The FCGR3A 158 V/V-genotype is associated with decreased survival of renal allografts with chronic active antibody-mediated rejection

Abstract

Natural killer (NK) cells express the Fc-gamma receptor CD16 (FCGR3A) and could therefore mediate renal endothelial cell damage in cases of chronic-active antibody mediated rejection (c-aABMR). The V/V-genotype of the FCGR3A 158 F/V 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. The distribution of the FGCR3A 158 F/V-genotypes was not different for c-aABMR cases (N = 133) compared to control kidney transplant recipients (N = 116, P = 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 < 0.001). 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. In conclusion, the FCGR3A V/V-genotype increases CD16-mediated NK cell cytotoxicity and is associated with a higher glomerulitis score and decreased graft survival in cases with c-aABMR.

Functional Fc Gamma Receptor Gene Polymorphisms and Long-Term Kidney Allograft Survival

“…At first sight our results may be in some contrast to other studies: for instance, a recent lung transplant study identified the V/V158 genotype of FcgRIIIA as an independent susceptibility factor associated with higher rates of acute rejection in the first three months after transplantation (26). An even more recent for-cause biopsy-based study by Litjens et al (19) revealed no different frequency of FCGR3A-V/F158 variants comparing chronic active ABMR patients and control kidney transplant recipients. However, this study suggested associations of genotype V/V158 with a higher degree of glomerulitis (g) (but not ptc) and with inferior 3-year graft survival after diagnosis.…”

“…There were no associations with renal functional course or graft loss rate, however, the study was not powered to detect subtle differences in renal allograft outcomes ( 18 ). Analyzing a cohort of 133 chronic active ABMR patients, Litjens et al ( 19 ) confirmed our finding of an association of FcγIIIA functional polymorphism V/F158 with morphologic features of microcirculation inflammation, and, in an experimental model, with NK cell activation. In some contrast to our study, however, they found a significant survival effect, a finding that needs to be validated by an adequately powered study design ( 19 ).…”

Deletion of the Natural Killer Cell Receptor NKG2C Encoding KLR2C Gene and Kidney Transplant Outcome

“…Microarray studies have suggested a critical involvement of FcγRIIIA-triggered NK cell cytotoxicity and IFN-γ release ( 6 , 7 ). These data were supported by two recent studies (one performed with the BORTEJECT cohort which is also analyzed in this study), suggesting a contribution of FcγRIIIA functionality - determined by a FCGR3A V/F158 polymorphism - to DSA-triggered MVI ( 9 , 10 ). Alternative pathways of NK cell activation in organ transplantation, however, may act independently of DSA, including recognition of missing self HLA via a set of inhibitory KIR receptors ( 12 , 13 ).…”

“…Moreover, in the specific context of anti-HLA donor-specific antibody (DSA)-triggered antibody-mediated rejection (ABMR), gene expression studies have suggested that NK cells activated via Fc gamma receptor (FcγR) IIIA may play a pathogenic role ( 5 – 8 ). In line with these results, two recent studies have suggested a relationship between a functional single nucleotide polymorphism (SNP) in the FcγRIIIA gene ( FCGR3A -V/F158) with microvascular inflammation (MVI), a prominent morphologic lesion in ABMR ( 9 , 10 ). Nevertheless, in a subsequent analysis of approximately 2,000 kidney transplant recipients, we failed to demonstrate any impact of this SNP on long-term death-censored graft survival, presumably because of the overwhelming detrimental impact of other relevant immunological and non-immunological injury mechanisms ( 11 ).…”

Causes of Kidney Graft Failure in a Cohort of Recipients With a Very Long-Time Follow-Up After Transplantation

“…DSA after transplantation were not routinely measured. If no serum donor-specific antibodies were present and/or C4d staining was negative or not stained for in the biopsy than the diagnosis of ABMR by histology (ABMRh, 34% of total ABMR cases) was made as described in detail before ( 15 ) and used in previous publications ( 16 – 18 ). The standard treatment protocol for TCMR consisted of high dose methylprednisolone (3 days of 1,000 mg per day intravenously) and T cell depletion by rabbit anti-thymocyte globulin or Alemtuzumab was added in cases of steroid-resistant rejection and/or vascular rejection.…”