Vasculitic Diseases of the Kidney
Julieanne G. McGregor
Patrick H. Nachman
Charles J. Jennette
Ronald J. Falk
The field of vasculitis has been one of continuous advancements in knowledge for the past quarter of a century. Evolving understanding of the pathogenesis of these disorders, including the role of antineutrophil cytoplasmic antibodies (ANCA) and exogenous and host factors that prime an individual for onset of disease or relapse, have led to improved treatment strategies. This chapter reflects our current understanding of large-, medium-, and small-vessel vasculitis.
EPIDEMIOLOGY OF VASCULITIS
The incidence of vasculitis has been difficult to determine, largely because of an inconsistent classification strategy. The advent of the Chapel Hill Nomenclature System allowed for a more precise estimation of incidence and prevalence. The incidence of giant cell arteritis varies from 15 to 30 per million in individuals older than 50 years. There is an increased incidence with age and a female-to-male ratio of 2:1.1 Giant cell arteritis is more common in Caucasians and is uncommon in African Americans. Takayasu arteritis has been described worldwide, but the disease is much more prevalent in Japan, where there are approximately 150 new cases per year. In Olmstead County, Minnesota, the incidence is 2.6 cases per mission per year.
The incidence of vasculitis associated with ANCA appears to be on the order of 10 to 20 cases per million.1 In contrast, polyarteritis nodosa has become a rare disease. It is possible that the perceived increase in the incidence of microscopic polyangiitis (MPA) is a consequence of the development and widespread use of ANCA testing. Nonetheless, the incidence of MPA appears to have been more common in the 1990s than in the 1980s (19.8 versus 7 cases per million). Two interesting studies reported a much higher incidence of ANCA vasculitis. One study reported a much higher incidence in Alaskan Indians in which all cases were associated with hepatitis B.2 The other report from Kuwait after the Gulf War found an increased incidence of 16 cases per million of polyarteritis nodosa and 24 cases per million of MPA.3 The incidence of GPA was 0.7 per million per year from 1980 to 1986, increasing to 2.8 per million per year from 1987 to 1989. There was an increase in the annual prevalence from 28.8 per million in 1990 to 64.8 per million in 2005 in a primary care population.4 In the 1990s the prevalence of granulomatosis with polyangiitis (GPA), formerly known as Wegener granulomatosis, was closer to 10.6 cases per million in the United Kingdom. The annual incidence of eosinophilic granulomatosis (EGPA) ranges between 0.5 and 6.8 cases per million.5 The prevalence of polyarteritis nodosa (PAN), MPA, GPA, and EGPA in a large multiethnic suburb of Paris based on a three-source capturerecapture method during the calendar year 2000 was estimated per 1,000,000 adults to be 30 for PAN, 25 for MPA, 24 for GPA, and 11 for EGPA. The overall prevalence was 2.0 times higher for subjects of European ancestry than for non-Europeans (P = .01).6
DIAGNOSTIC CLASSIFICATION AND PATHOLOGY OF VASCULITIDES
ANCA vasculitis can affect any vessel in the body and thus can cause various clinical signs and symptoms. Most of these manifestations are indicative of vessel involvement in a particular organ rather than a specific pathologic category of disease. Therefore, ANCA vasculitis cannot be accurately diagnosed on the basis of clinical features alone. Serologic and other laboratory data can be very helpful in narrowing the differential diagnosis or providing additional support to a presumptive diagnosis, but data are rarely definitive. As with all tissues, vessels have a limited number of nonspecific patterns of response to injury. For example, many different inflammatory stimuli cause histologically indistinguishable acute and chronic inflammation with and without necrotizing or granulomatous features. To further complicate pathologic evaluation, vasculitic lesions evolve through various stages of active (Fig. 48.1) and sclerosing injury (Fig. 48.2). Specific categories of vasculitis have a particular predilection for involvement of certain types of vessels, although there is so much overlap that type of vessel involvement alone does not provide adequate categorization (Table 48.1, Fig. 48.3). Therefore, vasculitis cannot be diagnosed accurately on
the basis of pathologic features alone, especially if these are evaluated only by routine light microscopy. Recently, a pathologic classification system for ANCA vasculitis has been validated for prognostication of renal outcomes based on renal biopsy,7 but the best approach to a specific diagnosis continues to be a combination of clinical, laboratory, and histologic data to identify distinctive clinicopathologic categories of vasculitis. Vasculitis categorization schemes will continue to be improved in the future; however, current systems provide valuable guidance for prognostication and for determining the most effective management strategy.
the basis of pathologic features alone, especially if these are evaluated only by routine light microscopy. Recently, a pathologic classification system for ANCA vasculitis has been validated for prognostication of renal outcomes based on renal biopsy,7 but the best approach to a specific diagnosis continues to be a combination of clinical, laboratory, and histologic data to identify distinctive clinicopathologic categories of vasculitis. Vasculitis categorization schemes will continue to be improved in the future; however, current systems provide valuable guidance for prognostication and for determining the most effective management strategy.
 FIGURE 48.1 Acute necrotizing arteritis affecting a renal interlobar artery in a patient with Kawasaki disease. There is (arrow) transmural inflammation and necrosis. (Hematoxylin and eosin stain, magnification X125.) |
There are a number of approaches to the categorization of vasculitis. The system used in this chapter is a proposed modification of the Chapel Hill Nomenclature System, a system agreed upon by an international group of clinicians and pathologists with a special interest in vasculitis (Table 48.2).8 There is a new nomenclature pending publication that recognizes a more specific categorization of vasculitides and abolishes eponyms.
