Application of complement component 4d immunohistochemistry to ABO-compatible and ABO-incompatible liver transplantation

Abstract

Antibody-mediated rejection (AMR) is difficult to diagnose after ABO-compatible or ABO-identical (ABO-C) liver transplantation. To determine whether complement component 4d (C4d) immunostaining would be useful for diagnosing AMR, we compared the results of C4d immunohistochemistry for allograft biopsy samples with assays for anti-donor antibodies performed at the time of biopsy. One hundred fourteen patients with ABO-C grafts and 29 patients with ABO-incompatible (ABO-I) grafts were included. Linear C4d endothelial staining (identifiable with a 43 objective lens) or staining seen in 50% or more of the portal tracts was considered positive. Five of the 114 patients (4%) with ABO-C grafts and 15 of the 29 patients (52%) with ABO-I grafts showed C4d positivity. In the ABO-C cases, C4d positivity in late biopsy samples (30 days after transplantation) was associated with stage 2 or higher fibrosis (METAVIR score; P 5 0.01) and with the presence of donorspecific anti-human leukocyte antigen DR antibodies (HLA-DR DSAs) with a mean fluorescence intensity > 5000 according to the Luminex single-antigen bead assay (P 5 0.04). Conversely, the presence of HLA-DR DSAs was associated with the presence of stage 2 or higher fibrosis, acute cellular rejection, and C4d positivity. During the 2-year follow-up, neither C4d positivity nor HLA-DR DSAs were related to graft loss. Among ABO-I patients, C4d positivity was not associated with allograft dysfunction or fibrosis. Only 3 of the 15 C4d-positive patients (20%) showed periportal hemorrhagic edema, which could be a histological sign of AMR in ABO-I grafts, and they were the only cases associated with elevations in anti-donor A/B antibody titers. In conclusion, C4d endothelial positivity among ABO-C patients is an uncommon event that could be associated with chronic graft damage with or without clinical AMR. C4d positivity is common among ABO-I patients and may not be associated with allograft dysfunction if alloantibody titers are not elevated.

ABO-Incompatible Adult Living Donor Liver Transplantation Under the Desensitization Protocol With Rituximab

“…cellular rejection, biliary obstruction and viral hepatitis (35)(36)(37). The diagnosis of AMR should be based on the combination of multiple parameters including clinical (eg, LFT and radiologic finding), serological (IA titer) and histological findings.…”

Progressive Fibrosis is Driven by Genetic Predisposition, Allo-Immunity, and Inflammation in Pediatric Liver Transplant Recipients

“…Among these, the donor specific class II HLA antibodies have been shown to play an important role in the allograft evolution. This proposition of antibody mediated subclinical inflammation gains more emphasis as the C4d deposition in the hepatic tissue has been shown to correlate with the antibody presence (Miyagawa-Hayashino et al, 2012;Kozlowski et al, 2011;Salah et al, 2014). While continuity between uncontrolled inflammation and hepatic fibrosis was documented in hepatitis C and auto-immune hepatitis (AIH), this was not the case for pediatric LT recipients.…”

Evaluation of donor workups and exclusions in a single‐center experience of living donor liver transplantation

“…The final issues in the selection process are immunological factors, including ABO typing and HLA typing. The acceptance of a potential donor with ABO incompatibility is mainly based on the center's ability to manage ABO‐incompatible LT. With the introduction of rituximab and plasma exchange to the ABO‐incompatible LT management, the reported hospital mortality has decreased to as low as 1.3% with acceptable biliary complication rates . We started an ABO‐incompatible program in 2012 with comparable outcomes to ABO‐compatible LT. Now we accept an ABO‐incompatible donor if there is no suitable ABO‐compatible donor.…”

“…The acceptance of a potential donor with ABO incompatibility is mainly based on the center's ability to manage ABO-incompatible LT. With the introduction of rituximab and plasma exchange to the ABO-incompatible LT management, the reported hospital mortality has decreased to as low as 1.3% with acceptable biliary complication rates. (37)(38)(39)(40)(41) We started an ABO-incompatible program in 2012 with comparable outcomes to ABO-compatible LT. Now we accept an ABO-incompatible donor if there is no suitable ABO-compatible donor. Because this study enrolled donors from July 2011, some potential donors in this study were excluded because of ABO incompatibility.…”