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    Atg3 promotes Atg8 lipidation via altering lipid diffusion and rearrangement. Wang Shen,Li Yun,Ma Cong Protein science : a publication of the Protein Society Atg3-catalyzed transferring of Atg8 to phosphatidylethanolamine (PE) in the phagophore membrane is essential for autophagy. Previous studies have demonstrated that this process requires Atg3 to interact with the phagophore membrane via its N-terminal amphipathic helix. In this study, by using combined biochemical and biophysical approaches, our data showed that in addition to binding to the membranes, Atg3 attenuates lipid diffusion and enriches lipid molecules with smaller headgroup. Our data suggest that Atg3 promotes Atg8 lipidation via altering lipid diffusion and rearrangement. 10.1002/pro.3866
    ANCA-Associated Vasculitis: Pathogenesis, Models, and Preclinical Testing. Hutton Holly L,Holdsworth Stephen R,Kitching A Richard Seminars in nephrology Our understanding of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis has developed greatly since the discovery of ANCA, directed against neutrophil components, in 1982. Observations in human disease, and increasingly sophisticated studies in vitro and in rodent models in vivo, have allowed a nuanced understanding of many aspects of the immunopathogenesis of disease, including the significance of ANCA as a diagnostic and monitoring tool as well as a mediator of microvascular injury. The mechanisms of leukocyte recruitment and tissue injury, and the role of T cells increasingly are understood. Unexpected findings, such as the role of complement, also have been uncovered through experimental studies and human observations. This review focusses on the pathogenesis of ANCA-associated vasculitis, highlighting the challenges in finding new, less-toxic treatments and potential therapeutic targets in this disease. The current suite of rodent models is reviewed, and future directions in the study of this complex and fascinating disease are suggested. 10.1016/j.semnephrol.2017.05.016
    Neutrophil extracellular traps can activate alternative complement pathways. Wang H,Wang C,Zhao M-H,Chen M Clinical and experimental immunology The interaction between neutrophils and activation of alternative complement pathway plays a pivotal role in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). ANCAs activate primed neutrophils to release neutrophil extracellular traps (NETs), which have recently gathered increasing attention in the development of AAV. The relationship between NETs and alternative complement pathway has not been elucidated. The current study aimed to investigate the relationship between NETs and alternative complement pathway. Detection of components of alternative complement pathway on NETs in vitro was assessed by immunostain and confocal microscopy. Complement deposition on NETs were detected after incubation with magnesium salt ethyleneglycol tetraacetic acid (Mg-EGTA)-treated human serum. After incubation of serum with supernatants enriched in ANCA-induced NETs, levels of complement components in supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Complement factor B (Bb) and properdin deposited on NETs in vitro. The deposition of C3b and C5b-9 on NETs incubated with heat-inactivated normal human serum (Hi-NHS) or EGTA-treated Hi-NHS (Mg-EGTA-Hi-NHS) were significantly less than that on NETs incubated with NHS or EGTA-treated NHS (Mg-EGTA-NHS). NETs induced by ANCA could activate the alternative complement cascade in the serum. In the presence of EGTA, C3a, C5a and SC5b-9 concentration decreased from 800·42 ± 244·81 ng/ml, 7·68 ± 1·50 ng/ml, 382·15 ± 159·75 ng/ml in the supernatants enriched in ANCA induced NETs to 479·07 ± 156·2 ng/ml, 4·86 ± 1·26 ng/ml, 212·65 ± 44·40 ng/ml in the supernatants of DNase I-degraded NETs (P < 0·001, P = 0·008, P < 0·001, respectively). NETs could activate the alternative complement pathway, and might thus participate in the pathogenesis of AAV. 10.1111/cei.12654
