M AY/J U N E 2 019
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VOLUME 18, ISSUE NUMBER 3
PSADT Predicts CRPC Mets Risk Findings could impact treatment decisions
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PSA DOUBLING TIME AND METASTASIS RISK As PSA doubling time decreases, the risk of metastatic disease increases in patients with nonmetastatic castration-resistant prostate cancer, according to a new study. The chart below shows how much the risk of metastasis is increased according to 2-month PSADT intervals compared with a reference value of more than 12 months. 35 30
33.8×
Reference >12
25 20
BY JODY A. CHARNOW CHICAGO—Men with nonmetastatic castration-resistant prostate cancer (nmCRPC) who have a relatively short PSA doubling time (PSADT) are at increased risk of progressing to metastatic disease, new study findings presented at the 2019 American Urological Association annual meeting confirm. In addition, the study, which included 3579 patients with nmCRPC who had a mean age of about 73 years identified using the Veterans Health Administration database, found that the risk of metastasis increased
as PSADT decreased. Men with a PSADT of 2 months or less had a 33.8-fold increased risk of metastasis compared with a PSADT greater than 12 months (reference), after adjusting for multiple variables. Patients with a PSADT of 4 months of less but greater than 2 months had a 14.3-fold increased risk of metastasis, according to investigators. “This is the largest study to date that very strongly confirms the value of PSADT in predicting metastatic disease in men with nmCRPC,” lead investigator Stephen J. Freedland, MD,
Left-Sided RCC Tumors Worse CHICAGO—Patients with left-sided renal cell carcinoma (RCC) tumors are more likely to present with higher-stage disease and in general have worse cancer-specific survival (CSS) compared with patients who have right-sided RCC tumors, according to new study data presented at the 2019 American Urological Association annual meeting.
Researchers report associations with higher-stage disease and reduced CSS.
Differences between left and right kidneys with respect to anatomic position, arterial blood supply, and venous and lymphatic drainage could explain the differences in outcomes between patients with left- and right-sided RCC, investigator Annemarie Uhlig, MD, MPH, of University Medical Center Goettingen in Germany, told Renal & Urology News. The study included 17,709 surgically treated adult patients with RCC from the Surveillance, Epidemiology and End Results (SEER) database and 41,967 from the German Centre for Cancer Registry Data (ZfKD) database. In the SEER and ZfKD continued on page 16
14.3×
15 10 5 0
1.8×
3.1×
>10 – ≤12
>8 – ≤10
6.6×
4.1×
>6 – ≤8 >4 – ≤6 PSADT in months
>2 – ≤4
≤2
Source: Freedland SJ, Ramaswamy K, Lechpammer S, et al. Impact of prostate specific antigen doubling time on metastasis and increased costs associated with progression to metastatic castrate-resistant prostate cancer. Presented at the 2019 AUA annual meeting held May 3-6 in Chicago. Abstract MP34-09.
of the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center in Los Angeles, told Renal & Urology News. “Moreover, costs and health care resource use for these men goes up dramatically, too. Importantly, most men had longer
TRT Is Safe in Selected PCa Patients BY JODY A. CHARNOW CHICAGO—Studies presented at the 2019 American Urological Association annual meeting add to a growing body of evidence showing that testosterone replacement therapy (TRT) is safe for selected men with a history of prostate cancer (PCa). The studies found no increase in the risk of adverse oncologic outcomes following treatment—even among men with high-risk PCa—or while on active surveillance. Two of these studies were co-led by J. Kellogg Parsons, MD, MHS, Professor of Urology at the University of California, San Diego, who told Renal & Urology News he believes the research to date, despite being mainly observational cohort studies, is sufficient to support the use of TRT in selected men with lowrisk PCa, particularly those who have undergone definitive treatment with surgery or radiation and have no evidence of residual disease. continued on page 16
doubling times (12 months or more) and thus are low-risk. However, for men with shorter PSADTs, given new options that can delay metastases in these men, consideration should be given to starting these men on therapy continued on page 16
IN THIS ISSUE 2
Extensive PSM predicts higher PCa recurrence risk
6
AKI following PN impedes longterm renal function recovery
10
Kidney stone incidence in the US is on the rise
14
ADT is associated with an increased risk of dementia
14
Bone pain predicts skeletalrelated events in mCRPC
15
Hydrophilic statin use linked to lower PCa diagnosis risk
19
Ask the Experts: Genetic testing for hereditary PCa
Fosfomycin shows benefit in patients with chronic bacterial prostatitis. PAGE 22
2 Renal & Urology News
MAY/JUNE 2019 www.renalandurologynews.com
Extensive PSM Ups Prostate Cancer BCR Risk EXTENSIVE POSITIVE surgical margins (PSM) at radical prostatectomy is strongly associated with biochemical recurrence (BCR), according to new study findings published in BMC Urology. Of 1275 radical prostatectomies performed in 2 university centers in France,
Yoann Koskas, MD, of Hôpital Nord in Marseille, and colleagues identified 189 cases (mean age 71.8 years) with PSM, 115 (60.9%) with focal PSM (fPSM) and 74 (39.1%) with extended PSM (ePSM). Compared with the ePSM group, the fPSM group was significantly younger (70.3 vs 74.1 years)
and had a significantly lower mean PSA level (8.1 vs 10 ng/mL). To minimize confounding, no patient had pT3b or pT4, detectable postoperative PSA, seminal vesicle or lymph node invasion, or neoadjuvant or adjuvant treatment. BCR, defined as a PSA rise to 0.2 ng/ mL or higher, occurred in just 12.1%
of cases with fPSM (a single PSM of ≤3 mm) compared with 54.1% of cases with ePSM (either a single PSM >3 mm or several positive margins of any length) over a median 8-year follow-up, the investigators reported. In a multivariate model, ePSM was significantly associated with a 6-fold greater
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risk of BCR compared with fPSM. Furthermore, men with ePSM experienced BCR significantly earlier than men with fPSM: 57.2 vs 89.2 months. Having ePSM significantly decreased BCR-free survival regardless of patients’ pathological stage (pT2, pT3a) or Gleason score. BCR-free survival at 5 years was 86.8% for fPSM vs 49.4% for ePSM; at 8 years, it was 85.1% vs 44.8%, respectively. Metastatic recurrence developed
in 1 patient, and no patient died from prostate cancer. “In the end,” Dr Koskas and colleagues wrote, “the therapeutic dilemma for patients with PSMs following radical prostatectomy is to distinguish those who need adjuvant therapy from those for whom simple monitoring would suffice. While it is still unclear what the best treatment is for patients with PSMs, our data may provide beneficial information
regarding how to best proceed, particularly for patients with fPSM.” With regard to patients with ePSM, the authors noted, it remains unclear whether early treatment could be beneficial. According to the investigators, their study clearly indicates that these patients experienced BCR much more frequently than those with fPSM, “and thus it would appear essential to treat them early. Nevertheless, in these cases
Renal & Urology News 3
we believe it essential that the final therapeutic decision integrate the other prognostic factors (Gleason, preoperative PSA, pT) and life expectancy in order to treat these patients as well as possible.” Study limitations included the retrospective design and the absence of data on PSM Gleason score. The investigators also did not take into account tumor volume and surgeon experience. ■
4 Renal & Urology News
MAY/JUNE 2019 www.renalandurologynews.com
ADPKD Imaging Most Commonly Performed With CT INVESTIGATORS WHO studied a national sample of patients with autosomal dominant polycystic kidney disease (ADPKD) found that computed tomography (CT) was the most common imaging modality, followed by ultrasonography, according to a poster presentation at the National
Kidney Foundation’s 2019 Spring Clinical Meetings in Boston. Nearly half of patients received at least 1 abdominal CT scan over 2 years, Myrlene Sanon, MPH, of Otsuka Pharmaceutical Development & Commercialization, Inc., of Princeton, New Jersey, and colleagues reported. Sanon’s team used
the IBM MarketScan Commercial and Medicare Supplemental databases to identify patients with ADPKD. A total of 4637 patients with a mean age of 51.2 years met study enrollment criteria. The mean follow-up time was 21.29 months. During the observation period, 46.5% of patients had CT scans, 25.06% had
ultrasound examinations, and 9.79% underwent magnetic resonance imaging, according to the investigators. Of the 37.8% of patients who had information on chronic kidney disease (CKD) stage, the frequency of CT imaging was higher among those with later stage (31%, 37%, 42%, 51%, and 69% of those with stage 1, 2, 3, 4, and 5 CKD, respectively. Overall, 12.9% of patients had a scan during an emergency department (ED) visit leading to hospitalization and 28% had a scan during an ED visit without subsequent hospital admission. In addition, results showed that without a prior ED visit, 30.7% of patients had a scan during inpatient hospitalization and 51% had scans as outpatients. ■
Death Rate May Be Lower With AVFs HEMODIALYSIS (HD) vascular access type affects patients’ hospital admission and mortality rates, according to study findings presented at the 2019 National Kidney Foundation’s Spring Clinical Meetings in Boston. In a 12-month prospective cohort study, HD access with a central venous catheter (CVC) was significantly associated with a 9-fold increased risk of death and 2-fold increased risk of hospitalization compared with arteriovenous fistula (AVF) access, in adjusted analyses, Janet Diaz-Martinez, a doctoral student at the Florida International University’s Robert Stempel College of Public Health in Miami, and colleagues reported in a poster presentation. Diaz-Martinez’s team studied 77 HD patients with a mean age of 62.3 years. Patients had been on HD for a median of 6.2 years. Vascular access was AVFs in 62 patients and CVCs in 15 patients. Mean body mass index (BMI) was significantly higher in the AVF than CVC group (27.9 vs 24.7 kg/m2). Mean survival times were 11.8 months for patients with AVFs compared with 9.8 months for those with CVCs. The 1-year hospitalization rate was 80% for the CVC patients compared with 40% for the AVF group. ■
Contents
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MAY/JUNE 2019
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Post-Nephrectomy AKI Impedes Renal Recovery Patients with acute kidney injury after partial nephrectomy had a lower rate of recovering 90% of baseline eGFR at 1-year follow-up. Dementia Tied to Prostate Cancer ADT In a study, receipt of any pharmacologic ADT, compared with no ADT, was significantly associated with a 22% increased risk of dementia from any cause. Only Hydrophilic Statins Lower PCa Diagnosis Risk Compared with men who did not use statins, those who took hydrophilic statins had an 18% decreased risk of a prostate cancer diagnosis.
