What are extrarenal manifestations in patients with Rapidly Progressive Glomerulonephritis (RPGN)?

Extrarenal Manifestations in Rapidly Progressive Glomerulonephritis (RPGN)

Extrarenal manifestations in RPGN commonly involve the respiratory tract, skin, eyes, and nervous system, and their presence significantly impacts treatment decisions and patient outcomes.

Overview of RPGN and Extrarenal Involvement

RPGN is characterized by rapid decline in kidney function over days to weeks, typically associated with necrotizing and crescentic glomerulonephritis. While kidney involvement is the defining feature, multiple organ systems are frequently affected, particularly in ANCA-associated vasculitis (AAV), which is the most common cause of RPGN 1.

Common Extrarenal Manifestations by System

Respiratory System

• Upper respiratory tract: Sinusitis, rhinitis, otitis, nasal crusting, epistaxis, nasal septum perforation
• Lower respiratory tract: Pulmonary hemorrhage (affects 10% of AAV patients and increases mortality risk), nodules, cavities, interstitial lung disease 1
• Pulmonary-renal syndrome: Simultaneous lung and kidney injury, particularly alveolar hemorrhage with RPGN 1

Skin

• Palpable purpura
• Nodules
• Ulcers
• Livedo reticularis
• Necrotic lesions 2

Eyes

• Episcleritis
• Scleritis
• Uveitis
• Retinal vasculitis
• Orbital inflammation 1, 2

Nervous System

• Mononeuritis multiplex
• Peripheral neuropathy
• Cranial nerve palsies
• Central nervous system vasculitis 1, 2

Gastrointestinal System

• Abdominal pain
• Gastrointestinal bleeding
• Bowel ischemia or perforation (particularly in IgA vasculitis) 1

Clinical Significance of Extrarenal Manifestations

Diagnostic Importance

• The presence of extrarenal manifestations should raise suspicion for systemic vasculitis as the underlying cause of RPGN 1
• Pulmonary-renal syndrome specifically suggests AAV or anti-GBM disease 1

Treatment Implications

1. Treatment Decisions: Extrarenal manifestations influence treatment choices:

   • Diffuse alveolar bleeding with hypoxemia may warrant plasma exchange in addition to standard immunosuppression 1
   • Life-threatening extrarenal manifestations may require more aggressive therapy 1

2. Treatment Continuation: Even if a patient becomes dialysis-dependent, immunosuppression should be continued if extrarenal manifestations persist 1

3. Treatment Intensity: The severity of extrarenal disease determines treatment approach:

   • Severe extrarenal disease requires cyclophosphamide or rituximab with glucocorticoids 1
   • Nonsevere extrarenal disease may be managed with methotrexate and corticosteroids 1

Monitoring and Follow-up

• Patients require monitoring for both renal and extrarenal disease activity 2
• Even patients who initially present with renal-limited disease may subsequently develop extrarenal manifestations 1

Management Considerations Based on Extrarenal Manifestations

Pulmonary Hemorrhage

• Severe pulmonary hemorrhage: Consider plasma exchange in addition to standard immunosuppression with cyclophosphamide or rituximab plus glucocorticoids 1
• Mechanical ventilation may be required in severe cases 1

Other Severe Extrarenal Manifestations

• Life-threatening manifestations: May benefit from plasma exchange in addition to standard immunosuppression 1
• Cyclophosphamide vs. Rituximab: Cyclophosphamide is often preferred for severe extrarenal disease, though rituximab is an alternative 1

Special Considerations

IgA Vasculitis with Extrarenal Manifestations

• IgA vasculitis nephropathy with RPGN may be associated with significant extrarenal involvement (pulmonary, gastrointestinal, skin) 1
• Uncontrolled case series suggest potential benefit of adding plasma exchange to glucocorticoid therapy for life- or organ-threatening extrarenal complications 1

Maintenance Therapy

• Maintenance immunosuppression is crucial in patients with extrarenal manifestations to prevent relapse 1
• Duration should be at least 18 months, with consideration for longer treatment in patients with severe or recurrent extrarenal disease 1

Clinical Pearls and Pitfalls

• Pearl: Always evaluate for extrarenal manifestations in any patient with RPGN, as their presence may indicate systemic vasculitis requiring specific treatment 1
• Pitfall: Discontinuing immunosuppression in dialysis-dependent patients who have extrarenal manifestations can lead to worsening of extrarenal disease 1
• Pearl: The combination of pulmonary hemorrhage and RPGN should immediately raise suspicion for AAV or anti-GBM disease and warrants urgent treatment 1

In conclusion, extrarenal manifestations in RPGN are common, particularly in AAV, and their presence significantly impacts diagnosis, treatment decisions, and prognosis. Prompt recognition and appropriate management of both renal and extrarenal manifestations are essential for improving outcomes in patients with RPGN.