Goodpasture Syndrome 

Goodpasture syndrome is an eponym that has been used to describe the clinical entity of diffuse pulmonary hemorrhage (as seen in the images below) and acute or rapidly progressive glomerulonephritis. Goodpasture disease is a term used to describe glomerulonephritis, with or without pulmonary hemorrhage, and the presence of circulating anti–glomerular basement membrane (anti-GBM) antibodies. The definitions of these terms have not been consistent, however. Anti-GBM disease, a more precise term, should be used to refer to either of the 2 distinct clinical manifestations of this disorder.

Goodpasture syndrome (ie, anti-GBM disease) is an uncommon disorder of complex pathogeneses. Early recognition and treatment of this syndrome are critical because the prognosis for recovery of renal function depends on the initial extent of injury.

Go to Pediatric Anti-GBM Disease (Goodpasture Syndrome) for complete information on this topic.

Historical background

Ernest Goodpasture first described the disorder in 1919. He reported a case of pulmonary hemorrhage and glomerulonephritis during an influenza epidemic. In 1955, Parkin described 3 cases of lung hemorrhage and nephritis that occurred in the absence of arteritis. In 1958, Stanton and Tang reported a series of young men with pulmonary hemorrhage and glomerulonephritis, similar to Goodpasture's original description.

In the 1950s, Krakower and Greenspun identified GBM as the antigen. In 1967, Lerner, Glassock, and Dixon confirmed that the antibodies taken from the diseased kidneys produced nephritis in experimental animals. The discovery of anti-GBM antibodies led to the understanding of the pathogenesis of Goodpasture syndrome.

Anti-GBM disease is an autoimmune disorder. The autoantibodies mediate the tissue injury by binding to their reactive epitopes in the basement membranes. This is a classic type II reaction in the Gell and Coombs classification of antigen-antibody reactions. This binding of antibodies can be visualized as the linear deposition of immunoglobulin along the glomerular basement membrane and, less commonly, the alveolar basement membranes, by direct immunofluorescent techniques.

The basement membranes are complex structures that support layers of endothelium and epithelium.

The principal component of basement membrane is type IV collagen, which acts as a support structure and is composed of building blocks that are linked end-to-end. The building blocks are composed of 3 alpha subunits of collagen, which form a triple helix. Type IV collagen can be expressed as 6 different chains, alpha1 to alpha6. The alpha chain itself has 3 structural domains, as follows: (1) 7-S domain at the amino terminus; (2) a triple helix of 3 alpha chains, which ends at the carboxyl terminus; and (3) a noncollagenous domain. The classic triple helix is composed of 2 alpha1 chains and 1 alpha2 chain.

In most patients, the autoantibody in Goodpasture syndrome is directed against a 28-kd monomeric subunit present within the noncollagenous domain of the alpha3 chain of type IV collagen.^[1] Autoantibodies may also be directed against other alpha chains.

Although basement membranes are ubiquitous, only the alveolar and glomerular basement membranes are affected clinically. The preferential binding to the alveolar and glomerular basement membranes appears to be caused by greater accessibility of epitopes and greater expansion of alpha3 collagen units. Furthermore, the alpha3 collagen chains of glomerular and basement membranes are structurally integrated in such a way that they are more accessible to the circulating antibodies.

Under normal conditions, the alveolar endothelium is a barrier to the anti–basement membrane antibodies. However, with increased vascular permeability, antibody binding to the basement membrane occurs in the alveoli. Therefore, for the deposition of antibody, an additional nonspecific lung injury that increases alveolar-capillary permeability is required.

A variety of factors that can result in increased alveolar-capillary permeability have been identified. These include the following:

• Increased capillary hydrostatic pressure
• High concentrations of inspired oxygen
• Bacteremia
• Endotoxemia
• Exposure to volatile hydrocarbons
• Upper respiratory infections
• Tobacco smoking^[2]

Strong evidence exists that genetics play an important role. Patients with specific human leukocyte antigen (HLA) types are more susceptible to disease and may have a worse prognosis.^[3]

There is an increased prevalence of HLA-DR2 and DR4 in patients with this disease and apparent negative associations with DR7, DR1, DR11, and DR13. HLA-DR2 is encoded by the closely related DRB1*15 and *16 alleles. Goodpasture disease is strongly associated with the DRB1*1501 and to a lesser extent the DRB1*1502 allele. Although a strong association exists between anti-GBM disease and HLA DRB1*1501, this allele is present in as many as one third of individuals in white populations. It is therefore clear that additional factors, either genetic or environmental, are required for disease expression.

Also of note, HLA-B7 is found more frequently and is associated with more severe anti-GBM nephritis.

An initial insult to the pulmonary vasculature is required for exposure of the alveolar capillaries to the anti-GBM antibodies. Predisposing factors for such exposure include the following:

• Association with HLA-DR2
• Exposure to organic solvents or hydrocarbons
• Smoking
• Infection (eg, influenza A2)
• Cocaine inhalation
• Exposure to metal dusts

Anti-GBM disease is an uncommon disorder; in the United States, approximately 1-2% of all cases of crescentic rapidly progressive glomerulonephritis are secondary to this disorder. In 1984, the incidence in England was 0.5 cases per million people per year, occurring over a 4-year period.^[4] This disorder, compared with Wegener granulomatosis, which has an incidence of approximately 0.5 cases per 100,000 people, is rare.

Racial, sexual, and age-related differences in incidence

Anti-GBM disease occurs more commonly in white people than in black people, but it also may be more common in certain ethnic groups, such as the Maoris of New Zealand. The age distribution is bimodal, 20-30 years and 60-70 years. The prevalence of the disease is higher in men in the younger age group and women in the older age subgroup.

In the past, Goodpasture syndrome was usually fatal. Aggressive therapy with plasmapheresis, corticosteroids, and immunosuppressive agents has dramatically improved prognosis.^[5] With this approach, the 5-year survival rate exceeds 80% and fewer than 30% of patients require long-term dialysis.

Patients presenting with serum creatinine levels greater than 4 mg/dL, oliguria, and more than 50% crescents on renal biopsy rarely recover. They usually progress to end-stage renal failure that requires long-term dialysis.