4
Death Rate May Be Lower with AVFs Hemodialysis access with a central venous catheter is significantly associated with a 9-fold increased risk of death compared with arteriovenous fistula access, researchers reported.
8
Dementia Predicts CKD Progression, Death in T2DM In a study, significantly more patients with than without dementia exceeded serum creatinine values of 1.5, 3, and 6 mg/dL.
16
News Coverage Visit our website for daily reports on the latest developments in clinical research.
Extensive PSM Ups Prostate Cancer BCR Risk Over a median 8-year follow-up, men with extensive vs focal positive surgical margins after radical prostatectomy had a 6-fold greater risk of biochemical recurrence.
CALENDAR 2019 Canadian Urological Association Annual Meeting Quebec City June 29–July 1 International Continence Society Annual Meeting Gothenburg, Sweden September 3–6 American Society of Nephrology Kidney Week 2019 Washington, DC November 5–10 Society of Urologic Oncology 20th Annual Meeting Washington, DC December 4–6 2020 Annual Dialysis Conference Kansas City, MO February 8–11 Genitourinary Cancers Symposium San Francisco, CA February 14–16
Nephrology
Job Board Be sure to check our latest listings for professional openings across the United States.
Renal & Urology News 5
VOLUME 18, ISSUE NUMBER 3
Urology 2
MAY/JUNE 2019
22
Upper Arm vs Forearm AVFs Offer Superior Patency According to researchers, forearm AVFs are associated with a 2-fold greater risk of access failure than upper arm AVFs. LN Response to Tx Linked to Survival Patients with lupus nephritis who achieved a complete response to induction therapy at 12 months had significant 82% decreased odds of death compared with those who did not.
Our data demonstrate that while restrictive diets
remain useful in the overweight and diabetic population, those recommendations may not be as useful in men who are otherwise healthy.” See our story on page 14
24
Departments 9
From the Medical Director Could new classes of drugs make dietary potassium restrictions unnecessary?
10
News in Brief Medicare dialysis patient mortality rates have flattened
23
Ethical Issues in Medicine Interacting with patients who make discriminatory or objectionable comments
24
Practice Management The benefit of giving patients prices upfront
6 Renal & Urology News
MAY/JUNE 2019 www.renalandurologynews.com
Post-Nephrectomy AKI Impedes Renal Recovery ACUTE KIDNEY injury (AKI) adversely affects long-term functional recovery following partial nephrectomy (PN) for renal masses, data show. Carlo Andrea Bravi, MD, of IRCCS Ospedale San Raffaele in Milan, Italy, and colleagues studied 1893 patients who underwent PN for cT1 N0 M0 renal masses. Of these, 388 (20%) experienced postoperative AKI, as defined by RIFLE criteria. The median age of these patients was higher than that of patients who did not develop AKI (62 vs 60 years). After 1-year follow-up, these patients had a significantly lower rate of recovering 90% of baseline estimated glomerular filtration rate (eGFR) after PN than those who did not experience AKI (30% vs 61%), Dr Bravi’s team reported in European Urology. The AKI group also had a significantly higher proportion of patients who had chronic kidney disease (CKD) upstaging (51% vs 23%). The eGFR at 1 year was significantly
“Our findings have important implications for clinical practice. First, efforts should be made to avoid AKI during partial nephrectomy,” the authors wrote. “Predictors of AKI have been identified, and thus, patients at risk should receive proper interventions for modifiable determinants of AKI (ie,
ischemia time and preoperative correction of medical conditions).” In addition, Dr Bravi and colleagues noted that the association between the duration of AKI and long-term damage has relevant implications for postoperative follow-up. If replicated, they observed, their data support inclusion
Study reveals an increased risk of chronic kidney disease upstaging. lower in the AKI than no-AKI group (60 vs 71 mL/min/1.73 m2). In addition, compared with baseline, the AKI group experienced a 17% decrease in eGFR, whereas the patients with no AKI had a 1% decrease, a significant difference between the groups. On multivariable analysis, AKI was associated with worse renal function 1 year after PN. The risk of CKD stage upgrading for an average patient who had 1–3 vs 4 or more days of AKI was 46% vs 67%, corresponding to an absolute risk increase of 21%, according to the investigators.
Effect of AKI duration Compared with patients who had no AKI, those with AKI for 1, 2–3, and 4 or more days had a significant 60%, 70%, and 92% decreased likelihood of recovering 90% of baseline eGFR, respectively, and 2.3-, 3.1-, and 6.2-fold increased risk of CKD upstaging. The investigators said they are confident about their results because of the large sample size, high number of events, and multiple end points, and noted that their finding of a negative effect of AKI on long-term renal function is biologically plausible. FS:9.75” 11176065_HP_CAF_Journal_Ad_M4.indd 1
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of AKI duration into classification systems as a way of discriminating transient from persistent AKI. “This distinction seems compelling when AKI is a onetime event such as after surgical operations, thereby improving postoperative stratification according to individual risk of functional deterioration.” ■
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Renal & Urology News 7
CRBSI Clinical Presentation Varies by Pathogen
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CLINICAL PRESENTATIONS of catheter-related bloodstream infections (CRBSIs) in patients on hemodialysis (HD) varies according to the causative pathogen, according to study findings presented at the National Kidney Foundation’s 2019 Spring Clinical Meetings in Boston.
Patients with Staphylococcus aureus and Gram negative CRBSIs, for exam ple, are the most likely to present with fever and/or rigors, Crystal A. Farrington, DO, and Michael Allon, MD, of the University of Alabama at Birmingham, reported in a poster presentation. Staphylococcus epidermidis
CRBSIs tend to present with nonspecific symptoms, they noted. The study, which was a retrospective analysis of CRBSIs in 249 HD patients, found S. aureus and S. epidermidis caused 34% and 38% of CRBSIs, respectively. Gram negative bacteria accounted for 20% of CRBSIs.
Polymicrobial infections accounted for 14% of CRBSIs and were associated with longer duration of catheter use, according to the investigators. Hospitalization occurred more frequently with S. aureus CRBSIs, but the median length of hospital stay was similar for all organisms. ■
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Dementia Predicts CKD Progression, Death in T2DM DEMENTIA IS an early predictor of chronic kidney disease (CKD) progression, vascular events, and all causemortality in patients with type 2 diabetes mellitus, according to researchers who presented study findings at the National Kidney Foundation’s 2019 Spring Clinical Meetings in Boston.
