removal of suspected toxins: a pathway for …table 5 reduction ratios (rrs) at the end of the 4-...

© 2008 Universitair Ziekenhuis Gent

REMOVAL OF SUSPECTED TOXINS:

A PATHWAY FOR IMPROVING

CARDIOVASCULAR OUTCOMES IN

DIALYSIS PATIENTS

R Vanholder

University Hospital, Gent,

Belgium

2 2 © 2008 Universitair Ziekenhuis Gent

BASIC PREMISES

We don’t discuss the toxicity of uremic toxins: apart from urea,

all compounds I will discuss have a cardiovascular impact

We will not discuss outcomes either

We only discuss removal

These molecules are categorized as small water soluble, protein

bound or middle moleules (small peptides).


HEMODIALYSIS


HEMO-STUDY: PRIMARY AND SECONDARY OUTCOMES

Eknoyan et al, NEJM, 25: 2010-2019; 2002


EVOLUTION OF 2-M OVER TIME

Locatelli et al, KI, 50: 1293-1302; 1996


Eloot et al, KI, 67: 1566-1575; 2005

Stiller et al, IJAO, 25: 411-420; 2002

Odell et al, KI, 39: 909-919; 1991

KINETICS MIDDLE MOLECULES: β2M

ref K12

(L)

Vtot V2/V1 G mg/kg/d

urea Eloot 822±345 42.7±6.0 7.16±4.06 238±86

B2M Stiller 56.3±25.7 10.0±1.6 4.6±1.8 2.50±0.66

Odell 42.9±6 12.7±1.8 2.8±0.8 3.76±0.88


PERCENTAGE CHANGE IN TSR 8 HRS VS. 4 HRS

Eloot et al, KI, 73: 765-770; 2008


Means (SD). aStudent’s t-test for unpaired data.

Table 5 Reduction ratios (RRs) at the end of the 4- and 8-h dialysis sessions compared to the pre-dialysis values

RR 4 h (%) RR 8 h (%) % increase (8 h vs 4 h)

Pa

Urea 69.3 (4.9) 74.6 (4.8) 7.6 < 0.0004

Creatinine 62.7 (6.7) 65.9 (5.7) 5.1 < 0.03

Uric acid 75.8 (6.4) 79.9 (5.3) 5.4 < 0.002

Phosphorus 40.9 (12.5) 50.7 (13.8) 23.9 < 0.01

β2M 58.9 (8.4) 65.3 (8.3) 10.9 < 0.01

Homocysteine 45 (22.2) 51 (15.8) 13.3 0.185

Hippuric acid 53.3 (10.4) 57 (13.5) 7.5 0.428

Indole-3-acetic acid 44.7 (9.4) 46.5 (11.3) 4.9 0.651

Indoxyl sulphate 61.4 (17.0) 71.5 (19.6) 16.3 0.102

REMOVAL WITH LONG VS. STANDARD DIALYSIS

Basile et al, NDT, 26:1296-1303; 2011


PRE-DIALYSIS CONCENTRATION WITH DAILY

VS. ALTERNATE DAY DIALYSIS

Fagugli et al, AJKD, 40: 339-347; 2002


PERITONEAL DIALYSIS


TOTAL CLEARANCES

Total clearances in HD (n=20) and PD (n=50) patients. & P<0.01, # P<0.0005, and $ P<0.0001, respectively, PD vs HD.

Evenepoel et al, KI, 70: 794-799; 2006

UN Cr P ß2M pcr

200

180

160

140

120

100

80

60

40

20

0

Uremic solute

Tota

l cl

eara

nce

(l/w

eek/1

.73 m

²)


P-CRESYL SULFATE AND INDOXYL SULFATE:

CONCENTRATIONS

p-cresyl sulfate (mg/dl)

PD with RRF 2.7 ± 1.6

PF without RRF 2.6 ± 1.3

HD (anuric) 4.5 ± 1.3

Indoxyl sulfate (mg/dl)

PD with RRF 1.8 ± 1.3

PD without RRF 3.4 ± 1.4

HD (anuric) 3.1 ± 0.9

Pham et al, CJASN, 3: 85-90; 2008


DECREASE INTESTINAL GENERATION


tyrosine

p-cresol

p-cresylglucuronide

p-cresylsulfate

intestinal flora intestinal wall

liver

ROLE INTESTINE IN GENERATION

CRESOLS


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


REDUCE INTESTINAL ABSORPTION


AST-120 AND SERUM INDOXYL SULFATE

Schulman G. et al, AJKD, 47: 565-577; 2006

Mean ± 95 % confidence interval

Week 8 Week 12 0.2

0.1

0

-0.1

-0.2

-0.3

-0.4

-0.5

-0.6

0.2

0.1

0

-0.1

-0.2

-0.3

-0.4

-0.5

-0.6

Ch

anges

in

ser

um

in

do

xyl

sulf

ate

(mg/d

L)

fro

m b

asel

ine

Ch

anges

in

ser

um

in

do

xyl

sulf

ate

(mg/d

L)

