• Vasculitides affecting the kidneys are typically associated with hematuria and proteinuria, frequently presenting as a rapidly progressive glomerulonephritis.
  
• Glomerular injury occurs in the setting of the small vessel vasculitides, associated with antineutrophil cytoplasmic autoantibodies (ANCA), antiglomerular basement membrane antibodies (anti-GBM), or the presence of immune complex formation such as with Henoch–Schönlein purpura (HSP), cryoglobulinemic vasculitis, and systemic lupus erythematosus (SLE).
  
• They may affect the kidneys alone, but are more frequently part of a multiorgan disease that may affect the skin, upper and lower respiratory tracts, and the musculoskeletal, gastrointestinal, and nervous systems.

The classification of vasculitides is based on the predilection for injury of the different vascular beds (Table 31–1). The following sections provide an overview of the various groups of vasculitides. The remainder of this chapter will focus on the clinical aspects of small vessel vasculitis (SVV) because of their association with glomerulonephritis.

Large Vessel Vasculitis: Takayasu’s Arteritis and Giant Cell Arteritis

Large vessel vasculitis affects the aorta and its major branches. During the acute phase of disease, large vessel vasculitis is characterized pathologically by chronic granulomatous inflammation that often contains giant cells in the inflammatory infiltrates. The chronic phase is characterized by extensive vascular sclerosis with little or no active inflammation. Inflammatory and sclerotic thickening of the aorta and the arteries causes narrowing of lumina, which in turn causes ischemia and the resultant clinical manifestations. Involvement of the renal artery may cause renovascular hypertension.

The two major large vessel vasculitides are Takayasu’s arteritis and giant cell arteritis. Takayasu’s arteritis most often involves the aorta and its major branches, although the pulmonary arteries may be affected. Takayasu’s arteritis is most common in Asia, and rarely occurs in patients older than 40 years. Clinically, it often presents with diminished pulses, vascular bruits, claudication, and renovascular hypertension.

Giant cell arteritis rarely occurs in patients younger than 50 years and is most common in patients of northern European ethnicity. Like Takayasu’s arteritis, giant cell arteritis affects the aorta and its major branches; however, it has a much greater predilection for the extracranial branches of the carotid artery. Frequent clinical manifestations include headache, jaw claudication, blindness, deafness, tongue dysfunction, extremity claudication, and reduced peripheral pulses. Pathologic involvement of the renal artery is common in giant cell arteritis, but symptomatic renovascular hypertension is rare. Polymyalgia rheumatica occurs in 40–60% of patients with giant cell arteritis. The presence of polymyalgia rheumatica may be useful for diagnosis, but symptoms may occur before, simultaneously, or after the onset of giant cell arteritis.

Medium-Sized Vessel Vasculitis: Polyarteritis Nodosa and Kawasaki’s Disease

The medium-sized vessel vasculitides have a predilection for arteries that lead to major viscera and their initial branches. In the kidneys, the major targets are the interlobar and arcuate arteries, with less frequent involvement of the main renal artery and interlobular arteries. The two major medium-sized vessel vasculitides are polyarteritis nodosa (PAN) and Kawasaki’s disease. Pathologically, both are characterized in the acute phase by necrotizing arteritis with transmural inflammation that can lead to the formation of pseudoaneurysms. In only a few days, the lesions evolve from an acute neutrophil-rich inflammation to a “chronic” inflammation with predominantly mononuclear leukocytes. Secondary complications of the arteritis include thrombosis, infarction, and hemorrhage. Sites of thrombosis and necrosis develop progressive scarring. Although medium-sized vessel vasculitides do not cause glomerulonephritis by definition, they can cause hematuria, proteinuria (usually less than 2 g/24 hours), and renal insufficiency as a result of renal infarction. Pseudoaneurysms near the renal surface may rupture and cause severe, even fatal, retroperitoneal, and intraperitoneal hemorrhage.

Although the diagnostic term “polyarteritis nodosa” previously included all patients with any pattern of necrotizing arteritis, the new classification distinguishes it from vasculitides that predominantly affect small arterioles, capillaries, and venules [such as Wegener’s granulomatosis, Churg–Strauss syndrome, and microscopic polyangiitis (MPA)]. By this approach, the presence of glomerulonephritis or pulmonary alveolar capillaritis with pulmonary hemorrhage rules out a diagnosis of polyarteritis nodosa and indicates the presence of some type of SVV. Testing for ANCA is typically negative in PAN as opposed to patients with small vessel vasculitides, MPA, Wegener’s granulomatosis, or Churg–Strauss syndrome. Table 31–2 compares some of the features of polyarteritis nodosa and MPA.

