Anti-GBM disease

Notes

Overview

Anti-glomerular basement membrane (Anti-GBM) disease is a rare small-vessel vasculitis.

Anti-glomerular basement membrane (Anti-GBM) disease is a small vessel vasculitis with an annual incidence of one care per million population.

It is characterised by the formation of anti-GBM antibodies that are directed against collagen in the kidneys and lungs. This can lead to life-threatening glomerulonephritis and/or pulmonary haemorrhage.

Anti-GBM disease is a relatively new term that encompasses the clinical spectrum of both renal and pulmonary manifestations. The condition is associated with two older terms named after Ernest Goodpasture, who initially discovered the condition in 1919:

  • Goodpasture syndrome: refers to clinically evident glomerulonephritis and pulmonary haemorrhage.
  • Goodpasture disease: refers to the presence of anti-GBM antibodies in tissue independent of clinical presentation.

Aetiology

Anti-GBM disease develops due to the formation of GBM antibodies directed against type IV collagen.

Anti-GBM disease is characterised by the formation of circulating antibodies directed against the alpha-3 chain of type IV collagen. This is found on the GBM in the kidneys and on the alveolar basement membrane of the lungs. These form an antigen-antibody complex, which stimulates an inflammatory response, activates complement and causes tissue injury. 

The formation of anti-GBM antibodies, which are predominantly IgG, are thought to occur secondary to an environmental trigger in a genetically predisposed, or ‘at risk’, individual. 

Environmental triggers

  • Lymphocyte-depleting agents (e.g. alemtuzumab): loss of regulatory T cells
  • Infections (e.g. influenza)
  • Smoking
  • Cocaine (inhalation)
  • Exposure to metal dust, organic solvents, or hydrocarbons

Genetic risk

There is a strong genetic susceptibility linked to the presence of the human leucocyte antigen (HLA) DR15, which is found in >80% of patients. HLAs are involved in antigen processing and presentation as part of the immune response.

Anti-GBM disease post transplant

Interestingly, 5-10% of patients with Alport syndrome may develop anti-GBM disease following transplant. 

Alport syndrome is predominantly an X-linked inherited condition, although autosomal recessive and autosomal dominant forms exist. It is a disorder of type IV collagen due to a variety of germline genetic mutations (e.g. COL4A5) that leads to progressive glomerular damage and sensorineural hearing loss.

Following transplant, the presence of a ‘normal’ type IV collagen in the basement membrane of the donor kidney may initiate an immune response leading to anti-GBM disease

Pathophysiology

Anti-GBM disease is characterised by a rapidly progressive crescentic glomerulonephritis.

The antigen-antibody complex due to anti-GBM autoantibodies leads in an inflammatory reaction In the kidneys. This inflammatory response results in crescentic glomerulonephritis, which is characterised by the histological finding of ‘crescents’ and rapid deterioration in renal function. 

In the lungs, damage to the alveolar basement membrane leads to pulmonary haemorrhage, which can cause progressive respiratory failure. Lung involvement is usually dependent on additional factors that affect the integrity of the pulmonary capillary network (e.g. smoking, respiratory infections), which allows access of circulating anti-GBM antibodies to the alveolar membrane.

Clinical features

Anti-GBM disease is characterised by haematuria and pulmonary haemorrhage.

Constitutional features

Like most systemic vasculitides, patients may develop preceding constitutional symptoms.

  • Lethargy
  • Fever
  • Anorexia
  • Weight loss
  • Myalgia
  • Arthralgia

Renal manifestations

Approximately 90% of patients with anti-GBM disease present with a rapidly progressive glomerulonephritis, which is characterised by nephritic syndrome: 

  • Oliguria/anuria: suggestive of acute kidney injury
  • Haematuria: visible or non-visible
  • Proteinuria: usually less marked than nephrotic syndrome
  • Hypertension

Pulmonary manifestations

Pulmonary features of anti-GBM disease are more variable, observed in 25-60% of patients. 

  • Cough
  • Shortness of breath
  • Haemoptysis
  • Pulmonary haemorrhage: may be seen in imaging

Diagnosis & investigations

Diagnosis of anti-GBM disease is made by identification of GBM antibodies in the serum or kidneys on biopsy.

