What is the mechanism of action (MOA) of Poststreptococcal Glomerulonephritis (PSGN)?

Mechanism of Action of Post-Streptococcal Glomerulonephritis (PSGN)

PSGN is an immune complex-mediated disease where streptococcal antigens trigger immune complex formation and deposition in glomerular tissue, activating the complement system (primarily the alternative pathway) and causing inflammatory kidney damage. 1

Primary Pathogenic Mechanism

Immune Complex Formation and Deposition:

• Streptococcal antigens from Group A beta-hemolytic streptococcus (Streptococcus pyogenes) trigger the formation of antigen-antibody immune complexes either in circulation or in situ on the glomerular basement membrane 2, 3
• These immune complexes deposit in the glomeruli, where they initiate the inflammatory cascade that leads to kidney injury 2
• The disease typically occurs 1-3 weeks after streptococcal pharyngitis or 4-6 weeks after impetigo 1, 4

Key Nephritogenic Antigens

Two leading streptococcal antigens have been identified:

• Nephritis-associated plasmin receptor (NAPlr), identified as glyceraldehyde-3-phosphate dehydrogenase, which binds plasminogen and maintains plasmin activity in the glomerulus 5, 3
• Streptococcal pyrogenic exotoxin B (SpeB), a cationic cysteine proteinase that contributes to glomerular inflammation 3

NAPlr has both immunologic and direct pathogenic functions:

• Glomerular NAPlr deposition is detected in essentially all patients with early-phase PSGN 5
• NAPlr functions as a plasmin receptor and maintains plasmin activity in the glomerulus, contributing to tissue damage through non-immunologic mechanisms 5
• Nephritogenic antigens can induce inflammatory processes early, even before immune complex formation is complete 6

Complement Activation

The complement system plays a central role in PSGN pathogenesis:

• Immune complexes activate complement primarily via the alternative pathway, though the lectin pathway also contributes 3
• This complement activation is critical for generating inflammation at sites of immune complex deposition 3
• C3 complement levels are characteristically low during active disease and typically normalize within 8-12 weeks 1
• C4 levels remain normal, distinguishing PSGN from classical pathway-mediated diseases 1

Inflammatory Cell Infiltration

Multiple immune cell types contribute to glomerular injury:

• Innate immune cells (neutrophils and monocytes/macrophages) infiltrate the glomeruli and induce damage through various inflammatory mechanisms 6
• Adaptive immune cells (CD4+ and CD8+ T lymphocytes) also participate in the inflammatory response 6
• The glomeruli show diffuse hypercellularity with proliferation of endothelial and mesangial cells 3

Mechanisms of Chronicity

In patients who progress to chronic kidney disease, several failure mechanisms have been identified:

• Failure to induce apoptosis in inflammatory cells and failure to phagocytose apoptotic cells, leading to membrane permeabilization and release of pro-inflammatory molecules that perpetuate inflammation 6
• Persistent infection with continued antigenic stimulation 6
• Genetic variations in the host's complement system that may predispose to prolonged complement activation 6
• Pre-existing kidney damage from comorbidities or advanced age 6

Clinical Implications of the Mechanism

Understanding the pathophysiology guides diagnostic and therapeutic approaches:

• The immune complex-mediated nature explains why C3 levels are low while C4 remains normal, helping differentiate PSGN from other glomerulonephritides 1
• Persistently low C3 beyond 12 weeks suggests alternative diagnoses such as C3 glomerulopathy and warrants kidney biopsy 1
• The role of streptococcal antigens in maintaining inflammation justifies antibiotic therapy even when active infection is no longer present, to reduce antigenic load 1, 4
• The self-limited nature in most cases reflects successful resolution of inflammation once antigenic stimulation ceases and immune complexes are cleared 7