Abstract BACKGROUND AND AIMS Uraemic toxins accumulate in the blood and tissues of patients with chronic kidney disease (CKD). Previous animal studies have shown that chronic kidney disease (CKD) not only alters the elimination of drugs excreted by the kidneys, but it also impacts the metabolism of drugs subject to non-renal clearance, which involves mainly the liver and the gut. The use of apixaban, an oral anticoagulant, has been approved in the USA for dialysis patients. However, the coexistence of thrombotic and haemorrhagic risk in patients with CKD makes dose adjustment difficult. The liver has a major role in drug metabolization. Hepatocytes express high levels of AhR, a ligand-inducible transcription factor that mediates the induction of various liver cytochrome P450 enzymes by xeno and endobiotic. Tryptophan-derived uraemic toxins (TDUT) are AhR agonists. Indoxyl sulfate (IS) is the main TDUT involved in uraemic syndrome. IS increases the expression and activity of P-glycoprotein (P-gp) in the liver. Apixaban metabolism is mediated by P-gp and Cyp3a4 (Cyp3a11 in mice). We aim to study the effect of apixaban and IS in the expression of drug metabolism genes. Our hypothesis is that AhR activation by IS could severely modify drug metabolism during CKD. METHOD C57BL/6J Wild-type mice purchased from The Jackson Laboratory were fed ad libitum with a standard diet. At 10 weeks of age, mice drinking water was substituted with a 5% sucrose water solution with either 0.1% indoxyl sulphate or KCl (control) added at equivalent concentrations. 48-h before sacrifice some mice were gavaged with an apixaban solution (0.6 mg/mL) twice a day with the last dose given 4 h prior to sacrifice. All mice were sacrificed at 11 weeks of age. Liver samples were stored in an RNA-later solution at −20°C. Samples were thawed and lysed in Trizol using the Tissue-Ruptor system (Qiagen). RNA was extracted and purified with chloroform and precipitated with isopropanol. RNA concentration was estimated by spectrophotometry. Gene expression was analysed by q-RT-PCR using Gusb as a housekeeping gene. Apixaban levels were quantified by LC-MS. Kruskal–Wallis followed by a two-stage linear step-up procedure of Benjamini, Krieger and Yekutieli (q < 0.05) was performed using GraphPad Prism 9.2.1. RESULTS Four groups of mice per sex were thus created: WT-KCl, WT-IS, WT-KCl Apix, WT-IS Apix. In the IS/KCl model we observe higher mRNA basal expression of Abcb1a (q = 0.008) and Sult1a1 (q = 0.006) and lower basal expression of Abcg2 (q = 0.0005) in females compared to males when treated with KCl. IS treatment increases Cyp1a2 expression in females (q = 0.0139) and Cyp1a1 in both males (q = 0.0145) and females (q = 0.026). In the IS/KCl-Apix model the same sex-related differences are maintained for Abcb1a (q = 0.0031), Sult1a1 (q = 0.0316) and Abcg2 (q < 0.0001). In males, CYP2e1 expression is increased by apixaban in KCl (q = 0.067) and IS (q = 0.0278) treated mice. Moreover, apixaban counteracts the increased expression of Cyp1a1 induced by IS (q = 0.0177). The expression of Cyp3a11 is augmented in males treated with KCl-apixaban (q = 0.0143), an effect that seems to be reversed by IS (q = 0.0066). In females, apixaban has no effect in gene expression. Apixaban serum concentration is higher in KCl (q = 0.0350) and IS (q = 0.0019) treated females when compared to males. CONCLUSION The effect of IS as an agonist of AhR in the liver is confirmed by the increased expression of Cyp1a1. Apixaban provokes a remarkable increase of Cyp3a11 in male mice, which could lead to higher degradation rates decreasing its activity. IS seems to reverse this effect. This could lead to increased activity of apixaban during CKD which could derive in an increased risk of bleeding. Higher BCRP rates could explain lower rates of apixaban in male serum. Apixaban did not alter gene expression in females. Clinical trials in CKD are generally biased regarding sex (fewer women represented) possibly masking important sex-dependent drug adverse effects. Our results show great differences in basal expression of various genes, confirming the importance to study men and women separately with respect to drug metabolism.

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.

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 99mTc-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 99mTc-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.