In a large cohort of veterans with type 2 diabetes, 9205 had dementia and 93,062 did not, Aditi Gupta, MD, of the University of Kansas Medical Center in Kansas City, andB:7.25" colleagues reported. At baseline, both groups were comparable after propensity score matching T:7.5" S:7" by sex, prior acute kidney injury, use of S:7"
angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, and follow-up time. Dementia diagnoses preceded vascular events by a mean 2998 days, or roughly 8 years. With respect to CKD progression, significantly more patients with than without dementia exceeded
serum creatinine values of 1.5 mg/dL (38.9% vs 12.6%), 3 mg/dL (8.6% vs 7.2%), and 6 mg/dL (3.2% vs 2.7%). Proteinuria was similar in both groups, the investigators reported. In addition, diabetes patients with dementia were significantly more likely to experience new vascular events, including coronary artery disease (9.2% vs 7.9%), myocardial infarction (2.8% vs 1.7%), and cerebrovascular accidents (10.6% vs 4.8%), according to Dr Gupta’s team. Nearly twice as many patients with dementia died from any cause (with no change in time to death): 24.7% vs 12.6%. Glucose control did not explain any of the associations. ■
Overweight, Mild Obesity Up in LKDs MOST LIVING kidney donors (LKDs) in the United States are either overweight or mildly obese, and their numbers continue to increase, new data presented at the National Kidney Foundation’s 2019 Spring Clinical Meetings in Boston suggest. The number of living B:10.25"
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kidney donors classified as moderately to morbidly obese is declining. Nupur Uppal, MD, and colleagues
at the Zucker School of Medicine at Hofstra/Northwell in Great Neck, New York, identified the trends by analyzing data from 105,913 living kidney donors reported to the Organ Procurement and Transplant Network from 1999 to 2018. Of these patients, 35%, 41%, 19%, and 4% were classified as normal weight (NW), overweight (OW), mildly obese (MO), and moderately to morbidly obese (MMo), respectively. The investigators divided the study period into 2 decades. Of 51,248 living donors during 1999 to 2008, 36%, 40%, 18%, and 5% were classified as NW, OW, MO, and MMo, respectively. Of 54,665 donors during 2009 to 2018, 34%, 43%, 20%, and 3% were classified as NW, OW, MO, and MMo respectively. NW, OW, MO, and MMo were defined as a body mass index (in kg/m2) of
18.5 to <25, 25 to <30, 30 to <35, and 35 or higher, respectively. ■
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Renal & Urology News 9
FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD Medical Director, Urology
Medical Director, Nephrology
Robert G. Uzzo, MD, FACS G. Willing “Wing” Pepper Chair in Cancer Research Professor and Chairman Department of Surgery Fox Chase Cancer Center Temple University School of Medicine Philadelphia
Kamyar Kalantar-Zadeh, MD, MPH, PhD Professor & Chief Division of Nephrology & Hypertension UC Irvine School of Medicine Orange, Calif.
Urologists
Nephrologists
Christopher S. Cooper, MD Director, Pediatric Urology Children’s Hospital of Iowa Iowa City
Anthony J. Bleyer, MD, MS Professor of Internal Medicine/Nephrology Wake Forest University School of Medicine Winston-Salem, N.C.
R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto
David S. Goldfarb, MD Professor, Department of Medicine Clinical Chief New York University Langone Medical Center Chief of Nephrology, NY Harbor VA Medical Center
Stanton Honig, MD Department of Urology Yale University School of Medicine New Haven, CT J. Stephen Jones, MD, FACS Chief Executive Officer Inova Health System Professor and Horvitz/Miller Distinguished Chair in Urologic Oncology CCLCM (ret.) Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology University of California Irvine James M. McKiernan, MD John K. Lattimer Professor of Urology Chair, Department of Urology Director, Urologic Oncology Columbia University College of Physicians and Surgeons, New York City Kenneth Pace, MD, MSc, FRCSC Assistant Professor, Division of Urology St. Michael’s Hospital University of Toronto Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada
Csaba P. Kovesdy, MD Chief of Nephrology Memphis VA Medical Center Fred Hatch Professor of Medicine University of Tennessee Health Science Center, Memphis Edgar V. Lerma, MD, FACP, FASN, FAHA Clinical Associate Professor of Medicine Section of Nephrology Department of Medicine University of Illinois at Chicago College of Medicine, Chicago Allen Nissenson, MD Emeritus Professor of Medicine The David Geffen School of Medicine at UCLA, Chief Medical Officer, DaVita Inc. Rulan Parekh, MD, MS Associate Professor of Pediatrics and Medicine University of Toronto Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center Detroit Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J.
Renal & Urology News Staff Editor Web editor Production editor Group art director, Haymarket Medical Senior production manager Director of production Assistant manager, audience development Director of audience insights National accounts manager Associate director, editorial services
Jody A. Charnow Natasha Persaud Kim Daigneau Jennifer Dvoretz Krassi Varbanov Louise Morrin Boyle Ashley Noelle Paul Silver William Canning Lauren Burke Vice president, content, medical communications Kathleen Walsh Tulley General manager, medical communications Jim Burke, RPh President, medical communications Michael Graziani CEO, Haymarket Media Inc. Lee Maniscalco
Renal & Urology News (ISSN 1550-9478) Volume 18, 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 © 2019.
Could Potassium-Restricted Diets Come to an End?
H
yperkalemia, defined as a serum potassium level above 5.3 mmol/L, develops in many patients with chronic kidney disease (CKD). The abnormality can precipitate serious adverse outcomes, including dysrhythmias and sudden cardiac death, so patients with elevated blood potassium levels may be referred to emergency departments or urgent care facilities for immediate therapy. As a result, nephrologists and dietitians universally instruct CKD patients to avoid foods rich in potassium. These include fresh fruits and vegetables with high fiber content. Consequently, CKD patients may not be getting enough dietary fiber, potentially resulting in constipation and other problems. The Recommended Dietary Allowance for total dietary fiber should reach 30 grams a day from natural foods. Currently, dietary fiber intake among adults in the United States is about 15 grams a day, and the intake is even lower in CKD patients, given the imposed dietary potassium restriction. This presents nephrologists with a conundrum. They universally prescribe ACE inhibitors and angiotensin receptor blockers (ARBs) to CKD patients in an attempt to slow kidney disease progression or mitigate proteinuria. These medications, however, are notorious for causing or aggravating hyperkalemia. So nephrologists not infrequently withhold ACE inhibitors and ARBs from patients who experience hyperkalemic episodes or acute kidney injury (AKI) events. But there may be alternative treatments for which dietary potassium restrictions aimed at preventing hyperkalemia may be unnecessary. Recently, emerging data suggest that additional groups of medications may be effective in slowing CKD progression. These include SGLT2 inhibitors, such as canagliflozin, dapagliflozin, and empagliflozin. Studies such as EMPAREG, CREATE, and CREDENCE have shown promising results regarding the use of SGLT2 inhibitors to manage CKD. Similar data exist for other classes of medications, including the endothelin antagonist atrasentan, as well as the NRF2 modulator bardoxolone and the epigenetic modulator apabetalone. With new classes of agents offering the promise of therapeutic alternatives to the use of ACE inhibitors and ARBs in CKD patients, we may be able to stop or at least relax restrictions on dietary potassium intake. Meanwhile, the use of potassium binding agents for hyperkalemia control may also allow for more consumption of heart-healthy diets with less risk of hyperkalemia. We may be on the cusp of a new era in which we can encourage CKD patients to increase their dietary intake of fresh fruits and vegetables.
Kam Kalantar-Zadeh, MD, MPH, PhD Professor & Chief, Division of Nephrology & Hypertension UC Irvine School of Medicine Orange, California Twitter/Facebook: @KamKalantar
10 Renal & Urology News
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News in Brief
Please visit us at www.renalandurologynews.com for the latest news updates from the fields of urology and nephrology
Short Takes Kidney Stone Incidence Increasing in the US
and colleagues identified all patients
CHICAGO—Kidney stone cases are
menting outpatient dialysis from 2014
increasing in incidence among adults
to 2017. Mean weekly mortality rates
in the United States, investigators
among Medicare dialysis patients
reported at the American Urological
were 34.9, 35.4, 35.2, and 35.7
Association’s annual meeting.
deaths per 10,000 patients in 2014,
An analysis of data from the Medical
with Medicare Part B claims docu-
2015, 2016, and 2017, respectively,
Expenditure Panel Survey showed that
the investigators reported. After
annual incidence of stone occurrences
adjusting for serial correlation and
rose significantly from 0.6% in 2005
seasonality, the authors found no
to 0.9% in 2015, according to Gina
evidence of a secular trend in weekly
Tundo, MD, of Dartmouth-Hitchcock
mortality rates.
Medical Center in Lebanon, New the mean age of stone formers was
NLR May Be Useful for Diagnosing ED
45 years and 92% were white. In
The neutrophil-lymphocyte ratio
2015, stone formers had a mean age
(NLR) may be helpful in predicting
of 51.7 years and 83% were white.
erectile dysfunction (ED), researchers
Hampshire, and colleagues. In 2005,
reported in the Urology Journal.
Medicare Dialysis Patient Mortality Rates Stabilize
tients with ED and 94 healthy controls
Mortality rates for Medicare fee-for-
(mean ages of 61 and 59.5 years,
service dialysis patients appear to
respectively). The mean NLR was
have flattened, researchers con-
significantly higher in the ED patients
cluded in a poster presentation at the
than among controls (2.38 vs 1.038).
National Kidney Foundation’s 2019
An NLR above 1.574 predicted ED
Spring Clinical Meetings in Boston.
with 81.8% sensitivity and 67% speci-
Using Medicare Limited Data Sets,
The finding is from a study of 90 pa-
ficity, according to investigators at
Debabrata Ray, MA, MS, of NxStage
Ordu University in Ordu, Turkey led by
Medical in Lawrence, Massachusetts,
Ali Aslan, MD.
