

John Pal

CEO, Haymarket Media Inc.

Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 14, Number 2. Published monthly, except for the combined January/February, June/July and November/ December issues, 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. 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 © 2015.

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Renal & Urology News 5

News in Brief

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

Short Takes Lycopene May Lower RCC Risk in Older Women

studies encompassing 214,114 individ-

Higher intake of lycopene is associated

a 37%, 86%, 44%, and 37% greater

with a lower risk of renal cell carcinoma

excess risk of all-cause mortality, fatal

(RCC) among postmenopausal women,

cardiovascular diseases, fatal kidney

researchers reported in Cancer

disease, and stroke, respectively, and

(2015;121:580-588).

a 2.5 times greater excess risk of inci-

uals. Women with type 1 diabetes had

Researchers led by Cathryn H. Bock,

dent coronary heart disease compared to men with type 1 diabetes.

PhD, MPH, of Wayne State University School of Medicine in Detroit, analyzed women who enrolled in the Women’s

Statins Cut Death Risk in Non-Obstructive CAD

Health Initiative study from 1993 to

Statin use is associated with a de-

1998 and were followed through July

creased risk of all-cause mortality

2013. During follow-up, 240 women

among patients with non-obstructive

were diagnosed with RCC. Compared

coronary artery disease (CAD), accord-

with women in the lowest quartile of

ing to a study published in Atherosclero-

lycopene intake, those in the highest

sis (2015;239:335-342).

data from 96,196 postmenopausal

quartile had a 39% lower risk of RCC.

The study included 8,372 patients with non-obstructive CAD documented

Type 1 Diabetes More Hazardous to Women

by coronary computed tomography

Female type 1 diabetics are at higher

were prescribed statins (23.7%). Statin

risk of all-cause mortality and fatal

users had a 60% decreased risk of all-

and non-fatal vascular events than

cause mortality and a 57% decreased

their male counterparts, according to

risk of a composite endpoint of death

a new meta-analysis published in The

or late coronary revascularization (more

Lancet Diabetes & Endocrinology.

than 90 days after CCTA) compared

angiography (CCTA). Of these, 1,983

The meta-analysis, by Rachel Huxley,

with non-users, regardless of age, sex,

MD, of the University of Queensland in

presence of hypertension or diabetes,

Australia, and colleagues, looked at 26

and other clinical factors.

Recognizing Measles In a recent online poll, Renal & Urology News asked readers: Would you recognize a case of measles if you saw it? Here are the results based on 113 responses.

Yes: 53.1%

No: 19.47%

Do not know: 27.43%

Prostate Cancer Not More Common in Hemophiliacs P

atients with hemophilia have a higher incidence of cancers overall compared with the general population, but not prostate cancer, according to a new study. Yung-Chieh Huang, MD, of the Taichung Veterans General Hospital in Taichung, Taiwan, and colleagues looked at the incidence of various cancers and associated survival among 1,054 patients with hemophilia and 10,540 age-and gender-matched healthy individuals from the general population. The cumulative incidences of cancer were 4.7% among the patients with hemophilia and 1.9% in the general population, the researchers reported online ahead of print in the American Journal of Hematology. The investigators found no significant differences in the incidences of prostate, lung, or colorectal cancer or in survival rate. Hepatocellular carcinoma was the major type of cancer observed in the hemophiliacs, occurring in 17 patients.

Extranasal S. aureus Common In Maintenance HD Patients E

xtranasal Staphylococcus aureus colonization is present in about one-third of maintenance hemodialysis (MHD) patients, according to a new study. Samantha J. Eells, MPH, of the Los Angeles Biomedical Research Institute at HarborUCLA Medical Center, surveyed 100 MHD patients at 3 body sites—anterior nares, oropharynx, and inguinal region—for S. aureus, a common cause of healthcare-associated infections in MHD patients. Results showed that 42% of patients were S. aureus colonized at more than 1 body site and 32% of patients had extranasal colonization. “Future S. aureus decolonization effects may need to consider not just nasal decolonization but also decolonization of the skin and oropharynx,” the authors concluded. In their acknowledgement of study limitations, the researchers noted that they enrolled study subjects from a single metropolitan area. so findings may not be generalizable to other HD populations.

Prospective Study Supports AS for Small Renal Masses A

ctive surveillance (AS) and primary intervention (PI) for small renal masses are associated with similar overall and cancer-specific survival, according to the findings of a prospective clinical trial. Phillip M. Pierorazio, MD, of Johns Hopkins University in Baltimore, and colleagues enrolled 497 patients with small renal masses (4 cm or less in diameter). Of these, 223 (45%) chose AS and 274 (55%) chose PI. For the AS and PI groups, overall survival rates were 75% and 92%, respectively, and cancer-specific survival rates were 100% and 99%, respectively, differences that were not statistically significant, the investigators reported online ahead of print in European Urology. “The current report is among the first prospective analyses of patients electing for active surveillance of a small renal mass,” the researchers concluded. “Discussion of active surveillance should become part of the standard discussion for management of small renal masses.”

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MARCH 2015 www.renalandurologynews.com

Vascular Calcification Worse in Stone Formers AORTIC CALCIFICATION and lower bone mineral density (BMD) are significantly more common among recurrent kidney stone formers (KSFs) than among non-stone formers, researchers found. The finding suggests that vascular calcification (VC) “may be an underlying mechanism explaining reported associations between nephrolithiasis and cardiovascular disease,” according to a report published online ahead of print in the Clinical Journal of the American Society of Nephrology. Linda Shavit, MD, of the Adult Nephrology Unit, Shaaare Zedek Medical Center in Jerusalem, Israel, and colleagues conducted a retrospective study that included 57 KSFs and 54 healthy age- and gender-matched controls

The researchers acknowledged some study limitations, including the retrospective collection of demographic and clinical variables. “Therefore, we cannot exclude known or unknown confounding factors entirely as an explanation for our results,” they stated.

