Vasculitis affecting the kidney

Seminars in Diagnostic Pathology (2009) 26, 89-102

Vasculitis affecting the kidney Rohan John, Andrew M. Herzenberg From the Department of Pathology, University Health Network, University of Toronto, Toronto, ON, Canada. KEYWORDS Vasculitis; Kidney; ANCA; Crescentic glomerulonephritis

Vasculitis refers to vessel wall leukocyte infiltration, often with necrosis, and can involve any of one or more vessels in the body. The kidney is commonly affected by vasculitis. Vasculitis is best classified based on the size of the involved vessels into large, medium, and small vessel disease. Small vessel vasculitis (SVV) that includes glomerulonephritis is by far the most frequent vasculitic lesion in the kidney, and the defining renal lesion is a necrotizing crescentic glomerulonephritis. Medium vessel vasculitis occasionally involves the kidney as necrotizing arteritis, and large vessel vasculitis only rarely affects the kidney, and most often secondarily by ischemia from proximal arterial narrowing. In this review, we describe the clinical and pathologic features of the various vasculitides that affect the kidney, with emphasis on SVV, particularly the type that is associated with anti-neutrophilic cytoplasmic antibodies (ANCA). We will also discuss the relevance of ANCA and describe evidence supporting the pathogenic role of these antibodies. It is important to remember that a histopathologic vasculitic lesion can be shared by several vasculitides, so that clinical data are most often required for disease classification. © 2009 Elsevier Inc. All rights reserved.

The vasculitides are a heterogeneous group of disorders defined by vessel wall inflammation and necrosis. A vessel involved in an inflammatory process beginning elsewhere, such as from an adjacent abscess or leukocyte diapedesis in postcapillary venules, is not classified as vasculitis. Vasculitis can be idiopathic (primary) or secondary to rheumatologic diseases, concurrent with infections, or caused by drugs. Direct invasion of endothelial cells by microorganisms produces a picture resembling vasculitis (infectious vasculitis), but is generally not considered a vasculitic lesion. The manifestations of disease are protean because the vasculitides can engage one or more vessels anywhere in the body from the aorta to the various capillaries and venules, and even veins. Clinical disease is a consequence of systemic inflammation, local inflammation, vascular narrow-

Address reprint requests and correspondence: Andrew M. Herzenberg, Department of Pathology, University Health Network, 11 Eaton, 200 Elizabeth St, Toronto, ON, M5G 2C4, Canada. E-mail address: [email protected].

0740-2570/$ -see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.semdp.2009.08.001

ing, occlusion, or rupture, and usually manifests in the skin, connective tissue, kidney, gastrointestinal tract, lung, or peripheral nerves. Renal involvement is common and may be the first expression of a systemic vasculitis. The nonspecific clinical features and the low incidence of disease make the diagnosis difficult in the absence of a biopsy, particularly in the case of small vessel vasculitis (SVV).1 Careful correlation with all available clinical and other laboratory data is usually required to make a definite diagnosis. A first attempt at classification of the vasculitides was made in 1952 and included hypersensitivity angiitis, allergic granulomatous angiitis, rheumatic arthritis, periarteritis nodosa, and temporal arteritis.2 Many classification systems have since been proposed, and none is universally accepted.3,4 The major two in use are the American College of Rheumatology classification from 1990, based largely on clinical criteria,5 and the subsequent Chapel Hill Nomenclature system from 1994, which provides definitions for the various vasculitides using pathologic features.6 According to the Chapel Hill classification system, which is probably the most accepted and the one we will follow, vasculitis is

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Table 1

Classification of primary vasculitis*

Large vessel vasculitis Giant cell (temporal) arteritis Takayasu’s arteritis Medium vessel vasculitis Polyarteritis nodosa Kawasaki disease Small vessel vasculitis ANCA-associated ● Wegener’s granulomatosis ● Microscopic polyangiitis ● Churg-Strauss syndrome ● Renal limited vasculitis Henoch-Schonlein purpura Essential cryoglobulinemic vasculitis Cutaneous leukocytoclastic angiitis *Chapel Hill classification (developed at the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis).7

classified based on size of involved vessels into large vessel vasculitis (LVV), medium vessel vasculitis (MVV), and SVV (Table 1). LVV primarily involves the aorta and its

branches; MVV primarily involves arteries other than the aorta; and SVV primarily involves arterioles and capillaries (Figure 1). The most important distinction lies in the recognition of involvement of arterioles or capillaries, which precludes a diagnosis of vasculitis other than that of the small vessels. Hence, in the context of primary vasculitis, glomerulonephritis is exclusive to the small vessel vasculitides, and the presence or absence of glomerulonephritis is helpful in evaluating vasculitis affecting the kidney (Table 2).

Small vessel vasculitis The small vessel vasculitides that affect the kidney include (1) anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (ANCA-SVV), which includes Wegener’s granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and renal limited vasculitis (sometimes referred to as idiopathic necrotizing crescentic glomerulonephritis); and (2) immune complex-mediated vasculitis, which includes

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Figure 1 (A, B) Necrotizing crescentic lesions in ANCA-SVV are typically segmental, and the remainder of the tuft appears normal without an increase in cellularity (A: PAS, ⫻200; B: PAS, ⫻400). (C) Large crescents are often associated with breaks (arrows) in Bowman’s capsule; the remainder of the glomerular tuft may still appear normal (PAS, ⫻200). (D) Glomerular basement membrane breaks (arrows) are a common finding and pathogenetically linked to crescent formation in cases of ANCA-SVV (PASML, ⫻400).

