Work

Impact of dose-adjusted tacrolimus exposure phenotype on outcomes in kidney transplantation: a large-scale multicenter cohort study

Year: 2026

Type: article

Abstract: Introduction Dose-adjusted tacrolimus exposure phenotype, expressed as the trough concentration-to-dose ratio (C0/Dose), may influence post-transplant outcomes, but supporting evidence remains limited. Methods We evaluated the association between tacrolimus exposure phenotype and short- and long-term allograft and patient outcomes in a multicenter retrospective cohort study using clinical data warehouse records from five tertiary transplant centers in South Korea (2005–2020). Patients were classified into fast- or slow-dose-adjusted exposure phenotypes using trajectory clustering. Primary outcomes included 1-year endpoints (graft failure, biopsy-proven acute rejection, de novo donor-specific antibodies, severe infection, cardiovascular events, malignancy, and death). Secondary outcomes were assessed using the same endpoints for 2–6 years. Inverse probability of treatment weighting (IPTW) and weighted Cox proportional hazards models were used to adjust for confounders. Results Among 5,965 recipients, 4,595 (77.0%) were classified as fast-exposure phenotype and 1,370 (23.0%) as slow-exposure phenotypes. Slow-exposure phenotypes received lower tacrolimus doses (time-weighted median 2.1 vs 4.6 mg/day, P < 0.001) but had higher trough levels (6.7 vs 6.1 ng/mL, P < 0.001), higher variability (27.8 vs 26.4%, P < 0.001), and greater time above the therapeutic range (19.7 vs 11.6%, P < 0.001). After IPTW, 1-year efficacy outcomes (biopsy-proven acute rejection, graft failure, and de novo donor-specific antibody development) did not differ significantly between groups. During years 2–6, slow-exposure phenotypes had higher risks of all-cause mortality (adjusted HR 1.616, 95% CI, 1.069–2.442), serious infection requiring hospitalization (adjusted HR 1.537, 95% CI, 1.166–2.026), and malignancy (adjusted HR 1.628, 95% CI, 1.077–2.460). Discussion A slow tacrolimus exposure phenotype (high C0/Dose) may serve as a risk marker of cumulative overexposure, associated with increased late mortality, serious infection, and malignancy. Phenotype-informed longitudinal exposure monitoring may improve long-term risk stratification, although whether targeted dose adjustment improves outcomes requires prospective interventional studies.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1811657