Knowledge of the historical evolution of vasculitis categorization is helpful to understand the current diagnostic criteria for the classification of vasculitides. The following discussion of diagnostic classification includes a brief review of the historical events in the recognition of each category. The discussion is divided into sections discussing large-vessel vasculitis, medium-sized vessel vasculitis, and small-vessel vasculitis (Tables 48.1, Figs. 48.2 and 48.3). Large-vessel vasculitides were first recognized because of the reduced pulses and ischemic manifestations caused by chronic narrowing of major arteries. Medium-sized vessel vasculitides were first recognized because of the pseudoaneurysms caused by necrotizing lesions of medium-sized arteries, and small-vessel vasculitides were first recognized because of the glomerulonephritis and purpura caused by involvement of glomerular capillaries and dermal venules, respectively. Much of the discussion focuses on small-vessel vasculitides because these cause a higher frequency of renal disease.
 FIGURE 48.2 Chronic scarring in an arcuate artery from a patient with polyarteritis nodosa. The muscularis is completely destroyed (arrows), indicating that the sclerosis is secondary to a necrotizing arteritis rather than severe arteriosclerosis. (Hematoxylin and eosin stain, magnification X75.) |
TAKAYASU ARTERITIS AND GIANT CELL (TEMPORAL) ARTERITIS
Large-vessel vasculitis affects the aorta and its major branches, such as the arteries to the extremities and to the head and neck.8 During the acute phase of disease, large-vessel vasculitis is characterized pathologically by inflammation that often
contains giant cells in the inflammatory infiltrates during the active phase of disease. 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 categories of large-vessel vasculitis are Takayasu arteritis and giant cell arteritis.
contains giant cells in the inflammatory infiltrates during the active phase of disease. 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 categories of large-vessel vasculitis are Takayasu arteritis and giant cell arteritis.
TABLE 48.1 Major Diagnostic Categories of Vasculitis | ||||||||||||||||||||||||||||
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In 1856, William Savory described patients with diminished peripheral pulses who probably had Takayasu arteritis involving the major arteries to the extremities.9 However, this category of vasculitis is named for Mikito Takayasu, a Japanese ophthalmologist who reported the ocular ischemic effects of this chronic granulomatous arteritis in 1908.10 Takayasu arteritis, which also includes “aortic arch syndrome” and “pulseless disease,” most often involves the aorta and its major branches, although the pulmonary arteries may be affected.11 Takayasu arteritis is most common in Asia, although it occurs worldwide. It rarely occurs in patients older than 40 years and is usually diagnosed during the second decade of life. Clinically, it often presents with reduced 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.12 Like Takayasu 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. This is in contradistinction to Takayasu arteritis, which often causes renovascular hypertension.
Giant cell arteritis has also been called “temporal arteritis,” partly because one of the earliest descriptions of this type of vasculitis in 1890 by Hutchinson emphasized temporal artery involvement.13 However, the term “giant cell arteritis” is more appropriate than “temporal arteritis” because (1) not all patients with giant cell arteritis have temporal artery involvement and (2) vasculitides other than giant cell arteritis can cause temporal artery inflammation, such as polyarteritis nodosa, granulomatosis with polyangiitis, and microscopic polyangiitis.8 If a patient with clinical manifestations of temporal artery inflammation is found by temporal artery biopsy to have a necrotizing rather than a granulomatous arteritis, the differential diagnosis should include polyarteritis nodosa, MPA, GPA, and other forms of necrotizing vasculitis. The frequent association of polymyalgia rheumatica with giant cell arteritis is a useful diagnostic aid, although not all patients with giant cell arteritis have polymyalgia rheumatica and not all patients with polymyalgia rheumatica have giant cell arteritis.
Takayasu arteritis and giant cell arteritis cannot be accurately distinguished on the basis of pathologic evaluation of involved arteries. Polymyalgia rheumatica and involvement of branches of the carotid artery are more in favor of giant cell arteritis, and preferential involvement of the aorta and arteries to the extremities is slightly in favor of Takayasu arteritis. However, the best diagnostic discriminator is age. If a patient with clinical or pathologic features of chronic granulomatous arteritis is older than 50 years, a diagnosis of giant cell arteritis is warranted, whereas a diagnosis of Takayasu arteritis is warranted if the patient is younger than 50 years.8 The presence of renovascular hypertension in a child or a young adult is suggestive of Takayasu arteritis. In a patient older than 50 years, renal artery involvement by a chronic sclerosing process is more likely secondary to atherosclerosis than to giant cell arteritis, and Takayasu arteritis is essentially ruled out by the age of the patient.
