|| Checking for direct PDF access through Ovid
The International SILVER study group.Renal 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.An 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.The 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.This 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.