Faculty Bibliography

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.

Background/UNASSIGNED:Limited data are available regarding clinical implications of lower renal function after living kidney donation. We examined a novel integrated database to study associations between postdonation estimated glomerular filtration rate (eGFR) and use of antihypertensive medication (AHM) treatment after living kidney donation. Methods/UNASSIGNED:) between AHM use and postdonation eGFR levels (random effect) with fixed effects for baseline donor factors. Results/UNASSIGNED:). Conclusions/UNASSIGNED:This novel linkage illustrates the ability to identify postdonation kidney function and associate it with clinically meaningful outcomes; lower eGFR after living kidney donation is a correlate of AHM treatment requirements. Further work should define relationships of postdonation renal function, hypertension, and other morbidity measures.

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.

INTRODUCTION:Newly discovered thyroid nodules in deceased donors are investigated to rule out cancer that can be transmitted, but there are no established protocols. The aim of the study was to compare fine needle aspiration versus intraoperative frozen section in the donor management with limited time. METHODS:Data were extracted only from the records of Italian second opinion consultation service in the years 2016 to 2017 and included donor details, pathology diagnoses, complications, transmission risk profile, and impact on transplantation. RESULTS:Among 31 deceased donors with thyroid nodules, we documented 4 with a clinical history of cancer and 27 with a newly discovered nodule. The latter was evaluated by thyroidectomy with frozen section in 22 and fine needle aspiration in 5. Among all donors, 7 had papillary thyroid carcinoma with negligible transmission risk, whereas 8 with unacceptable risk. Two donors presented major bleeding after thyroidectomy, with organ discard in 1 case. Transplantation was delayed in 4 cases that were evaluated with frozen section. DISCUSSION:There was no uniform approach for the investigation of thyroid nodules. Our results showed that fine needle aspiration was more accurate and useful than frozen section. Fine needle aspiration had minor economic impact and a far less rate of bleeding/hemodynamic complications, potentially delaying and compromising organ recovery. Our results suggested considering fine needle aspiration as a first step in the evaluation of thyroid nodules in donors.

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 AND OBJECTIVES:The risk of hypertension attributable to living kidney donation remains unknown as does the effect of developing postdonation hypertension on subsequent eGFR. We sought to understand the association between living kidney donation, hypertension, and long-term eGFR by comparing donors with a cohort of healthy nondonors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We compared 1295 living kidney donors with median 6 years of follow-up with a weighted cohort of 8233 healthy nondonors. We quantified the risk of self-reported hypertension using a parametric survival model. We examined the association of hypertension with yearly change in eGFR using multilevel linear regression and clustering by participant, with an interaction term for race. RESULTS:=0.01, respectively, after hypertension). CONCLUSIONS:Kidney donors are at higher risk of hypertension than similar healthy nondonors, regardless of race. Donors who developed hypertension had a plateau in the usual postdonation increase of eGFR.

BACKGROUND:Neighborhood poverty has been associated with worse outcomes after live donor kidney transplantation (LDKT), and prior work suggests that women with kidney disease may be more susceptible to the negative influence of poverty than men. As such, our goal was to examine whether poverty differentially affects women in influencing LDKT outcomes. METHODS:Using data from the Scientific Registry of Transplant Recipients and US Census, we performed multivariable Cox regression to compare outcomes among 18 955 women and 30 887 men who received a first LDKT in 2005-2014 with follow-up through December 31, 2016. RESULTS:Women living in poor (adjusted hazard ratio [aHR], 1.30; 95% confidence interval [CI], 1.13-1.50) and middle-income (aHR, 1.26; 95% CI, 1.14-1.40) neighborhoods had higher risk of graft loss than men, but there were no differences in wealthy areas (aHR, 1.07; 95% CI, 0.88-1.29). Women living in wealthy (aHR, 0.71; 95% CI, 0.59-0.87) and middle-income (aHR, 0.82; 95% CI, 0.74-0.92) neighborhoods incurred a survival advantage over men, but there were no statistically significant differences in mortality in poor areas (aHR, 0.85; 95% CI, 0.72-1.01). CONCLUSIONS:Given our findings that poverty is more strongly associated with graft loss in women, targeted efforts are needed to specifically address mechanisms driving these disparities in LDKT outcomes.