 FIGURE 48.3 Predominant vascular involvement by large-vessel vasculitides, medium-sized vessel vasculitides, and small-vessel vasculitides as indicated by the positions and heights of the solid triangles. The algorithm suggests clinical and pathologic features that discriminate among different diagnostic categories of vasculitis. yo, years old; MCLN, mucocutaneous lymph node syndrome; IF, immunofluorescence microscopy; ANCA, antineutrophil cytoplasmic autoantibodies; Im Cx, immune complex; SLE, systemic lupus erythematosus; H-S, Henoch-Schönlein. (From Jennette JC, Falk RJ. Renal involvement in systemic vasculitis. In: Greenberg A, Cheung AK, Coffman TM, et al., eds. National Kidney Foundation Nephrology Primer, 2nd ed. San Diego, CA: Academic Press; 1998:200, with permission.) |
TABLE 48.2 Names and Definitions of Vasculitis Adopted by the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis | ||||||||||||||||||||||||||||||
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Aortitis is a common feature of Takayasu and giant cell arteritis but is also associated with other vasculitides such as syphilis, tuberculosis, mycosis, Behçet disease, and Kawasaki disease. The most commonly involved vessels are the subclavian arteries in more than 90% of patients. Diagnostic differentiation between Takayasu and giant cell arteritis is largely based on age, with patients younger than 40 years having Takayasu arteritis and those older than 50 having giant cell arteritis. Aortic aneurysm rupture represents a morbid complication of giant cell arteritis. Aortitis may result in ischemic symptoms or infarction of the area supplied by the involved vessel. Asymptomatic aortitis may be a more common phenomenon than previously thought.14
Clinical Presentation
According to the Giant Cell Arteritis Guideline Development Group15 giant cell arteritis often presents with abrupt onset headache, which is classically temporal and unilateral but can be diffuse. Presenting complaints can also include scalp pain, jaw or tongue claudication, blurring of vision, diplopia or amaurosis fugax, fever, weight loss, fatigue, polymyalgic symptoms, or limb claudication. On physical exam, tender, thickened, or beaded temporal artery with diminished or absent pulse may be noted. Visual field defect, visual loss, or afferent papillary defect can be noted. Funduscopic exam classically reflects anterior ischemic optic neuritis with pale, swollen optic disc with hemorrhages. Central retinal artery occlusion, upper cranial nerve palsies, asymmetry of pulses and blood pressure, and bruits are also features of this disease.
Early presentation of Takayasu arteritis includes low-grade fever, malaise, night sweats, weight loss, arthralgia, and fatigue. Although clinical presentations vary significantly between patients, and Takayasu arteritis seems to be a relapsing and remitting syndrome, many patients have diminished or absent pulses, Reynaud phenomenon, vascular bruits, hypertension, mesenteric angina, retinopathy, aortic regurgitation, dizziness, seizures, or amaurosis fugax. Takayasu arteritis has been reported to accompany other autoimmune diseases including rheumatoid arthritis, ulcerative colitis, systemic lupus, Crohn disease, sarcoidosis, and amyloidosis.16,17
Laboratory Findings
Laboratory findings in large-vessel vasculitis include a mild anemia, elevated levels of C-reactive protein, elevated erythrocyte sedimentation rate, and a generalized elevation in γ-globulin levels. Takayasu arteritis patients may be p- or c-ANCA positive. Other serologic results, including tests for lupus and infections, are typically negative. Patients typically present with only mild hematuria and proteinuria, except in patients with concomitant amyloidosis. The most common presentation is associated with hypertension and renal insufficiency, whereas renal failure is uncommon.
Pathogenesis
The pathogenesis of giant cell and Takayasu arteritis is unknown. Current consensus is that large vessel vasculitis is likely autoimmune in origin. Chauhan et al. report that serum of patients with Takayasu arteritis contains antiaortic endothelial cell antibodies directed against 60 to 65 kDa heat-shock proteins.18 Serum-containing antiaortic endothelial cell antibodies induced apoptosis of aortic endothelial cells. There is scant evidence for a direct link between antiaortic endothelial cell antibodies and the development of Takayasu arteritis, however.
There are several tantalizing clues that infectious agents may play a role in these diseases. In animals, there is evidence that gamma herpes virus 68 causes arteritis in mice lacking the interferon-γ receptor. In humans, an association exists between giant cell arteritis and parvovirus B19 infection.19 However, a study using polymerase chain reaction (PCR) and immunohistochemistry techniques on 147 temporal artery biopsies found no evidence of parvovirus B19 DNA in the arteries of patients with giant cell arteritis.20 A cyclic occurrence of disease, with a peak incidence occurring every 5 to 7 years, suggests an infectious cycle. Certain genetic factors are associated with the development of giant cell arteritis. This form of vasculitis is more common in individuals of Northern European descent living in Europe or the United States,21 and there is clustering of cases among families.22 The development of giant cell arteritis also correlates with the expression of HLA-DR4, which is also found in high frequency among patients with polymyalgia rheumatica.23
Giant cell arteritis may be a consequence of either or both the humeral and cellular immune responses. The clinical and experimental findings suggest that a cell-mediated process is most likely.24 Most inflammatory cells that invade the vessel walls are CD4-positive T cells. Elevated levels of IL-6 correlate with the severity of the disease and decrease quite rapidly when glucocorticoids are administered.25 Levels of several other cytokines and chemokines are similarly elevated. It is hypothesized that activated monocytes infiltrate the adventitia of large vessel walls via the vasa vasorum and become macrophages that then produce interferon-γ and recruit additional leukocytes, including macrophages. Unfortunately, the antigen responsible for these interactions has yet to be elucidated.
Renal Involvement
Renal involvement in Takayasu arteritis and giant cell arteritis is usually a consequence of inflammation and scarring of the aorta adjacent to the orifice of the renal artery, leading to stenosis of the renal artery and ischemic renal failure. One of the most common clinical presentations of this phenomenon is renovascular hypertension affecting more than 50% of patients with Takayasu arteritis. In Japan, Takayasu arteritis is an important cause of hypertension in adolescents.
Glomerular lesions and necrosis occurs in patients with large-vessel vasculitis, but this may be an overlap of a small-vessel vasculitis. Several cases of glomerulonephritis in the setting of Takayasu arteritis have been reported in the literature. The renal pathology in these cases varies from case to case, including focal segmental sclerosis, mesangial proliferation, membranoproliferative lesions, and crescentic lesions.
