Suppression of Allograft Fibrosis by Regulation of Mammalian Target of Rapamycin-Related Protein Expression in Kidney-Transplanted Recipients Treated with Everolimus and Reduced Tacrolimus

BACKGROUND: Although renoprotective effects of everolimus (EVR) in kidney transplantation (KTx) have been widely reported, its pathophysiological mechanism remains unclear. MATERIAL/METHODS: We compared changes in eGFR (ΔGFR, ml/min/1.73 m(2)) and the ratio of the fibrotic area in biopsy specimens (ΔFI,%) from 3 months to 3 years after KTx between the EVR+ group (EVR addition and Tac reduction early after KTx, n=32), and the EVR− group (normal Tac without EVR, n=28). We also immunohistochemically evaluated mTOR-related protein expression. RESULTS: ΔGFR and ΔFI in the EVR+ vs. EVR− groups were −0.27±6.8 vs. −9.8±12.8 (p<0.001) and 2.4±4.9 vs. 9.5±10.5 (p<0.001), respectively. Phosphorylated mTOR and phosphorylated 4EBP1 expression at 3 years in the EVR+ group was significantly lower than that in the EVR− group. Moreover, in the subgroup analysis comparing ΔGFR and ΔFI among groups stratified by immunosuppressive regimen and mTOR signal enhancement, the ΔFI in patients with EVR+ with decreased mTOR signal enhancement was significantly milder than that in other patients. In addition, in the multivariate analysis, EVR addition was the only independent predictor for allograft fibrosis, whereas the Tac C(0) concentration at neither 1 nor 3 years proved to be a risk factor. CONCLUSIONS: These results suggested that EVR addition and Tac reduction may attenuate kidney allograft fibrosis, and that the suppression of mTOR signaling process may be involved in the anti-fibrotic effect of this immunosuppressive regimen. These results provide suggestions of how to utilize EVR for patients with KTx and improve graft function.