Chlordecone (CLD) is an organochlorine pesticide widely used in the past to control pest insects in banana plantations in the French West Indies. Due to its persistence in the environment, CLD has contaminated the soils where it has been spread, as well as the waters, and is still present in them. The objective of our study was to evaluate the effects of chronic exposure to environmentally relevant CLD concentrations in an animal model, the freshwater hydra ( Hydra circumcincta ). In a multi-marker approach, we have studied the expression of some target stress genes, the morphology, and the asexual reproduction rates. Our data showed that exposure to low concentrations of chlordecone leads to (i) a modulation of the expression of target genes involved in oxidative stress, detoxification, and neurobiological processes, and (ii) morphological damages and asexual reproduction impairment. We have observed non-monotonic dose-response curves, which agree with endocrine-disrupting chemical effects. Thus, “U-shaped” dose-response curves were observed for SOD, GRed, Hym355, and potentially GST gene expressions; inverted “U-shaped” curves for GPx and CYP1A gene expressions and reproductive rates; and a biphasic dose-response curve for morphological damages. Therefore, in the range of environmental concentrations tested, very low concentrations of CLD can produce equally or more important deleterious effects than higher ones. Finally, to our knowledge, this study is the first one to fill the lack of knowledge concerning the effects of CLD in Hydra circumcincta and confirms that this diploblastic organism is a pertinent freshwater model in the risk assessment.

Chronic kidney disease (CKD) is a major public health problem, since 300,000,000 people in the world display a glomerular filtration rate (GFR) below 60 mL/min/1.73m(2). Patients with CKD have high rates of complications and comorbidities. Thus, they require the prescription of numerous medications, making the management of patients very complex. The prescription of numerous drugs associated with an altered renal- and non-renal clearance makes dose adjustment challenging in these patients, with frequent drug-related adverse events. However, the mechanisms involved in this abnormal drug clearance during CKD are not still well identified. We propose here that the transcription factor, aryl hydrocarbon receptor, which is the cellular receptor for indolic uremic toxins, could worsen the metabolism and the excretion of drugs in CKD patients.

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.

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 µM, 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-κB site was essential in TF induction by IAA. In addition, TF induction by IAA was drastically decreased by an inhibitor of the NF-κB pathway. IAA induced the nuclear translocation of NF-κB 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-κB 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.

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.

In CKD, uremic solutes may induce endothelial dysfunction, inflammation, and oxidative stress, leading to increased cardiovascular risk. We investigated whether the uremic solute indole-3 acetic acid (IAA) predicts clinical outcomes in patients with CKD and has prooxidant and proinflammatory effects. We studied 120 patients with CKD. During the median study period of 966 days, 29 patients died and 35 experienced a major cardiovascular event. Kaplan-Meier analysis revealed that mortality and cardiovascular events were significantly higher in the higher IAA group (IAA>3.73 µM) than in the lower IAA group (IAA<3.73 µM). Multivariate Cox regression analysis demonstrated that serum IAA was a significant predictor of mortality and cardiovascular events after adjustments for age and sex; cholesterol, systolic BP, and smoking; C-reactive protein, phosphate, body mass index, and albumin; diastolic BP and history of cardiovascular disease; and uremic toxins p-cresyl sulfate and indoxyl sulfate. Notably, IAA level remained predictive of mortality when adjusted for CKD stage. IAA levels were positively correlated with markers of inflammation and oxidative stress: C-reactive protein and malondialdehyde, respectively. In cultured human endothelial cells, IAA activated an inflammatory nongenomic aryl hydrocarbon receptor (AhR)/p38MAPK/NF-κB pathway that induced the proinflammatory enzyme cyclooxygenase-2. Additionally, IAA increased production of endothelial reactive oxygen species. In conclusion, serum IAA may be an independent predictor of mortality and cardiovascular events in patients with CKD. In vitro, IAA induces endothelial inflammation and oxidative stress and activates an inflammatory AhR/p38MAPK/NF-κB pathway.

