depression undertreated in patients receiving chronic

New research indicates that many patients who are receiving chron-ic hemodialysis have depressive

symptoms but do not wish to receive ag-gressive treatment to alleviate them. The study, which is published in the Clinical

Journal of the American Society of Neph-rology, also found that when patients are willing to accept treatment for depression, renal providers commonly do not pre-

scribe it.Depression affects nearly one-

quarter of people receiving chronic hemodialysis, compared with an average population lifetime risk of between 8.3% and 9%. These high rates likely reflect the various physiological and psychosocial con-

sequences of living with impaired kidney function—from the adverse ef-

fects of frequent treatment to the poten-tial loss of social support and vocational capacity.

Depression in dialysis patients affects not only their mental health and quality of life but has also been linked to missed and abbreviated dialysis treatments, more frequent emergency department visits and hospitalizations, and an increased risk of premature death. To address the negative effects that depression can have on dialysis patients’ health and survival,

the Centers for Medicare & Medicaid Services Quality Improvement Program (QIP) for end stage renal disease recently mandated that all dialysis facilities report individual patient screening and treat-ment plans for depression for payment year 2018. Little information, however, is available on the effectiveness of anti-depressant therapy in patients on chronic hemodialysis or the acceptance of treat-ment by patients and clinicians.

To investigate, a team led by Steven Weisbord, MD, MSc, and Julio Pena-Po-lanco, MD, of the VA Pittsburgh Health-care System and University of Pittsburgh School of Medicine, asked 101 patients on hemodialysis who were participating in the Symptom Management Involv-ing ESRD (SMILE) trial to complete the Patient Health Questionnaire 9 (PHQ-9) each month. The prospective, multi-center, cluster-randomized SMILE trial compared 2 strategies for the manage-ment of 3 common symptoms in cog-nitively intact adults receiving chronic,

Many studies have noted a U-shaped association between blood pressure and cardiovas-

cular risk in patients with chronic kidney disease (CKD). A report in Hypertension suggests a possible explanation for this par-adoxical relationship: a confounding effect by subclinical cardiac disease.

“Confounding by disease is the chief explanation for the apparent weakening and reversal of the association between systolic BP and cardiovascular risk in mod-erate-to-advanced CKD,” said William G. Herrington, MD, MRCP(UK) of the Clinical Trial Service Unit & Epidemio-logical Studies Unit (CTSU), University of

Oxford. “Such confounding masks a causal association between blood pressure and risk in patients with CKD with established cardiovascular disease.”

Together with other recent evidence, these results add weight to the hypothesis that more-intensive BP reductions might reduce cardiovascular risk in patients with CKD, including those on dialysis.

U-shaped association between BP and mortality in CKD

The researchers analyzed data from The Study of Heart and Renal Protection

Depression Undertreated in Patients Receiving Chronic Dialysis

Why Is Low Blood Pressure Related to Increased Cardiovascular Risk in CKD?

Continued on page 2

Continued on page 2

Inside

Report: Kidney Disease Research UnderfundedUS government spends more on the Medicare ESRD program (nearly $32 billion) than it invests in the entire NIH budget (approximately $31 billion)

Kidney WorkforceTrends to watch in 2017 include shifts in nephrology GME, new training offerings, and the changing healthcare landscape

Fellows CornerA fellow looks at the clinical implications of low health literacy

FindingsMortality differs acccording to reason for starting dialysis

Practice PointersPregnancy and kidney failure

Study Suggests “Reverse Causality” from Subclinical Cardiac Disease

By Tracy Hampton

February 2017 | Vol. 9, Number 2

2 | ASN Kidney News | February 2017

thrice-weekly outpatient hemodialysis at 9 dialysis units in western Pennsylvania.

For depressed patients (PHQ-9 score ≥10), trained nurses generated treatment recommendations and helped implement therapy if patients and renal providers ac-cepted the recommendations.

Of the 101 patients who were followed for at least 1 year, 39 met criteria for de-pression based on their PHQ-9 scores. These 39 patients had depression on 147 of 373 (39%) monthly assessments. At 70% of these 147 assessments, patients were receiving anti-depressant therapy. and at 51 of 70 (70%) assessments, pa-tients did not accept nurses’ recommen-dations to intensify treatment. At 44 as-sessments, patients with depression were not receiving anti-depressant therapy and in 40 instances (91%) did not accept rec-ommendations to start treatment.

In most cases, patients refused the recommendations because they felt their depression was attributable to an acute event, chronic illness, or dialysis. Fac-tors associated with refusal of treatment recommendations were older age, being married, and African American race, al-though only the association of older age with treatment refusal was statistically significant.

In 11 of 18 instances (61%) in which patients accepted the recommendation related to treatment for depression, re-nal providers were unwilling to provide treatment. In 8 of these 11 instances, the renal provider offered no explanation for not accepting the recommendation; in 2 instances, the provider deferred treatment recommendations to the patients’ pri-mary care provider; and in 1 instance, the provider did not accept the recommenda-tion because the patient was hospitalized.

“We discovered that some patients are on anti-depressant treatment that does not appear to be effective, and most who are not on treatment do not wish to be treated,” Weisbord said. “We also noted

that when patients do request treatment, renal providers commonly do not pre-scribe treatment.”

Weisbord and his colleagues pointed to past research indicating that 90% of nephrologists provide primary care to their patients who are on dialysis and that as few as 20% of patients on chronic dial-ysis have a separate primary care provider.

“The apparent unwillingness of renal providers to consider implementing treat-ment for depression, particularly in the absence of primary providers who might assume this responsibility, represents a major obstacle to the systematic provision of therapy,” they wrote.

Considering Medicare’s recently re-leased criteria for the end stage renal disease QIP, the authors noted that the implementation of a performance meas-ure based on screening and treatment is logically based on the assumption that pa-tients wish to have the condition treated. Therefore, the results of this study suggest that the requirement to universally docu-ment and provide care for depression in dialysis patients may be premature.

In an accompanying editorial, Maree Hackett, PhD, and Meg Jardine, PhD, of the University of Sydney, in Australia, noted that there are many challenges to the detection and treatment of depression in people on dialysis. “The importance of the inner experience may get lost by pa-tients, carers and clinicians in a setting of intensive medical intervention, intercur-rent comorbidities, and high rates of un-welcome events,” they wrote. They argued that a safe, effective, low-cost treatment for managing depression could help pa-tients live well, rather than just survive, while on dialysis.

______________________

Article: “Acceptance of Anti-Depressant Treatment by Patients on Hemodialysis and their Renal Providers.” doi: 10.2215/CJN.07720716

Editorial: “We Need to Talk about De-pression and Dialysis: But What Ques-tions Should We Ask and Does Anyone Know the Answers?”

(SHARP)—a seminal trial in which 9270 patients with CKD were randomly assigned to ezetimibe/simvastatin versus placebo. The principal investiga-tors of the SHARP Study (www.sharpinfo.org) were Colin Baigent, FRCP, FFPH, and Martin J. Landray, PhD, FRCP, also of CTSU.

The main SHARP results—published in The Lancet in 2011—showed that cholesterol-lowering therapy can substantially reduce the risk of major atherosclerotic events in CKD. Subsequent analyses of the SHARP data have yielded further insights on the outcomes and prognostic factors among peo-ple with CKD. In this new analysis, the SHARP investigators explored the paradoxical relationship between BP and cardiovascular risk in patients with CKD.

In apparently healthy adults, as BP increases so does the risk of death from ischemic heart disease, stroke, or heart failure. Risk is approximately doubled for each 20 mm Hg increase in “usual” systolic BP and each 10 mm Hg in-crease in diastolic BP—there is no threshold below which lower SBP is not associated with lower risk.

However, in CKD, the association curve is often U-shaped—cardiovascu-lar risk is increased at both higher and lower BP values, including low-normal BP. One suggested reason is reverse causality: longstanding hypertension may lead to changes in cardiac structure and function, thus lowering BP while at the same time increasing cardiovascular risk.

Previous studies have found that at least half of patients with stage 4 to 5 CKD show cardiac structural abnormalities, often without signs or symp-toms. In the Chronic Renal Insufficiency Cohort (CRIC) study, 75% of pa-tients with an estimated glomerular filtration rate less than 30 mL/min per 1.73 m2 had left ventricular hypertrophy on echocardiography.

Herrington and colleagues tested the hypothesis that the association be-tween BP and cardiovascular risk might be confounded by the presence of such cardiac damage—patients who have CKD but have not yet developed cardiac disease might exhibit a positive loglinear association similar to that observed in apparently healthy adults.

To do this, the researchers needed a marker of cardiovascular risk. “The investigative trick was to use blood troponin to identify those at lowest risk of subclinical heart disease,” Herrington explained. “This was based on several previous studies showing that troponin-I is positively correlated with left ven-tricular mass and negatively correlated with cardiac function.”

In the SHARP cohort, higher baseline troponin-I was associated with male sex, older age, higher systolic BP, a higher prevalence of diabetes, and

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February 2017 | ASN Kidney News | 3

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worse renal function. During a median fol-low-up of nearly five years, 2188 subjects had one or more cardiovascular events—a rate of 6.7% per year.

On adjusted analysis, higher baseline troponin-I was a strong predictor of future cardiovascular events. Risk was increased 61% for CKD patients with baseline tro-ponin-I over 0.01 ng/mL and 182% for those over 0.03 ng/mL (compared to the reference value of 0.01 ng/mL or less). This association was apparent in both dialysis and non-dialysis CKD patients.

In the full cohort, the association be-tween systolic BP and cardiovascular risk was U-shaped. However, among the 7278 patients without previous cardiovascular disease, there was a positive loglinear asso-ciation. On adjusted analysis, each 10 mm Hg increment in usual systolic BP was as-sociated with a 16% increase in cardiovas-cular risk. This risk increased to 27% per 10 mm Hg when analyses were further re-stricted to those patients without evidence of subclinical cardiac disease—i.e., baseline troponin of 0.01 ng/mL or less. The asso-ciation was little affected by adjustment for baseline albumin:creatinine ratio, was about the same for atherosclerotic and nonatherosclerotic events, in dialysis and nondialysis patients, and among patients younger than 62 (the study median age) and those 62 years or older.

