Goodpasture Syndrome Workup
- Author: Pranay Kathuria, MD; Chief Editor: Vecihi Batuman, MD, FACP, FASN more...
Diffuse alveolar hemorrhage represents a medical emergency, and clinicians must have an expedient approach to its identification. In the appropriate clinical setting (ie, alveolar hemorrhage and urinary findings suggestive of an acute glomerulonephritis), the detection of circulating anti–glomerular basement membrane (anti-GBM) antibodies allows the clinician to make a firm diagnosis of anti-GBM disease. This obviates lung or kidney biopsy.
When the diagnosis remains in doubt, renal biopsy is the best method for detecting anti-GBM antibodies in tissues. Patients in whom the diagnosis of diffuse alveolar hemorrhage remains uncertain should undergo diagnostic bronchoscopy.
Urinalysis and blood studies
Urinalysis findings are characteristic of acute glomerulonephritis, usually demonstrating low-grade proteinuria, gross or microscopic hematuria, and red blood cell casts.
On the complete blood cell count, anemia may be observed secondary to iron deficiency caused by intrapulmonary bleeding. Leukocytosis is commonly present.
Elevated blood urea nitrogen (BUN) and serum creatinine levels secondary to renal dysfunction may be present.
Elevation of the erythrocyte sedimentation rate (ESR) is commonly observed in patients with vasculitis, but it is uncommon in anti-GBM disease.
Anti–GBM Antibody Testing
Serologic assays for anti-GBM antibodies are valuable for confirming the diagnosis and monitoring the adequacy of therapy. Radioimmunoassays or enzyme-linked immunosorbent assays (ELISAs) for anti-GBM antibodies are highly sensitive (>95%) and specific (>97%) but are performed in only a few laboratories. Positive results should be confirmed by Western blotting on collagenase-solubilized human GBM, especially if a kidney biopsy is not being performed.
In a comparison study of 4 immunoassay-based anti-GBM antibody kits, all the assays showed comparably good sensitivity (94.7-100.0%), whereas specificity varied considerably (90.9-100.0%). The recombinant antigen fluorescence immunoassay demonstrated the best sensitivity/specificity.
Healthy individuals may have circulating antibodies against GBM belonging to IgG2 and IgG4 subclasses. With onset of clinical disease, IgG1 and IgG3 subclasses increase and levels may correlate with disease severity.
A study by Yang et al indicated that higher levels of circulating anti-GBM antibodies against the epitopes EA and EB occurred in patients whose renal disease was more severe and that these patients had a worse prognosis. Correlation was noted between the levels of anti-GBM antibodies and the serum creatinine at diagnosis and the presence of oliguria. Correlation existed between the percentage of crescents on biopsy and levels of antibodies, but it was significant only for anti-EA antibodies (P < .05).
Antineutrophilic Cytoplasmic Antibody Testing
At some time during the course of illness, as many as one third of patients with Goodpasture syndrome have circulating antineutrophilic cytoplasmic antibodies (ANCAs) in addition to anti-GBM antibody. In most cases, the ANCA antibodies precede the development of anti-GBM antibodies by months to years. It is postulated that the renal involvement in ANCA vasculitis leads to the exposure of antigens from the basement membrane and the formation of antibodies. These patients are referred to as double-positive.
Cytoplasmic ANCA (c-ANCA) and perinuclear ANCA (p-ANCA) are seen in the images below.
In the majority of double-positive patients, the ANCAs have specificity for myeloperoxidase (MPO-ANCA).[22, 23] In patients with both anti-GBM antibodies and MPO-ANCAs, histological findings differ from those of patients with anti-GBM antibodies only. The renal survival in these patients is similar to anti-GBM–positive patients and is worse compared with patients with MPO-ANCAs only.
In an analysis of the diagnostic performance of two rapid ANCA and anti-GBM test methods in 260 patients with suspected ANCA-associated small vessel vasculitis, de Joode and colleagues found that both the Dotblot and Phadia ELiA on anti-GBM, anti-PR3(s) and anti-MPO(s) performed well. Results with these tests were almost identical to those achieved with routine ELISA.
Characteristically, the chest film shows patchy parenchymal consolidations, which are usually bilateral, symmetric perihilar, and bibasilar. The apices and costophrenic angles are usually spared (see the image below). However, as many as 18% of patients may have normal findings on chest radiographs.
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.
Pulmonary Function Testing
Routine pulmonary function testing is not helpful in the clinical evaluation of the patients with anti-GBM disease. Spirometry and lung volume tests may 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.
