Prognostic value of complement serum C3 level and glomerular C3 deposits in anti-glomerular basement membrane disease.

Background and objectives: Activation of the complement system is involved in the pathogenesis of anti-glomerular basement membrane (anti-GBM) disease. Glomerular deposits of complement 3 (C3) are often detected on kidney biopsies. The primary objective of this study was to analyze the prognostic value of the serum C3 level and the presence of C3 glomerular deposits in patients with anti-GBM disease. Methods: We conducted a retrospective cohort study of 150 single-positive patients with anti-GBM disease diagnosed between 1997 and 2017. Patients were categorized according to the serum C3 level (forming a low C3 (C3<1.23 g/L) and a high C3 (C3≥1.23 g/L) groups) and positivity for C3 glomerular staining (forming the C3+ and C3- groups). The main outcomes were kidney survival and patient survival. Results: Of the 150 patients included, 89 (65%) were men. The median [interquartile range (IQR)] age was 45 [26-64]. At diagnosis, kidney involvement was characterized by a median [IQR] peak serum creatinine (SCr) level of 578 [298-977] µmol/L, and 106 (71%) patients required dialysis. Patients in the low C3 group (72 patients) had more severe kidney disease at presentation, as characterized by higher prevalences of oligoanuria, peak SCr ≥500 µmol/L (69%, vs. 53% in the high C3 group; p=0.03), nephrotic syndrome (42%, vs. 24%, respectively; p=0.02) and fibrous forms on the kidney biopsy (21%, vs. 8%, respectively; p=0.04). Similarly, we observed a negative association between the presence of C3 glomerular deposits (in 52 (41%) patients) and the prevalence of cellular forms (83%, vs. 58% in the C3- group; p=0.003) and acute tubulo-interstitial lesions (60%, vs. 36% in the C3- group; p=0.007). When considering patients not on dialysis at diagnosis, the kidney survival rate at 12 months was poorer in the C3+ group (50% [25-76], vs. 91% [78-100] in the C3- group; p=0.01), with a hazard ratio [95% confidence interval] of 5.71 [1.13-28.85] (p=0.04, after adjusting for SCr). Conclusion: In patients with anti-GBM disease, a low serum C3 level and the presence of C3 glomerular deposits were associated with more severe disease and histological kidney involvement at diagnosis. In patients not on dialysis at diagnosis, the presence of C3 deposits was associated with worse kidney survival.

Clusterin Neutralizes the Inflammatory and Cytotoxic Properties of Extracellular Histones in Sepsis.

Rationale: Extracellular histones, released into the surrounding environment during extensive cell death, promote inflammation and cell death, and these deleterious roles have been well documented in sepsis. Clusterin (CLU) is a ubiquitous extracellular protein that chaperones misfolded proteins and promotes their removal. Objectives: We investigated whether CLU could protect against the deleterious properties of histones. Methods: We assessed CLU and histone expression in patients with sepsis and evaluated the protective role of CLU against histones in in vitro assays and in vivo models of experimental sepsis. Measurements and Main Results: We show that CLU binds to circulating histones and reduces their inflammatory, thrombotic, and cytotoxic properties. We observed that plasma CLU levels decreased in patients with sepsis and that the decrease was greater and more durable in nonsurvivors than in survivors. Accordingly, CLU deficiency was associated with increased mortality in mouse models of sepsis and endotoxemia. Finally, CLU supplementation improved mouse survival in a sepsis model. Conclusions: This study identifies CLU as a central endogenous histone-neutralizing molecule and suggests that, in pathologies with extensive cell death, CLU supplementation may improve disease tolerance and host survival.

Waiting for a kidney transplant, a source of unavoidable but reversible anxiety: a prospective pilot study investigating a psychological intervention.