In the full cohort, however, there were also U-shaped associations for diastolic BP (but not pulse pressure). Associations with

diastolic BP remained U-shaped among patients with a low troponin-I.

Support for studies of lower BP targets in CKD

The findings add to previous data on the complex relationship between BP and car-diovascular risk in CKD. Herrington and coauthors write: “The presence of a clear positive loglinear relationship between SBP (or pulse pressure) and cardiovascular events in patients with CKD at lowest risk of cardiac disease in SHARP suggests that reverse causality is a plausible explanation for previously observed U-shaped asso-ciations among patients with moderate-to-advanced CKD.”

Herrington commented: “This suggests that guidelines should not be using obser-vational analyses of BP to define optimum BP targets in diseased populations, as such analyses may wrongly conclude that lower BP is dangerous, when the opposite may be the case.”

Randomized trials, which control for such confounding, have supported the ef-fectiveness of lowering BP in other popu-lation groups where U-shaped associations between BP and cardiovascular risk have been observed, including patients with pri-or cardiovascular disease and older adults (e.g., the Systolic Blood Pressure Interven-tion Trial, or SPRINT). The same may therefore be true in CKD.

In the absence of sufficiently large tri-als, the optimal BP target in CKD remains

unknown, and current recommenda-tions vary widely. Recent studies, includ-ing SPRINT, “taken together with the evidence of reverse causality in the present analysis in the SHARP trial, suggest that trials of lower BP targets in patients with CKD are indicated,” the researchers write. Such studies would also address the po-tential harms as well as benefits of lower BP targets; in SPRINT, more intensive BP control was associated with an increased risk of acute kidney injury.

“The findings in this paper probably are most applicable to people with CKD not on dialysis,” commented Rajiv Agarwal, MBBS, of Indiana University School of Medicine, Indianapolis. In a 2004 review in Hemodialysis International, Agarwal hypothesized that reverse causality might account for the U-shaped association be-tween blood pressure and cardiovascular risk in CKD.

To understand the association between BP and cardiovascular risk would require home or ambulatory BP recordings—which weren’t available in the SHARP data.

“Nonetheless, observational studies show that low BP associates with higher mortality in dialysis, while meta-analyses of randomized trials suggest the opposite,” Agarwal said. ”While we don’t have a de-finitive trial on BP level and outcomes in dialysis, I believe that the meta-analyses trump the observational data. Clearly there is room for research in this important area.”

Baigent noted: “The observational data in SHARP only appear to show that lower BP associates with higher risk of cardio-vascular events. We argue that, if correctly analyzed with due regard to the presence of confounding by subclinical cardiac disease, the true association between BP and risk of major cardiovascular events is positive throughout the range studied.”

Suggested Reading

1. Herrington W, et al. Evidence for re-verse causality in the association be-tween blood pressure and cardiovascu-lar risk in patients with chronic kidney disease. Hypertension 2017; 69:314–322.

2. Agarwal R. Exploring the paradoxical relationship of hypertension with mor-tality in chronic hemodialysis. Hemo-dial Int 2004; 8:207–213.

3. Baigent C, et al. The effects of lower-ing LDL cholesterol with simvasta-tin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011; 377:2181–2192.

4. Park M, et al. Associations between kidney function and subclinical cardiac abnormalities in CKD. J Am Soc Neph-rol 2012; 23:1725–1734.

5. The SPRINT Research Group: A ran-domized trial of intensive versus stand-ard blood-pressure control. N Engl J Med 2015; 373:2103–2116.

Editorial StaffEditor-in-Chief: Richard Lafayette, MDExecutive Editor: Dawn McCoyDesign: Lisa Cain DesignCommunications Assistant: Sara Leeds

Editorial Board:Joseph Mattana, Kings County Hospital Center, Brooklyn, NYAndrew King, MD, Scripps, San Diego, CA Pascale Lane, MD, FASN, University of Oklahoma Health SciencesEdgar V. Lerma, MD, FASN, University of Illinois – Chicago /Associates in Nephrology, SCUday S. Nori, MD, Ohio State University Wexner Medical CenterGlenda Payne, MS, RN, CNN, Nephrology Clinical Solutions Jeffrey Petersen, MD, AmgenAmy Williams, MD, Mayo Clinic, Rochester, MN

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ASN Council:President: Eleanor D. Lederer, MD, FASNPresident-elect: Mark D. Okusa, MD, FASNPast-President: Raymond C. Harris, MD, FASNSecretary-Treasurer: John R. Sedor, MD, FASNCouncilors: Mark E. Rosenberg, MD, FASN, Anupam Agarwal, MD, FASN, Susan E. Quaggin, MD, Barbara Murphy, MD

Executive Vice President: Tod IbrahimDirector of Communications: Robert Henkel

ASN Kidney News is published by the American Society of Nephrology 1510 H Street NW, Suite 800, Washington, DC 20005. Phone: 202-640-4660

www.asn-online.org

ASN Kidney News is the authoritative source for analysis of trends in medicine, industry, and policy affecting all practitioners in nephrology. The statements and opinions expressed in ASN Kidney News are solely those of the authors and not of the American Society of Nephrology (ASN) or the editorial policy of the editors. The appearance of advertisements in ASN Kidney News is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality, or safety. The American Society of Nephrology disclaims responsibility for any injury to persons or property resulting from any ideas or products referred to in the articles or advertisements.

The American Society of Nephrology is organized and operated exclusively for scientific and educational purposes, including enhancing the field of nephrology by advancing the scientific knowledge and clinical practice of that discipline through stimulation of basic and clinical investigation, providing access to new knowledge through the publication of journals and the holding of scientific meetings, advocating for the development of national health policies to improve the quality of care for renal patients, cooperating with other national and international societies and organizations involved in the field of nephrology, and using other means as directed by the Council of the Society.

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ASN Kidney News (ISSN print 1943-8044 and online 1943-8052) is an official publication of the American Society of Nephrology, 1510 H Street NW #800, Washington DC 20005, and is published monthly. Periodicals postage paid at Washington, DC and at additional mailing offices. Subscription rates: $12 per year. To order, please email [email protected]. Subscription prices subject to change. Annual ASN membership dues include $12 for ASN Kidney News subscription.

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Policy Update

GAO Report Reveals Extent of Underfunding of Kidney Disease Research Relative to Health Burden Cost

The American Society of Nephrology (ASN) has repeatedly cautioned health care policy-makers that kidney diseases are at staggering

levels and, for decades, there have been too few new therapies for treating patients. Now, the US Govern-ment Accountability Office (GAO) has conducted a study and published its findings in a new report re-leased January 18, 2017, National Institutes of Health: Kidney Disease Research Funding and Priority Setting, that statistically validates these points. The report highlights the inadequacies of federally funded medi-cal research for kidney diseases in the face of a stagger-ing burden on patients and taxpayers.

GAO conducted the study at the request of mem-bers of Congress from both the House of Representa-tives and the Senate. Prior to that request in 2015, ASN had formally requested these members of Con-gress to call on GAO to conduct the study. GAO is a part of the federal legislative branch, and only mem-bers of Congress can direct the agency to undertake studies.

The study, a “performance audit,” was conducted from February 2016 to December 2016 and exam-ined two primary factors affecting federally funded kidney disease research: 1) the level of NIH fund-ing for biomedical research on kidney diseases, and for other leading diseases and conditions; and 2) how the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sets priorities for kidney disease research.

GAO reported that the “NIH, within the Depart-ment of Health and Human Services, is the primary federal agency that conducts biomedical research on kidney disease, as well as various other diseases and conditions. NIH’s budget—$30 billion in fiscal year 2015—mostly funds extramural research that sup-

ports research personnel working at universities, med-ical schools, and other institutions. The National In-stitute of Diabetes and Digestive and Kidney Diseases (NIDDK)—one of NIH’s 27 institutes and centers (IC)—has primary responsibility for kidney disease research.”

GAO began by identifying diseases and condi-tions with a high disease burden in the United States relative to other conditions based on data from the Centers for Disease Control and Prevention (CDC). Investigators analyzed CDC’s national survey data, and interviewed CDC officials to identify conditions that had high mortality, or were chronic conditions with high prevalence, or both. They then matched the diseases and conditions identified with fiscal year 2015 data—the most current available—from NIH’s Research, Condition, and Disease Categorization (RCDC) system, which categorizes NIH research pro-jects (and associated funding) into categories.

One unique aspect of kidney diseases in terms of policy is that Medicare covers every American suf-fering from kidney failure—regardless of age—and guarantees them access to dialysis or kidney trans-plants through the End-Stage Renal Disease (ESRD) Program. Kidney failure is the only condition covered by Medicare for patients under 65 years of age. More than 20 million Americans have kidney diseases and more than 650,000 have kidney failure.

Despite this commitment to care for patients with kidney diseases, the report demonstrates a significant gap between investment in research and the disease burden. Annually, the federal government spends more on the Medicare ESRD program (nearly $32 billion) than it invests in the entire National Institutes of Health (NIH) budget ($30 billion). With just $564 million dedicated to kidney disease research at NIH,

ASN analysis of the report reveals that the equivalent of 1.7% of the annual total cost of care for kidney failure is invested in research to improve therapies and discover cures.

“Kidney diseases are devastating the lives of mil-lions of Americans,” said ASN President Eleanor Lederer, MD, FASN. “Innovation has not kept pace with the magnitude of the diseases, and the current underinvestment in kidney research is detrimental to patients and taxpayers. Today’s GAO report highlights the extent of the gap between our investment in inno-vation to treat and cure kidney diseases and the out-sized burden they place on every American.”

