Faculty Bibliography

BACKGROUND AND OBJECTIVES:Frailty, a syndrome distinct from comorbidity and disability, is clinically manifested as a decreased resistance to stressors and is present in up to 35% of patient with ESKD. It is associated with falls, hospitalizations, poor cognitive function, and mortality. Also, frailty is associated with poor outcomes after kidney transplant, including delirium and mortality. Frailty is likely also associated with decreased access to kidney transplantation, given its association with poor outcomes on dialysis and post-transplant. Yet, clinicians have difficulty identifying which patients are frail; therefore, we sought to quantify if frail kidney transplant candidates had similar access to kidney transplantation as nonfrail candidates. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We studied 7078 kidney transplant candidates (2009-2018) in a three-center prospective cohort study of frailty. Fried frailty (unintentional weight loss, grip strength, walking speed, exhaustion, and activity level) was measured at outpatient kidney transplant evaluation. We estimated time to listing and transplant rate by frailty status using Cox proportional hazards and Poisson regression, adjusting for demographic and health factors. RESULTS:<0.001). CONCLUSIONS:Frailty is associated with lower chance of listing and lower rate of transplant, and is a potentially modifiable risk factor.

Low T cell counts and acute rejection are associated with increased cardiovascular events (CVEs); T cell-depleting agents decrease both. Thus, we aimed to characterize the risk of CVEs by using an induction agent used in kidney transplant recipients. We conducted a secondary data analysis of patients who received a kidney transplant and used Medicare as their primary insurance from 1999 to 2010. Outcomes of interest were incident CVE, all-cause mortality, CVE-related mortality, and a composite outcome of mortality and CVE. Of 47 258 recipients, 29.3% received IL-2 receptor antagonist (IL-2RA), 33.3% received anti-thymocyte globulin (ATG), 7.3% received alemtuzumab, and 30.0% received no induction. Compared with IL-2RA, there was no difference in the risk of CVE in the ATG (adjusted hazard ratio [aHR] 0.98, 95% confidence interval [CI] 0.92-1.05) and alemtuzumab group (aHR 1.01, 95% CI 0.89-1.16), but slightly higher in the no induction group (aHR 1.06, 95% CI 1.00-1.14). Acute rejection did not modify this association in the latter group but did increase CVE by 46% in the alemtuzumab group. There was no difference in the hazard of all-cause or CVE-related mortality. Only in the ATG group, a 7% lower hazard of the composite outcome of mortality and CVE was noted. Induction agents are not associated with incident CVE, although prospective trials are needed to determine a personalized approach to prevention.

A consensus conference on frailty in kidney, liver, heart, and lung transplantation sponsored by the American Society of Transplantation (AST) and endorsed by the American Society of Nephrology (ASN), the American Society of Transplant Surgeons (ASTS), and the Canadian Society of Transplantation (CST) took place on February 11, 2018 in Phoenix, Arizona. Input from the transplant community through scheduled conference calls enabled wide discussion of current concepts in frailty, exploration of best practices for frailty risk assessment of transplant candidates and for management after transplant, and development of ideas for future research. A current understanding of frailty was compiled by each of the solid organ groups and is presented in this paper. Frailty is a common entity in patients with end-stage organ disease who are awaiting organ transplantation, and affects mortality on the waitlist and in the posttransplant period. The optimal methods by which frailty should be measured in each organ group are yet to be determined, but studies are underway. Interventions to reverse frailty vary among organ groups and appear promising. This conference achieved its intent to highlight the importance of frailty in organ transplantation and to plant the seeds for further discussion and research in this field.

Purpose of review/UNASSIGNED:To highlight recent research about frailty and its role as a predictor of adverse, long-term post-kidney transplant (KT) outcomes. Recent findings/UNASSIGNED:Frailty is easily measured using the physical frailty phenotype (PFP) developed by gerontologist Dr. Linda Fried and colleagues. In recent studies, >50% of KT recipients were frail (20%) or intermediately frail (32%) at KT admission. Frail recipients were at 1.3-times higher risk of immunosuppression intolerance and 2.2-times higher risk of mortality, even after accounting for recipient, donor, and transplant factors; these findings were consistent with those on short-term post-KT outcomes. Pilot data suggests that prehabilitation may be an intervention that increases physiologic reserve in frail KT recipients. Summary/UNASSIGNED:The PFP is a effective tool to measure frailty in ESRD that improves risk stratification for short-term and long-term post-KT outcomes. Interventions to improve physiologic reserve and prevent adverse KT outcomes, particularly among frail KT recipients, are needed.

