Background Evidence for involvement of NK cells and monocytes as prime agents in the process of human kidney transplant rejection is expanding quickly. These cells express FCGR3A, used for antibody-dependent cellular cytotoxicity (ADCC) after engagement with donor-specific antibodies on graft cells. A functional genetic polymorphism in the Fc fragment of IgG IIIa receptor (CD16a) gene (FCGR3A) results in a high-affinity (V158 allele) or low-affinity receptor (F158 allele).

Methods We studied the impact of the FCGR3A F158V genotype on graft histology, function, and outcomes in a large, unselected observational cohort study of 1259 kidney transplants (40% F/F158, 46% F/V158 and 14% V/V158) with 5435 post-transplant transplant biopsies.

Results Presence of at least one V158 allele was proportionally and significantly associated with a lower rate of C4d without rejection (F/V158, HR=0.51 [0.29-0.92], p=0.026; V/V158, HR=0.28 [0.08-0.90], p=0.033). Additionally, V/V158 was strongly associated with chronic active antibody-mediated rejection (HR=9.13 [1.89–44], p=0.006) and transplant glomerulopathy (HR=1.67 [1.01–2.75], p=0.046). The V/V158 genotype significantly associated with accelerated graft functional decline (−1.68 mL/min/y versus −0.74 mL/min/y (F/F158), p=0.034) and a higher rate of graft failure (HR=1.49 [1.01-2.20], p=0.045). This association was driven by transplants with post-transplant rejection.

Conclusions Our findings suggest that FCGR3A affinity is key in AMR pathobiology. Low affinity of this receptor (F158 allele) might associate with abrogation of effective downstream ADCC, even in the presence of complement activation (C4d deposition), while high affinity of this receptor (V158 allele) might escalate AMR, accelerating evolution to more chronic AMR phenotypes (transplant glomerulopathy). This framework provides an immunobiological link between lower C4d without rejection rates, higher chronic active AMR/ transplant glomerulopathy rates and adverse graft outcomes associated with the FCGR3A V/V158 genotype.

Key study findings

V/V158 associates with higher rates of chronic active AMR/transplant glomerulopathy, and lower rates of C4d without rejection

V/V158 drives faster graft decline and graft failure, especially in transplants complicated with rejection

FCGR3A F158V might link complement activation and ADCC in AMR pathobiology, accelerating chronic alloimmune injury

The authors have declared no competing interest.

This work was supported by The Research Foundation Flanders (FWO)(11P1524N). Maarten Coemans is a postdoctoral researcher and MN is a senior clinical investigator of FWO (12D6423N and 1842919N, respectively). Karolien Wellekens and Angelica Paglizazzi hold a FWO fellowship grant (1S93023N and 11P1524N respectively). Elisabet Van Loon and Jasper Callemeyn held a FWO fellowship grant (1143919N and 1196119N respectively).

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The Ethics Committee of University Hospitals Leuven gave ethical approval for this work.

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The data supporting the findings of this study can be obtained upon reasonable request from the corresponding author, Maarten Naesens. However, these data cannot be made publicly available due to certain restrictions, such as containing sensitive information that could potentially compromise the privacy of research participants.