AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Anti–glomerular basement membrane (anti-GBM) antibody disease is a rare autoimmune disorder in which circulating antibodies are directed against an antigen normally present in the GBM and alveolar basement membrane. The target antigen is the alpha-3 chain of type IV collagen. The resultant clinical syndrome encompasses a spectrum ranging from mild or no renal involvement to rapidly progressive glomerulonephritis.

Many patients develop pulmonary hemorrhage, and most individuals have signs of a generalized systemic illness. The combination of glomerulonephritis and pulmonary hemorrhage is commonly referred to as Goodpasture syndrome. Pulmonary and/or renal manifestations can be encountered in a variety of conditions, such as antineutrophilic cytoplasmic antibody (ANCA)–positive vasculitis and other autoimmune disorders. As a consequence, the identification of anti-GBM antibodies in the patient's serum or tissues is of paramount importance in the diagnosis of Goodpasture disease.

In this article, Goodpasture disease and anti-GBM disease are used synonymously and refer to the presence of anti-GBM antibodies in tissues (eg, kidney, lungs, or both) independent of clinical manifestations. Goodpasture syndrome refers to clinically evident glomerulonephritis, pulmonary hemorrhage, or both in a patient with Goodpasture disease.

Pathophysiology

Type IV collagen is a polymeric structure. The basic monomer of this network is a triple-helical molecule composed of 3 alpha chains. Each chain is characterized by a long collagenous domain interrupted by short noncollagenous sequences, a noncollagenous amino terminus, and a long noncollagenous domain (NC1) at the carboxyl terminus.

Two adjacent, conformational disulfide-bond–dependent regions in the NC1 domain of the alpha-3 chain of type IV collagen are the principal targets for anti-GBM antibodies. These regions are called the Goodpasture epitopes. The 2 epitopes, designated EA and EB, are located at the amino acid residues 17-31 and 127-141 of the NC1 domain. Anti-GBM antibodies are almost exclusively of the immunoglobulin G (IgG) isotype, and their presence is considered pathognomonic. Low titers of antibodies to additional GBM components, particularly the NC1 domain of other collagen chains, are present in some anti-GBM sera. However, whether they represent an epiphenomena or whether they have a pathogenic importance remains unknown.

The limited tissue involvement in anti-GBM disease results from the tissue-specific distribution of the alpha-3 chain of type IV collagen, the specificity of the anti-GBM antibodies, and the accessibility of the Goodpasture epitopes in the glomerular and alveolar capillaries. The alpha-3 chain of type IV collagen is expressed in the basement membranes of the glomerulus, alveoli, choroid plexus, eye, cochlea, and testis. The prevalence of renal involvement in anti-GBM antibody disease may result from the unique structure of the glomerular capillaries that allows circulating antibodies to access the GBM.

Other organs expressing the Goodpasture epitopes, with the exception of the lung, are not obviously affected, presumably because of the limited access of the anti-GBM antibodies to the basement membrane or because of other regulatory mechanisms. Pulmonary hemorrhage is associated with factors that affect the integrity of lung capillaries and allow the anti-GBM antibodies to contact the alveolarbasement membrane. Examples of such factors are respiratory infections, smoking, or inhalation of toxins.

Cellular immunity may play a role in the pathogenesis of anti-GBM disease. Compelling experimental data suggest that T cells may have an indirect role in facilitating the anti-GBM antibody production by B cells and that they may also cause direct injury to the glomerulus and alveoli. Whether the T cell–mediated mechanisms play a similar role in human anti-GBM antibody disease remains to be established.

Differential susceptibility to anti-GBM disease in humans is strongly linked to class II major histocompatibility complex (MHC II). In addition, anti-GBM disease has a strong positive association with the human leukocyte antigen (HLA)–DR15 haplotype, particularly the DRB1*1501 allele, which is found in more that 80% of patients with anti-GBM disease. In contrast, strong dominant protection from the disease is associated with the expression of DRB1*0701 such that the risk of disease is the same in individuals inheriting DRB1*1501 and DRB1*0701 and in the general population. The DRB1*01 allele offers relatively weak protection.

Exactly how the expression of the DR molecules determines differences in a person's susceptibility to anti-GBM disease is not understood. However, the mechanism may reflect the different abilities of the DR molecules to bind autoantigen-derived peptides and to present the peptides to T helper cells.