ASN announced at a White House Organ Summit last year its pledge of the first $7 million to launch a prize competition incentivizing the development of novel technologies for renal replacement therapy to improve quality of life for patients with kidney diseas-es. The society has also pledged to work with Congress to ensure the United States’ investment in research to cure kidney diseases is adequate to meet the challenge it poses to patients and taxpayers.

“Despite the federal government’s commitment to care for patients with kidney failure, for decades we have seen too few new therapies for kidney patients,” said Crystal Gadegbeku, MD, Chair of the ASN Pol-icy and Advocacy Committee. “This report strength-ens ASN’s resolve to foster innovation that improves patients’ lives and extends the value to the Medicare program that has saved so many lives.”

Requesters of the GAO report were Congressional Kidney Caucus co-chair Rep. Tom Marino (R-PA), Rep. Barbara Comstock (R-VA), House Science Committee chair Rep. Lamar Smith (R-TX), Sen. Ben Cardin (D-MD), and Sen. Bill Nelson (D-FL).


Have you checked out the ASN Communities yet?

Connect with colleagues. Share knowledge and resources. Discuss issues that matter to you most.

The ASN Communities site allows ASN members from around the world to connect online, join discussions, and share knowledge and resources. Members can get advice on issues they face in daily practice or research, share ideas, and provide input to ASN.

Visit community.asn-online.org to join the conversation.

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Nephrology workforce research conducted last year by George Washington University–Health Workforce Institute (GWU-HWI) investigators and others revealed

some interesting facets of the nephrology work-force that will inform ongoing research activities in 2017. Here’s a brief look back at nephrology work-force research in 2016 and trends to watch for in the year ahead.

2016 GWU-HWI report

The most recent report from GWU-HWI inves-tigators led by Edward Salsberg, MPA, uncovered some interesting data points: • The number of nephrology fellows in training

has remained steady, despite a large number of positions going unfilled in the Match.

• University of North Carolina Sheps Center re-searchers working in collaboration with GWU project the number of adult nephrologists per 10,000 population will grow by 58% between 2016 and 2030.

Overall, the report details a mixed picture for the specialty. The job market for US medical gradu-ates is improving although it remains challenging for international medical graduates. However, the inflow of new nephrologists is outpacing the rate of retirement for older physicians.

“Our third annual report on the nephrology workforce finds both positive and negative signs,” said Salsberg. “For example, while the job market for new nephrologists is still challenging, there were some bright spots especially for US medical school graduates as job prospects improved along with incomes. And a new survey of nephrologists over 55 found that most were satisfied with their specialty, practice, and income.”

In addition to surveying nephrologists 55 and older, GWU conducted the annual Nephrology Fellows Survey and outlined the potential of re-cently introduced ESRD Seamless Care Organiza-tion (ESCO) demonstration projects to influence nephrologist demand, which they determined may make the specialty more fulfilling and economically rewarding.

Appointment year (AY) 2017 Match

Results of the AY 2017 nephrology Match released on December 7, 2016, were essentially flat to the previous year. An ASN Data Brief (http://asn.kdny.info/dyo6307Gh2r) highlighted several key points:• Despite a 4.4% increase in the number of train-

ing tracks compared with AY 2016, the number of slots offered was flat, suggesting nephrology training positions may be contracting slightly.

• Only 64 US MDs matched in nephrology in AY 2017, down 21% from last year and 52% from AY 2009.

2017 Workforce research portfolio

Nephrology workforce research is one part of ASN’s commitment to empower current and future mem-bers of the nephrology workforce and advance their professional goals and success. This year’s portfolio includes:

GWU-HWI Workforce SurveysResearchers from GWU-HWI will focus on ad-ministering three surveys assessing nephrology fel-lows and early career nephrologists:

• 2017 Nephrology Fellows Survey 4th iteration of the annual fellows survey will

capture longitudinal data on job market experi-ences

• Survey of Nephrologists One Year Out of Training

Assessment of nephrologists’ practice and em-ployment settings and experiences 1 year after

graduation, conducted in concert with/fulfilling ACGME-required 1-year postgraduate program assessments

• Survey of Nephrologists Five Years Out of Training

Detailed investigation of early career nephrolo-gists, including the first graduating class who completed the ASN Nephrology Fellows Survey assessments of training

Best Practices Project: Internal Medicine ResidenciesThe Best Practices Project is one of several initia-tives designed by the ASN Workforce Committee to assess best practices of institutions that success-fully attract trainees, in order to increase interest in nephrology careers among the brightest medical students and residents. The project identified top internal medicine residency producing physicians who subsequently specialize in nephrology and will isolate potentially translatable practices that could be disseminated and implemented at other institu-tions. Results of the first phase—focusing on medi-cal schools—were presented at ASN Kidney Week 2016.

ASN Data Analytics Program The Data Analytics Program was created in April 2016 to advance the goals of ASN’s new strategic plan. ASN is conducting in-house research and analysis projects, building on collaborations with GWU-HWI and expanding into new areas. The Data Analytics Program will support informed, strategic decision-making and implementation of

ASN initiatives and programs by collecting, man-aging, analyzing, and synthesizing data relevant to nephrology and nephrology professionals.

Data Analytics Program activities in 2016 included:

• ASN Pediatric Nephrology Fellows Survey Re-sponses—Brief Analysis Authored for the ASPN Workforce Committee. The full report is avail-able at http://asn.kdny.info/TZpf305BEAy

• Kidney News Online ASN Data Bytes Series. Quick takes on items of interest to ASN mem-bers. List of current articles available at http://www.kidneynews.org/search/node/Pivert

In 2017, the Program will focus on development of • ASN GME Database Allows monitoring of trends among training

programs and nephrology fellows• Data Collection Efforts Assessing and enumerating knowledge and data

resource gaps, as well as potential approaches to address them

• ASN Data Resource Center A central repository for ASN’s ongoing nephrol-

ogy workforce research and data collection

Workforce, Training, and Career Advancement Department In April 2016, ASN coalesced its workforce-cen-tered programs into a new Workforce, Training, and Career Advancement Department to foster ca-reer development for all kidney health profession-als. Among the department’s portfolio are Kidney STARS, Kidney TREKS, and the ASN Foundation for Kidney Research grants programs to which ASN commits more than $3 million each year. More than 40 physician volunteers serving on the newly created Career Advancement, Diversity and Inclusion, and Workforce and Training Commit-tees will inform the department’s strategic initia-tives. Expanding the range of resources available to kidney professionals across the entire career trajec-tory, from student to senior clinicians and inves-tigators, will advance their professional lives and improve treatment of kidney diseases.

Trends to watchAmong the trends to watch in 2017 are: • Shifts in nephrology GME The AY 2017 Match was flat year over year, yet

positions have continued to fill. Growing anec-dotal evidence demonstrates a shift in reducing the number of fellowship positions.

• Evolution of the Specialty New training offerings, such as critical care

nephrology, could kindle interest in the special-ty.

• A new Congress and administration A new healthcare landscape could result in

changing regulations and practice patterns and may influence specialty choice among trainees and future physician demand.

Workforce research reports and other resources are available at http://www.asn-online.org/workforce. If you have questions, concerns, or suggestions for future workforce research, data or knowledge gaps, please contact [email protected].

Looking Ahead at the Nephrology Workforce

Education | The ASN Advantagewww.asn-online.org/brcu

Maximize your readiness for the ABIM nephrology examination.ASN’s Board Review Course & Update is designed for fellows and practicing physicians preparing for certification or recertification in nephrology. Each topic and its time allocation are patterned after the ABIM nephrology examination, giving you the most efficient preparation. Lectures, interactive case discussions, and panel Q&A sessions contribute to ASN’s unparalleled review course.

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BRCU Reg 10.5X14.5.indd 1 1/18/2017 1:46:03 PM

Delay for CMS Rule on Premium AssistanceBy Bridget M. Kuehn


new CMS regulation that would potentially curtail third party pay-ments for insurance for dialysis pa-tients has been delayed by a U.S. District Court judge in Texas.

Fresenius Medical Care, Davita, U.S. Renal Care, along with Dialysis Patient Citizens, filed a lawsuit to block the CMS rule on Jan. 6, 2017. Issued as an interim rule in August 2016, the reg-ulation was set to go into effect Jan. 13, 2017. The judge’s temporary restraining order delaying the rule may stay in place for up to 14 days post-issuance.

In its lawsuit, the groups stated that the rule was pushed through without the proper notice or comment period that usually occurs before a new rule is adopted.

The U.S. District Court judge agreed, stating the organizations likely showed that the Depart-ment of Health and Human Services (HHS) im-plemented the final rule without time for thor-ough review and comment.

In a statement about the temporary restrain-ing order, Fresenius Medical Care said: “We are pleased that the court has issued a temporary re-straining order preventing this improperly issued regulation from going into effect. Today’s ruling will help ensure that Americans with kidney fail-ure have the same right as every other American to receive charitable assistance to pay their health insurance premiums. We look forward to working with the new administration on regulations that protect the sustainability of the Medicare program while protecting the ability of Americans to select the health coverage of their choosing, free from discrimination based on their health status or dis-ability.”

The rule grew out of a CMS investigation of reports that dialysis companies were paying for private insurance in order to boost their reim-bursements. It requires dialysis companies to fully disclose to a patient their insurance options, how the providers would benefit from a patient’s receiv-ing private coverage, and would require insurance company approval of coverage for the patient.

In a Jan. 11, 2017, letter to CMS commenting on the rule, the American Society of Nephrology (ASN) urged the agency to take more time and gather more input from stakeholders before final-izing the rule.

“The ASN firmly agrees with CMS that pay-ment of premiums and cost-sharing by third party entities should only be used to promote the best interests of the beneficiary,” ASN stated in its

comment letter. “For many patients in the vul-nerable dialysis population, third party assistance currently helps them achieve their goals, be it to work part time, gain access to transplant, or afford medications, and the society is concerned that the proposals in this [rule] would inadvertently jeop-ardize some individuals’ access to care.”

