Goodpasture syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2];Associate Editor(s)-in-Chief: Krzysztof Wierzbicki M.D. [3] Akshun Kalia M.B.B.S.[4] Ayesha A. Khan, MD[5]

Goodpasture’s disease is a rare condition characterised by rapid destruction of the kidneys and the lungs. It is a type type II hypersensitivity reaction in which autoantibodies are produced against glomerular basement membrane (GBM) and alveolar basement membrane. The term Goodpasture syndrome is named after American physician Dr. Ernest William Goodpasture. There are no known direct causes for Goodpasture syndrome. However, Goodpasture syndrome must be differentiated from other diseases that cause rapid progressive glomerulonephritis and pulmonary hemorrhage. The prevalence of Goodpasture syndrome worldwide is an estimated 1 case per million individuals, with high prevalence in Caucasians. Common risk factors in the development of Goodpasture syndrome may be occupational, environmental, genetic, and viral. Symptoms of Goodpasture syndrome include, malaise, pyrexia and chills and arthralgia, fatigue, lethargy, pallor, and anorexia. Laboratory findings consistent with the diagnosis of Goodpasture syndrome include presence of autoantibodies such as anti-glomerular basement membrane antibodies. Other diagnostic studies for Goodpasture syndrome include renal biopsy. The mainstay of therapy for Goodpasture syndrome consist of corticosteroids, cyclophosphamide and plasmapheresis.

Goodpasture syndrome was first discovered by Dr.Ernest William Goodpasture, an American pathologist and physician, who studied the influenza pandemic in 1919, described a fatal disease that was associated with glomerulonephritis and pulmonary hemorrhage.

There is no established system for the classification of Goodpasture syndrome.

The pathogenesis of Goodpasture syndrome includes the presence of autoantibodies directed against the glomerular or alveolar basement membrane. As with many autoimmune conditions, the precise cause of Goodpasture’s Syndrome is not yet known. It is believed to be a type II hypersensitivity reaction to Goodpasture’s antigens on the cells of the glomeruli of the kidneys and the pulmonary alveoli, specifically the basement membrane‘s (including a-3 chain of type IV collagen), whereby the immune system wrongly recognizes these cells as foreign and attacks and destroys them, as it would an invading pathogen. The target antigen that has the strongest pathogenic effect on anti-GBM disease is the non-collagenous 1 domain of alpha-3 type IV collagen. There is strong correlation of anti-glomerular basement membrane disease with allele HLA DRB1-1501. This allele is associated in causing renal injury. On gross pathology, Goodpasture syndrome with lung involvement may present with diffuse pulmonary hemorrhage. On microscopic histopathological analysis, early focal proliferative changes that display necrosis and crescent formation with an inflamed interstitial are seen. Under direct immunofluorescence, linear immunoglobulin G deposits are found encompassing the glomerular basement membrane and at times the distal tubular portion of the basement membrane.

There are no known direct causes for Goodpasture syndrome. Common risk factors for Goodpasture syndrome are viral or bacterial infections and certain environmental and behavioral risk factors such as smoking, hydrocarbons, formaldehyde and cocaine use.

Goodpasture syndrome must be differentiated from other diseases that cause rapid progressive glomerulonephritis and pulmonary hemorrhage. ANCA associated vasculitis, are disorders that affect the renal and pulmonary system, must be differentiated from Goodpasture syndrome.

The prevalence of Goodpasture syndrome worldwide is an estimated 1 case per million individuals, with high prevalence in Caucasians. The peak incidence of the disease occurs between the ages of 20 and 30 and again at 60 and 70. Goodpasture syndrome affects men and women equally.

Common risk factors in the development of Goodpasture syndrome may be occupational, environmental, genetic, and viral. However, we don’t known what causes the antibodies to form.

There is insufficient evidence to recommend routine screening for Goodpasture syndrome.

If left untreated, Goodpasture syndrome can progress to end stage renal disease and pulmonary failure. Complications of Goodpasture syndrome include, infections, alveolar hemorrhage, end stage renal disease, and pulmonary failure. The prognosis of Goodpasture syndrome is variable, as it depends upon the diagnosis, start of treatment and the level of serum creatinine.

