Goodpasture's Disease Is Characterized by the Association of Pulmonary Hemorrhage, Extracapillary Glomerulonephritis, and Anti-Glomerular Basement Membrane Antibodies

Goodpasture’s disease

Author: Professor Jerome Rossert 1 Creation Date: September 2002

Scientific Editor: Professor Jean-François Cordier

1Department of Nephrology, Hôpital Tenon, 4 Rue de la Chine, 75020 Paris, France. [email protected]

Abstract Keywords Disease name and synonyms Excluded diseases Diagonosis criteria Differential diagnoses Frequency Clinical description Management including treatment Etiology Diagnostic procedures Unresolved questions References

Abstract Goodpasture's disease is characterized by the association of pulmonary hemorrhage, extracapillary glomerulonephritis, and anti-glomerular basement membrane antibodies. It is due to autoantibodies against the NC1 domain of the alpha3 chain of type IV collagen. Goodpasture's disease is a very rare disease, and in Europe its annual incidence has been estimated to be about 0.5 to 1 cases per million inhabitants. This incidence is not constant all year long, and it increases in spring and early summer.Treatment is based on the association of corticosteroids, cyclophosphamide, and plasma exchange. With this treatment, patients' survival is about 75% at one year. Renal survival at one year is higher than 90% for patients who are treated early, but is lower than 10% when patients are dialysis- dependent at the start of treatment.

Keywords Goodpasture’s disease , Anti-GBM antibodies , Crescentic glomerulonephritis , Pulmonary hemorrhage

Disease name and synonyms glomerular basement membrane (GBM) - Goodpasture’s disease (eponym used since antibodies. 1958); - Anti-GBM antibody-mediated nephritis without - Antiglomerular basement membrane antibody- pulmonary hemorrhage. mediated nephritis with pulmonary hemorrhage; Diagonosis criteria - Antiglomerular basement membrane antibody - The diagnosis is based on the association of: disease with pulmonary hemorrhage. - extracapillary (i.e. crescentic) The name Goodpasture syndrome should be glomerulonephritis; abandoned, since it has been ambiguously - pulmonary hemorrhage; applied to both pulmonary-renal syndromes and - anti-GBM antibodies, that are characteristically Goodpasture’s disease. deposited along the renal and pulmonary GBM. Excluded diseases - All associations of pulmonary hemorrhage and glomerulonephritis that are not due to anti-

Rossert J. Goodpasture’s disease; Orphanet encyclopedia, September 2002 http://www.orpha.net/data/patho/GB/uk-goodpasture.pdf 1

