Abstract
Crescentic glomerulonephritis is a severe form of glomerular injury that is characterized by disruption of the glomerular basement membrane, cellular proliferation within Bowman space, and (often) fibrinoid necrosis. Pauci-immune crescentic glomerulonephritis, so called because it involves little or no glomerular immunoglobulin deposition, is one of the most common causes of rapidly progressive glomerulonephritis. In the majority of patients, pauci-immune crescentic glomerulonephritis is a manifestation of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. However, some patients with pauci-immune crescentic glomerulonephritis lack ANCAs. This Review compares the prevalence, clinical manifestations, histopathology, and outcomes of ANCA-negative pauci-immune crescentic glomerulonephritis with those of ANCA-positive disease. We also discuss the possible pathogenesis of ANCA-negative pauci-immune crescentic glomerulonephritis, paying particular attention to the mechanisms and role of neutrophil activation.
Key Points
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Approximately 10–30% of patients with pauci-immune crescentic glomerulonephritis lack antineutrophil cytoplasmic antibodies (ANCAs)
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ANCA-negative pauci-immune crescentic glomerulonephritis might be a distinct disease entity from ANCA-positive pauci-immune crescentic glomerulonephritis
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In pauci-immune crescentic glomerulonephritis, ANCA-negative patients have fewer extrarenal symptoms than those who are ANCA-positive
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The existence of differences in renal histopathology and prognosis between ANCA-negative and ANCA-positive pauci-immune crescentic glomerulonephritis remains controversial
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Neutrophils are thought to have a major role in the pathogenesis of ANCA-negative pauci-immune crescentic glomerulonephritis
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References
Jennette, J. C. & Hipp, C. G. The epithelial antigen phenotype of glomerular crescent cells. Am. J. Clin. Pathol. 86, 274–280 (1986).
Hancock, W. W. & Atkins, R. C. Cellular composition of crescents in human rapidly progressive glomerulonephritis identified using monoclonal antibodies. Am. J. Nephrol. 4, 177–181 (1984).
Jennette, J. C. Rapidly progressive crescentic glomerulonephritis. Kidney Int. 63, 1164–1177 (2003).
Jennette, J. C. & Falk, R. J. Small-vessel vasculitis. N. Engl. J. Med. 337, 1512–1523 (1997).
Harada, T. et al. ANCA-negative pauci-immune crescentic glomerulonephritis complicated with recurrent massive gastrointestinal hemorrhage. Clin. Exp. Nephrol. 9, 174–178 (2005).
Chow, K., Wang, A. Y., Mac-Moune Lai, F., Wong, T. Y. & Li, P. K. Rapid recurrence of ANCA-negative pauci-immune vasculitis after cadaveric renal transplantation. Am. J. Kidney Dis. 38, E3 (2001).
Moeckel, G. W., Jabs, K. & Fogo, A. B. An 11-year-old African-American girl with systemic lupus erythematosus and ANCA-negative renal vasculitis. Am. J. Kidney Dis. 39, 433–438 (2002).
Hedger, N., Stevens, J., Drey, N., Walker, S. & Roderick, P. Incidence and outcome of pauci-immune rapidly progressive glomerulonephritis in Wessex, UK: a 10-year retrospective study. Nephrol. Dial. Transplant. 15, 1593–1599 (2000).
Eisenberger, U. et al. ANCA-negative pauci-immune renal vasculitis: histology and outcome. Nephrol. Dial. Transplant. 20, 1392–1399 (2005).
Chen, M. et al. Antineutrophil cytoplasmic autoantibody negative pauci-immune crescentic glomerulonephritis. J. Am. Soc. Nephrol. 18, 599–605 (2007).
Hung, P. H. et al. Poor renal outcome of antineutrophil cytoplasmic antibody negative pauci-immune glomerulonephritis in Taiwanese. J. Formos. Med. Assoc. 105, 804–812 (2006).
Hagen, E. C. et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA Assay Standardization. Kidney Int. 53, 743–753 (1998).
Harris, A. A., Falk, R. J. & Jennette, J. C. Crescentic glomerulonephritis with a paucity of glomerular immunoglobulin localization. Am. J. Kidney Dis. 32, 179–184 (1998).
Falk, R. J., Terrell, R. S., Charles, L. A. & Jennette, J. C. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc. Natl Acad. Sci. USA 87, 4115–4119 (1990).
Charles, L. A., Caldas, M. L., Falk, R. J., Terrell, R. S. & Jennette, J. C. Antibodies against granule proteins activate neutrophils in vitro. J. Leukoc. Biol. 50, 539–546 (1991).
Keogan, M. T., Esnault, V. L., Green, A. J., Lockwood, C. M. & Brown, D. L. Activation of normal neutrophils by anti-neutrophil cytoplasm antibodies. Clin. Exp. Immunol. 90, 228–234 (1992).
Mulder, A. H. L., Heeringa, P., Brouwer, E., Limburg, P. C. & Kallenberg, C. G. Activation of granulocytes by anti-neutrophil cytoplasm antibodies: a FcRII-dependent process. Clin. Exp. Immunol. 98, 270–276 (1994).
Hewins, P. et al. IL-18 is upregulated in the kidney and primes neutrophil responsiveness in ANCA-associated vasculitis. Kidney Int. 69, 605–615 (2006).
Xiao, H. et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J. Clin. Invest. 110, 955–963 (2002).
