Faculty Bibliography

Currently, older adults comprise nearly one-third of prevalent US dialysis patients, and this proportion will increase as the population ages. Older dialysis patients experience greater morbidity and mortality than nondialysis patients of the same age, and in part, it is related to progressive functional decline. Progressive functional decline, characterized by need for assistance with more than 2 activities of daily living, contributes to risk of hospitalization, further functional decline, and subsequent nursing home placement when a patient no longer functions independently at home. Progressive functional decline may appear to be unavoidable for older dialysis patients; however, comprehensive geriatric assessment (CGA) may alleviate the prevalence and severity of functional decline. This editorial summarizes common risk factors of functional decline and introduces CGA as a potentially transformative approach to breaking the cycle of functional decline in older dialysis patients.

BACKGROUND:The risk of cardiovascular mortality is high among adults with end-stage renal disease (ESRD) undergoing hemodialysis. Waist-to-hip ratio (WHR), a metric of abdominal adiposity, is a predictor of cardiovascular disease (CVD) and mortality in the general population; however, no studies have examined the association with CVD mortality, particularly sudden cardiac death (SCD), in incident hemodialysis. METHODS:Among 379 participants incident (< 6 months) to hemodialysis enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in ESRD study, we evaluated associations between WHR and risk of CVD mortality, SCD, and non-CVD mortality in Cox proportional hazards regression models. RESULTS:At study enrollment, mean age was 55 years with 41% females, 73% African Americans, and 57% diabetics. Mean body mass index was 29.3 kg/m2, and mean WHR was 0.95. During a median follow-up time of 2.5 years, there were 35 CVD deaths, 15 SCDs, and 48 non-CVD deaths. Every 0.1 increase in WHR was associated with higher risk (hazard ratio [95% CI]) of CVD mortality (1.75 [1.06-2.86]) and SCD (2.45 [1.20-5.02]), but not non-CVD mortality (0.93 [0.59-1.45]), independently of demographics, body mass index, comorbidities, inflammation, and traditional CVD risk factors. CONCLUSIONS:WHR is significantly associated with CVD mortality including SCD, independently of other CVD risk factors in incident hemodialysis. This simple, easily obtained bedside metric may be useful in dialysis patients for CVD risk stratification.

Prediction models for post-kidney transplantation mortality have had limited success (C-statistics ≤0.70). Adding objective measures of potentially modifiable factors may improve prediction and, consequently, kidney transplant (KT) survival through intervention. The Short Physical Performance Battery (SPPB) is an easily administered objective test of lower extremity function consisting of three parts (balance, walking speed, chair stands), each with scores of 0-4, for a composite score of 0-12, with higher scores indicating better function. SPPB performance and frailty (Fried frailty phenotype) were assessed at admission for KT in a prospective cohort of 719 KT recipients at Johns Hopkins Hospital (8/2009 to 6/2016) and University of Michigan (2/2013 to 12/2016). The independent associations between SPPB impairment (SPPB composite score ≤10) and composite score with post-KT mortality were tested using adjusted competing risks models treating graft failure as a competing risk. The 5-year posttransplantation mortality for impaired recipients was 20.6% compared to 4.5% for unimpaired recipients (p < 0.001). Impaired recipients had a 2.30-fold (adjusted hazard ratio [aHR] 2.30, 95% confidence interval [CI] 1.12-4.74, p = 0.02) increased risk of postkidney transplantation mortality compared to unimpaired recipients. Each one-point decrease in SPPB score was independently associated with a 1.19-fold (95% CI 1.09-1.30, p < 0.001) higher risk of post-KT mortality. SPPB-derived lower extremity function is a potentially highly useful and modifiable objective measure for pre-KT risk prediction.

