Goodpasture Syndrome

Goodpasture syndrome, also known as anti-glomerular basement membrane (GBM) disease, is an autoimmune disease characterized by circulating antibodies directed against glomerular and alveolar basement membranes. The autoantibodies are thought to be generated in response to an inciting stimulus in genetically predisposed individuals. Affected individuals present with symptoms of rapidly progressive glomerulonephritis and alveolar hemorrhage. Constitutional symptoms such as malaise, chills, fever, arthralgia, and weight loss may also be present. Detection of anti-GBM antibodies and renal biopsy findings of crescent glomerulonephritis with linear IgG deposition along the basement membranes provide the diagnosis. Management includes plasmapheresis and immunosuppressants. Renal transplantation is an option in individuals who develop end-stage renal disease.

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Epidemiology and Etiology

Epidemiology

  • Rare: < 2 cases per million individuals
  • Accounts for:
    • Approximately 15% of all cases of crescentic glomerulonephritis
    • 1%–5% of all cases of glomerulonephritis
  • Bimodal age distribution:
    • 3rd decade
    • 6th–7th decades
  • Sex:
    • Slight male predominance in the younger age group 
    • Female predominance in the older age group

Etiology

  • Potential genetic predisposition:
    • HLA-DR15 (previously known as HLA-DR2)
    • HLA-DR4
  • Possible triggers:
    • Pulmonary injury:
      • Pulmonary infections
      • Cigarette smoking
      • Inhalation of hydrocarbon solvents
      • Pulmonary fibrosis
      • Lung cancer
    • Kidney injury:
      • Extracorporeal shock wave lithotripsy
      • Ureteral obstruction
      • Membranous nephropathy
      • ANCA-associated glomerulonephritis
    • Immune dysregulation:
      • Hematopoietic cell transplantation
      • Lymphocyte-depletion therapy (e.g., alemtuzumab)
      • T cell large granular lymphocyte leukemia
      • Common variable immunodeficiency
      • HIV

Pathophysiology

Goodpasture syndrome (anti-glomerular basement membrane (GBM) disease) is a type II hypersensitivity caused by circulating autoantibodies directed against an intrinsic antigen in the glomerular and alveolar basement membranes.

  • An environmental trigger (in conjunction with genetic predisposition) causing glomerular or alveolar damage → ↑ exposure to the target antigen
  • Immune dysregulation → production of anti-GBM antibodies
    • Specificity:
      • Targets the alpha-3 chain of type IV collagen
      • Alpha-3 chain is present in the highest concentrations in the basement membranes of the renal and pulmonary capillaries.
    • Usually IgG
    • Typically polyclonal
  • Circulating anti-GBM antibodies bind to basement membranes → fix complement → trigger a cell-mediated inflammatory response → tissue injury
    • Glomerulonephritis → proteinuria and renal failure
    • Pulmonary capillaritis → alveolar hemorrhage

Clinical Presentation

Age variations

  • Younger individuals (< 30 years) are more likely to: 
    • Develop pulmonary hemorrhage and glomerulonephritis
    • Be critically ill
  • Older individuals (> 50 years) are more likely to: 
    • Present with isolated glomerulonephritis
    • Follow a less severe course

Constitutional symptoms

  • Malaise
  • Fever
  • Chills
  • Arthralgia
  • Weight loss

Rapidly progressive glomerulonephritis

  • Renal failure
  • “Frothy” or “foamy” urine
  • Edema
  • Hematuria
  • Oliguria
  • Hypertension

Alveolar hemorrhage

  • Dyspnea
  • Tachypnea
  • Cough
  • Hemoptysis
  • Inspiratory crackles
  • Respiratory failure

“Double-positive” disease

Rarely, individuals may present with concurrent ANCA-associated vasculitis.

  • Granulomatosis with polyangiitis (GPA)
  • Microscopic polyangiitis

Diagnosis

Laboratory evaluation

  • Urinalysis:
    • Low-grade proteinuria (usually not in the nephrotic range)
    • Gross or microscopic hematuria
    • RBC and granular casts
  • CBC:
    • Anemia
    • Leukocytosis
  • Renal function tests:
    • ↑ BUN
    • ↑ Creatinine
  • Serologic testing:
    • Serum anti-GBM antibodies confirm the diagnosis and are detected using:
      • ELISA
      • Indirect immunofluorescence
    • Serum ANCA should also be tested to assess for concurrent ANCA vasculitis.

Imaging

Imaging may show evidence of alveolar hemorrhage.

  • Chest X-ray:
    • Patchy parenchymal opacifications that are usually:
      • Bilateral
      • Symmetric
      • Perihilar and bibasilar
    • Apices and costophrenic angles are spared.
  • High-resolution CT scan:
    • Ground-glass or consolidative opacities
    • Bilateral and diffuse distribution
  • Bronchoscopy with sequential bronchoalveolar lavage:
    • Alveolar hemorrhage is confirmed when lavage aliquots are progressively more hemorrhagic.
    • Prussian blue staining reveals characteristic hemosiderin-laden macrophages.

