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.[1] Anti-GBM disease, a more precise term, should be used to refer to either of the two distinct clinical manifestations of this disorder.
View Image | Goodpasture syndrome. A 45-year-old man was admitted to the intensive care unit with respiratory failure secondary to massive hemoptysis and acute ren.... |
View Image | Goodpasture syndrome. Close-up view of gross pathology in a 45-year-old man admitted to the intensive care unit with respiratory failure secondary to .... |
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.
The three principles of therapy are as follows (see Treatment)[2] :
Go to Pediatric Anti-GBM Disease (Goodpasture Syndrome) for complete information on this topic.
See Autoimmune Disorders: Making Sense of Nonspecific Symptoms, a Critical Images slideshow, to help identify several diseases that can cause a variety of nonspecific symptoms.
Ernest Goodpasture first described this disorder in 1919. He reported a case of pulmonary hemorrhage and glomerulonephritis during an influenza epidemic. In 1955, Parkin[3] described 3 cases of lung hemorrhage and nephritis that occurred in the absence of arteritis. In 1958, Stanton and Tang[4] reported a series of young men with pulmonary hemorrhage and glomerulonephritis, similar to Goodpasture's original description.
In the 1950s, Krakower and Greenspon[5] identified GBM as the antigen. In 1967, Lerner, Glassock, and Dixon[6] 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 characterized by autoantibodies directed against the glomerular/alveolar basement membrane. The autoantibodies bind to their reactive epitopes in the basement membranes and activate the complement cascade, resulting in tissue injury. 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 three alpha subunits of collagen, which form a triple helix. Type IV collagen can be expressed as six different chains, alpha1 to alpha6. The alpha chain itself has three structural domains, as follows:
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 (alpha3[IV]NC1).[7, 8] Two conformational epitopes of anti-GBM antibodies have been defined at residues 17-31 and 127-141 of alpha3(IV)NC1, which were named as EA and EB, respectively. The P14 peptide, which has been identified as one of the major linear epitopes recognized by sera from patients with anti-GBM disease, contains the amino acid sequence of EB, as well as one of the T cell epitopes found in anti-GBM disease.[9] 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.[10] These include the following:
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.
There is an increased prevalence of HLA-DR15 (previously known as HLA-DR2) and DRB1*03, DRB1*04 and a decreased frequency of DRB1*01 and DRB1*07.[11, 12] 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.
Although anti-GBM disease is seen as a prototypic autoantibody-mediated disease, T cells have a vital role in disease initiation and progression. T cells enhance B-cell function and antibody production and may play a direct pathogenic role in kidney and lung injury.[13] Autoreactive T cells against alpha3(IV)NC1 are rare in healthy individuals, owing to thymic deletion during fetal development. Autoreactive T cells in patients may form as a consequence of exposure of neoepitopes, altered antigen processing allowing pathogenic epitopes to be presented, or altered T-cell regulation.[12]
Like other autoimmune conditions, anti-GBM disease is thought to result from an environmental insult in a person with genetic susceptibility. The human leukocyte antigen (HLA) serotype HLA-DR15 has been strongly asssociated with anti-GBM disease. An initial insult to the pulmonary vasculature is required for exposure of the alveolar capillaries to the anti-GBM antibodies. Environmental factors that may lead to such exposure include the following:
Anti-GBM disease is an uncommon disorder. The incidence of anti-GBM disease is estimated to be 0.5-1.8 cases per million per year in both European white and Asian populations. It is responsible for 1-5% of all types of glomerulonephritis and for 10-20% of crescentic glomerulonephritis.[15, 16]
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.
A subgroup of patients is double-positive for anti-GBM antibodies and antineutrophilic cytoplasmic antibodies. The peak age incidence for this subgroup is 60-70 years, with a male predominance.[8]
In the past, Goodpasture syndrome was usually fatal. Aggressive therapy with plasmapheresis, corticosteroids, and immunosuppressive agents has dramatically improved prognosis.[17] With this approach, the 5-year survival rate exceeds 80% and fewer than 30% of patients require long-term dialysis. In a study of patients patients admitted to intensive care units for acute manifestation of small-vessel vasculitis, including anti-GBM disease, delayed administration of cyclophosphamide was associated with a higher mortality rate.[18]
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. In a retrospective analysis of patients with anti-GBM disease who started renal replacement therapy for end-stage renal disease (ESRD) in Australia and New Zealand (ANZDATA Registry), the median survival rate was 5.93 years with death predicted by older age and history of pulmonary hemorrhage.[16]
Substantial variation exists in the clinical manifestations of patients with anti–glomerular basement membrane (anti-GBM) disease. From 60-80% of patients have clinically apparent manifestations of pulmonary and renal disease, 20-40% have renal disease alone, and less than 10% have disease that is limited to the lungs.