Background:A high fructose intake has been shown to be associated with increased serum urate concentration, whereas ascorbate (vitamin C) may lower serum urate by competing with urate for renal reabsorption. Objective:We assessed the combined association, as the fructose:vitamin C intake ratio, and the separate associations of dietary fructose and vitamin C intakes on prevalent hyperuricemia. Methods:We conducted cross-sectional analyses of dietary intakes of fructose and vitamin C and serum urate concentrations among Jackson Heart Study participants, a cohort of African Americans in Jackson, Mississippi, aged 21-91 y. In the analytic sample (n = 4576), multivariable logistic regression was used to examine the separate associations of dietary intakes of fructose and vitamin C and the fructose:vitamin C intake ratio with prevalent hyperuricemia (serum urate ≥7 mg/dL), after adjusting for age, sex, smoking, waist circumference, systolic blood pressure, estimated glomerular filtration rate, diuretic medication use, vitamin C supplement use, total energy intake, alcohol consumption, and dietary intake of animal protein. Analyses for individual dietary factors (vitamin C, fructose) were adjusted for the other dietary factor. Results:In the fully adjusted model, there were 17% greater odds of hyperuricemia associated with a doubling of the fructose:vitamin C intake ratio (OR: 1.17; 95% CI: 1.08, 1.28), 20% greater odds associated with a doubling of fructose intake (OR: 1.20; 95% CI: 1.08, 1.34), and 13% lower odds associated with a doubling of vitamin C intake (OR: 0.87; 95% CI: 0.78, 0.97). Dietary fructose and the fructose:vitamin C intake ratio were more strongly associated with hyperuricemia among men than women (P-interaction ≤ 0.04). Conclusion:Dietary intakes of fructose and vitamin C are associated with prevalent hyperuricemia in a community-based population of African Americans.

PURPOSE:In 2008, the US Food and Drug Administration (FDA) issued Draft Guidance on investigating cardiovascular risk with oral diabetic drugs, including dipeptidyl peptidase-4 inhibitors (DPP-4i). In 2014, underpowered, post hoc analyses of clinical trials suggested an increased risk of heart failure with the use of these products. As such, we assessed disproportionate reporting of major adverse cardiac events (MACE) among reports for DPP-4i submitted to the FDA Adverse Event Reporting System (FAERS) from 2006 to 2015. METHODS:We assessed the empirical Bayes geometric mean (EBGM) and its lower bound (EB05) of the relative reporting ratio for MACE among DPP-4i reports in the full FAERS database and in a subset of reports limited to cardiovascular and diabetic drugs. We then compared the EB05 in these 2 analyses and calculated the percent positive agreement for signals of disproportional reporting (SDRs) involving MACE. RESULTS:Of 180.3 million adverse event reports, 13.4 million were for diabetic and cardiovascular drugs. In the cardiovascular subset, there was an SDR for heart failure with linagliptin (EB05 = 2782.47) and saxagliptin (EB05 = 2.40), myocardial infarction with alogliptin (EB05 = 290.11), and cerebral infarction with sitagliptin (EB05 = 2.80). Of the 14 MACE, 8 had a percent positive agreement ≥50% for an SDR in both analyses. Overall, the cardiovascular subset elicited 11 more SDRs for DPP-4i than the full dataset. CONCLUSIONS:Postmarketing surveillance of DPP-4i through FAERS suggest increased reporting of MACE, supporting the current FDA warning of heart failure risk. This suggests the need for additional longitudinal, observational research into the association of DPP-4i and other MACE.

Background/UNASSIGNED:Individuals with chronic kidney disease (CKD) have low levels of physical activity and physical function. Although guidelines endorse exercise counseling for individuals with CKD, it is not yet part of routine care. Objective/UNASSIGNED:We investigated the effect of attending a real-life exercise counseling clinic (ECC) on physical function in individuals with CKD. Design/UNASSIGNED:Retrospective analysis of prospectively collected observational data with quasi-experimental design. Setting and Participants/UNASSIGNED:Patients with all stages of CKD registered in a large provincial renal program were eligible. The exposed cohort who attended the ECC between January 1, 2011, and March 15, 2014, included 214 individuals. The control cohort included 292 individuals enrolled in an observational study investigating longitudinal change in frailty during the same time period. Predictor/Factor/UNASSIGNED:Attendance at an ECC. Outcomes and Measurements/UNASSIGNED:Change in physical function as measured by Short Physical Performance Battery (SPPB) score, physical activity level (Human Activity Profile [HAP]/Physical Activity Scale for the Elderly [PASE]), and health-related quality of life (HRQOL; EQ5D/VAS) over 1 year. Results/UNASSIGNED:= .72). There was no significant difference in the proportion of individuals in each cohort with an increase/decrease in SPPB score over time. There was no significant change in physical activity or HRQOL over time between groups. Limitations/UNASSIGNED:Quasi-experimental design, low rate of follow-up attendance. Conclusions/UNASSIGNED:In this pragmatic study, exercise counseling had no significant effect on change in SPPB score, suggesting that a single exercise counseling session alone is inadequate to improve physical function in CKD.

