Not all antibodies are created equal: total IgG glycosylation and severity of antibody-mediated rejection in kidney transplantation

: Antibody-mediated rejection (AMR) is a leading cause of kidney transplant failure and is primarily driven by donor-specific anti-HLA antibodies (DSA), although DSA presence alone does not fully explain the heterogeneity of AMR severity. We prospectively studied 79 kidney transplant recipients from 2 European centers, including 29 with active AMR (aAMR), 29 with chronic-active AMR (caAMR), and 21 controls without rejection, to investigate the association between total Immunoglobulin-G (IgG) glycosylation profiles and AMR. IgG glycosylation was quantified using lectin-based ELISA, assessing relative levels of mannose, core fucose, α2,6-linked sialic acid, and bisecting N-acetylglucosamine (GlcNAc). Bisecting GlcNAc levels were higher in caAMR compared with controls and aAMR (both p < 0.001), while core fucosylation and mannose levels were increased in aAMR and caAMR relative to controls. Higher levels of core fucose, mannose, and α2,6-sialylation were associated with increasing glomerulitis severity. We found that bisecting GlcNAc (PHA-E/Fc) was significantly associated with both higher g- and cg-score (in ordinal models, OR = 2.1 [95% CI: 1.2-4.1; p = 0.017], and OR = 2.0 [95% CI: 1.1-4.3; p = 0.046], respectively). Mannose level (ConA/Fc) was significantly associated with higher g-score (2.1 [1.1-4.2], p = 0.017]). These findings indicate that distinct total IgG glycosylation features are independently associated with specific histological patterns of AMR severity.