BACKGROUND: Kidney transplantation is the treatment of choice for end-stage renal disease. Psychological problems and the presence of high anxiety have been described at various times over the course of transplantation, starting early at inclusion on the waiting-list. The objective of this study was to investigate anxiety symptoms among patients waiting for a transplant and the efficacy of a psychological intervention in the management of the anxiety. METHODS: In this prospective trial, 30 patients waiting for a first kidney transplantation were included. Medico-psycho-sociodemographic data were collected. Anxiety symptoms were assessed at inclusion using the State-Trait Anxiety Inventory self-assessment questionnaire for state anxiety (Spielberger and Vagg in Inventaire d'anxiété état-trait, forme Y (STAI-Y) Paris, 1993). A second assessment was carried out after the psychological intervention, which consisted of three sessions conducted by a clinical psychologist. RESULTS: Anxiety scores were considerably higher in females compared to males (47.5 versus 33.0, p < 0.023) and among those who had a psychological treatment history (60 versus 37, p = 0.003). We found a correlation between the level of anxiety and the length of time spent on the waiting-list (r = 0.552, p = 0.002). Importantly, anxiety scores decreased significantly (44 versus 32, p < 0.0001) after the psychological intervention. CONCLUSION: This study suggests that early psychological support allows improving anxiety symptoms in patients wait-listed for a kidney transplant. TRIAL REGISTRATION: Clinical trial NCT02690272.

Association between kinetic of anti-neutrophil cytoplasmic antibody (ANCA), renal survival and relapse risk in ANCA glomerulonephritis.

BACKGROUND: Anti-neutrophil cytoplasmic antibody (ANCA) kinetic in ANCA-associated vasculitis with glomerulonephritis (AAV-GN) has been suggested to be associated with AAV relapse. Few studies have focused on its association with renal prognosis. Thus we aimed to investigate the relationship between ANCA specificity and the evolutive profile and renal outcomes. METHODS: This multicentric retrospective study included patients diagnosed with ANCA-GN since 1 January 2000. Patients without ANCA at diagnosis and with fewer than three ANCA determinations during follow-up were excluded. We analysed estimated glomerular filtration rate (eGFR) variation, renal-free survival and relapse-free survival according to three ANCA profiles (negative, recurrent and persistent) and to ANCA specificity [myeloperoxidase (MPO) or proteinase 3 (PR3)]. RESULTS: Over a follow-up of 56 months [interquartile range (IQR) 34-101], a median of 19 (IQR 13-25) ANCA determinations were performed for the 134 included patients. Patients with a recurrent/persistent ANCA profile had a lower relapse-free survival (P = .019) and tended to have a lower renal survival (P = .053) compared with those with a negative ANCA profile. Patients with a recurrent/persistent MPO-ANCA profile had the shortest renal survival (P = .015) and those with a recurrent/persistent PR3-ANCA profile had the worst relapse-free survival (P = .013) compared with other profiles. The negative ANCA profile was associated with a greater eGFR recovery. In multivariate regression analysis, it was an independent predictor of a 2-fold increase in eGFR at 2 years [odds ratio 6.79 (95% confidence interval 1.78-31.4), P = .008]). CONCLUSION: ANCA kinetic after an ANCA-GN diagnosis is associated with outcomes. MPO-ANCA recurrence/persistence identifies patients with a lower potential of renal recovery and a higher risk of kidney failure, while PR3-ANCA recurrence/persistence identifies patients with a greater relapse risk. Thus ANCA kinetics may help identify patients with a smouldering disease.

Assessment of Renal Risk Score and Histopathological Classification for Prediction of End-Stage Kidney Disease and Factors Associated With Change in eGFR After ANCA-Glomerulonephritis Diagnosis.

Introduction: The "Renal Risk Score" (RRS) and the histopathological classification have been proposed to predict the risk of end-stage kidney disease (ESKD) in ANCA-associated glomerulonephritis (ANCA-GN). Besides, factors associated with kidney function recovery after ANCA-GN onset remain to be more extensively studied. In the present study, we analyzed the value of the RRS and of the histopathological classification for ESKD prediction. Next, we analyzed factors associated with eGFR change within the first 2 years following ANCA-GN diagnosis. Materials and Methods: We included patients from the Maine-Anjou ANCA-associated vasculitis registry with at least 6 months of follow-up. The values of ANCA-GN, histopathological classification, and RRS, and the factors associated with eGFR variations between ANCA-GN diagnosis and 2 years of follow-up were assessed. Results: The predictive values of the histopathological classification and RRS were analyzed in 123 patients. After a median follow-up of 42 months, 33.3% patients developed ESKD. The predictive value of RRS for ESKD was greater than that of the histopathological classification. Determinants of eGFR variation were assessed in 80/123 patients with complete eGFR measurement. The median eGFR increased from ANCA-GN diagnosis to month 6 and stabilized thereafter. The only factor associated with eGFR variation in our study was eGFR at ANCA-GN diagnosis, with higher eGFR at diagnosis being associated with eGFR loss (p<0.001). Conclusion: The RRS has a better predictive value for ESKD than the histopathological classification. The main determinant of eGFR variation at 2 years was eGFR at ANCA-GN diagnosis. Thus, this study suggests that eGFR recovery is poorly predicted by histological damage at ANCA-GN diagnosis.

