ABO Incompatibility: Indications and Management

Introduction

The transplantation of ABO-identical or ABO-nonidentical ABO-compatible grafts has for decades been the mainstay of organ transplantation. As post-transplant survival improves and the demand for organ transplants grows, several attempts have historically been made to transplant liver grafts from ABO-incompatible (ABOi) donors, particularly in emergency situations, both in children and adults.

Historically, the transplantation of the kidney first broke the ABO blood group barrier, and since then, various therapeutic modalities have been introduced. In the 1980s and early 1990s, several trials of ABOi liver transplantation showed that the post-operative course was very poor, mainly because of severe rejection crises, thrombosis of the hepatic artery, and/or intrahepatic bile duct injury. Continuous improvement in liver transplantation and improved immunosuppression methods during the last decades brought back interest in more common use of ABOi grafts. A small number of cases reported by single centers showed good early results of ABOi transplantations. Since then, more ABOi liver transplantations have been performed, particularly in pediatric but also in adult recipients of the grafts from living donors under various protocols aimed at preventing typical complications resulting from blood group incompatibility. Improved immunosuppression has markedly decreased antibody-mediated rejection (AMR) and biliary complications but has increased infectious complications, which are now the major cause of morbidity and mortality after ABOi liver transplantation, but the outcome of ABOi liver transplantation has improved dramatically and now is similar to that of ABO blood type–matched transplantation.

To understand, however, the complex problems of ABOi organ, and particularly liver transplantation, one must take into consideration the basic immunological response for the ABOi organ developing within the liver graft and the differences between adults and children, as well as between infants and older children.

There are several differences between adults and children concerning the response to ABOi graft transplantation. Many reports show better outcomes in ABOi liver transplantation in infants. In early childhood, anti-A and anti-B antibody titers remain low because infants have limited ability to produce isohemagglutinins. Additionally, the activation of their complement system is suppressed. That is why AMR is not observed in children younger than 1 year of age and even up to 2 years.

In the clinical situation, there is a difference between emergency or elective transplantation and between the transplantation from a living donor or a deceased donor, particularly concerning the possibility of pretransplant treatment of the recipient. Therefore there is no single and best treatment protocol to propose as a standard.

Basic Pathophysiology and Pathological Findings

There are several responses triggered by antigen-antibody reactions between donor blood antigens on the graft and antibodies in the recipient’s serum. AMR initiates damage to ABOi liver graft by preformed isoagglutinins later triggered by antibodies produced by proliferating B cells activated by ABO antigens in the donor graft. ABO blood group antigens are expressed on all hepatic endothelial cells (vessels and bile ducts). The expression of human leukocyte antigens (HLA) class I (HLA-A or B) is weaker on hepatocytes, and HLA-DR class II expression is strongest on dendric cells (portal, perivenular, subcapsular) and Kupffer cells. The damage to the endothelial cells is caused by the production of cytokines, chemotactic factors, free radicals, and, later on, platelet and complement activation. It is followed by thrombus formation, migration of granulocytes and macrophages, and phagocytosis.

Complications that may develop with increased risk in patients after ABOi liver graft transplantation are multiple. The most rapid is the development of superacute or early acute AMR with a clinical course of intragraft disseminated intravascular coagulation (DIC), massive intrahepatic microcirculation thrombosis leading to hemorrhagic graft necrosis within a few days or weeks. The same mechanisms may be responsible for an increased incidence of hepatic artery thrombosis among recipients of ABOi liver transplants, which occur in up to 24% of these patients ( Figs. 9.1, 9.2, and 9.3 ).

This phenomenon is age dependent because production of anti-A/B isoagglutinins begins 3 to 4 months after birth and achieves the adult level between 4 and 7 years of age, whereas expression of A/B antigens in young children is lower. It explains, at least partially, the clinical observation that hyperacute or early AMR is almost nonexistent in infants and children younger than 2 years undergoing ABOi liver transplantation. The same was shown in heart transplantation in children.

There are also significant differences between the immunogenicity of grafts from A2 donors (about 20% of the population with blood group A) and from A1 or B donors because expression of A2 antigen is much weaker, and non-A group recipients possess a much lower titer of anti-A2 isoagglutinins. Therefore, differentiation of A donors to subgroups may be important in the elective living donor ABOi transplantations and the choice of perioperative immunosuppression.

