Analysis of the Association of Posttransplant Donor-Specific HLA Antibody with Liver Fibrosis After Pediatric Liver Transplantation

Abstract

Objectives Although the short-term outcomes of pediatric liver transplantation (LT) have improved, the long-term outcomes, which are especially important in pediatric LT, have not improved to the same extent. This is partly caused by immunological progression of liver graft fibrosis. However, liver function test results are commonly normal even among patients with liver fibrosis; therefore, the indication and timing of liver graft biopsy have not been established. The aim of this study was to identify predictive factors of immunological graft fibrosis during long-term follow-up after pediatric LT. Methods We retrospectively identified 90 patients who underwent pediatric living donor LT (LDLT) at our institution between July 1991 and October 2013. Out of 90 LDLT patients, donor-specific antibody (DSA) screening was performed for 71 patients. After the DSA screening, liver biopsies were subsequently performed and graft fibrosis plus findings of chronic rejection were evaluated for 18 patients. Patients were divided into two groups based on histological findings, and clinical characteristics among patients with immunological graft fibrosis were assessed. The degree of fibrosis was diagnosed based on the Metavir fibrosis staging, and the fibrosis group included patients with fibrosis of F2 or more and patients with F1 fibrosis plus findings of chronic rejection, especially including C4d deposition. The cut-off for a positive reaction of Single Antigen Beads assay was set at a mean fluorescence intensity (MFI) of 1,000 or more. Results Of 18 patients, seven were included in the fibrosis group. No significant between-group differences were found regarding pretransplant characteristics, including age, sex, primary disease, ABO incompatibility, and immunosuppressive regimen. Episodes of biopsy-proven acute rejection and non-adherence to immunosuppressive drugs were comparable between the two groups. The mean fluorescence intensity (MFI) for anti-DR DSAs was significantly higher in the fibrosis group than the non-fibrosis group (1655 vs. 216; p = 0.019). There were significant between-group differences regarding the positive rate of anti-DR DSAs (86% vs. 28%; p = 0.012). The MFI for anti-DQ DSA was higher among patients with liver fibrosis, although this between-group difference did not reach statistical significance. The immunosuppression minimization rate was more prevalent among patients with liver fibrosis, although this between-group difference did not reach statistical significance (71% vs. 45%; p = 0.37). Conclusion Posttransplant development of anti-DR DSA is a risk factor of liver fibrosis during long-term follow-up. This finding provides useful information for the implementation of valid histological examinations of liver grafts for patients with higher MFI, especially for anti-DR DSA, after pediatric LT. JSPS KAKENHI Grant Numbers JP17K16502. JSPS KAKENHI Grant Numbers JP26861036.