INTRODUCTION:

Good pastures syndrome is an uncommon autoimmune disease in which kidney and lung injury are caused by circulating autoantibodies against the non-collagenous domain of the α3 chain of collagen IV. The name Goodpasture’s syndrome is used in the honour of the investigator who first described the association during the American influenza endemic at the time of World war I^[1]. When renal disease is caused only by this antibody it is called antiglomerular basement membrane disease. When patients develop pulmonary hemorrhage in addition to renal disease the condition is designated as Good pasture’s syndrome. Antibodies initiate inflammatory destruction of basement membrane in renal glomeruli and pulmonary alveoli, leading to rapidly progressive glomerulonephritis and a necrotizing hemorrhagic interstitial pulmonitis^[1]. Good pastures syndrome consist of alveolar haemorrhage or haemoptysis and nephritis. It is now classified into four main conditions: Antiglomerular basement membrane disease, the Vasculitis and Collagen vascular disorders (although not all cases are associated with nephritis), Idiopathic rapidly progressive glomerulonephritis and D penicillamine induced disease. In most series of Good pastures syndrome Vasculitidies accounts for 40% to 60% of cases of alveolar haemorrhage, Idiopathic rapidly progressive glomerulonephritis for 15% to 30% and Antiglomerular basement membrane disease for 20% to 40%^[2].

HISTORY:

In 1919, Goodpasture, a Boston pathologist was attempting to define the specific pathological features of influenza infection in diseased lungs, and reported the autopsy findings in two patients. In one case death occurred several weeks after the attack of influenza and the lung showed extensive bilateral hemorrhage together with necrotizing angiitis of the systemic vessels and glomerulonephritis^[3]. The name ‘‘Goodpasture’s disease’’ was coined in 1958 by Stanton and Tange (from Melbourne University, Australia) while describing patients with renal failure and pulmonary haemorrhage similar to that described by Ernest W. Goodpasture . In 1964, Scheer and Grossman showed that two affected patients had antibodies to the kidney, and linear deposition of immunoglobulin in the kidney. In the next year, Duncan and colleagues used electron microscopy to demonstrate dense immunoglobulin deposition in the kidney. The link was thus made between the clinical syndrome and antibodies directed against a kidney antigen^[4].

EPIDEMIOLOGY:

The disease has an incidence of 0.5 to 1.8 cases per million each year in Europian whites and Asian population^[5]. The disease is more common in whites than in African-Americans and may be more common in certain other racial groups, such as the Maoris in New Zealand.

PREDOMINANCE:

The disease predominantly affects white population with bimodial age distribution in 20 to 30 years and 60 to 70 years. Prevalence is higher in men in younger age group and women in older age sub group^[2,5]. There is a 4:1 male predominance^[2] and majority of the patients are active smokers^[1].

ETIOLOGY:

The disease is thought to result from an environmental insult in a person with genetic susceptibility.

Environmental factors which trigger inflammatory response are:

· Exposure to hydrocarbon containing solvents

· Cigarette smoke

· Cocaine

· Hard metal dust

· Influenza A2 virus infection

· Chlorine gas

· D-penicillamine

· Extracorporeal shock wave lithotripsy^[6].

PATHOGENESIS:

The trigger that initiates the production of antibasement membrane antibodies is still unknown but both genetic and environmental factor may play roles.

Environmental factors:

The epitope that invoke anticollagen antibodies are normally hidden within the molecule.Some environmental insults such as viral infection, exposure to hydrocarbon solvents (used in dry cleaning industry), or smoking is required to unmask the cryptic epitopes. The exogenous factors may injure the basement membrane, resulting in increased capillary permeability, exposing the Goodpasture’s antigen.

Genetic factors:

Genetic predisposition is indicated by association with certain histocompatibility antigen subtypes (eg: HLA-DRB1^*501 and ^*502)^[1,6].

The antibodies bind to intrinsic antigens homogeneously distributed along the entire length of the glomerular basement membrane (GBM) and activate complement, initiating an inflammatory pathway that elicits injury. Antibodies cross react with other basement membranes especially those in the lung alveoli, resulting in simultaneous lung and kidney lesions. The resulting cresentic glomerulonephritis is the result of the antigen-antibody complexes that form at the basement membrane. In addition to circulating antibodies, autoreactive T lymphocytes directed against the α3 antigen are key mediators for development of Rapid Progressive Glomerular nephritis. This is followed by synthesis of immunoglobulin and deposits of IgG along alveolar and glomerular capillary basement membrane. The disease is monophasic and during course of the disease, self tolerance is restored. Late relapses are rare. This tolerance is achieved by regulatory CD4+ and CD25+ T cells or anti-idiotypic (blocking ) antibodies^[6].

