Experiences and problems pre-operative anti-CD20 monoclonal antibody infusion therapy with splenectomy and plasma exchange for ABO-incompatible living-donor liver transplantation

BACKGROUND: ABO-incompatible living-donor liver transplantation (LDLT) requires a reduction of the anti-ABO antibody titer to <16 before transplantation, which is usually achieved by pre-operative plasma exchange (PE) or double-filtration plasmapheresis. ABO-incompatible transplantations have been performed after a splenectomy with heavy drug immunosupression plus B-cell-specific drugs. Here, we evaluated a pre-transplantation infusion protocol with an anti-CD20 monoclonal antibody (rituximab) for ABO-incompatible LDLT. METHODS: Between March 2002 and December 2005, 73 adult patients underwent LDLT without retransplantation in our institution. Among these cases, 57 were ABO-identical, 11 were ABO-compatible and five were ABO-incompatible. The rituximab infusion protocol consisted of a weekly infusion of rituximab (375 mg/m(2)) for three wk, which was administered to three of the five ABO-incompatible LDLT patients. All three patients underwent a pre-operative PE, as well as a splenectomy during the operation. A triple immunosuppression protocol of tacrolimus, low-dose steroids and mycophenolate mofetil (1500 mg/d) was administered post-operatively. In addition, the patients received a continuous intra-arterial infusion of prostaglandin E(1) and methylprednisolone, and a continuous intra-portal infusion of a protease inhibitor for three and two wk after transplantation, respectively. RESULTS: After the first rituximab infusion, the peripheral blood CD19(+) B cell count rapidly decreased to <1%. All three patients treated with rituximab subsequently received an ABO-incompatible LDLT, with donor/recipient blood groups of B/O, A(1)/B and A(1)/O. In two cases, the ABO-antibody level transiently increased post-operatively, then decreased and remained low. Rituximab infusion therapy did not develop any direct side effect except for mild allergic reaction to the first infusion, but post-operatively all three patients suffered a cytomegalovirus and were successfully treated with ganciclovir, and one patient had a MRSA-positive intra-abdominal abscess. Two patients are currently alive at 20 and 18 months respectively, and show normal graft-liver function. But one patient died of sepsis because of intra-abdominal abscess. CONCLUSIONS: Although the protocol of rituximab administration is a conventional and safe regimen with no major side effects, the development of a new protocol is needed for prevention of the infection with bone suppression.     

ABO-incompatible deceased donor liver transplantation with the use of antigen-specific immunoadsorption and anti-CD20 monoclonal antibody

In patients with fulminant liver failure requiring emergency liver transplantation, the only donor organ that becomes available may be ABO incompatible. The risk of graft failure because of antibody-mediated acute rejection is high, but can be reduced by various means. We reported a deceased donor ABO-incompatible liver allograft recipient who was treated with antigen-specific immunoadsorption in combination with anti-CD20 monoclonal antibody and conventional plasmapheresis and immunosuppression. The patient was a 33-yr-old male with blood group A who presented with subacute liver failure of unknown aetiology and received a blood group AB liver graft. Pretransplant he underwent plasmapheresis and received one dose of rituximab. The immunosuppressive regimen consisted of methylprednisolone, tacrolimus and mycophenolate mofetil. Despite regular post-operative plasmapheresis sessions, anti-B antibody titres increased. Antigen-specific immunoadsorption with depletion of anti-B antibodies was performed from day nine to day 17. Thereafter, anti-B IgM and IgG antibody titres remained low. After one month the patient was reoperated with hepaticojejunostomy because of bile duct necrosis and with reconstruction of a stenotic hepatic artery. A mild rejection was successfully treated with methylprednisolone four months post-transplant. At six months post-transplant there was a stricture of the biliary-enteric anastomosis, but the graft was well functioning. We conclude that antigen-specific immunoadsorption can be an important adjuvant therapy to control recipient anti-A/B antibody levels and prevent acute rejection in ABO-incompatible deceased donor liver transplantation.     

