Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
1.
Kidney Int ; 104(1): 151-162, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37088424

RESUMO

Neutrophil extracellular traps (NET) have been implicated in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Here, we developed a novel, label-free, high-throughput bio-impedance technique to effectively measure serum NET-inducing activity. Using this technique, NET-inducing activity of serum derived from patients with AAV was assessed in a prospective cohort of 62 patients presenting with active AAV with major organ involvement. Thirty-five patients presented with new and 27 patients presented with relapsing AAV, of whom 38 had kidney and/or 31 had lung involvement. NET-inducing activity was assessed at diagnosis of active AAV (time zero), during the first 6 weeks of treatment, and after 6 months of treatment. Forty-seven patients revealed elevated NET-inducing activity at time zero. After initiation of immunosuppressive treatment, NET-inducing activity was reduced at six weeks. A subsequent increase at six months could potentially identify patients with relapsing disease (hazard ratio, 11.45 [interquartile range 1.36-96.74]). NET-inducing activity at time zero correlated with kidney function and proteinuria. Importantly, in kidney tissue, NETs co-localized with lesions typical of ANCA-associated glomerulonephritis and even correlated with systemic serum NET-inducing activity. Thus, our prospective data corroborate the importance of NET formation in AAV and ANCA-associated glomerulonephritis and the potential of longitudinal evaluation, as monitored by our novel bio-impedance assay and detailed histological evaluation.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Armadilhas Extracelulares , Glomerulonefrite , Humanos , Anticorpos Anticitoplasma de Neutrófilos , Impedância Elétrica , Estudos Prospectivos
2.
J Autoimmun ; 133: 102914, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36183584

RESUMO

INTRODUCTION: Macrophages are key players in the immunopathology of anti-neutrophil cytoplasmic antibody (ANCA) mediated-vasculitis (AAV) with glomerulonephritis (ANCA GN). Different macrophage phenotypes are expected to play distinct roles in ANCA GN. Macrophages expressing CD163 and CD206 are found in lesions associated with ANCA GN. Hence, we aimed to investigate the clinicopathological significance of CD206 and CD163 in ANCA GN in a multicenter retrospective cohort study. MATERIAL AND METHODS: Patients with ANCA-associated vasculitis, with clinical data, serum and urine samples were included from three cohorts. Serum soluble CD206 (ssCD206) and urinary soluble CD163 (usCD163) levels were measured. Human kidney tissue samples (n = 53) were stained for CD206 and CD163 using immunohistochemistry and immunofluorescence, and findings were correlated with clinical and pathological data. RESULTS: In total, 210 patients were included (i.e., ANCA GN, n = 134; AAV without GN, n = 24; AAV in remission n = 52). Increased levels of both ssCD206 and usCD163 were seen in ANCA GN. High levels of ssCD206 declined after reaching remission, however, ssCD206 did not improve the accuracy of usCD163 to detect ANCA GN. Soluble markers correlated with histopathological findings. CD163+CD206- macrophages were found in the glomerulus and may play pivotal roles in glomerulonephritis, whereas CD206+CD163- and CD206+CD163+ macrophages were located tubulointerstitially and likely play a more prominent role in ANCA-associated tubulointerstitial inflammation. In ANCA GN patients increasing levels of ssCD206 increased the risk for end-stage renal disease and mortality. CONCLUSIONS: Our results confirm and extend the notion that CD206+ and CD163+ macrophages are prominent components of the cellular infiltrate in ANCA GN. We found distinct macrophage phenotypes that may play distinct roles in the immunopathology of ANCA GN and elaborate on a potential mechanism underlying the findings of this study. usCD163 remains an excellent marker to detect active ANCA GN, whereas ssCD206 seems a more prominent marker for risk prediction.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos , Macrófagos , Humanos , Estudos Retrospectivos
6.
Blood Adv ; 8(5): 1295-1304, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38175623