Premium support scrutinyIn mid-August 2016, CMS announced it was investigating reports of inappropriate steering of dialysis patients into private insurance by dialy-sis providers to boost their own reimbursements. According to CMS, the investigation yielded re-ports of abuse with negative health and financial consequences for patients. This led CMS to issue the interim rule requiring that dialysis facilities disclose the risks of various coverage options to

their patients, be more transparent about how the provider benefits, and prevent potential disrup-tions in coverage by seeking insurer approval for coverage.

Third parties, including nonprofits, have long offered patients who require dialysis help paying for insurance. For example, the American Kidney Fund (AKF) offers such payment assistance for low-income patients to purchase Medicare Part B, Medigap, and private or employer-based insur-ance. Currently, the organization provides payment assistance to 80,000 patients, including 6400 in Affordable Care Act marketplace plans, according to a press release. The organization runs a health insurance premium assistance program established in 1997 according to guidelines laid out by the US Office of the Inspector General (OIG).

But a New York Times investigation, published December 25, 2016, suggested that the AKF had in some instances resisted offering assistance to patients from dialysis clinics not associated with companies that donated to the charity, contrary to OIG guidelines.

In a statement, the AKF argued the article was factually incorrect, that it had “never turned away a patient who was financially qualified,” and that 40% of dialysis providers who have patients re-ceiving AKF assistance do not contribute to the fund. But the AKF also expressed concern that so-cial workers from independent dialysis clinics who were interviewed by the New York Times believe that the fund is favoring patients from large dialy-sis companies who donate.

“This is simply not the case, and we want to correct the record, as well as take ownership of any way that AKF itself may have contributed to this misperception,” the statement said.

In a fact sheet, CMS noted that in recent years dialysis providers have been offering premium as-sistance, either directly or through charities, as a way to boost reimbursements. Premiums cost about $6000, but private insurance may pay as much as 4 times more for dialysis care than Medi-care, resulting in up to an additional $100,000 to $200,000 in reimbursement.

AKF said in a statement that it supported ef-forts to stop steering but had urged the agency to withdraw the rule, saying it would leave kidney disease patients with fewer options.

“HHS is irresponsibly upending the entire safety net that exists for dialysis patients who can’t afford their health coverage,” said Burton. “This cannot be the result that the agency intended to achieve when it set out to protect ESRD patients from improper steering.”

Insurance discriminationThe regulation also drew sharp criticism from the patient advocacy group Dialysis Patient Citizens, which said the rule, which requires insurance companies to approve private coverage, allows in-surers the chance to “veto” a patient’s choice of private coverage.

“It basically creates a two-tier system,” said Hrant Jamgochian, chief executive officer of Di-alysis Patient Citizens, which joined dialysis pro-viders in the lawsuit to block the rule. “If you can afford private coverage, you are protected from discrimination [under ACA], but if you can’t af-ford it [without premium assistance] you aren’t.”

Patients with HIV are protected from such discrimination, Jamgochian noted, because in-surers are required to accept charitable assistance for these patients under the Ryan White Care Act. His organization has proposed similar pro-tection for patients with kidney failure and has urged CMS to crack down on insurance compa-nies steering dialysis patients who could benefit from private insurance into Medicare.

A

[The rule requires] that dialysis facilities disclose the risks of various coverage options to their patients, be more transparent about how the provider benefits, and prevent potential disruptions in coverage by seeking insurer approval for coverage.

Fellows Corner

Medical students and residents are often intimidated by renal physiology and struggle to un-

derstand the many aspects of the kidney’s role in medical disease. If trainees have trouble grasping the complexities of the kidney, it should come as no surprise that our patients feel the same way.

Health literacy, or the ability of an in-dividual to be actively engaged in a dia-logue about his health, has been linked to patient outcomes. Adequate health lit-eracy is particularly important in chronic kidney disease (CKD), which often re-quires patients to navigate a complex health system and make drastic lifestyle changes. Patients may be faced with such critical decisions as choosing to begin re-nal replacement therapy with little to no understanding of its implications.

As a first-year Nephrology fellow, most of the patients I see are new to me as well as new to the clinic. I quickly realized that despite being referred to a clinic that ex-clusively sees patients with kidney disease, several of my patients were wholly una-ware of having renal dysfunction in the first place. When I asked them what they had trouble understanding, they often re-plied with, “everything,” and didn’t know where to begin.

Clinical implications of low health literacyThe clinical implications of low health literacy in kidney disease are being rec-ognized by the nephrology community.

Lower health literacy has been linked to worsened glomerular filtration rates (1,2). Patients with CKD and poor health lit-eracy tend to access preventive health services less frequently and have poorer self-care methods, all of which can con-tribute to rising healthcare costs. In addi-tion, one study showed that patients on dialysis with limited health literacy were 78% less likely to be referred for a renal transplant (3).

Further complicating this matter, the Department of Education has reported that 21% of adults in the United States read below a fifth-grade level, and 14% of the population is illiterate. A study of kidney disease–related patient education tools from the United States, Australia, and the United Kingdom revealed that most materials required a ninth-grade reading level for adequate comprehen-sion. In addition, many of these tools were geared toward those who had pro-gressed to hemodialysis with little focus on patients with earlier stages of kidney disease (4). Low health literacy, a high pill burden, and an unfamiliar health system can be an overwhelming combination for a patient with kidney disease.

It is also important to realize that we as providers may fail to recognize existing health literacy issues that are downplayed out of fear or embarrassment. When I asked one of my patients to read back the medication instructions I had writ-ten for him, it was only when he held the paper upside down that I realized he could not read.

Table 1 provides a helpful list of pa-tient characteristics that may be associated with low health literacy (5).

How can providers continue to ad-dress concerns about patient health liter-acy? Tools such as the Rapid Estimate of Adult Literacy in Medicine (REALM), Test of Functional Health Literacy in Adults (TOFHLA), and Brief Health Literacy Screen (BHLS) have all been used to successfully screen dialysis pa-tients for poor health literacy (5,6), al-though studies regarding their effective-ness in earlier stages of kidney disease are lacking. In addition to using these tools, there are simple steps that we can take

to help bridge the literacy gap between ourselves and our patients. We can ask open-ended questions, speak slowly with patient-oriented language, and limit the information we discuss at each visit. The “teach-back” method, or asking our pa-tients to repeat back and explain any in-structions given to them, can also be a useful tool to help confirm patient com-prehension.

Patients with no medical background seem to know what it means to have heart disease and diabetes, but many still struggle with understanding the impli-cations of kidney disease. Not only is it important to collaborate with educators and policy leaders to develop educational tools that provide simple representations of this complex disease process, it is also crucial to support health literacy training in the medical community. It is impor-tant that more of these efforts be geared toward patients during earlier stages of kidney disease as well as toward adoles-cents.

Each of us has a right to knowledge that informs decisions about our own health. It is our responsibility to ensure that this knowledge is delivered in a way that is both understandable and beneficial to our patients. Our health interventions are only as effective as our patients’ abil-ity to carry them out—a challenge that we must continue to try to overcome with regard to kidney disease.

Devika Nair, MD, is currently a first-year nephrology fellow at Vanderbilt Univer-sity. She completed her medical training and chief residency in Internal Medicine at Tulane University and her undergradu-ate studies at the University of California, Berkeley.

References1. Devraj R, et al. Relationship between

health literacy and kidney function. Nephrology 2015; 20:360–367.

2. Ricardo AC, et al. Limited health lit-eracy is associated with low glomeru-lar filtration in the Chronic Renal Insufficiency Cohort (CRIC) study. Clin Nephrol 2014; 81:30–37.

3. Grubbs V, Gregorich S, Perez-Stable

Health Literacy in CKD: A Fellow’s Perspective

Have a tip or idea you’d like to share with your fellow peers and the broader kidney community?

Send your idea to the Kidney News Fellows Corner column at [email protected]

By Devika Nair

Devika Nair

Table 1Clinical “red flags” for lim-ited health literacy

• Patient registration forms that are incomplete or inaccurately completed

• Non-adherence with medications or treatments

• Frequently missed appointments

• Lack of follow-through with labs, imaging tests, or referrals

• Unable to name medications, explain what medications are for, or explain timing of medication administration

• May offer excuses to deflect reading tasks

• “I forgot my glasses”

• “Let me bring this home so I can discuss it with my children”

• Seldom have questions

• Seek help only when illness is advanced

• Have difficulty explaining medical concerns


EJ, Hsu C. Health literacy and access to kidney transplantation. Clin J Am Soc Nephrol 2009; 4:195–200.

4. Morony S, Flynn M, McCaffery KJ, Jansen J, Webster AC. Readability of written materials for CKD patients: a systematic review. Am J Kidney Dis 2015; 65:842.

5. Jain D, Green JA. Health literacy in kidney disease: Review of the lit-erature and implications for clini-cal practice. World J Nephrol 2016; 5:147–151.

6. Dageforde LA, Cavanaugh KL. Health literacy: Emerging evidence and applications in kidney disease care. Adv Chronic Kidney Dis 2013; 20:311–319.

www.rayaldee.com

OP-US-0092-102016v.1

iPTH25D

Indication and Limitations of UseRayaldee® (calcifediol) extended-release 30 mcg capsules is indicated for the treatment of secondary hyperparathyroidism in adults with stage 3 or 4 chronic kidney disease and serum total 25-hydroxyvitamin D levels less than 30 ng/mL. Rayaldee is not indicated in patients with stage 5 chronic kidney disease or end-stage renal disease on dialysis.Important Safety Information Hypercalcemia: Excessive administration of vitamin D compounds, including Rayaldee, can cause hypercalcemia and hypercalciuria. Severe hypercalcemia due to substantial overdosage of vitamin D and its metabolites may require emergency attention. Patients should be informed about the symptoms of elevated calcium. • Digitalis toxicity: Potentiated by hypercalcemia of any cause. Monitor serum calcium and signs and symptoms of digitalis toxicity more frequently when

initiating or adjusting the dose of Rayaldee. • Adynamic Bone Disease: Monitor for abnormally low levels of intact PTH levels when using Rayaldee, and adjust dose if needed. • The most common adverse reactions (≥3% and more frequent than placebo) were anemia, nasopharyngitis, increased blood creatinine, dyspnea, cough, congestive heart failure and constipation. • Care should be taken while dosing Rayaldee with cytochrome P450 inhibitors, thiazides, cholestyramine or drugs stimulating microsomal hydroxylation due to the potential for drug interactions. • Serum calcium should be below 9.8 mg/dL before initiating treatment. • Monitor serum calcium, phosphorus, 25-hydroxyvitamin D and intact parathyroid hormone (iPTH) 3 months after starting therapy or changing dose.

