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Karbowska Malgorzata 1 , Kaminski Tomasz 1 , Misztal Tomasz 2 , Pawlak Dariusz 1

Medical University of Bialystok , Poland Faculty of Pharmacy with the Division of Laboratory Medicine. Indoxyl sulfate modulates the activity of coagulation system and fibrinolysis in animal model of experimental arterial thrombosis.

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Karbowska Malgorzata 1 , Kaminski Tomasz 1 , Misztal Tomasz 2 , Pawlak Dariusz 1

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  1. MedicalUniversity of Bialystok, PolandFaculty of Pharmacy with the Division of Laboratory Medicine Indoxylsulfate modulates the activity of coagulation system and fibrinolysis in animal model of experimental arterial thrombosis Karbowska Malgorzata1, KaminskiTomasz1, Misztal Tomasz2, Pawlak Dariusz1 1 Department of Pharmacodynamics, 2Department of Physical Chemistry This work was supported by funds from Leading National Research Centre 116/KNOW/15 and Polish National Science Centre 2015/17/N/NZ4/02334.

  2. Indoxyl sulfate modulates the activity of coagulation system and fibrinolysis in animal model of experimental arterial thrombosis Introduction Chronic kidney disease Cardiovascular events Indoxyl sulfate Materials and methods Results Conclusions

  3. Mortality due to cardiovascular events in the general population andin patients with chronic kidney disease (CKD) Deaths[%] Without CKD CKD Age [years] Sarnak MJ, Levey AS: Cardiovasculardisease and chronicrenaldisease: a newparadigm. Am. J. KidneyDis. 2000, 35(4), 117-131 RoblesN, Macias J: Cardiovascularrisk in uremicpatients: darknessafter AURORA. Ren. Fail. 2010, 32(2), 269-272 BrosnahanG, Fraer M: Management of chronickidneydisease: whatis the evidence? South. Med J. 2010, 103(3), 222-230

  4. Impaired renal function - independent risk factor forcardiovascular disease (CVD) Risk for CVD [%] GFR [ml/min] GFR - Glomerular Filtration Rate Nanayakkara P, Gaillard C: Vascular disease and chronic renal failure: new insights. Neth. J. Med. 2010, 68(1), 5-14

  5. Production and accumulationofindoxylsulfate (IS) in chronickidneydisease Karbowska M. et al.:Methods of reducing the level of indoxyl sulfate - one of the most potent protein-bound uremic toxins. Toxin Reviews 2016

  6. Impactof indoxylsulfateon the cardiovascular system Aortic calcification Decreased NO production Myocardial fibrosis Induction of oxidative stress Inhibition of endothelial cell proliferation and wound healing Hypertrophy of cardiomyocytes Endothelial cell senescence Enhancement of ICAM-1 and VCAM activity Induction of expression and activity of tissue factor (TF) in the smooth muscle cells of blood vessels Ellis RJ, Small DM, Vesey DA et al. Indoxyl sulphate and kidney disease: Causes, consequences and interventions. Nephrology (Carlton). 2016;21(3):170-7. Sallée M, Dou L, Cerini C et al. The aryl hydrocarbon receptor-activating effect of uremic toxins from tryptophan metabolism: a new concept to understand cardiovascular complications of chronic kidney disease.Toxins (Basel). 2014,4;6(3):934-49. Yisireyili M, Shimizu H, Saito S et al. Indoxyl sulfate promotes cardiac fibrosis with enhanced oxidative stress in hypertensive rats. Life Sci. 2013,10;92(24-26):1180-5. Chitalia VC, Shivanna S, Martorell J et al. Uremic serum and solutes increase post-vascular interventional thrombotic risk through altered stability of smooth muscle cell tissue factor. Circulation. 2013;22;127(3):365-76. Yu M, Kim YJ, Kang DH. Indoxyl sulfate-induced endothelial dysfunction in patients with chronic kidney disease via an induction of oxidative stress. Clin J Am Soc Nephrol. 2011;6(1):30-9.