Frequency

United States

Goodpasture disease is diagnosed in 1 per million persons each year. In adults, anti-GBM disease is responsible for approximately 5% of all cases of glomerulonephritis, and it is diagnosed in 1-2% of renal biopsy specimens. Anti-GBM glomerulonephritis accounts for 20% of all cases of rapidly progressive glomerulonephritis in adults and for <10% of such cases in children.

Mortality/Morbidity

• In untreated patients, the disease usually progresses to renal failure or death.
• Treated patients have a significant risk of morbidity and mortality from renal failure, pulmonary hemorrhage, or complications of treatment. With current therapy, >90% of patients survive the acute phase of the disease. However, the 2-year survival rate is <50%.
• End-stage renal disease develops in 40-70% of patients who have nephritic mediated by anti-GBM antibodies and accounts for 10-15% of all cases of end-stage renal disease in the United States.

Race

Anti-GBM antibody disease is reported in all racial groups, but it is primarily a disease of white populations. According to a recent review, 83% of cases in which race was identified occurred in whites.

Sex

The frequency distribution shows a male-female ratio of 3:2.

Age

The disease can manifest in persons of any age. However, a bimodal distribution exists, with the first peak at approximately 30 years of age and a second peak at 60 years. The youngest reported patient with anti-GBM disease was an 11-month-old girl.

CLINICAL

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History

Anti-GBM disease can occur year-round, but the incidence increases in the spring and in early summer. Most patients present with features of systemic illness and either acute nephritis or pulmonary involvement; a subset may have all 3 findings. Pulmonary involvement can precede the onset of glomerulonephritis by several years, or it can develop after renal disease is evident.

• Symptoms of systemic illness include low-grade fever, malaise, headache, anorexia, nausea, vomiting, weight loss, and fatigue.
• Symptoms of renal involvement include hematuria, oliguria, and edema.
• Symptoms of pulmonary involvement include shortness of breath, cough, and expectoration of material that ranges from blood-streaked sputum to massive hemoptysis. A feeling of warmth inside the chest may precede hemoptysis.
• Approximately 30% of patients with Goodpasture syndrome are ANCA positive sometime during the illness. Such patients may present with pruritic skin rashes and arthralgia.

Physical

Physical findings depend on the organ system involved and on the severity of the disease. No abnormalities may be evident in the absence of renal or pulmonary involvement.

• Signs of renal involvement include the following:
• • When renal involvement is severe, volume overload of the intracellular and extracellular fluid may result in tachycardia, tachypnea, hypertension, pulmonary rales, and pitting edema.
  • Patients with uremia may have a specific breath odor, bruises, pallor, tremor, myoclonus, asterixis, focal neurologic signs, mental status changes, and seizures.
• Signs of pulmonary involvement include the following:
• • Respiratory distress ranging from mild distress to respiratory failure
  • Pulmonary hemorrhage that may result in pallor, tachycardia, and shock
• Pulmonary manifestations can precede or follow signs of nephritis.
• Patients with high ANCA and low anti-GBM antibody titers may present with a variety of vasculitic skin rashes.

Causes

Anti-GBM disease is an autoimmune condition of known pathogenesis but unclear etiology. However, several factors play a permissive role in disease initiation.

• Respiratory infections (eg, influenza) or inhaled toxins (eg, hydrocarbons, gasoline vapors, hypercarbic oxygen, tobacco, hair spray) may trigger pulmonary involvement.
• Factors associated with renal manifestations are renal injury from ischemia, membranous glomerulonephritis, and, possibly, extracorporeal shock-wave lithotripsy. Only 3 cases of anti-GBM disease occurring after lithotripsy have been described, though several million procedures have been performed. Therefore, the number of cases is too small to establish a causative association. However, consider testing for anti-GBM antibodies when patients have declining renal function after lithotripsy.
• Individuals with Alport syndrome lack the Goodpasture epitopes. The transplantation of a kidney from a healthy donor to a patient with an Alport syndrome introduces the Goodpasture epitopes as neoantigens. Approximately 50% of kidney recipients with Alport syndrome develop anti-GBM antibodies; only a few of these patients have graft failure because of anti-GBM disease.
• In a review of 118 male patients with the X-linked dominant form of Alport syndrome, anti-GBM glomerulonephritis developed in only 3 (2.5%). All had a large deletion in the COLA4A5 gene. Sixteen other patients with a large rearrangement in COLA4A5 and 32 with a small mutation that was expected to produce a truncated alpha-5 (type IV collagen) protein lacking the NC1 domain did not develop anti-GBM glomerulonephritis in the graft.
• In some patients, the anti-GBM antibody has immunoblotting characteristics different from those of patients with the primary form of Goodpasture syndrome. These characteristics may result from differences in antigenic expression caused by the interaction of the various alpha chains in the basement membrane. This difference also may explain why the clinical expression of the disease is milder in patients with Alport syndrome than in those with the primary form of Goodpasture syndrome. The low incidence of the syndrome and its mild clinical manifestations make renal transplantation the treatment of choice for patients with Alport syndrome who have end-stage renal disease.
• Anti-GBM antibody disease has a strong positive association with the HLA-DR15 haplotype, particularly the DRB1*1501 allele, which is found in more that 80% of patients with anti-GBM antibody disease. Furthermore, a strong dominant protection from the disease is associated with the expression of DRB1*0701 such that individuals inheriting DRB1*1501 and DRB1*0701 have no higher risk of disease than does the general population. The DRB1*01 allele offers relatively weak protection.

