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| Year : 2000 | Volume
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| Issue : 3 | Page : 362-369 |
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| Anti-neutrophil Cytoplasmic Antibodies and Glomerulonephritis: An Update |
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Takashi Oda
Department of Medicine, Japan Self Defense Forces Kumamoto Hospital, Kumamoto, Japan
Click here for correspondence address and email
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How to cite this article:
Oda T. Anti-neutrophil Cytoplasmic Antibodies and Glomerulonephritis: An Update. Saudi J Kidney Dis Transpl 2000;11:362-9 |
 Introduction | |  |
Anti-neutrophil cytoplasmic antibodies (ANCA) in patients with segmental necrotizing glomerulonephritis (GN) was originally described by Davies et al, [1] and have since been identified in patients with systemic vasculitis. These autoantibodies remain the subject of extensive investigations for their role as diagnostic and followup tools, as well as being important factors in the pathogenesis of systemic vasculitis. Indeed, the discovery of ANCA has considerably changed the concept of this disease and its categories, and a new nomenclature for systemic vasculitis has recently been proposed. [2] The present report uses the terminology and definition of this classification. The key contribution of ANCA to GN is that of a changed concept of idiopathic crescentic GN, which was originally classified only as a type of GN. However, the high frequency of ANCA positivity and a similarity of renal histological manifestations led to the belief that crescentic GN is a renal restricted form of systemic vasculitis. In fact, most ANCA positive, pauci-immune (absence or paucity of immunohistological staining for immunoglobulins at sites of vasculitis) small vessel vasculitis such as Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Straus syndrome (CSS), are usually accompanied by GN. The histological features of this condition are characterized by focal glomerular tuft necrosis and the crescent formation; appearances that are identical to idiopathic crescentic GN. Moreover, the frequency of ANCA positivity in idiopathic crescentic GN is high and essentially identical to that of MPA. Some investigators use the terminology of "ANCA associated GN" for patients with positive ANCA and histologically pauci-immune necrotizing and crescentic GN.
This review summarizes the current status of ANCA testing as a diagnostic/follow-up tool and the pathogenesis of idiopathic crescentic GN and vasculitis. However, many issues remain controversial.
| ANCA: Significance as diagnostic and follow-up tools | | |
Significance as a diagnostic tool
ANCA are frequently identified in patients with pauci-immune systemic small vessel vasculitis such as WG, MPA, CSS (these diseases are now termed ANCA associated vasculitis) and idiopathic crescentic GN. Early reports described the specificity and sensitivity of ANCA for these diseases as being very high. [3],[4] Niles et al reported that the sensitivity and the specificity of ANCA for pauci-immune crescentic GN approaches 95% and 99%, respectively. [5] However, the popularization of the assay and availability of controls for various diseases revealed that the sensitivity and specificity of ANCA were actually quite low. [6],[7] The method of detecting ANCA may be a factor. The standard method is indirect immunofluorescence (IIF) using alcohol-fixed normal human neutrophils as the substrate. This method distinguishes cytoplasmic (cANCA), and perinuclear locations (pANCA). The target antigens recognized by most cANCA positive sera are proteinase 3 (PR3) whereas that of pANCA is usually myeloperoxidase (MPO), although other neutrophil cytoplasmic antigens such as elastase and lactoferrin have also been recognized. [8],[9],[10] These antigen specific ANCA (PR3-ANCA and MPO-ANCA) can be detected by enzyme-linked immunosorbent assay (ELISA). The results of ANCA positivity obtained by IIF and by ELISA do not always correlate, since some patients can be positive by ELISA and negative by IIF and vice versa. Among patients with WG, cANCA (or PR3-ANCA) are most frequent but are not specific for this