Objective To identify signals of tacrolimus (TAC)-associated renal injury using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), externally validate these signals using EudraVigilance (EV), and characterize the time-to-onset (TTO) characteristics of representative renal injury preferred terms (PTs).

Methods TAC-related reports in FAERS from Q1 2004 to Q1 2026 were extracted, deduplicated, and standardized according to MedDRA version 27.0. Signal detection was performed using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS). TTO was calculated for representative PTs. Renal and urinary disorder cases were retrieved from the publicly available EV Line Listing. The top 20 robust signals by reporting frequency in FAERS were externally validated at the case level, with cases originating from the European Economic Area (EEA) used for sensitivity validation.

Results A total of 65,247 independent TAC-related reports were included from FAERS, comprising 12,054 renal and urinary system disorders, with a ROR of 3.33 [95%CI (3.26, 3.39)]. Among 224 PTs under the system organ class (SOC), 93 were robust signals that met the positivity criteria of all four algorithms. The most frequently reported signals included acute kidney injury, renal impairment, renal failure, toxic nephropathy, and renal tubular necrosis. Renal fibrosis, renal tubular injury, and renal tubular atrophy showed RORs of 56.37, 54.85, and 53.76, respectively. By the EV data cutoff, 6,557 eligible renal and urinary disorder cases were available for external validation. All top 20 robust renal PTs ranked by reporting frequency from FAERS were repeatedly reported in both the overall EV dataset and the subset of EEA-origin cases. Among representative events, acute kidney injury, renal impairment, renal failure, and toxic nephropathy were reported in 1,371, 1,373, 910, and 585 EV cases, respectively, whereas renal tubular necrosis, renal fibrosis, renal tubular injury, and renal tubular atrophy were reported in 229, 100, 69, and 68 cases, respectively. A total of 1,662 FAERS drug-PT event records had valid TTO data. The median TTO was 110 days (IQR: 19-648 days); 32.6% of events occurred within 30 days, whereas 31.9% occurred more than 1 year after treatment initiation.

Conclusion Signal detection in FAERS and external validation using EV consistently suggest that acute deterioration of renal function, renal tubular injury, and chronic structural renal damage are key pharmacovigilance concerns associated with TAC. The recurrence of these core signals across databases strengthens their reproducibility. Nevertheless, as these results originate from spontaneous reporting systems, they should not be interpreted as true incidence rates or as evidence of causality. In clinical practice, continuous renal monitoring should be tailored according to baseline renal function and treatment stage.

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