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TRT Safe Despite History of PCa No increase in disease recurrence observed
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TRT AND ONCOLOGIC OUTCOMES Men with prostate cancer who receive testosterone replacement therapy (TRT) experience biochemical recurrence (BCR) rates after radical treatment and a progression rate on active surveillance comparable to previously reported rates among men not receiving TRT. 12
11.6%
10.6%
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■ BCR rate after RP
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BY JODY A. CHARNOW SAN FRANCISCO—Testosterone replacement therapy (TRT) for men with a history of prostate cancer (PCa) does not increase recurrence rates following radical treatment or progression rate after placement on active surveillance, investigators reported at the American Urological Association’s 2018 annual meeting. In a study examining the outcomes of 190 men with PCa (mean age 68 years) who received TRT after diagnosis and/ or treatment for PCa over the previous 5 years, Abraham Morgentaler, MD, of
IN THIS ISSUE 3 15
Bladder cancer mortality reduced in 5-ARI users Obesity linked to decreased death risk in CRPC
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Diabetes is associated with elevated RCC risk in women
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Dusting vs basketing for kidney stones debated
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URS found superior to ESWL for 5–20 mm stones
Bariatric surgery may decrease the risk of chronic kidney disease. PAGE 16
Beth Israel Deaconess Medical Center, Director of Men’s Health Boston, and Associate Clinical Professor of Urology at Harvard Medical School in Boston, and colleagues found that biochemical recurrence rates after radical prostatectomy (RP) and radiation therapy, and the progression rate while on active surveillance (AS), were consistent with published rates from other studies. After a mean follow-up of 47 months, the recurrence rates were 11.6% among the 86 men who underwent RP and 4.1% among the 49 men who had
Non-narcotic Drug Superior For Stone Pain BY JODY A. CHARNOW SAN FRANCISCO—Ketorolac is more effective than narcotics in the management of renal colic in the emergency department (ED), yet narcotics remain a common the first-line treatment, according to study findings presented at the American Urological Association’s 2018 annual meeting. Traditionally, renal colic, or stone pain, has been controlled by narcotics in the ED, as there were no good alternatives until the development of ketorolac in the early 1990s, lead investigator Andrew J. Portis, MD, of HealthEast Kidney Stone Institute continued on page 14
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■ BCR rate after RT
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■ Progression rate on AS
2 0 Key: RP=radical prostatectomy, RT=radiation therapy (external beam or brachytherapy), AS = active surveillance Source: Morgentaler A, Neel DV, Magauran D, Krakowsky Y. Recurrence rates following testosterone therapy in a large clinical cohort of men with prostate cancer. Poster presented at American Urological Association 2018 annual meeting, San Francisco, May 18–21.
either external beam radiation therapy or brachytherapy, Dr Morgentaler’s team reported. None of the 5 men treated with RP followed by salvage radiation had recurrence. The progression rate among the 47 men on AS was 10.6%.
“This is the largest series to date investigating the safety of testosterone therapy in men with prostate cancer,” Dr Morgentaler told Renal & Urology News. “Recurrence rates following prostate cancer treatment with surgery continued on page 14
De Novo Metastatic PCa Ebbs EARLY DETECTION OF prostate cancer (PCa) in the United States has resulted in a decrease in the number of men presenting with metastatic PCa, investigators reported at the European Association of Urology’s 33rd Congress in Copenhagen, Denmark. In an analysis of data from the Surveillance, Epidemiology and End Results (SEER) program, Thomas Helgstrand, MD, PhD, of the Copenhagen Prostate Cancer Center, and colleagues found that the incidence of de novo metastatic PCa declined from 12.0 cases per 100,000 men in 1980–1984 to 4.4 cases per 100,000 men in 2005–2011. The 5-year
PCa-specific mortality rate for the entire cohort was 56.5%. It increased from 54.2% in 1980–1984 to 61% in 2005–2009. The decreasing incidence of de novo metastatic PCa was followed by a decrease in overall PCa-specific mortality within 3 years, the investigators reported. Dr Helgstrand’s team compared the SEER findings with those from a cohort of men in Denmark using the Danish Prostate Cancer Registry (DaPCaR). In contrast to SEER results, the incidence of de novo metastatic PCa in the DaPCaR revealed an increase from 6.7 cases per 100,000 men in continued on page 14
ETHICAL ISSUES IN MEDICINE DEBUTS
Inaugural column explores shared decision-making. PAGE 31
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FDA approved for metastatic CRPC since 2012 Supported by 3 randomized, controlled trials
Upon progression on GnRH therapy* in mCRPC 1
In the US alone, 106,000 patients have been prescribed XTANDI—and counting†2
AFFIRM TRIAL
PREVAIL TRIAL
TERRAIN TRIAL
1199 patients with metastatic
1717 patients with metastatic
375 patients with metastatic
CRPC who were previously on docetaxel therapy were randomized to XTANDI + GnRH therapy* (n = 800) or placebo + GnRH therapy* (n = 399).1
CRPC who were asymptomatic or mildly symptomatic were randomized to XTANDI + GnRH therapy* (n = 872) or placebo + GnRH therapy* (n = 845).1,3
CRPC who were asymptomatic or mildly symptomatic were randomized to XTANDI + GnRH therapy* (n = 184) or bicalutamide + GnRH therapy* (n = 191).1,4
GnRH therapy, gonadotropin-releasing hormone therapy; mCRPC, metastatic castration-resistant prostate cancer. *Or after bilateral orchiectomy.1
†Estimate based on US sales and use data from September 2012 to December 2017. Reference: Astellas. XTANDI. Data on File. Source: Symphony Health.2
Visit XtandiHCP.com to learn more about XTANDI in metastatic CRPC patients
XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).
The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI patients from the two placebo-controlled clinical trials were asthenia/ fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. In the bicalutamide-controlled study of chemotherapy-naïve patients, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, upper respiratory tract infection, diarrhea, and weight loss. In the placebo-controlled study of 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 placebocontrolled study of chemotherapy-naïve 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 bicalutamide-controlled study of chemotherapynaïve patients, Grade 3-4 adverse reactions were reported in 38.8% of XTANDI patients and 37.6% of bicalutamide patients. Discontinuations due to adverse events were reported for 7.6% of XTANDI patients and 6.3% of bicalutamide patients.
Important Safety Information Contraindications XTANDI is not indicated for women. XTANDI can cause fetal harm and potential loss of pregnancy.
Warnings and Precautions Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors, seizures were reported in 2.2% of patients. See section 5.1 of the Prescribing Information for the list of predisposing factors. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. 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.
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References: 1. XTANDI [package insert]. Northbrook, IL: Astellas, Inc. 2. Astellas. XTANDI. Data on File. 3. 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. 4. Shore ND, Chowdhury S, Villers A, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol 2016;17(2):153-63.
© 2018 Astellas Pharma US, Inc. and Pfizer Inc. All rights reserved. Printed in USA. 076-3221-PM 3/18 XTANDI, Astellas, and the flying star logo are registered trademarks of Astellas Pharma Inc.
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JOB#: 1308327D CLIENT: Xtandi DESC: Heritage Spread Tabloid Journal Ad FILE NAME: MDV_XTN_1308327D_JA_D01.indd DATE: 3-23-2018 4:33 PMROUND: 1 PG: Lake, Kathleen/DilenaM AD: Leslie Bley x1303 PM: Brandon Allwood x4397 AE: Alyssa Gatto x3813 CW: Martin Arrascue x4091 Last Saved: 3-23-2018 4:33 PM TRIM: 21" x 13.5" BLEED: 22.5" x 15" SAFETY: 19" x 12" PROD: Mike Haight x4245 INK Spec: 4 Color Process PRINT SCALE: 100% FONTS: Frutiger LT Std (45 Light, 65 Bold, 77 Black Condensed, 55 Roman, 57 Condensed, 67 Bold Condensed) IMAGES: 1308327D_diagonal_call-out.ai (100%), 1308327_D_JA_fn.tif (CMYK; 300 ppi; 100%), Astellas_PfizerOnc_4C.eps (81%), 1308327D_curved_diagonal.ai (100%), Xtandi_4C_40mg.AI (90.2%) Cyan, Magenta, Yellow, Black INKS: DOC PATH: Macintosh HD:Users:lakek:Deskt...A_D01:MDV_XTN_1308327D_JA_D01.indd NOTES: None
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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 co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.
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Lab Abnormalities: In the two placebo-controlled trials, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4). Infections: In the study of patients taking XTANDI who previously received docetaxel, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In the study of chemotherapy-naïve patients, 1 patient in each treatment group (0.1%) had an infection resulting in death. Falls (including fall-related injuries) occurred in 9% of XTANDI patients and 4% of placebo patients in the two placebocontrolled trials. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas. Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.
Indication and Important Safety Information
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FDA approved for metastatic CRPC since 2012 Supported by 3 randomized, controlled trials
Upon progression on GnRH therapy* in mCRPC 1
In the US alone, 106,000 patients have been prescribed XTANDI—and counting†2
AFFIRM TRIAL
PREVAIL TRIAL
TERRAIN TRIAL
1199 patients with metastatic
1717 patients with metastatic
375 patients with metastatic
CRPC who were previously on docetaxel therapy were randomized to XTANDI + GnRH therapy* (n = 800) or placebo + GnRH therapy* (n = 399).1
CRPC who were asymptomatic or mildly symptomatic were randomized to XTANDI + GnRH therapy* (n = 872) or placebo + GnRH therapy* (n = 845).1,3
CRPC who were asymptomatic or mildly symptomatic were randomized to XTANDI + GnRH therapy* (n = 184) or bicalutamide + GnRH therapy* (n = 191).1,4
GnRH therapy, gonadotropin-releasing hormone therapy; mCRPC, metastatic castration-resistant prostate cancer. *Or after bilateral orchiectomy.1
†Estimate based on US sales and use data from September 2012 to December 2017. Reference: Astellas. XTANDI. Data on File. Source: Symphony Health.2
Visit XtandiHCP.com to learn more about XTANDI in metastatic CRPC patients
XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).
The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI patients from the two placebo-controlled clinical trials were asthenia/ fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. In the bicalutamide-controlled study of chemotherapy-naïve patients, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, upper respiratory tract infection, diarrhea, and weight loss. In the placebo-controlled study of 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 placebocontrolled study of chemotherapy-naïve 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 bicalutamide-controlled study of chemotherapynaïve patients, Grade 3-4 adverse reactions were reported in 38.8% of XTANDI patients and 37.6% of bicalutamide patients. Discontinuations due to adverse events were reported for 7.6% of XTANDI patients and 6.3% of bicalutamide patients.
Important Safety Information Contraindications XTANDI is not indicated for women. XTANDI can cause fetal harm and potential loss of pregnancy.
Warnings and Precautions Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors, seizures were reported in 2.2% of patients. See section 5.1 of the Prescribing Information for the list of predisposing factors. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. 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.
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References: 1. XTANDI [package insert]. Northbrook, IL: Astellas, Inc. 2. Astellas. XTANDI. Data on File. 3. 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. 4. Shore ND, Chowdhury S, Villers A, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol 2016;17(2):153-63.
© 2018 Astellas Pharma US, Inc. and Pfizer Inc. All rights reserved. Printed in USA. 076-3221-PM 3/18 XTANDI, Astellas, and the flying star logo are registered trademarks of Astellas Pharma Inc.
FS:9”
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Please see adjacent pages for Brief Summary of Full Prescribing Information.
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JOB#: 1308327D CLIENT: Xtandi DESC: Heritage Spread Tabloid Journal Ad FILE NAME: MDV_XTN_1308327D_JA_D01.indd DATE: 3-23-2018 4:33 PMROUND: 1 PG: Lake, Kathleen/DilenaM AD: Leslie Bley x1303 PM: Brandon Allwood x4397 AE: Alyssa Gatto x3813 CW: Martin Arrascue x4091 Last Saved: 3-23-2018 4:33 PM TRIM: 21" x 13.5" BLEED: 22.5" x 15" SAFETY: 19" x 12" PROD: Mike Haight x4245 INK Spec: 4 Color Process PRINT SCALE: 100% FONTS: Frutiger LT Std (45 Light, 65 Bold, 77 Black Condensed, 55 Roman, 57 Condensed, 67 Bold Condensed) IMAGES: 1308327D_diagonal_call-out.ai (100%), 1308327_D_JA_fn.tif (CMYK; 300 ppi; 100%), Astellas_PfizerOnc_4C.eps (81%), 1308327D_curved_diagonal.ai (100%), Xtandi_4C_40mg.AI (90.2%) Cyan, Magenta, Yellow, Black INKS: DOC PATH: Macintosh HD:Users:lakek:Deskt...A_D01:MDV_XTN_1308327D_JA_D01.indd NOTES: None
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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 co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.
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Lab Abnormalities: In the two placebo-controlled trials, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4). Infections: In the study of patients taking XTANDI who previously received docetaxel, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In the study of chemotherapy-naïve patients, 1 patient in each treatment group (0.1%) had an infection resulting in death. Falls (including fall-related injuries) occurred in 9% of XTANDI patients and 4% of placebo patients in the two placebocontrolled trials. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas. Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.
