What is the approach to ruling out IgA (Immunoglobulin A) nephropathy in a patient with suspected kidney damage, presenting with symptoms such as hematuria, proteinuria, or impaired renal function?

Ruling Out IgA Nephropathy

IgA nephropathy cannot be definitively ruled out without a kidney biopsy showing the absence of mesangial dominant or co-dominant IgA deposits on immunofluorescence microscopy. 1

Definitive Diagnostic Requirement

• Kidney biopsy is the gold standard and only definitive method to diagnose or exclude IgA nephropathy. 1
• The pathognomonic finding is mesangial dominant or co-dominant IgA deposits on immunofluorescence, typically accompanied by electron-dense deposits in the mesangium on electron microscopy. 1
• C3 is often present alongside IgA deposits, while C1q is less commonly found. 1

Clinical Evaluation Before Biopsy Decision

While biopsy is definitive, the following clinical assessment helps determine whether IgA nephropathy is likely and whether biopsy is warranted:

Key Clinical Features Suggesting IgA Nephropathy

• Episodic gross hematuria is relatively common (40-50% of cases), often following upper respiratory infections. 2
• Persistent microscopic hematuria with or without proteinuria. 3
• Family history of hematuria or renal failure may occur in isolated cases. 2
• Proteinuria ranging from minimal to nephrotic range (88% of patients have proteinuria). 3
• Median age at onset of clinical signs is typically around 20 years. 3

Critical Differential Diagnoses to Exclude

Thin basement membrane (TBM) disease must be distinguished from IgA nephropathy: 2

• TBM disease: gross hematuria in <10% of patients, positive family history of hematuria, typically negative family history of renal failure. 2
• IgA nephropathy: episodic gross hematuria in 40-50%, may have family history of renal failure. 2

Alport syndrome must be excluded: 2

• May have episodic gross hematuria with positive family history of renal failure. 2
• Deafness may be present in families with X-linked inheritance. 2
• TBM disease and early Alport syndrome may be difficult to differentiate histologically, requiring biopsy. 2

Secondary Causes Assessment

All patients with biopsy-proven IgA nephropathy must be assessed for secondary causes. 2

• Exclude systemic lupus erythematosus, liver disease, inflammatory bowel disease, and other conditions that can cause secondary IgA deposition. 2

When Biopsy is Indicated

Proceed with kidney biopsy when: 2

• Proteinuria ≥0.5 g/day is present. 4
• eGFR <60 ml/min per 1.73 m² without clear alternative explanation. 4
• Persistent hematuria with proteinuria and concern for progressive kidney disease. 2

Risk Stratification After Diagnosis

Once IgA nephropathy is confirmed by biopsy, assess progression risk: 2

Clinical risk factors: 2, 5

• Proteinuria >1 g/day is the single most important clinical predictor of outcome. 5, 6
• Uncontrolled hypertension is an independent predictor of adverse outcomes. 5
• Impaired eGFR at presentation is associated with end-stage renal disease. 5

Pathological risk factors using Oxford MEST-C classification: 5

• Mesangial hypercellularity, Endocapillary hypercellularity, Segmental glomerulosclerosis, Tubular atrophy/interstitial fibrosis, and Crescents provide independent prognostic information. 5

Critical Pitfalls

• Do not rely on clinical features alone to exclude IgA nephropathy—the presentation overlaps significantly with other glomerular diseases. 2
• Even patients with proteinuria <0.88 g/g (traditionally considered "low risk") have high rates of kidney failure within 10 years (approximately 20%). 4
• Most patients with IgA nephropathy progress to kidney failure within 10-15 years unless eGFR loss is maintained at ≤1 ml/min per 1.73 m² per year. 4
• The median kidney survival is only 11.4 years, with mean age at kidney failure of 48 years. 4