Relationship between immunoglobulin A1 lectin-binding specificities, mesangial C4d deposits and clinical phenotypes in immunoglobulin A nephropathy

Background The reason why mesangial C4d deposits are detected in only certain biopsies of immunoglobulin A nephropathy (IGAN) remains unclear. We analyse the association between IgA glycosylation patterns, mesangial C4 deposition and clinical phenotypes in IgAN. Methods This cross-sectional study included 145 patients with idiopathic IgAN. We measured the serum levels of three different IgA1 lectin-binding specificities using enzyme-linked immunosorbent assays with and without treatment with neuraminidase and we analysed the relationship between these glycoforms, C4d mesangial deposits and clinical phenotypes. Results C4d-positive versus Cd4-negative patients had higher proteinuria [median 3.1 g/g (0.9-4.2) versus 1.8 (1-2.2); P = 0.000], haematuria [223 cells/mu L (32-278) versus 99 (25-186); P = 0.000] and higher levels of IgA binding to neuraminidase untreated Helix aspersa (HA IgA1 neu(-); 150.6 +/- 52 U versus 96.2 +/- 64.1; P = 0.000), neuraminidase untreated Helix pomatia (HPA IgA1 neu(-); 0.34 +/- 0.15 U versus 0.27 +/- 0.13; P = 0.04), Triticum vulgaris (TV IgA1; 85.1 +/- 31.7 U versus 42.2 +/- 26.9; P = 0.000) and Canavalia ensiformis (ConA IgA1; 32.5 +/- 18 U versus 16.7 +/- 9.38; P = 0.000). The levels of HA IgA1 neu(-), HPA IgA1 neu(-), TV IgA1 and ConA IgA1 were all associated with the mesangial deposition of C4d, extracapillary proliferation and acute kidney injury. In receiver operating characteristics curves, HA IgA1 neu(-), HPA IgA1 neu(-), TV IgA1 and ConA IgA1 significantly discriminated between C4d-positive ad C4d-negative biopsies. In logistics models, TV IgA1 and ConA IgA1 were the only independent predictors of mesangial C4d deposits. Conclusions In IgAN, the severity of the disease is associated with the level of IgA exposing N-acetyl-d-galactosamine, N-acetyl-d-glucosamine or mannose, whereas C4d deposits are only associated with elevated levels of IgA1 glycoforms exhibiting glycan residues with specificity for mannose and N-acetyl-d-glucosamine binding lectins.