MP36-12: An immunosuppressive regimen containing everolimus decreases the interstitial fibrosis formation of kidney allograft by suppressing mTOR-related protein expression
Introduction: Calcineurin inhibitors, particularly tacrolimus (TAC), have dramatically improved kidney transplantation (Tx) clinical outcomes. However, TAC nephrotoxicity leading to interstitial fibrosis/tubular atrophy (IF/TA) is major cause of allograft loss even in the modern immunosuppressive era. Everolimus (EVR) can be used to reduce TAC exposure and decrease fibrosis formation of the renal graft. This study compared clinical outcomes between immunosuppressive regimens containing EVR or not and investigated the risk factors of fibrosis formation of kidney allografts.
Methods: In this study, we retrospectively analyzed 104 patients who underwent living kidney transplantation at Akita University Hospital between January 2011 and December 2017. Until September 2013, 43 patients (the non-EVR group) received the conventional immunosuppressive regimen comprising standard-dose TAC, mycophenolate mofetil (MMF), and prednisolone (PSL). From October 2013 to December 2017, 61 patients (the EVR group) received a new regimen consisting of low-dose TAC, MMF, PSL, and EVR (target trough level: 3–5 ng/mL, since two weeks after Tx). The interstitial fibrosis ratio (IFR) of the allograft in the biopsy specimen was measured using an image analyzer, and increase rates at 1-month and 1-year post-transplantation were calculated based on the IFR in the 0h biopsy specimen. Additionally, to assess the expression of mTOR-related proteins, immunohistochemical staining of p-P70S6K and p-4EBP1 was performed on biopsy specimens for 0h and 1-year after Tx.
Results: No difference in clinical outcomes, including the incidence of rejection, graft function, and death-censored graft survival at 1-year post-transplant was observed between the groups; however, viral infection was significantly lower in the EVR group (p = 0.001). In multivariate analysis, only the non-EVR regimen was an independent risk factor for increased IFR (p < 0.001). In an immunohistochemical study, the expression of p-P70S6K and p-4EBP1 one year after Tx was significantly lower (p = 0.018, p = 0.020, respectively) in the EVR group than in the non-EVR group.
Conclusions: In this study, the IFR of the renal allograft in an EVR-containing regimen was significantly lower than the conventional protocol. An EVR-containing regimen decreased the expression of mTOR-related proteins in the kidney allograft. This findings may be related to suppression of interstitial fibrosis after Tx.
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