Frailty as a dynamic process in a diverse cohort of older persons with dialysis-dependent CKD.

This study examines frailty status evolution observed in a two-year follow-up of a cohort of older persons (age ≥65) with chronic kidney disease (CKD) undergoing maintenance hemodialysis (HD) treatment. Frailty, a geriatric syndrome that connotes a state of low physiologic reserve and vulnerability to stressors, is associated with increased risk for multiple adverse health outcomes in studies of persons with CKD as well as older persons in the general population. The Fried frailty index defines frailty as the presence of 3 or more of 5 indicators-recent unintentional weight loss, slowed gait speed, decreased muscle strength, self-reported exhaustion, and low physical activity. In the seminal work by Fried and colleagues, persons who were characterized by 1-2 of the Fried index criteria were termed "pre-frail" and considered at risk for subsequently becoming frail, potentially providing insight regarding intervention targets that might slow or prevent individuals' transition from pre-frail to frail status. Other less frequently studied types of transitions may also be informative, including "recovery or reversion" (improvement) by people whose longitudinal assessments indicate movement from frailty to prefrailty or robust, or from prefrailty to robust. These status changes are also a potential source of insights relevant for prevention or remediation of frailty, but research focusing on the various ways that individuals may transition between frailty states over time remains limited, and no previous research has examined varying patterns of frailty status evolution in an older cohort of persons with dialysis-dependent CKD. In a study cohort of dialysis-dependent older persons, we characterized patterns of frailty status evolution by age, sex, race/ethnicity, and treatment vintage; by longitudinal profiles of non-sedentary behavior; and by self-report indicators relevant for dimensions emphasized in the Age-Friendly 4Ms Health System (What Matters, Mobility, Mentation). Our study suggests that strategies to promote resiliency among older persons with dialysis-dependent CKD can be informed not only by frailty status transition that indicates improvement over time but also by older adults' maintenance of (stable) robust status over time, and we concur that inclusion of both frailty and resilience measures is needed in future longitudinal studies and clinical trials.

Sphinganine is associated with 24-h MAP in the non-sleepy with OSA.

INTRODUCTION: Excessive daytime sleepiness is a debilitating symptom of obstructive sleep apnea (OSA) linked to cardiovascular disease, and metabolomic mechanisms underlying this relationship remain unknown. We examine whether metabolites from inflammatory and oxidative stress-related pathways that were identified in our prior work could be involved in connecting the two phenomena. METHODS: This study included 57 sleepy (Epworth Sleepiness Scale (ESS) ≥ 10) and 37 non-sleepy (ESS < 10) participants newly diagnosed and untreated for OSA that completed an overnight in-lab or at home sleep study who were recruited from the Emory Mechanisms of Sleepiness Symptoms Study (EMOSS). Differences in fasting blood samples of metabolites were explored in participants with sleepiness versus those without and multiple linear regression models were utilized to examine the association between metabolites and mean arterial pressure (MAP). RESULTS: The 24-h MAP was higher in sleepy 92.8 mmHg (8.4) as compared to non-sleepy 88.8 mmHg (8.1) individuals (P = 0.03). Although targeted metabolites were not significantly associated with MAP, when we stratified by sleepiness group, we found that sphinganine is significantly associated with MAP (Estimate = 8.7, SE = 3.7, P = 0.045) in non-sleepy patients when controlling for age, BMI, smoking status, and apnea-hypopnea index (AHI). CONCLUSION: This is the first study to evaluate the relationship of inflammation and oxidative stress related metabolites in sleepy versus non-sleepy participants with newly diagnosed OSA and their association with 24-h MAP. Our study suggests that Sphinganine is associated with 24 hour MAP in the non-sleepy participants with OSA.

Sleep Disturbances in MCI and AD: Neuroinflammation as a Possible Mediating Pathway.

Mild cognitive impairment (MCI) and Alzheimer's disease (AD) affect a high proportion of the elderly population with an increasing prevalence. Sleep disturbances are frequent in those with MCI and AD. This review summarizes existing research on sleep disturbances and neuroinflammation in MCI and AD. Although strong evidence supports various pathways linking sleep and AD pathology, the temporal direction of this central relationship is not yet known. Improved understanding of sleep disturbance and neuroinflammation in MCI and AD may aid in the identification of targets for their prevention.