Treatment
The cornerstone of treatment of giant cell arteritis is based on the use of high-dose corticosteroids. Typically, prednisone is started at 1 to 1.5 mg/kg/day until the erythrocyte sedimentation rate is normal and the patient is asymptomatic. Initial treatment on an alternate-day basis is ineffective in the treatment of giant cell arteritis. When compared with patients receiving daily corticosteroids, only 30% (versus 85%) of patients treated with alternate-day dosing enter an early remission, and 75% (versus 15%) experience a flare of disease activity.26 Intravenous pulses of methylprednisolone (1 g per day for 3 to 5 days) are recommended for patients with severe visual loss because this treatment seems to prevent additional visual loss or fellow-eye involvement after initiation of corticosteroids.27 The initiation of corticosteroids within 2 weeks before a temporal artery biopsy does not change the characteristic pathologic findings.28 A delay in treatment to obtain a temporal artery biopsy is therefore not warranted.
Once a clinical remission is attained, a slow taper of corticosteroids is undertaken by decreasing the dose by 10% every 2 weeks to a dose of 10 mg per day, then by 1 mg per day. Other similar tapering protocols have been suggested, but no critical assessment of these recommendations is available. Switching to an alternate-day regimen may be similarly efficacious and perhaps less toxic. Symptoms usually resolve within 2 to 3 days, and the erythrocyte sedimentation rate usually normalizes within 4 to 6 weeks. Most patients with giant cell arteritis require 2 years of corticosteroids, and a few remain on a low-dose regimen indefinitely. Patients who continue to require “maintenance” dosages of more than 15 mg per day may be considered “steroid resistant.”
The high rate of complications attributable to the prolonged duration of corticosteroid therapy and the age distribution of patients with giant cell arteritis has led to an interest in identifying steroid-sparing alternative drugs. Dapsone, azathioprine, cyclosporine, antimalarials, cyclophosphamide, or gold have not been found to reduce corticosteroid toxicity and still maintain therapeutic effectiveness.29 The reported beneficial effect on the rate of relapse of adding methotrexate to corticosteroids was not confirmed by a multicenter, placebo-controlled trial.30 A retrospective study suggests that the concomitant use of low-dose aspirin decreases the rate of visual loss and cerebrovascular events in patients with giant cell arteritis.31 Information on the use of tumor necrosis factor (TNF)-alpha-blocking agents in the treatment of giant cell arteritis is currently limited to very small case series.
The treatment of Takayasu arteritis is similarly based on high-dose corticosteroids. In a U.S. National Institutes of Health study, treatment was initiated at 1 mg per kg (up to 60 mg per day) for 1 to 3 months, followed by a slow taper to an alternate-day regimen over the following 4 to 8 weeks, and a subsequent slow taper over the following 6 to 12 months. This regimen is associated with a remission rate of 60% and an estimated median time to remission of 22 months.32
Unfortunately, relapses occur in as much as 45% of patients, leading to multiple or prolonged courses of corticosteroids. Up to 40% of patients require the addition of cytotoxic drugs such as cyclophosphamide or methotrexate. In an open-label study of 18 patients with persistent or refractory Takayasu arteritis despite treatment with corticosteroids alone, the use of methotrexate was associated with an 81% remission rate.33 Fifty percent of patients achieved a corticosteroid-free remission on methotrexate, and half of these patients remained in remission after methotrexate was withdrawn. About 20% of patients did not attain remission despite corticosteroids and methotrexate. The successful use of infliximab has been reported in several case reports of patients with active Takayasu arteritis despite conventional therapy with corticosteroids and cyclophosphamide34 or methotrexate.35 The use of anti-TNF therapy was assessed in a pilot, open-label trial involving a total of 15 patients with active, relapsing Takayasu arteritis. Seven patients were initially treated with etanercept and eight with infliximab. The use of anti-TNF agents led to remission in 10 of the 15 patients that was sustained for 1 to 3.3 years without glucocorticoid therapy. Four patients achieved partial remission, with a >50% reduction in the glucocorticoid requirement. Two relapses occurred during periods when etanercept was interrupted, but remission was reestablished upon reinstitution of therapy.36
The optimal treatment of patients with Takayasu arteritis is further complicated by the results of biopsies of affected vessels obtained at the time of bypass surgery. These data revealed evidence of persistent vascular inflammation even in the absence of clinical signs or symptoms of active disease and in the setting of a normal erythrocyte sedimentation rate.32,37 Surgical intervention is the definitive treatment of occlusive disease in patients with progressive Takayasu arteritis, especially in the absence of response to conventional therapy.
The diagnosis and treatment of hypertension represents a very important aspect of the care of patients with Takayasu arteritis because congestive heart failure, ischemic or hemorrhagic stroke, and renal failure account for most of the deaths from this disease.38 The diagnosis of hypertension may be missed if it is based on measurement of blood pressure in the upper extremities alone, because of the high incidence of subclavian artery stenoses, which may be bilateral. In some cases, lesions in the thoracic or abdominal aorta or the iliac or femoral arteries may give misleading normal blood pressures in the lower extremities as well. It is thus
recommended that arteriographic studies be performed with pressure transducers so that aortic pressures can be compared with extremity pressures, and to identify the extremity where blood pressure monitoring is most reliable and reflective of true blood pressure.38
recommended that arteriographic studies be performed with pressure transducers so that aortic pressures can be compared with extremity pressures, and to identify the extremity where blood pressure monitoring is most reliable and reflective of true blood pressure.38
MEDIUM-SIZED VESSEL VASCULITIS: POLYARTERITIS NODOSA AND KAWASAKI DISEASE
The medium-sized vessel vasculitides are necrotizing arteritides that 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 (Fig. 48.3). The two major categories of medium-sized vessel vasculitis are polyarteritis nodosa and Kawasaki disease. Pathologically, both are characterized in the acute phase by necrotizing arteritis with transmural inflammation that initially includes neutrophils and foci of fibrinoid necrosis (Fig. 48.1). The acute necrotizing inflammation often erodes completely through the artery wall and into the adjacent perivascular tissue, thereby forming a pseudoaneurysm (Fig. 48.4). Secondary complications of the arteritis include thrombosis, infarction, and hemorrhage. In only a few days, the lesions evolve from an acute neutrophil-rich inflammation to a “chronic” inflammation with predominantly mononuclear leukocytes. Sites of thrombosis and necrosis develop progressive scarring (Fig. 48.2). By definition, medium-sized vessel vasculitides do not cause glomerulonephritis, although they can cause hematuria, proteinuria (usually less than 2 g per 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.
