What is the appropriate workup and management for a patient presenting with rapid progressive Glomerulonephritis (RPGN)?

Rapid Progressive Glomerulonephritis Workup

Rapidly progressive glomerulonephritis (RPGN) is a medical emergency requiring immediate diagnostic workup and treatment initiation within hours to days, as irreversible kidney damage occurs within weeks if left untreated. 1, 2

Immediate Diagnostic Workup

Essential Laboratory Tests (Order Stat)

Urinalysis with microscopy is the critical first step—look specifically for:

• Glomerular hematuria with red blood cell casts (pathognomonic for glomerular disease) 1, 2
• Proteinuria (typically >500 mg/day) 1
• Dysmorphic red blood cells 1

Serum studies to order immediately:

• Creatinine and BUN to assess severity (creatinine >3 mg/dL severely limits treatment efficacy; >5 mg/dL may require urgent dialysis) 2
• Complete blood count to assess for anemia or thrombocytopenia 2
• Electrolytes to identify life-threatening abnormalities 2

Critical Autoimmune Serologies (Do Not Wait for Results to Treat)

Order all of the following simultaneously 1, 3:

• ANCA panel (MPO and PR3)—positive in ~90% of pauci-immune RPGN, which accounts for 50-60% of all RPGN cases 1
• Anti-GBM antibodies—accounts for ~20% of RPGN cases, often presents with pulmonary-renal syndrome 1, 3
• ANA and anti-dsDNA for lupus nephritis 1
• Complement levels (C3, C4) for immune complex disease 1
• Hepatitis B and C serologies before starting immunosuppression 4

Critical pitfall to avoid: Do not delay immunosuppressive therapy while waiting for serologies if clinical presentation is compatible with small-vessel vasculitis and patient is rapidly deteriorating 1, 3

Kidney Biopsy Timing

Kidney biopsy is essential to confirm diagnosis and assess disease activity versus chronicity 1. However:

• Do NOT delay treatment while waiting for biopsy if clinical presentation strongly suggests ANCA-associated vasculitis or anti-GBM disease with positive serology 1, 3
• Biopsy should be performed urgently (within 24-48 hours) but treatment initiation takes priority over biopsy 3
• Look for crescents in >50% of glomeruli (diagnostic hallmark of RPGN) 1
• Immunofluorescence pattern determines etiology: linear IgG (anti-GBM), granular deposits (immune complex), or pauci-immune (ANCA) 3

Major Etiologic Categories and Their Frequencies

Pauci-Immune RPGN (50-60% of cases)

• ANCA-associated vasculitis is the most common cause 1
• Includes granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) 1
• ~10% are ANCA-negative but still have pauci-immune disease on biopsy 1

Anti-GBM Disease (20% of cases)

• Goodpasture's syndrome with pulmonary-renal involvement 1, 3
• ~10% have falsely negative circulating antibodies—linear IgG on biopsy is pathognomonic 3
• Can be double-positive with ANCA (requires specific management considerations) 3

Immune Complex-Mediated (20-25% of cases)

• IgA nephropathy with extensive crescents 1
• Lupus nephritis 1
• Post-infectious glomerulonephritis 1
• HCV-associated cryoglobulinemic glomerulonephritis 4

Treatment Initiation Algorithm

For Crescentic/Necrotizing RPGN (Most Aggressive Treatment)

Start immediately with regimen similar to ANCA-associated vasculitis 4:

• Pulse IV methylprednisolone (500-1000 mg daily for 3 days) followed by oral prednisone 4
• Plus either:
  • Cyclophosphamide (traditional agent) 4, 1, OR
  • Rituximab (increasingly preferred) 4, 1

For anti-GBM disease specifically:

• Add plasmapheresis to the above regimen 3
• Begin while awaiting antibody confirmation if clinical presentation is highly compatible 3

For HCV-Associated RPGN with Cryoglobulinemic Flare

Treat with both direct-acting antivirals (DAAs) AND immunosuppressive agents with or without plasma exchange 4. This is a specific exception where infection treatment alone is insufficient 4.

Critical Pre-Treatment Requirement

The ONLY absolute requirement before starting immunosuppression is excluding active infection 1. Check:

• Chest X-ray for tuberculosis or fungal infection 1
• Blood and urine cultures if febrile 1
• Hepatitis B surface antigen (risk of reactivation with immunosuppression) 4

When NOT to Treat Aggressively

Withhold immunosuppression if eGFR <30 mL/min per 1.73 m² with chronic changes 4:

• This applies ONLY when biopsy shows high degree of interstitial fibrosis/tubular atrophy and glomerular sclerosis 4
• Does NOT apply to active necrotizing/crescentic GN causing the low GFR 4
• Does NOT apply if there is preserved renal parenchyma with acute tubular necrosis 4

Common Pitfalls to Avoid

• Never assume ANCA positivity excludes anti-GBM disease—double-positive patients exist and require specific management 3
• Never exclude anti-GBM disease based on absence of pulmonary symptoms—isolated renal-limited disease occurs frequently 3
• Never wait for biopsy results to start treatment in rapidly deteriorating patients with compatible clinical presentation 1, 3
• Never use the term "RPGN" for crescents on biopsy without rapid clinical deterioration—both histologic crescents AND rapid GFR decline over days to weeks are required 1