Faculty Bibliography

INTRODUCTION:Multifactorial biological processes underpin dysregulation over several individual physiological systems. However, it is challenging to characterize and model this multisystemic dysregulation and its relationship with individual physiologic systems. We operationalized a theory-driven measure of multisystem dysregulation and empirically tested for measurement differences by key characteristics. METHODS:We used the Women's Health and Aging Studies (WHAS) I and II (N = 649), and the Health ABC study (N = 1515). Twelve biomarkers representing multiple systems including stress response (e.g., inflammation), endocrine system, and energy regulation were identified. A series of confirmatory factor analyses (CFA) were conducted to evaluate the interplay between physiological systems and underlying multisystem dysregulation. We evaluated convergent criterion validity of a score for multisystem dysregulation against the physical frailty phenotype, and predictive criterion validity with incidence of walking difficulty and mortality. RESULTS:A bifactor CFA, a model in which dysregulation of individual systems proceeds independently of generalized dysregulation, fit data well in WHAS (RMSEA: 0.019; CFI: 0.977; TLI: 0.961) and Health ABC (RMSEA: 0.047; CFI: 0.874; TLI: 0.787). The general dysregulation factor was associated with frailty (OR: 2.2, 95 % CI: 1.4, 3.5), and elevated risk of incident walking difficulty and mortality. Findings were replicated in Health ABC. DISCUSSION:Biomarker data from two epidemiologic studies support the construct of multisystem physiological dysregulation. Results further suggest system-specific and system-wide processes have unique and non-overlapping contributions to dysregulation in biological markers.

OBJECTIVES:Over 40% of individuals in the United States with end-stage kidney disease have obesity. Little is known about renal dietitian perspectives on obesity management in the setting of dialysis dependence. DESIGN AND METHODS:An online 21-item survey was distributed to 118 renal dietitians via individual outreach and a professional organization e-mail listserv. Four themes were explored: the burden of obesity among dialysis patients, concepts of healthy weight loss, weight loss approaches, and challenges of obesity management in dialysis settings. Respondents were asked to rank approaches and biomarkers for obesity management from 0 (least important or not used) to 100 (most important). Free text fields were provided in each category for additional comments. RESULTS:Thirty-one renal dietitians responded to the survey (26% response rate). The majority of respondents (90%) indicated that access to kidney transplantation was the main reason that dialysis patients with obesity desired weight loss. Calorie restriction was rated as the most common weight loss approach, and dry weight as the most important weight loss biomarker. Nearly 40% of respondents do not alter their nutritional approach when dialysis patients with obesity are losing weight, and 42% of respondents do not monitor changes in waist circumference. Exercise, diet counseling, and stress management were variably prioritized as weight loss management strategies. Barriers to obesity management in dialysis settings included lack of time, lack of training in weight loss counseling, and gaps in current renal nutritional guidelines. CONCLUSION:Despite the high prevalence of obesity among individuals with end-stage kidney disease, the results of this survey suggest that current approaches to obesity management in dialysis settings are highly variable. Many renal dietitians lack time to counsel patients on healthy weight loss strategies. Nutritional guidelines are also needed to support people with dialysis dependence and obesity who desire or require weight loss.

INTRODUCTION:"Frailty" has attracted attention for its promise of identifying vulnerable older adults, hence its potential use to better tailor geriatric health care. There remains substantial controversy, however, regarding its nature and ascertainment. Recent years have seen a proliferation of frailty assessment methods. We argue that the development of frailty assessments should be grounded in "validation"-the process of substantiating that a measurement accurately and precisely measures what it intends, identify unresolved measurement issues, and highlight measurement-related considerations for clinical practice. METHODS:Principles for validating frailty measures are elucidated. We follow principles-articulated, for example, by Borsboom-in which a construct must be clearly defined and then analyses undertaken to substantiate that a measurement accurately and precisely measures what it intends. Key elements are content validity, criterion validity, and construct validity, with an emphasis on the latter. RESULTS:We illustrate the principles for a physical frailty phenotype construct. CONCLUSIONS:Unresolved conceptual issues include the roles of intersecting concepts such as cognition, disease severity, and disability in frailty measurement, conceptualization of frailty as a state versus a continuum, and the potential need for dynamic measures and systems concepts in furthering understanding of frailty. Clinical considerations include needs to distinguish interventions designed to address frailty "symptoms" versus underlying physiology, improve "prefrailty" measures intended to screen individuals early in their frailty progression, address feasibility demands, and further visioning followed by rigorous efficacy research to address the landscape of potential uses of frailty assessment in clinical practice.

