What are Human Leukocyte Antigen (HLA), Donor-Specific Antibody (DSA), crossmatch, and Panel Reactive Antibody (PRA) in the context of kidney transplantation?

Understanding HLA, DSA, Crossmatch, and PRA in Kidney Transplantation

These four concepts form the immunologic foundation of transplant compatibility assessment, working together to predict and prevent rejection by identifying the recipient's immune barriers to accepting a donor organ. 1

HLA (Human Leukocyte Antigen)

HLA molecules are proteins on cell surfaces that serve as the body's identification system—they're what the immune system uses to distinguish "self" from "foreign." 1

• HLA molecules are inherited from both parents and are expressed on the surface of all nucleated cells 2
• The main HLA loci evaluated in transplantation are HLA-A, HLA-B, HLA-DR, and increasingly HLA-DQ 1
• Each person has two copies of each HLA gene (one from each parent), creating a unique HLA "fingerprint" 2
• Better HLA matching between donor and recipient reduces rejection risk by 13-64% depending on the number of mismatches 1
• HLA-DQ mismatches are particularly problematic—they're the most common target for antibody formation after transplant, with 54-77% of de novo antibodies targeting HLA-DQ molecules 1, 3

DSA (Donor-Specific Antibodies)

DSAs are antibodies in the recipient's blood that specifically recognize and attack the donor's HLA molecules—they're the immune system's "wanted posters" for the transplanted organ. 1

• DSAs can exist before transplant (from prior transplants, blood transfusions, or pregnancy) or develop de novo after transplant 1, 2
• Preformed DSAs are a major contraindication to transplantation as they cause immediate antibody-mediated rejection 4
• Up to 30% of recipients develop de novo DSA within 10 years, and 40% of these patients lose their grafts within 5 years of DSA development 1
• DSAs cause chronic antibody-mediated rejection, which accounts for over half of long-term kidney graft failures 1
• The presence of DSAs leads to increased sensitization, making future transplants progressively more difficult 1

Crossmatch

The crossmatch is the final "go/no-go" test performed immediately before transplant—it directly mixes the recipient's serum with donor cells to detect preformed antibodies that would cause immediate rejection. 4

• A positive crossmatch with IgG antibodies to HLA antigens is an absolute contraindication to transplantation, regardless of how good the HLA matching appears 4
• Two main types are performed: complement-dependent cytotoxicity (CDC) and flow cytometry crossmatch 4
• Flow cytometry is more sensitive and can detect lower levels of antibodies 4
• A negative crossmatch is mandatory before proceeding with transplantation 4
• IgM antibody positivity alone does not contraindicate transplantation 4
• The crossmatch serves as the ultimate safety check—even with good HLA matching, hidden antibodies can still cause hyperacute rejection 4

PRA (Panel Reactive Antibody)

PRA is a percentage that tells you how "sensitized" a patient is—specifically, what percentage of potential donors in the population would be incompatible due to the patient's existing HLA antibodies. 1

• A PRA of 80% means the patient has antibodies that would react against 80% of potential donors, leaving only 20% of donors as compatible options 1
• PRA is calculated by testing the patient's serum against a standardized panel of HLA-typed donors 1
• Higher PRA values dramatically increase wait times and reduce transplant access 1
• Modern calculation uses "calculated PRA" (cPRA), which compares the patient's antibody profile against a database of 10,000 HLA-typed donors 1
• Patients who lose their first transplant often become highly sensitized (PRA >50%), making retransplantation extremely difficult 3
• Antibodies can cross-react—a patient with antibodies to HLA-B57 may also react to HLA-A2, A23, and B58, potentially blocking up to 75% of donors 1

How They Work Together

The clinical workflow integrates all four concepts sequentially: 4

1. HLA typing identifies both donor and recipient HLA molecules to assess compatibility 1, 4
2. PRA testing reveals the recipient's existing antibody profile and calculates what percentage of donors would be incompatible 1
3. Virtual crossmatch predicts compatibility by comparing donor HLA with recipient antibodies before physically testing 5
4. Physical crossmatch provides final confirmation that no preformed DSAs exist against this specific donor 4
5. Post-transplant DSA monitoring detects de novo antibody formation that threatens long-term graft survival 1, 3

Critical Clinical Pitfalls

The most important caveat is that good HLA matching doesn't guarantee a negative crossmatch—patients can have antibodies to HLA antigens not included in standard matching algorithms. 4

• HLA-DQ matching is often overlooked but critically important—most allocation systems don't adequately account for it despite its role in the majority of antibody-mediated rejections 1, 3
• Young patients are disproportionately affected by sensitization because they're more likely to need multiple transplants in their lifetime 1
• Each failed transplant increases sensitization, creating a vicious cycle that makes subsequent transplants progressively harder 1, 3