The Gut-Renal Connection in IgA Nephropathy

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The Gut-Renal Connection in IgA Nephropathy (1)

Some experimental models and pilot studies in patients with IgAN in the 1980s suggested that alimentary antigens and particularly gluten may have a role in the pathogenesis of IgAN is initiated by T-cell independent or T-cell dependent mechanisms. sIgA plays a pivotal role in intestinal homeostasis between the host and commensal bacteria, regulating the intestinal microbiome and preventing pathogen overgrowth. Under normal circumstances, ingested dietary proteins do not activate immunologic mechanisms because sIgA prevents antigen entry.

Increased plasma levels of IgA are frequent in patients with IgAN (35%-50% of cases), with a significant increase in the pIgA fraction (25% of total IgA compared with 10% in healthy controls). In the renal deposits of patients with IgAN the predominant variant is pIgA, and sIgA also is detectable, suggesting a mucosal origin. Patients with IgAN present with a peculiar defective galactosylation of IgA1. IgA1 subclass has short O-linked oligosaccharide chains in the hinge region, made by a N-acetyl galactosamine core extended with beta 1,3 linked galactose by the beta 1,3 galactosyltransferase (which needs a specific chaperone, Cosmc) and covered with sialic acid.

Most loci found at risk for developing IgAN also were associated with immune-mediated inflammatory bowel diseases, and with the maintenance of the intestinal barrier and the regulation of the response of the GALT to intestinal pathogens. The human gastrointestinal tract includes 10^14 bacteria with a biomass of 2 kg. The so-called leaky gut modifies gut permeability and mucosal immunity in other intestinal diseases as well (eg, celiac disease), and other apparently unrelated conditions, including obesity, diabetes, and Alzheimer’s disease. Gut microbiota plays a modulatory role in experimental autoimmune diseases, including autoimmune encephalomyelitis, rheumatoid arthritis, and systemic lupus erythematosus, with the contribution of dietary factors.

Gut dysbiosis was found to induce a disruption of the epithelial barrier, ultimately resulting in increased exposure of the host to endotoxins, including bacterial lipopolysaccharide endotoxin (LPS), contributing to uremic toxicity and systemic inflammation. In IgAN the role of microbiota became evident after the publication of some pivotal experimental models. IgAN develops in a spontaneous murine strain producing high levels of IgA.

The microbiota can affect intestinal repair and new injury by modulating TLR activity. TLR4 is the receptor for Escherichia coli LPS, these observations may indicate that increased intestinal permeability to common gut microbes triggers, via TLR4 activation, the systemic immune system activation, which was found to play a role in the development and progression of IgAN.

BALB/c mice were kept on a gluten-free diet from birth. Mice then fed with a gluten-rich diet developed greater IgA deposits in comparison with mice continuing on the gluten-free diet.

Celiac disease develops from an autoimmune response to dietary gluten. Patients with celiac disease have increased intestinal permeability, and antibodies against gluten, gliadin, and endomysium, and much data suggest some similarities between intestinal barrier disruption in patients with celiac disease and in patients with IgAN. Almost all patients with celiac disease carry the HLA-DQ2/HLA-DQ8 haplotype and present with antigliadin and anti-TG2 antibodies. In patients with IgAN a similar mechanism of intestinal permeability might be active, with release in circulation of IgA anti gliadin forming macromolecular aggregates eventually deposited in the mesangium.

1. R. Coppo, The Gut-Renal Connection in IgA Nephropathy. Semin. Nephrol. 38, 504–512 (2018).

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