RATIONALE & OBJECTIVE:The current clinical guidelines for vascular access do not have specific recommendations for older hemodialysis patients. Our study aimed to determine the association of age with arteriovenous fistula (AVF) placement, maturation, and primary and secondary patency loss among older hemodialysis recipients. STUDY DESIGN:Retrospective cohort study. SETTING & PARTICIPANTS:A US national cohort of incident hemodialysis patients 67 years or older (N = 43,851) assembled from the US Renal Data System. EXPOSURE:Age at dialysis initiation. OUTCOMES:AVF placement, maturation, primary patency loss, and abandonment. ANALYTICAL APPROACH:Cause-specific and subdistribution proportional hazards models were used to examine the association of age and AVF outcomes, with kidney transplantation, peritoneal dialysis, and death treated as competing events. Age cutoff was identified by restricted cubic splines. We compared crude and inverse probability-weighted cumulative incidence functions using Gray's test. RESULTS:As compared with those aged 67-<77 years, patients 77 years or older had significantly lower probabilities of AVF placement (adjusted cause-specific HR [cHR], 0.96 [95% CI, 0.92-0.99]; adjusted subdistribution HR [sHR], 0.92 [95% CI, 0.89-0.95]; Gray's test P < 0.001) and maturation (adjusted cHR, 0.95 [95% CI, 0.91-0.99]; adjusted sHR, 0.93 [95% CI, 0.90-0.97]; P < 0.001). However, age was not associated with AVF primary (adjusted cHR, 1.05 [95% CI, 1.00-1.11]; adjusted sHR, 1.04 [95% CI, 0.99-1.09]; P = 0.09) or secondary (adjusted cHR, 1.06 [95% CI, 0.94-1.20]; adjusted sHR, 1.05 [95% CI, 0.93-1.18]; P = 0.4) patency loss. LIMITATIONS:Reliance on administrative claims to ascertain AVF outcomes. CONCLUSIONS:The likelihood of AVF maturation is an important consideration for vascular access planning. Age alone should not be the basis for excluding older dialysis patients from AVF creation because maintenance of fistula patency was not reduced with older age despite a modest reduction in fistula maturation.

PURPOSE OF REVIEW:Chronic kidney disease (CKD) is characterized by poor levels of physical activity which contribute to increased morbidity across the disease trajectory. The short nature, small samples, and poor methodology across most studies have failed to translate the role of exercise in CKD into its adoption as a frontline adjunct therapeutic option. This review focuses on recent advances surrounding the benefits of exercise interventions across the CKD spectrum. RECENT FINDINGS:Key recent advances in exercise studies have focused on the efficacy of novel intervention strategies across the CKD spectrum. These include high-intensity interval training, virtual reality gaming, intradialytic yoga, electrical stimulation of muscles, blood flow restriction training, and protocols combining exercise with nutritional supplementation. Research is also beginning to explore the role of prehabilitation for patients prior to dialysis and kidney transplantation. SUMMARY:Studies continue to demonstrate wide-ranging benefits of exercise across CKD; however, implementation of exercise remains scarce. Future research needs include evaluating the efficacy of larger and/or more comprehensive interventions on clinically important outcomes. It is hoped with increasing global evidence, high-quality clinical studies, and sustained clinician and patient engagement, exercise programs will become better prioritized in the nephrology field.

BACKGROUND:Cardiovascular safety of dipeptidyl peptidase-IV inhibitors (DPP-4i) in patients without cardiovascular or renal disease, a majority of newly diagnosed patients with type 2 diabetes often excluded from clinical trials on this association, is poorly understood. Thus, we investigate the risk of major adverse cardiovascular events (MACE) associated with DPP-4i in low-risk patients with diabetes. METHODS:Using a new-user retrospective cohort derived from IBM MarketScan Commercial Claims and Encounters (2010-2015), we identified patients aged 35-65 with type 2 diabetes, without cardiovascular or renal disease, initiating DPP-4i, sulfonylureas, or metformin. Primary composite outcome of time to first MACE was defined as the first of any of the following: myocardial infarction, cardiac arrest, coronary artery bypass graft, coronary angioplasty, heart failure, and stroke. Secondary outcomes were time to first heart failure, acute myocardial infarction, and stroke. We compared outcomes for DPP-4i versus sulfonylurea and DPP-4i versus metformin using propensity score weighted Cox proportional hazards, adjusting for demographics, baseline comorbidities, concomitant medications, and cumulative exposure. RESULTS:Of 445,701 individuals, 236,431 (53.0%) were male, median age was 51 (interquartile range: [44, 57]), 30,267 (6.79%) initiated DPP-4i, 52,138 (11.70%) initiated sulfonylureas, and 367,908 (82.55%) initiated metformin. After adjustment, DPP-4i was associated with lower risk of MACE than sulfonylurea (adjusted hazard ratio (aHR) = 0.87; 95% confidence interval (CI): 0.78-0.98), and similar risk to metformin (aHR = 1.07; 95% CI: 0.97-1.18). Risk for acute myocardial infarction (aHR = 0.70; 95% CI: 0.51-0.96), stroke (aHR = 0.57; 95% CI: 0.41-0.79), and heart failure (aHR = 0.57; 95% CI: 0.41-0.79) with DPP-4i was lower compared to sulfonylureas. CONCLUSION:Our findings show that for this cohort of low-risk patients newly treated for type 2 diabetes, DPP-4i exhibited 13% lower risk for MACE compared to sulfonylureas and similar risk for MACE compared to metformin, suggesting DPP-4i is a low cardiovascular risk option for low-risk patients initiating antihyperglycemic treatment.

