Clinical meaning
Acute postinfectious glomerulonephritis (APIGN) represents a prototype of immune complex-mediated glomerular disease driven by the host immune response to nephritogenic strains of group A Streptococcus (GAS). The molecular pathogenesis involves formation of circulating IgG and IgA immune complexes against specific nephritogenic antigens, primarily nephritis-associated plasmin receptor (NAPlr) and streptococcal pyrogenic exotoxin B (SPE B). NAPlr binds plasmin and localizes to the glomerulus where it activates the complement cascade through the alternative pathway, generating C3 convertase (C3bBb) that cleaves C3 into C3a (anaphylatoxin) and C3b (opsonin). C3b deposition on the glomerular basement membrane amplifies through the alternative pathway feedback loop, while C5 convertase generates C5a (a potent neutrophil chemoattractant) and initiates formation of the membrane attack complex (C5b-9). The inflammatory cascade proceeds through Fc receptor-mediated mechanisms: deposited IgG immune complexes engage Fc-gamma receptors (FcγRIII and FcγRIV) on infiltrating neutrophils and macrophages, triggering release of reactive oxygen species, matrix metalloproteinases, and pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6). Podocyte injury occurs through both complement-mediated cytotoxicity (sublytic C5b-9 insertion disrupting slit diaphragm integrity) and neutrophil-derived proteases degrading nephrin and podocin proteins. Mesangial cell proliferation is driven by platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) released from activated macrophages and damaged endothelial cells. On electron microscopy, the pathognomonic subepithelial electron-dense deposits (humps) represent in situ immune complex formation on the outer surface of the GBM, corresponding to the granular (lumpy-bumpy) pattern of IgG and C3 deposition seen on immunofluorescence microscopy. Light microscopy demonstrates diffuse endocapillary proliferative glomerulonephritis with neutrophilic infiltration. The distinction between isolated C3 glomerulonephritis (C3 glomerulopathy) and APIGN is critical: C3 glomerulopathy involves dysregulation of the alternative complement pathway (often from C3 nephritic factor autoantibody or factor H mutations) and carries a worse prognosis with high recurrence rates, whereas APIGN is self-limiting with complement normalization within 6-8 weeks.