scholarly journals The Impact of Uremic Toxicity Induced Inflammatory Response on the Cardiovascular Burden in Chronic Kidney Disease

Toxins ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 384 ◽  
Author(s):  
Ligia Claro ◽  
Andrea Moreno-Amaral ◽  
Ana Gadotti ◽  
Carla Dolenga ◽  
Lia Nakao ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Adhesion Molecule ◽  
Cardiovascular Response ◽  
Total Mortality ◽  
Inflammatory Biomarkers ◽  
Intercellular Adhesion Molecule ◽  
Uremic Toxin ◽  
Intercellular Adhesion Molecule 1 ◽  
The Impact

Uremic toxin (UT) retention in chronic kidney disease (CKD) affects biological systems. We aimed to identify the associations between UT, inflammatory biomarkers and biomarkers of the uremic cardiovascular response (BUCVR) and their impact on cardiovascular status as well as their roles as predictors of outcome in CKD patients. CKD patients stages 3, 4 and 5 (n = 67) were recruited and UT (indoxyl sulfate/IS, p-cresil sulfate/pCS and indole-3-acetic acid/IAA); inflammatory biomarkers [Interleukin-6 (IL-6), high sensitivity C reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1), soluble vascular adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble Fas (sFas)] and BUCVRs [soluble CD36 (sCD36), soluble receptor for advanced glycation end products (sRAGE), fractalkine] was measured. Patients were followed for 5.2 years and all causes of death was used as the primary outcome. Artery segments collected at the moment of transplantation were used for the immunohistochemistry analysis in a separate cohort. Estimated glomerular filtration rate (eGFR), circulating UT, plasma biomarkers of systemic and vascular inflammation and BUCVR were strongly interrelated. Patients with plaque presented higher signs of UT-induced inflammation and arteries from CKD patients presented higher fractalkine receptor (CX3CR1) tissue expression. Circulating IS (p = 0.03), pCS (p = 0.007), IL-6 (p = 0.026), sFas (p = 0.001), sCD36 (p = 0.01) and fractalkine (p = 0.02) were independent predictors of total mortality risk in CKD patients. Our results reinforce the important role of uremic toxicity in the pathogenesis of cardiovascular disease (CVD) in CKD patients through an inflammatory pathway.

MO550INDOXYL SULFATE AFFECTS ERYTHROPOIESIS DURING THE COURSE OF CHRONIC KIDNEY DISEASE: A MOLECULAR STUDY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Eya Hamza ◽  
Hakim Ouled-Haddou ◽  
Nicolas Jankovsky ◽  
Yohann Demont ◽  
Benjamin Brigant ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Cell Line ◽  
Uremic Toxins ◽  
Erythroid Cell ◽  
Uremic Toxin ◽  
Cd34 Cells ◽  
Phase Cycle ◽  
The Impact

Abstract Background and Aims Chronic kidney disease (CKD) is a global health condition characterized by a progressive deterioration of renal function due to high serum levels of uremic toxins. Anemia is a major trouble in CKD patients that contributes to a faster deterioration of renal failure, leading to cardiovascular disease and increasing morbimortality. Erythropoietin (EPO) is known to contribute to CKD-associated anemia. Thus, accumulation of uremic toxins in blood impairs EPO synthesis, leading to a subsequent impairment of erythropoiesis in the bone marrow. Very few molecular clues explain why erythropoiesis is affected in CKD or explain why erythropoiesis-stimulating agents (ESA) are not efficient in some patients with CKD. The current study aims to characterize the impact of one of the most representative uremic toxins, Indoxyl Sulfate (IS), in CKD-related anemia. IS is a protein-bound uremic toxin derived from the tryptophan dietary metabolism which is difficult to remove by dialysis. Our study demonstrates the molecular effects of IS on the growth and the differentiation of red blood cells in an erythroid cell line and in primary cell cultures CD34+. Method Firstly, we examined in vitro the time-courses of IS under clinically relevant concentrations of IS (250 µM -1 mM) in a human leukemic cell line in which proliferation is induced by EPO, the UT7/EPO cell line. Cell apoptosis, proliferation, differentiation and cell cycle analysis were assessed by the MACSQuant flow cytometry. Erythroid gene expression analysis was assessed by RT-qPCR (Quantstudio 7 flex). The ratio A260/280 assessed the quality of nucleic acids. Western blotting experiments were performed to study protein expression. Human primary CD34+ cells were obtained from mobilized peripheral blood mononuclear cells (MNC) of healthy subjects and were isolated by magnetic microbeads separation on MACS columns. Results IS at 250 µM and 1 mM increased apoptosis of UT7/EPO cell line at 48h compared to control condition. On the other hand, we found no significant effect of IS on the phenotype of UT7/EPO, when using CD235a (Glycophorin A), as a marker for the detection of the erythroid cell lineage. Ki67 cellular levels, a cell proliferation marker, was not altered between control and IS experiments. This indicated that IS did not affect proliferation in UT7/EPO. At 48h, at the clinically relevant concentration of IS (250 µM), we observed an increase of the cell phase cycle Sub-G1. The analysis of erythropoiesis related genes shows that HIF2α was deregulated with IS (250 µM). Finally, in the Epo-EpoR signalling pathway, we studied the activation of the Jak2/Stat5 proteins. Results in human primary CD34+ cells confirmed the apoptotic effect of IS observed in UT7/EPO. Conclusion Our findings suggest that IS, a representative protein-bound uremic toxin, could affect cell viability, apoptosis and the cell cycle. This study suggests clues to develop new therapies for CKD-associated anemia.