Goodpasture’s autoantigen:

The α3 chain is an integral component of the collagen IV network which is the principal part of the glomerular filteration barrier. The network is assembled by the selective association of α3, α4 and α5 chains in a triple-helical protomer and oligomerization of protomers and intertwining of triple helices. Two protomers associate through carboxy terminal domains forming α345NC1 hexamer which is the Goodpasture’s autoantigen^[7].

Anti-Glomerular basement membrane antibodies:

In addition to the circulating antibodies to the α3NC1 domain, lower binding to other NC1 domains of collagen IV (α1, α2, α4 and α5) has been reported and this is interpreted as cross-reactivity. The second most abundant group of autoantibodies that occur in about 70% of patients is antibodies specific for α5NC1 domain. Elevated titers of these antibodies is associated with unfavorable renal outcome. Only autoantibodies against α3NC1 and α5NC1 domains are bound to basement membranes in kidney and lungs of Good pasture’s patients showing that both anti-α3NC1 and anti-α5NC1 antibodies contribute to the pathogenesis of Good pasture’s disease. Natural anti-GMB autoantibodies belonging to the IgG2 and IgG4 which bind specifically to the α3NC1 are also found at much lower titers and avidity compared to Good pastures autoantibody. But these natural antibodies does not elicit an autoimmune response. Good pastures antibodies predominantly belong to IgG1 and IgG3 and Good pastures patients with preserved renal function have autoantibodies restricted to the IgG4 subclass compared to severe renal damage in patients with predominance of IgG1^[7].

Conformational transition in α345NC1 hexamer:

The initiation of Good pastures disease involves conformational transition in crosslinked or uncrosslinked hexamers forming neoepitopes that elicit antibody production and binding. This transition may be triggered by a single factor or combination of factors like post-translational modifications (nitrosylation, glycation), oxidation damage or proteolytic cleavage. Formation of an alternative disulfide bond in α3NC1 results in a hexamer with enhanced autoantibody binding. A novel protein cross link, the sulfilime bond in the NC1 hexamers of collagen IV provides a constraint against transition into a pathogenic confirmation. Environmental factors such as smoking or exposure to organic solvents may inhibit the putative enzyme that catalyzes the formation of sulfilimine bonds thereby increasing the proportion of uncrosslinked hexamers that are more susceptible to conformational transitions. Thus the Goodpasture’s disease can be classified as an autoimmune conformational disease^[7].

CLINICAL MANIFESTATIONS:

Typical presentation consist of a combination of renal and pulmonary insufficiency. 60% to 80% of patients have clinically apparent manifestations of pulmonary and renal diseases. 20% to 40% have renal disease alone, less than 10% have disease limited to lungs alone^[5].

Respiratory symptoms:

Hemoptysis, cough, dyspnoea, upper respiratory tract infection, chest pain, hypoxia and shortness of breath. Massive pulmonary hemorrhage may occur leading to respiratory failure.

Radiology:

Radiographic evidence shows focal pulmonary consolidations.

Histology:

Histologically, there is focal necrosis of alveolar walls associated with intra-alveolar hemorrhages. The alveoli contain hemosiderin- laden macrophages. In later stages there may be fibrous thickening of septae, hypertrophy of type II pneumocytes and organization of blood in alveolar spaces.

Renal symptoms:

Glomerulonephritis occur leading to rapidly progressive renal failure. In patients with renal involvement, an active urinary sediment with dysmorphic red cells and red cell casts is extremely common, Proteinuria is usually present. Renal manifestations include hematuria, edema, high blood pressure and eventually uremia. Main cause of death is uremia. The kidneys have characteristic findings of focal proliferative glomerulonephrities in early cases or cresentric glomerulonephritis in patients with rapidly progressive glomerulonephrities^[1].

Other symptoms :

Malaise, chills, fever and arthralgias.

In more than 90% of the cases anemia occurs as a result of persistent intrapulmonary bleeding.

DIAGNOSIS:

Biopsy:

In patients with renal and pulmonary involvement biopsy should be considered to identify the underlying cause. Biopsy tissue is processed for light microscopy, immunofluorescence and electron microscopy.

Percutaneous kidney biopsy:

It is the preferred invasive procedure to substantiate the diagnosis of anti-GBM disease ^[6]. It provides significantly higher yield than lung biopsy. Renal biopsy shows a diffuse crescentic or focal glomerulonephritis ^[2] as shown in (Fig.1)

Fig.1: The renal biopsy image of patient with Goodpasture’s disease having cresentic glomerular nephritis.

Lung biopsy:

In cases where renal biopsy cannot be performed trans bronchial or open lung biopsy may be performed. It shows extensive haemorrhage with accumulation of hemosiderin laden macrophages within alveolar spaces^[2,6]. Neutrophillic capillarities, hyaline membrane and diffuse alveolar damage may also be found.