In patients with evidence of diffuse alveolar hemorrhage and renal involvement, kidney biopsy should be considered to identify the underlying cause and to help direct therapy. Percutaneous kidney biopsy is the preferred invasive procedure to substantiate the diagnosis of anti-GBM disease. Renal biopsy provides a significantly higher yield than lung biopsy, but transbronchial or open lung biopsy may be performed in cases where renal biopsy cannot be performed.
The biopsy tissue must be processed for light microscopy, immunofluorescence, and electron microscopy. Light microscopy demonstrates nonspecific features of a proliferative or necrotizing glomerulonephritis with cellular crescents (as seen in the image below). Over time, the crescents become fibrotic, and frank glomerulosclerosis, interstitial fibrosis, and tubular atrophy may be observed.
Immunofluorescence stains are confirmatory. These show bright linear deposits of immunoglobulin G (IgG), as seen in the image below, and complement (C3) along the glomerular basement membranes. Subclass IgG-1 predominates.
Lung biopsy shows extensive hemorrhage with accumulation of hemosiderin-laden macrophages within alveolar spaces. Neutrophilic capillaritis, hyaline membranes, and diffuse alveolar damage may also be found. Medium-vessel or large-vessel vasculitis is not a feature. Immunofluorescence staining may be diagnostic, but performing this study on lung tissue is technically difficult.
Parkin TW, Rusted IE, Burchell HB, Edwards JE. Hemorrhagic and interstitial pneumonitis with nephritis. Am J Med. 1955 Feb. 18(2):220-36. [Medline].
Stanton MC, Tange JD. Goodpasture's syndrome (pulmonary haemorrhage associated with glomerulonephritis). Australas Ann Med. 1958 May. 7(2):132-44. [Medline].
Krakower CA, Greenspon SA. Localization of the nephrotoxic antigen within the isolated renal glomerulus. AMA Arch Pathol. 1951 Jun. 51(6):629-39. [Medline].
Lerner RA, Glassock RJ, Dixon FJ. The role of anti-glomerular basement membrane antibody in the pathogenesis of human glomerulonephritis. J Exp Med. 1967 Dec 1. 126(6):989-1004. [Medline]. [Full Text].
Zhao J, Cui Z, Yang R, Jia XY, Zhang Y, Zhao MH. Anti-glomerular basement membrane autoantibodies against different target antigens are associated with disease severity. Kidney Int. 2009 Nov. 76(10):1108-15. [Medline].
Cui Z, Zhao MH. Advances in human antiglomerular basement membrane disease. Nat Rev Nephrol. 2011 Jul 19. 7(12):697-705. [Medline].
Jia XY, Cui Z, Li JN, Hu SY, Zhao MH. Identification of critical residues of linear B cell epitope on Goodpasture autoantigen. PLoS One. 2015. 10 (4):e0123277. [Medline]. [Full Text].
Chan AL, Louie S, Leslie KO, Juarez MM, Albertson TE. Cutting edge issues in Goodpasture's disease. Clin Rev Allergy Immunol. 2011 Oct. 41(2):151-62. [Medline].
Yang R, Cui Z, Zhao J, Zhao MH. The role of HLA-DRB1 alleles on susceptibility of Chinese patients with anti-GBM disease. Clin Immunol. 2009 Nov. 133(2):245-50. [Medline].
Peto P, Salama AD. Update on antiglomerular basement membrane disease. Curr Opin Rheumatol. 2011 Jan. 23(1):32-7. [Medline].
Cui Z, Zhao J, Jia XY, Zhu SN, Zhao MH. Clinical features and outcomes of anti-glomerular basement membrane disease in older patients. Am J Kidney Dis. 2011 Apr. 57(4):575-82. [Medline].
Cranfield A, Mathavakkannan S. Goodpasture's disease following extracorporeal shock wave lithotripsy: a case report & literature review. Clin Case Rep. 2015 Mar. 3 (3):160-4. [Medline]. [Full Text].
Kluth DC, Rees AJ. Anti-glomerular basement membrane disease. J Am Soc Nephrol. 1999 Nov. 10(11):2446-53. [Medline].
Tang W, McDonald SP, Hawley CM, et al. Anti-glomerular basement membrane antibody disease is an uncommon cause of end-stage renal disease. Kidney Int. 2013 Mar. 83(3):503-10. [Medline].