Comparative Efficacy of Therapies for Treatment of Depression for Patients Undergoing Maintenance Hemodialysis: A Randomized Clinical Trial.

Background: Although depression is common among patients receiving maintenance hemodialysis, data on their acceptance of treatment and on the comparative efficacy of various therapies are limited. Objective: To determine the effect of an engagement interview on treatment acceptance (phase 1) and to compare the efficacy of cognitive behavioral therapy (CBT) versus sertraline (phase 2) for treating depression in patients receiving hemodialysis. Design: Multicenter, parallel-group, open-label, randomized controlled trial. (ClinicalTrials.gov: NCT02358343). Setting: 41 dialysis facilities in 3 U.S. metropolitan areas. Participants: Patients who had been receiving hemodialysis for at least 3 months and had a Beck Depression Inventory-II score of 15 or greater; 184 patients participated in phase 1, and 120 subsequently participated in phase 2. Intervention: Engagement interview versus control visit (phase 1) and 12 weeks of CBT delivered in the dialysis facility versus sertraline treatment (phase 2). Measurements: The primary outcome for phase 1 was the proportion of participants who started depression treatment within 28 days. For phase 2, the primary outcome was depressive symptoms measured by the Quick Inventory of Depressive Symptoms-Clinician-Rated (QIDS-C) at 12 weeks. Results: The proportion of participants who initiated treatment after the engagement or control visit did not differ (66% vs. 64%, respectively; P = 0.77; estimated risk difference, 2.1 [95% CI, -12.1 to 16.4]). Compared with CBT, sertraline treatment resulted in lower QIDS-C depression scores at 12 weeks (effect estimate, -1.84 [CI, -3.54 to -0.13]; P = 0.035). Adverse events were more frequent in the sertraline than the CBT group. Limitation: No randomized comparison was made with no treatment, and persistence of treatment effect was not assessed. Conclusion: An engagement interview with patients receiving maintenance hemodialysis had no effect on their acceptance of treatment for depression. After 12 weeks of treatment, depression scores were modestly better with sertraline treatment than with CBT. Primary Funding Source: Patient-Centered Outcomes Research Institute, Dialysis Clinic, Kidney Research Institute, and National Institute of Diabetes and Digestive and Kidney Diseases.

Acupuncture for Treatment of Persistent Disturbed Sleep: A Randomized Clinical Trial in Veterans With Mild Traumatic Brain Injury and Posttraumatic Stress Disorder.

OBJECTIVE: To evaluate real, as compared with sham, acupuncture in improving persistent sleep disturbance in veterans with mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD). METHODS: This sham-controlled randomized clinical trial at a US Department of Veterans Affairs Medical Center (2010-2015) included 60 veterans aged 24-55 years (mean of 40 years) with history of mTBI of at least 3 months and refractory sleep disturbance. Most of these participants (66.7%) carried a concurrent DSM-IV clinical diagnosis of PTSD. For the present study, they were randomized into 2 groups and stratified by PTSD status using the PTSD Checklist-Military Version. Each participant received up to 10 treatment sessions. The primary outcome measure was change in baseline-adjusted global Pittsburgh Sleep Quality Index (PSQI) score following intervention. Secondary outcomes were wrist-actigraphy-assessed objective sleep measurements. Comorbid PTSD was analyzed as a covariate. RESULTS: Mean (SD) preintervention global PSQI score was 14.3 (3.2). Those receiving real acupuncture had a global PSQI score improvement of 4.4 points (relative to 2.4 points in sham, P = .04) and actigraphically measured sleep efficiency (absolute) improvement of 2.7% (relative to a decrement of 5.3% in sham, P = .0016). Effective blinding for active treatment was maintained in the study. PTSD participants presented with more clinically significant sleep difficulties at baseline; acupuncture was effective for both those with and without PTSD. CONCLUSIONS: Real acupuncture, compared with a sham needling procedure, resulted in a significant improvement in sleep measures for veterans with mTBI and disturbed sleep, even in the presence of PTSD. These results indicate that an alternative-medicine treatment modality like acupuncture can provide clinically significant relief for a particularly recalcitrant problem affecting large segments of the veteran population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01162317.

