Faculty Bibliography

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.

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.