disease. Patients with MPA, idiopathic crescentic GN, and CSS are usually positive for pANCA (or MPO-ANCA), but these antibodies are also associated with ulcerative colitis, rheumatoid arthritis and infective endocarditis. [11],[12] The European ANCA assay standardization project recently reported [13] that ANCA detected by IIF (cANCA or pANCA) are sensitive markers for WG, MPA and pauci-immune crescentic GN (sensitivity score 81-85%), but have low specificity (76%, related to disease control). The direct ELISA methods that they developed and standardized were not any more sensitive than the IIF tests, but when the results of the latter were combined with those of the ELISA (c/PR3-ANCA positive, p/MPO-ANCA positive), the diagnostic specificity increased to 99%. The sensitivity levels of this combination for WG, MPA and crescentic GN are 73%, 67% and 82%, respectively. Thus, in a significant number of patients with idiopathic small vessel vasculitis, ANCA test results (either in IIF or ELISA) are negative. Although ANCA are more frequently found in patients with pauci-immune necrotizing crescentic GN and vasculitis, about one third of those with anti-GBM GN have ANCA, [5],[14] as do 50% of patients with immune-complex crescentic GN. [15] In addition, Ronda et al have reported that ANCA of the IgA isotype are frequently detected in sera from adult patients with Henoch-Schonlein purpura, [16] whereas others could not detect any type of ANCA in such patients. [17]
In summary, c/PR3-ANCA is frequently associated with WG, while p/MPO-ANCA is usually detected in patients with MPA, idiopathic crescentic GN, and CSS. Yet, neither ANCA subtype provides a test that allows diagnostic differentiation among types of ANCA associated vasculitis. [18] However, ANCA can differentiate certain types of small vessel vasculitis (including crescentic GN) from non-vasculitic disease in a reasonably sensitive and highly specific manner when assayed by a combination of IIF and ELISA. [13],[19],[20]
Relationship between ANCA positivity, subtype, and renal involvement
Although ANCA is mostly prevalent in patients with crescentic GN, [21] those with small vessel vasculitis without renal involvement also sometimes have ANCA. The reported sensitivity for cANCA in WG patients with renal disease is identical to that in WG patients without renal disease (both 64%), although the pANCA was more prevalent in WG patients with GN (30%) than in those without renal disease (10%). [13] Some studies indicate modest clinical differences between MPO-ANCA and PR3ANCA associated renal disease, with the latter being more aggressive and having a worse prognosis. [22] However, Kallenberg et al found no clear distinction between patients with MPO-ANCA and those with PR3-ANCA, [23] and Bajema et al also reported that ANCA findings at the time of biopsy are not related to renal histopathology. [24] On the other hand, Apenberg et al reported that elastase-ANCA in patients with WG or MPA correlate with renal involvement, being more frequent in patients with dialysis-dependent renal failure. [3] ElastaseANCA actually upregulates elastase (one of the most powerful tissue destructive proteinases of neutrophils) activity in vitro and thereby might contribute to the tissue damage caused by the disease. [25]
Significance as a follow-up tool
Some investigators indicate that ANCA is useful as a follow-up tool, because ANCA titers seem to correlate with changes in disease activity, [26],[27] and an increasing ANCA titer can help to differentiate relapse from super-infection experienced during immunosuppressive therapy. [3] Persistent or intermittent positivity for ANCA in patients entering remission is a considerable risk factor for relapse. [28] However, others report that increasing ANCA titers are not necessarily followed by relapse, and ANCA titers do not change over time in some patients despite clinical quiescence. [29],[30] Some investigators indicate that not only levels of ANCA, but also their isotype or subclass distribution would be important factors for clinical expression of the disease. [31],[32] Indeed, IgG3 MPO-ANCA titers have been reported to correlate with renal involvement [33] and disease activity. [34] However, Kokolina et al reported that levels, isotype distribution and affinity of MPO-ANCA do not correlate with specific clinical manifestations. [35] Meanwhile, one investigator has reported that ANCA titers measured by capture ELISA reflect the activity of vasculitis, whereas those measured by direct ELISA do not. [36] As such, it is still debatable whether or not changes in ANCA titers or isotype distribution reflect disease activity. Therefore, others caution that ANCA titers should not be used as the sole criterion upon which to base a therapeutic strategy. [18],[20]
