ABO-incompatible Adult Living Donor Liver Research Articles

Factors associated with rituximab-mediated B cell depletion in ABO-incompatible adult living donor liver transplantation.

Pretransplant therapies such as rituximab and plasmapheresis have led to an increase in ABO-incompatible (ABOi) living donor liver transplantation (LDLT), thus helping to overcome organ shortages. This study evaluated the changes in anti-A/B titers and CD19 levels over time in patients undergoing ABOi LT and aimed to understand the effect of single-nucleotide polymorphisms (SNPs) in Fc gamma receptor (FcγR) on rituximab therapy. Two SNPs of FCGR2A (131H/R) and FCGR3A (158F/V) were identified. The clinical data on 44 patients who underwent ABOi LDLT between May 2019 and October 2021 at Seoul National University Hospital were reviewed retrospectively. Following desensitization with rituximab and subsequent LDLT, the anti-A/B titer recovered within 1 week, but decreased thereafter. The CD19 level increased at 3 months after LT. The genotyping data for FCGR3A (158F/V) indicated that two patients had the V/V genotype, and 42 had the F/V genotype. In the genotyping data for FCGR2A (131H/R), 21 patients had the H/H genotype, three had the R/R genotype, and 20 had the H/R genotype. However, there were no significant differences in anti-A/B and CD19 levels, bacteremia rates, T cell-mediated rejection, antibody-mediated rejection, or the survival rate among the FCGR2A types. There were significant changes in the anti-A/B titers and CD19 levels over time in each patient after ABOi LDLT. The difference in outcomes following LT according to the FcγR SNP type for rituximab was unclear. Further studies with larger sample sizes are needed to confirm the effect of FcγR SNPs on rituximab therapy.

The fate of donor-type ABO blood group antigen expression in liver grafts in ABO-incompatible adult living donor liver transplantation.

Donor-type ABO blood group antigens (dABOAgs) have been detected in ABO-incompatible adult living donor liver transplantation (ABOi ALDLT) grafts, but their fate and role in ABOi ALDLT rejection remain uncertain. The 0-day, <1-month, and 1-year serial liver graft biopsies from 30 ABOi ALDLT recipients were retrospectively evaluated. ABO antigen expression was quantitatively and serially measured by the mean number of positively stained vascular structures (endothelium of the capillaries, arteries, hepatic veins, and portal veins) within the portal tracts (sS). The dABOAg sS counts of 0-day, <1-month, and 1-year liver graft biopsies (32.3, 20.8, and 20.6, respectively) decreased significantly (p < .001). Early rejection in the <1-month biopsy was observed in 8/30 (26.7%) recipients, four (13.3%) of whom showed antibody-mediated rejection. The sS counts tended to rebound in grafts showing early rejection, with minimal changes from the 0-day to <1-month period, but increased to pre-transplantation levels after 1year, compared to that in grafts without early rejection (36.0, 20.4, 19.6 vs. 23.7, 21.9, 23.0, respectively; p=.040). While dABOAg expression decreased after ABOi ALDLT, recipients showing early rejection showed sustained graft dABOAg expression. Therefore, dABOAg expression may be involved in the mechanism of accommodation in ABOi transplantation.

Outcomes of ABO-incompatible adult living donor liver transplantation for patients with hepatocellular carcinoma beyond the milan criteria

Boram LEE, Jai Young CHO*, Suk Kyun HONG, YoungRok CHOI, Hae Won LEE, Nam-Joon YI, Kwang-Woong LEE, Kyung-Suk SUH, Ho-Seong HAN. Ann Hepatobiliary Pancreat Surg 2022;26:S327. https://doi.org/10.14701/ahbps.2022S1.EP-46

Outcomes of ABO-incompatible adult living donor liver transplantation for patients with hepatocellular carcinoma beyond the milan criteria

Boram LEE, Jai Young CHO*, Suk Kyun HONG, YoungRok CHOI, Hae Won LEE, Nam-Joon YI, Kwang-Woong LEE, Kyung-Suk SUH, Ho-Seong HAN. Ann Hepatobiliary Pancreat Surg 2022;26:S80. https://doi.org/10.14701/ahbps.2022S1.OP-3-6

Can Microscopic Biliary Reconstruction Reduce Biliary Complication Rate in ABO-Incompatible Adult Living Donor Liver Transplantation?