Symptoms include the following:
Physical examination findings in patients with anti-GBM disease include the following:
Diffuse alveolar hemorrhage represents a medical emergency, and clinicians must have an expedient approach to its identification.[20] In the appropriate clinical setting (ie, alveolar hemorrhage and urinary findings suggestive of an acute glomerulonephritis), the detection of circulating anti–glomerular basement membrane (anti-GBM) antibodies allows the clinician to make a firm diagnosis of anti-GBM disease. This obviates lung or kidney biopsy.
When the diagnosis remains in doubt, renal biopsy is the best method for detecting anti-GBM antibodies in tissues. Patients in whom the diagnosis of diffuse alveolar hemorrhage remains uncertain should undergo diagnostic bronchoscopy.
Urinalysis findings are characteristic of acute glomerulonephritis, usually demonstrating low-grade proteinuria, gross or microscopic hematuria, and red blood cell casts.
On the complete blood cell count, anemia may be observed secondary to iron deficiency caused by intrapulmonary bleeding. Leukocytosis is commonly present.
Elevated blood urea nitrogen (BUN) and serum creatinine levels secondary to renal dysfunction may be present.
Elevation of the erythrocyte sedimentation rate (ESR) is commonly observed in patients with vasculitis, but it is uncommon in anti-GBM disease.
Serologic assays for anti-GBM antibodies are valuable for confirming the diagnosis and monitoring the adequacy of therapy. Radioimmunoassays or enzyme-linked immunosorbent assays (ELISAs) for anti-GBM antibodies are highly sensitive (>95%) and specific (>97%) but are performed in only a few laboratories. Positive results should be confirmed by Western blotting on collagenase-solubilized human GBM, especially if a kidney biopsy is not being performed.
In a comparison study of 4 immunoassay-based anti-GBM antibody kits, all the assays showed comparably good sensitivity (94.7-100.0%), whereas specificity varied considerably (90.9-100.0%). The recombinant antigen fluorescence immunoassay demonstrated the best sensitivity/specificity.[21]
Healthy individuals may have circulating antibodies against GBM belonging to IgG2 and IgG4 subclasses. With onset of clinical disease, IgG1 and IgG3 subclasses increase and levels may correlate with disease severity.[7]
A study by Yang et al indicated that higher levels of circulating anti-GBM antibodies against the epitopes EA and EB occurred in patients whose renal disease was more severe and that these patients had a worse prognosis. Correlation was noted between the levels of anti-GBM antibodies and the serum creatinine at diagnosis and the presence of oliguria. Correlation existed between the percentage of crescents on biopsy and levels of antibodies, but it was significant only for anti-EA antibodies (P< .05).[22]
At some time during the course of illness, as many as one third of patients with Goodpasture syndrome have circulating antineutrophilic cytoplasmic antibodies (ANCAs) in addition to anti-GBM antibody.[19] In most cases, the ANCA antibodies precede the development of anti-GBM antibodies by months to years.[23] It is postulated that the renal involvement in ANCA vasculitis leads to the exposure of antigens from the basement membrane and the formation of antibodies. These patients are referred to as double-positive.
Cytoplasmic ANCA (c-ANCA) and perinuclear ANCA (p-ANCA) are seen in the images below.
View Image | Cytoplasmic antineutrophilic cytoplasmic antibodies (c-ANCA), which can appear in Goodpasture syndrome, are also commonly observed in Wegener granulom.... |
View Image | Perinuclear antineutrophilic cytoplasmic antibodies (p-ANCA), which can appear in Goodpasture syndrome, are also observed in Churg-Strauss vasculitis .... |
In the majority of double-positive patients, the ANCAs have specificity for myeloperoxidase (MPO-ANCA).[24, 25] In patients with both anti-GBM antibodies and MPO-ANCAs, histological findings differ from those of patients with anti-GBM antibodies only. The renal survival in these patients is similar to anti-GBM–positive patients and is worse compared with patients with MPO-ANCAs only.
