Abstract
Systemic vasculitides encompass a group of diseases that can affect different caliber vessels. Large-vessel vasculitides (giant cell arteritis and Takayasu arteritis) affect the kidney by predominantly affecting blood flow leading to renal ischemia and renovascular hypertension. Medium-vessel vasculitides (polyarteritis nodosa and Kawasaki disease) can reduce flow through the renal artery and may affect intrarenal arteries, resulting in infarction and hemorrhage. Small-vessel vasculitides (antineutrophil cytoplasmic antibody [ANCA] vasculitis, antiglomerular basement membrane [GBM] disease, immunoglobulin A [IgA] vasculitis, and cryoglobulinemic vasculitis) affect the glomerular capillaries resulting in glomerulonephritis. This chapter reviews the pathology, pathogenesis, clinical features, and management of each class of vasculitis with a primary focus on kidney involvement.
Keywords
systemic vasculitis, large-vessel vasculitis, medium-vessel vasculitis, small-vessel vasculitis, ANCA vasculitis, anti-GBM disease, microscopic polyangiitis, granulomatosis with polyangiitis, IgA vasculitis, giant cell arteritis, Takayasu arteritis, polyarteritis nodosa, Kawasaki disease, immune complex vasculitis, pauci-immune vasculitis
The kidneys are affected by many forms of system vasculitis ( Fig. 24.1 ), which cause a wide variety of sometimes confusing clinical manifestations. Large-vessel vasculitides, such as giant cell arteritis (GCA) and Takayasu arteritis (TA), can narrow the abdominal aorta or renal arteries, resulting in renal ischemia and renovascular hypertension. Vasculitides of the medium-sized vessels, such as polyarteritis nodosa and Kawasaki disease, also can reduce flow through the renal artery and may affect intrarenal arteries, resulting in infarction and hemorrhage. Small-vessel vasculitides, such as microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, previously called Wegener granulomatosis), antiglomerular basement membrane (anti-GBM) disease, (also known as Goodpasture disease), immunoglobulin A (IgA) vasculitis (Henoch-Schönlein purpura), and cryoglobulinemic vasculitis, frequently involve the kidneys and especially the glomerular capillaries, resulting in glomerulonephritis. IgA vasculitis (IgAV) is discussed in Chapter 20 .
Pathology
Different types of systemic vasculitis affect vessels of different caliber and type, as summarized in Fig. 24.1 and Table 24.1 . Each type of vasculitis has different histologic and immunohistologic features.
| Name a | Definition |
|---|---|
| Large-Vessel Vasculitides | |
| GCA | Arteritis, often granulomatous, usually affecting the aorta and/or its major branches, with a predilection for the branches of the carotid and vertebral arteries. Often involves the temporal artery. Onset usually in patients older than 50 years and often associated with polymyalgia rheumatica |
| TA | Arteritis, often granulomatous, predominantly affecting the aorta and/or its major branches. Onset usually in patients younger than 50 years |
| Medium-Vessel Vasculitides | |
| Polyarteritis nodosa | Necrotizing arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules and not associated with ANCA |
| Kawasaki disease | Arteritis associated with the mucocutaneous lymph node syndrome and predominantly affecting medium and small arteries. Coronary arteries are often involved. Aorta and large arteries may be involved. Usually occurs in infants and young children |
| Small-Vessel Vasculitides | |
| MPA b,c | Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e., capillaries, venules, or arterioles). Necrotizing arteritis involving small and medium arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. Granulomatous inflammation is absent. |
| GPA, formerly Wegener granulomatosis b,c | Necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract and necrotizing vasculitis affecting predominantly small to medium vessels (e.g., capillaries, venules, arterioles, arteries, and veins). Necrotizing glomerulonephritis is common. |
| EGPA, formerly Churg-Strauss syndrome b,c | Eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract and necrotizing vasculitis predominantly affecting small to medium vessels and associated with asthma and eosinophilia. ANCA is more frequent when glomerulonephritis is present. |
| IgAV, formerly Henoch-Schönlein purpura c | Vasculitis, with IgA1-dominant immune deposits, affecting small vessels (predominantly capillaries, venules, or arterioles). Often involves skin and gastrointestinal tract and frequently causes arthritis. Glomerulonephritis indistinguishable from IgA nephropathy may occur. |