  7. The relationship between the concentration of indoxyl sulfate and the prevalence of diseases of the cardiovascular systemin patients with chronic kidney disease Multivariable model included age, gender, smoking history (no/yes), statin therapy (no/yes), albumin, systolic blood pressure, body mass index (BMI), diabetes (no/yes) and toxin (entered separately). Odds ratio (OR) and Confidence Intervals (CI) presented are for the odds of a 10 μmol/L increase in the toxins. Rossi M, Campbell K, Johnson D et al.: Uraemic toxins and cardiovascular disease across the chronic kidney disease spectrum: an observational study. Nutr Metab Cardiovasc Dis. 2014;24(9):1035-42

  8. The efficiency of the elimination of indoxyl sulfate by hemodialysis (HD) • Protein-binding ratio – about 90% • Reduction rate after HD – about 30% ** p<0.001 vs healthy subjects; * p<0.01 vs healthy subjects Yoshiharu Itoh, Atsuko Ezawa, Kaori Kikuchi et al. Protein-bound uremic toxins in hemodialysis patients measured by liquid chromatography/tandem mass spectrometry and their effects on endothelial ROS production. Anal Bioanal Chem. 2012; 403:1841–1850.

  9. Aim of the study Evaluation of effect of indoxyl sulfate oncoagulation system and fibrinolysis in animal models Aim of the study Assesment of the effect of indoxyl sulfate on thrombotic process after acute treatment in electric current-induced arterial thrombosis in Wistar male rats Specific objectives of the study Evaluation of impact of indoxyl sulfate on parameters of coagulation and fibrynolysis Assesment of influence of indoxyl sulfate on blood morphology parameters Evaluation of effect of indoxyl sulfate on in vitro collagen-induced platelet aggregation

  10. Materials and methods

  11. Assesmentof the effect of indoxylsulfateon thrombotic process after acute treatment in electric current-induced arterial thrombosis in Wistar male rats 10min 10min 10min 45min n=10 24h VEH – 0.9% NaCl ***p<0.001 ; ****p<0.0001

  12. Evaluation of impact of indoxylsulfateon parameters of coagulation and fibrynolysis Activated Partial Thromboplastin Time (APTT) Prothrombin time (PT) n=10 *p<0.05 ; **p<0.01 ; ****p<0.0001

  13. Evaluation of impact of indoxylsulfate on parameters of coagulation and fibrynolysis Thrombin time (TT) Fibrynogen n=10 **p<0.01

  14. Assesment of influence of indoxyl sulfate on blood morphology parameters White Blood Cell Count (RBC) Red Blood Cell Count (RBC) Hemoglobin (HGB) Hematocrit (HCT) n=10

  15. Assesment of influence of indoxyl sulfate on blood morphology parameters Mean corpuscular hemoglobin (MCH) Mean corpuscular volume (MCV) Mean corpuscular hemoglobin concentration (MCHC) Platelets (PLT) n=10

  16. Evaluation of effect of indoxyl sulfate on in vitro collagen-induced platelet aggregation n=16 VEH – 0.9% NaCl *p<0.05

  17. Evaluation of effect of indoxyl sulfate on in vitro collagen-induced platelet aggregation n=16 VEH – 0.9% NaCl *p<0.05 ; ***p<0.001 ; ****p<0.0001

  18. Conclusions IS affects the coagulation systemin a dose-dependent way IS creates prothrombotic state IS can be one of crucial factors responsible for thromboembolic events in CKD

  19. Indoxyl sulfate modulates the activity of coagulation system and fibrinolysis in animal model of experimental arterial thrombosis THANK YOU FOR YOUR ATTENTION Małgorzata Karbowska malgorzatamichalowska@gmail.com Department of Pharmacodynamics Medical University of Bialystok, Poland

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