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.

OBJECTIVES:Older adults who undergo kidney transplantation (KT) are living longer with a functioning graft and are at risk for age-related adverse events including fractures. Understanding recipient, transplant, and donor factors and the outcomes associated with fractures may help identify older KT recipients at increased risk. We determined incidence of hip, vertebral, and extremity fractures; assessed factors associated with incident fractures; and estimated associations between fractures and subsequent death-censored graft loss (DCGL) and mortality. DESIGN:This was a prospective cohort study of patients who underwent their first KT between January 1, 1999, and December 31, 2014. SETTING:We linked data from the Scientific Registry of Transplant Recipients to Medicare claims through the US Renal Data System. PARTICIPANTS:The analytic population included 47 815 KT recipients aged 55 years or older. MEASUREMENTS:We assessed the cumulative incidence of and factors associated with post-KT fractures (hip, vertebral, or extremity) using competing risks models. We estimated risk of DCGL and mortality after fracture using adjusted Cox proportional hazards models. RESULTS:The 5-year incidence of post-KT hip, vertebral, and extremity fracture for those aged 65 to 69 years was 2.2%, 1.0%, and 1.7%, respectively. Increasing age was associated with higher hip (adjusted hazard ratio [aHR] = 1.37 per 5-y increase; 95% confidence interval [CI] = 1.30-1.45) and vertebral (aHR = 1.31; 95% CI = 1.20-1.42) but not extremity (aHR = .97; 95% CI = .91-1.04) fracture risk. DCGL risk was higher after hip (aHR = 1.34; 95% CI = 1.12-1.60) and extremity (aHR = 1.30; 95% CI = 1.08-1.57) fracture. Mortality risk was higher after hip (aHR = 2.31; 95% CI = 2.11-2.52), vertebral (aHR = 2.80; 95% CI = 2.44-3.21), and extremity (aHR = 1.85; 95% CI = 1.64-2.10) fracture. CONCLUSION:Our findings suggest that older KT recipients are at higher risk for hip and vertebral fracture but not extremity fracture; and those with hip, vertebral, or extremity fracture are more likely to experience subsequent graft loss or mortality. These findings underscore that different fracture types may have different underlying etiologies and risks, and they should be approached accordingly. J Am Geriatr Soc 67:1680-1688, 2019.

BACKGROUND:Inflammation is more common among African Americans (AAs), and it is associated with frailty, poor physical performance, and mortality in community-dwelling older adults. Given the elevated inflammation levels among end-stage renal disease (ESRD) patients, inflammation may be associated with adverse health outcomes such as frailty, physical impairment, and poor health-related quality of life (HRQOL), and these associations may differ between AA and non-AA ESRD patients. METHODS:One thousand three ESRD participants were recruited at kidney transplant evaluation (4/2014-5/2017), and inflammatory markers (interleukin-6 [IL-6], tumor necrosis factor-a receptor-1 [TNFR1], C-reactive protein [CRP]) were measured. We quantified the association with frailty (Fried phenotype), physical impairment (Short Physical Performance Battery [SPPB]), and fair/poor HRQOL at evaluation using adjusted modified Poisson regression and tested whether these associations differed by race (AA vs. non-AA). RESULTS:Non-AAs had lower levels of TNFR1 (9.7 ng/ml vs 14.0 ng/ml, p < 0.001) and inflammatory index (6.7 vs 6.8, p < 0.001) compared to AAs, but similar levels of IL-6 (4.5 pg/ml vs 4.3 pg/ml, p > 0.9) and CRP (4.7 μg/ml vs 4.9 μg/ml, p = 0.4). Non-AAs had an increased risk of frailty with elevated IL-6 (RR = 1.58, 95% CI:1.27-1.96, p < 0.001), TNFR1 (RR = 1.60, 95% CI:1.25-2.05, p < 0.001), CRP (RR = 1.41, 95% CI:1.10-1.82, p < 0.01), and inflammatory index (RR = 1.82, 95% CI:1.44-2.31, p < 0.001). The associations between elevated inflammatory markers and frailty were not present among AAs. Similar results were seen with SPPB impairment and poor/fair HRQOL. CONCLUSIONS:Non-AAs with elevated inflammatory markers may need closer follow-up and may benefit from prehabilitation to improve physical function, reduce frailty burden, and improve quality of life prior to transplant.