Ability to Work among Patients with ESKD: Relevance of Quality Care Metrics.

Enabling patient ability to work was a key rationale for enacting the United States (US) Medicare program that provides financial entitlement to renal replacement therapy for persons with end-stage kidney disease (ESKD). However, fewer than half of working-age individuals in the US report the ability to work after starting maintenance hemodialysis (HD). Quality improvement is a well-established objective in oversight of the dialysis program, but a more patient-centered quality assessment approach is increasingly advocated. The ESKD Quality Incentive Program (QIP) initiated in 2012 emphasizes clinical performance indicators, but a newly-added measure requires the monitoring of patient depression-an issue that is important for work ability and employment. We investigated depression scores and four dialysis-specific QIP measures in relation to work ability reported by a multi-clinic cohort of 528 working-age maintenance HD patients. The prevalence of elevated depression scores was substantially higher among patients who said they were not able to work, while only one of the four dialysis-specific clinical measures differed for patients able/not able to work. Ability to work may be among patients' top priorities. As the parameters of quality assessment continue to evolve, increased attention to patient priorities might facilitate work ability and employment outcomes.

Association of Nondisease-Specific Problems with Mortality, Long-Term Care, and Functional Impairment among Older Adults Who Require Skilled Nursing Care after Dialysis Initiation.

BACKGROUND AND OBJECTIVES: The majority of older adults who initiate dialysis do so during a hospitalization, and these patients may require post-acute skilled nursing facility (SNF) care. For these patients, a focus on nondisease-specific problems, including cognitive impairment, depressive symptoms, exhaustion, falls, impaired mobility, and polypharmacy, may be more relevant to outcomes than the traditional disease-oriented approach. However, the association of the burden of nondisease-specific problems with mortality, transition to long-term care (LTC), and functional impairment among older adults receiving SNF care after dialysis initiation has not been studied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We identified 40,615 Medicare beneficiaries ≥65 years old who received SNF care after dialysis initiation between 2000 and 2006 by linking renal disease registry data with the Minimum Data Set. Nondisease-specific problems were ascertained from the Minimum Data Set. We defined LTC as ≥100 SNF days and functional impairment as dependence in all four essential activities of daily living at SNF discharge. Associations of the number of nondisease-specific problems (≤1, 2, 3, and 4-6) with 6-month mortality, LTC, and functional impairment were examined. RESULTS: Overall, 39.2% of patients who received SNF care after dialysis initiation died within 6 months. Compared with those with ≤1 nondisease-specific problems, multivariable adjusted hazard ratios (95% confidence interval) for mortality were 1.26 (1.19 to 1.32), 1.40 (1.33 to 1.48), and 1.66 (1.57 to 1.76) for 2, 3, and 4-6 nondisease-specific problems, respectively. Among those who survived, 37.1% required LTC; of those remaining who did not require LTC, 74.7% had functional impairment. A higher likelihood of transition to LTC (among those who survived 6 months) and functional impairment (among those who survived and did not require LTC) was seen with a higher number of problems. CONCLUSIONS: Identifying nondisease-specific problems may help patients and families anticipate LTC needs and functional impairment after dialysis initiation.

Preemptive kidney transplantation is associated with survival benefits among pediatric patients with end-stage renal disease.

