- Email: [email protected]
Renal involvement in ANCA associated vasculitis
i n d i a n j o u r n a l o f r h e u m a t o l o g y 8 ( 2 0 1 3 ) 7 3 e7 8
Available online at www.indianjrheumatol.com and www.sciencedirect.com
Review Article
Renal involvement in ANCA associated vasculitis Subramanian Shankar a,*, Abhishek Pathak a, Rohit Tewari b a b
Department of Internal Medicine, Armed Forces Medical College, Pune 411040, India Department of Pathology, Armed Forces Medical College, Pune 411040, India
article info
abstract
Article history:
Kidney is involved in upto 75e80% of various ANCA associated vasculitis (AAV) and re-
Received 11 April 2013
mains the major cause of mortality and morbidity. The classic clinical presentation is that
Accepted 16 April 2013
of rapidly progressive renal failure with cresenteric glomerulonephritis being its pathologic
Available online 26 April 2013
correlate. ANCA positivity has been implicated in the pathogenesis and is useful for diagnosis.
Keywords:
The treatment of renal AAV involves the use of steroids in combination with other
ANCA associated vasculitis
immunosuppressive agents like cyclophosphamide to induce remission followed by
Renal involvement
maintenance therapy with a less potent agent like azathioprine. Plasmapharesis has a
Rapidly progressive
definite role especially in presence of renal failure while Rituximab is emerging as a
glomerulonephritis
promising alternative for remission induction.
Rapidly progressive renal failure
1.
Copyright ª 2013, Indian Rheumatology Association. All rights reserved.
Introduction
Kidney remains one of the most commonly affected organs in ANCA associated vasculitis (AAV). The AAV disorders include Granulomatosis with Polyangiitis (GPA, earlier termed Wegener’s granulomatosis), Microscopic polyangiitis (MPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA, earlier termed ChurgeStrauss syndrome), and renal limited vasculitis (earlier referred to as Idiopathic necrotizing crescentic glomerulonephritis). There is renal involvement in almost 71e88% in GPA and MPA and almost 25% in cases of EGPA.1,2 This article will address the pathology, clinical profile and management of renal AAV.
2. Pathological spectrum of renal involvement in AAV In 1979 Stilmant et al in their land mark study on crescentic glomerulonephritis, observed the absence of immune complex deposition or anti glomerular basement membrane antibodies in the glomeruli.3 In view of complete absence of immunoglobulin deposits on renal biopsies it was earlier referred to as pauci immune glomerulonephritis. It took almost a decade to find the association between this pauci immune glomerulonephritis and anti neutrophilic cytoplasmic antibodies (ANCA).4 However, with the advent of newer electron microscopes even the so called pauci immune GN revealed immune complexes in 54% cases.5
* Corresponding author. Tel.: þ91 2026330028. E-mail addresses: [email protected], [email protected] (S. Shankar). 0973-3698/$ e see front matter Copyright ª 2013, Indian Rheumatology Association. All rights reserved. http://dx.doi.org/10.1016/j.injr.2013.04.003
74
i n d i a n j o u r n a l o f r h e u m a t o l o g y 8 ( 2 0 1 3 ) 7 3 e7 8
The classic histologic lesions in the glomeruli of ANCA associated vasculitis are segmental fibrinoid necrosis (Fig. 1a) and crescentic glomerulonephritis (Fig. 1b). The severity of crescents between patients with Myeloperoxidase (MPO) ANCA and those with Proteinase 3 (PR3) ANCA is the same. The fibrinoid necrosis of the tuft is usually segmental and appears red on trichrome staining. Capillary lumina in areas adjacent to foci of necrosis may show accumulation of neutrophils. Crescent formation involves participation by parietal epithelial cells, neutrophils and monocytes with presence of fibrin (Fig. 1b). Although crescent formation usually begins adjacent to areas of fibrinoid necrosis, they gradually surround almost the entire tuft producing circumferential lesions. When the injury is severe there may be dissolution of the Bowman’s capsule (glomerulitis), resulting in a continuity between the glomerular and periglomerular inflammation which may be granulomatous with giant cells (Fig. 1c). The necrotic glomerular lesions tend to heal over time with segmental sclerosis which may progress on to global sclerosis. Similarly the crescents also progress from cellular to fibrocellular to fibrous. Lesions in the glomeruli may show different stages of development within the same biopsy. Recently, a histological classification was proposed for ANCA associated glomerulonephritis based on the number of cellular crescents and the number of globally sclerosed glomeruli.6 The validation of this schema in terms of outcome and prognostication is underway. Vessels other than the glomerular capillaries may be involved in ANCA associated vasculitis and usually include interlobular arteries, arterioles, and also occasionally the medullary vasa recta. The hallmark lesion is segmental fibrinoid necrosis with inflammatory cell infiltration in the wall as well as perivascular areas. Eosinophils in this infiltrate may be seen in any form of AAV, but should definitely alert one to the possibility of EGPA. The infiltrate around the vessel walls may occasionally have a vague granulomatous appearance with presence of palisaded macrophages around the lesions. The lesions of this vasculitis heal with segmental vascular scarring. Occasionally only a necrotising vasculitis of the medullary vasa recta may be seen (medullary angiitis). When the disease is severe, interstitial edema and tubular injury with epithelial flattening and RBC in the tubular lumina may be seen. Infiltration of the interstitium with leukocytes
may be seen with formation of interstitial granulomas, and occasionally the infiltrate may be periglomerular. Immunofluorescence microscopy in these cases helps to exclude anti-GBM disease and immune complex mediated crescentic glomerulonephritis. A low level of staining for immunoglobulin may be observed. Hence the term used is ‘pauci immune’ rather than ‘non immune’.7 Staining for fibrin may be seen in the necrotising lesions as well as the crescents. Either none or very scanty immune complex type of electron dense deposits may be seen in patients of ANCA vasculitis. This is consistent with the findings on immunofluorescence.5 Presence of glomerular deposits with positivity on immunofluorescence should prompt the consideration of the possibility of a co-existent immune complex mediated disease.
3.
Pathogenesis of renal affection in AAV
The primary insult leading to vasculitis is unknown. However there are many hypotheses which implicate infection as the primary triggering event which when uncontrolled lead to wide spread damage to renal tissues.8,9 In the affected tissue the endothelial cells are attacked by neutrophils and monocytes causing the release of auto antigens from these cells leading to production of auto antibodies to endothelial cell constituents (Anti-endothelial cell antibodies (AECAs)). However there remains a wide difference in the prevalence of these antibodies and controversy about their role in pathogenesis.
