Patel and Terasaki showed in 1969 that a positive cytotoxic crossmatch between a patient and donor due to pre-formed donor specific HLA antibodies (DSA) was associated with hyperacute rejection in kidney transplantation. This lead to a positive cytotoxic crossmatch becoming an absolute contraindication to transplantation in the absence of antibody removal. More recently however, improvements in immunosuppression and antibody definition have lead to a shift from a simplistic Pos/Neg. veto on transplantation to one of an assessment of the immunological risk posed.
HLA antibodies are known to contribute to all categories of rejection, including the Hyperacute, Accelerated, Acute and Chronic phases. Hyperacute rejection occurs within minutes and is due to pre-formed DSA present at the time of transplantation. Accelerated rejection takes place within days and is usually due to a memory or anamnestic response to pre-formed DSA which are absent at the time of transplantation. Acute rejection occurs within days or weeks and is usually due to de-novo DSA. Terasaki and others have also demonstrated a role for DSA in chronic rejection, though the timing of antibody formation and chronic rejection do not always coincide.
Consideration of the immunological risk associated with kidney transplantation needs to take into account the timing, duration, priming source, titre and specificity of any DSA. Antibodies formed as a result of transfusion are often IgM and IgG and may not be long lasting. Antibodies formed after transplantation or pregnancy are often IgG and involve immunological memory.
Gebel et al have proposed three levels of immunological risk associated with kidney transplantation, High, Intermediate and Low. In the UK, these categories have been incorporated into the BHSI/BTS guidelines on clinically relevant alloantibodies. Though the guidelines deal mainly with anti-HLA antibodies, other antibodies such as anti-ABO and anti-endothelial cell antibodies are also relevant.
High immunological risk is indicated when the patient has circulating antibodies specific for mismatched donors HLA antigens. An example is a T + B cell Complement Dependent Cytotoxicity (CDC) current sample positive crossmatch in the presence of HLA class I DSA. This carries a high risk of Hyperacute rejection in the absence of desensitisation. Another example of a High risk transplant is a B cell CDC current sample positive crossmatch in the presence of HLA class II DSA. Transplants can also be high risk if only the historical sample is positive. For example a T + B cell CDC historical sample positive, current sample negative crossmatch in the presence of HLA class I DSA or a B cell only CDC historical sample positive, current sample negative crossmatch in the presence of HLA class II DSA are both High risk. Both have the potential to trigger an anamnestic or memory T and/or B cell response resulting in Accelerated rejection. In most cases, High risk transplants would be avoided unless as part of a validated desensitisation program.
Intermediate immunological risk is indicated by a flowcytometry positive, CDC negative crossmatch result with both current and historical samples in the presence of HLA class I DSA. Examples include T + B cell flow Pos, CDC Neg. current and historical samples in the presence of HLA class I DSA. Another example of an Intermediate risk transplant is a B cell only positive CDC current and historical sample in the presence of weak IgG HLA class I DSA.
With Intermediate risk transplants, a clinical assessment is needed on the relative risk of proceeding to transplant with augmented immunosuppression and close post transplant monitoring versus remaining on the waiting list in the hope of obtaining a better match or taking part in a paired exchange if a live donor is available. Patients do die on the waiting list. The decision to transplant will be influenced by the experience of the transplant team and the H&I laboratory when it comes to monitoring and managing such patients, as well as the length of time the patient has already been on the waiting list, the cPRA and the matchability of the patient.
Low immunological risk is indicated when the crossmatch result is negative and the patient is unsensitised. Low immunological risk is also indicated when the crossmatch result is negative, even if the patient is sensitised, provided the sensitisation is clearly shown to be IgM only, is clearly shown to be Auto only or is otherwise considered to be non HLA.
Low immunological risk is also indicated when the crossmatch result is negative and any HLA antibodies present in the current and historical samples of the patient are not donor specific. In addition, Low immunological risk is also indicated when the crossmatch result is negative and any HLA class I or II IgG DSA detected in either the current or historical samples of the patient are detectable by Luminex SABs only.
Finally Low immunological risk is indicated when the crossmatch result is positive but the patient is either unsensitised or any HLA antibodies present in the current and historical samples are not donor specific.
Assessment of the immonological risks associated with a transplant requires close co-operation between the H&I laboratory and the transplant team. The lab should be informed of all potential sensitising event, including previous transplants, skin grafts, transfusion, pregnancies, miscarriages if known and recent infections or vaccinations. The laboratory crossmatch report to the transplant team should include appropriate advice on the clinical relevance of the results.
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