AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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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. 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.

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. 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. 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.

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 (~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.

CLINICAL

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History

Patients with anti-GBM nephritis can present with glomerulonephritis alone or with accompanying pulmonary hemorrhage. Although pulmonary hemorrhage may be minor, it is often severe and life threatening. Pulmonary hemorrhage occurs more frequently in young adult males, whereas anti-GBM nephritis without lung involvement tends to occur more frequently in women in their seventh decade of life.

The disease may begin with either renal or pulmonary manifestations. Usually, both organs are involved more or less simultaneously. However, in several cases, the interval to the second organ's involvement may be prolonged up to a year.

• Prodromal period
• • In 25-30% of patients, a prodromal period of flulike illness occurs.
  • In approximately 5% of patients, arthralgia, myalgia, and arthritis are prominent features.
• Pulmonary manifestations
• • The onset of pulmonary hemorrhage may be insidious, with symptoms such as anemia, pallor, weakness, lethargy, dyspnea upon exertion, and, sometimes, dry cough.
  • In some cases, onset is acute and includes fever, massive hemoptysis, acute respiratory failure, asphyxia, and death; however, in many cases, the symptoms, including hemoptysis, dyspnea, cough, fever, tachycardia, and fatigue, may be present intermittently for weeks to months before the diagnosis is established.
• Renal manifestations
• • The patient usually presents with an abrupt onset of oliguria or anuria. Hematuria or the passage of tea-colored urine is usually observed.
  • Rarely, the patient's renal involvement is more insidious in onset and he or she remains asymptomatic, progressing slowly until the development of uremic symptoms.

Physical

• Physical examination in the acute stage of the disease reveals respiratory distress, tachycardia, and cyanosis.
• The patient usually appears pale because of anemia.
• In severe cases, the patient may be in hemorrhagic shock and in respiratory failure, thus requiring volume resuscitation and ventilatory support, respectively.
• Chest examination may reveal fine rales and dullness to percussion over the affected lung areas.

Causes

The disease is caused by autoantibodies directed against the NC1 domain of the alpha-3 chain of type IV collagen.

• Genetic susceptibility
• • Anti-GBM disease shows a strong association with HLA-DR2.
  • 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.
  • 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
• • A number of studies suggest a strong association between pulmonary hemorrhage and smoking.
  • Pulmonary hemorrhage may also be associated with exposure to hydrocarbons or other agents (eg, respiratory pathogens).

DIFFERENTIALS

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WORKUP

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Lab Studies

• Urinalysis: A urinary dipstick test and a 24-hour urine collection to test for protein and creatinine should be performed for detection of hematuria and proteinuria. Urinary sediment should be analyzed using microscopy to detect dysmorphic red blood cells and cellular casts.
• • Hematuria: Urinary sediment frequently reveals dysmorphic red blood cells and red blood cell casts.
  • Proteinuria: This is usually absent in the early years of life. Proteinuria usually progresses with age and may be in the nephrotic range in up to 30% of patients.
• Blood chemistry and CBC count
• • Blood chemistry: Patients usually have elevated blood urea nitrogen and serum creatinine levels. Serum bicarbonate levels are usually low, and serum phosphate levels may be elevated because of renal failure.
  • CBC count: This may show low hemoglobin and hematocrit levels, reflecting blood loss from pulmonary hemorrhage. Serial analysis may be helpful for monitoring blood loss. Low hemoglobin levels can also be due to advanced renal failure. The platelet count is usually within reference ranges. A mild leukocytosis is often observed.
• Complement levels and serology
• • Complement: Levels are usually within reference ranges.
  • Antineutrophil cytoplasmic antibodies (ANCA): These test findings are usually negative. However, approximately 25-30% patients with anti-GBM disease have circulating ANCA. Of these patients, approximately 75% have perinuclear ANCA; the remaining 25% have cytoplasmic ANCA.
  • Circulating anti-GBM antibodies: More than 95% of patients with anti-GBM nephritis have circulating anti-GBM antibodies. The antibodies are usually of the immunoglobulin G (IgG) class, although immunoglobulin A or immunoglobulin M anti-GBM antibodies are occasionally observed. They can be detected using indirect immunofluorescence assays, usually using monkey kidneys as the substrate, or by radioimmunoassay or enzyme-linked immunosorbent assay. Radioimmunoassay and enzyme-linked immunosorbent assay are more sensitive and specific than indirect immunofluorescence assays.

