Increasing the liver donation pool: Eculizumab desensitization for ABO-incompatible living donor liver transplantation - A case series.

ABO incompatibility is the commonest reason for rejection of donors in living donor liver transplantation (LDLT). The donor pool could be expanded by 25 % to 35 % if the ABO barrier is overcome. In the absence of pre-conditioning, transplantation across the blood groups is fraught with the almost universal risk of antibody-mediated rejection (AMR) that rapidly leads to graft loss. However, AMR can be prevented by removal of preformed antibodies and reducing their production by B cells. We describe our initial experience of three cases of ABO-incompatible (ABO-i) LDLT: a 42-year-old male, an 8-month-old male and a 28-month-old female, all of blood group O+ who received blood group B + right lobe, B + left lateral segment, and A + left lateral segment liver grafts, respectively. Pre-LDLT conditioning included administration of anti-CD20 antibody (Rituximab(®)) to the adult 4 weeks prior, and four to seven sessions of double-filtration plasmapheresis to all, to remove preformed antibodies and achieve anti-donor blood group antibody (ADA) titers of ≤ 1:16 IgG and ≤ 1:8 IgM, respectively. In addition, cases 1 and 3 received mycophenolate mofetil for 7 days prior to LDLT. After LDLT, all three patients achieved normal graft function over 8-17 days with no evidence of AMR and without the need for further plasmapheresis. Postoperative complications included portal vein thrombosis (one successfully re-explored), CMV (one), Pseudomonas and Klebsiella sepsis (one each), and abdominal collection (one treated with percutaneous drainage). All are currently well with normal graft function and low ADA titers at 8, 16, and 19 months after ABO-i LDLT.

Successful ABO-Incompatible Living Donor Liver Transplantation in a Patient with an Anaphylactic Reaction to Fresh Frozen Plasma During Therapeutic Plasma Exchange: A Case Report

Antibody mediated rejection (AMR) after adult ABO-incompatible living donor liver transplantation (ABO-I LDLT) induced hepatic necrosis or diffuse intrahepatic biliary complications, which were related with poor graft and patient survival. Various desensitization protocols have been used to overcome these problems. Since using rituximab, the outcomes of ABO-I LDLT show a similar survival rate to those of ABO-compatible living donor liver transplantation. However, diffuse bile duct complications still occur after ABO-I LDLT. We have reviewed the past and current immune strategies for desensitization and to provide outcomes and ABO incompatibility-related complications in ABO-I LDLT.

Single-Center Experience of ABO-Incompatible Living-Donor Liver Transplantation With a New Simplified Intravenous Immunoglobulin Protocol: A Propensity Score-Matching Analysis

ABO-incompatible living donor liver transplantation is suitable in patients without ABO-matched donor

New desensitization strategies have made ABO-incompatible living donor liver transplant an attractive option for patients with end-stage liver disease. We aimed to report our experience with 20 consecutive patients who underwent ABO-incompatible living donor liver transplant using a simplified desensitization and immunosuppression regimen. We retrospectively analyzed 20 ABO-incompatible living donor liver transplant cases (August 2015 to July 2019). The ABO-incompatible living donor liver transplant protocol involved rituximab administration (375 mg/m2 body surface area) at 2 to 3 weeks before transplant, subsequent plasma exchanges (target isoagglutinin titer of ≤1:8), basiliximab administration (20 mg on day of surgery and on postoperative day 4), and intravenous immunoglobulin administration (2 g/day from day of surgery to postoperative day 7). No graft local infusion therapy or splenectomy was performed. The living donor liver transplant procedure involved a modified rightlobe graft(18 patients), a right posterior segment graft (1 patient), or a left lobe (1 patient). The most common reason for liver transplant was hepatitis B virus-associated liver cirrhosis (16 patients); 14 patients had hepatocellular carcinoma. The mean age was 55.4 ± 6.3 years, mean Model End-stage LiverDisease score was 14.7 ± 7.7, and mean graft-to-recipient weight ratio was 1.07 ± 0.2%. The median initial anti-ABO antibody titers were 1:16 forimmunoglobulin M (range, 1:2 to 1:256) and 1:48 for immunoglobulin G (range, 1:4 to 1:>2048). The median number of plasma exchanges was 2 (range, 0-12). No patients had biopsy-confirmed antibody-mediated rejection. No bacterial or fungal infections were observed. Biliary anastomotic stricture was observed in 9 patients. This ABO-incompatible living donor liver transplant protocol with rituximab, plasma exchange, low-dose intravenous immunoglobulin, and immunosuppression (equivalent to ABO-compatible living donor liver transplant) could be a safe and effective way to overcome antibody-mediated rejection and other complications.