BACKGROUND:Health-related quality of life (HRQOL) reflects a patient's disease burden, treatment effectiveness, and health status and is summarized by physical, mental, and kidney disease-specific scales among end-stage renal disease patients. Although on average HRQOL improves postkidney transplant (KT), the degree of change depends on the ability of the patient to withstand the stressor of dialysis versus the ability to tolerate the intense physiologic changes of KT. Frail KT recipients may be extra vulnerable to either of these stressors, thus affecting change in HRQOL after KT. METHODS:We ascertained frailty, as well as physical, mental, and kidney disease-specific HRQOL in a multicenter prospective cohort of 443 KT recipients (May 2014 to May 2017) using Kidney Disease Quality of Life Instrument Short Form. We quantified the short-term (3 months) rate of post-KT HRQOL change by frailty status using adjusted mixed-effects linear regression models. RESULTS:Mean HRQOL scores at KT were 43.3 (SD, 9.6) for physical, 52.8 (SD, 8.9) for mental, and 72.6 (SD, 12.8) for kidney disease-specific HRQOL; frail recipients had worse physical (P < 0.001) and kidney disease-specific HRQOL (P = 0.001), but similar mental HRQOL (P = 0.43). Frail recipients experienced significantly greater rates of improvement in physical HRQOL (frail, 1.35 points/month; 95% confidence interval [CI], 0.65-2.05; nonfrail, 0.34 points/month; 95% CI, -0.17-0.85; P = 0.02) and kidney disease-specific HRQOL (frail, 3.75 points/month; 95% CI, 2.89-4.60; nonfrail, 2.41 points/month; 95% CI, 1.78-3.04; P = 0.01), but no difference in mental HRQOL (frail, 0.54 points/month; 95% CI, -0.17-1.25; nonfrail, 0.46 points/month; 95% CI, -0.06-0.98; P = 0.85) post-KT. CONCLUSIONS:Despite decreased physiologic reserve, frail recipients experience improvement in post-KT physical and kidney disease-specific HRQOL better than nonfrail recipients.

To assess factors that influence the choice of induction regimen in contemporary kidney transplantation, we examined center-identified, national transplant registry data for 166 776 US recipients (2005-2014). Bilevel hierarchical models were constructed, wherein use of each regimen was compared pairwise with use of interleukin-2 receptor blocking antibodies (IL2rAb). Overall, 82% of patients received induction, including thymoglobulin (TMG, 46%), IL2rAb (22%), alemtuzumab (ALEM, 13%), and other agents (1%). However, proportions of patients receiving induction varied widely across centers (0-100%). Recipients of living donor transplants and self-pay patients were less likely to receive induction treatment. Clinical factors associated with use of TMG or ALEM (vs. IL2rAb) included age, black race, sensitization, retransplant status, nonstandard deceased donor, and delayed graft function. However, these characteristics explained only 10-33% of observed variation. Based on intraclass correlation analysis, "center effect" explained most of the variation in TMG (58%), ALEM (66%), other (51%), and no induction (58%) use. Median odds ratios generated from case-factor adjusted models (7.66-11.19) also supported large differences in the likelihood of induction choices between centers. The wide variation in induction therapy choice across US transplant centers is not dominantly explained by differences in patient or donor characteristics; rather, it reflects center choice and practice.

BACKGROUND:The Fried frailty phenotype, a measure of physiologic reserve defined by 5 components (exhaustion, unintentional weight loss, low physical activity, slow walking speed, and poor grip strength), is associated with poor outcomes among ESRD patients. However, these 5 components may not fully capture physiologic reserve in this population. We aimed to ascertain opinions of ESRD clinicians and patients about the usefulness of the Fried frailty phenotype and interventions to improve frailty in ESRD patients, and to identify novel components to further characterize frailty in ESRD. METHODS:Clinicians who treat adults with ESRD completed a 2-round Delphi study (n = 41 and n = 36, respectively; response rate = 87%). ESRD patients completed a survey at transplant evaluation (n = 460; response rate = 81%). We compared clinician and patient opinions on the constituent components of frailty. RESULTS:Clinicians were more likely than patients to say that ESRD makes patients frail (97.6% vs. 60.2%). There was consensus among clinicians that exhaustion, low physical activity, slow walking speed, and poor grip strength characterize frailty in ESRD patients; however, 29% of clinicians thought weight loss was not relevant. Patients were less likely than clinicians to say that the 5 Fried frailty components were relevant. Clinicians identified 10 new ESRD-specific potential components including falls (64%), physical decline (61%), and cognitive impairment (39%). Clinicians (83%) and patients (80%) agreed that intradialytic foot-peddlers might make ESRD patients less frail. CONCLUSIONS:There was consensus among clinicians and moderate consensus among patients that frailty is more common in ESRD. Weight loss was not seen as relevant, but new components were identified. These findings are first steps in refining the frailty phenotype and identifying interventions to improve physiologic reserve specific to ESRD patients.