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Background Myostatin and activin A induce muscle wasting by activating the ubiquitin proteasome system and inhibiting the Akt/mammalian target of rapamycin pathway. In chronic kidney disease (CKD), myostatin and activin A plasma concentrations are increased, but it is unclear if there is increased production or decreased renal clearance. Methods We measured myostatin and activin A concentrations in 232 CKD patients and studied their correlation with estimated glomerular filtration rate (eGFR). We analyzed the myostatin gene (MSTN) expression in muscle biopsies of hemodialysis (HD) patients. We then measured circulating myostatin and activin A in plasma and the Mstn and Inhba expression in muscles, kidney, liver and heart of two CKD mice models (adenine and 5/6 nephrectomy models). Finally, we analyzed whether the uremic toxin indoxyl sulfate (IS) increased Mstn expression in mice and cultured muscle cells. Results In patients, myostatin and activin A were inversely correlated with eGFR. MSTN expression was lower in HD patients’ muscles (vastus lateralis) than in controls. In mice with CKD, myostatin and activin A blood concentrations were increased. Mstn was not upregulated in CKD mice tissues. Inha was upregulated in kidney and heart. Exposure to IS did not induce Mstn upregulation in mouse muscles and in cultured myoblasts and myocytes. Conclusion During CKD, myostatin and activin A blood concentrations are increased. Myostatin is not overproduced, suggesting only an impaired renal clearance, but activin A is overproduced in the kidney and heart. We propose to add myostatin and activin A to the list of uremic toxins.

Background Chronic kidney disease (CKD) is a major public health issue associated with increased cardiovascular, infectious and all-cause mortality. The neutrophil:lymphocyte ratio (NLR) is a predictive marker of the risk of death and cardiovascular events. Uremic toxins, notably indoxyl sulfate (IS), are involved in immune deficiency and cardiovascular complications associated with CKD. The aim of this study was to assess whether the NLR was related to uremic toxins and could predict clinical outcome in hemodialysis (HD) patients. Methods We conducted a prospective cohort study of 183 patients on chronic HD. The main objective was to study the correlation between the NLR and uremic toxin serum levels. The secondary objective was to test if the NLR can predict the incidence of mortality, cardiovascular events and infectious events. Results Patients were separated into two groups according to the NLR median value (3.49). The NLR at inclusion was correlated with the NLR at the 6-month (r = 0.55, P Conclusions In HD patients, the NLR predicted mortality and cardiovascular events but not severe infections and correlated positively with the level of the uremic toxin IS. The NLR could be an interesting marker for monitoring the risk of clinical events in CKD patients.

International audience; Significance Statement Uremic toxicity may play a role in the elevated risk of developing cognitive impairment observed in patients with CKD. Some uremic toxins, such as indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor (AhR). The authors found that cognitive impairment in three models of CKD in rats is correlated with serum levels of indoxyl sulfate as well as blood-brain barrier disruption as detected by SPECT/CT imaging. Using AhR(?/?) knockout mice, the authors described for the first time that indoxyl sulfate?induced activation of AhR is responsible for blood-brain barrier disruption. These findings demonstrate that blood-brain barrier disruption seems to be an important mechanism involved in cognitive impairment in the context of CKD and that AhR may be a promising therapeutic target to prevent cognitive impairment in CKD.Background Uremic toxicity may play a role in the elevated risk of developing cognitive impairment found among patients with CKD. Some uremic toxins, like indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor (AhR), which is widely expressed in the central nervous system and which we previously identified as the receptor of indoxyl sulfate in endothelial cells.Methods To characterize involvement of uremic toxins in cerebral and neurobehavioral abnormalities in three rat models of CKD, we induced CKD in rats by an adenine-rich diet or by 5/6 nephrectomy; we also used AhR(?/?) knockout mice overloaded with indoxyl sulfate in drinking water. We assessed neurologic deficits by neurobehavioral tests and blood-brain barrier disruption by SPECT/CT imaging after injection of Tc-99m-DTPA, an imaging marker of blood-brain barrier permeability.Results In CKD rats, we found cognitive impairment in the novel object recognition test, the object location task, and social memory tests and an increase of blood-brain barrier permeability associated with renal dysfunction. We found a significant correlation between Tc-99m-DTPA content in brain and both the discrimination index in the novel object recognition test and indoxyl sulfate concentrations in serum. When we added indoxyl sulfate to the drinking water of rats fed an adenine-rich diet, we found an increase in indoxyl sulfate concentrations in serum associated with a stronger impairment in cognition and a higher permeability of the blood-brain barrier. In addition, non-CKD AhR(?/?) knockout mice were protected against indoxyl sulfate?induced blood-brain barrier disruption and cognitive impairment.Conclusions AhR activation by indoxyl sulfate, a uremic toxin, leads to blood-brain barrier disruption associated with cognitive impairment in animal models of CKD.

