title: Indoxyl sulfate - the uremic toxin linking hemostatic system disturbances with the prevalence of cardiovascular disease in patients with chronic kidney disease.
abstract: During chronic kidney disease progression, kidney-specific risk factors for cardiovascular disease come into play. The present study investigated the impact of indoxyl sulfate, dietary tryptophan-derived uremic toxin, accumulated in the blood of patients with chronic kidney disease on hemostatic parameters, markers of inflammation, oxidative stress and monocyte to macrophage transition.
  
  
  
  Fifty-one CKD patients not undergoing hemodialysis were enrolled in the study. Coagulation factors, fibrinolytic parameters, adhesion molecules, endothelial dysfunction markers, oxidative stress as well as inflammation markers were examined using immune-enzymatic method. Indoxyl sulfate levels were assessed using high-performance liquid chromatography. Biochemical parameters were determined by routine laboratory techniques using an automated analyzers. All assessed parameters were compared with controls and subjected to cross-sectional statistical analysis.
  
  
  
  Elevated concentrations of indoxyl sulfate, the vast majority of parameters affecting hemostasis, and markers of renal insufficiency conditions were observed. Part of hemostatic factors, namely tissue factor, von Willebrand factor, thrombomodulin, soluble urokinase-type plasminogen activator receptor, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion protein were correlated with the fraction of indoxyl sulfate. A significant quantity of assessed parameters showed strong correlations with superoxide-dismutase, renal insufficiency rate, C-reactive protein, and neopterin. Levels of indoxyl sulfate were independently associated with markers of impaired endothelial function (thrombomodulin, adhesion molecules), oxidative stress (superoxide-dismutase) and monocytes activation determinant (neopterin), which indicate unconventional links between these systems and the role of indoxyl sulfate. Furthermore, parameters that correlated with the levels of indoxyl sulfate (von Willebrand factor, soluble urokinase-type plasminogen activator receptor, soluble intercellular adhesion molecule-1) were positively associated with the prevalence of cardiovascular disease in a CKD patients.
  
  
  
  The study demonstrated that in conditions of chronic exposure to uremic toxins, indoxyl sulfate seems to be one of the "missing links" between impaired renal function and prevalence of cardiovascular events, especially hemostatic disorders. The main functions of the action appear to be altered monocytes activation, intensified inflammatory process, and augmented oxidative stress by this uremic toxin.
authors.affiliation: Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C Str., 15-222, Białystok, Poland.
authors.forename: Tomasz W
authors.initials: TW
authors.lastname: Kamiński
authors.affiliation: Department of Monitored Pharmacotherapy, Medical University of Bialystok, Mickiewicza 2C Str., 15-089, Białystok, Poland.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Pawlak
authors.affiliation: Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C Str., 15-222, Białystok, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Karbowska
authors.affiliation: Department of Nephrology and Clinical Transplantation, Medical University of Bialystok, Żurawia 14 Str., 15-540, Bialystok, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Myśliwiec
authors.affiliation: Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C Str., 15-222, Białystok, Poland. dariuszpawlak@poczta.onet.pl.
authors.forename: Dariusz
authors.identifier: 0000-0002-3751-0608
authors.initials: D
authors.lastname: Pawlak
mesh_terms: D000328:Adult; D000368:Aged; D002097:C-Reactive Protein; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D006487:Hemostasis; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007200:Indican / Q000378:metabolism*; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019798:Neopterin / Q000378:metabolism; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D015995:Prevalence; D011516:Prothrombin / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000453:epidemiology / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: C573420:ICAM1 protein, human; D008074:Lipoproteins; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D019010:Vascular Cell Adhesion Molecule-1; C051928:lipoprotein-associated coagulation inhibitor; D014841:von Willebrand Factor; D018799:Intercellular Adhesion Molecule-1; D019798:Neopterin; D011516:Prothrombin; D002097:C-Reactive Protein; D013925:Thromboplastin; D006861:Hydrogen Peroxide; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D007200:Indican
keywords: Cardiovascular disease; Chronic kidney disease; Hemostatic disorder; Indoxyl sulfate; Monocytes activation; Prothrombotic state; Tissue factor; Tryptophan derivatives; Uremic toxin; von Willebrand factor