Imaging Studies

• Renal ultrasound: In the early stages, renal ultrasound shows normal-sized kidneys. However, with advancing renal failure, the kidneys shrink and become echogenic.

Procedures

• Unless contraindicated, a renal biopsy should be promptly performed in every case. Rapid diagnosis is necessary to assess the degree of crescentic involvement and the extent of fibrosis and to exclude other disease processes. Furthermore, prompt diagnosis is essential in order to start specific treatment as early as possible to preserve renal function.

Histologic Findings

Light microscopy reveals the presence of crescents in more than 95% of patients, and approximately 80% of patients show crescents involving more than 50% glomeruli (see Media file 1). In early stages, the crescents are cellular and associated with necrotizing glomerular lesions. They gradually evolve into fibrotic crescents and glomerular sclerosis. Focal rupture of the GBM and fibrinoid necrosis of glomeruli are usually observed. In severe cases, rupture of the Bowman capsule ensues. Tubulointerstitial changes, including interstitial edema and inflammation and tubular damage, are usually observed along with glomerular injury. If necrotizing inflammation is observed in arteries or arterioles, the possibility of concurrent ANCA-associated glomerulonephritis should be considered.

Immunofluorescent examination of the biopsy specimen reveals the characteristic linear deposition of IgG (rarely immunoglobulin A or immunoglobulin M) antibodies along the GBM (see Media file 2). Linear staining for IgG may also occur along the tubular basement membrane. Weak linear staining of the GBM is frequently observed in persons with diabetic nephropathy, but clinical data and light microscopic features can easily distinguish the 2 conditions.

Electron microscopy findings reflect those observed with light microscopy and include the presence of crescents, disruption of the GBM, and cellular infiltration at the sites of necrosis.

TREATMENT

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Medical Care

Anti-GBM nephritis is a rapidly progressive disease with a high mortality rate if not treated. Therefore, a prompt diagnosis and early treatment are of paramount importance in preventing death and preserving renal function. The usual treatment for anti-GBM nephritis uses plasmapheresis in combination with intense immunosuppression consisting of corticosteroids and cyclophosphamide or azathioprine. Other therapeutic options include immunoadsorption using protein A affinity columns or treatment with cyclosporine.

• Plasmapheresis
• • Since the first successful treatment by Lockwood and colleagues in 1976, plasmapheresis has become the standard treatment of anti-GBM nephritis. The therapy effectively removes circulating anti-GBM antibodies and consists of removal of 1 volume of plasma (usually 4 L) and replacement with an equal volume of 5% albumin.
  • Plasmapheresis is continued daily until anti-GBM antibodies are undetectable in the blood. Usually, 10-14 treatments are required.
  • In patients with pulmonary hemorrhage, replace clotting factors by administering fresh frozen plasma at the end of treatment.
  • An early series of studies suggested that oliguric patients and those on dialysis before treatment rarely improve with plasmapheresis. However, more recent reports suggest that patients with advanced renal disease occasionally do respond, particularly if they are not anuric or if the biopsy specimen reveals a low proportion of sclerosed glomeruli.
• Protein A immunoadsorption
• • Several investigators have reported successful use of immunoadsorption with protein A in patients with anti-GBM nephritis who do not respond to plasmapheresis.
  • Protein A, isolated from the cell wall of the Staphylococcus aureus Cowan I strain, binds to the Fc portions of IgG. Thus, separated plasma from the patient is pumped through a protein A Sepharose column to enable anti-GBM antibodies to bind, and the plasma is then returned to the patient. This prevents depletion of coagulation factors and other essential plasma proteins and obviates the need for large-volume replacement of fluids.
• Immunosuppression
• • Immunosuppression usually includes high doses of steroids and cyclophosphamide. Cyclophosphamide is administered at a dose of 2-2.5 mg/kg/d. Adjust the dose of cyclophosphamide according to the degree of renal impairment. Administer cyclophosphamide for at least 1 year after remission, and then taper in 25-mg decrements every 2-3 months until discontinuation or disease recurrence.
  • Monitor the total leukocyte count frequently, and maintain it between 3000-5000/µL. High-dose steroids are also administered along with cyclophosphamide.
  • The role of pulse steroids is not clear in persons with anti-GBM nephritis, but some centers usually administer pulse steroids in patients with fulminant disease. Typically, methylprednisolone is given in dosages of 7-17 mg/kg/d for 3 consecutive days. Thereafter, oral prednisolone is started at a dosage of 1 mg/kg/d for 4 weeks and tapered slowly to 20 mg on alternate days by week 52 and withdrawn, as tolerated, thereafter (see Medication).