ABO-incompatible adult living donor liver transplantation for hepatocellular carcinoma

Living donor liver transplantation (LDLT) offers timely transplantation for patients with hepatocellular carcinoma (HCC). If ABO-incompatible LDLT is feasible, the need for pretransplantation treatment may be eliminated, which may reduce overall morbidity. In this article, we have described 8 adult HCC patients who successfully underwent LDLT from ABO-incompatible donors. Antirejection therapy included multiple preoperative plasmaphereses, splenectomy, and an immunosuppressive regimen with tacrolimus, methylprednisolone, and mycophenolate mofetil. The maintenance dose of immunosuppression did not differ from that of the ABO-identical cases. In addition, we also performed intrahepatic arterial infusion of prostaglandin E1. In 5 patients, we administered a single dose of rituximab, a chimeric CD20 monoclonal antibody. As a result of this treatment, 6/8 patients are still alive. Our experience has shown that it is possible to control antibody-mediated humoral rejection and other complications in adult ABO-incompatible LDLT.     

ABO-incompatible living donor liver transplantation with high preoperative antibody titer: A case report

Introduction and importanceABO-incompatible living donor liver transplantation (ABOi-LDLT) is essential for expanding the donor pool. ABOi-LDLT prognosis has improved since desensitization treatment with rituximab; however, patients with high antibody titers are considered to be at high risk of antibody mediated rejection (AMR). Nevertheless, the preoperative antibody titer cutoff levels that preclude ABOi-LDLT have not yet been determined. In this study, the highest preoperative antibody titer was 1:4096, and the recipient had good outcomes. There has been only one report of good outcomes with a preoperative antibody titer of more than 1:4096. We hypothesized that high preoperative antibody titers in ABOi-LDLT may not be associated with AMR in protocols involving rituximab.Case presentationThe recipient was a 22-year-old man with biliary atresia and underwent ABOi-LDLT (B to O). We administered 500 mg of rituximab 14 days prior and then 300 mg of rituximab one day prior to ABOi-LDLT. The recipients preoperative IgG antibody titer was 1:4096. Postoperative immunosuppressive protocol involved steroids, tacrolimus, and mycophenolate mofetil. The patient had satisfactory graft function three years following ABOi-LDLT.Clinical discussionThe antibody that is responsible for posttransplant AMR should be newly synthesized after transplantation as a result of sensitization by antigens on the vascular endothelial cells of the graft. In ABOi-LDLT, natural antibodies may not cause AMR.ConclusionsThe most important factor for preventing AMR in recipients undergoing ABOi-LDLT is the suppression of de novo antibodies. High preoperative antibody titers may not necessarily preclude ABOi-LDLT, provided that rituximab is used in desensitization.     

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.     

ABO-incompatible live donor renal transplantation using blood group A/B carbohydrate antigen immunoadsorption and anti-CD20 antibody treatment

