Goodpasture Syndrome and Kidney Disease

Goodpasture's syndrome, caused by the presence of specific antibodies to the basal membrane of the glomerular and / or alveolar capillaries, manifests itself by pulmonary bleeding and rapidly progressive glomerulonephritis.

[1], [2]

Epidemiology

Disease Goodpasture's syndrome was first described in 1919. EW Goodpasture in an 18-year-old boy with massive pulmonary hemorrhage and acute kidney failure that died during the flu epidemic.

The incidence of Goodpasture's syndrome in Europe does not exceed 1 case per 2 000 000 population. The proportion of Goodpasture's syndrome among all types of glomerulonephritis is 1-5%, and in the structure of the causes of extracapillary glomerulonephritis with the half-moon is 10-20%. Although the disease is ubiquitous, it often develops among representatives of the Caucasoid race. Goodpasture syndrome can occur in people of any age. The first peak of morbidity is noted at the age of 20-30 years, with men suffering mainly from both renal and pulmonary lesions. The second wave of morbidity falls on the age of over 50-60 years, and men and women get sick with the same frequency.

[3], [4], [5]

Causes of the goodpasture Syndrome

The causes of Goodpasture's syndrome are not known.

• The development of Goodpasture's syndrome is associated with a viral infection, in particular with the influenza A2 virus.
• Environmental factors are likely to play the role of triggers in the development of the disease: there are reports of the occurrence of Goodpasture's syndrome after exposure to gasoline, organic solvents, and the use of certain drugs (penicillamine). Regardless of the role of environmental factors in the development of the autoimmune process, they are important in the occurrence of lung damage: it is known that pulmonary hemorrhage develops mainly in smokers.
• In the last 10 years there have been descriptions of the development of Goodpasture's syndrome after shock wave lithotripsy and obstruction of the ureter.
• The mechanisms of producing antibodies to the basal membrane of the glomerular capillaries are unknown, but genetic predisposition can contribute to this. A relationship has been established between the development of Goodpasture's syndrome with antigens of HLA class DR (HLA-DR15 and HLA-DR4).

Goodpasture's syndrome is a classic example of an autoimmune disease with an anti-inflammatory mechanism of development. In pathogenesis, a key role is played by antibodies to the basal membrane of glomerular capillaries.

• The target of these antibodies is the non-collagen domain of the third chain of collagen type IV of the basal membrane of the glomeruli ("Goodpasture Antigen", NCI 3IV).
  • Collagen type IV is found only in the composition of basal membranes. It is known that it consists of 6 types of chains: a1-a6. In most basal membranes of different organs, the a1 and a2 chains predominate, whereas in the basal membrane of the glomeruli, the chains are a ₃, and ₄  and a ₅. Each type IV collagen chain consists of a central collagen domain, an N-terminal collagen site (7S domain) and a non-collagen C-terminal domain (NCI domain). Three a-chains of type IV collagen form a monomeric structure that binds to their NC1-domains by disulfide bonds.
  • When Goodpasture syndrome AT glomerular basement membrane of capillaries are directed against the NC1-domain and ₃ -chain of collagen type IV (NCI 3IV-AT). This antigen in addition to the basal membranes of the kidneys and lungs is found in other basal membranes: retinal capillaries, cochlea, choroid plexus of the brain.
• The binding of antibodies to the basal membrane of the glomerular capillaries with their targets in the glomerular and alveolar membranes is accompanied by the activation of complement and causes pronounced tissue damage.
• Recently, in the pathogenesis of nephritis, associated with antibodies to the basal membrane of glomerular capillaries, an important role is also assigned to the activation of cellular immunity mechanisms.

[6], [7]

Pathogenesis

The defeat of the kidneys in Goodpasture's syndrome is morphologically represented by a picture of focal segmental necrotizing glomerulonephritis.

• Already at an early stage of the disease in the glomeruli, segmental necrosis of the vascular loops, massive infiltration by leukocytes, ruptures of the basal membrane of the glomeruli are revealed in the glomeruli.
• This is followed by intensive formation of semi-moons consisting of epithelial cells of the capsule and macrophages. An important distinctive feature of jade associated with antibodies to the basal membrane of glomerular capillaries in Goodpasture syndrome is that all the half-moon are simultaneously in the same stage of evolution (epithelial), in contrast to other variants of rapidly progressing glomerulonephritis, in which the epithelial half-moon in biopsy combines with fibroids.
• As the disease progresses, all glomeruli (diffuse glomerulonephritis) with total necrosis of capillary loops can enter the pathological process, which quickly leads to widespread nephrosclerosis and terminal renal failure.