DIFFERENTIALS

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Other Problems to be Considered

Henoch-Schönlein purpura
Pulmonary infections

WORKUP

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Lab Studies

• Circulating anti-GBM antibodies
• • The presence of anti-GBM antibodies is pathognomonic.
  • Detection of the anti-GBM antibodies is achieved by means of direct enzyme-linked immunoassay (ELISA). This test can be performed with <1 mL of blood. ELISA requires the use of native or recombinant human alpha-3 (type IV collagen) NC1 antigen as a substrate, which makes this method more sensitive and specific than others.
  • The specificity of the antibody can be confirmed with Western blotting.
  • False-negative rates are less than 5% and may occur in patients with low anti-GBM antibody titers or in some patients with Alport syndrome who develop anti-GBM disease after transplantation. A false-positive rate of less than 1% is related to the detection of antibodies directed against other chains of type IV collagen.
  • Indirect immunofluorescent staining is rarely performed and requires an experienced renal pathologist. This test is performed by incubating normal renal tissue with the patient's serum and then treating it with fluorescein-labeled anti–IgG. Immunofluorescence indicates of IgG deposition and is diagnostic. False-negative results are seen in 10-40% of patients.
• Serum electrolytes and renal function
• • Renal function ranges from normal to rapidly deteriorating over a few weeks to months. Doubling of the serum creatinine level and halving of the glomerular filtration rate (GFR) within 3 months indicates rapidly progressive glomerulonephritis.
  • Electrolyte abnormalities, such as hyponatremia, hyperkalemia, hyperphosphatemia, and acidemia, may be seen with advanced disease.
• Urine
• • Gross or microscopic hematuria may be present.
  • Urinalysis may reveal nephritic urinary sediment with dysmorphic RBCs and RBC casts.
  • Proteinuria is usually present, but protein levels are not in the nephrotic range.
• Blood cells
• • A CBC may reveal hypochromic microcytic anemia secondary to iron deficiency.
  • Mild thrombocytopenia may be detected.
• Complements: The C3 level is below the reference range in 30-80% of pediatric patients.
• Antineutrophilic cytoplasmic antibodies
• • ANCA are autoantibodies directed against constituents of the primary granules of neutrophils and the peroxidase positive lysosomes of monocytes.
  • ANCA is detectable in as many as 30% of patients with anti-GBM disease. Titers of ANCA and anti-GBM antibodies tend to be inversely related.
  • The detection of ANCA is clinically relevant in anti-GBM disease because patients with this disease are more likely to respond to therapy.
  • Besides having prognostic value in anti-GBM disease, ANCA is an important diagnostic marker in the ANCA associated small-vessel vasculitis, such as Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and some forms of drug-induced vasculitis (eg, thiouracil). These conditions are included in the differential diagnosis of anti-GBM disease. Therefore, patients presenting with acute glomerulonephritis with or without pulmonary hemorrhage are routinely tested for ANCA.
• Sputum: Hemosiderin-laden macrophages indicate pulmonary hemorrhage.

Imaging Studies

• Renal sonograms usually reveal kidneys of normal size, with no anatomic abnormalities.
• When pulmonary hemorrhage is present, chest radiographs may show alveolar infiltrates spreading from the hilum.
• Chest CT is more accurate than chest radiography for the diagnosis of pulmonary hemorrhage.

