Antiglomerular Basement Membrane Disease - Goodpasture Syndrome

Antiglomerular basement membrane (anti-GBM) disease (often referred to as Goodpasture syndrome or Goodpasture disease, depending on presentation) is a rare autoimmune condition characterized by damage to capillaries of the kidneys and lungs due to the deposition of pathogenic anti-GBM autoantibodies. More than 80% of patients with anti-GBM disease will present with features of rapidly progressive glomerulonephritis and renal disease, and up to 60% will have evidence of lung hemorrhage. Early intervention has a significant effect on organ survival; rapid diagnosis and initiation of treatment are therefore essential. Laboratory testing in anti-GBM disease includes serologic (antibody) testing, deposited antibody testing, and renal histopathology for diagnosis, as well as testing for organ dysfunction and monitoring for treatment efficacy.

Quick Answers for Clinicians

What are the predictors of kidney survival in antiglomerular basement membrane disease?

The serum creatinine level at presentation, oligoanuria, the severity of kidney dysfunction and need for dialysis, and the percentage of glomeruli with crescents observed via histopathology are all predictors of kidney survival in antiglomerular basement membrane (anti-GBM) disease.

How is lung dysfunction evaluated in antiglomerular basement membrane disease?

Lung biopsy is generally not performed for suspected antiglomerular basement membrane (anti-GBM) disease. The diagnosis of pulmonary hemorrhage, which may or may not be present in anti-GBM disease, relies on clinical evidence, radiologic examination, bronchoalveolar lavage, bronchoscopy, and/or pulmonary function testing, depending on the needs and condition of the patient.

What is the connection between Alport syndrome and antiglomerular basement membrane disease, and how does this affect laboratory testing?

Alport syndrome arises due to pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes, which code for type IV collagen, a component of the basement membrane. Up to 10% of patients with Alport syndrome may develop antiglomerular basement membrane (anti-GBM) antibodies after kidney transplantation due to the presence of normal collagen in the transplanted kidney, which may or may not lead to glomerulonephritis. These antibodies differ from the anti-GBM antibodies that occur in most cases of anti-GBM disease, and may not be detected by commercial serologic assays. Patients with large COL4A5 deletions are most at risk for developing anti-GBM antibodies. Genetic testing and counseling to inform clinical decision-making are recommended.

Which genetic markers are associated with antiglomerular basement membrane disease?

Antiglomerular basement membrane (anti-GBM) disease is strongly associated with an HLA-DR2 haplotype. DRB1*1501 and *1401 alleles are highly prevalent in patients with anti-GBM and are consistent with a genetic susceptibility to autoimmunity in general. The DRB1*07 haplotype appears to be protective against the disease. Variants in some non-HLA genes have also been associated with susceptibility to anti-GBM disease.

Indications for Testing

Laboratory testing is used to:

Diagnose patients with symptoms of anti-GBM disease (particularly rapid, progressive renal disease that exists alone or in combination with pulmonary disease)
Identify organ dysfunction associated with anti-GBM disease
Monitor the efficacy of treatment

Laboratory Testing

Diagnosis

Serologic Testing

Serologic testing for anti-GBM antibodies can be performed using a number of immunoassays; however, enzyme-linked immunosorbent assays (ELISAs), multiplex bead-based assays, and indirect immunofluorescence (IIF) assays are the most common test methods used in clinical laboratories. Due to the rapidly progressive nature of glomerulonephritis in anti-GBM disease, fast turnaround of serologic testing is essential for timely treatment initiation. However, serologic testing is not recommended as a stand-alone diagnostic tool, and a small percentage of patients may have antibodies that are undetectable by current methods. Unless contraindicated, kidney biopsy should be performed to confirm the results of serologic testing.

Antineutrophil Cytoplasm Antibody Testing

Up to 30% of patients with anti-GBM disease are also antineutrophil cytoplasmic antibody (ANCA) positive. NCA testing should be performed concurrently with anti-GBM testing. Patients with anti-GBM disease who are ANCA positive have been found to be more susceptible to relapse than patients positive only for anti-GBM antibodies. Although this susceptibility has not been firmly established, patients positive for ANCAs may warrant additional monitoring. ANCA test results may also support the diagnosis of another form of vasculitis or rule out other causes of rapidly progressive glomerulonephritis.

Kidney Tissue Testing

Tissue examination is the gold standard for anti-GBM disease diagnosis.

Deposited Antibody Testing

Direct immunofluorescence testing of kidney tissue for anti-GBM immunoglobulin G (IgG) is very sensitive for anti-GBM disease. Linear deposits of IgG are generally visible; however, these deposits may be difficult to distinguish if there is severe inflammation and architectural disruption, and may arise for reasons other than anti-GBM disease.

Histopathology

The majority of patients with anti-GBM disease will exhibit glomerular crescents of uniform age, the hallmark of anti-GBM disease, on histopathologic examination. Infiltrating neutrophils and lymphocytes and periglomerular inflammation may also be observed, among other features.

Other Tests

A variety of nonspecific tests may be useful in anti-GBM disease. A CBC frequently reveals anemia in patients with anti-GBM disease. Creatinine and blood urea nitrogen (BUN) are likely to be elevated in response to kidney damage. Urinalysis may also show red blood cells (RBCs), blood, and protein.

C-reactive protein (CRP) is generally the preferred marker of inflammation and is usually elevated in anti-GBM disease. If CRP testing is not available, erythrocyte sedimentation rate (ESR) testing can be used.

Monitoring

Anti-GBM antibody concentrations generally decline with effective treatment, and increased antibody concentrations following remission may indicate relapse. A period of 6 months without detectable anti-GBM antibodies is suggested before kidney transplant due to the risk of recurrence if a transplant is performed in a patient who still has anti-GBM antibodies. However, definitive guidance is lacking on the appropriate methods for anti-GBM antibody testing for monitoring purposes (eg, direct immunofluorescence testing versus serologic testing), and information on the limitations of these tests in the context of monitoring is also scarce. Given the rare nature of anti-GBM disease, as well as the growing recognition of variant and atypical forms of anti-GBM disease, clinicians should be aware that the use of anti-GBM antibody testing for monitoring purposes may present challenges.