The anti-CD20 monoclonal antibody rituximab has significantly decreased the prevalence of antibody-mediated rejection of ABO-incompatible (ABOi) living donor liver transplantation (LDLT). However, little is known about acute kidney injury (AKI) following ABOi LDLT. The aim of this study was to identify the incidence of AKI in ABOi LDLT and compare it with that of ABO-compatible (ABOc) LDLT. We retrospectively collected and analyzed the data of 1617 patients who underwent liver transplant surgery from November 2008 to December 2014. Risk factors for AKI were investigated using multivariate regression analysis. In 271 ABOi LDLTs, AKI occurred in 184 (67.9%) according to Kidney Disease: Improving Global Outcomes criteria. After propensity score matching, the incidence of AKI was significantly higher after ABOi LDLT than after ABOc LDLT (67.0% versus 48.2%; P < 0.001). Furthermore, the intensive care unit stay (P = 0.01) was significantly prolonged, but there were no significant differences in mortality (P = 0.74), graft failure (P = 0.32), and postoperative dialysis (P = 0.74) between the 2 groups. Hemoglobin level and operation time were independent risk factors for AKI following ABOi LDLT. In conclusion, the incidence of AKI is higher in ABOi LDLT than ABOc LDLT. However, the impact of AKI on postoperative outcomes was not marked in our study. Therefore, ABOi LDLT in selected patients is promising with apparent good graft and survival outcomes. Liver Transplantation 22 1656-1665 2016 AASLD.

The current era of rituximab-based regimens brought improved survival in ABO-incompatible (ABO-I) living donor liver transplantation (LDLT). Nevertheless, the actual risk for hepatic artery thrombosis (HAT) still remains to be investigated. The aim of this study was to evaluate the impact of ABO-incompatibility on HAT in adult LDLT patients. Patients who received ABO-I LDLT were compared to those who received ABO-compatible (ABO-C) LDLT with a special focus on HAT. A total of 378 patients underwent LDLT from January 2012 to February 2018. Of those, ABO-I LDLT was performed in 78 consecutive patients. The other 300 patients with ABO-C LDLT constituted the comparator group. No significant differences were observed between the two groups in baseline and perioperative characteristics. HAT occurred in 11 (2.9%) patients, 2 and 9 patients in ABO-I and ABO-C LDLT groups, respectively, which didn't show any significant difference between the two groups (P=0.84). All were categorized into early HAT. Immediate revascularization by intraarterial thrombolysis was successfully employed in 8 patients. Surgical revision of anastomosis and retransplantation were performed in 1 and 2 patients, respectively. No one-year mortality was related to HAT in the two groups. The overall outcomes including biliary complications made no significant difference between the two groups. ABO-incompatibility has no adverse impact on the incidence and treatment outcome of HAT in the current rituximab-based desensitization.

Clinical features and prognosis of DIHBS (diffuse intrahepatic biliary stricture) after adult ABO-incompatible living donor liver transplantation

ABO-incompatible (ABO-I) living donor liver transplantation (LDLT) has a high success rate. This study compares hepatocellular carcinoma (HCC) recurrence in ABO-I LDLT with that in ABO-compatible (ABO-C) LDLT and explores the effects of rituximab prophylaxis and total plasma exchange on HCC recurrence after LDLT. Two hundred forty patients with a diagnosis of HCC underwent LDLT between 2010 and 2015. Fifty-nine patients underwent ABO-I LDLT. Baseline, perioperative, and tumor characteristics did not vary between the 2 groups. The 1-, 2-, and 3-year disease-free survival rates in the ABO-I LDLT and ABO-C LDLT groups were 90.3%, 79.7%, and 73.3% and 86.7%, 79.0%, and 75.3%, respectively (P = 0.96). The overall patient survival rates for the same period in the ABO-I LDLT and ABO-C LDLT groups were 90.6%, 85.0%, and 81.9% and 88.0%, 83.5%, and 82.5%, respectively (P = 0.77). Hepatocellular carcinoma recurrence after LDLT was associated with preoperative α-fetoprotein greater than 35 ng/mL, increased tumor size, encapsulation, and microvascular invasion. ABO incompatibility was not related to HCC recurrence after LDLT. Hepatocellular carcinoma recurrence and patient survival in the ABO-I LDLT group are comparable to those in the ABO-C LDLT group. Rituximab prophylaxis and total plasma exchange do not increase HCC recurrence after LT.