The meaning of the diagnostic term “polyarteritis nodosa” has evolved over the past century, and substantial confusion continues over how best to use it. The problem and the solution that we propose is best understood in historical context. Systemic necrotizing arteritis was first clearly described by Kussmaul and Maier in the mid-1800s.39 They reported a patient with widespread visceral nodules caused by acute inflammation of arteries and called the process “periarteritis nodosa.” Ferrari introduced the term “polyarteritis nodosa,”40 which is more appropriate because the inflammation is transmural rather than perivascular. For approximately 50 years, essentially all patients with any pattern of necrotizing arteritis were included in the polyarteritis nodosa category. During the early to mid-1900s, astute investigators recognized that many patients with necrotizing arteritis had distinctive distributions of vascular inflammation or characteristic pathologic processes that warranted their separation from patients with arteritis alone. For example, Kawasaki disease, GPA, EGPA, and MPA were initially included in the category of polyarteritis nodosa but now are recognized as distinct entities.8 The removal of these vasculitides from the polyarteritis nodosa category is justified not only on the basis of different patterns and distributions of vessel involvement, but also because they have different natural histories, prognoses, and treatment requirements.
 FIGURE 48.4 Acute necrotizing arteritis affecting a renal interlobar artery in a patient with Kawasaki disease. The necrotizing inflammation (arrows) has eroded into the perivascular tissue to produce a pseudoaneurysm. (Hematoxylin and eosin stain, magnification X350.) |
The reduction of polyarteritis nodosa to a more homogeneous and clinically useful category of vasculitis began when Arnaout, among others, recognized that some patients with necrotizing arteritis had lesions that could be seen only by microscopic examination.41 Circa 1950, Zeek et al.42,43 and Godman and Churg44 carried out careful evaluations of patients with arteritis and concluded that polyarteritis nodosa should be separated from the “microscopic” form of vasculitis that was characterized by involvement of not only small arteries but also venules and capillaries. As discussed later in the section on small-vessel vasculitis, Godman and Churg also concluded that polyarteritis nodosa was distinct not only from MPA but also from GPA and eosinophilic granulomatosis, and that MPA, GPA, and eosinophilic granulomatosis were related to one another.
The diagnostic approach that we advocate defines polyarteritis nodosa as necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules (Table 48.2).8 This allows the separation of polyarteritis nodosa from other types of vasculitis, such as GPA, MPA, and eosinophilic granulomatosis, which have necrotizing arteritis as a component of a systemic polyangiitis that affects capillaries, venules, and arteries. By using this approach, the presence of glomerulonephritis rules out a diagnosis of polyarteritis nodosa and indicates the presence of some type of small-vessel vasculitis. Table 48.3 compares some of the features of polyarteritis nodosa and MPA. Note that glomerular capillaritis (glomerulonephritis) or pulmonary alveolar capillaritis with pulmonary hemorrhage rule out a diagnosis of polyarteritis nodosa and raise the possibility of MPA. Peripheral neuropathy is not a discriminator, because involvement of small epineural arteries in peripheral nerves may occur with polyarteritis nodosa or MPA. As discussed in more detail later, testing for ANCA is useful for distinguishing between polyarteritis nodosa and the ANCA-associated small-vessel vasculitides.45,46,47,48,49 In a patient with necrotizing arteritis, a positive ANCA result decreases the likelihood of polyarteritis nodosa and increases the likelihood of MPA, GPA, or eosinophilic granulomatosis (i.e., increases the likelihood that the patient has or will develop necrotizing inflammation of vessels other than arteries, such as pulmonary alveolar capillaritis or glomerular capillaritis [glomerulonephritis]).
TABLE 48.3 Clinical Differences Between Polyarteritis Nodosa and Microscopic Polyangiitis | ||||||||||||||||||||||||||||||
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Necrotizing arteritis that is pathologically indistinguishable from the necrotizing arteritis of polyarteritis nodosa can occur in patients with Kawasaki disease (Figs. 48.1 and 48.3). Kawasaki disease is an acute self-limiting febrile illness, the second commonest vasculitis in childhood.50 Kawasaki disease is characterized by the mucocutaneous lymph node syndrome, which includes nonsuppurative lymphadenopathy, polymorphous erythematous rash, erythema of the oropharyngeal mucosa, erythema of the palms and soles, conjunctivitis, indurative edema, and desquamation of the extremities. A major cause for morbidity and mortality in patients with Kawasaki disease is the development of a necrotizing arteritis. This arteritis has a predilection for coronary arteries but can occur anywhere, including the kidney (Figs. 48.1 and 48.3). Kawasaki disease is the most common cause of childhood-acquired heart disease.50 Symptomatic renal involvement is rare in Kawasaki disease. Differentiation between the arteritis of Kawasaki disease and that of polyarteritis nodosa is very important because the treatment of Kawasaki disease differs from the treatment of polyarteritis nodosa (discussed in Treatment section).