International audience; In patients with chronic kidney disease (CKD) and in animal models of CKD, the transcription factor Aryl Hydrocabon Receptor (AhR) is overactivated. In addition to the canonical AhR targets constituting the AhR signature, numerous other genes are regulated by this factor. We identified neuronal pentraxin 1 (NPTX1) as a new AhR target. Belonging to the inflammatory protein family, NPTX1 seems of prime interest regarding the inflammatory state observed in CKD. Endothelial cells were exposed to tryptophan-derived toxins, indoxyl sulfate (IS) and indole-3-acetic acid (IAA). The adenine mouse model of CKD was used to analyze NPTX1 expression in the burden of uremia. NPTX1 expression was quantified by RT-PCR and western blot. AhR involvement was analyzed using silencing RNA. We found that IS and IAA upregulated NPTX1 expression in an AhR-dependent way. Furthermore, this effect was not restricted to uremic indolic toxins since the dioxin 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) do the same. In CKD mice, NPTX1 expression was increased in the aorta. Therefore, NPTX1 is a new target of AhR and further work is necessary to elucidate its exact role during CKD.

International audience; Chronic kidney disease (CKD) is associated with high risk of thrombosis. Indole-3 acetic acid (IAA), an indolic uremic toxin, induces the expression of tissue factor (TF) in human umbilical vein endothelial cells (HUVEC) via the transcription factor aryl hydrocarbon receptor (AhR). This study aimed to understand the signaling pathways involved in AhR-mediated TF induction by IAA. We incubated human endothelial cells with IAA at 50 mu M, the maximal concentration found in patients with CKD. IAA induced TF expression in different types of human endothelial cells: umbilical vein (HUVEC), aortic (HAoEC), and cardiac-derived microvascular (HMVEC-C). Using AhR inhibition and chromatin immunoprecipitation experiments, we showed that TF induction by IAA in HUVEC was controlled by AhR and that AhR did not bind to the TF promoter. The analysis of TF promoter activity using luciferase reporter plasmids showed that the NF-B site was essential in TF induction by IAA. In addition, TF induction by IAA was drastically decreased by an inhibitor of the NF-B pathway. IAA induced the nuclear translocation of NF-B p50 subunit, which was decreased by AhR and p38MAPK inhibition. Finally, in a cohort of 92 CKD patients on hemodialysis, circulating TF was independently related to serum IAA in multivariate analysis. In conclusion, TF up-regulation by IAA in human endothelial cells involves a non-genomic AhR/p38 MAPK/NF-B pathway. The understanding of signal transduction pathways related to AhR thrombotic/inflammatory pathway is of interest to find therapeutic targets to reduce TF expression and thrombotic risk in patients with CKD.

Cardiovascular complications observed in chronic kidney disease (CKD) are associated with aryl hydrocarbon receptor (AhR) activation by tryptophan-derived uremic toxins&mdash, mainly indoxyl sulfate (IS). AhR is a ligand-activated transcription factor originally characterized as a receptor of xenobiotics involved in detoxification. The aim of this study was to determine the role of AhR in a CKD mouse model based on an adenine diet. Wild-type (WT) and AhR&minus, /&minus, mice were fed by alternating an adenine-enriched diet and a regular diet for 6 weeks. Our results showed an increased mortality rate of AhR&minus, males. AhR&minus, females survived and developed a less severe renal insufficiency that WT mice, reflected by urea, creatinine, and IS measurement in serum. The protective effect was related to a decrease of pro-inflammatory and pro-fibrotic gene expression, an attenuation of tubular injury, and a decrease of 2,8-dihydroxyadenine crystal deposition in the kidneys of AhR&minus, mice. These mice expressed low levels of xanthine dehydrogenase, which oxidizes adenine into 2,8-dihydroxyadenine, and low levels of the IS metabolism enzymes. In conclusion, the CKD model of adenine diet is not suitable for AhR knockout mice when studying the role of this transcription factor in cardiovascular complications, as observed in human CKD.

