Pretransplant IgG Subclasses of Donor-Specific Human Leukocyte Antigen Antibodies and Development of Antibody-Mediated Rejection

Background. The subclass of IgG antibodies contributes to their capability to activate complement. It is currently unknown whether the pretransplant IgG subclass composition allows distinguishing harmful from presumably irrelevant donor-specific human leukocyte antigen (HLA) antibodies (HLA-DSA) detected by single-antigen flow beads (SAFB). Methods. Seventy-four patients transplanted in the presence of HLA-DSA were investigated. HLA-DSA characteristics were not different between patients experiencing antibody-mediated rejection (AMR) (n = 40) and patients who did not (n = 34) experience AMR. Sera were reanalyzed using SAFB with IgG subclass-specific reporter antibodies. Results. The 74 patients had in total 141 HLA-DSA. IgG(1) was the predominant subclass (78%), followed by IgG(2) (49%), IgG(3) (36%), and IgG(4) (20%). When grouped according to the complement-activating capability, only 4 of 74 patients (5%) had exclusively weak/no complement-activating HLA-DSA (i.e., IgG(2) and IgG(4)), 21 of 74 patients (28%) had isolated strong complement-activating HLA-DSA (i.e., IgG(1) and IgG(3)), and 46 of 74 patients (62%) had a mixture of both. There was no difference between the strong complement-activating and the mixture group regarding incidence of AMR (57% vs. 54%; P=0.81), phenotypes of AMR (P=0.70), and death-censored allograft survival at 5 years (78% vs. 78%; P=0.74). Interestingly, patients with exclusively weak/no complement-activating HLA-DSA (n=4) had a numerically lower incidence of AMR (25%) and no allograft loss has occurred yet. Conclusion. In 90% of patients, pretransplant HLA-DSA are composed of isolated strong or a mixture of strong and weak/no complement-activating IgG subclasses. Because outcomes in these two groups were similar, pretransplant IgG subclass analysis is likely not providing substantial value beyond the standard IgG SAFB assay for pretransplant risk stratification.