Enumerate four major primary glomerulonephritides presenting with nephrotic syndrome. Describe pathogenesis, light microscopic, immunofluorescence microscopy and electron microscopic findings of post-infectious glomerulonephritis.

Four Major Primary Glomerulonephritides Presenting with Nephrotic Syndrome

While many glomerular disorders can cause nephrotic syndrome, four primary glomerulonephritides commonly present with this clinical picture:

• Minimal Change Disease (MCD): This is the most common cause of nephrotic syndrome in children and accounts for a significant proportion in adults. It is characterized by the absence of significant changes on light microscopy, hence the "minimal change."
• Focal Segmental Glomerulosclerosis (FSGS): This disease involves scarring of some glomeruli (focal) and only parts of affected glomeruli (segmental). It is a leading cause of nephrotic syndrome in adults and children and can be primary or secondary.
• Membranous Nephropathy (MN): The most common cause of primary nephrotic syndrome in adults, characterized by diffuse thickening of the glomerular basement membrane due to immune complex deposition.
• Membranoproliferative Glomerulonephritis (MPGN) (also known as C3 Glomerulopathy): An uncommon type that can present with features of both nephrotic and nephritic syndromes. It is characterized by proliferation of mesangial and endothelial cells, and thickening of the glomerular basement membrane.

Post-Infectious Glomerulonephritis (PIGN)

Post-infectious glomerulonephritis (PIGN) is an immune-mediated glomerular disorder that develops after an infection, most commonly with nephritogenic strains of Group A beta-hemolytic streptococci (Post-streptococcal Glomerulonephritis or PSGN), but also by other bacteria, viruses, fungi, or parasites. It typically presents with acute nephritic syndrome, but can sometimes manifest with nephrotic-range proteinuria.

Pathogenesis of Post-Infectious Glomerulonephritis

The pathogenesis of PIGN primarily involves an immune response to microbial antigens that leads to the formation and deposition of immune complexes in the glomeruli. The key steps are:

• Infection: A preceding infection, often in the throat (e.g., pharyngitis by Streptococcus pyogenes, particularly type 12) or skin (e.g., impetigo by Streptococcus pyogenes, particularly type 49), triggers the immune response. There is typically a latent period of 1-2 weeks after a throat infection and 3-6 weeks after a skin infection before the onset of glomerulonephritis.
• Antigen-Antibody Complex Formation: Bacterial antigens, such as streptococcal pyrogenic exotoxin B (SpeB/zymogen) or nephritis-associated plasmin receptor (NAPlr), act as nephritogenic antigens. The host immune system produces antibodies against these antigens.
• Immune Complex Deposition: These antigen-antibody complexes can either form in the circulation and then deposit in the glomeruli, or bacterial antigens may directly bind to the glomerular basement membrane (in situ immune complex formation), followed by antibody binding.
• Complement Activation: The deposited immune complexes activate the complement system, primarily the alternative complement pathway. This leads to the consumption of complement components, particularly C3, resulting in low serum C3 levels, a hallmark of PIGN.
• Inflammatory Response and Glomerular Damage: Activation of the complement system attracts inflammatory cells, such as neutrophils and monocytes, to the glomeruli. These cells release lysosomal enzymes, reactive oxygen species, and other mediators, causing inflammation and damage to the glomerular capillaries and mesangium. This damage results in increased glomerular permeability, leading to hematuria, proteinuria, and reduced glomerular filtration rate.

Microscopic Findings of Post-Infectious Glomerulonephritis

The diagnosis of PIGN is often supported by characteristic findings on renal biopsy examined by light microscopy (LM), immunofluorescence (IF) microscopy, and electron microscopy (EM).

Light Microscopic Findings

Light microscopy typically reveals a diffuse proliferative and exudative glomerulonephritis. Key features include:

• Diffuse Glomerular Hypercellularity: All glomeruli are usually affected, showing an increase in cellularity. This is due to a combination of:
  • Endocapillary proliferation (proliferation of endothelial and mesangial cells).
  • Infiltration of inflammatory cells, predominantly neutrophils and monocytes (giving it an "exudative" appearance).
• Glomerular Swelling: The glomerular tufts appear enlarged and congested, with capillary lumens often obliterated or narrowed by the proliferating cells and inflammatory exudate.
• Normal Glomerular Basement Membrane: The glomerular basement membranes are usually of normal thickness and contour, although slight thickening may be observed in some areas.
• Absence of Necrosis: Typically, there is no glomerular necrosis, although severe cases can rarely develop focal crescents.

Immunofluorescence Microscopy Findings

Immunofluorescence microscopy demonstrates granular deposits of immune complexes within the glomeruli. The characteristic findings include:

• Granular Deposition of C3: Prominent, coarse granular deposits of the complement component C3 are consistently seen along the glomerular capillary walls and often in the mesangium. This is a very characteristic and often dominant finding.
• Immunoglobulin Deposition: IgG is commonly present in a granular pattern, often co-localizing with C3. IgM and sometimes IgA may also be present, especially in specific patterns.
• Staining Patterns: Distinct patterns of immune complex deposition have been described:
  • "Starry Sky" pattern: Diffuse, granular deposits of IgG, IgM, and/or IgA with C3, often seen in the early stages and associated with endocapillary-mesangial glomerulonephritis.
  • "Garland" pattern: Confluent staining along the capillary walls, suggesting active disease. This pattern often correlates with significant proteinuria.
  • "Mesangial" pattern: Predominantly C3 deposits in the mesangium, sometimes seen later in the disease course.

Electron Microscopic Findings

Electron microscopy provides the most definitive evidence of immune complex deposition in PIGN, characterized by:

• Subepithelial Humps: The most characteristic and pathognomonic finding is the presence of large, dome-shaped, electron-dense deposits located on the epithelial side of the glomerular basement membrane (between the basement membrane and the podocyte foot processes). These are widely referred to as "humps." They are most numerous in the early weeks of the disease and tend to diminish over time.
• Mesangial and Subendothelial Deposits: Smaller electron-dense deposits may also be seen in the mesangium and sometimes in the subendothelial space.
• Foot Process Effacement: The podocyte foot processes overlying the humps are often effaced or flattened, which contributes to proteinuria.
• Endothelial and Mesangial Proliferation: Electron microscopy can also confirm the proliferation of endothelial and mesangial cells, contributing to the hypercellularity seen on light microscopy.

The combination of these microscopic findings, along with clinical presentation and serological evidence (e.g., low C3, elevated anti-streptolysin O (ASO) titer), is crucial for confirming the diagnosis of post-infectious glomerulonephritis.