BACKGROUND: Blood group ABO-incompatible live donor (LD) renal transplantation may provide a significant source of organs. We report the results of our first 14 cases of ABO-incompatible LD renal transplantation using specific anti-A/B antibody (Ab) immunoadsorption (IA) and anti-CD20 monoclonal Ab (mAb) treatment. PATIENTS AND TREATMENT PROTOCOL: Recipients were blood group O (n = 12), A (n = 1) and B (n = 1). Donors were A1 (n = 2), A2 (n = 3), A2B (n = 1) and B (n = 8), and all were secretor positive. Anti-human leukocyte antigen (HLA) Ab panel reactivity was negative in all recipients except one. All recipients were pre-treated with 3 to 6 IA sessions, using A or B carbohydrate antigen columns, until their anti-A1/B RBC panel indirect antiglobulin test (IAT) titers were < or =8. CDC crossmatch was negative in all cases. Recipients received preoperative mycophenolic acid, and steroids/tacrolimus were started at transplantation. No splenectomy was performed. Eight recipients received one dose of anti-CD20 mAb (rituximab, 375 mg/m2) pre-operatively and 11 recipients had postoperative protocol IA. RESULTS: In the initial protocol, anti-CD20 mAbs were used only for recipients receiving A1 grafts. One B graft (HLA-identical donor, 84% panel reactivity) was lost in a severe anti-B Ab-mediated acute rejection. Subsequently, the protocol included anti-CD20 for recipients of both A1 and B grafts and postoperative protocol IA to all recipients. The subsequent 10 grafts had excellent function, giving a total graft survival of 13/14 (observation range 2 to 41 months). At 1 yr, mean serum creatinine was 113 micromol/l (n = 8) and mean glomerular filtration rate was 55 ml/min/1.73 m2 (range 24 to 77). In the remaining five cases, with less than 1 yr follow up, mean serum creatinine was 145 micromol/l at 2 to 9 months follow up. Pre-IA anti-A/B titers were in the range of 2 to 32 (NaCl technique) and 16 to 512 (IAT). More than 90 IA sessions were performed in 14 recipients without any significant side effects. Recipient anti-A/B titers returned after transplantation to pre-IA levels or slightly lower. Postoperative renal biopsies were performed in 10 patients. In the 13 patients with long-term function, one patient experienced cellular rejection (Banff IIB) at 3 months without anti-B titer rise. This rejection was concomitant with low tacrolimus plasma levels and was easily reversed by steroids. In 8 of 10 cases, C4d staining was positive in peritubular capillaries. CONCLUSION: Blood group ABO-incompatible LD renal transplantation using A and B carbohydrate-specific IA and anti-CD20 mAbs has excellent graft survival and function.     

Long-term follow-up ABO-incompatible adult living donor liver transplantation in cirrhotic patients

ABO-incompatible liver transplantation is usually contraindicated. The presence in the recipient of preformed anti-A/B antibodies located on endothelial cells raises the risk of antibody-mediated humoral rejection of the graft. We describe four successful cases of steroid withdrawal in adult patients who had living-donor liver transplantation from ABO-incompatible donors. Antirejection therapy included multiple perioperative plasmapheresis, splenectomy, and a triple immunosuppressive regimen with tacrolimus, methylprednisolone (MPSL), and cyclophosphamide or mycophenolate mofetil (MMF). The maintenance dose of immunosuppression did not differ from that of ABO-identical cases. After transplantation, intrahepatic arterial infusion therapy with prostaglandin E1 (PG E1) was used. As a result, all four patients were able to achieve long-term graft survival without steroid use. They all have good liver function and are leading normal lifestyles. Our experience with these four patients suggests the feasibility of controlling humoral rejection and other complications in adult ABO-incompatible living donor liver transplantations with intrahepatic arterial infusion of PGE1, splenectomy, and plasmapheresis with a regular base of immunosuppression protocol to prevent antibody-mediated humoral rejection.     

ABO-incompatible living donor liver transplantation: new insights into clinical relevance

Short-term outcome of the ABO-incompatible liver transplantation has been improved dramatically due to novel immnosuppressive protocols and apheresis. This review will discuss current understanding of the clinical relevance of ABO-incompatible liver transplantation including long-term outcome mainly from the Japanese experience.     

Lessons learned from ABO-incompatible living donor kidney transplantation: 20 years later