The presence or absence of the mucocutaneous lymph node syndrome is an effective diagnostic discriminator between Kawasaki disease and polyarteritis nodosa.
Clinical Features
Patients with polyarteritis nodosa typically have constitutional symptoms, including fever and weight loss. The presence of mononeuritis multiplex, myalgias, and arthralgias, as well as skin lesions including nodules, ulcers, livedo reticularis, and digital ischemia in half of patients, characterize the disease. There is a spectrum of disease referred to as cutaneous polyarteritis nodosa associated with streptococcal infection.50 Cutaneous polyarteritis nodosa has periodic exacerbations but is milder than classic polyarteritis nodosa. This presentation may be along the spectrum of systemic polyarteritis nodosa. Vasculitis of the coronary arteries may lead to cardiac symptoms. The renal disease seen in polyarteritis nodosa is primarily related to vasculitis of the renal arteries resulting in renovascular hypertension and/or renal parenchymal infarction. Patients with polyarteritis nodosa do not have evidence of small-vessel
vasculitis, glomerulonephritis, or pulmonary capillaritis. In fact, the lung is rarely injured in polyarteritis nodosa, in contrast to the frequency of pulmonary disease in patients with GPA, MPA, or EGPA. Although not distinguishing features, gastrointestinal complaints and peripheral neuropathy are more common among patients with polyarteritis nodosa than patients with MPA. The skin lesions of polyarteritis nodosa closely mimic cholesterol emboli and calciphylaxis and therefore histopathologic confirmation of diagnosis is required. The prognosis of polyarteritis nodosa is really a reflection of the involvement of the kidneys, heart, central nervous system, or gastrointestinal tract.51
vasculitis, glomerulonephritis, or pulmonary capillaritis. In fact, the lung is rarely injured in polyarteritis nodosa, in contrast to the frequency of pulmonary disease in patients with GPA, MPA, or EGPA. Although not distinguishing features, gastrointestinal complaints and peripheral neuropathy are more common among patients with polyarteritis nodosa than patients with MPA. The skin lesions of polyarteritis nodosa closely mimic cholesterol emboli and calciphylaxis and therefore histopathologic confirmation of diagnosis is required. The prognosis of polyarteritis nodosa is really a reflection of the involvement of the kidneys, heart, central nervous system, or gastrointestinal tract.51
Tc-99m dimercaptosuccinic acid (DMSA) scanning of the kidneys can indirectly support the diagnosis of a medium-vessel vasculitis affecting the renal arteries by manifesting patchy areas of decreased isotope in the renal parenchyma.52 Unquestionably, however, angiography of the renal, hepatic, and/or mesenteric vasculature via angiography is a superior approach for diagnosis of a medium vessel vasculitis. Demonstration of “aneurysms,” narrowing of arteries, or pruning of the peripheral vascular tree suggest medium-vessel vasculitis. Large pseudoaneurysms, stenosis of the renal arteries or large branches, and resultant areas of ischemia or infarct within the kidney can be demonstrated by magnetic resonance angiography or computed tomography (CT) angiography.
Pathogenesis
The etiology of polyarteritis nodosa remains unclear, and most cases of polyarteritis nodosa are probably idiopathic. An association between polyarteritis nodosa and hepatitis B infection is evident by the fact that patients with hepatitis B antigenemia are at greater risk of developing polyarteritis nodosa. Hepatitis B virus has been implicated in up to one third of cases of polyarteritis nodosa.54 A role for hepatitis B antigenemia in the pathogenesis of polyarteritis nodosa is further suggested by reports of vasculitis after hepatitis B vaccination.55 Furthermore, treatment with antiviral agents and plasma exchange has led to resolution of the vasculitis in patients whose serology converts from being positive for the HBe or HBs antigens to the corresponding antibodies.56,57
Polyarteritis nodosa has been associated with a number of cancers, especially hairy cell leukemia.58 Treatment of hairy cell leukemia with interferon-alpha (INF-α) may be associated with resolution of polyarteritis nodosa.59 As opposed to patients with small-vessel vasculitis, patients with polyarteritis nodosa are ANCA-negative.60
Renal Manifestations
Both polyarteritis nodosa and Kawasaki disease are medium-sized vessel vasculitides that affect the kidney. These arteritides result in necrotizing lesions in the major renal arteries and aneurysm formation with thrombosis and renal infarction. The aneurysms are not true aneurysms but rather pseudoaneurysms. The arteritis of Kawasaki disease most commonly involves the coronary arteries, but in at least 25% of patients the lesions also involve the kidney. Tubulointerstitial nephritis is a not uncommon renal presentation in Kawasaki disease.50 Renal manifestations of Kawasaki disease can lead to renal failure. Kawasaki disease is distinguished from polyarteritis nodosa by the pathognomonic sine qua non feature of mucocutaneous lymph node syndrome. Renal arterial involvement by polyarteritis nodosa, including interlobar and arcuate arteries, results in renal ischemia, infarction, and hemorrhage. One of the most painful and catastrophic consequences of this disease is rupture of an arterial pseudoaneurysm that causes retroperitoneal and sometimes intraperitoneal hemorrhage.