Obtaining a complete history is an important aspect of making a diagnosis of Goodpasture syndrome, as it can provide insight into cause, precipitating factors, and associated underlying conditions. Symptoms may develop acutely or rapidly affecting the renal and pulmonary system. Symptoms of Goodpasture syndrome include, malaise, pyrexia and chills and arthralgia, fatigue, lethargy, pallor, and anorexia.

A complete medical history and comprehensive renal and pulmonary exam must be performed to help identify and properly diagnose Goodpasture syndrome.The presence of tachypnea, inspiratory crackles, edema and hypertension on physical examination are suggestive of presence of renal and pulmonary disorders such as Goodpasture syndrome.

Laboratory findings consistent with the diagnosis of Goodpasture syndrome include presence of autoantibodies such as anti-glomerular basement membrane antibodies. Other findings associated with pulmonary and renal injury include elevated blood urea nitrogen, low-grade proteinuria, gross or microscopic hematuria, and red cell casts.

On chest X-ray, Goodpasture syndrome is characterized by parenchymal consolidations that are most often present in both lungs, perihilar, and bibasilar. When pulmonary hemorrhage is recurrent an interstitial pattern is observed.

There are no echocardiography findings associated with Goodpasture syndrome.

CT scan of the thorax may be helpful in the diagnosis of Goodpasture syndrome. Findings on CT scan suggestive of Goodpasture syndrome include parenchymal consolidation, ground glass appearance that may progress to reticular pattern and interlobular septal thickening in later stage of disease.

Other diagnostic studies for Goodpasture syndrome include renal biopsy. In patients with inconclusive lab and imaging findings, renal biopsy remains the gold standard in establishing the presence of Goodpasture syndrome. A renal biopsy can also identify the severity of disease and guide medical therapy.

Currently there is no cure for Goodpasture syndrome.The mainstay of therapy for Goodpasture syndrome consist of corticosteroids, cyclophosphamide and plasmapheresis.

Surgery is not the first-line treatment option for patients with Goodpasture syndrome. Renal transplantation is usually reserved for patients who present with undetectable circulating anti-glomerular basement antibodies in serum for 12 months and atleast 6 months after stopping the use of cytotoxic agents.

Effective measures for the secondary prevention of Goodpasture syndrome include patient education. Patients should be educated about the signs and symptoms of renal dysfunction as certain steroid and immunosuppressive therapy may have adverse effects on the kidneys. Patients should be monitored regularly for renal function and those with severe dysfunction should have be referred for dialysis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Krzysztof Wierzbicki M.D. [2]Ali Poyan Mehr, M.D. [3]

Goodpasture syndrome was first discovered by Dr.Ernest William Goodpasture, an American pathologist and physician. He studied the influenza pandemic in 1919 and described a fatal disease that was associated with glomerulonephritis and pulmonary hemorrhage.

• The name Goodpasture’s syndrome was first coined in 1957 by Stanton and Tange in Melbourne, Australia to describe 9 patients who presented with glomerulonephritis along with pulmonary hemorrhage.^[1]
• In a book titled “Earnest William Goodpasture: Scientist, Scholar, Gentelman” published by Dr. Robert D. Collins, it was stated Dr. Goodpasture believed that the name of this syndrome should not be named after him, and deemed it inappropriate as he had not studied the disease.^[2][3]
• However, the name was adopted and is used today when describing the syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

There is no established system for the classification of Goodpasture syndrome.

There is no established system for the classification of Goodpasture syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2];Associate Editor(s)-in-Chief: Krzysztof Wierzbicki M.D. [3] Akshun Kalia M.B.B.S.[4]

The pathogenesis of Goodpasture syndrome includes the presence of autoantibodies directed against the glomerular and/or alveolar basement membrane. As with many autoimmune conditions, the precise cause of Goodpasture’s Syndrome is not yet known. It is believed to be a type II hypersensitivity reaction to Goodpasture’s antigens on the cells of the glomeruli of the kidneys and the pulmonary alveoli. The basement membrane (including a triple chain type IV collagen) lining the alveoli and glomeruli is particularly damaged in patients suffering from Goodpasture syndrome. The immune system misreads self-tissues as foreign, which leads to attack and destruction, as it would happen in case of an invading pathogen. The target antigen that is associated with the strongest pathogenic effect in anti-GBM disease is the non-collagenous 1 domain of alpha-3 type IV collagen. There is strong correlation of anti-glomerular basement membrane disease with allele HLA DRB1-1501. This allele is associated with renal injury. On gross pathology, Goodpasture syndrome with lung involvement may present with diffuse pulmonary hemorrhage. On microscopic histopathological analysis, early focal proliferative changes that display necrosis and crescent formation (due to hypercellular glomeruli) with an inflamed interstitium are seen. Under direct immunofluorescence, linear immunoglobulin G deposits are found encompassing the glomerular basement membrane and at times the distal tubular portion of the basement membrane.

