HEMODIAFILTRATION. R Vanholder University Hospital, Gent, Belgium Universitair Ziekenhuis Gent

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1 HEMODIAFILTRATION R Vanholder University Hospital, Gent, Belgium

2 UREMIC SOLUTES LISTED Vanholder et al, KI, 63: ;

3 UREMIC SOLUTES LISTED Vanholder et al, KI, 63: ;

4 UREMIC SOLUTES LISTED Vanholder et al, KI, 63: ;

5 UREMIC SOLUTES LISTED Vanholder et al, KI, 63: ;

6 UREMIC SOLUTES LISTED Small water soluble compounds (<500D): 1-Methyladenosine, 1-Methylguanosine, 1-Methylinosine, ADMA, -Keto-guanidinovaleric acid, -N-acetylarginine, Arab(in)itol, Argininic acid, Benzylalcohol, ß- guanidinopropionic acid, Creatine, Creatinine, Cytidine, Dimethylglycine, Erythritol, - guanidinobutyric acid, Guanidine, Guanidinoacetic acid, Guanidonosuccinic acid, Hypoxanthine, Mannitol, Methylguanidine, Myoinositol, N4-acetylcytidine, N6-methyladenosine, Orotic acid, Orotidine, Oxalate, Phenylacetylglutamine, Pseudouridine, SDMA, Sorbitol, Taurocyamine, Threitol, Thymine, Uracil, Urea, Uric acid, Uridine, Xanthine, Xanthosine Protein-bound molecules: 2-Methoxyresorcinol, 3-deoxyglucosone, CMPF, Dimethylguanosine, Fructoselysine, Glyoxal, Hippuric acid, Homocysteine, Hydroquinone, Indole-3-acetic acid, Indoxyl sulfate, Interleukin 1ß, Interleukin 6, Kinurenine, Kynurenic acid, Leptin, Melatonin, Methylglyoxal, N- (carboxylmethyl)lysine, P-cresol, Pentosidine, Phenol, Phenylacetic acid, Phenylethylamine, P- OHhippuric acid, Putrescine, Quinolinic acid, Retinol binding protein, S-nitrosothiol, Spermidine, Spermine, Thiocyanate, Tumor Necrosis Factor Middle molecules (>500D): Adrenomedullin, Atrial natriuretic peptide, ß2-microglobulin, ß- endorphin, Cholecystokinin, Clara cell protein, Complement factor D, Cystatin C, Degranulation inhibiting protein I, Delta-sleep inducing peptide, Endothelin (ng/l), Ghrelin, Hyaluronic Acid, Interleukin 1ß, Interleukin 6, Interleukin-18, -Ig light chain, -Ig light chain, Leptin, MC-SF, Methionine-enkephalin, Neuropeptide Y, Orexin A, Parathyroid hormone, Retinol binding protein, Tumor Necrosis Factor Vanholder et al, KI, 63: ;

7 THE MIDDLE MOLECULES

8 PRE-DIALYSIS β2-m VS. OUTCOME HEMO- STUDY Cheung et al, JASN, 17: ;

9 Β2-MICROGLOBULIN MIGHT BE PARTLY INERT Neirynck et al, J Ren Nutr, 23: ;

10 Β2-MICROGLOBULIN MIGHT BE PARTLY INERT hb2m: unpurified dbm: dialysed D: dialysate Figure 3. Effects of hb2m, db2m, and dialysates on bursttest after stimulation with (A-C) E. coli and (D-F) with PMA show that db2m had no longer an effect on free radical production whereas d1 had similar effects as hb2m. PMA, phorbol myristate acetate; co, control (saline); LPS 1.5, lipopolysaccharide 1.5 endotoxin units (EU)/mL; hb2m, human b2 microglobulin (unpurified); db2m, dialyzed (purified) b2- microglobulin; 10, 10 mg/l; 50, 50 mg/l; d1, dialysate collection after 30 minutes (0-30 min); d2: dialysate at end (10h30-11h30), * P, 0.05, ** P, 0.01, *** P, vs.co,p, 0.05,P, 0.01,P, vs LPS, # P, 0.05, ### P, vs db2m10, 1 P, 0.05, 111 P, vs db2m50, P, 0.05, P, vs d2; Kruskall-Wallis 1 pairwise comparisons. Neirynck et al, J Ren Nutr, 23: ;