John and Herzenberg Table 2

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Classification of renal vasculitis, based on the presence of glomerulonephritis

With glomerulonephritis Pauci-immune/ANCA-associated* Wegener’s granulomatosis: Necrotizing crescentic glomerulonephritis, rarely with interstitial necrotizing granulomatous inflammation; mostly cANCA/PR3-positive; extrarenal: granulomatous inflammation involving the upper and lower respiratory tract. Microscopic polyangiitis: Necrotizing crescentic glomerulonephritis; often pANCA/MPO-positive. Churg-Strauss syndrome: Necrotizing crescentic glomerulonephritis, sometimes with eosinophil-rich granulomatous inflammation; pANCA/MPO-positive; extrarenal: eosinophil-rich granulomatous inflammation involving the lower respiratory tract, asthma, and eosinophilia. Renal limited vasculitis: Necrotizing crescentic glomerulonephritis; mostly pANCA/MPO-positive; no systemic symptoms. Drug-induced vasculitis: Necrotizing crescentic glomerulonephritis; exposure to propylthiouracil, hydralazine, methimazole, penicillamine; mostly pANCA/MPO-positive. Immune complex-mediated HSP nephritis: Endocapillary or mesangial proliferative glomerulonephritis with dominant/codominant staining for IgA immunoglobulin; extrarenal: purpura and abdominal pain, usually in children. Cryoglobulinemic vasculitis: MPGN pattern of glomerulonephritis with hyaline thrombi, significant staining for IgM immunoglobulin (mixed cryoglobulinemia), and microtubular substructure of deposits on electron microscopy; extrarenal: positive cryocrit. Lupus vasculitis: Intrarenal arteritis is extremely rare; segmental necrotizing crescentic glomerulonephritis may be a manifestation of vasculitis; extrarenal: symptoms and signs of SLE. No glomerulonephritis (no involvement of arterioles or capillaries) Polyarteritis nodosa: Necrotizing arteritis of intrarenal arteries; extrarenal: prominent systemic symptoms; active hepatitis B infection in 10%. Kawasaki disease: Arteritis (less necrotizing) of intrarenal arteries; extrarenal: child with mucocutaneous lymph node syndrome; coronary arteries often involved. Giant cell (temporal) arteritis: Rare involvement of renal artery ostia or main renal artery; extrarenal: granulomatous arteritis of the extracranial aortic branches, often involving the superficial temporal artery; ⬎50 years of age, usually elderly. Takayasu’s arteritis: Rare involvement of renal artery ostia or main renal artery; extrarenal: granulomatous arteritis of the aorta and its major branches; ⬍50 years of age, usually ⬍30 years of age. *Typically ANCA-positive (⬃90%) and negative by immunofluorescence for immunoglobulins/complement components; ANCA-negative or 1-2⫹ immunoglobulin staining are probably the same disease; also, cases of membranous or IgA nephropathy with necrotizing crescentic glomerulonephritis that are positive for ANCA behave similarly to the other ANCA-positive vasculitis.

Henoch-Schönlein purpura (HSP), cryoglobulinemic vasculitis, and lupus.6,7 As reflective of the frequency of ANCASVV among cases of renal vasculitis, of 313 consecutive cases collected from various hospitals in London, 246 were cases of ANCA-SVV, 25 were cases of HSP, 7 were cases of cryoglobulinemia, and 17 were cases of polyarteritis nodosa (PAN).8

ANCA-SVV It was a seminal publication in 1979 that first recognized that many patients with crescentic glomerulonephritis did not have immune complexes or anti-glomerular basement membrane (GBM) antibodies in the glomeruli, whereas other clinical and pathologic features were generally similar.9 That most cases of pauci-immune vasculitis would be associated with circulating antibodies against neutrophil cytoplasmic antigens was established a decade later.10,11 We now recognize ANCA-SVV to be systemic necrotizing small vessel diseases, with positive ANCAs against myeloperoxidase (MPO) or proteinase-3 (PR3), and a renal lesion of necrotizing crescentic glomerulonephritis with a paucity of immune complex deposits.12,13 The vasculitides were initially thought to be serum sickness-like diseases, associated with and believed to be due to vascular immune complex deposition.14 This may be true

for many forms of isolated cutaneous vasculitis15 but not for the large majority of systemic vasculitis. The latter show little or no immunoglobulin or complement deposition in the vessel wall, although this does not imply the absence of immunologically mediated injury.16 After all, immunosuppressive therapy had, for many years, been used effectively in systemic vasculitis.17 ANCA were first reported in 1982, as producing cytoplasmic staining by indirect immunofluorescence, when examining sera from patients with necrotizing glomerulonephritis for antinuclear antibodies against neutrophils.18 A succession of reports confirmed these ANCA, including a high sensitivity, and a relationship between ANCA presence and disease activity in patients with Wegener’s granulomatosis.19 A different perinuclear staining pattern was subsequently detected in sera from patients with microscopic polyangiitis and idiopathic necrotizing crescentic glomerulonephritis.20 The antigens producing cytoplasmic staining (cANCA) and perinuclear staining (pANCA) were identified as PR3 and MPO, respectively.20,21 It is now established that ANCA are IgG autoantibodies with specificity for proteins in the primary granules of neutrophils and lysosomes of monocytes. Atypical patterns of fluorescence different from the typical cytoplasmic or perinuclear staining also occur, and are usually produced by antigenic determinants other than PR3 and MPO, such as lactoferrin, lysozyme, elastase, cathepsin

92 Table 3

Seminars in Diagnostic Pathology, Vol 26, No 2, May 2009 Major evidence in support of ANCA pathogenicity

In vitro evidence ANCA-exposed TNF-␣ primed neutrophils degranulate and produce toxic enzymes and oxygen radicals, and cause endothelial cell lysis. In vivo evidence Clinical Correlation between disease relapse and ANCA titer. Drug-induced vasculitis is related to induction of ANCA and disappears on drug withdrawal. Single case of transplacental transfer of ANCA caused disease in the neonate. Laboratory MPO-immunized splenocytes and anti-MPO IgG from MPO knockout mice cause disease when injected into wild-type mice. Rats immunized with human MPO (cross-reacts with murine MPO) develop disease after renal perfusion of neutrophil granules, in the presence of low-dose anti-GBM antibody, or in the presence of a strong adjuvant.

