New Insights from the SILVER Study; A 50 % Reduction in Calcineurin Inhibitors at Day 30 Achieves a Temporary Renal-Sparing Effect but Does not Impact on Long-Term Renal Function after Liver Transplantation

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The International SILVER study group.IntroductionRenal dysfunction after liver transplantation (LT) is common and the long term use of calcineurin inhibitors (CNI) is associated with nephrotoxicity. The 50% reduction in CNI at 4-6 weeks post transplantation during the SILVER study enabled evaluation of this early reduction and its impact on long term renal function.MethodsAn immunosuppressive strategy with a 50 % reduction of CNI and introduction of the mTOR inhibitor Sirolimus within 4 to 6 weeks after LT (group B, n=252) was compared to standard CNI-based mTOR-free immunosuppression (group A, n=255). Data was retrieved from the randomised controlled multi-centre trial of Sirolimus in Liver Transplant Recipients with HCC (SiLVER) study and analyzed in both an intention-to-treat and per protocol approach over a study period of 5 years.ResultsThe intention-to treat analysis showed that the two groups were well-matched for recipient, donor and transplant procedure characteristics. Early CNI reduction was achieved as stipulated in the protocol with median CNI reduction of 10% vs 56% and 20% vs 55% for CNI trough and dose at 3 month post-transplantation in group A vs group B, respectively. Baseline renal function as measured by eGFR was similar for both groups. A temporary renal sparing effect was observed at 3 months in the Sirolimus arm [67 (55 - 85) vs 76 (59 - 95) ml/min, p=0.003] but renal function was not significantly different at all later time points (6 months, 12 months, and yearly intervals up to 5 years). Using generalized estimating equations with post-transplant day 28 as baseline, no difference was found for eGFR between the groups with further sub-stratification into CyclosporinA and tacrolimus as CNI.The per protocol analysis demonstrated that eGFR at 3 month was higher in the Sirolimus arm compared to standard CNI treatment if early CNI reduction was achieved [78 (60 - 95) vs 66 (55 - 87) ml/min, p=0.047]. The protective effect of early CNI reduction in the Sirolimus arm extended from 3 month [78 (61 - 95) vs 67 (55 - 85) ml/min, p=0.021] to 12 month [75 (59 - 96) vs 66 (55 - 82) ml/min, p=0.022] in LT recipients on concomitant mTOR immunosuppression. However, the renal-sparing effect was not sustained over time in any of these well-matched subgroups with similar kidney function at yearly intervals from 2 to 5 years. No additional benefit was observed for high MELD LT recipients (cut-off 15, 75th percentile of cohort) with early CNI reduction and mTOR-based immunosuppression.ConclusionThis analysis suggests that a 50% reduction in CNI dose at 4-6 weeks yields better renal function after liver transplantation; however, this renal-sparing effect is temporary and long-term renal function is not protected.

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