Goodpasture's syndrome and kidney damage

Goodpasture's syndrome, caused by the presence of specific antibodies to the basement membrane of glomerular capillaries and/or alveoli, is manifested by pulmonary hemorrhages and rapidly progressive glomerulonephritis.

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Epidemiology

Goodpasture's syndrome was first described in 1919 by E.W. Goodpasture in an 18-year-old boy with massive pulmonary hemorrhage and acute renal failure who died during an influenza epidemic.

The incidence of Goodpasture's syndrome in Europe does not exceed 1 case per 2,000,000 population. The share of Goodpasture's syndrome among all types of glomerulonephritis is 1-5%, and in the structure of causes of extracapillary glomerulonephritis with crescents - 10-20%. Although the disease is widespread, it most often develops in representatives of the Caucasian race. Goodpasture's syndrome can occur in people of any age. The first peak of the disease is noted at the age of 20-30 years, and mainly men suffer from it, who have signs of both renal and pulmonary damage. The second wave of the disease occurs at the age of over 50-60 years, and men and women get sick with the same frequency.

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Causes Goodpasture's syndrome

The causes of Goodpasture syndrome are unknown.

• The development of Goodpasture syndrome is associated with a viral infection, in particular the influenza A2 virus.
• Environmental factors probably play a role as triggers in the development of the disease: there are reports of the occurrence of Goodpasture's syndrome after contact with 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 hemorrhages develop mainly in smokers.
• In the last 10 years, there have been descriptions of the development of Goodpasture's syndrome after shock wave lithotripsy and ureteral obstruction.
• The mechanisms of production of antibodies to the glomerular capillary basement membrane are unknown, but genetic predisposition may contribute. A link has been established between the development of Goodpasture syndrome and HLA class DR antigens (HLA-DR15 and HLA-DR4).

Goodpasture's syndrome is a classic example of an autoimmune disease with an antibody mechanism of development. Antibodies to the glomerular capillary basement membrane play a key role in the pathogenesis.

• The target of these antibodies is the non-collagenous domain of the 3rd chain of type IV collagen of the glomerular basement membrane (Goodpasture antigen, NCI 3IV).
  • Collagen type IV is found only in basement membranes. It is known to consist of 6 types of chains: a1-a6. In most basement membranes of different organs, a1- and a2-chains predominate, while in the basement membrane of the glomeruli, chains a3 _, a4 _and a5 _are present. Each chain of collagen type IV consists of a central collagen domain, an N-terminal collagen region (7S-domain) and a non-collagenous C-terminal domain (NCI-domain). Three a-chains of collagen type IV form a monomeric structure that binds to its NC1-domains by disulfide bonds.
  • In Goodpasture syndrome, AT to the glomerular capillary basement membrane are directed against the NC1 domain of the a ₃ chain of type IV collagen (NCI 3IV-AT). In addition to the kidney and lung basement membranes, this antigen is found in other basement membranes: retinal capillaries, cochlea, and choroid plexus of the brain.
• Binding of antibodies to the glomerular capillary basement membrane to their targets in the glomerular and alveolar membranes is accompanied by activation of complement and causes severe tissue damage.
• Recently, in the pathogenesis of nephritis associated with antibodies to the glomerular capillary basement membrane, a significant role has also been attributed to the activation of cellular immune mechanisms.

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Pathogenesis

Renal damage in Goodpasture's syndrome is morphologically represented by a picture of focal segmental necrotizing glomerulonephritis.

• Already at an early stage of the disease, segmental necrosis of vascular loops, massive leukocyte infiltration, and ruptures of the glomerular basement membrane are detected in the glomeruli.
• This is followed by intensive formation of crescents consisting of epithelial cells of the capsule and macrophages. An important distinguishing feature of nephritis associated with antibodies to the glomerular capillary basement membrane in Goodpasture's syndrome is that all crescents are simultaneously in the same stage of evolution (epithelial), unlike other variants of rapidly progressive glomerulonephritis, in which epithelial crescents in biopsies are combined with fibrous ones.
• As the disease progresses, all glomeruli may become involved in the pathological process (diffuse glomerulonephritis) with total necrosis of the capillary loops, which quickly leads to widespread nephrosclerosis and terminal renal failure.