From June 1982 to November 1989, 39 ABO-incompatible living kidney transplants were performed in 38 recipients. Pretransplant therapies included platelets donor transfusion (21/39), 2 to 5 plasmapheresis sessions (39/39), cyclosporin A with or without azathioprine (33/39) along with polyclonal Abs (36/39) and splenectomy at the time of transplantation (37/39). The last patient who received 2 ABO-incompatible transplants was previously splenectomized (end-stage renal failure due to a cortical necrosis following a traumatic spleen rupture). Three other patients who did not undergo a splenectomy at the time of transplantation were not included in that series but hyperacutely rejected their transplants during the first postoperative week. The 31 ABO-incompatible living related donor graft recipients are alive. Graft loss occurred from acute and/or hyperacute rejection in 5 cases (none below 15 years of age) and from chronic rejection in 8 cases. By contrast, among the 8 ABO-incompatible living unrelated donor graft recipients, only one renal graft is still functioning 20 years later. Graft survival rates are better in the group of patients < 15 years (100%, 89%, 78%, and 78% at 2, 5, 10, and 15 years respectively) compared with the group > 15 years (77%, 77%, 64%, and 59% respectively; NS). Today, 20 years later, prospective randomized studies testing different steps in the preparation protocol are still lacking. Plasmaphereses were replaced by double filtration plasmapheresis and immunoadsorption. Splenectomy seems to be a prerequisite for successful ABO-incompatible living kidney transplantation but IV Ig globulins and rituximab are currently being successfully used without splenectomy along with the new immunosuppressive drugs. As the procedure remains unchanged, it might be reserved to patients where cadaver graft could not be a valuable alternative, especially for recipients < 15 years of age with a living related ABO-incompatible donor.     

ABO血型不合活体肝移植术后疗效的Meta分析

目的  系统评价ABO血型不合活体肝移植（ABO-I LDLT）术后的疗效,并与ABO血型相合活体肝移植（ABO-C LDLT）相比较。方法  系统检索国内外多个数据库,收集关于ABO-I LDLT及ABO-C LDLT疗效对比的文献。根据标准筛选文献,并进行文献质量评价,提取数据。采用Rev Man 5.3软件,应用随机效应模型或固定效应模型进行Meta分析。结果  检索文献432篇,按纳入标准筛选共纳入6篇英文文献。Meta分析结果表明ABO-I LDLT组与ABO-C LDLT组的受体及移植物术后1、3、5年存活率和排斥反应发生率差异均无统计学意义（均为P≥0.05）;ABO-I LDLT组术后胆道并发症发生率和肝动脉栓塞发生率均高于ABO-C LDLT组,差异均有统计学意义[比值比（OR）=2.08,95%可信区间（CI）1.25～3.45,P=0.005;OR=2.24,95%CI 1.03～4.89,P=0.04）。结论  与ABO-C LDLT相比,ABO-I LDLT疗效稍差,但仍是一种可供选择的治疗终末期肝病的有效手段。     

Characterization of the anti-A antibody binding in an ABO-incompatible living donor renal transplantation

A 57-year-old female, blood group B, with polycystic kidneydisease, received an ABO-identical, HLA-A,B,DR 5-mismatchedrenal allograft in 1986. Due to graft artery thrombosis andvascular rejection, she lost the kidney 6 months after transplantationand developed HLA antibodies with a panel reactivity of 99%.Despite 5 years on a European waiting list for highly immunizedpatients, she was not offered a second kidney. An attempt toremove her HLA antibodies by plasmapheresis combined with cyclophosphamidetherapy did not succeed. Her 53-year-old HLA-identical, butABO-incompatible sister (blood group A₁) was then accepted asa donor. After immunoadsorption on Biosynsorb-A columns, transplantationwas performed. The post-transplant course was uneventful withoutany signs of rejection. Studies on the anti-A antibody bindingcharacteristics before and after immunoadsorption and aftertransplantation, showed that IgM and IgG antibodies recognizingthe A trisaccharide epitope based on the type 1,2, and 4 coresaccharide chains, were effectively removed by Biosynsorb-Aadsorption, but the column failed to remove anti-A antibodiesrecognizing the A type 3 antigen. These antibodies probablyrequires part of the core saccharide chain for binding. Thepresence of these antibodies did not seem to influence the outcomeof the ABO-incompatible transplantation.     

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 x 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-immunoglobulin (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.     

