Oxidative Stress and Galactose-Deficient IgA1 as Markers of Progression in IgA Nephropathy

Abstract

Summary Background and objectives We assessed the activation of the oxidative stress pathway in patients with IgA nephropathy (IgAN), while evaluating the classic marker of the disease (galactose-deficient serum IgA1). Design, setting, participants, & measurements Sera from 292 patients and 69 healthy controls from Italy and the United States were assayed for advanced oxidation protein products (AOPPs), free sulfhydryl groups on albumin (SH-Alb), and IgA1 with galactose-deficient hinge-region O-glycans (Gd-IgA1). Gd-IgA1 was detected by binding to Helix aspersa agglutinin (HAA) and expressed as total Gd-IgA1 or as degree of galactose deficiency relative to a standard Gd-IgA1 myeloma protein (%HAA). Results Sera from IgAN patients showed higher levels of Gd-IgA1, %HAA, and AOPPs, but lower levels of SH-Alb in comparison to that from healthy controls. Serum levels of AOPPs significantly correlated with serum Gd-IgA1 and %HAA. The relationship between these biomarkers and clinical features at sampling and during follow-up was assessed in 62 patients with long-term follow-up. AOPPs and %HAA correlated with proteinuria at sampling and independently associated with subsequent proteinuria. Levels of AOPPs correlated with rate of decline in renal function after sampling. The combination of a high level of AOPPs and a high level of %HAA associated with decline in estimated GFR. Conclusions Serum levels of aberrantly glycosylated IgA1 are elevated and oxidative stress pathways are activated in patients with IgAN; the intensity of the stress correlated with expression and progression of the disease. We speculate that oxidative stress may modulate the nephrotoxicity of aberrantly glycosylated IgA1 in IgAN.

Autoantibodies Targeting Galactose-Deficient IgA1 Associate with Progression of IgA Nephropathy

“…In another study, an increased serum level of aberrantly glycosylated IgA1 correlated with worse proteinuria. 24 Furthermore, in that study, the combination of a high serum Gd-IgA1 level and a high circulating level of advanced oxidation protein products correlated with a faster decline in eGFR, suggesting that oxidative stress may modulate the nephrotoxicity of aberrantly glycosylated IgA1.…”

Glomerular Diseases

“…Camilla et al found elevated levels of advanced oxidation protein products in the sera of patients with IgAN, which correlated both with time-averaged proteinuria and with the rate of decline in eGFR (38). The association was strengthened by combining measurement of advanced oxidation protein products (AOPPs) with Gd-IgA1.…”

“…Systemic oxidative stress is an important mediator of the inflammatory damage triggered by nephritogenic immune complexes in IgAN (38). Camilla et al found elevated levels of advanced oxidation protein products in the sera of patients with IgAN, which correlated both with time-averaged proteinuria and with the rate of decline in eGFR (38).…”

The genetics and immunobiology of IgA nephropathy

“…Lectin-based assays progressed through a careful screening of GalNAc-specific binding (39) to the development of a quantitative ELISA (6). This assay was used for analyses of IgA1 in several clinical cohorts to demonstrate that most patients with IgAN have elevated serum levels of Gd-IgA1, including children and adults of various ethnicities (6,13,14,(40)(41)(42).…”