The Study of Endothelial Function in CKD and ESRD

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1 The Study of Endothelial Function in CKD and ESRD

2 Endothelial Diversity in the Human Body Aird WC. Circ Res 2007

3 Endothelial Diversity in the Human Body The endothelium should be viewed for what it is: an organ "teeming with life every bit as active and complex as any other organ in the body Aird WC. Circ Res 2007

4 Endothelial dysfunction

5 Evolution of Atherosclerosis Endothelial dysfunction Intima-media thickening Angina Myocardial infarction Modified after Libby et al. Circulation 1995

6 Healthy Endothelium laminar blood flow vasorelaxation NO permeability adhesion enos NO enos NO 6

7 Endothelial Cell Function Mediators Function Mediators Regulation of vascular tone Nitric oxide (NO) Cyclooxygenase derived products (e.g. prostacyclin) Endothelial-derived hyperpolarizing factor (EDHF) Endothelial-derived contracting factor (EDCF) Endothelin-1 Angiotensin II C-type natriuretic peptide Bradykinin Adrenomedullin

8 Endothelial Cell Function Mediators Function Mediators Regulation of thrombosis and hemostasis Nitric oxide (NO) Tissue plasmin activator (tpa) Thrombomodulin Prostaglandin Plasminogen activator inhibitor-1 (PAI-1) Tissue factor (TF) Tissue factor pathway inhibitor (TFPI) Platelet activating factor (PAF) Von Willebrand s factor (vwf) Endothelial protein C receptor

9 Endothelial Cell Function Mediators Function Mediators Regulation of vascular inflammation Monocyte chemotactic factor-1 (MCP-1) Cell adhesion molecules (VCAM-1, ICAM-1, etc.) Interleukin 1, 6, 18 Tumor necrosis factor α Nitric oxide (NO)

10 Endothelial Cell Function Mediators Function Mediators Regulation of cell proliferation Nitric oxide (NO) Transforming growth factor-β Endothelin-1 Angiotensin II Platelet derived growth factor (PDGF) Basic fibroblast growth factor Insulin like growth factor

11 Nitric Oxide and Endothelial Function Furchgott & Zawadzki. Nature 1980

12 Invasive Endothelial Function Tests Method Principle Quantitative angiography assessment of vessel diameter after intra-arterial infusion of acetylcholine represents the gold standard for clinical assessment of endothelial function acetylcholine or other agonists (bradykinin, prostacyclin, etc.) induce endothelial release of NO leading to vasodilation when endothelial dysfunction is present, acetylcholine causes vasoconstriction

13 Invasive Endothelial Function Tests

14 Invasive Endothelial Function Tests

15 Invasive Endothelial Function Tests Method Principle Venous occlusion plethysmography usually performed in the forearm vascular bed after intra-arterial infusion of NO agonists, as in quantitative angiography there is a correlation between acetycholine response in coronary arteries and in forearm blood vessels

16 Invasive Endothelial Function Tests

17 Invasive Endothelial Function Tests baseline blood flow after L-NMMA FBF (ml/min pro 100 ml Gewebe) 7 P < baseline Base L-NMMA

18 Non-invasive Endothelial Function Tests Method Principle Applanation tonometry measurement of markers of arterial stiffness (e.g. aortic pulse wave velocity and augmentation index) after β 2 - adrenoceptor stimulation Laser digital Doppler measurement of skin microcirculation during reactive hyperemia or local application of endothelium-dependent vasodilators by iontopheresis

19 Non-invasive Endothelial Function Tests Method Principle Flow-mediated vasodilation most widely used technique to assess endothelial function in-vivo the diameter of the brachial artery is measured after reactive hyperemia causing a release of NO by an increase of shear stress reactive hyperemia is indced by inflation of a sphygmomanometer cuff, which is placed distal to the brachial artery, inflated to 200 mmhg and 5 minutes later released (diameter change 8-11%) accordingly, endothelial-independent vasodilation can be tested after sublingual application of nitroglycerin (diameter change 13-18%)

20 Flow-Mediated Dilation Baseline cuff inflation 60 seconds after release of the cuff 4 minutes after 0,8 mg NG s.l. 4,5 mm FMD = 9% 4,9 mm NDD = 16% 5,2 mm 12MHz

21 Flow-Mediated Dilation FMD is reduced to 0-3% if endothelial dysfunction is present

22 Non-invasive Endothelial Function Tests Method Principle Flow-mediated vasodilation flow-mediated vasodilation was shown to correlate well with invasive measurements of endothelialdependent vasodilation in the coronary circulation accurate performance necessitates experienced operators many environmental factors confound results (e.g. coffee, smoking, exercise, medication, gender, etc.)