BackgroundWith the introduction of rituximab, ABO-incompatible (ABOi) living donor liver transplantation (LDLT) has been considered a feasible and safe procedure to overcome the shortage of organ donors. However, higher biliary complication rates remain an unresolved problem in the ABOi group. In our center, biliary anastomosis has been done with microscopic biliary reconstruction (MBR), which effectively reduced the biliary complication rate. The aim of the current study was to investigate whether the microscopic approach reduced anastomotic biliary complications in ABOi LDLT.Material/MethodsFrom March 2006 to December 2018, 30 adult ABOi and 60 ABO-compatible (ABOc) LDLT patients were selected from over 1300 recipients through 1: 2 propensity score-matched cohorts. All patients received MBR during the transplantation. Biliary complications included bile leakage and biliary stricture. Patients with diffuse intrahepatic biliary stricture were excluded from analysis.ResultsPatient characteristics were similar in the 2 groups. There was no in-hospital mortality in the ABOi LDLT. The long-term survival rates of the ABOi patients were comparable to those of the patients that underwent ABOc LDLT (87.1% vs 87.4%, P=0.964). Those in the ABOi group with anastomotic biliary complications were about 40%, which was higher than in the ABOc patients (40% vs 15%, P=0.01).ConclusionsMicroscopic biliary reconstruction does not help to reduce the high biliary complication rate in ABOi LDLT. Further investigation and identification regarding other risk factors and precautionary measures involving immunologic and adaptation mechanisms are needed.

No diffuse intrahepatic biliary stricture after ABO-incompatible adult living donor liver transplantation using tailored rituximab-based desensitization protocol.

BackgroundRituximab (RTx) desensitization protocol offered good outcome in ABO-incompatible (ABOi) living donor liver transplantation (LDLT). However, diffuse intrahepatic biliary stricture (DIHBS) is still inevitable hurdle. We selectively added postoperative high dose intravenous immunoglobulin (IVIG) and/or simultaneous splenectomy if ABO isoagglutinin titer just before liver transplantation after plasma exchange (PE) was higher than 1/16. Herein, we reported the excellent outcome of ABOi LDLT without DIHBS using tailored desensitization protocol and compared it with that of ABO-compatible (ABOc) LDLT.MethodsSixty-five cases (14.8%) of ABOi LDLTs were performed among 438 primary adult LDLTs in our center between March 2012 and June 2017. We performed 1-to-2 propensity score matching (PSM) to extract 60 cases of ABOi LDLTs and 120 cases of ABOc LDLTs.ResultsThere were no significant differences in clinical characteristics between ABOi and ABOc recipients. There were no significant differences in complications and rejection. There was no DIHBS in both groups. The 1-, 3-, and 5-year overall survival rates were 98.3%, 86.7%, and 82.9% in ABOi group and 96.7%, 86.7%, and 85.4% in ABOc group, respectively (P=0.88). Most common cause of deaths of both groups was hepatocellular recurrence. The 1-, 3-, and 5-year biliary complication (anastomosis leakage or stricture) free survival rates were 81.4%, 69.5%, and 67.5% in ABOi group and 83.0%, 81.3%, and 80.0% in ABOc group, with no significant differences (P=0.11).ConclusionsRTx-based tailored (optional IVIG + splenectomy) desensitization protocol for ABOi LDLT was feasible and acceptable.

Outcomes of a tailored rituximab-based desensitization protocol without local infusion therapy for ABO-incompatible adult living donor liver transplantation