Differential diagnoses alveolar infiltrates not seen on chest X-ray. This Goodpasture’s disease should be differentiated alveolar hemorrhage is almost always from the other pulmonary-renal syndromes, and responsible for iron deprivation and anemia. it is important to remember that only about 10% Lung hemorrhage is favored by cigarette of cases of pulmonary hemorrhage with acute smoking, lung infections, and possibly also by nephritis are due to Goodpasture’s disease. In inhalation of noxious substances such as particular, it should be distinguished from: hydrocarbon fumes. • vasculitides that are responsible for pulmonary hemorrhage and extracapillary Renal disease glomerulonephritis, not associated with Extracapillary glomerulonephritis is responsible glomerular deposition of anti-GBM for rapidly progressive renal failure, associated antibodies, but usually with blood with hematuria (which can be macroscopic, and antineutrophil cytoplasmic autoantibodies is associated with red-cell casts), and with (ANCA), such as microscopic polyangiitis or moderate proteinuria (typically 1 to 3 g/day). Wegener’s granulomatosis; Blood pressure is usually normal, in the absence • other causes of acute renal failure with of end-stage renal failure. pulmonary hemorrhage, such as In very rare cases, renal disease is mild, only cryoglobulinemia, systemic lupus responsible for microscopic hematuria, erythematosus, Schönlein-Henoch purpura, associated or not with a slight elevation of serum or hemolytic and uremic syndrome; creatinine. • acute renal failure associated with pulmonary edema; Management including treatment With the current therapeutic strategies, over 90% • pulmonary infections associated with acute of patients survive the acute phase of the renal failure. disease. Death usually is due to lung Frequency hemorrhage or to treatment-related infections. Goodpasture’s disease is a very rare disease, Nevertheless, Goodpasture’s disease is a and in Europe its annual incidence has been therapeutic emergency, since renal outcome is estimated to be about 0.5 to 1 cases per million tightly linked to renal function at the start of inhabitants. This incidence is not constant all treatment, and since sudden occurrence of year long, and it increases in spring and early dramatic lung hemorrhage is always a threat. summer. Immunosuppressive therapy Goodpasture’s disease occurs most often in The immunosuppressive therapy of Caucasian populations, and is slightly more Goodpasture’s disease is based on the frequent in male than in female. It can affect association of: people of any age, but it is more common in the - corticosteroids, started at a dose of 1 third and sixth decades. In more than 80% of mg/kg/day and then progressively tapered cases, it affects people carrying HLA-DR15 or - over 6 to 9 months; DR5. - oral cyclophosphamide, given at a daily dose Clinical description of 2 to 3 mg/kg (this dose being reduced in Usually, the first manifestations of patients over 60 years) for about 3 months; Goodpasture’s disease are non-specific, - plasma exchanges. The standard protocol consisting of flu-like syndrome, asthenia, mild consists of daily plasma exchanges (50 ml/kg, breathlessness, or dry cough. This explains that maximum 4L) for 14 days, or until circulating the diagnosis is often delayed. anti-GBM antibodies can no longer be detected. Human serum albumin is the Lung disease standard replacement fluid, but it may be Pulmonary hemorrhage is responsible for cough, necessary to use fresh frozen plasma to typically (but not always) associated with prevent bleeding. hemoptysis, and dyspnea. Physical examination With this treatment, patients' survival is about may reveal chest crackles. Chest X-ray films 75% at one year. Renal survival at one year is typically show bilateral alveolar infiltrates, which higher than 90% for patients who are treated may be confused with hemodynamic pulmonary early, but is lower than 10% when patients are edema. However, there is no pleural effusion dialysis-dependent at the start of treatment. and no cardiomegaly. Alveolar infiltrates can also disclose segmental infiltrates not seen on chest X-ray, or they can be completely normal. In that latter case, tomodensitometry can detect

Rossert J. Goodpasture’s disease; Orphanet encyclopedia, September 2002 http://www.orpha.net/data/patho/GB/uk-goodpasture.pdf 2

Other therapies Pulmonary hemorrhage Depending on the severity of renal failure and Bronchoalveolar lavage (BAL) is the most pulmonary hemorrhage, patients may require reliable procedure to confirm alveolar dialysis and/or respiratory support. hemorrhage. It usually shows a uniformly bloody It is essential to carefully avoid fluid overload BAL fluid. Fluid may not be macroscopically and to rapidly treat infections (and in particular bloody in patients with chronic alveolar pulmonary infections), in order to decrease hemorrhage but contain an elevated percentage pulmonary hemorrhage. of Perls-positive macrophages in the absence of Smoking should be prohibited, since it might lung infection or pulmonary edema. trigger further pulmonary hemorrhage. Some physicians used to rely on a raised corrected carbon monoxide gas transfer factor to Dialysis-dependent patients confirm the diagnosis of pulmonary hemorrhage. Recovery of renal function is very unlikely in However, this test has a low sensitivity and is patients who are dialysis-dependent at the time difficult to perform in patients with severe of diagnosis, and especially when all glomeruli dyspnea. contain crescents on renal biopsy. Thus, a less aggressive management of these patients has Circulating anti-GBM antibodies been advocated. In particular, it has been Circulating anti-GBM antibodies can be detected suggested to use pulses of methylprednisolone by ELISA or RIA in more than 98% of patients instead of plasma exchanges (as a first-line with Goodpasture’s disease, and this test is therapy), since pulmonary hemorrhage is usually highly specific with less than 1% false-positive well responsive to this treatment. results. It may occasionally be useful to confirm In case of end-stage renal disease, renal the specificity of the antibodies by Western transplantation carries no extra-risk if circulating blotting. The titer of anti-GBM antibodies has no anti-GBM antibodies has been undetectable (by prognostic value, but it is useful to follow efficacy ELISA or RIA) for at least 6 months. of plasma exchanges. Detection of anti-GBM antibodies by indirect Etiology fuorescence assays using normal kidney Goodpasture’s disease results from an immune samples is much less sensitive, with about 25% reaction against the NC1 domain of the alpha3 false negative results, and it is also less specific. chain of type IV collagen. The restricted distribution of this molecule explains that the Unresolved questions disease affects only specific organs, such as The major unsolved questions are probably: lung and kidney. The pathogenic role of anti-GBM antibodies has • the mechanisms by which an immune been clearly illustrated by transfer experiments reaction develops against a normal in animals, and by recurrence of Goodpasture’s component of basement membranes; disease in renal transplant patients who had • the respective roles of cell-mediated and circulating antibodies at the time of antibody-mediated immune responses; transplantation. Nevertheless, Goodpasture’s • the development of therapies that are more disease should not be viewed as solely due to selective and thus have fewer side effects. anti-GBM antibodies, and autoreactive T cells also appear to play a role in the pathogenesis References Diagnostic procedures 1 - Reviews Crescentic glomerulonephritis with anti-GBM Bolton WK. Goodpasture's syndrome. Kidney antibodies Int 1996; 50: 1753-66. Renal biopsy plays a key role in the diagnosis. Salama AD, Levy JB, Lightstone L, Pusey CD. On light microscopy, it shows the presence of Goodpasture's disease. Lancet 2001; 358: 917- crescents, usually of similar age and affecting 20. most glomeruli. Furthermore, immunohistochemistry analyses show linear 2 - Series of patients and therapy deposits of IgG along the GBM, which are of Johnson JP, Moore J Jr, Austin HA 3rd, Balow paramount importance for the diagnosis. Anti- JE, Antonovych TT, Wilson CB. Therapy of anti- GBM antibodies correspond much less often to glomerular basement membrane antibody IgA or IgM. disease: analysis of prognostic significance of clinical, pathologic and treatment factors. Medicine 1985; 64: 219-27.