Background:Frail obese community-dwelling older adults are at increased mortality risk. Among hemodialysis (HD) patients, frailty is common and associated with increased mortality risk; however, in dialysis, obesity is associated with decreased mortality risk. Whether the frail-obese phenotype is associated with increased mortality risk among HD patients remains unclear. Methods:This study included 370 incident HD patients enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study. We measured frailty using the Fried phenotype, general obesity [body mass index (BMI) ≥30 kg/m2] and abdominal obesity [waist:hip ratio (WHR) ≥median WHR] and estimated their associations with mortality. Results:The mean age was 55 years, with 42% female, 73% African American, 57% diabetic and 52% frail. Frail HD patients had higher mean BMI (frail = 30.3 kg/m2, non-frail = 28.3 kg/m2; P = 0.02) and similar WHR (P = 0.8). Twenty-two percent were frail with general obesity and 27% were frail with abdominal obesity. Frailty was associated with 1.66-fold increased mortality risk [95% confidence interval (CI) 1.03-2.67]. BMI was associated with a decreased mortality risk [25.0-29.9 kg/m2 hazard ratio (HR) 0.53 (95% CI 0.31-0.93); ≥30 kg/m2 HR 0.34 (95% CI 0.19-0.62)]. Frailty was associated with elevated mortality risk among HD patients with general [HR 3.77 (95% CI 1.10-12.92)] and abdominal obesity [HR 2.38 (95% CI 1.17-4.82)]. Frailty was not associated with mortality among HD patients without general or abdominal obesity. Conclusions:In adults initiating HD, frailty was associated with elevated mortality risk, even among the obese. Frail-obese HD patients may be a high-risk, often-overlooked population, as obesity is assumed to be protective. Measurement of frailty and obesity may facilitate risk stratification.

AIM/OBJECTIVE:There is conflicting evidence regarding the safety and effectiveness of warfarin for atrial fibrillation (AF) treatment among older end-stage renal disease (ESRD) patients, and differences among subgroups are unclear. METHODS:Older dialysis patients who were newly diagnosed with AF (7/2007-12/2011) were identified in the United States Renal Data System. The adjusted hazard ratios (HR) of the outcomes (any stroke, ischaemic stroke, major bleeding, severe gastrointestinal bleeding, and death) by time-varying warfarin use were estimated using Cox regression accounting for the inverse probability of treatment weight. RESULTS:Among 5765 older dialysis patients with incident AF, warfarin was associated with significantly increased risk of major bleeding (HR = 1.50, 95% CI 1.33-1.68), but was not statistically associated with any stroke (HR = 0.92, 95% CI 0.75-1.12), ischaemic stroke (HR = 0.88, 95%CI 0.70-1.11) or gastrointestinal bleeding (HR = 1.03, 95% CI 0.80-1.32). Warfarin use was associated with a reduced risk of mortality (HR = 0.72, 95%CI 0.65-0.80). The association between warfarin and major bleeding differed by sex (male: HR = 1.29; 95%CI 1.08-1.55; female: HR = 1.67; 95%CI 1.44-1.93; P-value for interaction = 0.03). CONCLUSION/CONCLUSIONS:Older ESRD patients with AF who were treated with warfarin had a no difference in stroke risk, lower mortality risk, but increased major bleeding risk. The bleeding risk associated with warfarin was greater among women than men. The risk/benefit ratio of warfarin may be less favourable among older women.

More than one-third of US adults have limited health literacy, putting them at risk of adverse clinical outcomes. We evaluated the prevalence of limited health literacy among 1578 adult kidney transplant (KT) candidates (May 2014-November 2017) and examined its association with listing for transplant and waitlist mortality in this pilot study. Limited health literacy was assessed at KT evaluation by using a standard cutoff score ≤5 on the Brief Health Literacy Screen (score range 0-12, lower scores indicate worse health literacy). We used logistic regression and adjusted Cox proportional hazards models to identify risk factors for limited health literacy and to quantify its association with listing and waitlist mortality. We found that 8.9% of candidates had limited health literacy; risk factors included less than college education (adjusted odds ratio [aOR] = 2.87, 95% confidence interval [CI]:1.86-4.43), frailty (aOR = 1.85, 95% CI:1.22-2.80), comorbidity (Charlson comorbidity index [1-point increase] aOR = 1.12, 95% CI: 1.04-1.20), and cognitive impairment (aOR = 3.45, 95% CI: 2.20-5.41) after adjusting for age, sex, race, and income. Candidates with limited health literacy had a 30% (adjusted hazard ratio = 0.70, 95% CI: 0.54-0.91) decreased likelihood of listing and a 2.42-fold (95% CI: 1.16- to 5.05-fold) increased risk of waitlist mortality. Limited health literacy may be a salient mechanism in access to KT; programs to aid candidates with limited health literacy may improve outcomes and reduce disparities.

