Age-Related Differences in Rejection Rates, Infections, and Tacrolimus Exposure in Pediatric Kidney Transplant Recipients in the CERTAIN Registry

Maral Baghai Arassi; Manuel Feißt; Kai Krupka; Atif Awan; Elisa Benetti; Ali Düzova; Isabella Guzzo; Jon Jin Kim; Birgitta Kranz; Mieczysław Litwin; Jun Oh; Anja Büscher; Lars Pape; Licia Peruzzi; Mohan Shenoy; Sara Testa; Lutz T Weber; Jakub Zieg; Britta Höcker; Alexander Fichtner; Burkhard Tönshoff; Cooperative European Pediatric Renal Transplant Initiative Research Network

doi:10.1016/j.ekir.2024.08.025

Age-Related Differences in Rejection Rates, Infections, and Tacrolimus Exposure in Pediatric Kidney Transplant Recipients in the CERTAIN Registry

Kidney Int Rep. 2024 Sep 2;9(11):3265-3277. doi: 10.1016/j.ekir.2024.08.025. eCollection 2024 Nov.

Authors

Maral Baghai Arassi^{1

2}, Manuel Feißt³, Kai Krupka¹, Atif Awan⁴, Elisa Benetti⁵, Ali Düzova⁶, Isabella Guzzo⁷, Jon Jin Kim⁸, Birgitta Kranz⁹, Mieczysław Litwin¹⁰, Jun Oh¹¹, Anja Büscher¹², Lars Pape¹², Licia Peruzzi¹³, Mohan Shenoy¹⁴, Sara Testa¹⁵, Lutz T Weber¹⁶, Jakub Zieg¹⁷, Britta Höcker¹, Alexander Fichtner¹, Burkhard Tönshoff¹; Cooperative European Pediatric Renal Transplant Initiative Research Network

Affiliations

¹ Department of Pediatrics I, Medical Faculty, Heidelberg University, University Children's Hospital Heidelberg, Heidelberg, Germany.
² Structural and Computational Biology Unit, European Molecular Biology Laboratory Heidelberg, Heidelberg, Germany.
³ Institute of Medical Biometry, Heidelberg University, Heidelberg, Germany.
⁴ National Pediatric Haemodialysis Centre and Renal Transplant Unit, Temple Street Children's University Hospital, Dublin, Ireland.
⁵ Pediatric Nephrology Unit, Department of Women's and Children's Health, Padua University Hospital, Italy.
⁶ Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Türkiye.
⁷ Division of Nephrology, Dialysis and Transplant Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁸ Department of Pediatric Nephrology, Nottingham University Hospitals, Nottingham, UK.
⁹ Department of General Pediatrics, University Children's Hospital Münster, Münster, Germany.
¹⁰ Department of Nephrology, Kidney Transplantation and Hypertension, The Children's Memorial Health Institute, Warsaw, Poland.
¹¹ Division of Pediatric Nephrology, University Hamburg-Eppendorf, Hamburg, Germany.
¹² Department of Pediatrics II, University Hospital of Essen, Essen, Germany.
¹³ Pediatric Nephrology Unit, Regina Margherita Department, Azienda Ospedaliero-Universitaria Città Della Salute e della Scienza, Torino, Italy.
¹⁴ Department of Pediatric Nephrology, Royal Manchester Children's Hospital, Manchester, UK.
¹⁵ Pediatric Nephrology Unit, Dialysis and Transplantation Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
¹⁶ Pediatric Nephrology, Children's and Adolescents' Hospital, University Hospital of Cologne, Faculty of Medicine, University of Cologne, Köln, Germany.
¹⁷ Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic.

Abstract

Introduction: Data on age-related differences in rejection rates, infectious episodes, and tacrolimus exposure in pediatric kidney transplant recipients (pKTRs) on a tacrolimus-based immunosuppressive regimen are scarce.

Methods: We performed a large-scale analysis of 802 pKTRs from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry from 40 centers in 14 countries. The inclusion criteria were a tacrolimus-based immunosuppressive regimen and at least 2 years of follow-up. The patient population was divided into 3 age groups (infants and young children aged <6 years, school-aged children 6-12 years, and adolescents aged >12 years) to assess age-related differences in outcome.

Results: Median follow-up was 48 months (interquartile range [IQR], 36-72). Within the first 2 years posttransplant, infants, and young children had a significantly higher incidence of infections (80.6% vs. 55.0% in adolescents, P < 0.001) and a significantly higher number of cumulative hospital days (median 13 days vs. 7 days in adolescents, P < 0.001). Adolescents had a significantly higher rate of biopsy-proven acute rejection episodes in the first-year posttransplant (21.7%) than infants and young children (12.6%, P = 0.007). Infants and young children had significantly lower tacrolimus trough levels, lower tacrolimus concentration-to-dose (C/D) ratios as an approximation for higher tacrolimus clearance, and higher tacrolimus interpatient variability (TacIPV) (all P < 0.01) than adolescents.

Conclusion: This is the largest study to date in European pKTRs on a tacrolimus-based immunosuppressive regimen, and it shows important age-related differences in rejection rates, infection episodes, as well as tacrolimus exposure and clearance. This data suggests that immunosuppressive therapy in pKTRs should be tailored and personalized according to the age-specific risk profiles of this heterogeneous patient population. The data may serve as a benchmark for future studies with novel immunosuppressive drugs.

Keywords: allograft rejection; hospitalization; infection; pediatric kidney transplantation; tacrolimus.