A formal diagnosis of anti-GBM disease is made on identification of GBM antibodies in the serum, which are subsequently identified in the kidneys on biopsy. However, anti-GBM disease should be suspected in any patient with rapidly deteriorating renal function. The diagnosis is more likely in the presence of visible haematuria and pulmonary haemorrhage.

Anti-GBM antibodies have a high sensitivity (95-100%) and specificity (91-100%) for anti-GBM disease.

In patients with rapidly progressive renal deterioration a series of investigations can be requested to determine the underlying cause. Anti-GBM disease is one of many potential causes. These series of investigations are usually referred to as an ‘acute renal screen’

Acute renal screen

An acute renal screen aims to determine the cause of any sudden deterioration in renal function. It is largely aimed at determining possible ‘intra-renal’ causes of acute kidney injury including glomerulonephritides. 

  • Urinalysis: blood and protein suggestive of intra-renal cause.
  • Protein:creatinine ratio: quantify amount of proteinuria (e.g. is it ‘nephrotic’ range?)
  • Routine bloods: FBC, U&E, LFT, Bone, CK, Coagulation, CRP
  • Special bloods: ANA, ENA, dsDNA, ANCA, Anti-GBM, Protein electrophoresis, serum free light chains, complement, immunoglobulins, virology (hepatitis C, hepatitis B, human immunodeficiency virus +/- cytomegalovirus and epstein-barr virus), cryoglobulins.
  • Imaging: renal ultrasound +/- dopplers (to exclude obstruction, thrombus or stenosis)

Renal biopsy

A biopsy of one of the kidneys should be completed in suspected anti-GBM disease unless contraindicated. The sample can be assessed with light microscopy and under immunofluorescence.

  • Light microscopy: shows evidence of glomerulonephritis with/without presence of crescents
  • Immunofluorescence: shows pathognomonic deposition of IgG anti-GBM antibodies on the basement membrane

Biopsy helps with both diagnosis and prognostication of renal impairment with chance of recovery. 

Pulmonary investigations

Chest radiograph +/- computed tomography can be used to assess the lungs in patients with suspected anti-GBM disease. In patients with massive pulmonary haemorrhage, pulmonary angiography with embolisation may be required. 

Pulmonary function tests are usually not required but will show a raised diffusing capacity for carbon monoxide (DLCO) due to haemorrhage and carbon monoxide binding.

Management

Treatment of anti-GBM disease is with plasmapheresis, immunosuppressive agents and supportive measures.

Plasmapheresis

Plasmapheresis is the process of removing a patients plasma from the body and replacing it with another solution such as human albumin. In anti-GBM disease, it is utilised to remove circulating autoantibodies and other inflammatory mediators. 

Plasmapheresis can continue for 2-3 weeks and a set protocol should be followed in most cases.

Immunosuppression

The use of immunosuppressive agents should be combined with plasmapheresis. The choice of agent includes steroids combined with cyclophosphamide. Again, a set protocol will be used to decide on the dose and timing of administration. 

Cyclophosphamide is traditionally an alkylating chemotherapeutic agent, which has been widely shown to improve outcomes in systemic inflammatory conditions such as anti-GBM disease and ANCA-vasculitis. 

Generally, if remission is achieved then maintenance immunosuppression does not need to be continued. 

Supportive renal measures

In patients with severe acute kidney injury (AKI), temporary initiation of haemodialysis may be required. The indications to start dialysis remain the same as any other cause of severe AKI. 

With the aggressive use of immunosuppressive agents patients should be able to come off dialysis. However, a proportion of patients will end up with established end-stage renal disease and ongoing need for dialysis. 

Supportive pulmonary measures

Patients with life-threatening pulmonary haemorrhage may require intubation and ventilation. This can be combined with measures to control bleeding including bronchoscopy or angiography and embolisation

Prognosis

It is estimated that <30% of patients will require long-term dialysis following anti-GBM disease.

Patients may be extremely unwell on presentation and develop complications secondary to renal impairment (e.g. hyperkalaemia, acidosis), or pulmonary involvement (e.g. massive haemorrhage).

With the instigation of aggressive early treatment, the overall prognosis has greatly improved and 5-year survival exceeds 80%. Patients require ongoing monitoring to assess for renal recovery or need to continue haemodialysis.

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