Immunologic strategies and outcomes in ABO-incompatible living donor liver transplantation

Plasmapheresis or total plasma exchange

Anti-ABO antibodies are thought to cause antibody mediated rejection (AMR) in ABO-I LT. It has been reported that hepatic necrosis and intrahepatic biliary complications in ABO-I LDLT are closely related to high perioperative anti-A or anti-B antibody titers [6]. Plasmapheresis has been reported as rapidly reducing antiblood type isoagglutinin titers for ABO-I LDLT [23]. Therefore, plasmapheresis has been applied prior to LT in order to reduce antiblood antibodies to levels considered safe enough to improve the outcomes of ABO-I LDLT. However, it has also been reported that even if antibody titers are reduced by plasmapheresis prior to ABO-I LDLT, isoagglutinin titers can rise again within 3–7 days after operation. Although plasmapheresis is able to remove antibodies from the peripheral blood prior to ABO-I LT, plasmapheresis cannot suppress the production of new antibodies from the preexisting plasma cells. For this reason, repetitive plasmapheresis has been considered an efficient therapeutic method in patients with a rise in isoagglutinin titers after ABO-I LDLT [16]. It has been previously reported that the target of pre-transplant antibody ABO-titer values following plasmapheresis were less than 1:8, 1:16, 1:32 or 1:64 to prevent posttransplant AMR [14]. The target titer differs markedly by center and a standard target titer has not yet been established.

Splenectomy

Splenectomy has been an important part of the protocol for ABO-I LDLT at many centers because the spleen is the body’s major antibody producing organ, and contains large amounts of B cells and plasma cells. It also fulfils particular functions in blood filtration, phagocytosis, erythrocyte destruction, antigen uptake and potential hemopoiesis. Splenectomy in ABO-I LDLT carries risks for severe post-transplant infection and portal vein thrombosis, pancreatic fistula, and sepsis [20]. In addition, splenectomy is time-consuming and can cause massive bleeding as a result of splenomegaly in patients with severe liver cirrhosis [19]. However, several studies have reported that splenectomy had not decreased the incidence of AMR [13,19]. Raut et al. had found no statistically significant difference in anti-ABO immunoglobulin M (IgM) and immunoglobulin G (IgG) antibody titers between splenectomy and non-splenectomy groups [20]. Therefore, the omission of splenectomy in ABO-I LDLT has recently emerged with the prophylactic use of rituximab.

IVIG

The mechanism of action of IVIG is complex and not completely understood. It has been proposed to include the blocking of Fc receptors to non-nuclear cells, direct antibody neutralization, suppression of CD19 presentation to activated B cells, suppression of complements, and suppression of all porous T cells [17-19]. Several previous studies have reported on the effectiveness of additional IVIG for preventing AMR. Kim et al. had reported that the combination of rituximab, plasmapheresis, and IVIG had excellent results [15]. However, a Japanese study had reported that AMR incidence does not significantly differ between desensitization regimens with or without IVIG [24].

Local graft infusion therapy

Local infusion therapy was reported in 1998, and involved methylprednisolone, prostaglandin E1, and gabexate mesilate administered via a catheter through the portal vein [25]. This regimen increased survival from 22% to 60% [26]. The theoretical basis of these local infusion agents is that they inhibit different key reactions in single-organ disseminated intravascular coagulation triggered by preformed antibodies against the donor antigen. Prostaglandin E1 improves microcirculation through vasodilatation and the prevention of platelet thrombi [27]. Gabexate mesilate is a protease inhibitor that inhibits platelet aggregation and coagulation factors [26]. Meanwhile, hepatic artery infusion therapy was introduced to avoid portal vein thrombosis by portal vein infusion therapy [28]. However, catheter-related complications, including vascular thrombosis, infection, bleeding, and dislocation, have been reported in 37% of patients undergoing portal vein infusion therapy, 22% of patients undergoing portal vein and hepatic artery infusion therapy, and 16% of patients underoing hepatic artery infusion therapy [8]. These complications can be life-threatening. Kim et al. showed no difference in liver function tests between patients undergoing local infusion therapy and systemic infusion, respectively [10]. Song et al. also reported that there were no significant differences in the incidence of AMR and patient survival between a “Local infusion group” and a “non-Local infusion group” after maintaining the pre-transplant ABO antibody titer within a limited range using plasmapheresis [13].

Rituximab

Rituximab is a monoclonal chimeric human-murine anti-CD20 antibody that depletes B cells by complement-dependent cellular cytotoxicity [8,29]. It depletes CD20-positive B cells from circulation and lymphoid tissues including the spleen [8,29]. Thus, rituximab acts as a form of chemical splenectomy. Several previous studies have shown that rituximab’s effect on B cells in peripheral blood lasts for several months, removing cells within 48-72 hours [24,29,30]. Moreover, most data show that a single dose of rituximab is sufficient for suppressing B cells in the peripheral blood. The number of B cells in peripheral blood decreased in three days after a single dose of rituximab (375 mg/m²), and the number of cells in the peripheral blood were completely eliminated after more than three weeks [31]. Regular and multiple rituximab doses increased the incidence of fungi and cytomegalovirus infections [13]. Therefore, repeated administration of rituximab may be unnecessary and may increase the risk of serious infection due to long-term hypoglycemia. Currently, most centers administer a single dose of rituximab (300 or 375 mg/m²), two weeks before surgery.

When the outcomes of ABO-I LDLT are divided into before and after the rituximab era, a Japanese nationwide survey revealed that the 3-year survival rates increased from 30% to 80% after the introduction of rituximab [8]. In a study that included 381 adult patients in the Japanese registry of ABO-I LDLT, only the absence of rituximab prophylaxis was a significant risk factor for AMR. Thus, rituximab prophylaxis significantly decreased the incidence of AMR. In that study, the incidence of AMR decreased from 23.5% to 6.2% after the introduction of rituximab [24]. Since the rituximab era, many centers are now trying to simplify the protocol, and avoid splenectomy, local graft infusion, IVIG, and plasmapheresis [14-20].

Desensitization trials without plasmapheresis

The role of preoperative ABO antibody titer in rejection of ABOI LDLT has not yet been established. Several studies have shown no significant correlation between ABO antibody titer and AMR, indicating that high preoperative antibody values have no significant effect on AMR frequency [8,32]. Another study suggested that sufficient desensitization could be achieved using rituximab alone [16]. In addition, another study included a simplified protocol using rituximab and IVIG without plasmapheresis for ABO-I LDLT. The study reported that the protocol was safe and effective in achieving sufficient desensitization and showed comparable outcomes in patients with titers no higher than 1:64 [15]. The incidence of diffuse intrahepatic biliary complications (DIHC) was 3–5% [11-13]. Considering intraoperative blood loss was much during ABO-I LDLT and very low incidence of DIHC, desensitization protocol without preoperative plasmapheresis required more search for validation.