Abstract
Background and ObjectivesThere is increasing evidence that galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1-containing immune complexes are important for the pathogenesis of IgA nephropathy (IgAN). In the present study, we assessed a novel noninvasive multi-biomarker approach in the diagnostic test for IgAN.Materials and MethodsWe compared serum levels of IgA, IgG, Gd-IgA1, Gd-IgA1-specific IgG and Gd-IgA1-specific IgA in 135 IgAN patients, 79 patients with non-IgAN chronic kidney disease (CKD) controls and 106 healthy controls. Serum was collected at the time of kidney biopsy from all IgAN and CKD patients.ResultsEach serum marker was significantly elevated in IgAN patients compared to CKD (P<0.001) and healthy controls (P<0.001). While 41% of IgAN patients had elevated serum Gd-IgA1 levels, 91% of these patients exhibited Gd-IgA1-specific IgG levels above the 90th percentile for healthy controls (sensitivity 89%, specificity 92%). Although up to 25% of CKD controls, particularly those with immune-mediated glomerular diseases including lupus nephritis, also had elevated serum levels of Gd-IgA1-specific IgG, most IgAN patients had elevated levels of Gd-IgA1-specific antibody of both isotypes. Serum levels of Gd-IgA1-specific IgG were associated with renal histological grading. Furthermore, there was a trend toward higher serum levels of Gd-IgA1-specific IgG in IgAN patients with at least moderate proteinuria (≥1.0 g/g), compared to patients with less proteinuria.ConclusionsSerum levels of Gd-IgA1-specific antibodies are elevated in most IgAN patients, and their assessment, together with serum levels of Gd-IgA1, improves the specificity of the assays. Our observations suggest that a panel of serum biomarkers may be helpful in differentiating IgAN from other glomerular diseases.
Highlights
IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide [1,2]
Each serum marker was significantly elevated in IgAN patients compared to chronic kidney disease (CKD) (P,0.001) and healthy controls (P,0.001)
There was a trend toward higher serum levels of Gd-IgA1-specific IgG in IgAN patients with at least moderate proteinuria ($1.0 g/g), compared to patients with less proteinuria
Summary
IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide [1,2]. The O-linked glycans in the hinge region of IgA1 are generally composed of Nacetylgalactosamine (GalNAc) and galactose; sialic acid may be attached to either or both sugars. Studies in different populations have shown that IgAN patients have significantly higher levels of circulating IgA1 with galactose-deficient, O-linked, hinge-region glycans [5,6,7,8,9]. Depending on the population studied, 50–75% of IgAN patients have levels above the 90th percentile for healthy controls. IgA1 eluted from renal tissues of IgAN patients exhibits a galactose deficiency in the O-linked glycans in the hinge-region [10,11]. There is increasing evidence that galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1-containing immune complexes are important for the pathogenesis of IgA nephropathy (IgAN). We assessed a novel noninvasive multi-biomarker approach in the diagnostic test for IgAN
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