    Complement in ANCA-associated glomerulonephritis. Hilhorst Marc,van Paassen Pieter,van Rie Henk,Bijnens Nele,Heerings-Rewinkel Petra,van Breda Vriesman Peter,Cohen Tervaert Jan Willem, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Background:Anti-neutrophil cytoplasmic antibodies (ANCA) are found in pauci-immune necrotizing crescentic glomerulonephritis. In the past, the role of complement in ANCA-associated vasculitis (AAV) was assumed to be minimal. More recently, however, it was found that blocking the complement cascade in a mouse model of AAV reduces glomerular damage. Immune complex deposits have been found in biopsies from AAV patients. In this study, we questioned whether immune complex formation or deposition may result in complement activation in ANCA-associated glomerulonephritis. Methods:ANCA-positive patients from the Limburg Renal Registry were included between 1979 and 2011. Renal histology was documented together with immunoglobulin and complement immunofluorescence. In addition, C3d, properdin, C4d and mannose-binding lectin (MBL) were stained. Electron microscopy was performed. Circulating immune complexes were determined in a subset of patients, as well as C3 allotypes. Results:C3c was found in 78 of 187 renal biopsies (41.7%) divided over 32.3% of proteinase-3 (PR3)-AAV patients and 52.3% of myeloperoxidase (MPO)-AAV patients (P = 0.006), whereas C3d was found positive in 51.1% of PR3-AAV patients and 70.4% of MPO-AAV patients (P = 0.105). C4d was found positive in 70.8%, properdin in 38.7% and MBL in 30.4% of patients. Whereas C4d and MBL positivity was similar between the AGN groups, properdin was more common in biopsies classified as crescentic compared with biopsies classified as focal or mixed. Renal biopsies positive for C3d and/or properdin showed more cellular crescents and less normal glomeruli compared with biopsies negative for C3d and/or properdin (P < 0.05). In 3 out of 43 renal biopsies analysed by electron microscopy, small electron dense deposits were found. In 14 of 46 patients analysed, circulating immune complexes were detectable. No association between histological findings and C3 allotypes was found. Conclusions:In the majority of AAV patients, no immune complex deposits were found in their renal biopsies. C3d, C4d and C5b-9 staining, however, was found to be positive in a majority of analysed renal biopsies. Importantly, C3d and properdin staining was associated with cellular crescents. We hypothesize that local immune complexes are quickly degraded in AAV and therefore not visible by electron microscopy. Our findings are compatible with the hypothesis that complement activation in AAV occurs predominantly via alternative pathway activation. 10.1093/ndt/gfv288
    Complement in ANCA-associated vasculitis: mechanisms and implications for management. Chen Min,Jayne David R W,Zhao Ming-Hui Nature reviews. Nephrology Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of potentially life-threatening autoimmune diseases. The main histological feature in the kidneys of patients with AAV is pauci-immune necrotizing crescentic glomerulonephritis with little immunoglobulin and complement deposition in the glomerular capillary walls. The complement system was not, therefore, initially thought to be associated with the development of AAV. Accumulating evidence from animal models and clinical observations indicate, however, that activation of the complement system - and the alternative pathway in particular - is crucial for the development of AAV, and that the complement activation product C5a has a central role. Stimulation of neutrophils with C5a and ANCA not only results in the neutrophil respiratory burst and degranulation, but also activates the coagulation system and generates thrombin, thus bridging the inflammation and coagulation systems. In this Review, we provide an overview of the clinical, in vivo and in vitro evidence for a role of complement activation in the development of AAV and discuss how targeting the complement system could provide opportunities for therapy. 10.1038/nrneph.2017.37
