Background The intra-patient variability in tacrolimus exposure (TAC-IPV) after paediatric liver transplantation and its impact on patient outcomes has been poorly studied. The present study aims to investigate whether there is a trend in TAC-IPV during the first 5 years post transplantation, which variables influence IPV and wheth-er the IPV during the first year is associated with liver transplantation outcomes in paediatric patients.
Methods We conducted a single centre retrospective study including 41 living paediatric patients transplanted between January 2003 and September 2016 at the Ghent University Hospital. The intra-patient variability in the dose-adjusted tacrolimus pre-dose concentrations was calculated yearly during the first five years following trans-plantation, expressed as coefficient of variation (CV%1–5) The difference in CV% in the years following transplanta-tion was analysed using the Friedman test. A linear uni-variate and multivariate regression analysis was applied to identify factors associated with TAC-IPV. The following parameters were tested: age, gender, origin, the number of missed clinic appointments as a surrogate marker for ther-apy adherence, the total number of medications, concom-itant medications potentially interfering with TAC metabo-lism-CYP3A4/A5 inductors or inhibitors and biochemical parameters. Logistic and linear regression models were fit-ted to test an association of TAC-IPV with patient outcomes: need for biopsy during year 1, 3 and 5; hypertension and renal function at 1, 3 and 5 years; acute rejection and CMV/EBV viremia during year 1 post-transplantation.
Results We identified a significant decrease in TAC-IPV during the first 3 years after transplantation with the me-dian CV%1=39,4%; CV%2=30,9%; CV%3=28,5% (p=0,004), after which the CV% reaches a plateau (CV%4=23,6% en CV%5=28,9%). Multivariate analysis showed that serum albumin in the first year (p=0,029), haematocrit in the third year (p=0,019) and the number of missed clin-ic appointments in the fifth year after transplantation (p=0,009) were associated with TAC-IPV.in the 1 st, 3rd and 5th year, respectively. Univariate analysis showed that CV%1 was significantly associated with the need for bi-opsy during the first year post-transplantation (p=0.036) and the occurrence of one or more episodes of acute al-lograft rejection during the first year post-transplantation (p=0.031). In univariate analysis a trend was observed for association with hypertension one year after transplan-tation (p=0,085). Multivariate logistic regression analysis confirmed that CV%1 was an independent factor associ-ated with the need for liver biopsy in the first year follow-ing liver transplantation. (p=0.05; Exp(B)=1.045).
Conclusion As expected, tacrolimus intra-patient vari-ability is higher during the first two years after transplantation. Our results suggest that while albumin and hae-matocrit are associated with TAC-IPV in the first 3 years, therapy adherence expressed as the number of missed clinic appointments is associated with TAC-IPV after a longer follow-up. A high TAC-IPV during the first year was an independent factor associated with the need for liver biopsy. Our results therefore highlight the importance of monitoring the variability of the tacrolimus trough levels.
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