RATIONALE & OBJECTIVE:There is debate on whether weight loss, a hallmark of frailty, signals higher risk for adverse outcomes among recipients of deceased donor kidney transplantation (DDKT). STUDY DESIGN:Retrospective cohort study. SETTING & PARTICIPANTS:Using national Organ Procurement and Transplantation Network data, we included all DDKT recipients in the United States between December 4, 2004, and December 3, 2014, who were adults (aged ≥ 18 years) when listed for DDKT. EXPOSURES:Relative pre-DDKT weight change as a continuous predictor and categorized as <5% weight change from listing to DDKT, ≥5% to <10% weight loss, ≥10% weight loss, ≥5% to <10% weight gain, and ≥10% weight gain. OUTCOMES:We examined 3 post-DDKT outcomes: (1) transplant hospitalization length of stay (LOS) in days, (2) all-cause graft failure, and (3) mortality. ANALYTIC APPROACH:Unadjusted fractional polynomial methods, multivariable log-gamma models, and multivariable Cox proportional hazards models. RESULTS:Among 94,465 recipients of DDKT, median pre-DDKT weight change was 0 (interquartile range, -3.5 to +3.9) kg. There were nonlinear unadjusted associations between relative pre-DDKT weight loss and longer transplant hospitalization LOS, higher all-cause graft loss, and higher mortality. Compared with recipients with <5% pre-DDKT weight change (n = 49,366; 52%), recipients who lost ≥10% of their listing weight (n = 10,614; 11%) had 0.66 (95% CI, 0.23-1.09) days longer average transplant hospitalization LOS (P = 0.003), 1.11-fold higher graft loss (adjusted HR [aHR], 1.11; 95% CI, 1.06-1.17; P < 0.001), and 1.18-fold higher mortality (aHR, 1.18; 95% CI, 1.11-1.25; P < 0.001) independent of recipient, donor, and transplant factors. Pre-DDKT dialysis exposure, listing body mass index category, and waiting time modified the association of pre-DDKT weight change with hospital LOS (interaction P < 0.10), but not with all-cause graft loss and mortality. LIMITATIONS:Unmeasured confounders and inability to identify volitional weight change. Also, the higher significance level set to increase the power of detecting interactions with the fixed sample size may have resulted in increased risk for type 1 error. CONCLUSIONS:DDKT recipients with ≥10% pre-DDKT weight loss are at increased risk for adverse outcomes and may benefit from augmented support post-DDKT.

BACKGROUND:Frail kidney transplant (KT) recipients have higher risk of adverse post-KT outcomes. Yet, there is interest in measuring frailty at KT evaluation and then using this information for post-KT risk stratification. Given long wait times for KT, frailty may improve or worsen between evaluation and KT. Patterns, predictors, and post-KT adverse outcomes associated with these changes are unclear. METHODS:Five hundred sixty-nine adult KT candidates were enrolled in a cohort study of frailty (November 2009-September 2017) at evaluation and followed up at KT. Patterns of frailty transitions were categorized as follows: (1) binary state change (frail/nonfrail), (2) 3-category state change (frail/intermediate/nonfrail), and (3) raw score change (-5 to 5). Adjusted Cox proportional hazard and logistic regression models were used to test whether patterns of frailty transitions were associated with adverse post-KT outcomes. RESULTS:Between evaluation and KT, 22.0% became more frail, while 24.4% became less frail. Black race (relative risk ratio, 1.98; 95% confidence interval [CI], 1.07-3.67) was associated with frail-to-nonfrail transition, and diabetes (relative risk ratio, 2.56; 95% CI, 1.22-5.39) was associated with remaining stably frail. Candidates who became more frail between 3-category states (hazard ratio, 2.27; 95% CI, 1.11-4.65) and frailty scores (hazard ratio, 2.36; 95% CI, 1.12-4.99) had increased risk of post-KT mortality and had higher odds of length of stay ≥2 weeks (3-category states: odds ratio, 2.02; 95% CI, 1.20-3.40; frailty scores: odds ratio, 1.92; 95% CI, 1.13-3.25). CONCLUSIONS:Almost half of KT candidates experienced change in frailty between evaluation and KT, and those transitions were associated with mortality and longer length of stay. Monitoring changes in frailty from evaluation to admission may improve post-KT risk stratification.

Impacts of the prescription opioid epidemic have not yet been examined in the context of heart transplantation. We examined a novel database in which national U.S. transplant registry records were linked to a large pharmaceutical claims warehouse (2007-2016) to characterize prescription opioid use before and after heart transplant, and associations (adjusted hazard ratio, _{95% LCL} aHR_{95% UCL} ) with death and graft loss. Among 13 958 eligible patients, 40% filled opioids in the year before transplant. Use was more common among recipients who were female, white, or unemployed, or who underwent transplant in more recent years. Of those with the highest level of pretransplant opioid use, 71% continued opioid use posttransplant. Pretransplant use had graded associations with 1-year posttransplant outcomes; compared with no use, the highest-level use (>1000 mg morphine equivalents) predicted 33% increased risk of death (aHR _1.10 1.33_1.61 ) in the year after transplant. Risk relationships with opioid use in the first year posttransplant were stronger, with highest level use predicting 70% higher mortality (aHR _1.46 1.70_1.98 ) over the subsequent 4 years (from >1 to 5 years posttransplant). While associations may, in part, reflect underlying conditions or behaviors, opioid use history is relevant in assessing and providing care to transplant candidates and recipients.