Hypogonadism Common in RC Patients Perioperative hypogonadism is highly prevalent and persistent among men undergoing radical cystectomy (RC) for non-metastatic bladder cancer, according to a new study. Shown here are the proportions of men with low testosterone at time points before and after surgery. 95%
100 80 60
63% 52.9% 37.5%
40 20 0 Pre-RC
Immediately postop
30 days postop
90 days postop
Source: Smelser W, Lee E, Nangia A, Glavin K, and Holzbeierlein J. Perioperative hypogonadism in men undergoing radical cystoprostatectomy for bladder cancer. Presented at the 2019 American Urological Association annual meeting held May 3-6 in Chicago. Abstract MP05-01.
FDA Orders Surgical Mesh for POP Pulled From Market T
he FDA has ordered all manufacturers of surgical mesh for transvaginal repair of anterior compartment prolapse (cystocele) to stop selling their products immediately. According to the agency, the manufacturers Boston Scientific and Coloplast have not provided sufficient evidence that the benefits of these products outweigh their high, class III risks, compared with transvaginal surgical tissue repair without the use of mesh. “In order for these mesh devices to stay on the market, we determined [in 2016] that we needed evidence that they worked better than surgery without the use of mesh to repair POP. That evidence was lacking in these premarket applications, and we couldn’t assure women that these devices were safe and effective long term,” Jeffrey Shuren, MD, director of the FDA’s Center for Devices and Radiological Health, stated in a news release.
Study: Post-TJA Incidence of AKI High in CKD Patients P
atients with chronic kidney disease who undergo total joint arthroplasty (TJA) have a high incidence of acute kidney injury (AKI) following the procedure, new data suggest. Karim M. Soliman, MD, and collaborators at the Medical University of South Carolina in Charleston studied 1212 patients undergoing total joint arthroplasty (TJA), of whom 285 (24%) had preexisting chronic kidney disease (CKD). The CKD group had an overall 30% incidence of AKI, according to a report published in the American Journal of Medical Sciences. None of the patients required dialysis or died during their hospital stay. Among CKD patients, AKI was more common among blacks and in those with diabetes mellitus, heart failure, and receiving diuretics. Of the CKD group with AKI, 55%, 1%, and 44% had AKI stage 1, 2, and 3, respectively.
Defendants Prevail In Most Kidney Stone-Related Suits C
HICAGO—Most kidney stone-related malpractice suits end in a verdict in favor of the physician or a hospital, even after appeal, investigators reported at the American Urological Association’s 2019 annual meeting. Brandon S. Childs, MD, of the Lahey Hospital & Medical Center in Burlington, Massachusetts, and colleagues analyzed 33 medical malpractice appeals court cases involving kidney stones. Patients or their spouses were the plaintiff in 23 cases (69.7%) and patients’ estates were the plaintiffs in 10 (30%). A urologist was the plaintiff in 57% of cases. Associated hospitals were named in 21 cases (64%), according to the investigators. Of the 33 suits, 28 (85%) cited an error of treatment as the primary negligence. Overall, defendants prevailed in 21 suits (63%). Four trials involved payments to a plaintiff, with the average payout of more than $1 million per case (range $193,000 to $3 million). Ten cases (30%) were reversed on appeal. The defendant prevailed initially and on appeal in the majority of cases.
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■ AUA 2019, Chicago
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American Urological Association 2019 annual meeting
Dementia Tied to Prostate Cancer ADT Investigators report a 22% increased risk of dementia from any cause ANDROGEN DEPRIVATION therapy (ADT) for prostate cancer is associated with an increased risk of dementia, according to multiple studies. In a study of 100,414 men with PCa aged 66 years or older—37,911 (38%) of whom received ADT within 6 months of diagnosis—receipt of any pharmacologic ADT, compared with no ADT, was significantly associated with a 22% increased risk of dementia from any cause, 29% increased risk of Alzheimer’s disease, and 15% increased risk of psychiatric services use, Karl Heinrich Tully, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, reported on behalf of his research team. The investigators observed a doseresponse relationship, with ADT duration of 7 months or longer significantly associated with a 30% and 41% increased risk of all-cause dementia and Alzheimer’s disease, respectively, compared with no ADT. They observed no dose-response relationship between ADT and use of psychiatric services. The findings come from a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. The study excluded men with a prior history of stroke, dementia, or
use of psychiatric services reported in Medicare claims. The cohort included men diagnosed with localized or locally advanced PCa from January 1992 to December 2009 and followed up until the administrative end of follow-up at 36 months or death.
A Taiwanese study linked ADT to a 51% higher risk of overall cognitive decline. Separately, in a population-based study of 24,464 men with newly diagnosed PCa, Ming-Chieh Kuo, MD, of Chung-Shan Medical University in Taipei City, Taiwan, and colleagues found a significant 51% increased risk of overall cognitive decline, 38% increased risk of dementia, and 83% increased risk of Parkinson’s disease among men who received ADT compared with those who did not. The increased risk differed by ADT type. Use of oral antiandrogens was significantly associated with 70% and 54% increased risks of overall cognitive dysfunction and overall dementia, but was not associated with Alzheimer’s
dementia. Combined androgen blockade was significantly associated with a 27% increased risk for overall cognitive dysfunction but not overall dementia or Alzheimer’s dementia. Luteinizing hormone-releasing hormone (LHRH) agonists and bilateral orchiectomy were not associated with cognitive dysfunction. In addition, the investigators found that oral antiandrogens were significantly associated with a 51% increased risk of non-Alzheimer’s dementia and 6.6-fold increased risk of Parkinson’s disease, whereas LHRH agonists were not associated with either of these conditions. Also at the meeting, South Korean investigators reported on populationbased study showing that ADT for PCa was associated with cognitive dysfunction. The study, presented by Jae Young Park, MD, of Korea University College of Medicine in Ansan, included 35,410 patients with PCa identified using South Korea’s National Health Insurance Service Database. Of these, 24,567 (69.4%) underwent ADT. During a mean follow-up of 4.1 years, 4741 patients were newly diagnosed with cognitive dysfunction. ADT was associated with a significant 17% increased risk of cognitive dysfunction. ■
Testosterone Levels Lower In Men on Low-Fat Diets BY NATASHA PERSAUD MEN WHO CONSUME a low-fat or Mediterranean-style diet may experience a reduction in their serum testosterone (T) levels. In a nationally representative sample of 3128 men from the National Health and Nutrition Examination Survey (NHANES) database, 14.6% followed a low-fat diet similar to that recommended by the American Heart Association, with 30% or fewer daily calories from fat, 10% or fewer calories from saturated fat, and less than 300 mg cholesterol. Another 24.4% of men adhered to a Mediterranean-style diet, with 40% of calories from fat, and roughly 60% of men ate what they pleased in a non-restrictive diet. Both the low-fat and Mediterranean diets were limited to 1800 calories per day.
Although mean serum T was 435.5 ng/ dL for the cohort overall, a proportion of men were actually hypogonadal, with serum T less than 300 ng/dL, Richard Fantus, MD, of University of Chicago Medicine, and colleagues reported. Men who limited their dietary intake had lower serum T levels than those who did not. Mean serum T was significantly lower among men on a low-fat diet (410 vs 443 ng/dL) or Mediterranean diet (412 vs 443 ng/dL) than men with an unlimited diet. In multivariable analysis, men with non-restrictive diets had higher serum T compared with those on low-fat (parameter estimate −57.2) or Mediterranean diets (parameter estimate −26.2). The findings held true after controlling for comorbidities, diabetes, prostate cancer, age, body mass index, and physical activity levels.