| Cryoglobulinemic vasculitis c | Vasculitis with cryoglobulin immune deposits affecting small vessels (predominantly capillaries, venules, or arterioles) and associated with cryoglobulins in serum. Skin, glomeruli, and peripheral nerves are often involved. |
| Hypocomplementemic urticarial vasculitis (Anti-C1q vasculitis) | Vasculitis accompanied by urticaria and hypocomplementemia affecting small vessels (i.e., capillaries, venules, or arterioles) and associated with anti-C1q antibodies. Glomerulonephritis, arthritis, obstructive pulmonary disease, and ocular inflammation are common. |
| Anti-GBM disease c | Vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with basement membrane deposition of antibasement membrane autoantibodies. Lung involvement causes pulmonary hemorrhage, and renal involvement causes glomerulonephritis with necrosis and crescents. |
a The term large vessels refers to the aorta and the largest branches directed toward major body regions (e.g., extremities, head, and neck); medium vessels refers to the main visceral arteries (e.g., renal, hepatic, coronary, mesenteric); and small vessels refers to the distal arterial branches that connect with arterioles (e.g., renal arcuate and interlobular arteries), as well as arterioles, capillaries, and venules. Note that some small- and large-vessel vasculitides may involve medium-sized arteries, but large- and medium-vessel vasculitides do not involve vessels other than arteries.
b Strongly associated with antineutrophil cytoplasmic antibodies.
c May be accompanied by glomerulonephritis and can manifest as nephritis or pulmonary-renal vasculitic syndrome.
Large-Vessel Vasculitis
The large-vessel vasculitides, GCA and TA, predominantly affect the aorta and its major branches. TA preferentially involves the aorta and its primary branches and is an important cause of renovascular hypertension, especially in young patients. GCA is generally localized in more peripheral arteries and only rarely causes clinically significant kidney disease, although asymptomatic pathologic involvement is common. GCA often involves the extracranial branches of the carotid arteries, including the temporal artery. However, some patients do not have temporal artery involvement, and patients with other types of vasculitis (e.g., MPA, GPA) may have temporal artery involvement. Therefore temporal artery disease is neither a required nor a sufficient pathologic feature of GCA.
Histologically, both GCA and TA are characterized by focal chronic inflammation within the vessel wall (without perivascular lesions) that frequently has a granulomatous appearance with or without multinucleated giant cells. Aortic involvement is more likely to lead to a destructive rather than a stenotic process, leading to aneurysm formation with rupture or dissection. With chronicity, the inflammatory injury evolves into fibrosis and frequently results in vascular narrowing of the branches of the aorta, which is the basis for renovascular hypertension when a renal artery is involved.
Medium-Vessel Vasculitis
Polyarteritis nodosa and Kawasaki disease affect medium-sized arteries (i.e., main visceral arteries), such as the mesenteric, hepatic, coronary, and main renal arteries. These diseases also may involve small arteries, such as arteries within the parenchyma of skeletal muscle, liver, heart, pancreas, spleen, and kidney (e.g., interlobar and arcuate arteries in the kidney). By the definitions in Table 24.1 , polyarteritis nodosa and Kawasaki disease exclusively affect arteries and do not affect capillaries or venules. Therefore they do not cause glomerulonephritis. The presence of arteritis with glomerulonephritis indicates some form of small-vessel vasculitis rather than medium-vessel vasculitis.
Histologically, the acute arterial injury of Kawasaki disease and polyarteritis nodosa is characterized by focal artery wall necrosis and infiltration of inflammatory cells. The acute injury of polyarteritis nodosa typically includes conspicuous fibrinoid necrosis, which is absent or less apparent in Kawasaki disease. Fibrinoid necrosis results from plasma coagulation factors spilling into the necrotic areas, where they are activated to form fibrin. Early in the acute injury of polyarteritis nodosa, neutrophils predominate, but within a few days mononuclear leukocytes are most numerous. Thrombosis may occur at the site of inflammation, resulting in infarction. Focal necrotizing injury to vessels erodes into the vessel wall and adjacent tissue, producing an inflammatory aneurysm, which may rupture and cause hemorrhage. Thrombosis of the inflamed arteries causes downstream ischemia and infarction.