Immunofluroscence stains:

Immunofluorescence stains are confirmatory. Bright linear deposits of Immunoglobulin (IgG) and Complement (C3) along GBM are pathognomic of anti-GBM disease (Fig. 2). All four subclasses of IgG are represented, but IgG₁and IgG₃predominate in Anti-GMB diseases^[6].

Fig.2: Immunofluorescence staining of biopsy tissue with linear deposits of IgG.

Light microscopy:

Light microscopy demonstrates a proliferative or necrotizing glomerular nephritis, often with cellular crescents. Overtime the cresents may fibrose. Frank glomerulosclerosis, interstitial fibrosis and tubular atrophy may be observed.

Serological assays:

Serological assays for anti-GBM antibodies are invaluable in confirming diagnosis and monitoring the adequacy of therapy. Radioimmunoassays or enzyme linked immunosorbent assay (ELISA) for anti-GBM antibody are highly sensitive and specific but are performed only in a few laboratories^[6]. The titer of circulating auto antibodies is a valid measure for the severity of the disease^[7]. Results are not available for several days and there will be a delay in institution of therapy precluding a favorable outcome. Therefore percutaneous renal biopsy is usually performed while awaiting results of serum assays^[6]. Up to one third of patients with circulating anti-GBM have concomitant C- antineutrophil cytoplasmic antibody (C-ANCA)^[6,8].

Chest Radiography:

Chest radiograph shows patchy parenchymal consolidations, which are usually bilateral, symmetric perihilar, and bibasilar. The apices and costophrenic angles are usually spared. Air bronchograms may be seen^[2]. 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.

Spirometry and lung volume tests:

These tests 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.

TREATMENT:

Before the availability of the current therapy and renal dialysis mortality exceeded 90%^[6].

Plasmapheresis:

This was introduced as a therapeutic option for anti-GBM disease in 1970’s. It is a central component in the therapy for anti-GBM disease. Plasmapheresis is done to remove circulating autoantibodies.

Immunosuppressive therapy:

Immunosuppressive therapy is required to inhibit antibody production and rebound hypersynthesis, which may occur following discontinuation of plasma exchange. Either Cyclophosphamide (oral or IV pulse) or Azathioprine should be initiated once the diagnosis of anti-GBM disease is substantiated. Pulse methylprednisolone (1g daily for 3 days) is given followed by a gradual corticosteroid taper. The corticosteroid dose is gradually tapered over several months. Immunosuppressive or cytotoxic therapy may be discontinued within 3 to 6 months provided a sustained remission has been achieved and anti GBM antibodies have disappeared^[6].

Immunoadsorption a technique for removing pathogenic autoantibody is a comparable alternative to plasma exchange therapy and can be considered depending on local availability^[9].

Other immunosuppressive agents like Rituximab, Mycophenolate mofetil, Cyclosporine use has been reported in individual cases or small series. Rituximab is either added to standard therapy or as a substitute for Cyclophosphamide in patients who are intolerant^[9].

Combination therapy:

A combination therapy including Plasmapheresis, Corticosteroids and Cyclophosphamide has reduced mortality to 20%^[6].

Management of critically ill patients:

Hemodialysis should be performed immediately followed by measures for respiratory failure and renal failure.

Respiratory failure: Respiratory failure is managed by intubation.

Renal failure:

Patients should be started on prednisone, cyclophosphamide, and daily plasmapheresis to improve renal survival and overall mortality. Renal transplantation has been successful in patients with irreversible renal failure, provided the serum anti-GBM antibodies are undetectable^[6].

RELAPSE:

The risk factors for relapse are infection, volume overload, cigarette smoking. Late recurrence following a remission is rare. Early recognition and treatment of this syndrome are critical as the prognosis for recovery of renal function depends upon the initial extend of injury.

CONCLUSION:

The management of Goodpasture syndrome requires careful coordination of several specialties involving pulmonary or critical care, nephrology, and rheumatology depending on the spectrum of clinical findings and severity of the disease. Recovery of renal fuction depends on early recognition and therefore early recognition of cases is mandatory and diagnosis is done by the use of sensitive assays. If left untreated the disease may progress and result in death of the patient. The disease has poor prognosis inspite of treatment with mortality of 11% and high morbidity. The recent studies suggesting the mechanism of conformational transition in Goodpasture’s antigen and the specificity of the autoantibody binding will pave the way for future research to elucidate the complete mechanism including identification of actual triggering factor and its activation, conformation of Goodpastures autoantigens and the three dimensional structure of epitopes leading to development of new treatment options that can produce successful cure rates.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 11.05.2019 Accepted on 14.06.2019

Asian J. Pharm. Res. 2019; 9(3):172-176.

DOI: 10.5958/2231-5691.2019.00027.3