*Purpose: Long-term allograft survival has shown little improvement over the last decades. An important factor compromising long-term allograft survival in kidney transplantation is chronic active antibody mediated rejection (c-aABMR). Histomorphologic lesions of c-aABMR develop over time and are associated with recurrent and episodic endothelial cell activation by immunoglobulin G (IgG)-antibodies recognizing donor-specific leukocyte antigens (HLA) (DSA) or non-HLA antigens. Immune cells expressing Fc-receptors (FCGRs) interact with IgG antibodies bound to endothelial cells and genetic variation in FCGR genes may affect susceptibility for antibody-mediated rejection. Natural killer (NK) cells express the Fc-receptor CD16 (FCGR3A) and could therefore mediate renal endothelial cell damage in cases of c-aABMR. The V/V-genotype of the FCGR3A 158 F/V single nucleotide polymorphism is associated with increased CD16 expression and cytotoxicity by NK cells. This study evaluated whether this genotype is associated with the diagnosis of c-aABMR and renal allograft loss.

*Methods: Cases of c-aABMR (N=133) and control kidney transplant recipients without c-aABMR (N=116) were genotyped for FCGR3A 158 F/V. In addition, CD16 expression by NK cells and CD16-dependent NK-cell function were evaluated. Follow-up of cases of c-aABMR was until 1^st of January 2020 and graft loss/failure was defined as the need for dialysis or a retransplantation. The date of diagnosis of c-aABMR and date of graft failure were used to calculate graft survival upon diagnosis.

*Results: The distribution of the FGCR3A 158 F/V-genotypes was not different for c-aABMR cases compared to control kidney transplant recipients (P-value =0.65). The V-allele was associated with increased median fluorescence intensity (MFI) of CD16 by NK cells (MFI 3.5×10⁴ versus 1.3×10⁴ for V/V and F/F-genotype, P&lt0.001). Increased expression of CD16 correlated with CD16-dependent degranulation of NK cells (R=0.4; P=0.02). Moreover, the V/V-genotype was significantly associated with a higher glomerulitis score and an independent risk factor (HR 1.98; P=0.04) for decreased allograft survival. Death-censored graft survival in c-aABMR cases at 3 years follow-up was 33% for the FCGR3A 158 V/V-genotype versus 62% for the F/F-genotype.

*Conclusions: In conclusion, the FCGR3A V/V-genotype increases CD16-mediated NK cell cytotoxicity and is associated with a higher glomerulitis score and decreased renal allograft survival in cases with c-aABMR.

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