G, or bactericidal/permeability increasing protein.22 Perinuclear staining is also not infrequently due to these latter antigens.23 Such MPO-negative pANCA and atypicalANCA are mostly found in patients with certain chronic inflammatory conditions, such as inflammatory bowel disease, autoimmune liver disease, and rheumatoid arthritis (RA).24,25 In the vast majority of cases of renal vasculitis, only PR3 and MPO are believed to be clinically significant. Immunofluorescence is sensitive but with lower specificity, so that it is recommended that positive ANCA testing by immunofluorescence be confirmed by ELISA for the specific antigens.23,26 Substantial evidence has accumulated over the years that strongly supports the disease pathogenicity of these antibodies,27-30 and the salient points have been presented in Table 3. Falk and coworkers were the first to show that ANCA could induce neutrophils in vitro to degranulate and produce toxic oxygen radicals and proteolytic enzymes.31 Many subsequent studies have confirmed the in vitro activity of ANCA-incubated neutrophils and their ability to secrete cytokines, express adhesion molecules, and ultimately, cause lysis of endothelial cells through both Fab binding and Fc receptor ligation.32,33 An important finding realized during these studies was that the neutrophil effects became most evident only when neutrophils were primed with tumor necrosis factor-alpha (TNF-␣), which increases the surface expression of PR3, MPO, and adhesion molecules. This has clinical relevance in that episodes of vasculitis are usually preceded by an infection that presumably has the same priming effect.34 Monocytes can also be stimulated by ANCA to release inflammatory cytokines and oxygen radicals.35,36 Clinically, although the relationship between ANCA titer and disease activity may not be that strong, there is a reasonable correlation between the occurrence of disease relapse and a preceding rise in ANCA, or by lack of suppression of ANCA after clinical remission on therapy.37,38 A compelling case for the role of ANCA in disease was documented in a neonate who developed pulmonary–renal disease after transplacental transmission of IgG anti-MPO antibody that was documented in the cord blood.39 The mother showed clinically active disease late during preg-

nancy, and the neonate manifested disease relatively soon after delivery. Various animal models of necrotizing glomerulonephritis have been used to substantiate a mechanism for ANCA in disease. Early models relied on polyclonal B cell activation that generated not just MPO but a host of other antibodies,40 ANCA-sensitized rats that were also administered anti-GBM antibodies,41 or ANCA-sensitized rats that required intrarenal perfusion of neutrophil granules.42 Rats immunized with human MPO (cross-reacts with murine MPO) in the presence of a complete Freund’s adjuvant, however, did develop disease.43 The best model so far is that of Xiao and coworkers, in which disease was produced in either wild-type or T cell/B cell-deficient mice after adoptive transfer of anti-MPO splenocytes or anti-MPO IgG from MPO knockout mice immunized with murine MPO.44 Using the same model, the authors have also shown the need for TNF priming to produce disease and that depletion of neutrophils abrogates disease.45,46 Recently, a role for complement, in particular the alternative pathway, has also been highlighted.47 Neutrophils contain complementactivating products, and complement activation is also needed for the pathologic manifestations.47,48 Although ANCA may be essential, other components of the immune system, such as T cell and macrophages, also likely have some effect on disease. Not only is T cell costimulation important for ANCA production, but T cells are also present in glomerular lesions, albeit in fewer numbers than monocytes.49,50 Monocytes are potent stimulators of proinflammatory cytokines, and like neutrophils, also respond to ANCA. It has been suggested that even low-level immune complex deposition may contribute toward disease.44 It is not clear why and how ANCA develop. Genetic and environmental influences, in particular silica, have been proposed to play a role.51,52 Many drugs are capable of inducing ANCA and subsequent vasculitis.53 The antithyroid drug propylthiouracil has been the most implicated.54 There is also a relationship between the degree of innate surface expression of PR3, which is genetically determined, and the incidence of vasculitis and the occurrence of disease relapse after therapy.55 An older theory that has gained favor is that idiotypic-anti-idiotypic networks may be in-

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volved and microbial antigens could be the trigger for autoantibody production. Some studies have shown that Staphylococcus aureus nasal carriage is associated with a greater likelihood of vasculitis and a higher incidence of disease relapse among patients with Wegener’s granulomatosis.56 It was recently shown that generation of anti-PR3 might be a consequence of an initial antibody response to the complementary peptide of PR3 (termed cPR3), and similarities between microbial antigens, including S. aureus, and cPR3 do exist.57 In this situation, an antibody to anti-cPR3 develops, and the antibody is ANCA with specificity for PR3. Interestingly, anti-cPR3 antibodies have specificity for plasminogen, and can be associated with deep venous thrombosis, as is seen in some cases of ANCASVV.58 Still, in most patients, the cause of ANCA is not known.