Lymphopaenia at diagnosis of anti-neutrophil cytoplasmic antibody-vasculitis with renal involvement is correlated with severity and renal prognosis.

BACKGROUND: Lymphopaenia is commonly observed in autoimmune diseases, where it has been associated with disease activity or prognosis. However, in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) only a few small-scale studies have been targeted towards this issue. Research has not yet focused on AAV with renal involvement (AAV-RI). Thus the aim of this study was to analyse the association between lymphocyte counts and outcomes in a large cohort of AAV-RI patients. METHODS: We used the Maine-Anjou AAV registry that retrospectively gathers data on consecutive patients affected by AAV in four French nephrology centres, recorded since January 2000. We analysed clinical, biological and histological data at diagnosis of AAV-RI. Risk factors for end-stage kidney disease (ESKD) were analysed. Event-free survival was also assessed. RESULTS: Among the 145 patients included in the study, those with lymphopaenia at diagnosis had a lower renal function at baseline [estimated glomerular filtration rate (eGFR) 13 versus 26 mL/min; P = 0.002] and were more likely to require kidney replacement therapy (51% versus 25%; P = 0.003). Lymphopaenia was correlated with histological lesions and especially with the percentage of sclerotic glomeruli (P = 0.0027). ESKD-free survival was lower in lymphopaenic patients (P < 0.0001). In multivariate Cox analysis, lymphopaenia was an independent risk factor for ESKD [hazard ratio 4.47 (95% confidence interval 2.06-9.72), P < 0.001]. CONCLUSIONS: Lymphopaenia correlates with the severity of AAV glomerulonephritis at diagnosis and predicts poor renal outcome. In this view, lymphopaenia could be used as a simple and cost-effective biomarker to assess renal prognosis at AAV-RI diagnosis.

Successful treatment of acute kidney allograft rejection using extracorporeal photopheresis in the context of post-transplant lymphoproliferative diseases: three successive cases.

We reported 3 kidney transplant patients with PTLD who developed mixed AR following IS treatment minimization. AR episodes were treated with extracorporeal photopheresis (ECP), methylprednisolone and IVIG. In all patients, graft function improved under ECP and stabilized in the long term. These observations suggest that ECP is safe and efficient for treatment of AR in the context of PTLD.

Apheresis in Adult With Refractory Idiopathic Nephrotic Syndrome on Native Kidneys.

BACKGROUND: Apheresis is the gold standard for idiopathic nephrotic syndrome (INS) relapse after transplantation, but it remains unknown whether such treatment is useful for adults with refractory INS on native kidneys. METHODS: This retrospective study included patients older than 16 years with biopsy-proven refractory (persistent nephrotic syndrome on corticosteroids plus at least 1 immunosuppressive drug) INS treated by apheresis and followed for at least 3 months. RESULTS: Between September 1997 and January 2020, 21 patients (focal segmental glomerulosclerosis: 12, minimal change nephrotic syndrome: 9, men: 67%, median age: 34 years) were identified. At last follow-up (12 months), 7 of 21 patients were in complete or partial remission. Remission was associated with older age (51 vs. 30 years, P = 0.05), lower proteinuria (3.9 vs. 7.3 g/d, P = 0.03), and lower estimated glomerular filtration rate (eGFR) (28.0 vs. 48.5 ml/min per 1.73 m2, P = 0.05) at apheresis. The need for dialysis before apheresis (odds ratio [OR] 22.0 [1.00-524], P = 0.026), age ≥50 years (OR: 22.6 [1.00-524], P = 0.006), a marked (>4.5 g/d) decrease in proteinuria (OR: 9.17 [1.15-73.2], P = 0.041), and a short (<12 months) time between diagnosis and apheresis (OR: 10.8 [1-117], P = 0.043) were significantly associated with remission. Three of 7 patients in remission who were initially on dialysis became dialysis-free; by contrast, none of the 14 patients without remission was initially on dialysis, but 5 of 14 had become dialysis-dependent (P = 0.01). CONCLUSION: Apheresis may result in remission in adult patients with refractory INS, particularly in those at risk of renal failure, with limited sensitivity to medical treatments, if apheresis is initiated within a year of diagnosis.