Interstitial changes are usually combined with glomerular and are represented by inflammatory infiltration of interstitium, which can develop as a result of the damaging effect of antibodies to the basal membrane of the tubules. In the future, interstitial fibrosis develops. Immunofluorescence microscopy reveals a linear type of luminescence of IgG on the basal membrane of the glomeruli in combination with a linear luminescence of the S3 complement component in 60-70% of patients. Nephritis, associated with antibodies to the basal membrane of the glomerular capillaries, in Goodpasture's syndrome is classified as type I fast-progressive glomerulonephritis according to the classification of R. Glassock (1997).

[8], [9], [10]

Symptoms of the goodpasture Syndrome

Goodpasture's syndrome can begin with the appearance of nonspecific symptoms (general weakness, malaise, fever, arthralgia, weight loss), less pronounced compared with similar symptoms in systemic vasculitis. Already in the debut of the disease, signs of anemia are possible,   even in the absence of hemoptysis. However, the main symptoms of Goodpasture's syndrome are progressive renal failure due to rapidly progressive glomerulonephritis and pulmonary hemorrhage.

Lesion of the lungs

Hemoptysis  is the first symptom of Goodpasture's syndrome in almost 70% of patients, which usually appears several months earlier than signs of kidney damage. Currently, there is a slight decrease in the incidence of pulmonary hemorrhage, which is believed to be a consequence of a reduction in the prevalence of smoking. Simultaneously with hemoptysis, patients are disturbed by shortness of breath, cough.

Severity hemoptysis in Goodpasture's syndrome does not correlate with the intensity of pulmonary hemorrhage, which can develop suddenly and lead to the patient's death within a few hours. In the case of pulmonary hemorrhage, rapid development of respiratory failure with increasing dyspnoea and cyanosis is noted. When auscultation of the lungs, they listen to crepitation in the basal parts, sometimes bronchial breathing. Both persistent hemoptysis and pulmonary hemorrhage lead to the development of posthemorrhagic iron deficiency anemia. Rapid reduction of hemoglobin in the blood, even with a slight hemoptysis, makes it possible to diagnose pulmonary hemorrhage. Radiologic examination reveals focal or diffuse infiltrates in the basal and central sections of both lungs, located, as a rule, symmetrically. Typically, infiltrates disappear within 48 hours, but often lung damage is complicated by the development of pulmonary edema or secondary infection, which is reflected in the radiographic picture. After arresting an acute episode, interstitial lung fibrosis usually does not develop.

[11]

Renal damage

The kidney damage in Goodpasture's syndrome may be isolated, but more often it is associated with pulmonary hemorrhage. In the latter case, the symptoms of glomerulonephritis appear several weeks after the lung's debut of the disease. Glomerulonephritis  is manifested either by microhematuria with moderate proteinuria, not exceeding 2-3 g / day, or by acute cold syndrome. Nephrotic syndrome and hypertension are rare in Goodpasture's syndrome. In most cases, the disease immediately acquires a rapidly progressing course with the development of oliguric renal failure within the next weeks after the appearance of the first symptoms of glomerulonephritis. Oliguria in Goodpasture's syndrome is an unfavorable prognostic sign. Progression of renal failure in these patients is also due to pulmonary hemorrhage with hypoxia, anemia, hyperhydration and secondary infection.

Diagnostics of the goodpasture Syndrome

Laboratory Diagnosis of Goodpasture Syndrome

The most characteristic laboratory symptoms of Goodpasture's syndrome are iron deficiency anemia and the presence of siderophages in sputum. In a laboratory study, leukocytosis and an increase in ESR are also detected.

Diagnostic sign of Goodpasture's syndrome is the detection of antibodies to the basal membrane of the glomerular capillaries in the blood with the help of an enzyme immunoassay.

[12], [13], [14]

Differential diagnosis

Goodpasture's syndrome should be suspected in the first place clinically: the combination of lung and kidney damage in a young person without signs of systemic disease makes this diagnosis very likely. Difficulties with the diagnosis of "Goodpasture's syndrome" can occur with kidney damage that outstrips the lungs. However, even in the absence of symptoms of pulmonary hemorrhage, the presence of a rapidly progressive glomerulonephritis without any signs of a systemic disease is likely to indicate Goodpasture's syndrome. Confirmation of this diagnosis is the antibodies to the basal membrane of the glomerular capillaries in the blood and the linear luminescence of IgG, more often in combination with the C3 component of the complement on the basal membrane of the glomeruli in the kidney biopsy.

