ReviewGoodpasture's disease: A report of ten cases and a review of the literature
Section snippets
Introduction and case series
Goodpasture's disease (GD) is a severe and often life-threatening organ-specific autoimmune condition associated with autoantibodies directed against glomerular basement membrane (GBM) antigens [1], [2]. It is uncommon in the general population, with an incidence of 1 per 2 million persons/year, and shows a bi-modal distribution. In the first peak, the patients are young (5–40 years), have a male:female ratio of 6:1, and usually exhibit hemorrhagic features. In the second, the patients are older
Hemorrhagic pulmonary–renal syndromes: historical clues and definitions
The eponym “Goodpasture's syndrome” was coined in 1958 by Stanton and Tange [3], in their report on a few patients with renal failure and pulmonary hemorrhage similar to the case first described in 1919 by Ernest W. Goodpasture, involving an 18-year-old man with influenza [4]. In 1964, Scheer and Grossman [5] detected the occurrence of serum antibodies to the kidney and the linear deposition of immunoglobulin along the GBM in two likewise affected patients. Three years later, Lerner et al. [6]
Clinical and pathological features
Clinically, GD is characterized by pulmonary hemorrhage and renal failure, although the clinical spectrum may range from only mild symptoms to a relentless and finally lethal outcome [1]. This disease accounts for 10–20% of the patients with acute renal failure following a rapidly progressive glomerulonephritis [1], [15]. Both pulmonary and renal involvement occur in 60–80% of the patients. Renal manifestations alone are seen in 20–40%, whereas symptoms limited to the respiratory tract
Immunochemical features of GD antibodies
In several studies natural autoantibodies reactive with the GBM were purified from normal human sera, although at lower titers and avidity than the pathological antibodies present in the sera of GD patients [9], [10]. These natural antibodies belong to the IgG class, as do the pathological ones, with the major difference being the IgG subclass restriction: natural anti-GBM antibodies largely belong to the IgG2 and IgG4 subclasses, whereas GD autoantibodies are prevalently of the IgG1 and IgG3
Structural features of GD autoantigen(s)
The GD autoantigen is the non-collagenase domain 1 of the alpha-3 chain of type IV collagen [α3(IV)NC1], which is located at the C-terminus of this protein [25]. NC1 is an ellipsoid-shaped hexamer with two identical trimeric caps, each of which is capable of swapping interactions involving the α3, α4, and α5 domains. Hydrophobic and hydrophilic ties provide for the firm stabilization of the planar interface between the caps [26], [27]. Sulfilimine bonds, acting as molecular fasteners, also
Possible pathogenetic mechanisms
Autoantibodies bound to basement membrane can induce the characteristic autoimmune response mainly through two distinct effector mechanisms. The first is activation of the complement system by the classical pathway, which leads to inflammatory processes such as the production of chemotactic fragments. These compounds mediate the mobilization and activation of leukocytes (neutrophils and macrophages), formation of the lytic membrane attack complex (C5b-9), and the release of inflammatory
Differential diagnosis
A number of hemorrhagic pulmonary–renal syndromes can be encountered in clinical practice, which can complicate a differential diagnosis that includes GD. Here, we mention the most typical and relevant conditions.
GPA is a necrotizing, systemic vasculitis involving the small and medium-size arterial and venous vessels by the formation of typical granulomatous lesions. The lungs are affected in about 85% of patients and cavitations are a frequent complication. Renal involvement is diagnosed in
Prognostic factors
Since GD rapidly progresses to end-stage renal failure and death if the diagnosis is sufficiently delayed and/or the extent of therapy is not proportional to disease severity, the recognition of prognostic factors is of the utmost importance. Among these, the titer of circulating autoantibodies is considered a valid measure of disease severity. Hellmark et al. [27] and Yang et al. [63] clearly showed a prognostically relevant correlation between the titer of circulating anti-GBM antibodies and
Therapy
Given the rarity of GD, controlled therapeutic trials on a sizable number of patients are not available. Fortunately, emergency bilateral nephrectomy in GD patients has been banished to the past. Today, patients are initially treated with several cycles of plasmapheresis until antibody titers become undetectable, associated with or followed by the daily administration of prednisone (0.5–1 mg/kg body weight), in combination with azathioprine (1.5–2 mg/kg body weight) or oral cyclophosphamide (1.5–2
Conclusion
All patients with hemoptysis and acute renal impairment in whom serum anti-GBM antibodies are detected should be further examined for GD. Natural circulating anti-GBM antibodies of restricted subclasses can also be detected in healthy people, in whom they have an immunoprotective function, either by masking autoantigen epitopes or by idiotypic regulation, thus preventing autoreactive B-cell stimulation. The major target antigen of GD is a component of the NC1 domain of the α-3 chain of type IV
Contributors
F.D. and V.R. designed the study, collected the patients, and wrote the paper. S.B. substantially contributed to the writing of the paper and to the literature search. L.G. designed the study, collected the majority of the patients, prepared the figures and critically read the manuscript.
Declaration of interest
All authors declare that they have no financial relationships with any organizations that might have an interest in the submitted work.
Take-home messages
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Goodpasture's disease is a rare autoimmune disease clinically characterized by invariable renal involvement differing in severity and often but not always associated with lung involvement.
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The hallmark of the disease is the occurrence of anti-GBM antibodies, which can be detected by direct immunofluorescence on renal biopsy specimens as a linear deposition along the glomerular basement membrane.
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The autoantigen has been identified as the non-collagenase domain-1 of the α3 chain of type IV
Acknowledgment
The study was supported by grants from the finalized project “Biotecnoter” of the Apulia Region; Cassa di Risparmio di Puglia Foundation; University of Bari and the Italian Association for Cancer Research (AIRC). The funding agencies had no role in the design, conduct, or analysis of the study.
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