Retrospective and Systematic Analysis of Causes and Outcomes of Thrombotic Microangiopathies in Routine Clinical Practice: An 11-Year Study.

Background: Thrombotic microangiopathies (TMAs) are highly suspected in patients showing mechanical hemolytic anemia, thrombocytopenia, and haptoglobin consumption. Primary [thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome] and secondary TMA are considered. Even if ADAMTS13 measurements and alternative complement pathway explorations have greatly improved the ability to identify primary TMA, their diagnosis remains difficult, and their frequency relative to that of secondary TMA is undetermined. The objectives of the present study were, therefore, to describe the etiologies, management, and the outcomes of patients presenting with TMA in real-life clinical practice. Methods: We conducted a retrospective study between 01/01/2008 and 31/12/2018 that included all consecutive patients presenting with biological TMA syndrome at admission or developing during hospitalization. Patients were identified from the laboratory databases, and their medical files were reviewed to confirm TMA diagnosis, to determine etiology, and to analyze their therapeutic management and outcomes. Results: During this period, 239 patients with a full TMA biological syndrome were identified, and the TMA diagnosis was finally confirmed in 216 (90.4%) after the cases were reviewed. Primary TMAs (thrombotic thrombocytopenic purpura or atypical hemolytic uremic syndrome) were diagnosed in 20 of 216 patients (9.3%). Typical HUS was diagnosed in eight patients (3.7%), and the most frequent secondary TMAs were HELLP syndrome (79/216, 36.6%) and active malignancies (30/219, 13.9%). ADAMTS13 measurements and alternative complement pathway analyses were performed in a minority of patients. Multiple factors identified as TMA triggers were present in most patients, in 55% of patients with primary TMA, vs. 44.7% of patients with secondary TMA (p = 0.377). Death occurred in 57 patients (23.4%) during follow-up, and dialysis was required in 51 patients (23.6%). Active malignancies [odds ratio (OR) 13.7], transplantation (OR 4.43), male sex (OR 2.89), and older age (OR 1.07) were significantly associated with death. Conclusion: Secondary TMAs represent many TMA causes in patients presenting a full TMA biological syndrome during routine clinical practice. Multiple factors favoring TMA are present in about half of primary or secondary TMA. ADAMTS13 and complement pathway were poorly explored in our cohort. The risk of death is particularly high in patients with malignancies as compared with patients with other TMA.

Refractory Auto-Immune Thrombotic Thrombocytopenic Pupura Successfully Treated With Caplacizumab.

