Renal & Urology News - March-April 2019

M A R C H /A P R I L 2 0 1 9

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VOLUME 18, ISSUE NUMBER 2

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www.renalandurologynews.com

Standard of Care for mRCC May Change Data support first-line treatment with combined regimens that include an immunotherapeutic agent FIRST-LINE DUAL REGIMEN SUPERIOR Combined therapy with pembrolizumab and axitinib is associated with better outcomes compared with sunitinib alone as first-line therapy for advanced renal cell carcinoma, new study findings suggest.

■ Pembrolizumab-axitinib

■ Sunitinib

89.9%

15.1%

78.3% 12-month survival rate

11.1% Median PFS (in months)

Source: Powles T, Rini BI, Plimack ER, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study. Data presented at the 2019 Genitourinary Cancers Symposium; San Francisco, February 14-16. Abstract 543.

BY JODY A. CHARNOW SAN FRANCISCO—New findings presented at the 2019 Genitourinary Cancers Symposium add to a growing body of data that could lead to a new standard of care for the first-line treatment of metastatic renal cell carcinoma (mRCC).

These data, from the KEYNOTE-426 phase 3 trial and the JAVELIN Renal 101 trial, support the use of an immunotherapy-based combination regimen rather than monotherapy with a tyrosine kinase inhibitor (TKI) such as sunitinib for previously untreated advanced kidney cancer.

“We’re heading towards a time very quickly when every new metastatic kidney cancer patient is going to get an immunotherapy-based combination

Unique Drug Cuts CRPC Mets Risk TRT Decreases

BY JODY A. CHARNOW study findings presented at the 2019 Recurrence Rate SAN FRANCISCO—Darolutamide, Genitourinary Cancers Symposium. a structurally unique androgen recep“This is really a very safe drug as of Low-Risk PCa tor antagonist, prolongs metastasis-free far as we can tell,” said lead investigasurvival (MFS) and decreases the risk of pain progression in men with nonmetastatic castration-resistant prostate cancer (nmCRPC), without adversely affecting quality of life, according to

tor Karim Fizazi, MD, PhD, a medical oncologist at the Institut Gustave Roussy, Université Paris-Sud, Villejuif, France. continued on page 9

© MAILSONPIGNATA / SHUTTERSTOCK

PROVIDERS TAKE ON A DIALYSIS ACCESS ISSUE

ESRD care is poor for undocumented immigrants.

PAGE 22

TESTOSTERONE replacement therapy (TRT) use in men with low-risk prostate cancer (PCa) decreases the risk of disease recurrence following radical prostatectomy, investigators reported at the 34th Annual European Association of Urology (EAU) Congress, which was held in Barcelona, Spain.

In a study of men who underwent robot-assisted radical prostatectomy for localized PCa and had a median follow-up of 2.75 years after surgery, Thomas Ahlering, MD, and colleagues at the University of California, Irvine, found that 15 (9.9%) of 152 men on TRT experienced biochemical recurrence (BCR) – defined as 2 consecutive PSA values of 0.2 ng/dL or greater after surgery – compared with 160 (23.5%) of 682 men not on TRT, a statistically significant difference in BCR rate.

Eighty-five patients had BCR within a year after surgery. Of these, 4 (4.7%) were on TRT compared with 81 (95.3%) not on TRT. In multivariate analysis, continued on page 9

regimen,” Brian I. Rini, MD, professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, in Cleveland, told Renal & Urology News.

Dr Rini was an investigator with the KEYNOTE-426 trial, the findings of which, he said, “are top line phase 3 results showing the best overall survival that’s ever been shown in a phase 3 [trial] in kidney cancer.”

If pembrolizumab and axitinib receive FDA approval as first-line therapy for advanced kidney cancer, he said, the combination will be a new standard of care.

In the KEYNOTE-426 trial, treatment with a dual regimen of pembrolizumab, continued on page 9

IN THIS ISSUE 2

Low-carb plus walking may ease adverse effects of ADT

4

TRT found to speed potency recovery after RARP

10

Kidney stones may predict osteoporotic fractures in CKD

14

Adolescent overweight and obesity increase RCC risk

15

Proton pump inhibitor use is associated with AKI

16

Decipher PCa test is more accurate in black vs white men

16

Urine microbiome may affect bladder cancer response to BCG

A novel program lowered post-surgery mortality rates at South Carolina hospitals.

PAGE 24

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

MARCH/APRIL 2019 www.renalandurologynews.com

Low-Carb Diet May Help Ease ADT’s Adverse Effects PATIENTS ON ANDROGEN deprivation therapy (ADT) for prostate cancer may be able to ease the adverse effects of the treatment by adhering to a regimen of a low-carbohydrate diet (LCD) plus walking, a small study suggests.

In a randomized trial of 42 men on ADT, those who followed this regimen—

which consisted of limiting carbohydrate intake to 20 grams per day or less and walking for at least 30 minutes for 5 days or more—experienced significant weight loss and improved hemoglobin A1c and lipid profiles compared with controls who maintained their usual diet and ­exercise patterns despite men not following the

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

diet exactly as recommended (average carbohydrate intake was 79 grams/day).

“Despite less than ideal compliance, if confirmed in larger studies, a low-­ carbohydrate diet may be a good option for men to avoid the side effects of hormonal therapy,” lead investigator Stephen J. Freedland, MD, of Cedarsplacebo 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

Sinai Medical Center in Los Angeles, said. “At the least, it is a potent means to lose weight with no clear increased risk of adverse effects due to ADT or no negative effects on PSA control. Future studies are planned to combine a low carbohydrate diet with exercise to see if we can achieve even greater responses.” 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 MARCH/APRIL 2019

For the study, investigators randomly assigned 20 patients to the LCD/walk­ ing group and 22 to the control group.

The primary outcome was change in insulin resistance at 6 months.

At 6 months, insulin resistance de­ creased by 4% in the intervention group and increased by 36% in the con­ trol group, but the difference was not statistically significant, Dr Freedland’s team reported in Prostate Cancer and 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

Prostatic Diseases. The investigators said the study was underpowered to detect a difference because of poor study ac­ crual, which resulted in a smaller-thanplanned study population. The inter­ vention arm, however, did experience a significant 36% improvement in in­ sulin resistance at 3 months compared with controls.

Also at 3 months, patients in the LCD/ walker group experienced significant 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

weight loss (median 7.8 kg) and a me­ dian 3.3% decrease in hemoglobin A1c, 13% improvement in high-density lipoprotein, and 37% decrease in tri­ glycerides compared with controls. At 6 months, the median weight loss in the intervention arm, relative to con­ trols, was 10.6 kg and median increase in HDL was 27%. The study found no significant difference in PSA levels be­ tween the groups. 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

In addition to the small sample size, study limitations included an inability to distinguish the effect of the LCD from the walking advice or from weight loss.

Another limitation was early dis­ continuation due to slow patient ac­ crual. They had planned to enroll 100 patients, but instead only enrolled 45, of whom 3 were dropped prior to ran­ domization because they met exclusion criteria or withdrew. ■

4 Renal & Urology News

MARCH/APRIL 2019 www.renalandurologynews.com

CKD Progression Linked to Diabetic Retinopathy DIABETIC retinopathy in patients with chronic kidney disease (CKD) is associated with an increased risk of CKD progression, according to a new study.

“Routine follow-up and management of ocular and retinal disorders in CKD patients with diabetes would be important for aggressive management of 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

diabetic retinopathy and prevention of CKD progression among these patients,” Hsin-Ting Lin, MD, of Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, and colleagues reported in Nutrients.

The study included 4050 patients with diabetes and CKD aged 20 to 85 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

years. Of these patients, 1481 had diabetic ret­i­nop­a­thy (518 with proliferative and 963 with non-proliferative disease) and 2569 did not. The investigators defined CKD progression as an average decrease in estimated glomerular filtration rate (eGFR) by more than 5 mL/ min/1.73 m2 per year. 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.

In a fully adjusted multivariate model, patients with diabetic retinopathy had significant 37% increased odds of CKD progression compared with those who did not have the condition. Among patients with CKD stage 3b-5, diabetic retinopathy was associated with significant 47% increased odds of CKD progression. In addition, patients with proliferative diabetic retinopathy had significant 82% increased odds of CKD progression compared with those who had non-proliferative diabetic retinopathy.

For the study, the investigators analyzed data from the National Health Insurance Research Database and the Epidemiology and Risk Factors Surveillance of the CKD project (2008–2013). ■

TRT Treats Post-RARP Impotency TESTOSTERONE replacement therapy (TRT) improves potency recovery following robot-assisted radical prostatectomy (RARP), investigators reported at the 34th European Association of Urology Congress in Barcelona, Spain.