A New Direction in SHPTRayaldee® is the first and only extended-release prohormone of the active form of vitamin D3 that raises 25-hydroxyvitamin D and lowers iPTH levels.

Please see Brief Summary of Prescribing Information on following page, and Full Prescribing Information at RAYALDEE.com.RAYALDEE is a registered trademark of OPKO Ireland Global Holdings Ltd. © 2016 OPKO Pharmaceuticals, LLC.


Findings

Diet Quality Affects Risk of eGFR Decline in Urban Patients In a diverse urban population, low dietary quality is associated with an increased risk of declining kidney function among adults with hypertension, reports a study in the Journal of Renal Nutrition.

The study included data on 1534 par-ticipants in the “Healthy Aging in Neigh-borhoods of Diversity across the Life Span” (HANDLS) study: African Ameri-cans and whites, aged 30 to 64 years, with a baseline estimated glomerular filtration

rate (eGFR) of 60 mL/min/1.73 m2 or higher. Mean age was 48 years; 59% of participants were African American.

A Dietary Approaches to Stop Hy-pertension (DASH) score, based on nine target nutrients, was calculated for each participant. Diet score was evaluated for association with rapid decline in kidney function (greater than 3 mL/min/1.73 m2 per year), incident chronic kidney disease, and eGFR decline greater than 25%.

Accordance with the DASH diet was “minimal”—median score 1.5 on a 0–8 scale. At a median 5 years’ follow-up, rapid eGFR decline occurred in 13.4% of patients overall, 15.2% of those with a DASH score of 1 or less, and 12.0% with a DASH score greater than 1. On adjusted analysis, the association with rapid eGFR decline was significant only for subjects with hypertension: risk ratio 1.68. The DASH score was unrelated to

incident chronic kidney disease or eGFR decline greater than 25%.

Previous studies have linked a health-ier diet to a lower risk of kidney disease outcomes, but none of these studies have focused on urban populations. The new results show that a low DASH score is as-sociated with an increased risk of rapid decline in eGFR, among urban adults with hypertension. The investigators conclude: “[D]iet quality may play an important role in determining kidney outcomes among individuals with risk factors for CKD” [Liu Y, et al. Dietary habits and risk of kidney function de-cline in an urban population. J Renal Nutr 2017; 27: 6–25].

Among patients initiating dialysis, mor-tality is higher for those with a primary indication of volume overload or hyper-tension, suggests a study in the American Journal of Kidney Diseases.

The retrospective analysis included 461 patients who initiated hemodialysis or peritoneal dialysis (24 patients) from 2004 through 2012 at 14 facilities. All-cause mortality was analyzed for patients with differing primary indications for dialysis initiation: laboratory evidence of kidney function decline (reference cat-egory), uremic symptoms, volume over-load, hypertension, or “other/unknown.”

At a median follow-up of 2.4 years, 40% percent of patients had died. Crude mortality was 21.7 per 100 patient-years for patients with volume overload or hy-pertension, compared to 10.0 for those with kidney function decline, 12.7 with uremic symptoms, and 12.2 for the “oth-er/unknown” category.

On adjusted analysis, volume over-load or hypertension was the only cate-gory associated with increased mortality: hazard ratio 1.69. Among patients using a permanent dialysis access, the risk of death was eight times higher for those in the volume overload/hypertension group, compared to those with decreased kidney function.

The results suggest increased mortal-ity among patients initiating dialysis due to volume overload, relative to those with laboratory evidence of kidney function decline. The researchers write: “Improved understanding of symptoms and clinical decision making at the time of the transi-tion to dialysis therapy has the potential to lead to innovation in identifying the optimal timing for the initiation of main-tenance dialysis therapy” [Rivara MB, et al. Indication for dialysis initiation and mortality in patients with chronic kidney failure: a retrospective cohort study. Am J Kidney Dis 2017; 69:41–50].

Mortality Differs by Reason for Starting Dialysis

Increase in Serum Calcium: Patients randomized to RAYALDEE experienced a greater mean (SE) increase in serum calcium (P<0.001) than patients randomized to placebo [i.e., 0.2 (0.02) mg/dL on RAYALDEE versus 0.1 (0.03) mg/dL on placebo from baseline to trial end]. Six subjects (2%) in the RAYALDEE treatment group and no subjects (0%) in the placebo group required dose reductions for protocol-defined hypercalcemia (two consecutive serum calcium values greater than 10.3 mg/dL). A total of 4.2% of RAYALDEE treated subjects and 2.1% of placebo treated subjects experienced at least 1 elevation in serum calcium above the upper limit of normal (10.5 mg/dL).Increase in Serum Phosphorus: Patients randomized to RAYALDEE experienced a greater mean (SE) increase in serum phosphorus than patients randomized to placebo [i.e., 0.2 (0.03) mg/dL on RAYALDEE versus 0.1 (0.04) mg/dL on placebo from baseline to trial end]. One subject (0.4%) in the RAYALDEE treatment group met protocol-defined hyperphosphatemia (two consecutive serum phosphorus values >5.5 mg/dL deemed to be study drug related) compared to no subjects in the placebo group. A total of 45% of RAYALDEE treated subjects and 44% of placebo treated subjects experienced at least one elevation in serum phosphorus above the upper limit of normal (4.5 mg/dL).

To report SUSPECTED ADVERSE REACTIONS, contact OPKO Pharmaceuticals, LLC at 1-844-729-2539 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS

CYP3A Inhibitors Cytochrome P450 inhibitors, such as ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1), and may alter serum levels of calcifediol. Dose adjustment of RAYALDEE may be required, and serum 25-hydroxyvitamin D, intact PTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor.

ThiazidesThiazides are known to induce hypercalcemia by reducing excretion of calcium in the urine.Concomitant administration of thiazides with RAYALDEE may cause hypercalcemia. Patients may require more frequent serum calcium monitoring in this setting.

CholestyramineCholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins and may impair the absorption of calcifediol, the active ingredient in RAYALDEE. Dose adjustment of RAYALDEE may be required, and serum total 25-hydroxyvitamin D, intact PTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with cholestyramine.

Other AgentsPhenobarbital or other anticonvulsants or other compounds that stimulate microsomal hydroxylation reduce the half-life of calcifediol, the active ingredient in RAYALDEE. Dose adjustment of RAYALDEE may be required, and serum total 25-hydroxyvitamin D, intact PTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with phenobarbital or other anticonvulsants.

HOW SUPPLIED

RAYALDEE is supplied as 30 mcg calcifediol in blue, oval extended-release capsules, imprinted O:

Bottles of 30 [NDC 70301-1001-1]

Bottles of 60 [NDC 70301-1001-2]

STORAGE AND HANDLING

Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

RAYALDEE is a registered trademark of OPKO Ireland Global Holdings Ltd.

Patent: http://www.opko.com/products/patents/

Rev. 06/2016

Manufactured for:OPKO Pharmaceuticals, LLC4400 Biscayne BlvdMiami FL 33137 © 2016 OPKO Ireland Global Holdings Ltd. OP-US-0071-092016v.1

Placebo RAYALDEE Adverse Reaction N=144 N=285

% %

Anemia 3.5 4.9 Nasopharyngitis 2.8 4.9 Blood creatinine increased 1.4 4.9 Dyspnea 2.8 4.2 Cough 2.1 3.5 Cardiac failure congestive 0.7 3.5 Constipation 2.8 3.2 Bronchitis 0.7 2.8 Hyperkalemia 0.7 2.5 Osteoarthritis 0.7 2.1 Hyperuricemia 0.7 1.8 Contusion 0.0 1.8 Pneumonia 0.7 1.4 Chronic obstructive pulmonary disease 0.0 1.4

BRIEF SUMMARYCONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

RAYALDEE® (calcifediol) extended-release capsules, for oral use

INDICATIONS AND USAGE:RAYALDEE® is a vitamin D3 analog indicated for the treatment of secondary hyperparathyroidism in adult patients with stage 3 or 4 chronic kidney disease and serum total 25-hydroxyvitamin D levels less than 30 ng/mL. RAYALDEE is not indi-cated for the treatment of secondary hyperparathyroidism in patients with stage 5 chronic kidney disease or in patients with end-stage renal disease on dialysis.

CONTRAINDICATIONS:None

WARNINGS AND PRECAUTIONSHypercalcemia may occur during RAYALDEE treatment. Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Severe hypercalcemia may require emergency attention.Hypercalcemia may be exacerbated by concomitant administration of high doses of calcium containing preparations, thiazide diuretics, or other vitamin D compounds. In addition, high intake of calcium and phosphate concomitantly with vitamin D compounds may lead to hypercalciuria and hyperphosphatemia. In these circumstances, frequent serum calcium monitoring and RAYALDEE dose adjustments may be required. Patients with a history of hypercalcemia prior to initiating therapy with RAYALDEE should be monitored more frequently for possible hypercalcemia during therapy.Patients should be informed about the symptoms of elevated serum calcium, which include feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination, and weight loss. Hypercalcemia of any cause, including RAYALDEE, increases the risk of digitalis toxicity. In patients using RAYALDEE concomitantly with digitalis compounds, monitor both serum calcium and patients for signs and symptoms of digitalis toxicity and increase the frequency of monitoring when initiating or adjusting the dose of RAYALDEE. Adynamic bone disease with subsequent increased risk of fractures may develop if intact PTH levels are suppressed by RAYALDEE to abnormally low levels. Monitor intact PTH levels and adjust RAYALDEE dose, if needed.

