Hidden in plain sight: high tacrolimus metabolism doubles kidney transplant failure and drives infection related mortality
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...
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| Main Authors: | , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
03 November 2025
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| In: |
Transplant international
Year: 2025, Volume: 38, Pages: 1-12 |
| ISSN: | 1432-2277 |
| DOI: | 10.3389/ti.2025.15207 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.3389/ti.2025.15207 Verlag, kostenfrei, Volltext: https://www.frontierspartnerships.org/journals/transplant-international/articles/10.3389/ti.2025.15207/full 
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| Author Notes: | Caner Süsal, Bernd Döhler, Erol Demir, Walaa Ibrahim and Medhat Askar |
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| 520 | |a 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 (HR up to 2.80) and infection-related mortality (HR = 1.63), 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 younger recipients (<50 years) had higher odds of having a low CDR. The CYP3A5*1A genotype was also strongly associated with low CDR (approximately 8-fold higher odds). Patients with a low tacrolimus CDR represent a large high-risk population. The normalization of tacrolimus CDR through 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. | ||
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