Farouk M. El-Khatib, MD, and colleagues from the University of California, Irvine, studied 442 men undergoing RARP who had a preoperative International Index of Erectile Function (IIEF-5) score of 22 to 25, free testosterone values below 5.1 ng/dL collected prospectively before RARP, and responses to Erections Sufficient for Intercourse questionnaires at 3 and 24 months.

Of the 442 men, 49 (11.1%) were never on TRT and 13 (2.9%) were

076-3717-PM

on TRT within 1 year of surgery.

Among men who received TRT within 1 year, 6 (46.2%) and 13 (100%) were potent at 3 and 24 months, respectively. Of the men who never received TRT, 30 (61.2%) and 41 (83.7%) were potent at 3 and 24 months, respectively.

“Men should be counseled about the risk of impotency and considered for perioperative TRT for faster potency recovery,” the authors concluded in their study abstract. ■

www.renalandurologynews.com MARCH/APRIL 2019

Renal & Urology News 5

FROM THE EDITOR 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 Web editor Production editor Group art director, Haymarket Medical Senior production manager Director of production Assistant manager, audience development Director of audience insights National accounts manager Associate director, editorial services Vice president, content, medical communications General manager, medical communications President, medical communications CEO, Haymarket Media Inc.

Jody A. Charnow Natasha Persaud Kim Daigneau Jennifer Dvoretz Krassi Varbanov Louise Morrin Boyle Ashley Noelle Paul Silver William Canning Lauren Burke Kathleen Walsh Tulley Jim Burke, RPh Michael Graziani Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 18, Number 2. 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.

That Nebulous Concept Called Standard of Care

D

uring a session at the 2019 Genitourinary Cancers Symposium (GUCS) held recently in San Francisco, researchers presented findings from phase 3 studies showing that immunotherapybased combination regimens are superior to sunitinib alone at improving progression-free survival among patients with previously untreated advanced kidney cancer. (See cover article.) One study demonstrated improved overall survival. The study presenters concluded that their findings support the combination regimens as a new standard of care.

Perhaps, but when does a new treatment actually become a standard of care? Is this a matter of how widely accepted and routinely used it is? The precise point at which a new medicine becomes a standard of care is difficult, if not impossible, to identify, unless the date on which a medical society announces its endorsement of the therapy, or releases guidelines recommending it, indicates an “official” acceptance of the therapy as a standard of care. In medical malpractice suits, standard of care is established on a case-by-case basis according to how a physician defendant’s peers in a particular community manage medical cases similar to the one being litigated.

Whatever milestone marks the ascendancy of a treatment to standard-of-care status, years may pass before it is reached even after pivotal clinical trials show the superiority of a new therapeutic approach. Physicians must be convinced that it really is better than the treatments they have been using. They may wait until trial data are published in a peer-reviewed journal so they can read more detailed information than typically is provided in a brief presentation at a medical conference. Even after a new treatment wins FDA approval, physicians may have lingering concerns about adverse effects, contraindications, patient comorbidities and therapeutic adherence, and whether patients’ insurance will cover it.

Regardless of how a new treatment evolves into a new standard of care, the process must start somewhere. Investigators presenting research findings before their peers, as in the aforementioned GUCS session, is an important beginning. Many of these peers are opinion leaders at the institutions with which they are affiliated, and, in some cases, in the international medical community as well. It is not inconceivable that some of those opinion leaders sitting in the session returned home believing in the promise of the new approach to managing untreated advanced kidney cancer. They may share their thoughts and enthusiasm with colleagues over coffee in the cafeteria, in casual chats in a hallway, during in-house meetings and lectures, or at a gathering of their local medical society. And a new treatment could well be on its way to becoming a new standard of care.

Jody A. Charnow Editor

6 Renal & Urology News

MARCH/ APRIL 2019

www.renalandurologynews.com

Contents

MARCH/APRIL 2019

■

Urology 2

ONLINE

this month at renalandurologynews.com Clinical Quiz

4

14

Test your knowledge by taking our latest quiz at renalandurologynews.com/ run-quiz 16

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.

TRT Treats Post-RARP Impotency All men who received testosterone replacement therapy within 1 year of surgery had fully recovered potency 24 month post-op.

Adolescent Overweight, Obesity Increase RCC Risk Men who were overweight or obese in adolescence had a significant 1.8- and 2.9-fold increased risk of renal cell carcinoma, respectively, compared with normal-weight men.

PCa Gene Test More Accurate in Black Men Decipher, a genomic test for prostate cancer, is better at predicting disease-specific outcomes among black vs white men.

CALENDAR 2019 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 International Continence Society Annual Meeting Gothenburg, Sweden September 3–6

Nephrology 4

CKD Progression Linked to Diabetic Retinopathy Diabetic retinopathy in patients with chronic kidney disease predicted significant 37% increased odds of worsening estimated glomerular filtration rate.

8

Data Support Sertraline for HD Patient Depression In a study, sertraline was found to be more effective than cognitive behavioral therapy.

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

Low-Carb Diet May Help Ease ADT’s Adverse Effects Limiting carbohydrate intake to 20 grams per day or less and walking for at least 30 minutes for 5 days or more led to improved hemoglobin A1c and lipid profiles.

VOLUME 18, ISSUE NUMBER 2

13

ESRD Found Not to Influence CAD Therapy Choice Patients with and without end-stage renal disease had similar rates of PCI, CABG, and medical treatment, a study found.

18

Departments 5

CKD-MBD Screening Suboptimal Laboratory testing for parathyroid hormone, phosphorus, calcium, and other biochemical markers of mineral bone disease falls short of guideline recommendations, researchers report.

From the Editor When does a new therapy become standard of care?

10

News in Brief High vitamin D levels are associated with lower RCC risk

Providers who are aware of undocumented patients

18

Ethical Issues in Medicine An examination of the barriers to continuous learning in medicine

24

Practice Management A checklist that could lower post-surgery mortality

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

23

in integrated health care systems should appeal to their administrators to develop policies that will cover outpatient dialysis services.

See our story on page 22

8 Renal & Urology News

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Data Support Sertraline for HD Patient Depression SERTRALINE IS modestly more effective than cognitive behavioral therapy (CBT) in treating depressive symptoms in patients on maintenance hemodialysis (HD), new study findings suggest.

The study, led by Rajnish Mehrotra, MD, MS, of the Kidney Research Institute at the University of Washington

in Seattle, also found that engagement interviews had no effect on patient acceptance of depression treatment.

The findings are from the ASCEND (A Trial of Sertraline vs. Cognitive Behavioral Therapy for End-stage Renal Disease Patients with Depression) openlabel trial, which involved 41 dialysis

centers in 3 US metropolitan areas. “The information in this clinical trial should facilitate individualized patient and provider decisions on options for treating depression in patients receiving maintenance hemodialysis,” the authors concluded in a paper published in Annals of Internal Medicine.

ASCEND enrolled patients who had been on HD for at least 3 months and had a Beck Depression Inventory-II score of 15 or higher. The trial consisted of 2 phases, with 184 patients participating in phase 1 and 120 in phase 2.

In phase 1, investigators randomly assigned patients to an engagement interview visit aimed at increasing patients’ willingness to accept the diagnosis and treatment of depression, or to a control visit. The engagement visit was conducted face to face by trained therapists while patients received outpatient HD. “The therapists used motivational interviewing to help participants articulate their ambivalence about treatment and echoed back to patients their expressions of wanting life to be different.” The primary outcome was the proportion of patients who initiated depression treatment within 28 days.

Sertraline is modestly more effective than cognitive behavioral therapy, study finds.

In phase 2, investigators randomly assigned patients to receive CBT or sertraline for 12 weeks. CBT consisted of 10 sessions of 60 minutes each while receiving outpatient HD. Therapists conducted sessions face to face with patients. The primary outcome measure was depressive symptoms measured using the Quick Inventory of Depressive Symptoms-Clinician-Rated (QIDS-C) instrument, on which higher scores indicate worse depression.

In phase 1, the proportion of patients initiating treatment after the engagement or control visit did not differ significantly (66% vs 64%, respectively).

In phase 2, the sertraline group had significantly lower QIDS-C depression scores at 12 weeks than the CBT group (5.9 vs 8.1), the investigators reported.

Adverse events occurred more frequently in the sertraline than CBT group, the authors stated.