Patients with chronic kidney disease (CKD) are exposed to uremic toxins and have an increased risk of cardiovascular disease. Some uremic toxins, like indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor (AHR). These toxins induce a vascular procoagulant phenotype. Here we investigated AHR activation in patients with CKD and in a murine model of CKD. We performed a prospective study in 116 patients with CKD stage 3 to 5D and measured the AHR-Activating Potential of serum by bioassay. Compared to sera from healthy controls, sera from CKD patients displayed a strong AHR-Activating Potential; strongly correlated with eGFR and with the indoxyl sulfate concentration. The expression of the AHR target genes Cyp1A1 and AHRR was up-regulated in whole blood from patients with CKD. Survival analyses revealed that cardiovascular events were more frequent in CKD patients with an AHR-Activating Potential above the median. In mice with 5/6 nephrectomy, there was an increased serum AHR-Activating Potential, and an induction of Cyp1a1 mRNA in the aorta and heart, absent in AhR –/– CKD mice. After serial indoxyl sulfate injections, we observed an increase in serum AHR-AP and in expression of Cyp1a1 mRNA in aorta and heart in WT mice, but not in AhR –/– mice. Thus, the AHR pathway is activated both in patients and mice with CKD. Hence, AHR activation could be a key mechanism involved in the deleterious cardiovascular effects observed in CKD.

Introduction La dysfonction cognitive est une complication de la maladie renale chronique (MRC) dont l’origine est mal comprise. Methodes Notre but etait de caracteriser les anomalies cerebrales et neurocomportementales au cours de la MRC chez le rat. La MRC etait provoquee par un regime enrichi en adenine (0,5 %–4 semaines) (ARD) ou une nephrectomie des 5/6e (5/6Nx). La MRC etait confirmee biologiquement et histologiquement. La memoire a court terme etait mesuree par le test de reconnaissance du nouvel objet (RNO). La permeabilite de la barriere hemato-encephalique (BHE) etait evaluee par scintigraphie cerebrale au 99mTc-DTPA. Un groupe de rats ARD a recu en plus un regime enrichi en indoxyl sulfate (IS). Resultats obtenus ou attendus Nous avons observe chez le rat ARD : une augmentation des taux seriques d’uree, de creatinine et d’IS, des lesions tubulo-interstitielles et de la fibrose renale ; une diminution de l’indice de discrimination au test RNO (IDRNO) (0,2 ± 0,3 (ARD) vs 0,7 ± 0,3 (controle) ; p Fig. 1 ). Conclusion La MRC est responsable chez le rat d’une augmentation de la permeabilite de la BHE associee a une dysfonction cognitive. L’accumulation d’IS est probablement un des mecanismes majeurs responsables de ces anomalies neurologiques.

International audience; Background: MicroRNAs (miRNAs) are innovative and informative blood-based biomarkers involved in numerous pathophysiological processes. In this study and based on our previous experimental data, we investigated miR-126, miR-143, miR-145, miR-155 and miR-223 as potential circulating biomarkers for the diagnosis and prognosis of patients with chronic kidney disease (CKD). The primary objective of this study was to assess the levels of miRNA expression at various stages of CKD.Methods: RNA was extracted from serum, and RT-qPCR was performed for the five miRNAs and cel-miR-39 (internal control).Results: Serum levels of miR-143, -145 and -223 were elevated in patients with CKD compared with healthy controls. They were further increased in chronic haemodialysis patients, but were below control levels in renal transplant recipients. In contrast, circulating levels of miR-126 and miR-155 levels, which were also elevated in CKD patients, were lower in the haemodialysis group and even lower in the transplant group. Four of the five miRNA species were correlated with estimated glomerular filtration rate, and three were correlated with circulating uraemic toxins.Conclusions: This exploratory study suggests that specific miRNAs could be biomarkers for complications of CKD, justifying further studies to link changes of miRNA levels with outcomes in CKD patients.

