Renal & Urology News - Jan-Feb 2019 Issue

JA N UA R Y/F E B R UA R Y 2 019

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V O L U M E 18 , I S S U E N U M B E R 1

RP Complications Mostly Due to Age Postoperative risks rise as age at surgery increases

BY JOHN SCHIESZER VIRTUALLY ALL EARLY postoperative radical prostatectomy (RP) complications are directly related to patient age, investigators concluded based on a recent retrospective study. The influence of age on postoperative complications is especially pronounced among patients aged 70 years or older.

As a result of study findings, older patients should be informed about potentially higher complication rates, according to investigators. “Similarly, older patients may require longer hospital stay, even though the absolute

IN THIS ISSUE 10

Metabolic syndrome may raise premature ejaculation risk

13

ADT for men with Gleason 9–10 PCa does not improve survival

15

Ask the Experts: Managing AEs of medications for advanced PCa

16

High zinc intake may increase the likelihood of PCa

18

NAC vs AC prolongs disease-free survival in MIBC Exome sequencing may improve CKD treatment PAGE 17

increase in individual patients may be marginal at best,” the authors wrote in European Urology Focus.

The study found that each 1-year increase in age at the time of surgery independently predicted significant 2% increased odds of complications overall and 3%, 3%, and 2% increased odds of intraoperative, cardiac, and pulmonary complications, respectively, after adjusting for multiple variables, Felix Preisser, MD, of University Hospital Frankfurt in Germany, and colleagues reported. Increasing age also was associated with longer hospital stays.

Kidney Stones Increase RCC, UTUC Risk

BY JODY A. CHARNOW KIDNEY STONES ARE associated with an increased risk of papillary renal cell carcinoma (RCC) and upper tract urothelial carcinoma (UTUC), according to investigators.

In a study of 4352 participants in the prospective Netherlands Cohort Study (NLCS), Jeroen A.A. van de Pol, PhD, and colleagues at Maastricht University in Maastricht, The Netherlands, found that individuals who reported a history of kidney stones had a significant 39% greater risk of RCC overall compared with those who did not, after adjusting for multiple variables, Dr van de Pol’s continued on page 12

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OLDER PROSTATE SURGERY PATIENTS FARE WORSE According to a new study, men aged 70 years or older are at higher risk of various complications from radical prostatectomy compared with younger men. The magnitude of the increased risks of some complications are shown here.

Source: Preisser F, Mazzone E, Nazzani S, et al.

Impact of age on perioperative outcomes at radical prostatectomy: A population-based study. Eur Urol Focus. 2018; published online ahead of print.

Further, compared with patients younger than 70 years, those aged 70 years and older had significant 26% increased odds of overall complications, 43% increased odds of intraoperative complications, and 40%, 25%, 27%, and 27% increased odds of

Vascular

27%

Overall

26%

Intraoperative Genitourinary

40%

43%

Complication type

genitourinary, miscellaneous surgical, miscellaneous medical, and vascular complications, respectively.

For the study, Dr Preisser’s team used the National Inpatient Sample database to identify 68,780 patients with prostate continued on page 12

Prostate Cancer Tied to IBD MEN WITH inflammatory bowel disease (IBD) are at elevated risk of prostate cancer (PCa) overall as well as clinically significant PCa, new data suggest.

In a retrospective study comparing 1033 men with IBD and 9306 men without IBD matched by age and race (controls), investigators found that the 10-year incidence of any PCa was 4.4% in the IBD group compared with 0.65% in the control arm. The 10-year incidence of clinically significant PCa—defined as Gleason grade group 2 or higher—was 2.4% in the IBD group compared with 0.42% among controls. In adjusted analyses, the presence of IBD, compared with its

absence, was associated with a significant 4.8- and 4.0-fold increased risk of any PCa and clinically significant PCa, respectively, Jacob A. Burns, MD, of the Northwestern University Feinberg School of Medicine in Chicago, and colleagues reported in European Urology.

In addition, the study revealed that after about age 60, PSA values were higher among patients with than without IBD. “It is conceivable that the local or systemic inflammatory state resulting from IBD may lead to chronic prostatic inflammation and, in some cases, eventual development of PCa,” the authors explained. continued on page 12

CARING FOR PATIENTS WHO IGNORE ADVICE

Physicians are obliged to probe why patients refuse treatment.

PAGE 19

METS? NO METS? START XTANDI.

Regardless of metastatic status, XTANDI offers your patients with castration-resistant prostate cancer (CRPC) the confidence of proven efficacy when PSA is rising* during LHRH therapy.†1

*PSA level ≥ 2 ng/mL with at least 2 consecutive rises despite castrate testosterone levels (≤ 50 ng/dL).2-4

Indication and Important Safety Information Indication

XTANDI (enzalutamide) is indicated for the treatment of patients with castration-resistant prostate cancer (CRPC).

Important Safety Information Warnings and Precautions

Seizure occurred in 0.4% of patients receiving XTANDI in clinical studies.

In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. Patients in the study had one or more of the following pre-disposing factors: use of medications that may lower the seizure threshold; history of traumatic brain or head injury, cerebrovascular accident or transient ischemic attack, Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES. Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in clinical trials. Pharyngeal edema has been reported in post-marketing cases.

Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care.

Permanently discontinue XTANDI for serious hypersensitivity reactions.

Ischemic Heart Disease In the placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.7% vs 1.2%).

Grade 3-4 ischemic events occurred in 1.2% of patients on XTANDI versus 0.5% on placebo. Ischemic events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease.

Falls and Fractures In the placebo-controlled clinical studies, falls occurred in 10% of patients treated with XTANDI compared to 4% of patients treated with placebo. Fractures occurred in 8% of patients treated with XTANDI and in 3% of patients treated with placebo. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

Embryo-Fetal Toxicity Safety and efficacy of XTANDI have not been established in females. XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI. XTANDI should not be handled by females who are or may become pregnant.

Adverse Reactions

The most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in the XTANDI patients from the randomized placebo-controlled trials were asthenia/fatigue, decreased appetite, hot flush, arthralgia, dizziness/vertigo, hypertension, headache and weight decreased. In the bicalutamide-controlled study, the most common adverse reactions (≥ 10%) reported in XTANDI patients

120,000 PATIENTS

‡

HAVE BEEN PRESCRIBED XTANDI—AND COUNTING5

XTANDI significantly prolonged metastasis-free survival§ in patients with nonmetastatic CRPC and significantly extended overall survival and radiographic progression-free survival in patients with metastatic CRPC1 Nonmetastatic CRPC: Median metastasis-free survival was 3 years (36.6 months [95% CI, 33.1-NR]) with XTANDI + LHRH therapy† vs 14.7 months (95% CI, 14.2-15.0) with placebo + LHRH therapy† (HR = 0.29 [95% CI, 0.24-0.35]; P < 0.0001).1 • As seen in the PROSPER trial: a multinational, randomized, doubleblind phase 3 trial that enrolled 1401 patients with nonmetastatic CRPC who progressed on LHRH therapy†. Eligibility criteria included PSA doubling time ≤ 10 months and no prior chemotherapy1,3,6

Metastatic CRPC: 23% reduction in the risk of death with XTANDI + LHRH therapy† vs placebo + LHRH therapy† (HR = 0.77 [95% CI, 0.670.88]) and 83% reduction in the risk of radiographic progression or death vs placebo + LHRH therapy† (HR = 0.17 [95% CI, 0.14-0.21]; P < 0.0001).1 • As seen in the PREVAIL trial: a multinational, randomized, double-blind phase 3 trial that enrolled 1717 patients with metastatic CRPC who progressed on LHRH therapy†. Eligibility criteria included no prior chemotherapy1,7

Visit XtandiHCP.com for clinical trial results

Castration-resistant prostate cancer is defined as disease progression on androgen deprivation therapy (LHRH therapy or prior bilateral orchiectomy).8 CI, confidence interval; HR, hazard ratio; LHRH, luteinizing hormone-releasing hormone; NR, not reached; PSA, prostate-specific antigen. †Or after bilateral orchiectomy.1 ‡ Estimate based on US sales and data usage from September 2012 to October 2018.5 § The primary endpoint of the study was metastasis-free survival, defined as the time from randomization to whichever of the following occurred first: 1) loco-regional and/or distant radiographic progression per BICR (blinded independent central review); or 2) death up to 112 days after treatment discontinuation without evidence of radiographic progression.1

were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In the placebo-controlled study of metastatic CRPC (mCRPC) patients taking XTANDI who previously received docetaxel, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In the placebo-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups. In the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher adverse reactions were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an adverse event as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients. In the bicalutamide-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AE as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.

Lab Abnormalities: In the two placebo-controlled trials in patients with mCRPC, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). In the placebo-controlled trial in patients with nmCRPC, Grade 1-4 neutropenia occurred in 8% of patients receiving XTANDI (0.5% Grade 3-4) and in 5% of patients receiving placebo (0.2% Grade 3-4).

Hypertension: In the two placebo-controlled trials in patients with mCRPC, hypertension was reported in 11% of XTANDI patients and 4% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm. In the placebo-controlled trial in patients with nmCRPC, hypertension was reported in 12% of patients receiving XTANDI and 5% of patients receiving placebo.

Drug Interactions

Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI. Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI. Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is coadministered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see adjacent pages for Brief Summary of Full Prescribing Information.

References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Pfizer.

XTANDI. Data on File. 3. Protocol for: Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2018;378(26):2465-74.

4. Protocol for: Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371(5):424-33. 5. Astellas. XTANDI. Data on File.

6. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2018;378(26):2465-74. 7. Beer TM, Armstrong AJ, Rathkopf DE, et al., for the PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy.

N Engl J Med 2014;371(5):424-33. 8. Eisenberger MA, Saad F. Introduction—castration resistant prostate cancer: a rapidly expanding clinical state and a model for new therapeutic opportunities.

In: Saad F, Eisenberger MA, eds. Management of Castration Resistant Prostate Cancer. 1st ed.

New York, NY: Springer, 2014:3-8.

© 2019 Astellas Pharma US, Inc. and Pfizer Inc. All rights reserved.

Printed in USA. 076-4062-PM 1/19 XTANDI, Astellas, and the flying star logo are registered trademarks of Astellas Pharma Inc.

2 Renal & Urology News

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Study: Statins Underused by Patients With CKD STATINS ARE UNDERUSED by patients with chronic kidney disease (CKD), according to a new study.

An analysis of data from the National Health and Nutrition Examination Surveys (NHANES) from 1999–2002 through 2011–2014 showed that although statins were r­ecommended

to more than 65% of adults with CKD based on the American College of Cardiology/American Heart Association (ACC/AHA) 2013 cholesterol guideline, only 35.7% of adults with CKD were taking a statin in 2011–2014, a team led by Paul Muntner, PhD, of the University of Alabama at

XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary. Please see the package insert for full prescribing information.

INDICATIONS AND USAGE XTANDI is an androgen receptor inhibitor indicated for the treatment of patients with castrationresistant prostate cancer.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Seizure Seizure occurred in 0.4% of patients receiving XTANDI in clinical studies. In these trials, patients with predisposing factors for seizure were generally excluded. Seizure occurred from 13 to 604 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved.

In a single-arm trial designed to assess the risk of seizure in patients with pre-disposing factors for seizure, 8 of 366 (2.2%) XTANDI-treated patients experienced a seizure. Three of the 8 patients experienced a second seizure during continued treatment with XTANDI after their first seizure resolved. It is unknown whether antiepileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following pre-disposing factors: the use of medications that may lower the seizure threshold (~ 54%), history of traumatic brain or head injury (~ 28%), history of cerebrovascular accident or transient ischemic attack (~ 24%), and Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, past history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection (all < 5%). Approximately 17% of patients had more than one risk factor.

Advise patients of the risk of developing a seizure while receiving XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue XTANDI in patients who develop PRES. Hypersensitivity Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with enzalutamide in four randomized clinical trials. Pharyngeal edema has been reported in post-marketing cases.

Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care.

Permanently discontinue XTANDI for serious hypersensitivity reactions.

Ischemic Heart Disease In the combined data of three randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the

Birmingham, reported in the Journal of the American Heart Association.