The necrotizing arteritis of Kawasaki’s disease is pathologically indistinguishable from polyarteritis nodosa. Kawasaki’s disease is an acute febrile illness of childhood that is characterized by the mucocutaneous lymph node syndrome, which includes nonsuppurative lymphadenopathy, polymorphous erythematosus rash, erythema of the oropharyngeal mucosa, erythema of the palms and soles, conjunctivitis, and indurative edema and desquamation of the extremities. A major cause for morbidity and mortality in patients with Kawasaki’s disease is the development of a necrotizing arteritis with a predilection for coronary arteries. Symptomatic renal involvement is rare in Kawasaki’s disease.

Because Kawasaki’s disease and polyarteritis nodosa are treated differently, differentiation between the two arteritides is very important. The presence or absence of the mucocutaneous lymph node syndrome is an effective diagnostic discriminator. Kawasaki’s disease usually is treated with aspirin and intravenous γ-globulin therapy. One of the main goals of treatment of Kawasaki’s disease is to reduce the incidence of coronary arteritis. Timely treatment with intravenous immunoglobulin (IVIG) and aspirin has been shown to reduce the incidence of cardiac lesions from 20–40% to <5%. Aspirin alone has not been shown to reduce cardiac sequelae but combined therapy with IVIG appears to have an additive anti-inflammatory effect. If the patient fails initial treatment, repeated doses of IVIG, pulse methylprednisolone, cyclophosphamide, methotrexate, cyclosporin, and plasmapheresis have been utilized. Recently data suggest that infliximab may be an alternative therapy for patients with refractory disease.

Idiopathic polyarteritis nodosa is usually treated with high-dose corticosteroids and cyclophosphamide. This form of therapy has been shown to be beneficial, especially in those who have adverse prognostic factors. The optimal length of treatment is unknown, but a recent study has suggested that 6 months of therapy may be less effective than 12 months. For patients with hepatitis B virus-associated PAN, therapy with antiviral agents improves outcomes.

Small Vessel Vasculitis: Microscopic Polyangiitis, Wegener’s Granulomatosis, and Churg–Strauss Syndrome

Small vessel vasculitides are characterized by necrotizing inflammation primarily targeting venules and capillaries, although arteries, arterioles, and veins may be affected. Unlike vasculitides of larger vascular beds, small vessel vasculitides frequently cause glomerulonephritis (Table 31–1).

The two major categories of SVV include the “pauci-immune small vessel vasculitides” and the “immune complex-mediated small vessel vasculitides” (Table 31–3). Immune complex-mediated vasculitides, such as HSP, cryoglobulinemic vasculitis, lupus vasculitis, and anti-GBM vasculitis, have extensive localization of immunoglobulin and complement in vessel walls as a consequence of deposition of circulating immune complexes or in situ immune complex formation between circulating antibodies and planted or constitutive antigens. The pauci-immune necrotizing small vessel vasculitides have little or no vascular wall localization of immunoglobulins, and often present with a necrotizing and crescentic glomerulonephritis, either alone or as a component of a systemic disease. Pauci-immune crescentic glomerulonephritis is the most common type of crescentic glomerulonephritis (Table 31–4).

The three major systemic pauci-immune small vessel vasculitides are MPA, Wegener’s granulomatosis, and Churg–Strauss syndrome. MPA is a necrotizing angiitis involving capillaries, venules, and arterioles of one or more organs either simultaneously or at different times, including the kidneys, lungs, skin, spleen, liver, heart, and muscle. Wegener’s granulomatosis is characterized by necrotizing granulomatous inflammation found in the upper or lower respiratory tract and may occur without overt vasculitis. The Churg–Strauss syndrome is defined by the presence of eosinophil-rich granulomatous inflammation and vasculitis in patients with a history of eosinophilia and asthma. The necrotizing glomerulonephritis and vasculitis found in Wegener’s granulomatosis and Churg–Strauss syndrome can be pathologically identical to that found in microscopic polyangiitis. It is characterized by segmental fibrinoid necrosis, crescent formation, and the absence of immune reactants.

ANCA SVV is more common in whites than in African-Americans, with a ratio of 7–8:1. Females and males are equally affected, and while patients are typically 55 years or older, patients of any age may have this disease.