ANCA: Pathogenetic or epiphenomenon? -Pathogenesis of crescentic GN/vasculitis
The close association of ANCA with idiopathic small vessel vasculitis and crescentic GN suggests important role for ANCA in the pathophysiology of these diseases. Although much in vitro data address the pathophysiological role of ANCA, the most probable role would be their capacity to activate neutrophils. Actually, ANCA activate tumor necrosis alpha (TNF)-primed neutrophils leading to the release of lysosomal enzymes and the generation of reactive oxygen radicals, [37] resulting in endothelial cell damage in vitro. [38],[39] On the other hand, several lines of evidence indicate more specific interactions between ANCA and endothelial cells. a). Mayet et al reported that human endothelial cells express PR3 that is upregulated and translocated from the cytoplasm into the cell membrane by cytokines (TNF-α), interleukin-1 (IL-1), interferon gamma (IF-γ) treatment. [40] Thus, the endothelial cells become accessible to ANCA and may result in antibody-dependent cellular cytotoxicity. However, others have not been able to demonstrate PR3 expression by endothelial cells. [41]
b). Anionic structures, such as glomerular basement membrane and the surface of vascular endothelial cells, may bind cationic MPO and PR3, where ANCA will bind to form immune complexes in situ, and may induce complement-dependent endothelial cell lysis. [42] However, the involvement of these mechanisms in vivo are somewhat questionable, because immunostaining for immunoglobulin is negative or faint within vascular lesions in patients with ANCA associated vasculitis.
c). Neutrophil adhesion to endothelial cells can be induced by ANCA via the upregulation of E-selectin (ELAM-1) expression on the surface of endothelial cells, [43] which may cause accumulation of activated neutrophils and induce vascular damage.
In general, the relevance of these in vitro phenomena for the pathophysiology of ANCA associated vasculitis in vivo is far from clear, either in experimental models or in human diseases. For example, HgCl 2 treated Brown Norway rats develop various autoantibodies including MPO-ANCA, and necrotizing vasculitis in the gut.[44],[45] Therefore, these animals are regarded as useful models of human ANCA associated vasculitis. However, despite the presence of MPO-ANCA, these rats did not develop crescentic GN. Furthermore, transferring sera containing ANCA from HgCl 2 treated rats into normal rats failed to induce vasculitis. [46] On the other hand, the experimental models described by Kobayashi et al [47] (MPO-ANCA injection itself did not cause pathological changes, but it did aggravate rat nephrotoxic serum nephritis) and Brouwer et al [48] (perfusion of a lysosomal enzyme extract and H 2O2 into the kidney of MPO-immunized rats resulted in the development of necrotizing crescentic GN and vasculitis) indicate the in vivo potential of ANCA to aggravate glomerular damage resulting in the development of overt GN. However, both studies support the contention that the presence of ANCA in itself is not sufficient to cause tissue injury, because they found that neither the transfer of MPO-ANCA nor the induction of MPO-ANCA by immunization induced histological changes. In addition, ANCA positive and negative patients did not seem to differ neither clinically nor histologically. [24] Moreover, high levels of ANCA can be present without signs of disease activity. [29],[30] These data suggest that ANCA do not constitute the initial or major cause of vasculitis, but are rather a consequence or epiphenomenon of severe inflammation, although experimental data indicate that ANCA may exacerbate crescentic GN and/or vasculitis.