The 2013 guideline did not include CKD as a statin benefit group, the investigators pointed out. The 2018 ACC/AHA guideline, however, considers CKD a risk-enhancing factor for the primary prevention of atherosclerotic placebo arm (2.7% vs 1.2%). Grade 3-4 ischemic events occurred in 1.2% of patients in the XTANDI arm compared to 0.5% in the placebo arm.

Ischemic events led to death in 0.4% of patients in the XTANDI arm compared to 0.1% in the placebo arm.

Monitor for signs and symptoms of ischemic heart disease. Optimize cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia.

Discontinue XTANDI for Grade 3-4 ischemic heart disease.

Falls and Fractures Falls and fractures occurred in patients receiving XTANDI. Evaluate patients for fracture and fall risk.

Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

In the combined data of three randomized, placebo-controlled clinical studies, falls occurred in 10% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fractures occurred in 8% of patients treated with XTANDI and in 3% of patients treated with placebo. Grade 3-4 fractures occurred in 2% of patients treated with XTANDI and in < 1% of patients treated with placebo. The median time to onset of fracture was 337 days (range: 2 to 996 days) for patients treated with XTANDI. Routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not performed in the studies.

Embryo-Fetal Toxicity The safety and efficacy of XTANDI have not been established in females. Based on animal reproductive studies and mechanism of action, XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI. XTANDI should not be handled by females who are or may become pregnant.

ADVERSE REACTIONS 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 practice.

Four randomized controlled clinical trials enrolled patients with CRPC that had progressed on androgen deprivation therapy (GnRH therapy or prior bilateral orchiectomy). Three trials were placebo-controlled and one trial was bicalutamidecontrolled. Patients received XTANDI 160 mg (2784 patients) or placebo orally once daily (1708 patients) or bicalutamide 50 mg orally once daily (189 patients). All patients continued androgen deprivation therapy (ADT).

The most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in the XTANDI-treated patients from the randomized placebo-controlled clinical trials were asthenia/ fatigue, decreased appetite, hot flush, arthralgia, dizziness/vertigo, hypertension, headache, and weight decreased.

AFFIRM (NCT00974311): XTANDI versus Placebo in Metastatic CRPC Following Chemotherapy AFFIRM enrolled 1199 patients with metastatic CRPC who had previously received docetaxel.

The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients.

Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most

cardiovascular disease (ASCVD) and recommends statins for adults with non-dialysis-dependent CKD who have LDL levels of 70 mg/dL or higher and a 10-year ASCVD risk of 7.5% or higher.

Implementation of this guideline, they noted, “may increase the appropriate use of statins in this high-risk population.” common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in AFFIRM that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in AFFIRM XTANDI Placebo N = 800 N = 399 Grade Grade Grade Grade 1 3-4 1-4 3-4 1-4 (%) (%) (%) (%) General Disorders Asthenic 51 9.0 44 9.3 Conditions2 Peripheral 15 1.0 13 0.8 Edema Musculoskeletal and Connective Tissue Disorders Back Pain 26 5.3 24 4.0 Arthralgia 21 2.5 17 1.8 Musculo15 1.3 12 0.3 skeletal Pain Muscular 9.8 1.5 6.8 1.8 Weakness Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness Gastrointestinal Disorders Diarrhea 22 1.1 18 0.3 Vascular Disorders Hot Flush 20 0.0 10 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12 0.9 5.5 0.0 Dizziness3 9.5 0.5 7.5 0.5 Spinal Cord Compression and Cauda 7.4 6.6 4.5 3.8 Equina Syndrome Paresthesia 6.6 0.0 4.5 0.0 Mental Impairment 4.3 0.3 1.8 0.0 Disorders4 Hypoesthesia 4.0 0.3 1.8 0.0 Infections and Infestations Upper Respiratory 11 0.0 6.5 0.3 Tract Infection5 Lower Respiratory 8.5 2.4 4.8 1.3 Tract and Lung Infection6 Psychiatric Disorders Insomnia 8.8 0.0 6.0 0.5 Anxiety 6.5 0.3 4.0 0.0 Renal and Urinary Disorders Hematuria 6.9 1.8 4.5 1.0 Pollakiuria 4.8 0.0 2.5 0.0 Injury, Poisoning and Procedural Complications Fall 4.6 0.3 1.3 0.0 Nonpathologic 4.0 1.4 0.8 0.3 Fractures Skin and Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin 3.5 0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 1.

2.

3.

4.

CTCAE v4 Includes asthenia and fatigue.

Includes dizziness and vertigo.

Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.

5. Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.

6. Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

www.renalandurologynews.com JANUARY/ FEBRUARY 2019

From 1999–2002 to 2011–2014, the proportion of adults taking statins increased from 17.6% to 35.7% for those with CKD and from 6.8% to 14.7% for those without CKD, Dr Muntner and his colleagues reported.

In 2011–2014, 65.3% of individuals with CKD had an indication for statin use based on the 2013 guideline compared with 27.4% of those without CKD. Among those with and without PREVAIL (NCT01212991): XTANDI versus Placebo in Chemotherapy-naïve Metastatic CRPC PREVAIL enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebo-treated patients.

Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in PREVAIL that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Table 2. Adverse Reactions in PREVAIL XTANDI Placebo N = 871 N = 844 Grade Grade Grade Grade 1 3-4 1-4 3-4 1-4 (%) (%) (%) (%) General Disorders Asthenic 47 3.4 33 2.8 Conditions2 Peripheral 12 0.2 8.2 0.4 Edema Musculoskeletal and Connective Tissue Disorders Back Pain 29 2.5 22 3.0 Arthralgia 21 1.6 16 1.1 Gastrointestinal Disorders Constipation 23 0.7 17 0.4 Diarrhea 17 0.3 14 0.4 Vascular Disorders Hot Flush 18 0.1 7.8 0.0 Hypertension 14 7.2 4.1 2.3 Nervous System Disorders 11 0.3 7.1 0.0 Dizziness3 Headache 11 0.2 7.0 0.4 Dysgeusia 7.6 0.1 3.7 0.0 Mental Impairment 5.7 0.0 1.3 0.1 Disorders4 Restless Legs 2.1 0.1 0.4 0.0 Syndrome Respiratory Disorders 11 0.6 8.5 0.6 Dyspnea5 Infections and Infestations Upper Respiratory 16 0.0 11 0.0 Tract Infection6 Lower Respiratory 7.9 1.5 4.7 1.1 Tract and Lung 7 Infection Psychiatric Disorders Insomnia 8.2 0.1 5.7 0.0 Renal and Urinary Disorders Hematuria 8.8 1.3 5.8 1.3 Injury, Poisoning and Procedural Complications Fall 13 1.6 5.3 0.7 NonPathological 8.8 2.1 3.0 1.1 Fracture Metabolism and Nutrition Disorders Decreased 19 0.3 16 0.7 Appetite Investigations Weight 12 0.8 8.5 0.2 Decreased Reproductive System and Breast Disorders 1.4 0.0 0.0 Gynecomastia 3.4

CKD, statin use increased in each CVD risk group except for adults who had CKD and a 10-year predicted ASCVD risk less than 7.5%, according to the investigators.

On multivariable analysis, individuals with CKD were not more likely to be taking statins compared with those who did not have CKD. Statin use was significantly lower among individuals with CKD in the Table 2. Adverse Reactions in PREVAIL 1.

2.

3.

4.

CTCAE v4 Includes asthenia and fatigue.

Includes dizziness and vertigo.

Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.

5. Includes dyspnea, exertional dyspnea, and dyspnea at rest.

6. Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.

7. Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

TERRAIN (NCT01288911): XTANDI versus Bicalutamide in Chemotherapy-naïve Metastatic CRPC TERRAIN enrolled 375 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 372 received at least one dose of study drug. The median duration of treatment was 11.6 months with XTANDI and 5.8 months with bicalutamide. Discontinuations with an adverse event as the primary reason were reported for 7.6% of XTANDI-treated patients and 6.3% of bicalutamide-treated patients. The most common adverse reactions leading to treatment discontinuation were back pain and pathological fracture, which occurred in 3.8% of XTANDI-treated patients for each event and in 2.1% and 1.6% of bicalutamide-treated patients, respectively. Table 3 shows overall and common adverse reactions (≥ 10%) in XTANDI-treated patients.

Table 3. Adverse Reactions in TERRAIN XTANDI Bicalutamide N = 183 N = 189 Grade Grade Grade Grade 1 3-4 1-4 3-4 1-4 (%) (%) (%) (%) Overall 94 39 94 38 General Disorders Asthenic 32 1.6 23 1.1 Conditions2 Musculoskeletal and Connective Tissue Disorders Back Pain 19 2.7 18 1.6 Musculo16 1.1 14 0.5 3 skeletal Pain Vascular Disorders Hot Flush 15 0 11 0 Hypertension 14 7.1 7.4 4.2 Gastrointestinal Disorders Nausea 14 0 18 0 Constipation 13 1.1 13 0.5 Diarrhea 12 0 9.0 1.1 Infections and Infestations Upper Respiratory 12 0 6.3 0.5 Tract Infection4 Investigational Weight 11 0.5 7.9 0.5 Loss 1.

2.

3.

4.

CTCAE v 4 Includes asthenia and fatigue.

Includes musculoskeletal pain and pain in extremity.

Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.

PROSPER (NCT02003924): XTANDI versus Placebo in Non-metastatic CRPC Patients PROSPER enrolled 1401 patients with nonmetastatic CRPC, of whom 1395 received at least one dose of study drug. Patients were randomized 2:1 and received either XTANDI at a dose of 160 mg once daily (N = 930) or placebo (N = 465). The median duration of treatment at the time of analysis was 18.4 months (range: 0.0 to 42 months) with XTANDI and 11.1 months (range: 0.0 to 43 months) with placebo.

Overall, 32 patients (3.4%) receiving XTANDI died from adverse events. The reasons for death with ≥ 2 patients included coronary artery disorders (n = 7), sudden death (n = 2), cardiac arrhythmias (n = 2), general physical health deterioration (n = 2), stroke (n = 2), and secondary malignancy (n = 5; one each of acute myeloid leukemia, brain neoplasm, mesothelioma, small cell lung cancer, and malignant neoplasm of unknown primary site). Three patients (0.6%) receiving placebo died from adverse events

absence of diabetes mellitus compared with those who had diabetes mellitus but not CKD. “This difference highlights the importance of recognizing the high CVD risk in patients with CKD and potential benefits of increased statin utilization,” the investigators wrote.

NHANES includes a nationally representative sample of the noninstitutionalized civilian US population. For of cardiac arrest (n = 1), left ventricular failure (n = 1), and pancreatic carcinoma (n = 1). Grade 3 or higher adverse reactions were reported among 31% of XTANDI-treated patients and 23% of placebo-treated patients. Discontinuations with an adverse event as the primary reason were reported for 9.4% of XTANDI-treated patients and 6.0% of placebo-treated patients. Of these, the most common adverse event leading to treatment discontinuation was fatigue, which occurred in 1.6% of the XTANDI-treated patients compared to none of the placebo-treated patients. Table 4 shows adverse reactions reported in PROSPER that occurred at a ≥ 2% higher frequency in the XTANDI arm than in the placebo arm.

Table 4. Adverse Reactions in PROSPER XTANDI Placebo N = 930 N = 465 Grade Grade Grade Grade 1 1-4 3-4 1-4 3-4 (%) (%) (%) (%) Metabolism and Nutrition Disorders Decreased 9.6 0.2 3.9 0.2 Appetite Nervous System Disorders Dizziness2 12 0.5 5.2 0 Headache 9.1 0.2 4.5 0 Cognitive 4.6 0.1 1.5 0 and Attention Disorders3 Vascular Disorders Hot Flush 13 0.1 7.7 0 Hypertension 12 4.6 5.2 2.2 Gastrointestinal Disorders Nausea 11 0.3 8.6 0 Constipation 9.1 0.2 6.9 0.4 General Disorders and Administration Site Conditions Asthenic 40 4.0 Conditions4 Investigations Weight 5.9 0.2 Decreased Injury, Poisoning and Procedural Complications Fractures5 9.8 2.0 Fall 11 1.3 Psychiatric Disorders Anxiety 2.8 0.2

20

0.9

1.5

0

4.9 4.1

1.7 0.6

0.4

0

1. CTCAE v4 2. Includes dizziness and vertigo.

3. Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.

