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DISEASEOF THE MONTH

ANCA Small-Vessel Vasculitis

RONALD J. FALK* and J. CHARLES JENNETTEt

*Department of Medicine and Department of Pathology and Laboratory Medicine, University of North

Carolina at Chapel Hill, Chapel Hi!!, North Carolina.

Small-vessel vasculitis (SVV) that is injurious to the kidney

includes immune complex-mediated vasculitis, such as He-

noch-Sch#{246}nlein purpura and cryogbobulinemic vasculitis, and

necrotizing vasculitis associated with anti-neutrophil cytoplas-

mic autoantibodies (ANCA), such as microscopic polyangiitis

and Wegeners granubomatosis. The most frequent renal lesion

caused by SVV is glomerubonephritis, whereas barge-vessel

vasculitis (LVV) and medium-sized-vessel vasculitis (MVV)

do not cause glomerubonephritis but may cause renal dysfunc-

tion secondary to ischemia.

In 1993, the Chapel Hill Consensus Conference for the

Nomenclature of Systemic Vasculitis ( 1 ) agreed on the namesand definitions of many vasculitides that affect the kidneys

(Table 1 ). These names and definitions are used in this review.

LVV, such as giant-cell arteritis and Takayasu arteritis, rarely

cause clinically significant renal disease (2). When a LVV does

cause renal dysfunction, it is usually in the form of the reno-

vascular hypertension secondary to disease in the main renal

arteries or in the aorta at the ostia of the renal arteries. MVV,

including pobyarteritis nodosa and Kawasaki disease, results in

necrotizing inflammation of arteries without inflammation in

vessels other than arteries, including no glomerulonephritis (2).

MVV may cause aneurysmal dilation, thrombosis, and rupture

of renal arteries, resulting in infarction and hemorrhage (1,2).

Patients with pauci-immune SVV, such as microscopic poly-

angiitis, Wegeners granubomatosis, and Churg-Strauss syn-

drome, have a high frequency of ANCA (1,2). ANCA react

with cytoplasmic constituents of neutrophils and monocytes

(3,4). Approximately 90% of cytoplasmic-staining ANCA

(C-ANCA) react with a serine proteinase called proteinase 3

(PR3-ANCA). In patients with SVV, approximately 90% of

perinuclear-staining ANCA (P-ANCA) react with myeboper-

oxidase (MPO-ANCA). In ANCA-positive patients who do not

have SVV or gbomerubonephritis, such as patients with ulcer-

ative colitis, primary sclerosing choleangiitis, or Feltys syn-

drome, many P-ANCA have specificity for antigens other than

MPO, such as lactoferrin and elastase.

PR3-ANCA are most common in patients with Wegeners

granubomatosis, but are not specific for this disease. Our own

data, as well as that of a recent European vascubitis study group

(E. Christiaan Hagen, personal communication), indicate that

Correspondence to Dr. Ronald J. Falk. UNC School of Medicine, Division of

Nephrology and Hypertension, 349 MacNider Bldg./CB 7155, Chapel Hill, NC27599-7155.

1046-6673/0802-03 14$03.00/0

Journal of the American Society of NephrologyCopyright U 1997 by the American Society of Nephrology

approximately 65% of patients with Wegeners granubomatosis

have PR3-ANCA and approximately 20% have MPO-ANCA

(Table 2). PR3-ANCA are also found in patients with micro-

scopic polyangiitis and necrotizing gbomerulonephritis without

evidence for systemic SVV, although MPO-ANCA are more

common in these diseases. MPO-ANCA and PR3-ANCA oc-

cur in patients with Churg-Strauss syndrome, but relative fre-

quencies are poorly defined because of the small numbers of

patients who have been studied. Thus, although there are

different frequencies of PR3-ANCA and MPO-ANCA among

different types of SVV, neither ANCA subtype provides a

diagnostic test that allows for the diagnostic differentiation

among different phenotypes of ANCA-SVV. However, in a

patient with signs and symptoms of SVV, ANCA positivity

does confirm the presence of some form of ANCA-associated

SVV, which is often useful for directing management even if

the specific type of ANCA-SVV has not yet been determined.