Differential diagnosis of Goodpasture syndrome is primarily carried out with systemic vasculitis, in the clinical picture of which the pulmonary-kidney syndrome occupies a central place. Severity of pulmonary hemorrhage in the presence of rapidly progressive glomerulonephritis particularly brings together the clinical picture of Goodpasture's syndrome and microscopic polyangiitis. Difficulties in differential diagnosis in these situations are exacerbated by the fact that almost 10% of patients with ANCA-associated vasculitis, the majority of which are determined by beta-ANCA (antibodies against myeloperoxidase), also have circulating antibodies to the basal membrane of glomerular capillaries in the blood serum. In such patients, the course of the disease is more reminiscent of vasculitis than the disease associated with the presence of antibodies to the basal membrane of the glomerular capillaries, with the best response to treatment.

[15], [16], [17], [18], [19], [20], [21],

Treatment of the goodpasture Syndrome

The treatment of Goodpasture's syndrome requires the use of glucocorticoids and cytotoxic drugs in combination with plasmapheresis sessions.

• When the concentration of creatinine in the blood is less than 600 μmol / l, prednisolone is administered orally at a dose of 1 mg / kg body weight per day and cyclophosphamide at a dose of 2-3 mg / kg body weight per day. After achieving a stable clinical effect, the dose of prednisolone is gradually reduced over the next 12 weeks, and cyclophosphamide is completely eliminated after 10 weeks of treatment. Therapy with immunosuppressive drugs is combined with intensive plasmapheresis, which is performed daily. In the case of a risk of developing pulmonary hemorrhage, some of the removed plasma is replaced by fresh frozen plasma. Stable effect develops after 10-14 sessions of plasmapheresis. This treatment mode Goodpasture syndrome allows you to improve kidney function in almost 80% of patients, and the reduction of azotemia begins a few days after the onset of plasmapheresis.
• When creatinine levels in the blood exceed 600 μmol / l, aggressive therapy is ineffective and renal function is only possible in a small number of patients with a recent history of the disease, rapid progression (within 1-2 weeks) and the presence of potentially reversible changes in the kidney biopsy. In these situations, the main therapy is carried out in combination with hemodialysis sessions.

In the case of development of exacerbations of Goodpasture's syndrome, the same therapeutic regimen is used as in the debut of the disease.

Data on kidney transplantation in patients with Goodpasture's syndrome are few. Taking into account the fact that after the transplantation the production of antibodies to the basal membrane of the glomerular capillaries is possible, it is recommended that in Goodpasture's syndrome it should be performed no earlier than 6 months after the disappearance of antibodies from the circulation. All patients with a transplanted kidney should be carefully monitored, including, in addition to hematuria control and creatinine concentration, determining the antibody titer to the basal membrane of the glomerular capillaries in dynamics. The recurrence of nephritis associated with antibodies to the basal membrane of glomerular capillaries is observed in the graft in 1-12% of cases.

Forecast

In the untimely diagnosis of Goodpasture's syndrome, which entails delaying the initiation of treatment, the prognosis in patients with Goodpasture's syndrome is unfavorable. In these cases, patients die from fulminant pulmonary hemorrhage or rapidly onset uremia.

Early treatment of Goodpasture's syndrome, aimed at removing antibodies to the basal membrane of the glomerular capillaries from the blood and suppressing their production (using plasmapheresis in combination with the appointment of glucocorticoids and cytotoxic drugs), can lead to relief of an acute episode of the disease. However, the concentration of creatinine in the blood, exceeding 600 μmol / l at the time of diagnosis, is unfavorable for renal prognosis, even in the absence of pulmonary hemorrhage. In such patients, as a rule, irreversible chronic renal failure develops, despite active immunosuppressive therapy.

In Goodpasture's syndrome, early relapses of the renal and pulmonary syndrome are possible, developing in those cases when the main clinical signs of the disease have already been suppressed with the help of glucocorticoids and immunosuppressive drugs, and the antibody titre to the basal membrane of the glomerular capillaries has not yet become normal. In such patients, discontinuation of plasmapheresis sessions or, more often, intercurrent infection can trigger a new growth of antibody titres to the basal membrane of glomerular capillaries and the development of clinical symptoms. Exacerbations of Goodpasture's syndrome after adequate treatment of the first episode are described, but they develop very rarely and occur many years after the onset of the illness spontaneously or after the infection. Since in these cases, the diagnosis of "Goodpasture's syndrome" does not cause difficulties, treatment begins earlier and the outcome is better than with the first episode of the disease.

Despite the current use of aggressive immunosuppressive therapy, mortality in the acute period of Goodpasture's syndrome varies from 10 to 40%.

[22], [23]