4. Includes asthenia and fatigue.

5. Includes all osseous fractures from all sites.

Laboratory Abnormalities In the AFFIRM and PREVAIL studies in metastatic CRPC, Grade 1-4 neutropenia occurred in 15% of patients receiving XTANDI (1% Grade 3-4) and in 6% of patients receiving placebo (0.5% Grade 3-4).

Table 5 shows laboratory abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the PROSPER study.

Table 5. Laboratory Abnormalities in PROSPER XTANDI Placebo N = 930 N = 465 Grade Grade Grade Grade 1-4 3-4 1-4 3-4 (%) (%) (%) (%) Hematology Neutropenia 8.2 0.5 5.4 0.2 Chemistry Hyponatremia 16 1.3 8.8 1.5 Hyperglycemia 78 2.9 73 1.3 Hyper26 0 21 0 magnesemia

Renal & Urology News 3

their analysis, Dr Muntner and his collaborators included 38,336 participants aged 20 years and older. The group included 7153 individuals with CKD and 31,183 without CKD. The researchers defined CKD as an estimated glomerular filtration rate below 60 mL/ min/1.73 m2. Adults with CKD were more likely than those without CKD to be obese and to have hypertension, diabetes mellitus, and a history of CVD. ■

4 Renal & Urology News

JANUARY/ FEBRUARY 2019 www.renalandurologynews.com

Dyskalemia Common in Patients With Heart Failure DYSKALEMIA OCCURS frequently among patients with heart failure (HF) and is associated with increased mortality, according to a study that identified independent predictors of hyper- and hypokalemia in this patient population.

The study included 5848 patients enrolled in the Swedish HF registry from Hypertension In the AFFIRM and PREVAIL studies in metastatic CRPC, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm. In the PROSPER study in nonmetastatic CRPC, hypertension was reported in 12% of patients receiving XTANDI and 5% of patients receiving placebo.

Post-Marketing Experience The following additional adverse reactions have been identified during post-approval use of XTANDI. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Body as a Whole: hypersensitivity (edema of the face, tongue, lip, or pharynx) Gastrointestinal Disorders: vomiting Neurological Disorders: posterior reversible encephalopathy syndrome (PRES) Skin and Subcutaneous Tissue Disorders: rash DRUG INTERACTIONS Drugs that Inhibit CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible.

If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI. Drugs that Induce CYP3A4 Co-administration of rifampin (strong CYP3A4 inducer and moderate CYP2C8 inducer) decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%. Coadministration of strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) with XTANDI should be avoided if possible. St John’s wort may decrease enzalutamide exposure and should be avoided. If co-administration of a strong CYP3A4 inducer with XTANDI cannot be avoided, increase the dose of XTANDI. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady-state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin, clopidogrel) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary The safety and efficacy of XTANDI have not been established in females. Based on animal reproductive studies and mechanism of action, XTANDI can cause fetal harm and loss of pregnancy.

There are no human data on the use of XTANDI in pregnant females. In animal reproduction studies, oral administration of enzalutamide in pregnant mice during organogenesis caused adverse developmental effects at doses lower than the maximum recommended human dose (see Data).

XTANDI should not be handled by females who are or may become pregnant.

Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity

2006 to 2011 in Stockholm, Sweden, and examined the 1-year incidence and predictors of dyskalemia and its outcomes.

Of these patients, 24.4% experienced hyperkalemia (potassium level above 5.0 mmol/L) at least once, 10.2% had moderate to severe hyperkalemia (potassium level greater than 5.5 mmol/L), and 3.7% when administered at oral doses of 10 or 30 mg/ kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryofetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/ day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients.

Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC).

In a pharmacokinetic study in pregnant rats with a single oral 30 mg/kg enzalutamide administration on gestation day 14, enzalutamide and/or its metabolites were present in the fetus at a Cmax that was approximately 0.3 times the concentration found in maternal plasma and occurred 4 hours after administration.

Lactation Risk Summary The safety and efficacy of XTANDI have not been established in females. There is no information available on the presence of XTANDI in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production.

Enzalutamide and/or its metabolites were present in milk of lactating rats (see Data).

Data Following a single oral administration in lactating rats on postnatal day 14, enzalutamide and/or its metabolites were present in milk at a Cmax that was 4 times higher than concentrations in the plasma and occurred 4 hours after administration.

Females and Males of Reproductive Potential Contraception Males Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of XTANDI. Infertility Males Based on animal studies, XTANDI may impair fertility in males of reproductive potential.

Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established.

Geriatric Use Of 2784 patients who received XTANDI in four randomized controlled clinical trials, 79% were 65 and over, while 36% were 75 and over. No overall differences in safety or effectiveness were observed between these 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 Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed.

Patients with Hepatic Impairment Dedicated hepatic impairment trials compared the composite systemic exposure of enzalutamide

had severe hypokalemia (potassium level below 3.0 mmol/L).

The risk of moderate or severe hyperkalemia was highest among patients with preserved ejection fraction (EF) and HF with mid-range EF, whereas the risk of hypokalemia was highest among those with preserved EF, plus N-desmethyl enzalutamide in volunteers with baseline mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild, moderate, or severe baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild, moderate, or severe hepatic impairment.

OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days.

In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Administration of enzalutamide to male and female rasH2 transgenic mice by oral gavage daily for 26 weeks did not result in increased incidence of neoplasms at doses up to 20 mg/kg/day.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay.

Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).

Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Pfizer Inc., New York, NY 10017 Revised: July 2018 198511-XTA-USA Rx Only © 2018 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

Gianluigi Savarese, MD, PhD, of the Karolinska Institutet in Stockholm, Sweden, and colleagues reported in JACC: Heart Failure.

Independent predictors of both hyper- and hypokalemia were sex, high and low baseline potassium level, low estimated glomerular filtration rate, chronic obstructive pulmonary disease, New York Heart Association functional class, and low hemoglobin, according to the investigators.

Dyskalemia was associated with increased mortality. Hypokalemia was associated with an increased risk of hospitalizations due to cardiovascular disease (HF-related excluded). The study found no association between dyskalemia and HF hospitalization risk, regardless of EF, the investigators reported. ■

Study: ESRD Risk Higher With Crohn’s PATIENTS WITH CROHN’S disease (CD) are at higher risk of end-stage renal disease (ESRD), investigators in South Korea reported.

In a retrospective study, Joo Sung Kim, MD, PhD, of Seoul National University College of Medicine, and colleagues compared 38,812 patients with inflammatory bowel disease (IBD)—either CD or ulcerative colitis (UC)—with 116,436 age- and sexmatched controls without IBD. During a mean follow-up period of .9 years, ESRD was diagnosed in 79 patients with IBD (0.2%) and 166 controls (0.1%). The incidence of ESRD, per 1000 person-years, was 0.42 in the IBD group compared with 0.29 among

076-3717-PM

controls. The incidence of ESRD was significantly higher among patients with CD compared with controls (0.51 vs 0.13), Dr Kim’s team reported in the World Journal of Gastroenterology. In adjusted analyses, the CD group had a significant 6.3-fold greater risk of ESRD than controls. In contrast, the incidence of ESRD in the UC and control patients did not differ significantly.

“Patients with CD should be monitored carefully for signs of renal insufficiency,” the investigators concluded. ■

www.renalandurologynews.com JANUARY/ FEBRUARY 2019

Renal & Urology News 5

FROM THE ADVISORY BOARD 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 Professor & Chief Division of Nephrology & Hypertension University of California, Irvine School of Medicine Orange, Calif.

Urologists

Nephrologists

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

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

R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto

David S. Goldfarb, MD Professor, Department of Medicine Clinical Chief New York University Langone Medical Center Chief of Nephrology, NY Harbor VA Medical Center

Stanton Honig, MD Department of Urology Yale University School of Medicine New Haven, CT J. Stephen Jones, MD, FACS Chief Executive Officer Inova Health System Professor and Horvitz/Miller Distinguished Chair in Urologic Oncology CCLCM (ret.)

Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology University of California Irvine James M. McKiernan, MD John K. Lattimer Professor of Urology Chair, Department of Urology Director, Urologic Oncology Columbia University College of Physicians and Surgeons, New York City Kenneth Pace, MD, MSc, FRCSC Assistant Professor, Division of Urology St. Michael’s Hospital University of Toronto Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada

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. Rulan Parekh, MD, MS Associate Professor of Pediatrics and Medicine 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.

Renal & Urology News Staff

Editor Jody A. Charnow Web editor

Natasha Persaud

Production editor Kim Daigneau

Group art director, Haymarket Medical Jennifer Dvoretz

Senior production manager Krassi Varbanov

Director of production Louise Morrin Boyle Assistant manager, audience development Ashley Noelle Director of audience insights Paul Silver National accounts manager William Canning

Vice president, content, medical communications

Kathleen Walsh Tulley

General manager, medical communications

Jim Burke, RPh

President, medical communications

CEO, Haymarket Media Inc.

Michael Graziani Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 18, Number 1. Published bimonthly by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales & Editorial, call (646) 638-6000 (M–F, 9am–5pm, ET). Postmaster: Send address changes to Renal & Urology News, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018.

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 © 2019.

Exome Sequencing Opens a New Chapter in CKD

A

recent article in The New England Journal of Medicine titled “Diagnostic Utility of Exome Sequencing for Kidney Disease” offers us unique insights into the future diagnostic evaluation of chronic kidney disease (CKD).

The most important takeaways from the article by Groopman et al. are that nearly 1 in 10 patients with CKD have a genetic cause of kidney disease, which often is undiagnosed, and that whole exome sequencing can be helpful in making these diagnoses.

The investigators undertook whole exome sequencing of 3315 individuals with CKD. In whole exome sequencing, the nucleotide sequence of the human genome that codes for proteins (exons) is determined. Results were compared with exome sequences of thousands of healthy individuals to determine genetic differences.

The investigators focused attention on genes that were expressed in the kidney and were likely to be relevant to kidney pathology.

The study found that 307 patients (9.3%) suffered from a monogenic disorder as the cause of kidney disease, with 66 different genetic conditions identified. As one would expect, autosomal dominant polycystic kidney disease was the most common cause, with 97 individuals affected (accounting for 2.9% of cases of kidney disease and 31% of cases with inherited kidney disease). The next most common causes of inherited kidney disease were mutations in the COL4A3, COL4A4, and COL4A5 genes, found in 91 individuals (30% of inherited kidney disease). Importantly, 39 of the 66 genetic disorders identified were each found in only a single individual.

Uncommon genetic disorders included mutations in the gene encoding hepatocyte nuclear factor-1 beta and branchio-oto-renal syndrome.

These results point to a future when whole exome sequencing will be the method of choice for identifying genetic causes of CKD. Instead of targeted gene analysis (for example, in Alport syndrome or polycystic kidney disease), clinicians will screen the whole genome at once. Study findings should encourage nephrologists to take a more thorough family history and give greater consideration to inherited kidney diseases in the differential diagnosis. Nephrologists should more actively pursue a genetic diagnosis, especially when multiple family members have CKD. Although many of the inherited kidney diseases are not currently treatable, a proper genetic diagnosis will provide families with the cause of CKD, avoid unnecessary kidney biopsies that may not be diagnostic, and allow for screening of family members as potential kidney donors. This year, let us resolve to think more not just about our own families, but the families we see with kidney disease.

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

6 Renal & Urology News

JANUARY/ FEBRUARY 2019

www.renalandurologynews.com

Contents

J A N U A R Y/ F E B R U A R Y 2 0 1 9 ■ V O L U M E 1 8 , I S S U E N U M B E R 1

Urology 10

ONLINE

this month at renalandurologynews.com Clinical Quiz Test your knowledge by taking our latest quiz at renalandurologynews.com/ run-quiz

11

13

15

HIPAA Compliance Read timely articles on various issues related to keeping protected health information secure.

Drug Information Search a comprehensive drug database for prescribing and other information on more than 4000 drugs.