3.1. Role of Anti Neutrophilic Cytoplasmic Antibodies (ANCA) These were the first recognised antibodies against the neutrophils in small vessels in necrotising glomerulonephritis and were detected in 1982.10 These antibodies are classified on the basis of their pattern of reactivity and the antigens against which these antibodies react. C-ANCA give rise to a coarse granular staining of neutrophil cytoplasm and are directed against proteolytic enzyme PR3 in azurophilic granules of neutrophils. Antibodies which cause staining of periphery of neutrophil nuclei are called Perinuclear ANCAs (P ANCA) and are directed against MPO. About 82e92% of GPA and MPA are positive for ANCA.11,12 GPA is primarily associated with PR3-
Fig. 1 e a: Section showing glomerulus with a segmental necrotising lesion (H&E X 40). b: Section showing glomerulus with a cellular crescent showing presence of fibrinous material (PAS X 40). c: Section showing glomerulus with a segmental necrotising lesion and periglomerular granulomatous inflammation with giant cells (H&E X 40).
i n d i a n j o u r n a l o f r h e u m a t o l o g y 8 ( 2 0 1 3 ) 7 3 e7 8
ANCA, while MPA is primarily associated with MPO ANCA. However, 20% of patients with GPA or MPA have the alternative ANCA, and at least 10% of patients are ANCA negative. Over the years, evidence has gradually accumulated for the pathogenic role of ANCA IgG in the development of crescentic glomerulonephritis as well as small vessel vasculitis. The strongest evidence comes from the induction of pauci immune crescentic glomerulonephritis in mice by IV injection of anti MPO IgG in mice.13,14 However, the exact mechanism by which these pathogenic ANCA induce the vasculitis has remained elusive. The exact trigger that stimulates production of ANCA has been postulated to be microbial pathogens.15 Once the ANCA is produced and is circulating, the mechanism proposed by Jennette et al may be operative (Fig. 2).16 They proposed that high levels of circulating cytokines, as could happen in a viral infection, could prime neutrophils to present more ANCA antigen on their surfaces. This ANCA antigen can interact with ANCA in the microenvironment and can activate neutrophils. Activated neutrophils can now adhere to endothelial cells by adhesion molecules like the alpha 2 integrins and induce severe damage.17 Other antigenic targets of ANCA are human leukocyte elastase, lysosomal membrane protein 2, lactoferrin, azurocidin, bactericidal permeability-increasing protein, and lysozyme.18 However these are not associated with AAV.
4. AAV
Clinical spectrum of renal involvement in
The renal presentation in AAV is consistent with that of acute glomerulonephritis and consists of a combination of proteinuria and hematuria that may be associated with renal failure. Indeed some of these patients can present with rapidly progressive renal failure (RPRF) whose pathological correlate is rapidly progressive cresenteric glomerulonephritis (RPGN).
4.1.
75
GPA
GPA is characterised by necrotising granulomatous inflammation of upper and lower respiratory tract and necrotising glomerulonephritis. The annual incidence is 0.5/million and prevalence of 8.5/million.19 Depending on renal involvement it can be divided into classical (presence of renal involvement) or limited (non renal form). The so-called granulomatous glomerulonephritis is seen in a small number of patients. The prognosis of generalised WG was very poor earlier with a 2-year mortality of almost 80% with pulmonary and renal complications being the most common cause of mortality.20,21 The same has changed dramatically in the last 2 decades with newer therapeutic modalities.
4.2.
MPA
MPA is a type of necrotising vasculitis affecting small vessels (arteries, capillaries and venules, hence called as angitis and not arteritis). Though first classified in 1994, however it was in 1998 that a research group from Japan made a complete diagnostic criteria for the same.22 It is a rare disorder with male to female ratio of 1e1.8.23 The classical symptoms are RPGN and pulmonary hemorrhage. Though clinical features are similar to classic PAN (c-PAN) however renal involvement is far more common in MPA.23 The clinical course is highly variable. Renal involvement is present in two thirds of the cases. Overall 5-year survival of MPA has improved from around 65% in the 1980’s to over 80% in the current era.23
4.3.
EGPA
EGPA is seen commonly in patients with history of asthma and atopic allergies.24 It is characterised by the presence of necrotising vasculitis, extra vascular granulomas and hypereo sinophilia.
Fig. 2 e Postulated mechanism through which ANCA induces neutrophils to cause vasculitis and necrosis.
76
i n d i a n j o u r n a l o f r h e u m a t o l o g y 8 ( 2 0 1 3 ) 7 3 e7 8
The frequency of renal involvement in CSS is highly variable. They generally present with microscopic hematuria and proteinuria. Acute renal failure is uncommon. Besides crescents, focal segmental glomerulosclerosis is a common histological finding.25 ANCA positivity is seen in 40e60% of cases and the overall 5-year survival rate is 62%. Mortality due to renal cause is much less in EGPA compared to other renal vasculitis.26e28
4.4.
However none of the studies revealed reduction in infectious complications.29,30 The Cochrane meta-analysis showed an increase in remission with pulse CPA (RR 1.17, 95% CI 1.00e1.35; P ¼ 0.03; NNT ¼ 8). However the risk of relapse too was higher with pulse therapy versus continuous therapy (RR 1.75, 95% CI 1.00e3.05; P ¼ 0.05; NNH ¼ 5). There was however no statistically significant difference in treatment failure, serious infection and mortality benefit between pulse and continuous CPA therapy.29
Renal limited vasculitis 5.1.2.
Renal limited vasculitis a type of pauci immune necrotising glomerulonephritis and almost 80% of cases are MPOANCA positive. Renal biopsies reveal glomerulosclerosis in majority of the cases as most of the cases are diagnosed in late stages due to absence of extra renal manifestations. About 5% of patients with pauci immune GN are ANCA negative. They are considered part of the spectrum of GPA and MPA.
5.1.3.
5.
Management of renal AAV
The treatment of renal vasculitis involves the use of steroids in combination with other immunosuppressive agents like cyclophosphamide (CPA) to induce remission of disease. In the presence of kidney failure, plasma exchange is often used as an adjunct to pharmacological treatment. On achieving remission, maintenance therapy with reduction in doses of steroids and replacing CPA by a less potent immunosuppressive like azathioprine (AZA) is used.
5.1.
Induction of remission
Complete remission in cases of systemic vasculitis is defined as Birmingham vasculitis activity score (BVAS) score of 0.20 In cases of renal involvement hematuria or red cell cast is taken as a sign of active disease and is included in the BVAS. Partial response in cases of kidney involvement refers to the persistence of dysmorphic hematuria with or without red cell casts in spite of stabilization of serum creatinine and disappearance of extra renal signs. The usual regimen comprises of CPA with glucocorticoids. Alternative regimens have used rituximab, methotrexate, mycophenolate mofetil, lymphocytapheresis and immunoadsorption. Intravenous immunoglobulins have been tried in refractory cases.
5.1.1.