11 Background Peripheral arterial disease (PAD) is common but commonly unrecognized. Improved recognition of PAD is needed. We used high-throughput proteomic profiling to find PAD-associated biomarkers. Methods and Results Plasma was collected from PAD patients (ankle brachial index of 0.90; n45) and subjects with risk factors but without PAD (n43). Plasma was analyzed with surfaceenhanced laser desorption/ionization time-of-flight mass spectrometry to quantify 1619 protein peaks. The peak intensity of a 12-kDa protein was higher in PAD patients. Western blot analyses and immunoaffinity studies confirmed that this protein was 2-microglobulin (B2M). In a validation study, B2M was measured by ELISA in plasma in age- and gender-matched PAD (n20) and non-pad (n20) subjects. Finally, we studied a larger cohort of subjects (n237) referred for coronary angiography but without known PAD. Plasma B2M levels were higher in PAD patients than in non-pad patients with coronary artery disease. Plasma B2M correlated with ankle brachial index and functional capacity. Independent predictors of PAD were diabetes mellitus, age, and the combination of B2M and C- reactive protein level. Conclusions In PAD patients, circulating B2M is elevated and correlates with the severity of disease independent of other risk factors. These findings might provide a needed biomarker for PAD and new insight into its pathophysiology. Further studies in other populations are needed to confirm the utility of measuring B2M in cardiovascular disease risk assessment. A.M. Wilson et al, Circulation. 2007;116:

12 AND ALSO Association with arterial stiffness in the general population Sajio, Hypertens Res, 2005 Association with bone turnover in hemodialysis patients Ferreira et al, NDT, 1995 Association with bone resorption in non-ckd post-menopausal women Ripoll et al, Eur J Clin Invest, 1996 Enhancement of bone resorption in mice Menaa et al, KI,

13 IL-6 AND MORTALITY IN CKD (a) Kaplan Meyer estimates of overall mortality for all patients (n=125) as a function of median plasma IL-6 levels. (b) Kaplan Meyer estimates of cardiovascular mortality for all patients (n=125) as a function of median plasma IL-6 levels. Barreto et al, KI, 77: ;

14 FGF-23: PATHO-PHYSIOLOGIC ROLE Larsson, NDT, 25: ;

15 PROGRESSION CKD VS. FGF-23 Kaplan-Meier curves of renal end points in patients with below and above optimal cutoff of plasma c-terminal (A) FGF23 concentrations and for intact (B) FGF23 concentrations below and above the median Fliser et al, JASN, 18: ;

16 PROGRESSION CKD VS. FGF-23 a Data are means ± SD and 25th, 50th (median), and 75th percentiles for skewed variables where appropriate. Fliser et al, JASN, 18: ;

17 ODDS OF DEATH VS. FGF-23 QUARTILES Guttierrez et al, NEJM, 359: ;

$FGF-23 AND LEFT VENTRICULAR DYSFUNCTION Figure 2 Fibroblast growth factor 23 levels after stratifying for the ejection fraction and for presence of$

18 FGF-23 AND LEFT VENTRICULAR DYSFUNCTION Figure 2 Fibroblast growth factor 23 levels after stratifying for the ejection fraction and for presence of left-ventricular hypertrophy in individuals in the total study cohort. Data are presented as mean ± SEM. Seiler et al, Eur Heart J, 32: ;