Dr. Shavit’s group cited epidemiologic studies showing that VC coexists with bone loss, “suggesting a relationship between osteoporosis and atherosclerosis.” As in patients with VC, the authors observed, bone demineralization frequently is found in KSFs. S:7” In these

patients, fasting hypercalciuria appears as the only biologic factor associated with low BMD. “Thus, both VC and nephrolithiasis can be defined as extraosseous sites of abnormal calcium deposition and both seem to be associated with bone demineralization,” the researchers wrote. n

Finding may explain reported links between nephrolithiasis and cardiovascular disease. selected from a list of potential living kidney donors. Both groups had a mean age of 47 years. The researchers used computed tomography (CT) to assess abdominal aortic calcification (AAC) and vertebral bone mineral density (BMD). AAC is considered a strong predictor of cardiovascular (CV)-related morbidity or death, the researchers explained. The prevalence of AAC was similar in the KSFs and controls (38% and 35%, respectively), but AAC severity score was significantly higher in the KSFs than controls and average CT BMD was significantly lower in KSFs (159 vs. 194 Hounsfield units). In multivariate analysis, KSFs had higher AAC scores and lower CT BMD compared with non-stone formers, according to the investigators. The association between AAC score and hypercalciuria among stone formers was not statistically significant. “Although our study cannot prove causality,” the authors wrote, “this is the first study to our knowledge to provide controlled evidence for a possible role of vessel calcification and associated osteoporosis in CV morbidity among KSFs. Our findings may serve as a useful basis for future prospective trials exploring the potential benefit fo therapeutically targeting the bones and cardiovascular system in KSFs as part of their routine management to mitigate CVD morbidity and mortality.”

INDICATION AURYXIA is a phosphate binder indicated for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis. IMPORTANT SAFETY INFORMATION Contraindication: AURYXIA is contraindicated in patients with iron overload syndromes. Iron Overload: Iron absorption from AURYXIA may lead to excessive elevations in iron stores. Assess iron parameters, serum ferritin and TSAT, prior to and while on AURYXIA. Patients receiving IV iron may require a reduction in dose or discontinuation of IV iron therapy.

Overdose: AURYXIA contains iron. Iron absorption from AURYXIA may lead to excessive elevations in iron stores, especially when concomitant IV iron is used. Accidental Overdose of Iron: Accidental overdose of iron containing products is a leading cause of fatal poisoning in children under 6 years of age. Keep this product out of the reach of children. Patients with Gastrointestinal Bleeding or Inflammation: Safety has not been established. Pregnancy Category B and Nursing Mothers: Overdosing of iron in pregnant women may carry

B:15.5” T:15.5”

www.renalandurologynews.com MARCH 2015

Renal & Urology News 7

Prior Pelvic Surgery Need Not Contraindicate RP B:15.5” T:15.5”

PREVIOUS PELVIC surgery should not be considered a contraindication to robotic or open radical prostatectomy (RP), researchers reported in the Korean Journal of Urology (2015;56:131-137). “Robotic or open RP is feasible and can achieve good overall results in patients who have previously under-

gone pelvic surgery,” the investigators concluded. Mahmoud Mustafa, MD, of An-Najah National University Hospital in Nablus, Palestine, and colleagues at MD Anderson Cancer Center in Houston studied 64 men with a median age of 65 years who underwent RP after previS:7”

ous pelvic surgery of the large intestine. Of these, 24 (37.5%) underwent robotic RP and 40 (62.5%) underwent open RP. The median period between previous pelvic surgery and RP was 8 years. The researchers observed no intraoperative complications. There were no conversions from robotic to open RP.

Postoperative complications included bowel obstruction and persistent bladder leakage in 2 patients, lymphocele in 1 patient, and urethral stricture in 1 patient. In addition, 88% of patients were continent at 7 months and 80% were able to achieve an erection with or without medical aid. n

For the control of serum phosphorus levels in patients with chronic kidney disease on dialysis

AURYXIA™ (ferric citrate) IS THE FIRST AND ONLY ABSORBABLE-IRON–BASED PHOSPHATE BINDER CLINICALLY PROVEN TO MANAGE HYPERPHOSPHATEMIA1-6

• Proven control of serum phosphorus within KDOQI guidelines (4.88 mg/dL at Week 56)7,8 • Demonstrated safety and tolerability profile over 52 weeks

a risk for spontaneous abortion, gestational diabetes, and fetal malformation. Rat studies have shown the transfer of iron into milk. There is possible infant exposure when AURYXIA is taken by a nursing woman.

e atal his

Pediatric: The safety and efficacy of AURYXIA have not been established in pediatric patients. Adverse Events: The most common adverse events with AURYXIA were diarrhea (21%), nausea (11%), constipation (8%), vomiting (7%), and cough (6%). Gastrointestinal adverse reactions were the most common reason for discontinuing AURYXIA (14%).

Drug Interactions: Doxycycline should be taken at least 1 hour before AURYXIA. Consider separation of the timing of the administration of AURYXIA with drugs where a reduction in their bioavailability would have a clinically significant effect on safety or efficacy. Please see Brief Summary on following page. You may report side effects to Keryx at 1-844-44KERYX (844-445-3799).

B:10.25”

S:10”

References: 1. Fosrenol [package insert]. Wayne, PA: Shire US, Inc.; 2014. 2. Phoslyra [package insert]. Waltham, MA: Fresenius Medical Care North America; 2011. 3. PhosLo Gelcaps [package insert]. Waltham, MA: Fresenius Medical Care North America; 2012. 4. Renagel [package insert]. Cambridge, MA: Genzyme Corporation; 2014. 5. Renvela [package insert]. Cambridge, MA: Genzyme Corporation; 2014. 6. Velphoro [package insert]. Waltham, MA: Fresenius Medical Care North America; 2014. 7. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 Suppl 3):S1-S201. 8. Data on File 1, Keryx Biopharmaceuticals, Inc.