We observed prominent infiltration and aggregation of neutrophils with intense deposition of neutrophil elastase in glomerular necrotizing and crescentic lesions and interstitial lesions of the kidney.[49],[50] Neutrophil elastase was localized not only in the cytoplasm of neutrophils, but also extracellularly in those lesions in a granular or diffuse manner [Figure - 1]. Moreover, the concentration of neutrophil elastase was high in the urine [Figure - 2]. [49] These findings indicated that activated neutrophils play important roles in the pathophysiology of vasculitis. Brouwer et al also found activated neutrophils and extracellular lysosomal enzymes (PR3, MPO, and elastase) in renal biopsies from patients with WG. [51] The report by Suzuki et al [52] provides support for this mechanism. They showed that neutrophil elastase inhibitor (ONO-5046) reduces proteinuria and hematuria, and suppresses the crescent formation caused by nephrotoxic serum nephritis in a dose-dependent manner. In line with these observations, several reports suggest that a severe deficiency of α1-antitrypsin (α1-AT) is associated with systemic vasculitis and crescentic GN. [53],[54] Because α1-AT is the major inhibitor of neutrophil serine proteinases (such as elastase and PR3), these reports support the notion presented above. Indeed, patients who have ANCA positive vasculitis with a decreased α1-AT concentration due to the PiZ gene carriage have a poorer prognosis and tend to have a larger number of organs affected than those with a normal α1-AT concentration. [55] Notably, ANCA interfere with the normal inhibitory activity of a1-AT for PR3. [56] As to the mechanism of how neutrophils accumulate into specific vascular sites, we suspect that adhesion molecules, especially E-selectin (ELAM-1) are involved.[57] We showed that in renal biopsies of patients with MPA, Eselectin is abundantly expressed on the renal vascular endothelium with neutrophil infiltration. [57] Mayet et al [43] reported that ANCA can directly induce endothelial Eselectin expression. However, we believe that E-selectin is expressed irrespective of the presence of ANCA, because E-selectin expression and ANCA positivity in our patients did not correlate (Intense E-selectin expression was observed in an ANCA negative patient with MPA).
These data indicate that the mechanism of renal tissue damage in vasculitis is as follows. Stimulation to specific vascular sites (from some yet-to-be-determined source, such as certain viral infections) leads to endothelial activation, which in turn causes endothelial adhesion molecules expression, cytokine expression and release. Through these mechanisms, leukocytes, especially neutrophils, are activated and infiltrate into renal tissues causing damage via proteinases and oxygen radicals.[49],[50]
| Summary | | |
ANCA constitute a useful marker with which it is possible to substantiate a diagnosis of idiopathic crescentic GN and/or systemic vasculitis. It is still debatable whether ANCA are directly involved in the pathogenesis, or are essentially epiphenomena of vasculitis. However, neutrophils and their tissue destructive mediators (proteinases such as elastase and PR3, as well as oxygen radicals) play a crucial role in the tissue destruction and development of crescentic GN and/or vasculitis. Further studies are necessary to define the initial factors that trigger these diseases.