Goodpasture syndrome is an autoimmune condition resulting from antibodies against the glomerular and alveolar basement membrane. It is thought that Goodpasture syndrome is the result of type II hypersensitivity reaction which leads to generation of antibodies which bind antigenic proteins of glomerular and alveolar basement membrane. The antigen–antibody complex leads to activation of complement system and tissue destruction.^[1][2]

The key for the renal corpuscle figure is: A – Renal corpuscle, B – Proximal tubule, C – Distal convoluted tubule, D – Juxtaglomerular apparatus, 1. Basement membrane (Basal lamina), 2. Bowman’s capsule – parietal layer, 3. Bowman’s capsule – visceral layer, 3a. Pedicels (Foot processes from podocytes), 3b. Podocyte, 4. Bowman’s space (urinary space), 5a. Mesangium – Intraglomerular cell, 5b. Mesangium – Extraglomerular cell, 6. Granular cells (Juxtaglomerular cells), 7. Macula densa, 8. Myocytes (smooth muscle), 9. Afferent arteriole, 10. Glomerulus Capillaries, 11. Efferent arteriole.

• The basement membrane (in general) is primarily made up of type IV collagen.
• The type IV collagen is made of three alpha subunits of collagen, which form a triple helix.
• The alpha subunits of type IV collagen can be of six different types and named as alpha1 to alpha6.
• Each alpha subunit is further bound to three components namely:
  • The amino terminus of alpha chain is bound by a short 7S domain.
  • The carboxyl terminus is bound by a triple helix of alpha chains.
  • Lastly the alpha chain has a non-collagenous component.
• The autoantibodies in Goodpasture syndrome are directed against the non-collagenous components of the alpha3 chain of type IV collagen.
• The target antigen that is associated with the strongest pathogenic effect in anti-GBM disease is the non-collagenous 1 domain of alpha-3 type IV collagen^[1]
• There are two dominant epitopes called epitope A (17-31) and epitope B(127-141) and are seen in the alpha-3 non-collagenous 1 domain of type IV collagen. The antibodies do not normally bind unless a change has occurred in the non-cross linked hexamers or trimers.
• In Goodpasture syndrome, these epitopes undergo a transitional change in the non-cross linked hexamers or trimers. This allows antibodies to be bound to these epitopes.^[3]
  • The pathogenic role of epitopes such as epitope A, has been shown to affect the renal function, especially of the alpha-3 type IV collagen of non-collagenous 1 domain.
  • Epitope B however is not able to induce Goodpasture syndrome by itself.
  • In addition, antibodies may be directed against other components of alpha3 chain.
• Even though the basement membrane of various tissues are similar in structure, the antibodies are reactive only against glomerular and alveolar membranes.
• This can be attributed to the fact that glomerular and alveolar basement membrane have greater expression and availability of epitopes for antibody binding. Moreover, the structure of glomerular and alveolar membrane is such that it promotes easy access to antibodies in these places.
• Under pathological conditions seen with any type of lung injury, vascular permeability of the respiratory membrane is increased, which further promotes antibody accumulation in the alveolar basement membrane.
• The cause of renal injury is due to anti-glomerular basement membrane antibodies ability to bind and activate complement system and proteases, resulting in an interruption between the filtration barrier and the Bowman’s capsule.
• The interruption of the Bowman’s capsule and filtration barrier, induces crescent shaped antigen-antibody complex formation in the renal corpuscles, invoking proteinuria and activating T cells (CD4+ and CD8+), macrophages, and neutrophils.^[4][5]
• Conditions such as oxidation, nitrosylation, glycation, increased body temperature, or proteolytic cleavage can further lead to increased antigen–antibody cross reaction and early symptom onset.^[6]
  • It has been shown that proteolytic cleavage of disulfide bonds in non-cross linked hexamers has shown greater affinity for Goodpasture syndrome antibodies to bind.
  • Environmental factors also contribute to the disease such as exposures to hydrocarbons, exposure to formaldehyde or smoking tobacco.
  • Smoking tobacco for instance causes inhibition of sulfilimine bond substances. Inhibition of the sulfilimine bond substances cause non-cross linked hexamers to form.^[7]