Clinical features ANCA-SVV affects men and women equally, peaking in the 6th and 7th decades of life, with a 7- to 8-fold predilection toward Caucasians. Disease is most often systemic, but limited to the kidney in ⬃20% of cases.34 Pulmonary hemorrhage from capillaritis and necrotizing glomerulonephritis are the most serious manifestations of disease. Among causes of the pulmonary–renal syndrome, ANCA-SVV is much more common than Goodpasture’s syndrome or any of the connective tissue disease-related vasculitides.59-61 The typical renal presentation is that of a rapidly progressive glomerulonephritis with acute renal failure, hematuria, red cell casts, and low-grade proteinuria. Infrequently, the disease is more indolent, with a remitting and relapsing course leading to chronic renal failure or acute on chronic renal failure because of prior episodes of disease.

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Pathologic features Light microscopy The typical lesion of small vessel vasculitis is segmental vascular leukocyte infiltration and fibrinoid necrosis that manifests in the glomerulus as crescentic glomerulonephritis. Leukocyte infiltration is generally not as prominent as seen in affected arteries, and involved glomerular segments usually contain only mild neutrophil or mononuclear cell infiltration. Fibrinoid necrosis is deeply acidophilic with hematoxylin and eosin stain, deep red with Trichrome stain, and has a coarse granular or smudgy appearance with PAS stain (different from hyalinosis or immune deposits, which are smooth and glassy). Karyorrhectic debris or apoptotic neutrophils are also often present, and a silver stain can be useful to highlight breaks in the GBM (Figure 1). Within glomeruli, fibrinoid necrosis and crescents are most often seen together and are likely pathogenetically related.62 Fibrin appears to be a potent stimulus for crescent formation. Cellular crescents are composed predominantly of monocyte/macrophages and epithelial cells, and the former are present in greater numbers when there are breaks in Bowman’s capsule.63,64 In some cases, the changes are more chronic and the crescents may appear fibrocellular or fibrous (Figure 2) without any fibrinoid necrosis, whereas prior necrotizing glomerular lesions may be evidenced by segmental glomerular scars or global glomerulosclerosis. It is worthwhile noting that fibrous crescents alone are not sufficient to confirm old healed vasculitis in the absence of active SVV that was previously confirmed histologically. In active ANCA glomerulonephritis, uninvolved glomerular segments glomeruli without crescents generally have no increase in cellularity, in contrast to immune complexmediated glomerulonephritis, where the glomeruli show

B

Figure 2 Active cellular crescents, in this case with little recognizable glomerular tuft remaining (A), resolve by becoming fibrous crescents (B) (A: PAS, ⫻400; B: PAS, ⫻200).

94 global and diffuse endocapillary hypercellularity and thick capillary walls from immune deposits. On average, half the glomeruli have crescents, although necrosis is usually identified in fewer.59,65 To make a diagnosis of ANCA-SVV, there is no minimum number of crescents that are required, although in the past, some have suggested that a minimum of 30% or 50% crescents are required. It is now clear that even a single crescent or necrotizing lesion is enough to establish the diagnosis in the right clinical setting. The other major causes of crescentic glomerulonephritis are anti-GBM and immune complex diseases (Table 4). ANCA glomerulonephritis is overall the most common cause of crescentic glomerulonephritis and accounts for ⬃80% of cases in patients over 60 years.66 Immune complex diseases such as lupus, poststreptococcal glomerulonephritis, IgA nephropathy, and membranoproliferative glomerulonephritis are together as common as ANCA crescentic glomerulonephritis in children and young adults. Anti-GBM disease accounts for 10% to 15% of cases in all age groups. In general, anti-GBM crescentic glomerulonephritis has greater (⬃80%) and immune complex-mediated crescentic glomerulonephritis fewer (⬃30%) numbers of glomeruli with crescents.59 The lack of glomerular hypercellularity within undamaged glomerular segments is shared by antiGBM and ANCA crescentic glomerulonephritis. Although

Table 4 Classification of necrotizing crescentic glomerulonephritis, based on pattern of immunofluorescence staining Pauci-immune (no or little staining) Wegener’s granulomatosis Microscopic polyangiitis Churg-Strauss syndrome Renal limited disease Drug-induced Immune complex mediated (strong granular staining for Ig and/or C3) Lupus Cryoglobulinemic vasculitis/idiopathic membranoproliferative glomerulonephritis* Henoch-Schonlein purpura/IgA nephropathy† Post-streptococcal glomerulonephritis Fibrillary glomerulonephritis Other Anti-GBM disease/Goodpasture’s syndrome‡ (strong linear staining for IgG) *Cryoglobulinemic and idiopathic membranoproliferative glomerulonephritis cannot often be distinguished in the renal biopsy; cryoglobulinemic glomerulonephritis may show luminal hyaline thrombi by LM, strong IgM staining by IF, and microtubular substructure to the immune deposits by EM. †HSP and IgA nephropathy manifest similarly in renal biopsies, and are defined by dominant/codominant staining for IgA; when groups of HSP and IgA nephropathy patients are compared, HSP shows more cases of endocapillary proliferation and crescents. ‡Approximately half of all patients with necrotizing crescentic glomerulonephritis due to anti-GBM disease have pulmonary involvement (Goodpasture’s syndrome); isolated pulmonary disease is rare (⬃5%).