BACKGROUND:Restoration of kidney function after kidney transplant generally improves cognitive function. It is unclear whether frail recipients, with higher susceptibility to surgical stressors, achieve such post-transplant cognitive improvements or whether they experience subsequent cognitive decline as they age with a functioning graft. METHODS:In this two-center cohort study, we assessed pretransplant frailty (Fried physical frailty phenotype) and cognitive function (Modified Mini-Mental State Examination) in adult kidney transplant recipients. To investigate potential short- and medium-term effects of frailty on post-transplant cognitive trajectories, we measured cognitive function up to 4 years post-transplant. Using an adjusted mixed effects model with a random slope (time) and intercept (person), we characterized post-transplant cognitive trajectories by pretransplant frailty, accounting for nonlinear trajectories. RESULTS:Of 665 recipients (mean age 52.0 years) followed for a median of 1.5 years, 15.0% were frail. After adjustment, pretransplant cognitive scores were significantly lower among frail patients compared with nonfrail patients (89.0 versus 90.8 points). By 3 months post-transplant, cognitive performance improved for both frail (slope =0.22 points per week) and nonfrail (slope =0.14 points per week) recipients. Between 1 and 4 years post-transplant, improvements plateaued among nonfrail recipients (slope =0.005 points per week), whereas cognitive function declined among frail recipients (slope =-0.04 points per week). At 4 years post-transplant, cognitive scores were 5.8 points lower for frail recipients compared with nonfrail recipients. CONCLUSIONS:On average, both frail and nonfrail recipients experience short-term cognitive improvement post-transplant. However, frailty is associated with medium-term cognitive decline post-transplant. Interventions to prevent cognitive decline among frail recipients should be identified.

Prehabilitation is the process of enhancing preoperative functional capacity to improve tolerance for the upcoming stressor; it was associated with improved postoperative outcomes in a handful of studies, but never evaluated in transplantation. Kidney transplant (KT) candidates may be uniquely suited for prehabilitation because they experience a profound loss of functional capacity while waiting years on dialysis. To better understand the feasibility and effectiveness of prehabilitation in KT, we conducted a pilot study of center-based prehabilitation for candidates; this intervention consisted of weekly physical therapy sessions at an outpatient center with at-home exercises. We enrolled 24 participants; 18 participated in prehabilitation (75% of enrolled; 17% of eligible). 61% were male, 72% were African American, and mean age = 52 (SD = 12.9); 71% of participants had lower-extremity impairment, and 31% were frail. By 2 months of prehabilitation, participants improved their physical activity by 64% (P = 0.004) based on accelerometry. Participants reported high satisfaction. Among 5 prehabilitation participants who received KT during the study, length of stay was shorter than for age-, sex-, and race-matched control (5 vs 10 days; RR = 0.69; 95% CI:0.50-0.94; P = 0.02). These pilot study findings suggest that prehabilitation is feasible in pretransplant patients and may potentially be a strategy to improve post-KT outcomes.

BACKGROUND:Hemodialysis (HD) patients frequently experience pain. Previous studies of HD patients suggest increased opioid prescribing through 2010. It remains unclear if this trend continued after 2010 or declined with national trends. METHODS:Longitudinal cohort study of 484,745 HD patients in the United States Renal Data System/Medicare data. We used Poisson/negative binomial regression to estimate annual incidence rates of opioid prescribing between 2007 and 2014. We compared prescribing rates with the general US population using IQVIA's National Prescription Audit data. Outcomes included the following: percent of HD patients receiving an opioid prescription, rate of opioid prescriptions, quantity, days supply, morphine milligram equivalents (MME) dispensed per 100 person-days, and prescriptions per person. RESULTS:In 2007, 62.4% of HD patients received an opioid prescription. This increased to 63.2% in 2010 then declined to 53.7% by 2014. Opioid quantity peaked in 2011 at 73.5 pills per 100 person-days and declined to 62.6 pills per 100 person-days in 2014. MME peaked between 2010 and 2012 then declined through 2014. In 2014, MME rates were 1.8-fold higher among non-Hispanic patients and 1.6-fold higher among low-income patients. HD patients received 3.2-fold more opioid prescriptions per person compared to the general US population and were primarily prescribed oxycodone and hydrocodone. Between 2012 and 2014, HD patients experienced greater declines in opioid prescriptions per person (18.2%) compared to the general US population (7.1%). CONCLUSION:Opioid prescribing among HD patients declined between 2012 and 2014. However, HD patients continue receiving substantially more opioids than the general US population.