Treatment
The treatment of Kawasaki disease differs from the treatment of polyarteritis nodosa. Kawasaki disease usually is treated with aspirin and intravenous γ-globulin therapy,53 whereas the treatment of polyarteritis nodosa classically has been based on the use of high-dose corticosteroids with the addition, in moderate to severe or organ-threatening cases, of cyclophosphamide. Unfortunately, most studies pertinent to the treatment of polyarteritis nodosa antedate the 1994 Chapel Hill consensus conference, which classified MPA among the small-vessel vasculitides separate from classic polyarteritis nodosa. Consequently, most of the older studies and reports include a substantial number of patients who would now be diagnosed with MPA and not classic polyarteritis nodosa. As a result of the consensus conference, the incidence of classic polyarteritis nodosa involving medium-sized vessels alone and without evidence for glomerulonephritis is very low and is not readily amenable to large-scale evaluation of various therapies. Fifty percent of classic polyarteritis nodosa is curable with 9 to 12 months of corticosteroid therapy alone.61 The other 50% of polyarteritis nodosa will require cyclophosphamide therapy but once remission is obtained relapses are very uncommon.62 The problem is compounded by the relatively recent recognition of the association of polyarteritis nodosa with hepatitis B virus (HBV) infection in a subset of patients with polyarteritis nodosa that varies from 10% to 50%, depending on the population studied.
In the absence of HBV infection, the mainstay of treatment of classic polyarteritis nodosa continues to rest on the use of high-dose corticosteroids. In patients without poor prognostic factors (no renal, cardiac, gastrointestinal, or central nervous system manifestations of disease), no survival difference was noted when treating polyarteritis nodosa with corticosteroids alone when compared to corticosteroids and cyclophosphamide.63 Typically, prednisone is initiated at a dosage of 1 mg/kg/day for the first month. Over the course of the second month, the dosage is tapered to an alternate-day regimen so that the patient is receiving 1 mg per kg every other day by the end of the second month. It is subsequently tapered slowly by 5 mg per day weekly as tolerated. Should relapse occur after corticosteroid therapy,
the addition of cyclophosphamide or azathioprine may be beneficial.64 The addition of an alkylating agent such as cyclophosphamide in the treatment of polyarteritis nodosa is not as well established as in the treatment of MPA or GPA, although some studies report improved patient survival when these agents were added, especially in patients with poor prognostic factors.64 In another study, the addition of cyclophosphamide to corticosteroids and plasma exchange led to decreased relapse in the cyclophosphamide-treated group, but no improvement in the 10-year survival rate.65 In current practice, cyclophosphamide should be reserved for patients with severe or organ-threatening disease, with disease that fails to respond to treatment with corticosteroids alone, for patients who require unacceptably high doses of corticosteroids, or for patients who are intolerant to corticosteroid side effects. No randomized study exists to critically assess the value of a daily oral regimen of cyclophosphamide compared with pulse cyclophosphamide in the outcome of patients with classic polyarteritis nodosa; however, intravenous cyclophosphamide rather than an oral regimen is recommended, not to exceed 12 pulses.64 In patients with poor prognostic factors, six intravenous pulse treatments with cyclophosphamide not followed by maintenance therapy were noted to have greater relapse rate than 12 intravenous infusions of cyclophosphamide. Although azathioprine has been used in the treatment of classic polyarteritis nodosa, this agent is better reserved for maintenance therapy or as a steroid-sparing agent. Current recommendations for patients with polyarteritis nodosa with poor prognostic factors are to obtain remission with pulse cyclophosphamide and then continue therapy with azathioprine for 12 to 18 total months of immunosuppression.66 Plasma exchange does not seem to improve the outcome, decrease relapse, or improve long-term survival of patients with polyarteritis nodosa not associated with HBV.67 The successful use of infliximab in PAN resistant to “conventional therapy” has been reported in a small number of cases.68,69
the addition of cyclophosphamide or azathioprine may be beneficial.64 The addition of an alkylating agent such as cyclophosphamide in the treatment of polyarteritis nodosa is not as well established as in the treatment of MPA or GPA, although some studies report improved patient survival when these agents were added, especially in patients with poor prognostic factors.64 In another study, the addition of cyclophosphamide to corticosteroids and plasma exchange led to decreased relapse in the cyclophosphamide-treated group, but no improvement in the 10-year survival rate.65 In current practice, cyclophosphamide should be reserved for patients with severe or organ-threatening disease, with disease that fails to respond to treatment with corticosteroids alone, for patients who require unacceptably high doses of corticosteroids, or for patients who are intolerant to corticosteroid side effects. No randomized study exists to critically assess the value of a daily oral regimen of cyclophosphamide compared with pulse cyclophosphamide in the outcome of patients with classic polyarteritis nodosa; however, intravenous cyclophosphamide rather than an oral regimen is recommended, not to exceed 12 pulses.64 In patients with poor prognostic factors, six intravenous pulse treatments with cyclophosphamide not followed by maintenance therapy were noted to have greater relapse rate than 12 intravenous infusions of cyclophosphamide. Although azathioprine has been used in the treatment of classic polyarteritis nodosa, this agent is better reserved for maintenance therapy or as a steroid-sparing agent. Current recommendations for patients with polyarteritis nodosa with poor prognostic factors are to obtain remission with pulse cyclophosphamide and then continue therapy with azathioprine for 12 to 18 total months of immunosuppression.66 Plasma exchange does not seem to improve the outcome, decrease relapse, or improve long-term survival of patients with polyarteritis nodosa not associated with HBV.67 The successful use of infliximab in PAN resistant to “conventional therapy” has been reported in a small number of cases.68,69
