Deep Diving into the Pathogenesis of C3 Glomerulopathy, With Sayna Norouzi

C3 glomerulopathy (C3G) is increasingly understood not as a single disease entity but as a histopathologic pattern of kidney injury driven by dysregulation of the alternative pathway of the complement system.1

Although rare, new insights into complement dysregulation are reshaping its diagnostic and therapeutic framework, according to this recently published review.1

“So I think the rarity of the disease is something that affects both sides,” said Sayna Norouzi, MD, clinical nephrologist and associate professor of medicine at Loma Linda University Medical Center. “A lot of physicians might not be comfortable treating C3G because they've never seen a patient before, and they don't feel comfortable starting treatment for these patients.”

With an estimated incidence of 0.2–2 cases per million people annually, C3G remains ultrarare and diagnostically challenging. Patients commonly present with proteinuria, hematuria, and progressive kidney function decline—features that overlap with other glomerular diseases. As a result, accurate diagnosis increasingly depends on understanding the underlying complement-mediated mechanism driving injury.1,2

The complement system can be activated through 3 pathways: classical, lectin, and alternative. The classical pathway is triggered by antigen–antibody complexes, while the lectin pathway is activated by carbohydrate patterns on microbial surfaces. The alternative pathway is distinct in its ability to activate spontaneously through continuous low-level hydrolysis of C3, a process known as “C3 tick-over,” which generates C3a and C3b fragments.1

Once initiated, the alternative pathway undergoes amplification through an enzymatic loop in which C3b binds factor B and is cleaved by factor D, forming the alternative pathway C3 convertase. This complex drives further C3 cleavage, creating a powerful amplification system. Under normal physiologic conditions, regulatory proteins, including complement factor H, complement factor I, and membrane cofactor protein (CD46), control this process by inactivating C3b and limiting C3 convertase activity to prevent host tissue injury.1

Both genetic and acquired abnormalities contribute to dysregulation of the alternative pathway. Genetic variants have been identified in approximately 25%–40% of patients and affect complement components such as C3 and factor B, as well as regulatory proteins including factor H, factor I, complement factor H-related protein 5, and membrane cofactor protein. Acquired drivers, including autoantibodies stabilizing C3 convertase, may further amplify complement activation.1

The downstream effect is uncontrolled alternative pathway activity, excessive C3 convertase formation, and dominant C3 deposition within the glomeruli, which has been described as the defining histopathologic feature of C3G.1

According to investigators, the kidney appears particularly vulnerable to this dysregulation. The glomerular basement membrane lacks membrane-bound complement regulators and relies heavily on circulating regulators such as factor H for protection.1

When this regulation fails, persistent complement activation generates proinflammatory mediators, including C3a and C5a, promotes opsonization through C3b, and culminates in the formation of the terminal membrane attack complex (C5b-9), ultimately driving glomerular cell injury and progressive renal dysfunction.1,2

As understanding of these mechanisms deepens, clinicians are increasingly able to connect histopathology with molecular drivers of disease. For Norouzi and others in the field, this evolving insight represents more than scientific progress; it may help reduce diagnostic uncertainty and increase clinician confidence in managing a condition that, while rare, carries significant morbidity.

Editor's Note: Norouzi reports relevant disclosures with Calliditas, Travere, Apellis, and others.

References

1. Mashayekhi M, Zuckerman JE, Barratt J, et al. C3 Glomerulopathy Diagnosis, Current Treatments, and Emerging Therapies. Kidney Medicine. 2026;8(3):101258. doi:https://doi.org/10.1016/j.xkme.2026.101258

2. Gashu Ayehu, Atari M, Hassanein M, Jhaveri KD. C3 Glomerulopathy. Nih.gov. Published November 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK609090/