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Figure 3 Necrotizing arteritis in an interlobular artery with deeply acidophilic fibrinoid necrosis and perivascular acute and chronic inflammatory cells in a case of Wegener’s granulomatosis; some eosinophils are present but do not imply Churg-Strauss syndrome (H&E, ⫻200).

immunofluorescence is required to separate these two entities, anti-GBM disease usually appears histologically more severe and uniform, often allowing for a presumptive diagnosis of one or the other on light microscopy alone. Extraglomerular vascular involvement can be seen in 10% to 20% of renal biopsy specimens.67,68 Vasculitis is most often seen in the interlobular arteries, although larger arteries can be affected as well. Affected arteries show fibrinoid necrosis with prominent mural and perivascular infiltration by neutrophils and mononuclear cells (Figure 3). The presence of intrarenal arteritis has been associated with the presence of systemic disease and also greater glomerular involvement.68,69 It should be remembered that the presence of necrotizing arteritis does not distinguish SVV from MVV, and only identifying glomerulonephritis can exclude MVV, such as PAN. Occasionally, the medullary vasa recta can show a necrotizing leukocytoclastic angiitis, with hemorrhage and marked neutrophilic infiltration with leukocytoclasia that is reminiscent of the histopathology of cutaneous vasculitis.70 Overall, medullary angiitis is uncommon, so that a renal biopsy specimen with only medulla has low sensitivity for SVV. Rarely, papillary necrosis can occur. Tubulointerstitial changes, such as interstitial edema, inflammation, and tubular degeneration, are common with severe glomerulonephritis. If the specimen has only a few glomeruli and these appear uninvolved, such tubulointerstitial changes may be a clue to severe glomerular injury when the clinical picture is that of severe glomerulonephritis. A mixed interstitial leukocytic infiltration is most prominent close to inflamed glomeruli, but is often diffuse, and is also related to the tubular degenerative changes.50 Periglomerular granulomatous inflammation that may include multinucleated giant cells is often associated with breaks in Bowman’s capsule.71 Periglomerular granulomas can be seen in all types of ANCA-associated glomerulonephritis and are

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not specific for Wegener’s granulomatosis.68 By contrast, interstitial necrotizing granulomatous inflammation is typical of Wegener’s granulomatosis, but is seen in ⬍10% of cases.72 Some eosinophil infiltration can be seen in any of the ANCA-SVV, but when numerous, raises the possibility of Churg Straus syndrome. Immunofluorescence and electron microscopy By definition, pauci-immune crescentic glomerulonephritis has little or no glomerular staining for immunoglobulin or complement components and no corresponding electron dense deposits. This contrasts with the other crescentic glomerulonephritis, anti-GBM disease, and immune complex-mediated diseases, which show linear and granular capillary wall immunoglobulin staining, respectively. It has recently become appreciated that low-level immune complex deposition is not uncommon in the ANCA-associated glomerulonephritis, and the presence of small immune-type deposits may be seen by electron microscopy in many cases.73,74 Both 1⫹ and 2⫹ staining on a scale of 1 to 4 have been advocated as pauci-immune. In the absence of significant light microscopic changes of immune complex diseases, we feel that the presence of immune deposits should not dissuade one from diagnosing ANCA-type SVV. In some cases, a definite underlying immune complex disease, which is commonly IgA nephropathy, or sometimes membranous glomerulonephritis can be diagnosed.75,76 In fact, many cases of ANCA-SVV probably have underlying mild IgA nephropathy (Figure 4). In these situations, it appears that ANCA dictates disease expression on a background of immune complex disease. The absence of significant glomerular hypercellularity is a clue to the presence of ANCA when crescents are present in a case of IgA nephropathy. This would be corroborated by the absence of subendothelial immune deposits by electron microscopy. Up to

Figure 4 A case of PR3-positive ANCA-SVV. Mild mesangial prominence (arrows) in the segment away from the necrotizing lesion attests to an underlying immune complex disease, which in this case, and not uncommonly, is IgA nephropathy (PAS, ⫻400).

95 25% of all cases of immune complex glomerulonephritis may be ANCA-positive, although the majority do not manifest crescentic glomerulonephritis and often do not have SVV. Additionally, approximately 30% of cases of antiGBM disease are positive for ANCA.77 In these latter cases, however, the pathology and outcome are modified by the presence of ANCA and show overlapping features of both diseases.74 Clinicians and pathologists should also remember that 5% to 10% of renal SVV is ANCA-negative. The pathologic features or the severity of involvement do not usually distinguish between Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome.11 The frequency (⬃75%) of renal involvement is the same in Wegener’s granulomatosis and microscopic polyangiitis, and less in Churg-Strauss syndrome (30-40%).78 Once renal involvement by vasculitis is diagnosed, the prompt institution of therapy, usually with high-dose corticosteroids and cyclophosphamide, is more important than deciding the accurate disease category. The degree of renal failure at the start of therapy is probably the best predictor for outcome for all types of crescentic glomerulonephritis.8 A pending or even negative ANCA should not dissuade the pathologist from diagnosing ANCA-type vasculitis. Regardless of what term is used to denote ANCA-associated SVV, one term that we particularly discourage using is “microscopic PAN” because it can be easily confused with PAN, which is not associated with ANCA.79 The use of the eponymic terms to describe these diseases is starting to fall out of favor, and is instead replaced by anti-PR3-SVV and anti-MPO-SVV. It should be noted that, because Friedrich Wegener was a Nazi SA officer, there are some who advocate not keeping this eponym in particular.80,81 Over 90% of active Wegener’s granulomatosis and microscopic polyangiitis patients are positive for ANCA. Most cases of Wegener’s granulomatosis are associated with PR3, and most cases of microscopic polyangiitis are associated with MPO. However, there is frequent overlap, and the specificities cannot be used to distinguish between the two. When separated by ANCA specificity, MPO-associated disease tends to be more chronic than PR3 disease.65 Systemically, Wegener’s granulomatosis has granulomatous inflammation; Churg-Strauss syndrome has granulomatous inflammation, asthma, and eosinophilia; and microscopic polyangiitis does not have granulomas or asthma.12 In contrast to Wegener’s granulomatosis and microscopic polyangiitis, ANCA are positive in only ⬃40% of patients with Churg-Strauss syndrome.82,83 It has been suggested that Churg-Strauss syndrome may manifest two different phenotypes dichotomized by ANCA.84 In keeping with this, ANCA-positive Churg-Strauss syndrome has more glomerulonephritis and pulmonary vasculitis, whereas ANCA-negative Churg-Strauss syndrome shows more cardiac involvement and pulmonary inflammation with eosinophils.

