UREMIC TOXINS / MICROBIOME

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1 UREMIC TOXINS / MICROBIOME R Vanholder University Hospital, Gent, Belgium

2 COMPLEX PATHO-PHYSIOLOGY Ikizler et al, KI, 84: ;

3 UREMIC TOXINS NUTRITION 3 3

4 THE IMPACT OF NUTRITION ON THE UREMIC SYNDROME

5 UREMIC TOXINS NUTRITION 5 5

6 ROLE INTESTINE IN GENERATION CRESOLS p-cresol thyrosine intestinal flora intestinal wall liver p-cresylsulfate p-cresylglucuronide Schepers et al, Blood Purif, 29: ;

7 Vanholder et al, JASN, 25: ;

8 FLOW CHART REVIEW PROCEDURES Figure 1. Flowchart of the review procedure and quality scoring. Vanholder et al, JASN, 25: ;

9 INDOXYLSULFATE AND P-CRESYLSULFATE HAVE BEEN LINKED TO A MYRIAD OF TOXIC EFFECTS: Leukocyte activation Endothelial morphological and functional changes Endothelial/leukocyte interaction Smooth muscle cell proliferation Whole vessel calcification & senescence Cardiac fibrosis and myohypertrophy Skeletal resistance to PTH Insulin resistance Renal tubular damage 9 9

10 COMMON PATHWAYS IN ENDOTHELIUM Vanholder et al, JASN, 25: ;

11 TMAO ENHANCES ATHEROGENESIS Wang et al, Nature, 472: 57-63;

12 TMAO ENHANCES ATHEROGENESIS Metabolomic analysis unraveled TMAO as linked to vascular disease Sources of TMAO: Choline, fosfatidyl choline, betaine Red meat, shellfish, eggs, dairy products Wang et al, Nature, 472: 57-63;

13 TMAO ENHANCES ATHEROGENESIS Role of intestinal microbiota: effect precursors TMAO neutralized by antibiotics Wang et al, Nature, 472: 57-63;

14 TMAO CLEARANCE BY DIALYSIS IS IN THE RANGE OF OTHER SMALL WATER SOLUBLE COMPOUNDS Hai et al, Plos One, e ,;

15 TMAO CLEARANCE BY DIALYSIS IS IN THE RANGE OF OTHER SMALL WATER SOLUBLE COMPOUNDS Urea Creatinine TMAO Normals* 55 ± ± ±78 ESRD** 258 ± ± ±72 *: renal clearance; **: dialyzer clearance Hai et al, Plos One, e ,;

16 INDOXYL SULFATE + P-CRESYL SULFATE: OUTCOME Clin J Am Soc Nephrol 4: ;

17 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: ;

18 PROOF OF CONCEPT

19 PLASMA PROTEIN BOUND SOLUTES ARE DECREASED IN GERMFREE MICE Wikoff et al, PNAS, 106: ;

20 PLASMA PROTEIN BOUND SOLUTES ARE DECREASED IN GERMFREE MICE Fig. 3. Sulfate profiling based on constant neutral loss scanning of 80 m/z in ESI mode for conv (Upper) and GF (Lower) pooled plasma samples. The m/z values for several species are listed above their respective peak. Identified sulfates include: phenyl sulfate (a), indoxyl sulfate (b), p-cresol sulfate (c), equol sulfate (d), and methyl equol sulfate (e). Wikoff et al, PNAS, 106: ;

21 THE COLON CONTRIBUTES TO UREMIC TOXIN GENERATION Aronov et al, JASN, 22: ;

22 THE COLON CONTRIBUTES TO UREMIC TOXIN GENERATION Aronov et al, JASN, 22: ;

23 THE COLON CONTRIBUTES TO UREMIC TOXIN GENERATION Aronov et al, JASN, 22: ;

24 THE COLON CONTRIBUTES TO UREMIC TOXIN GENERATION Aronov et al, JASN, 22: ;

25 BUT THERE IS MORE THAN THAT

26 INTESTINAL MICROBIOTA ARE MODIFIED IN CKD Vaziri et al, KI, 83: ;

Fig. 4 - Hierarchical clustering of probe sets representing significantly different operational taxonomic units (OTUs) between groups with a minimum two-fold change in untransformed intensities