Shah MK, Hugghins SY. Characteristics and outcomes of patients with Goodpasture's syndrome. South Med J. 2002 Dec. 95(12):1411-8. [Medline].
Kimmoun A, Baux E, Das V, Terzi N, Talec P, Asfar P, et al. Outcomes of patients admitted to intensive care units for acute manifestation of small-vessel vasculitis: a multicenter, retrospective study. Crit Care. 2016 Jan 26. 20:27. [Medline].
Weber MF, Andrassy K, Pullig O, Koderisch J, Netzer K. Antineutrophil-cytoplasmic antibodies and antiglomerular basement membrane antibodies in Goodpasture's syndrome and in Wegener's granulomatosis. J Am Soc Nephrol. 1992 Jan. 2(7):1227-34. [Medline].
Collard HR, Schwarz MI. Diffuse alveolar hemorrhage. Clin Chest Med. 2004 Sep. 25(3):583-92, vii. [Medline].
Sinico RA, Radice A, Corace C, Sabadini E, Bollini B. Anti-glomerular basement membrane antibodies in the diagnosis of Goodpasture syndrome: a comparison of different assays. Nephrol Dial Transplant. 2006 Feb. 21(2):397-401. [Medline].
Yang R, Hellmark T, Zhao J, et al. Levels of epitope-specific autoantibodies correlate with renal damage in anti-GBM disease. Nephrol Dial Transplant. 2009 Jun. 24(6):1838-44. [Medline].
Olson SW, Arbogast CB, Baker TP, et al. Asymptomatic autoantibodies associate with future anti-glomerular basement membrane disease. J Am Soc Nephrol. 2011 Oct. 22(10):1946-52. [Medline]. [Full Text].
Levy JB, Hammad T, Coulthart A, Dougan T, Pusey CD. Clinical features and outcome of patients with both ANCA and anti-GBM antibodies. Kidney Int. 2004 Oct. 66(4):1535-40. [Medline].
Rutgers A, Slot M, van Paassen P, van Breda Vriesman P, Heeringa P, Tervaert JW. Coexistence of anti-glomerular basement membrane antibodies and myeloperoxidase-ANCAs in crescentic glomerulonephritis. Am J Kidney Dis. 2005 Aug. 46(2):253-62. [Medline].
de Joode AA, Roozendaal C, van der Leij MJ, Bungener LB, Sanders JS, Stegeman CA. Performance of two strategies for urgent ANCA and anti-GBM analysis in vasculitis. Eur J Intern Med. 2014 Feb. 25(2):182-6. [Medline].
Zhao J, Yan Y, Cui Z, Yang R, Zhao MH. The immunoglobulin G subclass distribution of anti-GBM autoantibodies against rHalpha3(IV)NC1 is associated with disease severity. Hum Immunol. 2009 Jun. 70(6):425-9. [Medline].
Frankel SK, Cosgrove GP, Fischer A, Meehan RT, Brown KK. Update in the diagnosis and management of pulmonary vasculitis. Chest. 2006 Feb. 129(2):452-65. [Medline].
Johnson JP, Moore J Jr, Austin HA 3rd, Balow JE, Antonovych TT, Wilson CB. Therapy of anti-glomerular basement membrane antibody disease: analysis of prognostic significance of clinical, pathologic and treatment factors. Medicine (Baltimore). 1985 Jul. 64(4):219-27. [Medline].
Levy JB, Turner AN, Rees AJ, Pusey CD. Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med. 2001 Jun 5. 134(11):1033-42. [Medline].
Zhang YY, Tang Z, Chen DM, Gong DH, Ji DX, Liu ZH. Comparison of double filtration plasmapheresis with immunoadsorption therapy in patients with anti-glomerular basement membrane nephritis. BMC Nephrol. 2014 Aug 3. 15:128. [Medline]. [Full Text].
Bolton WK. Goodpasture's syndrome. Kidney Int. 1996 Nov. 50(5):1753-66. [Medline].
Shah Y, Mohiuddin A, Sluman C, et al. Rituximab in anti-glomerular basement membrane disease. QJM. 2012 Feb. 105(2):195-7. [Medline].
Syeda UA, Singer NG, Magrey M. Anti-glomerular basement membrane antibody disease treated with rituximab: A case based review. Semin Arthritis Rheum. 2013 Jan 24. [Medline].
Kashtan CE. Renal transplantation in patients with Alport syndrome. Pediatr Transplant. 2006 Sep. 10(6):651-7. [Medline].