DOSAGE AND ADMINISTRATIONImportant Dosage and Administration Information• Ensure serum calcium is below 9.8 mg/dL before initiating treatment.• Instruct patients to swallow RAYALDEE capsules whole. • Instruct patients to skip a missed dose and to resume taking the medicine at

the next regularly scheduled time. Do not administer an extra dose.

Starting Dose and Dose Titration

• The initial dose of RAYALDEE is 30 mcg administered orally once daily at bedtime.

• The maintenance dose of RAYALDEE should target serum total 25-hydroxyvita-min D levels between 30 and 100 ng/mL, intact parathyroid hormone (PTH) levels within the desired therapeutic range, serum calcium (corrected for low albumin) within the normal range and serum phosphorus below 5.5 mg/dL.

• Monitor serum calcium, serum phosphorus, serum total 25-hydroxyvitamin D and intact PTH levels at a minimum of 3 months after initiation of therapy or dose adjustment, and subsequently at least every 6 to 12 months.

• Increase the dose to 60 mcg orally once daily at bedtime after approximately 3 months, if intact PTH remains above the desired therapeutic range. Prior to raising the dose, ensure serum calcium is below 9.8 mg/dL, serum phosphorus is below 5.5 mg/dL and serum total 25-hydroxyvitamin D is below 100 ng/mL.

• Suspend dosing if intact PTH is persistently and abnormally low to reduce the risk of adynamic bone disease [see Warnings and Precautions], if serum calcium is consistently above the normal range to reduce the risk of hypercalcemia [see Warnings and Precautions], or if serum total 25-hydroxyvitamin D is consistently above 100 ng/mL. Restart at a reduced dose after these laboratory values have normalized.

USE IN SPECIFIC POPULATIONSTeratogenic Effects - Pregnancy Category C: Calcifediol has been shown to be teratogenic in rabbits when given in doses of 8 to 16 times the human dose of 60 mcg/day, based on body surface area. There are no adequate and well-controlled studies in pregnant women. RAYALDEE should be used during pregnancy only if the potential benefit justifies potential risk to the fetus. When calcifediol was given orally to bred rabbits on the 6th through the 18th day of gestation, gross visceral and skeletal examination of pups indicated that the

compound was teratogenic at doses of 25 and 50 mcg/kg/day. A dose of 5 mcg/kg/day was not teratogenic. In a similar study in rats, calcifediol was not teratogenic at doses up to and including 60 mcg/kg/day.

Carcinogenesis, Mutagenesis, Impairment of FertilityNo neoplastic changes attributable to calcifediol were observed at subcutaneous doses of 3, 10 and 33 mcg/kg/day in a 26-week rasH2 transgenic mouse study. In vitro or in vivo mutagenicity studies have not been performed with RAYALDEE. No genotoxic or mutagenic effects have been reported with calcifediol.Calcifediol has not been shown to have significant effects on fertility in rats.Labor and Delivery: The effect of this drug on the mother and fetus during labor and delivery is not known.Nursing Mothers: Limited available evidence indicates that calcifediol is poorly excreted in human milk. Caution should be exercised when RAYALDEE is administered to a nursing woman.Pediatric Use: The safety and efficacy of RAYALDEE have not been established in pediatric patients.Geriatric Use: Of the total number of subjects in phase 3 placebo-controlled clinical studies of RAYALDEE, 63% were ≥65 years of age and 22% were ≥75 years of age. No overall differences in the safety or efficacy of RAYALDEE were observed between subjects older than 65 years and younger subjects.Renal ImpairmentNo difference in efficacy was observed between patients with stage 3 chronic kidney disease or those with stage 4 disease in subgroup analysis. Safety outcomes were similar in these subgroups. The safety and efficacy of RAYALDEE in the treatment of secondary hyperparathyroidism in patients with stage 2 or stage 5 chronic kidney disease and patients with end-stage renal disease on dialysis have not been established [see Indications and Usage]. OverdosageExcessive administration of RAYALDEE can cause hypercalciuria, hypercalcemia, hyperphosphatemia, or oversuppression of intact PTH. Common symptoms of vitamin D overdosage may include constipation, decreased appetite, dehydration, fatigue, irritability, muscle weakness, or vomiting.Treatment of acute accidental overdosage with RAYALDEE should consist of general supportive measures. If the overdosage is discovered within a short time, induce emesis or perform gastric lavage to prevent further absorption. Obtain serial serum and urine calcium measurements, and assess any electrocardiographic abnormalities due to hypercalcemia. Discontinue supplemental calcium. Treat with standard medical care if persistent and markedly elevated serum calcium levels occur.Calcifediol is not significantly removed by dialysis.

ADVERSE REACTIONSThe data in Table 1 are derived from two pivotal studies described below. These data reflect exposure of 285 subjects to RAYALDEE 30 or 60 mcg daily for up to 6 months (mean 24 weeks, range 1 to 31 weeks). The mean age of the study population was 66 years old (range 25-85 years). Half of the subjects were male, 65% were White, and 32% were African-American or Black. At baseline, subjects had secondary hyperparathyroidism, stage 3 (52%) or 4 (48%) chronic kidney disease without macroalbuminuria and serum total 25-hydroxyvitamin D levels less than 30 ng/mL. The most common causes of chronic kidney disease were diabetes and hypertension and the mean estimated GFR at baseline was 31 mL/min/1.73 m2. At baseline, mean plasma intact PTH was 148 pg/mL, mean serum calcium was 9.2 mg/dL, mean serum phosphorus was 3.7 mg/dL and mean serum 25-hydroxyvitamin D was 20 ng/mL. Table 1 shows common adverse reactions associated with the use of RAYALDEE in the pooled placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on RAYALDEE than on placebo, and occurred in at least 1.4% of patients treated with RAYALDEE.

Table 1. Common Adverse Reactions in Placebo-controlled Trials Reported in ≥1.4% of RAYALDEE-Treated Subjects

RAYA16AGRX4627_Brief_PI_V2_1_r3_FSU.indd 1 10/18/16 5:17 PM


Obese Living Kidney Donors at Increased ESRD Risk

Albuminuria Screening May Predict Rapid eGFR Decline

No Reduction in AVF Failure with Fish Oil and Aspirin

Among living kidney donors, the long-term risk of ESRD is close to doubled for those who are obese, reports a study in Kidney International.

The study included data on 119,769 living kidney donors, linked to Cent-ers for Medicare & Medicaid Services data to determine ESRD status. There were 20,588 obese donors, body mass index (BMI) 30 kg/m2 or higher; and 58,004 nonobese donors. (The remain-ing 41,177 donors had missing data on BMI.) Postdonation risk of ESRD was compared between groups, with adjust-

ment for potential confounders.Twenty years after living kidney

donation, the cumulative incidence of ESRD was 93.9 per 10,000 for obese donors versus 39.7 per 10,000 for non-obese donors. In adjusted models, obe-sity was the only potentially modifiable risk factor associated with increased ESRD risk: adjusted hazard ratio 1.86. For each one-unit increase in BMI over 27 kg/m2, there was a 7% increase in ESRD risk.

While the absolute risk of ESRD af-ter living kidney donation is low, the

risk is significantly higher for obese donors. The increase in risk begins at a donor BMI of 27 kg/m2—below the standard cutoff for obesity. The authors discuss the implications for living donor selection prac-tices, including the possibility of predonation rehabilitation or weight loss programs [Locke JE, et al. Obesity increases the risk of end-stage renal disease among liv-ing kidney donors. Kidney Int 2016; DOI: http://dx.doi.org/10.1016/j.kint.2016.10.014].

Screening for elevated albuminuria and hypertension may identify a group of pa-tients at increased risk of faster decline in kidney function, reports a study in Neph-rology Dialysis Transplantation.

The study included 6471 participants from the population-based Prevention of Renal and Vascular End-stage Disease (PREVEND) study. All had at least two (median four) measurements of estimated glomerular filtration rate (eGFR) over a median 11.3 years’ follow-up. Elevated albuminuria was defined as an albumin concentration of 20 mg/L or higher in a

first morning urine sample, confirmed by an albumin excretion of 30 mg/d or higher in two 24-hour urine collections. Hyper-tension was defined as a blood pressure of 140/90 mm Hg or higher or use of antihy-pertensive drugs.

Participants with elevated albuminu-ria had a faster rate of decline in eGFR during follow-up. This was so in subjects with known hypertension, −1.84 ver-sus −1.16 mL/min/1.73 m2 per year; newly diagnosed hypertension, −1.59 versus −1.14 mL/min/1.73 m2 per year; and normal blood pressure, −1.18 versus

−0.81 mL/min/1.73 m2 per year.The association was strongest in par-

ticipants aged 55 or older and in men. Participants with elevated albuminuria had consistently higher blood pressure. Elevated albuminuria and as yet un-known hypertension was associated with the highest blood pressure. This combi-nation was more than twice as common as elevated albuminuria with known hy-pertension.

Identifying CKD at an early stage might help to prevent ESRD by manag-ing hypertension and albuminuria. Popu-

lation screening for albuminuria might aid in identifying patients at risk of faster decline in kidney function, who could benefit from treatment. This strategy may be most effective in men and in older pa-tients; the authors suggest the possibility of combining albuminuria screening with colorectal cancer screening [Özyilmaz A, et al. Screening for elevated albuminuria and subsequently hypertension identifies subjects in which treatment may be war-ranted to prevent renal function decline. Nephrol Dial Transpl 2016; doi: 10.1093/ndt/gfw414].

