Impact des Toxines Urmiques sur les Cellules Endothliales Pr S Burtey Centre de nphrologie et transplantation rnale Marseille

Uremia and Endothelial Cells

Pr S. BurteyCentre de nphrologie et transplantation rnaleVascular Resarch Center MarseilleMarseille

Ladies and gentlemen good morning, I thank the organizators to give the opportunity to talk about the impact of uremic toxins on endothelial cells1

Confluence of interestOtsukaAmgenFreseniusGambroAlexionIm nephrologistI lead a team working on uremic toxins and endothelial cellsJAMA. 2015;314(17):1791-1792

Fear is the enemy of logic.

First my confluenc of interest, i think the main one is that I have a group working on uremic toxins and EC.2

EndotheliumA tissu, in fact numerous tissuesSurface: 3000 to 6000 m2 Thickness: 2 mWeight: 720 g (600 g of capillaries)Each organ has its endotheliumTranscriptomePatterns of ReceptorsAbility to react to an agressionArtery Vs Vein Vs capillary

Physiological Reviews Vol. 89 no. 4, 1269-1339

Endothelium is a real tissue, in fact numerous tissues as the number of organs or subregion in organ. As you know for exemple the glomerular endothelium is different from the peritubular. Endothelium is a large organe but thin organe, its thickness is the thikness of the monolayer of endothelial cell. Each organ have its endothelium with its transcriptomic landscape, its pattern of receptor and various properities. IN addition you could differentiate in each organ arteries, veins endothelium and capollary beds with various functions3

Endothelial Functions

Endothelial CellMetabolism

Angiogenesis

Vascular permeabilityVascular toneControl of vSMC proliferation

NOH2SPGI2EndothelinTXA2PGH2Hemostasis

TMGlycocalyxT-PATFPIPGI2vWFTFTXA2PAI-1InflammationLeucocytes traffic

ICAM1, VCAM, E-Selectin, MCP1

Endothelium controls the vascular tone mainly by the balance betwen nitrous oxyde ad endothelin. It control the vacular permeability and the proliferation of vascular smooth muscle cell. Endothelium plays important role in inflammation mainly by controlin the leucocytes traffic from blood to the tissues. One of its most important fonction is hemostatis. It could produce numerous protein involved in primary hemostasis, coagulation and fibrinolysis. Finally it plays a role in angiogenesis normal and pathologic and the metabolism of tissues via its permability.4

Endothelial dysfunctionA defect of endothelium to produce NO.

Evaluation: Flow-mediated vasodilatation et Tonometry (Tousoulis et al. Pharmacology & Therapeutics 144 (2014) 253267)Biomarkers (Walczak et al. Pharmacological Reports 67 (2015) 771777)

Furchgott, Nobel 1998Healthy Endothelium

Vasodilatator (NO,H2S, PGI2)Minimal oxydative stressAnticoagulant (t-Pa, TFPI, Glycocalyx)Anti-inflammatoryBalance lesion-regeneration in favor of regenerationUnhealthy Endothelium

Defect in VasodilatationIncreased oxydative stressProcoagulant (vWF, Tissue Factor, PAI-1)Pro-inflammatory (ICAM,VCAM, E-Selectin, MCP-1, IL6, TNF)Reduced regeneration potentienal (reduced number of progenitors, Increase in eMP )Lost of glycocalyx (endocan)

HyperglycemiaBlood PressureTurbulent flowOx-LDLInflammationTobaccoROSAGEsObesityAging

Endothelium could dysfunction, the main marker of it its inability to produce NO. In fact it could be better to talk of a transition from an healthy to an unhealthy endothelume. Healthy iis vasodilatation the unhealthy is defective, the healthy have a low level of oxydative stress, and it avoid formation of clots the unhealthy is clearly procoagulant and proinflamatory. And fiany the balance between lesion and regenration and lost of glycocalyx. Numerous causes could induce activation of endothelium frome physiological like aging to exposur to tobacco.You could evaluate the health of the endotheiluum by its ability to release NO and you study the flow mediated vasodilatation or you measure various biomarkers produce by unhealthy endothelium.5

Clinical impact of endothelial dysfunction

World J Cardiol 2014; 6(8): 824-835

In general population there is a large amount of studies showing a relation betwen endothelial dysfunction and cardiovascular risk.6

Why nephrologist must be aware of endothelium ?

As you know CKD is associated with an increased cardiovascular risk. The traditionnal risk factor di not explain the overrisk. So major endothelial dysfunction could be a mediator of CV risk during CKD. 7

Is the endothelium dysfunctionnal during CKD?Yes and at each stage.

Hirata et al. International Journal of Cardiology 173 (2014) 481486eGFR: 50 ml/mn

Chen et al. PLoS ONE 2015 10(7): e0132047eGFR: 43 ml/mnJourde-Chiche et al. Seminars in dialysis 2011 p327337

Recio-Mayoral et al. / Atherosclerosis 216 (2011) 446451

Verbeke et al. Clin J Am Soc Nephrol 6: 20092015, 2011

The endothelium during CKD is unhealthy and associated with and increase risk of CV events. The level of dysfunction prodress with CKD and regress with successful kidney transplantation.8

Unhealthy endothelium and AVF

Hemodialysis Fistula Maturation Study Group

Resistance to NO

IN addition it is also associated with the risk of dysfunctionnal arteriovenous fistula in human and rodents. As you can see. The severity of ED is associated with a reduced diameter and flow in the AVF interestingly the same results was observed in rat with CKD compared to control. SO endothelium could control the patency of vascular access.9

Endothelial dysfunction during CKDUremic Toxins

Healthy Endothelium

Vasodilatator (NO,H2S, PGI2)Minimal oxydative stressAnticoagulant (t-Pa, TFPI, Glycocalyx)Anti-inflammatoryBalance lesion-regeneration in favor of regenerationMalfunctionning Endothelium

Defect in VasodilatationIncreased oxydative stressProcoagulant (vWF, Tissue Factor, PAI-1)Pro-inflammatory (ICAM,VCAM, E-Selectin, MCP-1, IL6, TNF)Reduced regeneration potentienal (reduced number of progenitors, Increase in eMP )Lost of glycocalyx (endocan)

HyperglycemiaBlood PressureTurbulent flowOx-LDLInflammationTobaccoROSAGEsObesityAging

During CKD beside traditionnals aggresors of the endotelium one unique is present: the uremic toxins10

One of the strongest proof is given by the kidney donor.

Rossi et al. Transplantation 2014;97: 548Y554)

The best proof of the role of the uremic toxins could induced endothelial dysfunction is provide by this australian study. They measure two uremic toxin and endothelial function in kidney donor and they observed n increase of uremic toxins and an impaired endothelium function.

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Uremic ToxinsGlomerular flow rate decline is associated with retention of solutes:Negative interactions with biological functionsAssociation with clinical eventsThree familiesFree water-soluble low molecular mass compounds (