Human Leukocyte Antigen Homozygosity Contributes to Sensitization in Kidney Transplant Candidates

Background: Homozygosity for human leukocyte antigens (HLA) has been associated with adverse outcomes after viral infection as well as pregnancy-induced HLA sensitization. We sought to assess the relationship between HLA locus homozygosity and the level of HLA antibody sensitization. Methods: We measured sensitization using the calculated panel reactive antibody (CPRA) value for a large cohort of 147,461 patients added to the US OPTN/UNOS kidney transplant waitlist between December 2014 and December 2019. We used multinomial logistic modeling to compare 62,510 sensitized patients to 84,955 unsensitized controls. Results: We found that the number of homozygous HLA loci was strongly associated with the level of sensitization. Within highly- or extremely-sensitized candidates, women displayed a higher relative abundance of HLA homozygosity at multiple HLA loci as compared to men, with attenuation of this effect in Black candidates. In multinomial logistic modeling, the number of homozygous HLA loci was an independent predictor of sensitization and interacted with female sex but not with other factors associated with sensitization. Conclusions: This study shows that HLA homozygosity is an innate genetic factor that contributes to HLA sensitization, and enhances the effect of pregnancy-related sensitization.