In the setting of HBV-associated polyarteritis nodosa, treatment with immunosuppression consisting of corticosteroids with or without cyclophosphamide is thought to be deleterious because it facilitates viral replication, delays the development of protective anti-HBV antibodies, and may lead to an aggravation of hepatic involvement.70 For this reason, it has been advocated that only a short course of corticosteroids (1 mg/kg/day) be used for 1 week, followed by a rapid taper over the following week. The prompt institution of antiviral therapy may ameliorate the vascular inflammation. Treatment with plasma exchange has been advocated to clear circulating immune complexes thought to be important in the pathogenesis of this disease,71 although no controlled trial has critically assessed the need for plasmapheresis. The antiviral agents used have included vidarabine, INF-α-2b, or more recently combination therapy of INF-α-2b in addition to lamivudine72 or famciclovir.57 No large-scale trials of antiviral therapy are available to critically assess the efficacy of these combinations in patients with HBV-related polyarteritis nodosa. Current work in the treatment of chronic HBV focuses on the use of INF-α-2b, modified purine analogs such as famciclovir, or L-stereoisomers of pyrimidine derivatives such as lamivudine.73 In an uncontrolled study, the combination of a short course of corticosteroids followed by a 6-month course of lamivudine and scheduled plasma exchange (until hepatitis B antigen or anti-HBe antibody seroconversion) resulted in a clinical remission of the vasculitis.74 In a recent retrospective analysis of 115 patients with HBV-associated polyarteritis nodosa (according to the Chapel Hill nomenclature) followed by the French Vasculitis Study Group between 1972 and 2002, the overall remission rate was 80.9% with a subsequent overall 9.7% relapse rate.54 The rates of relapse or death were not significantly different among patients treated with antiviral agents (vidarabine, INF-α, or lamivudine) (n = 80) when compared to patients treated with corticosteroids alone, or with cyclophosphamide, or plasma exchanges (n = 35) (5% vs. 14.3% relapse; and 30% vs. 48.6% death, respectively). However, the use of antiviral agents has led to a significantly higher rate of seroconversions from HBeAg to anti-HBeAb (49.4% vs. 14.7%; P < .001). Such seroconversion was associated with a clinical remission and absence of relapse.
Outcome
Most studies examining patient outcome and predictors of patient survival in polyarteritis nodosa antedate the Chapel Hill consensus conference of 1994. These studies are based on cohorts of patients that include those with MPA, EGPA, and hepatitis B-associated classic polyarteritis nodosa. Earlier studies report a 5-year survival rate of approximately 55% in patients primarily treated with corticosteroids alone.75 The addition of cyclophosphamide or immunosuppressive therapy to glucocorticoids seems to have improved the 5-year survival rate to about 80%. Patients with bowel infarction, serious gastrointestinal bleeding, or renal insufficiency had particularly poor prognosis. In a more recent prospective study including 342 patients, of whom 119 had classic polyarteritis nodosa without HBV (89 patients with HBV, 52 patients with MPA, 82 patients with EGPA),51 proteinuria of 10 g per day, renal insufficiency, and gastrointestinal tract involvement were the major prognostic markers for a worse outcome.
SMALL VESSEL VASCULITIS
Microscopic Polyangiitis, Granulomatosis with Polyangiitis, and Eosinophilic Granulomatosis
Small-vessel vasculitides are characterized by necrotizing inflammation of multiple types of vessels. Arteries, veins, arterioles, venules, and capillaries may be affected; however, venules and capillaries are the most frequent targets. An understanding of the small-vessel vasculitides is important for nephrologists because these diseases often involve
the kidneys and frequently cause glomerulonephritis. All of the small-vessel vasculitides listed in Table 48.1 can involve the kidneys. As mentioned in the discussion about the evolution of the definition of polyarteritis nodosa, small-vessel vasculitides with arterial involvement once were subsumed in the polyarteritis nodosa category. Zeek et al.42,43 and Godman and Churg44 were among the first to recognize that vasculitides that involve capillaries and venules in addition to arteries have clinical and pathologic features that are clearly distinct from those of polyarteritis nodosa.
the kidneys and frequently cause glomerulonephritis. All of the small-vessel vasculitides listed in Table 48.1 can involve the kidneys. As mentioned in the discussion about the evolution of the definition of polyarteritis nodosa, small-vessel vasculitides with arterial involvement once were subsumed in the polyarteritis nodosa category. Zeek et al.42,43 and Godman and Churg44 were among the first to recognize that vasculitides that involve capillaries and venules in addition to arteries have clinical and pathologic features that are clearly distinct from those of polyarteritis nodosa.
The two major categories of small-vessel vasculitis include the “pauci-immune small vessel vasculitides” and the “immune complex-mediated small vessel vasculitides” (Table 48.1). Immune complex-mediated vasculitides, such as Henoch-Schönlein purpura (HSP), cryoglobulinemic vasculitis, lupus vasculitis, and antiglomerular basement membrane (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 small-vessel vasculitides have little or no vascular wall localization of immunoglobulins.45 The pauci-immune small-vessel vasculitides often have necrotizing and crescentic glomerulonephritis as a component of the systemic necrotizing vasculitis. A pathologically identical pauci-immune necrotizing and crescentic glomerulonephritis also occurs as a renal-limited process, sometimes referred to as “idiopathic crescentic glomerulonephritis” or “renal vasculitis.”76 Pauci-immune crescentic glomerulonephritis, usually a component of systemic pauci-immune small-vessel vasculitis, is the most common type of crescentic glomerulonephritis (Table 48.4).
TABLE 48.4 Frequency of Immunopathologic Categories of Crescentic Glomerulonephritis in More Than 3,000 Consecutive Nontransplant Renal Biopsies Evaluated by Immunofluorescence Microscopy in the University of North Carolina Nephropathology Laboratory | ||||||||||||||||||||||||
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