HLA Matching of Blood Components for Solid Organ Transplant Recipients
Transfusion-associated immunosuppression has been well documented. Suppression of cytotoxic T-lymphocytes may play a role in graft survival. Other suggested mechanisms include the development of anti-idiotype antibodies or pre-transplant selection. Prior to the era of immunosuppressive drugs, clinical studies found that blood transfusion enhanced renal graft survival. This response was transfusion dose-dependent and white cell-depleted red cells were less effective in promoting graft survival. These results led to the consideration of blood transfusion as a strategy to improve graft survival in transplant recipients. With the rapid improvement in immunosuppression therapy, the additional effect of transfusion became marginal. The practice of infusion of one unit of donor’s blood preoperatively for immunomodulation is no longer practiced.
ABO grouping is still the primary test for organ donation and transplantation. The first and foremost step in graft rejection is the binding of anti-A and anti-B antibodies to endothelial cells. This binding initiates a cycle of complement fixation, vascular damage, and thrombosis that leads to ischemia and rejection. ABO incompatible liver transplants are less susceptible to hyper-acute rejection than are other organs but the risk of eventual rejection is still high.
Matching for Class 1 and Class 2 major histocompatibility antigens (A, B, and DR) is associated with significant improvement in graft survival after heart, kidney and pancreas transplantation, even with the use of immunosuppressant drugs. Kidney and pancreas transplants, together or separate, must be HLA Class I (T lymphocyte) crossmatch-compatible. HLA matching is rarely undertaken for liver transplantation because early studies failed to show any benefit in graft survival.
Non-hepatic transplant candidates are evaluated for a history of HLA exposure through pregnancy, transfusion, or prior transplant. Among patients who are waiting for a kidney transplant in the U.S., approximately 14% are sensitized to HLA antigens due to exposures from prior transplants, transfusions or pregnancies.
Primary cardiac transplant without prior cardiac surgery poses less risk of alloimmunization toward HLA or red cell antigens. After prior coronary artery bypass surgery, leukocyte antibodies have been found in 10 to15% and red cell antibodies in 3 to 5% of patients. Heart transplantation requires similar transfusion support as coronary artery bypass surgery. In primary transplants, 0 to 2 units of red cells are required. Twice this amount is generally needed when there has been prior surgery. In particular, patients who have left ventricular assist devices (LVADs) implanted as a bridge to transplantation need multiple blood components and approximately 30% develop HLA antibodies, reducing the chance of a cross match-negative graft. DR-shared heart transplants have a better outcome than DR-mismatched grafts
HLA antibodies formed in the recipients against the transplanted organ play a major role in the graft rejection. These antibodies should be removed from the recipient’s circulation as far as possible. Options for antibody depletion in sensitized patients include plasma exchange with or without antibody adsorption columns; intravenous immunoglobulin (IVIG); monoclonal antibodies, e.g. rituximab; and other immunosuppressive drugs.
HLA antigens are present on both platelets and white blood cells. RBCs do not express HLA antigens, but Bennett-Goodspeed antigens may occasionally be present and lead to HLA alloimmunization. Today, all RBC transfusions are leukocyte reduced. Leukocyte reduced RBC units reduces the incidence of febrile nonhemolytic transfusion reactions and transmission of leukotropic viruses such as CMV.
Even though leukocyte reduction filters remove 99.9% of white blood cells, leukocyte reduced RBC units still may contain up to 5 million lymphocytes and stimulate HLA antibody formation against Class 1 and Class 2 HLA epitopes. Apheresis platelet transfusions contain less than 5 million lymphocytes and are considered to be leukocyte reduced. Transfusion of platelets may lead to formation of HLA antibodies directed against Class 1 HLA epitopes. HLA sensitization from transfusion is less robust and generally shorter lived than sensitization from transplantation. However, regardless of the route of sensitization, IgG HLA antibodies to a transplanted organ negatively impact graft function and survival. The use of these leukocyte-reduced products should be restricted for prospective renal and heart transplant patients.
Patients who are transfused while on the waiting list for a solid organ transplant are more likely to form HLA antibodies. Transfusion increases the breadth and strength of HLA antibodies in sensitized patients. Transfusion can increase patients' calculated panel reactive assay (cPRA) and make it more difficult to find compatible donor organs. The University of Minnesota reported in 2017 that approximately 25% develop at least one additional high threshold HLA antibody. Patients that developed HLA antibodies with MFI>3000 had a greater risk of treatment for rejection within the first post-transplant year.
CMV seronegative patients receiving seronegative organs should receive CMV safe blood products (leukocyte-reduced or from CMV seronegative donors). There is no documented benefit to providing CMV safe products to patients who are already CMV seropositive.
Transfusion-associated graft vs. host disease is rare (only 4 published cases) despite immune suppression. Therefore routine irradiation of blood components for solid organ transplants is not recommended on a routine basis. Irradiation of RBCs damages cell membranes and increases potassium leakage, which can increase the risk of hyperkalemia, especially in patients with poor renal function and metabolic acidosis.