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy characterized by mechanical hemolytic anemia, profound thrombocytopenia, and neurological manifestations. Acquired auto-immune TTP, the most prevalent cause of TTP, is induced by the presence of inhibitory anti-ADAMTS13 auto-antibodies. Modern treatment of acquired TTP relies on plasma exchange, rituximab, and steroids. Caplacizumab (Cablivi®), a humanized single-variable domain immunoglobulin that targets the A1 domain of the ultra-large von Willebrand factor, inhibits the interaction between ultra-large vWFand platelets. In two clinical trials, caplacizumab, in addition to conventional treatment, shortened the delay to platelet count normalization in comparison to conventional treatment plus placebo, without increasing significantly hemorrhagic complications. Moreover, caplacizumab was associated with reduced occurrence of a secondary endpoint associating death, TTP recurrence, and major thromboembolic events. Here, we report the off-label use of caplacizumab in a 68-year-old patient with confirmed acquired TTP, severe thrombocytopenia, and generalized tonic-clonic seizures requiring mechanical ventilation and admission in the intensive care unit. Conventional treatment was rapidly started. Despite the intensification of plasma exchange treatment with twice-daily sessions, steroid continuation, and a second rituximab infusion on day 6, thrombotic microangiopathy worsened with thrombocytopenia at 21 g/L on day 8 from admission. We also considered using caplacizumab, which we could obtain and start on day 12 from admission, as it was available under a temporary authorization use in France. As soon as 12 h after caplacizumab initiation, we observed a significant increase of platelet count and improvement of other hemolytic parameters. We observed resolution of encephalopathy and complete recovery of motor paralysis, allowing us to stop mechanical ventilation on day 14. Caplacizumab was maintained for 128 days until day 139 from initial admission. The patient is going well 10 months after initial admission, without any neurological sequelae, and TTP did not relapse. To the best of our knowledge, this is the first reported use of caplacizumab in such a condition. This case report suggests that caplacizumab use may help to reduce the rate of refractory TTP episodes.

Incidence and Risk Factors of Venous Thromboembolic Events in Patients with ANCA-Glomerulonephritis: A Cohort Study from the Maine-Anjou Registry.

(1) Introduction: The incidence of venous thromboembolisms (VTE) has not been extensively analyzed in patients with antineutrophil cytoplasmic antibody (ANCA)-glomerulonephritis (ANCA-GN). Thus, the aim of the present study was to assess the frequency and the risk factors of VTE in patients with ANCA-GN. (2) Methods: Patients from the Maine-Anjou ANCA-associated vasculitis (AAV) registry with a biopsy showing pauci-immune glomerulonephritis were included. VTE events, site, and interval from AAV diagnosis were analyzed. (3) Results: 133 patients fulfilled the inclusion criteria of the study and were analyzed. VTE episodes were diagnosed in 23/133 (17.3%) patients at a median delay of 3 months from ANCA-GN diagnosis. Patients with VTE had lower serum albumin (p = 0.040), were less frequently on statin therapy (p = 0.009) and had less frequently proteinase-3 (PR3)-ANCAs (p = 0.078). Univariate analysis identified higher age (p = 0.022), lower serum albumin (p = 0.030), lack of statin therapy (p = 0.009), and rituximab treatment (p = 0.018) as significant risk factors of VTE. In multivariate analysis, only lack of statin therapy (HR 4.873; p = 0.042) was significantly associated with VTE. (4) Conclusion: Patients with ANCA-GN are at high risk of VTE, especially within the first months following AAV diagnosis. Our results suggest that statin therapy is associated with a lower risk of VTE in ANCA-GN patients.

High Incidence of Amoxicillin-Induced Crystal Nephropathy in Patients Receiving High Dose of Intravenous Amoxicillin.

BACKGROUND: Amoxicillin (AMX)-induced crystal nephropathy (AICN) is considered as a rare complication of high dose intravenous (IV) AMX administration. However, recently, its incidence seems to be increasing based on French pharmacovigilance centers. Occurrence of AICN has been observed mainly with IV administration of AMX and mostly under doses over 8 g/day. Given that pharmacovigilance data are based on declaration, the real incidence of AICN may be underestimated. Thus, the primary objective of the present study was to determine the incidence of AICN in the current practice. MATERIALS AND METHODS: We conducted a retrospective study between 1 January 2015 and 31 December 2017 in Angers University Hospital. Inclusion criteria were age over 18 years-old and IV AMX administration of at least 8 g/day for more than 24 h. Patients admitted directly into the intensive care units were excluded. Medical records of patients that developed Kidney Disease:Improving Global Outcome (KDIGO) stage 2-3 acute kidney injury (AKI) were reviewed by a nephrologist and a specialist in pharmacovigilance. AICN was retained if temporality analysis was conclusive, after exclusion of other causes of AKI, in absence of other nephrotoxic drug administration. RESULTS: A total of 1303 patients received IV AMX for at least 24 h. Among them, 358 (27.5%) were exposed to AMX doses of at least 8 g/day and were included. Patients were predominantly males (68.2%) with a mean age of 69.1 years-old. AMX was administered for a medical reason in 78.5% of cases. Patients received a median dose of AMX of 12 g/day (152.0 mg/kg/day). Seventy-three patients (20.4%) developed AKI, 42 (56.8%) of which were KDIGO stage 2 or 3. Among the latter, AICN diagnosis was retained in 16 (38.1%) patients, representing an incidence of 4.47% of total patients exposed to high IV AMX doses. Only female gender was associated with an increased risk of AICN. AMX dose was not significantly associated with AICN development. CONCLUSION: This study suggests a high incidence of AICN in patients receiving high IV AMX doses, representing one third of AKI causes in our study. Female gender appeared as the sole risk factor for AICN in this study.