活体肝移植进展(附视频)

1996年香港大学玛丽医院开展包含肝中静脉的活体肝移植,扩大了活体肝移植应用范围,全球活体肝移植逐渐增多。活体肝移植的开展能缓解尸体器官捐赠数不足时的肝移植需求。只要关注供者安全和受者预后,活体肝移植仍是目前终末期器官疾病患者一种可行的选择。活体肝移植的发展对移植和非移植肝脏手术均有贡献。     

The efficacy and safety of high-dose mizoribine in ABO-incompatible kidney transplantation using anti-CD20 and anti-CD25 antibody without splenectomy treatment

Background

Mizoribine (MZR) has been developed as an immunosuppressive agent in Japan, but it shows less potent immunosuppressive effects at doses up to 3 mg/kg/d. In this study, we investigated whether high-dose MZR (6 mg/kg/d) was effective for ABO-incompatible (ABO-i) living donor kidney transplantation (LKT) using treatment with anti-CD25 and anti-CD20 monoclonal antibodies without splenectomy.

Methods

Since 2007, we encountered 24 cases of ABO-i LKT using anti-CD20 and anti-CD25 monoclonal antibody without splenectomy. The pretransplant immunosuppressive regimen consisted of two doses of anti-CD20 antibody, mycophenolate mofetil (MMF), prednisolone, a calcineurin inhibitor (cyclosporine [7 mg/kg] or tacrolimus [0.2 mg/kg] and two doses of anti-CD25 antibody. Antibody removal by plasmapheresis was performed before LKT up to several times according to the antibody titer. The posttransplant regimen consisted of high-dose mizoribine (6 mg/kg/d) instead of MMF (MZR group, n = 12).

Results

The 1-year graft survival rates for the MZR and MMF groups were both 100%. The rejection rate in the MZR group (eight %) was not significantly higher than that in the MMF group (seventeen %) Serum creatinine level was not significantly different between the two groups. In the MZR group 6 (50%) patients developed CMV antigenemia-positivity versus 11 (92%) in the MMF group (P < .05). The number of patients who developed CMV disease was 0 in the MZR group and 1 (8%) in the MMF group. The number of patients treated with ganciclovir was 0% and 8%, respectively (not significant).

Conclusions

We obtain good clinical results with high-dose MZR in ABO-i LKT using anti-CD20 and anti-CD25 antibody treatment without splenectomy.     

活体肝移植的术前评估

随着外科技术的发展进步,活体肝移植的生存率不断提高,外科医生在活体肝移植手术前的评估工作与过去相比也更谨慎、细致.近年来,彩超、CT、MRI等先进影像学手段和肝穿刺活检等检查方法在评估工作中的普遍应用,使外科医生能更清楚地了解患者病情、供肝功能情况和内部解剖结构.本文就国内外对活体肝移植术前评估方法的研究进展做一综述.     

Small graft for living donor liver transplantation

OBJECTIVE: To evaluate the impact of graft size on recipients in living donor liver transplantation (LDLT) to establish a clinical guideline for the minimum requirement. SUMMARY BACKGROUND DATA: Although the minimum graft size required for LDLT has been reported to be 30% to 40% of graft volume (GV)/standard liver volume (SLV), the safety limit of the graft size was unknown. METHODS: A total of 33 cases of LDLT, excluding auxiliary transplantation, were reviewed with a minimum observation period of 4 months. The 33 patients were divided into three groups according to GV/SLV: medium-size graft group, small-size graft group, and extra-small graft group. The effect of GV/SLV on graft function, graft regeneration, and survival was evaluated. RESULTS: The overall patient survival rate was 94% at a mean follow-up of 15 months with a minimum observation period of 4 months. There were no statistically significant differences in postoperative bilirubin clearance, alanine aminotransferase, prothrombin time, and frequency of postoperative complications among the three groups. One week after transplantation, the regeneration rate (GV at 1 week/harvested GV) in the extra-small and small groups was significantly higher than that of the medium group. The graft and patient survival rates were both 100% in the extra-small group, 75% and 88% in the small group, and 90% and 95% in the medium group. CONCLUSIONS: Small-for-size grafts less than 30% of SLV can be used with careful intraoperative and postoperative management until the grafts regenerate.