Modifications post-traductionnelles des lipoprotéines de haute densité (HDL) et risque cardio-vasculaire dans l’insuffisance rénale chronique

Cardiovascular complications remain the main problem in chronic kidney disease (CKD) but all the reasons of this risk are not fully understood. there is an addition of traditional risk factors and uremia-related ones. Among the latter, the generation of post-translational modifications of HDL could play a role. In this work, we highlighted an excess of carbonylation by 4-HNE onto the protein part of HDL in CKD in a rabbit model of CKD and in hemodialysis and peritoneal dialysis patients. This carbonylation by 4-HNE is responsible for ablunted anti-aggregant properties of HDL mediated by a CD36-dependant pathway. We also showed that the proteome of HDL from non diabetic hemodialysis patients is deeply modified and that there were several post-translational modifications onto the protein cargo of these HDL. The generation of carboxylate-methyl-lysine from non-enzymatic glycation processes was the main modification in our patients. The origin of such glycation could be from a favorable chemical environment but a potential load from hemodialysis fluids should be addressedLes complications cardiovasculaires restent prépondérantes dans l’insuffisance rénale chronique bien que les causes demeurent assez méconnues. Il existe une addition chez les patients insuffisants rénaux chroniques de facteurs de risque cardiovasculaires classiques et d’autres plus spécifiques à l’insuffisance rénale. Parmi ces derniers, la formation de modifications post-traductionnelles (adduits issus de réactions oxydatives et non-oxydatives) sur les lipoprotéines HDL pourrait jouer un rôle. Dans ce travail nous avons mis en évidence d’une part, un excès de carbonylation par le 4-HNE sur les HDL dans l’IRC sur un modèle animal de lapin et chez le patient hémodialysé ou dialysé péritonéal. Cette carbonylation par le 4-HNE est responsable d’une altération des propriétés anti-agrégantes des HDL et ce par une voie médiée par le récepteur scavenger CD36. Nous avons aussi montré que le protéome des HDL était modifié chez le patient HD et qu’il existait un large éventail d’adduits covalents sur les HDL de patients hémodialysés non-diabétiques. La formation de carboxy-méthyl-lysine issue de la glycation était la principale modification post-traductionnelle observée chez les patients HD. Cela questionne sur l’origine de cet excès de glycation qui pourrait être dû à un environnement chimique favorable chez les patients mais un apport exogène par les solutés utilisés en hémodialyse est aussi possibl

Cardiorenal Syndrome: Ebony and Ivory

The kidney and cardiovascular systems are closely interconnected and interact continuously in both physiological and pathological conditions [...

Proteomic Characterization of High-Density Lipoprotein Particles from Non-Diabetic Hemodialysis Patients

Chronic kidney disease is associated with an increased cardiovascular risk, and altered biological properties of high-density lipoproteins (HDL) may play a role in these events. This study aimed to describe the HDL proteome from non-diabetic hemodialysis patients and identify potential pathways affected by the dysregulated expression of HDL proteins. HDL were sampled from nine non-diabetic hemodialysis (HD) and eight control patients. Samples were analyzed using a nano-RSLC coupled with a Q-Orbitrap. Data were processed by database searching using SequestHT against a human Swissprot database and quantified with a label-free quantification approach. Proteins that were in at least five of the eight control and six of the nine HD patients were analyzed. Analysis was based on pairwise ratios and the ANOVA hypothesis test. Among 522 potential proteins, 326 proteins were identified to be in the HDL proteome from HD and control patients, among which 10 were significantly upregulated and nine downregulated in HD patients compared to the control patients (p < 0.05). Up and downregulated proteins were involved in lipid metabolism, hemostasis, wound healing, oxidative stress, and apoptosis pathways. This difference in composition could partly explain HDL dysfunction in the chronic kidney disease (CKD) population and participate in the higher cardiovascular risk observed in this population

Post-translational modifications of HDL and cardio-vascular risk in chronic kidney disease

