Introduction: Clinical study results are still controversial about the start of everolimus (ERL) with and without calcineurin inhibitor (CNI) after heart transplantation (HTx). Thus, we analyzed long-term data of the effect of ERL on renal function and the incidence of biopsy proven acute cellular rejection (BPACR) apart from clinical studies in a real-life scenario. 
Methods: 105 patients, who received HTx between 2005 and 2015, were divided into three groups (Gs) according to the time of ERL start; G1≤ 3 months (mo) after HTx (n=46), G2 4-12 mo after HTx (n=33) or G3 >12 mo after HTx (n=26). Additionally, we analyzed patients either with CNI withdrawal ≤3mo (sub-group, SG1, n=25) after ERL start, or with concomitant CNI therapy >12mo (SG2, n=71) after ERL start. Renal function was calculated using the MDRD formula for the glomerular filtration rate (GFR) in relation of baseline value before ERL, and at 12 and 60mo after ERL start (ΔGFR mL/min). Iincidence of BPACR (≥2R) was compared between the study groups at 12 and 60mo after HTx.
Results: At 12mo after ERL start ΔGFR was a significant better in patients of G2 compared to patients of G3 (G2: +3.98 vs G3: -4.98, p=0.04). Furthermore, CNI withdrawal did not further improved renal function compared to concomitant CNI therapy at this early time point. However, patients of G1 had a higher ΔGFR at 60mo after ERL start compared to patients of either G2 or 3 (G1: +1.59, G2: -12.71, G3: -6.26, p1vs2=0.035 and p1vs3=0.27). In all three Gs, patients with early CNI withdrawal had a higher ΔGFR than patients with concomitant CNI therapy at 60mo (SG1: G1: +5.53; G2: +0.36; G3: -22.26, p1vs3=0.01, p1vs2=0.02; SG2: G1 -0.83, G2: -22.12, G3: -6.73, p1vs3=0.045; p1vs2=0.02). Incidence of BPACR at 12mo after HTx was not different between the study groups (G1: 15.2%, G2: 19.1%, G3: 19.2%, p=0.72).  However, CNI-free patients of G1 had a higher incidence of BPACR than patients with concomitant CNI therapy of G1 at 12mo (SG1: 33,3% vs SG 2: 6,9%, p=0.03) and at 60mo (SG1: 22% vs. SG2: 0%, p=0.049). All BPACR were without hemodynamic compromise. 
Conclusion: We showed that an early ERL therapy within 3mo of HTx had a long-term beneficial effect on renal function in a real-life scenario. Early CNI withdrawal enhanced the nephroprotective effect further. While the incidence of BPACR was increased by early CNI-withdrawal, graft function, however, was not severely impaired.