    Plasma complement factor H is associated with disease activity of patients with ANCA-associated vasculitis. Chen Su-Fang,Wang Feng-Mei,Li Zhi-Ying,Yu Feng,Zhao Ming-Hui,Chen Min Arthritis research & therapy INTRODUCTION:Increasing evidences have demonstrated that activation of alternative complement pathway plays an important role in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current study aimed to investigate the association of complement factor H (CFH), a key regulator of the alternative complement pathway, with the disease activity of AAV. METHODS:Plasma CFH levels were measured in 82 patients with myeloperoxidase (MPO)-AAV in active stage. Of the 82 patients, plasma CFH levels of 27 patients were longitudinally measured. Serum anti-CFH autoantibodies were screened in AAV patients. Circulating complement activation profiles including C4d, Bb, C3a, C5a and soluble C5b-9 of AAV patients in active stage were further detected. Associations between plasma CFH levels and clinicopathological parameters as well as the prognosis were analyzed. RESULTS:Plasma CFH levels were significantly lower in active AAV patients compared with AAV patients in remission and normal controls. Correlation analysis showed that plasma CFH levels inversely correlated with initial serum creatinine, Birmingham Vasculitis Activity Score (BVAS), proportion of total crescents and cellular crescents in renal specimens, and circulating levels of C3a, C5a and Sc5b-9, meanwhile positively correlated with estimated glomerular filtration rate (eGFR), hemoglobin levels and circulating levels of C3. Moreover, multivariate survival analysis revealed that plasma CFH levels were independently associated with composite outcome of death or end stage renal disease (ESRD) in AAV patients, after adjusting for age, gender, hemoglobin level and urinary protein (P = 0.03, HR 0.85, 95 % CI 0.73-0.98) or adjusting for age, gender, total crescents (%) and urinary protein (P = 0.03, HR 0.85, 95 % CI 0.73-0.98), while not as an independent predictor after adjusting for age, gender, serum creatinine and urinary protein (P = 0.57, HR 0.96, 95 % CI 0.83-1.11). CONCLUSION:In conclusion, plasma CFH levels are associated with disease activity, and, to some extent, associated with composite outcomes of patients with MPO-ANCA-associated vasculitis. 10.1186/s13075-015-0656-8
    The Plasma Soluble Urokinase Plasminogen Activator Receptor Is Related to Disease Activity of Patients with ANCA-Associated Vasculitis. Huang Fei,Li Yueqiang,Xu Ranran,Cheng Anying,Lv Yongman,Liu Qingquan Mediators of inflammation Objective:The soluble urokinase plasminogen activator receptor (suPAR) is associated with kidney diseases and is used as a prognostic factor of renal function progression. The aim of this study was to explore whether circulating suPAR was associated with antineutrophil cytoplasmic autoantibody- (ANCA-) associated vasculitis (AAV) disease activity. Methods:We evaluated 90 AAV patients with follow-up data and 35 normal controls; their plasma suPAR and C-reactive protein (CRP) levels were measured by ELISA. Associations between these levels, clinical parameters, and prognosis were analyzed. Results:Plasma suPAR levels in AAV patients were significantly higher than in healthy controls (5,920.08 ± 3,447.17 vs. 1,441.97 ± 835.04 pg/mL, < 0.001). Furthermore, suPAR was significantly elevated in AAV patients in active stage compared to those in partial remissions (6,492.19 ± 3,689.48 vs. 5,031.86 ± 2,489.01 pg/mL, = 0.039). Correlation analyses demonstrated that suPAR levels positively correlated with initial serum creatinine, BVAS, CRP, and procalcitonin concentration, and negatively correlated with eGFR and C3 circulating levels. In a Kaplan-Meier survival analysis, patients with plasma suPAR levels >5683.3 pg/mL showed poorer survival than patients with lower levels (log-rank, = 