Indication and Important Safety Information
2 Renal & Urology News
MAY/JUNE 2018 www.renalandurologynews.com
Smoking Ups Bladder Cancer Risk, Lowers PCa Risk MEN AND WOMEN smokers are at increased risk of bladder cancer, and men who smoke are at increased risk of kidney cancer and decreased risk of prostate cancer (PCa), according to a retrospective study of 211,005 smokers and a matched group of non-smokers in the United Kingdom.
Men and women smokers had a significant 2.3-fold and 2.7-fold increased risk of bladder cancer, respectively, compared with nonsmokers, Louis Jacob, PhD, of the Faculty of Medicine at the University of Paris, and colleagues reported in Oncotarget (2018;9:17420-17429). Men
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 indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm and potential loss of pregnancy. WARNINGS AND PRECAUTIONS Seizure Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In these trials patients with predisposing factors for seizure were generally excluded. Seizure occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizures 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 anti-epileptic 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. 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. Three randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. Two trials were placebo-controlled (Studies 1 and 2), and one trial was bicalutamidecontrolled (Study 3). In Studies 1 and 2, patients received XTANDI 160 mg or placebo orally once daily. In Study 3, patients received XTANDI 160 mg or bicalutamide 50 mg orally once daily. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients from the two randomized placebo-controlled clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.
who smoked had a significant 26% increased risk of kidney cancer and 2.8-fold increased risk of liver cancer, but they had a significant 29% decreased risk of PCa. The study found no association between smoking and kidney or liver cancer in women. Smoking was associated with Study 1: XTANDI versus Placebo in Metastatic CRPC Following Chemotherapy Study 1 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 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 Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in Study 1 XTANDI Placebo N = 800 N = 399 Grade Grade Grade Grade a 3-4 1-4 3-4 1-4 (%) (%) (%) (%) General Disorders Asthenic 50.6 9.0 44.4 9.3 Conditionsb Peripheral 15.4 1.0 13.3 0.8 Edema Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 5.3 24.3 4.0 Arthralgia 20.5 2.5 17.3 1.8 Musculoskeletal 15.0 1.3 11.5 0.3 Pain Muscular 9.8 1.5 6.8 1.8 Weakness Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness Gastrointestinal Disorders Diarrhea 21.8 1.1 17.5 0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9 5.5 0.0 Dizzinessc 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 4.3 0.3 1.8 0.0 Impairment Disordersd Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations Upper 10.9 0.0 6.5 0.3 Respiratory Tract Infectione Lower Respiratory 8.5 2.4 4.8 1.3 Tract And Lung Infectionf 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 Non-pathologic 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 a b c d
CTCAE v4. Includes asthenia and fatigue. Includes dizziness and vertigo. Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. f Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.
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a significant 8% decreased risk of breast cancer in women. The strongest positive association between smoking and cancer was found for bronchus and lung cancer, with men and women smokers at 10-fold and 14-fold increased risk of these malignancies compared with non-smokers. n Study 2: XTANDI versus Placebo in Chemotherapynaïve Metastatic CRPC Study 2 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 Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm. Table 2. Adverse Reactions in Study 2 XTANDI Placebo N = 871 N = 844 Grade Grade Grade Grade 3-4 1-4 3-4 1-4a (%) (%) (%) (%) General Disorders Asthenic 46.9 3.4 33.0 2.8 Conditionsb Peripheral 11.5 0.2 8.2 0.4 Edema Musculoskeletal And Connective Tissue Disorders Back Pain 28.6 2.5 22.4 3.0 Arthralgia 21.4 1.6 16.1 1.1 Gastrointestinal Disorders Constipation 23.2 0.7 17.3 0.4 Diarrhea 16.8 0.3 14.3 0.4 Vascular Disorders Hot Flush 18.0 0.1 7.8 0.0 Hypertension 14.2 7.2 4.1 2.3 Nervous System Disorders 11.3 0.3 7.1 0.0 Dizzinessc Headache 11.0 0.2 7.0 0.4 Dysgeusia 7.6 0.1 3.7 0.0 Mental 5.7 0.0 1.3 0.1 Impairment Disordersd Restless Legs 2.1 0.1 0.4 0.0 Syndrome Respiratory Disorders 11.0 0.6 8.5 0.6 Dyspneae Infections And Infestations Upper 16.4 0.0 10.5 0.0 Respiratory Tract Infectionf Lower Respiratory 7.9 1.5 4.7 1.1 Tract And Lung Infectiong 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 12.7 1.6 5.3 0.7 Non-Pathological 8.8 2.1 3.0 1.1 Fracture Metabolism and Nutrition Disorders Decreased 18.9 0.3 16.4 0.7 Appetite Investigations Weight 12.4 0.8 8.5 0.2 Decreased Reproductive System and Breast Disorders 1.4 3.4 0.0 0.0 Gynecomastia a b c d
CTCAE v4. Includes asthenia and fatigue. Includes dizziness and vertigo. Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes dyspnea, exertional dyspnea, and dyspnea at rest. f Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. g Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.
Study 3: XTANDI versus Bicalutamide in Chemotherapynaïve Metastatic CRPC Study 3 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
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Bladder Cancer Mortality Lower in 5-ARI Users USE OF 5-ALPHA-reductase inhibitors (5-ARIs) is associated with a lower risk of dying from bladder cancer among men newly diagnosed with the malignancy, according to study findings presented at the 33rd European Association of Urology Congress in Copenhagen, Denmark, and p ublished 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 bicalutamidetreated patients. The most common adverse reactions leading to treatment discontinuation were back pain and pathological fracture, which occurred in 3.8% of XTANDItreated 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 XTANDItreated patients. Table 3. Adverse Reactions in Study 3 XTANDI Bicalutamide N = 183 N = 189 Grade Grade Grade Grade a 1-4 3-4 1-4a 3-4 (%) (%) (%) (%) Overall 94.0 38.8 94.2 37.6 General Disorders Asthenic 31.7 1.6 22.8 1.1 Conditionsb Musculoskeletal And Connective Tissue Disorders Back Pain 19.1 2.7 18.0 1.6 Musculoskeletal 16.4 1.1 14.3 0.5 c Pain Vascular Disorders Hot Flush 14.8 0.0 11.1 0.0 Hypertension 14.2 7.1 7.4 4.2 Gastrointestinal Disorders Nausea 14.2 0.0 17.5 0.0 Constipation 12.6 1.1 13.2 0.5 Diarrhea 11.5 0.0 9.0 1.1 Infections And Infestations Upper 12.0 0.0 6.3 0.5 Respiratory Tract Infectiond Investigational Weight Loss 10.9 0.5 7.9 0.5 a b c d
CTCAE v 4. Including asthenia and fatigue. Including musculoskeletal pain and pain in extremity. Including nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.
Laboratory Abnormalities In the two randomized placebo-controlled clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4). Infections In Study 1, 1% of patients treated with XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death. Falls and Fall-related Injuries In the two randomized placebo-controlled clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. Hypertension In the two randomized placebo-controlled trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm. 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 (tongue edema, lip edema, and pharyngeal edema)
online ahead of print in The Journal of Urology. In a study of 10,720 men newly diagnosed with bladder cancer during 1997 to 2012, first author Ville J. Mäkelä, a medical student at the University of Tampere in Finland, and colleagues found that 5-ARI use before diagnosis 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%. Co-administration 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) 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 XTANDI is contraindicated for use in pregnant women because the drug can cause fetal harm and potential loss of pregnancy. XTANDI is not indicated for use in females. There are no human data on the use of XTANDI in pregnant women. 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. Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal 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). Lactation Risk Summary XTANDI is not indicated for use 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. 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 final dose of XTANDI. Infertility 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.
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and after diagnosis was associated with a significant 16% and 23% decreased risk of bladder cancer-specific death, respectively, compared with non-use. Results also showed that pre- and postdiagnostic use of alpha-blockers was not associated with death from bladder cancer. The investigators included alphaGeriatric Use Of 1671 patients who received XTANDI in the two randomized placebo-controlled clinical trials, 75% were 65 and over, while 31% 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 plus N-desmethyl enzalutamide in volunteers with baseline mild, moderate, or severe hepatic impairment (ChildPugh 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 Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. 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 2017
blockers in their study to account for possible confounding by indication, such as concomitant BPH, for which both alphablockers and 5-ARIs are prescribed. The study supports the role of androgens and benefits of 5-alpha-reductase inhibition in the progression of bladder cancer, the investigators concluded. The study consisted of 3208 5-ARI users (1328 before bladder cancer diagnosis and 1880 after diagnosis), 6603 alpha-blocker users (2353 before diagnosis and 4250 after diagnosis), and 5090 non-users of either medication class. The men who used 5-ARIs before and after diagnosis had a median age of 78 and 75 years, respectively. The men who used alpha-blockers before after diagnosis had a median age of 76 and 74 years. Non-users had a median age of 70 years. n
RDW Change Predicts Death Risk in HD AUSTIN, Texas—Patients whose red blood cell distribution width (RDW) increased over the first year of hemodialysis (HD) had worse survival than those whose RDW decreased or stayed the same, researchers reported at the National Kidney Foundation 2018 Spring Clinical Meetings. Kamyar Kalantar-Zadeh, MD, PhD, of the University of California Irvine School of Medicine, and colleagues analyzed RDW, a measure of variability in erythrocyte size, over the first dialysis year among 62,546 HD patients. RDW displayed an inverse linear relationship with all-cause mortality in all models. HD patients with a change in RDW above 0% had a 28% higher risk for mortality compared
16K089-XTA-WPI
with those with an RDW change of -1%
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to 0%. The investigators adjusted for
© 2017 Astellas Pharma US, Inc.
case-mix, comorbidities, markers of
XTANDI® is a registered trademark of Astellas Pharma Inc.
malnutrition and inflammation, medications, and imbalanced covariates.
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“Further studies should examine the utility of RDW as a predictive marker of mortality in hemodialysis patients and the underlying pathophysiology of this relationship,” the authors concluded. n
4 Renal & Urology News
MAY/JUNE 2018 www.renalandurologynews.com
FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD
Longer Dialysis Time and Patient Suffering
I
n recent years, there has been a trend to extend hemodialysis (HD) treatment time to 4 hours or longer. Longer dialysis time may be associated with worse patient suffering. Patients can experience worsening muscle cramps, low blood pressure episodes, and fainting towards the end of, or immediately after, a dialysis session. Reimbursement is likely the main reason for the trend toward longer HD sessions. The Center for Medicare and Medicaid Services (CMS) has stipulated a minimum dialysis dose adequacy, also known as Kt/V, of 1.2 (and major dialysis companies have required a Kt/V >1.4 to ensure compliance). Kt/V is based on the reduction of blood urea nitrogen during each dialysis treatment. This minimum Kt/V criterion is a core component of the Quality Incentive Plan (QIP), meaning that a dialysis clinic may lose a portion of its CMS reimbursement if the minimum dialysis dose requirement is not met. Hence, when a dialysis patient has a lower calculated Kt/V, the treatment time is often increased. CMS also has upcoming plans to impose fiscal penalties related to dialysis treatment with fluid removal (ultrafiltration) greater than 13 mL/kg hourly unless the patient dialyzes 4 hours or longer. Mostly women are affected by this because they generally have a lower body weight than men. Not only may small women not benefit, they might suffer from 4-hour dialyzing sessions. In prescribing longer treatments, residual renal function (RRF) is often ignored. Many incident and prevalent dialysis patients continue to make substantial amounts of urine even after they transition to dialysis. A patient whose native kidney urea clearance is greater than 3 mL/min may benefit more from incremental dialysis because the time and frequency of treatment is gradually increased as the urine output decreases over time. I have recently suggested to dialysis practice stakeholders to discuss with CMS the pressing urgency to avoid mandatory HD times of 4 hours or more for patients with so-called “low” dialysis adequacy or low fluid removal rates. These recent practices ignore the fundamental patient-centeredness and precision medicine, i.e., personalized therapy, and pay little attention to dialysis patient voice. The rigid view that “longer dialysis is better” is being imposed on hundreds of thousands of dialysis patients with little consideration of patient-related factors and patient preferences. Many patients have significant RRF and do not need long dialysis sessions. Mandatory prolonged dialysis times have led to major suffering for tens of thousands of dialysis patients nationwide. The National Forum of ESRD Networks detailed its concerns in a letter to CMS. The group deserves the support of the entire nephrology community. Kam Kalantar-Zadeh, MD, MPH, PhD Professor & Chief, Division of Nephrology & Hypertension University of California Irvine School of Medicine Orange, California
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
Csaba P. Kovesdy, MD Chief of Nephrology Memphis VA Medical Center Fred Hatch Professor of Medicine University of Tennessee Health Science Center, Memphis Edgar V. Lerma, MD, FACP, FASN, FAHA Clinical Associate Professor of Medicine Section of Nephrology Department of Medicine University of Illinois at Chicago College of Medicine, Chicago Allen Nissenson, MD Emeritus Professor of Medicine The David Geffen School of Medicine at UCLA, Chief Medical Officer, DaVita Inc.
