Abstract
The functional Fc gamma receptor (FcγR) IIIA polymorphism FCGR3A-V/F158 was earlier suggested to determine the potential of donor-specific HLA antibodies to trigger microcirculation inflammation, a key lesion of antibody-mediated renal allograft rejection. Associations with long-term transplant outcomes, however, have not been evaluated to date. To clarify the impact of FCGR3A-V/F158 polymorphism on kidney transplant survival, we genotyped a cohort of 1,940 recipient/donor pairs. Analyzing 10-year death-censored allograft survival, we found no significant differences in relation to FCGR3A-V/F158. There was also no independent survival effect in a multivariable Cox model. Similarly, functional polymorphisms in two other activating FcγR, FCGR2A-H/R131 (FcγRIIA) and FCGR3B-NA1/NA2 (FcγRIIIB), were not associated with outcome. There were also no significant survival differences among patient subgroups at increased risk of rejection-related injury, such as pre-sensitized recipients (> 0% panel reactivity; n = 438) or recipients treated for rejection within the first year after transplantation (n = 229). Our study results suggest that the earlier shown association of FcγR polymorphism with microcirculation inflammation may not be strong enough to exert a meaningful effect on graft survival.
Highlights
Antibody-mediated rejection (ABMR) is a major obstacle to long time transplant survival [1, 2]
There was no difference in 10-year death-censored graft survival between the donor genotype groups in any of the three loci FCGR3A-V/F158, FCGR2A-H/R131 and FCGR3B-NA1/ NA2 (Figure 4 and Supplemental Figure S5). In this large retrospective study of approximately 2,000 kidney transplant recipients, we investigated whether recipient or donor Fc gamma receptor (FcgR) gene variants have an impact on long-term allograft survival
Analyzing death-censored graft survival, there was no association of the function-determining polymorphisms in any of the three receptors FcgRIIIA, FcgRIIA and FcgRIIIB, neither in recipients nor in donors, on 10-year survival
Summary
Antibody-mediated rejection (ABMR) is a major obstacle to long time transplant survival [1, 2]. Donor-specific antibodies against HLA antigens (DSA), which are predominantly of the IgG subtype, may exert their detrimental action via complement activation and/or antibody-dependent cell cytotoxicity (ADCC) The latter includes the binding of the antibody’s Fc domain to Fc receptors on a variety of different immune cells, such as natural killer (NK) cells, which are suspected to play a key role in rejection [6, 7]. A single nucleotide polymorphism (SNP) in the coding sequence of FcgRIIIA, which is expressed on the surface of monocytes/ macrophages and natural killer (NK) cells, encodes a valine (V) to phenylalanine (F) amino acid substitution at position 158 (FCGR3A-V/F158) and is associated with decreased immune cell activation and altered binding characteristics to IgG1 and IgG3 [9, 10] Another functional polymorphism is located in the sequence of the myeloid cell receptor FcgRIIA. These constitute two isoforms NA1 and NA2 consisting of 4 amino acid differences which result in different N-linked glycosylation and receptor function [12]
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