# Hidden in Plain Sight: High Tacrolimus Metabolism Doubles Kidney Transplant Failure and Drives Infection Related Mortality

## TL;DR

Low tacrolimus metabolism in kidney transplant patients is linked to higher graft failure and infection-related deaths, but adjusting medication can improve outcomes.

## Contribution

Identifies a high-risk group with low tacrolimus metabolism and suggests clinical interventions to improve graft survival.

## Key findings

- Low CDR at year 1 is associated with a 2.80 hazard ratio for graft failure and 1.63 for infection-related mortality.
- 25.2% of patients had low CDR, with higher odds among Black, female, and younger recipients.
- CYP3A5*1A genotype is associated with an 8-fold higher risk of low CDR.

## 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 (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.

Study on low tacrolimus metabolism in kidney transplants involving 21,865 cases from 2000 to 2019. Highlights include a 25.2% prevalence of low concentration-dose ratio (CDR) linked to poor outcomes, with a hazard ratio of up to 2.80 and a 63% increase in infection-related mortality. High-risk groups: females, Black people, those under 50, and those with CYP3A5*1A (eight-fold increase). Diltiazem co-medication and steroid tapering are suggested to improve long-term graft outcomes. The study is by Caner Süsal, Transpl. Int. 2025. ESOT and Transplant International logos are included.