Due to shortage of cadaveric organ donation, living donor liver transplantation (LDLT) is the primary form of liver transplantation (LT) in India. In the LDLT scenario, donors are restricted to family members and it is not always possible to find a healthy blood group-compatible donor in time. Liver transplant across the ABO blood group barrier is a promising approach in such patients. Antibody-mediated rejection along with biliary and vascular complications are the usual limiting factors in ABO-incompatible (ABOi) LT [1]. Determining optimal immunosuppression to avoid complications in ABOi LT is challenging. Desensitization with use of plasmapheresis and anti-CD20 monoclonal antibody (rituximab) plays an important role in successful outcome of ABOi LT [2]. Our aim was to study the course and outcomes of pediatric ABOi LT.

Data of all patients (<18 years) undergoing ABOi LDLT at our hospital, India between January, 2011 and November, 2018 were retrospectively analyzed. ABOi LT was performed only in cases where compatible related donors were unavailable even after exploring option of swap transplant between two families. Informed consent was taken for ABOi LDLT. Hospital liver transplant committee clearance was obtained. Demographic details, primary diagnosis and severity of liver disease using Pediatric end-stage liver disease (PELD) score were noted. Recipient and donor blood group and pre-transplant antibody titres were recorded. Surgical details and post-operative course including antibody titres, duration of ICU and hospital stay, incidence of hemolysis, rejection, biliary and vascular issues and infections were recorded.

A total of 203 pediatric LDLT were performed at our institute during the study period; 8 these were ABOi LT. All 8 (3 males) patients had underlying cholestatic liver disease of which 5 had biliary atresia. Median (range) age was 28 (7-91), months and median (range) PELD score was 24.5 (14-42). Four of the 8 recipients had blood group O, two each had blood group A and B. Pre-transplant baseline antibody titer ranged from 32 to 1024 units. Mean (range) pre-transplant hospital stay was 12.5 (1-44) days. Number of pre-transplant plasmapheresis sessions ranged from 1-6 and was proportional to the initial titer. Conventional plasmapheresis was used in the first two patients, prior to 2012. Thereafter, cascade plasmapheresis was used for 5 cases; immune-adsorption was used in 2. One patient had high initial antibody titer of 1024 units which reduced to 256 units after two sessions of cascade plasmapheresis. There was a subsequent rise of antibody titer to 1024 units during an episode of sepsis. After recovery, three sessions of immune-adsorption plasmapheresis decreased antibody titer to 8. Another patient underwent ABOi transplant in limited preparation time with a domino graft using the explanted liver of a child of maple syrup disease undergoing liver transplant using immune-adsorption plasmapheresis. A single cycle decreased the antibody titer from 128 to 4 units. IVIG was used in first 3 cases, prior to 2016 and rituximab was used thereafter in 3 patients. Two of these were between 2-8 years with risk factors of high initial antibody titer (> 256) and re-transplantation.

Post-transplant, mean (range) ICU stay was 7.3 (5-11) days and post-transplant hospital stay was 19.1 (13-22) days. Post-operatively two patients had rise in antibody titer up to 256 (on sixth day) and 64 (on seventh day), respectively which required 4 and 3 sessions of cascade plasmapheresis to reduce antibody titer <32. One patient developed E. coli sepsis which responded to antibiotics. Two patients developed vascular complications. No biliary or bowel complications were noted. Two patients developed hemolysis (peripheral smear changes, LDH >1000 U/L and reticulocytes >2%) which resolved spontaneously. All eight patients survived without any evidence of acute/chronic rejection. The mean (range) follow-up period was 38.1 (7.1-84.4) months.

Pediatric graft survival rates were reported similar after ABOi LT and blood group compatible LT, whereas graft survival in adults after ABOi LT were lower [4]. Antibody-mediated rejection is a catastrophic complication which can occur in the first 2-4 weeks. The risk of ischemic cholangitis, bile leak, biliary stricture formation, and hepatic artery thrombosis is higher in ABOi LT [5]. The approach in ABOi LT is directed towards reducing antibodies pre-transplant and inhibiting its production post-transplant for at least 2-4 weeks by effective immunosuppression [6].

Plasmapheresis is the most effective way to control humoral antibody response to prevent rejection [7]. We used all the methods of plasmapheresis: conventional, cascade and immune-adsorption. IVIG inhibits complement and T-cell-mediated graft injury by FC-receptor-dependent B-cell apoptosis [3]. With availability of effective drugs like rituximab the use of prophylactic IVIG has become less relevant. However, IVIG is more effective for treating antibody-mediated rejection as exerts faster effects than rituximab [3]. We used CD19 as a surrogate marker for patients who received rituximab as it mirrors the expression of CD20 [8].

Recipient blood group O is the most susceptible group antibody-mediated rejection [9]. Although, half of our patients had blood group none of them developed antibody-mediated rejection or biliary complications probably due to optimal immunosuppression. The vascular complications seen in two patients were diagnosed early and timely surgical management prevented any permanent hepatic damage, thus emphasizing the importance of vigilant postoperative monitoring.

Our experience in pediatric ABOi LT suggests that it is a promising alternative in India when compatible graft donor is unavailable.

Contributors: NM,VR: wrote the manuscript; MD: contributed to design, data compilation and analysis; MD, AT: data compilation and manuscript writing; PB,AS: contributed to the surgical aspects of the manuscript. VR,PB,MD: involved in coordination of the study and revision of the manuscript; NM, AS: final editing of the manuscript. All authors approved the final manuscript.

Funding: None; Competing interests: None stated.

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