Treatment with fish oil and/or aspirin does not reduce the risk of arteriovenous fistula (AVF) failure, reports a rand-omized trial in JAMA Internal Medicine.

The “Omega-3 Fatty Acids (Fish Oils) and Aspirin in Vascular Access Outcomes in Renal Disease” (FAVOURED) study included 567 patients at 35 dialysis cent-ers in Australia, Malaysia, New Zealand, and the United Kingdom. All patients had stage 4 or 5 chronic kidney disease and were undergoing surgical AVF crea-

tion.Patients were randomly assigned

to receive fish oil, 4 g/d, or placebo. A subset of 406 patients were further as-signed to aspirin, 100 mg/d, or placebo. Study treatments began 1 day before sur-gery and continued for 12 weeks. At 12 months, a composite endpoint of fistula thrombosis or abandonment or cannula-tion failure was assessed.

The fistula failure rate was 47% in patients assigned to fish oil or placebo,

with no difference in the composite outcome or its individual components. There was also no difference between the aspirin and placebo groups: fistula failure rate 45% and 43%, respectively. Adverse events, including bleeding, were similar between groups.

Fish oil and aspirin have differing ef-fects that might make them useful for re-ducing the high rates of early thrombosis and maturation failure in AVFs. How-ever, the FAVOURED results show no

significant difference in AVF failure over 12 months, with either fish oil, aspirin, or the combination of the two. The high failure rate of nearly 50% emphasizes the urgent need to improve AVF outcomes [Irish AB, et al. Effect of fish oil sup-plementation and aspirin use on arterio-venous fistula failure in patients requiring hemodialysis: a randomized clinical trial. JAMA Intern Med 2017; doi:10.1001/ja-mainternmed.2016.8029].

Continued on page 14

AKI Linked to Unplanned ReadmissionsAcute kidney injury (AKI) is strongly asso-ciated with an increased risk of unplanned hospital readmissions—especially for acute pulmonary edema, according to a study in BMC Nephrology.

The researchers analyzed Scottish population-based data on 16,453 patients who were hospitalized and survived to dis-charge in 2003. Of these, 2623 patients had AKI, based on KDIGO criteria. AKI and other candidate predictors were ana-lyzed as risk factors for unplanned read-mission or death within 90 days.

The main study outcome occurred in 18.6% of patients: readmission in 2701

and death without readmission in 363. On multivariable analysis, AKI was a strong risk factor for the combined outcome: odds ratio 1.50 for stage 1, 2.23 for stage 2, and 2.80 for stage 3. The reason for re-admission was acute pulmonary edema in 26.6% of AKI cases, compared to 4.0% of those with no AKI and normal kidney function. Although AKI was a strong pre-dictor, it added little incremental value when added to other predictive models.

Acute kidney injury is a common and serious condition; coordinated care is need-ed to prevent avoidable complications. The new analysis finds that AKI is a “strong,

consistent, and independent risk factor” for unplanned hospital readmissions.

More than one-fourth of readmissions in AKI patients may be related to acute pulmonary edema—a potentially modifiable condition. Some readmis-sions “may be avoidable by careful pre-emptive planning after AKI to prevent the development of pulmo-nary edema,” the investigators con-clude [Sawhney S, et al. Acute kidney injury as an independent risk factor for unplanned 90-day hospital readmissions. BMC Nephrol 2017; 18: 9 DOI: 10.1186/s12882-016-0430-4].


Findings

Worldwide Trends in Hypertension: 40-Year Analysis

How Does Switching to HDHPs Affect Diabetes Care?

More than 1 billion people worldwide now have hypertension, with the highest levels now seen in low-income countries in south Asia and sub-Saharan Africa, ac-cording to a report in The Lancet.

The NCD Risk Factor Collaboration analyzed pooled data from 1479 studies that had measured blood pressure in 19.1 million adults. The researchers analyzed trends in mean systolic and diastolic blood pressure from 1975 to 2015, as well as the prevalence of raised blood pressure (140/90 mm Hg or higher) in 200 countries.

In 2015, global age-standardized mean blood pressure increased systolic blood pressure was 127.0/78.7 mm Hg in men and 122.3/76.7 mm Hg in women. The age-standardized prevalence of raised blood pressure was 24.1% and 20.1%, re-spectively.

High-income western and Asia Pacific countries went from having some of the highest measured blood pressure values in the world in 1975 to the lowest in 2015. By 2015, the regions with the highest measured blood pressure levels were cen-

tral and eastern Europe, sub-Saharan Af-rica, and south Asia.

The overall number of adults with raised blood pressure increased from 594 million in 1975 to 1.13 billion in 2015, with most of the increase occurring in low- and middle-income countries. The global increase was attributable to popu-lation growth and ageing, partly offset by decreases in age-specific prevalence.

Over the past 40 years, the high-est measured blood pressure values have shifted from high- to low-income coun-

tries, especially in sub-Saharan Africa. The total number of adults with raised blood pressure has increased by 90%. The au-thors call for multifaceted approaches to address the “large and inequitable burden of cardiovascular diseases and kidney dis-ease associated with high blood pressure” [NCD Risk Factor Collaboration: World-wide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 pop-ulation-based measurement studies with 19.1 million participants. Lancet 2017; 389:37–55].

For patients with diabetes—including but not limited to low-income patients—switching to high-deductible health plan (HDHPs) leads to major increases in emergency department visits for prevent-able acute diabetic complications, reports a study in JAMA Internal Medicine.

The researchers analyzed the effects of an employer-mandated switch to HDHPs in 12,084 diabetic patients, aged 12 to 64 years. All were enrolled in a low-deducti-ble plan ($500 or less) for 1 year, followed by 2 years in an HDHP ($1000 or high-er). The HDHP patients were propensity score-matched to patients who remained

on low-deductible plans only.The effects of switching to an HDHP

on diabetes outpatient care and acute complications were assessed, including ED visits for preventable complications. Subgroup analyses focused on 4121 low-income patients and 1899 patients eligi-ble for health savings accounts (HSAs).

Out-of-pocket costs increased for dia-betic patients in the year after switching to HDHPs: by 49.4% overall, 51.7% for low-income patients, and 67.8% for HSA-eligible patients. There was no change in high-priority primary care visits or use of disease monitoring tests. Howev-

er, high-priority specialist visits decreased by 5.5% in the first year and 7.1% in the second year.

After the switch to an HDHP, outpa-tient visits for acute diabetes complica-tions were delayed in both the overall and low-income cohorts: adjusted hazard ratio 0.94 and 0.89, respectively. Annual ED visits for acute complications increased by 8.0% for all patients, 15.5% in HSA-eli-gible patients, and 21.7% in low-income patients.

Switching to an HDHP does not ap-pear to affect outpatient visits and dis-ease monitoring for diabetic patients.

However, rates of ED visits for prevent-able acute diabetes complications are substantially increased, particularly for low-income, high-morbidity, and HSA-eligible patients. With the increasing fo-cus on HDHPs in the US healthcare sys-tem, the authors discuss implications for preventing adverse effects on diabetes care [Wharam FJ, et al. Diabetes outpatient care and acute complications before and after high-deductible insurance enroll-ment: a Natural Experiment for Transla-tion in Diabetes (NEXT-D) study. JAMA Intern Med 2017; doi:10.1001/jamain-ternmed.2016.8411].

Continued from page 13

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Better Data on Living Donor Risks Improves Consent By Bridget M. Kuehn

growing understanding of the health and psychosocial risks associated with being a living kidney donor is helping drive innovations that will improve the informed consent process, according

to recent research. Receiving a kidney donated by a living donor

greatly improves the outcomes of patients with kidney failure. But it also creates risks for the 30,000 otherwise healthy donors around the world who donate kidneys each year. Ensuring that living donors give proper informed consent is essential. Now, a growing body of evidence on the risks associated with living kidney donation and emerging tools to help clinicians and patients assess them are helping to improve the process of informed consent.

“Our ability to walk donors through informed consent has exponentially improved,” said Robert S. Gaston, MD, director of the Comprehensive Transplantation Institute at the University of Alabama-Birmingham. “I think we will be able to plug [infor-mation] into a calculator really soon and give an absolute risk.” Gaston spoke at a Kidney Week 2016 symposium.

Modeling riskScientists have created models that can help clinicians assess the risks faced by an individual donor based on several demographic and health characteristics (Grams ME, et al. N Engl J Med 2016; 374:411–421). Living donors have about a 3.5- to 5.3-fold higher risk of kidney failure than comparable individuals in the US population, said Robert Foley, MD, associate profes-sor of medicine in the division of renal diseases at the University of Minnesota. Fagan noted that the absolute risks of end stage renal disease (ESRD) are still low.

Among the factors that increase the risk of living donors developing ESRD are the development of post-donation diabetes or hypertension, which boost the risk of proteinuria fourfold and the risk of ESRD by more than twofold, respectively (Ibrahim HN, et al. J Am Soc Nephrol 2016; 27:2885–2893).

Even then, predonation factors can help identify individuals at greatest risk.

“What I’d really like to get to is a clinical model that would help donors,” Foley said. Ideally, he said such a tool would be very simple and use a spreadsheet program or graphs to explain individual risks and how they might be managed, for example, by keeping blood pressure within the normal range or making lifestyle choices to minimize the risk of diabetes posttransplant.

Pregnancy risksEmerging data also suggest that women who have

donated a kidney may have worse pregnancy outcomes. Women who donate a kidney have an elevated risk

of gestational hypertension compared with those who have never donated a kidney (OR 2.4; 95% confidence interval, 1.2 to 5.0; p=0.01) (Garg AX, et al. N Engl J Med 2015; 372:124–133).

Another study that compared donors’ pre- and post-donation pregnancies found a higher risk of preterm delivery, fetal loss, gestational diabetes, hypertension, proteinuria, and preeclampsia postdonation (Ibrahim HN, et al. Am J Transplant 2009; 9:825–834).