4

Job Board

17

News Coverage Visit our website for daily reports on the latest developments in clinical research.

Prostate RT May Be Beneficial in Metastatic PCa Prostate radiotherapy appears to improve survival among prostate cancer patients with low-burden metastatic disease.

Mortality Unaffected by ADT for Gleason 9–10 PCa Lack of a survival benefit might be related to the Gleason pattern 5 disease, according to investigators.

Managing the Adverse Effects of Prostate Cancer Medications Three experts provide insight into common problems associated with pharmacotherapy for advanced prostate cancer.

CALENDAR 2019 European Association of Urology 34th Congress Barcelona, Spain March 15–19 American Urological Association Annual Meeting Chicago May 3–6 National Kidney Foundation Spring Clinical Meetings Boston May 7–11 American Transplant Congress Boston June 1–5 ERA-EDTA 56th Congress Budapest, Hungary June 13–16 Canadian Urological Association Annual Meeting Quebec City June 29–July 1

Nephrology

14 Be sure to check our latest listings for professional openings across the United States.

NAC Not Linked to Post-RC Short-Term Complications Radical cystectomy patients who received neoadjuvant chemotherapy had an overall 30-day postoperative complication rate similar to those who did not.

18

Dyskalemia Common in Patients With Heart Failure The 1-year incidence of hyper- and hypokalemia was 24.4% and 3.7%, respectively, and both conditions were associated with increased mortality, a new study found.

Gout Raises Parkinson’s Disease Risk Among patients at least 65 but less than 75 years of age, gout was associated with a significant 27% increased risk of the progressive nervous system disorder.

Genetic Test Zeroes In on Hereditary CKD Whole exome sequencing found diagnostic genetic variants in nearly 1 in 10 individuals with chronic kidney disease.

Study: CKD Burden Growing in the US Increased risk exposure, aging, and population are among the factors contributing to the trend, according to investigators.

20

Departments 5

10

News in Brief Testosterone could have a role in urate homeostasis

19

Ethical Issues in Medicine Managing patients who refuse treatment recommendations

20

Practice Management Employee errors are a common cause of information breaches

Prostate radiotherapy should be a standard

treatment option for men with newly diagnosed disease with a low metastatic burden.

See our story on page 11

From the Advisory Board Exome sequencing in CKD is a possible game changer

10 Renal & Urology News

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News in Brief

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

Short Takes MetS May Increase Risk of Premature Ejaculation

related deaths in the general popula-

Metabolic syndrome (MetS) may be an

University of Sydney in Australia, and

independent risk factor for acquired

colleagues reported. Excess stroke-

premature ejaculation (PE).

related deaths among patients with

In a study of 1029 men, Seong Uk Jeh, MD, of Gyeongsang National

tion, Nicole L. De La Mata, PhD, of the

ESRD were markedly higher among younger patients and women.

­University Hospital, Gyeongsang Medicine, Jinju, Korea, and col-

Study Links Testosterone to Urate Homeostasis

leagues found that men with MetS had

Testosterone could have a role in

significant 2.2-fold greater odds of

urate homeostasis, according to a

acquired PE than those without MetS,

new study published in PLoS One

in multivariable analysis, according to

(2018;13:e0209049).

­National University School of

study findings published in the World Journal of Men’s Health.

150 received androgen deprivation

Death from Stroke is More Common in ESRD Patients

therapy (ADT) and 339 underwent

Death from stroke is much more

groups had similar baseline serum

common among patients with end-

urate levels (5.8 vs 5.7 mg/dL) and

stage renal disease (ESRD) than in the

proportions of hyperuricemia (18% vs

general population, according to study

15.9%).

surgery. The ADT and surgery

At 6 months, urate levels had decreased significantly by 0.66 mg/dL

print in Stroke.

The study included 60,823 patients

in the ADT group compared with base-

with incident ESRD in Australia and

line, but did not change significantly

New Zealand. Of these, 941 died from

in the surgery group. In addition, the

stroke during 381,874 person-years,

proportion of patients with hyperurice-

an incidence 3.4 times greater than

mia was significantly lower in the ADT

the incidence of expected stroke-

than surgery group (4.7% vs 16.5%).

PCa Survival Trends By Race Five-year survival rates among white and black men diagnosed with prostate cancer have been on the rise from 1975 to 2013, as shown below, but survival among blacks continues to lag behind that of whites. >99%

100

97% ■ Whites ■ Blacks

84% 80 60

69%

71% 61%

40 20 0

1975–77

1987–89 Yearly range

Source: American Cancer Society. Cancer Facts & Figures 2018.

n selected patients undergoing radical cystectomy (RC) for muscle-invasive bladder cancer, neoadjuvant chemotherapy (NAC) is not associated with an increased risk of short-term postoperative complications, new findings suggest.

In a retrospective study of 491 patients undergoing RC—of whom 102 (20.8%) received NAC—a team led by Steven Joniau, MD, of University Hospitals Leuven in Louvain, Belgium, observed no significant difference in overall 30-day postoperative complications between the NAC and RC-only groups (69% and 66%, respectively), after propensity score covariate adjustment. The study, published in the World Journal of Urology, found no significant difference in 30-day high-grade complications (11.76% and 11.83%). Although the NAC group had worse prognostic factors at baseline, the 5-year overall survival rates and 5-year cancer-specific survival rates did not differ significantly between the NAC and RC-only group (61.3% vs 50.2% and 61.8% vs 57.9%, respectively).

The study compared 489 patients with prostate cancer (PCa), of whom

findings published online ahead of

NAC Not Linked to Post-RC Short-Term Complications I

2007–13

Continuing Loop Diuretics May Benefit HD Patients C

ontinuing patients on loop diuretics following hemodialysis (HD) initiation is associated with decreased rates of hospitalization and intradialytic hypotension.

Scott Sibbel, PhD, of DaVita Clinical Research in Minneapolis, Minnesota, and colleagues identified 11,297 patients who had an active supply of a loop diuretic at the start of HD. Of these, 5219 patients refilled a loop diuretic following HD initiation and 6078 did not (controls). Patients had up to 12 months of follow-up.

The hospitalization rate was 1.84 admissions per patient-year among patients who continued on loop diuretics compared with 2.10 among controls, the investigators reported in the Clinical Journal of the American Society of Nephrology. The intradialytic hypotension rate was 22.7 episodes per patient-year in the diuretic continuation group compared with 24.3 in the control arm. The diuretic continuation group also experienced less interdialytic weight gain than controls (mean 1.8 vs 1.9 kg). The death rate did not differ between the groups.

Royal Jelly May Ease Adverse Effects of RCC Drug Therapy R

oyal jelly (RJ), a substance secreted by worker honeybees that is the exclusive food for queen bees, may ease the adverse effects of tyrosine kinase inhibitor (TKI) therapy for advanced renal cell carcinoma (RCC), a small study suggests.

The double-blind, placebo-controlled, randomized study enrolled 33 patients with advanced RCC who were randomly assigned to receive RJ orally or placebo at the start of TKI therapy, which was sunitinib in 63% of cases. Overall, no fatigue and no anorexia occurred in 68.8% of the RJ group compared with 11.8% and 23.5% in the placebo arm, respectively, Kyohei Araki, MD, of Nagasaki University Graduate School of Biomedical Sciences in Nagasaki, Japan, and colleagues reported in Medicines. The protective effect of RJ was only significant among sunitinib recipients.

In this group, 60% and 80% of RJ recipients experienced no fatigue or anorexia, respectively, compared with 9.1% and 27.3% of placebo recipients, respectively.

www.renalandurologynews.com JANUARY/FEBRUARY 2019

Renal & Urology News 11

Prostate RT May Be Beneficial in Metastatic PCa PROSTATE radiotherapy (RT) may improve survival of men with newly diagnosed metastatic prostate cancer (PCa) as long as metastatic burden is low, according to a new report.

In a study of men with metastatic PCa in the phase 3 STAMPEDE trial, the overall survival (OS) rate among men with low metastatic burden at 3 years was 81% among recipients of prostate RT compared with 73% among control patients who received standard of care alone. Prostate RT was associated with a significant 32% decreased risk of death in adjusted analyses, Christopher C. Parker, MD, of Royal Marsden Hospital and Institute of Cancer Research, both in London, reported in The Lancet. The study found no OS benefit for radiotherapy recipients overall and for patients with high metastatic burden.

Study demonstrates improved outcomes in patients with low metastatic burden.

In addition, results showed that radiotherapy was associated with a significant 24% decreased risk of biochemical failure overall and a significant 22% decreased risk of disease progression among men with low metastatic burden.

“Prostate radiotherapy should be a standard treatment option for men with newly diagnosed disease with a low metastatic burden,” Dr Parker’s team concluded.

He and his team said it is possible that other forms of local therapy, such as radical prostatectomy, also might be beneficial. “If the benefit of radiotherapy is mediated by local tumour eradication, one would expect surgery to be at least as effective,” they wrote. They cautioned, however, that radiotherapy might be effective via other mechanisms, such as immune modulation, “so the role of surgery in men with metastatic prostate cancer remains unproven.”

From January 22, 2013 to September 2, 2016, investigators at 117 hospitals in the UK and Switzerland randomly assigned 1032 men to a radiotherapy group and 1029 to a control arm that received standard of care alone.

Standard of care was lifelong androgen deprivation therapy, with upfront

docetaxel permitted after December 17, 2015, when the drug was approved in the UK, according to the researchers. Patients assigned to the radiotherapy group received either a daily or weekly schedule (55 Gy in 20 fractions over 4 weeks or 36 Gy in 6 fractions over 6 weeks, respectively). Of the

2061 men in the study, 819 (40%) had low metastatic burden and 1120 (54%) had high metastatic burden. Metastatic burden was unknown for 122 patients (6%). The median follow-up duration was 37 months.

The investigators classified metastatic burden according to the definition

used in the CHAARTED trial: high metastatic burden was defined as the presence of 4 or more bone metastases with 1 or more outside the vertebral bodies or pelvis, or visceral metastases, or both. They considered all other assessable patients to have low metastatic burden. ■

12 Renal & Urology News

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RP complications continued from page 1

cancer (PCa) who underwent roboticassisted or open RP from 2008 to 2013.

Patients had a median age of 62 years.

The database includes 20% of US inpatient hospitalizations, with discharge abstracts from 8 million hospital stays, the authors noted. In the study cohort as a whole, 57.3% underwent roboticassisted RP (RARP). Overall complications developed in 12.4% of patients.

Dr Preisser and his colleagues analyzed the subgroup of patients who underwent RARP and found that the effect of patient age on the risk of overall and other complications was similar to that of the entire cohort.

Most men who undergo RP are aged 45 to 75 years, the authors noted, but with an aging population, physicians will need to separate biological age from chronological age and provide individualized care.

Kidney stones and RCC continued from page 1

team reported in the British Journal of Cancer. When the investigators examined the association by RCC type, they found that a history of kidney stones was associated with a significant 3-fold increased risk of papillary RCC (pRCC), but was not significantly associated with clear-cell RCC (ccRCC).

“We hypothesize that the difference in risk between these RCC subtypes may be rather due to differences in metabolism between these cancer subtypes rather than a direct effect from the kidney stones,” Dr van de Pol told Renal & Urology News. “Potentially, these RCC subtypes are affected by a lifestyle that is related to kidney stone formation. In our study, we have taken multiple risk factors into account, such as alcohol usage, hypertension and obesity, but it might be that other factors also affect both the risk of developing a kidney stone and the risk of developing RCC.”

PCa tied to IBD continued from page 1

Dr Burns and his collaborators also noted that both PCa and IBD have significant genetic predispositions. Genomewide association studies have identified numerous susceptibility alleles for IBD and PCa, they pointed out. “Shared risk alleles could partially explain the association between IBD and PCa.”

In addition to its retrospective design, limitations of the study included an inability to adjust for tumor characteristics. “Indeed, patients with locally advanced PCa may suffer from a higher complication rate than those with localized cancers,” the authors wrote.

Older patients should be informed about their greater post-op complication risks.