James M. McKiernan, MD John K. Lattimer Professor of Urology Chair, Department of Urology Director, Urologic Oncology Columbia University College of Physicians and Surgeons, New York City
Rulan Parekh, MD, MS Associate Professor of Pediatrics and Medicine University of Toronto
Kenneth Pace, MD, MSc, FRCSC Assistant Professor, Division of Urology St. Michael’s Hospital University of Toronto
Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center Detroit
Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada
Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J.
Renal & Urology News Staff
Editor Jody A. Charnow Web editor
Natasha Persaud
Production editor Kim Daigneau Group art director, Haymarket Medical Jennifer Dvoretz Production manager Krassi Varbanov Director of production Louise Morrin Boyle Circulation manager Paul Silver National accounts manager William Canning Editorial director
Kathleen Walsh Tulley
General manager, medical communications
Jim Burke, RPh
Lee Maniscalco
CEO, Haymarket Media Inc.
Renal & Urology News (ISSN 1550-9478) Volume 17, Number 3. 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 © 2018.
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this month at renalandurologynews.com
Test your knowledge by taking our latest quiz at renalandurologynews.com/ ClinicalQuiz
Drug Information Search a comprehensive drug database for prescribing and other information on more than 4000 drugs.
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More Extensive LND at RP Beneficial The risk of prostate cancer recurrence after salvage radiotherapy is inversely related to the number of resected lymph nodes at radical prostatectomy.
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Outpatient AKI Associated with Adverse Outcomes Acute kidney injury not requiring hospital admission ups the risks of death and renal events by 90% and 33%, respectively.
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Graft Failure Tied to Low Uromodulin Kidney transplant recipients in the lowest tertile had a 2-fold higher risk of graft failure compared with those in the highest tertile.
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Caffeine May Lower AKI Risk in Preterm Neonates Caffeine administration was associated with a significant 80% reduced odds of AKI in adjusted analyses.
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ADPKD Tied to Lower Mortality in PD In a meta-analysis of patients on peritoneal dialysis, those with autosomal dominant polycystic kidney disease vs other causes of renal failure had a 32% decreased risk of death.
News Coverage Visit our website for daily reports from the International Continence Society annual meeting in Philadelphia, August 28–31.
CALENDAR Canadian Urological Association Annual Meeting Halifax, Nova Scotia June 23–26. International Continence Society Annual Meeting Philadelphia August 28–31 American Society of Nephrology Kidney Week New Orleans October 23–28 Large Urology Group Practice Association (LUGPA) 2018 Annual Meeting Chicago November 2–3 2019 Genitourinary Cancers Symposium San Francisco February 14–16 European Association of Urology 34th Congress Barcelona, Spain March 15–19
Nephrology
Job Board Be sure to check our latest listings for professional openings across the United States.
Older Age Ups RCC Death Risk After Nephrectomy Compared with patients younger than 50 years, those aged 80 years and older had a 7.6 times higher risk of cancer-specific mortality. Renal Cell Carcinoma Linked to Diabetes in Women Women with type 2 diabetes have a 1.5-fold higher risk of RCC compared with non-diabetic women.
HIPAA Compliance Read timely articles on various issues related to keeping protected health information secure.
Biopsy-to-RP Delay May Up PCa Recurrence Risk Men who delayed radical prostatectomy beyond 90 days had a significantly increased risk of biochemical recurrence vs men who had a less than 90-day delay.
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Clinical Quiz
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In ADPKD, until further data are available,
it may be prudent to consider black race as an additional risk factor for progression to ESKD, as seen in other forms of kidney disease. See our story on page 8
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Departments 4
From the Medical Director A push for longer dialysis times results in patient suffering
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News in Brief High urate levels may reduce Parkinson’s disease risk
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Ethical Issues in Medicine The importance of shared decision-making
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Practice Management Hiring cybersecurity personnel can present a challenge
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Outpatient AKI Associated With Adverse Outcomes OUTPATIENT ACUTE kidney injury (AKI), defined as AKI not requiring hospital admission, is more common than hospital AKI and is associated with an increased risk of death and renal events, investigators reported. In a retrospective study, a team at the University of Minnesota in Minneapolis led by Paul E. Drawz, MD, found that outpatient AKI was associated with a significant 90% increased risk of death and 33% increased risk of renal events compared with the absence of AKI, after adjusting for potential confounders. For the study, Dr Drawz and his collaborators defined outpatient AKI as a 50% increase in serum creatinine compared with baseline. They defined a renal event as a decrease in estimated glomerular filtration rate (eGFR) to less than 30 mL/min/1.73 m2 on at least 2 measurements with at least a 50% decline from the last value during an 18-month exposure period.
utcomes than a sustained decline in o renal function.” The study included 384,869 eligible adult patients receiving primary care from Fairview Health Services, a large health system that serves the Twin Cities metropolitan area in Minnesota. The overall cohort had a mean age of
45.9 years, and 43% of patients were male. Patients with any outpatient AKI were older than those with no AKI (mean 60 vs 52.5 years). All patients had at least 1 serum creatinine measurement available. “Our study is the most comprehensive analysis of outpatient AKI and is
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the first American cohort,” Dr Drawz and his team noted. During the 18-month exposure period, outpatient AKI developed in 1.4% of patients, whereas hospital AKI developed in only 0.3%, according to the investigators. During an average follow-up period of 5.3 years,
Study finds patients are at elevated risk of death and kidney function decline. “The findings of this study reveal the significant consequences of AKI in the outpatient setting,” the investigators stated in a report published online ahead of print in Nephrology Dialysis Transplantation. “This burden is managed primarily in primary care clinics and efforts should now focus on prevention, early detection and rapid intervention. Unfortunately, evidence on how and where to focus these efforts is limited.”
Recovery vs no recovery Patients who recovered from outpatient AKI had a significant 2.1-fold increased risk of death and 73% increased risk of a renal event compared with patients who had no AKI, after adjustment for potential confounders. Patients who did not recover from outpatient AKI had a significant 71% increased risk of death, but they were not at increased risk for a renal event, the investigators reported. “Patients with AKI without recovery may have actually had a period of rapid decline in renal function rather than an acute isolated event,” Dr Drawz’s team explained. “It is possible that AKI poses a greater risk for adverse
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the overall mortality rate for the cohort was 3.2%. The study’s size, length of follow-up, and robust comparator arm are among its strengths, as well as the availability of comprehensive clinical data that allowed for adjustment of potential confounders and assessment of multiple important outcomes. The authors acknowledged limitations of the study, which include its retrospective and observational design.
In addition, their definition of outpatient AKI is not consistent with the KDIGO (Kidney Disease: Improving Global Outcomes) definition, which is mainly applicable in the inpatient setting, the authors stated. “Our definition may also capture what is sometimes known as acute kidney disease, or AKD. Our definition could classify some patients with significant variability in kidney function as having AKI.”
Dr Drawz and his colleagues also noted that they used a single health system database in a metropolitan area with multiple health systems, which may not be representative of the general population. They added, however, that this problem “is limited given the size and expansive nature of the health system and by selecting patients who received their primary care within the system.”
The investigators said they are planning a prospective observational study “to better understand potential inciting events, assess kidney injury biomarkers and closely monitor renal function in the period after an outpatient AKI event. “The results will help differentiate outpatient AKI from variability in renal function, AKD and development/progression of CKD.” n
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ADPKD-related ESRD Occurs Earlier in Black Patients AUSTIN, Texas—Non-Hispanic blacks have a lower incidence of autosomal dominant polycystic kidney disease (ADPKD) than non-Hispanic whites, but those with the disease progress to end-stage renal disease (ESRD) at an earlier age, according to investigators.
Erin L. Murphy, MHS, of the Yale School of Medicine in New Haven, Connecticut, and colleagues arrived at these findings in a study comparT:7.875” and outcomes ing ADPKD incidence in non-Hispanic S:7” blacks (NHBs) and non-Hispanic whites (NHWs). Study results, which were presented at the
National Kidney Foundation’s 2018 Spring Clinical Meetings, showed that non-Hispanic blacks were 62% less likely than non-Hispanic whites to have ADPKD, but among patients younger than 40 years, the proportion of individuals with ESRD secondary to ADPKD was significantly higher
among NHBs than NHWs (9.94% vs 7.68%). Among patients older than 50 years, however, ESRD secondary to ADPKD was more common among NHWs than NHBs. Patients aged 40 to 44 years and 45 to 49 years had a similar prevalence of ADPKD-related ESRD. NHBs with ADPKD had a significantly lower mean age at ESRD onset than NHWs (54.4 vs 55.9 years). The researchers used the US Renal Data System database to identify NHBs and NHWs classified as having ESRD secondary to ADPKD, hypertension/ large vessel disease, or diabetes mellitus for the period 2004 to 2013. “This analysis suggests that nonHispanic blacks with ADPKD progress to ESKD at a younger age than non-Hispanic whites with ADPKD,” Murphy told Renal & Urology News. “In ADPKD, until further data are available, it may be prudent to consider black race as an additional risk factor for progression to ESKD, as seen in other forms of kidney disease.” n
Hyponatremia Increases Risk of Fracture T:10.75”
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AUSTIN, Texas—Hyponatremia is strongly associated with an increased risk of fracture and osteoporosis, according to the findings of a new systematic review and meta-analysis presented at the National Kidney Foundation’s 2018 Spring Clinical Meetings. The meta-analysis, which included 25 studies, found that hyponatremia, defined as a serum sodium level below 135 mmol/L, was associated with 2.7and 2.5-fold greater odds of fracture in prospective and retrospective studies, respectively, and 2.7-fold increased odds of osteoporosis, Kalyani Murthy, MD, MS of Lahey Hospital & Medical Center in Burlington, Massachusetts, and colleagues reported in a poster presentation. Patients had a mean age of 73 years. The proportion of female patients ranged from 60% to 90%. Eleven studies evaluated all fractures and 4 evaluated hip fractures. n
www.renalandurologynews.com MAY/JUNE 2018
Renal & Urology News 9
News in Brief
Please visit us at www.renalandurologynews.com for the latest news updates from the fields of urology and nephrology
Short Takes High Urate May Lower Parkinson’s Disease Risk
diabetes mellitus, according to study
HIGH URATE levels may protect
Research and Clinical Practice.
findings published online in Diabetes
against Parkinson’s disease (PD) in
In a study of 174 patients with type
both men and women, investigators
2 diabetes mellitus and biopsy-proven
reported in Parkinsonism & Related
diabetic nephropathy, Junlin Zhang,
Disorders (2018; published online
MD, PhD, and colleagues at West
ahead of print).
China Hospital of Sichuan University in
Marianna Cortese, MD, PhD, of
Chengdu, China, found that patients
the University of Bergen in Bergen,
in the 2nd, 3rd, and 4th quartiles of
Norway, and colleagues based that
serum fibrinogen had a significant
conclusion on a study of the entire
7.1-, 5.8-, and 8.8-fold increased risk
Norwegian population alive and at
of progressing to ESRD, respectively,
least 18 years old as of January 1,
compared with those in the 1st quartile.
Predictors of Pediatric OAB Healing Time ID’d B
ladder wall thickness and the pattern of uroflowmetry curve shape are associated with the healing period in pediatric patients with overactive bladder (OAB), according to researchers. The finding is from a retrospective study of 117 children with OAB aged 5 to 15 years who, at initial presentation, underwent abdominal ultrasound examinations and uroflowmetry and initiation of behavior modifications such as timed voiding and constipation therapy. The average healing period was 11.9 months. The healing period was significantly shorter in the group with a bladder wall thickness of 5 mm or more compared with patients whose bladder wall thickness was less than 5 mm, Masaki Fuyama, MD, and colleagues from Showa University in Yokohama, Kanagawa, Japan, reported online in Pediatrics International. In addition, patients with a tower-shaped curve on uroflowmetry had a significantly shorter healing period than those with a bell-shaped curve, according to the investigators.
2004. In adjusted analyses, exposure of high urate levels or gout—was as-
Drug Combo Approved for Advanced RCC
sociated with a 23% and 11% lower
THE FDA HAS approved nivolumab +
PD risk among men and women, re-
ipilimumab (Opdivo + Yervoy) combi-
spectively. Among women, a protec-
nation therapy for previously untreated
tive effect was observed only among
patients with intermediate- or poor-risk
those older than 70 years, in whom
advanced renal cell carcinoma.
to urate-lowering drugs—a marker
high urate levels were associated with a 35% decreased PD risk.
The agency based its approval on the results of the CheckMate-214 clinical trial, which found that nivolumab
Diabetic ESRD Linked to Elevated Fibrinogen
+ ipilimumab decreased the risk of
ELEVATED SERUM levels of fibrinogen
with sunitinib treatment. The objec-
are associated with the develop-
tive response rate was 41.6% for the
ment of diabetic end-stage renal
combination treatment compared with
disease (ESRD) in patients with type 2
26.5% for sunitinib.
death by a significant 37% compared
Urology Patient Visits/Encounters In 2017, the United States had 12,517 practicing urologists. Shown below are the proportions of urologists according to the number of patient visits/encounters they have in a typical week. 40
32% 28.3%
30
24.2%
20
8.8%
10 0
50 or less
51–75
76–100
101–125
No. patient visits/encounters Source: American Urological Association. The State of the Urology Workforce and Practice in the United States: 2017.