CPA induction
CPA is used either in daily dose (1.5e2 mg/kg per day) or pulse therapy (15 mg/kg, max 1.2 g) every two week for first three doses followed by infusion every three weeks for next 3e6 pulses as per EUVAS regimen. They are given until remission is achieved which usually takes 3e6 months. Monitoring of total leucocyte count (TLC) is done periodically and the TLC should be above 3000/ml with absolute neutrophil count above 1500/ml. IV pulse cyclophosphamide has been shown to be equally effective as oral cyclophosphamide with advantage of lower cumulative dose and hence fewer episodes of leukopenia.
Glucocorticoid usage
Pulse methylprednisolone of 7e15 mg/kg to a maximum dose of 500e1000 mg/day for three days followed by oral glucocorticoid therapy. Prednisolone 1 mg/Kg or its equivalent can be given initially for two to four weeks and are slowly tapered with improvement as per EUVAS regimen. When both CPA and glucocorticoids are used together the rate of partial remission is 85e90% and complete remission is achieved in approximately 75% of patients.31
Rituximab
The RAVE study and RITUXVAS study compared rituximab and CPA with primary end point of inducing remission at 6 months. Rituximab was equal to CPA for induction of remission in severe renal AAV. It was possibly superior in relapsing disease.32,33 The current data on the use of MMF, intravenous immunoglobulin, lymphocytopharesis and immunoadsor ption for remission induction is sparse and their role still controversial.29 Plasmapheresis/Plasma Exchange is generally used as an adjunctive therapy in cases of severe renal involvement (defined as serum creatinine>3 mg/dl) has been shown to reduce the incidence of end stage renal disease (ESRD) at three months. Cochrane analysis revealed reduced incidence of ESRD at three months (RR 0.45 95% CI 0.24e0.84; P ¼ 0.01; NNT ¼ 5) and 12 months (RR0.47, 95% CI 0.30e0.75; P ¼ 0.002 NNT ¼ 5) posttreatment.29,30 A minimum of seven plasma exchanges in 14 days with each exchange of at least 60 mg/kg, volume replacement with 5% albumin is advocated. The PEXIVAS study (Plasma Exchange and Glucocorticoids for Treatment of ANCA Associated Vasculitis) is the largest ongoing study comparing various regimens of plasma exchange and steroid dosing in the treatment of severe ANCA associated vasculitis that is likely to yield valuable results.34
5.2.
Maintenance therapy
Since long term usage of cyclophosphamide is associated with significant toxicity, almost all patients are switched to less toxic non cyclophosphamide based therapy as maintenance regime.29 For maintenance therapy to be started, the minimum white blood cell count is 4000 cells/ml with the absolute neutrophil count of >1500 cells/ml. It can be started within two to four weeks after the last monthly dose of intravenous cyclophosphamide or days after cessation of oral cyclophosphamide. The various drugs used in maintenance therapy are Azathioprine, Methotrexate and Mycophenolate mofetil (MMF). MMF therapy was associated with a greater relapse rate than azathioprine.35
i n d i a n j o u r n a l o f r h e u m a t o l o g y 8 ( 2 0 1 3 ) 7 3 e7 8
Azathioprine (1.5 kg/day) oral can be used after induction therapy. The number of relapses were similar to that of cyclophosphamide but with fewer episodes of leukopenia, infertility and neoplasia.30 Both Methotrexate (0.3 mg/kg per week, maximum dose 15 mg) and leflunomide are potential choices for remission maintenance.30 Methotrexate is contradicated if GFR <50 ml/h.
6.
Cyclophosphamide resistance
Resistance to cyclophosphamide is defined as presence of active disease involving one major organ in spite of optimal dosing of cyclophosphamide and steroids. In most cases what is thought to be as a case of cyclophosphamide resistance is actually presence of some other disease or some new infection. Drugs used in case of cyclophosphamide resistance are TNF Blockers (etanercept, infliximab) anti B cell therapy (rituximab) anti T cell therapy antibodies against CAMPATH-1H or Antithymocyte globulin (ATG). However the use of etanercept has no additional benefit in maintenance of remission and on other hand they are associated with high risk of malignancy.36
7.
Relapse
Relapse is defined by worsening of renal function or new extra renal manifestation involving the typical organs. Worsening renal function is evidenced by rising serum creatinine or presence of active urinary sediments. Oral co-trimoxazole did not reduce relapses significantly in GPA.30
8.
How long to continue steroids?
The question of how long should steroids be continued remains unanswered. Walsh et al34 did a meta-analysis and included thirteen studies (983 patients). There were no studies directly comparing GC regimens. The patients were classified as having a nonzero GC target dose by study end (n ¼ 288 patient) and as having a zero GC target dose by study end (n ¼ 695 patients). The pooled proportion of patients with a relapse was 36% (95% CI ¼ 25e47%). GC regimen was the most significant variable explaining the variability between the proportions of patients with relapses. The proportion of patients with a relapse was 14% (95% CI 10e19%) in nonzero GC target dose studies and 43% (95% CI 33e52%) in zero GC target dose studies.37
9.
Renal transplant in AAV
Earlier series found that 20e40% of the patients develop ESRD, however current prognosis is much better with much lesser rates of ESRD.38 Renal transplant is a well tried treatment in these patients. Various studies have shown that the graft survival was better in cases where transplant was done 12 months after achieving remission than in cases where transplant was done earlier.
77
The overall recurrence rates of ANCA associated vasculitis is about 17% with an average time from transplant to relapse of 31 months.39 The study also found that 60% of these cases had recurrent glomerulonephritis and 40% had recurrent extra renal vasculitis only. The severity of the recurrence is highly variable. However, usually the recurrence takes the form of a pauci immune necrotising glomerulonephritis. It has also been seen that relapse was more likely to occur in patients who had undergone shorter duration of hemodialysis prior to transplant. Also, unlike anti-GBM disease where persisting anti-GBM antibodies at the time of transplant are associated with a higher rate of recurrence, persistent ANCA levels are not significantly associated with increased risk of recurrence.40
10.
Conclusions
AAV is one of the best studied renal vasculitis. ANCA has been implicated in pathogenesis and is useful for diagnosis. Early diagnosis and treatment remains the key to management of renal vasculitis associated with ANCA. In severe cases of acute renal failure due to vasculitis, plasma exchange is effective but the long term management is on the principle of induction and maintenance therapy. Though many immunomodulators are being studied, induction with CPA and steroids followed by maintenance with azathioprine remains the corner stone of therapy with rituximab showing a lot of promise.