“It is possible that a larger proportion of elderly patients may have harbored more advanced PCa at the time of RP.” Dr Preisser’s team also pointed out that they were unable to adjust for other cancer-related variables, such as the use of neoadjuvant chemotherapy, neoadjuvant androgen deprivation therapy, and preoperative radiotherapy, in

addition to some patient characteristics, such as performance status, differences in laboratory values, and opioid use.

Gerald Andriole, MD, professor and chief of the division of urologic surgery at Washington University School of Medicine in St. Louis, Missouri, said the new study validates the importance of considering age when recommending RP and provides important data for clinicians when counseling their patients.

Guidelines validated “Even with adjustment for common baseline co-morbidities, rising age was associated with higher rates of certain post-op complications,” Dr Andriole told Renal & Urology News. “This observation validates the guidelines of many entities, such as the NCCN [National Comprehensive Cancer Center] and the AUA [American Urological Association], that before recommending radical prostatectomy to men with aggressive prostate cancer, history and RCC. Among men, a history of kidney stones, compared with no history, was associated with a significant 1.42-fold greater overall risk of RCC and 2.4-fold greater risk of pRCC, but was not associated with ccRCC. Among women, kidney stone history was associated with a significant 16.4fold increased risk of pRCC, but was not significantly associated with the risk of RCC overall or ccRCC risk.

surgeons should be confident that the patient has a high probability of at least a 10- to 15-year survival.”

James Mohler, MD, professor of oncology and chief of ­Inter-Institutional Academics at Roswell Park Comprehensive Cancer Center, Buffalo, New York, said he is not surprised by the study findings. NCCN has advocated for considering physiological age/ life expectancy versus chance of PCarelated death and chance of cure versus chance of complications when counseling patients regarding the various treatment options for localized PCa. Dr Mohler, who chairs the NCCN Clinical Practice Guidelines in Oncology Panel for Prostate Cancer, said the guidance provided by the new study may help improve outcomes. “First, the findings may stimulate more complete discussions of radical prostatectomy as a treatment option. Second, the findings should help raise awareness that chronologic and physiologic age are different.” ■

Younger age a risk factor Results also showed that younger age at kidney stone diagnosis was a risk factor for RCC overall. A diagnosis of kidney stones among individuals younger than 40 years was associated with a significant 2-fold greater overall risk of RCC compared with those diagnosed later.

The study also identified sex disparities in the association between stone

The 4352 study participants were a subcohort of the 120,852 individuals enrolled in the NLCS. Of the 4352 participants, 365 (8.4%) had a history of kidney stones and 3987 (91.6%) did not.

During 20.3 years of follow-up, 544 RCC cases and 140 UTUC cases developed.

In a previous meta-analysis published in QJM (2015;108:205-212), a team led

by Wisit Cheungpasitporn, MD, now with the University of Mississippi Medical Center in Jackson, found that a history of kidney stones was associated with a significant 76% increased risk of RCC overall. A subgroup analysis, however, revealed that a history of kidney stones increased RCC risk only in men.

Commenting on the new study, Dr Cheungpasitporn pointed out that the researchers had limited data on kidney stone composition, urinary supersaturation, family history of kidney cancer, and occupational and other exposures shown to be associated with kidney cancer. In addition, previous studies have shown the link between kidney stones and kidney cancer may be subject to surveillance bias, as patients with kidney stones would be more likely to have follow-up imaging studies. Thus, patients with kidney stones are more likely than individuals without kidney stones to have kidney cancer detected. ■

Another possibility is that high rates of PCa among men with IBD may result from greater outcome ascertainment in the IBD group, as patients with IBD commonly have frequent encounters with the health care system. “Additionally, based on the nature of the disease, men with IBD would be more likely to undergo rectal examinations,” they wrote.

“Indeed, we noted more abnormal rectal examinations among men with IBD.”

Strengths of the study include the size of the cohort and distribution of patients over a representative age range, as well as longitudinal follow-up of all patients over a period of nearly 21 years. In a discussion of study limitations, the authors noted that because of the retrospective design, they could not account for unmeasured variables, such as disease location in IBD, markers of IBD severity, family history of

PCa, and socioeconomic data. In addition, the study was conducted at an academic medical center, which limits the external validity of its findings.

The study was conducted at a single academic medical center from 1996 to 2017. Median follow-up was longer for cases than controls (6.5 vs 4.7 years). All men had at least 1 PSA test. The median age of cases and controls was 53 years at the time of the first PSA measurement. ■

The investigators said the study, to their knowledge, is the first to find an increased pRCC risk among individuals with kidney stones.

Kidney stone history was associated with a significant 1.7-fold increased risk of UTUC. The study found no difference between localization of tumors in the renal pelvis or ureter. “In contrast to the proximal tubule, stone formation is common in the renal pelvis and ureter, which enables kidney stones to cause chronic irritation and inflammation to urothelial cells,” the authors explained.

“In turn, this may explain the increased UTUC risk in relation to kidney stones.”

Kidney stone history is associated with a 3-fold increase in papillary RCC risk.

www.renalandurologynews.com JANUARY/FEBRUARY 2019

Renal & Urology News 13

Mortality Unaffected by ADT for Gleason 9 –10 PCa ANDROGEN DEPRIVATION ther­a­ py (ADT) significantly improves sur­vi­ val for patients with Gleason 8 but not Gleason 9–10 prostate cancer (PCa), re­ search­ers reported in European Urology.

Using the National Cancer Data Base, Paul L. Nguyen, MD, of Harvard Medical School in Boston, and his col­ laborators identified 20,139 men with localized or locally advanced Gleason 8–10 PCa treated with external beam radiation therapy (EBRT). Of these, 60% had Gleason 8, 36% Gleason 9, and 4% Gleason 10 disease. In addition to radiation therapy, 78% of Gleason 8 and 87% of Gleason 9–10 patients received ADT. In multivariable analysis, ADT was associated with a significant 22% decreased risk of death among patients with Gleason 8 cancer, but was not associated with improved survival among those with Gleason 9–10 can­ cer. As Gleason score increased from 8 to 9 to 10, overall survival (OS) odds diminished.

Lack of survival benefit might be linked to Gleason pattern 5 disease.

The 5-year adjusted OS for men who received ADT, compared with those who did not, was 86% vs 82% for Gleason 8, 81% vs 80% for Gleason 9, and 74% vs 77% for Gleason 10, respectively.

“Our study challenges the current para­ digm of treating all patients with Gleason 8–10 disease similarly, as our results indicate that any survival advantage from the use of ADT is significantly weaker for Gleason 9–10 disease than for Gleason 8 disease,” the investigators wrote.

The investigators postulated that Gleason pattern 5 disease, which occurs more often in Gleason 9–10 can­ cer, may have developed mechanisms to escape androgen dependence.

Optimal treatment for men in Gleason grade group 5 remains unclear.

“Consideration should be given to treatment intensification for Gleason 9–10 patients through enrollment in clinical trials or potentially add­ ing novel antiandrogens or docetaxel, which have shown efficacy in both cas­ tration-resistant and castration-sensitive settings,” Dr Nguyen’s team wrote.

The investigators acknowledged some study limitations, including a short

median follow-up (4 years) period. In addition, they noted that the NCDB does not provide information on the type and duration of hormone therapy and type of metastatic workup each patient received.

“There is clearly a need to explore bet­ ter therapeutic options and, ­importantly,

genetically profile Gleason pattern 5 disease to allow for precision medicine approaches in the hopes of improving cancer-specific outcomes,” Matthew P. Deek, MD, and colleagues from Johns Hopkins University School of Medicine in Baltimore wrote in an accompanying editorial.

Dr Deek and his coauthors said it may be that Gleason pattern 5 disease more rapidly achieves castration resis­ tance or the presence of Gleason 9–10 disease at diagnosis “is a surrogate for more rapidly progressive disease which is also more likely to have disseminated microscopically.” ■

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Molidustat Promising for CKD Anemia The investigational drug appeared safe and effective in 3 phase 2b trials, researchers report

BY NATASHA PERSAUD MOLIDUSTAT, an investigational medication, effectively treats anemia in patients on hemodialysis (HD) and those with chronic kidney disease (CKD) not on dialysis, according to results from 3 phase 2b trials.

In all 3 DIALOGUE (DaIly orAL treatment increasing endOGenoUs Erythropoietin) trials, which included 100 to 200 participants each, molidustat, a novel, oral hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, increased or maintained Hb levels over 16 weeks.

In DIALOGUE 1, mean estimated Hb increased by 1.4 to 2.0 g/dL in nondialysis CKD patients treated with molidustat (25 or 50 mg once or twice daily or 75 mg once daily) compared with placebo, Iain C. Macdougall, MBChB, MD, of King’s College Hospital, Denmark Hill in London and ­colleagues reported

in the Clinical Journal of the American Society of Nephrology. In DIALOGUE 2, molidustat (starting dose 25 to 75 mg daily) maintained mean Hb within a target range of 10 to 12 g/dL in nondialysis patients switched from d ­ arbepoetin.

Patients’ hemoglobin levels were increased or maintained after switching from ESAs. In DIALOGUE 4, molidustat (75 and 150 mg daily) maintained Hb within the target range in HD patients switched from epoetin.

In DIALOGUE 2, Hb increased by a mean 0.6 g/dL more in the molidustat than darbepoetin arm. In DIALOGUE 4, Hb changed by −0.1 and 0.4 g/dL

Spironolactone Benefits Heart Failure Patients With CKD SPIRONOLACTONE treatment is

Failure. The decrease in risk was sig-

associated with better cardiovascular

nificantly greater only among patients

outcomes but increased risk of hyper-

with an eGFR (in mL/min/1.73 m2) of

kalemia among patients with chronic

60 or above. In this group, spironolac-

kidney disease (CKD) who have heart

tone decreased the risk of the primary

failure with preserved ejection fraction

outcome by 34%.

(HFpEF), new study findings suggest.

In a post-hoc analysis of data from

Spironolactone, however, increased the absolute risk of worsening renal

1767 participants in the Americas region

function (doubling of serum creatinine

of the TOPCAT (Treatment of Preserved

values) and hyperkalemia (serum potas-

Cardiac Function Heart Failure With an

sium level above 5.5 mmol/L).

Aldosterone Antagonist Trial) trial, a team

The incidence of hyperkalemia

led by Akshay S. Desai, MD, of Brigham

increased with decreasing renal func-

and Women’s Hospital in Boston, found

tion in both the spironolactone and

that spironolactone-treated patients

placebo groups, but the incidence was

had a lower risk of the primary efficacy

significantly greater among spironolac-

outcome—a composite of cardiovascu-

tone-treated patients across ranges of

lar death, heart failure hospitalization, or

eGFR. The incidence in the spironolac-

aborted cardiac arrest—compared with

tone and placebo groups was 6.8 and

placebo recipients across all categories

1.4 per 100 patient-years, respectively,

of estimated glomerular filtration rate

among patients with an eGFR of 60 or

(eGFR).

higher, 11.9 and 3.6 per 100 patient-

Overall, spironolactone decreased

years among patients with an eGFR

the risk of the primary outcome by 12%

of 45 to 60, and 14.7 and 5.3 per

compared with placebo, Dr Desai and

100 patient-years among those with

colleagues reported in JACC: Heart

an eGFR below 45. ■

in the molidustat versus epoetin arm, depending on dose. In the CKD patients not on dialysis, a molidustat starting dose of 25 or 50 mg once daily may be more appropriate than 75 mg once daily, “which appears to be associated with an increased likelihood of hemoglobin levels rising above prespecified limits compared with continued darbepoetin. For HD patients, only molidustat starting doses of 75 and 150 mg once daily were effective.

Most adverse events with molidustat were mild or moderate in severity. No serious thromboembolic events were related to treatment.

Studies of other HIF-PH inhibitors, including vadadustat, roxadustat, and daprodustat, have also demonstrated efficacy.

“In conclusion, results of these phase 2b studies indicate that the overall efficacy/safety profile of molidustat enables further development in both

patients with CKD who are not on dialysis and those with CKD who are on dialysis,” the authors wrote.

