What is IgA (Immunoglobulin A) nephropathy?

What is IgA Nephropathy?

IgA nephropathy is an autoimmune kidney disease characterized by the deposition of galactose-deficient IgA1 immune complexes in the glomerular mesangium, making it the most common primary glomerulonephritis worldwide. 1, 2, 3

Pathophysiology

The disease develops through a multi-step immune dysregulation process:

• Abnormal IgA1 production: The immune system produces galactose-deficient IgA1 (Gd-IgA1), which lacks normal glycosylation patterns 3, 4
• Autoantibody formation: Anti-glycan IgG or IgA antibodies form against the abnormal Gd-IgA1, creating pathogenic immune complexes 2, 5
• Mesangial deposition: These immune complexes deposit predominantly in the glomerular mesangium, the definitive diagnostic hallmark visible on kidney biopsy 2, 3
• Inflammatory cascade: The deposits trigger mesangial cell activation and proliferation, inflammatory cell recruitment, complement activation (particularly the alternative pathway), and ultimately podocyte damage 4, 6

Clinical Presentation

The clinical spectrum ranges from asymptomatic microscopic hematuria to rapidly progressive kidney failure:

• Hematuria patterns: Episodic gross hematuria occurs in 40-50% of cases, characteristically following upper respiratory infections by 1-2 days 2
• Proteinuria: Present in varying degrees, with proteinuria >1 g/day indicating high risk for progression 2
• Hypertension: Develops in approximately 50% of patients during disease course 7
• Family history: May be present in isolated cases, though most cases are sporadic 2

Diagnostic Approach

Kidney biopsy remains the gold-standard diagnostic test and is required for definitive diagnosis:

• Biopsy indication: Proceed when persistent hematuria occurs with proteinuria and concern for progressive kidney disease 2
• Immunofluorescence findings: Mesangial dominant or co-dominant IgA deposits are the pathognomonic feature 2, 3
• Additional staining: C3 is often co-deposited with IgA, while C1q is typically absent (helping distinguish from lupus nephritis) 2
• Electron microscopy: Reveals electron-dense deposits in the mesangium 2, 3
• Oxford Classification: Standardizes histological reporting to assess risk of progression based on specific lesions 1, 6

Critical Differential Diagnoses

Several conditions mimic IgA nephropathy and must be excluded:

• Thin basement membrane disease: Presents with hematuria but gross hematuria occurs in <10% of patients, family history of hematuria is common, but renal failure is rare 2
• Alport syndrome: May show episodic gross hematuria with positive family history of renal failure; deafness may be present in X-linked inheritance 2
• Secondary IgA deposition: Must exclude systemic lupus erythematosus, liver disease (cirrhosis), inflammatory bowel disease, and chronic infections that can cause secondary IgA deposition 2, 3

Prognosis and Risk Stratification

Approximately 20-50% of patients progress to kidney failure, though the disease course is highly variable:

• High-risk features at presentation: Proteinuria >1 g/day, uncontrolled hypertension, and impaired renal function predict worse outcomes 2, 7
• Long-term outcomes: 15-year kidney survival rates typically exceed 70% from apparent disease onset 7
• Spontaneous remission: Occurs in approximately 7% of patients 7
• Progression pattern: When it occurs, progression is usually slow and indolent over years to decades 7, 6

Epidemiology

IgA nephropathy shows striking geographic and ethnic variation:

• Global distribution: Most common in Asian-Pacific populations, relatively rare in those of African descent 4
• Prevalence: Accounts for 20-25% of glomerular diseases in kidney failure registries 1
• Age groups: Affects individuals of all ages but is a leading cause of irreversible kidney damage in children, teenagers, and young adults 1

Common Diagnostic Pitfalls

• Do not rely on clinical features alone: The presentation overlaps significantly with other glomerular diseases, making biopsy essential 2
• Recognize secondary causes: Always assess for systemic conditions that can cause secondary IgA deposition before attributing disease to primary IgAN 2
• Interpret hematuria context: The significance of persisting isolated hematuria without proteinuria or declining kidney function remains uncertain for predicting outcomes 4