RENAL PATHOLOGY LEARNING

ANCA-associated vasculitis (Part I)

by

Franco Ferrario and Maria Pia Rastaldi

Dr Franco Ferrario
Renal Immunopathology Center
San Carlo Borromeo Hospital
Milan, Italy

 

"ANCA-associated vasculitis" are Wegener's Granulomatosis, Micropolyarteritis and its renal-limited variant (previously called idiopathic necrotizing glomerulonephritis).

According to the "Chapel Hill Consensus Conference" classification, ANCA-associated vasculitis is characterized by prevalent involvement of small-size vessels, whereas medium and large-size artery  involvement is the marker of Polyarteritis Nodosa. 

However,  the vessel size-based classification is not always powerful enough, because also in ANCA-associated vasculitis the involvement of medium and large-size arteries is possible. Therefore, the presence of necrotizing extracapillary glomerulonephritis that is always absent in Polyarteritis Nodosa has become the distinctive marker of ANCA-associated renal vasculitis.

Small vessel vasculitis is morphologically defined by massive necrosis of the vascular wall with endo- and peri-vascular inflammatory infiltrates. This lesion should be the diagnostic hallmark of the disease, but is histologically detected in only 20-30% of cases, confirming the diagnostic importance of necrotizing extracapillary nephritis. Furthermore, a similar arteritis can be found in other diseases, such as anti-GBM antibody disease, HS nephritis, cryoglobulinemic nephritis and lupus nephritis.

anca1

Focal or diffuse necrotizing extracapillary glomerulonephritis is the histological hallmark of ANCA-associated Vasculitis. It is noteworthy that Wegener’s Granulomatosis, Micropolyarteritis and its renal-limited variant share similar morphological lesions and are therefore considered as one pathological entity with different systemic involvement.

anca2

 

Tuft necrosis and extracapillary proliferation are very variable in intensity and diffusion, even among glomeruli of the same biopsy. Some cases show isolated segmental necrosis of the glomerular tuft without extracapillary reaction.

 

anca3

A segmental extracapillary reaction in close proximity of the necrotizing lesion is more frequently present. The remaining part of the tuft, not affected by the lesion, appears completely normal.

 

anca4

 

Although segmental, the necrotizing extracapillary lesion can be larger and involve a higher percentage of glomeruli.

 

anca5

 

Massive necrosis is usually associated to diffuse circumferential extracapillary proliferation. From a clinical point of view, the patient is affected by rapidly progressive renal failure.

 

anca6

 

Periglomerular leukocyte infiltration is another distinctive feature of ANCA-associated renal vasculitis. The entity of leukocyte infiltration is variable, but leukocytes always localize in close proximity of the necrotizing extracapillary lesion. A rupture of the Bowman’s capsule can be commonly observed.

 

anca7

 

Extensive ruptures of the Bowman's capsule make it difficult to discriminate between extracapillary proliferation and periglomerular infiltration. 

anca8

 

The massive circumferential leukocyte infiltration gives a picture of "glomerular granuloma-like lesion." This feature is not exclusively found in Wegener's granulomatosis, but can be observed in cases of Micropolyarteritis and even in its renal-limited variant. A similar lesion can be found in anti-GBM antibody disease.

 

anca9

 

It is noteworthy that these granulomatous reactions in ANCA-associated vasculitis are mainly glomerular, as witnessed by the presence of "glomerular remnants" in the middle of the lesion.

 

anca10

 

The simultaneous presence in the same biopsy of active and sclerotic lesions is the expression of repeated ‘poussées’ of necrotizing extracapillary damage.

 

anca11

 

Besides the typical periglomerular localization, a diffuse interstitial leukocyte infiltration is very common in ANCA-associated vasculitis. 

 

anca12

 

When interstitial leukocyte infiltration is massive, "tubulitis" is frequently observed, with tubular basement membrane rupture and both endo- and peri-tubular infiltration. 

 

anca13

 

ANCA-associated renal vasculitis are by definition "pauci-immune" glomerulonephritis. Immunofluorescence can be either negative or characterized by scattered C3 granular deposition. 

 

anca14

 

Instead, in 20% of cases, a more consistent mesangial and parietal deposition of IgG and C3 can be observed. It is still controversial whether cell-mediated immune mechanisms or immune-complex deposition are at the basis of ANCA-associated vasculitis.  

 

anca15

 

In active lesions, fibrin deposition is invariably present and its entity and distribution are related to the entity of glomerular damage. Focal and segmental forms show fibrin deposition in segmental well delineated areas of the tuft. This aspect is shared by other segmental necrotizing diseases, such as anti-GBM antibody disease, lupus nephritis, HS nephritis, and necrotizing IgA GN. 

 

anca16

 

Bowman's capsule ruptures are accompanied by fibrin deposition not only in the glomerulus but also in periglomerular areas.

 

anca17

 

QUESTIONS

 

REFERENCES
1.
    de Lind van Wijnguarden RA, Hauer HA, Wolterbeek R, Jayne DR, Gaskin G, Rasmussen N, Noel LH, Ferrario F, Waldherr R, Hagen EC, Bruijn JA, Bajema JM. Clinical and Histologic determinants of renal outcome in ANCA-associated vasculitis: A prospective analysis of 100 patients with severe renal involvement. J Am Soc Neprol. 2006 Aug; 17(8): 2264-74.
2.
    Ferrario F, Rastaldi MP. Histopathological atlas of renal diseases: ANCA-associated vasculitis (first part). J Nephrol. 2005 Mar-Apr; 18(2): 113-6.
3.
    Hauer HA, Bajema JM, Van Houwelingen HC, Ferrario F, Noel JH, Waldherr R, Jayne DR, Rasmussen N, Bruijn JA, Hagen EC; European Vasculitis Study Group (EUVAS). Determinants of outcome in ANCA-associated glomerulonephritis: a prospective clinico-histopathological analysis of 96 patients. Kidney Int 2002 Nov; 62(5): 1732-42.
4.
    Hauer HA, Bajema JM, Hagen EC, Noel LH, Ferrario F, Waldherr R, van Houwelingen HC, Lesavre P, Sinico RA, van der Woude F, Gaskin G, Verburgh CA, de Heer E, Bruijn JA. Long-term renal injury in ANCA-associated vasculitis: an analysis of patients with follow-up biopsies. Nephrol Dial Transplant. 2002 Apr; 17(4): 587-96.
5.
    Hauer HA, Bajema IM, van Houwelingen HC, Ferrario F, Noel LH, Waldherr R, Jayne DR, Rasmussen N, Bruijn JA, Hagen EC; European Vasculitis Study Group (EUVAS). Renal histology in ANCA-associated vasculitis: differences between diagnostic and serologic subgroups. Kidney Int. 2002 Jan; 61(1): 80-9.
6.
    Rastaldi MP, Ferrario F, Crippa A, Dell’Antonio G, Casartelli D, Grillo C, D’Amico G. Glomerular monocyte-macrophage features in ANCA-positive renal vasculitis and cryoglobulinemic nephritis. J Am Soc Nephrol 2000 Nov; 11(11): 2036-43.
7.
    Ferrario F, Rastaldi MP. Necrotizing-crescentic glomerulonephritis in ANCA-associated vasculitis role of monocytes. Nephrol Dial Transplant, 1999 Jul; 14(7); 1627-31.