In an accompanying editorial, Jennifer E. Flythe, MD, MPH, of the University of North Carolina School of Medicine in Chapel Hill, commented that “Mehrotra and colleagues conducted a rigorous trial that will allow dialysis clinicians to ASCEND to new heights in their therapeutic approach to depressive symptoms, a patient-prioritized outcome indeed.” ■

www.renalandurologynews.com MARCH/APRIL 2019

mRCC standard of care continued from page 1

an immunotherapeutic agent that inhibits programmed death-ligand 1 (PDL1), and axitinib, a TKI, was associated with significantly longer overall and progression-free survival (PFS) compared with sunitinib in untreated locally advanced or metastatic renal cell carcinoma (RCC). The JAVELIN trial, which is ongoing, demonstrated that combined treatment with avelumab, also a PD-LI inhibitor, and axitinib was associated with superior PFS compared with sunitinib in patients with advanced RCC.

KEYNOTE-426 The KEYNOTE-426 trial included 861 patients randomly assigned to receive either pembrolizumab plus axitinib (432 patients) or sunitinib (429 patients). After a median follow-up of 12.8 months, 59% of patients in the combined treatment arm remained on treatment compared with 43.1% of the sunitinib arm, Thomas Powles, MD, PhD, of Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, and Queen Mary University of London, UK, reported at the conference. The 12-month survival rate was 89.9% in the ­pembrolizumab-axitinib

Drug cuts CRPC Mets risk continued from page 1

The findings are from the ARAMIS (Androgen Receptor Antagonizing Agent for Metastasis-free Survival) trial, a ­double-blind, placebo-­controlled phase 3 trial in which investigators randomly assigned 955 men with nmCRPC to receive darolutamide (two 300 mg tablets twice daily) and 554 to receive placebo. All patients continued on androgen deprivation therapy. The primary endpoint was MFS. The median MFS was 40.4 months in the darolutamide arm compared with 18.4 months in the placebo arm, Dr Fizazi reported. The darolutamidetreated patients had a significant 59% decreased risk of metastasis compared with placebo recipients. In addition, darolutamide decreased the risk of death and pain progression by 29% and 35%, respectively.

The incidences of treatment-emergent adverse events with 5% or greater frequency or grade 3–5 severity were comparable between the study arms.

Discontinuation rates due to adverse events were 8.9% in the darolutamide arm and 8.7% with placebo.

arm compared with 78.3% in the sunitinib-treated patients. Median PFS was 15.1 months in the combined therapy arm compared with 11.1 months among sunitinib-treated patients. Recipients of the combined therapy had a significant 47% decreased risk of death and 31% decreased risk of disease progression compared with the sunitinib arm. The ORR was significantly higher in the pembrolizumab-axitinib group than the sunitinib group (59.3% vs 35.7%).

First-line treatment with dual regimens was associated with prolonged PFS. All of the subgroups examined, including all IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) risk and PD-Ll expression subgroups, benefited from the dual regimen, Dr Powles said.

Treatment-related adverse events (AEs) were grade 3–5 in 62.9% of patients in the pembrolizumab-axitinib group and 58.1% in the sunitinib arm.

These events led to discontinuation of treatment with both pembrolizumab and axitinib in the combined treatment

The results of the ARAMIS trial confirm the benefits of early and potent inhibition of androgen-receptor signaling in men with nmCRPC, according to Dr Fizazi and his collaborators.

Dr Fizazi emphasized that darolutamide has a much better safety profile compared with apalutamide and enzalutamide. “This is very important because we’re talking about an asymptomatic population of men. …We can maintain their quality of life,” Dr Fizazi told Renal & Urology News.

Darolutamide, he noted, does not penetrate the blood-brain barrier, which probably explains why he and his team did not observe some of the side effects seen with apalutamide and enzalutamide, such as cognitive impairment and fatigue. Unlike enzalutamide and apalutamide, darolutamide was not associated with a higher risk of falls and fractures, which are probably due to central nervous system toxicity, Dr Fizazi stated.

Fatigue or other asthenic conditions occurred in 16% of darolutamidetreated patients and 11% of placebo recipients, a nonsignificant difference.

The ARAMIS trial was sponsored by Bayer HealthCare and Orion Pharma. ■

group (8.2% of patients), but no patient in the sunitinib arm discontinued treatment due to treatment-related AEs, according to investigators.

JAVELIN Renal 101 The JAVELIN trial previously had demonstrated longer PFS (median 13.8 vs 8.4 months) and objective response rate (ORR, 51% vs 26%) with avelumab plus axitinib compared with sunitinib.

Of 886 patients randomized, 560 (63%) had PD-L1-positive tumors. At data cut-off in June 2018, the median followup time was 12 months for the combination therapy arm and 11.5 months for the sunitinib arm. The findings presented at the 2019 symposium are from a subgroup analysis of patients with previously untreated advanced RCC. Co-lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at DanaFarber Cancer Institute and professor of medicine at Harvard Medical School in Boston, and colleagues compared the effects of the treatment approach according to Memorial Sloan Kettering Cancer Center (MSKCC) and IMDC risk groups (favorable-, intermediate-, and poor-risk).

Among patients with MSKCC favorable-risk disease, the median PFS, in months, was not estimable (NE) and

TRT possibly beneficial continued from page 1

TRT was associated with a statistically significant median 1.5-year delay in disease progression, after adjusting for pathologic grade and stage, according to Dr Ahlering’s team.

“This is not what we set out to prove, so it was a big surprise: not only did testosterone replacement not increase

Disease progression was delayed by a median of 1.5 years, researchers reported. recurrence, but it actually lowered recurrence rates,” Dr Ahlering said in a statement issued by the EAU. “While the testosterone is not curing the cancer per se, it is slowing the growth of the cancer, giving an average of an extra 1.5 years before traces of cancer can be found. We already know that testosterone can help with physiological markers such as muscle mass, better cholesterol and triglyceride levels and

Renal & Urology News 9

the ORR was 66% in the avelumabaxitinib group, whereas the median PFS and ORR were 16.7 months and 38%, respectively in the sunitinib arm.

For patients with MSKCC intermediate-risk disease, the median PFS was 13.3 months and the ORR was 50% in the combination arm compared with 7.9 months and 24% in the sunitinibtreated patients. In the MSKCC poorrisk patients, the median PFS and ORR were 5.6 months and 31% for those treated with the dual regimen and 2.8 months and 9%, respectively.

The findings for the IMDC risk groups were similar.

Treatment effect by PD-L1 status For patients with PD-L1-positive tumors, the median PFS and ORR were 13.8 months and 55%, respectively, in the avelumab-axitinib group, compared with 7.2 months and 26% in the sunitinib arm. Among patients PD-L1-negative tumors, the median PFS and ORR were 16.1 months and 47%, respectively, for recipients of the combination therapy, compared with 11.1 months and 28% for the sunitinib group.

“These results do support avelumab plus axitinib as a new first-line-standard of care for patients with advanced RCC,” Dr Choueiri told symposium attendees. ■ increased sexual activity, so this seems to be a win-win.”

He noted that smaller studies have suggested that testosterone may not be a risk for some patients, but the new study is the largest of its kind ever conducted. “We’re not suggesting that treatment methods be changed just yet, but this puts us at the stage where we need to question the taboo against testosterone use in prostate cancer therapy — especially for low-risk patients after radical prostatectomy. We need the oncology/urology community to begin to review testosterone use.”

“The paper is indeed important, as it stresses the importance of checking testosterone levels as a part of the management of patients with sexual disorders following radical prostatectomy,” Francesco Montorsi, MD, the EAU’s Adjunct Secretary General for Science and professor and chairman of the department of urology at University Vita-Salute San Raffaele in Milan, said in the EAU statement. “Obviously selection of the right patients is vital, but if confirmed, this may have immediate benefits on quality of life; the possibility of reducing mortality would be an unexpected bonus. We now need bigger studies to support this work.” ■

10 Renal & Urology News

MARCH/ APRIL 2019 www.renalandurologynews.com

News in Brief

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

Short Takes Microwave Ablation May Offer Alternative to PTx

allows physicians to make dosage

Microwave ablation (MWA) shows poten-

according to a Romeg press release.

tial as an alternative to parathyroidec-

The product also is beneficial for

tomy (PTx) for secondary hyperpara-

patients who cannot swallow solid

thyroidism, according to a new study

doses or pills.

adjustments easily for their patients,

published in Hemodialysis International. in a study of 81 maintenance hemodial-

Cutting Down on Salt May Ease Some Nocturia Cases

ysis patients with secondary hyperpara-

Patients with nocturia who are heavy

thyroidism, Binghu Jiang, MD, of North

consumers of salt may be able to

Sichuan Medical College, Nanchong,

ease the condition by cutting down on

China, and colleagues found that the

salt intake, investigators reported in

rates of achieving the recommended

Neurourology and Urodynamics.

In a study comparing the procedures

target for intact parathyroid hormone

In a prospective study of 321 patients

levels were significantly higher in the

with nocturia and excessive salt intake

MWA group than in the PTx group at 1

(8 grams per day for men and 7 grams

day, 1 week, 2 weeks, and 1, 3, 6, 12,

or more per day for women), Tomohiro

and 2 months post-procedure.