Introduction Des experiences in vitro ont incrimine les toxines uremiques dans la survenue de l’anemie des patients hemodialyses (HD), mais peu de donnees cliniques ont ete publiees. Nous avons etudie si l’acide indole 3-acetique (IAA), l’indoxyl sulfate (IS), et le para-cresyl sulfate (PCS) sont impliques dans l’anemie des HD en correlant leurs concentrations plasmatiques avec le taux d’hemoglobine (Hb) et les besoins en erythropoietine (EPO). Patients et methodes Etude observationnelle transversale incluant les patients HD de 2 centres. 3 approches statistiques differentes : – comparaison des HD traites ou non traites par EPO ; – regression lineaire entre les concentrations plasmatiques des toxines uremiques et l’Hb, le ratio Dose d’EPO/Hb, ou l’indice de resistance a l’EPO (IRE ; EPO/Hb/kg de poids corporel) ; – regression logistique multinomiale de 6 groupes de patients classes selon le traitement par EPO ou non et les taux d’Hb ( 12 g/dL). Resultats Deux cent quarante patients HD ont ete inclus, dont 55,4 % d’hommes ; 42,5 % etaient diabetiques. L’âge moyen etait de 67,6 ± 16,0 ans. Les patients avec et sans EPO avaient des concentrations identiques de IAA, IS ou PCS. Dans le modele lineaire multivarie les correlations entre la concentration plasmatique d’IAA, d’IS et de PCS et l’Hb, l’EPO/Hb et l’IRE n’etaient pas statistiquement significatives. Enfin, le modele multinomial ne retrouvait pas non plus de relation entre la concentration en IAA, IS ou PCS et l’appartenance aux differents groupes. Discussion Malgre 3 approches statistiques differentes, nous n’avons pas pu etablir de lien entre les concentrations plasmatiques d’IAA, IS et PCS, et les marqueurs de l’anemie des HD. Nos donnees in vivo ne vont pas dans le sens des donnees in vitro concernant l’implication de ces toxines uremiques dans la survenue de l’anemie des HD. Par exemple, il a ete montre in vitro que l’IS inhibe l’activation de HIF en conditions d’hypoxie et donc la production d’EPO [1] . Les donnees de cette etude observationnelle transversale necessitent d’etre confirmees dans des etudes prospectives. Neanmoins, il s’agit de la premiere etude clinique sur ce sujet. Conclusion Les toxines uremiques indoliques (IS et IAA) ainsi que le PCS n’ont pas ou peu d’effet sur les parametres de l’anemie des patients HD chroniques.

Introduction La maladie renale chronique (MRC) est associee a une augmentation du risque thrombotique. La comprehension des mecanismes moleculaires de ce risque est indispensable pour identifier de nouveaux traitements. La toxine uremique indole-3 acetique acide (IAA) entraine une expression endotheliale du facteur tissulaire (FT) via le facteur de transcription aryl hydrocarbon receptor (AHR). L’objectif de ce travail est de comprendre les voies de signalisation activees par AHR dans ce contexte. Patients/materiels et methodes Nous avons incube des cellules endotheliales (CE) humaines en presence de 50 μM d’IAA (la concentration la plus haute retrouvee chez les patients avec une MRC). Nous avons utilise des constructions du promoteur du FT et la technique du CHIP pour etudier les facteurs de transcription impliques. Nous avons etudie le role des voies AHR, NF-KB et P38MAPK a l’aide d’inhibiteurs pharmacologiques. Pour etudier la relevance clinique de notre travail, nous avons mesure les taux de facteur tissulaire circulant (Elisa) et la concentration d’IAA (HPLC) dans une cohorte de 92 patients hemodialyses. Resultats L’IAA induit l’expression du TF dans differents types de CE humaines (veine ombilicale, aortiques et microvasculaires cardiaques). L’induction du TF dans ces cellules est dependante de la presence d’AHR. AHR ne se fixe pas sur le promoteur du FT. En analysant le promoteur du FT, nous avons montre que le site NF-KB est essentiel a l’induction du TF par l’IAA. Nous avons pu montrer que la cascade de signalisation activee par AHR induit l’activation de NF-KB (sous-unite p50) par l’intermediaire de P38MAPK. Dans une cohorte de patients avec une MRC, le taux circulant de FT est correle en analyse multivariee a la concentration d’IAA (estimate = 3,36, IC95 % [0,41 a 6,3], p Conclusion L’IAA active une voie de signalisation AhR/p38 MAPK/NF-KB induisant une augmentation d’expression endotheliale du facteur tissulaire. L’IAA a un potentiel procoagulant independant des autres toxines uremiques chez l’homme. La modulation de la voie non genomique d’AHR pourrait permettre de reduire le risque prothrombotique au cours de la MRC.