T:10.25”

• Each AURYXIA tablet contains 210 mg ferric iron, equivalent to 1 g ferric citrate

8 Renal & Urology News

MARCH 2015 www.renalandurologynews.com

Study May Offer Insight into Managing AMH Cases NEW FINDINGS from a large study may improve clinical management of patients with asymptomatic microscopic hematuria (AMH). Although patients with gross hematuria should be fully investigated, the management of patients with AMH is controversial. Recently updated

AMH guidelines from the American Urological Association (AUA) provide insufficient information for decisionmaking due to a shortage of research, the study’s authors noted. AMH is a potential early sign of urologic disorders, but how to define clinically significant AMH, which patients T:7”

require complete urologic workup, and how patients should be examined remain unclear, according to a team led by Chang Wook Jeong, MD, of Seoul National University Hospital. “Even when no disorder is detected at initial work-up, some patients with AMH are later diagnosed with a sig-

BRIEF SUMMARY AURYXIA™ (ferric citrate) tablets contain 210 mg of ferric iron equivalent to 1 g ferric citrate for oral use. INDICATIONS AND USAGE AURYXIA is a phosphate binder indicated for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis. CONTRAINDICATIONS AURYXIA is contraindicated in patients with iron overload syndromes (eg, hemochromatosis). WARNINGS AND PRECAUTIONS Iron Overload: Iron absorption from AURYXIA may lead to excessive elevations in iron stores. Increases in serum ferritin and transferrin saturation (TSAT) levels were observed in clinical trials. In a 56-week safety and efficacy trial in which concomitant use of AURYXIA and IV iron was permitted, 55 (19%) patients treated with AURYXIA had a ferritin level >1500 ng/mL as compared with 13 (9%) patients treated with active control. Assess iron parameters (eg, serum ferritin and TSAT) prior to initiating AURYXIA and monitor iron parameters while on therapy. Patients receiving IV iron may require a reduction in dose or discontinuation of IV iron therapy. Accidental Overdose of Iron: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6 years of age. Keep this product out of the reach of children. In case of accidental overdose, call a doctor or poison control center immediately. Patients with Gastrointestinal Bleeding or Inflammation: Patients with inflammatory bowel disease or active, symptomatic gastrointestinal bleeding were excluded from clinical trials. Safety has not been established in these populations. ADVERSE REACTIONS Adverse reactions to a drug are most readily ascertained by comparison with placebo, but there is little placebo-controlled experience with AURYXIA, so this section describes adverse events with AURYXIA, some of which may be disease-related, rather than treatment-related. A total of 289 patients were treated with AURYXIA and 149 patients were treated with active control (sevelamer carbonate and/or calcium acetate) during the 52-week, randomized, open-label, active control phase of a trial in patients on dialysis. A total of 322 patients were treated with AURYXIA for up to 28 days in three short-term trials. Across these trials, 557 unique patients were treated with AURYXIA; dosage regimens in these trials ranged from 210 mg to 2,520 mg of ferric iron per day, equivalent to 1 to 12 tablets of AURYXIA. In these trials, adverse events reported for AURYXIA were similar to those reported for the active control group. Adverse events reported in more than 5% of patients treated with AURYXIA in these trials included diarrhea (21%), nausea (11%), constipation (8%), vomiting (7%), and cough (6%). During the 52-week active control period, 60 patients (21%) on AURYXIA discontinued study drug because of an adverse event, as compared to 21 patients (14%) in the active control arm. Patients who were previously intolerant to any of the active control treatments (calcium acetate and sevelamer carbonate) were not eligible to enroll in the study. Gastrointestinal adverse events were the most common reason for discontinuing AURYXIA (14%). AURYXIA is associated with discolored feces (dark stools) related to the iron content, but this staining is not clinically relevant and does not affect laboratory tests for occult bleeding, which detect heme rather than non-heme iron in the stool.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. It is not known whether AURYXIA can cause fetal harm when administered to a pregnant woman. Animal reproduction studies have not been conducted. The effect of AURYXIA on the absorption of vitamins and other nutrients has not been studied in pregnant women. Requirements for vitamins and other nutrients are increased in pregnancy. An overdose of iron in pregnant women may carry a risk for spontaneous abortion, gestational diabetes, and fetal malformation. Labor and Delivery: The effects of AURYXIA on labor and delivery are unknown. Nursing Mothers: Data from rat studies have shown the transfer of iron into milk by divalent metal transporter-1 (DMT-1) and ferroportin-1 (FPN-1). Hence, there is a possibility of infant exposure when AURYXIA is administered to a nursing woman. Pediatric Use: The safety and efficacy of AURYXIA have not been established in pediatric patients. Geriatric Use: Clinical studies of AURYXIA included 106 subjects aged 65 years and older (33 subjects aged 75 years and older). Overall, the clinical study experience has not identified any obvious differences in responses between the elderly and younger patients in the tolerability or efficacy of AURYXIA. OVERDOSAGE No data are available regarding overdose of AURYXIA in patients. In patients with chronic kidney disease on dialysis, the maximum dose studied was 2,520 mg ferric iron (12 tablets of AURYXIA) per day. Iron absorption from AURYXIA may lead to excessive elevations in iron stores, especially when concomitant IV iron is used. In clinical trials, one case of elevated iron in the liver as confirmed by biopsy was reported in a patient administered IV iron and AURYXIA. PATIENT COUNSELING INFORMATION Dosing Recommendations: Inform patients to take AURYXIA as directed with meals and adhere to their prescribed diets. Instruct patients on concomitant medications that should be dosed apart from AURYXIA. Adverse Reactions: Advise patients that AURYXIA may cause discolored (dark) stools, but this staining of the stool is considered normal with oral medications containing iron. AURYXIA may cause diarrhea, nausea, constipation, and vomiting. Advise patients to report severe or persistent gastrointestinal symptoms to their physician. Keryx Biopharmaceuticals, Inc. ©2015 Keryx Biopharmaceuticals, Inc. Printed in USA

PP-AUR-US-0075

01/15

A positive dipstick test does not reliably predict asymptomatic microscopic hematuria. T:10”