The impact of selectins on mortality in stable carotid atherosclerosis

2015 ◽  
Vol 114 (09) ◽  
pp. 632-638 ◽  
Author(s):  
Matthias Hoke ◽  
Max-Paul Winter ◽  
Oswald Wagner ◽  
Markus Exner ◽  
Martin Schillinger ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Cardiovascular Mortality ◽  
Carotid Atherosclerosis ◽  
Leukocyte Adhesion ◽  
Inflammatory Cells ◽  
Endothelial Activation ◽  
Cellular Adhesion ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
The Impact

SummaryCellular adhesion molecules also known as selectins promote recruitment of inflammatory cells into the arterial wall where they interact with lipid particles leading subsequently to plaque formation. The intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule-1 (VCAM-1) and the endothelial-leukocyte adhesion molecule 1 (ELAM-1) also known as E-selectin mediate the attachment of leukocytes and have been implicated in the destabilisation of atherosclerotic plaques. Therefore, we hypothesised that plasma selectin levels are associated with adverse clinical outcome. We prospectively studied 855 patients with sonographically confirmed carotid atherosclerosis. During a median follow-up of 6.2 years, corresponding to 5,551 overall person-years, 275 patients (26 %) died. We detected a significant association between cardiovascular mortality and ICAM-1 (adjusted hazard ratio [HR]: 3.43, 95 % confidence interval [CI] 2.00–5.88, p< 0.001) as well as VCAM-1 (adjusted HR: 2.51, 95 % CI 1.45–4.34, p=0.001) when comparing the fourth with the first quartile. Comparable results were obtained for all-cause mortality. In contrast, we could not detect a significant association between E-selectin and all-cause or cardiovascular mortality. We identified the selectins ICAM-1 and VCAM-1 as strong and independent predictors of all-cause and cardiovascular mortality in patients with stable carotid atherosclerosis. These molecules are elevated in states of endothelial activation and might assist to monitor anti-atherosclerotic therapy and select those patients with carotid atherosclerosis, who are at higher risk for cardiovascular events.

Alteration of connexin expression is an early signal for chronic kidney disease

2011 ◽  
Vol 301 (1) ◽  
pp. F24-F32 ◽  
Author(s):  
Julie Toubas ◽  
Samantha Beck ◽  
Anne-Laure Pageaud ◽  
Anne-Cecile Huby ◽  
Mouna Mael-Ainin ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Disease ◽  
Gap Junction ◽  
Adhesion Molecule ◽  
Renal Cortex ◽  
Chronic Renal Disease ◽  
Intercellular Adhesion Molecule ◽  
Obstructive Nephropathy ◽  
Cx43 Expression

Chronic kidney disease is promoted by a variety of factors that induce chronic inflammation and fibrosis. Inflammation and excessive scaring have been recently associated with disruptions of the gap junction-mediated intercellular communication. Nevertheless, little is known about alterations of the expression of gap junction proteins such as connexin (Cx) 43 and 37 in chronic renal disease. In this study, we investigated the expression of these two Cxs in the hypertensive RenTg mice, the anti-glomerular basement membrane glomerulonephritis, and the unilateral ureteral obstruction models, all leading to the development of chronic kidney disease in mice. Expression of Cx43 was almost negligible in the renal cortex of control mice. In contrast, Cx43 was markedly increased in the endothelium of peritubular and glomerular capillaries of the 3-mo-old RenTg mice, in the glomeruli of mice suffering from glomerulonephritis, and in the tubules after obstructive nephropathy. The Cx43 expression pattern was paralleled closely by that of the adhesion markers such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 as well as the inflammatory biomarker monocyte chemoattractant protein-1. In contrast, Cx37 that was abundantly expressed in the renal cortex of healthy mice was markedly decreased in the three experimental models. Interestingly, Cx43+/− mice showed restricted expression of VCAM-1 after 2 wk of obstructive nephropathy. These findings suggest the importance of Cxs as markers of chronic renal disease and indicate that these proteins may participate in the inflammatory process during the development of this pathology.

