Acute kidney injury related to acute vascular disorders. A broad spectrum of vascular disease characterized by primary vessel involvement may be associated with acute renal failure. These diseases ...are usually classified according to the size of the injured vessel that include the small vessels (thrombotic microangiopathy, kidney injury due to malignant hypertension, scleroderma renal crisis, and cholesterol crystal embolism disease), the medium vessels (polyarteritis nodosa) or the large size vessels (acute renal infarction). Regardless of the primary pathogenic mechanisms and/or the size of the involved vessels, increased of blood pressure associated with acute kidney injury is a major and common feature of these acute renal disorders. A prompt diagnosis of the vascular disease causing acute kidney damage is required to reduce the risk of morbi-mortality due to renal impairment and to the systemic consequences of the underlying disease and to start an appropriate therapeutic management that should systematically include blood pressure control.
Levels of the soluble form of the receptor for advanced glycation end-products (sRAGE) are elevated during acute respiratory distress syndrome (ARDS) and correlate with severity and prognosis. ...Alveolar fluid clearance (AFC) is necessary for the resolution of lung edema but is impaired in most patients with ARDS. No reliable marker of this process has been investigated to date.
To verify whether sRAGE could predict AFC during ARDS.
Anesthetized CD-1 mice underwent orotracheal instillation of hydrochloric acid. At specified time points, lung injury was assessed by analysis of blood gases, alveolar permeability, lung histology, AFC, and plasma/bronchoalveolar fluid measurements of proinflammatory cytokines and sRAGE. Plasma sRAGE and AFC rates were also prospectively assessed in 30 patients with ARDS.
The rate of AFC was inversely correlated with sRAGE levels in the plasma and the bronchoalveolar fluid of acid-injured mice (Spearman's ρ = -0.73 and -0.69, respectively; P < 10(-3)), and plasma sRAGE correlated with AFC in patients with ARDS (Spearman's ρ = -0.59; P < 10(-3)). Similarly, sRAGE levels were significantly associated with lung injury severity, and decreased over time in mice, whereas AFC was restored and lung injury resolved.
Our results indicate that sRAGE levels could be a reliable predictor of impaired AFC during ARDS, and should stimulate further studies on the pathophysiologic implications of RAGE axis in the mechanisms leading to edema resolution. Clinical trial registered with www.clinicaltrials.gov (NCT 00811629).
The receptor for advanced glycation end-products (RAGE) is involved in inflammatory response during acute respiratory distress syndrome (ARDS). Growing body of evidence support strategies of RAGE ...inhibition in experimental lung injury, but its modalities and effects remain underinvestigated. Anesthetised C57BL/6JRj mice were divided in four groups; three of them underwent orotracheal instillation of acid and were treated with anti-RAGE monoclonal antibody (mAb) or recombinant soluble RAGE (sRAGE), acting as a decoy receptor. The fourth group served as a control. Lung injury was assessed by the analysis of blood gases, alveolar permeability, histology, AFC, and cytokines. Lung expression and distribution epithelial channels ENaC, Na,K-ATPase, and aquaporin (AQP)-5 were assessed. Treatment with either anti-RAGE mAb or sRAGE improved lung injury, arterial oxygenation and decreased alveolar inflammation in acid-injured animals. Anti-RAGE therapies were associated with restored AFC and increased lung expression of AQP-5 in alveolar cell. Blocking RAGE had potential therapeutic effects in a translational mouse model of ARDS, possibly through a decrease in alveolar type 1 epithelial cell injury as shown by restored AFC and lung AQP-5 expression. Further mechanistic studies are warranted to describe intracellular pathways that may control such effects of RAGE on lung epithelial injury and repair.
Subphenotypes were recently reported within clinical acute respiratory distress syndrome (ARDS), with distinct outcomes and therapeutic responses. Experimental models have long been used to mimic ...features of ARDS pathophysiology, but the presence of distinct subphenotypes among preclinical ARDS remains unknown. This review will investigate whether: 1) subphenotypes can be identified among preclinical ARDS models; 2) such subphenotypes can identify some responsive traits.
We will include comparative preclinical (in vivo and ex vivo) ARDS studies published between 2009 and 2019 in which pre-specified therapies were assessed (interleukin (IL)-10, IL-2, stem cells, beta-agonists, corticosteroids, fibroblast growth factors, modulators of the receptor for advanced glycation end-products pathway, anticoagulants, and halogenated agents) and outcomes compared to a control condition. The primary outcome will be a composite of the four key features of preclinical ARDS as per the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar-capillary barrier, lung inflammatory response, and physiological dysfunction). Secondary outcomes will include the single components of the primary composite outcome, net alveolar fluid clearance, and death. MEDLINE, Embase, and Cochrane databases will be searched electronically and data from eligible studies will be extracted, pooled, and analyzed using random-effects models. Individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments guidelines. Meta-regressions will be performed to identify subphenotypes prior to comparing outcomes across subphenotypes and treatment effects.
This study will inform on the presence and underlying pathophysiological features of subphenotypes among preclinical models of ARDS and should help to determine whether sufficient evidence exists to perform preclinical trials of subphenotype-targeted therapies, prior to potential clinical translation.
PROSPERO (ID: CRD42019157236).