6.7%
126 or more
MET Found Not to Improve Spontaneous Stone Passage M
edical expulsive therapy (MET) does not improve spontaneous stone passage (SSP) in patients with acute ureteric colic, new findings presented at the European Association of Urology 33rd Congress in Copenhagen, Denmark, suggest. As part of the MIMIC study, Taimur T. Shah, MBBS, of University College London, and colleagues collected data from 4181 patients admitted with acute ureteric colic. Of these, 3127 (75%) were discharged with conservative management, and 2516 of them (80%) had confirmed SSP. In this group, 952 patients (44%) were prescribed MET in the form of tamsulosin and 1234 (56%) were not. The rate of SSP was 78% and 72%, respectively. On multivariable analysis, which included adjustment for stone size and position, the investigators found no significant difference in SSP. All patients included in the study had acute renal colic with an obstructing ureteral stone confirmed by computed tomography of the kidneys, ureters, and bladder.
Low-level Lead Exposure Found to Increase CKD Risk L
ow-level exposure to lead is associated with decreased kidney function, according to a recent study published online ahead of print in the American Journal of Kidney Diseases. In a prospective population-based cohort, Florencia Harari, MD, PhD, of Sahlrenska University Hospital and University of Gothenburg, Sweden, and colleagues found that individuals with blood lead levels in quartiles 3 and 4 (median 29 and 46 µg/L, respectively) experienced significantly greater decreases in estimated glomerular filtration rate from baseline to follow-up (about 16 years later) than those with blood levels in quartile 1 (median 15 µg/L). In a model adjusted for age, sex, smoking alcohol intake, and other potential confounders, individuals in quartile 4 had a significant 49% increased risk of chronic kidney disease compared with those in the quartiles 1–3 (reference), the investigators reported.
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Biopsy-to-RP Delay May Up PCa Recurrence Risk A GREATER THAN 90-day delay from
grade, the largest group of patients,
prostate biopsy to radical prostatec-
those with Gleason 3+4 disease, had
tomy (RP) for localized prostate cancer
a significantly elevated risk of BCR
(PCa) may increase the risk of biochem-
after a 90-day delay from biopsy to
ical recurrence of disease, according
RP. Patients with Gleason 3+4 disease
to study findings presented at the
who had a greater than 90-day delay
33rd European Association of Urology
from biopsy to RP had a significantly
Congress in Copenhagen, Denmark.
increased risk of upgrading at RP. In
In a retrospective study of 513 men
In addition, men with Gleason 8–10
who underwent RP for localized PCa at a
cancer who delayed RP more than
single center, Matthias Meunier, MD, and
60 days from the time of biopsy also
colleagues at Hôpital Foch in Suresnes,
had a significantly increased risk of
France, found a linear correlation of the
upgrading at RP. The investigators
delay between biopsy and RP and the
identified no delay thres-hold for men
risk of biochemical recurrence (BCR).
with Gleason 6 cancer.
Patients who delayed RP beyond 90
Dr Meunier and his colleagues
days had a significantly increased risk of
concluded that the maximum time
BCR compared with men who had a less
from biopsy to RP should be 90 days.
than 90-day delay.
It could be extended for men with
When the investigators classified patients according to biopsy Gleason
Non-narcotic drug continued from page 1
(HKSI) in St. Paul, Minnesota, explained. Research has repeatedly shown ketorolac to be more effective than opioids for both pain management and avoiding opioid-related side effects, such as nausea and disorientation. Yet, the new study, which assessed treatment patterns of ED physicians in a major US metropolitan hospital, showed that traditional narcotic-based treatment persisted. “Now, in our current opioid crisis, attention has refocused on decreasing narcotic utilization,” Dr Portis told Renal & Urology News. “Stone patients are at particularly high risk of opioid dependence because of repeated symptomatic episodes and surgical procedures. Many patients begin their stone
De novo PCa in decline continued from page 1
1995–1999 to 9.9 per 100,000 in 2005– 2011. The 5-year PCa-specific mortality rate for the entire cohort was 64%. The rate decreased significantly from 73.4% in 1995–1999 to 56.8% in 2005–2009, the researchers reported. This decrease was accompanied by a non-significant decrease in median age from 74.2 to 73.2 years and a significant decrease in
low-risk cancer and must shortened for those with high-risk cancer. n
experience in the ED, often arriving by ambulance. HKSI initiatives have demonstrated that non-narcotic management after discharge from the ED is both highly effective and associated with superior clinical outcomes, including a 20% decline in surgical intervention.”
TRT safe despite PCa continued from page 1
or radiation were low for men treated with testosterone, and were quite similar to expected recurrence rates based on numerous published studies. This was also true for men on active surveillance.” He added: “For decades, physicians have feared offering testosterone therapy to men with prostate cancer because we were taught that raising testosterone would be like ‘pouring gasoline on a fire.’ From this study, and smaller studies before it, we know this concept can no longer be correct.” Eric A. Klein, MD, Chair of the Cleveland Clinic’s Glickman Urological & Kidney Institute, who was not involved in the study, said the investigation by Dr Morgentaler’s team “adds to the existing data that T replacement in men with early stage low-grade prostate cancer or those treated for cancer is safe and does not appear to increase the risk of progression.” Dr Klein cautioned, however, that testosterone replacement should only be considered for men who have symp-
toms related to documented low testosterone levels. In a separate study presented at the conference, Unwanaobong Nseyo, MD, and colleagues at the University of California, San Diego, looked at outcomes among men who were on AS for PCa—19 patients on TRT and 19 not on TRT. Six men in each group
Recurrence rates are in line with prior studies of men not receiving TRT. experienced progression on repeat biopsy while on AS. Five of 6 in the TRT group vs 1 of 6 in the non-TRT group underwent definitive treatment. Dr Nseyo’s group found that men on TRT were subject to more rigorous PCa screening. They concluded that TRT does not increase the risk of cancer progression, but TRT might influence a patient’s decision to undergo definitive treatment. n
Dr Portis and his colleagues studied 1335 ED patients treated for renal colic. Initial medical management consisted of ketorolac alone in 383 patients (29%), opioid alone in 530
patients (40%), and ketorolac and opioid in 423 patients (32%). Ketorolac was more effective than opioids even after accounting for variations in patient-reported initial pain scores and other patient- and stone-related factors. Ketorolac treatment was associated with a shorter ED length of stay and quicker discharge rate compared with opioid treatment, the investigators reported in a poster presentation. Compared with patients treated with ketorolac only, those treated with opioid only had significant 2-fold increased odds of an ED length of stay more than 3 hours. The investigators observed no significant difference in the odds of an ED length of stay more than 3 hours between patients treated with both ketorolac and an opioid and those treated with ketorolac alone.
Further, patients treated with an opioid alone and ketorolac plus an opioid had significant 4-fold and 2-fold increased odds of hospital admission, respectively, compared with those treated with ketorolac alone. Ketorolac monotherapy was associated with lower use of rescue medications and anti-nausea medications. Dr Portis advised clinicians to allow enough time for the ketorolac to have an effect—typically 30–45 minutes—before reaching for second-line medications. “We are optimistic that if non-narcotic approaches can be successful for renal colic, the epitome of acute painful conditions presenting to the ED,” Dr Portis said, “overall narcotic use can be sharply curtailed by transitioning to higher-effectiveness methods, not just by setting limits to patientrequested relief.” n
median PSA levels from 320 to 145 ng/ mL at diagnosis. The results from this populationbased analysis indicate that early detection identifies patients with PCa at an earlier time in the course of the disease and to an increasing extent before patients have developed metastatic disease, Dr Helgstrand told Renal & Urology News. “An unwanted consequence of this earlier detection, however, is overdiagnosis and
overtreatment of men harboring nonlethal localized prostate cancer whose remaining length of life would be unchanged and whose quality of life would possibly would be greater if not diagnosed at all.” He also observed: “Our findings from the US population suggest that prostate cancer-specific mortality is highly affected by the incidence of de novo metastatic disease. If the patterns of incidence continue to mimic
the American [data], a drop in prostate cancer-specific mortality might be anticipated in Denmark within a few years.” Using the SEER database, Dr Helgstrand’s team identified 426,266 men diagnosed with PCa from 1980 to 2011. Using the DaPCaR, they identified 47,024 men diagnosed with PCa from 1995 to 2011. Of these, 29,555 from SEER and 6,874 from DaPCaR were diagnosed with de novo metastatic PCa. n
Ketorolac vs opioid therapy was associated with a shorter length of stay in the ED.
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Renal & Urology News 15
Obesity Associated With Lower Death Risk in CRPC OBESITY IS ASSOCIATED with a lower risk of death among men with non-metastatic castration-resistant prostate cancer (nmCRPC), new study findings suggest. Using the Shared Equal Access Regional Cancer Hospital database, first author Adriana C. Vidal, MD, of Cedars-Sinai Medical Center in Los Angeles, and colleagues identified 1192 men with non-metastatic CRPC. Of these, 438 (37%), 464 (39%), 239 (25%), and 51 (4%) were obese, overweight, normal weight, and underweight, respectively. In adjusted analyses, each 1 kg/m2 increment in body mass index was associated with a statistically significant 2% decreased risk of all-cause mortality. Obesity was associated with a statistically significant 21% decreased risk of all-cause mortality compared with normal weight (reference), the investigators reported online ahead of print in BJU International. Obesity was not associated with the risk of prostate cancer (PCa)-specific mortality or metastasis.
Obesity vs normal weight was associated with a 21% lower risk of all-cause mortality. The investigators defined obesity, overweight, normal weight, and underweight as a BMI (in kg/m2) of 30 or higher, 25–29.9, 21–24.9, and less than 21, respectively. During follow-up, metastases developed in 686 patients, 848 died, and 548 died from PCa. The median follow-up time among patients who were alive during the study was 34 months. The authors noted that it is well established that obesity is associated with aggressive PCa and worse long-term outcomes among men with localized PCa, and a few studies have evaluated the link between BMI and PCa outcomes among men with metastatic CRPC. The current study, led by Stephen J. Freedland, MD, of Cedars-Sinai, is the first to investigate PCa outcomes among patients with non-metastatic CRPC. The investigators said their data suggest that obesity may be unrelated to PCa aggressiveness and progression in men with non-metastatic CPRC, but, overall, is a favorable prognostic sign. In a discussion of possible explanations for their findings, the authors noted that while tumor-related cachexia is unlikely among patients with non-metastatic
CRPC, patients might have cachexia from other causes such as heart disease, chronic obstructive pulmonary disease, and/or other types of cancer. “Thus, a greater BMI may demonstrate a current lack of cachexia but also perhaps provide some protection from future cachexia, allowing patients to live longer.”
Dr Vidal and her colleagues pointed out that they observed that the risks of all-cause and cancer-specific mortality, although not statistically significant, were greatest among underweight patients compared with normal weight men, “arguing this could be in part cachexia-related.”
Study strengths include the large number of men with non-metastatic CRPC and PCa events. With regard to study limitations, the authors pointed out that they lacked data on additional treatments after CPRC diagnosis as well as data reflecting changes in nutritional and lifestyle regiments prior to CRPC. n
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Bariatric Surgery May Lower CKD Risk At 7 years, 56% of patients at high CKD risk before surgery had an improvement in CKD risk category BARIATRIC SURGERY may result in improvements in the risk of chronic kidney disease (CKD), data suggest. Allon N. Friedman, MD, of the Indiana University School of Medicine in Indianapolis, and collaborators examined whether bariatric surgery influences CKD risk in a study that included 2144 adults who underwent the procedure and participated in the Longitudinal Assessment of Bariatric Surgery-2 Study cohort. They placed patients into 3 CKD risk categories: low (83.4%), moderate (11.9%), and high (3.4%). None of the patients at low CKD risk experienced an improvement in their risk category because they already were in the lowest-risk category, Dr Friedman’s team reported online ahead of print in the Journal of the American Society of Nephrology. Among patients who had moderate baseline CKD risk, 63% and 53% had improvement in their CKD risk category (from moderate to low risk) at 1 and 7 years, respectively. Approximately 5% to 8% of the patients had a worsening in their risk category over 7 years. Among patients who had high CKD risk at baseline, 78% and 56% experienced an improvement in their risk
New findings support consideration of CKD risk in evaluating patients for bariatric surgery.
category at 1 and 7 years, respectively, whereas about 3% to 10% had a worsening in the risk category over 7 years. “These findings support consideration of CKD risk in evaluation for bariatric surgery and further study of bariatric surgery as a treatment for high-risk patients with CKD,” the authors concluded. The study population had a median age of 46 years; 79% were women and 87% were white. Most patients (71%) underwent Roux-en-Y gastric bypass.