The absolute risks of these outcomes are low, and generally on par with or lower than the risk of this outcome in the general population because donors are healthier than the general population, said Mirna Boumitri, MD, an assistant professor of medicine in the division of renal diseases at the University of Minnesota. Still, “women should be counseled about postdonation risks to pregnancy,” Boumitri said.

Paying to donateLiving kidney donors may also face financial or psy-chosocial consequences of their decision to donate. But better and more consistent screening can help identify donors at risk.

Cheryl Jacobs, MSW, a clinical transplant social worker at the University of Minnesota Medical Center, said her institution has taken steps to ensure that donors are properly screened. They also use a donor advocate who is not involved in the donor’s medi-cal care, which is now required by the Centers for Medicare & Medicaid Services.

“We really wanted to make sure we did things con-sistently,” she said.

Many donors report unchanged or even improved quality of life and other psychosocial function after donating a kidney (Clemens KK, et al. Am J Transplant 2006; 6:2965–2977). But a small number may face poor psychosocial outcomes, Jacobs noted.

A number of factors, including having good family or other support, viewing the donation process posi-tively, having a higher level of education, and greater comfort with the decision to donate, all appear to protect against poor outcomes, Jacobs said. But other factors, including having poor mental health, lim-ited support, a longer recovery, or financial hardships related to the donation, may lead to poorer outcomes.

Many donors report lost income, dependent care costs, as well as travel and health care costs related to their donation. One study found that 89% of donors suffered a financial loss during the first year after dona-tion, with one-third reporting a loss of more than $2500 (Rodrigue JR, et al. Am J Transplant 2016; 16:869–876)

“Donors are paying to donate,” Jacobs said. Donors may also have a harder time accessing health

or life insurance, Jacobs said. Some programs have been created to help neutralize the costs to donors. For example, travel grants may be available for some donors. Additionally, the US Living Donor Protection Act, which would prevent insurers from punishing donors, was introduced recently.

“We owe it to donors to advocate where there are gaps,” Jacobs said.

A

Pregnancy and End Stage Renal Disease

Practice Pointers

How frequent is pregnancy in ESRD? What are the current out-comes?Fertility is reduced in dialysis patients. The reasons are multifactorial and include hor-monal abnormalities, such as hyperprolactinemia and hypergonadotrophic hypog-onadism, anovulatory cycles, and sexual dysfunction (1). In the United States, among women of childbearing age on dialysis, frequency of pregnancy is around 0.5% per year on the basis of survey results (1). Some countries have reported up to 1.4% per year frequency rates. For reasons that are not well understood, patients on hemo-dialysis have a two to three times greater likelihood of conception than patients on peritoneal dialysis (2). Experts think peritoneal solution may cause interference with implantation and ovum transport.

Approximately 50% of pregnancies result in survival of infants. However, many of these infants are premature and small for gestational age. These infants can have multiple medical and developmental problems (1).

What treatment modalities are best for mother and child? When is fetal monitoring initiated?Pregnancy requires more aggressive dialysis. This means more frequent dialysis, at least six times a week with a target BUN <45 mg/dL (3). Better outcomes are reported for infants born to pregnant women dialyzed more than 36 hours per week. Intense dialy-sis improves uremic and maternal volume status. Therefore, these infants have a higher live birth rate compared with those of pregnant women who were dialyzed less fre-quently (4). Kidney Disease Outcomes Quality Initiative guidelines also recommend long frequent dialysis. However, the standard method to calculate Spkt/V cannot be used, because the equation applies to thrice weekly hemodialysis.

It is also a challenge to adjust the ultrafiltration goal and/or establish a dry weight for the patient. Elevated BP in pregnancy may not always be volume mediated and may be related to preeclampsia. Careful attention is needed to avoid hypotension, which can lead to placental hypoperfusion. Daily dialysis does help in assisting vol-ume balance.

Frequent hemodialysis will mean very careful adjustments in potassium, calcium, and bicarbonate to avoid hypercalcemia and alkalosis (5). A regimen of daily dialysis can lead to alkalosis, and the the bicarbonate bath needs to be adjusted to maintain bicarbonate levels around 20 mEq/L (1). Typical dialysate potassium of 3 mEq/L and bicarbonate concentration of 25 mEq/L are needed.

Peritoneal dialysis may be used and may also be useful in avoiding rapid metabolic changes. However, as pregnancy progresses, it can become difficult to tolerate the exchange volumes (1).

Fetal monitoring is done as per obstetric guidelines using serial ultrasound to ex-amine fetal growth and evaluate the placenta and amniotic fluid. Weekly fetal surveil-lance is started around 24 to 26 weeks using ultrasound and biophysical profile (6).

What medications are safe?Antihypertensive medications that are safe and commonly used are methyldopa, la-betalol, hydralazine, and dihydropyridine calcium channel blockers. b-blockers other than labetalol can cause fetal bradycardia. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are contraindicated, because they can increase the risk of major congenital malformations (7).

As patients are dialyzed more often, caution and proper medication adjustment are needed to avoid hypotension. Target postdialysis BP should be less than 140/90 mm Hg.

In terms of anticoagulation, heparin can be used in dialysis. It does not cross the placenta, and it is not teratogenic (8). Coumadin cannot be used, and patients who are on Coumadin for access-related clotting problems will have to be changed to sub-cutaneous heparin (9). Low molecular weight heparins, such as enoxaparin, and novel oral anticoagulants, such as rivoraxaban, dabigatran, and apixaban, are not approved for use in dialysis patients.

Calcium-based phosphorus binders are probably the safest to continue as long as calcium concentration is monitored and maintained within normal limits. Active vitamin D derivatives and vinacalcet are all category C drugs with only case reports of their use. There are not enough reports to show safety. A higher dose of folic acid (at least 5 mg/d) is also needed during pregnancy owing to higher dosage needs and removal of water-soluble vitamins caused by intensive dialysis. The multivitamin dose is also doubled daily.

Is anemia management different? Are there concerns regarding erythropoietin or transfusion?Anemia, especially hemoglobin levels <8 g/dL, can have adverse effects on the fetus (2). Erythropoietic agents can be used in pregnancy, because there are no reports of teratogenicity (10). Previous studies do not show transfer of epoetin alfa (epogen) across the placenta (11). Multidose formulations containing benzyl alcohol are con-traindicated, and single-dose preparations should be used. Dose requirements are 50 to 100% more for pregnant women on dialysis and can be increased right away (1). Intravenous iron preparations can be continued as well, although safety data are lack-ing. There are sparse reports about packed red blood cell transfusion during preg-nancy; therefore, it should be used cautiously following current transfusion guidelines.

What are the postpartum issues for the mother and the baby?The pregnant dialysis patient requires a highly specialized team, including the neph-rologist, a high-risk pregnancy obstetrician, and a neonatologist. The number one issue encountered in pregnant dialysis patients is prematurity, which in turn, is the greatest cause of morbidity and mortality in the infants (1).

Other complications include preeclampsia, polyhydramnios, and premature labor. Most commonly used medicines, such as intravenous magnesium to stop preterm labor, are difficult to use, because they can lead to magnesium toxicity and cause respiratory depression (12). Timing of delivery is usually around 34 to 36 weeks, but the mean gestational age has been noted to be only 32 to 36 weeks. Infants of dialysis patients are born with BUN and creatinine levels similar to the levels of the mother. After birth, these infants can have an osmotic diuresis and develop volume contraction with metabolic alkalosis (13).

AcknowledgmentsAs a practicing nephrologist, I am indebted to my patients for giving me the opportu-nity to provide care for them and the inspiration to learn.

SuggestionsSearch for this topic revealed multiple review articles but few prospective studies ex-amining management and outcomes of pregnant dialysis patients. I recommend an ongoing registry for pregnant patients on dialysis.

References1. Hou S. Pregnancy in chronic renal insufficiency and end stage renal disease. Am

J Kidney Dis 1999; 33:2235–2252.2. Okyndaye IB, Abrinko P, Hou S. Registry for pregnancy in dialysis patients. Am

J Kidney Dis 1998; 31:766–773.3. August P. Pregnancy in Women with Underlying Renal Disease. www.uptodate.

com.4. Hiadunewich MA, et al. Intensive hemodialysis associated with improved preg-

nancy outcomes: A Canadian and United States Cohort Comparison. J Am Soc Nephrol 2014; 25:1103–1109.

5. Hou S. Pregnancy in dialysis patients: Where do we go from here? Semin Dial 2003; 16:376–378.

6. Bagon JA, et al. Pregnancy and dialysis. Am J Kidney Dis 1998; 31:756–765.7. Krane NK, Hamrahian M. Pregnancy: Kidney diseases and hypertension. Am J

Kidney Dis 2007; 49:336–345.8. Ginsberg JS, et al. Heparin therapy during pregnancy. Risks to the fetus and

mother. Arch Intern Med 1989; 149:2233–2236.9. Briggs GG, Freeman RK, Jaffe SJ. Drugs in Pregnancy and Lactation, Baltimore,

MD, Williams and Wilkins, 1994.10. Hou SH, et al. Pregnancy in women with end stage renal disease: Treatment of

anemia and premature labor. Am J Kidney Dis 1993; 21:16–22.11. Zanjani ED, et al. Erythropoietin does not cross the placenta into the fetus.

Pathobiology 1993; 61:211–215.12. Redrow M, et al. Dialysis in the management of pregnant patients with renal

insufficiency. Medicine (Baltimore) 1998; 67:199–208.13. Bolwey DL, Warady BA. Neonatal outcome in pregnancies associated with renal

replacement therapy. Adv Ren Replace Ther 1998; 5:45–52.

Rhaki Khanna, DO, is a nephrologist in Gurnee, IL.

By Rakhi Khanna

Continued from page 15


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Challenge your knowledge and diagnostic skills.

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depression undertreated in patients receiving chronic

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