Les complications cardiovasculaires restent prépondérantes dans l’insuffisance rénale chronique bien que les causes demeurent assez méconnues. Il existe une addition chez les patients insuffisants rénaux chroniques de facteurs de risque cardiovasculaires classiques et d’autres plus spécifiques à l’insuffisance rénale. Parmi ces derniers, la formation de modifications post-traductionnelles (adduits issus de réactions oxydatives et non-oxydatives) sur les lipoprotéines HDL pourrait jouer un rôle. Dans ce travail nous avons mis en évidence d’une part, un excès de carbonylation par le 4-HNE sur les HDL dans l’IRC sur un modèle animal de lapin et chez le patient hémodialysé ou dialysé péritonéal. Cette carbonylation par le 4-HNE est responsable d’une altération des propriétés anti-agrégantes des HDL et ce par une voie médiée par le récepteur scavenger CD36. Nous avons aussi montré que le protéome des HDL était modifié chez le patient HD et qu’il existait un large éventail d’adduits covalents sur les HDL de patients hémodialysés non-diabétiques. La formation de carboxy-méthyl-lysine issue de la glycation était la principale modification post-traductionnelle observée chez les patients HD. Cela questionne sur l’origine de cet excès de glycation qui pourrait être dû à un environnement chimique favorable chez les patients mais un apport exogène par les solutés utilisés en hémodialyse est aussi possibleCardiovascular complications remain the main problem in chronic kidney disease (CKD) but all the reasons of this risk are not fully understood. there is an addition of traditional risk factors and uremia-related ones. Among the latter, the generation of post-translational modifications of HDL could play a role. In this work, we highlighted an excess of carbonylation by 4-HNE onto the protein part of HDL in CKD in a rabbit model of CKD and in hemodialysis and peritoneal dialysis patients. This carbonylation by 4-HNE is responsible for ablunted anti-aggregant properties of HDL mediated by a CD36-dependant pathway. We also showed that the proteome of HDL from non diabetic hemodialysis patients is deeply modified and that there were several post-translational modifications onto the protein cargo of these HDL. The generation of carboxylate-methyl-lysine from non-enzymatic glycation processes was the main modification in our patients. The origin of such glycation could be from a favorable chemical environment but a potential load from hemodialysis fluids should be addresse

Expanded haemodialysis: news from the field

International audienceExpanded haemodialysis (HDx) has emerged as a promising solution to improve haemodialysis effectiveness. A medium cutoff membrane allows the removal of a wider range of uraemic toxins. However, little is known about the potential interesting applications of HDx therapy. Feedback from the first routine use of HDx therapy under real-life conditions in European facilities was excellent for priming and rinse back. There was no adverse event after 5191 HDx treatments. Patients suffering from itching, restless legs syndrome, persistent asthenia or malnourishment could benefit from HDx therapy. Moreover, we discuss here the promising applications in which HDx could be valuable (myeloma, rhabdomyolysis or cardiovascular diseases). This enthusiastic message is mitigated by reminding why and how prudence should be taken in the design of future HDx studies

Reconsidering adsorption in hemodialysis: is it just an epiphenomenon? A narrative review

International audienceSince the first attempt at extracorporeal renal replacement therapy, renal replacement therapy has been constantly improved. In the field of hemodialysis, substantial efforts have been made to improve toxin removal and biocompatibility. The advent of hemodiafiltration (HDF) and, more recently, of mid cut-off membranes have contributed to management of patients with end-stage renal disease (ESRD). Although several uremic toxins have been discovered, we know little about the clinical impact of their clearance in hemodialysis patients. In addition, a great deal of progress has been made in the areas of filtration and diffusion, but the adsorptive properties of hemodialysis membranes remain under-studied. The mechanism of action of adsorption is based on the attraction between the polymer of the dialysis membrane and the solutes, through hydrophobic interactions, ionic or electrostatic forces, hydrogen bonds or van der Waals forces. Adsorption on the dialysis membrane depends on the membrane surface, pore size, structure and electric load. Its involvement in toxin removal and biocompatibility is significant, and is not just an epiphenomenon. Diffusive and convective properties cannot be improved indefinitely and high permeability membranes, despite their high performance in the clearance of many toxins, have several limitations for long-term use in hemodialysis. This review will discuss why adsorption should be reconsidered and better characterized to improve efficiency and adequacy of dialysis

Using binding competitors of albumin to promote the removal of protein-bound uremic toxins in hemodialysis: Hope or pipe dream?