Men a dhering to a low-fat diet were more likely to be hypogonadal than nondieters. “While multiple studies have examined the benefits of low-fat and Mediterranean diets, the effects of these diet regimens on serum testosterone are unknown,” Dr Fantus told Renal & Urology News. Clinicians can help men presenting with testosterone deficiency by initially adjusting their diet and exercise routines, he said. “Our data demonstrate that while restrictive diets remain useful in the overweight and diabetic population, those recommendations may not be as useful in men who are otherwise healthy. Therefore, clinicians should individualize recommendations based on patient characteristics rather than giving the same counseling to all patients.” ■
SREs Tied to Bone Pain in mCRPC BONE PAIN in men with metastatic castration-resistant prostate cancer (mCRPC) is the strongest predictor of skeletal-related events (SREs), researchers concluded. In addition, the number of bone metastases at mCRPC diagnosis is the strongest predictor of death from any cause. The findings are from a retrospective review of data from 837 men — 605 non-black (72%) and 22 black (28%) — initially diagnosed with nonmetastatic CRPC who later developed bone metastases. The median age at mCRPC was 76 years. Of these, 362 (43%) reported bone pain and 44 (5%) had visceral metastases at the time of mCRPC. SREs occurred in 287 men (33%) and 740 (88%) died. The median follow-up was 26 months. Of the 287 men, 236 (82%) who experienced an SRE received bone radiation. Bone pain was significantly associated with a 3-fold increased risk of SREs, Ingrid Lorese Tablazon, of the Durham VA Medical Center in Durham, North Carolina, and collaborators reported in a poster presentation. Other factors significantly associated with increased SRE risk were shorter time from ADT to CRPC, shorter time from CRPC to metastasis, and presence of visceral metastases, according to the investigators. In addition, compared with patients who had 1 bone metastasis, those with 10 or more bone metastases had a significant 2-fold increased mortality risk. Patients with 2 bone metastases and 3 to 9 bone metastases had a significant 1.36and 1.4-fold increased mortality risk, respectively. “Among men with bone mCRPC, bone pain was the strongest predictor for SREs and number of bone metastases was a strong predictor for mortality,” the authors concluded. ■
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Only Hydrophilic Statins Lower PCa Diagnosis Risk USE OF HYDROPHILIC statins, but not hydrophobic statins, is associated with a significantly lower risk of being diagnosed with prostate cancer (PCa), according to investigators. To investigators’ knowledge, the study is the first to demonstrate a clear advantage of hydrophilic over hydrophobic statins in terms of PCa outcomes. Men who had ever used hydrophilic statins, compared with those who never did, had a significant 18% decreased risk of being diagnosed with PCa and 20% decreased risk of undergoing an additional prostate biopsy, Hanan Goldberg, MD, a urooncology clinical fellow at the University of Toronto, and colleagues reported. Use of both types of statins was associated with a significantly decreased risk of dying from PCa, but the protective effect was more pronounced
Researchers report an 18% decreased risk of a prostate cancer diagnosis. with hydrophilic statins. Ever-use of hydrophilic statins was associated with a 32.4% decreased risk of PCa-specific death compared with never-use, whereas ever-use of hydrophobic statins was associated with a 17.2% decreased risk compared with never-use. Additionally, each cumulative 6 months of hydrophilic statin use was associated with a significant 3.3%, 2.7%, and 4.3% decreased risk of having another prostate biopsy, being diagnosed with PCa, and dying from it, respectively. The investigators found no significant association between 6-month cumulative use of hydrophobic statins and the risk of having another prostate biopsy or being diagnosed with PCa. Each 6-month cumulative use of hydrophobic statins, however, was associated with a significant 1.7% decreased risk of PCa-specific death. “Statins are usually prescribed to men without any specific predilection for a specific type of statin,” Dr Goldberg told Renal & Urology News. “In this study, we present data showing clear evidence to choose hydrophilic statins … in men in need of this treatment.” These medications include pravastatin and rosuvastatin.
Previous studies looking at the effect of statins on PCa outcomes have yielded conflicting results, with some studies showing benefit and others no benefit. “We believe the reason for this was that
statins were analyzed as a whole group and not divided into hydrophilic and hydrophobic, as was performed in our study,” Dr Goldberg said. The study included 21,562 men aged
66 years or older from Ontario who had a negative first prostate biopsy from 1994 to 2016. Of these, 5187 (24%) were diagnosed with PCa, 7861 (36.5%) died, and 647 (3%) died from PCa. ■
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TRT safe in men with PCa continued from page 1
“It is highly unlikely that we will ever have a randomized clinical trial of hypogonadal men with prostate cancer who are randomized to testosterone replacement or no testosterone replacement,” Dr Parsons said. Such a trial would pose substantial ethical problems, and the extremely large number of patients needed would be a major challenge, he said.
TRT danger unproven in hypogonadism Although testosterone promotes prostate tumor growth, no solid scientific evidence exists to prove that use of TRT to achieve normal testosterone levels in hypogonadal men with a history of localized PCa worsens outcomes, he said, adding that he is comfortable prescribing TRT to “appropriately selected patients.” At the conference, Dr Parsons and his colleagues presented findings from 2 population-based national cohorts identified using a Veterans Affairs health system database. The cohorts included 28,651 men who underwent RP and 41,544 who underwent RT. Both studies demonstrated that the risks of biochemical recurrence (BCR), death from PCa, death from causes other than cancer, and death from any cause did not differ significantly between patients who received TRT after treatment and those who
CRPC metastasis risk continued from page 1
to delay metastases and reduce health care resource utilization.”
Health care resource use Dr Freedland and his colleagues placed patients into PSADT groups based on 2-month intervals: ≤2, >2 to ≤4, >4 to ≤6, >6 to ≤8, >8 to ≤10, >10 to ≤12, and >12 months. Patients with a shorter PSADT had higher all-cause and PCa-related health care resource use and costs. Compared with the reference group, patients with a PSADT of 8 months or less had significantly more PCa-related inpatient visits, longer hospital lengths of stay, greater numbers of outpatient and pharmacy visits, and higher all-cause and PCarelated costs. Outpatient visits The number of PCa-related outpatient visits decreased from 1.11 visits per patient per month (PPPM) in the
did not, after adjusting for potential confounders. In the RP cohort, 1.6% of patients received TRT following surgery. The median time from surgery to TRT was 3 years. Patients had a median followup of 7.4 years. The investigators defined BCR as a post-RP PSA level of 0.2 ng/mL or higher. In the RT cohort, the median time from RT to TRT was 3.5 years. For patients who received androgen deprivation therapy (ADT), the median duration of treatment was similar between the TRT and no-TRT groups (185 vs 186 days, respectively). The investigators defined BCR as a post-RT PSA level of 0.2 ng/mL or higher. Dr Parsons and his collaborators stated that, to their knowledge, the RP and RT population-based cohorts combined made possible the largest comparative analyses to date of TRT following definitive treatment in an equal access health system.
High-risk prostate cancer In another study, Helen Levey Bernie, MD, and colleagues at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York found that TRT was not associated with worse outcomes in men who underwent RP for high-risk PCa, defined as a Gleason score of 6 or 7 accompanied by positive surgical margins, lymph node involvement, seminal vesicle involvement, or as Gleason score 8 or higher disease ≤2 month group to 0.46 and 0.44 visits PPPM in the >10 to ≤12 and >12 month PSADT groups, respectively, according to the investigators. The number of pharmacy visits in these groups decreased from 0.45 PPPM to 0.26 and 0.20 PPPM in these groups, respectively.
regardless of pathologic findings. The study included 1407 patients, of whom 614 (44%) had low testosterone (low T, defined as an early morning total testosterone [TT] level <300 ng/dL). The low T group included 24 patients who received TRT and 590 who did not. A total of 906 men (64%) experienced BCR: 57% of men with normal TT, 75% of those not on TRT, and 46% of those on TRT. In adjusted analyses, low T and TRT were not associated with BCR, Dr Bernie’s group reported. The investigators defined
Risk of biochemical relapse not elevated in men with low-risk prostate cancer. BCR as a postoperative PSA level of 0.1 ng/mL or higher. In a fourth study, John P. Mulhall, MD, of MSKCC, and collaborators examined the effect of TRT prescribed to men following RP for organ-confined Gleason 6 or 7 PCa. The study included 360 patients who had low T (less than 300 ng/dL) and post-RP undetectable PSA levels prior to the start of TRT. The men had a mean age of 59 years and a mean preoperative PSA level of 4 ng/dL. The median time post-RP before TRT was started was 9 months. The median post-RP
Left-sided RCC tumors continued from page 1
Higher all-cause and PCa-related total costs increased with decreasing PSADT.
datasets, left-sided tumors were significantly associated with a 19% and 16% increased risk of cancer-specific mortality, respectively, compared with right-sided tumors, after adjusting for multiple confounders, including, but not limited to, histology, TNM status, cancer grade, and age at diagnosis, the investigators reported in a poster presentation. Patients with left-sided RCC had higher T status and more often presented with node positive or metastatic disease, according to the investigators.
Average all-cause and PCa-related total costs increased with decreasing PSADT, with average all-cause total costs increasing from $1778 PPPM for the reference group to $6161 for those in the ≤2 month group and average PCa-related total costs increasing from $699 to $4248 PPPM. Pfizer Inc., and Astellas Pharma Inc. sponsored the study. ■
Lymphadenectomy a factor In the SEER dataset, site-specific CSS differences were driven by whether lymphadenectomy (LAD) had been performed. Among patients who underwent LAD, investigators found no significant difference in CSS with regard to laterality, but in the absence of LAD, patients with left-side tumors had a significant 18% decreased CSS.
duration of TRT was 66 months. One patient experienced BCR 2.5 years post-RP. Dr Mulhall’s team concluded that TRT in this carefully selected group of patients appears to be safe 3 years post-TRT administration.
Men on active surveillance Dr Mulhall also presented findings from a study of 86 testosterone-deficient men who received TRT while on AS for PCa. Data suggested that TRT did not result in significant PSA changes. The mean duration on AS prior to initiation of TRT was 13 months. Mean duration on TRT at last follow-up was 19 months. The mean PSA level change per patient was 0.6 ng/mL, with 26% of men experiencing a PSA level increase of 1 ng/mL or higher. Sixteen percent of men opted for definitive therapy for their cancer, a rate of progression to definitive therapy similar to previously reported data, according to the investigators. At the 34th Annual European Association of Urology Congress in Barcelona, Spain, in March, a team from the University of California, Irvine, led by Thomas Ahlering, MD, reported on a study demonstrating that TRT in men with low-risk PCa was associated with a significant decreased risk of BCR following robot-assisted RP. The study found that 9.9% of men who received TRT experienced BCR compared with 23.5% of men who did not. ■ “Although the overall survival difference was only marginal, left-sided RCC in surgically treated patients tends to present at more advanced stage and has in general worse CSS, especially in patients without LAD,” the authors concluded. “Site-specific lymphogenic spread patterns might contribute to these findings.”
