Everolimus with early withdrawal or reduced‐dose calcineurin inhibitors improves renal function in liver transplant recipients: A systematic review and meta‐analysis

Abstract

Calcineurin inhibitors (CNI) are the mainstay of immunosuppression after liver transplantation (LT), but CNIs are associated with significant nephrotoxicity. Recently, mTOR inhibitors such as sirolimus and everolimus (EVR) have been used with or without CNIs in LT recipients for their renal-sparing effect. We conducted a systematic review and meta-analysis of randomized controlled trials (RCT) that examined the effect of EVR with CNI minimization or withdrawal on renal function in LT recipients. RCT of primary adult LT recipients with baseline GFR >30 mL/min who received EVR with CNI minimization or withdrawal were included. Four RCTs (EVR n=465, control n=428) were included. In three RCTs, EVR was initiated 4 weeks following LT; these studies were used to assess the primary outcome. All four studies were used to assess the secondary outcomes. Based on this study, EVR use with CNI minimization in LT recipients is associated with improved renal function at 12 months by GFR of 10.2 mL/min (95% CI: 2.75-17.8). EVR use was not associated with an increased risk of biopsy-proven acute rejection (RR 0.68, 95% CI: 0.31-1.46), graft loss (RR 1.60, 95% CI: 0.51-5.00), or mortality (RR 1.34, 95% CI 0.62-2.90). However, it was associated with an increased risk of overall infections (RR 1.45, 95% CI: 1.10-1.91).

Efficacy and safety of everolimus treatment on liver transplant recipients: A meta‐analysis

“…Infections frequently occur among the solid organ transplant recipients due to the immunosuppressive property of mTOR inhibitors. Previous meta‐analyses reported that everolimus treatment significantly increased the risk of infection . However, the present study did not show identical outcomes.…”

“…This result was in agreement with the previous findings from meta‐analyses. Lin et al reported that the use of everolimus combined with CNI minimization improved the GFR by 10.2 mL/min. Tang et al reported that everolimus plus reduced concentration of CNIs improved the GFR by 5.13 ml/min and everolimus plus CNIs elimination improved the GFR by 10.42 ml/min.…”

“…Tang et al combined four randomized controlled trails in 2015 and concluded that early introduction of everolimus combined with low‐dose CNIs in de novo LT patients decreases the risk of acute graft rejection, improves the renal function and increases the risk of infection. Similarly, another meta‐analysis performed in 2016 demonstrated that everolimus application induces the overall infection and preserves the kidney function . However, a decreased risk of graft rejection, graft loss or overall survival was not detected .…”

Very Early Introduction of Everolimus in De Novo Liver Transplantation: Results of a Multicenter, Prospective, Randomized Trial

“…Different strategies, including the use of induction therapy at the time of transplantation followed by delayed and low‐dose CNIs and CNI minimization/withdrawal associated with the initiation of a different class of immunosuppressive agents, have been investigated to overcome CNI‐induced renal toxicity . Studies on EVR introduction after de novo LT confirmed the safety of a minimization/withdrawal mTOR inhibitor–based approach …”

The Use of Everolimus for Renal-Transplant Patients with Nephrotoxicity by Calcineurin Inhibitors in our Center: Case Report

“…Chronic allograft nephropathy (CAN) / interstitial fibrosis and tubular atrophy (IFTA) is factor disturbing the long-term survival of the renal transplantation [2][3][4][5]. One of the factors of CAN is CNI nephropathy.…”