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Non-ANCA-SVV (immune complex vasculitis) The non-ANCA-related small vessel vasculitides that affect the kidney include cryoglobulinemic vasculitis and HenochSchönlein purpura/nephritis (Table 1). Vasculitis associated with connective tissue disease are not among the primary vasculitides, but will be discussed here. Lupus is the major connective tissue disease that involves the kidney and does so often. All the non-ANCA-SVV are immune complexmediated diseases. Varying degrees of either deposition of circulating immune complexes or in situ formation of immune complexes occur, and tissue damage is largely a result of complement activation.

Cryoglobulinemic vasculitis The syndrome of cryoglobulinemia involves the kidney in about 25% of cases, and renal disease is largely due to type 2 (formerly essential mixed cryoglobulinemia, usually due to hepatitis C virus) or less commonly, type 3 (due to chronic infections, particularly hepatitis C, or connective tissue diseases) cryoglobulinemia.85,86 Type 1 (monoclonal) cryoglobulinemic renal disease has only rarely been reported, in association with Waldenström’s macroglobulinemia or chronic lymphocytic leukemia.87 Renal involvement presents with proteinuria and hematuria with overlapping nephrotic–nephritic presentations. Clinically, hypocomplementemia is almost always present, and the detection of cryoglobulins is a supportive finding. The cryocrit or level of cryoglobulinemia weakly correlates with disease activity, although the incidence of disease is higher at higher cryocrit levels. In one study, 21% of patients with cryocrit ⬎5% had glomerulonephritis compared with 9% of patients with levels ⬍5%.85 In another study among patients with renal involvement, a cryocrit ⬎10% was associated with a worse renal outcome.88 The typical histopathologic pattern in the kidney is membranoproliferative glomerulonephritis (MPGN), in which there is both capillary wall thickening from immune complex deposits and increased glomerular cellularity (Figure 5).86,89 The glomeruli tend to be diffusely involved and are enlarged and hypercellular with an accentuated lobular architecture. The cellularity is increased in both the mesangium and the capillary lumina, but the mesangial areas may appear to coalesce into the endocapillary area and may be hard to distinguish. In older literature, this pattern has also been referred to as mesangiocapillary glomerulonephritis because of the tendency for mesangial cells to interpose into the capillary wall. Of note is that the increased glomerular cellularity is mostly due to increased numbers of infiltrating monocytes, higher than seen in idiopathic MPGN or other glomerulonephritis.90 Luminal hyaline thrombi, which consist of the cryoglobulin–immune complexes, are also characteristic. Double contouring, which refers to duplication of the GBM, is typical of MPGN in general, and is best seen

Figure 5 Typical pattern of MPGN with mesangial and endocapillary hypercellularity and thick capillary walls with double contouring. The case is subacute with a degree of glomerular cellularity in between acute and chronic. Hyaline thrombi were not seen in this case (PAS, ⫻200).

with a silver stain. A crescentic glomerulonephritis is present in approximately 20% of patients.59,86 Occasionally, the biopsy may show only mesangial proliferation with patent capillary loops, termed mesangial proliferative glomerulonephritis.86 Chronic cases of cryoglobulinemic glomerulonephritis show sclerotic mesangial centers in a pattern of nodular mesangial sclerosis resembling nodular diabetic glomerulosclerosis. Still there is some endocapillary hypercellularity and the glomerular nodularity is uniform, unlike that of diabetes. Arterial fibrinoid necrosis, mostly of the interlobular arteries, occurs in roughly 5% of cases, although higher numbers have also been reported.86,91 Immunofluorescence shows granular capillary staining for immunoglobulins, usually with prominent IgM, which is a clue to cryoglobulinemia. By electron microscopy, widespread subendothelial electron-dense deposits are typical of MPGN. Mesangial deposits are also present, but the mesangial area is not always clearly recognizable. Mesangial interpositioning can be seen as mesangial cells extending into the peripheral capillary walls. Typical of cryoglobulins, the electron-dense deposits at higher magnification sometimes resolve into a substructure composed of microtubules or annular–tubular deposits with some similarity to fingerprint structures in lupus.92

Henoch-Schönlein purpura/nephritis HSP is a systemic vasculitis defined by the presence of IgA dominant immune deposits in small vessels in a distribution that mirrors the symptomatology.93 The disease is much more commonly seen in children and typically presents with abdominal pain, purpura due to leukocytoclastic vasculitis, arthralgias, and nephritic signs and symptoms. Adult cases

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of HSP are not that uncommon and do occur at an incidence of approximately 5% of that in children.94 Although glomerular IgA deposition is specific, all forms of cutaneous vasculitis that show IgA deposits are not necessarily HSP.95 Like IgA nephropathy, the type of renal disease is quite variable. HSP nephritis commonly presents as different degrees of hematuria with proteinuria, and the histopathology often reflects the diverse clinical presentation. Glomeruli can show only mesangial hypercellularity, or different degrees of endocapillary hypercellularity that can include crescents. Some biopsies may show only segmental sclerosing lesions. In general, HSP shows more severe disease than IgA nephropathy, and adults with HSP have worse disease than children.93,96 As in IgA nephropathy, immunofluorescence is diagnostic and shows the presence of IgA dominant or codominant staining, with C3 in most cases, and IgG or IgM is also often present. Necrotizing arteritis like that seen in the skin is only rarely seen in the renal biopsy. In a large series of 250 adults with HSP, there were only 2 cases of arteritis involving the interlobular arteries.96

