Membranoproliferative Glomerulonephritis (MPGN)
General information
MPGN is a pattern of glomerular injury in medical renal pathology, rather than a single specific disease entity.
Traditionally classified into Types I, II, and III based on electron microscopy (EM), but modern classification relies on immunofluorescence (IF) pathogenesis: Immune-complex mediated vs. Complement-mediated (C3 glomerulopathy).
Typically presents with nephrotic syndrome, nephritic syndrome, or a mixed picture with hematuria and proteinuria.
Pathogenesis
Immune-complex mediated: Chronic antigenemia (e.g., Hepatitis C, autoimmune diseases, monoclonal gammopathy) → formation and deposition of antigen-antibody complexes in the glomerulus → classical complement pathway activation.
Complement mediated: Dysregulation of the alternative complement pathway (e.g., genetic mutations in complement regulatory proteins or C3 nephritic factor) → isolated C3 deposition.
Common endpoint: Deposition of immune elements → recruitment of inflammatory cells and mesangial cell proliferation → mesangial cytoplasm interposes into the capillary wall → synthesis of new glomerular basement membrane (GBM) → capillary wall thickening and impaired filtration.
Histologic picture
Architecture: Enlarged, hypercellular glomeruli with a lobular appearance.
Cellularity: Prominent mesangial hypercellularity and endocapillary proliferation (inflammatory cells within capillary lumens).
Capillary walls: Thickened capillary loops.
Special stains: Jones methenamine silver or PAS stains highlight splitting or reduplication of the GBM, forming characteristic "double contours" or "tram-tracks" due to mesangial interposition.
IHC, IF, and Molecular
Immunofluorescence (IF): Essential for subclassification.
Immune-complex MPGN: Granular capillary wall and mesangial positivity for IgG, IgM, C3, and sometimes C1q/C4.
Complement-mediated MPGN (C3 Glomerulopathy): Dominant or exclusive C3 positivity with negative/trace immunoglobulins.
Electron Microscopy (EM):
Type I: Subendothelial and mesangial electron-dense deposits.
Type II (Dense Deposit Disease): Continuous, highly electron-dense "sausage-like" deposits within the lamina densa of the GBM.
Type III: Complex subendothelial, mesangial, and subepithelial deposits with GBM disruption.
H&E Diagnostic Status: H&E and silver stains can identify the pattern of injury, but IF and EM are absolutely required to determine the underlying etiology and make a definitive diagnosis.
Differential diagnoses
Lupus Nephritis (Class IV):
Distinction: Can show an MPGN-like pattern with "tram-tracking," but IF will show a "full house" pattern (positive for IgG, IgA, IgM, C3, and C1q). Associated with clinical systemic lupus erythematosus.
Post-Infectious Glomerulonephritis:
Distinction: Can also present with endocapillary proliferation and a lobular appearance. IF shows "starry sky" or chunky granular C3/IgG, and EM shows characteristic large, dome-shaped subepithelial humps.
Thrombotic Microangiopathy (TMA):
Distinction: Chronic TMA causes GBM double contours and mesangial interposition, but IF is generally negative for significant immune complexes or C3 deposition. EM shows subendothelial electron-lucent widening (fluff) rather than electron-dense immune deposits.