In multivariable analysis, variables significantly associated with high or very high CKD risk during the followup period included baseline body mass index (BMI), HbA1c, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), less weight loss, male sex, and lack of private medical insurance. The risk of moving into a high or very high CKD risk category during follow-up increased by 12% with each 5-kg/m2
increment in BMI at baseline, 25% with each 1% increment in HbA1c, 38% with the use of ACE inhibitors or ARBs, and 5% with each 5% lower weight loss. High or very high CKD risk was 34% more likely to develop in men compared with women and 34% more likely to develop in patients who lacked private health insurance. “What is notable is that greater weight loss and not the mechanism through which weight loss was achieved…was an independent predictor of reduced CKD risk,” the authors wrote. “This important and novel finding is consistent with reports in rats in which equivalent weight loss from surgical or medical interventions led to similar histologic improvements in the kidney.” Dr Friedman and his colleagues explained that higher risk associated with the use of ACE inhibitors/ARBs may reflect the fact that these medications were reserved for sicker patients in light of reports suggesting that they are renoprotective in obese individuals. “Similarly, the protective association with private medical insurance could be indicative of better access to health care,” they wrote. n
RATES OF RENAL function decline and end-stage renal disease (ESRD) differ significantly among the 5 most common glomerulonephropathies, according to new study findings. Using electronic health records (EHRs) from the Kaiser Permanente Southern California integrated health system, John J. Sim, MD, of Kaiser Permanente Los Angeles Medical Center, and colleagues identified a group of 2350 racially, ethnically, and socioeconomically diverse patients with glomerulonephropathy (GN, 9% younger than 18 years). Of these, 1006 had focal segmental glomerulosclerosis (FSGS), 350 had membranous glomerulonephritis (MN), 314 had minimal change disease (MCD), 269 had immunoglobulin A nephropathy (IgAN), and 411 had lupus nephritis (LN), according to biopsy results. During 4.5 years of follow-up, 497 (21%) progressed to ESRD and 195 (8%) died of other causes.
According to results published online ahead of print in Mayo Clinic Proceedings, estimated glomerular filtration rate (eGFR) declined by a median of 1.0 mL/min/1.73 m2 annually, but the rate varied by type of glomerulonephropathy. The largest annual drop in
Patients with FSGS were the most likely to progress to end-stage renal disease. eGFR was found in patients with FSGS (−1.8 mL/min/1.73 m2), followed by MN and IgAN (−0.8 mL/min/1.73 m2 for both). Progression to ESRD was most common among patients with FSGS (8.72 cases per 100 person-years), followed by IgAN, MN, MCD (4.54, 2.38, and 1.67 cases per 100 person-years,
respectively). ESRD was 3.43, 2.35, 1.28, and 1.02 times more likely to develop in patients with FSGS, IgAN, LN, and MN patients, respectively, compared with patients who had MCD. Mortality, however, was not significantly different among groups. “Although GNs are often referred to as a single disease entity, there are considerable differences in clinical presentation/characteristics and outcomes,” Dr Sim and his colleagues wrote. “Given the differences in eGFR decline and ESRD risk, our findings underscore the importance of individualizing treatment strategies and managing expectations for patients with these specific GN types.” Dr Sim’s team acknowledged some potential limitations of their study. The study cohort was identified from a realworld practice environment, “and thus we could not account for heterogeneity in management and treatment by different clinicians. These include m edications
prescribed, diagnostic testing, followup patterns, and time of dialysis.” In addition, certain GNs and CKD in their study population may have been underreported. The authors noted that previous studies of GNs have mostly been conducted using smaller, specialized populations or were limited to homogenous population, thus limiting the generalizability of the findings. “The information from our EHRbased cohort has the potential to affect patient care throughout large health systems such as Kaiser Permanente,” Dr Sim and his collaborators wrote. “Glomerulonephropathies are relatively uncommon, and individual nephrologists generally manage a small number throughout their practicing careers.” Aside from major referral centers, they noted, GNs often are managed in a “silo”-type manner throughout the community. “This can lead to considerable heterogeneity in care.” n
© DR. P. MARAZZI / SCIENCE SOURCE
ESRD Risk Varies by Glomerulonephropathy Type
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Fistula, Graft PTA Success Linked to Aspirin Use AUSTIN, Texas—Aspirin use may be associated with successful outcomes after percutaneous transluminal angioplasty (PTA) of hemodialysis (HD) fistulas and grafts, according to study findings presented at the National Kidney Foundation’s 2018 Spring Clinical Meetings. In a study of 80 HD patients who underwent PTA for venous stenoses in arteriovenous fistulas or grafts, Malgorzata A. Kochanek, MD, and colleagues from the University of Chicago found that 66.1% of the 56 patients who had a successful outcome were aspirin users compared with 33.3% of the 24 patients who did not have a successful outcome, a significant difference between the groups.
Graft Failure Tied to Low Uromodulin AUSTIN, Texas—Low levels of uromodulin, a surrogate for less well-preserved renal tubular function, may predict a higher risk of renal graft failure in longterm stable kidney transplant recipients (KTRs), investigators reported at the National Kidney Foundation’s 2018 Spring Clinical Meetings. The finding is from a study of a randomly selected sub-cohort of 433 long-term KTRs who participated in the FAVORIT (Folic Acid for Vascular Outcome Reduction in Transplantation) trial. During follow-up, graft failure occurred in 226 patients. The rate of graft failure was 4.58, 2.45, and 1.57 per 100 person-years, respectively, for patients in the first, second, and third tertiles of serum modulin concentration, according to findings presented by Andrew G. Bostom, MD, MS, of the Center for Primary Care & Prevention, Memorial Hospital of Rhode Island, Pawtucket, and colleagues. Compared with patients in the highest uromodulin tertile (greater than 74.05 to 309.59 ng/mL), those in the lowest tertile (5.62 to 46.81 ng/mL) had a significant 2-fold higher risk of graft failure compared with those in the highest tertile, in adjusted analyses. n
The investigators defined a successful outcome as a dialyzer blood flow rate of 450 mL/min during dialysis without prolonged bleeding, cannulation pain, high venous pressure, low arterial pressure, pulling clots, infiltrations, poor clearance, infections, or swelling of the arm, neck, or head.
Dr Kochanek’s group found that patients with a successful vs u nsuccessful outcome were significantly more likely to have high venous pressure as the indication for PTA (64.3% vs 33.3%). “We could not demonstrate any significant associations between procedural success and any anatomic features or
measurements,” the authors concluded. The study population, which was 98.8% black and 52.5% women, had a mean age of 58.4 years and mean body mass index of 28.8 kg/m2. Of the 80 patients, 42.5% had multiple venous stenoses. The investigators ascertained clinical outcomes 1 month after PTA. n
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Nicotinic Acid May Improve Hyperphosphatemia NICOTINIC ACID and its analogs and derivatives can significantly reduce serum phosphorus levels in patients on hemodialysis, according to a new study. These compounds may be associated with a high rate of adverse events, however. In a meta-analysis of 12 preclinical and clinical trials, serum phosphorus
concentration declined significantly during 4 to 8 weeks of treatment, but not afterward, Xianhua Liu, MD, and colleagues reported in Medicine. The calcium × phosphorus product declined significantly during all drug exposure time intervals (4, 8, and 12 weeks), with no rebound effect.
Nicotinic acid also appeared to improve lipid profile. Mean levels of high-density lipoprotein increased and triglycerides decreased significantly after 8 weeks. The team found that 41% of patients had adverse effects from treatment, with 8% of patients experiencing diarrhea.
The researchers suggested that future studies investigate nicotinic acid’s longterm safety. “Our study concludes that nicotinic acid and related compounds can significantly reduce serum phosphorus concentration with additive antilipemic effects,” the authors wrote. n
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Older Age Ups RCC Death Risk After Nephrectomy OLDER AGE APPEARS to be associated with higher cancer-specific mortality (CSM) among patients treated surgically for small renal tumors. Marco Bandini, MD, of the IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University in Milan, Italy, used the Surveillance, Epidemiology
and End Results (SEER) database to identify 37,121 patients with pT1a renal cell carcinoma (RCC) who underwent partial or radical nephrectomy. The investigators stratified patients according to 5 age categories: younger than 50, 50 to 59, 60 to 69, 70 to 79, and 80 years and older. Compared with patients
younger than 50 years, those aged 50 to 59, 60 to 69, 70 to 79, and 80 years and older had a 2.1, 3.0, 4.4, and 7.6 times higher risk of CSM, investigators reported online in the Canadian Urological Association Journal. Results suggested that the effect of older age on CSM was moreT:6.875” pronounced among
patients with Fuhrman grade 1–2 disease. Among patients with Fuhrman grade 1–2 disease, patients in the aforementioned age categories have a 2.0- to 8.2-fold increased risk of CSM, respectively, whereas those with Fuhrman grade 3–4 disease had 2.3- to 5.9-fold increased risk. n
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Renal Cell Carcinoma Linked to Diabetes in Women TYPE 2 DIABETES is independently associated with an increased risk of renal cell carcinoma in women, but not men, according to a new study published in Diabetes Care. In a study of 117,570 women in the Nurses’ Health Study (NHS) and 48,866 men in the Health Professionals
Follow-up Study (HPFS), Rebecca E. Graff, ScD, of the Harvard T. H. Chan School of Public Health in Boston, and colleagues found that women with type 2 diabetes had a significant 1.5-fold increased risk of RCC compared with non-diabetic women in multivariate analysis. WomenT:6.875” with type 2 d iabetes
for 5 years or less had a significant 2-fold greater risk of RCC compared with non-diabetic women; women with type 2 diabetes for more than 5 years were not at significantly elevated risk of RCC, the investigators reported. Among men, type 2 diabetes was not significantly associated with RCC risk.
NHS and HPFS participants were followed up from 1976 and 1986, respectively, through 2014. The investigators confirmed 418 RCC cases, of which 120 were fatal, during 38 years of follow-up in the NHS, and 302 RCC cases, including 87 fatal cases, during 28 years of follow-up in the HPFS. n
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Caffeine May Lower AKI Risk in Preterm Neonates CAFFEINE MAY OFFER a way to reduce the risk and severity of acute kidney injury (AKI) in preterm neonates, new research findings suggest. In a multicenter study of 675 preterm neonates (gestation less than 33 weeks), a team led by Jennifer R. Charlton, MD, MSc, of the University of Virginia
in Charlottesville, found that AKI developed significantly less frequently among infants who received caffeine within the first 7 days after birth compared with those who did not (11.2% vs 31.6%). In adjusted analyses, caffeine administration was associated T:6.875” with a significant 80% reduced odds
of AKI. Further, among neonates with early AKI, the odds of developing stage 2 or 3 AKI were 80% lower among caffeine recipients than those not exposed to caffeine. The investigators calculated that 1 case of AKI was prevented for every 4.3 neonates exposed to caffeine.
“Because of the benefits and favorable adverse effect profile of caffeine, it may be reasonable to consider routine use of prophylactic caffeine in neonates of 28 and 32 weeks’ gestational age to prevent or reduce AKI, even when apnea of prematurity or the need for positive pressure respiratory support is absent,” Dr Charlton’s team concluded in a paper published online ahead of print in JAMA Pediatrics. The investigators noted that AKI is a common occurrence in preterm neonates and it is associated with increased morbidity and mortality. For the study, the investigators defined AKI based on the modified neonatal Kidney Disease: Improving Global Outcomes definition in the first 7 days after birth.
Premature neonates exposed to caffeine had 80% decreased odds of AKI.