Consultations

Consultation with pulmonary and critical care specialists is needed in patients presenting with hypoxia due to severe pulmonary hemorrhage. These patients may require intubation and mechanical ventilation. Furthermore, they may present with hemorrhagic shock and require hemodynamic monitoring in an intensive care unit.

Diet

Place patients with renal failure on a diet restricted to 2 g of sodium per day, 60 mEq of potassium per day, and 0.85 g/kg of protein per day.

Activity

Patients may engage in activities as tolerated.

MEDICATION

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The standard treatment of anti-GBM nephritis consists of plasmapheresis in combination with intense immunosuppression. The latter involves high-dose corticosteroids in combination with cyclophosphamide. Rarely, azathioprine or cyclosporine may be used in patients who cannot tolerate cyclophosphamide.

Drug Category: Corticosteroids

Anti-GBM nephritis is a rapidly progressive disease associated with a high mortality rate if not treated. However, early diagnosis and prompt treatment can prevent progression, preserve renal function, and reduce mortality. High doses of corticosteroids constitute an important component of the intense immunosuppression for anti-GBM nephritis.

Drug Category: Immunosuppressives

Cyclophosphamide (an alkylating agent) and corticosteroids constitute the standard immunosuppression regimen for anti-GBM nephritis.

FOLLOW-UP

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Further Inpatient Care

• Patients presenting with respiratory failure may require intubation and mechanical ventilation. Furthermore, patients may present with hemorrhagic shock and require blood transfusion and hemodynamic monitoring. Patients presenting with advanced renal failure may require short- or long-term dialysis.
• While in the hospital, patients should also receive supportive care (eg, adequate nutrition, prophylaxis for deep vein thrombosis and stress ulcers, good blood pressure control).

Further Outpatient Care

• After discharge from the hospital, patients need a detailed follow-up visit with a nephrologist. Renal function should be closely monitored for progression of renal disease or recurrence of anti-GBM nephritis. Patients should also have their blood cell counts checked frequently while they are taking cyclophosphamide because they are at high risk for hemorrhagic cystitis or transitional cell carcinoma of the urinary bladder. Therefore, their urine should be screened for nonglomerular hematuria; all patients with nonglomerular hematuria should undergo a further urological evaluation.
• Patients with anti-GBM nephritis who are taking high doses of steroids are at a high risk of developing osteoporosis. Therefore, they should receive calcium and vitamin D supplements (1000 mg/d elemental calcium for men and 1500 mg/d for women). Bone densitometry may also be performed to check for osteoporosis.
• Patients receiving immunosuppression in high doses are also at risk for opportunistic infections. They should be placed on a single-strength tablet of trimethoprim-sulfamethoxazole per day for prophylaxis of Pneumocystis carinii infection. In addition, patients should rinse their mouths several times a day to prevent oral thrush and, if necessary, be given nystatin swish and swallows.
• Patients who take high doses of steroids are prone to develop diabetes and hypertension. Thus, they should be screened for diabetes and have their blood pressure checked frequently.

In/Out Patient Meds

• Methylprednisolone at 7-17 mg/kg/d intravenously for 3 days should be administered to patients with fulminant disease.
• The starting dose of prednisolone is 1 mg/kg/d. In patients receiving intravenous methylprednisolone, oral prednisolone should be started on the fourth day. Administration should be continued after discharge in tapering doses for one year.
• Cyclophosphamide should be administered orally at 1 mg/kg/d. This agent should be started once the diagnosis is confirmed and should be continued in an outpatient setting for a total of one year.
• Calcium carbonate at 500 mg orally 2-3 times/d should be administered for osteoporosis prevention.
• Double-strength trimethoprim-sulfamethoxazole (Bactrim) or equivalent should be administered at a dose of one tablet every other day for prophylaxis of P carinii infection.
• Omeprazole at 20 mg or an equivalent proton pump inhibitor should be administered once or twice a day for prophylaxis of stress ulcers.

Transfer

• Anti-GBM nephritis is a rare disease with a fulminant course if left untreated. The patient should be transferred to a well-equipped tertiary care center for prompt diagnosis and treatment.

