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Year : 2000  |  Volume : 11  |  Issue : 3  |  Page : 362-369
Anti-neutrophil Cytoplasmic Antibodies and Glomerulonephritis: An Update

Department of Medicine, Japan Self Defense Forces Kumamoto Hospital, Kumamoto, Japan

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How to cite this article:
Oda T. Anti-neutrophil Cytoplasmic Antibodies and Glomerulonephritis: An Update. Saudi J Kidney Dis Transpl 2000;11:362-9

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Oda T. Anti-neutrophil Cytoplasmic Antibodies and Glomerulonephritis: An Update. Saudi J Kidney Dis Transpl [serial online] 2000 [cited 2022 Jan 18];11:362-9. Available from: https://www.sjkdt.org/text.asp?2000/11/3/362/36658

   Introduction Top

Anti-neutrophil cytoplasmic antibodies (ANCA) in patients with segmental necrotizing glomerulonephritis (GN) was originally described by Davies et al, [1] and have since been identified in patients with systemic vasculitis. These autoantibodies remain the subject of extensive investiga­tions for their role as diagnostic and follow­up tools, as well as being important factors in the pathogenesis of systemic vasculitis. Indeed, the discovery of ANCA has considerably changed the concept of this disease and its categories, and a new nomenclature for systemic vasculitis has recently been proposed. [2] The present report uses the terminology and definition of this classification. The key contribution of ANCA to GN is that of a changed concept of idiopathic crescentic GN, which was originally classified only as a type of GN. However, the high frequency of ANCA positivity and a similarity of renal histological manifes­tations led to the belief that crescentic GN is a renal restricted form of systemic vasculitis. In fact, most ANCA positive, pauci-immune (absence or paucity of immunohistological staining for immuno­globulins at sites of vasculitis) small vessel vasculitis such as Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Straus syndrome (CSS), are usually accompanied by GN. The histological features of this condition are characterized by focal glomerular tuft necrosis and the crescent formation; appearances that are identical to idiopathic crescentic GN. More­over, the frequency of ANCA positivity in idiopathic crescentic GN is high and essentially identical to that of MPA. Some investigators use the terminology of "ANCA associated GN" for patients with positive ANCA and histologically pauci-immune necrotizing and crescentic GN.

This review summarizes the current status of ANCA testing as a diagnostic/follow-up tool and the pathogenesis of idiopathic crescentic GN and vasculitis. However, many issues remain controversial.

   ANCA: Significance as diagnostic and follow-up tools Top

Significance as a diagnostic tool

ANCA are frequently identified in patients with pauci-immune systemic small vessel vasculitis such as WG, MPA, CSS (these diseases are now termed ANCA associated vasculitis) and idiopathic crescentic GN. Early reports described the specificity and sensitivity of ANCA for these diseases as being very high. [3],[4] Niles et al reported that the sensitivity and the specificity of ANCA for pauci-immune crescentic GN approaches 95% and 99%, respectively. [5] However, the popularization of the assay and availability of controls for various diseases revealed that the sensitivity and specificity of ANCA were actually quite low. [6],[7] The method of detecting ANCA may be a factor. The standard method is indirect immunofluo­rescence (IIF) using alcohol-fixed normal human neutrophils as the substrate. This method distinguishes cytoplasmic (cANCA), and perinuclear locations (pANCA). The target antigens recognized by most cANCA positive sera are proteinase 3 (PR3) whereas that of pANCA is usually myeloperoxidase (MPO), although other neutrophil cyto­plasmic antigens such as elastase and lactoferrin have also been recognized. [8],[9],[10] These antigen specific ANCA (PR3-ANCA and MPO-ANCA) can be detected by enzyme-linked immunosorbent assay (ELISA). The results of ANCA positivity obtained by IIF and by ELISA do not always correlate, since some patients can be positive by ELISA and negative by IIF and vice versa. Among patients with WG, cANCA (or PR3-ANCA) are most frequent but are not specific for this disease. Patients with MPA, idiopathic crescentic GN, and CSS are usually positive for pANCA (or MPO-ANCA), but these antibodies are also associated with ulcerative colitis, rheumatoid arthritis and infective endocarditis. [11],[12] The European ANCA assay standardization project recently reported [13] that ANCA detected by IIF (cANCA or pANCA) are sensitive markers for WG, MPA and pauci­-immune crescentic GN (sensitivity score 81-85%), but have low specificity (76%, related to disease control). The direct ELISA methods that they developed and standardized were not any more sensitive than the IIF tests, but when the results of the latter were combined with those of the ELISA (c/PR3-ANCA positive, p/MPO­-ANCA positive), the diagnostic specificity increased to 99%. The sensitivity levels of this combination for WG, MPA and crescentic GN are 73%, 67% and 82%, respectively. Thus, in a significant number of patients with idiopathic small vessel vasculitis, ANCA test results (either in IIF or ELISA) are negative. Although ANCA are more frequently found in patients with pauci-immune necrotizing crescentic GN and vasculitis, about one third of those with anti-GBM GN have ANCA, [5],[14] as do 50% of patients with immune-complex crescentic GN. [15] In addition, Ronda et al have reported that ANCA of the IgA isotype are frequently detected in sera from adult patients with Henoch-Schonlein purpura, [16] whereas others could not detect any type of ANCA in such patients. [17]