Residual confounding possible Dr Uhlig cautioned that “some of the effect we report can be due to residual confounding because you can never adjust for all the potential confounders.” The next research step would be pathologic examination of lymph nodes taken out at the time of surgery or to use computed tomography to try to discriminate positive from negative lymph nodes in patients with left-sided and right-sided tumors, she said. Confirmation of site-specific differences in outcomes in future studies could renew debate about LAD in left-sided malignant disease surgery, Dr Uhlig said. ■
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n ASK THE EXPERTS
Genetic Testing for Hereditary Prostate Cancer: An Update Two specialists discuss key considerations when selecting men for testing BY JODY A. CHARNOW
R
esearchers continue to make strides in understanding the hereditary basis for prostate cancer. For a state-of-the-art update on the field, Renal & Urology News spoke with 2 specialists in this area: Veda N. Giri, MD, Director, Cancer Risk Assessment and Clinical Cancer Genetics, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia; and Manish Kohli, MD, Vice Chair, Department of Genitourinary Oncology & Senior Member, Moffitt Distinguished Scholar, Director, DeBartolo Family Personalized Medicine Institute Moffitt Cancer Center, Tampa, Florida.
Where are we in the science of genetic testing for hereditary prostate cancer?
Dr Giri: Multiple genes have been identified that provide variable estimates of risk for inherited prostate cancer. The genes with the strongest level of risk for prostate cancer include BRCA2, BRCA1, and HOXB13. Other genes with more modest risk are the DNA mismatch repair genes. There are also genes that can give insights into risk for aggressive prostate cancer, such as BRCA2. The highest rates of inherited mutations are in men with metastatic disease, where up to 12% of men may carry inherited mutations predominantly in DNA repair genes. Genetic testing is now available through multiple commercial labs that offer the ability to test several genes at a time for men interested in genetic testing. For hereditary cancer testing, such as for hereditary prostate cancer, it is really important to choose a lab that has
long-standing experience with clinical genetic testing, reliable variant reclassification program, robust molecular approaches to classify genetic variants, and contributes their data to public databases such as ClinVar. Currently, there are approximately 5 clinical genetic labs that may be used for genetic testing for men with prostate cancer that have long-standing experience with clinical germline genetic testing. It is important to speak to a genetics professional who has experience with ordering genetic tests and working with genetic testing labs to ensure high quality genetic testing. Additionally, several genetic mutations in genes involved in DNA repair have been identified in men with metastatic prostate cancer, such as BRCA2, BRCA1, ATM, PALB2, CHEK2, DNA mismatch repair genes, and RAD51C/D. While some of these genes have variable risk for prostate cancer predisposition, it may be reasonable to test for these genes in men with metastatic disease
to inform targeted therapy or clinical trial options. Dr Kohli: Hereditary prostate cancer is a small subset of all prostate cancers. There are specific gene mutations we know indicate an increased risk. The number of genes that we are most sure about, such as BRCA1 and BRCA2, are those in which we have a high degree of confidence in terms of hereditary prostate cancer. But there are many unknowns. There are many commercially available tests as well as in-house tests developed at institutions that look at a bunch of culprit DNA repair genes and homologous repair deficiency genes, such as BRCA1 and BRAC2. Less frequent genes such as TP53, PTEN, CDH1, ATM, CHEK2 or PALB2 can be implicated. Identification of one of these mutated genes can be done using age-old sequencing techniques that are very reliable. Testing for multiple mutations can also be done with multi-gene panels which simultaneously test for
suspected genes beyond these known genes. The sensitivity and specificity of these tests are very high, but in a very small fraction, despite the central mutations in these genes, if there is an unknown mutation in the same genes that are not tested for in the panel, we can sometimes miss them. That is why multi-gene panel testing can sometimes be negative even though a patient’s clinical profile is highly suggestive of hereditary prostate cancer. In these cases, we will go with singlegene Sanger sequencing, which is more specific for mutations than a multi-gene panel. Together, between gene panel testing and Sanger sequencing, we can nail down vast numbers of these hereditary mutations, in the context of the patient’s clinical presentation.
What are the key questions that clinicians need to ask men when selecting them for testing?
Dr Giri: What is your family history of cancer, on your mother’s side and father’s side? What is your Gleason score (if the man has had a diagnosis of prostate cancer), and do you know the Gleason score for any male relatives with prostate cancer? What stage is your prostate cancer? What was your age at the diagnosis of cancer? If applicable, what was the age of family members when they were diagnosed with cancer? Do you have Ashkenazi Jewish ancestry?
Veda N. Giri, MD
Manish Kohli, MD
Dr Kohli: Questions should focus on family history of cancer. In particular, for men diagnosed with prostate cancer younger than 60 years of age, clinicians continued on page 20
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Genetic testing for PCa continued from page 19
should ask about a family history of prostate cancer, breast cancer, ovarian cancer, and pancreatic cancer, especially in first-degree relatives who might have been younger than 50 years of age. These raise red flags for us. At the very least, ask if the patient’s father, male siblings, or paternal grandfather had a history of prostate cancer or if the patient’s female siblings or mother or maternal grandmother had a history of breast, ovarian, or pancreatic cancers at an early age.
Should genetic testing be offered to all men who have a family history of prostate cancer or any cancer?
Dr Giri: That depends on the details of the family history. Current NCCN [National Comprehensive Cancer Network] guidelines state to offer genetic testing to men who have a brother, father, or multiple male relatives diagnosed with prostate cancer when they were younger than 60 years, or a family history suggestive of hereditary breast and ovarian cancer or Lynch syndrome. Our research team has reported that breast cancer family history is a strong predictor of prostate cancer risk and increased risk for carrying an inherited mutation in DNA repair genes. Current NCCN guidelines state that the following men consider genetic testing: Men with metastatic prostate cancer regardless of family history; men with high-risk to regional disease regardless of family history; men with very low-to-unfavorable intermediaterisk disease with a brother, father, or multiple male relatives diagnosed with prostate cancer before age 60; a family history of 1 or more blood relatives with ovarian, pancreatic, metastatic prostate cancer, or breast cancer diagnosed before age 50; a family history of 2 or more blood relatives with breast, ovarian, pancreatic, colorectal, endometrial, gastric, small bowel, UTUC [upper tract urothelial carcinoma], or bile duct cancer; men with Ashkenazi Jewish ancestry and Gleason score of 7 or higher; and BRCA mutations in
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tumor profiling. These guidelines are updated periodically and, therefore, they may change over time. Dr Kohli: Patients should be offered genetic testing if they present with metastatic prostate cancer before the age of 60 years; patients presenting with localized stage disease if there is a strong family history suggestive of the hereditary breast and ovarian cancer syndrome (HBOC), such as a history of cancer in first-degree relatives with prostate, breast, ovarian, and pancreatic cancers; and patients who have no history of prostate cancer but are concerned about developing cancer because of a strong family history (brother, father).
During patient counseling, what aspects of testing must patients understand clearly?
Dr Giri: There are many aspects to genetic testing to understand before proceeding with genetic testing, including cancer inheritance, benefits/risks/limitations of genetic testing, types of test results to expect, implications of test results for men and their families, additional cancer risks that may be identified, genetic discrimination laws, and reproductive implications. After testing, men need to understand their results in order to follow recommendations appropriately and communicate information to their providers and family members. Dr Kohli: If a relatively young patient newly diagnosed with prostate cancer says he has a brother with a history of prostate cancer, we should ask whether the brother had undergone gene panel testing for hereditary prostate cancer perhaps as a result of a history of multiple cancers in the family. If not, the patient becomes the proband: the first patient in the family being referred for genetic testing. If the answer is yes, and testing had been done in the family previously, we ask whether the results were positive or negative. If positive, then we know the patient has been sensitized to understand what genetic testing and counseling will entail. If negative, or if the patient does not know, we have to start from scratch with counseling the patient about how genetic testing is per-
formed, what these tests look for, and the ramifications of genetic testing. If the patient tests positive for mutations that increase the risk of prostate cancer, we explain to the patient that the test results may have implications for siblings and children, including adverse psychological and occupational effects. Psychologically, this could entail loss of a “sense of good health and a feeling of helplessness,” as the patient realizes that despite enjoying good health and maintaining healthy habits, he could still be destined to be at high-risk for developing cancers. Counseling can help relay context in the interpretation of test results so as to ease anxiety about the implications of a positive test result. Even though there is a federal law (the Genetic Information Nondiscrimination Act) that protects individuals from employment discrimination on the basis of genetic information, electronic medical records of the patient could be used illegally to deny employment perks. Counseling provides education to the patient on his or her rights in this regard.