scholarly journals The Impact of Uremia and Intestinal Dysbiosis on Hepatic Drug Metabolism in a Rat Model of Progressive Chronic Kidney Disease

2019 ◽  
Author(s):  
Emily D Hartjes ◽  
Yong Jin Lim ◽  
Thomas J Velenosi ◽  
Kait F Al ◽  
Jean M Macklaim ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Drug Metabolism ◽  
Gut Microbiota ◽  
Uremic Toxins ◽  
Uremic Toxin ◽  
Bacterial Microbiota ◽  
Intestinal Dysbiosis ◽  
Metabolite Profiles ◽  
The Impact

AbstractNonrenal clearance pathways such as drug metabolism are decreased in chronic kidney disease (CKD). Although the mechanism remains elusive, uremic toxin retention and an altered gut microbiota are suspected to influence cytochrome P450s (CYPs) contributing to the unpredictable pharmacokinetics in patients with CKD. We characterized dysbiosis and uremia in CKD to elucidate associations between CYP expression and CKD progression. Rats fed control or CKD-inducing adenine diet were subsequently studied at five time points over 42 days. CYP expression and activity were compared to alterations in the 1) plasma and liver metabolome and 2) gut bacterial microbiota. CYP3A2 and CYP2C11 were downregulated in CKD by ≥76% (p<0.001) concurrently with or slightly prior to CKD onset as defined by serum creatinine. Metabolite profiles were altered prior to changes in the gut microbiota, and gut-derived uremic toxins including indoxyl sulfate, phenyl sulfate and 4-ethylphenyl sulfate correlated with CYP3A2 or CYP2C11 expression. Bacterial genera Turicibacter and Parabacteroides were identified as being characteristic of CKD. In conclusion, CYP3A2 and CYP2C11 are downregulated before dysbiosis and correlate with select uremic toxins.

Paraoxonase-1 and myeloperoxidase correlate with vascular biomarkers in overweight patients with newly diagnosed untreated hyperlipidaemia

VASA ◽  
2017 ◽  
Vol 46 (5) ◽  
pp. 370-376 ◽  
Author(s):  
Anita Szentpéteri ◽  
Noémi Zsíros ◽  
Viktória E. Varga ◽  
Hajnalka Lőrincz ◽  
Mónika Katkó ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Oxidized Ldl ◽  
Vascular Complications ◽  
Cd40 Ligand ◽  
Paraoxonase 1 ◽  
Intercellular Adhesion Molecule ◽  
Pon1 Activity ◽  
Intercellular Adhesion Molecule 1 ◽  
Inflammatory Parameters ◽  
Vascular Biomarkers

Abstract. Background: In hyperlipidaemic state, increased levels of myeloperoxidase (MPO) and decreased paraoxonase-1 (PON1) activity have been reported; however, their relationships with other atherosclerotic biomarkers have not been completely clarified. Patients and methods: Serum concentrations of lipid and inflammatory parameters, MPO levels, and PON1 activities were investigated in 167 untreated hyperlipidaemic patients with and without vascular complications and in 32 healthy controls. Additionally, levels of CD40 ligand (sCD40L) and asymmetric dimethyl arginine (ADMA), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1, and oxidized LDL were determined. Results: We found elevated C-reactive protein (CRP), ADMA, sCD40L, sICAM-1 concentrations, and higher MPO levels in patients with vascular complications compared to those without. The PON1 arylesterase activity correlated negatively with sCD40L, ADMA, and sICAM-1 levels, respectively. In contrast, MPO concentrations showed positive correlations with sCD40L, ADMA, and sICAM-1 levels, respectively. Conclusions: It can therefore be stated that PON1 activity and MPO level correlate strongly with the vascular biomarkers, highlighting the importance of the HDL-associated pro- and antioxidant enzymes in the development of endothelial dysfunction and atherogenesis.

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