Matsuo, MD, and colleagues from Nagasaki University Graduate School

FDA Approves Liquid Colchicine Formulation

of Biomedical Sciences in Nagasaki,

For the first time, the FDA has

patients who successfully decreased

approved a liquid formulation of

their daily salt intake had a significant

colchicine for the prophylaxis of gout

decrease in nocturia episodes (from

flares in adults. The product, made by

2.3 to 1.4) and improvement in noc-

Romeg Therapeutics, of Woburn, Mas-

turnal polyuria index, which decreased

sachusetts, is called Gloperba.

from 30.2 to 27.7. Investigators

Compared with available capsule

Japan, found that the 223 (69.5%)

observed no improvement in any

and tablet formulations of colchicine,

symptoms among patients who failed

Gloperba oral solution (0.6 mg/5 mL)

to decrease their salt intake.

Dialysis vs Cancer Patient Survival Men and women with incident prostate cancer and breast cancer, respectively, have higher unadjusted 5-year survival probabilities compared with incident maintenance dialysis patients.

Shown below are the survival probabilities, by sex, for patients on maintenance dialysis vs those with various cancers.

100

83.3%

82.1%

■ Men ■ Women

80 60

56.1% 56.8%

50.8% 49.8%

40

14.0% 19.7%

20 0

9.1% Dialysis

Prostate

Breast

Colorectal

Lung

9.4%

Pancreatic

Source: Naylor KL, Kim SJ, McArthur E, et al. Mortality in incident maintenance dialysis patients versus incident solid organ cancers: A population-based cohort. Am J Kidney Dis. 2019; published online ahead of print.

Kidney Stones May Predict Osteoporotic Fracture in CKD K

idney stones predict an increased risk of osteoporotic fracture in patients with chronic kidney disease (CKD), new data suggest.

“Our findings suggest that the presence of kidney stones should be considered as a clinical risk factor for osteoporotic fracture in patients with CKD,” investigators wrote in a paper published online ahead of print in Scientific Reports.

A team led by Dong Ho Shin, MD, of Hallym University, Kandong Sacred Heart Hospital, Seoul, Korea, conducted a retrospective medical record-based study that included 2282 patients with stable stage 3–4 CKD who were treated from 2007 to 2017. Kidney stones developed in 113 patients. Investigators matched these patients by propensity score with 113 patients without kidney stones.

During a mean follow-up period of 64.7 months, osteoporotic fractures occurred more frequently in patients with than without kidney stones (29.2% vs 14.2%). After adjusting for age, sex, body mass index, and other potential confounders, kidney stones were significantly associated with a 2.3-fold increased risk of osteoporotic fracture.

Better BP Control Associated With Decreased ED Risk T

ighter blood pressure (BP) control in men with hypertension is associated with a lower risk of erectile dysfunction (ED), investigators concluded in a paper published in the Journal of Sexual Medicine (2019;16:410-417).

In a study of 39,320 men with newly diagnosed hypertension, Wayland Hsiao, MD, and colleagues found an overall ED incidence of 13.9%. Higher average systolic BP (SBP) in the last 2 years before the study end point (development of ED) was associated with a higher risk of ED in a dose-dependent manner. Compared with SBP measurements below 120 mm Hg, SBP values of 120 to 139, 140 to 159, and 160 mm Hg or higher were significantly associated with a 23%, 49%, and 84% increased risk of ED, respectively, in adjusted analyses. Wide variation in BP control was associated with a higher incidence and short time to development of ED.

Higher Vitamin D Levels Lower Kidney Cancer Risk H

igher circulating concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with a lower risk of renal cell carcinoma (RCC), investigators reported in the International Brazilian Journal of Urology.

The data are from a study in which investigators in China compared with 135 newly diagnosed cases of RCC with 135 controls matched by age and sex. Average plasma levels of 25(OH)D were significantly lower in cases compared with controls (21.5 vs 24.1 ng/mL), Fei Li, MD, of Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China, and colleagues reported. Each 10 ng/ mL increment in 25(OH)D level was associated with significant 13% decreased odds of RCC. In addition, compared with patients who had 25(OH)D deficiency (defined as levels below 20 ng/mL), those with levels of 20–29.9 and 30 ng/mL or higher had significant 50% and 70% decreased odds of RCC, after adjusting for age, sex, body mass index, and other potential confounders.

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Aspirin Overused for AF in Advanced CKD, Study Finds ASPIRIN IS OVERUSED and oral anticoagulation (OAC) medications are under­used for stroke prevention in patients with advanced chronic kidney disease (CKD) and atrial fibrillation, investigators concluded in a presentation at the American College of Cardiology’s 68th Annual Scientific Session & Expo in New Orleans.

American College of Cardiology/ American Heart Association/Heart Rhythm Society guidelines recommend OAC therapy for patients with atrial fibrillation (AF) and a CHA2DS2VASc stroke risk score of 2 or higher.

In a study of 136,385 patients with a mean age of 76.7 years who had AF and CKD stage 1 or higher and a CHA 2DS2VASc score of 2 or higher, Michael Dorsch, PharmD, of the University of Michigan in Ann Arbor, and colleagues found that OAC use decreased with worsening CKD stage.

The proportion of patients on OAC

compared with warfarin use, according to the investigators.

The findings are from the QUANTUMAF study, a national quality improvement initiative aimed at increasing the use of guideline-directed OAC in patients with AF. The researchers analyzed data from the Premier Health

Database, which represents 20% of hospital discharges across the United States.

The investigators acknowledged study limitations, which included the use of an administrative database. As a result, they noted, they were unable to valid the clinical diagnosis of AF. They also could not determine and ­incorporate

In a study, 25.1% of patients with ESRD used aspirin only for atrial fibrillation. drugs decreased from 61.4% of those with CKD stage 1 to 45.7% of those with end-stage renal disease (ESRD).

Direct OAC (DOAC) use declined from 18.7% of patients with CKD stage 1 to 2.2% of those with ESRD. In contrast, aspirin use alone increased with CKD stage, rising from 17.7% of patients with CKD stage 1 to 25.1% of those with ESRD.

Mortality lower with DOAC The study also demonstrated that DOAC use decreased bleeding risk and mortality compared with warfarin therapy. Among patients with stage 4 to end-stage renal disease (ESRD), 1-year bleeding rates were 3.9% with DOAC use compared with 4.6% for warfarin therapy. In adjusted analyses, DOAC use among these patients was associated with a significant 16% decreased 1-year bleeding risk. The 1-year mortality rates were significantly lower with DOAC use than warfarin therapy among patients with CKD stage 1-3 (4.4% vs 5.0%) and CKD stage 4 to ESRD (6.3% vs 8.1%). DOAC use was associated with a ­significant 12% and 23% decreased risk of 1-year mortality, respectively,

FS:7.125”

patient refusal to take drugs despite adequate education and understanding.

In addition, the data represent inpatient OAC use and thus may not represent outpatient prescription fills or adherence to treatment.

The study was funded by Janssen Pharmaceuticals. n

B:16.75” T:16.25” S:15.25”

www.renalandurologynews.com MARCH/APRIL 2019

Renal & Urology News 13

ESRD Found Not to Influence CAD Therapy Choice B:16.75” T:16.25” S:15.25”

END-STAGE renal disease (ESRD) alone does not influence choice of therapy for coronary artery disease (CAD), researchers concluded in a presented at the American College of Cardiology’s 68th Annual Scientific Session & Expo in New Orleans. Patients with ESRD, however, had significantly higher 30-day

and 6-month readmission rates and longer hospital length of stay (LOS) than non-ESRD patients.

In a retrospective study of 9027 patients who underwent cardiac catheterization from 2005 to 2015, 127 (1.4%) had ESRD and were on hemodialysis.

The ESRD and non-ESRD patients

showed no ­significant difference in the rates of percutaneous intervention (33.3% vs 33.6%, respectively), coronary artery bypass grafting (35.9% vs 30.2%), and medical therapy (30.8% vs 36.2%) for CAD, Preetham Reddy Muskula, MBBS, and colleagues at Saint Louis University in St. Louis, Missouri, reported.

The 30-day and 6-month readmission rates were 17.3% and 35.4%, respectively, in the ESRD group compared with 9.6% and 16.9%, respectively, in the non-ESRD group. The average LOS was 4.5% in the ESRD group compared with 2.8 days in the nonESRD group. n

B:11.25”

T:10.875”

S:9.875”

FS:7.125”

14 Renal & Urology News

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Adolescent Overweight, Obesity Increase RCC Risk OVERWEIGHT AND obesity during adolescence increase the risk of renal cell carcinoma (RCC), according to investigators.

