Co-presentation with both ANCA and anti-GBM antibodies is thought to be relatively rare. Current studies of such 'double-positive' cases report small numbers and variable outcomes. To study this further we retrospectively analyzed clinical features and long-term outcomes of a large cohort of 568 contemporary patients with ANCA-associated vasculitis, 41 patients with anti-GBM disease, and 37 double-positive patients with ANCA and anti-GBM disease from four European centers. Double-positive patients shared characteristics of ANCA-associated vasculitis (AAV), such as older age distribution and longer symptom duration before diagnosis, and features of anti-GBM disease, such as severe renal disease and high frequency of lung hemorrhage at presentation. Despite having more evidence of chronic injury on renal biopsy compared to patients with anti-GBM disease, double-positive patients had a greater tendency to recover from being dialysis-dependent after treatment and had intermediate long-term renal survival compared to the single-positive patients. However, overall patient survival was similar in all three groups. Predictors of poor patient survival included advanced age, severe renal failure, and lung hemorrhage at presentation. No single-positive anti-GBM patients experienced disease relapse, whereas approximately half of surviving patients with AAV and double-positive patients had recurrent disease during a median follow-up of 4.8 years. Thus, double-positive patients have a truly hybrid disease phenotype, requiring aggressive early treatment for anti-GBM disease, and careful long-term follow-up and consideration for maintenance immunosuppression for AAV. Since double-positivity appears common, further work is required to define the underlying mechanisms of this association and define optimum treatment strategies.

Department of Nephrology and Department of Medical and Health Sciences Linköping University Linköping Sweden

Department of Nephrology and Transplantation Skånes University Hospital Lund Sweden

Department of Nephrology General University Hospital Prague and 1st Faculty of Medicine Charles University Prague Czech Republic

Renal and Vascular Inflammation Section Department of Medicine Imperial College London London UK

Kidney Int. 2017 Sep;92(3):544-546. doi: 10.1016/j.kint.2017.04.024. PubMed

See more in PubMed

Pusey C.D. Anti-glomerular basement membrane disease. Kidney Int. 2003;64:1535–1550. PubMed

Watts R.A., Mahr A., Mohammad A.J. Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Nephrol Dial Transplant. 2015;30(Suppl 1):i14–i22. PubMed

O’Donoghue D.J., Short C.D., Brenchley P.E. Sequential development of systemic vasculitis with anti-neutrophil cytoplasmic antibodies complicating anti-glomerular basement membrane disease. Clin Nephrol. 1989;32:251–255. PubMed

Jayne D.R., Marshall P.D., Jones S.J. Autoantibodies to GBM and neutrophil cytoplasm in rapidly progressive glomerulonephritis. Kidney Int. 1990;37:965–970. PubMed

Levy J.B., Hammad T., Coulthart A. Clinical features and outcome of patients with both ANCA and anti-GBM antibodies. Kidney Int. 2004;66:1535–1540. PubMed

Rutgers A., Slot M., van Paassen P. Coexistence of anti-glomerular basement membrane antibodies and myeloperoxidase-ANCAs in crescentic glomerulonephritis. Am J Kidney Dis. 2005;46:253–262. PubMed

Zhao J., Yang R., Cui Z. Characteristics and outcome of Chinese patients with both antineutrophil cytoplasmic antibody and antiglomerular basement membrane antibodies. Nephron Clin Pract. 2007;107:c56–c62. PubMed

J DEZ, Taylor D., Thein H. Incidence and features of dual anti-GBM-positive and ANCA-positive patients. Nephrology. 2011;16:725–729. PubMed

Short A.K., Esnault V.L., Lockwood C.M. Anti-neutrophil cytoplasm antibodies and anti-glomerular basement membrane antibodies: two coexisting distinct autoreactivities detectable in patients with rapidly progressive glomerulonephritis. Am J Kidney Dis. 1995;26:439–445. PubMed

Bosch X., Mirapeix E., Font J. Prognostic implication of anti-neutrophil cytoplasmic autoantibodies with myeloperoxidase specificity in anti-glomerular basement membrane disease. Clin Nephrol. 1991;36:107–113. PubMed

Segelmark M., Hellmark T., Wieslander J. The prognostic significance in Goodpasture's disease of specificity, titre and affinity of anti-glomerular-basement-membrane antibodies. Nephron Clin Pract. 2003;94:c59–c68. PubMed

Weber M.F., Andrassy K., Pullig O. Antineutrophil-cytoplasmic antibodies and antiglomerular basement membrane antibodies in Goodpasture’s syndrome and in Wegener's granulomatosis. J Am Soc Nephrol. 1992;2:1227–1234. PubMed

Lindic J., Vizjak A., Ferluga D. Clinical outcome of patients with coexistent antineutrophil cytoplasmic antibodies and antibodies against glomerular basement membrane. Ther Apher Dial. 2009;13:278–281. PubMed

Srivastava A., Rao G.K., Segal P.E. Characteristics and outcome of crescentic glomerulonephritis in patients with both antineutrophil cytoplasmic antibody and anti-glomerular basement membrane antibody. Clin Rheumatol. 2013;32:1317–1322. PubMed

