Timing of First Acute Rejection and Long-Term Kidney Allograft Survival in the Contemporary Calcineurin-Inhibitor Era: A Single-Center Cohort Study (2000–2018)

Background: Acute rejection (AR) is an established risk factor for kidney allograft loss, but whether the timing of the first AR episode adds prognostic information independent of secular changes in immunosuppression remains incompletely defined. We re-examined this question in a cohort restricted to the contemporary calcineurin-inhibitor (CNI) era and explicitly accounted for the maintenance CNI (tacrolimus vs. cyclosporine). Methods: We studied 2470 recipients of an isolated kidney transplant performed between 2000 and 2018 at a single academic center. Recipients were classified by the timing of the first AR episode as AR-free, Early AR (≤6 months), Intermediate AR (6–12 months), or Late AR (>12 months). Co-primary outcomes were estimated glomerular filtration rate (eGFR) and death-censored graft survival. Multivariable Cox regression adjusted for recipient and donor age, recipient sex, HLA mismatch, donor type, ABO incompatibility, diabetes, retransplantation, transplant year, and maintenance CNI. A pre-specified secondary analysis evaluated whether the observed AR-timing association was explained by the maintenance CNI. Results: AR occurred in 294 of 2470 recipients (11.9%): 253 Early, 10 Intermediate, and 31 Late. Median follow-up was 105 months. Mean 5-year eGFR was 67.1 (AR-free), 56.5 (Early), 47.5 (Intermediate), and 47.2 mL/min/1.73 m2 (Late) (p < 0.001). Kaplan–Meier 10-year death-censored graft survival was 90.5%, 80.7%, 77.8%, and 52.2%, respectively (log-rank p < 0.001). After adjustment, the hazard of graft failure relative to AR-free recipients was 2.25 (95% CI 1.68–3.01) for Early AR and 7.03 (4.28–11.54) for Late AR (both p < 0.001). The Intermediate AR estimate was directionally consistent but imprecise because of the small number of cases. Tacrolimus use was associated with a lower observed incidence of AR (8.5% vs. 20.0%, p < 0.001), but the observational CNI comparison was confounded by era and follow-up duration and did not explain the AR-timing gradient. Conclusions: Within a contemporary CNI-era cohort and after adjustment for maintenance immunosuppression and transplant year, late-onset AR—particularly onset beyond the first post-transplant year—provided strong prognostic information for long-term graft dysfunction and graft failure.