BACKGROUND:Choice of vascular access for older hemodialysis patients presents a special challenge since the rate of arteriovenous fistula (AVF) primary failure is high. The Lok's risk equation predicting AVF primary failure has achieved good prediction accuracy and holds great potential for clinical use, but it has not been validated in the United States older hemodialysis patients. METHODS:We assembled a validation data set of 14,892 patients aged 67 years and older who initiated hemodialysis with a central venous catheter between July 1, 2010, and June 30, 2012, and had a subsequent, incident AVF placement from the United States Renal Data System. We examined the external validity of Lok's model by applying it to this validation data set. The discriminatory accuracy and calibration were evaluated by the concordance index (C-statistics) and calibration plot, respectively. RESULTS:The observed frequency of AVF primary failure varied from 0.45 to 0.53 in hemodialysis patients in the validation data set. The predicted probabilities of AVF primary failure calculated by using the Lok's risk equation ranged from 0.08 to 0.61, and 77.8, 40.5, and 51.7% of patients were categorized as having high, intermediate, and low risk of AVF primary failure, respectively. The C-statistics of the Lok's risk equation in the validation data set was 0.53 (95% CI 0.52-0.54). The predicted probabilities of AVF primary failure corresponded poorly with the observed proportions in the calibration plot. CONCLUSIONS:When externally applied to a cohort of U.S. older hemodialysis patients, the Lok's risk equation exhibited poor discrimination and calibration accuracy. It is invalid to use it to predict AVF primary failure. A more complex model with strong predictors is expected to better serve clinical determination for AVF placement in this population.

Purpose of Review/UNASSIGNED:To summarize the research on effective interventions for preserving cognitive function and prevent cognitive decline in patients with end-stage kidney disease (ESKD) who are undergoing dialysis and/or kidney transplantation (KT). Recent Findings/UNASSIGNED:Among ESKD patients undergoing hemodialysis, exercise training has been administered through home-based and intradialytic interventions. Additionally, one pilot study identified intradialytic cognitive training, electronic brain games, as an intervention to preserve cognitive function among patients undergoing hemodialysis. Fewer studies have investigated interventions to preserver cognitive function among KT recipients. To date, the only randomized controlled trial in this population identified B-vitamin supplements as an intervention to preserve cognitive function. The evidence from these trials support a short-term benefit of cognitive and exercise training as well as B-vitamin supplementation among patients with ESKD. Future studies should: 1) replicate these findings, 2) identify interventions specific to KT candidates, and 3) investigate the synergistic impact of both cognitive and exercise training. Summary/UNASSIGNED:Cognitive prehabilitation, with cognitive and/or exercise training, may be novel interventions for KT candidates that not only reduces delirium risk and long-term post-KT cognitive decline but also prevents dementia.

BACKGROUND:Older (≥65) KT recipients differ from their younger counterparts in their immune response to immunosuppression (IS) and may have a different risk of malignancy after receiving induction. METHODS:We identified 66 700 adult KT recipients treated with anti-thymocyte globulin (ATG) (n = 40 443) or interleukin-2 receptor antagonist (IL-2RA) (n = 26 327) induction (1/1/1999-12/31/2014) using USRDS/Medicare data. We estimated the risk of first-diagnosed post-KT malignancy associated with induction (ATG vs. IL-2RA) using Cox proportional hazard models. We then tested whether these risks differed between older and younger recipients (Wald test for interaction). Models incorporated inverse probability of treatment weights to adjust for confounders. RESULTS: = 0.01) between younger (HR = 1.18; 95%CI:1.08-1.29) and older (HR = 1.01; 95%CI:0.93-1.09) recipients. CONCLUSIONS:Compared with IL-2RA induction, ATG was associated with elevated post-KT malignancy risk but only among younger recipients. Transplant centers may need to tailor induction IS for younger recipients to mitigate malignancy risk.