Indole 3-acetic acid, indoxyl sulfate and paracresyl-sulfate do not influence anemia parameters in hemodialysis patients

International audienceBackground: The main reason for anemia in renal failure patients is the insufficient erythropoietin production by the kidneys. Beside erythropoietin deficiency, in vitro studies have incriminated uremic toxins in the pathophysiology of anemia but clinical data are sparse. In order to assess if indole 3-acetic acid (IAA), indoxyl sulfate (IS), and paracresyl sulfate (PCS)-three protein bound uremic toxins-are clinically implicated in end-stage renal disease anemia we studied the correlation between IAA, IS and PCS plasmatic concentrations with hemoglobin and Erythropoietin Stimulating Agents (ESA) use in hemodialysis patients. Methods: Between June and July 2014, we conducted an observational cross sectional study in two hemodialysis center. Three statistical approaches were conducted. First, we compared patients treated with ESA and those not treated. Second, we performed linear regression models between IAA, IS, and PCS plasma concentrations and hemoglobin, the ESA dose over hemoglobin ratio (ESA/Hemoglobin) or the ESA resistance index (ERI). Third, we used a polytomous logistic regression model to compare groups of patients with no/low/high ESA dose and low/high hemoglobin statuses

Myeloma cast nephropathy: the dusk of high cutoff haemodialysis

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Les atteintes rénales de la COVID-19

International audienceCOVID-19 is a disease caused by the RNA virus SARS-CoV-2. It is characterised by an attack mainly affecting the respiratory system. There is renal involvement which is characterised by three main types of damage, acute tubular necrosis occurring in the most severe cases, proximal tubulopathy which is a prognostic marker of the disease and segmental and focal hyalinosis occurring in a genetically predisposed terrain. The pathophysiology of SARS-CoV-2 renal involvement is not yet defined. The direct role of the virus is debated, whereas the cytokine storm and the hypoxic and thrombotic complications seem more important. The long-term outcome of the renal damage appears to be quite good. Long-term follow-up will allow us to say whether the renal damage is part of the long COVID. (C) 2021 Societe francophone de nephrologie, dialyse et transplantation.La COVID-19 est une affection due à un virus à ARN, le SARS-CoV-2. Elle se caractérise par une atteinte touchant essentiellement l’appareil respiratoire. Il existe une atteinte rénale qui se caractérise par trois atteintes principales : une nécrose tubulaire aiguë survenant dans les cas les plus sévères, une tubulopathie proximale, qui est un marqueur pronostique de la maladie, et une hyalinose segmentaire et focale survenant sur un terrain génétiquement prédisposé. La physiopathologie de l’atteinte rénale du SARS-CoV-2 n’est pas encore définie. Le rôle direct du virus est discuté alors que la tempête cytokinique et les complications hypoxiques et thrombotiques semblent plus importantes. Le devenir à long terme des atteintes rénales paraît plutôt bon. Un suivi au long cours permettra de dire si l’atteinte rénale fait partie du COVID long

The Aryl Hydrocarbon Receptor-Activating Effect of Uremic Toxins from Tryptophan Metabolism: A New Concept to Understand Cardiovascular Complications of Chronic Kidney Disease

International audiencePatients with chronic kidney disease (CKD) have a higher risk of cardiovascular diseases and suffer from accelerated atherosclerosis. CKD patients are permanently exposed to uremic toxins, making them good candidates as pathogenic agents. We focus here on uremic toxins from tryptophan metabolism because of their potential involvement in cardiovascular toxicity: indolic uremic toxins (indoxyl sulfate, indole-3 acetic acid, and indoxyl-beta-d-glucuronide) and uremic toxins from the kynurenine pathway (kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and quinolinic acid). Uremic toxins derived from tryptophan are endogenous ligands of the transcription factor aryl hydrocarbon receptor (AhR). AhR, also known as the dioxin receptor, interacts with various regulatory and signaling proteins, including protein kinases and phosphatases, and Nuclear Factor-Kappa-B. AhR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin and some polychlorinated biphenyls is associated with an increase in cardiovascular disease in humans and in mice. In addition, this AhR activation mediates cardiotoxicity, vascular inflammation, and a procoagulant and prooxidant phenotype of vascular cells. Uremic toxins derived from tryptophan have prooxidant, proinflammatory, procoagulant, and pro-apoptotic effects on cells involved in the cardiovascular system, and some of them are related with cardiovascular complications in CKD. We discuss here how the cardiovascular effects of these uremic toxins could be mediated by AhR activation, in a ``dioxin-like'' effect

Alternative splicing events is not a key event for gene expression regulation in uremia.

BACKGROUND: The control of gene expression in the course of chronic kidney disease (CKD) is not well addressed. Alternative splicing is a common way to increase complexity of proteins. More than 90% of human transcripts are alternatively spliced. We hypothesised that CKD can induce modification of the alternative splicing machinery. METHODS: During mutation screening in autosomal dominant polycystic kidney disease, we identified in mononuclear cells (PBMC), an alternative splicing event on the exon 30 of PKD1 gene, the gene implicated in this disease. This alternative splice variant was not correlated with the cystic disease but with CKD. To confirm the association between this variant and CKD, a monocentric clinical study was performed with 3 different groups according to their kidney function (CKD5D, CKD3-5 and normal kidney function). An exon microarray approach was used to highlight splicing events in whole human genome in a normal cell model (fibroblasts) incubated with uremic serum. Alternative splicing variants identified were confirmed by RT-PCR. RESULTS: The splicing variant of the exon 30 of PKD1 was more frequent in PBMCs from patients with CKD compared to control. With the microarray approach, despite the analysis of more than 230 000 probes, we identified 36 genes with an abnormal splicing index evocating splicing event in fibroblasts exposed to uremic serum. Only one abnormal splicing event in one gene, ADH1B, was confirmed by RT-PCR. CONCLUSION: We observed two alternative spliced genes in two different cell types associated with CKD. Alternative splicing could play a role in the control of gene expression during CKD but it does not seem to be a major mechanism