0.001). Besides, multivariate analyses confirmed that plasma suPAR levels were an independent adverse prognostic factor for a composite outcome of end-stage renal disease (ESRD) or death, after adjusting for age and gender (HR 1.05, 95% CI = 1.01 - 1.11, = 0.043). Receiver operating characteristic curves showed a suPAR cutoff value >6662.2 pg/mL for composite outcome with 68% sensitivity and 88% specificity, with an AUC = 0.82, (95% CI = 0.68 - 0.96, < 0.001). Conclusion:Circulating suPAR levels might be a marker of activity correlated with disease activity in AAV patients, and, to some extent, could be a factor of poor prognosis. 10.1155/2020/7850179
    Hypocomplementemia is associated with worse renal survival in ANCA-positive granulomatosis with polyangiitis and microscopic polyangiitis. Deshayes Samuel,Aouba Achille,Khoy Kathy,Mariotte Delphine,Lobbedez Thierry,Martin Silva Nicolas PloS one Recent data suggest the existence of a complement alternative pathway activation in the pathogenesis of antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a condition that remains poorly understood. This study aims to assess the clinical characteristics and outcomes of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) patients with regard to their plasma complement levels at diagnosis. A retrospective monocentric study carried out at Caen University Hospital led to the identification of proteinase-3- or myeloperoxidase-ANCA-positive GPA and MPA patients from January 2000 to June 2016 and from September 2011 to June 2016, respectively. All patients with available C3 and C4 levels at diagnosis were included. Patients were categorized in the hypocomplementemia group if their C3 and/or C4 levels at diagnosis were below the lower limit of the normal range. Among the 76 AAV patients (43 GPA, 33 MPA), 4 (5%) had hypocomplementemia, and the 72 remaining patients exhibited normal plasma complement levels. All 4 hypocomplementemia patients had renal involvement. Hypocomplementemia was followed in 1 patient whose post-treatment complement level normalized within 1 month. Among all clinical and ANCA specificity, including relapse-free survival (p = 0.093), only overall and renal survival rates were significantly lower in the hypocomplementemia group (p = 0.0011 and p<0.001, respectively). Hypocomplementemia with low C3 and/or C4 levels at GPA or MPA diagnosis may be responsible for worse survival and renal prognosis. These results argue for larger and prospective studies to better determine the epidemiology of the disease and to assess complement-targeting therapy in these patients. 10.1371/journal.pone.0195680
    Clinical associations of renal involvement in ANCA-associated vasculitis. Kronbichler Andreas,Shin Jae Il,Lee Keum Hwa,Nakagomi Daiki,Quintana Luis F,Busch Martin,Craven Anthea,Luqmani Raashid A,Merkel Peter A,Mayer Gert,Jayne David R W,Watts Richard A Autoimmunity reviews OBJECTIVE:Renal involvement in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis is associated with significant morbidity and higher mortality rates. This study examined clinical manifestations associated with renal involvement in ANCA-associated vasculitis within a large, international cross-sectional cohort. METHODS:Univariate and multivariate analyses were performed to identify clinical factors associated with renal disease, which was defined as i) a serum-creatinine >30% above normal and a fall in creatinine-clearance >25%; or ii) haematuria attributable to active vasculitis. RESULTS:The study cohort include 1230 patients from 31 countries; 723 (58.8%) presented with renal involvement: microscopic polyangiitis (82.2%), granulomatosis with polyangiitis (58.6%), and eosinophilic granulomatosis with polyangiitis (26.4%). The following clinical and laboratory factors were more common among patients with renal disease: age (OR 1.01, 95% CI 1.01-1.02), fever (OR 1.97, 95% CI 1.35-2.88), fatigue (OR 1.55, 95% CI 1.14-2.10), weight loss (OR 1.62, 95% CI 1.23-2.12), polyarthritis (OR 1.39, 95% CI 1.02-1.89), petechiae/purpura (OR 1.47, 95% CI 1.06-2.05), pulmonary haemorrhage (OR 5.23, 95% CI 1.39-19.63), gastrointestinal symptoms (OR 2.19, 95% CI 1.34-3.58), seizures (OR 3.42, 95% CI 1.26-9.30), lower serum albumin (OR 2.42, 95% CI 1.64-3.57), higher CRP (OR 2.06, 95% CI 1.04-4.06), low serum C3 at baseline (OR 3.86, 95% CI 1.30-11.53), myeloperoxidase- (OR 7.97, 95% CI 2.74-23.20) and proteinase 3-ANCA (OR 3.40, 95% CI 1.22-9.50). The following clinical factors were less common among patients with renal disease: mononeuritis multiplex (OR 0.63, 95% CI 0.41-0.98), proptosis/exophthalmos (OR 0.19, 95% CI 0.06-0.59), nasal polyps (OR 0.32, 95% CI 0.19-0.55), septal defect/perforation (OR 0.29, 95% CI 0.14-0.60), respiratory distress/pulmonary fibrosis/asthma (OR 0.08, 95% CI 0.04-0.19), and wheeze/obstructive airway disease (OR 0.29, 95% CI 0.16-0.52). CONCLUSION:In this large international study, several clinical and laboratory factors were identified as associated with renal involvement in ANCA-associated vasculitis. 10.1016/j.autrev.2020.102495
    Low serum complement 3 level is associated with severe ANCA-associated vasculitis at diagnosis. Choi Hyeok,Kim Youhyun,Jung Seung Min,Song Jason Jungsik,Park Yong-Beom,Lee Sang-Won Clinical and experimental nephrology OBJECTIVES:We investigated whether low serum C3 level can cross-sectionally estimate severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in immunosuppressive drug-naïve patients at diagnosis. METHODS:We retrospectively reviewed the medical records of 139 patients with AAV, who were first classified as AAV at Severance Hospital. We obtained clinical and laboratory data including serum complement 3 (C3) level and calculated Birmingham vasculitis activity score (BVAS) at diagnosis. We stratified AAV patients into three groups according to the tertile of BVAS and defined the lower limit of the highest tertile as the cutoff for severe AAV (BVAS at diagnosis ≥ 16) at diagnosis. Low serum C3 level was defined as C3 < 90 mg/dL. The odds ratio (OR) was assessed using the multivariable logistic regression. RESULTS:The mean age at diagnosis was 56.3 years and 41 patients were men (29.5%). The mean initial BVAS was 12.8. The mean serum C3 and C4 levels were 110.6 and 26.8 mg/dL. Thirty-one patients (22.3%) exhibited low serum C3 level at diagnosis. In the multivariable analysis, serum C3 level at diagnosis < 90 mg/dL (OR 2.963) exhibited the significant association with severe AAV at diagnosis. Patients with low serum C3 level exhibited a significantly high relative risk (RR) for severe AAV at diagnosis compared to those without (RR 3.600). Patients with low serum C3 level at diagnosis exhibited poor renal prognosis than those without. CONCLUSION:Low serum C3 level can estimate severe AAV and predict poor renal outcome in immunosuppressive drug-naïve patients at diagnosis. 10.1007/s10157-018-1634-7
    Hypocomplementemia is associated with more severe renal disease and worse renal outcomes in patients with ANCA-associated vasculitis: a retrospective cohort study. Chalkia Aglaia,Thomas Konstantinos,Giannou Panagiota,Panagiotopoulos Alexandros,Hadziyannis Emilia,Kapota Athanasia,Gakiopoulou Harikleia,Vassilopoulos Dimitrios,Petras Dimitrios Renal failure BACKGROUND:The complement system has been recently proposed to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). This study evaluated the value of serum and kidney deposited C3 in predicting renal outcomes in AAV. METHODS:This was a retrospective study of 47 patients with AAV, who were categorized according to their serum C3 levels as hypo- or normo-complementemic and to those with positive or negative kidney biopsy immunofluorescence (IF) for C3. Baseline characteristics as well as progression to end-stage renal disease (ESRD) between the 2 groups were compared. RESULTS:In total, 23% (11/47) were hypo-complementemic; these patients were older (74 vs. 65 years,  = 0.013), had higher creatinine levels (4.9 vs. 