What is the approach to diagnosing and treating glomerulonephritis (inflammation of the glomeruli)?

Diagnosis of Glomerulonephritis

Kidney biopsy remains the gold standard for diagnosing glomerulonephritis, but proceed with urgent immunosuppressive therapy without waiting for biopsy if clinical presentation and positive ANCA serology strongly suggest rapidly progressive disease. 1

Initial Clinical Assessment

When evaluating suspected glomerulonephritis, immediately assess for warning signs of rapidly progressive disease: rapid decline in kidney function over days to weeks, oliguria, severe hypertension, and pulmonary hemorrhage. 2 These findings demand urgent action.

Essential Laboratory Workup

• Urinalysis with microscopy: Perform urine dipstick for protein and blood, followed by microscopic examination specifically looking for glomerular hematuria (dysmorphic red blood cells), red blood cell casts, and acanthocytes—these are pathognomonic for glomerular disease. 1

• Quantify proteinuria: Obtain 24-hour urine collection in adults (at least 8-10 glomeruli needed for adequate diagnosis). In children, use first morning protein-creatinine ratio instead, as 24-hour collections are inaccurate and cumbersome. 1

• Serologic testing: Order a comprehensive autoimmune panel including:

  • ANCA (anti-MPO and anti-PR3) for ANCA-associated vasculitis
  • Anti-GBM antibodies for Goodpasture syndrome
  • ANA and anti-dsDNA for lupus nephritis
  • Complement levels (C3, C4) to distinguish immune complex from complement-mediated disease
  • Cryoglobulins, hepatitis B/C serologies for infection-related GN
  • PLA2R antibodies for membranous nephropathy 1, 3

• Assess kidney function: Use CKD-EPI creatinine equation for adults and modified Schwartz equation for children to calculate eGFR. 1

Kidney Biopsy: When and How

Perform kidney biopsy when the result will modify treatment or provide critical prognostic information. 1 The biopsy requires adequate tissue: at least 8-10 glomeruli for light microscopy, though more may be needed for focal and segmental lesions. 1

Critical Exception—When to Skip Biopsy

Treatment may proceed without biopsy confirmation in these specific scenarios: 1

• MPO+ or PR3+ ANCA vasculitis with compatible clinical presentation—do not delay immunosuppression
• Anti-GBM disease with positive serology and pulmonary-renal syndrome
• PLA2R+ membranous nephropathy, especially with normal eGFR
• Systemic lupus erythematosus with clear extrarenal manifestations
• Alport disease or familial FSGS with well-characterized mutations
• Biopsy contraindicated by bleeding risk or other medical factors

Biopsy Adequacy Standards

The pathology evaluation must include three components: 1

1. Light microscopy: Evaluate with PAS, H&E, trichrome, and Jones' silver stains. Document number of glomeruli (total, globally sclerosed, segmentally sclerosed), pattern of injury (focal vs. diffuse, segmental vs. global), presence of crescents (cellular, fibrocellular, or fibrous), mesangial hypercellularity, endocapillary proliferation, capillary wall thickening, GBM abnormalities, and fibrinoid necrosis.

2. Immunofluorescence: Detect immunoreactants (IgG, IgA, IgM, C3, C4, C1q, fibrin, kappa/lambda light chains) and target antigens (PLA2R, THSD7A, DNAJB9). The immunofluorescence pattern guides classification into immune complex-mediated, complement-mediated, or pauci-immune disease. 1, 4

3. Electron microscopy: Define location and characteristics of immune deposits, extent of foot process effacement, and structural GBM alterations.

Classification Framework

Use immunofluorescence findings to direct the diagnostic workup: 1, 4

If immunoglobulin-positive (with or without complement): Evaluate for immune complex glomerulonephritis—distinguish between infection-related (hepatitis B/C, endocarditis), autoimmune (SLE, Sjögren's), or monoclonal gammopathy-related disease. In adults, idiopathic immune complex GN is rare; exhaust all other possibilities first. 1

If complement-dominant (C3 or C4) without immunoglobulin: Consider C3 or C4 glomerulopathy. Investigate for complement dysregulation by testing for C3 nephritic factor, anti-factor H antibodies, and genetic mutations in complement factors (CFH, CFI, CFB, CD46). 1

If immunofluorescence-negative: Suspect thrombotic microangiopathy, chronic TMA, scleroderma renal crisis, or antiphospholipid syndrome. 1

Common Pitfalls to Avoid

• Random spot urine collections are inadequate for proteinuria quantification due to temporal variation in protein and creatinine excretion. 1

• First morning collections may underestimate 24-hour protein excretion in orthostatic proteinuria. 1

• Do not delay treatment in ANCA+ vasculitis waiting for biopsy—mortality increases with delayed immunosuppression. 1, 2

• Persistently low C3 beyond 12 weeks in presumed post-infectious GN warrants repeat biopsy to exclude C3 glomerulopathy. 1

• Repeat biopsy is indicated if clinical course changes unexpectedly or if information would alter therapeutic decisions. 1

Monitoring Disease Activity

• Screen for latent infections (tuberculosis, hepatitis B) before initiating immunosuppression. 1, 2
• Monitor proteinuria reduction as the primary surrogate endpoint for treatment response. 1, 2
• Assess for ≥40% decline in eGFR from baseline over 2-3 years as a surrogate outcome for kidney failure. 1, 2