Mean Platelet Volume Predicts Vascular Access Events in Hemodialysis Patients

Arteriovenous fistula (AVF) and arteriovenous graft (AVG) is the vascular access (VA) of 78% of hemodialysis patients (HD) in France. VA dysfunction corresponding to either stenosis requiring angioplasty or acute thrombosis is responsible for 30% of hospitalizations. Mean platelet volume (MPV) is a biological marker of cardiovascular events. We studied MPV in a cohort of HD patients as a predictive marker of VA dysfunction. We conducted a prospective monocentric cohort study that included patients with AVF or AVG on chronic HD (n = 153). The primary outcome was the incidence of VA dysfunction regarding MPV value. The median MPV was 10.8 fL (7.8−13.5), and four groups were designed according to MPV quartiles. Fifty-four patients experienced the first event of VA dysfunction. The incidence of VA dysfunction was higher in patients with the highest MPV: 59% (23 events), 34% (14 events), 27% (11 events), and 18% (6 events), respectively, for the fourth, third, second, and first quartiles (p = 0.001). Multivariate analysis confirmed an independent association between MPV and VA dysfunction—OR 1.52 (1.13−2.07), p < 0.001. VA dysfunction is predicted by MPV level. Patients with the highest MPV have the highest risk of VA events

Neutrophil:lymphocyte ratio correlates with the uremic toxin indoxyl sulfate and predicts the risk of death in patients on hemodialysis

International audienceABSTRACT 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 < 0.0001) and 12-month (r = 0.62, P < 0.0001) follow-up. Among uremic toxins, IS levels were higher in the group with high NLR (104 µmol/L versus 81 µmol/L; P = 0.004). In multivariate analysis, the NLR remained correlated with IS (P = 0.03). The incidence of death, cardiovascular events and severe infectious events was higher in the group with high NLR [respectively, 38% versus 18% (P = 0.004), 45% versus 26% (P = 0.01) and 33% versus 21% (P = 0.02)] than in the low NLR group. Multivariate analysis showed an independent association of the NLR with mortality (P = 0.02) and cardiovascular events (P = 0.03) but not with severe infectious events. 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

Drivers of Antarctic sea ice advance

International audienceAntarctic sea ice is mostly seasonal. While changes in sea ice seasonality have been observed in recent decades, the lack of process understanding remains a key challenge to interpret these changes. To address this knowledge gap, we investigate the processes driving the ice season onset, known as sea ice advance, using remote sensing and in situ observations. Here, we find that seawater freezing predominantly drives advance in the inner seasonal ice zone. By contrast, in an outer band a few degrees wide, advance is due to the import of drifting ice into warmer waters. We show that advance dates are strongly related to the heat stored in the summer ocean mixed layer. This heat is controlled by the timing of sea ice retreat, explaining the tight link between retreat and advance dates. Such a thermodynamic linkage strongly constrains the climatology and interannual variations, albeit with less influence on the latter

Ice Shelf Basal Melt and Influence on Dense Water Outflow in the Southern Weddell Sea

International audienceWe use new observations of stable water isotopes from a research cruise in early 2017 to highlight ocean-ice interactions occurring under Filchner-Ronne Ice Shelf, the largest Antarctic ice shelf. In particular, we investigate the properties of Ice Shelf Water with temperature lower than the surface freezing point, in the Filchner Depression. We identify two main flavors of Ice Shelf Water emerging from beneath the Filchner Ice Shelf, which originate from High Salinity Shelf Water end members with distinct characteristics. Furthermore, these two High Salinity Shelf Water end members interact with areas of the ice shelves with different basal properties to produce different versions of Ice Shelf Water. These water masses are associated with different rates of basal melting and refreezing, which we quantify. Ice Shelf Water types that flow out of the ice shelf cavity are composed of 0.4% of mass from ice shelf (melt minus freeze) when sampled at the front of Filchner Ice Shelf. The slightly lighter Ice Shelf Water version mixes directly with ambient water masses as it flows northward on the continental shelf. The resulting Ice Shelf Water mixture with temperature below the surface freezing point ultimately sinks along the continental slope into the deep ocean, as a precursor of the Weddell Sea bottom waters

Thermodynamics Drive Post-2016 Changes in the Antarctic Sea Ice Seasonal Cycle

International audienceAntarctic sea ice extent has been persistently low since late 2016, possibly owing to changes in atmospheric and oceanic conditions. However, the relative contributions of the ocean, the atmosphere and the underlying mechanisms by which they have affected sea ice remain uncertain. To investigate possible causes for this sea-ice decrease, we establish a seasonal timeline of sea ice changes following 2016, using remote sensing observations. Anomalies in the timing of sea ice retreat and advance are examined along with their spatial and interannual relations with various indicators of seasonal sea ice and oceanic changes. They include anomalies in winter ice thickness, spring ice removal rate due to ice melt and transport, and summer sea surface temperature. We find that the ice season has shortened at an unprecedented rate and magnitude, due to earlier retreat and later advance. We attribute this shortening to a winter ice thinning, in line with ice-albedo feedback processes, with ice transport playing a smaller role. Reduced ice thickness has accelerated spring ice area removal as thinner sea ice requires less time to melt. The consequent earlier sea ice retreat has in turn increased ocean solar heat uptake in summer, ultimately delaying sea ice advance. We speculate that the observed winter sea ice thinning is consistent with previous evidence of subsurface warming of the Southern Ocean