How is chronic glomerulonephritis diagnosed?

Diagnosis of Chronic Glomerulonephritis

Chronic glomerulonephritis is definitively diagnosed by kidney biopsy, which remains the gold standard for identifying the specific pattern of glomerular injury, determining the underlying etiology, and assessing the degree of chronic damage. 1, 2, 3

Clinical Presentation and Initial Evaluation

Key Clinical Features to Identify

• Asymptomatic hematuria and proteinuria with or without reduced kidney function are the most common presentations, rather than acute nephritic syndrome 3
• Hypertension and edema resulting from sodium and water retention in the setting of renal impairment 2
• Progressive decline in kidney function over months to years, distinguishing chronic from acute presentations 3
• History of disease flares particularly in IgA nephropathy or C3 glomerulopathy 3

Essential Laboratory Workup

Urinalysis must demonstrate:

• Glomerular hematuria (dysmorphic red blood cells) and/or pyuria without infection 1
• Proteinuria on urine dipstick 1
• Quantification of proteinuria to assess nephrotic-range (>3.5 g/day) versus sub-nephrotic levels 2

Serologic testing should include:

• ANCA (MPO and PR3) to evaluate for ANCA-associated vasculitis 1, 4
• ANA and anti-dsDNA for lupus nephritis 1
• Anti-GBM antibodies to exclude anti-GBM disease 1
• Complement levels (C3, C4) which are reduced in immune complex-mediated disease and C3 glomerulopathy 1, 4
• Serum and urine immunofixation with free light chains when monoclonal immunoglobulin-associated disease is suspected 1, 5

Renal function assessment:

• Serum creatinine and estimated GFR to determine severity of kidney impairment 6
• Creatinine >3 mg/dL indicates severe limitation requiring urgent intervention 4

Kidney Biopsy: The Definitive Diagnostic Tool

Indications for Biopsy

Kidney biopsy should be performed when:

• Clinical presentation and serologies suggest glomerulonephritis requiring specific diagnosis 1
• Rapidly progressive glomerulonephritis is suspected, though immunosuppression should not be delayed if ANCA, anti-GBM, or lupus nephritis is highly suspected 1
• Differentiation between primary and secondary causes is needed 1
• Assessment of disease activity versus chronicity is required for treatment decisions 1, 4

Critical Biopsy Components

The kidney biopsy must include:

1. Light microscopy to identify the pattern of glomerular injury (membranoproliferative, crescentic, sclerosing, etc.) 1

2. Immunofluorescence to determine:

   • Immune complex deposition patterns (IgA, IgG, IgM, C3, C1q) 1, 3
   • Complement-dominant patterns (C3 glomerulopathy) 1, 4
   • Pauci-immune patterns (ANCA-associated vasculitis) 3
   • Light chain restriction (kappa vs lambda) when monoclonal immunoglobulin disease is suspected 1, 5

3. Electron microscopy to localize immune deposits (subepithelial, subendothelial, mesangial, intramembranous) 1

4. Special stains:

   • Congo red to exclude amyloidosis 1, 5
   • Pronase digestion if routine immunofluorescence is negative but monoclonal immunoglobulin disease is suspected 5

Quantification of Chronic Damage

The biopsy report must specify:

• Percentage of globally sclerotic glomeruli 1
• Extent of tubular atrophy and interstitial fibrosis (IFTA) quantified as a percentage (mild <25%, moderate 25-50%, severe >50%) 1, 4
• Severity of vascular changes including arteriosclerosis and arteriolosclerosis (mild, moderate, or severe) 1
• Chronicity index score to guide prognosis and treatment decisions 1

Advanced Diagnostic Techniques

When Standard Immunofluorescence is Inconclusive

Mass spectrometry of laser-microdissected kidney tissue is strongly recommended when immunofluorescence/immunohistochemistry results are equivocal, particularly for typing amyloidosis 5

Genetic and Autoantibody Testing

For C3 glomerulopathy:

• Genetic screening for mutations in C3, complement factors H/I/B, CD46, and CFHR 1-5 in children 4
• Testing for C3 nephritic factor (C3Nef) and anti-factor H antibody in adults 4

Imaging Considerations

Renal ultrasound may demonstrate:

• Increased cortical echogenicity suggesting chronic glomerular disease 1, 6
• Small, atrophic kidneys indicating advanced chronic disease 4
• Normal or enlarged kidneys in acute presentations or early chronic disease 1

Advanced imaging (CT, MRI) is NOT routinely indicated for diagnosis of chronic glomerulonephritis unless evaluating for structural abnormalities or complications 1, 6

Common Diagnostic Pitfalls

• Delaying biopsy in rapidly progressive disease: If ANCA-associated vasculitis, anti-GBM disease, or lupus nephritis is strongly suspected with compatible serology, start immunosuppression immediately and perform biopsy soon after when feasible 1
• Inadequate biopsy tissue: Ensure sufficient glomeruli are obtained for accurate diagnosis; the Mayo Clinic/Renal Pathology Society recommends adequate sampling 1
• Missing monoclonal immunoglobulin disease: Always perform serum/urine immunofixation with free light chains when membranoproliferative pattern is identified, even if routine immunofluorescence is negative 1, 5
• Treating patients with advanced chronic disease: Patients with extensive glomerulosclerosis (>60%), severe IFTA (>70%), or small kidneys should NOT receive immunosuppression as the disease is irreversible 4

HCV-Associated Glomerulonephritis

Renal biopsy is mandatory in any HCV patient with urinary abnormalities and/or unexplained renal impairment, as diffuse membranoproliferative glomerulonephritis occurs in approximately 80% of HCV-related glomerulonephritis cases 1, 4