IntroductionGuidelines for the treatment of steroid-dependent nephrotic syndrome (SDNS) and frequently relapsing nephrotic syndrome (FRNS) are lacking. Given the substantial impact of SDNS/FRNS on ...quality of life, strategies aiming to provide long-term remission while minimising treatment side effects are needed. Several studies confirm that rituximab is effective in preventing early relapses in SDNS/FRNS; however, the long-term relapse rate remains high (~70% at 2 years). This trial will assess the association of intravenous immunoglobulins (IVIgs) to rituximab in patients with SDNS/FRNS and inform clinicians on whether IVIg’s immunomodulatory properties can alter the course of the disease and reduce the use of immunosuppressive drugs and their side effects.Methods and analysisWe conduct an open-label multicentre, randomised, parallel group in a 1:1 ratio, controlled, superiority trial to assess the safety and efficacy of a single infusion of rituximab followed by IVIg compared with rituximab alone in childhood-onset FRNS/SDNS. The primary outcome is the occurrence of first relapse within 24 months. Patients are allocated to receive either rituximab alone (375 mg/m²) or rituximab followed by IVIg, which includes an initial Ig dose of 2 g/kg, followed by 1.5 g/kg injections once a month for the following 5 months (maximum dose: 100 g).Ethics and disseminationThe study has been approved by the ethics committee (Comité de Protection des Personnes) of Ouest I and authorised by the French drug regulatory agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé). Results of the primary study and the secondary aims will be disseminated through peer-reviewed publications.Trial registration numberNCT03560011.
Re-epithelialization of the alveolar surface is a key process of lung alveolar epithelial barrier repair after acute lung injury. The receptor for advanced glycation end-products (RAGE) pathway plays ...key roles in lung homeostasis, and its involvement in wound repair has been already reported in human bronchial epithelial cells. However, its effects on lung alveolar epithelial repair after injury remain unknown. We investigated whether RAGE stimulation with its ligands high–mobility group box 1 protein (HMGB1) or advanced glycation end-products (AGEs), alone or associated with RAGE inhibition using RAGE antagonist peptide, affects in vitro wound healing in human alveolar epithelial A549 cells. We further asked whether these effects could be associated with changes in cell proliferation and migration. We found that treatment of A549 cells with HMGB1 or AGEs promotes RAGE-dependent wound healing after a scratch assay. In addition, both RAGE ligands increased cell proliferation in a RAGE-dependent manner. Treatment with HMGB1 increased migration of alveolar epithelial cells at 12 h, independently of RAGE, whereas AGEs stimulated migration as measured 48 h after injury in a RAGE-dependent manner. Taken together, these results suggest that RAGE pathway is involved in lung alveolar epithelial wound repair, possibly through enhanced cell migration and proliferation.
•Re-epithelialization of the alveolar surface is a key process of epithelial barrier repair after acute lung injury.•The receptor for advanced glycation end-products (RAGE) pathway plays a key role in lung homeostasis.•However, its effects on lung alveolar epithelial repair after injury remain unknown.•Both RAGE ligands HMGB1 and AGEs promoted RAGE-dependent wound healing of lung epithelial A549 cells in vitro.•RAGE pathway is involved in lung epithelial cell migration and proliferation.
The receptor for advanced glycation end-products (RAGE) modulates the pathogenesis of acute respiratory distress syndrome (ARDS). RAGE inhibition attenuated lung injury and restored alveolar fluid ...clearance (AFC) in a mouse model of ARDS. However, clinical translation will require assessment of this strategy in larger animals. Forty-eight anaesthetised Landrace piglets were randomised into a control group and three treatment groups. Animals allocated to treatment groups underwent orotracheal instillation of hydrochloric acid (i) alone; (ii) in combination with intravenous administration of a RAGE antagonist peptide (RAP), or (iii) recombinant soluble (s)RAGE. The primary outcome was net AFC at 4 h. Arterial oxygenation was assessed hourly and alveolar-capillary permeability, alveolar inflammation and lung histology were assessed at 4 h. Treatment with either RAP or sRAGE improved net AFC (median interquartile range, 21.2 18.8-21.7 and 19.5 17.1-21.5 %/h, respectively, versus 12.6 3.2-18.8 %/h in injured, untreated controls), oxygenation and decreased alveolar inflammation and histological evidence of tissue injury after ARDS. These findings suggest that RAGE inhibition restored AFC and attenuated lung injury in a piglet model of acid-induced ARDS.
Acute respiratory distress syndrome (ARDS) is heterogeneous by definition and patient response varies depending on underlying biology and their severity of illness. Although ARDS subtypes have been ...identified with different prognoses in past studies, the concept of phenotypes or endotypes does not extend to the clinical definition of ARDS. This has possibly hampered the development of therapeutic interventions that target select biological mechanisms of ARDS. Recently, a major advance may have been achieved as it may now be possible to identify ARDS subtypes that may confer different responses to therapy. The aim of personalised medicine is to identify, select, and test therapies that are most likely to be associated with a favourable outcome in a specific patient. Several promising approaches to ARDS subtypes capable of predicting therapeutic response, and not just prognosis, are highlighted in this perspective paper. An overview is also provided of current and future directions regarding the provision of personalised ARDS medicine. The importance of delivering the right care, at the right time, to the right patient, is emphasised.
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