The DIALOGUE trials were funded

by Bayer AG. Dr Macdougall’s team acknowledged study limitations that included low patient numbers in each treatment arm and a relatively short duration of treatment contributing to changes in Hb levels observed after treatment initiation.

They noted, however, that these limitations are customary in phase 2 trials, “which serve to provide data from which to design larger, longer phase 3 trials.”

DIALOGUE 1 included 121 patients (101 and 20 in the molidustat and placebo arms, respectively), DIALOGUE 2 included 124 patients (92 and 32 in the molidustat and darbepoetin arms, respectively), and DIALOGUE 4 included 199 patients (157 and 42 in the molidustat and epoetin arms, respectively). ■

Gout Raises Parkinson’s Disease Risk

Previous studies looking at an association between gout and PD have yielded inconsistent findings. A study conducted in the United Kingdom found an 11% increase of PD among gout patients, whereas a study of Canadians aged 65 years and older found a 30% decreased risk of PD among gout patients.

GOUT IN ELDERLY individuals is associated with a modest increase in the risk of Parkinson’s disease (PD), according to a new study.

From a 5% random sample of Medicare claims data, Jasvinder A. Singh, MD, and John D. Cleveland, MD, of the University of Alabama at Birmingham, found 22,636 patients with PD: 1129 with and 21,507 without gout. The crude incidence rates of incident PD were higher in patients with gout than without it (3.7 vs 2.2 per 1000 person-years), the investigators reported in BMC Neurology. In multivariable analysis, gout was associated with a significant 14% increased risk of PD overall.

Among patients at least 65 but less than 75 years of age, gout was associated with a significant 27% increased risk of PD. Gout was not associated with PD among patients aged 75 years or older, the authors reported.

Drs Singh and Cleveland observed no significant difference in PD risk by gender or race/ethnicity.

Inflammation a possible factor As for how gout might influence PD risk, the authors noted that inflammatory arthritis conditions common in the elderly, such as gout, are associated with increased oxidative stress and chronic inflammation, which have the potential to increase PD risk. Previous studies have demonstrated an antioxidant effect of urate, they noted, but acute and chronic inflammatory states in gout patients could negate these antioxidant effects of urate, if this exists physiologically.

With regard to study limitations, the authors noted that misclassification bias is possible “since we used database diagnosis of PD and gout, and both under-diagnosis and over-diagnosis are possible.” In addition, their study was observational, and this “puts our finding at the risk of confounding bias, despite our attempt to include several covariates and potential confounders, including medications and disease ­conditions.” ■

www.renalandurologynews.com JANUARY/ FEBRUARY 2019

Renal & Urology News 15

n ASK THE EXPERTS

Managing the Adverse Effects of Prostate Cancer Medications Hot flushes, sexual dysfunction, and fatigue are among the common patient complaints

BY JODY A. CHARNOW

P Judd W Moul, MD

harmacotherapy for advanced prostate cancer (PCa) is associated with adverse effects (AEs) that frequently have a major impact on patients’ quality of life.

For insight into this common problem, Renal & Urology News interviewed 3 experts experienced in the treatment of advanced PCa: Judd W. Moul, MD, of Duke Prostate Center, Duke University Medical Center, Durham, North Carolina; Neal D. Shore, MD, of Carolina Urologic Research Center, Myrtle Beach, South Carolina; and Richard Harris, MD, of UroPartners, Chicago, and president of the Large Urology Group Practice Association.

In your practice, what are the most frequent AEs related to the use of medications for advanced PCa?

Neal D. Shore, MD

Richard Harris MD

Dr Moul: With traditional hormonal therapy, it is hot flushes, weight gain, loss of libido, erectile dysfunction, and loss of muscle mass/loss of strength. In men on long-term androgen deprivation therapy, I worry about loss of bone mineral density and increased risk for diabetes. There is also the concern that luteinizing hormone releasing hormone (LH-RH) agonists might increase the risk of cardiovascular disease.

Dr Shore: Of course, there may occur adverse events of interest specific to a particular approved CRPC [castration-resistant prostate cancer] therapy (cognitive impairment, rash, GI upset, myalgia, fracture, etc.). However, in my experience, fatigue and inanition are the most frequently cited adverse events by patients and caregivers and which may have a very significant impact upon quality of life.

Dr Harris: We have a plethora of treatment options for advanced prostate cancer.

It’s almost an embarrassment of riches.

Each treatment has potential side effects, but across the whole treatment class, the side effects are relatively mild. In fact, we rarely see men discontinue treatment for advanced prostate cancer due to AEs. Side effects do vary by treatment and require urologists to manage each individually. For example, treatment with immunotherapy is very well-tolerated generally. Patients occasionally experience chills during administration, which is easily rectified with warming blankets, and they may have flu-like symptoms (e.g., low-grade fever, muscle aches, or headaches) for a day or 2 after infusion.

Asthenia brought on by testosteronetargeting agents (e.g., ADT, abiraterone, or enzalutamide) is perhaps the most frequently reported AE in my experience.

Fortunately, in regard to the novel oral oncolytics, we have the ability to dose reduce or switch to another agent if warranted. The combination of abiraterone and prednisone can also affect the mineralocorticoid axis, and, therefore, close monitoring with CMPs is indicated when putting patients on these medications.

Which of these AEs do you find has the biggest impact on patients’ quality of life?

Dr Moul: I think for some men, hot flushes are a real challenge. Other men report weight gain as their biggest concern. Loss of muscle mass/loss of muscle strength is also an issue for more active and younger men as is loss of libido.

Dr Shore: Both cognitive impairment and fractures can result in very deleterious effects, oftentimes requiring

additional medical interventions as well as drug cessation.

Dr Harris: Erectile dysfunction in those who are sexually active and asthenia have the greatest impact on patients from a quality-of-life standpoint. Asthenia is distinct from the typical tiredness, and my patients often complain of abnormal physical weakness and lack of energy.

We encourage patients to keep active, do some light resistance training, exercise and even just walk to offset the symptoms. Additionally, with the ADT agents involving testosterone, we often hear patients are unhappy about weight gain and some gynecomastia. Another agent, radium-223, can also result in gastrointestinal problems, neutropenia, and anemia.

What AEs present the greatest management challenge?

Dr Moul: None of the side effects are easy to deal with. Because of this, I like to use intermittent hormonal therapy (IHT) for as many men as possible.

However, for men with M1 disease, I worry that IHT may be less effective than continuous ADT. Dr Shore: Cancer-related fatigue and the neurocognitive effects of therapy pose a significant challenge to patient quality-of-life parameters, and oftentimes clinicians are at a loss to ameliorate these tolerability issues, especially when a specific therapy is achieving clinical, laboratory, and imaging benefits.

Dr Harris: As stated previously, there is a cadre of AEs in managing these patients, but bone health is a c­ ritical continued on page 16

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Prostate Cancer Linked to High Dietary Zinc Intake HIGH DIETARY intake of zinc, a key trace element in normal prostate cell metabolism, may be associated with an elevated risk of low-grade prostate cancer (PCa), a new study suggests.

In a case-control study conducted in Spain, investigators found that men in the highest tertile of dietary zinc intake (greater than 10.53 mg/day) had a significant 66% increased relative risk of Gleason 6 PCa compared with those in the lowest tertile (less than 8.34 mg/day), in adjusted analyses, Enrique GutiérrezGonzález, MD, of the National School of Public Health, Carlos III Institute of Health, Madrid, and colleagues reported in Nutrients.

The study found no significant associations between zinc intake and highergrade or more advanced PCa tumors.

The investigators also looked at genotype information from selected patients with available DNA (514 cases and 81 controls) and found evidence suggesting that the possible deleterious effect of higher zinc intake on PCa risk is greater among men with a stronger genetic predisposition to PCa. The study included 733 incident PCa cases and 1228 population-based controls. Investigators assessed dietary zinc intake using a food frequency questionnaire. Compared with controls, PCa patients had a higher percentage of men

with a family history of PCa (21% vs 7%), greater daily alcohol consumption, and lower educational level.

Managing AEs

Dr Harris: We make preliminary decisions about what therapies we might want to administer to our patients, which are based on comorbidities, risks and benefits. For the appropriate castrationresistant metastatic patient, we get them started with immunotherapy right away.

The National Comprehensive Cancer Network recommends use of immunotherapy as a first-line treatment in these men, and data suggest earlier is when the treatment has the greatest impact.

For the second-generation orals it’s kind of a “dealer’s choice,” but there are a few caveats we take into account when choosing 1 treatment over another. For example, if a patient had a seizure disorder or any past history of strokes, we might go with abiraterone acetate. Severe diabetics may be better managed with enzalutamide because abiraterone with prednisone may make controlling blood sugar more challenging. Once patients are placed on any treatment, we monitor how the treatment is working and which side effects they’re experiencing, and tailor their regimens accordingly. It remains important for clinicians to not only monitor patients for AEs, but also track disease progression via regular PSA screening (3–4 months) and appropriate scanning based on PSA doubling times to ensure they are offering patients the most appropriate therapy.

Understanding RADAR III imaging guidelines is imperative to appropriate management of this class of patient.

and for borderline low-T patients.

When men are diagnosed with prostate cancer, the classic teaching was that we needed to discontinue testosterone supplements. However, more contemporary thinking suggests that a normal testosterone level is beneficial and that low T is harmful for men with localized prostate cancer. Over the past few years, I have been more inclined to continue T therapy for men who are on active surveillance for low-risk or very-low-risk prostate cancer. For men with intermediate- and high-risk disease, I tend to ask patients to discontinue T until they are treated. In men who undergo radical prostatectomy and have favorable pathology and who achieve an undetectable PSA at 3–6 month follow-up, I will support them to restart T therapy.

continued from page 15

issue in advanced prostate cancer patients treated with ADT. While ADT is a mainstay of treatment for advanced prostate cancer, it can increase the likelihood of osteoporosis and subsequent fractures, requiring that we closely monitor any bone loss using bone densitometry. There are several osteoprotective therapies like denosumab (injection) or alendronate sodium (oral) that I often prescribe to minimize fracture risk.

Do you have any prescribing dilemmas when weighing the benefits and AEs of treatment?

Dr Moul: I wonder if there is any benefit of degarelix as compared to LH-RH agonists with regard to the risk of cardiovascular toxicity. There are retrospective data that suggest degarelix might be a safer choice, especially in men with preexisting cardiovascular disease. On the other hand, this possible benefit remains controversial and deserves further study.

The challenge with degarelix is that it is only available as a monthly depot injection, so it is more inconvenient than longer-acting LH-RH agonist agents.

Dr. Shore: In addition to reviewing the primary goal of survival prolongation when choosing a specific therapy, both avoiding complications of therapy (including emergency department visits and inpatient hospitalizations) and maintenance of positive qualityof-life metrics, especially in the elderly population, are essential to the patientphysician discussion, and yet may not always appear straightforward.

What medications do patients take concomitantly for other conditions that might affect your PCa treatment strategy?

Dr Moul: Certainly, testosterone supplements are popular to treat h ­ ypogonadism

Risk may be higher among men with a genetic predisposition to prostate cancer.

Dr Gutiérrez-González and his colleagues cited previous research showing that zinc is involved in the process of proliferation and apoptosis cell regulation in the prostate, and zinc ­concentrations are

Dr Shore: Over-the-counter supplements, which may contribute to hepatic or renal impairment and occasionally impact hormonal levels. Of course, prescription medications which may augment or impede hepatic and renal pharmacologic clearance must also be reviewed with virtually all advanced PCa therapies.

Dr Harris: Virtually everybody that we see with advanced prostate cancer has multiple comorbidities given the age population. Quite a few of them are either hypertensive or diabetic and are generally on multiple pharmacotherapy.

Of course, every drug must be cross-referenced against what patients are already on. As an example, metoprolol and abiraterone is a relative contraindication.

Although possible to co-administer, one must be careful when prescribing enzalutamide with warfarin. We check

consistently lower in PCa tissue than in normal cells. Previous studies looking at zinc intake and PCa have yielded inconsistent findings. A previous hospital-based case-control study of AfricanAmerican men found no significant association between self-reported zinc intake and PCa risk, according to a 2016 report in PLOS ONE. In a study of a prospective cohort published in 2009 in Nutrition and Cancer, researchers found that long-term intake of supplemental zinc was associated with a decreased risk of clinically relevant advanced PCa, but not overall PCa risk. The study found no association between dietary zinc and PCa risk. ■

their medication lists and make sure there’s no reactivity or contraindications and adjust accordingly.