Complications

• Respiratory failure
• • Patients with severe pulmonary hemorrhage may present with profound hypoxia and respiratory failure. They usually require admission to an intensive care unit for intubation and ventilation support. Furthermore, patients may present with hemorrhagic shock and may require blood transfusion and hemodynamic monitoring.
  • Patients presenting with advanced renal failure may require short- or long-term dialysis.
• Hemorrhagic shock
• • In addition to respiratory failure, patients with severe pulmonary hemorrhage may present with hemorrhagic shock. They may require blood transfusion and hemodynamic monitoring. They also may require transfusion of other blood products, such as fresh frozen plasma and platelets, to replenish clotting factors and to prevent further bleeding.
  • Because many of these patients are young and are potential candidates for kidney transplantation, every attempt should be made to use leukocyte-poor blood to prevent allosensitization.
• Renal failure
• • Patients with anti-GBM nephritis usually present with rapidly progressive renal failure.
  • Patients with an advanced degree of renal failure may require short- or long-term dialysis.

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 renal failure.
• • 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.
  • 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.
  • Patients who present with dialysis-dependent renal failure have 1-year patient and renal survival rates of 65% and 8%, respectively.
• Importantly, patients with advanced renal 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 extensive crescent formation (>50%), the presence of significant tubular atrophy, interstitial fibrosis or glomerulosclerosis, oliguria or anuria, and a serum creatinine level of more than 6 mg/dL. Patients with HLA-DR W2 and HLA-B7 appear to have a more malignant course.

Patient Education

• 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. Patients 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.
  • Furthermore, 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, P carinii, yeast) and should contact their physician if they develop fever, sore throat, cough with expectoration, or any other signs of infection.
• For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education article Blood in the Urine.
• For further information, see Mayo Clinic - Kidney Transplant Information.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to reach an early and precise diagnosis in order to prevent death and preserve renal function

Special Concerns

• Anti-GBM nephritis after renal transplantation in patients with Alport syndrome
• • Approximately 3-5% of patients who receive a transplant for Alport syndrome develop anti-GBM nephritis. These patients have circulating antibodies that are directed against the NC1 component of the alpha-3 chain of type IV collagen, similar to those in persons with Goodpasture syndrome. This antigen is not expressed in the native kidneys of patients with Alport syndrome but is present in the transplanted kidney and is recognized as a foreign antigen by the immune system of the recipient.
  • The reason only a small number of patients with Alport syndrome develop anti-GBM disease after transplantation is unclear. At present, the only way to determine whether a patient with Alport syndrome will develop posttransplant anti-GBM nephritis is to perform the transplant; however, certain patients are at very low risk for developing posttransplant anti-GBM nephritis, including patients with normal hearing, patients with a late progression to end-stage renal disease, and females with X-linked Alport syndrome.
• Anti-GBM nephritis associated with ANCA
• • Approximately 20-25% of patients with anti-GBM nephritis have circulating ANCA at some point during the course of the disease. In most cases, the pattern of ANCA is perinuclear, although cytoplasmic ANCA may also be observed in some patients. The clinical course of disease in these patients is milder compared with those who have anti-GBM antibodies alone. Only 40-50% of these patients require dialysis, and a substantial number regain renal function enough to be free of the need for dialysis.
  • An ANCA-positive patient with anti-GBM disease who has vague systemic findings (eg, fever, rash, myalgia, arthralgia) may have a vasculitic process. These patients have a tendency for frequent relapses seldom observed in patients with anti-GBM nephritis. An inverse correlation seems to exist between the titers of the 2 antibodies and the disease course. Patients with high ANCA and low anti-GBM antibody titers have a milder course and a better therapeutic response than those with high anti-GBM antibodies and low ANCA titers.
• Recurrent anti-GBM disease in kidney transplantation
• • Patients with anti-GBM disease usually do well after kidney transplantation. Recurrence, as defined by the appearance of linear IgG deposition along the GBM, is reported in more than 55% of cases. However, clinical manifestations of the recurrent disease and graft loss are very rare.
  • Given the compelling evidence that anti-GBM antibodies are pathogenic in this disease, standard practice is to delay transplantation for 6-12 months beyond the time the circulating anti-GBM antibodies become undetectable.

MULTIMEDIA

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Media file 1:  Antiglomerular basement membrane disease. 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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Media type:  Photo

Media file 2:  Antiglomerular basement membrane disease. 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.
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Media type:  Image

REFERENCES

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Article Last Updated: Nov 16, 2006