Kidney transplantation is the preferred treatment for pediatric end-stage renal disease (ESRD). Preemptive transplantation avoids the increased morbidity and mortality of dialysis. Yet, previous studies have not demonstrated significant graft or patient survival benefits for children undergoing transplantation preemptively versus nonpreemptively. These previous studies were limited by small samples sizes and low rates of adverse events. Here we compared graft failure and mortality rates using Kaplan-Meier methods and Cox regression among a large national cohort of children with ESRD undergoing preemptive versus nonpreemptive kidney transplantation between 2000 and 2012. Among 7527 pediatric kidney transplant recipients in the United States Renal Data System, 1668 underwent preemptive transplantation. Over a median 4.8 years follow-up, 1314 experienced graft failure, and over a median 5.2 years of follow-up, 334 died. Dialysis exposure versus preemptive transplantation conferred a higher risk of graft failure (hazard ratio 1.32; 95% confidence interval: 1.10-1.56) and a higher risk of death (hazard ratio 1.69; 95% confidence interval: 1.22-2.33) in multivariable analysis. Compared with children undergoing preemptive transplantation, children on dialysis for >1 year had a 52% higher risk of graft failure and those on dialysis >18 months had an 89% higher risk of death, regardless of donor source. Thus, preemptive transplantation is associated with substantial benefits in allograft and patient survival among children with ESRD, particularly when compared with children who receive dialysis for >1 year. These findings support policies to promote early access to transplantation and avoidance of dialysis for children with ESRD whenever feasible.

Patient and Other Stakeholder Engagement in Patient-Centered Outcomes Research Institute Funded Studies of Patients with Kidney Diseases.

Including target populations in the design and implementation of research trials has been one response to the growing health disparities endemic to our health care system, as well as an aid to study generalizability. One type of community-based participatory research is "Patient Centered-Research", in which patient perspectives on the germane research questions and methodologies are incorporated into the study. The Patient-Centered Outcomes Research Institute (PCORI) has mandated that meaningful patient and stakeholder engagement be incorporated into all applications. As of March 2015, PCORI funded seven clinically-focused studies of patients with kidney disease. The goal of this paper is to synthesize the experiences of these studies to gain an understanding of how meaningful patient and stakeholder engagement can occur in clinical research of kidney diseases, and what the key barriers are to its implementation. Our collective experience suggests that successful implementation of a patient- and stakeholder-engaged research paradigm involves: (1) defining the roles and process for the incorporation of input; (2) identifying the particular patients and other stakeholders; (3) engaging patients and other stakeholders so they appreciate the value of their own participation and have personal investment in the research process; and (4) overcoming barriers and challenges that arise and threaten the productivity of the collaboration. It is our hope that the experiences of these studies will further interest and capacity for incorporating patient and stakeholder perspectives in research of kidney diseases.

Lower C-reactive protein and better hemodialysis survival are associated with regular exercise activity: Longitudinal outcomes from the ACTIVE-ADIPOSE special study.

Introduction Cross-sectional and longitudinal studies in the general population have shown that a physically active lifestyle may have anti-inflammatory properties, but evidence from studies conducted with maintenance hemodialysis (HD) patients is limited. Methods A multicenter prospective cohort of 755 HD participants aged 20-92 was evaluated in a USRDS special study 2009-2013. Kilocalories/week (kcal/week) of leisure time physical activity (LTPA) was estimated from the Minnesota Leisure Time Activity questionnaire. Predialysis serum samples were obtained concurrent with LTPA report date. Generalized estimating equations (GEE) examined association of participants' LTPA and log-normalized CRP across 24 months. Cox proportional hazards models investigated LTPA and survival over a median follow-up of 718 days. Findings Baseline median CRP concentration was lower for participants with 500+ kcal/week LTPA vs. those with <500 kcal/week LTPA (3.4 mg/L vs. 4.6 mg/L; P = 0.03). Participants who reported lower LTPA (<500 kcal/week) at both baseline and 12 months had a borderline significant increase in CRP concentration (within-group change 4.8 [1.9-10.4] to 5.8 [1.6-15.7]; P = 0.08). Lower LTPA was associated with higher log CRP over 24 months in adjusted GEE analyses (ß coefficient = 0.16 [95% CI 0.02-0.31]; P = 0.03). 67/364 (18%) and 43/391 (11%) deaths occurred, respectively, among participants reporting <500 vs. 500+ kcal/week LTPA [adjusted mortality hazard ratio 1.63 (CI, 1.07, 2.47)]. Discussion The data suggest that increased estimated levels of LTPA, a physical activity/exercise opportunity widely applicable to HD patients, may be associated with lower CRP concentration as well as better survival outcome.

Rationale and design of A Trial of Sertraline vs. Cognitive Behavioral Therapy for End-stage Renal Disease Patients with Depression (ASCEND).