DRUG INTERACTIONS Doxycycline is an oral drug that has to be taken at least 1 hour before AURYXIA. Oral drugs that can be administered concomitantly with AURYXIA are: amlodipine, aspirin, atorvastatin, calcitriol, clopidogrel, digoxin, doxercalciferol, enalapril, fluvastatin, levofloxacin, metoprolol, pravastatin, propranolol, sitagliptin, and warfarin. There are no empirical data on avoiding drug interactions between AURYXIA and most concomitant oral drugs. For oral medications where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, consider separation of the timing of the administration of the two drugs. The duration of separation depends upon the absorption characteristics of the medication concomitantly administered, such as the time to reach peak systemic levels and whether the drug is an immediate release or an extended release product. Consider monitoring clinical responses or blood levels of concomitant medications that have a narrow therapeutic range.

nificant lesion,” they wrote in an online report in the International Journal of Urology. “However, AMH is often inadequately managed for lack of highquality evidence.” For the study, the investigators analyzed data from healthy adults age 20 and older who voluntarily participated in the hospital’s health screening program from 2005 to 2010. Among the 57,000 Korean patients, 6.2% had AMH based on initial urinalysis; of these, 1,619 patients agreed to undergo a repeat urinalysis, and 911 again had AMH. The study defined AMH more strictly than existing guidelines: 5 or more red blood cells per field viewed under a microscope. The investigators then identified 131 lesions as underlying disease. Urinary stones were the most common cause (69.5%), followed by benign renal masses, such as angiomyolipoma (10.7%). Just 6 lesions were malignant: 3 renal cell carcinomas and 3 bladder cancers. Male sex and diabetes were significant predictors for detecting underlying diseases of AMH, more likely benign conditions such as urinary stones.

According to the researchers, their findings demonstrate that a positive dipstick test does not reliably predict AMH, indicating that urine microscopy is a better baseline tool. In addition, AMH risk does not differ for daily users of aspirin or other anticoagulants, in line with a previous study. Thus, clinicians may conduct further urologic evaluation as usual. The study also showed that female sex, older age, chronic renal failure, and current smoking significantly increases AMH risk, whereas male sex and diabetes mellitus decreased the risk. The 2012 AUA guidelines suggest that further urologic evaluation is not required for benign causes of AMH, such as pyuria. However, in this study, the detection of abnormal urologic findings did not differ between patients with or without pyuria. Further examination should be carried out even in AMH patients with pyuria, the researchers noted. Renal function should be monitored carefully because renal disease might cause clinical problems during evaluation of AMH. n

www.renalandurologynews.com MARCH 2015

Hypothyroidism risk continued from page 1

The study, published in Nephrology Dialysis Transplantation (2015;30:282287), also found that a 10 mL/min/1.73 m2 lower eGFR was associated with a 0.11 mIU/L higher serum level of thyrotropin (TSH). “To our knowledge, this is the largest examination of the relationship between eGFR and thyroid functional status conducted to date,” wrote senior author Csaba P. Kovesdy, MD, of the University of Tennessee Health Science Center in Memphis and the Memphis Veterans Affairs Medical Center, and first author Connie M. Rhee, MD, MSc, of the University of California Irvine School of Medicine. Study subjects underwent repeated measurements of serum creatinine and TSH at identical time points from October 2004 to September 2006. The investigators estimated GFR using the Chronic Kidney Disease Epidemiology Collaboration formula. Dr. Kovesdy and his collaborators cited case series showing that hypothyroid patients have decreased renal plasma flow and GFR measured by creatinine-based estimated equations and isotopic scans, which were reversed with thyroid hormone supplementation. “Our findings add to a growing body of literature demonstrating a relationship between impaired kidney

AVF use increasing continued from page 1

Vascular access use also differed considerably by sex. AVF use was 50% among black women compared with 65% for black men and 65% for nonblack women compared with 75% for non-black men, the researchers reported. “Despite the large improvement in vascular access use for prevalent hemodialysis patients in the United States during the past 17 years, there has been no improvement in access use for new hemodialysis patients in the United States, with nearly 80% initiating hemodialysis therapy with a CVC.”

CIT study

continued from page 1

hours for 853 (22.2%), and longer than 36 hours for 181 (4.7%), the researchers reported. Of the 3,839 transplant recipients, 449 lost their graft and 238 died with a functioning graft.

function and hypothyroidism,” the authors wrote. Dr. Kovesdy’s group pointed out that the observational design of their study cannot establish a causal relationship between decreased eGFR and hypothyroidism. They noted that it has been hypothesized that hypothyroidism may directly worsen kidney function via decreases in cardiac output, increases in peripheral vascular resistance, intrarenal vasoconstriction, and alterations in glomerular structure. One of the study’s strengths was its examination of a large sample size of nationally representative CKD patients, with comprehensive capture of sociodemographics, serum TSH, and creatinine and prescription data. Another strength was comprehensive adjustment for comorbidity factors as potential confounders of the kidneythyroid function association. The study also had some limitations. For example, the indications for which TSH were measured were unknown, “and it is possible that the requirement for TSH measurement may have resulted in a cohort with a higher-thanaverage perceived risk of thyroid functional disease.” Additionally, hypothyroidism may influence serum creatinine levels due to changes in muscle metabolism and volume status independent of its effects on GFR, “and we cannot exclude the possibility of residual confounding by these factors and other unmeasured covariates.” n

Dr. Pisoni’s team noted that the native AVF is widely recognized “as the vascular access of first choice for most hemodialysis patients in that it provides the best outcomes overall” compared with an AVG or CVC. “Use of catheters has been associated with substantially higher rates of mortality, infection-related complications, central venous stenosis, hospitalization, and costs.” The DOPPS is an international prospective cohort study of in-center HD patients and practices that began in 1996. The study by Dr. Pisoni’s team included 3,442 U.S. patients and 8,478 patients from 19 other DOPPS countries. n

They pointed out that “there is no consensus whether CIT should be considered as a continuous risk factor or whether threshold values can be considered to identify subgroups with a relevant excess in the risk of mid-term graft and patient outcomes.” The investigators stated that their results “suggest that

Renal & Urology News 9

Updated HTN Guidelines Could Save 13,000 Lives Yearly IMPLEMENTATION of the 2014 hyper-

blood pressure (BP) of 140/90 mm

tension guidelines for U.S. adults aged

Hg for such patients was projected to

35 to 74 years potentially could prevent

prevent about 16,000 cardiovascular

about 56,000 cardiovascular events

events and 6,000 deaths from car-

and 13,000 deaths yearly, according to

diovascular causes annually. Another

a recent study.

