IgA nephropathy—also known as Berger’s disease—is the most common primary glomerulonephritis worldwide. Characterized by the deposition of immunoglobulin A (IgA) in the glomeruli, this condition gradually impairs kidney function. Understanding the pathophysiology of IgA nephropathy is essential for identifying early markers, managing risk, and tailoring treatment strategies.
What Triggers IgA Deposition in the Kidneys?
The hallmark of IgA nephropathy is mesangial deposition of IgA1-containing immune complexes within the glomerulus. This deposition initiates inflammation and scarring in the kidney’s filtering units, leading to hematuria, proteinuria, and, over time, decreased renal function.
The disease process involves multiple immune and biochemical steps, beginning with the production of abnormal IgA1.
Step-by-Step Breakdown of IgA Nephropathy Pathogenesis
1. Production of Galactose-Deficient IgA1 (Gd-IgA1)
The pathogenesis starts in mucosal immune tissues (like the gut or respiratory tract), where B cells produce structurally altered IgA1 molecules lacking galactose in the hinge region. These galactose-deficient IgA1 molecules are considered autoantigenic.
2. Formation of Autoantibodies Against Gd-IgA1
The body then generates autoantibodies (usually IgG or IgA) that target the galactose-deficient IgA1. These antibodies bind to Gd-IgA1 and form circulating immune complexes.
3. Immune Complex Deposition in the Glomerular Mesangium
The immune complexes deposit in the mesangial region of the glomeruli, leading to activation of mesangial cells and the release of pro-inflammatory cytokines, complement factors (especially C3), and matrix proteins.
4. Inflammation and Mesangial Proliferation
The deposited complexes trigger mesangial cell proliferation, glomerular inflammation, and subsequent expansion of the extracellular matrix. This stage is associated with the classic signs of the disease—microscopic hematuria, proteinuria, and variable degrees of glomerular injury.
5. Chronic Damage and Fibrosis
Over time, persistent immune activation leads to segmental glomerulosclerosis, tubularatrophy, and interstitial fibrosis—hallmarks of chronic kidney damage. The rate of progression depends on several clinical factors, including proteinuria, blood pressure, and initial kidney function.
Role of the Complement System
The alternative and lectin pathways of the complement system are implicated in the pathophysiology of IgA nephropathy. Deposits of complement components, particularly C3, are commonly observed in biopsies, even when C1q is absent. Complement activation worsens inflammation and contributes to renal scarring.
Genetic and Environmental Influences
Susceptibility to IgA nephropathy has been linked to several genetic loci, especially in patients of Asian or Caucasian descent. Environmental triggers such as respiratory or gastrointestinal infections can worsen symptoms or trigger disease onset, supporting the role of mucosal immunity in disease progression.
Summary of Key Pathophysiological Mechanisms
Abnormal mucosal immune response leads to galactose-deficient IgA1 production
Autoantibody formation targets the modified IgA1
Circulating immune complexes deposit in the glomerular mesangium
Complement activation, inflammation, and mesangial proliferation ensue
Chronic immune injury leads to glomerulosclerosis and kidney function decline
Clinical Relevance
Understanding the pathophysiology of IgA nephropathy helps explain:
Why patients present with hematuria following infections
How disease severity correlates with immune complex deposition and complement activity
Why therapies targeting immune suppression, complement inhibition, and mucosal immunity are under investigation
It also provides the rationale for monitoring proteinuria, eGFR, and biopsy findings as indicators of disease activity and progression.
Final Thoughts
The pathophysiology of IgA nephropathy is a complex interaction of abnormal immune regulation, immune complex formation, complement activation, and chronic glomerular injury. As research continues to uncover the molecular mechanisms of this disease, targeted therapies may become more refined, offering patients new hope for disease-specific treatment beyond general immunosuppression and blood pressure control.