Genes involved in the pathogenesis of Goodpasture syndrome include certain alleles of human leukocyte antigen (HLA).^{[2] [8]}

• HLA-B27 has been found to be more frequently associated with severe nephritic form of Goodpasture syndrome.
• Other alleles associated with Goodpasture syndrome include increased frequency of HLA-DR15 and DRB1*03, DRB1*04 and a decreased frequency of DRB1*01 and DRB1*07.
• Goodpasture disease is also strongly associated with the DRB1*1501 and to DRB1*1502 allele.
• The allele DRB1*1501 is primarily associated with causing renal injury and estimated to be present in 80% of patients with Goodpasture syndrome,
• Recent studies have shown that DRB1*1501 allele is found in approximately one third of Caucasian patients with Goodpasture syndrome.

On gross pathology, Goddpasture syndrome with lung involvement may present with diffuse pulmonary hemorrhage.

On microscopic histopathological analysis, findings include:^{[9][10][11][12]}

• In kidneys, early focal proliferative changes that display necrosis and crescent formation (in 75% of glomeruli) with an inflamed interstitium are seen.
• Linear staining of IgG & C3 along the glomerular basement membrane (characteristic) with renal tubular necrosis and loss of tubular portion of the basement membrane
• Other features of proliferative or necrotizing glomerulonephritis.
• In lungs, findings include neutrophilic infiltration of the capillaries, hyaline membrane (in alveoli) and diffuse alveolar hemorrhage.

• The following are images of the microscopic pathology of crescent glomerulonephritis and the immunofluorescence of linear IgG and C3 deposition.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2]; Associate Editor(s)-in-Chief: Krzysztof Wierzbicki M.D. [3] Akshun Kalia M.B.B.S.[4]

There are no known direct causes for Goodpasture syndrome. Common risk factors for Goodpasture syndrome are viral or bacterial infections and certain environmental and behavioral risk factors such as smoking, hydrocarbons, formaldehyde and cocaine use.

Goodpasture syndrome is an autoimmune condition and is seen in individuals with susceptible HLA subtypes who when exposed certain environmental stimuli leads to autoantibody production. Goodpasture syndrome may be caused by either viral or bacterial infections, occupational, environmental or behavioral risk factors.^[1][2]

Viral and bacterial risk factors causing Goodpasture syndrome

It is not clear how viral or bacterial infections play a role in Goodpasture syndrome. However, any injury to the lungs can lead to disruption of alveolar blood vessels and increased exposure of autoantibodies to alveolar basement membrane. It is presumed that certain infections such as the influenza virus may play a role in the development of Goodpasture syndrome from cross-reactivity in the basement membrane.^[3]

Occupational, Environmental and Behavioral risk factors causing Goodpasture syndrome^[2][4][5]

Occupational, environmental and behavioral risk factors that cause Goodpasture syndrome include:

• Smoking tobacco
• Volatile hydrocarbons
• Exposure to organic solvents
• Upper respiratory tract infections (such as influenza)
• Immunosuppressive drugs (such as alemtuzumab)
• Cocaine
• Silicosis
• Mineral dust
• D-penicillamine

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2]; Associate Editor(s)-in-Chief: Krzysztof Wierzbicki M.D. [3] Akshun Kalia M.B.B.S.[4]

The prevalence of Goodpasture syndrome worldwide is an estimated 1 case per million individuals, with high prevalence in Caucasians. The peak incidence of the disease occurs between the ages of 20 and 30 and again at 60 and 70. Goodpasture syndrome affects men and women equally.

• The incidence of Goodpasture syndrome is approximately 0.18 cases per 100,000 individuals worldwide.^[1]
• The annual incidence of Goodpasture syndrome in Europe is estimated to range from 0.5 to 1 per 1 million individuals .^[2]
• The incidence of Goodpasture syndrome is around 1- 2 per million individuals per year.