| References | | |
| 1. | Davies DJ, Moran JE, Niall JF, Ryan GB. Segmental necrotizing glomerulonephritis with anti-neutrophil antibody: possible arbovirus aetiology? Br Med J 1982; 285(6342):606.  |
| 2. | Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994;37(2):187-92. |
| 3. | Nolle B, Specks U, Ludemann J, Rohrbach MS, DeRemee RA, Gross WL. Anticytoplasmic autoantibodies: their immunodiagnostic value in Wegener granulomatosis. Ann Intern Med 1989;111(1):28-40. |
| 4. | van der Woude FJ, Rasmussen N, Lobatto S, et al. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet 1985;1(8426):425-9. |
| 5. | Niles JL, Pan GL, Collins AB, et al. Antigenspecific radio-immunoassays for antineutrophil cytoplasmic antibodies in the diagnosis of rapidly progressive glomerulonephritis. J Am Soc Nephrol 1991;2(1):27-36. |
| 6. | Davenport A, Lock RJ, Wallington TB, Feest TG. Clinical significance of antineutrophil cytoplasm antibodies detected by a standardized indirect immunofluorescence assay. Q J Med 1994;87(5):291-9. |
| 7. | Gross WL, Schmitt WH, Csernok E. ANCA and associated diseases: immunodiagnostic and pathogenetic aspects. Clin Exp Immunol 1993;91(1):1-12. |
| 8. | Coremans IE, Hagen EC, Daha MR, et al. Antilactoferrin antibodies in patients with rheumatoid arthritis are associated with vasculitis. Arthritis Rheum 1992;35(12): 1466-75. |
| 9. | Nassberger L, Jonsson H, Sjoholm AG, Sturfelt G, Heubner A. Circulating antielastase in systemic lupus erythematosus. Lancet 1989;1(8636):509. |
| 10. | Apenberg S, Andrassy K, Worner I, et al. Antibodies to neutrophil elastase: a study in patients with vasculitis. Am J Kidney Disease 1996;28(2):178-85. |
| 11. | Braun MG, Csernok E, Schmitt WH, Gross WL. Incidence and specificity of p-ANCA in rheumatic diseases. Adv Exp Med Biol 1993;336:371-3. [PUBMED] |
| 12. | Peter HH, Metzger D, Rump A, Rother E. ANCA in diseases other than systemic vasculitis. Clin Exp Immunol 1993;93 Suppl 1:12-4. |
| 13. | Hagen EC, Daha MR, Hermans J, 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 1998;53(3):743-53. |
| 14. | Jayne DR, Marshall PD, Jones SJ, Lockwood CM. Autoantibodies to GBM and neutrophil cytoplasm in rapidly progressive glomerulonephritis. Kidney Int 1990;37(3):965-70. |
| 15. | Lim LC, Taylor JG 3rd, Schmitz JL, et al. Diagnostic usefulness of antineutrophil cytoplasmic autoantibody serology. Comparative evaluation of commercial indirect fluorescent antibody kits and enzyme immunoassay kits. Am J Clin Pathol 1999; 111(3):363-9. |
| 16. | Ronda N, Esnault VL, Layward L, et al. Antineutrophil cytoplasm antibodies (ANCA) of IgA isotype in adult HenochSchonlein purpura. Clin Exp Immunol 1994;95(1):49-55. |
| 17. | Robson WL, Leung AK, Woodman RC. The absence of anti-neutrophil cytoplasmic antibodies in patients with Henoch-Schonlein purpura. Pediatr Nephrol 1994;8(3):295-8. |
| 18. | Falk RJ, Jennette JC. ANCA small-vessel vasculitis. J Am Soc Nephrol 1997;8(2): 314-22. |
| 19. | Merkel PA, Polisson RP, Chang Y, Skates SJ, Niles JL. Prevalence of antineutrophil cytoplasmic antibodies in a large inception cohort of patients with connective tissue disease. Ann Intern Med 1997;126(11): 866-73. |
| 20. | Savige J, Gillis D, Benson E, et al. International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies (ANCA). Am J Clin Pathol 1999;111(4):507-13. |
| 21. | Byrd VM, Fogo A. The double-edged sword of ANCA: a useful but limited test for screening of Pauci-immune vasculitides. Am J Kidney Dis 1998;32(2):344-9. |
