FCGR3A F158V Genotype Accelerates Progression to Chronic Alloimmune Injury in Antibody-Mediated Kidney Transplant Rejection: A Population-Based Cohort Study

BackgroundEvidence 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). MethodsWe 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. ResultsPresence 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. ConclusionsOur 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 findingsO_LIV/V158 associates with higher rates of chronic active AMR/transplant glomerulopathy, and lower rates of C4d without rejection C_LIO_LIV/V158 drives faster graft decline and graft failure, especially in transplants complicated with rejection C_LIO_LIFCGR3A F158V might link complement activation and ADCC in AMR pathobiology, accelerating chronic alloimmune injury C_LI