Pathologic FeaturesThe characteristic acute vascular lesion of ANCA-SVV is

focal fibrinoid necrosis of vessels with associated leukocyte

infiltration, frequently with leukocytoclasia. In a given patient,

this lesion may affect any or all of the following vessels:

arteries, arterioles, venules, and capillaries, especially gbomer-

ular capillaries and pulmonary alveolar capillaries (2,5). The

major clinicopathologic categories of systemic ANCA-vascu-

bitis are microscopic polyangiitis, Wegeners granubomatosis,

and Churg-Strauss syndrome. Crescentic gbomerubonephritis is

a frequent component of systemic ANCA-vasculitis, and also

occurs as a renal-limited form of ANCA-vasculitis (ANCA-

ON). Microscopic polyangiitis, Wegener s granulomatosis,

and Churg-Strauss syndrome all share pathologically identical

necrotizing inflammation in small vessels. Wegeners granu-

bomatosis is distinguished by the presence of necrotizing gran-

ubomatous inflammation, Churg-Strauss syndrome by the pres-

ence of asthma and eosinophilia, and microscopic pobyangiitis

by the absence of granulomatous inflammation and asthma

(Table 1). Severe necrotizing gbomerulonephritis is a frequent

component of the vascular inflammation in Wegeners granu-

lomatosis and microscopic polyangiitis, but necrotizing gb-

merulonephritis is less frequent and usually less severe in

Churg-Strauss syndrome.

In the kidneys of patients with any type of ANCA-SVV,

gbomerular capillaries are affected most often, resulting in

necrotizing glomerubonephritis, usually with crescent forma-

tion (Figure 1 , A and B). Arterioles, arteries, and interstitial

capillaries/venubes (especially medullary vasa recta) may also

be involved (Figure 1 , C and D). Interlobular and arcuate

Large-vessel vasculitis

giant-cell (temporal) arteritis

Takayasu arteritis

Medium-sized vessel vasculitis

polyarteritis nodosa

Kawasaki disease

Small-vessel vasculitis

Wegener 5 granulomatosis

Churg-Strauss syndrome

microscopic polyangiitis

Henoch-Sch#{246}nbein purpura

essential cryoglobubinemic vasculitis

cutaneous leukocytoclastic angiitis

ANCA Small-Vessel Vasculitis 315

ANCA-SVV typically has an absence or paucity of immu-

Table 1. Names and definitions of vasculitis adopted by the Chapel Hill Consensus Conference on the Nomenclature of

Systemic Vasculitisa

Granubomatous arteritis of the aorta and its major branches, with a

predilection for the extracranial branches of the carotid artery. Often

involves the temporal artery. Usually occurs in patients older than 50

and is often associated with polymyalgia rheumatica.

Granulomatous inflammation of the aorta and its major branches. Usually

occurs in patients younger than 50.

Necrotizing inflammation of medium-sized or small arteries without

gbomerulonephritis or vasculitis in arterioles, capillaries, or venules.

Arteritis involving large, medium-sized, and small arteries, and associated

with mucocutaneous lymph node syndrome. Coronary arteries are often

involved. Aorta and veins may be involved. Usually occurs in children.

Granulomatous inflammation involving the respiratory tract, and necrotizing

vasculitis affecting small- to medium-sized vessels, e.g., capillaries,

venules, arterioles, and arteries. Necrotizing glomerulonephritis is

common.

Eosinophib-rich and granubomatous inflammation involving the respiratory

tract and necrotizing vasculitis affecting small- to medium-sized vessels,

and associated with asthma and blood eosinophibia.

Necrotizing vascubitis with few or no immune deposits, affecting small

vessels, i.e., capillaries, venubes, or arterioles. Necrotizing arteritis

involving small- and medium-sized arteries may be present. Necrotizing

glomerulonephritis is very common. Pulmonary capi!laritis often occurs.

Vascubitis with immunogbobubin A-dominant immune deposits, affecting

small vessels, i.e. , capillaries, venules, or arterioles. Typically involves

skin, gut, and glomeruli, and is associated with arthralgias or arthritis.

Vasculitis with cryogbobubin immune deposits, affecting small vessels, i.e.,

capillaries, venules, or arterioles, and associated with cryogbobulins in

serum. Skin and glomeruli are often involved.

Isolated cutaneous beukocytoclastic angiitis without systemic vasculitis or

glomerulonephntis.

a The ANCA-associated vasculitides are Wegeners granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. (Modified

from Jennette et al. [I] with permission.).

Table 2. Approximate frequencies of PR3-ANCA (C-ANCA) and MPO-ANCA (P-ANCA) in patients with

glomerulonephritis caused by Wegeners granubomatosis (WG), microscopic polyangiitis (MPA), and

pauci-immune necrotizing and crescentic gbomerubonephritis without systemic vascubitis (NCON)

ANCA Result WG MPA NCGN

Positive PR3-ANCAIC-ANCA 65 to 75% 35 to 45% 30 to 40%

Positive

Negative

MPO-ANCA/P-ANCA

ANCA

15

10

to 25%

to 20%

45

10

to 55%

to 20%

60 to 70%

10 to 20%

arteries are affected more often than larger arteries, but a few SVV. Necrotizing leukocytoclastic angiitis in medullary vasa

patients with ANCA-SVV will have involvement