Introduction: De novo use of low dose Everolimus in combination with reduced-exposure of Tacrolimus (EVR+rTAC) is still limited by lack of evidences from long term follow-up data and by the wound healing issues reported in the early clinical experiences. For these reasons the combination of tacrolimus and mycophenolatemofetil (TAC+MMF) is more frequently adopted as immunosuppressive treatment in renal transplantation. Aim of this study was to analyze clinical safety and efficacy of once a day combination of EVR+rTAC vs standard TAC+MMF in de novo Renal Transplant Recipients (RTR).

Methodology: We are reporting our preliminary data of a prospective clinical study in RTR who completed their first 5 years follow-up after renal transplantation.  After randomization RTR received once a day low dose EVR (blood levels: 3 - 5 ng/ml) plus TAC (blood levels: 3 – 5 ng/ml) or standard TAC plus once a day mycophenolate mofetil (MMF+TAC) immunosuppression.

Results: One hundred two renal transplant recipients entered the study and completed the 5 years follow-up. No significant differences were found between the two recipients groups EVR+rTAC  (51 pts) and MMF+TAC (51 pts) in the demographic data: age, sex, BMI, time on dialysis, transplant waiting time, native renal disease, pre-transplant diabetes, ischemic heart disease. All patients received as induction low fixed dose of Thymoglobuline (50mg IV x 4 days: pre-op and on day1, 2, 3). The incidence of acute rejection was not significantly different between the two groups (EVR+rTAC: Rey 7.2% vs MMF+TAC  Rey 9.4%). One year estimated GFR also was not significantly different: EVR+rTAC: eGFR 50 ml/min vs MMF+TAC: eGFR 51 ml/min).  Early surgical complications (within 30 days post-op) were also not significantly different in the two groups: EVR+rTAC: 20% vs MMF+TAC: 17%. The analysis of the severity of these surgical complications according with the Clavien-Dindo classification, also found no significant differences in the grade of complications: EVR+rTAC:class1 #5, class 2 #1, class 3 #4 vs MMF+TAC: class1 #4, class 2 #0, class 3 #5. Finally, we adopted the preemptive strategy to prevent CMV infection in our RTR, by monitoring PCR-CMV-DNA without pre-emptive pharmacologic antiviral prophylaxis, in both the study groups.  Our data indicate that pre-emptive CMV prophylaxis with PCR-CMV-DNA monitoring in the presence of the combination of EVE+TAC is very effective in the diagnosis of CMV reactivation up to month 6 after transplantation: EVR+rTAC, PCR-CMV-DNA positive 36% vs MMF+TAC: PCR-CMV-DNA positive 65%, p 0.003. This preemptive strategy, showing the significant inhibition of CMV replication by the mTOR inhibitor Everolimus is effective in RTR, cheaper respect to antiviral drugs and avoiding emergent CMV resistance.

Conclusion: In conclusion, the immunosuppressive combination of low dose Everolimus and low dose Tacrolimus allows the same excellent clinical results of standard Tacrolimus and MMF therapy, without increasing early surgical complications, with the significant advantages of  less CMV infections.