What is the pathogenesis of minimal change disease?

Pathogenesis of Minimal Change Disease

Primary Mechanism: Immune Dysregulation Leading to Podocyte Injury

The pathogenesis of minimal change disease involves immune system dysregulation—particularly T cell and B cell dysfunction—that leads to release of circulating factors causing direct podocyte injury, foot process effacement, and disruption of the glomerular filtration barrier. 1, 2

Key Pathogenic Components

Immune-Mediated Mechanisms

• T cell dysfunction is central to MCD pathogenesis, with abnormal T cell activation thought to release circulating permeability factors that directly target podocytes 1, 3
• B cell involvement has been increasingly recognized, particularly given the therapeutic response to rituximab (anti-CD20 antibody), suggesting B cells may activate T cells or release autoantibodies against podocyte antigens 3, 2
• The disease is characterized by absence of inflammatory changes or immune complex deposits in kidney tissue, distinguishing it from other glomerular diseases and supporting the circulating factor hypothesis 2

Podocyte Injury Cascade

• Podocyte foot process effacement is the pathologic hallmark visible on electron microscopy, while light microscopy appears normal 4, 1
• Decreased expression of critical podocyte proteins occurs, including:
  • Slit diaphragm proteins: nephrin and podocin
  • Cytoskeletal protein: synaptopodin (expression correlates with steroid responsiveness) 5
• Upregulation of pathogenic podocyte proteins contributes to injury:
  • CD80 (B7-1): A T cell co-stimulatory molecule abnormally expressed on podocytes in MCD; activation of NF-κB pathways by external antigens induces CD80 upregulation, causing cytoskeletal damage and proteinuria 5
  • Angiopoietin-like-4: Overexpression damages the glomerular basement membrane charge barrier and induces foot process fusion 5

Glomerular Basement Membrane Disruption

• Synergistic interaction between immune dysregulation and podocyte modifications alters the integrity of the glomerular basement membrane, resulting in massive proteinuria 1
• The charge barrier of the GBM is specifically compromised by factors like angiopoietin-like-4 5

Genetic Susceptibility

• Genome-wide association studies have identified links between MCD and specific human leukocyte antigen (HLA) variants, indicating genetic susceptibility 2
• Whole-exome sequencing has revealed pathogenic mutations in familial cases of steroid-sensitive nephrotic syndrome, though genetic defects are less common in MCD compared to other podocytopathies 3

Clinical-Pathologic Correlation

• The steroid-sensitive nature of most MCD cases (70-90% in children >1 year) supports the immune-mediated pathogenesis 1
• Recurrent relapse/remission course is consistent with episodic immune activation rather than fixed structural defects 3
• Steroid-resistant forms may represent early FSGS or a distinct pathogenic mechanism, as unresolved MCD can progress to focal segmental glomerulosclerosis 1, 6

Important Caveats

• The exact circulating permeability factor(s) remain unidentified despite decades of research, representing a major gap in understanding 3, 2
• Lack of adequate animal models hampers mechanistic studies; humanized mouse models may better reflect MCD pathophysiology for investigating T cell-podocyte interactions 3
• Disease heterogeneity suggests distinct underlying triggers or mechanisms among different patients with MCD, complicating efforts to identify a unified pathogenic pathway 2