Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation

Abstract

Everolimus permits reduced calcineurin inhibitor (CNI) exposure, but the efficacy and safety outcomes of this treatment after kidney transplant require confirmation. In a multicenter noninferiority trial, we randomized 2037 kidney transplant recipients to receive, in combination with induction therapy and corticosteroids, everolimus with reduced-exposure CNI (everolimus arm) or mycophenolic acid (MPA) with standard-exposure CNI (MPA arm). The primary end point was treated biopsy-proven acute rejection or eGFR<50 ml/min per 1.73 m at post-transplant month 12 using a 10% noninferiority margin. In the intent-to-treat population (everolimus =1022, MPA=1015), the primary end point incidence was 48.2% (493) with everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, -1.3% to 7.6%). Similar between-treatment differences in incidence were observed in the subgroups of patients who received tacrolimus or cyclosporine. Treated biopsy-proven acute rejection, graft loss, or death at post-transplant month 12 occurred in 14.9% and 12.5% of patients treated with everolimus and MPA, respectively (difference 2.3%; 95% confidence interval, -1.7% to 6.4%). donor-specific antibody incidence at 12 months and antibody-mediated rejection rate did not differ between arms. Cytomegalovirus (3.6% versus 13.3%) and BK virus infections (4.3% versus 8.0%) were less frequent in the everolimus arm than in the MPA arm. Overall, 23.0% and 11.9% of patients treated with everolimus and MPA, respectively, discontinued the study drug because of adverse events. In kidney transplant recipients at mild-to-moderate immunologic risk, everolimus was noninferior to MPA for a binary composite end point assessing immunosuppressive efficacy and preservation of graft function.

Prospective randomized study comparing everolimus and mycophenolate sodium inde novokidney transplant recipients from expanded criteria deceased donor

“…Patients receiving EVR showed a higher incidence of BPAR compared with MPS, but there were no obvious differences in severity. The recent TRANSFORM trial showed that the incidence of BPAR is not different comparing EVR and MPA, regardless of the type of induction therapy . Two factors inherent to our study design may account for the observed difference: first, the delayed introduction of TAC and second, the proportion of patients with EVR exposure below the lower therapeutic range during the first weeks after transplantation.…”

“…Patients receiving EVR showed longer DGF period and lower eGFR reached at month 1. In two recent large prospective multicenter trials, no significant differences in the incidence and duration of DGF were observed . Even in patients at high risk of DGF, no difference in the incidence and duration was observed comparing immediate or delayed introduction of EVR .…”

“…The analysis of the secondary endpoints highlights the difficulties in using the combination of CNI and mTORi in transplant recipients with expected lower renal function, even using more recent and optimized strategies . The use of r‐ATG and delayed introduction of reduced TAC exposure was associated with delayed and incomplete recovery of renal function, higher incidence of AR, higher treatment discontinuation, and ultimately higher incidence of graft loss and death among patients receiving EVR compared with MPS, all leading to early termination of the trial.…”

No clinical benefit of rapid versus gradual tapering of immunosuppression to treat sustained BK virus viremia after kidney transplantation: a single‐center experience

“…In vitro studies suggest that mTORi could have an antiviral effect . Moreover, recent randomized trials have shown that a combination of reduced doses of calcineurin inhibitor (CNI) with everolimus was associated with a decreased incidence of BKV reactivation after kidney transplantation compared to a combination of standard doses of CNI with MPA . The impact of mTORi after BK viremia remains more conflicted.…”

The impact of everolimus in reducing cytomegalovirus events in kidney transplant recipients on steroid-avoidance strategy: 3-year follow-up of a randomized clinical trial

“…Robust evidence has shown that, in patients on steroids, EVR and MPS present the same anti-rejection efficacy when used with cyclosporine (CsA) [25] or TAC [26]. The results of patients on steroid-free regimens are conflicting [27,28].…”