Could genetic test results be helpful in therapeutic decision making?
Dr Giri: Genetic testing is now increasingly informing therapeutic options for men with metastatic castration-resistant prostate cancer. PARP inhibitors such as olaparib and rucaparib have been given “breakthrough therapy” designation by the FDA to be used in men with metastatic castration-resistant prostate cancer who have specific germline mutations and/or after progression on specific lines of therapy. Clinical trials based on germline genetic testing are also increasing. In the early-stage setting, genetic testing may increasingly inform discussions of active surveillance. Dr Kohli: Yes. Prostate cancer, as it evolves, goes through successive stages of progression to advanced metastatic castration-resistant states. There are drugs approved by the FDA for advanced prostate cancer that target deleterious mutations in genes such as BRCA1 and BRCA2. Patients with these mutations may respond to PARP inhibitors, such as olaparib, as well as platinum compounds.
What are the drawbacks of genetic testing?
Dr Giri: Genetic testing may not always provide concrete answers as to why a man or his relatives developed cancer. Even if the result does not show a mutation, there may be elevated risk for cancer based on family history. And population-level risk for cancer remains. The interpretation of test results can also be unclear. For example, about a third of men undergoing genetic testing may have a “variant of uncertain significance (VUS)” identified. A VUS refers to genetic changes that do not meet criteria as “mutation.” While the majority of VUS will be reclassified to “benign,” some may be reclassified to “mutation” in the future pending more data. There are no management changes based upon a VUS, but men may feel anxious that an uncertain genetic change was identified. The choice of lab is really important to consider. Some labs do not fully sequence genes of interest, or may call variants differently and so this may lead to uncertainty regarding the thoroughness of testing. Overall, these and other issues are important to having a working knowledge of and/or to discuss with a cancer genetics specialist such as a genetic counselor. An additional consideration is the GINA Law that provides protections from genetic discrimination for health insurance and employment in most scenarios. However, there are gaps in coverage for health insurance and employment that need to be understood. Furthermore, GINA does not cover life insurance, long-term care, or disability insurance plans. Therefore, patients need to have clear understanding of these issues prior to proceeding with genetic testing Dr Kohli: Most prostate cancers are sporadic. Genetic testing for hereditary prostate cancer is not appropriate as a population-based strategy because it would greatly increase the amount testing to identify a very small percentage of men with prostate cancer-causing mutations. In addition, if genetic testing is done without consultation with a genetic counselor, but performed using commercially available testing kits available online, patients would not understand how to interpret test results and their implications for the patients and perhaps their families. ■
Renal & Urology News will be covering the Canadian Urological Association’s 74th Annual Meeting in Quebec City, June 29 – July 1. Go to www.renalandurologynews.com for daily reports on noteworthy studies.
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Fosfomycin Shows Effectiveness for Chronic Bacterial Prostatitis The drug could be an alternative to fluoroquinolones era of MDR prevalence, represents an attractive, safe, and effective alternative to fluoroquinolones for the treatment of CBP,” the authors concluded. CBP is difficult to treat, the authors explained, with few oral antibiotics capable of achieving therapeutic concentrations in the prostate. Fluoroquin olones are considered the cornerstone
© MOLECULE MEDICAL ARTS / SCIENCE SOURCE
ORAL FOSFOMYCIN may be a good alternative to fluoroquinolones for treating chronic bacterial prostatitis (CBP), according to the findings of a small study. In a prospective observational study of 44 men, an oral regimen of 3 g of fosfomycin once daily for 1 week followed by 3 g of the drug once every 2 days for 6 to 12 weeks resulted in a cure rate of
In a prospective study of 44 men with chronic bacterial prostatitis, a regimen of oral fosmomycin resulted in an 82% cure rate at the end of treatment.
82% at the end of treatment (EOT) and 80% and 73% at 3 and 6 months, respectively, Ilias Karaiskos, MD, of Hygeia General Hospital in Athens, and colleagues reported in the Journal of Antimicrobial Chemotherapy. More than half of patients (59%) had multidrug-resistant (MDR) bacterial strains, and 33 strains were resistant to fluoroquinolones. All strains were susceptible to fosfomycin. Microbiologic eradication was achieved in 86% and 77% of patients at EOT and 6 months, respectively. Twelve patients experienced treatment failure, defined as persistence or relapse of clinical symptoms during therapy or follow-up and signs of inflammation on transrectal ultrasound (TRUS) or magnetic resonance imaging (MRI). Diarrhea was the most frequent adverse event, occurring in 18% of patients “Oral fosfomycin, particularly in the
of treatment because of their in vitro activity and advantageous pharmacokinetics in prostatic tissue, they stated. Urinary and prostatic infections due to multidrug-resistant (MDR) Gramnegative Enterobacteriaceae, however, are increasing sharply worldwide, even in community settings, Dr Karaiskos’ team noted. The prevalence of fluoroquinolone-resistant community uropathogens in many countries is greater than 10%, they added. “Fosfomycin is in an antimicrobial class of its own and is structurally unrelated to any other agent currently approved for clinical use,” Dr Karaiskos’ team pointed out. The most common pathogen detected in the study population was Escherichia coli (66%), followed by Klebsiella spp. (14%), and Enterococcus faecalis (14%). The causative pathogens were identified using the gold-standard Meares-Stamey
examination in 19 cases and urine cultures in 25 cases. During follow-up, all patients were re-evaluated with urine cultures at 6 and 12 weeks (except for 5 patients who underwent a second Meares-Stamey procedure) and at 3 and 6 months. TRUS was performed in 31 cases, prostate MRI in 26 cases, and both in 13 at the start of treatment. With regard to study limitations, the authors acknowledged that the study was conducted at a single center and included a small sample size without a control group receiving the best available treatment. J. Curtis Nickel, MD, professor of urology at Queen’s University in Kingston, Ontario, who has conducted extensive research on chronic prostatitis, told Renal & Urology News in an email that he has been using fosfomycin for difficult urinary tract infections and bacterial prostatitis since 1995. “The fact that this older antibiotic has retained its favorable antibiotic sensitivities, while other classes of antimicrobials have either lost theirs (MDR pathogens) or are worrisome because of known side effects (the fluoroquinolones) has made fosfomycin even more appealing for urinary tract infections in general and bacterial prostatitis specifically.” Dr Nickel said he has been interested in using fosfomycin since he and his colleagues first studied the drug in the early 1990s, particularly when the researchers “showed its superior ability to penetrate bacterial biofilms, a problem that can result in treatment resistant chronic bacterial prostatitis.” The findings of that research were published in 1995 in Antimicrobial Agents and Chemotherapy. He pointed out, however, that fosfomycin is difficult to administer. It is a granular powder that needs to be dissolved in water and taken immediately on an empty stomach and/or at bedtime with an empty bladder. Some patients find this more difficult than taking an antibiotic pill, and others say it causes indigestion on an empty stomach and diarrhea. The drug also is expensive. “But these issues are offset by its excellent penetration into prostatic tissue, and as these authors have pointed out in their study, beneficial clinical results,” Dr Nickel said. ■
LN Response to Tx Linked to Survival SURVIVAL AMONG patients with lupus nephritis (LN) is associated with achievement of complete response (CR) to induction therapy at 12 months, new data suggest. Compared with patients not achieving CR, those who had CR at 12 months had significant 82% decreased odds of death, Kunihiro Ichinose, MD, of Nagasaki University Graduate School of Biomedical Sciences in Nagasaki, Japan, and colleagues reported in Lupus. Male gender and a higher index of activity (0–24) predicted failure to achieve CR at 6 and 12 months. “Our results suggest that the attainment of CR at 12 months could predict the survival rate and that male patients and the histological score should be carefully followed for the prediction of renal outcomes and the prevention of renal flares,” the authors concluded.
