Transplant Trial Watch

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

Buchholz, B. M., Ferguson, J. W. et al. (2019).

Transplantation; [record in progress].

This study was a 5 year follow-up to the SiLVER trial, which explored the long-term use of calcineurin inhibitors (CNI) after liver transplantation (LT) on nephrotoxicity.

Patients from the SiLVER trial were randomized into two groups: Group A - the standard CNI-based mTOR-free immunosuppression (n=264) was compared to Group B - a 50 % reduction of CNI and introduction of the mTOR inhibitor Sirolimus within 4 to 6 weeks after LT (n=261).

525 randomized patients from the SiLVER trial were analysed at 5 years.

The primary outcome was to investigate whether the early CNI reduction in group B as stipulated in the SiLVER study protocol impacts early and late renal outcomes, as measured by eGFR and incidence of chronic kidney disease (CKD). Further to this, the extent of CNI reduction actually achieved and its effect on drug levels and renal outcomes during the full study duration of 5 years was also assessed.

5 years

CET Conclusions
This manuscript reports the 5-year renal function outcomes from the large multicenter SILVER study, a randomized controlled trial of early CNI-reduction and mTOR inhibitor use in low-risk liver transplant recipients with HCC. In intention-to-treat analysis, renal function improved in the mTORi arm at 3 months, but this improvement was not sustained and decline in renal function was equivalent at later time-points. The reason for this finding is two-fold – (1) as with previous studies, mTORi was poorly tolerated with 1/3 patients stopping it by 5 years, and (2) reduction in CNI dose was common in the control arm. Per-protocol analysis suggests a renal function benefit in those who are able to continue on mTORi, but in a real-world population long-term benefit is absent.

Jadad score

Data analysis
Modified intention-to-treat analysis

Allocation concealment

Trial registration
EudraCT: 2005-005362-36; NCT0035586

Funding source
Non-industry funded