(Background) Previous studies have demonstrated the safety of ABO-incompatible living donor liver transplantation (LDLT) using preoperative plasmapheresis and rituximab. However, no reports have so far described the timing and dosage of rituximab administration for pediatric LDLT. The aim of this study is to determine the optimal dosage and timing of rituximab treatment in patients undergoing pediatric ABO-incompatible LDLT. (Methods) Between May 2001 and July 2013, 222 LDLTs were performed for 217 patients. Emergency LDLTs were excluded, because there was not adequate time to prepare these patients for ABO-incompatible LDLT. Those cases included 32 ABO-incompatible LDLTs in 31 patients, and 12 cases (11 patients) were administered rituximab. The anti-ABO antibody titers were reduced preoperatively by plasmapheresis in all cases who were administered rituximab. Rituximab was used from January 2004 for recipients over two years of age (first period; 375 mg/m2 two weeks before LDLT in two cases, second period; 50 mg/m2 two weeks before LDLT in two cases and third period: 200 mg/m2 three weeks before LDLT in eight cases). (Results) The ABO-incompatible LDLT recipient survival rate (87.1%) was significantly lower than that of the other recipients (97.3%) (p=0.008). Two patients who were administered 375 mg/m2 of rituximab died of Pneumocystis jiroveci pneumonia and hemophagocytic syndrome, respectively. One patient who was administered 50 mg/m2 of rituximab underwent re-transplantation due to antibody-mediated complications (intrahepatic biliary strictures). All eight patients who were administered 200 mg/m2 of rituximab survived. The mean CD20+ lymphocyte count was 0.1% at the time of LDLT and 5.4% six months after LDLT. (Conclusion) In the preoperative management of patients undergoing pediatric ABO-incompatible LDLT, the administration of 200 mg/m2 of rituximab three weeks before LDLT is optimally safe and effective.

Our aim was to clarify the significance of phenotype of circulating CD8 T+ cells on the outcome of ABO-incompatible (ABO-I) living donor liver transplantation (LDLT). Twenty-six recipients undergoing ABO-I LDLT and 92 undergoing ABO-compatible (ABO-C) LDLT were classified into three groups according to preoperative proportion of CD8 T+ cells: naive-dominant (group I), effector memory-dominant (group II), and effector-dominant (group III) recipients. The clinical courses were analyzed. The results showed that in ABO-C groups I and II and in ABO-I group I, effector cells remained above the pretransplant levels after tacrolimus administration. However, in ABO-C group III and ABO-I groups II and III, effector cells were down-regulated for a prolonged period, along with markedly decreased perforin expression and frequent life-threatening complications. ABO-I group II and group III recipients had higher infection rates. It was concluded that recipients with preexisting high effector CD8 T+ cells are unfavorable candidates for ABO-I LDLT.

Living donor liver transplant (LDLT) is a predominant form of liver transplant in countries with scarce availability of cadaveric donors. In East and South Asian countries, more than 80% of liver transplants are LDLT. Breaching of ABO barrier has led to further expansion of donor pools in these countries and ABO-incompatible (ABOi) LDLT constitutes a significant number of living donor liver transplants. One of the most important steps in ABOi LDLT is pretransplant desensitization to prevent ABO antibodies-related rejection and graft dysfunction. Desensitization is achieved by preoperative rituximab and plasmapheresis. ABOi liver transplant has higher risk of AMR, non-anastomotic biliary strictures and sepsis. Improvement in immunosuppression and pretransplant desensitization protocols has led to comparable outcomes of graft and patient survival in ABOi liver transplant and ABO compatible (ABOc) liver transplant. Regular monitoring with liver biochemistry and imaging for graft function and vigilance for infectious complications are important for the prevention and management of complications in these patients.

Previous studies have reported comparable oncologic outcome between ABO-incompatible (ABOi) living donor liver transplantation (LDLT) and ABO-compatible (ABOc) LDLT in patients with hepatocellular carcinoma (HCC). We aimed to analyze the relationship between number of therapeutic plasma exchanges (TPE) before LDLT and HCC outcomes in ABOi LDLT. In this single-center retrospective study, 428 adult LDLT recipients with HCC were categorized into three groups according to ABO incompatibility and the number of pretransplant TPE: ABOc (n = 323), ABOi/TPE ≤5 (n = 75), and ABOi/TPE ≥6 (n = 30). The RFS and HCC recurrence rates were compared. Three groups showed similar characteristics in most demographics, pretransplant tumor markers and pathologies. The median initial isoagglutinin (IA) titer was 1:64 (range negative-1:512) in ABOi/TPE ≤5 group and 1:512 (range 1:128–1:4,096) in ABOi/TPE ≥6 group. Five-year RFS was significantly lower (75.7% vs. 72.7% vs. 50.0%, P = 0.005) and HCC recurrence was significantly higher in the ABOi/TPE ≥6 group than in the other groups(16.4% vs. 17.0% vs. 39.4%, P = 0.014). In multivariable Cox regression analysis, ABOi/TPE ≥6 was an independent risk factor for RFS (aHR 1.99, 95% CI:1.02–3.86, P = 0.042) and HCC recurrence (aHR 2.42, 95% CI:1.05–5.57, P = 0.037). More than six pretransplant TPE sessions may increase the risk of HCC recurrence after ABOi LDLT. Reducing TPE sessions to fewer than six should be considered while maintaining immunological stability through IA titer control.

Effect of recipient gender and donor-specific antibodies on antibody-mediated rejection after heart transplantation.