In a study of 238,788 Swedish men (mean age 18.5 years) who underwent mandatory military conscription assessment from 1969 to 1976, each 1 kg/m2

increase in body mass index (BMI) during adolescence was associated with a significant 6% increased risk of RCC, after adjusting for age and health status at conscription, blood pressure, and other possible confounders, T:7.5" Anna Landberg, of Örebro University in Örebro, Sweden, S:7" and c­olleagues

reported in the International Journal of Cancer. In addition, compared with normal weight men (reference), men who were overweight or obese had a significant 1.8- and 2.9-fold increased risk of RCC, respectively.

The link between overweight and obesity and RCC appears to be already

established during late adolescence, the authors concluded. “Prevention of unhealthy weight gain during childhood and adolescence may thus be a target in efforts to decrease the burden of RCC in the adult population.”

Obesity is a well-established risk factor for RCC in both men and women, the authors noted, but most studies looking at the association have focused on adults. Obesity among teenagers has increased dramatically in prevalence over recent decades, yet few studies have looked at the potential influence of overweight and obesity in adolescence on RCC risk, they added.

“A better understanding of the role of overweight and obesity earlier in life is needed to target relevant time-windows for prevention efforts,” they wrote.

For their study, Landberg and her collaborators followed the men through linkage to the Swedish Cancer Registry to identify new diagnoses of RCC.

RCC risk increased 6% with each 1 kg/m2 increase in body mass index, study found.

T:10.25" S:9.75"

During a mean follow-up of 35.4 years, 266 men received a diagnosis of RCC at a mean age 49.4 years.

The investigators defined normal weight as a BMI (in kg/m2) of 18.5 or higher but less than 25, overweight as a BMI of 25 or higher but less than 30, and obesity as 30 or greater.

Strengths of the study include the large sample size, prospective design, and long follow-up, the authors noted.

They also acknowledged limitations, pointing out, for example, that the maximum age at the end of follow-up was 57 years. The incidence of RCC increases with age, reaching a plateau at around age 70 years; thus, their follow-up period does not cover the ages with the highest incidence rates, they pointed out. “The aetiology of our cases of early-life RCC could differ from those occurring later in life, and the results may therefore not be directly generalizable to older populations,” they wrote.

Lack of data on smoking is another potential weakness, the authors stated, noting that a previous meta-analysis found an increased relative risk of RCC among people who ever smoked compared with lifetime never-smokers. ■

11110434_2019_HP_Brief_Summary_M4.indd 1

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Renal & Urology News 15

CKD Progression Tied to Low Potassium Excretion LOW URINARY POTASSIUM excretion is significantly associated with progression of chronic kidney disease (CKD), regardless of age or the presence of diabetes or proteinuria, a study suggests.

In a study of 1821 patients from the Korean Cohort Study for Outcomes in Patients with CKD, patients in the lowest quartile of urinary potassium-tocreatinine ratio had a significant 47% increased risk of CKD progression compared with those in the highest quartile, in a fully adjusted model, investigators reported in the Clinical Journal of the American Society of Nephrology. Of the 1821 patients, 855 provided 24-hour urine specimens. In this subset, patients in lowest quartile of spot urinary potassium, 24-hour urinary potassium excretion, and spot urinary potassium-to-

PPIs Again Found to Up AKI Risk INDIVIDUALS WHO TAKE proton pump inhibitors (PPIs) are at increased risk of kidney impairment, according to a large populationbased study published online ahead of print in Pharmacotherapy.

Investigators at the University at Buffalo School of Pharmacy and Pharmaceutical Sciences in Buffalo, New York, found that patients who used PPIs had a significant 4-fold increased risk of acute kidney injury (AKI) and 1.2-fold increased risk of chronic kidney disease (CKD) compared with nonusers, in adjusted analyses.

The study, led by David M. Jacobs, PharmD, PhD, included 93,335 patients with AKI and 84,600 patients with CKD. Of the patients in the AKI and CKD cohorts, 16,593 and 14,514 used PPIs, respectively. The incidence rates of AKI and CKD were significantly higher among PPI users than nonusers (36.4 vs 3.54 per 1000 person-years and 34.3 vs 8.75 per 1000 person-years, respectively), Dr Jacobs and his collaborators reported.

Patients with AKI were followed for up to 90 days, and patients with CKD required at least 1 year of follow-up. ■

creatinine ratio had a significant 3.8-, 3.0, and 1.9-fold increased risk of CKD progression, respectively, ­compared with those in the highest quartile.

The investigators, led by Seung Hyeok Han, MD, of the Institute of Kidney Disease Research at Yonsei University in Seoul, Korea, defined

CKD progression as a 50% of greater decrease in estimated glomerular filtration rate from baseline and onset of end-stage renal disease. CKD progression occurred in 392 patients (22%) during 5326 person-years of follow-up.

The association between low urinary potassium excretion and CKD pro-

gression remained significant regardless of age (less than 60 vs 60 years or older) or the presence or absence of diabetes and proteinuria.

“Our robust findings suggest potential prognostic value of urinary potassium excretion for progression of CKD,” Dr Han’s group concluded. ■

16 Renal & Urology News

■ GUCS 2019, San Francisco

MARCH/APRIL 2019 www.renalandurologynews.com

2019 Genitourinary Cancers Symposium

Study Confirms Benefits of Apalutamide Decreased risk of metastasis or death in patients with nmCRPC persisted after longer follow-up

BY JODY A. CHARNOW AN UPDATED ANALYSIS of patients in the SPARTAN trial show that apalutamide continues to demonstrate benefit for patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC), researchers reported.

SPARTAN is a phase 3 multicenter, randomized, double-blind trial that enrolled 1207 patients with nmCRPC who had a PSA doubling time of 10 months or less. Investigators randomly assigned 806 patients to receive apalutamide plus androgen deprivation therapy (ADT) and 401 to receive placebo plus ADT. Results of the primary analysis reported 1 year ago showed that apalutamide decreased the risk of distant metastases or death (metastasisfree survival [MFS]) by 72% compared with placebo. The updated analysis,

by Eric J. Small, MD, of the Helen

PCa Gene Test More Accurate in Black Men DECIPHER, A GENOMIC test for prostate cancer (PCa), may perform better at predicting poor diseasespecific outcomes among blacks than whites, according to investigators.

Using Decipher, a team led by Stephen J. Freedland, MD, who is affiliated with Cedars-Sinai Medical Center in Los Angeles and has a joint appointment at the Durham VA Health Care System in Durham, North Carolina, calculated genomic classifier (GC) scores for 554 men with PCa (306 black and 239 white) who underwent radical prostatectomy (RP) at the VA medical center from 1989 to 2016.

The study population was a clinically high-risk cohort, with patients having either stage T3a disease, positive surgical margins, seminal vesicle invasion, or who received post-RP radiation. Dr Freedland and his colleagues compared GC score and Cancer of the Prostate Risk Assessment score (CAPRA-S) with respect to their ability

Diller Family Comprehensive Cancer Center, University of California, San Francisco, and collaborators, looked at second progression-free survival (PFS2)—defined as the time from randomization, through the development

New findings are from an updated analysis of the SPARTAN trial. of metastases, and through to disease progression on subsequent anticancer therapy or death—and safety after 1 year of additional follow-up.

The median treatment duration with apalutamide and placebo was 25.7 months and 11.5 months, respectively.

to predict metastasis and PCa-specific mortality (PCSM).

With a median follow-up of 9 years, metastases developed in 40 patients and 18 died from PCa. Among the black patients, 154 (50%) were Decipher low risk and 218 (71%) were CAPRA-S low/ intermediate risk.

On multivariable analysis, GC score and CAPRA-S significantly predicted metastasis in the white patients. Among black patients, GC score, but not CAPRA-S, significantly predicted metastasis. In both white and black men, GC score, but not CAPRA-S, significantly predicted PCSM. GC score had greater accuracy for predicting these outcomes in black men. GC score predicted metastasis and PCSM 8 years after RP with 84% and 82% accuracy, respectively, in the black patients compared with 70% and 73% in the white patients, respectively.

“These data add to the growing data that Decipher is a robust measure of clinical outcomes across many cohorts and many disease settings,” Dr Freedland said. “To that we can now add that Decipher predicts outcomes regardless of race, which is important given black men are at the highest risk of aggressive prostate cancer in the world.”

The study was funded by GenomeDx Biosciences, the maker of Decipher. ■

(Compared with the placebo group, the apalutamide group had a significant 50% decreased risk of PFS2. The median time to PFS2 was not reached in the apalutamide arm and was 39.3 months among placebo recipients.

