What is the pathophysiology of membranous nephropathy?

Pathophysiology of Membranous Nephropathy

Membranous nephropathy is fundamentally an autoimmune disease characterized by the formation of immune complexes containing IgG antibodies and target podocyte antigens in the subepithelial space of the glomerular basement membrane.

Primary Autoimmune Mechanism

Membranous nephropathy (MN) is characterized by a specific pathological process:

1. Autoantibody Production:

   • In primary MN, circulating autoantibodies target podocyte antigens
   • PLA2R1 (phospholipase A2 receptor) is the predominant target antigen in 70-80% of primary MN cases 1
   • THSD7A (thrombospondin type-1 domain-containing 7A) accounts for 1-5% of cases 2

2. Immune Complex Formation:

   • Autoantibodies bind to podocyte membrane antigens
   • These form in situ immune complexes in the subepithelial space between podocytes and the glomerular basement membrane
   • The immune complexes appear as electron-dense deposits on electron microscopy 3

3. Complement Activation:

   • The immune complexes activate the complement cascade
   • This leads to formation of the membrane attack complex (C5b-9)
   • C5b-9 damages the podocyte membrane, causing structural and functional changes 4

4. Podocyte Injury:

   • Complement-mediated damage leads to:
     • Disruption of the actin cytoskeleton
     • Loss of slit diaphragm proteins
     • Detachment of foot processes
     • Proteinuria development

5. Basement Membrane Changes:

   • Thickening of the glomerular basement membrane
   • Formation of characteristic "spikes" seen on silver stains
   • These represent projections of basement membrane material between immune deposits

Recently Identified Target Antigens

The understanding of MN has evolved significantly with the identification of multiple target antigens beyond PLA2R1 and THSD7A:

• NELL1 (neural epidermal growth factor-like 1)
• EXT1/EXT2 (exostosin 1/2)
• NCAM1 (neural cell adhesion molecule 1)
• SEMA3B (semaphorin 3B)
• PCDH7 (protocadherin 7)
• FAT1, CNTN1, NTNG1, PCSK6, NDNF 2, 5

Each antigen-associated MN appears to have distinct clinical and pathological characteristics, suggesting that MN may represent a pattern of injury resulting from specific diseases rather than a single disease entity 3.

Secondary Membranous Nephropathy

Secondary MN occurs in association with:

1. Systemic autoimmune diseases:

   • Lupus nephritis
   • Rheumatoid arthritis

2. Infections:

   • Hepatitis B and C
   • Parasitic infections

3. Malignancies:

   • Solid tumors
   • Hematological malignancies

4. Medications:

   • NSAIDs
   • Gold
   • Penicillamine

In secondary MN, immune complexes may form by:

• Deposition of circulating immune complexes
• In situ formation with planted exogenous antigens
• Autoantibodies against altered podocyte antigens 6

Diagnostic Classification

Modern classification of MN is based on:

1. Immunofluorescence patterns:

   • Immune complex-mediated (immunoglobulin-positive with or without complement)
   • Complement dominant (immunoglobulin-negative, complement-positive)
   • Immunofluorescence-negative 6

2. Target antigen identification:

   • PLA2R-associated MN
   • THSD7A-associated MN
   • Other antigen-associated MN
   • MN with unidentified antigens 2

Clinical Implications

The identification of specific target antigens has important implications:

• Diagnostic approach: Allows for non-invasive diagnosis through serum antibody testing
• Disease monitoring: Antibody levels correlate with disease activity
• Treatment decisions: Different antigen-associated MN may respond differently to therapy
• Prognosis: Antigen type may influence disease course and outcomes 4

The pathophysiological understanding of MN continues to evolve, with recent research suggesting that what was once considered a single disease entity may actually represent a common pattern of injury resulting from distinct disease processes, each characterized by specific target antigens.