What is the cutoff for eplet mismatch for someone considered a good match for kidney donation?

HLA Eplet Mismatch Cutoffs for Kidney Donation

The optimal cutoff for HLA eplet mismatch in kidney transplantation is <20 total eplet mismatches, with particular emphasis on minimizing HLA-DQ eplet mismatches to <7, as these thresholds are associated with significantly lower risk of rejection, donor-specific antibody formation, and graft failure. 1, 2, 3

Understanding HLA Matching and Eplet Mismatches

HLA matching remains a critical factor in kidney transplantation outcomes despite advances in immunosuppression. While traditional matching focuses on HLA-A, HLA-B, and HLA-DR antigens, emerging evidence highlights the importance of eplet-based matching as a more refined approach 4:

• Eplets are small patches of surface-exposed amino acids on HLA molecules that serve as potential targets for antibody responses 5
• Traditional antigen matching may miss important immunogenic differences that eplet analysis can detect 2
• Each additional eplet mismatch increases the risk of rejection in a dose-dependent manner 1, 5

Specific Eplet Mismatch Thresholds

Total Eplet Mismatches

• Recipients with ≥20 total eplet mismatches have 2.16 times higher risk of acute rejection compared to those with 0-2 eplet mismatches 2
• Even in patients considered low immunological risk by traditional matching (0-2 broad antigen HLA-ABDR mismatch), those with ≥20 eplet mismatches experience 1.85 times increased rejection risk 2

Class II (HLA-DR and HLA-DQ) Eplet Mismatches

• HLA class II eplet mismatches, particularly HLA-DQ, are most strongly associated with adverse outcomes 5
• High HLA-DQ eplet mismatch load (≥7) is associated with significantly higher risk of antibody-mediated rejection compared to low mismatch load (0-1) 3
• High HLA-DR eplet mismatch load (≥6) similarly increases antibody-mediated rejection risk 3
• The effect of HLA eplet load on donor-specific antibody formation and graft failure is primarily mediated by eplet mismatches in the HLA-DQ locus 5

Clinical Implications of Exceeding Eplet Mismatch Thresholds

Exceeding these eplet mismatch thresholds has significant consequences:

• 54-77% of patients with de novo donor-specific antibodies develop antibodies against HLA-DQ 4
• These antibodies are associated with antibody-mediated rejection, transplant glomerulopathy, and graft loss 4
• Patients with two HLA-DQ mismatches who experience graft failure often become highly sensitized (>50%), making re-transplantation more difficult 4, 1
• Each additional mismatch at critical HLA loci can reduce survival by 5-10% depending on disease risk status 1

Monitoring and Management Based on Eplet Mismatch Load

When eplet mismatches exceed recommended thresholds, consider:

• More intensive immunosuppression protocols 1
• More frequent monitoring for donor-specific antibodies: weekly for the first month, monthly for 6 months, then quarterly 1
• Protocol biopsies to detect subclinical rejection, especially in the first year 1
• Higher target levels of maintenance immunosuppression 1

Important Caveats and Considerations

• No absolute "safe" threshold exists for HLA-DQ eplet mismatches; the relationship appears linear 5
• Medication adherence and lower donor-specific antibody strength (MFI <3000) may mitigate some risk in patients with high eplet mismatch loads 6
• Current allocation systems vary in how they prioritize HLA matching, with some (like Eurotransplant) giving substantial weight to matching and others (like UNOS) giving less emphasis 4
• Balancing equity of access with optimizing outcomes remains challenging, as strict HLA matching requirements can disadvantage certain ethnic groups 4