Major Depressive Disorder (MDD) is highly prevalent in patients with End Stage Renal Disease (ESRD) treated with maintenance hemodialysis (HD). Despite the high prevalence and robust data demonstrating an independent association between depression and poor clinical and patient-reported outcomes, MDD is under-treated when identified in such patients. This may in part be due to the paucity of evidence confirming the safety and efficacy of treatments for depression in this population. It is also unclear whether HD patients are interested in receiving treatment for depression. ASCEND (Clinical Trials Identifier Number NCT02358343), A Trial of Sertraline vs. Cognitive Behavioral Therapy (CBT) for End-stage Renal Disease Patients with Depression, was designed as a multi-center, 12-week, open-label, randomized, controlled trial of prevalent HD patients with comorbid MDD or dysthymia. It will compare (1) a single Engagement Interview vs. a control visit for the probability of initiating treatment for comorbid depression in up to 400 patients; and (2) individual chair-side CBT vs. flexible-dose treatment with a selective serotonin reuptake inhibitor, sertraline, for improvement of depressive symptoms in 180 of the up to 400 patients. The evolution of depressive symptoms will also be examined in a prospective longitudinal cohort of 90 HD patients who choose not to be treated for depression. We discuss the rationale and design of ASCEND, the first large-scale randomized controlled trial evaluating efficacy of non-pharmacologic vs. pharmacologic treatment of depression in HD patients for patient-centered outcomes.

Estimated pulmonary artery systolic pressure and self-reported physical function in patients on hemodialysis.

BACKGROUND/AIMS: Patients on chronic hemodialysis have a high prevalence of heart disease and poor self-reported physical function. The association between structural heart disease and self-reported physical function in patients on hemodialysis is unknown. METHODS: We studied the association between elevated pulmonary artery systolic pressure (PASP) and self-reported physical function in ESRD in 253 patients in the USRDS ACTIVE/ADIPOSE study between 2009 and 2011. We used multivariate linear regression with PASP obtained from clinical echocardiogram reports as the primary predictor and the Physical Function (PF) subscale of the SF-36 as the primary outcome. To determine whether associations between PASP and PF were driven by fluid overload or left ventricular hypertrophy, we assessed whether PASP was associated with bioimpedance spectroscopy (BIS)-derived extracellular water (ECW) and with left ventricular posterior wall thickness. RESULTS: In a multivariable model, each 10 mm Hg higher PASP was associated with a 3.32-point lower PF score (95% CI -5.95, -0.68). In a multivariable model that included BIS estimates, both left ventricular posterior wall thickness (LVPW, per 5 mm) and ECW were associated with a higher PASP (LVPW 4.21 mm Hg, 95% 0.38-8.04; ECW 1.12 mm Hg per liter, 95% CI 0.07-2.18). Higher LVPW and ECW were independently associated with a lower PF score. CONCLUSION: Left ventricular hypertrophy and elevated pulmonary pressure are associated with worse self-reported physical function in patients on hemodialysis. The role of chronic volume overload on PASP and PF score should be evaluated in a prospective manner.

Gait Speed and Mortality, Hospitalization, and Functional Status Change Among Hemodialysis Patients: A US Renal Data System Special Study.