Do you ever recommend complementary/ alternative therapies to manage AEs?

Dr Moul: I recommend patients maintaining or striving for a healthy weight/ body-mass-index of 25 kg/m2 or less. I do not recommend any specific supplements and certainly do not recommend mega-doses of any supplement or mineral. If a patient desires “something,” I think a good general multivitamin supplement is reasonable. I also feel that a Mediterranean-style diet rich in fruits, vegetables, olive oil, tomato products and lower in saturated fat and red meat is a reasonable recommendation for both heart and prostate health.

Dr Shore: Very infrequently, although I regularly review the published trial literature. There are, unfortunately, many over-the-counter products which are advertised with minimal basis for efficacy or adequate safety studies. Generally, I encourage a heart-healthy diet, regular exercise, smoking cessation, alcohol use in moderation, stress avoidance, and adequate sleep, in addition to either an approved advanced PCa regimen or clinical trial participation.

Dr Harris: Clearly, in this day in age, people are starting to use THC or marijuana for pain control. I’ve seen that in a number of patients. I don’t personally have a lot of experience recommending alternative therapies for patients with advanced prostate cancer and really encourage patients to focus on exercise, which carries a lot of benefits. ■

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Renal & Urology News 17

Genetic Test Zeroes In on Hereditary CKD New study demonstrates diagnostic utility of exome sequencing in patients with chronic kidney disease dominant disease, 42 (14%) had an autosomal recessive disease, and 54 (18%) had an X-linked disease. The 3315 patients included 1128 from AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardio­ vascular Events) and 2187 patients from the Columbia University Medical Center (CUMC) Genetic Studies of Chronic Kidney Disease.

© ISM / PR J.L. KEMENY / MEDICALIMAGES.COM

BY JODY A. CHARNOW WHOLE EXOME sequencing, a technique for sequencing the protein-coding genes in the genome, can identify multiple potential genetic causes of inherited kidney disease, according to a new study that could have implications for clinical management.

For some patients in the study, genetic findings led to reclassification of disease and provided a molecular cause of

Focal segmental glomerulosclerosis (above) is among the kidney diseases for which whole exome sequencing may provide therapeutic guidance.

nephropathy that previously had been of unknown origin. In certain cases, genetic findings could inform therapeutic decisions.

“Altogether, our findings support a broader utility of ES [exome sequencing] for patients with kidney disease, and highlight the potential of both the primary and secondary genetic findings identified via ES to empower personalized care for these individuals,” principal investigator Ali G. Gharavi, MD, and first author Emily Groopman, both of Columbia University College of Physicians and Surgeons in New York, said in a joint statement to Renal & Urology News. They and their colleagues reported study findings in the New England Journal of Medicine (2019;380:142-151).

Inherited disease in 9.3% of cases In a study of 2 cohorts totaling 3315 patients with chronic kidney disease (CKD), whole exome sequencing, detected di­ag­nostic variants in 307 (9.3%).

Of these, 206 (67%) had an autosomal

Diagnostic yield was highest among patients with a clinical diagnosis of congenital or cystic renal disease (23.9%) and patients with nephropathy of unknown origin (17.1%), according to Dr Gharavi’s team. Genetic diagnoses “gave new clinical insight” for 122 (73%) of 167 patients in the CUMC cohort who had a genetic diagnosis. “For 65 patients, it enabled identification of a specific underlying cause within the broader category of clinically suspected disease—for example, by pinpointing the precise genetic subtype of focal segmental glomerulosclerosis or cystic disease.”

Potential impact on therapy Genetic findings reclassified disease in 18 patients. For 39 patients who had been referred with nephropathy of unknown origin, exome sequencing identified a molecular cause of the nephropathy. Genetic diagnoses could inform therapeutic decisions for 84 patients (50%), for example, by avoiding immunosuppression among

patients with monogenic forms of focal segmental glomerulosclerosis, the investigators stated.

“ES is currently available as a diagnostic test,” Dr Gharavi and Groopman said. “Our findings and those of others support that ES has great potential as a tool for specific diagnosis and targeted management of inherited kidney and urologic disease. However, for this potential to be fully achieved, we must address the many challenges associated with its broader application in nephrology, including developing systematic and efficient workflows for interpreting genetic variants and applying them in diverse clinical contexts.”

Dr Gharavi and his colleagues addressed some of the challenges associated with interpretation of variants in a recent paper published in Annals of Internal Medicine (2019;170:11-21), where they concluded, “Widespread reporting of incidental genetic findings related to kidney and genitourinary disorders will require stringent curation of clinical variant databases and detailed case-level review to avoid genetic misdiagnosis and unnecessary referrals.”

Large-scale studies are needed to ­define clinical indications for ES and the long-term impact of use of genomic sequencing on health care outcomes and costs, according to Dr Gharavi and Groopman. “These initiatives will help fill in the current gaps in our ­knowledge and help guide effective use of ES for ­patients with kidney disease.”

Most patients with diagnostic variants had an autosomal dominant disease.

“In routine genetic testing, we can test a patient for 1 genetic condition,” said Anthony J. Bleyer, MD, a professor in the Section on Nephrology at Wake Forest School of Medicine in Winston-Salem, North Carolina, where he is part of the Wake Forest Rare Inherited ­Disease ­Research Team. “Thus, we have to have a strong clinical suspicion before we perform this testing. With whole exome sequencing, we can test for all known genetic disorders of the kidney, even for those that we have little or no clinical

suspicion. Given that [almost] 10% of individuals tested had inherited kidney disease, many without clinical suspicion, it is highly likely that all patients will undergo whole exome sequencing in the future, when the cost of testing is much less.”

Implementation challenges Joseph Vassalotti, MD, chief medical officer for the National Kidney Foundation (NKF), said the new study suggests exome sequencing could be useful in the diagnosis and management of patients with CKD. He noted, however, that exome sequencing would entail implementation challenges, as this testing is predominantly a research tool that would not be widely available in clinical practice. In addition, even simple testing for the genes polycystin-1 (PKD1) and polycystin-2 (PKD2) for autosomal dominant polycystic kidney disease may not be reimbursed by health insurers. Still, the study shows that exome sequencing offers a promising way to identify genetic causes of CKD. “There may be more we can offer patients if we can make this more available,” Dr Vassalotti said. For example, patients with the kidney biopsy finding of focal segmental glomerulosclerosis could benefit from knowing there was no associated exome mutation identified, since this finding supports an acquired, immunologic etiology and a potential favorable response to immunosuppressive therapy.

Generalizability questioned Although the new study provides insight into the value of exome sequencing in zeroing in on the various hereditary kidney diseases, Dr Vassalotti cautioned about the generalizability of the findings because the study looked at special populations. The AURORA study included only HD patients and the Columbia University cohort likely consisted of nephrology-referred patients. These are patients likely to have undergone more thorough CKD workups and, as such, might be different from the broader population of patients seen in primary care practices and those with earlier stages of CKD, he explained. ■ Editor’s note: See the related editorial on page 5 by Anthony J. Bleyer, MD, who is on the editorial advisory board of Renal & Urology News.

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Study: CKD Burden Growing in the US Increased risk exposure may be among the contributing factors CHRONIC KIDNEY disease (CKD) burden has increased substantially in the United States since the start of the new millennium.

From 2002 to 2016, the number of disability-adjusted life-years (DALYs) due to CKD increased by 52.6% (from 1,269,049 to 1,935,954) and CKDrelated deaths increased by 58.3% (from 52,127 to 82,539), Ziyad Al-Aly, MD, of Veterans Affairs St Louis Health Care System, and colleagues reported in JAMA Network Open.

“These changes may be associated with increased risk exposure and demographic expansion leading to increased probability of death due to CKD, especially among young adults,” they wrote.

Increased risk exposure, aging, and population growth accounted for 40.3%, 32.3%, and 27.4% of the increase in CKD DALYs, respectively.

CKD burden increased at a faster pace than other noncommunicable diseases, according to researchers.

According to Dr Al-Aly’s team, the following states experienced the greatest percentage increases in age-standardized CKD DALY rates from 2002 to 2016, in descending order: Oklahoma (32.9%), West Virginia (31.3%), Texas (30.9%), New Mexico (30.7%), Iowa (30.1%), Washington (28.5%), Idaho (28.2%), Tennessee (27.9%), Arkansas (27.8%), and Kentucky (26.3%). The states with

States Hit Hardest by CKD The 5 states with the largest ­percentage increases in the age-standardized CKD DALY* rates from 2002 to 2016 (in descending order) were: Oklahoma

32.9%

West Virginia

31.3%

Texas

30.9%

New Mexico

30.7%

Iowa

30.1%

*Disability-adjusted life-years Source: Bowe B, Xie Y, Li T, et al. Changes in the US burden of chronic kidney disease from 2002 to 2016: an analysis of the Global Burden of Disease Study.

JAMA Network Open. 2018;1(7):e184412.

the lowest percentage increases, in ascending order, were Nevada (6.3%), New Jersey (6.8%), Massachusetts (8.8%), Maryland (9.3%), Illinois (10.4%), New York (10.8%), Connecticut (11.3%), Pennsylvania (12%), Georgia (12.7%), and Colorado (13.6%).

Age-standardized CKD DALY rates increased by 18.6%, with metabolic and dietary risk factors contributing to 93.8% and 5.3% of this change.

Age-standardized DALY rates increased by 18.6% from 371 per 100,000 population in 2002 to 440 per 100,000 population in 2016. Changes in the age-standardized DALY rates were

primarily associated with increases in CKD due to diabetes and hypertension.

From 2002 to 2016, a 21.8% increase in CKD due to diabetes contributed to an overall 11.8% increase in age-standardized DALY rates. A 22% increase in CKD due to hypertension contributed to an overall 4% increase in age-standardized DALY rates.

CKD from diabetes contributed to a 26.8% and 25.6% increased risk of CKD-related death among adults aged 20 to 54 and 55 to 89 years, respectively.

Metabolic risk factors contributing to increases in CKD DALYs included high fasting plasma glucose levels, high body mass index, and high systolic blood pressure, Dr Al-Aly’s team reported. With regard to dietary risk factors increasing CKD burden, the authors implicated high intake of sugarsweetened beverages and sodium.

“Earlier in life, CKD portends serious consequences, which manifest in a higher probability of death among the segment of the population that contributes considerably to economic prosperity, representing significant loss of human capital,” Dr Al-Aly and his colleagues stated.

“The findings suggest that an effort to target the reduction of CKD through greater attention to metabolic and dietary risks, especially among younger adults, is necessary.” ■

ESRD Risk in CKD May Vary by Sex CHRONIC KIDNEY disease (CKD) ­progresses more slowly in women than men, according to a new study.

In a study of 3939 adults to mildto-moderate CKD, women had a significant 28% decreased risk of end-stage renal disease (ESRD) and 18% decreased risk of a 50% decline in estimated glomerular filtration rate (eGFR) from baseline compared with men, in a fully adjusted model, a team led by Ana C. Ricardo, MD, of the University of Illinois at Chicago, reported in the Journal of the American Society of Nephrology.

Women also had a significant 44% lower risk of death from any cause.

The investigators observed no significant difference in the annual rate of eGFR decline between the sexes.

The study included 3939 adults with mild-to-moderate CKD (1778 women and 2161 men) enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Investigators enrolled patients at 7 clinical centers in the United States. A total of 844 ESRD events and 853 deaths occurred during a median follow-up of 7 years.

Dr Ricardo and her colleagues adjusted for sociodemographic

NAC vs AC Ups Disease-Free Survival in MIBC NEOADJUVANT vs adjuvant chemotherapy for muscle-invasive bladder cancer (MIBC) offers superior diseasefree survival, but this does not translate into improved cancer-specific and overall survival, according to investigators.