23 Event-free surivval (%) FMD and Survival in non-ckd vasodilation p=0.022 vasoconstriction Schächinger et al. Circulation 2000

24 FMD and Survival in ESRD London et al. Kidney Int 2004

25 Intima-Media-Thickness distant arterial wall IMT of internal carotis a. IMT of common carotis a. IMT of the bifurcation

26 Evolution of Atherosclerosis Endothelial dysfunction Intima-media thickening Angina Myocardial infarction Modified after Libby et al. Circulation 1995

27 Endothelial Dysfunction cytokine- and chemokineproduction diabetes hypertension smoking etc. leucocyte rolling adhesion impaired vasodilation NO increased permeability selectins ICAMs enos enos endothelial activation NO ROS cytokines 27

28 Leukocyte Adhesion on Endothelium

29 Leukocyte Adhesion on Endothelium

30 Leukocyte Migration through Endothelium

31 Endothelial (Dys)Function Marker Marker Circulating adhesion molecules Intercellular adhesion molecule 1 (ICAM-1) Vascular cell adhesion molecule 1 (VCAM-1) E-selectin P-selection scd40 Ligand CD146 Cytokines Interleukin 6 Tumor necrosis factor α (TNFα) High-sensitivity C-reactive protein (hscrp) Pentraxin 3 Soluble tumor necrosis factor-like weak inducer of apoptosis (stweak) Endothelin 1 Vascular function Stabilizing endothelial cell-cell interactions Leukocyte transmigration Endothelial adhesion of leukocytes Endothelial adhesion and rolling of leukocytes Endothelial adhesion of leukocytes Recruitment and aggregation of platelets Expressed on CD4 + T-cells and platelets Adhesion to CD40 on endothelial cells Control of endothelial cohesion Endothelial inflammatory activation Production of proinflammatory cytokines Expression of cell adhesion molecules Endothelial inflammatory activation Endothelial inflammatory activation Induction of apoptosis and production of proinflammatory cytokines Contraction of vascular smooth muscle cells

32 Endothelial (Dys)Function Marker Marker Coagulation markers Von Willebrand factor (vwf) sthrombomodulin Tissue factor Vascular function Binding to factor VIII, collagen, platelets Platelet adhesion Cofactor in thrombin-induced activation of protein C Activation of factor X thereby initiation of thrombin formation Other markers ADMA, SDMA Visfatin Adiponectin Circulating cells / particles Endothelial microparticles Endothelial cells Endothelial repair cells Inhibition of endothelial NO production Adipokine Associated with endothelial dysfunction Adipokine Associated with endothelial dysfunction Released in response to proinflammatory stimuli Activation of endothelial cells and coagulation Released during advanced endothelial damage Surrogate marker for endothelial damage Heterogeneous group of cells Repair of injured endothelial layer mainly by paracrine effects

33 ADMA and Endothelial Dysfunction

34 ADMA and Endothelial Dysfunction Segarra et al. Stroke 1999

35 ADMA and Cardiovascular Function * = p<0.05 Cardiac Output infusion of ADMA to healthy volunteers assessment of cardiac indices by right heart catheter * = p<0.05 Systemic Vascular Resistance Kielstein et al. Circulation 2004

36 ADMA and Cardiovascular Outcome in CKD Schwedhelm & Böger. Nat Rev Nephrol 2011

37 ADMA and Renal Outcome in CKD 177 patients with primary kidney disease Fliser et al. J Am Soc Nephrol 2005

PAH-clearance methods these methods together with infusion of

38 ADMA and Kidney Perfusion GFR ERPF ADMA FF L-NAME infusion of ADMA to healthy volunteers assessment of renal indices using inulin- and PAH-clearance methods these methods together with infusion of vasodilators can be used as renal endothelial function tests RVR Kielstein et al. Circulation 2004

39 Thank you!

40 ADMA and AV-shunt restenosis in ESRD 100 patients with AV-shunt dysfunction Wu et al. J Am Soc Nephrol 2009

Classification of Endothelial Dysfunction. Stefano Taddei Department of Internal Medicine University of Pisa, Italy

Classification of Endothelial Dysfunction Stefano Taddei Department of Internal Medicine University of Pisa, Italy Pathogenesis of atherosclerosis from endothelial dysfunction to clinical disease endothelial