27 Fig. 4 - Hierarchical clustering of probe sets representing significantly different operational taxonomic units (OTUs) between groups with a minimum two-fold change in untransformed intensities between samples to show relative abundance. Yellow indicates increased abundance and red indicates decreased abundance relative to the mean for each OTU. Columns represent rat fecal microbiota composition for control (CTL) and chronic renal failure (CRF) individual rats. Rows are OTUs with mean fold change among samples and cluster based on the similarity of their abundance profiles across the data set, with similar OTUs connected at the hierarchical tree on the left. Bars on the right represent (1) OTUs from the Firmicutes (especially Lactobacillaceae and a few Coprococcus within the Lachnospiraceae), Bacteroidetes (Prevotellaceae, two Rikenellaceae OTUs) that had higher abundances in CTL samples, or (2) OTUs from the Firmicutes (unclassified Lachnospiraceae) and other Rikenellaceae (in Bacteroides) that have higher abundances in CRF samples. Vaziri et al, KI, 83: ;

28 CHANGES IN ASSIMILATION MODIFY THE GENERATION OF P-CRESYLSUFATE Bammens et al, KI, 64: ;

CHANGES IN ASSIMILATION MODIFY THE GENERATION OF P-CRESYLSUFATE Group A: GFR > 60 Group B: GFR 30-60 Group C: GFR < 30 (A) The median values of urinary p-cresol output (mg/24 hours) in the

29 CHANGES IN ASSIMILATION MODIFY THE GENERATION OF P-CRESYLSUFATE Group A: GFR > 60 Group B: GFR Group C: GFR < 30 (A) The median values of urinary p-cresol output (mg/24 hours) in the three study groups. (B) The median values of the urinary p-cresol (mg/24 hours)/urinary urea nitrogen (g/24 hours) ratio. *P < 0.05 vs. group A. Bammens et al, KI, 64: ;

30 CKD DISTURBS INTEGRITY OF THE INTESTINAL EPITHELIUM Vaziri et al, NDT, 27: ;

31 CKD DISTURBS INTEGRITY OF THE INTESTINAL EPITHELIUM Vaziri et al, NDT, 27: ;

32 CKD IS ASSOCIATED WITH TRANSLOCATION OF GUT BACTERIAL DNA GUT GENUS DETECTED IN BLOOD (% OF TOTAL GUT GENUS) Wang et al, Nephrology, 17: ;

33 CKD IS ASSOCIATED WITH TRANSLOCATION OF GUT BACTERIAL DNA GUT GENUS DETECTED IN BLOOD (% OF TOTAL GUT GENUS) Wang et al, Nephrology, 17: ;

34 CKD IS ASSOCIATED WITH TRANSLOCATION OF GUT BACTERIAL DNA GUT GENUS DETECTED IN BLOOD (% OF TOTAL GUT GENUS) Controls (n=10) ESRD (n=30) Klebsiella spp Proteus spp Escherichia spp Enterobacter spp Pseudomonas spp P Wang et al, Nephrology, 17: ;

35 THERAPEUTIC OPTIONS Diet Cave malnutrition Prebiotics Non-digestible compounds beneficially modifying composition and/or function of intestinal flora Probiotics Bacteria adminstered as food components or supplements providing specific benefits themselves Synbiotics Prebiotics + probiotics Sorbents Schepers et al, Blood Purif, 29: ;

36 Vanholder and Glorieux, Clin Kidney J, 8: ;

37 Unfortunately, the quality and the evidence base of many of these studies are debatable, especially in uraemia, and often results within one study or among studies are contradictory. Vanholder and Glorieux, Clin Kidney J, 8: ;