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The study was a secondary analysis of the AWAKEN (Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates) study. Of the 675 neonates in the analysis, 374 were male (55.4%). The cohort had a mean gestational age of 28.9 weeks and mean birth weight of 1285 grams. AKI developed in 122 patients (18.1%) in the first 7 days after birth. It developed in 50 (11.2%) of 447 neonates who received caffeine compared with 72 (31.6%) of 228 who did not. As for potential mechanisms by which caffeine might offer renal protection, Dr Charlton and her colleagues cited a previous study published in Pediatric Research (1987;21:615-618) showing that newborn rabbits exposed to caffeine or theophylline (which, like caffeine, is a methylxanthine) had increased renal blood flow, enhanced sodium excretion, and a higher g lomerular filtration rate. Another possible explanation may involve attenuation of oxidative stress and injury on endoplasmic reticulum, the authors noted. In a previous retrospective study published in the Journal of Pediatrics (2016;172:63-68), Dr Charlton and colleagues found that AKI developed significantly less frequently in very low birth weight neonates exposed to caffeine compared with those who were not (17.8% vs 43.6%). n
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Renal & Urology News 23
More Extensive LND at RP Beneficial PCa recurrence risk after salvage radiotherapy is inversely related to the number of resected nodes BY JOHN SCHIESZER RESEARCHERS FOUND that a more extensive lymph node dissection (LND) during radical prostatectomy (RP) is associated with improved outcomes following salvage radiotherapy in men with rising PSA levels following RP, according to a recent study The study, senior authored by Stephen A. Boorjian, MD, Carl Rosen Professor of Urology at Mayo Clinic in Rochester, Minnesota, included 728 men with a rising PSA following RP treated with salvage radiotherapy. The median follow-up was 8.4 years (range: 4.2– 11.2 years). The investigators looked at clinical and pathologic variables and the associations between lymph node yield and biochemical recurrence (BCR) and clinical recurrence (CR). On multivariable analysis, the researchers found that the risk of BCR after salvage radiotherapy was inversely associated with the number of nodes resected at RP, according to a report published online ahead of print in European Urology. Increased extent of dissection was also independently associated with a decreased risk of CR. “The extent of dissection at the time of prostatectomy could, pending validation of these findings, be a prognostic variable for men
being considered for salvage radiotherapy,” Dr Boorjian said. If these findings are confirmed by others, the extent of lymphadenectomy may be considered a prognostic variable in patients with BCR after surgery who are considering salvage radiotherapy, and could help guide counseling. With regard to study limitations, the authors noted that the reasons for salvage therapies were not analyzed, and the timing of salvage therapies was not standardized. In addition, there may be systematic differences between men receiving whole pelvic radiation vs fossa-only radiotherapy (RT). The team was unable to completely adjust for this factor. In this cohort, whole pelvic RT was used more frequently in pN1 patients (33% vs 3%), and the number of resected nodes was greater among patients treated with whole pelvic radiotherapy (median: 12 vs 9). Dr Boorjian offered some possible mechanisms by which more extended lymph node dissection (eLND) may be linked to improved patient outcomes in this patient population. For example, a more extended node dissection could improve the accuracy of pathologic staging. “This in turn may lead to an increased utilization of additional therapies which further improve patient
Stephen A. Boorjian, MD
outcomes,” he said. “At the same time, it remains possible that a more extended dissection eliminates a greater proportion of micrometastatic disease and thereby leads to improved cancer control.” Radiation oncologist Neil Desai, MD, Assistant Professor of Radiation Oncology at UT Southwestern, said that as with any retrospective dataset, potential confounders in baseline therapy—particularly the timing of adjuvant vs early salvage radiation and use of a ndrogen-deprivation therapy—are hard to completely address even with
statistical adjustments. “This limits the ability to uniformly recommend a procedure with added potential complication risk, particularly in patients with low risk for nodal involvement,” Dr Desai said. James Mohler, MD, Professor of Oncology in the Department of Urology at Roswell Park Comprehensive Cancer Center in Buffalo, New York, and chair of the National Comprehensive Cancer Network (NCCN) Guidelines Panel for Prostate Cancer, said that based on current data, the NCCN PCa treatment guidelines recommend that an eLND be performed whenever a pelvic lymph node dissection is warranted. He said the findings from the current study must be viewed with caution. “The authors have used number of pelvic lymph nodes procured as a surrogate for extent of pelvic lymph node dissection, which is problematic, and advocated number of pelvic lymph nodes procured as a meaningful biomarker of response to salvage radiation,” Dr Mohler said. “The differences found in biochemical recurrence and clinical recurrence were statistically significant but so small as probably not to be clinically meaningful. Finally, such a retrospective review should not be advocated for clinical use until studied further.” n
MRI Can Spare Men Unnecessary Prostate Biopsies MULTIPARAMETRIC magnetic resonance imaging (MRI) of the prostate prior to biopsy can safely decrease the number of unnecessary biopsies and increase the number of significant prostate tumors diagnosed compared with standard biopsy, according to study findings presented at the 33rd Annual European Association of Urology (EAU) Congress and published concurrently in the New England Journal of Medicine. In the PRECISION trial, which enrolled 500 men with a clinical suspicion of prostate cancer (PCa) and no prior prostate biopsy, 71 (28%) of the 252 men randomly assigned to receive prostate MRI scans prior to biopsy did not undergo biopsy because their MRI results were not suggestive of PCa. Those who had MRI findings suggestive of cancer underwent a targeted biopsy based on MRI findings. Clinically significant cancer, defined as the presence of a single biopsy core
indicating Gleason score 3+4 disease or greater, was detected in 95 men (38%) who underwent pre-biopsy MRI followed by MRI-targeted biopsy compared with 64 (26%) of 248 men who underwent standard transrectal ultrasonography (TRUS)-guided 10–12 core
MRI prior to biopsy can help identify men with clinically significant cancer. biopsy. A significantly smaller proportion of men in the MRI group compared with the standard-biopsy group received a diagnosis of clinically insignificant cancer (9% vs 22%), the investigators reported. In addition, among men who underwent further biopsy, clinically significant
cancer was detected in none of the 4 men in the MRI-targeted biopsy group and in 3 (33%) of men in the standard-biopsy group. Of the 71 men with negative results on MRI and no biopsy, 3 (4%) were discharged, 62 (87%) were referred for monitoring of PSA levels, and 3 (4%) underwent further biopsy and had negative results, according to the investigators. One patient (1%) had an additional multiparametric MRI and 2 (3%) had missing information. “The ideal test for prostate cancer would be minimally invasive, have few side effects, identify a high proportion of men who would benefit from treatment, and minimize the identification of men with clinically insignificant cancer in order to prevent overtreatment,” Veeru Kasivisvanathan, MRCS, of University College London (UCL) and UCL Hospitals NHS Foundation, and colleagues wrote in their journal
report. “In men with a clinical suspicion of prostate cancer who had not undergone biopsy of the prostate previously, the PRECISION trial showed that MRI, with or with or without targeted biopsy, appeared to achieve these goals better than the traditional standard of care, transrectal ultrasonography-guided biopsy.” In a news release issued by the EAU, Hein Van Poppel, MD, PhD, of University Hospitals of the Leuven in Belgium, who was not involved the trial, commented, “This work shows that using MRI to decide whether or not to perform a biopsy has the potential to save around a quarter of a million European men each year from going through the biopsy procedure, and so may be cost-effective in the long run.” He added, “We need time to digest the study, but at first reading, it looks like it has the potential to change clinical practice.”n
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Renal & Urology News 27
n ASK THE EXPERTS
Dusting vs Basketing for Stones Urologists debate which is the better approach for renal calculi 5 to 20 mm in diameter BY NATASHA PERSAUD
I Jodi Antonelli, MD
n the May 2018 issue of the Journal of Urology, the EDGE Research Consortium formally published their trial results on the efficacy of dusting vs basketing during ureteroscopy. The study found no significant differences between the procedures with respect to stone-free and complication rates, hospital readmissions, or additional procedures among patients with renal stones 5 to 20 mm in diameter. Renal & Urology News asked 3 urologists with experience in the procedures to offer their perspective: Khurshid Ghani, MBChB, MS, Associate Professor of Urology at the University of Michigan in Ann Arbor; Sara Best, MD, Assistant Professor of Urology at the University of Wisconsin in Madison; and Jodi Antonelli, MD, Assistant Professor of Urology at the University of Texas Southwestern Medical Center in Dallas. [Editor’s note: All had participated in a debate at the 2017 American Urological Association annual meeting in Boston titled, Ureteroscopy: Has the Dust Settled?”]
Stone-free rates are still not as high as we want. Drs Kristina Penniston and Stephen Nakada [of the University of Wisconsin in Madison] are working with a multinational group of endourologists to study quality of life outcomes in stone formers. Their work may help further elucidate the role “stone-free status” plays in the overall lives of our patients and give us further strategies to improve our patients’ experiences. Dr Ghani: Although optimal stone clearance is the goal for urologists, we must consider patients’ preferences and quality of life. Stone-free status may not matter as much to the patient who is focused on avoiding pain or missing work and prefers the least traumatic ureteroscopy. Dr Manoj Monga’s group [at Cleveland Clinic] published an interesting study which showed that patients preferred shock wave lithotripsy to URS, even when informed the stone-free rate was lower.
What are the advantages of dusting? What is the main goal of ureteroscopy (URS)? Sara Best, MD
Khurshid Ghani, MBChB, MS
Dr Best and Dr Antonelli: The top goals of any stone surgery have long been the safe resolution of renal obstruction and obtaining a stone-free status for the patient. However, increased use of computed tomograpy has shown us that our truly “stone-free” rates aren’t as high as we thought. Studies lead-authored by Amanda Macejko (2009), Christopher Rippel (2012), and Andrew Portis (2006) suggest that even after diligent efforts, only 38% to 54% of patients were free of stones. In a previous study, Ben Chew and colleagues from the EDGE Consortium found that in 232 patients with residual fragments after ureteroscopy, 15% had complications and 29% required another procedure.
Dr Ghani: In the EDGE study, the operating time was significantly lower in the dusting group despite that group having larger stones. We’ve noticed that pure dusting in appropriately selected patients also is faster in our practice. In select cases, pure dusting results in less trauma than pure basketing because no access sheath is placed. In about 30% of dusting patients, we also may be able to avoid a stent and its accompanying pain, which is a huge quality of life benefit. Stent problems drive costly emergency department visits after URS.
What are the advantages of basketing?
Dr Best and Dr Antonelli: Basketing potentially results in a higher stone-free rate because stones are actively extracted.
Collected stones then can be analyzed for composition. Information on stone type may suggest underlying medical conditions contributing to stone formation, such as renal tubular acidosis. Results also can guide targeted therapy, such as alkalinization for uric acid stones. While dusting is likely faster to perform, patients can be left with residual stone fragments that have to be passed. Some surgeons also worry that significant heat can be generated within the collecting system when high power, high frequency lasers are used.
Have the published EDGE study findings settled which approach is best?
Dr Ghani: Although the EDGE study findings provided valuable information, stone size was a confounder. The dusting group had much larger stones than the basketing group: stone area was 96.1 vs 63.3 mm2. This difference might have contributed to the finding of more residual fragments after dusting. In addition, urologists frequently stage the procedure when larger renal stones are treated to get optimal stone-free outcomes. However, staged procedures were not allowed in the EDGE study. I wonder whether the stone-free rate in the dusting group would have been better with staging. Dr Best and Dr Antonelli: The EDGE Consortium studied ureteroscopy techniques prospectively and targeted some key questions. Now we can more accurately counsel patients and guide expectations.
Some argue that both dusting and basketing are needed, that equipment, stone size, and stone composition dictate the approach. Would you agree? continued on page 28
28 Renal & Urology News
MAY/JUNE 2018 www.renalandurologynews.com
Stone Risk, Oral Antibiotics Linked Recent exposure to antibiotics and exposure at a younger age are associated with the greatest risk BY NATASHA PERSAUD USE OF CERTAIN antibiotics may be contributing to the rise of kidney stones among children and adults, new study findings suggest. Of 12 classes of oral antibiotics, 5 were associated with increased odds of nephrolithiasis, Gregory Edward Tasian, MD, of the Children’s Hospital of Philadelphia, and colleagues reported in the Journal of the American Society of Nephrology. The odds increased by 2.33 times with the use of sulfas, 1.88 with cephalosporins, 1.70 times with nitrofurantoin/methenamine, 1.67 times with fluoroquinolones, and 1.27 times with broad-spectrum penicillins. Exposure to any of the 5 antibiotic classes within 3 to 12 months was associated with greater risks.
Children and adolescents appeared particularly susceptible. In exploratory analyses, antibiotic exposures at a younger age or within 3 to 6 months were strongly associated with nephrolithiasis. This relationship remained statistically significant for 3 to 5 years for all 5 antibiotic classes except for broad-spectrum penicillins. “Our findings support the hypothesis that antibiotics may be contributing to the increasing prevalence and earlier age at onset of nephrolithiasis,” Dr Tasian and his collaborators stated. “Given that children receive more antibiotics than any other age group, and 30% of antibiotics prescribed during ambulatory care visits are inappropriate, these findings provide another reason to reduce inappropriate outpatient antibiotic use.”
