Three‐Year Efficacy and Safety Results from a Study of Everolimus Versus Mycophenolate Mofetil in de novo Renal Transplant Patients

Abstract

Everolimus 1.5 or 3 mg/day was compared with mycophenolate mofetil (MMF) 2 g/day in a randomized, multicenter 36-month trial in de novo renal allograft recipients (n = 588) receiving cyclosporine microemulsion (CsA) and corticosteroids. The study was doubleblind until all patients had completed 12 months, then open-label. By 36 months, graft loss occurred in 7.2, 16.7 and 10.7% of patients in the everolimus 1.5, 3 mg/day, and MMF groups, respectively (p = 0.0048 for everolimus 1.5 mg/day vs. 3 mg/day); efficacy failure (biopsy-proven acute rejection (BPAR), graft loss, death or lost to follow-up) occurred in 33.0, 38.9 and 37.2% of patients (p = 0.455 overall), respectively. Mortality and incidence of BPAR were comparable in all groups. Creatinine values were higher in everolimus groups, requiring a protocol amendment that recommended lower CsA exposure. Diarrhea, lymphocele, peripheral edema and hyperlipidemia were more common among everolimus-treated patients, whereas viral infections, particularly cytomegalovirus infection, increased in the MMF group. Overall safety and tolerability were better with MMF and everolimus 1.5 mg/day than with everolimus 3 mg/day. In conclusion, at 36 months, an immunosuppressive regimen containing everolimus 1.5 mg/day had equivalent patient, and graft survival and rejection rates compared with MMF in de novo renal transplant recipients, whereas everolimus 3 mg/day had inferior graft survival. Renal dysfunction in everolimus cohorts necessitates close monitoring.

Successful Conversion to Everolimus After Cytomegalovirus Infection in a Heart Transplant Recipient

“…7) A lower incidence rate for CMV infection was also observed in a randomized trial of renal transplant recipients treated with EVL compared with MMF. 9,10) Although there is little molecular evidence supporting a relationship between EVL and CMV, Johnson and colleagues have reported that CMV up-regulates the phosphatidylinositol 3-kinase (PI3-K) pathway and inhibition of PI3-K activity in turn inhibits viral replication.…”

“…7) Meanwhile, everolimus (EVL), which has been approved for HTx patients in Europe and Japan, 8) is also known to reduce the rate of CMV infection. 7,9,10) We here report a recipient with positive CMV antigenemia, neutropenia, and renal impairment, whose neutrophil count and renal function recovered by conversion from MMF to EVL and reduction of the tacrolimus dose. Assay for CMV antigenemia was continuously negative in spite of VGC discontinuation in this case.…”

Calcineurin Inhibitor Nephrotoxicity

“…First, there is the observation that both sirolimus and everolimus increase chronic nephrotoxicity of CNIs, both in rats (272) and in humans (273)(274)(275). This is explained by robust evidence that these mTOR inhibitors interact with cyclosporine excretion in tubular epithelial cells through competition for P-glycoprotein (276,277), and hence lead to accumulation of cyclosporine in these cells.…”

Subclinical rejection and sirolimus associated edema in renal allograft recipients

“…Immunosuppressive treatment was continued with prednisone (7.5 mg/day), SRL and tacrolimus and the patient remained without edema as also with a good clinical condition. Edema is considered as a drug class effect in patients treated with mTOR inhibitors, either SRL or everolimus [6]. It could be argued that edema is a very common complication in renal allograft recipients whatever immunosuppressive treatment is taken [4].…”