HLA Homozygosity and Likelihood of Sensitization in Kidney Transplant Candidates

Abstract

Background. Homozygosity for HLAs 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 value for a large cohort of 147 461 patients added to the US OPTN/United Network for Organ Sharing 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 mildly, highly, or extremely sensitized candidates, women displayed a higher relative abundance of HLA homozygosity at multiple HLA loci as compared with men, with attenuation of this effect in Black candidates. In a multivariable logistic model, the number of homozygous HLA loci interacted with female sex but not with other factors associated with sensitization, including recipient ethnicity and a history of prior kidney transplant. Conclusions. This study shows that HLA homozygosity is an innate genetic factor that affects the likelihood of HLA sensitization. Further research is needed to identify the immunologic mechanisms that underlie this observation.

Calibration of Priority Points for Sensitization Status of Kidney Transplant Candidates in the United States

“…The results indicated significantly lower likelihood of high sensitization with older age, which has been demonstrated for both heart and kidney transplant candidates. 22,23 However, in this study, the effects were generally linear among men (including approximate odds of high sensitization equal to half among candidates older than 70 years compared with younger candidates), but were lower only after age 60 years among women. These results raise questions about whether increasing time after a sensitizing event ( e.g ., pregnancy) attenuates measured levels of sensitization.…”

“…(B) Model adjusted for candidate age, sex, race and ethnicity, dialysis years at the time of waitlist placement, blood type, and primary diagnosis; solid sensitization among patients with longer prelisting dialysis as evidenced in the current and prior studies may be explained by the disproportionate need for blood transfusions. 21,22 There were several additional factors associated with sensitization illustrated in these findings. The results indicated significantly lower likelihood of high sensitization with older age, which has been demonstrated for both heart and kidney transplant candidates.…”

“…The reason for this association is not entirely clear, but has been demonstrated in prior studies. 22,24,25 Another interesting finding was lower likelihood of high sensitization levels among morbidly obese candidates, evident for both male and female candidates. The reason for this association warrants further study, but potentially could be related to impaired immune responses among obese individuals or selection biases for potential candidates with multiple potential risk factors.…”

“…19,20 The association of higher sensitization among patients with longer prelisting dialysis as evidenced in the current and prior studies may be explained by the disproportionate need for blood transfusions. 21,22…”

Homozygosity in any HLA locus is a risk factor for specific antibody production: the taboo concept 2.0

“…It is well accepted that there is no association of specific HLA determinants with the fact of being a patient awaiting an organ reported so far, besides some renal diseases such as HUS, IgA nephropathy ( 28 , 29 ). Homozygosity for HLA-A, HLA-B, and HLA-DRB1 are usually prioritised in different allocation schemes worldwide; however, the patient being homozygous in one of the clinically relevant eight other loci is rather neglected, although they tend to produce more specific antibodies ( 4 , 12 ). Furthermore, the data presented above show a direct correlation of homozygous loci (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, and DPB1) to antibody production and, moreover, of variants to antibody production towards other alleles of the same locus.…”