“These data suggest that earlier treatment, prior to the development of overt metastases, is likely to provide an advantage over delaying therapy until metastases develop,” Dr Small said.

In addition, at a median follow-up of 32 months, 51.3% of patients in the apalutamide group, 8% of the 75 patients who crossed over from the placebo to the apalutamide group, and 99.7% of remaining placebo recipients had discontinued study treatment.

Rates of discontinuation due to progressive disease and adverse events (AEs) were 27.3% and 12.7%, respectively, in the apalutamide-treated patients and

73.4% and 8.4% in the placebo arm.

Dr Small’s team found no substantial change in the incidence of treatmentemergent AEs in the apalutamide group at the 1-year update, despite a longer exposure time to apalutamide.

With respect to drug-related treatment-emergent AEs, the investigators reported no grade 4 or 5 events. Grade 3 treatment-emergent AEs included rash (5.2%), falls (2.4%), and fractures (3.1%).

In Lancet Oncology last year, investigators led by Fred Saad, MD, of the University of Monreal Hospital Center, published the findings of another analysis of the SPARTAN trial showing that apalutamide maintains patients’ healthrelated quality of life (HRQoL) in addition to prolonging time to metastasis.

The FDA approved apalutamide for treatment of patients with nmCRPC on February 24, 2018. ■

Urine Microbiome May Affect Bladder CA Response to BCG URINE MICROBIOME composition var-

newly diagnosed with NMIBC who were

ies in patients with non-muscle-invasive

enrolled prior to undergoing transure-

bladder cancer (NMIBC), which could

thral resection of bladder tumor (TURBT).

provide a way to predict response to

Patients had a median age of 69 years.

immunotherapy with bacillus Calmette-

Clinicians instilled adjuvant BCG to

Guérin (BCG), investigators reported.

high-risk patients according to surgical

“It is first important to appreciate that urine, even in the absence of any uri-

histologic findings.

After a median follow-up time of 6

nary tract infection, is not sterile,” said

months, 10 patients (32%) experienced

lead investigator Randy F. Sweis, MD,

disease recurrence and 21 (68%) did

of the University of Chicago. “A urinary

not. The most abundant phyla observed

commensal microbiome has recently

were Actinobacteria, Bacteroidetes,

been characterized, and we sought to

Firmicutes, Proteobacteria, and

determine if baseline variation in its com-

Tenericutes. Collectively, these bacteria

position can impact the efficacy of BCG,

accounted for more than 99% of the

a local therapy for non-muscle invasive

phyla detected in this cohort. The abun-

bladder cancer. Our early data suggest

dance of Proteobacteria was significantly

that variation in the composition of bacte-

higher among patients who had disease

ria present is associated with response

recurrence, with stronger differences

to BCG, and both translational and

observed for specific classes, such as

pre-clinical work is ongoing to elucidate a

Gammaproteobacteria. Firmicutes such

mechanism by which this might occur.”

as Lactobacillales were more abundant

Dr Sweis and his colleagues assessed urine biome composition in 31 patients

in patients who did not have disease recurrence, the investigators reported. ■

18 Renal & Urology News

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Ethical Issues in Medicine L

ast month, a colleague interrupted our conference call to apologize. She was having trouble taking notes on our discussion because she recently switched to using her mouse with her other hand. She found that the active process of training her non-dominant hand and brain to work together kept her sharper and more focused and engaged with her work.

That sounded too interesting not to try. So the next day at work I switched my mouse to my non-dominant left hand. I became immediately annoyed.

Typing and editing was drastically less efficient. My mental efforts were drained by having to focus on adjusting to using my left hand to do basic maneuvers like placing the cursor. I thought learning some new keyboard shortcuts would help, but that just took more time and I never could remember them. By the end of the day I had enough.

A right-handed mouse When I went back to work the next day, I tried it again and found myself slightly better at manipulating the mouse. By the third day, I was getting even better at it, being less conscious of my handeye coordination, and more productive at work. I thought I was making real strides, but when I returned home that

Presented with the need to adapt to medical advancement, I have often resisted and tried to offer justifiable excuses for my resistance. I have told myself the newer way is unnecessary, less efficient, a fad, short-sighted, or even wrong.

Change has always been hard, but, for physicians, learning is an ongoing process. Although learning during medical school and post-graduate training was explicit, coordinated, and paired with evaluations and feedback, practitioners must continually learn over the course of their careers, often with less formal structure.1 Physicians also have an ethical obligation to learn continuously because this ensures acquisition of knowledge about the safe and effective practice of medicine that promotes competency and public trust in the profession.

These professional obligations are so vital to the practice of medicine that they are codified in law and policy for professional licensing and board certification.

Even without the regulatory and licensing requirements for continuing professional education, it is likely that many physicians would continue to pursue regular learning opportunities to stay current and competent in their field. Internal motivation is inherent for many practitioners, and the field of medicine draws those with a love of learning. It is diffi-

Physicians engaged with continuous learning often find that the process enables an active commitment to their profession and patients. night, I noticed that my mouse was designed for right-handed users and thus could not be used with my nondominant hand. Tired and ready to give up, I recognized that I have had this feeling of exasperation before.

Many times throughout my career, I have felt frustrated when trying to learn new ideas, concepts, or medical procedures. These challenges started in medical school, continued during residency, and still occasionally dog me today.

cult to get through medical school and residency without enjoying the learning process at some level. Physicians engaged with continuous learning often find that the process enables an active commitment to their profession and patients.

Some of them also probably find it fun.

Possessing internal motivation or a recognition and commitment to the ethical obligations to continuous learning, however, does not ensure that such learning comes easy. As the analogy

© KINO BROD / ILLUSTRATION SOURCE

Physicians face various barriers in fulfilling their continuing medical education obligation BY DAVID J. ALFANDRE, MD, MSPH

with my mouse suggests, there are significant barriers to adult learning that may keep more practitioners from continuous learning.

Willingness to change First, learning requires an openness and willingness to change that might entail a retreat from the comfort of routine. Leaving the safe harbor of one’s regular practice and experience may be a significant barrier for some to even attempt new learning. Second, learning requires both diligence and persistence.

Learning something new, as many physicians have heard, requires at least 3 separate attempts (i.e., see one, do one, teach one), but in reality, requires much more than that. Developing new habits and changing practice patterns for the better can take time. Finally, structural barriers can thwart learning opportunities. My right-handed mouse was an unexpected, though remediable barrier.

In medical education, barriers can result from inadequate technology that makes learning unproductive and inefficient. Thankfully, structural barriers in conventional continuing professional education offerings are adapting to the ever changing needs of practicing medical professionals. Educational offerings are now more likely to incorporate

available technology and basic principles of adult learning theory.2 More useful and effective web-based interactive technology, simulation-based education, and directed offerings for specific learning cohorts help self-directed learners make better use of available options.3 What keeps physicians from advancing their learning? If they have the motivation and the desire, perhaps there is a “right-handed mouse” that is holding them back. ■ 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. Brandt K. From residency to lifelong learning.

J Craniofac Surg. 2015;26:2287-2288.

2. Kokemueller P, Osguthorpe JD. Trends and developments in continuing medical education. Otolaryngol Clin North Am. 2007;40:1331-1345.

3. Sehgal NL, Wachter RM, Vidyarthi AR. Bringing continuing medical education to the bedside: the University of California, San Francisco Hospitalist Mini-College. J Hosp Med. 2014;9:129-134.

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n FEATURE

Standard Dialysis Access Poor for Undocumented Immigrants Some individuals resort to emergency-only dialysis under the 1986 federal Emergency Medical Treatment and Active Labor Act BY NATASHA PERSAUD

U

ndocumented immigrants with end-stage renal disease (ESRD) in the United States are ineligible for federal assistance from Medicare, traditional Medicaid, and the provisions from the Patient Protection and Affordable Care Act exchanges. Many of the 50 states do not fund standard (thriceweekly) dialysis for this population, with a few notable exceptions that use various funding strategies. Some undocumented immigrants are forced to resort to emergency-only dialysis under the 1986 federal Emergency Medical Treatment and Active Labor Act. In certain states, life-threatening indications must exist—such as metabolic acidosis, hyperkalemia, uremia, or volume overload—before dialysis will be administered. A common refrain in the medical community is that this approach to providing dialysis to undocumented immigrants needs to change.

“Dialysis for all people should be covered in every state,” A. Taylor Kelley, MD, MPH, of the University of Michigan in Ann Arbor, told Renal & Urology News. “These are people who have special needs, and the care they receive is very important for them individually and for us as a society collectively.”