Alchi B., Griffiths M., Sivalingam M. Predictors of renal and patient outcomes in anti-GBM disease: clinicopathologic analysis of a two-centre cohort. Nephrol Dial Transplant. 2015;30:814–821. PubMed

Cui Z., Zhao J., Jia X.Y. Anti-glomerular basement membrane disease: outcomes of different therapeutic regimens in a large single-center Chinese cohort study. Medicine (Baltimore) 2011;90:303–311. PubMed

Levy J.B., Turner A.N., Rees A.J., Pusey C.D. Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med. 2001;134:1033–1042. PubMed

McAdoo S.P., Tanna A., Randone O. Necrotizing and crescentic glomerulonephritis presenting with preserved renal function in patients with underlying multisystem autoimmune disease: a retrospective case series. Rheumatology (Oxford) 2015;54:1025–1032. PubMed PMC

Ohlsson S., Herlitz H., Lundberg S. Circulating anti-glomerular basement membrane antibodies with predominance of subclass IgG4 and false-negative immunoassay test results in anti-glomerular basement membrane disease. Am J Kidney Dis. 2014;63:289–293. PubMed

Nasr S.H., Collins A.B., Alexander M.P. The clinicopathologic characteristics and outcome of atypical anti-glomerular basement membrane nephritis. Kidney Int. 2016;89:897–908. PubMed

Yang R., Hellmark T., Zhao J. Antigen and epitope specificity of anti-glomerular basement membrane antibodies in patients with goodpasture disease with or without anti-neutrophil cytoplasmic antibodies. J Am Soc Nephrol. 2007;18:1338–1343. PubMed

Hellmark T., Niles J.L., Collins A.B. Comparison of anti-GBM antibodies in sera with or without ANCA. J Am Soc Nephrol. 1997;8:376–385. PubMed

Fischer E.G., Lager D.J. Anti-glomerular basement membrane glomerulonephritis: a morphologic study of 80 cases. Am J Clin Pathol. 2006;125:445–450. PubMed

Berden A.E., Ferrario F., Hagen E.C. Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol. 2010;21:1628–1636. PubMed

Tanna A., Guarino L., Tam F.W. Long-term outcome of anti-neutrophil cytoplasm antibody-associated glomerulonephritis: evaluation of the international histological classification and other prognostic factors. Nephrol Dial Transplant. 2015;30:1185–1192. PubMed

Kobayashi K., Shibata T., Sugisaki T. Aggravation of rat nephrotoxic serum nephritis by anti-myeloperoxidase antibodies. Kidney Int. 1995;47:454–463. PubMed

Heeringa P., Brouwer E., Klok P.A. Autoantibodies to myeloperoxidase aggravate mild anti-glomerular-basement-membrane-mediated glomerular injury in the rat. Am J Pathol. 1996;149:1695–1706. PubMed PMC

Kanzaki G., Nagasaka S., Higo S. Impact of anti-glomerular basement membrane antibodies and glomerular neutrophil activation on glomerulonephritis in experimental myeloperoxidase-antineutrophil cytoplasmic antibody vasculitis. Nephrol Dial Transplant. 2016;31:574–585. PubMed

Olson S.W., Arbogast C.B., Baker T.P. Asymptomatic autoantibodies associate with future anti-glomerular basement membrane disease. J Am Soc Nephrol. 2011;22:1946–1952. PubMed PMC

Pedchenko V., Bondar O., Fogo A.B. Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis. The New England journal of medicine. 2010;363:343–354. PubMed PMC

Nakazawa D., Tomaru U., Suzuki A. Abnormal conformation and impaired degradation of propylthiouracil-induced neutrophil extracellular traps: implications of disordered neutrophil extracellular traps in a rat model of myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2012;64:3779–3787. PubMed

Kumar S.V., Kulkarni O.P., Mulay S.R. Neutrophil extracellular trap-related extracellular histones cause vascular necrosis in severe GN. J Am Soc Nephrol. 2015;26:2399–2413. PubMed PMC

Li J.N., Cui Z., Wang J. Autoantibodies against linear epitopes of myeloperoxidase in anti-glomerular basement membrane disease. Clin J Am Soc Nephrol. 2016;11:568–575. PubMed PMC

Rahmattulla C., Mooyaart A.L., van Hooven D. Genetic variants in ANCA-associated vasculitis: a meta-analysis. Ann Rheum Dis. 2016;75:1687–1692. PubMed

Zhou X.J., Lv J.C., Zhao M.H. Advances in the genetics of anti-glomerular basement membrane disease. Am J Nephrol. 2010;32:482–490. PubMed

Persson U., Hertz J.M., Carlsson M. Patients with Goodpasture’s disease have two normal COL4A3 alleles encoding the NC1 domain of the type IV collagen alpha 3 chain. Nephrol Dial Transplant. 2004;19:2030–2035. PubMed

Jennette J.C., Falk R.J., Bacon P.A. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65:1–11. PubMed

Levey A.S., Bosch J.P., Lewis J.B. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461–470. PubMed

Risk Stratification to Predict Renal Survival in Anti-Glomerular Basement Membrane Disease

Endopeptidase Cleavage of Anti-Glomerular Basement Membrane Antibodies in vivo in Severe Kidney Disease: An Open-Label Phase 2a Study