Background and Aims: Apolipoprotein (apo) C1 is a protein associated with HDL and VLDL. ApoC1 alters triglyceride clearance by inhibiting lipolysis and VLDL uptake, and it also favors cholesterol accumulation in HDL, especially by inhibiting cholesteryl ester transfer protein (CETP). Apart from studies in mice, which lack CETP, the impact of apoC1 on atherosclerosis in animal models which express active CETP, like in humans, is not known. Here, we aimed to determine the net effect of human apoC1 on atherosclerosis in rabbits, a species with naturally high CETP activity but dysfunctional apoC1.

BACKGROUND/AIMS:Fatty acid oxidation (FAO), the main source of energy produced by tubular epithelial cells in the kidney, was found to be defective in tubulo-interstitial samples dissected out in kidney biopsies from patients with chronic kidney disease (CKD). Experimental data indicated that this decrease was a strong determinant of renal fibrogenesis, hence a focus for therapeutic interventions. Nevertheless, whether persistently differentiated renal tubules, surviving in a pro-fibrotic environment, also suffer from a decrease in FAO, is currently unknown.METHODS:To address this question, we isolated proximal tubules captured ex vivo on the basis of the expression of an intact brush border antigen (Prominin-1) in C57BL6/J mice subjected to a controlled, two-hit model of renal fibrosis (reversible ischemic acute kidney injury (AKI) or sham surgery, followed by angiotensin 2 administration). A transcriptomic high throughput sequencing was performed on total mRNA from these cells, and on whole kidneys.RESULTS:In contrast to mice subjected to sham surgery, mice with a history of AKI displayed histologically more renal fibrosis when exposed to angiotensin 2. High throughput RNA sequencing, principal component analysis and clustering showed marked consistency within experimental groups. As expected, FAO transcripts were decreased in whole fibrotic kidneys. Surprisingly, however, up- rather than down-regulation of metabolic pathways (oxidative phosphorylation, fatty acid metabolism, glycolysis, and PPAR signalling pathway) was a hallmark of the differentiated tubules captured from fibrotic kidneys. Immunofluorescence co-staining analysis confirmed that the expression of FAO enzymes was dependent of tubular trophicity.CONCLUSIONS:These data suggest that in differentiated proximal tubules energetic hyperactivity is promoted concurrently with organ fibrogenesis.

BACKGROUND Hypnosis has a positive effect on perioperative anxiety and pain. OBJECTIVE The objective of this study was to assess the impact of a formal deep hypnosis session on the consumption of propofol for anaesthetic induction using automated administration of propofol guided by the bispectral index (BIS) in a closed loop. DESIGN A 1 : 1 randomised, usual-care-controlled, single-centre trial. SETTING Tertiary care centre in France from April 2014 to December 2015. PATIENTS Female adult patients scheduled for outpatient gynaecological surgery under general anaesthesia. INTERVENTION Before surgery, patients were randomised to receive either a deep hypnosis session or routine care. Anaesthetic induction was performed automatically by propofol without opioids and was assisted by the BIS in a closed loop. MAIN OUTCOME MEASURES The primary endpoint was the propofol dose required for anaesthesia induction, defined as a BIS less than 60 for at least 30 s. RESULTS Data for 31 patients in the hypnosis group and 35 in the control group were analysed. There was no evidence of a difference in the mean required propofol dose for anaesthetic induction between the hypnosis and the control groups (2.06 mg kg(-1) (95% confidence interval [1.68 to 2.431) versus 1.79mg kg(-1) (95% CI [1.54 to 2.031), P = 0.25, respectively). CONCLUSION The current study, which was designed to determine the effect of a deep hypnosis session on anaesthesia induction using an automated tool for propofol administration, failed to detect a difference in the required dose of propofol.

Il est désormais admis qu’un épisode d’insuffisance rénale aiguë (IRA) ne s’accompagne pas d’une réparation ad integrum mais qu’une cicatrice rénale persiste. Ainsi le risque de développer une insuffisance rénale chronique après un épisode d’IRA est augmenté. Cette cicatrice rénale apparaît être secondaire à la mise en jeu de processus fibrotiques. Un suivi néphrologique à distance par certaines équipes dans les suites d’une IRA a été proposé, dans l’espoir de diagnostiquer plus rapidement l’éventuel développement d’une IRC et d’engager des mesures de protection rénale non spécifiques. À ce jour, aucune mesure spécifique n’a cependant été identifiée pour limiter les conséquences de l’IRA.