In an analysis of the diagnostic performance of two rapid ANCA and anti-GBM test methods in 260 patients with suspected ANCA-associated small vessel vasculitis, de Joode and colleagues found that both the Dotblot and Phadia ELiA on anti-GBM, anti-PR3(s) and anti-MPO(s) performed well. Results with these tests were almost identical to those achieved with routine ELISA.[26]
Characteristically, the chest film shows patchy parenchymal consolidations, which are usually bilateral, symmetric perihilar, and bibasilar. The apices and costophrenic angles are usually spared (see the image below). However, as many as 18% of patients may have normal findings on chest radiographs.
The consolidation resolves over 2-3 days, and it gradually progresses to an interstitial pattern as patients experience repeated episodes of hemorrhage. Pleural effusions are unusual.
View Image | Goodpasture syndrome. A 35-year-old man who previously smoked cigarettes heavily, developed massive hemoptysis. The blood work showed positive anti–gl.... |
Routine pulmonary function testing is not helpful in the clinical evaluation of the patients with anti-GBM disease. Spirometry and lung volume tests may reveal evidence of restriction.
The diffusing capacity for carbon monoxide (DLCO) is elevated secondary to binding of carbon monoxide to intra-alveolar hemoglobin. Recurrent pulmonary hemorrhage may be diagnosed with new opacities observed on chest radiographs and a 30% rise in DLCO.
In patients with evidence of diffuse alveolar hemorrhage and renal involvement, kidney biopsy should be considered to identify the underlying cause and to help direct therapy. Percutaneous kidney biopsy is the preferred invasive procedure to substantiate the diagnosis of anti-GBM disease. Renal biopsy provides a significantly higher yield than lung biopsy, but transbronchial or open lung biopsy may be performed in cases where renal biopsy cannot be performed.
The biopsy tissue must be processed for light microscopy, immunofluorescence, and electron microscopy. Light microscopy demonstrates nonspecific features of a proliferative or necrotizing glomerulonephritis with cellular crescents (as seen in the image below). Over time, the crescents become fibrotic, and frank glomerulosclerosis, interstitial fibrosis, and tubular atrophy may be observed.
View Image | This is a renal biopsy slide of a patient who presented with hemoptysis and hematuria. The renal biopsy revealed crescentic glomerulonephritis, which .... |
Immunofluorescence stains are confirmatory. These show bright linear deposits of immunoglobulin G (IgG), as seen in the image below, and complement (C3) along the glomerular basement membranes. Subclass IgG-1 predominates.[27]
View Image | Immunofluorescence staining for immunoglobulin (IgG) reveals diffuse, high-intensity, linear staining of the glomerular basement membrane in a patient.... |
Lung biopsy shows extensive hemorrhage with accumulation of hemosiderin-laden macrophages within alveolar spaces. Neutrophilic capillaritis, hyaline membranes, and diffuse alveolar damage may also be found. Medium-vessel or large-vessel vasculitis is not a feature.[28] Immunofluorescence staining may be diagnostic, but performing this study on lung tissue is technically difficult.
The three principles of therapy in anti–glomerular basement membrane (anti-GBM) disease are as follows:
The rapid institution of appropriate therapy depends on distinguishing anti-GBM disease from other pulmonary renal syndromes with similar presentations. Beginning therapy despite a pending or preliminary negative test result for serum anti-GBM antibodies may be necessary; a delay in this setting can be associated with adverse clinical outcomes.
Patients who develop massive hemoptysis or acute respiratory failure should be cared for in an intensive care unit (ICU). Transfer to a hospital where plasmapheresis and/or hemodialysis is available may be necessary. Standard indications for dialysis are followed.
After hospital discharge, patients require long-term regular visits for monitoring of renal function and immunosuppressive therapy. If renal function does not return, dialysis is continued indefinitely and the patient should be referred for renal transplantation.