Conflicts of interest All authors have none to declare.
references
1. Pagnoux C, Hogan SL, Chin H, et al. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis: comparison of two independent cohorts. Arthritis Rheum. 2008;58:2908e2918. 2. Sinico RA, Di Toma L, Maggiore U, et al. Renal involvement in ChurgeStrauss syndrome. Am J Kidney Dis. 2006;47:770e779. 3. Stilmant MM, Bolton WK, Sturgill BC, et al. Crescentic glomerulonephritis without immune deposits: clinicopathologic features. Kidney Int. 1979;15:184e195. 4. Kallenberg CG. Antineutrophil cytoplasmic antibodies (ANCA) and vasculitis. Clin Rheumatol. 1990;9:132e135. 5. Haas M, Eustace JA. Immune complex deposits in ANCAassociated crescentic glomerulonephritis: a study of 126 cases. Kidney Int. 2004;65:2145e2152. 6. Berden AE, Ferrario F, Hagen EC, Jayne DR, Jennette C, Joh K. Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol. 2010;21:1628e1636. 7. Harris AA, Falk RJ, Jennette JC. Crescentic glomerulonephritis with a paucity of glomerular immunoglobulin localization. Am J Kidney Dis. 1998;32:179e184. 8. Brons RH, Bakker HI, van Wijk RT, et al. Staphylococcal acid phosphatase binds to endothelial cells via charge interaction; a pathogenic role in Wegener’s granulomatosis? Clin Exp Immunol. 2000;119:566e573.
78
i n d i a n j o u r n a l o f r h e u m a t o l o g y 8 ( 2 0 1 3 ) 7 3 e7 8
9. Wijngaarden RA, Hauer HA, Wolterbeek R, et al. Clinical and histologic determinants of renal outcome in ANCA-associated vasculitis: a prospective analysis of 100 patients with severe renal involvement. J Am Soc Nephrol. 2006;17:2264e2274. 10. Davies D, Moran ME, Niall JF, et al. Segmental glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology. Br Med J. 1982;285:606. 11. Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum. 1999;42:421. 12. Finkielman JD, Lee AS, Hummel AM, et al, WGET Research Group. ANCA are detectable in nearly all patients with active severe Wegener’s granulomatosis. Am J Med. 2007;120:643. e9-14. 13. Xiao H, Heeringa P, Liu Z, et al. The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies. Am J Pathol. 2005;167:39. 14. Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest. 2002;110:955. 15. Pendergraft III WF, Preston GA, Shah RR, et al. Autoimmunity is triggered by cPR-3 (105-201), a protein complementary to human autoantigen proteinase-3. Nat Med. 2004;10:72e79. 16. Jennette JC, Falk RJ. Pathogenesis of the vascular and glomerular damage in ANCA-positive vasculitis. Nephrol Dial Transplant. 1998;13(suppl 1):16e20. 17. Ewert BH, Becker ME, Jennette JC, Falk RJ. Antimyeloperoxidase antibodies induce neutrophil adherence to cultured human endothelial cells. Ren Fail. 1995;17:125e133. 18. Nakabayashi K, Hashimoto H. Microscopic polyangiitis. In: Hashimoto H, ed. Clinical Manual for Vasculitis. Tokyo: Research Group of Intractable Vasculitis, Ministry of Health, Labor, and Welfare of Japan; 2002:24e26. 19. Aasarod K, Iversen BM, Hammerstrom J, Bostad L, Vatten L, Jorstad S. Wegener’s granulomatosis: clinical course in 108 patients with renal involvement. Nephrol Dial Transplant. 2000;15:611e618. 20. Luqmani RA, Bacon PA, Moots RJ, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. 1994;87:671e681. 21. Nachman PH, Hogan SL, Jennette JC, Falk RJ. Treatment response and relapse in antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol. 1996;7:33e39. 22. Gross WL. Systemic necrotizing vasculitis baillieres. Clin Rheumatol. 1997;11:259e284. 23. Savage CO, Winearls CG, Evans DJ, Rees AJ, Lockwood CM. Microscopic polyarteritis: presentation, pathology and prognosis. QJM. 1985;56:467e483. 24. Chumbley LC, Harrison EGJ, DeRemee RA. Allergic granulomatosis and angiitis (ChurgeStrauss syndrome). Report and analysis of 30 cases. Mayo Clin Proc. 1977;52: 477e484. 25. Mahr A, Guillevin L, Poissonnet M, Ayme S. Prevalences of polyarteritisnodosa, microscopic polyangiitis, Wegener’s
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
granulomatosis, and Churg-Strauss syndrome in a French urban multiethnic population in2000: a capture-recapture estimate. Arthritis Rheum. 2004;51:92e99. Wiik AS. Clinical use of serological tests for antineutrophil cytoplasmic antibodies. What do the studies say? Rheum Dis Clin North Am. 2001;27:799e803. Venning MC, Quinn A, Broomhead V, Bird AG. Antibodies directed against neutrophils (C-ANCA and P-ANCA) are of distinct diagnostic value in systemic vasculitis. QJM. 1990;77:1287e1296. Hagen EC, Daha MR, Hermans J, et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR project for ANCA assay standardization. Kidney Int. 1998;53:743e753. Walters G, Willis NS, Craig JC. Interventions for renal vasculitis in adults. Cochrane Database Syst Rev. 2008 Jul;16:CD003232. Walters GD, Willis NS, Craig JC. Interventions for renal vasculitis in adults. A systematic review. BMC Nephrol. 2010 Jun 24;11:12. Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009;150:670e680. Stone JH, Merkel PA, Spiera R, et al, RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCAassociated vasculitis. N Engl J Med. 2010;363:221e232. Jones RB, Tervaert JW, Hauser T, et al, European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCAassociated renal vasculitis. N Engl J Med. 2010;363:211e220. Walsh M, Merkel PA, Peh CA, et al, PEXIVAS Investigators. Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS): protocol for a randomized controlled trial. Trial. 2013 Mar 14;14:73. Andrassy K, Erb A, Koderisch J, et al. Wegener’s granulomatosis with renal involvement: patient survival and correlations between initial renal function, renal histology, therapy and renal outcome. Clin Nephrol. 1991;35:139. Hiemstra TF, Walsh M, Mahr A, et al, European Vasculitis Study Group (EUVAS). Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA. 2010;304:2381e2388. Stone JH, Holbrook JT, Marriott MA, et al. Solid malignancies among patients in the Wegener’s Granulomatosis Etanercept trial. Arthritis Rheum. 2006;54:1608e1618. Walsh M, Merkel PA, Mahr A, Jayne D. Effects of duration of glucocorticoid therapy on relapse rate in antineutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis. Arthritis Care Res (Hoboken). 2010;62:1166e1173. Nachman PH, Segelmark M, Westman K, et al. Recurrent ANCA-associated small vessel vasculitis after transplantation: a pooled analysis. Kidney Int. 1999;56:1544. Nyberg G, Akesson P, Norden G, Wieslander J. Systemic vasculitis in a kidney transplant population. Transplantation. 1997;63:1273e1277.
