Tacrolimus–Sirolimus Combined Exposure and Acute Rejection in Kidney Transplant Recipients Undergoing Early Conversion to Sirolimus: A Multicenter Retrospective Cohort Threshold Analysis

<b>Background/Objectives</b>: Combining calcineurin inhibitors (CNIs) with mTOR inhibitors has been explored to reduce CNI exposure. However, the safety of this early conversion approach remains uncertain, and the optimal therapeutic targets for tacrolimus and sirolimus trough concentrations in patients have not been clearly established. <b>Method</b>: In this retrospective multicenter cohort, we analyzed 8027 kidney transplant recipients and compared a standard group (tacrolimus + MMF) with an early conversion group (MMF to sirolimus within 3 months post-transplant). To address group-size and baseline imbalances-including differences in age, induction therapy, and diabetes-we performed 4:1 propensity score matching, yielding a cohort of 1180 patients. The primary endpoint was biopsy-proven acute rejection between 3 and 12 months post-transplant. <b>Results</b>: The early conversion group had a higher acute rejection rate (7.6%) than the standard group (2.9%; <i>p</i> = 0.001). Stepwise threshold analysis suggested a combined tacrolimus-sirolimus exposure (Tacro-Siro Csum) of 11.6 ng/mL as the level associated with the lowest rejection risk, whereas levels < 8.5 ng/mL were substantially higher risk. Patients with Tacro-Siro Csum < 8.5 ng/mL showed a higher rejection rate even when CNI trough levels were adequate (<i>p</i> = 0.031). Tacro-Siro Csum showed the strongest inverse correlation with rejection (r = -0.33), underscoring its utility as a composite indicator. <b>Conclusions</b>: In early sirolimus conversion, the combined trough level of tacrolimus and sirolimus is more important than either drug alone. To reduce the risk of acute rejection, it is crucial to maintain this combined concentration at a therapeutic level.