Small-Vessel Vasculitis
Although small-vessel vasculitides may affect medium-sized arteries, these disorders favor small vessels, such as arterioles, venules (e.g., in the dermis), and capillaries (e.g., in glomeruli and pulmonary alveoli; see Fig. 24.1 ). As described in Table 24.1 , there are a variety of clinically and pathogenetically distinct forms of small-vessel vasculitis that have the focal necrotizing inflammation of small vessels in common. In the acute phase, this injury is characterized histologically by segmental fibrinoid necrosis and leukocyte infiltration ( Fig. 24.2 ), sometimes with secondary thrombosis. The neutrophils often undergo karyorrhexis (leukocytoclasia). With chronicity, mononuclear leukocytes become predominant and fibrosis develops.
The various forms of small-vessel vasculitis differ from one another with respect to the presence or absence of distinctive features, as summarized in Table 24.1 and Fig. 24.1 . For example, GPA is characterized by necrotizing granulomatous inflammation; eosinophilic granulomatosis with polyangiitis (EGPA) by eosinophil-rich granulomas, blood eosinophilia, and asthma; IgAV by IgA-dominant vascular immune deposits; and cryoglobulinemic vasculitis by circulating cryoglobulins.
The glomerular lesions of MPA, GPA, and EGPA are pathologically identical and are characterized by segmental fibrinoid necrosis, crescent formation ( Fig. 24.3 ), and a paucity of glomerular staining for immunoglobulin (i.e., pauci-immune glomerulonephritis). Leukocytoclastic angiitis of the medullary vasa recta ( Fig. 24.4 ) also occurs in the antineutrophil cytoplasmic antibody (ANCA) vasculitides and is rarely severe enough to cause papillary necrosis. About 90% of patients with active MPA and GPA, and about 40% of patients with EGPA, have circulating ANCAs ( Table 24.2 ).
| Antibody | MPA (%) | GPA (%) | EGPA (%) | Renal-Limited Vasculitis (Pauci-Immune Crescentic Glomerulonephritis) (%) |
|---|---|---|---|---|
| PR3-ANCA | 40 | 75 | 5 | 25 |
| MPO-ANCA | 50 | 20 | 40 | 65 |
| ANCA-negative | 10 | 5 | 55 | 10 |
The glomerular lesion of anti-GBM disease is also characterized by a segmental necrotizing and crescentic glomerulonephritis. It is distinguishable from the lesions of MPA, GPA, and EGPA by the presence, on immunofluorescence microscopy, of linear continuous deposits of IgG (sometimes accompanied by complement C3, IgA, or IgM) along the GBM ( Fig. 24.5 ). No electron dense deposits are seen by electron microscopy.
The glomerulonephritis of IgAV is pathologically identical to IgA nephropathy and is characterized by the predominant mesangial deposition of IgA (mostly IgA1 subclass), and these patients have the same abnormal hinge region glycosylation of IgA1. The glomerulonephritis of cryoglobulinemic vasculitis usually manifests as type I membranoproliferative glomerulonephritis (mesangiocapillary glomerulonephritis), although other patterns of proliferative glomerulonephritis occur less often. Cryoglobulinemic vasculitis is frequently associated with hepatitis C infection.
Pathogenesis
Vasculitis is caused by the activation of inflammatory mediator systems in vessel walls. However, the initiating event (cause) is unknown for many forms of vasculitis. An immune response to heterologous antigens (e.g., hepatitis B or C antigens in some forms of immune complex vasculitis) or autoantigens (e.g., proteinase 3 or myeloperoxidase in ANCA vasculitis) is presumed to be the etiologic event in many patients with vasculitis. A number of types of vasculitis are categorized based on the putative or confirmed immunologic mechanisms listed in Box 24.1 .
Immune Complex–Mediated
IgA vasculitis (Henoch-Schönlein purpura) a
a May be accompanied by glomerulonephritis and can manifest as nephritis or pulmonary-renal vasculitic syndrome.
Cryoglobulinemic vasculitis
Lupus vasculitis
Serum sickness vasculitis
Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis)
Anti-GBM disease
ANCA – Mediated
MPA
GPA
Cell-Mediated
Allograft cellular vascular rejection
GCA
TA
ANCA, Antineutrophil cytoplasmic antibody; anti-GBM, antiglomerular basement membrane; GCA , giant cell arteritis; GPA , granulomatosis with polyangiitis; IgA , immunoglobulin A; MPA , microscopic polyangiitis; TA , Takayasu arteritis.
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