38 URINARY PROTEIN BOUND TOXINS ARE LOWER IN VEGETARIANS Patel et al, cjasn, 7: ;

39 URINARY PROTEIN BOUND TOXINS ARE LOWER IN VEGETARIANS Table 2. Urinary excretion of PCS and IS Vegetarian Unrestricted P Value (Vegetarian versus Unrestricted) Period 1 Period 2 Period 1 Period 2 Period 1 Period 2 PCS (mg/d per 1.73 m2) 30 (11 74) 23 (17 47) 100 (47 124) 95 (20 124) IS (mg/d per 1.73 m2) 24 (12 42) 19 ( 17 26) 47 (40 59) 52 (39 58) <0.001 Patel et al, cjasn, 7: ;

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

41 PREBIOTIC AXOS REDUCES P-CRESYLSULFATE AND CORRECTS UREMIC INSULIN RESISTANCE IN MICE Koppe et al, JASN, 24: 88-99;

42 DECREASE UREMIC TOXINS WITH SYNBIOTICS: RCT Rossi et al, cjasn, 11: ;

43 DECREASE UREMIC TOXINS WITH SYNBIOTICS: RCT IS - AB FREE (N=21) IS -TOTAL (N=31) PCS - AB FREE (N=21) PCS - TOTAL (N=31) Figure 3. Treatment effect of synbiotics on serum uremic toxins in all completing patients (n=31) and patients who were antibiotic free (n=21). a Treatment effect (95% confidence interval) derived from regression modeling accounting for period effect. *P=0.03; **P= Rossi et al, cjasn, 11: ;

44 REMOVAL OF INDOXYLSULFATE BY AST-120 PROTECTS GLOMERULAR FILTRATION RATE Akizawa T. et al, AJKD, 54: ;

45 egfr, relative to baseline REMOVAL OF INDOXYLSULFATE BY AST-120 PROTECTS GLOMERULAR FILTRATION RATE AST-120 Control Time (weeks) P<0.001 Akizawa T. et al, AJKD, 54: ;

46 AST-120 HAS NO PROTECTIVE EFFECT ON KIDNEY FUNCTION Schulman et al, JASN, 26: ;

47 AST-120 HAS NO PROTECTIVE EFFECT ON KIDNEY FUNCTION Schulman et al, doi: /ASN

48 AST-120 DOES NOT IMPACT ON PROGRESSION OF CKD Cha et al, cjasn, 2016, doi: /CJN

49 AST-120 DOES NOT IMPACT ON PROGRESSION OF CKD Progression (primary endpoint): - Screa x 2 - egfr / 2 - ESRD Figure 2. Occurrence of composite primary outcomes in each treatment arm. Log-rank P=0.45. Cha et al, cjasn, 2016, doi: /CJN

50 NOT DISCUSSED Uric acid Urea Advanced glycation end products Guanidines Other protein bound solutes (apart from indoxyl sulfate: e.g. p- cresyl sulfate, p-oh-hippuric acid, phenylacetic acid) Phenylacetylglutamine 50 50

51 NOT DISCUSSED Uric acid Urea Advanced glycation end products Guanidines Other protein bound solutes (apart from indoxyl sulfate and p- cresyl sulfate: p-oh-hippuric acid, phenylacetic acid) Phenylacetylglutamine 51 51

52 CONCLUSIONS The intestine plays a crucial role in the generation of uremic toxins 52 52

53 CONCLUSIONS The intestine plays a crucial role in the generation of uremic toxins This effect is further enhanced by: 53 53

54 CONCLUSIONS The intestine plays a crucial role in the generation of uremic toxins This effect is further enhanced by: Intestinal overgrowth of bacteria 54 54

55 CONCLUSIONS The intestine plays a crucial role in the generation of uremic toxins This effect is further enhanced by: Intestinal overgrowth of bacteria Disturbances of the intestinal epithelial barrier 55 55

56 CONCLUSIONS The intestine plays a crucial role in the generation of uremic toxins This effect is further enhanced by: Intestinal overgrowth of bacteria Disturbances of the intestinal epithelial barrier Translocation of intestinal microbiota 56 56

57 CONCLUSIONS The intestine plays a crucial role in the generation of uremic toxins This effect is further enhanced by: Intestinal overgrowth of bacteria Disturbances of the intestinal epithelial barrier Translocation of intestinal microbiota The results of therapeutic interventions to modify uremic toxin uptake via the intestine up to now have been deceiving but quality of most studies may be a matter of debate 57 57

