Randomized Sirolimus-based early calcineurin inhibitor reduction in liver transplantation: Impact on renal function

BACKGROUND: The long-term use of calcineurin inhibitors (CNI) after liver transplantation (LT) is associated with nephrotoxicity. METHODS: 5-year follow-up data was retrieved from the randomized controlled multicenter SiLVER trial. Standard CNI-based mTOR-free immunosuppression (group A, n=264) was compared to a 50 % reduction of CNI and introduction of the mTOR inhibitor Sirolimus within 4 to 6 weeks after LT (group B, n=261). RESULTS: Median MELD at LT was low with 10 (7 - 15) (group A) and 11 (8 - 15) (group B) in the intention-to-treat approach. CNI dose and CNI trough were reduced by 20% and 8% (group A) versus 55% and 56% (group B) at 3 months post transplantation. Renal function was preserved at 3 months after LT in the Sirolimus arm [eGFR 74 (57-95) versus 67 (55-85) ml/min/1.73m2, p=0.004] but was similarly impaired thereafter compared to group A. The per protocol analysis identified LT recipients in group B with concomitant early CNI minimization and Sirolimus treatment > year 1 with significantly superior eGFR and lowest rate of chronic kidney disease (> stage 3) from year 1 onwards until study end. Competing risk factors for renal disease (arterial hypertension, fat metabolism disorder and hyperglycemia) were not associated with worse kidney function. CONCLUSIONS: Prevention of CNI nephrotoxicity by Sirolimus-based early CNI minimization protects renal function only short-term after LT in the intention-to-treat analysis of this low MELD cohort. Yet, selected LT recipients compliant with early CNI minimization and Sirolimus maintenance achieved better long- term renal outcomes compared to real-world practice.