Introduction: Pediatric living donor liver transplant (LDLT) patients sometimes develop graft fibrosis. Everolimus (EVR), a mammalian target of rapamycin inhibitor, is a derivative of sirolimus with a similar mechanism of action and demonstrates an anti-fibrosis effect and less renal toxicity than calcineurin inhibitors. However, the anti-fibrotic effect of EVR for graft fibrosis is currently unknown for pediatric LDLT. The purpose of this study was to examine the impact of EVR treatment for graft fibrosis based on pathological findings after pediatric LDLT. 
Methods: Patients who received EVR for graft fibrosis under 19-year-old after LDLT in our institution were gathered. All patients received tacrolimus based on our standard immunosuppression. Some patients received mycophenolate mofetil (MMF) and/or prednisolone (PSL). Protocol biopsies were performed yearly basis. Pathological findings were assessed before initiation of EVR and by the last available biopsy with Hematoxylin-Eosin and Masson trichrome stein. Fibrosis was staged with the Metavir score system. Fibrosis exceeding F1 but below F2 was described as F1-2. EVR was initiated pathological proven graft fibrosis (METAVIR score > 1). EVR was added to children as rescue treatment by adding tacrolimus. Pathological findings, EVR trough level, cystatin C as renal function, and adverse effects were assessed.
Results: 12 patients enrolled in this study. The original diseases of patients were biliary atresia (n=9), Alagille syndrome (n=1), and fulminant hepatitis (n=2). The median patient age at transplant was 1.2-year-olds (ranged 0.6- to 2.7-year-olds). The median patient age at initial EVR administration was 8.5 years (ranged 2.4- to 18.9-year-olds). EVR was initiated as conversion from MMF (n=6), PSL(n=4), and none (n=2). Stage of graft fibrosis for EVR initiation were F1-2 (n=9), F2 (n=2) and F2-3 (n=1). The median administration period was 33 months (ranged 6 to 53 months). The mean EVR trough level was 2.2ng/ml (ranged 1.5 to 3.4 ng/ml). Stage of graft fibrosis after EVR treatment were F1 (n=9), F1-2 (n=2) and F2 (n=1). Graft fibrosis was improved in 9 patients (75%). Pre EVR treatment mean cystatin C was 0.75mg/L (SD 0.029mg/L), whereas post EVR treatment cystatin C was 0.76mg/L(SD 0.029mg/L). There was no statistically significance (p=0.74). Eight patients (75%) experienced mouth ulcers as an adverse effect of EVR. One patient switched from EVR to MMF for severe intolerable mouth ulcers.