In an analysis of MIBC cases in the RISC (Retrospective International Study of Cancers of the Urothelial Tract) database, Cora N. Sternberg, MD, of San Camillo-Forlanini Hospital in Rome, and colleagues found that the median disease-free survival (DFS) was significantly longer among recipients of neoadjuvant chemotherapy (NAC) than adjuvant chemotherapy (AC): 34.6 vs 24.9 months.

NAC was associated with a significant 22% decreased risk of disease progression compared with AC, the investigators reported in Frontiers in Oncology.

The study found no significant difference between the NAC and AC arms

with regard to median cancer-specific survival (CSS, 115.2 vs 92.8 months, respectively) and overall survival (OS, 51.7 vs 66.8 months, respectively).

The absence of a significant difference in CSS and OS between the treatment arms may result from the “not-negligible” percentage of patients (20.5%) with positive lymph nodes in the NAC group and the percentage of patients without adequate pathologic lymph node staging (2.7%). “These patients may have poorer outcome due to the lack of chemotherapy responsiveness, micrometastatic disease that would later progress or a greater disease burden,” Dr Sternberg’s team wrote, adding that many of these patients may have been understaged and therefore not adequately treated.

The study included 656 patients with MIBC who underwent radical cystectomy. Of these, 331 received NAC and

325 received AC. The study excluded patients who received adjuvant radiotherapy or a combination of radiation and chemotherapy. In both the NAC and AC treatment arms, the majority of patients were male: 77.6% and 83.4%, respectively. Both treatment arms had similar proportions of patients aged 65 years or older and younger than 65 years.

The absence of an OS advantage with NAC vs AC contradicts findings of a study presented at the 2018 American Urological Association annual meeting in San Francisco. The study included 792 MIBC patients who underwent radical cystectomy, of whom 509 received NAC and 283 received AC. The 5-year OS rate was 50.3% among NAC recipients compared with 38% among AC recipients, investigators reported. NAC was associated with a significant 32% decreased risk of death compared with AC. ■

characteristics, cardiovascular risk factors, baseline kidney function, medications, and markers of bone mineral metabolism.

“The findings of our study need to be interpreted in light of its limitations,” the authors cautioned. “The CRIC Study did not use a populationbased sample strategy; therefore, it is possible that the risk for CKD progression differs between men and women enrolled in the study compared with those not enrolled.”

They noted, for example, that it is well known that CKD awareness is lower among women than men, and women are less likely to undergo CKD screening or have nephrology consults after being diagnosed with CKD. Consequently, they wrote, their clinicbased sample of women might have had a lower risk profile compared with women not recruited into the study. ■

www.renalandurologynews.com JANUARY/ FEBRUARY 2019

Renal & Urology News 19

Ethical Issues in Medicine “When you don’t take your medication, you’re more likely to get sick.”

“I hear you doc, but I can manage this.”

C

onversations like these can make physicians uncomfortable. When patients refuse recommended treatments, physicians are apt to worry not just about their patients’ health and if they are doing everything they can to help them, but also if they will be to blame if patients suffer a poor outcome.

Patients have been refusing medical advice for as long as there have been doctors, and they do so across the spectrum of care, from the outpatient clinic to the hospital to the nursing home. A dramatic example of this is when an inpatient leaves the hospital against medical advice (AMA). More commonly, conflicts can arise over other declinations of care, including nonadherence with medication, treatment, or screening recommendations, by disengaging with their health care providers, or failing to follow-up regularly.

Balancing obligations Although the tendency is to frame these conflicts over rules, regulations, and legal liability, these dilemmas are primarily about physicians’ ­obligations and patients’ rights, and thus benefit

about their care. Still, simply providing a technical listing of the relevant medical information and standing aside so patients can decide is not what physicians or patients want. Patients want their physicians to contextualize the information and make a recommendation based on medical evidence and patients’ goals. At the same time, patients do not necessarily want their physicians to decide for them.

Such paternalism is no longer ethically acceptable. Where does that leave the clinician, who is trying to help patients promote their health but avoid being paternalistic? The answer lies in 1) engaging patients in the decision-making process, 2) respecting competent patient’s choices, and 3) promoting harm reduction when patients make choices that do not prioritize their health.

The most common reason patients decline recommended care is because they lack information.1 In these cases, a physician’s ethical obligation is to ensure patients understand exactly what they are declining. This includes clarifying the indication for the treatment, its risks and benefits, any alternatives, and the risks and benefits of the ­alternatives.

Often, patients can be persuaded to agree to a beneficial treatment simply by identifying the source of their misunderstanding and correcting it.

Patients have been refusing medical advice for as long as there have been doctors, and they do so across the spectrum of care. from an ethical perspective. In general, ethical tension exists when a physician’s obligation to promote a patient’s best interests competes with the physician’s obligation to respect the patient’s autonomy, that is, a patient’s right to decide about what care they accept. Trying to balance these obligations without inappropriately favoring one of them can be a regular challenge for clinicians.

Physicians promote patient autonomy when they involve patients in discussions

Understanding why If a physician has determined that a patient understands the available options but continues to decline the recommended option, the physician can try to understand how the patient arrived at his or her decision. Understanding the why behind the declination can create an opportunity to intervene. A clinician might say, “You told me you don’t want the surgery because ‘it’s just not right for me.’ What about it isn’t right? Are you

© PLANET FLEM / GETTY IMAGES

Understanding why patients refuse recommended treatments can provide an opportunity to intervene BY DAVID J. ALFANDRE, MD

worried about surgical complications?

The anesthesia? Staying in the hospital after the procedure? Something else?”

Creating space for patients to voice their concerns can help identify previously undiscovered reasons for declining a recommended option.

Harm reduction Another consideration is harm reduction, which maintains the therapeutic relationship while helping to promote a patient’s best interests. It attempts to reduce the adverse health consequences that may come from a patient’s unhealthy behaviors while accepting that such patients are likely to continue these behaviors.

This is practiced on large scales with needle exchange programs and on smaller scales in physicians’ offices with nicotine replacement therapy.

Practicing harm reduction means identifying other medically acceptable options that the patient is willing to accept.2 It does not mean suggesting treatment options that are not in accord with accepted standards of medical practice. Doing so would threaten the integrity of the medical profession because it would harm patients without a potential for benefit. Identifying other medically acceptable options that are preferable to the patient maintains the treatment alliance and promotes the patient’s health more than doing nothing.3 For example, a patient who wishes to leave the hospital AMA may be behaving in ways that

undermine his or her health. But if a clinician can arrange follow-up with the patient’s primary care provider in 24 to 48 hours, the patient may find that preferable to continued hospitalization and will remain engaged in care.

Competent patients have a right to decline recommended treatments and physicians have an obligation to respect that right. Although it is frustrating to stand by when patients decline recommended care, it does not mean they wish to decline all help. Keeping patients engaged in their care allows physicians to help when and where they can. ■ David J. Alfandre MD, MSPH, is a health care ethicist for the National Center for Ethics in Health Care (NCEHC) at the Department of Veterans Affairs (VA) and an Associate Professor in the Department of Medicine and the Department of Population Health at the NYU School of Medicine in New York.

The views expressed in this article are those of the author and do not necessarily reflect the position or policy of the NCEHC or the VA. REFERENCES 1. Appelbaum PS, Roth LH. Patients who refuse treatment in medical hospitals. JAMA. 1983;250:1296-1301.

2. Stratton K, Shetty P, Wallace R, Bondurant S. Clearing the smoke: the science base for tobacco harm reduction—executive summary. Tob Control.

2001;10:189-195.

3. Alfandre D. Clinical recommendations in medical practice: A proposed framework to reduce bias and improve the quality of medical decisions. J Clin Ethics. 2016:27:21-27.

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Practice Management F

or years, industry reports have estimated that a large number of health information breaches occur because of internal slip ups and mishandling of records. A new study supports this hypothesis.

John (Xeufeng) Jiang, PhD, of Michigan State University in East Lansing, and Ge Bai, PhD, of Johns Hopkins Carey Business School in Washington, DC, analyzed data from 1138 breaches reported to the Office for Civil Rights (OCR) from 2009 to 2017 to identify the breach triggers. They found that 53% were due to internal issues that included sending emails to the wrong recipient, taking home devices with protected health information (PHI), and misplacing paper health records.

Under HIPAA, covered entities are supposed to perform annual training, but gaps clearly remain. But providers can learn something about prevention from the study. “If you look at what happened, you see some common themes,” he said. “And the corrective actions people took who had issues provide some lessons that are useful.”

Lessons learned In a research letter published recently in the JAMA Internal Medicine, Drs Jiang and Bai reported finding a handful of

information in an electronic format, some moved to a cloud-based system instead of using their own server.”

If information is being stored electronically, though, he cautions against allowing staff to keep it on mobile devices, which appear, from the breaches he and Dr Bai analyzed, to be easily lost or stolen.

A small percentage of the breaches were caused by employee theft. For instance, after being fired, a person might download patient data to take to a competitor’s firm. In a handful of cases, employees had downloaded credit card or Social Security information with the intent of committing fraud.

But these types of cases account for a small minority of breaches, Dr Jiang said. Most were due to errors that could have easily been avoided, like sending letters via the postal service that have Social Security numbers visible through the envelope window or copying unauthorized individuals on emails containing PHI. “A lot were simple mistakes that cause a lot of trouble,” he said.

Corrective action A common refrain among providers is a lack of funds to put toward HIPAA compliance efforts, but breaches even occur at big organizations that spend large sums on security. The answers,

Researcher cautions against allowing staff to keep electronically stored patient information on mobile devices. areas tripping up health care providers.

First, a majority of the affected providers were still using paper documentation, some of which got lost in storage or during transportation or disposal.

Many of these organizations planned to move to electronic documentation as detailed in their corrective action plans (as required by OCR after a breach).

“They used the breach as an opportunity to upgrade their systems,” Dr Jiang said. “And if they already had

Dr Jiang said, are simpler than that. “As far as I can see, even if they [providers] are resource-constrained, if they use common sense and follow some simple security principles, they can eliminate some risks,” he said.

Among the solutions in the corrective action plans he and Dr Bai analyzed were the use of a 2-step verification protocol before sending out mail, with 1 person preparing it and another verifying information before sending

© ARIEL SKELLEY / GETTY IMAGES

Simple security procedures can prevent breaches of patient confidentiality due to employee errors BY TAMMY WORTH

Most electronic medical record systems can be used to monitor staff access to information.

it. Some providers implement audits to ensure people were only accessing appropriate information in the system.

Most electronic medical record systems can be used to monitor who is accessing records, according to Chris Bennington, an attorney-consultant with INCompliance, a Columbus, Ohio-based health care consulting firm. Random records can be pulled to see who accessed them at various times. Paper audits can be more difficult, but a quick walk-through of a facility can show if records are being left out or thrown in a trash receptacle instead of being disposed of properly.

Bennington said he recommends doing audits twice a year. “And if you are going to take the time to do them, document that you did them. In the eyes of the government, if you didn’t document, you didn’t do it.”

Organizational training programs also should be well documented.

Marc Haskelson, president and CEO of Compliancy Group, LLC, based in Greenlawn, New York, said improper training is bound to lead to HIPAA problems. A majority of breaches, he said, occur because people failed to follow their employer’s policies and procedures.

Determining repercussions Training programs also can be used to detail disciplinary actions that would

be imposed on employees who make HIPAA errors. Organizations must follow through on disciplinary actions against an employee who is responsible for a breach because this is among the areas OCR checks when it investigates breaches.

“Many have a [disciplinary] policy but when faced with a breach, don’t want to apply sanctions in the manner laid out,” Haskelson said. “It’s really important for covered entities to follow through because it sends a clear message that not only do they have policies, but they will apply them in a consistent manner.”

Breaches and their resulting sanctions should be looked at on a case-by-case basis, but there are some general rules that can guide policies, Bennington said. Sanctions should be categorized by intent and frequency. Breaches can be accidental, careless, or intentional.

Sanctions can be tailored to these categories.

“There are times when you have a violation that is so clear cut and serious there won’t be a warning; it will just go right to termination [of an employee] because of the severity,” Bennington said. “But I don’t think every instance should result in termination.” ■ Tammy Worth is a freelance medical journalist based in Blue Springs, MO.