Interstitial changes are usually combined with glomerular ones and are represented by inflammatory infiltration of the interstitium, which can develop as a result of the damaging effect of antibodies to the tubular basement membrane. Subsequently, interstitial fibrosis develops. Immunofluorescence microscopy reveals a linear type of IgG luminescence on the glomerular basement membrane in combination with a linear luminescence of the complement component C3 in 60-70% of patients. Nephritis associated with antibodies to the glomerular capillary basement membrane in Goodpasture's syndrome is classified as type I rapidly progressive glomerulonephritis according to the classification of R. Glassock (1997).

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Symptoms Goodpasture's syndrome

Goodpasture's syndrome may begin with the appearance of non-specific symptoms (general weakness, malaise, fever, arthralgia, weight loss), less pronounced compared to similar symptoms in systemic vasculitis. Already at the onset 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 progressing glomerulonephritis and pulmonary hemorrhage.

Lung damage

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

The severity of hemoptysis in Goodpasture's syndrome does not correlate with the intensity of pulmonary hemorrhage, which can develop suddenly and lead to the death of the patient within a few hours. In the case of pulmonary hemorrhage, rapid development of respiratory failure with increasing dyspnea and cyanosis is noted. During auscultation of the lungs, crepitations in the basal sections, sometimes bronchial breathing, are heard. Both persistent hemoptysis and pulmonary hemorrhage lead to the development of posthemorrhagic iron deficiency anemia. A rapid decrease in the hemoglobin content in the blood even with minor hemoptysis allows diagnosing pulmonary hemorrhage. X-ray examination reveals focal or diffuse infiltrates in the basal and central sections of both lungs, usually located symmetrically. Infiltrates usually disappear within 48 hours, but lung damage is often complicated by the development of pulmonary edema or secondary infection, which is reflected in the radiographic picture. After the acute episode has been stopped, interstitial pulmonary fibrosis usually does not develop.

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Kidney damage

Renal damage in Goodpasture's syndrome may be isolated, but more often it is combined with pulmonary hemorrhage. In the latter case, symptoms of glomerulonephritis appear several weeks after the pulmonary debut of the disease. Glomerulonephritis is manifested either by microhematuria with moderate proteinuria not exceeding 2-3 g/day, or by acute nephritic syndrome. Nephrotic syndrome and arterial hypertension in Goodpasture's syndrome rarely develop. In most cases, the disease immediately acquires a rapidly progressive course with the development of oliguric renal failure within the next few weeks after the appearance of the first symptoms of glomerulonephritis. Oliguria in Goodpasture's syndrome is an unfavorable prognostic sign. The progression of renal failure in such patients is also caused by pulmonary hemorrhage with hypoxia, anemia, hyperhydration and the addition of a secondary infection.

Diagnostics Goodpasture's syndrome

Laboratory diagnostics of Goodpasture syndrome

The most characteristic laboratory symptoms of Goodpasture's syndrome are iron deficiency anemia and the presence of siderophages in sputum. Laboratory testing also reveals leukocytosis and an increase in ESR.

The diagnostic sign of Goodpasture's syndrome is the detection of antibodies to the glomerular capillary basement membrane in the blood using enzyme immunoassay.

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Differential diagnosis

Goodpasture's syndrome should be suspected primarily clinically: the combination of lung and kidney involvement in a young person without signs of systemic disease makes this diagnosis very likely. Difficulties in establishing the diagnosis of "Goodpasture's syndrome" may arise when kidney involvement precedes lung involvement. However, even in the absence of symptoms of pulmonary hemorrhage, the presence of rapidly progressive glomerulonephritis without any signs of systemic disease most likely indicates Goodpasture's syndrome. This diagnosis is confirmed by antibodies to the glomerular capillary basement membrane in the blood and linear fluorescence of IgG, often in combination with the C3 component of complement on the glomerular basement membrane in a kidney biopsy.