Introduction: Rituximab (RTx) desensitization protocol in ABO-incompatible (ABOi) living donor liver transplantation (LDLT) offered new paradigm shift beyond ABO blood barrier to obtain donor pool expanding. The Aim of our study is to evaluate the outcome of ABOi adult LDLT using tailored desensitization protocol and to compare with that of ABO compatible (ABOc) LT in single center experience. Method: Between March 2012 and June 2017, 65 cases (14.8%) of ABOi LDLTs were performed in our center among 438 primary adult LDLTs. In ABOi cases, reduced RTx (300mg/m2) was administered around 3 weeks before LDLT, followed by 3 times of plasmapheresis at one week before LT regardless initial and final isoagglutinin titer. If issoagglutinin titer was higher than x32 after plasmapheresis, simultaneous splenectomy with perioperative high dose intravenous immunoglobulin (5 day s/0.8g/Kg) was selectively added. The immunosuppression was maintained with triple therapy (tacrolimus, steroids and mycophenolate mofetil). We performed propensity score matching and 120 ABOc cases and 60 ABOi cases were selected. Outcomes were then retrospectively compared between two groups. Result: There were no significant differences in recipients’ characteristics including MELD score, with HCC or not, and final graft to recipient weight ratio (GRWR) between two groups. Overall survival rates at 5 years are 89.2% in ABOc cases, and 87.8% in ABOi cases without any significant differences. There were also no significant differences in complication rates such as biliary complication, infection, acute cellular rejection. There were no cases with antibody-mediated rejection in ABOi cases. In cases with HCC (89 cases of ABOc group, and 42 cases of ABOi group), recurrence-free survival at 5 years were 90.4% in ABOc, and 77.5% in ABOi. There was also no significant difference. Conclusion: Our RTx-based tailored desensitization protocol for ABOi LDLT was feasible and the outcome was considered acceptable.

Successful experiences of ABO-incompatible adult living donor liver transplantation for high-urgency patients in a single institute

ABO-incompatible (ABOi) adult living donor liver transplantation (ALDLT) is not a suitable treatment option for high-urgency patients because of a preparatory period (about two weeks). This report presents our experience in ABOi ALDLT in 3 patients with high-urgent circumstances between December 2014 and August 2015. The mean age of recipients was 48.5 ± 5.7 years (range, 40–54 years). The mean Model for End-stage Liver-Disease score was 20 ± 4.0 (range, 9–22). The plasma exchange (PE) was performed 3 days after administration of rituximab. Two times of PE were done in all case before ALDLT. Isoagglutinin (IA) titers and CD19+/CD20% ratios of all patients were below 1:8 and 1.0%. The one patient experienced postoperative complication that need to surgical approach (wound dehiscence). The all of the patients and graft survivals were 100% at a mean follow-up period of 6months. There was no episode of antibody-mediated rejection (AMR). ABOi ALDLT for high-urgency patients, therefore seems to be a safe and feasible therapeutic modality.

Biliary stricture is the only concern in ABO-incompatible adult living donor liver transplantation in the rituximab era

With the introduction of rituximab prophylaxis, the survival of ABO-incompatible (ABOi) adult living donor liver transplant (ALDLT) has been strikingly improved due to the decreased incidence of antibody-mediated rejection. However, biliary stricture (BS) related to ABO incompatibility remains an unresolved concern. Excluding 105 dual graft ALDLTs, 1102 ALDLT cases including 142 ABOi recipients were included in this study. The desensitization protocol for overcoming the ABO blood group barrier comprised pretransplant plasma exchange, and rituximab (300-375 mg/m(2) BSA). The mean follow-up period was 34.2 ± 15.4 months. The cumulative graft and patient survival rates were comparable in the two groups. The 1- and 3-year BS-free survival rates of ABOi ALDLT were 81.5 and 79.0%, respectively, lower than those of ABOc ALDLT (87.6 and 85.7%, respectively, p=0.022). In the risk factor analysis, diameter of graft bile duct opening <5mm, antecedent acute cellular rejection, and ABO incompatibility were independent risk factors for BS. Diffuse intrahepatic biliary stricture (DIHBS) exclusively occurred in 12 patients (8.5%) receiving ABOi ALDLT. The deaths of 3 patients and 4 cases of re-transplantation were related to DIHBS. Graft and patient survival rates were significantly reduced in ABOi ALDLT recipients with DIHBS. However, we failed to identify any significant risk factors for DIHBS. The incidence of BS in ABOi ALDLT is higher than in ABOc, mainly due to the fact of DIHBS which significantly affected survival outcomes. To predict and prevent DIHBS, we need further studies to identify significant risk factors.