| 22. | Franssen CF, Huitema MG, Muller Kobold AC, et al. In vitro neutrophil activation by antibodies to proteinase 3 and myeloperoxidase from patients with crescentic glomerulonephritis. J Am Soc Nephrol 1999;10(7):1506-15. |
| 23. | Kallenberg CG, Brouwer E, Weening JJ, Tervaert JW. Anti-neutrophil cytoplasmic antibodies: current diagnostic and pathophysiological potential. Kidney Int 1994; 46(1):1-15. |
| 24. | Bajema IM, Hagen EC, Hermans J, et al. Kidney biopsy as a predictor for renal outcome in ANCA-associated necrotizing glomerulonephritis. Kidney Int. 1999; 56(5):1751-8. |
| 25. | Morcos M, Zimmermann F, Radsak M, et al. Autoantibodies to polymorphonuclear neutrophil elastase do not inhibit but enhance elastase activity. Am J Kidney Dis 1998;31(6):978-85. |
| 26. | Egner W, Chapel HM. Titration of antibodies against neutrophil cytoplasmic antigens is useful in monitoring disease activity in systemic vasculitides. Clin Exp Immunol 1990;82(2):244-9. |
| 27. | Cohen Tervaert JW, Huitema MG, Hene RJ, et al. Prevention of relapses in Wegener's granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre. Lancet 1990;336(8717):709-11. |
| 28. | Stegeman CA, Tervaert JW, Sluiter WJ, Manson WL, de Jong PE, Kallenberg CG. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med 1994;120(1):12-7. |
| 29. | Geffriaud-Ricouard C, Noel LH, Chauveau D, Houhou S, Grunfeld JP, Lesavre P. Clinical spectrum associated with ANCA of defined antigen specificities in 98 selected patients. Clin Nephrol 1993;39(3):125-36. |
| 30. | Kerr GS, Fleisher TA, Hallahan CW, Leavitt RY, Fauci AS, Hoffman GS. Limited prognostic value of changes in antineutrophil cytoplasmic antibody titer in patients with Wegener's granulomatosis. Arthritis Rheum 1993;36(3):365-71. |
| 31. | Jayne DR, Jones SJ, Severn A, Shaunak S, Murphy J, Lockwood CM. Severe pulmonary hemorrhage and systemic vasculitis in association with circulating anti-neutrophil cytoplasm antibodies of IgM class only. Clin Nephrol 1989; 32(3):101-6. |
| 32. | Esnault VL, Soleimani B, Keogan MT, Brownlee AA, Jayne DR, Lockwood CM. Association of IgM with IgG ANCA in patients presenting with pulmonary hemorrhage. Kidney Int 1992;41(5):1304-10. |
| 33. | Brouwer E, Cohen Tervaert JW, Horst G, et al. Predominance of IgG1 and IgG4 subclasses of anti-neutrophil cytoplasmic autoantibodies (ANCA) in patients with Wegener's granulomatosis and clinically related disorders. Clin Exp Immunol 1991;83(3):379-86. |
| 34. | Segelmark M, Wieslander J. IgG subclasses of antineutrophil cytoplasm autoantibodies (ANCA). Nephrol Dial Transplant 1993; 8(8):696-702. |
| 35. | Kokolina E, Noel LH, Nusbaum P, et al. Isotype and affinity of anti-myeloperoxidase autoantibodies in systemic vasculitis. Kidney Int. 1994;46(1):177-84. |
| 36. | Westman KW, Selga D, Bygren P, et al. Clinical evaluation of a capture ELISA for detection of proteinase-3 antineutrophil cytoplasmic antibody. Kidney Int 1998; 53(5):1230-6. |
| 37. | Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci USA 1990;87(11):4115-9. |
| 38. | Savage CO, Pottinger BE, Gaskin G, Pusey CD, Pearson JD. Autoantibodies developing to myeloperoxidase and proteinase 3 in systemic vasculitis stimulate neutrophil cytotoxicity toward cultured endothelial cells. Am J Pathol 1992;141(2):335-42. |
| 39. | Ewert BH, Jennette JC, Falk RJ. Antimyeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells. Kidney Int 1992;41(2):375-83. |