Ambulatory BP Measurements Are a Better Outcome Predictor AMBULATORY BLOOD pressure (BP)
increased risk of all-cause and cardio-
measurements are a stronger predic-
vascular mortality, whereas each 1 SD
tor of all-cause and cardiovascular
in clinic systolic pressure was associ-
mortality than clinic BP measurements,
ated with a 2% increased risk of both
new study findings suggest.
outcomes, Dr Banegas’ team reported
In addition, masked hypertension is associated with a greater mortality risk than sustained and white coat hypertension. José R. Banegas, MD, of the
in the New England Journal of Medicine (2018;378:1509-1520). Masked hypertension was associated with a significant 2.8-fold increased risk of both all-cause and cardiovascular
Universidad Autónoma de Madrid,
mortality compared with normotension,
and colleagues analyzed data from a
whereas sustained hypertension was
national cohort that included 63,910
associated with a significant 80% and
adults in Spain. They examined
94% increased risk of these outcomes,
clinic and 24-hour ambulatory BP in
respectively, and white coat hyperten-
the following categories: sustained
sion was associated with a significant
hypertension (elevated clinic and
79% and 96% increased risk.
elevated 24-hour ambulatory BP);
With regard to study limitations, the
white coat hypertension (elevated clinic
authors noted that clinic BP values rep-
and normal 24-hour ambulatory BP);
resented the average of only 2 read-
masked hypertension (normal clinic
ings at each clinical visit, so “the mean
and elevated 24-hour ambulatory BP);
clinic pressure could be overestimated
and normotension.
because it tends to be come lower with
During a median follow-up of 4.7 years, 3808 patients died from
repeated measurements.” “Nevertheless,” they pointed out,
any cause, and 1295 of these patients
“this is a pragmatic study of real-world
died from cardiovascular causes. In
clinical practice where this approach
adjusted analyses, each 1 standard
to clinic blood-pressure measurement
deviation (SD) in 24-hour systolic
is more typical than that adopted in
pressure was associated with a 58%
clinical trials.” n
As for a possible explanation for the association between antibiotic use and stone risk, antibiotic-induced changes in the gut microbiome might affect macronutrient metabolism and lead to kidney stones. However, the authors could not
Cephalosporins and sulfas are among the antibiotics found to increase stone risk. rule out direct antibiotic crystallization in the kidney. The short period between antibiotic use and nephrolithiasis also might be explained by temporary,
Dusting vs basketing continued from page 27
Dr Best and Dr Antonelli: Studies to date tell us that there is likely a role for both basketing and dusting. Some stones, such as those composed of calcium oxalate dihydrate, are very brittle and may more easily disintegrate with lithotripsy. Other stones, such as calcium oxalate monohydrate, are very hard to dust by any method. Since we know that most stones are of mixed composition, a reasonable approach may be to try to dust a stone first to decrease its size, and then change the laser settings to fragment the stone into smaller pieces for extraction. This approach works well for larger stones, which are increasingly being treated ureteroscopically. Dr Ghani: I completely agree that you can’t say one strategy will work best all of the time for renal stones. You have to adapt and do what is best based on stone durility and patient factors. I predict that many pure basketers over the next few years will start to dust the stone in the beginning, and then retrieve fragments at the end. This will speed up cases for those who do pure retrieval.
What should practicing urologists do?
Dr Best and Dr Antonelli: Skills, equipment, and resources vary, so there is no “one-size-fits-all” approach to URS.
a ntibiotic-induced changes in the urinary environment leading to stone formation in susceptible individuals. The investigators adjusted models for the rate of health care encounters, comorbidities, urinary tract infections, and use of medications including thiazide and loop diuretics, proton-pump inhibitors, and statins. In the case-control study, the team matched 25,981 nephrolithiasis patients to 259,797 controls by age, sex, and date of diagnosis using electronic health records from the Health Improvement Network. This database included infor mation from more than 13 million children and adults from 641 general practices in the United Kingdom during 1994 to 2015. n
Urologist should consider their institution’s successes when deciding how to approach a stone case. Dr Ghani: Urologists need to learn about the parameters available in new generation holmium systems. By tweaking pulse joule, frequency, and pulse width, they can optimize stone fragmentation. For those who like to try and do pure dusting like me, the key to a successful outcome is how well the popcorn technique is employed at the end.
Are new technologies on the horizon that will change the landscape?
Dr Ghani: We are witnessing a renaissance in laser technology in endourology, and it is an exciting time. We anticipate new pulse modulation and optimization systems, as well as laser fiber technologies that will allow us to really achieve a sand effect with dusting. New scopes and devices that will aid the dusting technique, such as a suction device, are in development. Dr Best and Dr Antonelli: Our colleagues in practice and industry are working to help us define and achieve optimal outcomes after ureteroscopy. We’d like to see future innovations that help us assess and manage intra-renal pressures and temperatures to avoid complicat ions such as sepsis and pain. Pioneering work that identifies factors influencing patient experience and quality of life would be welcome. n
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Renal & Urology News 29
ADPKD Tied To Lower Mortality in PD Patients with autosomal dominant polycystic kidney disease had 32% lower odds of death, study finds BY JODY A. CHARNOW AUSTIN, Texas—Patients with autosomal dominant polycystic kidney disease (ADPKD) who are on peritoneal dialysis (PD) have a lower death risk than non-ADPKD patients on PD, findings from a new meta-analysis presented at the National Kidney Foundation’s 2018 Spring Clinical Meetings suggest. The meta-analysis, which was presented by first author Boonphiphop Boonpheng, MD, of East Tennessee University in Johnson City, included 12 observational studies with a total of 14,673 patients on PD (931 with and 13,742 without ADPKD). Compared with the non-ADPKD group, the patients with ADPKD had a significant 32% decreased odds of death in a pooled analysis. The investigators found no significant associations between ADPKD status and the risks of technique failure or peritonitis. In patients with ADPKD-associated ESRD, enlarged polycystic kidneys
within the peritoneal cavity raise concerns about increased risks of abdominal hernia and dialysate leak related to increased abdominal pressure, explained senior author Wisit Cheungpasitporn, MD, of the University of Mississippi Medical Center in Jackson, senior author of the meta-analysis. “However, in our meta-analysis, we demonstrated that the risk of technique failure was not significantly different between ADPKD patients and non-ADPKD patients on PD,” he told Renal & Urology News. “Thus, notably, the concerns about increased risks of abdominal hernia and dialysate leak did not translate to higher technique failure of PD requiring the need to transfer to hemodialysis.” Dr Cheungpasitporn noted that the follow-up time for all studies included in this meta-analysis was less than 5 years, which is relatively short. Consequently, future studies are required if survival benefits of PD over
IV Iron Use Not Associated With Reduced Platelet Counts AUSTIN, Texas—Intravenous iron
increase at week 4. The study also
repletion with sodium ferric gluconate
found a very weak correlation between
complex (SFG) does not reduce platelet
baseline platelet counts and iron or
counts in patients with chronic kidney
transferrin saturation.
disease (CKD) and iron deficiency anemia,
In a poster presentation, Dr Dossabhoy
according to study findings presented at
and his colleagues explained that
the National Kidney Foundation’s 2018
iron deficiency may lead to reactive
Spring Clinical Meetings.
thrombocytosis, though the underlying
The finding contrasts with the results of previous studies demonstrating that
causes are not fully known. They pointed out that the previous
IV iron repletion using iron dextran was
DRIVE [Dialysis Patients’ Response
associated with significant decreases in
to IV Iron With Elevated Ferritin] trial
platelet counts.
showed that platelet counts decreased
The new study, led by Neville R.
following IV administration of ferric
Dossabhoy, MD, Professor of Medicine
gluconate, and a study by Anatole
at Louisiana State University School of
Besarab, MD, and colleagues showed
Medicine and Chief of the Nephrology
that correction of iron deficiency with
Section at the VA Medical Center in
IV iron decreases platelet counts in
Shreveport, Louisiana, examined
patients with non-dialysis CKD.
platelet counts in approximately 100
These findings had “led to a hypoth-
patients with CKD-associated iron defi-
esis that iron deficiency could produce
ciency anemia who received a total of
a relative thrombocytosis that may con-
362 doses of SFG over a 4-month study
tribute to thrombotic events observed
period. The investigators observed a
in clinical trials of erythropoiesis-stim-
significant rise in platelet counts at week
ulating agents (ESAs) in CKD patients,”
3 post-infusion, and a non-significant
Dr Dossabhoy’s team wrote. n
hemodialysis among ESRD patients with ADPKD may decrease over time. Separately, in a 12-year study presented at the 2018 Annual Dialysis Conference in Orlando, Florida, researchers found lower mortality
Peritoneal dialysis does not increase the risk of technique failure, data show. rates among patients with vs without ADPKD regardless of whether their initial ESRD treatment modality was PD (17.4% vs 24.7%) or intermittent hemodialysis (26.8% vs 39%). In a paper published in Nephrology Dialysis Transplantation in January, researchers reported the details of study showing that ADPKD is not associated
Urea Therapy Safely Treats Hyponatremia AUSTIN, Texas—Treatment of inpatient hyponatremia with a novel American formulation of urea is safe and effective, according to study findings presented at the National Kidney Foundation’s 2018 Spring Clinical Meetings. The study, by Helbert Rondon-Berrios, MD, Associate Professor of Medicine in the Renal-Electrolyte Division at the University of Pittsburgh School of Medicine, and colleagues, included 58 hospitalized patients with hyponatremia (plasma sodium level below 135 mEq/L) and treated with a new formulation of urea among other therapies. The median age of these patients was 67.5 years, and 35 patients (60%) were male. Patient received urea at a dosage of 7.5 to 90 g/ day for a median duration of 4.5 days. Among patients in this cohort, the investigator found 14 patients who received urea as the sole drug therapy for hyponatremia (cases) and matched them 1:1 to 14 hyponatremic patients hospitalized in the prior year and who did not receive urea treatment
with an increased risk of PD technique failure or an increased risk of peritonitis, and that PD is not associated with mortality. The study by Michael Signogne, MD, of the University Hospital of Reims, France, and colleagues included 5291 ADPKD patients (638 on PD and 4653 on hemodialysis) and 12,059 nonADPKD patients on PD. Compared with ADPKD patients on HD, those on PD had higher serum albumin levels and less likely to have diabetes. A study published in International Urology and Nephrology (2015;47:17391744) that compared 106 ADPKD and 1606 non-ADPKD incident PD patients found no difference in patient survival or technique failure after a median followup of 32 months. The risk of abdominal hernias and dialysis fluid leaks was twice as high in the patients with ADPKD, but these complications did not result in a need for a permanent transplant to HD, according to investigators. n
(controls). The investigators matched cases and controls by sex, etiology, and degree of hyponatremia. Urea therapy was associated with a significant increase in median plasma sodium level from 124 to 130.5 mEq/L in the entire cohort and from a median of 125 to 132 mEq/L in cases, Dr RondonBerrios’ group reported. A significantly greater proportion of cases achieved a normal plasma sodium level than controls (43% vs 7%). The investigators observed no significant difference in the change in plasma sodium levels at the end of therapy or in length of hospital stay in cases compared with controls. In the entire cohort of patients who received urea, the researchers observed no episodes of overcorrection of plasma sodium and no adverse events associated with the use of urea. They noted that 1 patient discontinued urea as a result of poor palatability. He and his colleagues noted that the study was limited by retrospective design, small sample size and relatively short duration of urea therapy. “The significance of this study relates to the finding that a novel formulation of urea now available for use in the United States appears to be effective and safe for the management of inpatient hyponatremia and is well tolerated by patients,” Dr Rondon-Berrios told Renal & Urology News. n
30 Renal & Urology News
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Anticoagulants Found to Increase Stroke, Hemorrhage Risk in CKD BY NATASHA PERSAUD OLDER PATIENTS with chronic kidney disease (CKD) who take anticoagulants for coexisting atrial fibrillation appear to have greater risks for ischemic stroke and bleeding, but a lower risk of death, according to a new study. In a large study, anticoagulant recipients had a significant 2.6- and 2.4-fold increased risk of ischemic stroke and hemorrhage, respectively, but a 28% decreased risk of death compared with patients not exposed to the medications, Shankar Kumar, MD, of the University College London (UCL) Centre for Medical Imaging, and colleagues reported online ahead of print in BMJ (2018;360:k342). Since previous studies yielded mixed findings on risks associated with anticoagulants in this population, Dr Kumar’s group examined The Royal College of General Practitioners Research and Surveillance Centre database population of 2.7 million real-world patients from England and Wales. The investigators identified 6977 patients with CKD (estimated glomerular filtration rate less than 50 mL/min/1.73m2, not on dialysis) and newly diagnosed atrial fibrillation older than age 65. Of these, 2434 received a new prescription for
anticoagulants within 60 days of diagnosis, including vitamin K antagonists (71.7%), rivaroxaban (12.7%), apixaban (10.8%), dabigatran (2.8%), unfractionated or low molecular weight heparin (1.8%), and edoxaban (0.17%). Drugexposed patients were then matched to unexposed patients by propensity score and followed for a median 506 days.
New study raises concerns about starting therapy for new-onset Afib. Ischemic stroke developed more frequently in anticoagulant exposed vs unexposed patients (4.6 vs 1.5 cases per 100 persons per year), as did cerebral or gastrointestinal hemorrhage (1.2 vs 0.4 cases per 100 persons per year). “Given the present lack of guidelines, the decision to start anticoagulant treatment in patients with chronic kidney disease and new onset atrial fibrillation should be made on an individual basis,” the authors wrote. In a news release issued by UCL, Dr Kumar commented, “As we found
a paradoxical reduced mortality rate alongside increased rates of stroke and major bleeding, this is clearly a very complex area.” The findings of increased bleeding corroborate previous research, but the association between anticoagulants and ischemic stroke is new. The investigators suggested that vascular calcification and anticoagulant-related renal effects might contribute to ischemic stroke in older patients. In a discussion of study limitations, the investigators noted that misclassification bias may have occurred since they were unable to review electrocardiography and neuroimaging findings. “We cannot exclude the possibility that some clinical coding was incomplete resulting in events being undetected,” they wrote. Dr Kumar and colleagues pointed out that their study lacked the statistical power to perform separate sub-analyses for gastrointestinal and cerebral bleeding. “Despite well matched groups after propensity score matching, we cannot exclude that the reported associations were confounded by indication. Those taking anticoagulants may have had an inherent increased baseline rate of stroke.” n
ICD Use in CKD Patients Questioned IMPLANTABLE cardioverter defibrillators (ICDs) may not offer a survival benefit to patients with chronic kidney disease (CKD) and co-existing heart failure and reduced left ventricular ejection fraction (LVEF), according to new findings published online ahead of print in JAMA Internal Medicine. Nisha Bansal, MD, MAS, of the University of Washington in Seattle, and colleagues studied 5877 matched adults with CKD (estimated glomerular filtration rate below 60 mL/min/1.72m2) and heart failure and an LVEF of 40% or less. Patients with end-stage renal disease were excluded from the study. The group included 1156 patients with an ICD and 4321 without an ICD. The all-cause mortality rate among the ICD and non-ICD groups were 14.9 and 13.6 deaths per 100 personyears, respectively. In a fully adjusted model, the investigators found no significant difference in all-cause mortality. ICD recipients, however, had a significant 49% and 25% greater risk for hospitalizations due to heart failure and for any cause, respectively, compared with the non-ICD group.
