What is IgA (Immunoglobulin A) kidney disease?

IgA Nephropathy (IgAN)

IgA nephropathy is the most common primary glomerulonephritis worldwide, characterized by mesangial deposition of immunoglobulin A, which triggers inflammation and can lead to progressive kidney damage with up to 20-40% of patients developing end-stage kidney disease within 20 years. 1

Pathophysiology

IgA nephropathy pathogenesis follows the "four-hit hypothesis":

1. Production of galactose-deficient IgA1 (gd-IgA1) - Abnormal O-glycosylation of IgA1 molecules
2. Formation of autoantibodies - Anti-gd-IgA1 IgG or IgA1 autoantibodies develop
3. Immune complex formation - These autoantibodies bind to gd-IgA1, forming immune complexes
4. Mesangial deposition - Complexes deposit in the glomerular mesangium, triggering inflammation and kidney injury 1

The disease likely involves dysregulation of the mucosal immune system, with plasma cells being the main source of pathogenic antibodies 2.

Diagnosis

Diagnosis of IgA nephropathy requires a kidney biopsy, as it is the only definitive way to confirm the condition 3. Clinical features that may suggest IgA nephropathy include:

• Nephritic urinary sediment (erythrocytes, acanthocytes, erythrocyte casts)
• Proteinuria (variable degrees)
• Impaired renal function
• Arterial hypertension
• Intermittent painless macrohematuria, especially during upper respiratory tract infections 4

Biopsy Findings

Key diagnostic findings on kidney biopsy include:

• Immunofluorescence/Immunohistochemistry: Mesangial dominant or co-dominant IgA deposits 3
• Light Microscopy: Variable mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity, tubular atrophy/interstitial fibrosis, and crescents (MEST-C scoring system) 3
• Electron Microscopy: Electron-dense deposits in the mesangium 3

Prognosis Assessment

After diagnosis, prognosis assessment is essential using:

1. MEST-C histologic scoring system: Evaluates mesangial (M) and endocapillary (E) hypercellularity, segmental glomerulosclerosis (S), interstitial fibrosis/tubular atrophy (T), and crescents (C) 3
2. International IgAN Prediction Tool: Helps estimate disease progression risk 3
3. Clinical risk factors: Persistent proteinuria >1 g/day, hypertension, and reduced GFR are the strongest predictors of progression 3, 5

Management

Supportive Care (First-Line for All Patients)

All patients with IgA nephropathy should receive optimized supportive care as the backbone of management, including:

• RAS blockade (ACE inhibitors or ARBs) for all patients with proteinuria >0.5 g/day, regardless of hypertension status (Grade 1B) 3, 6
• Blood pressure control with targets of <130/80 mmHg if proteinuria <1 g/day and <125/75 mmHg if proteinuria ≥1 g/day 6
• Sodium restriction (<2.0 g/day) to enhance antiproteinuric effects 3, 6
• Lifestyle modifications: Weight management, smoking cessation, regular exercise 5
• SGLT2 inhibitors as emerging therapy for renoprotection 3, 6, 7

Immunosuppressive Therapy

For patients with persistent proteinuria despite supportive care:

• Consider a 6-month course of glucocorticoid therapy (Grade 2B) if proteinuria remains >0.75-1 g/day despite at least 90 days of optimized supportive care 3

Glucocorticoids should be avoided or used with extreme caution in patients with:

• eGFR <30 ml/min per 1.73 m²
• Diabetes
• Obesity (BMI >30 kg/m²)
• Latent infections (hepatitis, tuberculosis)
• Secondary disease (liver cirrhosis)
• Active peptic ulceration
• Uncontrolled psychiatric disease
• Severe osteoporosis 3

Emerging Therapies

Several promising therapies are under investigation:

• Enteric-coated budesonide
• Sparsentan (dual angiotensin-II-receptor and endothelin-receptor antagonist)
• Atrasentan
• Hydroxychloroquine
• Complement inhibitors
• Targeted B-cell therapies 3, 6, 7, 4

Special Considerations

• Rapidly progressive IgAN: Treat with corticosteroids and cyclophosphamide similar to ANCA-associated vasculitis 4
• Secondary IgAN: Rule out underlying conditions (inflammatory bowel disease, infections, tumors, rheumatic diseases) 4
• Infection prevention: Consider pneumococcal and influenza vaccines, especially if immunosuppression is planned 3

Monitoring

Regular monitoring should include:

• Proteinuria levels
• Renal function (serum creatinine, eGFR)
• Blood pressure
• Hematuria 6

A reduction in proteinuria to under 1 g/day is a surrogate marker of improved kidney outcome in IgAN and represents a reasonable treatment target 3.