What causes anti-GBM (anti-glomerular basement membrane) disease?

What Causes Anti-GBM Disease?

Anti-GBM disease is an autoimmune disorder triggered by the development of pathogenic autoantibodies against type IV collagen antigens in the glomerular and alveolar basement membranes, though the exact etiology remains unknown and is thought to involve environmental triggers in genetically predisposed individuals. 1, 2

Pathophysiology

The fundamental mechanism involves autoantibody formation:

• Pathogenic autoantibodies develop specifically against type IV collagen antigens expressed in both glomerular and alveolar basement membranes 2
• Once these autoantibodies deposit in tissue, they incite a local capillaritis that manifests as rapidly progressive glomerulonephritis in 80-90% of patients 2
• Concurrent alveolar hemorrhage occurs in approximately 50% of cases, creating the classic Goodpasture syndrome presentation 2
• The disease appears to be monophasic and self-limited, with antibodies often disappearing spontaneously after 6-18 months 3

Triggering Factors

While the precise etiology remains unclear, several potential triggers have been identified:

Environmental Exposures

• Hydrocarbon exposure is associated with disease activity, making smoking cessation strongly recommended 3
• The disease is thought to be triggered by environmental factors in genetically predisposed individuals 1

Infectious or Vaccine-Related Triggers

• Recent case reports have linked COVID-19 vaccination to the development of anti-GBM disease, with rapidly progressive glomerulonephritis occurring within days of vaccination 1
• These vaccine-associated cases raise concerns about potential immunologic triggers, though causality remains under investigation 1

Genetic Predisposition

• A genetic predisposition cannot be excluded in the development of anti-GBM disease 4
• Patients with Alport syndrome can develop anti-GBM antibodies (in 2-3% of cases) to the foreign collagen chain in transplanted kidneys 3

Special Populations and Variants

Double-positive disease (anti-GBM with ANCA):

• Approximately 30-40% of anti-GBM patients have concomitant antineutrophil cytoplasm antibodies (ANCA) 2
• These "double-positive patients" have different relapse patterns equivalent to ANCA-associated vasculitis, requiring maintenance immunosuppression 3
• Treatment approach differs from isolated anti-GBM disease due to higher relapse risk 3

Monoclonal gammopathy-associated anti-GBM:

• Rare cases of anti-GBM disease can occur secondary to monoclonal gammopathy 3
• The anti-GBM monoclonal antibody can be IgG or IgA 3
• These patients experience frequent relapses and disease recurrence after kidney transplantation, unlike typical anti-GBM disease 3
• The anti-GBM antibody is often not detectable in serum by commercially available assays designed to detect antibodies against only α3NC1 3

Clinical Implications

Understanding causation impacts management:

• Relapses are rare (<5%) in treated isolated anti-GBM disease, so maintenance therapy is unnecessary 3
• However, ongoing monitoring is important for at least the first 2 years, as relapses have rarely been reported 3
• Patients with persistent low levels of anti-GBM antibodies may benefit from azathioprine after cyclophosphamide 3
• Kidney transplantation should be postponed until anti-GBM antibodies remain undetectable for ≥6 months to minimize recurrence risk 3