In patients with CKD, not only renal but also, nonrenal clearance of drugs is altered. Uremic toxins could modify the expression and/or activity of drug transporters in the liver. We tested whether the uremic toxin indoxyl sulfate (IS), an endogenous ligand of the transcription factor aryl hydrocarbon receptor, could change the expression of the following liver transporters involved in drug clearance: SLC10A1, SLC22A1, SLC22A7, SLC47A1, SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCB11, ABCC2, ABCC3, ABCC4, ABCC6, and ABCG2. We showed that IS increases the expression and activity of the efflux transporter P-glycoprotein (P-gp) encoded by ABCB1 in human hepatoma cells (HepG2) without modifying the expression of the other transporters. This effect depended on the aryl hydrocarbon receptor pathway. Presence of human albumin at physiologic concentration in the culture medium did not abolish the effect of IS. In two mouse models of CKD, the decline in renal function associated with the accumulation of IS in serum and the specific upregulation of Abcb1a in the liver. Additionally, among 109 heart or kidney transplant recipients with CKD, those with higher serum levels of IS needed higher doses of cyclosporin, a P-gp substrate, to obtain the cyclosporin target blood concentration. This need associated with serum levels of IS independent of renal function. These findings suggest that increased activity of P-gp could be responsible for increased hepatic cyclosporin clearance. Altogether, these results suggest that uremic toxins, such as IS, through effects on drug transporters, may modify the nonrenal clearance of drugs in patients with CKD.

Introduction Aryl Hydrocarbon Receptor (AhR) est un facteur transcriptionnel ubiquitaire implique dans la reponse aux xenobiotiques tels que la dioxine. L’activation d’AhR s’accompagne d’une immunomodulation. Certains travaux vont dans le sens d’un potentiel immunostimulant d’AhR, d’autres d’un role immunosuppresseur. Au cours de l’insuffisance renale chronique, l’accumulation des toxines uremiques indoliques s’accompagnent d’une activation d’AhR. Notre objectif est d’etudier le lien entre le potentiel activateur d’AhR du serum des patients en hemodialyse et leur risque infectieux. Patients et methodes Il s’agit d’une etude monocentrique prospective sur un an, conduite entre juin 2014 et juin 2015. Le dosage du potentiel activateur d’AhR serique (PAhRS) de patients hemodialyses a ete realise en debut d’etude et a 6 mois (test CALUX). Il est exprime en unites arbitraires (UA). Les evenements infectieux ont ete recueillis de maniere prospective. Nous avons egalement correle le PAhRS aux leucocytes et au taux d’anticorps anti-Hbs (reflet de la reponse immune B). Resultats Cent quatre-vingt-sept patients ont ete inclus. L’âge median etait de 69 ans. La mediane du PAhRS etait de 96 UA. Nous n’avons pas retrouve de lien entre le PAhRS et la survenue d’une septicemie ou d’un episode infectieux (p = 0,6 et p = 0,95 respectivement). Le PAhRS n’etait pas correle au nombre de globules blancs totaux, aux lymphocytes, ni au taux d’anticorps anti-Hbs. En revanche, il existait une correlation positive lors des deux prelevements (juin 2014 et janvier 2015) (r = 0,147 et p = 0,02 ; r = 0,302 et p Discussion Le PAhRS n’est pas predictif de la survenue d’evenements infectieux. Il est correle au taux de PNN. Nous sommes les premiers a trouver ce lien. Les PNN jouent un role dans la survenue des evenements thrombotiques. Nous avons deja montre que l’activation d’AhR favorise l’apparition d’un etat pro-coagulant. Conclusion Le lien entre PAhRS, PNN et risque thrombotique au cours de l’IRC est a explorer.

