Elsevier

Autoimmunity Reviews

Volume 12, Issue 11, September 2013, Pages 1101-1108
Autoimmunity Reviews

Review
Goodpasture's disease: A report of ten cases and a review of the literature

https://doi.org/10.1016/j.autrev.2013.06.014Get rights and content

Abstract

This review is based on our experience with ten patients diagnosed with Goodpasture's disease (GD). Six of the patients presented with combined renal and pulmonary insufficiencies; in the remaining four patients the clinical findings were limited to renal involvement. Circulating anti-glomerular basement membrane (GBM) autoantibodies were detected at diagnosis in all patients. Two patients were double-positive for anti-GBM and anti-proteinase-3 neutrophil cytoplasmic antibodies (c-ANCA). Another patient was double positive for anti-GBM and anti-myeloperoxidase cytoplasmic antibodies (p-ANCA). Four patients with rapidly progressive glomerulonephritis underwent hemodialysis: two of these patients died 6 and 8 months after diagnosis, and the other two required maintenance dialysis. The remaining six patients were administered variable combinations of plasma-exchange, corticosteroids, and immunosuppressive drugs, which resulted in a remarkable and progressive improvement in renal function and one-year renal survival in all of them. Building on these observations, we provide an update on this relatively rare, frequently severe, and sometimes lethal autoimmune disease of unknown etiology. GD patients typically present with rapidly progressive renal insufficiency and pulmonary hemorrhage. Involvement restricted to the kidneys alone, as in our series, is also seen. The unfailing immunological hallmark of the disease is the occurrence of circulating anti-GBM antibodies, whose titer is directly related to the clinical severity of GD. The antibodies are associated with serum ANCAs in 10% to almost 40% of GD patients, with double positivity indicative of a worse renal prognosis. The target antigen of anti-GBM antibodies is a component of the non-collagenous-1 (NC1) domain of the α3 chain of type IV collagen, α345NC1. The prevalent expression of this hexamer on the basement membrane of both the glomeruli and the pulmonary alveoli accounts for the frequently combined renal and pulmonary involvement. A strong positive association of GD with the HLA-DRB1*15:01 allele has been described, but the factor(s) responsible for the loss of self-tolerance to NC1 autoantigen has not yet been identified. A conformational change in the quaternary structure of the α345NC1 likely plays a crucial role in triggering an immune response and justifies the proposed description of GD as an autoimmune “conformeropathy.” The function of autoreactive T-cells in GD is poorly defined but may involve a shift from TH2 to TH1 cytokine regulation, such that affinity maturation and the antigen specificity of the antibody response are enhanced. The timely diagnosis of GD and the adoption of a triple therapeutic regimen comprising plasmapheresis, corticosteroids, and immunosuppressive drugs have remarkably improved the previously dismal outcome of these patients, resulting in a one-year survival rate of 70–90%.

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

  • 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.

  • 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.

  • 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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