Renal biopsy

  • Light microscopy: crescents in the Bowman’s space and necrosis within the tuft
  • Immunofluorescence: linear IgG deposition along the glomerular capillaries (basement membranes)

Management

Supportive management

  • Severe renal failure → hemodialysis
  • Respiratory failure and life-threatening pulmonary hemorrhage → intubation and mechanical ventilation

Specific therapies

  • Immunosuppressive therapies:
    • Glucocorticoids (e.g., methylprednisolone, prednisone)
    • Cyclophosphamide
    • Alternatives (for those who cannot tolerate cyclophosphamide):
      • Rituximab
      • Mycophenolate mofetil
  • Plasmapheresis:
    • Directly removes anti-GBM antibodies from the plasma
    • Performed until antibody levels are undetectable
  • Renal transplant:
    • Considered in individuals with end-stage renal disease
    • Requires 6 months of negative anti-GBM antibody levels
    • Recurrence after transplant is very rare.

Prognosis

  • Rapidly progressive and fatal if prompt recognition and treatment are delayed
  • Prognosis is generally good after aggressive treatment.
    • The 5-year survival rate is > 80%.
    • < 30% of individuals require long-term dialysis.
  • Survival correlates with the degree of renal impairment on presentation.
  • Poor prognosis if (< 2 years, unless renal transplantation is pursued):
    • Dialysis is needed within 72 hours of presentation, or
    • > 50% of glomeruli show crescents on biopsy

Differential Diagnosis

  • GPA: small- and medium-vessel vasculitis characterized by necrotizing granulomatous inflammation that commonly affect the sinuses, lungs, and kidneys. Clinical manifestations may include constitutional symptoms, recurrent nasal discharge or epistaxis, cough, pulmonary hemorrhage, and renal failure. Diagnosis is based on c-ANCA positivity and biopsy of the affected tissue. Management is with corticosteroids and immunosuppressants. Plasmapheresis can be used in severe cases.
  • Microscopic polyangiitis: small-vessel necrotizing vasculitis that typically affects the lungs, skin, and kidneys. Clinical presentation is based on the affected organs and may include rapidly progressing glomerulonephritis, alveolar hemorrhage, and palpable purpura. Diagnosis is based on positive p-ANCA and biopsy of the affected tissue. Treatment is using corticosteroids and immunosuppressants. 
  • IgA vasculitis: small-vessel vasculitis, formerly known as Henoch-Schönlein purpura, which commonly affects children. Affected individuals may present with palpable purpura, arthralgias, GI symptoms, and glomerulonephritis. The diagnosis is confirmed with a biopsy of the affected organ, which shows IgA deposition on immunofluorescence. The disease is usually self-limiting in children. Corticosteroids and cyclophosphamide can be used for management, particularly in the case of severe renal involvement.
  • Lupus nephritis: glomerulonephritis caused by systemic lupus erythematosus. Clinical presentation includes hematuria, nephrotic-range proteinuria, and renal failure. Diagnosis is based on renal biopsy, which helps classify the disease, guide management, and provide an indication of prognosis. Management includes ACE inhibitors and immunosuppressants.

References

  1. Pusey, C.D., et al. (2020). Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis. In Glassock R.J., et al. (Ed.), UpToDate. Retrieved August 24, 2021, from: https://www.uptodate.com/contents/anti-gbm-goodpasture-disease-pathogenesis-clinical-manifestations-and-diagnosis
  2. Kaplan, A.A., et al. (2021). Anti-GBM (Goodpasture) disease: Treatment and prognosis. In Glassock R.J., et al. (Ed.), UpToDate. Retrieved August 24, 2021, from: https://www.uptodate.com/contents/anti-gbm-goodpasture-disease-treatment-and-prognosis
  3. Lee, J. (2020). Goodpasture syndrome. [online] MSD Manual Professional Version. Retrieved August 24, 2021, from: https://www.msdmanuals.com/professional/pulmonary-disorders/diffuse-alveolar-hemorrhage-and-pulmonary-renal-syndrome/goodpasture-syndrome
  4. King, T.E. (2021). The diffuse alveolar hemorrhage syndromes. In Flaherty K.R., et al. (Ed.), UpToDate. Retrieved August 24, 2021, from: https://www.uptodate.com/contents/the-diffuse-alveolar-hemorrhage-syndromes
  5. Kathuria, P. (2021). Goodpasture syndrome. In Batuman V., et al. (Ed.), Medscape. Retrieved August 24, 2021, from: https://emedicine.medscape.com/article/240556
  6. DeVrieze, B.W., Hurley, J.A. Goodpasture syndrome. [Updated 2021 Jul 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459291/

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