Severe Infection in Anti-Glomerular Basement Membrane Disease: A Retrospective Multicenter French Study.

In patients presenting with anti-glomerular basement membrane (GBM) disease with advanced isolated kidney involvement, the benefit of intensive therapy remains controversial due to adverse events, particularly infection. We aim to describe the burden of severe infections (SI) (requiring hospitalization or intravenous antibiotics) and identify predictive factors of SI in a large cohort of patients with anti-GBM disease. Among the 201 patients (median [IQR] age, 53 [30-71] years) included, 74 had pulmonary involvement and 127 isolated glomerulonephritis. A total of 161 SI occurred in 116 patients during the first year after diagnosis. These infections occurred during the early stage of care (median [IQR] time, 13 [8-19] days after diagnosis) with mainly pulmonary (45%), catheter-associated bacteremia (22%) and urinary tract (21%) infections. In multivariable analysis, positive ANCA (HR [95\% CI] 1.62 [1.07--2.44]; p = 0.02) and age at diagnosis (HR [95% CI] 1.10 [1.00-1.21]; p = 0.047) remained independently associated with SI. Age-adjusted severe infection during the first three months was associated with an increased three-year mortality rate (HR [95% CI] 3.13 [1.24-7.88]; p = 0.01). Thus, SI is a common early complication in anti-GBM disease, particularly in the elderly and those with positive anti-neutrophil cytoplasmic antibodies (ANCA). No significant association was observed between immunosuppressive strategy and occurrence of SI.

Renal biopsy in very elderly patients (over 80 years): clinical presentation, histological diagnosis, and long-term outcome.

PURPOSE: Data regarding the long-term outcome of very elderly (VE) patients undergoing renal biopsy (RB) are lacking. The objective of this study was to analyse the outcome of VE patients undergoing RB. METHODS: All patients over 65 years that underwent native RB between 2004 and 2016 in our center were included. Among the 206 included patients, those over 80 years (VE, 46 patients) were analysed and compared to those aged 65-80 years (160 patients). The outcomes of the VE group were analysed. RESULTS: Baseline characteristics, renal presentation, safety of RB and RB-related diagnosis were not different between VE patients and 65-80-year-old patients. Survival of VE patients was 73.1, 50.6 and 21.8% at 2, 4 and 6 years after RB, significantly poorer than those of 65-80-year-old group. Early death (< 1 year) occurred in 10 VE patients, was associated with a higher proteinuria-to-creatininuria ratio and tended to be associated with a more frequent dialysis need at RB. Of the 46 VE patients, 31 (67.4%) were diagnosed with a potentially reversible kidney disease, of whom 17 (40%) were started on immunosuppressive regimens. Survival of patients with a reversible kidney disease tended to be better than those with other diseases. CONCLUSION: RB appears as a safe and valuable procedure to assess diagnosis of kidney disease in VE patients. Our data suggest that RB is critical for the identification and treatment decision of patients with potentially reversible diseases and may translate in clinical improvement.

Anti-Pentraxin Antibodies in Autoimmune Diseases: Bystanders or Pathophysiological Actors?

