Goodpasture’s Syndrome (Lung-Kidney Syndrome)

Background

Goodpasture syndrome is an eponym that has been used to describe the clinical entity of diffuse pulmonary hemorrhage and 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.

History

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.

Pathophysiology

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 circulating anti-GBM antibodies react with an epitope contained within the basement membranes.

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. The Goodpasture antigen has been localized to the carboxyl terminus of the noncollagenous domain of the alpha3 chain of type IV collagen.[1] The antibodies are directed against a 28-kd monomeric subunit present within the noncollagenous domain.

The anti-GBM antibody can usually be found in serum. In some patients, this antibody also reacts with the pulmonary alveolar basement membrane and causes alveolar hemorrhage. 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

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.

The prevalence of HLA-DR2 is higher in patients with Goodpasture disease than in control populations. The association is caused by an excess of the haplotype bearing DR-W 15. In addition, HLA-B7 is found more frequently and is associated with more severe anti-GBM nephritis. The exact role of these genetic findings in the pathogeneses of disease is not clear.

Sophisticated immunologic and molecular techniques have shown that immune response against Goodpasture autoantigen and synthesis of autoantibodies depend not only on the association of antigen with HLA molecules but also on how fragments of the antigen are handled by antigen-processing cells, such as B lymphocytes, monocytes and macrophages, and dendritic cells.

Reports have shown that presentation of Goodpasture autoantigen to CD4 T lymphocytes, which is strongly associated with HLA-DR 15 alloantigen, is largely dependent on the ability of antigen antigenic epitopes to be processed. It is less clearly dependent on the binding affinity to the DR-15 molecule.

Etiology

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

Epidemiology

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 disease shows a male predominance, with the male-to-female ratio reported as 2-9:1.

The age distribution is bimodal. Young men present with a pulmonary-renal syndrome at ages 20 and 30 years, and elderly women (ie, aged 60-70 y) present primarily with glomerulonephritis.

Sign and Symptoms

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:

  • Hemoptysis is the presenting symptom when the disease affects the lungs. The level of hemoptysis may vary and, in a small percentage of patients, may be absent. Other pulmonary symptoms include cough and dyspnea
  • Chills and fever are present in approximately 25% of patients
  • Nausea and vomiting are present in 41%
  • Approximately 14% of patients report weight loss
  • Chest pain is present in approximately 40% of patients
  • Significant anemia may result from persistent intrapulmonary bleeding
  • Massive pulmonary hemorrhage leading to respiratory failure may occur
  • Renal manifestations are rapidly progressive glomerulonephritis that may lead to azotemia and volume overload
  • Arthralgias

Physical examination

Physical examination findings in patients with anti-GBM disease include the following:

  • Tachypnea
  • Inspiratory crackles over lung bases
  • Cyanosis
  • Hepatosplenomegaly (may be present)
  • Hypertension (present in 20% of cases)
  • Skin rash

Diagnosis

1. Approach Considerations:

Diffuse alveolar hemorrhage represents a medical emergency, and clinicians must have an expedient approach to its identification. 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.

2. Urinalysis:

Urinalysis findings are characteristic of acute glomerulonephritis, usually demonstrating low-grade proteinuria, gross or microscopic hematuria, and red blood cell casts.

3. Blood studies:

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.

4. Anti–GBM Antibody Testing:

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.

Although the peak of serum anti-GBM antibody titer does not correlate with the severity of disease, changes in titers over time may be a guide to the efficacy of therapy. IgG subclass distribution of anti-GBM antibodies may correlate with disease severity, however.

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.

A study by Yang et al indicated that high levels of circulating anti-GBM antibodies against the epitopes EA and EB may occur in patients whose renal disease is more severe and that these patients have a worse prognosis than patients with lower levels of these antibodies.

5. Antineutrophilic Cytoplasmic Antibody Testing:

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.

In a substantial proportion of patients with crescentic glomerulonephritis (CGN), both anti-GBM antibodies and antineutrophil cytoplasmic antibodies (ANCAs) with specificity for myeloperoxidase (MPO-ANCA) are detected. 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.

6. Chest Radiograph:

Characteristically, the chest film shows patchy parenchymal consolidations, which are usually bilateral, symmetric perihilar, and bibasilar. The apices and costophrenic angles are usually spared. 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.

7. Pulmonary Function Testing:

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.

8. Biopsy:

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 not only for light microscopy but also for immunofluorescence and electron microscopy. In the renal biopsy, light microscopy demonstrates nonspecific features of a proliferative or necrotizing glomerulonephritis with cellular crescents (as seen in the image below). Over time, the crescents may fibrose, and frank glomerulosclerosis, interstitial fibrosis, and tubular atrophy may be observed.

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.

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.

Immunofluorescence staining may be diagnostic, but performing this study on lung tissue is technically difficult.

Differential Diagnoses

1. Diagnostic Considerations:

There are many causes of diffuse alveolar hemorrhage, including vasculitides, immunologic conditions such as Goodpasture syndrome, collagen vascular disease, and idiopathic conditions. Careful attention to the medical history, physical examination, and targeted laboratory evaluation often suggests the underlying cause.

