Practice Essentials
Anti–glomerular basement membrane (anti-GBM) disease is a classic autoimmune disorder characterized by the presence of circulating pathogenic autoantibodies directed against proteins in the glomerular and alveolar basement membranes. [1, 2, 3] In the kidneys, binding of these autoantibodies with the GBM results in activation of the complement cascade and can lead to rapidly progressive glomerulonephritis. In Goodpasture syndrome, glomerulonephritis is accompanied by pulmonary hemorrhage due to anti-GBM antibodies acting on the alveolar basement membrane. [4]
An early and precise diagnosis of anti-GBM disease is extremely important for preventing death and preserving renal function. [5] 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. [6]
Go to Pediatric Anti-GBM Disease (Goodpasture Syndrome) for complete information on this topic.
Background
In 1919, E.W. Goodpasture described a 19-year-old man with fatal lung hemorrhage and glomerulonephritis. The syndrome was subsequently shown to be caused by an antibody response against antigens present in the alveolar and glomerular basement membranes. [7] Immunofluorescent examination of affected kidneys demonstrated that these antibodies were localized in a continuous linear deposit along the GBM.
In 1958, Stanton and Tange introduced the term Goodpasture syndrome to describe patients with these conditions. In 1967, in a classic experiment, Lerner and colleagues transferred anti-GBM disease to monkeys by injecting them with kidney-bound antibodies from patients with anti-GBM nephritis. [8]
Over the years, tremendous gains have been made in knowledge of the pathogenic mechanisms underlying anti-GBM nephritis. 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.
Pathophysiology
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 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. [9, 10]
Approximately 20-40% of patients positive for anti-GBM antibodies also have antineutrophilic cytoplasmic antibodies (ANCAs). Coexistence of ANCAs (mostly myeloperoxidase [MPO-ANCAs]) with anti-GBM antibodies is thought to occur when the renal involvement in ANCA vasculitis leads to the exposure of antigens from the basement membrane and the formation of anti-GBM antibodies. [11]
Etiology
Anti-GBM disease is caused by autoantibodies directed against the NC1 domain of the alpha-3 chain of type IV collagen. Both genetic susceptibility and environmental features are typically involved.
Genetic susceptibility includes the following:
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Anti-GBM disease shows a strong association with HLA-DR2.
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Further molecular genetics studies of HLA-DR2 reveal that the association of anti-GBM nephritis is with HLA-DRB1 alleles (HLA-DRB1 1501 and 1502 alleles), HLA-DQA1 01 alleles, and HLA-DQB1 06 alleles.
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Anti-GBM nephritis is major histocompatibility complex–restricted. HLA-DRB1*1501 and 1502 alleles increase the susceptibility, while HLA-DR1 and HLA-DR7 are protective.
Environmental factors include the following:
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A number of studies suggest a strong association between pulmonary hemorrhage and smoking.
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Pulmonary hemorrhage may also be associated with exposure to hydrocarbons or other agents (eg, respiratory pathogens).
COVID-19 has been associated with both new and recurrent cases anti-GBM disease. [12]
Epidemiology
In the United States the disease is rare, accounting for only 5% of human glomerulonephritides and approximately 10-20% of patients with rapidly progressive crescentic glomerulonephritides. Internationallly, the disease accounts for 10-20% of rapidly progressive glomerulonephritis.
Whites are affected more often than blacks. With respect to sex and age, the incidence of anti-GBM nephritis is bimodal. The first, and larger, peak occurs in the second and third decades of life. In this age group, men are more susceptible than women. The second, and smaller, peak occurs in the sixth and seventh decades of life, and in this age group, women have a higher preponderance of the disease than men.
Prognosis
Anti-GBM disease is an aggressive disease with a rapidly progressive course. In the early years, the mortality rate was extremely high (90-95%). With the introduction of immunosuppression and plasmapheresis, the prognosis has improved considerably, with patient and renal survival rates of approximately 85% and 60%, respectively.
Both renal survival and patient survival depend on the severity of the disease at the time of presentation. The following reported survival rates underscore the importance of rapid diagnosis and prompt institution of aggressive immunosuppression therapy for patients with Goodpasture syndrome and severe kidney failure:
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Patients who present with a serum creatinine level of less than 500 µmol/L (5.7 mg/dL) have 1-year patient and renal survival rates of 100% and 95%, respectively.
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Patients who present with a serum creatinine level of more than 500 µmol/L (5.7 mg/dL) but do not require dialysis have 1-year patient and renal survival rates of 83% and 82%, respectively.
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Patients who present with dialysis-dependent kidney failure have 1-year patient and renal survival rates of 65% and 8%, respectively.
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Importantly, patients with advanced kidney disease at the time of presentation (ie, oliguric or dialysis dependent) do not usually respond to plasmapheresis, methylprednisolone, or other immunosuppressive therapy.
Other poor prognostic factors include the following:
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Extensive crescent formation (> 50%)
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Significant tubular atrophy
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Interstitial fibrosis or glomerulosclerosis
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Oliguria or anuria
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Serum creatinine level of more than 6 mg/dL
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HLA-DR W2 and HLA-B7
Nasr and colleagues reported 20 cases of "atypical anti-GBM disease," characterized by bright, linear GBM immunoglobulin deposition but without a diffuse crescentic phenotype, pulmonary involvement, or detectable circulating α3NC1 antibodies. The 1-year patient and renal survival rates were 93% and 85%, respectively, indicating an indolent course for this rare variant. [13]
Patient Education
Patient education should cover the following risks:
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Bladder cancer
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Osteoporosis
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Opportunistic infections
Risk of bladder cancer
Patients with anti-GBM nephritis receive large doses of cyclophosphamide for a prolonged period. This makes them high-risk candidates for the development of hemorrhagic cystitis and bladder cancer. They should drink large quantities of water to ensure urine output of at least 2 L/d and should avoid becoming dehydrated.
They should also watch for gross hematuria and report it promptly to their physician. Patients should have regular urinalyses to screen for nonglomerular hematuria.
Cigarette smoking has been shown to increase the risk of bladder cancer in patients receiving cyclophosphamide. Therefore, patients should be encouraged to quit smoking.
Risk of osteoporosis
Patients are at a high risk for developing steroid-induced osteoporosis. They should be encouraged to take adequate calcium in their diets and to take additional calcium supplements. Postmenopausal women should also receive estrogen.
Risk of opportunistic infections
Intense immunosuppression can make patients susceptible to opportunistic infections. Therefore, patients should be advised to avoid close contact with ill people. They should receive prophylaxis against certain infections (eg, Pneumocystis jiroveci, yeast) and should contact their physician if they develop fever, sore throat, cough with expectoration, or any other signs of infection.
Patient education information sources
For patient education information, see Chronic Kidney Disease, Blood in the Urine, and Kidney Transplant.
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Light microscopy of kidney biopsy specimen from a patient with antiglomerular basement membrane nephritis showing extensive crescent formation and the collapse of glomerular tuft.
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Immunofluorescent examination of a kidney biopsy specimen from a patient with antiglomerular basement membrane nephritis showing a linear deposition of immunoglobulin G along the glomerular basement membrane.
