What causes IgA (Immunoglobulin A) nephropathy or Minimal Change Disease (MCD) kidney disease?

Causes of IgA Nephropathy and Minimal Change Disease

IgA nephropathy is caused by a "four-hit" pathogenic process involving production of galactose-deficient IgA1, formation of autoantibodies against this abnormal IgA1, immune complex formation, and mesangial deposition leading to kidney damage, while minimal change disease is primarily a podocytopathy with immune dysregulation as the underlying mechanism.

IgA Nephropathy Pathogenesis

IgA nephropathy (IgAN) has a well-established pathogenic mechanism involving four key steps:

1. Production of galactose-deficient IgA1 (Gd-IgA1): The first hit in the disease process 1
2. Formation of autoantibodies: These antibodies target the abnormal Gd-IgA1 1
3. Immune complex formation: Gd-IgA1 and autoantibodies form immune complexes 1
4. Mesangial deposition: These immune complexes deposit in the mesangium, triggering kidney damage 1

The definitive diagnosis requires kidney biopsy showing:

• Mesangial dominant or co-dominant IgA deposits by immunofluorescence
• Often accompanied by C3 deposition
• Electron-dense deposits in the mesangium on electron microscopy 1

Clinical Characteristics of IgA Nephropathy

• Most commonly presents as asymptomatic microscopic hematuria with varying degrees of proteinuria
• Some patients may present with macroscopic hematuria
• Approximately 30% progress to end-stage kidney disease within 20 years despite treatment 1

Minimal Change Disease Pathogenesis

Minimal change disease (MCD) has a different pathophysiological basis:

• Primary podocyte injury: MCD is classified as a "podocytopathy" affecting the glomerular podocytes 2
• Immune dysregulation: Evidence suggests immunologic dysregulation plays a central role 3
• T-cell involvement: A T-cell-driven circulating factor that interferes with glomerular permselectivity to albumin has been proposed 4
• Cytoskeletal disruption: Alterations in the podocyte cytoskeleton and foot processes are key features 2

The diagnostic hallmarks of MCD include:

• Absence of visible alterations by light microscopy
• Extensive foot process effacement on electron microscopy 3
• Hypertrophic podocytes may be seen on light microscopy 5

Clinical Characteristics of MCD

• Presents with nephrotic syndrome (proteinuria >3.5g/day, hypoalbuminemia, edema)
• Typically responsive to glucocorticoid therapy
• Usually does not lead to chronic renal damage if responsive to steroids 3

Overlap Between IgA Nephropathy and MCD

Interestingly, some patients present with features of both conditions:

• Cases of IgA nephropathy with nephrotic syndrome and minimal histologic changes have been reported 6
• These patients typically show:
  • IgA-dominant or codominant deposits with mesangial proliferation
  • Extensive foot process effacement (median 90%)
  • Clinical presentation and treatment response more typical of MCD 6
  • Good response to corticosteroids

This raises the question of whether some cases represent a dual glomerulopathy or a common pathophysiologic variant 5, 6.

Prognostic Factors

For IgA nephropathy, poor prognostic factors include:

• Proteinuria >1 g/day
• Hypertension
• Reduced eGFR at diagnosis
• Unfavorable histological features
• Persistent hematuria 1

For MCD, relapsing disease requiring long-term immunosuppression is associated with significant morbidity due to medication side effects 3.

Common Pitfalls

1. Misdiagnosis: Both conditions require kidney biopsy for definitive diagnosis, as clinical presentation alone can be misleading
2. Overlooking overlap syndromes: Failing to recognize cases with features of both diseases may lead to suboptimal treatment
3. Assuming all nephrotic syndrome in IgAN has poor prognosis: Cases with MCD-like features may have favorable outcomes with appropriate therapy 6
4. Underestimating the importance of electron microscopy: Essential for identifying foot process effacement in MCD and mesangial deposits in IgAN

Understanding the distinct pathogenic mechanisms of these diseases is crucial for appropriate management and prognostication.