19 FGF-23: MORE THAN A SIMPLE MARKER Faul et al, J Clin Invest, 121: ;

20 EFFECT OF SPECIFIC AGEs ON LEUKOCYTE CL-RESPONSE Glorieux et al, KI, 66: ;

21 LEPTIN INDUCES TISSUE FACTOR ACTIVATION Napoleone et al J Thromb Haemost, 5: ;

22 MM WITH BIOLOGICAL POTENTIAL Adrenomedullin AGE Angiogenin AOPP Atrial natriuretic peptide Cholecystokin Clara cell protein Complement factor D Cystatin C Cytokines Delta sleep inducing protein Endothelin -Endorphin Ghrelin Glomerulopressin GIP I GIP II Leptin -Lipotropin Macrophage-colony-stimulating factor Methionine-enkephalin ß 2 -Microglobulin Neuropeptide Y Orexin A Retinol binding protein Red: pro-inflammatory 22 22

23 MM WITH BIOLOGICAL POTENTIAL Adrenomedullin Adiponectin AGE Angiogenin AOPP Atrial natriuretic peptide Cholecystokin Clara cell protein Cholecystokinin Complement factor D Cystatin C Cytokines Delta sleep inducing protein Endothelin -Endorphin Ghrelin Glomerulopressin GIP I GIP II Leptin -Lipotropin Macrophage-colony-stimulating factor Methionine-enkephalin ß 2 -Microglobulin Neuropeptide Y Orexin A Pentraxin-3 Peptide YY Prolactin Resistin Retinol binding protein Visfatin Red: pro-inflamatory or anorexic Green: new Carrero et al,sem Nephrol, in press 23 23

24 PROTEIN BOUND UREMIC TOXINS R Vanholder University Hospital, Gent, Belgium

25 PROTEIN BOUND UREMIC TOXINS Indoxylsulfate P-cresylsulfate Indoxylglucuronide P-cresylglucuronide Phenylacetic acid Hippuric acid P-OHhippuric acid Homocysteine 25 25

26 AN INCREASING NUMBER OF PUBLICATIONS Neirynck et al, Int Urol Nephrol, 45: ;

27 1 st Author, year, ref Country Cell/organ system toxin concentration albumin 1) In vitro, albumin Dou, 2004 {207} France Endothelium IS mg/l 4 g/l Odamaki, 2004 {205} Japan Hepatocytes IS mg/l 4 g/l Faure, 2006 {194} France Endothelium IS 256 mg/l 4 g/l Yamamoto, 2006 {191} Japan Smooth muscle cells IS µm 4 g/l Dou, 2007 {170} France Endothelium IS mg/l 4 g/l Schepers, 2007 {183} Belgium Leukocytes PCS mg/l Whole blood Itoh, 2012 {12} Japan Endothelium IS mg/l 4 g/l Chitalia, 2013 {394} USA Smooth Muscle Cells IS 25 mg/l 4 g/l 2) In vitro, low Tsujimoto, 2010 {91} Japan Liver Microsomes IS 30 µm - Lekawanvijit, 2010 {113} Australia Cardiac Fibroblasts / Myocytes IS > 1µM - Yu, 2011 {86} S-Korea Endothelium IS mg/l - (no m) Sun NDT, 2012 {5} Taiwan Proximal Tubular Cells IS, PCS 1 & 5 mg/l - Sun Plos1, 2012 {10} Taiwan Proximal Tubular Cells IS, PCS > 1 mg/l - Sun, 2012 {17} Taiwan Proximal Tubular Cells IS, PCS IPCS & IS 1&5 - (no m) mg/l Tsujimoto, 2012 {396} Japan Intestinal Cells (hepatic no effect) IS 20 µmol - Vanholder et al, JASN, in press 27 27

28 1 st Author, year, ref Country Cell/organ system toxin concentration albumin 3) Animal Adijang, 2008 {159} Japan Aorta, kidney IS 23.1 mg/l rat Ito, 2010 {83} Japan Endolium/leukocyte interaction IS 15.7 mg/l mouse Adijang, 2010 {94} Japan Aorta IS mg/l rat Bolati, 2011 {44} Japan Proximal Tubular Cells IS mg/l rat Sun Plos1, 2012 {10} Taiwan Proximal Tubular Cells IS, PCS? No mouse concentration Watanabe, 2012 {392} Japan Renal Tubular Cells PCS 32.6 mg/l rat Sun, 2012 {17} Taiwan Proximal Tubular Cells IS, PCS IS 8.5, PCS 5.6 mouse mg/l Shimizu, 2012 {14} Japan Proximal Tubular Cells IS mg/l rat Vanholder et al, JASN, in press 28 28

