Anti-Glomerular Basement Membrane Antibody

Anti-glomerular basement membrane (anti-GBM) antibodies are IgG autoantibodies against the non-collagenous domain of the alpha-3 chain of type IV collagen (Goodpasture antigen) in glomerular and alveolar basement membranes. They cause anti-GBM disease: rapidly progressive crescentic glomerulonephritis, with or without pulmonary haemorrhage (Goodpasture syndrome).

Serum is tested by ELISA, chemiluminescence or fluorescence enzyme immunoassay using purified or recombinant alpha-3 (IV) NC1, and kidney biopsy shows linear IgG deposits along the basement membrane on immunofluorescence.

Anti-GBM disease is rare (about 1 in a million people each year) and causes up to 20% of crescentic glomerulonephritis. It has two peaks: young men in the third decade (often with pulmonary haemorrhage) and older women in the sixth to seventh decade (renal limited). Risk factors are HLA-DRB1*15:01, smoking, hydrocarbon exposure, respiratory infection and lung injury.

Renal recovery depends on creatinine at presentation: patients presenting with creatinine over 500 micromol/L or on dialysis and over 50% crescents rarely recover independent renal function, so speed of diagnosis is the main determinant of outcome. About 10 to 30% are also ANCA positive.

Indications. Rapidly progressive glomerulonephritis. Pulmonary renal syndrome (haemoptysis with haematuria and renal failure). Unexplained acute kidney injury with active urinary sediment. Haemoptysis with iron deficiency anaemia and pulmonary infiltrates. Monitoring of antibody clearance during treatment. Pre-transplant check in Alport syndrome patients (post-transplant anti-GBM nephritis can develop in 3 to 5%).

Specimen. Serum 1 mL, no fasting. Stable for days at 2 to 8 °C. A positive result is acted on urgently, and results within 24 hours are required.

Reference values (assay dependent).

• Negative: under 7 to 10 U/mL (ELISA), or under 20 units for some platforms.
• Borderline: 7 to 10 U/mL (repeat).
• Positive: over 10 U/mL.
• Sensitivity of modern assays is 95 to 100% and specificity over 95%, with rare false positives at low titres.

Interpretation.

• Positive anti-GBM with rapidly progressive glomerulonephritis: anti-GBM disease, with biopsy confirming linear IgG staining and crescents. Treatment must not wait for biopsy if the antibody is strongly positive and the patient is critical.
• Positive anti-GBM and ANCA (double positive): behaves like anti-GBM disease for renal prognosis, but has a relapsing course like ANCA vasculitis.
• Negative anti-GBM with biopsy proven linear staining: rare (under 5%), non-IgG or atypical antibodies, or assay sensitivity limits, and repeat testing or alternate assay is considered.
• Positive anti-GBM without clinical disease: rare, low titre, possible assay false positive, repeat before action.
• Titres correlate with disease activity, and treatment aims to clear circulating antibody, which usually takes 2 to 3 weeks of plasma exchange. Monitoring is done until negative.
• Recurrence is rare (under 5%) and late. Kidney transplantation is delayed until antibody has been undetectable for at least 6 months.

Critical values and findings needing immediate action.

• Positive anti-GBM with rising creatinine, haematuria and crescents: emergency plasma exchange (daily for 14 days or until antibody undetectable), high dose methylprednisolone and cyclophosphamide, in a renal unit, started on clinical grounds without waiting for biopsy.
• Positive anti-GBM with haemoptysis and hypoxia: pulmonary haemorrhage, high dependency or intensive care, oxygen and ventilatory support, with plasma exchange.
• Dialysis dependent at presentation with 100% crescents on biopsy: renal recovery is unlikely, and plasma exchange and immunosuppression are used only if there is pulmonary haemorrhage.
• Positive anti-GBM in a smoker or a patient exposed to solvents: stop exposure, since lung injury exposes alveolar antigen.

Interferences and pitfalls.

• Delay in diagnosis is the main cause of poor outcome. Anti-GBM testing is requested urgently in any rapidly progressive glomerulonephritis, and the assay is not a send away test.
• A negative result in strong clinical suspicion does not rule out disease. Repeat testing, biopsy and an alternative assay are used.
• High titre ANCA positivity may coexist and does not exclude anti-GBM disease.
• Assay variation: older indirect immunofluorescence on monkey kidney is less sensitive than antigen specific immunoassays.
• Plasma exchange reduces antibody titre rapidly, and a result taken after exchange is falsely low. A pre-treatment sample is taken first.
• Immunosuppression is continued for 6 months, and relapse is monitored with antibody levels.
• Linear IgG staining on immunofluorescence also occurs in diabetic nephropathy and other conditions (non-specific), and must be interpreted with serology and light microscopy.
• Anti-GBM is not part of ANCA vasculitis monitoring, and both antibodies are requested at presentation.

Special groups.

• Alport syndrome after transplant: de novo anti-GBM nephritis in the graft, where the antibody targets the collagen IV chains absent from the patient's own kidney.
• Children: very rare.
• Pregnancy: rare, with high risk of foetal loss in active disease, and transplacental IgG may cause neonatal disease.
• Older adults: renal limited disease in women, with dialysis dependence common.
• Regions: late presentation with advanced renal failure is common where access to renal replacement and plasma exchange is limited.

Follow up tests. Creatinine and eGFR repeated at least daily, urinalysis with microscopy, urine protein to creatinine ratio, full blood count and iron studies, ANCA (PR3, MPO), complement C3 and C4, ANA, hepatitis B and C, HIV, chest radiograph and CT, spirometry with carbon monoxide transfer factor (raised in alveolar haemorrhage), bronchoalveolar lavage (haemosiderin laden macrophages), kidney biopsy with immunofluorescence, and serial anti-GBM titres.