8.6 million untreated patients aged 35

Andrew E. Moran, MD, MPH, of

to 74 years with hypertension but no

Columbia University in New York, and

CVD also would be eligible for treat-

colleagues used the Cardiovascular

ment each year. Achieving guideline

Disease Policy Model to simulate drug-

targets in these patients would prevent

treatment and monitoring costs, costs

about 41,000 cardiovascular events

averted for treating cardiovascular

and 7,000 deaths from cardiovascular

disease (CVD), and quality-adjusted life-

causes annual and result in cost sav-

years (QALY) gained by treating previ-

ings compared with the status quo.

ously treated untreated adults aged 35

Treatment of stage 1 hypertension

to 74 years from 2014 through 2024,

was cost-effective for all men and for

assuming that untreated patients would

women aged 45 to 74 years. Treating

remain untreated. The researchers

women aged 35 to 44 years with stage

considered a QALY cost below $50,000

1 hypertension but without cardiovas-

to be cost effective.

cular disease had low or intermediate

“Among the groups that we con-

cost-effectiveness.

sidered, the treatment of men and

The 2014 guidelines from the Eighth

women with cardiovascular disease

Joint National Committee update 2003

and those with stage 2 hyperten-

guidelines with 3 important changes: a

sion without cardiovascular disease

focus on diastolic rather than systolic

appeared to provide the most value,

pressure in adults younger than 60 years

and the treatment of women under the

and the establishment of more conser-

age of 60 years with stage 1 hyperten-

vative BP goals for those aged 60 or

sion appeared to provide the least

older (150/90 mm Hg) and for patients

value,” the researchers reported in

with diabetes or chronic kidney disease

The New England Journal of Medicine

(140/90 mm Hg). Compared with 2003

(2015;372;447-455).

recommendations, the 2014 guidelines

Treatment of men or women with

would make about 1% young adults and

existing CVD or men with stage 2

8% of older adults ineligible to receive

hypertension but without CVD would

BP-lowering treatment, the investigators

remain cost-saving even if strategies

reported. “However, an estimated 28

to increase medication adherence

million adults still would have uncon-

doubled treatment costs, Dr. Moran’s

trolled hypertension according to the

team stated.

relaxed standards,” they wrote.

On average, based on 2014 guide-

The model that the researchers used

lines, about 860,000 individuals with

to make their projections is a computer-

existing CVD and hypertension who are

simulation, state-transition model of the

not being treated with anti-hypertension

incidence, prevalence, mortality, and

drugs would be eligible for treatment

costs of coronary heart disease and

every year during the period from 2014

stroke among individuals aged 35 to

through 2024. Treatment with a target

94 in the United States. n

every additional hour of CIT matters.” “These data provide solid evidence that even a short lengthening of CIT may worsen the outcome of renal transplantation,” commented Claudio E. Ponticelli, MD, of Humanitas Clinical and Research Center in Milan, Italy, in an accompanying editorial (pp. 272–275).

Dr. Ponticelli explained that “cold ischemia may initiate a cascade of reactions that are amplified by blood reperfusion. The consequent injuries can lead to kidney damage and to the activation of the immune response, both of which may impact on the outcome after transplantation.” n

www.renalandurologynews.com MARCH 2015

Higher-risk PCa

continued from page 1

versus high-risk disease, the investigators predict that at least 1,400 more men may die from PCa each year. Dr. Schultheiss said the study is the first to measure changes in PCa presentation in the period following release of the 2011 USPTF recommendations. “Given the rise in intermediate- and high-risk prostate cancers seen in our analysis during this timeframe, men who are at increased risk for prostate cancer, especially those with a family history of prostate can-

PN lowers ESRD risk

continued from page 1

PN was associated with a significant 53% decreased risk of ESRD. In the modern cohort, the RN and PN patients had a median time of progression to ESRD of 5 months and 16 months, respectively. “Although it is well-known that RN is associated with more CKD than PN, we provide the first direct evidence that PN is associated with ESRD requiring renal replacement therapy than RN in a modern cohort of patients with RCC,” the authors concluded. They also stated, “The distinction of a modern cohort is important, as it consists of patients that encompass a more accurate representation of current practice,” the investigators wrote. “During earlier years of the present cohort, PN had yet to gain widespread use and acceptance.” Of the 11,937 patients in the full cohort, 9,830 (82%) and 2,107 (18%) underwent RN or PN, respectively.

Nerve wrap continued from page 1

compared these patients with a propensity score-matched group of 58 RARP patients who did not receive the allograft. The allograft was cut into 2 longitudinal pieces and placed over each NVB as a nerve wrap, which was placed circumferentially around the NVB after extirpative RARP, following anastomosis. At 8 weeks, continence and potency returned in 81% and 65.5% of the allograft group, respectively, and 74.1% and 51.7%, respectively, of the no-allograft group, Dr. Patel’s group reported online ahead of print in European Urology. These between-group differences were not statistically significant, but the mean time to return of con-

cer, should consider talking with their doctor about PSA screening,” he said. For the study, Dr. Schultheiss’ team used data from the National Oncology Data Alliance, a proprietary database of merged tumor registries that captures newly diagnosed cancer cases at more than 150 hospitals in the United States. “This study, while preliminary, adds new insight to the ongoing debate on the risks and benefits of PSA screening for prostate cancer,” said Charles J. Ryan, MD, speaking on behalf of the American Society of Clinical Oncology, which sponsors the annual symposium. n

Renal & Urology News 9

Study: Each Additional Hour of Cold Ischemia Time Matters GRAFT FAILURE and mortality risk

minimized by improved management

among kidney transplant recipients

of the peri-transplantation period,” the

increases along with cold ischemia time

researchers wrote.

