- and -Glycosylation of Serum Immunoglobulin A is Associated with IgA Nephropathy and Glomerular Function.

BACKGROUND

IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and is a leading cause of renal failure. The disease mechanisms are not completely understood, but a higher abundance of galactose-deficient IgA is recognized to play a crucial role in IgAN pathogenesis. Although both types of human IgA (IgA1 and IgA2) have several -glycans as post-translational modification, only IgA1 features extensive hinge-region -glycosylation. IgA1 galactose deficiency on the -glycans is commonly detected by a lectin-based method. To date, limited detail is known about IgA and glycosylation in IgAN.

METHODS

To gain insights into the complex and -glycosylation of serum IgA1 and IgA2 in IgAN, we used liquid chromatography-mass spectrometry (LC-MS) for the analysis of tryptic glycopeptides of serum IgA from 83 patients with IgAN and 244 age- and sex-matched healthy controls.

RESULTS

Multiple structural features of glycosylation of IgA1 and IgA2 were associated with IgAN and glomerular function in our cross-sectional study. These features included differences in galactosylation, sialylation, bisection, fucosylation, and glycan complexity. Moreover, IgA1 glycan sialylation was associated with both the disease and glomerular function. Finally, glycopeptides were a better predictor of IgAN and glomerular function than galactose-deficient IgA1 levels measured by lectin-based ELISA.

CONCLUSIONS

Our high-resolution data suggest that IgA - and glycopeptides are promising targets for future investigations on the pathophysiology of IgAN and as potential noninvasive biomarkers for disease prediction and deteriorating kidney function.