Patients receiving renal transplants must be informed that anti-GBM disease can recur in the transplanted kidney, although graft loss due to this is very rare.
Go to Pediatric Anti-GBM Disease (Goodpasture Syndrome) for complete information on this topic.
In published case series and one randomized trial, plasmapheresis has been shown to be beneficial in the treatment of Goodpasture syndrome by removal of anti-GBM antibodies.[29, 30, 31] Plasmapheresis is generally instituted after the diagnosis of Goodpasture syndrome is established either by renal biopsy or by detection of anti-GBM antibodies.
When a patient presents in a life-threatening situation secondary to pulmonary hemorrhage, however, plasmapheresis may be initiated if the diagnosis appears very likely, even though confirmation is not available immediately.
The extent and duration of plasmapheresis is not known, but 4-liter plasma exchanges daily or every other day is usually performed. The plasmapheresis is continued for 2-3 weeks or until the patient's clinical course has improved and serum anti-GBM antibodies are not detected.
A study by Zhang and colleagues in 28 patients with anti-GBM nephritis found that double filtration plasmapheresis cleared anti-GBM antibody about as effectively as immunoadsorption therapy (59.0% vs. 71.2% efficacy, respectively; P = 1.00). However, significantly fewer patients in the plasmapheresis group experienced reduced IgG (62.7% vs. 83.5%), and the plasmapheresis group also experienced fewer plasma-associated side effects. Patient survival and renal survival were similar in the two groups.[32]
Immunosuppressive therapy is required to inhibit antibody production and rebound hypersynthesis, which may occur following discontinuation of plasma exchange.[29, 30, 33]
Initial therapy includes cyclophosphamide at 2 mg/kg orally, adjusted to maintain a white blood cell count of approximately 5000, and corticosteroids (eg, prednisone at 1-1.5 mg/kg). Treatment of acute life-threatening alveolar hemorrhage in patients with Goodpasture syndrome is with pulse methylprednisolone at 1 g/day for 3 days, followed by a gradual corticosteroid taper. Intravenous cyclophosphamide is begun concomitantly at 1 g/m2 and repeated 3-4 weeks later, depending on the recovery of bone marrow.
The duration of immunosuppressive therapy is not well established. Anti-GBM antibody levels must be monitored at regular intervals. In patients who achieve a prompt remission, immunosuppression with cyclophosphamide is continued for 2-3 months and steroids for 6 months. Patients with clinically or serologically active disease at 3-4 months need longer immunosuppression (6-9 mo). Azathioprine may be substituted for cyclophosphamide to reduce adverse effects, especially in patients needing prolonged immunosuppression.
Rituximab, a chimeric monoclonal antibody, effectively depletes CD20-positive B cells over 6-9 months and has been used in several case reports as an alternative approach in the treatment of anti-GBM antibody disease. In these reports, rituximab was used as either an initial or a second-line agent in patients in whom cyclophosphamide failed or yielded adverse effects. The anti-GBM antibodies became undetectable in all these patients, but they had variable renal outcomes.[34, 35]
Pneumocystis jiroveci pneumonia has an annual incidence of 1% but is a potentially deadly complication of immunosuppressive therapy in patients with Goodpasture syndrome. Prophylaxis with trimethoprim-sulfamethoxazole (160 mg trimethoprim and 800 mg sulfamethoxazole 3 times per week) may be a cost-effective method of prolonging life in these patients.
The circulating antibodies clear within 8 weeks, but an early relapse (ie, within the first 2 mo) may occur when circulating antibodies are still present. This typically manifests as alveolar hemorrhage. The risk factors for relapse include infection, volume overload, and cigarette smoking. Late relapse has been documented only rarely.
Renal transplantation has been used for end-stage renal disease secondary to Goodpasture syndrome. It is optimal to delay renal transplantation until anti-GBM antibodies are undetectable in the serum for 12 months and the disease has been in remission for at least 6 months without the use of cytotoxic agents.
Many patients develop linear deposits of IgG along glomeruli of the renal allograft. However, this development does not cause histologic or functional damage to the transplanted kidney.