Objective: We aimed at assessing the predictive value of plasmatic Neutrophil Gelatinase Associated Lipocalin (pNGAL) at admission and severity scores to predict major adverse kidney events (MAKE, defined as death and/or need for renal replacement therapy (RRT) and/or non-renal recovery at day 90) in critically ill burn patients. Material and methods: Single-center cohort study in a burn critical care unit in a tertiary center, including all consecutive severely burn patients (total burned body surface >20%) from January 2012 until January 2015 with a pNGAL dosage at admission. Reclassification of patients was assessed by Integrated Discrimination Improvement (IDI). Measurements and results: 87 patients were included. Mean age was 47.7 (IQ 25-75: 33.4-65.2) years; total burn body surface area was 40 (IQ 25-75: 30-55) % and ICU mortality 36%. 39(44.8%) patients presented a MAKE, 32(88.9%) patients died at day 90. pNGAL was higher in the MAKE group (423 [IQ25-75: 327-518] pg/mL vs 184 [IQ25-75: 147-220] pg/mL, p<0.001). In multivariate analysis, pNGAL and abbreviated burn severity index (ABSI) remained associated with MAKE (OR 1.005 [CI 95% 1.0005-1.009], p=0.03 and OR 1.682 [CI95%1.038-2.726], p=0.035 respectively). Adding pNGAL to abbreviated burn severity index, simplified organ failure assessment and the simplified acute physiology score 2 did outperform clinical scores for the prediction of MAKE and AKI and for most severe forms of AKI and allowed a statistically significant reclassification of patients compared to ABSI for MAKE, RRT, AKI at Day 7 and AKI during hospitalization with a number of patients needed to screen to detect one extra episode of MAKE was 44, 13 for severe AKI and 15 for AKI. Conclusions: pNGAL at admission is associated with the risk of MAKE in this population, and outperform severity scores when associated. Interventional studies are now needed to assess if impact of biomarkers-guided strategies would improve outcome. (C) 2018 Elsevier Ltd and ISBI. All rights reserved.

L’aggravation de la fonction rénale en periopératoire est une éventualité plus fréquente qu’il n’y paraît qui doit faire l’objet d’une politique de prévention compte tenu de son impact sur la fonction rénale à moyen et long terme. Les facteurs de risque sont les comorbidités du patient incluant l’état préalable de la fonction rénale et le type d’interventions pratiquées. Les patients concernés doivent bénéficier d’une surveillance étroite de la créatininémie et du débit urinaire en périopératoire.

Objective: As with any biomarker, interpretation of changes of NGAL concentration must consider its variability in a specific clinical setting. The aim of this study was to calculate the reference change value (RCV) and the index of individuality (II) of plasma and urine NGAL in the context of coronary artery bypass graft surgery with cardiopulmonary bypass, in patients without postoperative acute kidney injury. Methods: This prospective single-center observational study included patients with a preoperative glomerular filtration rate of > 30 ml min(-1) 1.73 m(-2), scheduled for elective coronary artery bypass graft with cardiopulmonary bypass and free from postoperative renal injury according to KDIGO criteria during hospital stay or a plasma creatinine Delta < 0(Delta = day1-induction). Plasma and urine NGAL were measured at anesthesia induction, 4 h after intensive care admission and on the first and 2nd postoperative day and normalized to plasma proteins or urine creatinine. The RCV was given by the formula: 1.96 x root 2 x root(CVa(2) + CVi(2)), were CVi is the intra-individual variability and CVa the reported analytical coefficient of variation of 5%. The II was calculated using the formula II = CVi/CVg for the four previous parameters, where CVg is the inter-individual variability. Results: Of the 100 patients enrolled in the study, 73 or 25 were considered free from acute kidney injury ( KDIGO and creatinine criteria, respectively) and included in the analysis. The RCV was 104% and 109% for plasma NGAL and 321% and 608% for urine NGAL. The II was < 0.6 for both plasma and urine NGAL. Conclusions: In patients who underwent coronary artery bypass grafting with normal post-operative kidney function, two-fold change in plasma NGAL and three to six-fold change in urine NGAL occur. In this specific clinical context, pathological variations must consider this biological "noise" for correct interpretation.