Other Tests

• Results of pulmonary function tests are abnormal with pulmonary hemorrhage and may help in evaluating therapeutic effectiveness.

Procedures

• Renal biopsy is not required for diagnosis if circulating anti-GBM antibodies are unequivocally present. However, histologic findings are an important guide to therapy and prognosis.
• Most experts recommend renal biopsy unless the procedure is contraindicated.

Histologic Findings

During the active phase of the disease, cellular crescents are usually seen in the glomeruli. In advanced cases, fibrous (rather than cellular) crescents and tubulointerstitial involvement (eg, tubular atrophy, interstitial infiltrate, fibrosis) may be present. The lungs have intra-alveolar hemorrhages and are iron loaded. Vasculitis of the kidneys or lungs is uncommon but may be present in ANCA-positive patients.

Under immunofluorescent microscopy, the finding of linear deposition of IgG along the glomerular capillaries and, occasionally, along the tubules is nearly pathognomonic. Only 2 other renal conditions are associated with linear glomerular IgG staining: diabetic nephropathy and fibrillary glomerulonephritis. Focal and interrupted linear deposits of IgG along the alveolar basement membrane may also be seen in anti-GBM disease. Electron microscopy reveals frequent breaks of the GBM.

TREATMENT

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Medical Care

Hospitalization is required for prompt diagnosis and treatment, close monitoring, and supportive care. Patients may initially require intensive care.

• The therapeutic regimen depends on the patient's potential to respond.
• • Patients with moderate glomerulonephritis (serum creatinine level <5 mg/dL and crescents in <50-75% of glomeruli) and patients with acute disease (brief illness, lack of chronicity on histology) are likely to respond to therapy. The treatment of choice consists of repeated plasmapheresis combined with glucocorticosteroids and cyclophosphamide.
  • Patients with advanced disease (serum creatinine level >5 mg/dL and crescents in >75% of glomeruli) and histologic signs of chronicity are unlikely to improve with any therapy and should be spared the clinically significant risks of aggressive treatment. Supportive care and eventual renal transplantation are recommended.
  • Patients who are ANCA positive with clinical presentations consistent with vasculitis are likely to benefit from aggressive therapy independent of the severity of disease.
  • Most patients with pulmonary hemorrhage respond rapidly to methylprednisolone pulses, plasma exchange, or plasmapheresis.
  • Patients with mild renal disease who do not have pulmonary hemorrhage may be successfully treated with prednisone alone.
• In patients with renal insufficiency, treatment should be commensurate with the severity of disease and includes therapy for hypertension, fluid overload, and electrolyte and acid-base imbalances.
• Early plasmapheresis
• • Early plasmapheresis removes circulating anti-GBM antibodies and other mediators of inflammation and has been advocated as the treatment of choice.
  • Plasmapheresis with immunosuppression is effective in the treatment of pulmonary hemorrhage and substantially improves renal function in patients with serum creatinine levels of <7 mg/dL or with crescents in <50% of the glomeruli.
  • Therapy usually consists of 14 treatments during 2-3 weeks.
  • Concomitant administration of cyclophosphamide and steroids is essential to prevent rebound antibody formation.
  • Additional plasmapheresis may be required if anti-GBM antibody titers remain elevated after the treatments.
  • Patients undergoing plasmapheresis who develop serious infections benefit from intravenous administration of immunoglobulins.
• Experimental and future treatment
• • Preliminary data suggest that removal of anti-GBM antibody by means of immunoadsorption may be beneficial in patients with Goodpasture disease. These results must be verified before immunoadsorption can be recommended.
  • The effect of blocking CD28-B7, the costimulatory pathway for T-cell activation, was evaluated in a rat model of anti-GBM disease. The rationale for this attempt was the observation that T cell–mediated mechanisms may play a direct role in the glomerular and alveolar injury that occurs in anti-GBM disease.

Surgical Care

In patients with irreversible renal failure, renal transplantation is usually deferred for at least 1 year to decrease the risk of recurrence.

Consultations

• A nephrologist may be needed to manage glomerulonephritis and renal insufficiency.
• A pulmonologist may be needed to manage pulmonary hemorrhage.
• An intense care specialist may need to be consulted to treat critically ill patients.
• A surgeon may need to be consulted to establish dialysis access and perform renal transplantation.