Available online at www.indianjrheumatol.com and www.sciencedirect.com
Review Article
Renal involvement in ANCA associated vasculitis Subramanian Shankar a,*, Abhishek Pathak a, Rohit Tewari b a b
Department of Internal Medicine, Armed Forces Medical College, Pune 411040, India Department of Pathology, Armed Forces Medical College, Pune 411040, India
article info
abstract
Article history:
Kidney is involved in upto 75e80% of various ANCA associated vasculitis (AAV) and re-
Received 11 April 2013
mains the major cause of mortality and morbidity. The classic clinical presentation is that
Accepted 16 April 2013
of rapidly progressive renal failure with cresenteric glomerulonephritis being its pathologic
Available online 26 April 2013
correlate. ANCA positivity has been implicated in the pathogenesis and is useful for diagnosis.
Keywords:
The treatment of renal AAV involves the use of steroids in combination with other
ANCA associated vasculitis
immunosuppressive agents like cyclophosphamide to induce remission followed by
Renal involvement
maintenance therapy with a less potent agent like azathioprine. Plasmapharesis has a
Rapidly progressive
definite role especially in presence of renal failure while Rituximab is emerging as a
glomerulonephritis
promising alternative for remission induction.
Rapidly progressive renal failure
1.
Copyright ª 2013, Indian Rheumatology Association. All rights reserved.
Introduction
Kidney remains one of the most commonly affected organs in ANCA associated vasculitis (AAV). The AAV disorders include Granulomatosis with Polyangiitis (GPA, earlier termed Wegener’s granulomatosis), Microscopic polyangiitis (MPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA, earlier termed ChurgeStrauss syndrome), and renal limited vasculitis (earlier referred to as Idiopathic necrotizing crescentic glomerulonephritis). There is renal involvement in almost 71e88% in GPA and MPA and almost 25% in cases of EGPA.1,2 This article will address the pathology, clinical profile and management of renal AAV.
2. Pathological spectrum of renal involvement in AAV In 1979 Stilmant et al in their land mark study on crescentic glomerulonephritis, observed the absence of immune complex deposition or anti glomerular basement membrane antibodies in the glomeruli.3 In view of complete absence of immunoglobulin deposits on renal biopsies it was earlier referred to as pauci immune glomerulonephritis. It took almost a decade to find the association between this pauci immune glomerulonephritis and anti neutrophilic cytoplasmic antibodies (ANCA).4 However, with the advent of newer electron microscopes even the so called pauci immune GN revealed immune complexes in 54% cases.5
* Corresponding author. Tel.: þ91 2026330028. E-mail addresses: [email protected], [email protected] (S. Shankar). 0973-3698/$ e see front matter Copyright ª 2013, Indian Rheumatology Association. All rights reserved. http://dx.doi.org/10.1016/j.injr.2013.04.003
74
i n d i a n j o u r n a l o f r h e u m a t o l o g y 8 ( 2 0 1 3 ) 7 3 e7 8
The classic histologic lesions in the glomeruli of ANCA associated vasculitis are segmental fibrinoid necrosis (Fig. 1a) and crescentic glomerulonephritis (Fig. 1b). The severity of crescents between patients with Myeloperoxidase (MPO) ANCA and those with Proteinase 3 (PR3) ANCA is the same. The fibrinoid necrosis of the tuft is usually segmental and appears red on trichrome staining. Capillary lumina in areas adjacent to foci of necrosis may show accumulation of neutrophils. Crescent formation involves participation by parietal epithelial cells, neutrophils and monocytes with presence of fibrin (Fig. 1b). Although crescent formation usually begins adjacent to areas of fibrinoid necrosis, they gradually surround almost the entire tuft producing circumferential lesions. When the injury is severe there may be dissolution of the Bowman’s capsule (glomerulitis), resulting in a continuity between the glomerular and periglomerular inflammation which may be granulomatous with giant cells (Fig. 1c). The necrotic glomerular lesions tend to heal over time with segmental sclerosis which may progress on to global sclerosis. Similarly the crescents also progress from cellular to fibrocellular to fibrous. Lesions in the glomeruli may show different stages of development within the same biopsy. Recently, a histological classification was proposed for ANCA associated glomerulonephritis based on the number of cellular crescents and the number of globally sclerosed glomeruli.6 The validation of this schema in terms of outcome and prognostication is underway. Vessels other than the glomerular capillaries may be involved in ANCA associated vasculitis and usually include interlobular arteries, arterioles, and also occasionally the medullary vasa recta. The hallmark lesion is segmental fibrinoid necrosis with inflammatory cell infiltration in the wall as well as perivascular areas. Eosinophils in this infiltrate may be seen in any form of AAV, but should definitely alert one to the possibility of EGPA. The infiltrate around the vessel walls may occasionally have a vague granulomatous appearance with presence of palisaded macrophages around the lesions. The lesions of this vasculitis heal with segmental vascular scarring. Occasionally only a necrotising vasculitis of the medullary vasa recta may be seen (medullary angiitis). When the disease is severe, interstitial edema and tubular injury with epithelial flattening and RBC in the tubular lumina may be seen. Infiltration of the interstitium with leukocytes
may be seen with formation of interstitial granulomas, and occasionally the infiltrate may be periglomerular. Immunofluorescence microscopy in these cases helps to exclude anti-GBM disease and immune complex mediated crescentic glomerulonephritis. A low level of staining for immunoglobulin may be observed. Hence the term used is ‘pauci immune’ rather than ‘non immune’.7 Staining for fibrin may be seen in the necrotising lesions as well as the crescents. Either none or very scanty immune complex type of electron dense deposits may be seen in patients of ANCA vasculitis. This is consistent with the findings on immunofluorescence.5 Presence of glomerular deposits with positivity on immunofluorescence should prompt the consideration of the possibility of a co-existent immune complex mediated disease.
3.
Pathogenesis of renal affection in AAV
The primary insult leading to vasculitis is unknown. However there are many hypotheses which implicate infection as the primary triggering event which when uncontrolled lead to wide spread damage to renal tissues.8,9 In the affected tissue the endothelial cells are attacked by neutrophils and monocytes causing the release of auto antigens from these cells leading to production of auto antibodies to endothelial cell constituents (Anti-endothelial cell antibodies (AECAs)). However there remains a wide difference in the prevalence of these antibodies and controversy about their role in pathogenesis.
