Which eplets are most important to consider in kidney transplants?

Most Important Eplets for Kidney Transplantation

HLA-DQ eplets are the most important to consider in kidney transplantation as they confer the highest risk for donor-specific antibody formation, rejection, and graft failure compared to other HLA loci. 1, 2

Hierarchy of Eplet Importance in Kidney Transplantation

Primary Importance: HLA-DQ Eplets

• HLA-DQ eplets have the strongest association with adverse transplant outcomes with a hazard ratio of 1.411 for graft failure 3
• DQ eplets show a linear relationship with de novo donor-specific antibody (DSA) formation without a safe threshold 2
• Each antibody-verified DQ eplet mismatch increases the odds of antibody-mediated rejection by 12% 2
• The relationship between eplet mismatches and rejection is particularly strong for the HLA-DQ locus, which has been shown to be especially immunogenic 1

Secondary Importance: HLA-DR Eplets

• HLA-DRB1 eplets have the second highest impact with a hazard ratio of 1.268 for graft failure 3
• Even in subcohorts without HLA-DQB1 mismatches, HLA-DRB1 eplet mismatches independently predict graft failure (HR 1.384) 3
• HLA-DRB1 eplet mismatches are strong independent predictors of transplant glomerulopathy (HR 5.511) 3

Tertiary Importance: HLA Class I Eplets (HLA-A, B, C)

• Class I eplets (HLA-A, B, and C) have a hazard ratio of 1.231 for graft failure 3
• While still important, these have less impact on outcomes compared to Class II eplets

Clinical Implications for Transplantation

Risk Assessment

• High eplet mismatch load (≥20 eplets) is associated with a 2.16-fold increased risk of acute rejection compared to 0-2 eplet mismatches 4
• Even in recipients traditionally considered low immunological risk (0-2 broad antigen HLA-ABDR mismatch), those with ≥20 eplet mismatches have an 85% higher risk of rejection 4
• High eplet exposition (≥0.40 according to René Duquesnoy's classification) significantly increases the risk of developing DSAs and subsequent graft failure 1

Immunosuppression Considerations

• Patients with high eplet mismatches require more careful monitoring and potentially higher levels of immunosuppression 1
• Intermediate and high-risk patients based on eplet exposition need adequate tacrolimus levels (>8 ng/ml vs <6 ng/ml) to reduce risk of developing DR/DQ de novo DSA 1
• Belatacept-based immunosuppression may modify the risk associated with eplet mismatches, showing decreased rates of DSA formation (HR 0.4) and antibody-mediated rejection (HR 0.2) compared to tacrolimus alone 5

Organ Allocation Implications

• Current allocation systems generally prioritize matching for HLA-A, HLA-B, and HLA-DR antigens 6
• Only the British National Health System Blood and Transplant considers 5 HLA loci (HLA-A, HLA-B, HLA-Cw, HLA-DR, and HLA-DQ) for matching purposes 6
• The French system introduced HLA-DQ matching in 2015, allocating 100 points for full DQ matching 6

Practical Challenges in Eplet Matching

• Implementation requires allele-level donor genotyping for multiple HLA loci at the time of organ allocation 7
• Standardization of methods to verify eplets as determinants of immune-mediated injuries is needed 7
• Balancing eplet matching with other allocation priorities such as waiting time and geographic considerations remains challenging 6

Key Takeaways for Clinical Practice

• Focus on minimizing HLA-DQ eplet mismatches as the highest priority when possible
• Consider eplet matching particularly for sensitized patients and those likely to need future transplants
• Use eplet mismatch load to stratify immunological risk and personalize immunosuppression protocols
• Recognize that molecular matching for DQA1 and DQB1 alleles could help minimize de novo DSA formation and potentially improve outcomes 2