Dysfonction Endothéliale, et toxines urémiques des patients dialysés Impact de la convection Ziad A. Massy Ambroise Paré Hospital, University Hospitals Paris Ile de France West, UVSQ, Boulogne Billancourt (Paris), France And INSERM U-1018, CESP, Villejuif(Paris), France
Angiogenèse Fonctions endothéliales Métabolisme Perméabilité vasculaire NO H2S PGI2 Endothéline TXA2 PGH2 Tonus vasculaire Hémostase TM Glycocalyx T-PA TFPI PGI2 vwf TF TXA2 PAI-1 Cellule endothéliale Trafic leucocytaire Inflammation ICAM1, VCAM, E-Selectin, MCP1 Prolifération des cellules musculaires lisses
Cause-specific Deaths in CTT and 4D Baigent, Landray, Wheeler, Sem Dial 2007;20:498-503 Non-vascular CHD Other heart disease Stroke n=90,056 n=1,255 CTT General Population 4D Hemodialysis CTT - Cholesterol Treatment Trialists Lancet 2005;366:1267-1273 4D Study group N Engl J Med 2005: 353; 238-248
Systolic aortic expansion rate (ESAO)
* * * * * * * * Left ventricular mass (LV mass), Isovolumic relaxation time (IVRT), Tei index and Systolic aortic expansion rate (ESAO)
CKD Other varaibles MORTALITY PWV (Temmar et al. J Hypertens 2009)
Cai et al. JASN 2014
Cai et al. JASN 2014
Drueke and Massy Nat Rev Nephrol 2010;6(12):723
Uremic Toxins and Endothelium Dysfunction Chronic Kidney Disease Uremic Toxins (or Toxicities) CKD Progression Endothelium Dysfunction
Phosphate PTH FGF23 Cardiovascular Disease (Endothelium dysfunction, LVH ) Cardiovascular Calcification All-cause and Cardiovascular Mortality
Male Apo E KO mice Ellam et al. ATVB 2011; 31:1988
11 young healthy men Shuto et al. JASN 2009,20:1504
Gross et al. Circ J 2014
Six et al. Cardiovasc Res 2012,96:130
Maizel et al. KI 2013; Apr 17 [Epub ahead of print]
Finch et al. KI 2013; 84:1145-58
Gross et al. Circ J 2014
Gross et al. Circ J 2014
Zoccali et al. JASN 2011
CKD Other Factors IL6 FGF23 PWV (J Hypertens 2009) MORTALITY B2M Myoglobin? AGEs? Calcification (J Hypertens 2009)
Evidence of Intestinal Barrier Dysfunction in CKD Anders et al. KI 2012
Barreto et al, CJASN 2010 *: p < 0.05 vs. IRC stade 2, 3 et 5D : p < 0.05 versus IRC stade 2,3,4 et 5D
Aronov et al. JASN 2011
Effects of p-cresyl sulfate on vasc. reactivity and remodeling Myosin phosphatase target subunit 1 (MYPT1) Gross P et al. J Cell Physiol 2015;230:2927-35
Effects of Indoxyl sulfate (IS) and 3 acetic acid (IAA) on endothelial cells COX2 IS AhR F3,PTGS2 CYP1A1,CYP1A2 Inflammation Coagulation IAA P38 MAPK NF-KB TF NF-KB Endothelial Cell Dou et al. Kidney Int. 2004;65:442-51; and Gondouin et al. Kidney Int. 2013;84:733-44
Rossi et al. Arch Med Res 2014;45:309
CKD Other Factors Free P-cresylsulfate (NDT 2009) PWV (J Hypertens 2009) MORTALITY Total or Free Indoxylsulfate (CJASN 2009) Calcification (J Hypertens 2009)
Indole 3 acetic acid and outcomes 120 CKD patients Dou et al. JASN 2014
Stinghen et al. JASN 2015; [Epub ahead of print]
FMD (% change B.A. diam) FMD (% change B.A. diam) Circulating MPs (per ul) Circulating MPs and Endothelial Function (End-Stage Renal Failure ) Endothelial MPs 2000 1500 ESRF * Platelet MPs 20000 ESRF 15000 * 1000 500 Healthy Patients 10000 5000 Healthy Patients 0 0 Amabile et al., JASN 2005
Survivorship Pronostic value of plasma Endothelial MP end-stage renal disease All-cause mortality Cardiovascular mortality 1.00 1.00 P = 0.030 0.75 0.75 P < 0.0001 0.50 P = 0.02 P < 0.01 0.50 P = 0.015 0.25 2=9.62 P < 0.01 0.25 2=18.5 P < 0.0001 0.00 0 20 40 60 80 Follow-up (months) 0.00 0 20 40 60 80 Follow-up (months) 1 st tertile EMP 2 nd tertile EMP 3 rd tertile EMP Amabile et al. Nephr. Dial. Transpl. 2011, in press
Therapeutic Options RAS inhibition Statins Antioxidants Activator NrF2 Dialysis techniques (HDF) Intestinal absorption
Bellien et al. NDT 2014
Bellien et al. NDT 2014
Bellien et al. NDT 2014
Ariza et al. Blood Purif 2013
Ohtake et al. Ther Aphertesis Dial 2012
Krieter et al. NDT 2010;25:212
Esquivias-Motta et al, HDF and reinfusion Art Org 2016
The Gut: The Forgotten Organ in Uremia Schepers et al. Blood Purif 2010
Vlassara et al. Kidney Int 2013
AST 120 AST120 = oral adsorbant microspheres made from porous carbon material. Clinically used in Japan since 1991 Niwa et al. KI 1997
Six et al. Atherosclerosis 2015
Six et al. Atherosclerosis 2015
AST-120 AND SERUM INDOXYL SULFATE Schulman G. et al, AJKD, 47: 565-577; 2006
AST-120 IMPROVES OUTCOME OF DIALYSIS PATIENTS Ueda et al, Ren Fail, 30, 856-860, 2008
AST 120 : interventional study EPPIC study design : international study No CV endpoint, and no serum Indoxyl sulphate determination Initiation of dialysis Kidney transplantation Doubling of serum creatinine Schulman AJKD 2006 Schulman Poster ASN congress 2012
AST 120 : interventional study EPPIC study design : international study No CV endpoint, and no serum Indoxyl sulphate determination Schulman JASN 2014
Take Home Messages Uremia and the uremic syndrome are the consequence of the retention of more molecules than urea alone Accumulation of uremic toxins favours the development of non-atherosclerotic (arteriosclerosis via endothelial dysfunction) early on, initially even in the absence of atherosclerosis Convective strategies removing middle molecules seem to have survival advantage but studies may be skewed Classical removal strategies have not much impact on protein bound solute removal Concentration may be influenced by affecting their intestinal absorption and/or by conceptual changes in dialysis treatment