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Hidden in Plain Sight: Low Tacrolimus Metabolism Doubles Kidney Transplant Failure and Drives Infection Related Mortality
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Hidden in Plain Sight: Low Tacrolimus Metabolism Doubles Kidney Transplant Failure and Drives Infection Related Mortality
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Journal Article
Hidden in Plain Sight: Low Tacrolimus Metabolism Doubles Kidney Transplant Failure and Drives Infection Related Mortality
2025
Overview
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.
Publisher
Frontiers Media SA
Subject
/ Aged
/ Cytochrome P-450 CYP3A - genetics
/ Diabetes
/ Disease
/ Dosage
/ Enzymes
/ Female
/ Grafting
/ Humans
/ Immunosuppressive Agents - administration & dosage
/ Immunosuppressive Agents - metabolism
/ Immunosuppressive Agents - pharmacokinetics
/ Immunosuppressive Agents - therapeutic use
/ Kidney Transplantation - adverse effects
/ Kidney Transplantation - mortality
/ Kidneys
/ Male
/ Patients
/ Survival
/ Tacrolimus - administration & dosage
/ Tacrolimus - pharmacokinetics