58 Back-ups

59 MULTIFACTORIAL ANALYSIS: SOLUTE CONCENTRATION VS. VARIOUS FACTORS Eloot et al, Plos One, 8: e76838;

60 MULTIFACTORIAL ANALYSIS: SOLUTE CONCENTRATION VS. VARIOUS FACTORS Solute Covariates / R² full model Urea Normalized protein catabolic rate / Crea Normalized protein catabolic rate / Asymmetric dimethylarginine Symmetric dimethylarginine Uric acid Normalized protein catabolic rate / beta-2-microglobulin Residual renal function/ Hippuric acid Residual renal function / Normalized protein catabolic rate / Indoxyl sulfate Residual renal function / Indole acetic acid p-cresylsulfate Normalized protein catabolic rate / p-cresylglucuronide Residual renal function / Normalized protein catabolic rate / carboxy-4-methyl-5-propyl-2- furanpropionic acid age / Free hippuric acid Residual renal function / Free indoxyl sulfate Residual renal function / Free indole acetic acid Residual renal function / Free p-cresylsulfate Normalized protein catabolic rate / Residual renal function / Free p-cresylglucuronide Residual renal function / Normalized protein catabolic rate / Included: Age, gender, npcr, Kt/V, RRF, diabetes, body weight, vintage Eloot et al, Plos One, 8: e76838;

61 MULTIFACTORIAL ANALYSIS: SOLUTE CONCENTRATION VS. VARIOUS FACTORS Solute Covariates / R² full model Urea Normalized protein catabolic rate / Crea Normalized protein catabolic rate / Asymmetric dimethylarginine Symmetric dimethylarginine Uric acid Normalized protein catabolic rate / beta-2-microglobulin Residual renal function/ Hippuric acid Residual renal function / Normalized protein catabolic rate / Indoxyl sulfate Residual renal function / Indole acetic acid p-cresylsulfate Normalized protein catabolic rate / p-cresylglucuronide Residual renal function / Normalized protein catabolic rate / carboxy-4-methyl-5-propyl- 2-furanpropionic acid age / Free hippuric acid Residual renal function / Free indoxyl sulfate Residual renal function / Free indole acetic acid Residual renal function / Free p-cresylsulfate Normalized protein catabolic rate / Residual renal function / Free p-cresylglucuronide Residual renal function / Normalized protein catabolic rate / Included: Age, gender, npcr, Kt/V, RRF, diabetes, body weight, vintage Eloot et al, Plos One, 8: e76838;

62 DIET: UNCOOKED VEGAN DECREASES PROTEIN BOUND SOLUTES Ling et al, J Nutr, 122: ;

63 Serum concentration Serum concentration DIET: UNCOOKED VEGAN DECREASES PROTEIN BOUND SOLUTES Test Test Ling et al, J Nutr, 122: ;

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

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

66 PREBIOTIC AXOS REDUCES P-CRESYLSULFATE AND CORRECTS UREMIC INSULIN RESISTANCE IN MICE Koppe et al, JASN, 24: 88-99;

67 COMMON PATHWAYS IN ENDOTHELIUM Vanholder et al, JASN, 25: ;

68 PLASMA PROTEIN BOUND SOLUTES ARE DECREASED IN GERMFREE MICE Fig. 3. Sulfate profiling based on constant neutral loss scanning of 80 m/z in ESI mode for conv (Upper) and GF (Lower) pooled plasma samples. The m/z values for several species are listed above their respective peak. Identified sulfates include: phenyl sulfate (a), indoxyl sulfate (b), p-cresol sulfate (c), equol sulfate (d), and methyl equol sulfate (e). Wikoff et al, PNAS, 106: ;

69 DECREASE UREMIC TOXINS WITH SYNBIOTICS: RCT N=31 N=21 N=31 N=21 Figure 3. Treatment effect of synbiotics on serum uremic toxins in all completing patients (n=31) and patients who were antibiotic free (n=21). a Treatment effect (95% confidence interval) derived from regression modeling accounting for period effect. *P=0.03; **P= Rossi et al, cjasn, 11: ;

Impact de la convection

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