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

Abstract

Early everolimus (EVR) introduction and tacrolimus (TAC) minimization after liver transplantation may represent a novel immunosuppressant approach. This phase 2, multicenter, randomized, open‐label trial evaluated the safety and efficacy of early EVR initiation. Patients treated with corticosteroids, TAC, and basiliximab were randomized (2:1) to receive EVR (1.5 mg twice daily) on day 8 and to gradually minimize or withdraw TAC when EVR was stable at >5 ng/mL or to continue TAC at 6‐12 ng/mL. The primary endpoint was the proportion of treated biopsy‐proven acute rejection (tBPAR)–free patients at 3 months after transplant. As secondary endpoints, composite tBPAR plus graft/patient loss rate, renal function, TAC discontinuation rate, and adverse events were assessed. A total of 93 patients were treated with EVR, and 47 were controls. After 3 months from transplantation, 87.1% of patients with EVR and 95.7% of controls were tBPAR‐free (P = 0.09); composite endpoint‐free patients with EVR were 85% (versus 94%; P = 0.15). Also at 3 months, 37.6% patients were in monotherapy with EVR, and the tBPAR rate was 11.4%. Estimated glomerular filtration rate was significantly higher with EVR, as early as 2 weeks after randomization. In the study group, higher rates of dyslipidemia (15% versus 6.4%), wound complication (18.32% versus 0%), and incisional hernia (25.8% versus 6.4%) were observed, whereas neurological disorders were more frequent in the control group (13.9% versus 31.9%; P < 0.05). In conclusion, an early EVR introduction and TAC minimization may represent a suitable approach when immediate preservation of renal function is crucial.

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

“…Everolimus binds to the intracellular receptor immunophilin FK506‐binding protein 12 (FKBP12), which is adjacent to the catalytic site of mTORC1 in an allosteric fashion. This binding weakens the interaction between mTORC1 and raptor, arrests the cells in the G1 stage of the cell cycle and, subsequently, inhibits the downstream events including functional regulation of immune cells . On the other hand, mTORC2 is recognized as a resistant molecule to mTOR inhibitors.…”

“…This binding weakens the interaction between mTORC1 and raptor, arrests the cells in the G1 stage of the cell cycle and, subsequently, inhibits the downstream events including functional regulation of immune cells. 25,26 On the other hand, mTORC2 is recognized as a resistant molecule to mTOR inhibitors. Nevertheless, at the clinically relevant concentrations, everolimus was effective in inhibiting class-I-stimulated mTORC2 activation by dissociating Rictor and Sin1 from mTOR.…”

“…The process of study inclusion is illustrated in Figure 1. A total of eight trials reported in 12 articles [7][8][9]13,14,[20][21][22][23][24][25][26] were included in the present study. De Simone et al 21 recruited the maintenance liver transplant recipients.…”

Position paper on liver and kidney diseases from the Italian Association for the Study of Liver (AISF), in collaboration with the Italian Society of Nephrology (SIN)

“…Some studies explored various CNI-minimization regimens (delayed CNI initiation, reduced CNI exposure, CNI withdrawal) but some immunological concerns have arisen. The association of a "CNI tailored regimen" to an induction therapy with an IL-2 antagonist receptor, association with mycophenolic acid or an early everolimus based CNI-free immunosuppression seems to improve renal function after transplantation [164][165][166] .…”

Kidney Failure after Liver Transplantation

“…Several studies have demonstrated a favorable effect of everolimus (EVR) in preserving renal function [163]. A reduction in CNIs with an early [164][165][166][167][168][169][170][171][172][173][174] or delayed [39,175,176] introduction of EVRs is associated with improved kidney function (GFR increase by +5 to +10 mL/min/1.73 m 2 ) without excess risk of rejection or mortality [162,172]. On the other hand, conversion after the first year of transplantation has shown no benefit for kidney function [149,164].…”