Kidney transplantation is a complex medical procedure whose long-term success relies heavily on biological compatibility between the donor and the recipient. The human immune system is designed to identify and eliminate anything foreign, including a transplanted organ that is not genetically similar enough to the recipient’s own tissues. Assessing this genetic compatibility is the purpose of Human Leukocyte Antigen (HLA) typing, which serves as the foundational step in the matching process. Without this analysis, the recipient’s body would quickly mount a powerful defense against the new kidney, making HLA typing paramount to ensuring the organ is accepted.
Defining Human Leukocyte Antigens
The Human Leukocyte Antigens are specialized proteins found on the surface of nearly every cell in the body. They function as a genetic identity tag, allowing the immune system to recognize which cells belong to the body and which do not. These proteins are encoded by genes located within the Major Histocompatibility Complex (MHC) on chromosome six. The HLA system is the most diverse and variable genetic system in humans, a phenomenon called polymorphism.
This high degree of variability makes finding a perfectly matched kidney challenging, especially between unrelated individuals. HLA genes are grouped into classes, with the most relevant for transplantation being Class I (HLA-A and HLA-B) and Class II (HLA-DR). Each person inherits one set of these genes from each parent, resulting in two versions, or alleles, for each major locus. This inheritance pattern results in millions of possible combinations across the population.
The immune system uses these unique protein markers to differentiate between “self” and “non-self.” When a kidney is transplanted, the HLA proteins on the donor organ are seen as foreign markers by the recipient’s immune cells. The same biological function that protects a person from infection is what threatens the transplanted kidney.
How HLA Differences Trigger Organ Rejection
When a donor kidney is placed into a recipient, differences in HLA markers signal danger to the recipient’s immune system. Specialized white blood cells, such as T-cells, quickly detect the unfamiliar HLA proteins on the new organ. These T-cells become activated, initiating a cellular attack intended to destroy the foreign tissue, which causes organ rejection.
The primary concern addressed by HLA typing is the risk of acute rejection, which occurs most often within the first few months after transplantation. This rejection involves the rapid mobilization of T-cells and the production of antibodies targeting the donor HLA markers. The intensity of this acute response is directly related to the number of HLA differences, or mismatches, between the donor and recipient. A higher number of mismatches leads to a more vigorous immune attack on the kidney.
A successful HLA match reduces the intensity of the immune response, minimizing the amount of powerful immunosuppressive medication the recipient needs. While these medications are necessary to prevent rejection, they carry significant side effects. The goal of matching is to minimize the “foreignness” of the new organ, lowering the long-term biological burden on the patient. A better HLA match is associated with a longer-lasting kidney.
The Process of HLA Typing and Matching
HLA typing is a specialized laboratory procedure that identifies the specific set of HLA genes in both the potential donor and the recipient. The process begins with a simple blood sample, which is analyzed using molecular methods to determine the specific HLA alleles present. For kidney transplantation, the focus is on matching the two alleles for HLA-A, HLA-B, and HLA-DR, resulting in a total of six markers.
The results are communicated using a “matching score,” which reflects the number of mismatched antigens out of the six markers examined. A perfect match is 0/6, meaning all six markers are identical between the donor and the recipient. The worst possible match is 6/6, meaning none of the six primary markers are shared. A 0/6 match is ideal but exceedingly rare outside of identical twins.
The matching score helps transplant teams and organ registries prioritize recipients on the waiting list. For deceased donors, the kidney allocation system uses these scores to offer the best possible match to the most compatible recipient. Although a high degree of matching is preferred, successful transplants can occur with less than a perfect score due to advances in anti-rejection medications. However, a lower number of mismatches correlates with better long-term kidney survival.
Final Screening Steps Before Transplantation
Once a potential donor and recipient show acceptable HLA compatibility, two final tests are performed to confirm that immediate rejection will not occur. The first is the Panel Reactive Antibody (PRA) test, which measures the recipient’s level of sensitization. This test assesses how many different HLA types the recipient’s immune system has already developed antibodies against, often due to previous blood transfusions, pregnancy, or failed transplants.
The PRA result is expressed as a percentage. A high percentage indicates the recipient is highly sensitized and will have greater difficulty finding a compatible donor. A high PRA suggests the recipient is pre-primed to reject a large percentage of the general donor pool, guiding the search for a kidney lacking the specific HLA markers the recipient is armed against.
The second hurdle is the crossmatch test, performed immediately before surgery. This test mixes the recipient’s blood serum (containing antibodies) with cells from the donor organ. If the recipient’s antibodies immediately attack and destroy the donor cells in the lab, the crossmatch is positive, and the transplant must not proceed. A positive crossmatch signifies pre-formed antibodies that would cause hyperacute rejection, resulting in the immediate destruction of the new kidney.