| 40. | Mayet WJ, Csernok E, Szymkowiak C, Gross WL, Meyer zum Buschenfelde KH. Human endothelial cells express proteinase 3, the target antigen of anticytoplasmic antibodies in Wegener's granulomatosis. Blood 1993;82(4):1221-9. |
| 41. | King WJ, Adu D, Daha MR, et al. Endothelial cells and renal epithelial cells do not express the Wegener's autoantigen, proteinase 3. Clin Exp Immunol 1995; 102(1):98-105. |
| 42. | Varagunam M, Adu D, Taylor CM, et al. Endothelium, myeloperoxidase, antimyeloperoxidase interaction in vasculitis. Adv Exp Med Biol. 1993;336:129-32. |
| 43. | Mayet WJ, Meyer zum Buschenfelde KH: Antibodies to proteinase 3 increase adhesion of neutrophils to human endothelial cells. Clin Exp Immunol 1993;94(3):440-6. |
| 44. | Mathieson PW, Thiru S, Oliveira DB. Mercuric chloride-treated brown Norway rats develop widespread tissue injury including necrotizing vasculitis. Lab Invest 1992;67(1):121-9. |
| 45. | Esnault VL, Mathieson PW, Thiru S, Oliveira DB, Martin-Lockwood C. Autoantibodies to myeloperoxidase in brown Norway rats treated with mercuric chloride. Lab Invest 1992;67(1):114-20. |
| 46. | Mathieson PW, Qasim FJ, Esnault VL, Oliveira DB. Animal models of systemic vasculitis. J Autoimmun 1993;6(2):251-64. |
| 47. | Kobayashi K, Shibata T, Sugisaki T. Aggravation of rat nephrotoxic serum nephritis by anti-myeloperoxidase anti bodies. Kidney Int 1995;47(2):454-63. |
| 48. | Brouwer E, Huitema MG, Klok PA, et al. Antimyeloperoxidase-associated proliferative glomerulonephritis: an animal model. J Exp Med 1993;177(4):905-14. |
| 49. | Oda T, Hotta O, Taguma Y, et al. Involvement of neutrophil elastase in crescentic glomerulonephritis. Hum Pathol 1997; 28(6):720-8. |
| 50. | Hotta O, Oda T, Taguma Y, et al. Role of neutrophil elastase in the development of renal necrotizing vasculitis. Clin Nephrol 1996;45(4):211-6. |
| 51. | Brouwer E, Huitema MG, Mulder AH, et al. Neutrophil activation in vitro and in vivo in Wegener's granulomatosis. Kidney Int 1994; 45(4):1120-31. |
| 52. | Suzuki S, Gejyo F, Kuroda T, et al. Effects of a novel elastase inhibitor, ONO-5046, on nephrotoxic serum nephritis in rats. Kidney Int 1998;53(5):1201-8. |
| 53. | Lewis M, Kallenbach J, Zaltzman M, et al. Severe deficiency of alpha 1-antitrypsin associated with cutaneous vasculitis, rapidly progressive glomerulonephritis, and colitis. Am J Med 1985;79(4):489-94. |
| 54. | Miller F, Kuschner M. Alpha1-antitrypsin deficiency, emphysema, necrotizing angiitis and glomerulonephritis. Am J Med 1969;46(4): 615-23. |
| 55. | Segelmark M, Elzouki AN, Wieslander J, Eriksson S. The PiZ gene of a1-antitrypsin as a determinant of outcome in PR3-ANCA-positive vasculitis. Kidney Int 1995;48(3):844-50. |
| 56. | van de Wiel BA, Dolman KM, van der MeerGerritsen CH, Hack CE, von dem Borne AE, Goldschmeding R. Interference of Wegener's granulomatosis autoantibodies with neutrophil Proteinase 3 activity. Clin Exp Immunol 1992;90(3):409-14. |
| 57. | Oda T, Takeuchi A, Suzuki Y, et al. Expression of ELAM-1 in the renal vascular endothelium of polyarteritis nodosa. (Abstract). J Am Soc Nephrol 1993;4:686. |
Correspondence Address:
Takashi Oda
Department of Medicine, Japan Self Defense Forces, Kumamoto Hospital, 15-1 Higashihonmachi, Kumamoto-shi, Kumamoto 862-0902
Japan
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PMID: 18209328 
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