Importance:Among liver transplant candidates, obesity and frailty are associated with increased risk of death while they are on the wait-list. However, use of body mass index (BMI) may not detect candidates at a higher risk of death owing to the fact that ascites and muscle wasting are seen across transplant candidates of all BMI measurements. Objective:To evaluate whether the association between wait-list mortality and frailty varied by BMI of liver transplant candidates. Design, Setting, and Participants:A prospective cohort study was conducted at 9 liver transplant centers in the United States from March 1, 2012, to May 1, 2018, among 1108 adult liver transplant candidates without hepatocellular carcinoma. Exposures:At outpatient evaluation, the Liver Frailty Index score was calculated (grip strength, chair stands, and balance), with frailty defined as a Liver Frailty Index score of 4.5 or more. Candidates' BMI was categorized as nonobese (18.5-29.9), class 1 obesity (30.0-34.9), and class 2 or greater obesity (≥35.0). Main Outcomes and Measures:The risk of wait-list mortality was quantified using competing risks regression by candidate frailty, adjusting for age, sex, race/ethnicity, Model for End-stage Liver Disease Sodium score, cause of liver disease, and ascites, including an interaction with candidate BMI. Results:Of 1108 liver transplant candidates (474 women and 634 men; mean [SD] age, 55 [10] years), 290 (26.2%) were frail; 170 of 670 nonobese candidates (25.4%), 64 of 246 candidates with class 1 obesity (26.0%), and 56 of 192 candidates with class 2 or greater obesity (29.2%) were frail (P = .57). Frail nonobese candidates and frail candidates with class 1 obesity had a higher risk of wait-list mortality compared with their nonfrail counterparts (nonobese candidates: adjusted subhazard ratio, 1.54; 95% CI, 1.02-2.33; P = .04; and candidates with class 1 obesity: adjusted subhazard ratio, 1.72; 95% CI, 0.99-2.99; P = .06; P = .75 for interaction). However, frail candidates with class 2 or greater obesity had a 3.19-fold higher adjusted risk of wait-list mortality compared with nonfrail candidates with class 2 or greater obesity (95% CI, 1.75-5.82; P < .001; P = .047 for interaction). Conclusions and Relevance:This study's finding suggest that among nonobese liver transplant candidates and candidates with class 1 obesity, frailty was associated with a 2-fold higher risk of wait-list mortality. However, the mortality risk associated with frailty differed for candidates with class 2 or greater obesity, with frail candidates having a more than 3-fold higher risk of wait-list mortality compared with nonfrail patients. Frailty assessments may help to identify vulnerable patients, particularly those with a BMI of 35.0 or more, in whom a clinician's visual evaluation may be less reliable to assess muscle mass and nutritional status.

End-stage liver disease (ESLD) is associated with cognitive impairment ranging from subtle alterations in attention to overt hepatic encephalopathy that resolves after transplant. Natural language processing (NLP) may provide a useful method to assess cognitive status in this population. We identified 81 liver transplant recipients with ESLD (4/2013-2/2018) who sent at least one patient-to-provider electronic message pre-transplant and post-transplant, and matched them 1:1 to "healthy" controls-who had similar disease, but had not been evaluated for liver transplant-by age, gender, race/ethnicity, and liver disease. Messages written by patients pre-transplant and post-transplant and controls was compared across 19 NLP measures using paired Wilcoxon signed-rank tests. While there was no difference overall in word length, patients with Model for End-Stage Liver Disease Score (MELD) ≥ 30 (n = 31) had decreased word length in pre-transplant messages (3.95 [interquartile range (IQR) 3.79, 4.14]) compared to post-transplant (4.13 [3.96, 4.28], p = 0.01) and controls (4.2 [4.0, 4.4], p = 0.01); there was no difference between post-transplant and controls (p = 0.4). Patients with MELD ≥ 30 had fewer 6+ letter words in pre-transplant messages (19.5% [16.4, 25.9] compared to post-transplant (23.4% [20.0, 26.7] p = 0.02) and controls (25.0% [19.2, 29.4]; p = 0.01). Overall, patients had increased sentence length pre-transplant (12.0 [9.8, 13.7]) compared to post-transplant (11.0 [9.2, 13.3]; p = 0.046); the same was seen for MELD ≥ 30 (12.3 [9.8, 13.7] pre-transplant vs. 10.8 [9.6, 13.0] post-transplant; p = 0.050). Application of NLP to patient-generated messages identified language differences-longer sentences with shorter words-that resolved after transplant. NLP may provide opportunities to detect cognitive impairment in ESLD.

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.