Calpains are ubiquitous pro-inflammatory proteases, whose activity is controlled by calpastatin, their specific inhibitor. Transgenic mice over-expressing rabbit calpastatin (CalpTG) are protected against vascular remodelling and angiotensin II-dependent inflammation. We hypothesized that specific calpain inhibition would protect against aging-related lesions in arteries and kidneys. We analysed tissues from 2-months and 2-years-old CalpTG and wild-type mice and performed high throughput RNA-Sequencing of kidney tissue in aged mice. In addition, we analysed inflammatory response in the kidney of aged CalpTG and wild-type mice, and in both in vivo (monosodium urate peritonitis) and in vitro models of inflammation. At two years, CalpTG mice had preserved kidney tissue, less vascular remodelling and less markers of senescence than wild-type mice. Nevertheless, CalpTG mice lifespan was not extended, due to the development of lethal spleen tumors. Inflammatory pathways were less expressed in aged CalpTG mice, especially cytokines related to NF-κB and NLRP3 inflammasome activation. CalpTG mice had reduced macrophage infiltration with aging and CalpTG mice produced less IL-1α and IL-1β in vivo in response to inflammasome activators. In vitro , macrophages from CalpTG mice produced less IL-1α in response to particulate activators of inflammasome. Calpains inhibition protects against inflammaging, limiting kidney and vascular lesions related to aging.

Objective: The automated administration of propofol in a closed loop could be used to objectively evaluate the nonpharmacological anesthetic action of hypnotherapy. The objective of this study was to evaluate the impact of a conversational hypnosis session on the consumption of propofol for anesthetic induction. Design: A randomized, usual care-controlled, single-center, patient-blind trial. Setting: Tertiary care center in France from November 2012 to December 2013. Participants: Adult patients scheduled for a surgical procedure under general anesthesia. Interventions: Before surgery, patients were randomized with a computer-generated random list for a preoperative conversational hypnosis session or for usual care. The conversational hypnosis session was conducted and individualized by the therapist with an academic degree in hypnosis in a quiet environment. Anesthetic induction was automatically performed by propofol without opioids and was assisted by the bispectral index in a closed loop. Outcome: Primary endpoint was the propofol dose required for anesthesia induction, defined as a Bispectral index less than 60 for at least 30 seconds. Results: The study included 48 patients in the hypnosis group and 49 patients in the control group. No difference in propofol consumption to obtain anesthesia induction was observed between the groups (total dose: 138.6 [67.5] and 130 [47.9] mg, P = .47; adjusted dose: 2.15 [1.09] and 1.95 [0.66] mg/kg, P = .28, for the hypnosis and control groups, respectively). Hetero-evaluation of arm movement during propofol injection (no reaction: 98% and 74%; P = .004, in the hypnosis and control groups, respectively) and face reaction at venous access placement (no reaction 59% and 30%; P = .017, in the hypnosis and control groups, respectively) were lower in the hypnosis group. No adverse event was reported. Conclusions: No difference in propofol consumption was observed in this study designed to evaluate the effect of a hypnotic conversational session on anesthesia induction using an automated tool for propofol administration.

Intravascular haemolysis has been associated with acute kidney injury (AKI) in different clinical settings (cardiac surgery, sickle cell disease). Haemolysis occurs frequently in critically ill burn patients. The aim of this study was to assess the predictive value of haptoglobin at admission to predict major adverse kidney events (MAKE) and AKI in critically ill burn patients.