Interestingly anti-GBM disease can occur in approximately 3-5% of male patients who have hereditary nephritis (Alport syndrome) undergoing renal transplantation, known as de novo anti-GBM disease.[36] In Alport syndrome (X-linked), the antibodies are directed against the alpha5 (IV) chain and, in patients who develop posttransplant anti-GBM disease, the antibody is directed against the alpha3 (IV) chain. Anti-GBM disease occurs most commonly in this subset of patients within the first year, and up to 75% patients have serum anti-GBM antibodies. The diagnosis is achieved with a renal biopsy with the characteristic findings of linear deposition of IgG along the capillaries and sometimes the distal tubules. Treatment consists of plasmapheresis and cyclophosphamide, but this appears to be limited. Retransplantation of patients with posttransplant anti-GBM nephritis has a very poor prognosis owing to recurrent disease.
Consult a nephrologist for evaluation of the patient in regard to the differential diagnosis of the renal disease, indication for renal biopsy, requirement for hemodialysis or plasmapheresis, and therapeutic input.
Consult a pulmonologist for patients with significant hemoptysis or respiratory compromise because these patients may deteriorate very rapidly and require bronchoscopy and/or intubation.
A consultation with a vascular surgeon may be required for establishment of vascular access for hemodialysis or plasmapheresis.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. The treatment of choice is a combination of plasmapheresis to remove the circulating anti–glomerular basement membrane (anti-GBM) antibodies and immunosuppression with glucocorticoids and cytotoxic agents to inhibit further autoantibody formation. In addition, antibiotic prophylaxis is indicated to reduce the risk of opportunistic infection secondary to immunosuppressive therapy.
Clinical Context: Prednisone is used as an immunosuppressant in the treatment of autoimmune disorders. This agent may reduce inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity.
Clinical Context: Methylprednisolone is the drug of choice for severe disease. It should be started concomitantly with plasmapheresis. This agent decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.
Clinical Context: Azathioprine antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins. It may decrease the proliferation of immune cells, which results in lower autoimmune activity.
For induction therapy, prednisone and cyclophosphamide are initiated. For severe or rapidly progressing disease, methylprednisolone at a dose of 250 mg every 6 hours should be administered. Once the patient is stabilized, continue oral therapy with prednisone.
Azathioprine may be used for patients who do not tolerate cyclophosphamide.
Clinical Context: Cyclophosphamide is chemically related to nitrogen mustards. It is a potent immunosuppressant used as an adjunct to corticosteroids and plasma exchange. This agent interferes with the inflammatory response by decreasing bone marrow response through the interference of DNA cross-linking and decreases anti–glomerular basement membrane (anti-GBM) antibody production.
Alkylating agents bind with DNA and interfere with cell growth and differentiation.
Clinical Context: This combination inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid, thus inhibiting folic acid synthesis. It results in inhibition of bacterial growth. The antibacterial activity of trimethoprim-sulfamethoxazole (TMP-SMZ) includes common urinary tract pathogens, except Pseudomonas aeruginosa. Each double strength (DS) tablet contains 160 mg of TMP and 800 mg SMZ.
Patients receiving immunosuppressive therapy should also receive prophylaxis against Pneumocystisjiroveci pneumonia.
Goodpasture syndrome. A 45-year-old man was admitted to the intensive care unit with respiratory failure secondary to massive hemoptysis and acute renal failure. The antiglomerular basement membrane antibodies were strongly positive. The autopsy showed consolidated lung from extensive bleeding, which led to asphyxiation.
Goodpasture syndrome. Close-up view of gross pathology in a 45-year-old man admitted to the intensive care unit with respiratory failure secondary to massive hemoptysis and acute renal failure. The antiglomerular basement membrane antibodies were strongly positive. The autopsy showed consolidated lung from extensive bleeding, which led to asphyxiation.
Goodpasture syndrome. A 45-year-old man was admitted to the intensive care unit with respiratory failure secondary to massive hemoptysis and acute renal failure. The antiglomerular basement membrane antibodies were strongly positive. The autopsy showed consolidated lung from extensive bleeding, which led to asphyxiation.
Goodpasture syndrome. Close-up view of gross pathology in a 45-year-old man admitted to the intensive care unit with respiratory failure secondary to massive hemoptysis and acute renal failure. The antiglomerular basement membrane antibodies were strongly positive. The autopsy showed consolidated lung from extensive bleeding, which led to asphyxiation.