What Causes IgA Nephropathy?

IgA nephropathy, also known as Berger’s disease, is the most common primary glomerulonephritis worldwide. It is characterized by the deposition of immunoglobulin A (IgA) immune complexes in the mesangial region of the glomeruli, triggering inflammation and progressive kidney injury. While the precise etiology remains incompletely understood, current evidence points to a multifactorial pathogenesis involving mucosal immunity dysregulation, genetic susceptibility, and environmental triggers.

A key underlying mechanism involves aberrant glycosylation of IgA1 molecules—specifically, a deficiency in galactose residues on the hinge region of IgA1. This abnormal glycosylation renders IgA1 autoantigenic, prompting the production of IgG or IgA autoantibodies. The resulting immune complexes deposit in the glomerular mesangium, activating complement pathways and recruiting inflammatory cells, which ultimately leads to mesangial proliferation and matrix expansion.

Genetic factors significantly influence disease risk and progression. Genome-wide association studies have identified multiple susceptibility loci, particularly within the major histocompatibility complex (MHC) region on chromosome 6, as well as genes involved in IgA production and mucosal immunity (e.g., *CFHR1*, *TNFSF13*). Familial clustering is observed in approximately 10% of cases, supporting a hereditary component.

Environmental and mucosal triggers are also critical. Recurrent mucosal infections—especially upper respiratory tract infections—are strongly associated with disease onset and episodic hematuria flares. Gastrointestinal and urogenital infections may similarly provoke IgA immune responses. Additionally, dysbiosis of the gut microbiome has emerged as a potential contributor, given the gut’s central role in IgA synthesis and immune tolerance.

Other contributing factors include certain autoimmune conditions (e.g., celiac disease, lupus erythematosus), chronic liver disease (notably cirrhosis), and less commonly, HIV infection or dermatitis herpetiformis. Importantly, while these associations exist, they do not imply causation in all individuals—and many patients present without identifiable comorbidities or exposures.

Understanding these interrelated mechanisms is essential for risk stratification, guiding monitoring strategies, and informing emerging targeted therapies—including those aimed at modulating IgA1 glycosylation, blocking B-cell activation, or inhibiting the alternative complement pathway.