3.1. Role of Anti Neutrophilic Cytoplasmic Antibodies (ANCA) These were the first recognised antibodies against the neutrophils in small vessels in necrotising glomerulonephritis and were detected in 1982.10 These antibodies are classified on the basis of their pattern of reactivity and the antigens against which these antibodies react. C-ANCA give rise to a coarse granular staining of neutrophil cytoplasm and are directed against proteolytic enzyme PR3 in azurophilic granules of neutrophils. Antibodies which cause staining of periphery of neutrophil nuclei are called Perinuclear ANCAs (P ANCA) and are directed against MPO. About 82e92% of GPA and MPA are positive for ANCA.11,12 GPA is primarily associated with PR3-
Fig. 1 e a: Section showing glomerulus with a segmental necrotising lesion (H&E X 40). b: Section showing glomerulus with a cellular crescent showing presence of fibrinous material (PAS X 40). c: Section showing glomerulus with a segmental necrotising lesion and periglomerular granulomatous inflammation with giant cells (H&E X 40).
i n d i a n j o u r n a l o f r h e u m a t o l o g y 8 ( 2 0 1 3 ) 7 3 e7 8
ANCA, while MPA is primarily associated with MPO ANCA. However, 20% of patients with GPA or MPA have the alternative ANCA, and at least 10% of patients are ANCA negative. Over the years, evidence has gradually accumulated for the pathogenic role of ANCA IgG in the development of crescentic glomerulonephritis as well as small vessel vasculitis. The strongest evidence comes from the induction of pauci immune crescentic glomerulonephritis in mice by IV injection of anti MPO IgG in mice.13,14 However, the exact mechanism by which these pathogenic ANCA induce the vasculitis has remained elusive. The exact trigger that stimulates production of ANCA has been postulated to be microbial pathogens.15 Once the ANCA is produced and is circulating, the mechanism proposed by Jennette et al may be operative (Fig. 2).16 They proposed that high levels of circulating cytokines, as could happen in a viral infection, could prime neutrophils to present more ANCA antigen on their surfaces. This ANCA antigen can interact with ANCA in the microenvironment and can activate neutrophils. Activated neutrophils can now adhere to endothelial cells by adhesion molecules like the alpha 2 integrins and induce severe damage.17 Other antigenic targets of ANCA are human leukocyte elastase, lysosomal membrane protein 2, lactoferrin, azurocidin, bactericidal permeability-increasing protein, and lysozyme.18 However these are not associated with AAV.
4. AAV
Clinical spectrum of renal involvement in
The renal presentation in AAV is consistent with that of acute glomerulonephritis and consists of a combination of proteinuria and hematuria that may be associated with renal failure. Indeed some of these patients can present with rapidly progressive renal failure (RPRF) whose pathological correlate is rapidly progressive cresenteric glomerulonephritis (RPGN).
4.1.
75
GPA
GPA is characterised by necrotising granulomatous inflammation of upper and lower respiratory tract and necrotising glomerulonephritis. The annual incidence is 0.5/million and prevalence of 8.5/million.19 Depending on renal involvement it can be divided into classical (presence of renal involvement) or limited (non renal form). The so-called granulomatous glomerulonephritis is seen in a small number of patients. The prognosis of generalised WG was very poor earlier with a 2-year mortality of almost 80% with pulmonary and renal complications being the most common cause of mortality.20,21 The same has changed dramatically in the last 2 decades with newer therapeutic modalities.
4.2.
MPA
MPA is a type of necrotising vasculitis affecting small vessels (arteries, capillaries and venules, hence called as angitis and not arteritis). Though first classified in 1994, however it was in 1998 that a research group from Japan made a complete diagnostic criteria for the same.22 It is a rare disorder with male to female ratio of 1e1.8.23 The classical symptoms are RPGN and pulmonary hemorrhage. Though clinical features are similar to classic PAN (c-PAN) however renal involvement is far more common in MPA.23 The clinical course is highly variable. Renal involvement is present in two thirds of the cases. Overall 5-year survival of MPA has improved from around 65% in the 1980’s to over 80% in the current era.23
4.3.
EGPA
EGPA is seen commonly in patients with history of asthma and atopic allergies.24 It is characterised by the presence of necrotising vasculitis, extra vascular granulomas and hypereo sinophilia.
Fig. 2 e Postulated mechanism through which ANCA induces neutrophils to cause vasculitis and necrosis.
76
i n d i a n j o u r n a l o f r h e u m a t o l o g y 8 ( 2 0 1 3 ) 7 3 e7 8
The frequency of renal involvement in CSS is highly variable. They generally present with microscopic hematuria and proteinuria. Acute renal failure is uncommon. Besides crescents, focal segmental glomerulosclerosis is a common histological finding.25 ANCA positivity is seen in 40e60% of cases and the overall 5-year survival rate is 62%. Mortality due to renal cause is much less in EGPA compared to other renal vasculitis.26e28
4.4.
However none of the studies revealed reduction in infectious complications.29,30 The Cochrane meta-analysis showed an increase in remission with pulse CPA (RR 1.17, 95% CI 1.00e1.35; P ¼ 0.03; NNT ¼ 8). However the risk of relapse too was higher with pulse therapy versus continuous therapy (RR 1.75, 95% CI 1.00e3.05; P ¼ 0.05; NNH ¼ 5). There was however no statistically significant difference in treatment failure, serious infection and mortality benefit between pulse and continuous CPA therapy.29
Renal limited vasculitis 5.1.2.
Renal limited vasculitis a type of pauci immune necrotising glomerulonephritis and almost 80% of cases are MPOANCA positive. Renal biopsies reveal glomerulosclerosis in majority of the cases as most of the cases are diagnosed in late stages due to absence of extra renal manifestations. About 5% of patients with pauci immune GN are ANCA negative. They are considered part of the spectrum of GPA and MPA.
5.1.3.
5.
Management of renal AAV
The treatment of renal vasculitis involves the use of steroids in combination with other immunosuppressive agents like cyclophosphamide (CPA) to induce remission of disease. In the presence of kidney failure, plasma exchange is often used as an adjunct to pharmacological treatment. On achieving remission, maintenance therapy with reduction in doses of steroids and replacing CPA by a less potent immunosuppressive like azathioprine (AZA) is used.
5.1.
Induction of remission
Complete remission in cases of systemic vasculitis is defined as Birmingham vasculitis activity score (BVAS) score of 0.20 In cases of renal involvement hematuria or red cell cast is taken as a sign of active disease and is included in the BVAS. Partial response in cases of kidney involvement refers to the persistence of dysmorphic hematuria with or without red cell casts in spite of stabilization of serum creatinine and disappearance of extra renal signs. The usual regimen comprises of CPA with glucocorticoids. Alternative regimens have used rituximab, methotrexate, mycophenolate mofetil, lymphocytapheresis and immunoadsorption. Intravenous immunoglobulins have been tried in refractory cases.
5.1.1.