Introduction L’insuffisance renale chronique (IRC) est associee a des modifications importantes du metabolisme et de l’elimination des medicaments. La diminution de leur elimination renale constitue la principale cause mais certains medicaments avec une elimination principalement hepatique ont aussi des demi-vies alterees. L’IRC peut modifier la fonction et l’expression d’enzymes et de transporteurs impliques dans le metabolisme des medicaments. Les toxines uremiques indoliques telles que l’indoxyl sulfate (IS) activent un facteur de transcription, aryl hydrocarbon receptor (AhR). L’objectif de ce travail est d’etudier les effets de l’IS sur l’expression et l’activite du transporteur d’efflux cellulaire P-glycoproteine (P-gp), code par ABCB1. Materiels et methodes Les taux d’ARNm d’ABCB1 ont ete etudies par RT-PCR, les taux de P-gp par cytometrie en flux et par western-blot. L’activite de P-gp a ete mesuree a l’aide de la rhodamine 123 en presence ou non d’un inhibiteur, le verapamil. Le role d’AhR a ete etudie en utilisant des ARN interferant. Les patients transplantes ont ete recrutes a l’AP-HM. Resultats Dans la lignee cellulaire de carcinome hepatocellulaire humain (HepG2), l’IS augmente le taux d’ARNm codant pour P-gp ainsi que celui de la proteine. L’IS augmente egalement l’activite d’efflux de ce transporteur, effet partiellement inhibe en presence de verapamil. Ces effets de l’IS sont AhR-dependants. La dioxine, un agoniste tres connu d’AhR, a l’instar de l’IS, augmente l’expression de P-gp. Chez des patients transplantes cardiaques et renaux traites par la ciclosporine (un substrat de P-gp) et presentant une IRC (n = 109), ceux qui presentent des taux plus eleves d’IS ont besoin de doses plus elevees de ciclosporine pour atteindre le niveau sanguin cible de ce medicament. Discussion Nous avons montre que l’IS augmente l’activite de P-gp, un transporteur d’efflux de xenobiotiques, via l’activation d’AhR. Ces resultats suggerent que les toxines uremiques indoliques et d’autres agonistes d’AhR pourraient moduler la biodisponibilite des medicaments a elimination non renale au cours de l’IRC. Conclusion Les transporteurs de medicaments sont une nouvelle cible des toxines uremiques, via l’activation d’AhR, ouvrant de nouvelles perspectives pour comprendre les effets secondaires des medicaments au cours de l’IRC.

Introduction Les taux d’Indoxyl Sulfate (IS), de p-Cresyl Sulfate (pCS) et d’acide indole 3-acetique (IAA) sont associes a une augmentation du risque de deces et d’evenements cardiovasculaires au cours de l’insuffisance renale chronique. Le role du microbiote et de l’alimentation dans la production de d’IS et de pCS est documente. Dans le cadre de l’etude EVITUPH qui etudiait les determinants de la variabilite des taux d’IS, de pCS et d’IAA, nous presentons l’impact du regime alimentaire. Patients et methodes Etude monocentrique sur 1 an incluant 75 patients hemodialyses chroniques. Le questionnaire alimentaire realise a l’inclusion a ete analyse chez 53 patients. Ce questionnaire relevait l’ensemble des prises alimentaires sur 7 jours consecutifs. Nous avons analyse les donnees alimentaires et les donnees biologiques correspondantes notamment les taux seriques d’IS, de pCS et d’IAA (dosage par HPLC) sur la meme periode. Resultats L’apport calorique est faible, la mediane est de 20 Kcal/kg/j [17,5–22,6] avec des apports proteiques medians de 0,92 g/kg/j [0,69–1,15]. L’analyse de l’ensemble des 53 patients n’a pas pu mettre en evidence de lien entre apports alimentaires et taux de toxines. Vingt-quatre patients n’avaient aucune diurese residuelle (DR) et 29 la conservaient. L’analyse comparative des patients avec ou sans DR ne met pas en evidence de difference quant aux apports alimentaires. Les taux d’IS sont moins importants chez ceux avec une DR compares a ceux sans DR (mediane de 89,8 μM et 132,4 μM respectivement, p = 0,005). Chez les patients sans DR, il existe une correlation negative entre les taux d’IS et les apports alimentaires en fibres notamment insolubles (R = −0,54, p = 0,006). Discussion Nous montrons que la diurese residuelle a un impact important sur les taux d’IS chez les hemodialyses. Le maintien de la diurese est associe a une meilleure survie des patients. La moindre accumulation des toxines uremiques pourrait etre un element majeur dans cette reduction du risque. L’effet de la diurese residuelle masque l’effet de l’alimentation. Conclusion Chez les patients sans diurese residuelle, l’apport en fibres est associe a une reduction des taux d’IS. Leur utilisation pourrait reduire le risque cardiovasculaire associe a l’accumulation de l’IS.