Pentraxins are soluble innate immunity receptors involved in sensing danger molecules. They are classified as short (CRP, SAP) and long pentraxin subfamilies, including the prototypic long pentraxin PTX3. Pentraxins act mainly as bridging molecules favoring the clearance of microbes and dead cells. They are also involved in many other biological processes, such as regulation of complement activation, inflammation and tissue homeostasis. Autoantibodies directed against pentraxins have been reported in various autoimmune diseases, especially in systemic lupus erythematosus and ANCA-associated vasculitis. In this review, we review the main biological characteristics and functions of pentraxins and summarize data concerning autoantibodies directed against pentraxins in the context of autoimmune diseases and discuss their potential pathological role.

Complement alternative pathway in ANCA-associated vasculitis: Two decades from bench to bedside.

Anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitides (AAVs) are small vessel vasculitides involving predominantly ear-nose-throat, kidneys, lungs and nerves. AAVs are life-threatening diseases, especially in their most severe forms such as necrotizing crescentic glomerulonephritis (GN) and/or intra-alveolar hemorrhage. Unlike immune complex GN or anti-glomerular basement membrane GN, AAVs are classified as pauci-immune GN. However, based on recent insights from animal models, the view of AAVs as a complement-unrelated disease has been challenged. Indeed, complement activation, and especially complement alternative pathway (cAP) activation, has been shown to be determinant in AAV pathogenesis through C5a generation, a potent chemoattractant for neutrophils with priming capacities. Here, we review in vitro and in vivo data supporting the role of cAP in murine models and in human AAVs. These findings, together with the need to eradicate glucocorticoid toxicity, led to the development of an anti-C5aR molecule, CCX168, also known as avacopan. Its development and future opportunities are also discussed.

Spectrum and Prognosis of Antineutrophil Cytoplasmic Antibody-associated Vasculitis-related Bronchiectasis: Data from 61 Patients.

OBJECTIVE: To report on a large series of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and bronchiectasis, with a specific focus on the timeline of occurrence of both features. METHODS: Retrospective nationwide multicenter study of patients diagnosed with both AAV and bronchiectasis. RESULTS: Sixty-one patients were included, among whom 27 (44.25%) had microscopic polyangiitis (MPA), 27 (44.25%) had granulomatosis with polyangiitis (GPA), and 7 (11.5%) had eosinophilic GPA. Thirty-nine (64%) had myeloperoxidase (MPO)-ANCA and 13 (21%) had proteinase 3-ANCA. The diagnosis of bronchiectasis either preceded (n = 25; median time between both diagnoses: 16 yrs, IQR 4-54 yrs), was concomitant to (n = 12), or followed (n = 24; median time between both diagnoses: 1, IQR 0-6 yrs) that of AAV. Patients in whom bronchiectasis precedes the onset of AAV (B-AAV group) have more frequent mononeuritis multiplex, MPA, MPO-ANCA, and a 5-fold increase of death. The occurrence of an AAV relapse tended to be protective against bronchiectasis worsening (HR 0.6, 95% CI 0.4-0.99, P = 0.049), while a diagnosis of bronchiectasis before AAV (HR 5.8, 95% CI 1.2-28.7, P = 0.03) or MPA (HR 18.1, 95% CI 2.2-146.3, P = 0.01) were associated with shorter survival during AAV follow-up. CONCLUSION: The association of bronchiectasis with AAV is likely not accidental and is mostly associated with MPO-ANCA. Patients in whom bronchiectasis precedes the onset of AAV tend to have distinct clinical and biological features and could carry a worse prognosis.

T Cell Dysregulation in Non-silicotic Silica Exposed Workers: A Step Toward Immune Tolerance Breakdown.