Section 16. Update on Experience in Paired-Exchange Donors in Living Donor Liver Transplantation For Adult Patients at ASAN Medical Center

An exchange living donor program for liver transplantation, similar to the exchange living donor kidney program, was proposed to avoid ABO-incompatible adult living donor liver transplantation (LDLT). The objective of this study was to present updated changes in exchange adult LDLT program at our institution. Between January 2003 and December 2011, approximately 2,182 adult LDLT cases were included in this study. During this period, 26 paired-exchange donor LDLT cases were performed (1.2%). Of the 26 paired-exchange donor LDLT cases, 22 pairs were matched due to ABO-incompatibility, and 4 pairs were matched because of cascade allocation of unrelated donors or relatively small graft volume to the recipients. A total of 28 living donors were included in the 26 paired-exchange donor LDLT cases because of inclusion of two dual-graft transplants. Elective surgery was performed in 22 cases, and urgent operation was performed in 4 cases. The overall 1-year and 5-year patient and graft survivals were both 96.2% and 90.1%, respectively. Our experience suggests that the paired-exchange donor program for adult LDLT seems to be a feasible modality to overcome donor ABO incompatibility. Reasonably acceptable indications for donor exchange LDLT will be proposed in near future.

Successful Experiences of ABO-Incompatible Adult Living Donor Liver Transplantation In a Single Institute: No Immunological Failure in 10 Consecutive Cases

ABO-incompatible (ABOi) adult living donor liver transplantation (ALDLT) is a feasible therapeutic option for countries with a scarcity of deceased donors. This report presents our initial experiences in ABOi ALDLT in 10 patients between December 2008 and September 2009. The mean age of recipients was 48.5 ± 5.7 years (range, 40–54 years). The mean Model for End-stage Liver-Disease score was 13.9 ± 4.0 (range, 9–22). All patients were administered preoperative rituximab once and plasma exchanges according to the hemagglutinin titer. The spleen was preserved in all cases. For local infusion therapy, hepatic arterial infusion was performed in 9 patients and portal vein infusion in 1 subject. The 10 patients experienced no in-hospital mortality. At a mean follow-up period of 31.8 ± 2.9 months (range, 4.1–34.9 months), 1 patient has died (postoperative month 4 due to sepsis following a biliary stricture. The 3-month patient and graft survivals were 100%, and 1- and 2-year survivals, 90.0%. There was no episode of antibody-mediated rejection. The promising results of our initial experience may have been due to the use of preoperative rituximab and the good preoperative conditions of the patients.

Adult Living Donor Liver Transplantation with ABO-Incompatible Grafts: A German Single Center Experience.

Adult living donor liver transplantations (ALDLTs) across the ABO blood group barrier have been reported in Asia, North Americas, and Europe, but not yet in Germany. Several strategies have been established to overcome the detrimental effects that are attached with such a disparity between donor and host, but no gold standard has yet emerged. Here, we present the first experiences with three ABO-incompatible adult living donor liver transplantations in Germany applying different immunosuppressive strategies. Four patient-donor couples were considered for ABO-incompatible ALDLT. In these patients, resident ABO blood group antibodies (isoagglutinins) were depleted by plasmapheresis or immunoadsorption and replenishment was inhibited by splenectomy and/or B-cell-targeted immunosuppression. Despite different treatments ALDLT could safely be performed in three patients and all patients had good initial graft function without signs for antibody-mediated rejection (AMR). Two patients had long-term graft survival with stable graft function. We thus propose the feasibility of ABO-incompatible ALDLT with these protocols and advocate further expansion of ABO incompatible ALDLT in multicenter trials to improve efficacy and safety.

Effects and Problems of Adult ABO-Incompatible Living Donor Liver Transplantation Using Protocol of Plasma Exchange, Intra-arterial Infusion Therapy, and Anti-CD20 Monoclonal Antibody Without Splenectomy: Case Reports of Initial Experiences and Results in Korea

