What is Rapidly Progressive Glomerulonephritis (RPGN)?

Rapidly Progressive Glomerulonephritis (RPGN)

Rapidly Progressive Glomerulonephritis (RPGN) is a severe clinical syndrome characterized by rapid decline in kidney function over days to weeks that leads to irreversible kidney failure if not diagnosed and treated promptly. 1

Definition and Pathophysiology

RPGN is not a specific disease but a clinical syndrome resulting from severe glomerular injury with the following characteristics:

• Rapid decline in kidney function (over days to weeks)
• Histologically characterized by crescent formation in >50% of glomeruli
• Often accompanied by glomerular necrosis
• Potentially reversible with early diagnosis and appropriate treatment

Classification

RPGN can be classified into three major categories based on immunopathology:

1. Anti-GBM antibody disease (Type I):

   • Characterized by linear deposition of antibodies against glomerular basement membrane
   • Includes Goodpasture syndrome when associated with pulmonary hemorrhage

2. Immune complex-mediated (Type II):

   • Characterized by granular immune deposits
   • Associated with conditions like lupus nephritis, IgA nephropathy, post-infectious glomerulonephritis

3. Pauci-immune (Type III):

   • Most common form (>50% of cases)
   • Minimal or absent immune deposits
   • Usually associated with ANCA-positive vasculitis
   • Includes granulomatosis with polyangiitis, microscopic polyangiitis, and renal-limited vasculitis

Clinical Presentation

Common clinical manifestations include:

• Rapid decline in kidney function
• Hematuria (often with red cell casts)
• Proteinuria (variable, often non-nephrotic)
• Hypertension
• Oliguria or anuria
• Systemic symptoms: fever, fatigue, weight loss, joint pain
• Extrarenal manifestations (depending on underlying cause):
  • Pulmonary hemorrhage (in Goodpasture syndrome)
  • Upper respiratory tract involvement (in granulomatosis with polyangiitis)
  • Skin lesions, neuropathy (in systemic vasculitis)

Diagnostic Approach

The diagnostic strategy for RPGN should include:

1. Recognition of clinical pattern:

   • Rapid decline in kidney function
   • Active urinary sediment (hematuria, proteinuria)

2. Laboratory evaluation:

   • Urinalysis: proteinuria and hematuria
   • Urine microscopy: red cell casts, dysmorphic red cells
   • Serum creatinine and eGFR to assess kidney function
   • Autoimmune serologies:
     • ANCA (MPO and PR3)
     • Anti-GBM antibodies
     • ANA and anti-dsDNA (for lupus)
     • Complement levels (C3, C4)

3. Kidney biopsy:

   • Gold standard for diagnosis
   • Reveals crescents in >50% of glomeruli
   • Helps determine underlying pathology
   • Provides prognostic information

Treatment Approach

Treatment should be initiated promptly without waiting for kidney biopsy results if clinical presentation strongly suggests RPGN and serologies are positive for ANCA or anti-GBM antibodies. 1

General Principles:

1. Exclude infection before starting immunosuppression
2. Initiate treatment early to prevent irreversible kidney damage
3. Tailor treatment to underlying cause

Treatment by Type:

ANCA-Associated Vasculitis (most common cause):

Induction Therapy:

• Glucocorticoids plus either cyclophosphamide or rituximab 1, 2
  • IV pulse methylprednisolone (500-1000 mg daily for 3 days)
  • Followed by oral prednisone (initially 1 mg/kg/day, max 60-80 mg)
  • Cyclophosphamide (oral 2 mg/kg/day or IV 15 mg/kg every 2-3 weeks)
  • OR Rituximab (375 mg/m² weekly for 4 weeks or 1000 mg on days 1 and 15)

For severe kidney disease (creatinine >4 mg/dl):

• Cyclophosphamide is preferred over rituximab
• Consider combination of cyclophosphamide (2 IV pulses) plus rituximab in very severe cases 1, 2

Maintenance Therapy:

• Rituximab or azathioprine plus low-dose glucocorticoids
• Duration: at least 18 months 1

Anti-GBM Disease:

• Plasma exchange (daily for 14 days or until antibodies are undetectable)
• High-dose glucocorticoids
• Cyclophosphamide

Immune Complex RPGN:

• Treatment depends on underlying cause (lupus nephritis, IgA nephropathy, etc.)
• For IgAN with RPGN: treat with cyclophosphamide and glucocorticoids as per AAV guidelines 1

Monitoring and Follow-up

• Regular assessment of kidney function
• Urinalysis to monitor active disease
• Complete blood count to monitor for treatment toxicity
• ANCA titers (though treatment decisions should not be based solely on ANCA titers)

Prognosis

Prognosis depends on:

• Severity of kidney dysfunction at presentation
• Percentage of crescents on biopsy
• Underlying cause
• Promptness of treatment initiation

Without treatment, RPGN leads to end-stage kidney disease in approximately 90% of cases 3. With appropriate and timely treatment, renal function can improve in about 50% of patients 4.

Common Pitfalls to Avoid

1. Delaying treatment while waiting for biopsy results in highly suspicious cases
2. Inadequate immunosuppression leading to irreversible kidney damage
3. Failing to exclude infection before starting immunosuppression
4. Overreliance on ANCA titers to guide treatment decisions
5. Neglecting maintenance therapy after successful induction
6. Missing extrarenal manifestations that may require additional treatment approaches

Early recognition of even seemingly nonspecific manifestations like "flu-like syndrome" with glomerular hematuria is crucial, as these may be early signs before significant kidney function decline 3.