Introduction Les taux d’indoxyl sulfate (IS), de p-cresyl sulfate (pCS) et d’acide indole 3 acetique (IAA) sont associes a une augmentation du risque de mortalite et cardiovasculaire au cours de l’insuffisance renale chronique. Le role du microbiote dans la production d’IS et de pCS est documente. La regulation des taux d’IAA semble differente. Aucune etude ne s’est interessee a la variabilite de ces toxines uremiques dans le temps. L’objectif de l’etude EVITUPH (AORC 2014) est d’etudier la variabilite des taux d’IS, de pCS et d’IAA. Patients et methodes Nous menons une etude monocentrique sur un an incluant 75 patients. Un dosage mensuel serique d’IS, de pCS et d’IAA est realise. Seuls les 5 premiers mois d’inclusion ont ete analyses (juillet a novembre 2015). La variabilite des taux des toxines est calculee chez tout patient ayant au moins 3 dosages de toxines en dehors de toute antibiotherapie. Quand une antibiotherapie est prescrite, le dosage mensuel suivant est analyse separement pour evaluer l’impact de l’antibiotherapie sur les taux seriques de toxines. Resultats L’analyse de la variabilite des taux seriques d’IS, de pCS et d’IAA est realisee sur 55 patients avec en moyenne 4 dosages. La variabilite mediane d’IS, de PCS et d’IAA des patients est de 18 %, 26 % et 26 %, respectivement ( p Discussion Les taux seriques de pCS et d’IAA sont plus variables que ceux de l’IS ou de l’uree. Le peu d’impact de l’antibiotherapie sur les dosages d’IAA confirme que le microbiote est peu implique dans sa production. Conclusion La moindre variabilite de l’IS suggere que les donnees obtenues dans les etudes avec l’IS sont plus fiables que celles obtenues avec l’IAA et le pCS. Les determinants de la variabilite en particulier l’influence du regime alimentaire seront analyses sur 1 an dans cette cohorte.

Microtubule-targeted drugs (MTDs) are widely used to treat human malignancies such as ovarian and breast cancers. However, a major limitation of their efficacy is the development of resistance modulated by P-gp over-expression or modification of the microtubular target and/or the expression/function of apoptotic pathway proteins such as Bcl-2 [1]. BAL27862 is a novel, orally bioavailable synthetic MTD that triggers apoptosis in cancer cell lines. BAL27862 induces a G2/M arrest, destabilizing microtubules (MT) to produce a unique MT phenotype distinct from that observed with vinca alkaloids (e.g. vinblastine), colchicine and taxanes. Moreover, BAL27862 retains its anti-proliferative activity against multi-drug-resistant, P-gp over-expressing tumor cells [2]. To investigate the mechanism of action of BAL27862, we analyzed its effects on MT dynamics in living breast cancer cells (SKBr3 cells). As measurements were not possible using equipotent cytotoxic concentrations of the MT destabilizer vinblastine, it was compared to the MT stabilizer paclitaxel. BAL27862 suppressed MT dynamic instability, supressing MT catastrophes and growth rate and increasing the mean duration of pauses. In contrast, paclitaxel suppressed the MT shortening rate and did not affect the MT growth rate. At equipotent cytotoxic concentrations, the suppression of MT dynamics by BAL27862 was 2-fold lower than paclitaxel. Strikingly, BAL27862 displayed a unique MT severing activity. We then determined the anti-proliferative potency of BAL27862 in paclitaxel- and Vinca-alkaloid-resistant ovarian cancer cells (A2780-TC1 cells) in comparison to the chemosensitive parental line (A2780-wt cells). A2780-TC1 cell resistance is mediated by P-gp over-expression, Bcl-2 down-regulation and modifications in tubulin subtype composition [1]. Importantly, BAL27862 remained fully active against A2780-TC1 cells. Indeed, when comparing EC50, the resistance factors observed were 1.14 (NS) and 147 (p In conclusion, BAL27862 shares properties with other MTDs such as suppression of MT dynamics, but displays unique features such as MT severing. In ovarian tumor cells, activity appears independent of Bcl-2 and tubulin modifications. These features make BAL27862 a promising compound for clinical development. 1. Estève MA et al, Mol Cancer Ther, 2006 2. Lane H. et al, EORTC-NCI-AACR 2008, Abstract 444 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1977.