Rossert J. Goodpasture’s disease; Orphanet encyclopedia, September 2002 http://www.orpha.net/data/patho/GB/uk-goodpasture.pdf 3

Kelly PT, Haponik EF. Goodpasture syndrome: Burns AP, Fisher M, Li P, Pusey CD, Rees AJ. molecular and clinical advances. Medicine Molecular analysis of HLA class II genes in (Baltimore) 1994; 73: 171-85. Goodpasture's disease. QJM. 1995; 88: 93-100. Levy JB, Turner AN, Rees AJ, Pusey CD. Long- David M, Borza DB, Leinonen A, Belmont JM, term outcome of anti-glomerular basement Hudson BG. Hydrophobic amino acid residues membrane antibody disease treated with plasma are critical for the immunodominant epitope of exchange and immunosuppression. Ann Intern the Goodpasture autoantigen. A molecular basis Med. 2001; 134: 1033-42. for the cryptic nature of the epitope. J Biol Chem Lockwood CM, Rees AJ, Pearson TA, Evans 2001; 276: 6370-7. DJ, Peters DK, Wilson CB. Immunosuppression Netzer KO, Leinonen A, Boutaud A, Borza DB, and plasma-exchange in the treatment of Todd P, Gunwar S, Langeveld JP, Hudson BG. Goodpasture's syndrome. Lancet 1976; 1:7 11- The goodpasture autoantigen. Mapping the 5. major conformational epitope(s) of alpha3(IV) Savage CO, Pusey CD, Bowman C, Rees AJ, collagen to residues 17-31 and 127-141 of the Lockwood CM. Antiglomerular basement NC1 domain. J Biol Chem 1999; 274: 11267-74. membrane antibody mediated disease in the Salama AD, Chaudhry AN, Ryan JJ, Eren E, British Isles 1980-4. Br Med J (Clin Res Ed) Levy JB, Pusey CD, Lightstone L, Lechler RI. In 1986; 292: 301-4. Goodpasture's disease, CD4(+) T cells escape thymic deletion and are reactive with the 3 - Immunological studies autoantigen alpha3(IV)NC1. J Am Soc Nephrol Borza DB, Netzer KO, Leinonen A, Todd P, 2001; 12: 1908-15. Cervera J, Saus J, Hudson BG. The Turner N, Mason PJ, Brown R, Fox M, Povey S, goodpasture autoantigen. Identification of Rees A, Pusey CD. Molecular cloning of the multiple cryptic epitopes on the NC1 domain of human Goodpasture antigen demonstrates it to the alpha3(IV) collagen chain. J Biol Chem 2000; be the alpha 3 chain of type IV collagen. J Clin 275: 6030-7. Invest 1992; 89: 592-601.

Rossert J. Goodpasture’s disease; Orphanet encyclopedia, September 2002 http://www.orpha.net/data/patho/GB/uk-goodpasture.pdf 4