*Purpose: Chronic-active antibody mediated rejection (c-aABMR) is the leading cause of long-term renal allograft loss. Fc-receptor CD16 bearing natural killer (NK) cells may be involved in mediating renal endothelial cell damage in c-aABMR. A single nucleotide polymorphism within CD16 gene, i.e. the GG- but not the GT- or TT-genotype, is associated with increased CD16 expression and function of NK cells. The GG-genotype could therefore be a risk factor for developing c-aABMR. This study investigated NK cells and their CD16 expression in cases of c-aABMR.

*Methods: Cases of c-aABMR in renal allografts (N=148) and controls (N=137, kidney transplant recipients without c-aABMR) were genotyped for the G or T allele of the CD16 gene. Frequencies of circulating NK cells and their expression of CD16 were measured in 25 cases of c-aABMR and compared to matched controls of kidney transplant recipients. Furthermore, the presence of NK cells in renal biopsies of 20 c-aABMR cases (CD3^–CD57⁺ cells) was studied.

*Results: The allelic distribution of the GG, GT and TT-genotype within CD16 was respectively, 16%, 41% and 43% for c-aABMR cases and 13%, 39% and 48% for controls (p=0.73). Individuals with TT had the lowest expression of CD16 on their circulating NK cells (median MFI 3.7 x10⁴) compared to GT (median MFI 6.3 x10⁴) and GG (median MFI 5.8 x10⁴), (p=0.01). In addition, the % of CD16⁺ NK cells was lowest in the TT group (median 80% vs 93% and 87%, p=0.02). However, independent of T/G genotype, cases with c-aABMR showed a significantly higher expression of CD16 on their circulating NK compared to the matched controls (p= 0.01). Frequencies of NK cells were similar between both groups. NK cells in renal biopsies of c-aABMR cases were absent in glomeruli in 40% of the cases and present at low numbers in the remaining 60% of cases. NK cells were observed in the interstitium but at low numbers (<5% of infiltrating cells).

*Conclusions: Cases of c-aABMR have a significant higher expression of CD16 on circulating NK cells which cannot be explained by a difference in allelic distribution pattern for the T/G variants within the CD16 gene. NK cells are rarely found in kidney biopsies of c- aABMR patients suggesting that an ephemeral interaction between NK cells and renal endothelial cells may explain the increased CD16 expression.

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