Bansal, P. J. & Tobin, M. C. Neonatal microscopic polyangiitis secondary to transfer of maternal myeloperoxidase–antineutrophil cytoplasmic antibody resulting in neonatal pulmonary hemorrhage and renal involvement. Ann. Allergy Asthma Immunol. 93, 398–401 (2004).
Schlieben, D. J., Korbet, S. M., Kimura, R. E., Schwartz, M. M. & Lewis, E. J. Pulmonary–renal syndrome in a newborn with placental transmission of ANCAs. Am. J. Kidney Dis. 45, 758–761 (2005).
Jayne, D. R. et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J. Am. Soc. Nephrol. 18, 2180–2188 (2007).
Brouwer, E. et al. Neutrophil activation in vitro and in vivo in Wegener's granulomatosis. Kidney Int. 45, 1120–1131 (1994).
Xiao, H. et al. The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies. Am. J. Pathol. 167, 39–45 (2005).
Kitching, A. R., Holdsworth, S. R. & Hickey, M. J. Targeting leukocytes in immune glomerular diseases. Curr. Med. Chem. 15, 448–458 (2008).
Couser, W. G. Pathogenesis of glomerular damage in glomerulonephritis. Nephrol. Dial. Transplant. 13, s10–s15 (1998).
Coxon, A. et al. Fcγ RIII mediates neutrophil recruitment to immune complexes. A mechanism for neutrophil accumulation in immune-mediated inflammation. Immunity 14, 693–704 (2001).
Sheerin, N. S., Springall, T., Carroll, M. C., Hartley, B. & Sacks, S. H. Protection against anti-glomerular basement membrane (GBM)-mediated nephritis in C3- and C4-deficient mice. Clin. Exp. Immunol. 110, 403–409 (1997).
Wang, F. et al. Neutrophil degranulation in antineutrophil cytoplasmic antibodies-negative pauci-immune crescentic glomerulonephritis. J. Nephrol. (in press).
Xu, S. & Venge, P. Lipocalins as biochemical markers of disease. Biochim. Biophys. Acta 1482, 298–307 (2000).
Metz-Boutigue, M. H. et al. Human lactotransferrin: amino acid sequence and structural comparisons with other transferrins. Eur. J. Biochem. 145, 659–676 (1984).
Lonnerdal, B. & Iyer, S. Lactoferrin: molecular structure and biological function. Annu. Rev. Nutr. 15, 93–110 (1995).
Radford, D. J., Luu, N. T., Hewins, P., Nash, G. B. & Savage, C. O. Antineutrophil cytoplasmic antibodies stabilize adhesion and promote migration of flowing neutrophils on endothelial cells. Arthritis Rheum. 44, 2851–2861 (2001).
Ewert, B. H., Jennette, J. C. & Falk, R. J. Anti-myeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells. Kidney Int. 41, 375–383 (1992).
Cid, M. C., Segarra, M., García-Martínez, A. & Hernández-Rodríguez, J. Endothelial cells, antineutrophil cytoplasmic antibodies, and cytokines in the pathogenesis of systemic vasculitis. Curr. Rheumatol. Rep. 6, 184–194 (2004).
D'Cruz, D. P., Keser, G., Direskeneli, H., Khamashta, M. A. & Hughes, G. R. Anti-endothelial cell antibodies in systemic vasculitis and systemic lupus erythematosus (SLE): effects of heat inactivation on binding and specificity. Clin. Exp. Immunol. 115, 567–570 (1999).
Cong, M., Chen, M., Zhang, J. J., Hu, Z. & Zhao, M. H. Anti-endothelial cell antibodies in antineutrophil cytoplasmic antibodies negative pauci-immune crescentic glomerulonephritis. Nephrology (Carlton) 13, 228–234 (2008).
Vercellotti, G. M., Platt, J. L., Bach, F. H. & Dalmasso, A. P. Neutrophil adhesion to xenogeneic endothelium via iC3b. J. Immunol. 146, 730–734 (1991).
Kain, R. et al. A novel class of autoantigens of anti-neutrophil cytoplasmic antibodies (ANCA) in necrotizing and crescentic glomerulonephritis. J. Exp. Med. 181, 585–597 (1995).
Kain, R. et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat. Med. 14, 1088–1096 (2008).
Kallenberg, C. G., Stegeman, C. A. & Heeringa, P. Autoantibodies vex the vasculature. Nat. Med. 14, 1018–1019 (2008).
Cockwell, P., Brooks, C. J., Adu, D. & Savage, C. O. Interleukin-8: a pathogenetic role in antineutrophil cytoplasmic autoantibody-associated glomerulonephritis. Kidney Int. 55, 852–863 (1999).
Abdulahad, W. H., Stegeman, C. A., Limburg, P. C. & Kallenberg, C. G. Skewed distribution of TH17 lymphocytes in patients with Wegener's granulomatosis in remission. Arthritis Rheum. 58, 2196–2205 (2008).
Laan, M. et al. Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. J. Immunol. 162, 2347–2352 (1999).
Luqmani, R. A. et al. Birmingham vasculitis activity score (BVAS) in systemic necrotizing vasculitis. QJM 87, 671–678 (1994).
Acknowledgements
This Review was supported by a grant from the Chinese 985 project (985-2-104-113).
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Chen, M., Kallenberg, C. & Zhao, MH. ANCA-negative pauci-immune crescentic glomerulonephritis. Nat Rev Nephrol 5, 313–318 (2009). https://doi.org/10.1038/nrneph.2009.67
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DOI: https://doi.org/10.1038/nrneph.2009.67
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