*Purpose: Frailty, a state of decreased physiologic reserve and increased vulnerability to health stressors, has an inflammatory biologic basis and has been associated with dysregulation of the immune system. Acute cellular rejection is a clinically important outcome in liver transplant (LT) recipients that is immune-mediated. We hypothesized that frailty would be associated with differential rates of acute cellular rejection in LT recipients and designed this study to test this hypothesis.

*Methods: Included were LT recipients from 2014-16 at a single center who had a frailty assessment prior to LT using the Liver Frailty index, consisting of grip strength, chair stands, and balance. Frailty was defined as a Liver Frailty Index ≥ 4.5. Data on acute cellular rejection at 3 months (primary outcome) and immunosuppression regimens were collected from medical chart review. Univariable and multivariable logistic regression assessed the associations between frailty and acute cellular rejection at 3 months.

*Results: A total of 241 LT recipients were included: 46 (19%) were classified as frail pre-LT. Of these 241 LT recipients, 37% were female, and median (IQR) age was 60 (54-65). Median (IQR) time from frailty assessment to LT was 66 days (34-122). 98% of patients were on mycophenolate, corticosteroids, and tacrolimus on discharge post-LT; 80% were on this triple-drug regimen at 3 months. There were no significant differences in median tacrolimus trough levels, mycophenolate doses, or corticosteroid doses at discharge, 1-month, or 3-months [p>0.05 for comparisons between frail and nonfrail]. Within the first 3 months post-LT, 7 (15%) of frail patients versus 10 (5%) (p=0.02) of non-frail patients experienced an episode of acute cellular rejection. In univariable logistic regression, frailty was associated with a 3.3 times higher odds of acute cellular rejection at 3 months (95%CI 1.19, 9.26, p=0.02). Age (OR 0.9), Black race (OR 3.2), autoimmune disease (OR 2.3), and diabetes (OR 0.3) were also associated with acute cellular rejection at 3 months [p<0.20]. In multivariate analysis, adjusting for age, frailty remained significantly associated with acute cellular rejection at 3 months (OR 3.06, 95%CI 1.04, 9.01, p=0.04). There were no significant differences in immunosuppression regimens or rates of mycophenolate dose reduction in the first 3 months between frail and non-frail patients.

*Conclusions: Frailty is associated with an increased rate of acute cellular rejection within 3 months post-LT, despite similar immunosuppression regimens and tacrolimus trough levels. Future studies should evaluate whether frailty should be considered in the management of immunosuppression in the early post-transplant period.

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