Glomerulonephritis, Pauci-Immune

Key Features

• ANCA-associated vasculitides that cause pauci-immune necrotizing glomerulonephritis

  • Granulomatosis with polyangiitis

  • Microscopic polyangiitis

  • Eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome)

• Antineutrophil cytoplasmic antibody (ANCA)–associated glomerulonephritis can also present as a kidney-limited disease without systemic vasculitis

• Circulating ANCAs bind to antigens and activate a neutrophil respiratory burst with consequent vascular damage; primed neutrophils also appear to activate the alternative complement pathway

• Renal involvement classically presents as a rapid progressive glomerulonephritis, but more indolent presentations can be seen as well

• Putative environmental exposures that may incite the initial response include Staphylococcus aureus and silica

• Immunofluorescence of kidney biopsy specimens do not reveal any evidence of immunoglobulin or complement deposition, hence the term "pauci-immune"

• Most cases are idiopathic, but others may be linked

  • To an infection (including COVID-19)

  • Environmental exposure (silica)

  • To a drug (hydralazine or levamisole)

Clinical Findings

• Fever, malaise, and weight loss, may be present, sometimes for months

• Hematuria and proteinuria

• Purpura and mononeuritis multiplex

• Sinus or lower respiratory tract symptoms present in 90% of patients with granulomatosis with polyangiitis

• Hemoptysis may be a sign of alveolar hemorrhage

Diagnosis

• ANCA subtype analysis is done to determine whether antiproteinase-3 antibodies (PR3-ANCA) or antimyeloperoxidase antibodies (MPO-ANCA) are present

• Most patients with granulomatosis with polyangiitis are PR3 positive; the remainder are MPO positive or, rarely, do not demonstrate circulating ANCA

• Microscopic angiitis is generally associated with MPO ANCA

• Kidney biopsy demonstrates necrotizing lesions and crescents on light microscopy

• Immunofluorescence is negative for immune complex deposition ("pauci-immune")

Treatment

• Institute treatment early if aggressive disease is present; prognosis depends mainly on extent of renal involvement before treatment is started

• Hemoptysis usually warrants hospitalization and aggressive immunosuppression

• Induction therapy

  • High-dose corticosteroids (methylprednisolone, 1–2 g/day intravenously for 3 days, followed by prednisone, 1 mg/kg orally for 1 mo, with a slow taper over the next 6 mo) and cytotoxic agents (cyclophosphamide, 0.5–1.0 g/m² intravenously per month or 1.5–2 mg/kg orally for 3–6 months)

• Maintenance of remission: Long-term azathioprine or mycophenolate mofetil

• Rituximab

  • Shown to be noninferior to cyclophosphamide for induction

  • Also used in refractory or relapsing cases and as an alternative to azathioprine for maintenance of remission

• Avacopan

  • Oral complement inhibitor

  • Shown to be noninferior to oral glucocorticoids for induction in patients treated with either cyclophosphamide or rituximab

• Plasma exchange is likely helpful in conjunction with induction therapy for cases complicated by pulmonary hemorrhage

• Monitor ANCA levels to help determine efficacy of treatment