RESUMO

ABSTRACT: The risk of a venous thrombotic event (VTE) is increased in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV); however, a detailed understanding of the underlying mechanisms of hypercoagulability is limited. We assessed prospectively different coagulation parameters in 71 patients with active AAV at baseline and after 6 months of follow-up. D-dimers and fibrinogen were increased in most patients at presentation and remained elevated in half of the patients. Particularly, thrombin-antithrombin (T:AT) complex and activated coagulation factors in complex with their natural inhibitors of the intrinsic coagulation pathway (ie, activated FXII:C1 esterase inhibitor [FXIIa:C1Inh], FXIa:AT, and FXIa:alpha1-antitrypsin [FXIa:α1AT]) were profoundly elevated in patients at baseline. Thrombin formation was dominantly correlated with coagulation factors of the intrinsic pathway (ie, FXIIa:AT, FXIa:AT, FXIa:α1AT, and FXIa:C1Inh) compared to the extrinsic pathway (ie, FVIIa:AT). Hypercoagulability correlated with higher disease activity, ANCA levels, C-reactive protein, serum creatinine, and proteinuria. VTEs were observed in 5 out of 71 (7%) patients within 1 month (interquartile range, 1-5) after inclusion. Baseline T:AT levels were significantly higher in patients with VTE than in those without VTE (P = .044), but other clinical or laboratory markers were comparable between both groups. Hypercoagulability is dominantly characterized by activation of the intrinsic coagulation pathway and elevated D-dimers in active AAV. The driving factors of hypercoagulability are yet to be studied but are most likely related to an interplay of increased disease activity, vascular inflammation, and endothelial damage. Future targets for intervention could include inhibitors of the intrinsic coagulation pathway and compounds specifically reducing the hyperinflammatory state.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Trombofilia , Humanos , Anticorpos Anticitoplasma de Neutrófilos , Trombina , Coagulação Sanguínea , Trombofilia/etiologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações
7.
J Transl Autoimmun ; 6: 100178, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36589266

RESUMO

Objective: Rituximab (RTX) and cyclophosphamide (CYC) are effective remission-induction therapies in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, combining these therapies may favor prognosis in patients with a major disease presentation. We conducted a retrospective study to compare patients treated with a combination of RTX and low dose CYC (RTX-CYC) or with RTX only, both followed by tailored maintenance with RTX, with regard to long-term outcomes. Methods: Patients treated in the Maastricht University Medical Center between March 2007 and January 2019, were screened for eligibility. The primary outcome variable was major relapse rate after two and five years. Secondary outcome variables were clinical data and laboratory parameters. Results: Of the 246 screened patients, 34 received RTX-CYC and 28 RTX only for remission-induction. All patients were followed for at least two years, with a median follow-up of 48 months (IQR 24-60). At baseline, renal involvement was more prevalent in the RTX-CYC patients (85% vs. 61%, P = 0.028). Major relapse rates within two years, but not after five years, were significantly lower in the RTX-CYC group (3% vs. 24%, P = 0.032). The rate of infections, hypogammaglobulinemia, end-stage renal disease, malignancies, and mortality did not differ after two and five years. Conclusion: Adding low dose CYC to RTX is safe and may prevent major relapses in patients with severe AAV in the first two years after remission-induction. Randomized controlled trials that compare the efficacy and safety between RTX and a combination of RTX with CYC are needed.

8.
J Clin Med ; 11(24)2022 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-36556102

RESUMO

Severe coronavirus disease 2019 (COVID-19) is characterized by hyperinflammation, vascular damage, and hypercoagulability. Insufficient responses of Annexin A1 (AnxA1), a pro-resolving inhibitor of neutrophil infiltration and activation, might contribute to a severe course of the disease. We longitudinally evaluated AnxA1's role in terms of inflammation, vascular damage, and clinical outcomes in a large prospective cohort of patients with COVID-19. AnxA1 was measured at presentation and during follow-up in the sera of 220 consecutive patients who presented at our hospital during the first wave. AnxA1 was significantly higher in the moderate and severe cases of COVID-19 compared to the healthy controls. Elevated AnxA1 was associated with markers of inflammation and endothelial damage. AnxA1 was significantly higher in patients with thrombotic events and ICU admission. Multivariable logistic regression indicated baseline AnxA1 (per ten units) as a predictor of thrombotic events. Linear mixed models predicted that AnxA1 tended to increase more steeply over time in patients without adverse events, with a statistically significant rise in patients without thrombotic events. These findings might reflect an insufficient increase in AnxA1 as a response to the excessive hyperinflammation in COVID-19. Future studies should evaluate whether hyperinflammation could be reduced through the administration of human recombinant AnxA1 or Ac2-26 peptide.