Background: There is recent evidence to show that patients suffering from acute kidney injury are at increased risk of developing chronic kidney disease despite the fact that surviving tubular epithelial cells have the capacity to fully regenerate renal tubules and restore renal function within days or weeks. The aim of the study was to investigate the impact of acute kidney injury on de novo chronic kidney disease. Methods: The authors conducted a retrospective population-based cohort study of patients initially free from chronic kidney disease who were scheduled for elective cardiac surgery with cardiopulmonary bypass and who developed an episode of acute kidney injury from which they recovered. The study was conducted at two French university hospitals between 2005 and 2015. These individuals were matched with patients without acute kidney injury according to a propensity score for developing acute kidney injury. Results: Among the 4,791 patients meeting the authors’ inclusion criteria, 1,375 (29%) developed acute kidney injury and 685 fully recovered. Propensity score matching was used to balance the distribution of covariates between acute kidney injury and non- acute kidney injury control patients. Matching was possible for 597 cases. During follow-up, 34 (5.7%) had reached a diagnosis of chronic kidney disease as opposed to 17 (2.8%) in the control population (hazard ratio, 2.3; bootstrapping 95% CI, 1.9 to 2.6). Conclusions: The authors’ data consolidate the recent paradigm shift, reporting acute kidney injury as a strong risk factor for the rapid development of chronic kidney disease.

Les calpaïnes sont des cystéines protéases ubiquitaires. La calpastatine, leur inhibiteur naturel, est également ubiquitaire. Il a été montré grâce à un modèle murin sur-exprimant la calpastatine (souris transgéniques : CalpTG) que la diminution de l’activité des calpaïnes protège contre les lésions rénales, vasculaires et inflammatoires induites par l’angiotensine II. Or, l’angiotensine II favorise le vieillissement cardiovasculaire. Nous avons émis l’hypothèse que les souris CalpTG seraient protégées des lésions liées au vieillissement. Nous avons analysé les reins, cœurs, aortes, cerveaux et peaux de souris contrôles et CalpTG âgées de 2 mois et 2 ans, et effectué une analyse transcriptomique comparative du cortex rénal de ces 4 groupes (RNA-Seq). Nous avons effectué une analyse de l’infiltrat inflammatoire par cytométrie tissulaire sur un deuxième groupe d’animaux indépendant. La réponse inflammatoire a été étudiée in vivo dans un modèle de péritonite à cristaux d’urate de sodium (MSU) et in vitro sur des macrophages de souris contrôles et CalpTG. Les souris CalpTG de 2 ans sont protégées contre la fibrose et la dégradation de la fonction rénale et contre le remodelage cardiovasculaire alors que les souris contrôles présentent des lésions dues au vieillissement dans l’ensemble des organes étudiés. De plus, les marqueurs de sénescence au niveau rénal (p21, β-galactosidase, décroissance de la longueur des télomères) sont plus faibles chez les souris CalpTG. L’analyse comparative par RNA-Seq révèle des différences marquées entre CalpTG et contrôles âgées, principalement dans les voies de signalisation impliquées dans la fibrose et l’inflammation. Les souris CalpTG présentent moins d’infiltrat macrophagique lié au vieillissement et une moindre production d’IL-1α et IL-1β en réponse au MSU. In vitro, la synthèse d’ARNm d’IL-1α et IL-1β par les macrophages issus des souris CalpTG est réduite et la sécrétion d’IL-1α est diminuée en réponse aux activateurs de l’inflammasome. L’inhibition spécifique des calpaïnes limite le développement des lésions inflammatoires liées à l’âge notamment en diminuant la synthèse et la maturation de l’IL-1α, suggérant que les calpaïnes sont un médiateur important du vieillissement rénal. Les calpaïnes sont des médiateurs du vieillissement rénal et vasculaire, leur inhibition pourrait protéger contre la progression de la maladie rénale chronique.

Comptes Rendus Chimie - In Press.Proof corrected by the author Available online since lundi 25 avril 2016

Epigenetics is the study of how cells, organs, and even individuals utilize their genes over specific periods of time, and under specific environmental constraints. Very importantly, epigenetics is now expanding into the field of medicine and hence should provide new information for the development of drugs. Bomsztyk and colleagues have detected major epigenetic changes occurring in several organs as early as 6 h after the onset of a mouse model of multiple organ dysfunction syndrome induced by Staphylococcus aureus lung injury. Decrease in mRNA of key genes involved in endothelial function was found to be associated with (and potentially explained by) a decrease in permissive histone marks, while repressive marks were unchanged. We discuss here the limitations of a whole-organ as opposed to a cell-specific approach, the nature of the controls that were chosen, and the pitfalls of histone modifications as a cause of the eventual phenotype. While the use of ‘epidrugs’ is definitely welcome in the clinic, how and when they will be used in sepsis-related multiple organ dysfunction will require further experimental studies.