2.2 mg/dL,  = 0.006), were more often hemodialysis dependent (64% vs. 19%,  = 0.009) and progressed more often to ESRD (55% vs. 11%,  = 0.01) compared to normo-complementemic patients ( = 36). On multivariate analysis, serum creatinine at diagnosis (HR = 16.8, 95%CI: 1.354-208.62,  = 0.028) and low serum C3 (HR = 2.492; 95% CI: 1.537-11.567;  = 0.044) were independent predictors for ESRD. Among 25 patients with an available kidney biopsy, 56% had C3 deposition by IF and displayed more often a mixed histological pattern (72% vs. 27%,  = 0.033), low serum C3 levels (42% vs. 18%,  < 0.001) and serious infections during follow-up (57% vs. 18%,  = 0.047) compared to those with negative ( = 11) IF staining. CONCLUSION:Almost one of four patients with AAV has low C3 levels at diagnosis which is associated with more severe renal disease and worse renal outcomes (ESRD). This should be taken into account in therapeutic and monitoring strategies. 10.1080/0886022X.2020.1803086
    Low Serum Complement C3 Levels at Diagnosis of Renal ANCA-Associated Vasculitis Is Associated with Poor Prognosis. Augusto Jean-François,Langs Virginie,Demiselle Julien,Lavigne Christian,Brilland Benoit,Duveau Agnès,Poli Caroline,Chevailler Alain,Croue Anne,Tollis Frederic,Sayegh Johnny,Subra Jean-François PloS one BACKGROUND:Recent studies have demonstrated the key role of the complement alternative pathway (cAP) in the pathophysiology of experimental ANCA-associated vasculitis (AAV). However, in human AAV the role of cAP has not been extensively explored. In the present work, we analysed circulating serum C3 levels measured at AAV onset and their relation to outcomes. METHODS:We conducted a retrospective observational cohort study including 45 consecutive patients with AAV diagnosed between 2000 and 2014 with serum C3 measurement at diagnosis, before immunosuppressive treatment initiation. Two groups were defined according to the median serum C3 level value: the low C3 group (C3<120 mg/dL) and the high C3 level group (C3≥120 mg/dL). Patient and renal survivals, association between C3 level and renal pathology were analysed. RESULTS:Serum complement C3 concentration remained in the normal range [78-184 mg/dL]. Compared with the high C3 level, the patients in the low C3 level group had lower complement C4 concentrations (P = 0.008) and lower eGFR (P = 0.002) at diagnosis. The low C3 level group had poorer patient and death-censored renal survivals, compared with the high C3 level group (P = 0.047 and P = 0.001, respectively). We observed a significant negative correlation between C3 levels and the percentage of glomeruli affected by cellular crescent (P = 0.017, r = -0.407). According to the Berden et al renal histologic classification, patients in the crescentic/mixed category had low C3 levels more frequently (P<0.01). Interestingly, we observed that when patients with the crescentic/mixed histologic form were analysed according to C3 level, long term renal survival was significantly greater in the high C3 level group than in the low C3 level group (100% vs 40.7% at 6 years, p = 0.046). No relationship between serum C4 and renal outcome was observed. CONCLUSION:A Low C3 serum level in AAV patients at diagnosis is associated with worse long-term patient and renal survival. 10.1371/journal.pone.0158871
    Circulating C3 levels predict renal and global outcome in patients with renal vasculitis. Villacorta Javier,Diaz-Crespo Francisco,Acevedo Mercedes,Cavero Teresa,Guerrero Carmen,Praga Manuel,Fernandez-Juarez Gema Clinical rheumatology Several studies have demonstrated the crucial role of complement activation in the pathogenesis of ANCA-associated vasculitis. We aimed to assess the association between baseline serum C3 (sC3) levels and long-term outcomes in patients with renal vasculitis. This retrospective study included 111 patients with renal vasculitis from three hospitals who underwent a renal biopsy between 1997 and 2014. Serum levels of C3 were measured at the onset and