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      Impact of Proteinase 3 versus Myeloperoxidase Positivity on Risk of End-Stage Renal Disease in ANCA-Associated Glomerulonephritis Stratified by Histological Classification: A Population-Based Cohort Study

      1 , 2 , 3 , , 1 , 4

      Disease Markers

      Hindawi

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          Abstract

          Background

          End-stage renal disease (ESRD) risk in patients with antineutrophil cytoplasmic antibody- (ANCA-) associated glomerulonephritis (ANCA-GN) according to ANCA serotype and stratified by histological classification has not been previously investigated.

          Methods

          Patients from the Norwegian Kidney Biopsy Registry (NKBR) between 1991 and 2012 who had biopsy-verified pauci-immune glomerulonephritis and positive antineutrophil cytoplasmic antibody serology were included. Cases with ESRD during follow-up were identified in the Norwegian Renal Registry. ESRD-free survival with proteinase 3 (PR3) versus myeloperoxidase- (MPO-) ANCA positivity stratified into 4 histological classes was investigated.

          Results

          Three hundred fifty-eight patients, of whom 87 progressed to ESRD during follow-up, were included. Patients with PR3- as compared to MPO-ANCA were younger (58 versus 64 years, p = 0.001), had a higher percentage of males (62 versus 41%, p < 0.001), had a lower percentage with a sclerozing glomerulonephritis pattern (4 versus 16%, p < 0.001), and had a significantly higher cumulative ESRD-free survival (90 versus 80%, p = 0.007) at 1-year follow-up. No significant differences in cumulative ESRD-free survival with PR3- as compared to MPO-ANCA were observed by histological stratification.

          Conclusion

          Advanced glomerular sclerosis is found more frequently in patients with MPO-ANCA, explaining the higher risk of ESRD. ANCA serotypes have no impact on prognosis of patients with similar histological findings.

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          Most cited references 29

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          C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis.

          Anti-neutrophil cytoplasmic autoantibody (ANCA)-induced necrotizing crescentic glomerulonephritis (NCGN) requires complement participation in its pathogenesis. We tested the hypothesis that the anaphylatoxin C5a is pivotal to disease induction via the neutrophil C5a receptor (C5aR). Supernatants from ANCA-activated neutrophils activated the complement cascade in normal serum, producing C5a. This conditioned serum primed neutrophils for ANCA-induced respiratory burst; neutrophil C5aR blockade abrogated this priming, but C3aR blockade did not. Furthermore, recombinant C5a but not C3a dosage-dependently primed neutrophils for ANCA-induced respiratory burst. To test the role of C5aR in a model of NCGN, we immunized myeloperoxidase-deficient mice with myeloperoxidase, irradiated them, and transplanted bone marrow from wild-type mice or C5aR-deficient mice into them. All mice that received wild-type marrow (six of six) but only one of eight mice that received C5aR-deficient marrow developed NCGN (P < 0.05). Albuminuria and neutrophil influx into glomeruli were also significantly attenuated in the mice that received C5aR-deficient marrow (P < 0.05). In summary, C5a and the neutrophil C5aR may compose an amplification loop for ANCA-mediated neutrophil activation. The C5aR may provide a new therapeutic target for ANCA-induced necrotizing crescentic glomerulonephritis.
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            Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force.

            We undertook a systematic literature review as a background to the European League Against Rheumatism (EULAR) recommendations for conducting clinical trials in anti-neutrophil cytoplasm antibody associated vasculitis (AAV), and to assess the quality of evidence for outcome measures in AAV. Using a systematic Medline search, we categorised the identified studies according to diagnoses. Factors affecting remission, relapse, renal function and overall survival were identified. A total of 44 papers were reviewed from 502 identified by our search criteria. There was considerable inconsistency in definitions of end points. Remission rates varied from 30% to 93% in Wegener granulomatosis (WG), 75% to 89% in microscopic polyangiitis (MPA) and 81% to 91% in Churg-Strauss syndrome (CSS). The 5-year survival for WG, MPA and CSS was 74-91%, 45-76% and 60-97%. Relapse (variably defined) was common in the first 2 years but the frequency varied: 18% to 60% in WG, 8% in MPA, and 35% in CSS. The rate of renal survival in WG varied from 23% at 15 months to 23% at 120 months. used to assess morbidity varied between studies. Ignoring the variations in definitions of the stage of disease, factors influencing remission, relapse, renal and overall survival included immunosuppressive therapy used, type of organ involvement, presence of ANCA, older age and male gender. Factors influencing remission, relapse, renal and overall survival include the type of immunosuppressive therapy used, pattern of organ involvement, presence of ANCA, older age and male gender. Methodological variations between studies highlight the need for a consensus on terminology and definitions for future conduct of clinical studies in AAV.
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              Clinical and histologic determinants of renal outcome in ANCA-associated vasculitis: A prospective analysis of 100 patients with severe renal involvement.

              This study aimed to identify clinical and histologic prognostic indicators of renal outcome in patients with ANCA-associated vasculitis and severe renal involvement (serum creatinine >500 micromol/L). One hundred patients who were enrolled in an international, randomized, clinical trial to compare plasma exchange with intravenous methylprednisolone as an additional initial treatment were analyzed prospectively. Diagnostic renal biopsies were performed upon entry into the study. Thirty-nine histologic and nine clinical parameters were determined as candidate predictors of renal outcome. The end points were renal function at the time of diagnosis (GFR0) and 12 mo after diagnosis (GFR12), dialysis at entry and 12 mo after diagnosis, and death. Multivariate analyses were performed. Predictive of GFR0 were age (r = -0.40, P = 0.04), arteriosclerosis (r = -0.53, P = 0.01), segmental crescents (r = 0.35, P = 0.07), and eosinophilic infiltrate (r = -0.41, P = 0.04). Prognostic indicators for GFR12 were age (r = -0.32, P = 0.01), normal glomeruli (r = 0.24, P = 0.04), tubular atrophy (r = -0.28, P = 0.02), intraepithelial infiltrate (r = -0.26, P = 0.03), and GFR0 (r = 0.29, P = 0.01). Fibrous crescents (r = 0.22, P = 0.03) were predictive of dialysis at entry. Normal glomeruli (r = -0.30, P = 0.01) and treatment arm (r = -0.28, P = 0.02) were predictive of dialysis after 12 mo. No parameter predicted death. Both chronic and acute tubulointerstitial lesions predicted GFR12 in severe ANCA-associated glomerulonephritis, whereas plasma exchange was a positive predictor of dialysis independence after 12 mo for the entire patient group. Plasma exchange remained a positive predictor when patients who were dialysis dependent at presentation were analyzed separately (r = -0.36, P = 0.01). Normal glomeruli were a positive predictor of dialysis independence and improved renal function after 12 mo, indicating that the unaffected part of the kidney is vital in determining renal outcome.
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                Author and article information

                Contributors
                Journal
                Dis Markers
                Dis. Markers
                DM
                Disease Markers
                Hindawi
                0278-0240
                1875-8630
                2018
                9 May 2018
                : 2018
                Affiliations
                1Department of Clinical Medicine, University of Bergen, Bergen, Norway
                2Faculty of Health and Social Sciences, Western Norway University of Applied Sciences, Bergen, Norway
                3Department of Pathology, Haukeland University Hospital, Bergen, Norway
                4Emergency Care Clinic, Haukeland University Hospital, Bergen, Norway
                Author notes

                Academic Editor: Eric A. Singer

                Article
                10.1155/2018/3251517
                5966671
                Copyright © 2018 Vilde Solbakken et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Research Article

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