Anti-glomerular basement membrane disease (ORPHA:375)
A rare, fulminant small vessel vasculitis that affects the capillary beds of the kidneys and lungs and characterized by the presence of anti-glomerular basement membrane (GBM) and, in its full-blown form, anti-alveolar basement membrane (ABM) antibodies. Consequently, it may manifest as a rapidly progressive, isolated glomerulonephritis (anti-GBM nephritis) or as a pulmonary-renal syndrome with severe lung hemorrhage.
Epidemiology
The incidence of the disease is estimated to be approximately 0.6-1.8 cases per million per year in both Asian and European Caucasian (more frequently affected) populations. Men and women seem equally affected. The disorder is responsible for 1-5% of all cases of glomerulonephritis and is the cause in up to 10-15% of patients with rapidly progressive crescentic glomerulonephritis.
Clinical description
Anti-GBM disease onset is bimodal, occurring mainly in the third and the seventh decades of life. The majority of patients (80-90%) will present with features of rapidly progressive glomerulonephritis. 40 to 60% will have concurrent lung hemorrhage, and a small minority of patients may present with isolated pulmonary disease. Features of lung involvement may include cough, shortness of breath, hemoptysis, chest pain and hypoxia. Anemia is often encountered and fatal respiratory failure may occur in more severe cases. Nephritis mainly presents with a rapidly progressive course. Rarely, renal function may be preserved for several months, despite severe pulmonary hemorrhage. Systemic features (i.e. malaise, fatigue, mild fever, pallor, weight loss) have been reported.
Etiology
Anti-GBM disease is considered to be a vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with deposition of anti-basement membrane antibodies against the non-collagenous domain 1 of the alpha 3 chain of type IV collagen (alpha3(IV)NC1). The production of anti-GBM autoantibodies usually precedes the development of clinical manifestations by months. About one-third of the patients will also develop anti-neutrophilic cytoplasmic antibodies (ANCA). Autoreactive T cells may play a role in its pathogenesis and a strong correlation between the condition and HLA-DRB1*1501 and DRB1*1502 has been reported in Caucasian populations.
Diagnostic methods
Diagnosis is based on the detection of anti-GBM antibodies either in serum or deposited in tissue, along with pathologic features of crescentic GN, with or without evidence of alveolar hemorrhage. Histologic examination on biopsy may show extensive formation of crescents (extra-capillary cell proliferation), GBM destruction, interstitial inflammation and tissue necrosis.
Differential diagnosis
Differential diagnosis includes systemic vasculitis (e.g. Wegener's granulomatosis (GPA), microscopic polyarteritis (MPA), systemic lupus erythematosus, Churg-Strauss syndrome (EGPA)) and other vasculitides (e.g. Behçets disease, cryoglobulinemia). Idiopathic progressive glomerulonephritis, severe pneumonia, pulmonary edema with acute renal failure, and renal vein thrombosis with pulmonary embolism should also be considered.
Management and treatment
Standard therapy consists in plasma exchange combined with high doses of glucocorticoids and cyclophosphamide. Recently, several reports of rituximab use have been reported, either as an adjuvant to standard therapy or as a substitute for cyclophosphamide. Dialysis may be required in severe cases, as well as medications that regulate fluid and electrolyte balance and blood pressure. Renal transplantation is not recommended as long as circulating autoantibodies are detected. Sustained remission in the absence of clinical signs of recurrence should be confirmed every 6 months.
Prognosis
If untreated, anti-GBM disease prognosis is poor. Alveolar hemorrhage is the main cause of early death in the disorder. The severity and prognosis of renal disease are correlated with levels of circulating anti-GBM. Relapses are rare.

                            Last update: 
                            November 2020


                            - Expert reviewer(s): 
                            Pr Dario ROCCATELLO | ERKNet*


                                * European Reference Network