Use of everolimus in liver transplantation

Abstract

In recent years, the use of mammalian target of rapamycin inhibitors has gained traction in their use as alternative or adjunct immunosuppressants in the post-liver transplantation (LT) setting. The efficacy of everolimus (EVR) in de novo LT is established and a reasonable time to initiate EVR is 30 d from LT surgery. Initiating EVR early post-LT allows for calcineurin inhibitor (CNI) reduction, thus reducing nephrotoxicity in LT recipients. However, data is inadequate on the appropriate timing for conversion from CNI to EVR maintenance in order to achieve optimal renoprotective effect without compromising drug efficacy. Adverse effects of proteinuria, hypercholesterolemia and hyperlipidemia are significantly higher as compared to standard CNI and long-term implications on graft and patient survival in LT is still unclear. Future research to explore strategies to minimise EVR adverse effects will be crucial for the success of EVR as an important alternative or adjunct immunosuppressive therapy in LT.

Center-driven and Clinically Driven Variation in US Liver Transplant Maintenance Immunosuppression Therapy: A National Practice Patterns Analysis

“…Finally, the years of data collection in our study ended in 2014, and ongoing research is needed to evaluate use of and trends in recently approved agents, such as everolimus. 27 …”

Novel Factors of Viral Origin Inhibit TOR Pathway Gene Expression

“…TOR therefore represents one of the major therapeutic targets in these pathological alterations. The macrolide rapamycin and its analogs are highly specific inhibitors of TOR and they are considered therapeutic molecules with antitumor ( Calimeri and Ferreri, 2017 ; Faes et al, 2017 ; Liu et al, 2017 ) and immunosuppressive activity ( McMahon et al, 2011 ; Hamdani et al, 2017 ; Yee and Tan, 2017 ), and with promising activity against neurological disease ( Wang et al, 2014 ; Maiese, 2016 ). These molecules have a unique mechanism of action: they first bind FK506-binding protein (FKBP12), a 12 kDa immunophilin, and then this complex inhibits the serine/threonine kinase TOR ( Russell et al, 2011 ).…”

Update on Immunosuppression in Liver Transplantation

“…24 Apart from its immunosuppressive effects, mTOR inhibitors (mTORi) are known to have antiproliferative effects, reducing the risk of posttransplant recurrence and de novo malignancies. 25 Pronounced side effects of mTORi are dosedependent dyslipidemia, thrombocytopenia, anemia, leukopenia, oral sores, hypertension, 26,27 hindered epithelial regeneration, and fluid retention. Patients treated with mTORi, particularly patients who received LT for NASH, should be counseled on appropriate preventive lifestyle changes.…”

“…29 However, several other trials evaluated the safety of mTORi 30 days post-LT and did not find an increased risk of HAT. 27,30 In contrast to CNI's promoting carcinogenesis, 31 experimental and clinical trials showed that mTORi have antiproliferative effects. 32 Posttransplant hepatocellular carcinoma (HCC) recurrence is shown to be reduced by mTORi.…”