Tacrolimus Trough Variability- Predictors and Outcomes in Pediatric Heart Transplantation

Abstract

Tacrolimus is a narrow therapeutic index drug, requiring consistent levels to maximize solid organ transplant success while reducing adverse effects. High tacrolimus trough level variability (TTLV) is a significant predictor of late rejection in both kidney and liver transplant. We sought to describe the prevalence of high TTLV in our pediatric heart transplant (HT) population, and identify whether this variability is associated with patient specific factors and poor outcomes. Single center, retrospective study of HT patients from 1/2002 - 12/2018. Multi-organ recipients and retransplants were excluded. Records were reviewed for demographics, tacrolimus trough levels (TTLs) and outcomes (rejection, coronary vasculopathy, need for re-transplantation, death). Variability was calculated as the TTL standard deviation (SD) using each patient's TTLs from 1 year post-HT to last follow-up. High TTLV was defined as SD ≥3. Statistical analysis included Kruskal-Wallis, Chi-squared, and Wilcoxon rank sum testing. A total of 119 patients were included (male, 57%) with pre-HT diagnoses of congenital heart disease (57%) and cardiomyopathy (42%). The median age at HT was 2.7 yrs (IQR 0.8, 12.2) with a follow-up time post HT of 5.7 yrs (IQR 3.3, 9.9). A total of 6,344 TTLs were included, with a median of 33 TTLs/pt (IQR 14, 76). The median SD for the entire cohort was 3.1 (IQR 2.3, 4.0) with 55% of the population having a SD ≥3. Levels obtained from 1-5 yrs of age were found to have significantly greater variability (median SD 3.1 [IQR 2.4, 4.1]; p-value< 0.01) than 6-12 yrs (SD 2.5) and 12+ yrs (SD 2.5). After dichotomizing patients for higher variability (SD ≥ 3), there were no significant associations with patient specific factors including: sex, pre-HT diagnosis, pre-HT clinical course (acute vs chronic), age at HT, time with HT and Hollingshead Socioeconomic Score. High TTLV was associated with increased rejection treatment (74% vs 44%, p<0.01), higher frequency of coronary vasculopathy (23% vs 7%, p=0.02), and death (20% vs 6%, p=0.02). TTLV is high in pediatric HT recipients, especially in those < 5 yrs. Patients with a SD ≥3 experienced a higher frequency of poor outcomes including rejection, coronary vasculopathy and death.