In a Perspective article in the New England Journal of Medicine, Dr Kelley and Renuka Tipirneni, MD, discussed preserving solvency for safety-net hospitals by securing funds for uncompensated care. 1 They encouraged providers practicing in an individual health center to seek partnerships with safety net hospital systems and institutions so uncompensated care funding is managed effectively for the health of patients.

Address patient needs in the hospital “Providers who are aware of undocumented patients in integrated health care systems should appeal to their administrators to develop policies that will cover outpatient dialysis services,” Dr Kelley said. “Where emergency care and outpatient care are fragmented, care is more challenging.” Dr Kelley called for addressing patient needs inside the hospital as much as possible before the patient goes home, where resources may not be available.

“A national policy ensuring dialysis coverage for undocumented individuals is one approach,” Dr Kelley said.

“Development of national standards for implementing cost-reducing, quality-oflife-improving practices is another. Use of standards would encourage adoption of beneficial practices such as kidney transplant—something Illinois has already done for undocumented individuals.”

“There is a case to be made for integrating changes of emergency-only dialysis practice into the broader legislation priorities that the US Government is focusing on,” according to an editorial

A. Taylor Kelley, MD, MPH

in The Lancet Hematology,2 which noted that approximately 6500 undocumented immigrants with ESRD are estimated to live in the United States. “It should not be so hard to justify the importance of revising a problematic health-care policy that leaves patients’ life in danger on a weekly basis, presents clinicians with a moral dilemma, and piles on financial burdens that American tax payers consequently have to shoulder.”

In its position statement on uncompensated care for both citizens and noncitizens, the Renal Physicians’ Association said the “federal government has an ethical and fiscal responsibility to provide care for patients within our borders.”

Scheduled dialysis should be standard “Scheduled dialysis should be the universal standard of care for all individuals with ESRD in the United States,” Oanh Kieu Nguyen, MD, of the University of California, San Francisco, and coauthors concluded based on a study published in JAMA Internal Medicine.3 The study examined the comparative

Lilia Cervantes, MD

effectiveness and costs of scheduled vs emergency-only dialysis. Of 181 undocumented adults with ESRD attending a safety-net hospital in Dallas, Texas, who applied for off-exchange private health insurance coverage in 2015 (financed by nonprofit charitable premium assistance), 105 (mean age 45 years) started scheduled dialysis, and 76 (mean age 52 years) continued with emergency-only dialysis. Patients did not receive insurance coverage because they could not be placed in a participating dialysis center due to capacity or distance, rather than any clinical consideration.

Patients receiving scheduled dialysis were significantly less likely to die than emergency-only dialysis patients (1-year mortality 3% vs 17%, respectively). In contrast, the risk for death was 4.6-fold higher for those remaining on emergencyonly dialysis. For every 7 patients treated with emergency dialysis, 1 more would die, compared with standard dialysis.

Patients receiving scheduled dialysis also had significantly fewer emergency department visits (−5.2 vs 1.1 visits/month), hospitalizations (−2.1 vs −0.5 hospitalizations/6 months), and days in hospital (−9.2 vs +0.8 days/6 months) than those receiving emergency-only dialysis.

Investigators estimated a cost savings of $4316 per person per month among patients switched to scheduled dialysis.

Meanwhile, costs for emergency-only dialysis patients increased $1452 compared with baseline. Costs included estimated bills for emergency visits, hospitalizations, observation visits, scheduled hemodialysis (HD), and vascular access placement and complications.

In this study, most patients continuing on emergency-only dialysis enrolled in scheduled dialysis at the next available opportunity a year later.

www.renalandurologynews.com

In an accompanying editorial, Marlene Martin, MD, of the University of California, San Francisco, argued, as others have, that many undocumented immigrants work and contribute to Social Security and Medicare without reaping benefits from these programs.4 “It is reasonable for undocumented people to benefit from the programs they support,” Dr Martin stated.

According to a 2013 study by Leah Zallman and colleagues published in Health Affairs, undocumented immigrants’ net contribution to Medicare was about $2.5 billion.5 “Providing standard hemodialysis and/ or kidney transplantation would allow undocumented immigrants to rejoin the workforce,” said Lilia Cervantes, MD, of Denver Health, who has studied the issue of dialysis care for undocumented immigrants. Without a federal policy, “a state by state change in the dialysis and emergency Medicaid policies can provide undocumented immigrants with standard, outpatient dialysis treatments,” she said. Data from California and New York show no surges in undocumented immigrants seeking care when standard HD is available, Dr Cervantes added.

Emotional distress is high Other recent qualitative studies highlight the strain emergency-only dialysis causes on patients and physicians. In a 2017 qualitative study published in JAMA Internal Medicine, Dr Cervantes and colleagues recorded the experiences of undocumented patients using emergency-only dialysis in Denver.6 One patient said: “You cannot explain your illness…when you enter through the emergency department, you arrive in bad shape…you need to have a high potassium or they send you home even though you feel you are dying.”

In a July 2018 research letter published in the Clinical Journal of the American Society of Nephrology, Dr Cervantes and fellow investigators reported that more than half of 35 undocumented patients attending Denver Health died of a cardiac arrest or arrhythmia likely related to an emergent circumstance such as hyperkalemia.7 And in an editorial published in the American Journal of Kidney Diseases, she and her coauthors commented: “Emergency-only hemodialysis should raise serious ethical concerns due to the physical and psychological suffering associated with this practice.”8 Providers of emergency dialysis likewise experience emotional turmoil. In a study by Dr Cervantes and her team published in 2018 in Annals of Internal Medicine, 50 clinicians in Denver and

SCHEDULED

VS

MARCH/APRIL 2019

EMERGENCY-ONLY DIALYSIS

In a cohort of undocumented immigrants with end-stage renal disease, scheduled dialysis was associated with a reduction in mortality, emergency department visits, hospitalizations, and costs compared with emergency-only dialysis, a study found.

■ Scheduled dialysis ■ Emergency-only dialysis

1-year mortality rate

3.0%

17.0%

Adjusted emergency department visits (per month)

−5.2%

+1.1%

Adjusted hospitalizations (per 6 months)

−2.1%

−0.5%

Adjusted costs

−4316

+1452

Source: Nguyen OK, Vazquez MA, Charles L, et al. Association of scheduled vs emergency-only dialysis with health outcomes and costs in undocumented immigrants with end-stage renal disease. JAMA Intern Med. 2019;179:175-183.

Houston safety-net hospitals described experiencing moral distress and being driven toward burnout.9 A nephrology physician confessed: “Emergency hemodialysis makes us feel very inhumane and I don’t like to call it ‘compassionate hemodialysis.’ We’re torturing them.”

A co-investigator on the study, Rajeev Raghavan, MD, of Baylor College of Medicine in Houston, commented in a public policy article in the Clinical Journal of the American Society of Nephrology: “Nephrologists caring for patients who receive emergent dialysis are tasked with the difficult moral dilemma of determining ‘who gets dialysis that day.’”10 “The emergent dialysis approach does not allow nephrologists to act in the best interest of the patient or to respect the patient’s autonomy,” Rudolph A. Rodriguez, MD, of VA Puget Sound Health Care System in Seattle, remarked in an opinion piece in Advances in Chronic Kidney Disease.11 States variably fund dialysis care for undocumented immigrants using assorted strategies. The Centers for Medicare & Medicaid Services give states the liberty to define what constitutes an emergency medical condition.

As a result, several states have modified their emergency Medicaid definition to include the diagnosis of ESRD and offer standard, outpatient dialysis. In January 2019, New York City announced a universal health care program, NYC Care, which aims to provide medical services for all city residents, including undocumented immigrants, using a sliding fee scale; details on dialysis coverage are unknown.

Clinicians may ponder how to respond given the uncertainties surrounding patient care and payment. Thirty-nine percent of undocumented immigrants are uninsured compared with 9% of

US citizens, according to the Henry J. Kaiser Family Foundation.12 “Providing charity care is part of the work of many providers, but when it reaches its limits and payment becomes an issue, more creative and collaborative community approaches are needed,” Dr Kelley said.

The theme of World Kidney Day 2019 is “Kidney Health for Everyone Everywhere.”13 It calls for “transparent policies governing equitable and sustainable access to advanced health care services (eg, dialysis and transplantation) and better financial protection (eg, subsidies) as more resources become available.” Many believe that ensuring standard outpatient dialysis for undocumented immigrants is in keeping with this mission. ■ REFERENCES 1. Kelley AT and Tipirneni R. Care for undocumented immigrants — rethinking state flexibility in Medicaid waivers. N Eng J Med. 2018;378;18:1661-1663.

2. The undocumented struggle with emergency-only dialysis. Lancet Haematol. 2018;5:e378 3. Nguyen OK, Vazquez MA, Charles L, et al. Association of scheduled vs emergency-only dialysis with health outcomes and costs in undocumented immigrants with end-stage renal disease. JAMA Intern Med. 2019;179:175-183.