Diet

Dietary modifications for patients with renal insufficiency include the following:

• Adjustments in fluid intake based on urine output
• Eating foods with low levels of sodium and phosphate

Activity

Patients should avoid strenuous activity.

MEDICATION

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The treatment of choice is a combination of plasmapheresis to remove circulating anti-GBM antibodies and immunosuppression with glucocorticoids and cytotoxic agents to inhibit further autoantibody formation.

Drug Category: Glucocorticoids

These agents are used as adjuncts to plasmapheresis to minimize antibody formation. Glucocorticoids have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Drug Category: Immunosuppressive agents

Immunosuppressants are used as adjuncts to plasmapheresis and glucocorticoids to minimize new antibody formation. Therapy is continued for 6-12 months, the time usually required to stop the formation of anti-GBM antibodies.

FOLLOW-UP

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Further Inpatient Care

• Care for critically ill patients (eg, those with pulmonary hemorrhage, severe hypertension, or renal failure) in the intensive care unit.
• Acute dialysis is indicated in patients with anuria, pulmonary edema, uncontrolled hypertension, and hyperkalemia.
• If renal function remains poor, prepare the patient for long-term dialysis.

Further Outpatient Care

• After discharge, a nephrologist should follow up with the patient to monitor drug therapy, potential adverse effects, and renal function.
• When necessary, the nephrologist should direct renal replacement therapy.

Deterrence/Prevention

• The patient should avoid exposure to known initiating factors, such as influenza, cigarette smoke, hydrocarbons, gasoline vapors, and hair sprays.

Complications

• Complications of renal failure include hyperkalemia, pulmonary edema, hypertension, and seizures.
• Complications of pulmonary hemorrhage include hemorrhagic shock and respiratory failure.
• Complications of immunosuppressive medications include infection, avascular bone necrosis, and bone marrow suppression.
• Complications of plasmapheresis include infection, bleeding, hypocalcemia, and immunoglobulin deficiency.
• Complications of renal transplantation include a recurrence rate of linear IgG staining in the graft as high as 50%. However, most patients remain asymptomatic, probably because of inhibition of autoantibody production with routine posttransplantational immunosuppression. The risk of graft loss due to recurrent anti-GBM disease is low.

Prognosis

• The prognosis is poor but not uniform. Without treatment, 90% of patients progress to dialysis or die, and only 10% improve. With current therapies, improvement occurs in 50%. Patients who survive the first year with normal renal function have a good long-term prognosis, though late relapses can occur. Several clinical, laboratory, and histologic features have prognostic relevance independent of the type of therapy.
• Chronic disease (weeks vs days), a need for dialysis, a serum creatinine level >5 mg/dL, and crescent formation in 50-75% of the glomeruli at the time of diagnosis are associated with a poor outcome. Other histologic findings, including fibrous crescents, widespread necrosis, and tubulointerstitial changes, indicate advanced disease and a high likelihood of progression to renal failure.
• Patients who are ANCA positive and who have a clinical course resembling that of vasculitis tend to respond well to treatment and recover renal function despite an increased frequency of vasculitic relapses. Anti-GBM disease is usually not reactivated.

Patient Education

• Patients should seek prompt medical attention if symptoms of recurrent renal and/or pulmonary involvement, including cough, bloody sputum, oliguria, discoloration of urine, or edema, develop.
• Patients should be informed about their long-term prognosis and the risks of treatment.
• Patients should be made aware of known risk factors such as exposure to influenza, cigarette smoke, and inhaled toxins.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to consider the diagnosis in patients with hemoptysis and/or nephritis
• Failure to consider the diagnosis in renal transplantation patients with deteriorating graft function and a previous history of Alport syndrome
• Failure to recognize or inform patients of adverse effects of treatment

MULTIMEDIA

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Media file 1:  Immunofluorescence staining for immunoglobulin (IgG) reveals diffuse, high-intensity, linear staining of the glomerular basement membrane in a patient with anti–glomerular basement membrane (GBM) disease. Courtesy of Glen Markowitz, MD, Department of Pathology, Columbia University.
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Media type:  Photo

REFERENCES

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• Salama AD, Pusey CD. Immunology of anti-glomerular basement membrane disease. Curr Opin Nephrol Hypertens. May 2002;11(3):279-86. [Medline].
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Article Last Updated: Nov 30, 2006