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C4d immunostaining in acute humoral rejection after ABO blood group‐incompatible liver transplantation

Clinical experiences with ABO blood group-incompatible hepatic grafts have shown that, unlike kidney and heart grafts, the liver is more resistant to antibodymediated hyperacute rejection although cases of hyperacute rejections have been reported. Nevertheless, liver transplantation across the ABO blood barrier has been associated with a significantly higher rate of graft failure and patient mortality. Especially in large series, the decreased survival figures in ABO-incompatible liver transplantation became evident. This survival disadvantage was not only due to emergency conditions, but also due to immunological damage such as hyperacute rejections, vascular complications, and biliary injury. To improve graft survival among ABO-incompatible grafts, several approaches including quadruple immunosuppression, preand posttransplantation plasmapheresis, and splenectomy were tested. However, the long-term risk of postsplenectomy sepsis, especially in immunosuppressed patients, makes the routine splenectomy undesirable. Furthermore, the efficacy of plasmapheresis in preventing humoral-mediated rejection remains questionable, since it has been reported that a decline of up to 44% in isoagglutinin titers might lead to infectious disorders, bleeding diathesis, and viral transmission. After the clinical introduction of monoclonal anti-CD 20 antibody, the optimal management of ABO-incompatible transplantation does however still require further investigation. Another major problem of ABO-incompatible liver transplantation is the lack of markers and predictors for occurrence of humoral rejection. The published literature confirmed inferior survival figures and increased biliary complications after crossing the blood group in liver transplantation, but the exact mechanism for these detrimental effects remained unclear. C4d, the activated component of C4, a central factor of the classical complement pathway, has been established as an indispensable marker tool for acute humoral as well as chronic rejection in kidney transplant patients. Since C4d was first described by Feucht et al., it has proven to be a reliable indicator of rejection mechanisms present in the transplanted kidney tissue. After activation of the complement component C4, its degradation product C4d covalently binds to protein and carbon structures directly at the point where it is expressed, enabling us to detect it in tissue biopsies. In kidney transplantation with de novo donor specific antibodies, C4d is expressed in 95% and humoral rejection accounts for as much as 25% of all rejection episodes. The study of Haga et al. in this issue of Liver Transplantation focuses on the predictive value of C4d expression on outcome in ABO-incompatible living related liver transplantation. Altogether, 82 patients received a liver graft across the blood group barrier and 34 of these patients, who were included in this retrospective analysis, received a liver biopsy within 3 weeks after transplantation. The treatment protocol of the 34 enrolled patients included intraarterial prostaglandin E1 infusion, splenectomy or rituximab treatment and perioperative plasmapheresis. Strong portal stroma C4d expression during the postoperative course was defined as a C4d-positive case, which was associated with increased anti-donor antibody titer, number of