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-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 <i>CYP3A5*1A</i> 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.