(CIT), according to French researchers. “Even though CIT is a well-known risk

The mean CIT for study subjects was 20.6 hours. CIT duration was 6 to 16

factor among the renal transplantation

hours for 1,274 patients (33.2%), 16 to

community, its precise etiological role

24 hours for 1,531 (39.9%), 24 to 36

on mid-term graft outcomes is still

hours for 853 (22.2%), and longer than

under debate as illustrated by the wide

36 hours for 181 (4.7%). Of the 3,839

heterogeneity of results observed in the

transplant recipients, 449 lost their graft

literature,” Agnes Debout, MD, of CHU

and 238 died with a functioning graft.

Overall, during the postoperative period, ESRD developed in 292 patients (2.5%). The group included 47 patients in the PN group (2.2%) compared with 245 patients in the RN group (2.5%). The mean time to progression to ESRD was 19 months and 38 months for patients in the RN and PN groups, respectively. The early cohort included 4,297 RN patients and 360 PN patients, which had unadjusted rates of ESRD of 3.7% and 8.6%, respectively. The modern cohort included 5,484 (76%) and 1,746 (24%) patients who underwent RN and PN, respectively, and their unadjusted rates of ESRD were 1.6% and 0.9, respectively. Dr. Yap and his colleagues noted that their study was limited by a lack of pathological and staging data. Patients initially presenting with T1a tumors (4 cm or less) represent an important subpopulation in which it is considered a standard of care to perform PN instead of RN, they pointed. “The major limitation of our pathological data is the inability to isolate this population.” n

Nantes, RTRS, and colleagues noted.

They pointed out that “there is no

tinence was significantly shorter in the allograft than no-allograft group (1.21 vs. 1.83 months) and the mean time to return of potency was significantly shorter in the allograft than no-allograft group (1.34 vs. 3.39 months). In addition, postoperative scores on the Sexual Health Inventory for Men questionnaire were significantly higher in the allograft than no-allograft group at maximal follow-up (16.2 vs. 9.1). The authors explained that despite RARP’s advantages, even patients with well-preserved NVBs experience a convalescent period characterized by incontinence and impotence. The researchers noted that they have been awaiting the next step in innovation that transcends the technical aspect of nerve sparing by biologically altering the prostatic NVB neuropraxia induced

by surgical dissection. Clinical use of growth factors and anti-inflammatory substances for prostatic NBV regeneration is novel, and dehydrated human amniotic membrane is source of implantable neurotrophic factors and cytokines, Dr. Patel and his colleagues explained. “While this approach appears promising, like any new advance, the scientific process will take its own time before we can pinpoint its impact on nerve and tissue regeneration,” said Ash Tewari, MBBS, MCh, Kyung Hyun Kim, MD Chair in Urology, Icahn School of Medicine at Mount Sinai and Chairman, Milton and Carroll Petrie Department of Urology at the Mount Sinai Health System in New York. Dr. Tewari, who has performed more than 5,000 robotic radical prostatec-

In a study of 3,839 adult recipients

consensus whether CIT should be

of a first deceased-donor kidney,

considered as a continuous risk factor

Dr. Debout’s team found that each

or whether threshold values can be con-

additional hour of CIT was associated

sidered to identify subgroups with a rel-

with a significant 1.3% increased risk of

evant excess in the risk of mid-term graft

graft failure and 1.8% increased risk of

and patient outcomes.” The investigators

death. Patients who received a kidney

stated that their results “suggest that

with a CIT of 30 hours had a significant

every additional hour of CIT matters.”

40% higher risk of graft failure and 53%

“These data provide solid evidence

higher risk of death than patients who

that even a short lengthening of CIT

received a kidney with a CIT of 6 hours,

may worsen the outcome of renal

the researchers reported in Kidney

transplantation,” commented Claudio

International (2015;87:343-349).

E. Ponticelli, MD, of Humanitas Clinical

At 1 year and 10 years, the risk of

and Research Center in Milan, Italy, in an

graft failure was 4% and 20%, respec-

accompanying editorial (pp. 272–275).

tively, for CIT less than 16 hours, 5%

Dr. Ponticelli explained that “cold

and 25% for CIT of 16 to 36 hours,

ischemia may initiate a cascade of

and 8% and 36% for CIT more than 36

reactions that are amplified by blood

hours, the study found.

reperfusion. The consequent injuries

“These findings are of practical clini-

can lead to kidney damage and to the

cal interest, as cold ischemia time is

activation of the immune response,

among one of the main modifiable pre-

both of which may impact on the out-

transplantation risk factors that can be

come after transplantation.” n

tomies, noted that recovery of urinary and sexual function following nervesparing prostatectomy is a multifactorial process involving baseline medical and anatomical variables, a nerve-sparing technique, a continence-sparing approach, postoperative rehabilitation, and the body’s ability to heal, which is determined by tissue injury, ischemia, inflammation, and residual scarring. “Optimal recovery requires a perfect interplay between these diverse processes, and dehydrated human amniotic membrane allograft nerve wrap could minimize excessive inflammation and scarring,” said Dr. Tewari, who added that he and his colleagues have submitted an application to his hospital’s institutional review board to study the utility of this membrane in their patients. n

www.renalandurologynews.com MARCH 2015

Renal & Urology News 13

NKF PREVIEW FEATURE n

Diagnosing and Managing Low Testosterone in CKD Low testosterone in men with CKD should not be treated routinely, but can be considered on an individual basis in some cases BY GUITY FARAHMAND, MD, AND KIRSTEN L. JOHANSEN, MD

Editor’s Note: Dr. Johansen will be presenting on this topic at the National Kidney Foundation’s 2015 Spring Clinical Meetings in Las Vegas. Her session, entitled, “What the Nephrologist Needs to Know About Under-recognized Endocrine Disorders in CKD,” is on Sunday, March 29, from 10:00 am to 11:30 am.