the study population was divided into three tertiles according to sC3 concentrations (tertile 1 <106 mg/dl; tertile 2 106-128 mg/dl; tertile 3 >128 mg/dl). Patients with lower sC3 (tertile 1) were compared with those having higher levels of sC3 (tertile 2 and tertile 3). Histological, clinical, and laboratory data were recorded for analysis. The primary end point was the composite of end-stage renal disease (ESRD) and death from any cause. Lower sC3 levels were associated with a higher need for dialysis and lower response rate to treatment (p = 0.04 and p = 0.007, respectively). Renal and global survival at 1 and 5 years was 53 and 46 % in patients with lower sC3 (tertile 1) compared with 72 and 65 % in patients with higher sC3 (upper two tertiles) (p = 0.04). In a multivariate Cox-regression model, when adjusted by renal function and histopatholologic categories, lower sC3 remained as an independent predictor of ESRD and death (HR, 1.9; 95 % CI, 1.1 to 3.4; p = 0.02). Baseline serum C3 levels have an independent prognostic value in predicting long-term renal and global survival in patients with renal vasculitis. 10.1007/s10067-016-3384-9
    Serum C3 complement levels in ANCA associated vasculitis at diagnosis is a predictor of patient and renal outcome. Crnogorac Matija,Horvatic Ivica,Kacinari Patricia,Ljubanovic Danica Galesic,Galesic Kresimir Journal of nephrology AIM:To determinate the prognostic significance of low serum C3 at the time of diagnosis of ANCA-associated vasculitis (AAV). METHODS:Our cohort included 75 consecutive patients with AAV diagnosed from January 2005 to December 2015. C3 levels were measured at the time of diagnosis. Patients were divided into two groups, those with low serum C3 levels (< 0.9 g/l) and those with normal serum C3 levels (0.9-1.8 g/l). We analysed association between serum C3 levels and both combined and singularly patient and renal survival (ESRD). Small number of relapsed patients did not allow for the statistical analysis to be performed as to weather the low serum C3 is associated with relapse rate in AAV patients. RESULTS:Low serum C3 levels were significantly associated with worse combined end-point patient and renal survival (HR 3.079; 95% CI 1.231-7.701; p = 0.016), and on multivariate adjusted analysis association remained significant (HR 2.831; 95% CI 1.093-7.338; p = 0.032). For both end-points individually low serum C3 levels were significantly associated with poorer patient survival (HR 6.378; 95% CI 2.252-18.065; p < 0.001; on multivariate adjusted analysis HR 4.315 95% CI 1.350-13.799; p = 0.014) and renal survival (HR 3.207; 95% CI 1.040-9.830; p = 0.043; on multivariate adjusted analysis HR 3.679; 95% CI 1.144-11.827; p = 0.029). In our study there was no significant association between serological and patohistological phenotypes and serum C3 levels. CONCLUSION:Lower serum C3 levels at the diagnosis is associated with poorer patient and renal outcomes in AAV patients. 10.1007/s40620-017-0445-3
    Association of Serum C3 Concentration and Histologic Signs of Thrombotic Microangiopathy with Outcomes among Patients with ANCA-Associated Renal Vasculitis. Manenti Lucio,Vaglio Augusto,Gnappi Elisa,Maggiore Umberto,Allegri Landino,Allinovi Marco,Urban Maria L,Delsante Marco,Galetti Maricla,Nicastro Maria,Pilato Francesco P,Buzio Carlo Clinical journal of the American Society of Nephrology : CJASN BACKGROUND AND OBJECTIVES:Complement alternative pathway (cAP) activation has recently been recognized as a key pathogenic event in ANCA-associated vasculitis (AAV). cAP dysregulation is also a major determinant of thrombotic microangiopathies (TMA), which can in turn complicate AAV. We explored the prognostic significance of cAP activation and of histologic evidence of TMA in a cohort of patients with renal AAV. