The impact of standard- versus reduced-dose tacrolimus exposure on clinical outcomes in adult kidney transplant recipients: A systematic review and meta-analysis

Abstract

Concerns around calcineurin inhibitor–induced nephrotoxicity after kidney transplantation have led to dose-reduction practices. However, “reduced dose” remains poorly defined, and evidence comparing outcomes for standard- versus reduced-dose tacrolimus trough concentration (C₀) above 5 ng/mL is limited. We searched multiple electronic databases (Jan 1, 2000-June 30, 2024) for randomized controlled or observational studies that reported clinical outcomes (acute rejection, nephrotoxicity, graft survival, patient survival, and estimated glomerular filtration rate) directly against tacrolimus C₀ as an independent clinical variable in adult kidney transplant recipients who received tacrolimus. Ten publications were included. No eligible study of tacrolimus with mammalian target of rapamycin inhibitors was identified, so results focused on patients treated with tacrolimus plus mycophenolic acid. Four randomized controlled trials with similar immunosuppression regimens were included in the meta-analysis to compare the impact of standard- versus reduced-dose tacrolimus exposure (per study definition) on C₀ and clinical outcomes. Standard-dose tacrolimus exposure was associated with significantly lower acute rejection rates versus reduced-dose exposure (odds ratio, 0.4 [95 % confidence interval: 0.17, 0.95]; P = 0.037). There were no significant differences between groups in graft loss or patient survival. An overlap in drug concentrations between standard- and reduced-dose tacrolimus C₀ suggests that reduced-dose tacrolimus regimens can often result in an exposure that falls within the standard range (i.e., 5–10 ng/mL). Clinicians should consider the precise tacrolimus dose ranges reported in publications and optimize tacrolimus concentration levels for individual patients, potentially contradicting some recommendations for calcineurin inhibitor minimization.