he prevalence of testosterone deficiency is reported to be 40%–60% among men on dialysis. Although there is insufficient information regarding the prevalence of testosterone deficiency in men with non-dialysis dependent chronic kidney disease (CKD), it appears to increase as renal function declines.1 Testosterone deficiency is associated with higher levels of inflammatory markers (interleukin-6, C-reactive protein) and also with all-cause and cardiovascular (CV)-related mortality among patients with end-stage renal disease.2 With this in mind, consensus on the diagnosis and management of testosterone deficiency in CKD patients remains important and is still evolving. Most testosterone in the circulation is bound to sex hormone-binding globulin (SHBG) or to albumin, with approximately 0.5%–3% present as free testosterone, the biologically active hormone. Under most circumstances, measuring total testosterone is adequate for diagnosing testosterone deficiency. Total testosterone, however, can provide inaccurate estimates of bioactive testosterone in situations where SHBG values are altered, including several that are common among patients with CKD. Specifically, SHBG

concentration may be low in patients with obesity, diabetes, and nephrotic syndrome and may be high in older patients. The Endocrine Society suggests measuring free testosterone levels in some men where total testosterone concentrations are near the lower limit of normal but alterations of SHBG are suspected.

Diagnosis The diagnosis of hypogonadism is usually based on at least 2 consecutive morning (when levels are highest) low serum testosterone levels in conjunction with clinical symptoms.3 Because serum testosterone concentrations decline with age, some argue that the reference range should be age-specific. For example, consider 2 studies that measure testosterone in young and elderly men. Bhasin et al.4 found the 2.5th percentile of total testosterone to be 348.3 ng/dL in a sample of young men compared with 184 ng/dL for a sample of elderly men studied by Yeap et al.5 Therefore, using the standard reference range could lead to over diagnosis in the elderly population if symptoms are not considered as part of the diagnosis.

Symptoms The diagnosis of hypogonadism is challenging because the signs and symptoms are non-specific and can vary based on age and comorbidities. Common symptoms that should be clearly defined include decreased libido, or the lack of sexual desire, and erectile dysfunction, the inability to acquire or maintain an erection needed for sexual intercourse. Other relatively specific signs include gynecomastia, loss of body hair, shrinking of testes, low sperm count, low bone

mineral density, and hot flushes. Less specific symptoms include decreased energy, motivation, self confidence, depressed mood, poor concentration and memory, sleep disturbances, anemia, reduced muscle mass and strength, increased body fat and body mass index, and decreased physical performance. Therefore, a thorough history and physical examination should be performed to assess for these signs and symptoms.

Testosterone replacement Clinical observations have suggested that low testosterone levels may have several adverse consequences, but the effect of testosterone replacement remains unclear. Trials have been limited by small sample size, different inclusion criteria, and variable testosterone regimens. There are even fewer data for the CKD population, so extrapolation from the general population is often necessary.

tion in patients with ESRD. In 1 study, researchers showed that administration of nandrolone deconate, a synthetic testosterone derivative, improved physical performance and increased lean body mass.9 In addition, studies of testosterone replacement among elderly men have generally shown improvement in the lean body mass, strength and physical function.10,11

Bone mineral density Studies of the effects of testosterone on outcomes related to bone mineral density in patients with CKD are also limited, but some data are available in the general elderly population. Although results of these studies are mixed, improvements are more pronounced for patients with lower pre-treatment testosterone levels.12,13 Given that the causes of bone disease in patients with CKD are multifactorial, with secondary hyperparathyroidism as a major underlying mechanism, it

Sexual function In the general population, a meta-analysis of 17 randomized controlled trials of testosterone replacement with 862 participants showed moderate improvements in libido with only a small effect on erectile dysfunction.6 In addition, 2 small studies that evaluated effects of testosterone on sexual function in ESRD patients found that most patients experienced improvement in but not normalization of sexual function.7,8

Physical function

Key Points n Testosterone deficiency is associ-

ated with all-cause and cardio vascular-related mortality in men with end-stage renal disease. n Testosterone deficiency appears

to increase as renal function declines. n Under most circumstances,

measuring total testosterone is adequate for diagnosing deficiency.

Although not specifically aimed at patients with hypogonadism, there have been a few trials evaluating the effects of androgen therapy on physical func-

n Patients receiving testosterone

replacement therapy should be reassessed frequently.

14 Renal & Urology News

MARCH 2015 www.renalandurologynews.com

may not be reasonable to generalize from the general elderly population to the CKD population.

Adverse effects Treatment with testosterone has known side effects, which include acne, male pattern baldness, gynecomastia, as well as more serious side effects, such as worsening sleep apnea, adverse CV outcomes, and accelerated growth of prostate cancer. With regard to CV outcomes, in a meta-analysis of 51 clinical trials, testosterone treatment was not associated with higher CV risk.14 Other evidence has been more concerning, however. A randomized controlled trial evaluating testosterone treatment in elderly men with mobility limitations and chronic disease was halted due to adverse CV events in the testosterone group.15 In addition, 2 retrospective studies showed a higher risk of myocardial infarction (MI) in patients treated with testosterone, although the absolute risks were low.16,17 These retro-

spective studies were limited by the lack of available data on total testosterone concentrations and the indications for, and doses of, testosterone treatment. As yet, the FDA has not concluded that testosterone therapy increases the risk of MI or mortality; however, it warns clinicians to be aware of the concerns while investigations are underway.

Conclusion Given the possible risk, especially among CKD patients who are already at high risk of cardiovascular disease, low testosterone levels should not be routinely treated among patients with CKD. However, treatment can be considered on an individual basis in symptomatic patients with poor physical function, fracture risk, and documented low testosterone levels. Patients receiving testosterone replacement therapy should be reassessed frequently, and therapy should be discontinued if benefit is not observed after a 3- to 6-month trial. n

Guity Farahmand, MD, is a clinical fellow and Kirsten L. Johansen, MD, is a professor of medicine in the D ivision of Nephrology at the University of California San Francisco.