URS Superior to ESWL for 5–20 mm Stones FLEXIBLE ureterorenoscopy (URS) more effectively treats kidney stones 5 to 20 mm in diameter—including stones outside the lower pole—than extracorporeal shock wave lithotripsy (ESWL), researchers have concluded. Christian D. Fankhauser, MD, of the University of Zurich in Switzerland, and his team retrospectively studied a cohort of 1282 patients treated at their center from 2003 to 2015. Of these, 999 (78%) and 283 (22%) underwent ESWL and URS, respectively. All patients had previously untreated kidney stones and a stone diameter of 5 to 20 mm. The investigators determined stone-free rates for each modality during follow-up with ultrasonography (US), X-ray, or computed tomography. After propensity score matching, URS exhibited both significantly higher stone-free (84% vs 71%) and freedom from reintervention (79% vs 55%) rates, according to results published in Clinical
Kidney Journal. Subgroup analyses revealed the same trend, with URS showing superiority to ESWL for non-lowerpole stones with respect to stone-free rate (82.4% vs 68.2%) and freedom from reintervention rate (77.2% vs 52.5%). “In the absence of RCTs [randomized controlled trials] for non-lower pole kidney stones, this study is the largest comparative study of treatment efficacy and safety between ESWL and URS, providing evidence that URS might be the better treatment option in untreated kidney stones up to 20 mm in size,” the investigators concluded. In multivariable regression analysis, ESWL was independently associated with a significant 58% decreased odds of being stone free and 66% decreased odds of freedom from reintervention compared with URS. Stone size also independently predicted both outcomes. Results for lower pole stones agreed with those from a previous meta-anal-
ysis. In the current study, URS had a nonsignificant higher stone-free rate (88.9% vs 80.2%) and a significantly higher freedom from reintervention rate (91.7% vs 61.1%). The authors said freedom from reintervention more strongly reflected efficacy. Few complications occurred with either treatment. Clavien Grade 3a complications developed in 0.8% and 0% and Grade 3b complications in 0.5% and 0.4% of ESWL and URS patients, respectively. The most common complication was urinary tract infection, which occurred in 6.4% and 2.2% of the URS and ESWL cohorts, respectively. The authors noted that their results must be interpreted in the context of the study’s retrospective design. “Although the study was controlled for known confounders, residual confounding by disregarded or unknown variables may still have occurred,” they noted. n
“The findings of this noninterventional study may have important therapeutic implications, particularly given the paucity of clinical trial data related to ICD placement in patients with CKD,” the authors wrote. “These data call for a more comprehensive view of the net risks and benefits of ICD placement in eligible patients with reduced LVEF heart failure and CKD and for future trials to help directly address these questions.” With regard to study limitations, the investigators noted that 32% of their study population had known coronary artery disease, so the findings “may not be generalizable to all patients with reduced LVEF heart failure, particularly those with ischemic heart failure.” They also noted that they cannot completely exclude residual or unmeasured confounding or selection bias, which may have affected the findings. n
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Renal & Urology News 31
Ethical Issues in Medicine T
he winter our heating pipes burst because of structural problems with our home’s foundation, my spouse and I were forced to embark on a renovation. We needed a contractor, whom I will call Sam, to manage the complicated details of the project and coordinate all of the sub-contractors. Sam came with strong references and a demeanor that suggested we could work easily with him. Over the course of the project, however, I was struck by how Sam withheld information that I thought was important for my wife and me to inform our decision-making about the project. This problem reminded me of my work promoting high quality informed consent and shared decision-making (SDM) with other health care professionals. As a physician and ethics consultant, I am continually challenged with finding creative and compelling ways of sensitizing other health care professionals to the principles of medical ethics and their practical and fundamental relationship to everyday patient care. Busted pipes and building contractors seemed to offer a compelling analogy that might resonate where dry explanations of policy and informed consent would not. Advocates for preventing sexual assault have already successfully engaged the public with this type of approach by dis-
the experiential process of submitting one’s home to “major surgery” might help physicians better understand the patient’s experience of the informed consent process and how it is central to providing high quality care. Sam did not always provide me all the information I needed to make building decisions that were right for my wife and me. When the bathroom pocket door was finished, I asked why the door’s roller hardware was not exposed like I had seen before. “We could have done that, but it wouldn’t look as good. This is better,” he said. Well, in fact, I thought his choice did not look better, and I was not prepared to prioritize his aesthetic opinion. I thought it highlighted an aspect of SDM that physicians are likely to overlook. SDM promotes patients and physicians working together to identify an optimal treatment recommendation by combining the evidence for a range of available treatment options with a patient’s articulated values and preferences. Making treatment recommendations and engaging in SDM requires that physicians differentiate their personal values from their patient’s because patients appreciate and experience risks and benefits of treatments differently than physicians. Providing clinical recommendations without adequate
Identifying a patient’s preferences and goals leads to a care plan that can reflect those goals, and this may improve patient satisfaction. armingly comparing affirmative consent for sexual contact with offering someone a cup of tea.1 Physicians have turned to fairy tales and the power of storytelling to teach medical students about the power of empathy for interviewing and engaging with difficult-to-help patients.2 In this analogy, my house was the patient and my wife and I were the parents. Sam was the “house doctor” with vast expertise and experience in the care and repair of houses. I offer that
SDM could leave physicians subject to cognitive bias based on their personal values.3,4 For example, when discussing the role of anticoagulation in nonvalvular atrial fibrillation, physicians should help patients understand and appreciate the evidence-based bleeding risks and stroke-reduction benefits associated with treatment, and then decide together if anticoagulation is right for the patient. There is not necessarily a “right” answer about anticoagulation, but rather
© IKON IMAGES / ALAMY STOCK PHOTO
What a building contractor taught me about shared decision-making and its importance in patient care BY DAVID J. ALFANDRE, MD
Understanding patients’ values, preferences, and needs is key to medical decision-making.
what is “right for an individual patient” based on the patient’s values and preferences elicited as part of a SDM process. Sam unilaterally deciding that exposed door hardware looks worse is conceptually no different than a physician unilaterally deciding that a patient should tolerate the increased risks of bleeding on anticoagulation to prevent a future stroke. Both decisions are preferencesensitive—a term used in medical ethics to denote health care decisions that are related to patient’s values, preferences, and needs—and thus should be considered by physicians as part of the decision-making process. Most medical decisions are preference-sensitive. My colleagues readily recognize the analog of this process when making decisions together with patients about PSA screening or even when deciding to initiate dialysis. For sure, the physician needs the medical expertise and experience to identify safe and appropriate care options. But identifying a patient’s preferences and goals leads to a care plan that can reflect those goals, and this may improve patient satisfaction. Even though I like to imagine that my house has discrete organ systems, I know I am stretching the analogy too far. The high-pressure water pipes are not arteries and snaking a clogged pipe is not
just like a TURP. Although contractors obviously have more dissimilarity with physicians than the few things they might share in common, I have found that comparative exercises like these help to lower my intellectual defenses to consider new ideas. I am eager to see where these conversations can take us. ■ 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. Consent: Not actually that complicated. 2015; http://rockstardinosaurpirateprincess. com/2015/03/02/consent-not-actually-that-complicated/. Accessed December 16, 2016. 2. Joachim N. Teaching the art of empathic interviewing to third-year medical students using a fairy tale—”The prince who turned into a rooster.” Am J Psychother. 2008;62:395-418. 3. Alonso-Coello P, Montori VM, Diaz MG, et al. Values and preferences for oral antithrombotic therapy in patients with atrial fibrillation: physician and patient perspectives. Health Expect. 2015;18:2318-2327. 4. Ubel PA, Angott AM, Zikmund-Fisher BJ. Physicians recommend different treatments for patients than they would choose for themselves. Arch Intern Med. 2011;171:630-634.
32 Renal & Urology News
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Practice Management I
n a recent study sponsored by Merlin International, 62% of health care executives reported having a cyber attack in the past year, and almost three-quarters said their organizations were too short staffed to protect against future breaches. The respondents said staffing was the biggest challenge in ensuring security of health information. Only half had a dedicated chief information security officer (CISO). HIPAA does not require health care organizations to have somebody in this position, but an individual who sets and manages an organization’s security plan is a must for larger organizations. “I was surprised that many didn’t have a CISO,” said Brian Wells, chief technology officer for Merlin, which sponsored the study. “I knew there was understaffing but figured that most had one. This is a key position for making progress. Without that cheerleader in charge, it is difficult to make a lot of headway in security.”
Workforce shortage Cybersecurity staffing at all levels is a major challenge, in part because of a workforce shortage. In its 2017 Global Information Security Workforce Study, the business consulting and market research firm Frost & Sullivan p redicted
the Frost & Sullivan report, unemployment in this space is only about 2% in the United States, and the average pay is $120,000 a year. “CISOs can charge a lot of money right now, and they can go somewhere and work for 4 or 5 years, build a program, and then move on to a bigger organization,” Wells said. According to Wells, the health care industry lags behind many others in this regard. The banking sector puts 11% and 15% of its budget toward security. Health care organization, he said, spend about half of that. Many allot about 7%, but he recommends spending closer to 10% on all cybersecurity measures, including staff. “When it comes to IT security, you need experience and training, and it won’t work to just wing it or use a 16-year-old who is good with computers to help out on weekends,” he said. Wells recommends 1 full-time employee dedicated solely to security work for a hospital with at least 100 beds or a medical group of about 200 physicians. Small practices do not necessarily need to hire someone dedicated to security, but they should find a local person who can handle servers, backup, firewalls, basic security, and laptop encryption, Wells said.
People trained in cybersecurity are in short supply and demand for them is strong, so these individuals can command high salaries. a global cybersecurity personnel shortage of 1.8 million individuals by 2020. “There’s an insufficient supply of people trained in security,” Wells said. “Colleges aren’t cranking out enough students, or there just aren’t enough people interested in this career.” Caps on foreign workers coming into the country has also contributed to the problem, he said. When demand is high and supply low, the cost for these workers goes up. According to
Filling the gap According to the Frost & Sullivan report, 87% of the global cybersecurity workforce came to the field from other industries, many of which were non-technical. That means recruiting can be expanded beyond the traditional IT or cybersecurity personnel. “You can hire a smart technical person with energy and pay for their certifications and training to learn cybersecurity,” Wells said. “It’s cheaper to hire at a lower level and train.”
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A paucity of qualified cybersecurity specialists presents medical groups and other health care organizations with hiring challenges BY TAMMY WORTH
According to a report, many cybersecurity workers come to the field from other industries.
To address market demand for health care cybersecurity personnel, the McCombs School of Business at The University of Texas (UT) at Austin offers a 9-week Health Informatics and Health IT Certificate Program for generalists. So far, the program has trained more than 1,200 students since its inception in 2010. Leanne Field, PhD, the program’s director, said they are working with industry experts to build a new certification using the same approach they have used with their generalist program. They also determined that the health care cybersecurity job is not as technical as one might think. “Based on what we’ve learned, it’s going to be a program about managing risk in large health care organizations,” Dr Field said. “We’re going to train people to work in a variety of settings including consulting organizations or directly under CISOs.” Program staff are beginning with a pilot program they hope to complete before the year’s end, and then scale up to an online certificate that may be ready in early 2019. This health care cybersecurity focus is an “area that has severe need that no one seems to be addressing right now,” said Kent Nutt, communications director for the Health Informatics and Health IT
Certificate Program at UT Austin. The planned health care cybersecurity certificate program will train new college graduates, existing security personnel, and members of the military transitioning to civilian life to equip them to enter this workforce. The latter group has expressed interest in this emerging field and are well-suited because of their intelligence training received in the military. “This is about health care organizations having well-trained teams in place that are quick to understand risk and are able to communicate and respond appropriately if there is a breach,” Nutt said. Nutt cites a recent report by KPMG showing that more than half of 151 health care and life science leaders polled during a teleconference said they were either unaware of how to respond or that written instructions for responding did not exist in their organization. “The McCombs School of Business at UT Austin looks forward to developing innovative, healthcare, cybersecurity programs to meet this acute workforce need,” Field noted. ■ Tammy Worth is a freelance medical journalist based in Blue Springs, MO.