29 P-CRESYLSULFATE INDUCES INSULIN RESISTANCE Koppe et al, JASN, 24: 88-99;

30 P-CRESYLSULFATE INDUCES INSULIN RESISTANCE Koppe et al, JASN, 24: 88-99;

31 P-CRESYLSULFATE INDUCES INSULIN RESISTANCE Koppe et al, JASN, 24: 88-99;

32 Pletinck et al, JASN, doi: /ASN

33 LEUKOCYTE RECRUITMENT IS ENHANCED IN RESPONSE TO LPS (1), IS (2), pcs and pcspcg (3) Pletinck et al, JASN, 24, ,

34 RED BLOOD CELL VELOCITY IS HAMPERED IN INDOXYLSULFATE TREATED RATS Pletinck et al, JASN, 24, ,

35 INTRAVITAL MICROCOPY Pletinck et al, JASN, 24, ,

36 INTRAVITAL MICROCOPY CONTROL INDOXYLSULFATE Pletinck et al, JASN, 24, ,

37 Pletinck et al, JASN, 24, ,

38 INDOXYL SULFATE + P-CRESYL SULFATE: OUTCOME 38 38

39 INDOXYL SULFATE + P-CRESYL SULFATE: OUTCOME 39 39

40 INDOXYL SULFATE + P-CRESYL SULFATE: OUTCOME Rev Diabet stud, 7: ;

41 INDOXYL SULFATE + P-CRESYL SULFATE: OUTCOME Rev Diabet stud, 7: ;

42 INDOXYL SULFATE + P-CRESYL SULFATE: OUTCOME Rev Diabet stud, 7: ;

43 INDOXYL SULFATE + P-CRESYL SULFATE: OUTCOME Rev Diabet stud, 7: ;

44 INDOXYL SULFATE + P-CRESYL SULFATE: OUTCOME Rev Diabet stud, 7: ;

45 INDOXYL SULFATE + P-CRESYL SULFATE: OUTCOME Rev Diabet stud, 7: ;

46 INDOXYL SULFATE + P-CRESYL SULFATE: OUTCOME Rev Diabet stud, 7: ;

47 INDOXYL SULFATE + P-CRESYL SULFATE: OUTCOME Rev Diabet stud, 7: ;

48 INDOXYL SULFATE + P-CRESYL SULFATE: OUTCOME Rev Diabet stud, 7: ; 2010 Clin J Am Soc Nephrol 4: ;

49 INDOXYL SULFATE + P-CRESYL SULFATE: OUTCOME Rev Diabet stud, 7: ; 2010 Clin J Am Soc Nephrol 4: ;

50 INDOXYL SULFATE AND SURVIVAL Kaplan-Meyer estimates of overall mortality for patients as a function of tertiles for serum IS levels Number of patients at risk Barreto et al, CJASN, 4: ;

51 REMOVAL

52 OSTEOCALCIN AND MYOGLOBIN Maduell et al, AJKD, 40: ;

53 POST-DILUTION HEMODIAFILTRATION IS SUPERIOR TO PREDILUTION HEMODIAFILTRATION AND HIGH FLUX DIALYSIS FOR REMOVAL OF MIDDLE MOLECULES Meert et al, NDT, 26: ;

54 EVOLUTION OF 2-M OVER TIME Locatelli et al, KI, 50: ;

55 mg/l mg/l ß2-MICROGLOBULIN IS LOWER WITH HIGH-FLUX 4g/dl Alb Total * * * * * High-flux Month Low-flux *Changes vs. month 0 are significantly different (p<0.05) between LF and HF from month 12 onwards * * * * * High-flux Month Low-flux Locatelli et al, JASN, 20: ;

4 hrs 4 hrs 6 hrs 8 hrs P QB and QD 72L 72L 72L NS Kt/V 1.