In summary, c/PR3-ANCA is frequently associated with WG, while p/MPO-ANCA is usually detected in patients with MPA, idiopathic crescentic GN, and CSS. Yet, neither ANCA subtype provides a test that allows diagnostic differentiation among types of ANCA associated vasculitis. [18] However, ANCA can differentiate certain types of small vessel vasculitis (including crescentic GN) from non-vasculitic disease in a reasonably sensitive and highly specific manner when assayed by a combination of IIF and ELISA. [13],[19],[20]

Relationship between ANCA positivity, subtype, and renal involvement

Although ANCA is mostly prevalent in patients with crescentic GN, [21] those with small vessel vasculitis without renal involvement also sometimes have ANCA. The reported sensitivity for cANCA in WG patients with renal disease is identical to that in WG patients without renal disease (both 64%), although the pANCA was more prevalent in WG patients with GN (30%) than in those without renal disease (10%). [13] Some studies indicate modest clinical differences between MPO-ANCA and PR3­ANCA associated renal disease, with the latter being more aggressive and having a worse prognosis. [22] However, Kallenberg et al found no clear distinction between patients with MPO-ANCA and those with PR3-ANCA, [23] and Bajema et al also reported that ANCA findings at the time of biopsy are not related to renal histopathology. [24] On the other hand, Apenberg et al reported that elastase-ANCA in patients with WG or MPA correlate with renal involvement, being more frequent in patients with dialysis-dependent renal failure. [3] Elastase­ANCA actually upregulates elastase (one of the most powerful tissue destructive proteinases of neutrophils) activity in vitro and thereby might contribute to the tissue damage caused by the disease. [25]

Significance as a follow-up tool

Some investigators indicate that ANCA is useful as a follow-up tool, because ANCA titers seem to correlate with changes in disease activity, [26],[27] and an increasing ANCA titer can help to differentiate relapse from super-infection experienced during immunosuppressive therapy. [3] Persistent or intermittent positivity for ANCA in patients entering remission is a considerable risk factor for relapse. [28] However, others report that increasing ANCA titers are not necessarily followed by relapse, and ANCA titers do not change over time in some patients despite clinical quiescence. [29],[30] Some investigators indicate that not only levels of ANCA, but also their isotype or subclass distribution would be important factors for clinical expression of the disease. [31],[32] Indeed, IgG3 MPO-ANCA titers have been reported to correlate with renal involvement [33] and disease activity. [34] However, Kokolina et al reported that levels, isotype distribution and affinity of MPO-ANCA do not correlate with specific clinical manifestations. [35] Meanwhile, one investigator has reported that ANCA titers measured by capture ELISA reflect the activity of vasculitis, whereas those measured by direct ELISA do not. [36] As such, it is still debatable whether or not changes in ANCA titers or isotype distribution reflect disease activity. Therefore, others caution that ANCA titers should not be used as the sole criterion upon which to base a therapeutic strategy. [18],[20]

ANCA: Pathogenetic or epiphenomenon? -Pathogenesis of crescentic GN/vasculitis

The close association of ANCA with idiopathic small vessel vasculitis and crescentic GN suggests important role for ANCA in the pathophysiology of these diseases. Although much in vitro data address the pathophysiological role of ANCA, the most probable role would be their capacity to activate neutrophils. Actually, ANCA activate tumor necrosis alpha (TNF)-primed neutrophils leading to the release of lysosomal enzymes and the generation of reactive oxygen radicals, [37] resulting in endothelial cell damage in vitro. [38],[39] On the other hand, several lines of evidence indicate more specific interactions between ANCA and endothelial cells. a). Mayet et al reported that human endo­thelial cells express PR3 that is upregulated and translocated from the cytoplasm into the cell membrane by cytokines (TNF-α), interleukin-1 (IL-1), interferon gamma (IF-γ) treatment. [40] Thus, the endothelial cells become accessible to ANCA and may result in antibody-dependent cellular cytotoxicity. However, others have not been able to demonstrate PR3 expression by endothelial cells. [41]

b). Anionic structures, such as glomerular basement membrane and the surface of vascular endothelial cells, may bind cationic MPO and PR3, where ANCA will bind to form immune complexes in situ, and may induce complement-dependent endothelial cell lysis. [42] However, the involvement of these mechanisms in vivo are somewhat questionable, because immunostaining for immunoglobulin is negative or faint within vascular lesions in patients with ANCA associated vasculitis.

c). Neutrophil adhesion to endothelial cells can be induced by ANCA via the up­regulation of E-selectin (ELAM-1) expres­sion on the surface of endothelial cells, [43] which may cause accumulation of activated neutrophils and induce vascular damage.