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We studied 46 patients with AAV diagnosed between January 1990 and December 2011 at the Nephrology Unit of Parma University Hospital; 30 of them had undergone renal biopsy. We analyzed serum levels of C3 (sC3) and C4 (sC4) and, for 19 patients who had frozen plasma, plasma Bb and C5b-9 levels. We also reviewed all kidney biopsy specimens, specifically searching for histologic signs of TMA, and performed immunofluorescence or immunohistochemistry for C3d, C4d, Bb and C5b-9. RESULTS:sC3 was below the lower limit of normal in 35% of the patients, whereas C4 was low in only 2%. Patients with low sC3 tended to be older (P=0.04) and to have lower eGFR at diagnosis (P=0.06). The median follow-up was 78 months (interquartile range, 18-135 months); 18 patients reached ESRD (10 of 14 and 8 of 26 in the low and normal sC3 groups, respectively). Death-censored renal survival was lower in the low sC3 group than in the normal sC3 group (log-rank test, P=0.01). Eight of the 30 patients who had undergone biopsy (27%) had histologic signs of TMA; these signs were more frequent in patients with low sC3 (5 of 10 versus 3 of 20; P=0.04). Notably, patients with histologic signs of TMA had a dramatically worse death-censored renal survival than patients without TMA (log-rank test, P=0.01), with ESRD occurring in 8 of 8 patients with TMA versus 8 of 22 patients without TMA. CONCLUSIONS:Low sC3 levels and histologic signs of TMA are associated with a poor renal prognosis in patients with AAV. 10.2215/CJN.00120115
    Increased renal damage in hypocomplementemic patients with ANCA-associated vasculitis: retrospective cohort study. García L,Pena C E,Maldonado R Águila,Costi C,Mamberti M,Martins E,García M A Clinical rheumatology INTRODUCTION:The complement system has an important role in the pathogenesis of vasculitis associated with antineutrophilic cytoplasmic antibody (AAV) mainly at the level of the kidneys because patients with complement deposits on the glomerular basal membrane present more aggressive disease compared with those with pauci-immune vasculitis. AIM:To analyze the association of hypocomplementemia with the clinical manifestations, laboratory data, renal histology, progress to renal insufficiency, and mortality of patients with AAV. METHODS:Retrospective cohort study (2000-2007) included 93 patients with AAV. Hypocomplementemia is defined as having C3 values lower than 80 mg/dL or C4 values below 15 mg/dL. Demographic, statistical, clinical, hematological, serological, and histopathological characteristics of all the patients with and without diagnosis of hypocomplementemia were compared. In order to evaluate variable independence, a logistic regression analysis was used. RESULTS:Ninety-three patients were studied of whom 63 (67.7%) had complement dosage at the moment of AAV diagnosis. Seven patients (11.1%) presented hypocomplementemia and a greater kidney involvement compared with normocomplementemic patients. Thirty renal biopsies were analyzed and 4 (13.3%) showed immunocomplex (IC) or complement deposits by an immunofluorescence test (IFT). Patients with "non-pauci-immune" AAV also presented terminal chronic renal disease (TCRD). CONCLUSION:There is an association between low complement and the degree of renal damage in patients with AAV. Patients with renal biopsies confirming IC and/or complement deposits showed more aggressive renal disease. Key Points • The complement system has an important role in the pathogenesis of vasculitis associated to antineutrophilic cytoplasmic antibody. • The studies in murine models confirming the complement activation by alternative pathway and particularly the receptor C5a (C5aR) is necessary for the development of glomerulonefritis. • Complement deposit observed in the renal biopsies of patients diagnosed with AAV was correlated to greater kidney damage, greater proteinuria and major disease activity compared to patients diagnosed with typical pauci-immune vasculitis. • The presence of hypocomplementemia at the onset of the disease was also associated with a greater organ involvement, poor prognosis and greater mortality. 10.1007/s10067-019-04636-9