CPA induction
CPA is used either in daily dose (1.5e2 mg/kg per day) or pulse therapy (15 mg/kg, max 1.2 g) every two week for first three doses followed by infusion every three weeks for next 3e6 pulses as per EUVAS regimen. They are given until remission is achieved which usually takes 3e6 months. Monitoring of total leucocyte count (TLC) is done periodically and the TLC should be above 3000/ml with absolute neutrophil count above 1500/ml. IV pulse cyclophosphamide has been shown to be equally effective as oral cyclophosphamide with advantage of lower cumulative dose and hence fewer episodes of leukopenia.
Glucocorticoid usage
Pulse methylprednisolone of 7e15 mg/kg to a maximum dose of 500e1000 mg/day for three days followed by oral glucocorticoid therapy. Prednisolone 1 mg/Kg or its equivalent can be given initially for two to four weeks and are slowly tapered with improvement as per EUVAS regimen. When both CPA and glucocorticoids are used together the rate of partial remission is 85e90% and complete remission is achieved in approximately 75% of patients.31
Rituximab
The RAVE study and RITUXVAS study compared rituximab and CPA with primary end point of inducing remission at 6 months. Rituximab was equal to CPA for induction of remission in severe renal AAV. It was possibly superior in relapsing disease.32,33 The current data on the use of MMF, intravenous immunoglobulin, lymphocytopharesis and immunoadsor ption for remission induction is sparse and their role still controversial.29 Plasmapheresis/Plasma Exchange is generally used as an adjunctive therapy in cases of severe renal involvement (defined as serum creatinine>3 mg/dl) has been shown to reduce the incidence of end stage renal disease (ESRD) at three months. Cochrane analysis revealed reduced incidence of ESRD at three months (RR 0.45 95% CI 0.24e0.84; P ¼ 0.01; NNT ¼ 5) and 12 months (RR0.47, 95% CI 0.30e0.75; P ¼ 0.002 NNT ¼ 5) posttreatment.29,30 A minimum of seven plasma exchanges in 14 days with each exchange of at least 60 mg/kg, volume replacement with 5% albumin is advocated. The PEXIVAS study (Plasma Exchange and Glucocorticoids for Treatment of ANCA Associated Vasculitis) is the largest ongoing study comparing various regimens of plasma exchange and steroid dosing in the treatment of severe ANCA associated vasculitis that is likely to yield valuable results.34
5.2.
Maintenance therapy
Since long term usage of cyclophosphamide is associated with significant toxicity, almost all patients are switched to less toxic non cyclophosphamide based therapy as maintenance regime.29 For maintenance therapy to be started, the minimum white blood cell count is 4000 cells/ml with the absolute neutrophil count of >1500 cells/ml. It can be started within two to four weeks after the last monthly dose of intravenous cyclophosphamide or days after cessation of oral cyclophosphamide. The various drugs used in maintenance therapy are Azathioprine, Methotrexate and Mycophenolate mofetil (MMF). MMF therapy was associated with a greater relapse rate than azathioprine.35
i n d i a n j o u r n a l o f r h e u m a t o l o g y 8 ( 2 0 1 3 ) 7 3 e7 8
Azathioprine (1.5 kg/day) oral can be used after induction therapy. The number of relapses were similar to that of cyclophosphamide but with fewer episodes of leukopenia, infertility and neoplasia.30 Both Methotrexate (0.3 mg/kg per week, maximum dose 15 mg) and leflunomide are potential choices for remission maintenance.30 Methotrexate is contradicated if GFR <50 ml/h.
6.
Cyclophosphamide resistance
Resistance to cyclophosphamide is defined as presence of active disease involving one major organ in spite of optimal dosing of cyclophosphamide and steroids. In most cases what is thought to be as a case of cyclophosphamide resistance is actually presence of some other disease or some new infection. Drugs used in case of cyclophosphamide resistance are TNF Blockers (etanercept, infliximab) anti B cell therapy (rituximab) anti T cell therapy antibodies against CAMPATH-1H or Antithymocyte globulin (ATG). However the use of etanercept has no additional benefit in maintenance of remission and on other hand they are associated with high risk of malignancy.36
7.
Relapse
Relapse is defined by worsening of renal function or new extra renal manifestation involving the typical organs. Worsening renal function is evidenced by rising serum creatinine or presence of active urinary sediments. Oral co-trimoxazole did not reduce relapses significantly in GPA.30
8.
How long to continue steroids?
The question of how long should steroids be continued remains unanswered. Walsh et al34 did a meta-analysis and included thirteen studies (983 patients). There were no studies directly comparing GC regimens. The patients were classified as having a nonzero GC target dose by study end (n ¼ 288 patient) and as having a zero GC target dose by study end (n ¼ 695 patients). The pooled proportion of patients with a relapse was 36% (95% CI ¼ 25e47%). GC regimen was the most significant variable explaining the variability between the proportions of patients with relapses. The proportion of patients with a relapse was 14% (95% CI 10e19%) in nonzero GC target dose studies and 43% (95% CI 33e52%) in zero GC target dose studies.37
9.
Renal transplant in AAV
Earlier series found that 20e40% of the patients develop ESRD, however current prognosis is much better with much lesser rates of ESRD.38 Renal transplant is a well tried treatment in these patients. Various studies have shown that the graft survival was better in cases where transplant was done 12 months after achieving remission than in cases where transplant was done earlier.
77
The overall recurrence rates of ANCA associated vasculitis is about 17% with an average time from transplant to relapse of 31 months.39 The study also found that 60% of these cases had recurrent glomerulonephritis and 40% had recurrent extra renal vasculitis only. The severity of the recurrence is highly variable. However, usually the recurrence takes the form of a pauci immune necrotising glomerulonephritis. It has also been seen that relapse was more likely to occur in patients who had undergone shorter duration of hemodialysis prior to transplant. Also, unlike anti-GBM disease where persisting anti-GBM antibodies at the time of transplant are associated with a higher rate of recurrence, persistent ANCA levels are not significantly associated with increased risk of recurrence.40
10.
Conclusions
AAV is one of the best studied renal vasculitis. ANCA has been implicated in pathogenesis and is useful for diagnosis. Early diagnosis and treatment remains the key to management of renal vasculitis associated with ANCA. In severe cases of acute renal failure due to vasculitis, plasma exchange is effective but the long term management is on the principle of induction and maintenance therapy. Though many immunomodulators are being studied, induction with CPA and steroids followed by maintenance with azathioprine remains the corner stone of therapy with rituximab showing a lot of promise.
