# Elevated tacrolimus exposure variability predicts transplant renal insufficiency

## TL;DR

High variability in tacrolimus levels after kidney transplant increases the risk of kidney failure, suggesting the need for tighter control of drug exposure.

## Contribution

This study identifies elevated tacrolimus exposure variability as a novel predictor of graft renal insufficiency in kidney transplant recipients.

## Key findings

- A standard deviation of tacrolimus trough concentration ≥5 is linked to a 4.55-fold higher risk of graft renal insufficiency.
- Higher coefficient of variation in tacrolimus levels correlates with increased risk of kidney failure.
- Tacrolimus mean trough >8 ng/mL and time in therapeutic range <0.3 are associated with worse outcomes.

## Abstract

Optimizing immunosuppression based on immunological risk profiles remains the preferred regimen for improving long-term graft outcomes after renal transplantation. Tacrolimus (TAC), the cornerstone drug of the calcineurin inhibitors, is currently the most commonly used immunosuppressant for renal transplantation. Under-exposure can lead to rejection events, while overexposure has been shown to cause drug-related renal injury. This study aims to assess the impact of TAC exposure on graft renal function to identify high-risk individuals of post-transplantation.

The present study employed a single-center retrospective cohort design to enroll adult recipients who underwent allogeneic kidney transplantation from 1 January 2019 to 31 December 2023. Cox regression analysis was used to analyze the independent risk effects of exposure parameters, which included mean, median, standard deviation (STD) and coefficient of variation (CV). Hereafter, the Kaplan-Meier method was applied to perform the survival analysis of stabilized graft renal function.

69 cases (19.22%) in the study cohort developed graft renal insufficiency. And a STD of TAC target trough concentration≥5 was associated with a 4.55-fold elevated risk (95% CI 1.60-12.95, p = 0.004). Recipients in the higher CV had an increased risk of graft renal insufficiency in comparison with those in low CV tertile. As indicated by the survival analysis curves, it was determined that TAC mean trough concentrations >8 ng/mL, CV>0.5 and TTR<0.3 were associated with a higher risk of graft renal insufficiency.

Higher TAC trough concentrations, higher CV, and lower TTR post-transplantation significantly increases the risk of transplant renal insufficiency. Identifying these high-risk transplant recipients, correcting potentially influential factors and keeping TAC within recommended concentrations will significantly improve the outcomes and survival of renal transplant recipients.