• The prevalence of Goodpasture syndrome is estimated to be 1 per million individuals annually.^[3]

• Goodpasture syndrome occurs in two age peaks.^[4]
• The early onset Goodpasture syndrome is seen with individuals in the age group of 20 and 30.
• The late onset Goodpasture syndrome is seen with individuals in the age group of 60 to 70.

• Goodpasture syndrome affects men and women equally.^[4]
• Males are at increased risk of developing Goodpasture syndrome in the second and third decade.
• Females are at an increased risk of developing the syndrome in the sixth to seventh decade.

• Goodpasture syndrome usually affects individuals of the white race. Black individuals are less likely to develop Goodpasture syndrome.
• In European populations between 0.5-1 case per million individuals are seen every year. It is rarer in non-European populations.

• The majority of Goodpasture syndrome cases are reported in ethnic groups of New Zealand.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2]Associate Editor(s)-in-Chief: Krzysztof Wierzbicki M.D. [3]

Common risk factors in the development of Goodpasture syndrome may be occupational, environmental, genetic, and viral. However, we don’t known what causes the antibodies to form.

Common risk factors in the development of Goodpasture syndrome may be occupational, environmental, genetic, and viral. ^[1][2]

• Recent studies suggest that infections such as viral or bacterial may play a role through molecular mimicry and increase the risk of developing Goodpasture syndrome.
• Other factors that may increase the risk of Goodpasture syndrome and early initiation of disease include behavioral and social factors.
  • An example of environmental, genetic, behavioral and social factors include smoking, using cocaine, being exposed to solvents such as formaldehyde and hydrocarbons.
  • Genetically, the presence of allele HLA DRB1-1501 is strongly correlated to the disease.^[3]
  • The allele HLA DRB1-1501 is present in over 80% of patients would Goodpasture syndrome.^[4]
  • It is also suggestive that the disease may be initiated following a viral or bacterial infection, however, there is no specific cause of why this occurs. Possible antigens such as that found in the influenza virus may play a role due to cross-reactivity in the basement membrane.^[5]
• In addition, any of the following conditions may also increase antibody access to the alveolar and glomerular basement membranes.
  • Upper respiratory infections
  • Septicemia
  • Volatile hydrocarbons
  • Increased capillary hydrostatic pressure
  • Tobacco smoking
  • High concentrations of FiO2 (oxygen)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2]; Associate Editor(s)-in-Chief: Krzysztof Wierzbicki M.D. [3] Akshun Kalia M.B.B.S.[4]

If left untreated, Goodpasture syndrome can progress to end stage renal disease and pulmonary failure. Complications of Goodpasture syndrome include, infections, alveolar hemorrhage, end stage renal disease, and pulmonary failure. The prognosis of Goodpasture syndrome is variable, as it depends upon the diagnosis, start of treatment and the level of serum creatinine.

• The symptoms of Goodpasture syndrome usually develop in either 20-40 or 60-70 years of age.
• The symptoms start with low grade fever, cough, malaise, and joint pain.
• If left untreated, patients with Goodpasture syndrome have a progressive increase in the severity of symptoms due to autoantibody induced tissue damage.
• Over time, the autoantibody induced pulmonary and renal injury will aggravate and may progress to end stage renal disease and pulmonary failure.

Possible complications of Goodpasture syndrome include:^[1][2]

• Infections with P. jiroveci
• Alveolar hemorrhage
• End stage renal disease
• Pulmonary failure

• Prognosis is generally good for patients with Goodpasture syndrome who receive treatment.^[3]
• The 5 survival rate of patients with Goodpasture syndrome who receive treatment is approximately 80%.
• Recent advances in pharmacotherapy and use of immunosuppressive agents and plasmapheresis have further improved the outcome of patients with Goodpasture syndrome^[4].
• Today, the prognosis of Goodpasture syndrome is heavily dependent on the time of diagnosis, the start of medication, and the level of serum creatinine.^[5]

The following are favorable prognostic factors:^[6]

• Aggressive treatment with corticosteroids, plasmapheresis, and immunosuppressants.
• Serum creatinine of less than 5.7 mg/dL

The following are poor prognostic factors:

• Serum creatinine that is greater than 5.7 mg/dL
• Patients who require long term dialysis
• Glomerular Filtration Rate (GFR) of less than 15 mL/min
• Advanced age
• Low hemoglobin
• High white blood cell count
• Crescent formation that have extended greater than 80% of glomeruli
• ANCA and anti-GBM antibodies present together

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