References

1. Carrero JJ, Stenvinkel P. The vulnerable man: impact of testosterone deficiency on the uraemic phenotype. Nephrology Dial Transplant. 2012;27;4030-4031. 2. Carrero JJ, Qureshi AR, Parini P, et al. Low serum testosterone increases mortality risk among male dialysis patients. J Am Soc Nephrol. 2009;20:613-620. 3. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:2536-2559. 4. Bhasin S, Pencina M, Jasuja GK, et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab. 2011;96:2430-2439). 5. Yeap BB, Alfonso H, Chubb SA, et al. Reference ranges and determinants of testosterone, dihydro testosterone, and estradiol levels measured using liquid chromatography-tandem mass spectrometry in a population-based cohort of older men. J Clin Endocrinol Metab. 2012;97:4030-4039. 6. Boloña ER, Uraga MV, Haddad RM, et al. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebocontrolled trials. Mayo Clin Proc. 2007;82:20-28. 7. Canguven O, Aykose G, Albayrak S, et al. Efficacy of testosterone gel in the treatment of erectile dysfunction in hypogonadal hemodialysis patients: a pilot study. Int J Impot Res. 2009;22:140-145.

8. Lawrence IG, Price DE, Howlett TA, et al. Correcting impotence in the male dialysis patient: experience with testosterone replacement and vacuum tumescence therapy. Am J Kidney Dis. 1998;31:313-319. 9. Johansen KL, Mulligan K, Schambelan M. Anabolic effects of nandrolone decanoate in patients receiving dialysis: a randomized controlled trial. JAMA. 1999;281:1275-1281. 10. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2010;95(2):639-650. 11. Travison TG, Basaria S, Storer TW, et al. Clinical meaningfulness of the changes in muscle performance and physical function associated with testosterone administration in older men with mobility limitation. J Gerontol A Biol Sci Med Sci. 2011;66:1090-1099. 12. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab. 1999;84:1966-1972. 13. Kenny AM, Prestwood KM, Gruman CA, et al. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci. 2001;56:M266-M272. 14. Fernandez-Balsells MM, Murad MH, et al. Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2010;95:2560-2575. 15. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363:109-122. 16. Vigen R, O’Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310:1829-1836. 17. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of nonfatal myocardial infarction following testosterone therapy prescription in men. PLoS One;2014;9:e85805.

Study Quantifies Lives Saved by Organ Transplants IN A STUDY believed to be the largest yet conducted in the field of transplantation, researchers found that solid-organ transplantation saved about 2.3 million life-years in the United States over a 25-year period, an accomplishment they called “stellar.” “These life-years saved are in patients with end-organ failure, who are among the sickest patients,” the investigators wrote in an online report in JAMA Surgery. “Of note, the life-years saved were observed; there are no projections in this analysis.” In a retrospective study, Abbas Rana, MD, of Baylor College of Medicine in Houston, and colleagues analyzed data from the United Network for Organ Sharing data for solid-organ transplantation from September 1, 1987 through

December 13, 2012. They reviewed the records of 1,112,835 patients, including 533,329 who underwent a transplant and 579,506 who were placed on a waiting list but did not undergo a transplant.

About 2.3 million life-years were saved in the United States over a 25-year period. The researchers calculated the life-years saved by comparing patients who were on the waiting list but did not receive a transplant with patients who did. The observed number of life-years saved to date was 2,270,859 overall and

1,372,969, 465,296, 269,715, 64,575, 79,198, 14,903, and 4,402 for kidney, liver, heart, lung, pancreas-kidney, pancreas, and intestine recipients, respectively. Solid-organ transplants saved a mean of 4.3 life-years per solid-organ transplant recipient overall, according to the investigators. Kidney, liver, heart, lung, pancreas-kidney, pancreas, and intestine transplants saved a mean of 4.4, 4.3, 4.9, 2.6, 4.6, 2.4, and 2.8 life-years per recipient, respectively. The median survival time of patients with end-stage renal disease was 12.4 years for those who received a kidney transplant compared with 5.4 years for patients on a waiting list. The study also found a survival advantage for adult kidney transplant recipients of living-donor

transplants compared with deceaseddonor transplants (median survival time 18.5 years vs. 9.8 years). “These results refute any lingering perception of transplantation as a niche field with limited practical benefit,” Dr. Rana’s group concluded. “Furthermore, focusing exclusively on the survival benefit does not capture the vast improvements in quality of life and the drastically lowered morbidity rates after a transplant.” The researchers also observed, “Our analysis indicated that, as a nation, we achieved the peak volume in transplantation in 2006. The critical shortage of donors continues to hamper this field: only 47.9% of patients on the waiting list during the 25-year study period underwent a transplant.” n

Infection Risk Higher in Diabetic Patients with Chronic Kidney Disease BRITISH RESEARCHERS have found a high burden of infections among older adults with diabetes who have chronic kidney disease (CKD) not treated by dialysis or a kidney transplant. A reduced estimated glomerular filtration rate (eGFR) and a history of proteinuria were independent risk factors for lower respiratory tract infections (such as influenza and bronchitis), pneumonia, and sepsis.

The findings “appeared to be due in part to underlying accrued cardiovascular and cerebrovascular comorbid conditions,” the researchers stated. Still, a strong association remained after adjustment for these conditions. For the study, investigators led by Helen I. McDonald, BM BCh MSc, of the London School of Hygiene & Tropical Medicine analyzed data for more than 191,000 diabetes patients age 65 or older

with non-dialysis CKD from the United Kingdom’s Clinical Practice Research Datalink 1997– 2011.They found strong graded associations between lower eGFR and community-acquired infections, according to results published online ahead of print in the American Journal of Kidney Diseases. Sepsis was up to 5.5 times more prevalent among patients with an eGFR below 60 mL/min/1.73 m2. Patients with impaired kidney function

also had 1 to 3 times more cases of pneumonia. The chances of lower respiratory tract infections were also elevated. These findings can help clinicians identify patients at risk of infection and prompt discussions about possibly helpful vaccinations, according to the researchers. Treatment may raise the risk of infection in CKD patients receiving renal replacement therapy, the researchers noted. n