Background: Chronic silica exposure can lead to silicosis, complicated or not by autoimmune diseases (AID). The pathophysiology of silica-induced AID remains not fully understood, especially immune mechanisms that may develop in patients without yet established silicosis. We conducted a prospective clinical study to analyze the impact of crystalline silica (CS) on T cell phenotype and regulatory T cells (Tregs) frequency, as well as on auto-antibodies development in non-silicotic workers exposed to CS. Methods: Workers with moderate to high exposure level to CS and aged between 30 and 60 years-old were considered for inclusion. Peripheral blood mononuclear cells were analyzed by flow cytometry. Auto-antibodies were screened in serum by immunofluorescence. Blood from 42 and 45 healthy subjects (HC) was used as control for T cell phenotype and serum analyses, respectively. Results: Among the 63 included workers exposed to CS, 55 had full data available and were analyzed. Ten were exposed to CS for <5 years, 18 for 5-10 years and 27 for more than 10 years. The frequency of Tregs (CD4+CD25+CD127-FoxP3+) was significantly lower in CS exposed workers as compared to HC. We found an increased expression of the activation marker HLA-DR on T cells (CD3+, CD4+, and CD8+) of CS exposed workers as compared to HC. Tregs to activated T cells ratio was also lower in exposed subjects. In the latter, HLA-DR expression level and Tregs frequency were significantly associated with CS exposure duration. Serum autoantibody detection was significantly higher in CS exposed workers as compared to HC. Especially, among workers exposed more than 10 years, antinuclear antibodies and ANCA were detected in 44 and 22% among them, as compared to 5 and 2.5% in HC, respectively. Conclusion: This work shows that CS exposure is associated with a decrease of Tregs frequency, an increase of T cell activation status, and a tolerance breakdown against auto-antigens. These results show that alterations of the T cell compartment can be detected early over the course of CS exposure, preceding silicosis development or AID onset.

Patients with ANCA-Associated Glomerulonephritis and Connective Tissue Diseases: A Comparative Study from the Maine-Anjou AAV Registry.

BACKGROUND AND OBJECTIVES: The overlap between antineutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis (ANCA-GN) and connective tissue diseases (CTD) has been reported mainly as case series in the literature. Frequency of this association, as well as presentation and outcomes are unknown. MATERIALS AND METHODS: Patients from the Maine-Anjou ANCA-associated vasculitides (AAV) registry with ANCA-GN diagnosed between 01/01/2000 and 01/01/2018, ANCA positivity, and at least six months of follow-up, were included. RESULTS: 106 out of 142 patients fulfilled the inclusion criteria and were analyzed. CTD was present at ANCA-GN diagnosis in 16 (15.1%) patients. The most common CTD were rheumatoid arthritis, Sjogren syndrome and systemic sclerosis. Compared to the control group, females were more represented in the CTD group (75%, p = 0.001). Renal presentation was comparable between groups, including the pathological analysis of renal biopsies. Patients of CTD group presented a higher rate of non-renal relapse (25% versus 7.7%, p = 0.037), and experienced more frequently a venous thrombotic event (31.2% versus 10%, p = 0.021). No difference between groups was observed according to major outcomes. CONCLUSION: Association between CTD and ANCA-GN is not a rare condition and predominantly affects females. While AAV presentation is not significantly different, CTD patients experience more frequently non-renal relapse and venous thrombotic events.

CD45RC Expression of Circulating CD8+ T Cells Predicts Acute Allograft Rejection: A Cohort Study of 128 Kidney Transplant Patients.

Predictive biomarkers of acute rejection (AR) are lacking. Pre-transplant expression of CD45RC on blood CD8+ T cells has been shown to predict AR in kidney transplant (KT) patients. The objective of the present study was to study CD45RC expression in a large cohort of KT recipients exposed to modern immunosuppressive regimens. CD45RC expression on T cells was analyzed in 128 KT patients, where 31 patients developed AR, of which 24 were found to be T-cell mediated (TCMR). Pre-transplant CD4+ and CD8+ CR45RChigh T cell proportions were significantly higher in patients with AR. The frequency of CD45RChigh T cells was significantly associated with age at transplantation but was not significantly different according to gender, history of transplantation, pre-transplant immunization, and de novo donor specific anti-Human Leucocyte Antigen (HLA) antibody. Survival-free AR was significantly better in patients with CD8+ CD45RChigh T cells below 58.4% (p = 0.0005), but not different according to CD4+ T cells (p = 0.073). According to multivariate analysis, CD8+ CD45RChigh T cells above 58.4% increased the risk of AR 4-fold (HR 3.96, p = 0.003). Thus, pre-transplant CD45RC expression on CD8+ T cells predicted AR, mainly TCMR, in KT patients under modern immunosuppressive therapies. We suggest that CD45RC expression should be evaluated in a prospective study to validate its usefulness to quantify the pre-transplant risk of AR.