Differential diagnosis of Goodpasture's syndrome is carried out primarily with systemic vasculitides, in the clinical picture of which the pulmonary-renal syndrome occupies a central place. The severity of pulmonary hemorrhages in the presence of rapidly progressing glomerulonephritis especially brings the clinical picture of Goodpasture's syndrome and microscopic polyangiitis closer. The difficulties of differential diagnosis in these situations are aggravated by the fact that almost 10% of patients with ANCA-associated vasculitides, most of whom have beta-ANCA (antibodies against myeloperoxidase), also have circulating antibodies to the glomerular capillary basement membrane in the blood serum. In such patients, the course of the disease is more reminiscent of vasculitis than a disease associated with the presence of antibodies to the glomerular capillary basement membrane, with a better response to treatment.

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Treatment Goodpasture's syndrome

Treatment of Goodpasture's syndrome requires the use of glucocorticoids and cytostatic drugs in combination with plasmapheresis sessions.

• If the creatinine concentration in the blood is less than 600 μmol/l, prednisolone is prescribed orally at a dose of 1 mg/kg of body weight per day and cyclophosphamide at a dose of 2-3 mg/kg of body weight per day. Upon achieving a stable clinical effect, the dose of prednisolone is gradually reduced over the next 12 weeks, and cyclophosphamide is completely discontinued after 10 weeks of treatment. Therapy with immunosuppressive drugs is combined with intensive plasmapheresis, which is carried out daily. In case of risk of pulmonary hemorrhage, part of the removed plasma is replaced with fresh frozen plasma. A stable effect develops after 10-14 plasmapheresis sessions. This treatment regimen for Goodpasture's syndrome allows for improved renal function in almost 80% of patients, with a decrease in azotemia beginning within a few days after the start of plasmapheresis.
• When the creatinine content in the blood is more than 600 μmol/l, aggressive therapy is ineffective and improvement of kidney function is possible only 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 case of exacerbation of Goodpasture's syndrome, the same therapeutic regimen is used as at the onset of the disease.

There are few data on kidney transplantation in patients with Goodpasture's syndrome. Considering the fact that after transplantation, the production of antibodies to the glomerular basement membrane may increase, it is recommended to perform it in Goodpasture's syndrome no earlier than 6 months after the disappearance of antibodies from the circulation. All patients with a transplanted kidney should undergo careful monitoring, including, in addition to monitoring hematuria and creatinine concentration, determining the titer of antibodies to the glomerular basement membrane in dynamics. Recurrence of nephritis associated with antibodies to the glomerular basement membrane in the transplant is observed in 1-12% of cases.

Forecast

If Goodpasture syndrome is not diagnosed in a timely manner, leading to a delay in treatment, the prognosis for patients with Goodpasture syndrome is unfavorable. In these cases, patients die from fulminant pulmonary hemorrhage or rapidly developing uremia.

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

In Goodpasture's syndrome, early relapses of the renal-pulmonary syndrome are possible, developing in cases where the main clinical signs of the disease have already been suppressed with glucocorticoids and immunosuppressive drugs, and the titer of antibodies to the glomerular capillary basement membrane in the blood has not yet become normal. In such patients, cessation of plasmapheresis sessions or, more often, the addition of an intercurrent infection can provoke a new increase in titers of antibodies to the glomerular capillary basement membrane and the development of clinical symptoms. Exacerbations of Goodpasture's syndrome after adequate treatment of the first episode have been described, but they develop extremely rarely and occur many years after the onset of the disease spontaneously or after an infection. Since in these cases the diagnosis of "Goodpasture's syndrome" does not cause difficulties, treatment is started earlier and the outcome is better than in the first episode of the disease.

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

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