Introduction Adult ABO-incompatible liver transplantation is associated with a high risk of graft failure due to antibody-mediated humoral rejection (AMR). We evaluated the effects of a protocol using preoperative removal of isohemagglutinin, rituximab prophylaxis, and intrahepatic arterial infusion (HAI) therapy for ABO-incompatible adult living donor liver transplantation (LDLT). Patients and Methods Between March 2005 and September 2007, we performed 94 adult LDLTs, including 3 ABO-incompatible cases. All ABO-incompatible LDLT patients underwent administration of 375 mg/m 2 rituximab on preoperative days 15 and 8 without splenectomy, as well as preoperative removal of isohemagglutinin using plasma exchange, and HAI therapy for postoperative 21 days. Results Postoperative anti-donor blood-type antibody titer and B-cell level were effectively suppressed by early rituximab prophylaxis in all patients. HAI therapy was effective to prevent AMR and even resolved mild AMR. However, all patients suffered bacterial infections, and 1 died of septicemia with good graft function. Another subject died of late-onset AMR that occurred after discontinuation of HAI therapy. Conclusion An ABO-incompatible LDLT protocol using plasma exchange, rituximab prophylaxis, and intra-HAI therapy effectively suppressed anti-A/B antibody and prevented AMR. But this protocol should be further improved to reduce infectious complications and late onset of AMR.

B-cell surface marker analysis for improvement of rituximab prophylaxis in ABO-incompatible adult living donor liver transplantation

Although the effectiveness of rituximab has been reported in ABO blood group (ABO)-incompatible (ABO-I) organ transplantation, the protocol is not yet established. We studied the impact of the timing of rituximab prophylaxis and the humoral immune response of patients undergoing ABO-I living donor liver transplantation (LDLT), focusing on clinicopathological findings and the B-cell subset. From July 2003 to December 2005, 30 adult patients were treated with hepatic artery infusion (HAI) protocol without splenectomy for ABO-I LDLT. A total of 17 patients were treated only with HAI (no prophylaxis), and the other 13 were treated with rituximab prophylaxis at various times prior to transplantation. For B-cell study of the spleen, another 4 patients undergoing ABO-I LDLT both with HAI after prophylaxis and eventual splenectomy, and 3 patients with ABO-compatible LDLT with splenectomy were enrolled. The mortality of the 30 patients with HAI, without splenectomy, and with/without rituximab prophylaxis was 33% and the main cause of death was sepsis. Peripheral blood B cells were completely depleted, anti-donor blood-type antibody titer was lower, and clinical and pathological antibody-mediated rejection was not observed in patients with prophylaxis earlier than 7 days before transplantation (early prophylaxis). Early rituximab prophylaxis significantly depleted B cells and memory B cells in the spleen but not in lymph nodes. On the other hand, B cells and memory B cells increased and memory B cells became dominant during antibody-mediated rejection. In conclusion, early prophylaxis with rituximab depletes B cells, including memory B cells, in the spleen and is associated with a trend toward lower humoral rejection rates and lower peak immunoglobulin (Ig)G titers in ABO-I LDLT patients.

The Role of Plasmapheresis Therapy for Perioperative Management in ABO-Incompatible Adult Living Donor Liver Transplantation

Background Although living donor liver transplantation (LDLT) was established as a treatment for end-stage liver disease in Japan, the indication for LDLT across an ABO-incompatible barrier remains controversial. The purpose of this study was to elucidate the role of plasmapheresis in incompatible LDLT. Methods Eleven adult patients (seven men and four women) who underwent incompatible LDLT were enrolled in this study. Of these three patients had hepatocellular carcinoma, three chronic hepatitis C, one Wilson’s disease, one autoimmune hepatitis, one chronic hepatitis B, one hemochromatosis, and one fulminant hepatic failure. The immunosuppressive regimen consisted of tacrolimus, prednisolone, mycophenolate mofetil (or cyclophosphamide), and prostaglandin E1 in all patients. Multiple plasmapheresis was performed perioperatively to reduce the recipient’s antibody titers against the donor’s blood type. Results Plasmapheresis was useful for the reduction of the recipient’s antibody titers to ×16 or lower before and after transplantation. There was no difference in transplant outcome between the 11 patients with incompatible blood group and 30 patients with identical or compatible blood groups. Discussion Major postoperative complications such as intrahepatic biliary complications and hepatic necrosis may occur in incompatible transplantation. Several investigators suggested that anti-imunoglobulin (Ig) M and anti-IgG antibody titers sustained these complications. The antibody titers must be decreased sufficiently with plasmapheresis. An elevation of anti-ABO titers after transplantation may be a predictive risk factor for increased mortality and morbidity. In order to perform LDLT in a safer manner, plasmapheresis is an indispensable treatment to improve the outcome of ABO-incompatible cases.