BACKGROUND: Slow walk (gait) speed predicts functional decline, institutionalization, and mortality risks in the geriatric population. A gait speed evidence base for dialysis patient outcomes is needed. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 752 prevalent hemodialysis (HD) patients aged 20 to 92 years evaluated in 2009 to 2012 in 7 Atlanta and 7 San Francisco clinics in a US Renal Data System special study. PREDICTOR: Usual walk speed in meters per second, categorized as ≥0.6 m/s (baseline n=575), <0.6 m/s (baseline n=94), and unable to perform walk test (baseline n=83). OUTCOMES: Survival; hospitalization; activities of daily living (ADL) difficulty; 36-Item Short Form Health Survey (SF-36) Physical Function score. MEASUREMENTS: Cox proportional hazards models investigated gait speed and mortality over a median follow-up of 703 days. Multivariable logistic or linear regression models estimated associations of baseline gait speed with hospitalization, need for ADL assistance, and SF-36 Physical Function score after 12 months. RESULTS: Participants who walked ≥0.6 m/s had 53 (9%) deaths, those who walked <0.6 m/s had 19 (20%) deaths, and those unable to walk had 37 (44%) deaths. Adjusted mortality hazard ratios were 2.17 (95% CI, 1.19-3.98) for participants who walked <0.6 m/s and 6.93 (95% CI, 4.01-11.96) for those unable to walk, compared with participants walking ≥0.6 m/s. After 12 months, compared with baseline walk speed ≥ 1.0 m/s (n=169 participants), baseline walk speed of 0.6 to <0.8 m/s (n=116) was associated with increased odds of hospitalization (OR, 2.04; 95% CI, 1.19-3.49) and ADL difficulty (OR, 3.88; 95% CI, 1.46-10.33) and a -8.20 (95% CI, -13.57 to -2.82) estimated change in SF-36 Physical Function score. LIMITATIONS: Cohort not highly representative of overall US in-center HD population. CONCLUSIONS: Because walking challenges the heart, lungs, and circulatory, nervous, and musculoskeletal systems, gait speed provides an informative marker of health status. The association of gait speed with HD patients' risk for functional decline warrants continued study.

Underreporting of nursing home utilization on the CMS-2728 in older incident dialysis patients and implications for assessing mortality risk.

BACKGROUND: The usage of nursing home (NH) services is a marker of frailty among older adults. Although the Centers for Medicare & Medicaid Services (CMS) revised the Medical Evidence Report Form CMS-2728 in 2005 to include data collection on NH institutionalization, the validity of this item has not been reported. METHODS: There were 27,913 patients ≥ 75 years of age with incident end-stage renal disease (ESRD) in 2006, which constituted our analysis cohort. We determined the accuracy of the CMS-2728 using a matched cohort that included the CMS Minimum Data Set (MDS) 2.0, often employed as a "gold standard" metric for identifying patients receiving NH care. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the CMS-2728 NH item. Next, we compared characteristics and mortality risk by CMS-2728 and MDS NH status agreement. RESULTS: The sensitivity, specificity, PPV and NPV of the CMS-2728 for NH status were 33%, 97%, 80% and 79%, respectively. Compared to those without the MDS or CMS-2728 NH indicator (No MDS/No 2728), multivariable adjusted hazard ratios (95% confidence interval) for mortality associated with NH status were 1.55 (1.46 - 1.64) for MDS/2728, 1.48 (1.42 - 1.54) for MDS/No 2728, and 1.38 (1.25 - 1.52) for No MDS/2728. NH utilization was more strongly associated with mortality than other CMS-2728 items in the model. CONCLUSIONS: The CMS-2728 underestimated NH utilization among older adults with incident ESRD. The potential for misclassification may have important ramifications for assessing prognosis, developing advanced care plans and providing coordinated care.

Racial and ethnic disparities in pediatric renal allograft survival in the United States.

This study was undertaken to describe the association of patient race/ethnicity and renal allograft survival among the national cohort of pediatric renal allograft recipients. Additionally, we determined whether racial and ethnic differences in graft survival exist among individuals living in low- or high-poverty neighborhoods and those with private or public insurance. Among 6216 incident, pediatric end-stage renal disease patients in the United States Renal Data System (kidney transplant from 2000 through September, 2011), 14.4% experienced graft failure, with a median follow-up time of 4.5 years. After controlling for multiple covariates, black race, but not Hispanic ethnicity, was significantly associated with a higher rate of graft failure for both deceased and living donor transplant recipients. Disparities were particularly stark by 5 years post transplant, when black living donor transplant recipients experienced only 63.0% graft survival compared with 82.8 and 80.8% for Hispanics and whites, respectively. These disparities persisted among high- and low-poverty neighborhoods and among both privately and publicly insured patients. Notably profound declines in both deceased and living donor graft survival rates for black, compared with white and Hispanic, children preceded the 3-year mark when transplant Medicare eligibility ends. Further research is needed to identify the unique barriers to long-term graft success among black pediatric transplant recipients.