BACKGROUND Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive. METHODS We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity. We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR–Cas9 genome editing in samples from patients. RESULTS Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. This results in a cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from participants with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by CRISPR–Cas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7. CONCLUSIONS Our results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects. (Funded by the German Research Center for Environmental Health and others.)

Background & Aims: Frailty is associated with mortality in patients with cirrhosis. We measured frailty using 3 simple tests and calculated liver frailty index (LFI) scores for patients at multiple ambulatory centers. We investigated associations between LFI scores, ascites, and hepatic encephalopathy (HE) and mortality. Methods: Adults without hepatocellular carcinoma who were on the liver transplant waitlist at 9 centers in the United States (n=1044) were evaluated using the LFI; LFI scores of 4.5 or more indicated that patients were frail. We performed logistic regression analyses to assess associations between frailty and ascites or HE and competing risk regression analyses (with liver transplantation as the competing risk) to estimate subhazard ratios (sHR) of waitlist mortality (death or removal from the waitlist). Results: Of study subjects, 36% had ascites, 41% had HE, and 25% were frail. The odds of frailty were higher for patients with ascites (adjusted odd ratio, 1.56; 95% CI, 1.15-2.14) or HE (OR, 2.45; 95% CI, 1.80-3.33) than without these features. Higher proportions of frail patients with ascites (29%) or HE (30%) died while on the waitlist compared to patients who were not frail (17% of patients with ascites and 20% with HE). In univariable analysis, ascites (sHR, 1.52; 95% CI, 1.14-2.05), HE (sHR, 1.84; 95% CI, 1.38-2.45), and frailty (sHR, 2.38; 95% CI, 1.77-3.20) were associated with waitlist mortality. In adjusted models, only frailty remained significantly associated with waitlist mortality (sHR, 1.82; 95% CI, 1.31-2.52)-ascites and HE were not. Conclusions: Frailty is a prevalent complication of cirrhosis that is observed more frequently in patients with ascites or HE and independently associated with waitlist mortality. LFI scores can be Lai et al.

In this pilot with carefully selected patients, early liver transplant provided excellent short-term survival, and similar rates of alcohol relapse compared with patients with 6 months of abstinence. Harmful patterns of relapse remain challenging in this population, highlighting the need for validated models to predict alcohol relapse, and need for extreme caution in selecting patients for this exceptional indication. Larger prospective studies and longer follow up are necessary.

Background Frailty increases early hospital readmission and mortality risk among kidney transplant (KT) recipients. While frailty represents a high-risk state for this population, the correlates of frailty, the patterns of the 5 frailty components, and the risk associated with these patterns are unclear. Methods 663 KT recipients were enrolled in a cohort study of frailty in transplantation (12/2008-8/2015). Frailty, ADL/IADL disability, CESD depression, education, and HRQOL were measured. We used multinomial regression to identify frailty correlates. We identified which patterns of the 5 components were associated with mortality using adjusted Cox proportional hazards models. Results Frailty prevalence was 19.5%. Older recipients (adjusted prevalence ratio [PR]=2.22, 95%CI:1.21-4.07) were more likely to be frail. The only other factors that were independently associated with frailty were IADL disability (3.22, 95%CI:1.72-6.06), depressive symptoms (11.31, 95%CI:3.02-31.82), less than a high school education (3.10, 95% CI:1.30-7.36) and low HRQOL (Fair/Poor:3.71, 95%CI:1.48-9.31). The most common pattern was poor grip strength, low physical activity and slowed walk speed (19.4%). Only 2 patterns of the 5 components emerged as having an association with post-KT mortality. KT recipients with exhaustion and slowed walking speed (HR=2.43, 95%CI:1.17-5.03) and poor grip strength, exhaustion, and slowed walking speed (HR=2.61, 95%CI:1.14-5.97) were at increased mortality risk. Conclusion Age was the only conventional factor associated with frailty among KT recipients; however, factors rarely measured as part of clinical practice, namely HRQOL, IADL disability and depressive symptoms, were significant correlates of frailty. Redefining the frailty phenotype may be needed to improve risk stratification for KT recipients.

Objective To test whether frailty, a novel measure of physiologic reserve, is associated with longer kidney transplant (KT) length of stay (LOS), and modifies the association between LOS and mortality. Background Better understanding of LOS is necessary for informed consent and discharge planning. Mortality resulting from longer LOS has important regulatory implications for hospital and transplant programs. Which recipients are at risk of prolonged LOS and its impact on mortality are unclear. Frailty is a novel preoperative predictor of poor KT outcomes including DGF, early hospital readmission, immunosuppression intolerance, and mortality. Methods We used registry-augmented hybrid methods, a novel approach to risk adjustment, to adjust for LOS risk factors from the Scientific Registry of Transplant Recipients (n=74,859) and tested whether 1) frailty, measured immediately prior to KT in a novel cohort (n=589), was associated with LOS (LOS: negative binomial regression; LOS≥2 weeks: logistic regression) and 2) whether frailty modified the association between LOS and mortality (interaction term analysis). Results Frailty was independently associated with longer LOS (RR=1.15, 95%CI: 1.03-1.29; P=0.01) and LOS≥2 weeks (OR=1.57, 95%CI:1.06-2.33; P=0.03) after accounting for registry-based risk factors, including DGF. Frailty also attenuated the association between LOS and mortality (nonfrail HR:1.55 95%CI:1.30-1.86, P<0.001; frail HR=0.97, 95%CI:0.79-1.19, P=0.80; P for interaction=0.001). Conclusions Frail KT recipients are more likely to experience a longer LOS. Longer LOS among nonfrail recipients may be a marker of increased mortality risk. Frailty is a measure of physiologic reserve that may be an important clinical marker of longer surgical length of stay.

Background and objectivesFrailty, 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, & measurementsWe 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.ResultsThe mean age was 54 years (SD 13; range, 18–89), 40% were women, 34% were black, and 21% were frail. Frail participants were almost half as likely to be listed for kidney transplantation (hazard ratio, 0.62; 95% confidence interval, 0.56 to 0.69; P<0.001) compared with nonfrail participants, independent of age and other demographic factors. Furthermore, frail candidates were transplanted 32% less frequently than nonfrail candidates (incidence rate ratio, 0.68; 95% confidence interval, 0.58 to 0.81; P<0.001).ConclusionsFrailty is associated with lower chance of listing and lower rate of transplant, and is a potentially modifiable risk factor.

Prehabilitation is the process of enhancing pre-operative functional capacity to improve tolerance for the upcoming stressor; it was associated with improved post-operative 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 pre-transplant patients and may potentially be a strategy to improve post-KT outcomes.

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