4. Martin M. Providing comprehensive health care for undocumented people in the United States. JAMA Intern Med. 2019;179:183-185.

5. Zallman L, Woolhandler S, Himmelstein D, et al.

Immigrants contributed an estimated $115.2 billion more to the Medicare Trust Fund than they took out in 2002–09. Health Aff. 2013;32:1153-1160.

6. Cervantes L, Fischer S, Berlinger N, et al. The illness experience of undocumented immigrants with end-stage renal disease. JAMA Intern Med. 2017;177:529-535.

7. Cervantes L, O’Hare A, Chonchol M, et al. Circumstances of death among undocumented immigrants who rely on emergency-only hemodialysis. Clin J Am Soc Nephrol. 2018;13:1405-1406.

8. Cervantes L, Grafals M, Rodriguez RA. The United States needs a national policy on dialysis for undocumented immigrants with ESRD. Am J Kidney Dis. 2018;71:157-159.

9. Cervantes L, Richardson S, Raghavan R, et al.

Clinicians’ perspectives on providing emergencyonly hemodialysis to undocumented immigrants: A qualitative study. Ann Intern Med. 2018;169:78-86.

10. Raghavan R. New opportunities for funding dialysisdependent undocumented individuals. Clin J Am Soc Nephrol. 2017;12:370-375.

11. Rodriguez RA. Dialysis for undocumented immigrants in the United States. Adv Chronic Kidney Dis. 2015; 22:60-65.

12. Health Coverage of Immigrants. Henry J. Kaiser Family Foundation; December 13, 2017. Accessed on January 2, 2019 at https://www.kff.org/disparitiespolicy/fact-sheet/health-coverage-of-immigrants/ 13. Kidney Health for Everyone Everywhere. World Kidney Day 2019. Accessed on January 9, 2019. https://www.worldkidneyday.org/2019campaign/2019-wkd-theme/

Renal & Urology News 23

CKD-MBD Screening Suboptimal LABORATORY testing for biochemical markers of mineral bone disease (MBD) in patients with moderate-to-severe chronic kidney disease (CKD) falls short of guideline recommendations, investigators reported in the American Journal of Nephrology.

These markers include parathyroid hormone (PTH), phosphorus, 25-hydroxyvitamin D [25(OH)D], calcium, and alkaline phosphatase (ALP).

Nicholas S. Roetker, MD, and collaborators at the Hennepin Healthcare Research Institute in Minneapolis, Minnesota, looked at administrative claims records from a 20% sample of Medicare beneficiaries with Parts A, B, and D coverage during the period 2007 to 2015. They identified patients with nondialysis stage 3, 4, or 5 CKD and compared the frequency of testing for

Laboratory testing for biochemical markers is lower than recommended.

PTH, 25(OH)D, phosphorus calcium, and ALP with what is recommended in the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines.

Dr Roetker’s team divided the patients into 3 cohorts (640,946 patients with stage 3 CKD, 136,278 patients with stage 4 CKD, and 22,076 patients with stage 5 CKD). The 3 cohorts were slightly more female (50.2% to 52.9%). The mean age ranged from 74.4 to 78.0 years. The cohorts had mean followup durations of 2.5, 1.3, and 0.7 years, respectively.

Testing frequency was lower for PTH (35.2% to 48.2%), phosphorus (46.6% to 62.0%), and 25(OH)D (29.3% to 46.7%) compared with guideline recommendations. Testing rates were slightly higher for calcium (88.1% to 95.4%) and ALP (63.5% to 88.1%).

Older age, a greater number of comorbid conditions, and lack of prior nephrology care were associated with a lower likelihood of testing.

“Competing priorities, such as management of comorbid disease and preparation for renal replacement therapy, may distract from CKD-MBD monitoring,” the authors concluded. ■

24 Renal & Urology News

MARCH/APRIL 2019 www.renalandurologynews.com

Practice Management A

s part of a novel program, 14 hospitals in South Carolina reduced post-surgery mortality rates by 22% through the simple act of using a checklist in their operating rooms. The hospitals, which account for almost 40% of the state’s inpatient surgeries, completed the Safe Surgery South Carolina program from 2010 to 2013. During that time, their post-­ surgical death rates dropped from 3.38% to 2.84%. For hospitals not completing the program, the rates rose from 3.5% to 3.71% during the same period.

The key to the program was a checklist used by surgical teams before, during, and after surgery. It lists practical checkpoints such as identifying the surgical site, providing the operative plan, anticipating aspiration risk, and counting the instruments, needles, and sponges before the patient leaves the room.

But the checklist is not simply about marking off boxes showing that certain procedures and protocols are being followed. Rather, the checklist is designed to foster interaction among surgical team members.

“It’s less about specific things on the checklist and more about the process of engaging a team and creating an environment where people are sharing information and feel safe to speak

safety checklist in 2007. The checklist was tested in 8 hospitals in 8 cities worldwide. Prior to using the checklist, the death rate in these hospitals was 1.5%, and 11% of inpatients had ­surgery-related complications. After implementation, the death and complication rates fell to 0.8% and 7%, respectively.

After its introduction, a wide range of hospitals embraced the checklist, but over time the hospitals began to see signs of implementation failure, Dr Haynes said. “Hospitals were putting it [the checklist] up on the wall, telling everyone to use it and thinking that would work,” he said. “We knew a structured approach would yield more tangible benefits.”

Dr Haynes and his colleagues (including surgeon Atul Gawande, MD, director of Ariadne Labs) looked to South Carolina because of the state’s large-scale work mobilizing hospitals to reduce the number of early elective deliveries and improve heart attack care. After discussion and consultation, the Ariadne group struck a partnership with the South Carolina Hospital Association.

The organizations had a kickoff where all the state’s hospitals committed to implementing the checklist.

Every enlisted hospital went through a multi-step program to s­uccessfully

From 2010 to 2013, post-surgery death rates at South Carolina hospitals that implemented a novel program dropped from 3.38% to 2.84%. up when concerns arise,” said Alex B. Haynes, MD, MPH, associate professor of surgery at Harvard Medical School in Boston and director of the Safe Surgery program at Ariadne Labs. “That’s far more important than any particular item on the checklist. It’s not about steps to do to have a safe operation, but about the type of information they need to have.”

Dr Haynes was part of the World Health Organization (WHO) program that developed the original surgery

implement the checklist. Lorri Gibbons, vice president of development for the association, said the process was not only about the clinical steps, but communication as well. Implementation included customizing the checklist for each hospital, small-scale testing, observation, and coaching.

“The checklist should be used to enhance, not supplant, the teams,” Dr Haynes said. “It’s not there to tell them how to do surgery or to be a burden. It’s

© PETE SALOUTOS / GETTY IMAGES

A checklist aimed at improving communication among surgical teams cut down on surgery-related deaths BY TAMMY WORTH

A new checklist attempts to encourage better interaction among surgical team members.

to make sure people talk to each other in ways that promote awareness of what they are there to do that day.”

Only 14 hospitals ended up completing everything that was asked of them for the study, but all hospitals committed to implementing the checklist to some degree, Gibbons said.

A team approach When the checklist was first put in place, Gibbons said, people thought it was a “check-off list” or a more demanding version of The Joint Commission’s “time-out” (where the surgical team pauses to make sure they are working on the right patient, procedure, and anatomic site).

But Gibbons said the list is more about empowering communication among team members in the operating room. It offers a scripted list of things that should be discussed by each member of the team and encourages introductions.

“There has been a lot of research that shows when people are given the chance to introduce themselves in a group of people, they are more likely to speak up in group,” she said. “It’s meant to enhance communication of the entire team from the circulator to the anesthesiologist, and the surgeon to the scrub nurse.”

The list focuses on the time prior to administering anesthesia, the period

before incision, and the sign out, before the patient leaves the room. It is designed to be a universal template and can be used for any type of procedure. He added: “You need to meet people where they are and work with them to do something that works at their institution with their priorities, resources, and needs.”

Gibbons said she hopes to have similar checklists in a range of areas, including in specialty suites or for procedures like colonoscopies. “They don’t have to be long, involved things,” she said. “It’s about getting the team to talk to make sure they know about the patient, have everything ready, and have any special instructions.”

The hospitals had to report on their safety procedures before and after putting the checklist in place. Dr Haynes said there were definite improvements in the safety culture of the hospitals.

Lessons learned The checklists take buy-in from every person on the team, especially those at the top. It is best to identify someone at each organization to champion the efforts and collect a team that can integrate the checklist into their current safety practices and workflow. ■ Tammy Worth is a freelance medical journalist based in Blue Springs, MO.