International audienceChronic kidney disease is associated with the accumulation of a large range of uremic retention solutes as referred to as uremic toxins. Some of these compounds belong to the group of Protein Bound Uremic Toxins (PBUT) due to their tight interactions with plasma proteins and especially serum albumin. These PBUT therefore exist in the bloodstream into two forms: a major bound (and non-diffusible) fraction and a minor free fraction. As a result, these compounds are poorly removed by most of the renal replacement therapies (such as hemodialysis) and their concentration can hardly be decreased in end-stage renal disease patients. An increase of the free fraction of PBUT could be achieved using chemical displacers that could compete with PBUT for binding to serum albumin. This review summarizes and discusses the interest of chemicals displacers as a valuable option to enhance PBUT removal in CKD patients. (C) 2017 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM)

Using binding competitors on albumin to promote the removal of protein-bound uremic toxins in hemodialysis: proof of concept and screening of candidates

National audienc

Distal colon motor dysfunction in mice with chronic kidney disease: Putative role of uremic toxins

Although gastrointestinal complications are a common feature of patients with chronic kidney disease (CKD), the impact of uremia on bowel motility remains poorly understood. The present study was, therefore, designed to investigate the impact of uremia on gut motility. Kidney failure was induced in mice by chemical nephrectomy using an adenine diet (0.25% w/w). Gastrointestinal transit time and colon motility were explored in vivo and ex vivo. Colons from control mice were incubated with uremic plasma or uremic toxins (urea, indoxyl-sulfate or p-cresyl-sulfate) at concentrations encountered in patients with end-stage renal disease. Mice fed an adenine diet for 3 weeks exhibited a 3-fold increase in plasma urea (p < 0.001) evidencing kidney failure. The median gastrointestinal transit time was doubled (1.8-fold, p < 0.001) while a reduction in colonic propulsive motility was observed in CKD mice (3-fold, p < 0.001). Colon from CKD mice exhibited an abnormal pattern of contraction associated with a blunted maximal force of contraction. Control colons incubated with plasma from hemodialysis patients exhibited a blunted level of maximal contraction (p < 0.01). Incubation with urea did not elicit any difference but incubation with indoxyl-sulfate or p-cresyl-sulfate decreased the maximal force of contraction (-66% and -55%, respectively. p < 0.01). Taken together, these data suggest that uremia impairs colon motility probably through the retention of uremic toxins. Colon dysmotility might contribute to the gastrointestinal symptoms often reported in patients with CKD

Modified Lipids and Lipoproteins in Chronic Kidney Disease: A New Class of Uremic Toxins

Chronic kidney disease (CKD) is associated with an enhanced oxidative stress and deep modifications in lipid and lipoprotein metabolism. First, many oxidized lipids accumulate in CKD and were shown to exert toxic effects on cells and tissues. These lipids are known to interfere with many cell functions and to be pro-apoptotic and pro-inflammatory, especially in the cardiovascular system. Some, like F2-isoprostanes, are directly correlated with CKD progression. Their accumulation, added to their noxious effects, rendered their nomination as uremic toxins credible. Similarly, lipoproteins are deeply altered by CKD modifications, either in their metabolism or composition. These impairments lead to impaired effects of HDL on their normal effectors and may strongly participate in accelerated atherosclerosis and failure of statins in end-stage renal disease patients. This review describes the impact of oxidized lipids and other modifications in the natural history of CKD and its complications. Moreover, this review focuses on the modifications of lipoproteins and their impact on the emergence of cardiovascular diseases in CKD as well as the appropriateness of considering them as actual mediators of uremic toxicity