Kishida et al. described the increased risk of development of thrombotic microangiopathy (TMA) in ABOi liver transplantation (LT) recipients. TMA is caused by the destruction of the microvascular endothelium and primary aggregation of platelets. It is demonstrated by thrombocytopenia and microangiopathic hemolytic anemia. Endothelial injury results in the release of large amounts of von Willebrand factor, which enhances adhesion of platelet formation of microthrombi.

The second common complication of ABOi liver transplantation is diffuse damage to the biliary tree, resulting in the development of multiple intrahepatic biliary stenoses. This complication usually develops within the first 3 months after transplantation and is also caused by immunological mechanisms related to humoral reactions because the donor blood group antigens are present on the epithelium of the graft bile ducts for about 3 to 6 months after transplantation ( Fig. 9.4 ). Some authors reported that high perioperative titers of specific anti-A/B antibodies are connected with acute hepatic necrosis (immunoglobulin G [IgG] isoagglutinins) and biliary complications (IgM isoagglutinins), as well as both immunoglobulins’ high post-operative titers.

All of the abovementioned complications usually lead to graft loss and the need for retransplantation or the patient’s death. In children, the incidence is very much age dependent; the lowest risk is in infants under 1 year of age, and the larger is in children older than 8 years of age.

The main characteristic pathological finding includes the deposition of antibody to sinusoidal and arteriolar endotheliums and hemorrhagic necrosis of the liver parenchyma. Periportal edema and necrosis seem to be the histological indication of an early phase of severe humoral rejection, causing massive parenchymal or biliary necrosis. The resulting vascular thrombosis causes graft ischemia, whereas bile duct strictures result in severe cholestasis. C4d staining facilitates an AMR diagnosis and should always be carried out when acute or chronic AMR is suspected. The Banff Working Group recommends C4d staining of frozen tissue immunofluorescence as well as of formalin-fixed, paraffin-embedded tissue using rabbit polyclonal or monoclonal antigen in several compartments (portal veins, portal capillaries, portal stroma, sinusoidal, and central vein endothelium). The result may be negative, minimal (< 10%), focal (10%–50%), and diffuse if more than 50% of structures are involved. Although C4d-positive staining is not a pathognomonic feature of AMR, detection of C4d has both a diagnostic and prognostic value and may be a hallmark of AMR in liver biopsies ( Fig. 9.5 ).

Strategies to Overcome ABO Incompatibility in Liver Transplantation

According to Warner’s statement, there are three preconditions for long-term survival of ABO-incompatible solid organ allografts:

• -

  low expression of antigen on the graft (as in the case of A2-positive organs, or organs from deceased young pediatric donors)

• -

  low titer of antidonor A/B antibodies in the recipient before transplantation

• -

  ability to maintain low titers of antidonor A/B antibodies in the recipient for at least 3 to 6 weeks after transplantation until a state of accommodation develops.

All these preconditions are necessary to prevent the development of early AMR in recipients of ABOi liver grafts. The safe recipient’s titers of anti-A/B isoagglutinins are considered to be 1:16 or less in the majority of publications, whereas titers 1:64 or above should be considered as a contraindication for ABOi transplantation. Because the anti-A/B antibody titer may increase early after transplantation, it should be monitored and adequately treated for the critical period of at least 6 weeks after transplantation. Several measures have been proposed and introduced historically to fulfill Warner’s conditions, and then various strategies combining these measures were proposed depending on the urgency of the transplant and type of donor. In an elective transplantation from a living related donor, treatment of the recipient may be started several days or even weeks before the transplant takes place, whereas in emergency transplantation or even elective transplantation with a graft from a deceased donor, pre-transplant treatment is limited to a few hours at most.

The measures used in the prevention of AMR of ABOi graft can be categorized into the following according to their effects:

• 1.

  Procedures aiming at B-cell depletion

  • i.

    splenectomy

  • ii.

    rituximab

  • iii.

    basiliximab

• 2.

  Procedures resulting in inhibition of antibody production

  • i.

    intravenous immunoglobulins (IVIG)

• 3.

  Procedures eliminating anti-A/B antibodies

  • i.

    nonselective or semiselective plasmapheresis

  • ii.

    selective apheresis: immunoadsorption (IA)

• 4.

  Graft local treatment to prevent single-organ DIC

  • i.

    portal vein infusion therapy

  • ii.

    hepatic artery infusion therapy

Procedures Aimed at B-Cell Depletion

Procedures of B-cell depletion should be introduced early enough before transplantation to effectively suppress antibody production and prevent the development of AMR, which, once started, may be very difficult to reverse, leading to graft loss.