Acute tubular damage is a major cause of renal failure, especially at the early phase of kidney transplant when ischemia-reperfusion injury and cyclosporin A toxicity may coexist. The mechanisms of the latter are largely unknown. Using an mRNA microarray on microdissected tubules from a rat model of cyclosporin A toxicity to describe the related epithelial-specific transcriptional signature in vivo , we found that cyclosporin A induces pathways dependent on the transcription factor ATF4 and identified nuclear protein transcriptional regulator 1 ( Nupr1 ), a stress response gene induced by ATF4, as the gene most strongly upregulated. Upon cyclosporin A treatment, Nupr1 -deficient mice exhibited worse renal tubular lesions than wild-type mice. In primary cultures treated with cyclosporin A, renal tubular cells isolated from Nupr1 -deficient mice exhibited more apoptosis and ATP depletion than cells from wild-type mice. Furthermore, cyclosporin A decreased protein synthesis and abolished proliferation in wild-type tubular cells, but only reduced proliferation in Nupr1 -deficient cells. Compared with controls, mouse models of ischemia-reperfusion injury, urinary obstruction, and hypertension exhibited upregulated expression of renal NUPR1, and cyclosporin A induced Nupr1 expression in cultured human tubular epithelial cells. Finally, immunohistochemical analysis revealed strong expression of NUPR1 in the nuclei of renal proximal tubules of injured human kidney allografts, but not in those of stable allografts. Taken together, these results suggest that epithelial expression of NUPR1 has a protective role in response to injury after renal transplant and, presumably, in other forms of acute tubular damage.

Le patient en hémodialyse chronique a un risque d’arrêt cardio-respiratoire (ACR) 10 à 20 fois plus élevé que la population générale. Il s’agit d’un événement rare (environ 1 événement par 10 000 séances), mais le taux de mortalité reste très élevé. Les données épidémiologiques actuelles proviennent quasi exclusivement d’études nord-américaines et l’on manque de données issues de registres européens sur le sujet. Les troubles du rythme ventriculaires graves sont le mode de survenue majoritaire de l’ACR dans cette population de dialysés chroniques qui cumule, d’une part, un terrain de sensibilité accrue de par la forte prévalence de la cardiopathie ischémique et l’hypertrophie ventriculaire gauche principalement, et, d’autre part, un événement déclencheur fréquent : les variations électrolytiques et volémiques inhérentes aux séances de dialyse. Les marqueurs prédictifs de la survenue d’ACR sont encore imparfaitement définis. Des études de prévention primaire médicamenteuse utilisant les bêtabloquants ou les bloqueurs du système rénine-angiotensine-aldostérone sont encourageantes, tandis que l’utilisation des défibrillateurs automatisés implantables dans la population de dialysés chroniques reste controversée. L’identification des patients à risque, la minimisation des événements déclencheurs comme les variations électrolytiques, et l’amélioration de la formation des équipes au diagnostic et aux premières mesures de réanimation grâce aux dernières recommandations datant de 2010 semblent nécessaires afin de diminuer l’incidence et d’améliorer la survie dans cette population à fort risque. L’organisation d’études européennes permettrait par ailleurs d’avoir une vision plus précise de cette réalité dans nos centres.

It has been suggested that bone marrow derived stem cells have the ability to engraft the kidney and improve the outcome of severe acute kidney injury (AKI) in mice exposed to high doses of cisplatin, providing hope for cancer patients in whom irreversible renal damage occasionally occurs following the use of this highly effective anti-tumor drug. We tested the therapeutic potential of bone marrow derived cells injected during the acute phase (day 3 after cisplatin administration) of experimentally-induced AKI in C57Bl6/J mice, characterized by massive tubular necrosis, apoptosis, and a low proliferation capacity. We failed to show any benefit of bone marrow derived cells versus a regular homogenate of intact renal cells, or normal saline. Using cell tracers and flow cytometry, we demonstrated that bone marrow derived cells did indeed home to the bone marrow of the recipients but failed to settle in the kidney. Conversely, renal cells homed to injured kidneys. However, neither cell therapy protected the animals against cisplatin-induced death. We therefore question the short-term efficacy of bone marrow derived cells used to repair established injuries of the tubular epithelium.