Essentials of Diagnosis
- Rapidly deteriorating renal function, with or without hemoptysis and pulmonary shadowing on chest radiograph.
- Hematuria and proteinuria on urine dipstick and erythrocyte casts and/or dysmorphic erythrocytes on urine microscopy.
- Circulating antibodies directed against the glomerular basement membrane (GBM).
- Renal biopsy showing focal necrotizing glomerulonephritis with linear deposition of immunoglobulin.
General Considerations
Anti-glomerular basement membrane disease is a rare but well-characterized cause of glomerulonephritis, with an incidence of 1 case per million per year in white populations. All ages can be affected, but the peak incidence is in the third decade in young men and in the sixth and seventh decades in either sex. Lung hemorrhage occurs more often in younger patients, and isolated glomerulonephritis is more common in older patients. The disease is defined by the presence of pathogenic anti-GBM antibodies directed against the NC1 domain of the α3 chain of type IV collagen [α3(IV)NC1], a component of selected basement membranes including those of glomeruli and pulmonary alveoli. These cause focal necrotizing glomerulonephritis and result in widespread crescent formation on renal biopsy; clinically, the result is rapidly progressive glomerulonephritis. When this occurs in association with pulmonary hemorrhage, the condition is known as Goodpasture’s syndrome.
The disease occurs in genetically susceptible individuals exposed to an environmental trigger. The HLA type strongly influences susceptibility; HLA types DR15 and DR4 predispose to disease, while HLA DR7 and DR1 are protective.
Environmental factors are involved in both triggering the disease and influencing its clinical presentation. Several reports describe clusters of cases, suggesting that an infective or other exogenous agent is involved in the pathogenesis, but no specific cause has been identified. Cigarette smoking has an important influence on the extent of lung injury, with pulmonary hemorrhage affecting almost all current smokers and being almost exclusively confined to this group. Lung hemorrhage following hydrocarbon exposure has also been described. In addition, genetic factors affect disease susceptibility.
Clinical Findings
Patients often have a history of malaise, arthralgia, and weight loss, but these features are generally far milder than in other causes of focal necrotizing glomerulonephritis, such as antineutrophilic cytoplasmic antibody (ANCA)-associated systemic vasculitis. Anemia is common, and may be symptomatic even in patients with minimal hemoptysis. The principal clinical symptoms relate either to pulmonary hemorrhage or to the development of renal failure. The severity of pulmonary hemorrhage varies and can range from minor hemoptysis to life-threatening hemorrhage with respiratory failure. Typically, hemoptysis is intermittent at the outset and can occur spontaneously or can be precipitated by intercurrent infections or fluid overload. There is a poor correlation between the severity of hemoptysis and the quantity of pulmonary blood loss, with other clinical signs being variable. These include inspiratory crackles and bronchial breathing, with patients often tachypnoeic and cyanosed. Historically hemoptysis has been the most common presenting feature, but its incidence is decreasing with the reduced prevalence of cigarette smoking. It now occurs in about 50% of cases. Even in those with life-threatening pulmonary hemorrhage, the lungs of patients who survive the acute illness recover completely and have no residual pulmonary symptoms of radiologic abnormalities. Histologically they are left with little residual lung pathology or fibrosis.
Renal disease can occur either alone or in association with pulmonary hemorrhage. Mild renal impairment may improve spontaneously, but once significant renal injury has occurred, improvement is rare and deterioration may be extremely rapid. Evolution from normal renal function to established renal failure is less than 12 hours in some patients. Microscopic hematuria is an early sign of renal pathology, and dysmorphic red cells and red cell casts are seen in the urine as the disease progresses. Proteinuria is present, but is usually modest (<3 g/L). Some patients present with macroscopic hematuria and severe loin pain, which are often features of very severe disease. Oliguria is a poor prognostic sign.
Without treatment anti-GBM disease almost always progresses to renal failure, but anti-GBM antibody synthesis is transient, often lasting for less than 2 months. Patients are treated with cytotoxic drugs and plasma exchange. Recurrence of anti-GBM disease is rare, but has been reported, sometimes precipitated by infection or exposure to a toxic agent. The outcome in these cases is generally better than with the original presentation, since the diagnosis is often made more quickly. The disease almost invariably recurs in renal allografts performed when circulating anti-GBM antibodies are still present, but transplantation is safe once they are no longer detectable. Exceptionally, however, renal transplantation can reinitiate anti-GBM antibody production, but this probably occurs in less than 1% of cases. Accordingly, transplantation is normally deferred for at least 6 months after the disappearance of circulating anti-GBM antibodies, and transplanted patients should be monitored closely for changes in urinary sediment or antibody titers.
The diagnosis of Goodpasture’s disease is dependent on the detection of anti-GBM antibodies either in the circulation or at renal biopsy. These antibodies are usually detected using an enzyme-linked immunosorbent assay (ELISA), and equivocal results can be confirmed by Western blotting. There is a clear correlation between the titer of anti-GBM antibodies and the severity of renal injury, but the pattern of lung disease is independent of antibody titer.
Other laboratory findings are nonspecific. Anemia is common, and is often microcytic and hypochromic. As in other types of rapidly progressive glomerulonephritis, there may be evidence of microangiopathy on the blood film, but this is mild. Abnormalities of the urinary sediment are an early sign of renal pathology, and are often followed by increases in serum urea nitrogen and creatinine as renal failure develops.