RA only occasionally affects the kidney as amyloidosis, interstitial nephritis, membranous glomerulonephritis, or mesangial proliferative glomerulonephritis.106,107 Necrotizing glomerulonephritis has also been reported in RA, and many of these patients also have systemic vasculitis.108 It is now felt that most, if not all, of such cases are associated with ANCA, including some induced by TNF-␣ antagonist therapy.109,110 In a cohort of 246 patients with RA from Finland, ⬃20% of patients demonstrated positivity for pANCA, and nephropathy was more common in those with ANCA.111 Rare cases of vasculitis in RA may involve a larger intrarenal artery.112 Sjögren’s syndrome most commonly manifests in the kidney as tubulointerstitial nephritis.113 Various forms of immune complex glomerulonephritis and vasculitis can occur, but these are most often related to accompanying cryoglobulinemia or associated connective tissue diseases, such as lupus.114,115

Connective tissue disease-associated small vessel vasculitis

The MVV include PAN and Kawasaki disease, both of which cause necrotizing arteritis of medium-sized arteries. The MVV differ from SVV in that the disease is limited to arteries and does not affect arterioles or capillaries. From a renal perspective, this implies that glomerulonephritis precludes PAN or Kawasaki disease. Although both diseases show a not dissimilar frequency of renal involvement at autopsy, clinically significant renal disease occurs less often with Kawasaki disease.

Many connective tissue diseases, including lupus, RA and Sjögren’s syndrome, have been associated with vasculitis. Lupus in particular is not an uncommon cause of systemic vasculitis, although isolated cutaneous vasculitis probably occurs most frequently. The renal manifestations of lupus are varied, including many forms of vascular pathology.97-99 Vascular lesions can manifest as uncomplicated immune complex deposits, necrotizing noninflammatory deposits (lupus vasculopathy), thrombotic microangiopathy (TMA), necrotizing vasculitis, and nonspecific arteriosclerosis.99 The distinction in the expression of lupus-related vascular disease is not always made, in part because of inherent morphologic difficulty, and because the otherwise rigorous lupus classification does not include vascular changes. Banfi and coworkers reported 28% of 285 patients with lupus nephritis to have renal vascular lesions: 51 cases were either lupus vasculopathy or TMA, 20 cases were hypertensive-type arterial sclerosis/ arteriolar hyalinosis, and 8 cases were vasculitis.100 Vasculitis, similar to ANCA-type vasculitis with necrosis and leukocyte infiltration, is rare, with a reported frequency of 0.3% to 2.8% of all cases of lupus nephritis.100-102 The independence of pathogenesis has been questioned, particularly in the context of necrotizing glomerulonephritis. It has been suggested that ANCA may be involved in such cases of renal vasculitis.103 Overall, ANCA has been identified in up to 25% of cases of lupus. Lewis and coworkers have argued that some cases of lupus nephritis with segmental necrotizing glomerular lesions are of a vasculitic nature, and portend poor outcome.104 Others disagree, and still whether ANCA play a role in such cases is not known.105

Medium vessel vasculitis

Polyarteritis nodosa PAN is the prototypic vasculitis.4 The earliest descriptions of necrotizing arteritis consisting of segmental arterial fibrinoid necrosis and neutrophil infiltration were referred to as PAN because of the grossly observed nodular arterial lesions. The name was later changed to PAN nodosa to reflected multiple vessel involvement, and when it was recognized that the inflammation was within the vessel wall and not outside. For a long time, PAN remained a somewhat inclusive term for many vasculitic diseases. Most of the literature before 1994 includes microscopic polyangiitis with PAN, and the clinical features and pathology are difficult to ascribe to one or the other. The Chapel Hill classification excludes the presence of glomerulonephritis when diagnosing PAN, and clinical and epidemiologic differences have helped separate PAN from microscopic polyangiitis.6,79 A recent study examined the features of almost 1000 patients with vasculitis and suggested that inclusion of neuropathy and arteriographic abnormalities, as well as the exclusion of features seen in the SVV, particularly the absence of ANCA, improves the specificity of a diagnosis of PAN.116 PAN presents as systemic vasculitis most often with a combination of fever, weight loss, arthral-

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gias, myalgias, peripheral neuropathy, and gastrointestinal and renal involvement.117 There is a definite association between PAN and active hepatitis B infection. However, there has been marked decline in the incidence of hepatitis B-related PAN, largely due to the declining incidence of hepatitis B infection.118 Currently, only approximately 10% of PAN is attributed to hepatitis B. Renal involvement occurs in approximately 40% of cases, manifesting as flank pain and hematuria, and rarely, with hemorrhage from arterial rupture.119 The disease causes a necrotizing arteritis, commonly of the main renal artery, but also of the interlobar and arcuate arteries. Because the lesions are often focal, and renal biopsies usually only include limited sampling of these arteries, renal biopsy is a very insensitive technique of diagnosing PAN. Rather than on kidney biopsy, the diagnosis is usually confirmed radiographically by various angiographic techniques. If PAN is seen histologically, the acute lesions show fibrinoid necrosis with neutrophilic infiltration (Figure 6) that is often segmental and, in the early stages, confined to the intima and media.119 Later, mononuclear cells infiltrate the lesion and inflammation becomes transmural. Immunofluorescence and electron microscopic examination show evidence for immune complex deposition only in the cases that are associated with hepatitis B.120

and often appears more edematous with a prominent infiltrate of monocytes even in the acute stage.124

