ORIGINAL RESEARCH
Transpl. Int.
Hidden in Plain Sight: High Tacrolimus Metabolism Doubles Kidney Transplant Failure and Drives Infection Related Mortality
1. Transplant Immunology Research Center of Excellence, Koç Üniversitesi, Istanbul, Türkiye
2. Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
3. Department of Internal Medicine & Nephrology, Faculty of Medicine, Assiut University, Assiut, Egypt
4. Health Sector and Department of Immunology, College of Medicine, Qatar University, Doha, Qatar
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Abstract
Low tacrolimus trough concentration-to-dose ratio (CDR) is recognized as an indicator of high tacrolimus metabolism. However, its impact on long-term transplant outcomes and potential for clinical intervention remains unclear. In the largest study to date, we analyzed the impact of a low CDR at post-transplant year 1 on graft loss and patient mortality in 21,865 kidney transplants. We also performed a longitudinal analysis of CDR dynamics and conducted a genetic correlation in a subset of 1,257 patients. Low CDR at year 1 was significantly associated with increased hazards of graft failure and infection-related mortality, even in patients with therapeutic trough levels and good graft function. In the longitudinal analysis, normalizing initially low CDR by year 2 significantly improves graft survival. Low CDR was identified in a substantial proportion of the cohort(25.2%). Black, female, and recipients younger than 50 years had higher odds of having a low CDR. The CYP3A5*1A genotype was also strongly associated with low CDR. Patients with a low tacrolimus CDR represent a large high-risk population. The normalization of tacrolimus CDR with co-medication with diltiazem and reductions in steroid dosing may improve graft survival. Our findings support personalized tacrolimus management based on metabolic profiling and genetic testing.
Summary
Keywords
Kidney transplant, Tacrolimus concentration-to-dose ratio, allograft loss, Mortality, infection
Received
01 July 2025
Accepted
17 October 2025
Copyright
© 2025 Süsal, Bernd, Demir, Ibrahim and Askar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Caner Süsal, caner.suesal@outlook.com; Medhat Askar, maskar@qu.edu.qa
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.