Background: Chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. Oxidative stress seems to play a pivotal role in this process, and purine metabolism may be involved in CKD-related oxidative stress. Xanthine oxidase (XO) is an enzyme involved in purine metabolism and is also responsible for the production of reactive oxygen species. Methods: This prospective study aimed to analyze the relation between plasma dosages of molecules involved in redox balance, purine metabolism and cardiovascular events in patients with non-diabetic CKD stages 3-5 or on chronic hemodialysis (HD). CKD (n = 51) and HD (n = 50) patients were compared to matched healthy controls (n = 38) and followed-up for 3 years. Results: Both CKD and HD patients had decreased plasma levels of antioxidants (selenium, zinc, vitamin C). HD patients had decreased levels of the antioxidant enzyme superoxide dismutase and increased levels of oxidation products (ischemia-modified albumin, malondialdehyde [MDA]). The following substrates and enzymes involved in purine metabolism were increased in the HD cohort: adenosine, adenosine deaminase and the pro-oxidant XO. XO activity was negatively correlated with super oxide dismutase and positively with MDA. Interestingly, XO activity was an independent predictor of cardiovascular events in CKD and HD patients, regardless of uric acid levels. Uric acid was not predictive of events. Conclusion: This highlights a possible role of XO itself in CKD-related cardiovascular disease (CVD) and raises the hypothesis that beneficial effects observed with XO inhibitors on CVD in CKD may also be due to the reduction of oxidative stress.

Indoxylsulfate (IS) and p-cresylsulfate (PCS) are natural compounds endowed with toxicity. These molecules are harmful to the environment and removed by the procedure of dialysis. Knowledge of their interaction with biologic compounds such as proteins and particularly human serum albumin (HSA) is limited. This study was therefore designed to determine the thermodynamic parameters of the interaction of IS with HSA and in competition with PCS. Results showed that IS binding is moderate (K a = 1,750 ± 39 M−1). The interaction is mainly electrostatic (∆H° = −36.2 ± 1.7 kJ mol−1) and yields a modification of conformation upon binding (∆conf S° < 0). The thermodynamic parameters obtained at different temperatures show an enthalpy–entropy compensation process. Competition with PCS reveals that affinity for IS decreased by 36 %, with profound modification of the binding forces involved and a release of PCS from the binding site.

Patients 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-β-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.

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.

In chronic kidney disease (CKD), uremic solutes accumulate in blood and tissues. These compounds probably contribute to the marked increase in cardiovascular risk during the progression of CKD. The uremic solutes indoxyl sulfate and indole-3-acetic acid (IAA) are particularly deleterious for endothelial cells. Here we performed microarray and comparative PCR analyses to identify genes in endothelial cells targeted by these two uremic solutes. We found an increase in endothelial expression of tissue factor in response to indoxyl sulfate and IAA and upregulation of eight genes regulated by the transcription factor aryl hydrocarbon receptor (AHR). The suggestion by microarray analysis of an involvement of AHR in tissue factor production was confirmed by siRNA inhibition and the indirect AHR inhibitor geldanamycin. These observations were extended to peripheral blood mononuclear cells. Tissue factor expression and activity were also increased by AHR agonist dioxin. Finally, we measured circulating tissue factor concentration and activity in healthy control subjects and in patients with CKD (stages 3-5d), and found that each was elevated in patients with CKD. Circulating tissue factor levels were positively correlated with plasma indoxyl sulfate and IAA. Thus, indolic uremic solutes increase tissue factor production in endothelial and peripheral blood mononuclear cells by AHR activation, evoking a 'dioxin-like' effect. This newly described mechanism of uremic solute toxicity may help understand the high cardiovascular risk of CKD patients.

Introduction and Aims: Chronic kidney disease (CKD) markedly increases cardiovascular risk. Tissue Factor (TF), whose levels are elevated in CKD patients, may participate in the development of cardiovascular diseases.We hypothesized that indolic uremic solutes, indoxyl sulfate (IS) and indole-3-acetic acid (IAA), are involved in increased TF production. Methods: IAA, IS and plasma tissue factor levels were measured in 72 hemodialysis (HD) patients, 50 undialyzed CKD patients (CKD) and 37 control subjects (controls). We then studied in vitro the effect of IAA and IS at maximal uremic concentrations (9 μg/mL and 250 μg/mL respectively) on TF production in Human Umbilical Vein Endothelial Cells (HUVEC) and Peripheral Blood Mononuclear Cells (PBMC) . We also measured TF-dependent procoagulant activity in HUVEC incubated with IS and IAA. Finally, we studied the involvement of aryl hydrocarbon receptor (AhR) in this TF production by using pharmacological antagonists and siRNA experiments. Results: Soluble TF (sTF) levels were respectively 142+/- 48 pg/mL in HD, 77 +/- 66 pg/mL in CKD and 36+/-14 pg/mL in controls, with significant differences between all groups. In CKD patients, sTF levels were negatively correlated with renal function estimated by MDRD formula (r= - 0,333, p < 0,05). IS and IAA levels were positively correlated with sTF (r= - 0,333, p < 0,05 and r= 0,32, p < 0,01). In vitro, IS and IAA increased TF protein levels and TF membrane expression in HUVEC and PBMC. IAA and IS also increased TF-dependent procoagulant activity in HUVEC. This increased TF antigen production is preceded by increased mRNA levels suggesting an elevated transcriptional activity. siRNA directed against AhR abolished the increase in TF protein, procoagulant activity and mRNA levels induced by IS and IAA. TF expression and activity were also increased by dioxin, a well-known AHR agonist. Conclusions: In conclusion, the indolic uremic solutes increase TF production in endothelial cells and PBMC via AHR activation, evoking a “dioxin-like” effect. These newly described mechanisms of uremic solute toxicity might help understand the high cardiovascular risk of CKD patients.

