Tacrolimus Exposure is Associated with Acute Rejection in the Early Phase After Kidney Transplantation
A Joint Modeling Approach
Maaike R. Schagen (Rotterdam Clinical Pharmacometrics Group, Erasmus MC)
Alvaro Assis de Souza (Erasmus MC)
Karin Boer (Erasmus MC)
J.H. Krijthe (TU Delft - Pattern Recognition and Bioinformatics)
Rachida Bouamar (Erasmus MC)
Andrew P. Stubbs (Erasmus MC)
Dennis A. Hesselink (Erasmus MC)
B.C.M. de Winter (TU Delft - Biomechanical Engineering)
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Abstract
Background: – Reports regarding the relationship between tacrolimus exposure and the risk of acute kidney allograft rejection are conflicting. This may be explained by the previous use of methodological approaches that disregarded important factors in the analysis of longitudinal measurements and time-to-event data. Therefore, in this study, joint models were used to investigate the relationship between repeated measurements of tacrolimus predose concentrations (C
0) and time to acute biopsy-proven acute rejection (BPAR).Methods: – This was a post hoc analysis of a randomized controlled trial in which living-donor kidney transplant recipients (KTR) received either a standard, bodyweight-based or CYP3A5 genotype-based tacrolimus starting dose. Joint modeling was performed by coupling a mixed-effects model for tacrolimus C
0 with a Cox proportional hazards model for the risk of rejection. Only the first episode of rejection was considered.Results: – A total of 229 KTRs were included, of whom the incidence of BPAR was 10.5% (n = 24 KTRs) in the first 3 months posttransplant. A total of 3069 tacrolimus measurements were available for the analysis. A joint model adjusted for recipient age and peak panel reactive antibodies demonstrated that tacrolimus C
0 was associated with risk of rejection. A 1-unit increase in the time-normalized area under the curve for logarithmically (log)-transformed C
0 represented a change of −2.65 in the log of the relative hazard (95% credible interval: −5.05 to −0.36, P = 0.022).Conclusions: – A negative association between the cumulative effect of tacrolimus C
0 and BPAR was observed using joint modeling. This demonstrated that KTRs with lower tacrolimus exposure were at a higher risk of rejection.
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