Association of intraindividual tacrolimus variability and concentration-to-dose ratio with allograft rejection in pediatric kidney transplant recipients
Maral Baghai Arassi1,2, Nora Fisch1, Manuel Feißt3, Kai Krupka1, Britta Höcker1, Alexander Fichtner1, Nele Kanzelmeyer4, Jens König5, Anette Melk4, Jun Oh6, Lars Pape8, Lutz T Weber7, Marcus Weitz9, Burkhard Tönshoff1.
1Medical Faculty, Department of Pediatrics I, Heidelberg University, Heidelberg, Germany; 2Molecular Systems Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany; 3Institute of Medical Biometry, Heidelberg University, Heidelberg, Germany; 4Department of Pediatric Kidney, Liver and Metabolic Diseases and Neuropediatrics, Hannover Medical School, Heidelberg, Germany; 5Department of General Pediatrics, University Children's Hospital Münster, Münster, Germany; 6Department of Pediatric Nephrology, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 7Pediatric Nephrology, Children´s and Adolescents´ Hospital, University Hospital of Cologne, Cologne, Germany; 8Clinic for Paediatrics III, Essen University Hospital, Essen, Germany; 9Department of General Pediatrics and Hematology/Oncology, University Children’s Hospital, University Hospital Tübingen, Tübingen, Germany
Background: The value of tacrolimus intraindividual variability (TacIPV) as a marker of fluctuating tacrolimus exposure and concentration-to-dose ratio (C/D ratio) as a marker of tacrolimus metabolism for the prediction of outcome in pediatric kidney transplant recipients remains poorly understood. This study evaluated the impact of TacIPV and C/D ratio on allograft rejection in pediatric transplant recipients.
Methods: We conducted a multi-center retrospective study of 255 pediatric kidney transplant recipients from the CERTAIN registry. TacIPV was quantified as the coefficient of variation (CV%) during months 6–12 post-transplant, as it is highly variable in the early post-transplant period. The C/D ratio, corrected for body surface area, was calculated for the first 6 months post-transplant due to its relative stability early on. Cut-offs were determined using minimization of log-rank P values: 23% for TacIPV and 1.0 for the C/D ratio. Rejection episodes were classified based on Banff criteria in the period following biomarker quantification.
Results: A total of 13,159 tacrolimus blood trough levels were analyzed, with a median of 52 (IQR, 41-63) measurements per patient. High TacIPV (>23%) during months 6-12 post-transplant was associated with an increased risk of rejection beyond 12 months post-transplant (HR 1.04, 95% CI 1.01-1.06, P = 0.002; Kaplan-Meier analysis P = 0.002). Similarly, a low C/D ratio (<1.0) during the first six months was associated with a higher risk of rejection between months 6-12 (HR 0.32, 95% CI 0.11-0.95, P = 0.04; Kaplan-Meier analysis P = 0.01).
Conclusions: This is the largest study to date investigating the relevance of TacIPV and C/D ratio in pediatric kidney transplant recipients. High TacIPV is associated with an increased risk of rejection episodes beyond 12 months post-transplant, while low C/D ratio is associated with an increased risk of rejection episodes between 6-12 months post-transplant. High TacIPV may serve as a marker for late rejection risk, while a low C/D ratio as a marker for rapid tacrolimus metabolism may be used to identify patients at risk of earlier rejection. Patients with these risk factors should be closely monitored, and their immunosuppressive therapy adjusted accordingly.
[1] Pediatric kidney transplantation, tacrolimus, intrapatient variability, concentration-to-dose ratio, allograft rejection