9.
Autoimmunity ; 54(1): 45-50, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33215537

RESUMO

The use of high-quality antigen-specific immunoassays for detecting anti-neutrophil cytoplasmic antibodies (ANCA) and anti-glomerular basement membrane (GBM) autoantibodies is recommended in patients with suspected ANCA vasculitis and/or anti-GBM disease. We analysed the diagnostic performance of a semi-quantitative and rapid immunoblot (EUROIMMUN AG, Lübeck, Germany) in two settings. Patient sera from different cohorts (ANCA vasculitis n = 187, anti-GBM disease n = 19, and disease controls n = 51) were used. The diagnostic performance of the immunoblot was assessed when used as a confirmatory test for the presence of ANCA in suspected ANCA vasculitis and when evaluating the presence of ANCA and/or anti-GBM antibodies in AAV and/or anti-GBM disease patients with a rapidly progressive glomerulonephritis (RPGN). In a confirmatory test setting, the immunoblot had an optimal sensitivity and specificity of 97.4 and 98.1% for PR3-ANCA and 98.5 and 96.4% for MPO-ANCA, respectively. With increasing test result ranges, a higher interval likelihood ratio (LR) was found for both ANCA entities. When evaluating for ANCA in patients with RPGN, the highest diagnostic accuracy (sensitivity 92.9% and specificity 100%) was obtained by using different cut-off values of positivity for PR3- (>5) and MPO-ANCA (>10). Also, the diagnostic performance for detecting anti-GBM was good (sensitivity 100% and specificity 100%). There are advantages over other assays in terms of time, costs, and interpretation of results. The immunoblot is a useful addition to current guidelines, particularly when a rapid diagnosis is necessary.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Autoanticorpos/sangue , Immunoblotting/métodos , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Autoanticorpos/imunologia , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico , Biomarcadores , Biópsia , Suscetibilidade a Doenças/imunologia , Glomerulonefrite/sangue , Glomerulonefrite/diagnóstico , Glomerulonefrite/etiologia , Humanos , Immunoblotting/normas , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
10.
Clin J Am Soc Nephrol ; 15(12): 1740-1748, 2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-33203735

RESUMO

BACKGROUND AND OBJECTIVES: ANCA-associated GN is a common cause of rapidly progressive GN, with high relapse rates. The early recognition of an ANCA-associated GN relapse is of importance to prevent loss of kidney function. Urinary soluble CD163 has been identified as a promising marker of active ANCA-associated GN. Previous studies, however, are limited by the lack of histologic data. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed urinary soluble CD163 in 95 patients with ANCA-associated vasculitis who underwent a kidney biopsy. In total, 125 kidney tissue sections (first kidney biopsy, n=67; repeated biopsy, n=58) with concurrent 24-hour urine samples were studied. Correlation analyses comparing urinary soluble CD163 levels and morphologic features of ANCA-associated GN were performed using Spearman rank correlation analysis. The diagnostic performance of biomarkers to detect relapsing ANCA-associated GN was evaluated using receiver operating characteristics curve analysis. RESULTS: High levels of urinary soluble CD163 were found in 96 (87%) of 110 biopsies with active ANCA-associated GN compared with one (7%) of 15 biopsies without active ANCA-associated GN and one (6%) of 17 healthy controls. Urinary soluble CD163 correlated with fibrinoid necrosis (Rho=0.48, P<0.001) and cellular crescents (Rho=0.70, P<0.001) on kidney biopsy. In repeated biopsies, urinary soluble CD163's sensitivity of 0.94 and specificity of 0.91 for the recognition of relapsing ANCA-associated GN appeared better than routine clinical measures. The presence of CD163+ cells in affected glomeruli confirmed urinary soluble CD163's origin. CONCLUSIONS: Urinary soluble CD163 is associated with active ANCA-associated GN and correlates with histologic features as seen in ANCA-associated GN. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_11_17_CJN07210520_final.mp3.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Antígenos CD/urina , Antígenos de Diferenciação Mielomonocítica/urina , Glomerulonefrite/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/urina , Biomarcadores/urina , Biópsia , Feminino , Glomerulonefrite/patologia , Glomerulonefrite/urina , Humanos , Masculino , Valor Preditivo dos Testes , Receptores de Superfície Celular , Sistema de Registros , Urinálise
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa