Randomized Sirolimus-based Early Calcineurin Inhibitor Reduction in Liver Transplantation: Impact on Renal Function

Transplantation. 2020 May;104(5):1003-1018 doi: 10.1097/TP.0000000000002980.
Abstract
BACKGROUND:

The long-term use of calcineurin inhibitors (CNIs) after liver transplantation (LT) is associated with nephrotoxicity.

METHODS:

Five-year follow-up data were retrieved from the randomized controlled multicenter SiLVER trial. Standard CNI-based mammalian target of rapamycin-free immunosuppression (group A, n = 264) was compared with a 50% reduction of CNI and introduction of the mammalian target of rapamycin inhibitor Sirolimus (SIR) within 4-6 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 posttransplantation. Renal function was preserved at 3 months after LT in the SIR arm (estimated glomerular filtration rate 74 [57-95] versus 67 [55-85] mL/min/1.73m2 P = 0.004) but was similarly impaired thereafter compared with group A. The per protocol analysis identified LT recipients in group B with concomitant early CNI minimization and SIR treatment ≥ year 1 with significantly superior estimated glomerular filtration rate 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 SIR-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 SIR maintenance achieved better long-term renal outcomes compared with real-world practice.

CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: 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.
Methodological quality
Jadad score 3
Allocation concealment YES
Data analysis MODIFIED INTENTION TO TREAT
Study Details
Aims: 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.
Interventions: 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).
Participants: 525 randomized patients from the SiLVER trial were analysed at 5 years.
Outcomes: 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.
Follow Up: 5 years
Metadata
Publication type: Multicenter Study, Randomized Controlled Trial, Randomised Controlled Trial
Organ: Liver
Language: Engish
MeSH terms: Calcineurin Inhibitors; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Liver Transplantation; Male; Middle Aged; Prognosis; Retrospective Studies; Sirolimus; Time Factors; 0 (Calcineurin Inhibitors); 0 (Immunosuppressive Agents); W36ZG6FT64 (Sirolimus)