Antiglomerular Basement Membrane Disease

Updated: Dec 04, 2015
  • Author: Ramesh Saxena, MD, PhD; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Overview

Background

In 1919, E.W. Goodpasture described a 19-year-old man with fatal lung hemorrhage and glomerulonephritis. In 1958, Stanton and Tange introduced the term Goodpasture syndrome to describe patients with these conditions. The syndrome was subsequently shown to be caused by an antibody response against antigens present in the glomerular basement membrane (GBM). Immunofluorescent examination of the kidneys demonstrated that these antibodies were localized in a continuous linear deposit along the GBM.

Over the years, tremendous gains have been made in our knowledge of the pathogenic mechanisms underlying anti-GBM nephritis, and the fact that the anti-GBM antibodies are directed against the noncollagenous globular domain (NC1 domain) of the alpha-3 chain of type IV GBM collagen is well known.

Goodpasture syndrome can be defined by the presence of a triad of glomerulonephritis, pulmonary hemorrhage, and anti-GBM antibodies. Most patients present with rapidly progressive glomerulonephritis. An early and precise diagnosis is extremely important for preventing death and preserving renal function. [1] Immunosuppression with high-dose steroids and oral cyclophosphamide, together with plasmapheresis, is used in the treatment of severe forms of this disease. Early diagnosis and aggressive treatment have substantially reduced overall mortality rates from 95% in earlier years to 10-20% in recent years. However, current therapy remains less than optimal, with many adverse effects and unacceptably high mortality rates. A better understanding of the pathogenic mechanisms should lead to the development of more specific treatment strategies. [2]

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Pathophysiology

Anti-GBM nephritis is a classic autoimmune disease characterized by the presence of circulating pathogenic autoantibodies directed against proteins in the glomerular and alveolar basement membranes. [3, 4] In 1967, in a classic experiment, Lerner and colleagues transferred the disease to monkeys by injecting them with kidney-bound antibodies from patients with anti-GBM nephritis. [5] Again, the anti-GBM antibodies are directed against an epitope located at the NC1 domain at the C-terminal of the alpha-3 chain of type IV collagen. The alpha-3 chain of type IV collagen has a limited distribution in the body; it is found only in a few specialized basement membranes, including the glomerular and alveolar basement membranes.

This distribution helps explains the specific organ involvement (ie, glomerulonephritis and pulmonary hemorrhage) in persons with anti-GBM nephritis. When bound to the specific antigens in the kidneys and lungs, the antibodies initiate an inflammatory destruction of tissues by complement activation and recruitment of proinflammatory cells, leading to rapidly proliferative glomerulonephritis, often accompanied by pulmonary hemorrhage. Antibodies reacting with the alpha-3 chain of type IV collagen can be detected in the serum and can be eluted from kidneys of patients with anti-GBM nephritis.

Because the antigenic epitope is hidden within the triple helix of the collagen, an environmental factor (eg, smoking, hydrocarbon exposure) presumably is required to unmask the cryptic Goodpasture antigen to the immune system.

Once the anti-GBM antibodies bind to the specific GBM antigen, complement is activated. Proinflammatory cells and CD4+ and CD8+ cells are recruited to the site, and, subsequently, proinflammatory cytokines, chemokines, and proteolytic enzymes are released. This leads to endothelial damage, endothelial cell detachment from the underlying GBM, and fibrin accumulation beneath the disrupted endothelial cells. Breaks develop in the GBM, plasma proteins and cells leak into the Bowman space, and, eventually, crescents develop. [6, 7]

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Epidemiology

Frequency

United States

The disease is rare, accounting for only 5% of human glomerulonephritides and approximately 10-20% of patients with rapidly progressive crescentic glomerulonephritides.

International

The disease accounts for 10-20% of rapidly progressive glomerulonephritis.

Mortality/Morbidity

In the early years, the mortality rate was extremely high (approximately 90-95%). With the introduction of immunosuppression and plasmapheresis, patient and renal survival rates are approximately 85% and 60%, respectively.

Race

Whites are affected more often than blacks.

Sex

Young men and elderly women are more prone to anti-GBM disease.

Age

The incidence of anti-GBM nephritis is bimodal. The first, and larger, peak occurs in the second and third decades of life. Men in this age group are more susceptible than women in this age group. The second, and smaller, peak occurs in the sixth and seventh decades of life, and women in this age group have a higher preponderance of the disease than men in this age group.

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