Conflicts of interest All authors have none to declare.
references
1. Pagnoux C, Hogan SL, Chin H, et al. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis: comparison of two independent cohorts. Arthritis Rheum. 2008;58:2908e2918. 2. Sinico RA, Di Toma L, Maggiore U, et al. Renal involvement in ChurgeStrauss syndrome. Am J Kidney Dis. 2006;47:770e779. 3. Stilmant MM, Bolton WK, Sturgill BC, et al. Crescentic glomerulonephritis without immune deposits: clinicopathologic features. Kidney Int. 1979;15:184e195. 4. Kallenberg CG. Antineutrophil cytoplasmic antibodies (ANCA) and vasculitis. Clin Rheumatol. 1990;9:132e135. 5. Haas M, Eustace JA. Immune complex deposits in ANCAassociated crescentic glomerulonephritis: a study of 126 cases. Kidney Int. 2004;65:2145e2152. 6. Berden AE, Ferrario F, Hagen EC, Jayne DR, Jennette C, Joh K. Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol. 2010;21:1628e1636. 7. Harris AA, Falk RJ, Jennette JC. Crescentic glomerulonephritis with a paucity of glomerular immunoglobulin localization. Am J Kidney Dis. 1998;32:179e184. 8. Brons RH, Bakker HI, van Wijk RT, et al. Staphylococcal acid phosphatase binds to endothelial cells via charge interaction; a pathogenic role in Wegener’s granulomatosis? Clin Exp Immunol. 2000;119:566e573.
78
i n d i a n j o u r n a l o f r h e u m a t o l o g y 8 ( 2 0 1 3 ) 7 3 e7 8
9. Wijngaarden RA, Hauer HA, Wolterbeek R, et al. Clinical and histologic determinants of renal outcome in ANCA-associated vasculitis: a prospective analysis of 100 patients with severe renal involvement. J Am Soc Nephrol. 2006;17:2264e2274. 10. Davies D, Moran ME, Niall JF, et al. Segmental glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology. Br Med J. 1982;285:606. 11. Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum. 1999;42:421. 12. Finkielman JD, Lee AS, Hummel AM, et al, WGET Research Group. ANCA are detectable in nearly all patients with active severe Wegener’s granulomatosis. Am J Med. 2007;120:643. e9-14. 13. Xiao H, Heeringa P, Liu Z, et al. The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies. Am J Pathol. 2005;167:39. 14. Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest. 2002;110:955. 15. Pendergraft III WF, Preston GA, Shah RR, et al. Autoimmunity is triggered by cPR-3 (105-201), a protein complementary to human autoantigen proteinase-3. Nat Med. 2004;10:72e79. 16. Jennette JC, Falk RJ. Pathogenesis of the vascular and glomerular damage in ANCA-positive vasculitis. Nephrol Dial Transplant. 1998;13(suppl 1):16e20. 17. Ewert BH, Becker ME, Jennette JC, Falk RJ. Antimyeloperoxidase antibodies induce neutrophil adherence to cultured human endothelial cells. Ren Fail. 1995;17:125e133. 18. Nakabayashi K, Hashimoto H. Microscopic polyangiitis. In: Hashimoto H, ed. Clinical Manual for Vasculitis. Tokyo: Research Group of Intractable Vasculitis, Ministry of Health, Labor, and Welfare of Japan; 2002:24e26. 19. Aasarod K, Iversen BM, Hammerstrom J, Bostad L, Vatten L, Jorstad S. Wegener’s granulomatosis: clinical course in 108 patients with renal involvement. Nephrol Dial Transplant. 2000;15:611e618. 20. Luqmani RA, Bacon PA, Moots RJ, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. 1994;87:671e681. 21. Nachman PH, Hogan SL, Jennette JC, Falk RJ. Treatment response and relapse in antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol. 1996;7:33e39. 22. Gross WL. Systemic necrotizing vasculitis baillieres. Clin Rheumatol. 1997;11:259e284. 23. Savage CO, Winearls CG, Evans DJ, Rees AJ, Lockwood CM. Microscopic polyarteritis: presentation, pathology and prognosis. QJM. 1985;56:467e483. 24. Chumbley LC, Harrison EGJ, DeRemee RA. Allergic granulomatosis and angiitis (ChurgeStrauss syndrome). Report and analysis of 30 cases. Mayo Clin Proc. 1977;52: 477e484. 25. Mahr A, Guillevin L, Poissonnet M, Ayme S. Prevalences of polyarteritisnodosa, microscopic polyangiitis, Wegener’s
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
granulomatosis, and Churg-Strauss syndrome in a French urban multiethnic population in2000: a capture-recapture estimate. Arthritis Rheum. 2004;51:92e99. Wiik AS. Clinical use of serological tests for antineutrophil cytoplasmic antibodies. What do the studies say? Rheum Dis Clin North Am. 2001;27:799e803. Venning MC, Quinn A, Broomhead V, Bird AG. Antibodies directed against neutrophils (C-ANCA and P-ANCA) are of distinct diagnostic value in systemic vasculitis. QJM. 1990;77:1287e1296. Hagen EC, Daha MR, Hermans J, et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR project for ANCA assay standardization. Kidney Int. 1998;53:743e753. Walters G, Willis NS, Craig JC. Interventions for renal vasculitis in adults. Cochrane Database Syst Rev. 2008 Jul;16:CD003232. Walters GD, Willis NS, Craig JC. Interventions for renal vasculitis in adults. A systematic review. BMC Nephrol. 2010 Jun 24;11:12. Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009;150:670e680. Stone JH, Merkel PA, Spiera R, et al, RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCAassociated vasculitis. N Engl J Med. 2010;363:221e232. Jones RB, Tervaert JW, Hauser T, et al, European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCAassociated renal vasculitis. N Engl J Med. 2010;363:211e220. Walsh M, Merkel PA, Peh CA, et al, PEXIVAS Investigators. Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS): protocol for a randomized controlled trial. Trial. 2013 Mar 14;14:73. Andrassy K, Erb A, Koderisch J, et al. Wegener’s granulomatosis with renal involvement: patient survival and correlations between initial renal function, renal histology, therapy and renal outcome. Clin Nephrol. 1991;35:139. Hiemstra TF, Walsh M, Mahr A, et al, European Vasculitis Study Group (EUVAS). Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA. 2010;304:2381e2388. Stone JH, Holbrook JT, Marriott MA, et al. Solid malignancies among patients in the Wegener’s Granulomatosis Etanercept trial. Arthritis Rheum. 2006;54:1608e1618. Walsh M, Merkel PA, Mahr A, Jayne D. Effects of duration of glucocorticoid therapy on relapse rate in antineutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis. Arthritis Care Res (Hoboken). 2010;62:1166e1173. Nachman PH, Segelmark M, Westman K, et al. Recurrent ANCA-associated small vessel vasculitis after transplantation: a pooled analysis. Kidney Int. 1999;56:1544. Nyberg G, Akesson P, Norden G, Wieslander J. Systemic vasculitis in a kidney transplant population. Transplantation. 1997;63:1273e1277.