What is IgA (Immunoglobulin A) nephropathy?

IgA Nephropathy: Definition, Pathogenesis, and Clinical Features

IgA nephropathy is the most common primary glomerulonephritis worldwide, characterized by the presence of dominant or co-dominant mesangial IgA1 deposits in the glomeruli, leading to progressive kidney damage through immune complex-mediated inflammation. 1

Pathogenesis

IgA nephropathy develops through a multi-hit process:

1. Abnormal IgA1 production: The disease begins with production of galactose-deficient IgA1 (Gd-IgA1) molecules that have incomplete O-linked oligosaccharide side chains lacking terminal galactose residues 2, 3

2. Autoantibody formation: These structurally altered IgA1 molecules trigger formation of autoantibodies (IgG or IgA1) that bind to the exposed N-acetylgalactosamine residues 3

3. Immune complex formation: The resulting immune complexes containing Gd-IgA1 and anti-Gd-IgA1 antibodies circulate in the bloodstream 4

4. Mesangial deposition: These immune complexes deposit in the glomerular mesangium 1

5. Inflammatory response: Deposited complexes activate complement and mesangial cells, triggering inflammation and glomerular injury 3, 4

Diagnostic Features

Kidney Biopsy Findings

• Light microscopy: May show mesangial proliferation, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, and crescents (MEST-C scoring system) 1

• Immunofluorescence: The hallmark finding is mesangial dominant or co-dominant IgA deposits 1

  • Often accompanied by C3 deposits
  • May also show IgG and IgM deposits

• Electron microscopy: Shows electron-dense deposits in the mesangium 1

  • Glomerular basement membrane may show normal architecture or alterations
  • Podocyte effacement may be present in varying degrees

Clinical Presentation

IgA nephropathy typically presents with:

1. Early stage:

   • Microscopic or macroscopic hematuria (often following upper respiratory infections)
   • Minimal or no proteinuria
   • Normal kidney function 2

2. Late stage (variable progression):

   • Clinical remission in some patients
   • Persistent hematuria in others
   • Progressive disease in approximately one-third of patients, characterized by:
     • Increasing proteinuria
     • Hypertension
     • Declining kidney function 2, 5

Risk Factors for Progression

The most reliable predictors of poor prognosis include:

• Persistent proteinuria >1 g/day
• Hypertension
• Reduced estimated glomerular filtration rate (eGFR) at diagnosis
• Histological features: tubular atrophy and interstitial fibrosis 1, 2

Special Variants

Several variants of IgA nephropathy exist:

• IgA nephropathy with minimal change disease features: Treated according to minimal change disease guidelines 1
• IgA nephropathy with acute kidney injury: Often associated with gross hematuria episodes 1
• Rapidly progressive IgA nephropathy: Characterized by extensive crescent formation (>50% of glomeruli) and rapid decline in kidney function 1

Management Approach

The cornerstone of management is optimized supportive care:

• Blood pressure control
• Renin-angiotensin system blockade (ACE inhibitors/ARBs) for patients with proteinuria >0.5 g/day
• Lifestyle modifications (dietary sodium restriction, weight control, smoking cessation)
• Cardiovascular risk reduction 1

For patients with persistent proteinuria >1 g/day despite optimized supportive care, additional therapies may be considered, including glucocorticoids in selected patients with eGFR ≥30 ml/min/1.73m² 1.

Prognosis

Without treatment, approximately 30-40% of patients will progress to end-stage kidney disease. The rate of progression varies widely, with some patients experiencing rapid decline in kidney function while others remain stable for decades 5.

IgA nephropathy can recur after kidney transplantation in many patients, highlighting the systemic nature of the underlying immune dysregulation 3.

Emerging Therapies

Novel therapeutic approaches targeting specific pathogenic mechanisms are under investigation:

• Targeted B-cell and plasma cell depletion therapies
• Complement pathway inhibitors
• Drugs targeting the mucosal immune system 4, 5

These approaches aim to disrupt the formation of pathogenic immune complexes and prevent subsequent kidney injury.

AI Assistant: I've provided a comprehensive overview of IgA nephropathy, focusing on its definition, pathogenesis, diagnostic features, clinical presentation, and management approaches based on the most recent guidelines.