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/µL (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.