56 INCREASING LENGTH OF DIALYSIS WITHOUT CHANGING ANY OTHER PARAMETER IMPROVES REMOVAL Percentage change vs. 4 hrs 4 hrs 6 hrs 8 hrs P QB and QD 72L 72L 72L NS Kt/V NS Eloot et al, KI, 73: ;

57 HEMODIAFILTRATION (POST AND PRE) IS SUPERIOR TO PREDILUTION HEMOFILTRATION AND HIGH FLUX DIALYSIS FOR REMOVAL OF PROTEIN BOUND TOXINS Meert et al, NDT, 24: ;

58 OUTCOME STUDIES

59 Convective treatments and risk of mortality adapted from Pozzoni et al. J Nephrol 17 Suppl, 8:S87-S95;

60 Survival of patients (%) KAPLAN-MEIER SURVIVAL ANALYSIS 4g/dl Al Figure 7 : Survival time - whole study time - Albumin <= 4 - Kaplan-Meier analysis - Intention-to-treat, n= failed censored P= High-flux membrane Low-flux membrane No. at risk Months since month 0 High-flux Low-flux Locatelli et al, JASN, 20: ;

61 Kaplan Meier Survival Analysis Subgroup Analysis Diabetics (Alb 4 g/dl) 61 61

62 % Patients with Serum Albumin < 4 g/dl Data from the DOPPS Study 62 62

63 Increasing incidence of Diabetes mellitus as PRD Data from 10 European registries Van Dijk et al. Kidney Int 67: ;

64 HEMODIAFILTRATION: SURVIVAL ADVANTAGE VS. HEMODIALYSIS ESHOL- trial Substitution volume: L Death: 22.8% HR: 0.7 [ ] Maduell et al, JASN, 24, ,

65 CONCLUSIONS Several of the larger middle molecules and of the protein bound molecules have the potential for biological (toxic) effects, especially on the cardiovascular system

66 CONCLUSIONS Several of the larger middle molecules and of the protein bound molecules have the potential for biological (toxic) effects, especially on the cardiovascular system. Larger middle molecules are better removed by increasing dialyzer pore size (high-flux)

67 CONCLUSIONS Several of the larger middle molecules and of the protein bound molecules have the potential for biological (toxic) effects, especially on the cardiovascular system. Larger middle molecules are better removed by increasing dialyzer pore size (high-flux). Removal of those molecules is further enhanced by using the same dialyzers in a convective mode and/or by increasing dialysis length

68 CONCLUSIONS Several of the larger middle molecules and of the protein bound molecules have the potential for biological (toxic) effects, especially on the cardiovascular system. Larger middle molecules are better removed by increasing dialyzer pore size (high-flux). Removal of those molecules is further enhanced by using the same dialyzers in a convective mode and/or by increasing dialysis length. Also protein bound uremic solutes are better removed in a convective mode, be it less spectacularly than the middle molecules

69 CONCLUSIONS Several of the larger middle molecules and of the protein bound molecules have the potential for biological (toxic) effects, especially on the cardiovascular system. Larger middle molecules are better removed by increasing dialyzer pore size (high-flux). Removal of those molecules is further enhanced by using the same dialyzers in a convective mode and/or by increasing dialysis length. Also protein bound uremic solutes are better removed in a convective mode, be it less spectacularly than the middle molecules. Clinical outcome studies suggest that increasing dialyzer pore and adding convection might improve outcomes

UREMIC TOXINS / MICROBIOME

UREMIC TOXINS / MICROBIOME R Vanholder University Hospital, Gent, Belgium COMPLEX PATHO-PHYSIOLOGY Ikizler et al, KI, 84: 1096-1107; 2013 2 2 UREMIC TOXINS NUTRITION 3 3 THE IMPACT OF NUTRITION ON THE