Background

The number of HLA-DR eplet mismatches (eplet load) is a risk factor for the development of anti-HLA antibodies and transplant glomerulopathy (TG). In the case of TG, our group has recently demonstrated an odds ratio (OR) of 1.63 (95% confidence interval (95% CI): 1.14, 2.33, p = 0.008) for the development of TG per 10 HLA-DR eplet mismatches. Using the same study sample, the current analysis sought to ascertain whether HLA-DR eplet load limited to immunogenic HLA-DR eplets confers an even greater risk for TG and to ascertain whether a particular risk threshold of eplet load can be identified.

Methods

In a nested case-control study, patients with TG (N=52) were matched with randomly selected controls from the underlying cohort who had a similar follow-up time from transplantation (N=104). HLAMatchmaker was used to ascertain HLA-DRB1/3/4/5 eplet load from HLA types obtained using molecular methods with 4-digit HLA-types assigned from the catalogue of common and well-documented alleles. Immunogenic HLA-DR eplets were defined as either antibody-verified eplets from the HLA epitope registry (http://epregistry.com.br) or as eplets corresponding to Terasaki epitopes (TerEp). The OR of developing TG per 10 additional HLA-DR immunogenic eplets was assessed by multivariable conditional logistic regression models. Restricted cubic splines were used to flexibly capture the continuous relationship between immunogenic HLA-DR eplet load and TG and to evaluate for a threshold effect.

Results

An adjusted OR of 2.11 (95% CI: 1.23, 3.63, p = 0.007) was identified for the development of TG per 10 additional antibody-verified HLA-DR eplet mismatches. When immunogenic eplets were defined as HLA-DR eplet mismatches corresponding to TerEps, an adjusted OR for TG of 3.55 (95% CI: 1.42, 8.91, p = 0.007) per 10 additional eplet mismatches was found. Models considering antibody-verified HLA-DR eplet load or HLA-DR eplet load corresponding to TerEps as linearly associated with the risk of TG demonstrated better model fit than non-linear functions derived from restricted cubic splines.

Conclusion

Immunogenic HLA-DR eplets, defined as eplets corresponding to TerEps or antibody-verified eplets pose a quantitatively greater risk for TG in comparison to the overall eplet load. Avoiding immunogenic HLA-DR eplet mismatches between donors and recipients may be an effective means of reducing the risk of TG.

CITATION INFORMATION: Blum D, Tinckam K, Marrari M, Kim J, Sapir-Pichhadze R. Immunogenic HLA-DR Eplet Mismatches as Predictors of Transplant Glomerulopathy. Am J Transplant. 2016;16 (suppl 3).

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