Patients with chronic kidney disease (CKD) have a much higher risk of cardiovascular diseases than the general population. Endothelial dysfunction, which participates in accelerated atherosclerosis, is a hallmark of CKD. Patients with CKD display impaired endothelium‐dependent vasodilatation, elevated soluble biomarkers of endothelial dysfunction, and increased oxidative stress. They also present an imbalance between circulating endothelial populations reflecting endothelial injury (endothelial microparticles and circulating endothelial cells) and repair (endothelial progenitor cells). Endothelial damage induced by a uremic environment suggests an involvement of uremia‐specific factors. Several uremic toxins, mostly protein‐bound, have been shown to have specific endothelial toxicity: ADMA, homocysteine, AGEs, and more recently, p‐cresyl sulfate and indoxyl sulfate. These toxins, all poorly removed by hemodialysis therapies, share mechanisms of endothelial toxicity: they promote pro‐oxidant and pro‐inflammatory response and inhibit endothelial repair. This article (i) reviews the evidence for endothelial dysfunction in CKD, (ii) specifies the involvement of protein‐bound uremic toxins in this dysfunction, and (iii) discusses therapeutic strategies for lowering uremic toxin concentrations or for countering the effects of uremic toxins on the endothelium.

Vascular dysfunction induced by uremia has 4 main aspects. (1) Atherosclerosis is increased. Intima-media thickness is increased, and animal studies have established that uremia accelerates atherosclerosis. Uremic toxins are involved in several steps of atherosclerosis. Leukocyte activation is stimulated by guanidines, advanced glycation end products (AGE), p-cresyl sulfate, platelet diadenosine polyphosphates, and indoxyl sulfate. Endothelial adhesion molecules are stimulated by indoxyl sulfate. Migration and proliferation of vascular smooth muscle cells (VSMC) are stimulated by local inflammation which could be triggered by indoxyl sulfate and AGE. Uremia is associated with an increase in von Willebrand factor, thrombomodulin, plasminogen activator inhibitor 1, and matrix metalloproteinases. These factors contribute to thrombosis and plaque destabilization. There is also a decrease in nitric oxide (NO) availability, due to asymmetric dimethylarginine (ADMA), AGE, and oxidative stress. Moreover, circulating endothelial microparticles (EMP) are increased in uremia, and inhibit the NO pathway. EMP are induced in vitro by indoxyl sulfate and p-cresyl sulfate. (2) Arterial stiffness occurs due to the loss of compliance of the vascular wall which induces an increase in pulse pressure leading to left ventricular hypertrophy and a decrease in coronary perfusion. Implicated uremic toxins are ADMA, AGE, and oxidative stress. (3) Vascular calcifications are increased in uremia. Their formation involves a transdifferentiation process of VSMC into osteoblast-like cells. Implicated uremic toxins are mainly inorganic phosphate, as well as reactive oxygen species, tumor necrosis factor and leptin. (4) Abnormalities of vascular repair and neointimal hyperplasia are due to VSMC proliferation and lead to severe reduction of vascular lumen. Restenosis after coronary angioplasty is higher in dialysis than in nondialysis patients. Arteriovenous fistula stenosis is the most common cause of thrombosis. Uremic toxins such as indoxyl sulfate and some guanidine compounds inhibit endothelial proliferation and wound repair. Endothelial progenitor cells which contribute to vessel repair are decreased and impaired in uremia, related to high serum levels of β2-microglobulin and indole-3 acetic acid. Overall, there is a link between kidney function and cardiovascular risk, as emphasized by recent meta-analyses. Moreover, an association has been reported between cardiovascular mortality and uremic toxins such as indoxyl sulfate, p-cresol and p-cresyl sulfate.