In general, the relevance of these in vitro phenomena for the pathophysiology of ANCA associated vasculitis in vivo is far from clear, either in experimental models or in human diseases. For example, HgCl 2 ­treated Brown Norway rats develop various autoantibodies including MPO-ANCA, and necrotizing vasculitis in the gut.[44],[45] Therefore, these animals are regarded as useful models of human ANCA associated vasculitis. However, despite the presence of MPO-ANCA, these rats did not develop crescentic GN. Furthermore, transferring sera containing ANCA from HgCl 2 treated rats into normal rats failed to induce vasculitis. [46] On the other hand, the experi­mental models described by Kobayashi et al [47] (MPO-ANCA injection itself did not cause pathological changes, but it did aggravate rat nephrotoxic serum nephritis) and Brouwer et al [48] (perfusion of a lyso­somal enzyme extract and H 2O2 into the kidney of MPO-immunized rats resulted in the development of necrotizing crescentic GN and vasculitis) indicate the in vivo potential of ANCA to aggravate glomerular damage resulting in the development of overt GN. However, both studies support the contention that the presence of ANCA in itself is not sufficient to cause tissue injury, because they found that neither the transfer of MPO-ANCA nor the induction of MPO-ANCA by immunization induced histological changes. In addition, ANCA positive and negative patients did not seem to differ neither clinically nor histolo­gically. [24] Moreover, high levels of ANCA can be present without signs of disease activity. [29],[30] These data suggest that ANCA do not constitute the initial or major cause of vasculitis, but are rather a consequence or epiphenomenon of severe inflammation, although experimental data indicate that ANCA may exacerbate crescentic GN and/or vasculitis.

We observed prominent infiltration and aggregation of neutrophils with intense deposition of neutrophil elastase in glomerular necrotizing and crescentic lesions and interstitial lesions of the kidney.[49],[50] Neutrophil elastase was localized not only in the cytoplasm of neutrophils, but also extracellularly in those lesions in a granular or diffuse manner [Figure - 1]. Moreover, the concentration of neutrophil elastase was high in the urine [Figure - 2]. [49] These findings indicated that activated neutrophils play important roles in the pathophysiology of vasculitis. Brouwer et al also found activated neutrophils and extracellular lysosomal enzymes (PR3, MPO, and elastase) in renal biopsies from patients with WG. [51] The report by Suzuki et al [52] provides support for this mechanism. They showed that neutro­phil elastase inhibitor (ONO-5046) reduces proteinuria and hematuria, and suppresses the crescent formation caused by nephro­toxic serum nephritis in a dose-dependent manner. In line with these observations, several reports suggest that a severe deficiency of α1-antitrypsin (α1-AT) is associated with systemic vasculitis and crescentic GN. [53],[54] Because α1-AT is the major inhibitor of neutrophil serine protei­nases (such as elastase and PR3), these reports support the notion presented above. Indeed, patients who have ANCA positive vasculitis with a decreased α1-AT concen­tration due to the PiZ gene carriage have a poorer prognosis and tend to have a larger number of organs affected than those with a normal α1-AT concentration. [55] Notably, ANCA interfere with the normal inhibitory activity of a1-AT for PR3. [56] As to the mechanism of how neutrophils accumulate into specific vascular sites, we suspect that adhesion molecules, especially E-selectin (ELAM-1) are involved.[57] We showed that in renal biopsies of patients with MPA, E­selectin is abundantly expressed on the renal vascular endothelium with neutrophil infiltration. [57] Mayet et al [43] reported that ANCA can directly induce endothelial E­selectin expression. However, we believe that E-selectin is expressed irrespective of the presence of ANCA, because E-selectin expression and ANCA positivity in our patients did not correlate (Intense E-selectin expression was observed in an ANCA negative patient with MPA).

These data indicate that the mechanism of renal tissue damage in vasculitis is as follows. Stimulation to specific vascular sites (from some yet-to-be-determined source, such as certain viral infections) leads to endothelial activation, which in turn causes endothelial adhesion molecules expression, cytokine expression and release. Through these mechanisms, leukocytes, especially neutrophils, are activated and infiltrate into renal tissues causing damage via proteinases and oxygen radicals.[49],[50]

   Summary Top

ANCA constitute a useful marker with which it is possible to substantiate a diagnosis of idiopathic crescentic GN and/or systemic vasculitis. It is still debatable whether ANCA are directly involved in the patho­genesis, or are essentially epiphenomena of vasculitis. However, neutrophils and their tissue destructive mediators (proteinases such as elastase and PR3, as well as oxygen radicals) play a crucial role in the tissue destruction and development of crescentic GN and/or vasculitis. Further studies are necessary to define the initial factors that trigger these diseases.

   References Top

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Correspondence Address:
Takashi Oda
Department of Medicine, Japan Self Defense Forces, Kumamoto Hospital, 15-1 Higashihonmachi, Kumamoto-shi, Kumamoto 862-0902
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