Other problems to be considered include mesangial glomerulonephritis and nephrotic syndrome with pulmonary emboli. Distinguishing Wegener granulomatosis from Goodpasture syndrome is particularly important. Interestingly, some patients with Goodpasture syndrome may present with antineutrophilic cytoplasmic antibodies (ANCAs), which are predominantly observed in patients with Wegener granulomatosis.

2. Differentials:

  • Acute Glomerulonephritis
  • Infective Endocarditis
  • Pneumococcal Infections
  • Pneumocystis Carinii Pneumonia
  • Bacterial Pneumonia
  • Community-Acquired Pneumonia
  • Polymyositis
  • Pulmonary Eosinophilia
  • Respiratory Failure
  • Undifferentiated Connective-Tissue Disease

Treatment and Management

1. Approach Considerations:

The 3 principles of therapy in anti–glomerular basement membrane (anti-GBM) disease are:

  1. to rapidly remove circulating antibody, primarily by plasmapheresis;
  2. to stop further production of antibodies using immunosuppression with medications; and
  3. to remove offending agents that may have initiated the antibody production.

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 ICU. Patients who develop renal failure are placed immediately into dialytic therapy. Renal diet is instituted. Transfer to a hospital where plasmapheresis and/or hemodialysis is available may be necessary.

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.

2. Plasmapheresis:

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. 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 plasma exchanges (1 L each) daily or every other day are 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.

3. Immunosuppressive Therapy:

Immunosuppressive therapy is required to inhibit antibody production and rebound hypersynthesis, which may occur following discontinuation of plasma exchange.

Cyclophosphamide at 2 mg/kg orally, adjusted to maintain a white blood cell count of approximately 5000, is instituted and continued for 6 months. Corticosteroids (eg, prednisone at 1-1.5 mg/kg) are also initiated and gradually tapered over 6 months following clinical remission.

Treatment of acute life-threatening alveolar hemorrhage in patients with Goodpasture syndrome is with pulse methylprednisolone at 1 g/d 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. Treatment is continued for 3-6 months, provided a sustained remission has been achieved and anti-GBM antibodies have disappeared.

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.

Relapse???

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.

4. Renal Transplantation:

Renal transplantation has been used for end-stage renal disease secondary to Goodpasture syndrome. Most transplant centers prefer to wait 6-12 months after serologic evidence indicates that anti-GBM antibodies have cleared before performing transplantation.

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.

5. Consultations:

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.

Prognosis

In the past, Goodpasture syndrome was usually fatal. Aggressive therapy with plasmapheresis, corticosteroids, and immunosuppressive agents has dramatically improved prognosis. With this approach, the 5-year survival rate exceeds 80% and fewer than 30% of patients require long-term dialysis. In a literature review of all published cases, most patients were treated with immunosuppression and plasma exchange and were alive at follow-up.

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.

References:
1. Frazier T Stevenson, MD; Vecihi Batuman, MD, FACP, FASN. Goodpasture Syndrome: Overview. Available from: http://emedicine.medscape.com/article/240556-overview#showall. [Accessed on September 4th, 2011]
2. Frazier T Stevenson, MD; Vecihi Batuman, MD, FACP, FASN. Goodpasture Syndrome: Clinical Presentation. Available from: http://emedicine.medscape.com/article/240556-clinical#showall. [Accessed on September 4th, 2011]
3. Frazier T Stevenson, MD; Vecihi Batuman, MD, FACP, FASN. Goodpasture Syndrome: Workup. Available from: http://emedicine.medscape.com/article/240556-workup#showall. [Accessed on September 4th, 2011]
4. Frazier T Stevenson, MD; Vecihi Batuman, MD, FACP, FASN. Goodpasture Syndrome: Differential Diagnoses. Available from: http://emedicine.medscape.com/article/240556-differential. [Accessed on September 4th, 2011]
5. Frazier T Stevenson, MD; Vecihi Batuman, MD, FACP, FASN. Goodpasture Syndrome: Treatment and Management. Available from: http://emedicine.medscape.com/article/240556-treatment#showall. [Accessed on September 4th, 2011]

This entry was posted in Allergy and Immunology, Genitourinary System., Hematology and Immunology., Internal Medicine, Medicine, Nephrology, Pulmunology, Respiratory System., Syndromes. Bookmark the permalink.

3 Responses to Goodpasture’s Syndrome (Lung-Kidney Syndrome)

  1. Peggy says:

    Some information for your further research. My husband was diagnosed with anti-GBM disease, following hospitalization for acute diverticulitis, while hospitalized was treated for a suspected case of fleeting gout with allopurinol and indocin, with his kidney function already taxed. His creatinine climbed to 8 while on these medications resulting in the anti-GBM diagnosis. Perhaps some correlation?

    • Thanks for the question. Based on my knowledge, Indocin not recomended to kidney failure patients especially to severe kidney failure patients because it may effect patient’s kidney function. That’s why your husband’s creatinine level climbs to 8. But my advise is, please consult to your husband’s doctor about the usage of Indocin to your husband, i believe your husband’s doctor have strong reason why Indocin given to your husband even Indocin not recomended to kidney failure patient.

  2. Peggy says:

    Thanks for the response, but it did not all come through. Could you please repost your answer?

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