Kawasaki disease The disease occurs almost exclusively in children and presents with mucocutaneous rash and nonsuppurative lymphadenopathy (mucocutaneous lymph node syndrome).121 Renal involvement has been documented at autopsy or by imaging, although clinically significant disease is rare.122 Kawasaki disease can lead to renovascular hypertension, but is a much less common cause than Takayasu’s arteritis.123 The arteritis in Kawasaki disease usually has less fibrinoid necrosis than PAN

Large vessel vasculitis The LVV include giant cell (temporal) arteritis and Takayasu’s arteritis, both of which are diseases of the aorta and its main branches. LVV are chronic inflammatory conditions, so in contrast to both MVV and SVV, the histologic findings consist of granulomatous infiltrates and not neutrophils or fibrinoid necrosis. The renal lesion in LVV is usually a result of hypertension secondary to renal ischemia from inflammatory obstruction at the ostia of the renal arteries or the main renal artery, and the intraparenchymal arteries are only rarely involved.

Giant cell arteritis Giant cell arteritis is a granulomatous vasculitis of large arteries, preferentially involving the extracranial branches of the aorta, in particular the superficial temporal artery. The disease usually presents as new onset headache in a person over the age of 50 years in association with an elevated erythrocyte sedimentation rate (or C-reactive protein).125 Polymyalgia rheumatica is an overlapping vasculitic process related to giant cell arteritis.126,127 The use of the term temporal arteritis is discouraged, because not only is the temporal artery not always involved,128 but both small and medium vessel vasculitides can also affect the temporal artery.129,130 Although renal disease usually manifests as ischemic induced hypertensive disease from proximal arterial obstruction, microscopic hematuria can be seen in ⬃30% of cases.131 Intraparenchymal renal arteries are rarely involved.132 Histologically, mononuclear cells, including lymphocytes and macrophages, can be seen throughout the arterial wall but may be seen only in the adventitia or media. Multinucleated giant cells are seen in many cases and tend to be centered on a fragmented elastic lamina. Small areas of necrosis can be seen, but the LVV do not typically show the fibrinoid necrosis of SVV or MVV. Chronic disease is manifested by fibrosis of the arterial wall, and inflammatory cells may be few.

Takayasu’s arteritis

Figure 6 Necrotizing arteritis in an arcuate artery with deeply acidophilic fibrinoid necrosis and a marked acute inflammatory infiltrate in a case of PAN (H&E, ⫻100).

Takayasu’s arteritis is another type of granulomatous LVV affecting the aorta and its major branches. The disease occurs in persons ⬍50 years of age, usually before the 4th decade, and is 9-fold more common in women.133 The clinical features include reduced pulses (pulseless disease), bruits, claudication, and hypertension, in addition to constitutional symptoms of fever, arthralgias, and weight loss. Renal arterial involvement with hypertension has been reported in 40% to 60% of cases, and renal artery stenosis

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results in ischemic atrophy of the renal cortex.134 Among 205 patients with renovascular hypertension in one study from India, 61% were attributed to Takayasu’s arteritis.135 Affected arterial segments often have thickened walls. Disease frequently results in stenosis, but there may also be dilatation with or without aneurysmal degeneration. Microscopically, the disease is a panarteritis with mononuclear cell infiltration in the intima, media, and adventitia. The inflammatory infiltrate is often a mixture of lymphocytes and macrophages with varying numbers of multinucleated giant cells. As in giant cell arteritis, chronic disease is represented by fibrosis, which may be marked, and only a few inflammatory cells, whereas an irregular and partly destroyed elastic lamina supports a diagnosis of prior arteritis. There are reports of unusual proliferative glomerular lesions in patients with Takayasu’s arteritis, and most of these are likely coincidental. The one type of lesion, however, that may be a result of proximal arteritis includes the findings of mesangiolysis, microaneurysms, and mesangial nodular expansion.136 A similar lesion is typical of advanced diabetic glomerulosclerosis and presumably results from a combination of glomerular hypertension and ischemia.

Conclusions SVV that includes glomerulonephritis is the most frequent vasculitic lesion in the kidney. Medium vessel disease as intrarenal arteritis is uncommon, whereas large vessel disease is rare and mostly results in renal ischemia. SVV can be pauci-immune, due to IgA (Henoch-Schönlein nephritis) or cryoglobulin deposition in the vessel wall, or secondary from systemic rheumatologic diseases, such as lupus. The defining histopathologic lesion of the pauci-immune SVV, which includes microscopic polyangiitis, Wegener’s granulomatosis, and Churg-Strauss syndrome, is a necrotizing crescentic glomerulonephritis. Other less common causes of crescentic glomerulonephritis include immune complex disease, mainly lupus, and anti-GBM disease. ANCA can be detected in 90% of patients with Wegener’s granulomatosis and microscopic polyangiitis, but ⬍50% of patients with Churg-Strauss syndrome. cANCA is due to PR3, and pANCA is due to MPO or other antigens that are not clinically relevant. Wegener’s granulomatosis more commonly has PR3, and microscopic polyangiitis more commonly has MPO, but overlap is sufficient to preclude diagnosis based on ANCA type. The renal disease caused by ANCA-SVV are remarkably similar. Systemically, Wegener’s granulomatosis has necrotizing granulomatous inflammation; Churg-Strauss syndrome has granulomatous inflammation, asthma, and eosinophilia; and microscopic polyangiitis has neither granulomas nor asthma. The arteritis of PAN, although often causing renal insufficiency, does not involve arterioles or capillaries (glomeruli), and therefore is only very rarely seen in renal biopsies.

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