Immunoglobulin A (IgA) nephropathy is an autoimmune disease characterized by the deposition of circulating IgA-containing immune complexes (IgA-ICs) in the glomerular mesangium, leading to mesangial cell proliferation, increased extracellular matrix production, and variable infiltration of inflammatory cells. IgA nephropathy carries a lifelong risk of progressing to end-stage renal disease and requires optimal treatment strategies to arrest kidney deterioration.
According to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for IgA nephropathy and IgA vasculitis, treatment strategies are divided into two groups. One targets IgAN-specific drivers of nephron loss, and the other addresses the host genetic response to IgAN-induced nephron loss. The former is typified by immunosuppressants, whereas the latter consists of comprehensive supportive care that primarily focuses on the management of cardiovascular and metabolic risk factors. However, systemic corticosteroid therapy has raised safety concerns and is therefore used only in carefully selected patients who can tolerate its side effects. Therefore, it is crucial to elucidate the molecular pathogenesis of IgA nephropathy and identify reliable biomarkers and practical therapeutic targets.
”The key IgA-IC-related molecules and pathways involved in the development of glomerulonephritis remain unclear“Professor Kazuo Takahashi of the Department of Biomolecular Science, School of Medicine, Fujita Health University said, “In order to elucidate the molecular components of IgA-IC and the molecules involved in glomerular damage in patients with IgA nephropathy, Professor Kazuo Takahashi and a research team including Senior Assistant Professor Yukako Oyama and Assistant Professor Dai Tsuji of the Institute conducted proteomic research.The team conducted proteomic analysis of preserved remnants.” FFPE kidney tissue, IgA The study results on IgA-IC isolated from nephropathy patients and samples obtained from controls were published online on November 26, 2025, in volume 15 of the journal. scientific report December 30, 2025.
The research team found that complement pathway proteins associated with both the classical and alternative pathways and the terminal pathway were overexpressed in the glomeruli of patients with IgA nephropathy compared to normal kidney sections removed due to cancer. These include complement factor H-related protein (CFHR) 1, CFHR2, CFHR3, CFHR5, C1q chains B and C, and properdin. Serum CFHR1 levels and CFHR1 levels in circulating IgA-IC were also significantly higher in patients than in healthy and diseased controls. Furthermore, colocalization of CFHR1 and mesangial IgA deposits was confirmed by double immunofluorescence staining of CFHR1 and IgA using frozen kidney biopsy sections.
A longitudinal study showed that CFHR1 levels in circulating IgA-IC were significantly reduced after 2 years of immunosuppressive treatment, whereas no significant changes were observed in patients receiving supportive care. Interestingly, serum CFHR1 levels remained unchanged in both treatment groups.
What does this mean for the progression of IgA nephropathy? Professor Takahashi speculated that elevated CFHR1 in circulating IgA-ICs may increase the likelihood of developing this disease, adding:Elevated circulating total CFHR1 levels in patients with IgA nephropathy may reflect activation of the alternative complement pathway upon exposure to IgA-bound mucosal microbial antigens.Therefore, CFHR1 catalyzes the formation of IgA-ICs around abnormal IgA molecules, which can ultimately be deposited in the kidney and cause inflammation.
These findings indicate that CFHR1 may serve as a new diagnostic marker for IgA nephropathy. ”Quantification of CFHR1 within circulating IgA immune complexes holds promise as a novel diagnostic and prognostic biomarker for IgA nephropathy. Of note, several new therapeutic agents with different mechanisms of action are currently under development and clinical evaluation for IgA nephropathy, including complement-targeted drugs. CFHR1 may also serve as a potential companion diagnostic marker to guide these new therapies.” said Professor Takahashi, adding that a deeper understanding of the mechanisms of IgA-IC formation, including the role played by complement pathway proteins, will lead to optimal patient management and better treatment outcomes.
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Tsuji, Y., Others. (2025). Complement proteins associated with IgA-containing immune complexes in the circulation and glomeruli of patients with IgA nephropathy. scientific report. DOI: 10.1038/s41598-025-29024-z. https://www.nature.com/articles/s41598-025-29024-z
