What is IgA Nephropathy?
IgA nephropathy is an autoimmune kidney disease characterized by the deposition of immunoglobulin A (IgA) in the glomerular mesangium, making it the most common primary glomerulonephritis worldwide and a leading cause of chronic kidney disease that progresses to end-stage renal disease in 20-40% of patients within 20 years of diagnosis. 1, 2, 3
Pathophysiology
The disease involves a multi-step autoimmune process where galactose-deficient IgA1 (Gd-IgA1) antibodies form immune complexes that deposit in the kidney's glomerular mesangium, triggering complement-mediated inflammation and progressive kidney damage 4, 3. The definitive diagnostic feature is mesangial dominant or co-dominant IgA deposits on kidney biopsy, typically accompanied by C3 co-deposition, while C1q is less commonly present (which helps distinguish it from lupus nephritis) 5, 6.
Clinical Presentation
Common Manifestations
- Episodic gross hematuria occurs in 40-50% of cases, often following upper respiratory infections 5
- Persistent microscopic hematuria with or without proteinuria is the hallmark presentation 2, 7
- Proteinuria serves as the best marker for disease progression and treatment response 7
- The disease predominantly affects young males 2
Family History Considerations
A family history of hematuria or renal failure may occur in isolated cases, though this is not typical 5.
Diagnostic Approach
When to Suspect IgA Nephropathy
Proceed with kidney biopsy when persistent hematuria with proteinuria and concern for progressive kidney disease is present 5. Kidney biopsy remains the gold-standard diagnostic test, as no biomarker is sufficiently specific and sensitive to replace it 8, 3.
Histologic Assessment
Following biopsy-confirmed diagnosis, histologic scoring via the MEST-C system (mesangial and endocapillary hypercellularity, segmental glomerulosclerosis, interstitial fibrosis/tubular atrophy, and crescents) is essential to assess disease prognosis 1. Electron microscopy reveals electron-dense deposits in the mesangium 5, 6.
Critical Differential Diagnoses
- Thin basement membrane disease: Distinguished by gross hematuria in <10% of patients, positive family history of hematuria but typically negative family history of renal failure 5
- Alport syndrome: May present with episodic gross hematuria, positive family history of renal failure, and deafness in X-linked inheritance patterns 5
- Lupus nephritis: More commonly shows C1q deposition compared to IgA nephropathy 6
Exclude Secondary Causes
Always assess for conditions causing secondary IgA deposition, including systemic lupus erythematosus, chronic liver disease (particularly cirrhosis), inflammatory bowel disease, infections, tumors, and rheumatic diseases 5, 6, 2.
Risk Stratification for Disease Progression
High-Risk Clinical Features
Patients with the following features at diagnosis are at high risk for progressive kidney disease 5, 6, 2:
- Proteinuria >1 g/day (persistent protein excretion is the strongest modifiable risk factor) 8
- Uncontrolled hypertension 5, 8
- Elevated serum creatinine at presentation 2
- eGFR <30 ml/min per 1.73 m² 1
High-Risk Histologic Features
Progression correlates more closely with tubulointerstitial lesions than glomerular lesions 2:
- Glomerulosclerosis
- Tubular atrophy/interstitial fibrosis
- Extension of immune deposits to the perivascular space
- Crescent formation
Prognostic Tools
The International IgAN Prediction Tool (available at Calculate by QxMD) provides valuable prognostic information, though neither this calculator, the MEST-C score, nor the presence of crescents can currently determine the likely impact of specific treatment regimens 1.
Common Pitfalls
Never rely on clinical features alone to exclude IgA nephropathy, as the presentation overlaps significantly with other glomerular diseases 5. The diagnosis requires kidney biopsy confirmation with demonstration of mesangial IgA deposits 5, 6.