ANCA-associated vasculitis (Part II)


Franco Ferrario and Maria Pia Rastaldi

Dr Franco Ferrario
Renal Immunopathology Center
San Carlo Borromeo Hospital
and “Nuova Nefrologia” Research Association
Milan, Italy


As shown in the previous chapter ANCA-associated renal vasculitis is characterized by pauci-immune necrotizing crescentic glomerulonephritis

Crescent’s pathogenesis and morphogenesis remain not completely understood, in particular which cells are mainly involved in crescent formation.

Several studies have clearly demonstrated that monocyte-macrophages  are  deeply  involved in  extracapillary  glomerulonephritis,  both  at  glomerular  and  interstitial  level. Especially   at   glomerular   level   their participation  to  crescent  formation,  firstly demonstrated  in  1976  by  Atkins  in  human RPGN, has been confirmed by many Authors both  in  human  and  experimental  models.



By immunohistochemical methods, we have recently confirmed the presence of monocyte-macrophages (CD68 positive cells) in necrotizing-extracapillary lesions. When the lesion is segmental, also macrophage infiltration is limited to segmental areas of the tuft.




A massive intraglomerular macrophage infiltration can be detected in cases with diffuse lesions and circumferential extracapillary proliferation.




Monocyte-macrophages also participate in the periglomerular inflammatory lesion. 




They are present in the highest amounts when glomerular granuloma-like lesions are evident.



Through antibodies against cytokeratins it is possible to confirm that in ANCA-associated renal vasculitis the crescents are mainly composed by monocyte-macrophages and there are very few epithelial cells. These features are completely different from intra-extracapillary glomerulonephritis (such as idiopathic MPGN) and suggest a different morphogenetic and pathogenetic mechanism of  crescent formation.




Monocyte-macrophages contribute to the inflammatory infiltration that characterizes the arteritis, and are especially numerous when granulomatous lesions are present.



Similar aspects can also be detected  in few cases of large-size vessel involvement.



Glomerular leukocyte infiltration is mediated by the endothelial expression of the "Ig-like" adhesion molecules ICAM-1 and VCAM-1, that allow a firm leukocyte adhesion to the endothelium.


ICAM-1, constitutively expressed by the normal glomerular endothelium, is markedly upregulated in glomeruli of ANCA-associated vasculitis.



In our experience, VCAM-1 has shown a more specific correlation to the entity and diffusion of glomerular lesions in ANCA-associated vasculitis. VCAM-1 expression in glomeruli affected by necrotizing extracapillary lesions follows exactly the entity and the distribution of the glomerular damage. Cases with segmental necrotizing lesions show a localized expression of VCAM-1.



Whereas a diffuse and intense VCAM-1 expression is  typical of cases with diffuse necrotizing lesions and circumferential extracapillary proliferation. 



In situ hybridization confirms that VCAM-1 positivity in these areas is caused by a "de novo" synthesis of the molecule.



HLA class II expression suggests that glomerular and interstitial monocyte-macrophages are acutely activated cells



The 27E10 antigen, a more specific marker of acutely activated monocyte-macrophages and endothelial cells, shows a strong expression in areas of necrotizing extracapillary lesions



Acutely activated monocyte-macrophages actively produce proinflammatory cytokines. We have demonstrated both by immunohistochemistry and in situ hybridization that TNF-alpha production is present in glomeruli affected by necrotizing extracapillary lesions.



Proliferation markers, such as PCNA (proliferating cell nuclear antigen), stain several glomerular cells in the areas of necrotizing extracapillary lesion and in the granuloma-like reactions.



Reparative sclerotic lesions are the consequence of inflammatory processes. In focal and segmental forms, sclerosing lesions have the characteristic feature of well delineated rounded areas of glomerular sclerosis, with Bowman's capsule adhesion. This typical sclerotic lesion is present also in reparative phases of other necrotizing-extracapillary nephritis, such as anti-GBM antibody disease, HS nephritis, IgA GN. The accurate diagnosis of these sclerotic areas is very important from both a prognostic and therapeutic point of view, given that frequent acute poussées characterize the natural history of these diseases.



Repeat biopsies confirm the transformation from active necrotizing to sclerotic lesions.


First renal biopsy


Second renal biopsy


As already stated, the same biopsy can show both active and reparative lesions






M. Isome, H. Fujinaka, L.P. Adhikary, P. Kovalenko, A.G.A. El-Shemi, Y. Yoshida, E. Yaoita, T. Takeishi, M. Takeya, M. Naito, H. Suzuki, T. Yamamoto. Important role for macrophages in induction of crescentic anti-GBM glomerulonephritis in WKY rats. Nephrology Dialysis Transplantation 2004, 19(12): 2997-3004.
H. Xiao, P. Heeringa, Z. Liu, D. Huugen, P. Hu, N. Maeda, R.J. Falk, C. Jennette. The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies. American Journal of Pathology 2005, 167(1): 39-45.
J.S. Duffield, P.G. Tipping, T. Kipari, J.F. Cailhier, S. Clay, R. Lang, J.V. Bonventre, J. Hughes. Conditional ablation of macrophages halts progression of crescentic glomerulonephritis. American Journal of Pathology 2005, 167(5): 1207-19.
G.E. Garcia, Y. Xia, J. Harrison, C.B. Wilson, R.J. Johnson, K.B. Bacon, L. Feng. Mononuclear cell-infiltrate inhibition by blocking macrophage-derived chemokine results in attenuation of developing crescentic glomerulonephritis. American Journal of Pathology 2003, 162: 1061-73.
M.P. Rastaldi, F. Ferrario, S. Tunesi, L. Yang, G. D’Amico. Intraglomerular and interstitial leukocyte infiltration, adhesion molecules, and interleukin-1 alpha expression in 15 cases of antineutrophil cytoplasmic autoantibody-associated renal vasculitis. American Journal of Kidney Diseases 1996, 27(1): 48-57.
F. Ferrario, M.P. Rastaldi. Necrotizing-crescentic glomerulonephritis in ANCA-associated vasculitis: the role of monocytes. Nephrology Dialysis and Transplantation 1999, 14(7): 1627-31.
F.J. Van der Woude, F. Ferrario. Renal involvement in ANCA-associated systemic vasculitis. Journal of Nephrology 1999, 12(2): 105-28.
J. Bariety, G.S. Hill, C. Mandet, T. Irinopoulou, C. Jacquot, A. Meyrier, P. Bruneval. Glomerular epithelial-mesenchymal transdifferentiation in pauci-immune crescentic glomerulonephritis. Nephrology Dialysis and Transplantation 2003, 18(9): 1777-84.