Decreased death risk observed in patients who had a complete response at 12 months. Dr Ichinose’s group studied 172 patients with LN for whom data on therapeutic response at 6 and 12 months after induction therapy were available. Of the 172 patients, 79 (5.9%) achieved CR at 6 months and 10 (58.7%) achieved CR at 12 months. The investigators defined CR as a urine protein/creatinine ratio less than 50 mg/mmol (approximately equivalent to proteinuria < 0.5 g per 24 hours) and a normal or near-normal estimated glomerular filtration rate (eGFR), defined as a rate within 10% of a normal eGFR if previously abnormal. The survival rates were 99.3%, 94.6%, 92%, and 85.4% at 5, 10, 15, and 20 years, respectively, rates similar those found in previous studies, according to the investigators. During the study’s observation period, 9 patients (5.2%) died and 6 (3.5%) progressed to end-stage renal disease. At the onset of LN, the patients who died, compared with those who did not, were significantly older (median 42 vs 34 years) and had significantly higher serum creatinine levels (median 0.9 vs 0.7 mg/dL), and significantly lower eGFR (56.4 vs 78.7 mL/min/1.73 m2). ■
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Renal & Urology News 23
Ethical Issues in Medicine I
magine a patient who, during a consultation, says to a clinician, “You sure are an attractive doctor. I wish I could date you,” or, “I don’t want a foreigner taking care of me. Can I see a real doctor?” or, “I was hoping for a white doctor.” How should physicians respond when confronted with biased and offensive remarks from patients? An instinctive response could range from surprise, anger, frustration, disgust, to pity.1 The moral outrage at being discriminated against often is justifiable, even when it threatens physicians’ role as health care provider. But strong negative emotional responses may interfere with our ability to respond effectively and disrupt our professional commitment to patients. These difficult clinical encounters become ethical concerns when physicians find themselves caught between competing professional values. There is the expectation, and in some cases, a legal right for health care professionals to practice in a workplace free of discrimination. Simultaneously, there is the professional obligation to ensure patient primacy, to hold unconditional regard for all patients no matter how objectionable their behavior, and to put their interests above those of the physician. Kicking patients out of a medical or surgical practice is almost an instinctive
to doing so, however, clinicians have a number of considerations and conditions they should address. First, by virtue of their illness, not all patients are necessarily fully responsible for their behavior. Patients with advanced neurological illness or dementia may be sexually disinhibited as part of their disease process. Patients with posttraumatic stress disorder (PTSD) may have biased perspectives or behave inappropriately as a result of their illness. For example, veterans with combatrelated PTSD from their military service in the Middle East may have trouble accepting care from a Muslim provider.2 Reasonable accommodation may be appropriate to address a patient’s legitimate needs and preferences and, in some cases, may be necessary for good care.3 Women frequently request to have a female gynecologic provider, which is often willingly accommodated and without controversy. Physicians should accommodate similar requests that are based on legitimate values and preferences.4 For example, a patient’s request to be examined by a member of the same gender in order to adhere to their sincerely held religious practice should be accommodated. African-American patients cared for by a physician of the same race have higher satisfaction,
Physicians should set clear limits on problematic behavior, an important strategy for managing uncomfortable encounters. response when confronted with unjust discrimination. However, “firing” patients or removing them from a clinical practice can undermine their access to care, especially in underserved areas. Doing so also minimizes the profession’s ability to help the patient. Rather than preventing patients from coming to their practice, physicians should set clear limits on problematic behavior, an important strategy for managing these uncomfortable encounters. Prior
improved trust, and better health outcomes. Accommodating such a patient’s request for a race-concordant physician would be reasonable and promote quality care. Accommodation, however, does not mean tolerating disrespectful comments or behaviors. Physicians need not condone comments or preferences that are clearly rooted in sexist or racist ideology. As in most challenging situations with patients, responding with anger is not likely to be effective and may escalate a
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Clinicians should keep their anger in check when patients make discriminatory or objectionable comments BY DAVID J. ALFANDRE, MD
Accommodating patients does not mean tolerating disrespectful comments or behaviors.
conflict. Patients can be calmly informed that such comments are not welcome and that the shared goal in a health care relationship is to promote the patient’s care. Clinically stable patients who willingly and continually ignore or disregard a physician’s appropriate behavioral limits should be referred for care to another colleague of equal competency. Let’s return to the hypothetical patient described earlier to play out the scenario. What if a patient were to say to a physician, “I think you’re attractive. I wish I could see what you look like without that white coat,” or, “I didn’t realize my doctor was going to be a foreigner. Did you train in a real hospital?” The physician can pause to collect his/her thoughts and allow themselves to remain calm. The physician can then respond, “Your comments make me uncomfortable. I will not permit you to talk that way with me. I trust that you know that you will receive excellent care from me. I’m here to help and I wish to do that. Now, tell me what you hope to get out of today’s visit.” If this phrasing doesn’t work for you, or doesn’t seem like something you would say, consider modifying it to fit your personality. Physicians should decide what works and practice it so they are prepared to say it confidently and calmly if the need arises.
Physicians have a right to protect themselves from unjust discrimination. Doing so, however, should not interfere with their professional commitments to promote patients’ access to care, even when their behavior is objectionable. These competing values should be managed, balanced, and addressed so physicians continue to meet our professional obligations to our patients and ourselves. ■ 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. Jain SH. The racist patient. Ann Intern Med. 2013;158:632. 2. Kheirbek, RE. At the VA, healing the doctor-patient relationship. Health Aff. 2017;36:1848-1851. 3. Anstey K, Wright L. Responding to discriminatory requests for a different healthcare provider. Nurs Ethics. 2014;21:86-96. 4. Paul-Emile K, Smith AK, Lo B, Fernández A. Dealing with racist patients. N Engl J Med. 2016;374:708-711.
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Practice Management Informing patients upfront about the prices of health care services can boost practice income BY TAMMY WORTH with a charity process that is costly to providers and burdensome to patients.”
From request to requirement It was legislation that prompted Scott Glennie, CEO of Spokane Digestive Disease Center in Spokane, Washington, to push transparency at the practice. In 2014, state legislators required payers to submit claims for the website WAhealthcarecompare.com, where patients can look up a procedure and get the average price and estimated price at individual practices. Glennie’s patient portal links to that website, and he hopes to soon post cash prices. His group, he said, uses price transparency as a marketing tool. Their fees are much lower than those of area hospitals, so it could be a competitive advantage to highlight. According to the state’s site, for instance, a colonoscopy in Spokane ranges from $992 to $2540. At Glennie’s practice, it is $1082. Providing patients with accurate, upfront estimates and having a payment plan will help patients focus on their health and not money, Shorrosh said. “Nobody likes to be surprised a month later with a bill for $1000 when they thought it would be $100,” he said. “They want to know so they can prepare and have it settled in advance,
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E
xperian Health conducted a study in 2018 to gain insight into what patients find to be good and bad in the health care system. Not surprisingly, cost is a major concern. A survey released in March from Consumers for Quality Care found that more than half of those surveyed said their insurance plans cover fewer treatments and prescriptions than they once did. Eighty-three percent of respondents said they want more cost transparency from providers. “At some point in the not-too-distant future, price transparency is going to be table stakes if providers want to attract new patients,” said Jason Considine, general manager and senior vice president of patient engagement and collections for Experian Health. Although the Centers for Medicare and Medicaid Services (CMS) requires hospitals to post fees, transparency in the industry remains elusive. Though it is a difficult process, it can be done well, and this can increase practice income and engender patient loyalty. Perhaps the most important aspect of offering prices in advance is the ability to create a dialogue between patients and practices about the cost of care. “They can set the cost expectation upfront and have a good, healthy,
Price transparency for medical services may engender patient loyalty and build practices.
If a group lands on a predictable schedule that works for doctors most of the time, then legitimate reasons for change should be defined.
providing patients with a good price estimate on procedures remains a difficult task. Providers can do it low-tech, but it is so time consuming that this option is really only manageable for small groups, Shorrosh said. For instance, if a group negotiates with 5 different payers, business managers can look up the contracted rates for their most common procedures. They can then create a page for each payer with the agreed-upon price of each of those top procedures. When a patient requests a price, they can call the payer or check the payer’s website to determine co-pay and remaining deductible, but often the largest component is co-insurance, which can be difficult to calculate.
instead of going into a procedure wondering if they can afford it.” Glennie said he knows some patients have moved from other doctors to his practice mainly because of their price transparency. “If you are a physician practice and you aren’t differentiating who you are in meaningful ways, like price, you probably won’t be in business in 10 years,” he said. Even with the availability of websites that make price comparisons possible,
Upfront collections Upfront collections can complicate matters, however. If practices over-collect, the practices have to return money to the patients, Considine said. “If they undercollect, they have to chase down the rest, and there is still as much work involved.” Shorrosh observed, “In health care, the only time a dollar is worth a dollar is prior to service. With every day that passes after service is provided, the likelihood of getting paid goes down and the cost to collect it goes up.”
meaningful conversation about what to pay and write off,” said Paul Shorrosh, founder and CEO of AccuReg, a technology company offering patient-centered, front-end revenue cycle solutions for hospitals. “If a provider can estimate a patient’s liability and their propensity to pay it, they can offer appropriate financial assistance options to patients that need help, including presumptive charity, which saves them from paying staff or agencies to figure that out later
Companies such as Experian and AccuReg offer tools to automate the process of providing accurate estimates. These products essentially load providers’ fees and insurance contract terms into a database. When office staff input patient insurance and procedure information, the system electronically retrieves copay and deductible information from the payer, calculates coinsurance, and generates an estimate in real time. The tools vary in their sophistication, Shorrosh said. AccuReg, for example, fully automates the process and uses predictive analytics and machine learning rules to intelligently determine the right payer, procedure, benefits, co-pay, deductible and co-insurance. Both AccuReg and Experian provide printed scripts for office staff to use when discussing the estimated balance due as well as financial assistance options. The goal is to secure payment in full prior to service when possible, which increases the likelihood of payment, and reduces bad debt and the cost to collect. At the same time, it makes care affordable for those who need it. ■ Tammy Worth is a freelance medical journalist based in Blue Springs, MO.