Long-term outcomes of a quadruple calcineurin inhibitor-minimization regimen with everolimus introduced 3–6 months after kidney transplantation

BACKGROUND: Quadruple maintenance immunosuppression with everolimus (EVR), low-dose tacrolimus (TAC), mycophenolate mofetil, and methylprednisolone may improve allograft survival by reducing calcineurin inhibitor exposure; however, real-world long-term data on delayed EVR introduction remain limited. METHODS: We retrospectively analyzed 186 adult primary kidney transplant recipients who received this quadruple regimen with EVR introduced 3-6 months post-transplantation in 2013-2023. Outcomes included graft and patient survival, post-transplant complications, and EVR-related adverse events (AEs). The association between the initial EVR dose adjusted for body surface area (BSA) and AEs was evaluated. In a secondary landmark analysis from 1 year, outcomes were compared with contemporaneous recipients on triple therapy using overlap weighting. RESULTS: Death-censored graft survival was 99.5%, 99.5%, and 97.0% at 3, 5, and 10 years, and patient survival was 98.9%, 98.2%, and 97.4%. Clinical rejection occurred in 4.8% within the first year. EVR-related AEs occurred in 28.0% of patients, leading to discontinuation in 9.1%. A higher initial EVR dose per BSA was associated with AEs on univariate analysis but not after multivariable adjustment. In the weighted comparison with triple therapy, graft survival, renal function, and proteinuria did not differ, whereas patient survival was higher (HR 0.17, 95% CI 0.03-0.82), a difference possibly reflecting confounding by indication. CONCLUSIONS: Delayed EVR introduction at 3-6 months with low-dose TAC was well tolerated. Long-term graft and patient survival were favorable, but patient selection may have contributed, and prospective evaluation is needed.