OBJECTIVE:To develop and validate an integrative system to predict long term kidney allograft failure. DESIGN:International cohort study. SETTING:Three cohorts including kidney transplant recipients from 10 academic medical centres from Europe and the United States. PARTICIPANTS:Derivation cohort: 4000 consecutive kidney recipients prospectively recruited in four French centres between 2005 and 2014. Validation cohorts: 2129 kidney recipients from three centres in Europe and 1428 from three centres in North America, recruited between 2002 and 2014. Additional validation in three randomised controlled trials (NCT01079143, EudraCT 2007-003213-13, and NCT01873157). MAIN OUTCOME MEASURE:Allograft failure (return to dialysis or pre-emptive retransplantation). 32 candidate prognostic factors for kidney allograft survival were assessed. RESULTS:Among the 7557 kidney transplant recipients included, 1067 (14.1%) allografts failed after a median post-transplant follow-up time of 7.12 (interquartile range 3.51-8.77) years. In the derivation cohort, eight functional, histological, and immunological prognostic factors were independently associated with allograft failure and were then combined into a risk prediction score (iBox). This score showed accurate calibration and discrimination (C index 0.81, 95% confidence interval 0.79 to 0.83). The performance of the iBox was also confirmed in the validation cohorts from Europe (C index 0.81, 0.78 to 0.84) and the US (0.80, 0.76 to 0.84). The iBox system showed accuracy when assessed at different times of evaluation post-transplant, was validated in different clinical scenarios including type of immunosuppressive regimen used and response to rejection therapy, and outperformed previous risk prediction scores as well as a risk score based solely on functional parameters including estimated glomerular filtration rate and proteinuria. Finally, the accuracy of the iBox risk score in predicting long term allograft loss was confirmed in the three randomised controlled trials. CONCLUSION:An integrative, accurate, and readily implementable risk prediction score for kidney allograft failure has been developed, which shows generalisability across centres worldwide and common clinical scenarios. The iBox risk prediction score may help to guide monitoring of patients and further improve the design and development of a valid and early surrogate endpoint for clinical trials. TRIAL REGISTRATION:Clinicaltrials.gov NCT03474003.

Delayed graft function (DGF) complicates 20%-40% of deceased-donor kidney transplants and is associated with increased length of stay and subsequent allograft failure. Accurate prediction of DGF risk for a particular allograft could influence organ allocation, patient counseling, and postoperative planning. Mitochondrial dysfunction, a reported surrogate of tissue health in ischemia-perfusion injury, might also be a surrogate for tissue health after organ transplantation. To understand the potential of mitochondrial membrane potential (MMP) in clinical decision-making, we analyzed whether lower MMP, a measure of mitochondrial dysfunction, was associated with DGF. In a prospective, single-center proof-of-concept study, we measured pretransplant MMP in 28 deceased donor kidneys and analyzed the association between MMP and DGF. We used hybrid registry-augmented regression to adjust for donor and recipient characteristics, minimizing overfitting by leveraging Scientific Registry of Transplant Recipients data. The range of MMP levels was 964-28 333 units. Low-MMP kidneys (MMP<4000) were more likely from female donors (75% vs 10%, P = .002) and donation after cardiac death donors (75% vs 12%, P = .004). For every 10% decrease in MMP levels, there were 38% higher odds of DGF (adjusted odds ratio = _1.08 1.38_1.78 , P = .01). In summary, MMP might be a promising pretransplant surrogate for tissue health in kidney transplantation and, after further validation, could improve clinical decision-making through its independent association with DGF.