Faculty Bibliography

PURPOSE:In 2008, the US Food and Drug Administration (FDA) issued Draft Guidance on investigating cardiovascular risk with oral diabetic drugs, including dipeptidyl peptidase-4 inhibitors (DPP-4i).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.

Introduction:Cognitive decline is common and increases mortality risk in hemodialysis patients. Intradialytic interventions like cognitive training (CT) and exercise training (ET) may preserve cognitive function. Methods:values were generated from linear regression. Results: = 0.16) for ET. Conclusion:Preliminary findings of our pilot study suggested that cognitive decline in psychomotor speed and executive function is possibly prevented by intradialytic CT and ET. These preliminary pilot findings should be replicated.

BACKGROUND:Frailty has been recognized as an important medical syndrome in older adults. Growing literature supports the clinical application of frailty but US older adults' perceptions of frailty have not been explored. We aim to examine perceptions and informational needs about frailty among older adults. METHODS:This was a qualitative study involving focus groups of community-dwelling older adults with diverse age and frailty status. We explored participants' beliefs and knowledge about frailty and informational needs about frailty as a medical syndrome. RESULTS:The participants' mean age was 76.3. Of the 29 participants, 21 (72%) were female, and 21 (72%) were white. We identified three major themes: 1) Older adults' perceptions of frailty differed from the definition used in medical literature; they often perceived a psychological component to being frailty and some were skeptical of the syndromic definition based on multiple symptoms. 2) Compared to participants who were non-frail or pre-frail, participants who were frail were more receptive to discussing their frailty status with clinicians; 3) Participants wanted know about how to treat or prevent frailty and the risks associated with being frail. Many participants felt that these information can be conveyed without necessarily using the specific term "frail", which they perceived to have a negative connotation. CONCLUSIONS:Older adults, especially those who are frail, may be interested to discuss frailty as a medical syndrome. However, negative perceptions are associated with the term "frail" and may be a barrier to clinical application of frailty. Further research is needed to understand acceptable ways for communicating about frailty in clinical practice.

BACKGROUND:Among community-dwelling older adults, frailty is associated with heightened markers of inflammation and subsequent mortality. Although frailty is common among end-stage renal disease (ESRD) patients, the role of frailty and markers of inflammation in this population remains unclear. We quantified these associations in patients on the kidney transplant waitlist and tested whether frailty and/or markers of inflammation improve waitlist mortality risk prediction. METHODS:We studied 1975 ESRD patients on the kidney transplant waitlist (November 1, 2009, to February 28, 2017) in a multi-center cohort study of frailty. Serum inflammatory markers (interleukin-6 [IL-6], soluble tumor necrosis factor-α receptor-1 [sTNFR1], and C-reactive protein [CRP]) were analyzed in 605 of these participants; we calculated the inflammatory index score using IL-6 and sTNFR1. We compared the C-statistic of an established registry-based prediction model for waitlist mortality adding frailty and/or inflammatory markers (1 SD change in log IL-6, sTNFR1, CRP, or inflammatory index). RESULTS:The registry-based model had moderate predictive ability (c-statistic = 0.655). Frailty was associated with increased mortality (2.19; 95% confidence interval [CI], 1.26-3.79) but did not improve risk prediction (c-statistic = 0.646; P = 0.65). Like frailty, IL-6 (2.13; 95% CI, 1.41-3.22), sTNFR1 (1.70; 95% CI, 1.12-2.59), CRP (1.68; 95% CI, 1.06-2.67), and the inflammatory index (2.09; 95% CI, 1.38-3.16) were associated with increased mortality risk; unlike frailty, adding IL-6 (c-statistic = 0.777; P = 0.02), CRP (c-statistic = 0.728; P = 0.02), or inflammatory index (c-statistic = 0.777; P = 0.02) substantially improved mortality risk prediction. CONCLUSIONS:Frailty and markers of inflammation were associated with increased waitlist mortality risk, but only markers of inflammation significantly improved ESRD risk prediction. These findings help clarify the accelerated aging physiology of ESRD and highlight easy-to-measure markers of increased waitlist mortality risk.