fro

m b

asel

ine

9 g 6.9 g 2.7 g P 9 g 6.9 g 2.7 g P

A: p<0.001

B: p<0.001

A: p<0.001

B: p<0.001

A: p=0.180

B: p=0.002

A: p<0.977

A: p<0.001

B: p<0.001

A: p=0.002

B: p=0.026

A: p=0.726

B: p=0.252

A: p=0.655


PAI-1 AS AN INDICATOR OF OXIDATIVE

STRESS IN RENAL TUBULAR CELLS

Motojima et al, KI, 63: 1671-1680; 2003

Effects of uremic toxins on the expression of immunoreactive plasminogen activator inhibitor-1 (PAI-1) antigen in human renal

proximal tubular cells (HK-2). HK-2 were seeded in 24-well tissue culture plates at a cell density of 2 104 cells/well. The cells were

incubated with indicated amount of uremic toxins for 24 hours. The amount of immunoreactive PAI-1 antigen in medium was

determined by the PAI-1 enzyme-linked immunosorbent assay (ELISA). Values are mean SD (N = 4). (A) Effect of indoxyl sulfate.

(B) Effect of indoleacetic acid. *P < 0.05 vs. nontreated control.


PREVENTION OF PROGRESSION OF KIDNEY

DISEASE


ESTIMATED GLOMERULAR FILTRATION RATE

Akizawa T. et al, AJKD, 54:459-467; 2009

P<0.001

AST-120

Control

1.0

0.9

0.8

0.7

eGF

R, re

lati

ve

to b

asel

ine

0 8 16 24 32 40 48 56

Time (weeks)


LACK OF CORRELATION BETWEEN

SOLUTE CONCENTRATION AND eGFR

Eloot et al, cJASN, 6:1266-1273; 2011


EXTRACORPOREAL ADSORPTION


FRACTIONATED PLASMA SEPARATION AND

ABSORPTION

Meijers et al, Artif Organs, 32: 214-219; 2008

p-Cresol RR (RR%) during Prometheus FPSA and during matched high-flux HD. There

are no data available on the fourth included patient.


CONCLUSIONS

Several options are available to enhance the removal of uremic

toxins:

High flux hemodialysis / Hemodiafiltration

Extended dialysis

Decrease intestinal generation

Induce intestinal adsorption

Prevention of progression of kidney failure

Extracorporeal adsorption


BACK-UPS


ALSO GUANIDINO COMPOUNDS ARE

AFFECTED

Toyohara et al, JASN; 20: 2546-2555; 2009




Eloot et al, cJASN, 6:1266-1273; 2011


DIET: UNCOOKED VEGAN

Ling et al, J Nutr, 122: 924-930; 1992


COMPARTMENTALISATION GUANIDINES

Eloot et al, AJKD, 50: 279; 2007


LONG-TERM EVOLUTıON OF PRE-TREATMENT

CONCENTRATıON: 9 WEEKS POST-DıLUTıON HDF

Meert et al, Artif Organs, 34: 580-585; 2010


KINETICS: Indoxyl Sulfate, Hippuric Acid, Indole

Acetic Acid

Compound Gs mg/24h V1 L Vtot L Vtot / BW

L/kg

Kblood

mL/min

K12

mL/min

Urea 18600±5160 6.4±3.3 42.7±6.0 0.55±0.09 261±17 822±345

Hippuric acid 347±9 5.2±1.7 29.8±2.6 0.42±0.03 184±9 426±303

Indoxyl

sulphate 54±21 3.9±0.5 25.6±7.5 0.36±0.10 31±9 288±320

IAA 7.4±4.0 4.5±1.9 42.8±9.9 0.60±0.15 69±8 526±671


PREBIOTIC: OLIGOFRUCTOSE-ENRICHED

INULIN

Meijers et al, NDT, 25: 219-224; 2010



AFFECTED

Toyohara et al, JASN; 20: 2546-2555; 2009

38 38 © 2008 Universitair Ziekenhuis Gent Toyohara et al, JASN; 20: 2546-2555; 2009


AFFECTED


A SPECIES WITHOUT GLOMERULI Anglerfish FASEB J

Lowenstein, FASEB J, 25: 1781-1785; 2011




Eloot et al, cJASN, 6:1266-1273; 2011


A SPECIES WITHOUT GLOMERULI Anglerfish FASEB J

Lowenstein, FASEB J, 25: 1781-1785; 2011


ARTIFICIAL TUBULE

Sanechika, NDT, (2011)

doi: 10.1093/ndt/gfr066


ARTIFICIAL TUBULE


MAGNETIC BLOOD PURIFICATION

Herrmann et al, NDT (2011)

doi: 10.1093/ndt/gfq846


POST-DILUTION HEMODIAFILTRATION VS PRE-

DILUTION HEMOFILTRATION: REDUCTION RATIO (%)

Meert et al, NDT, 24: 562-570; 2008


LONG 8 HOUR DILALYSIS

High KoA, high QD, low

QB

Low KoA, high QB, low

QD

Urea clearance 204±20 193±16

Urea in dialysate 19±5 20±3

PCS clearance 27±9 14±6*

PCS in dialysate 375±200 207±86*

IS clearance 26±8 14±5*

IS in dialysate 201±137 153±74

*: p<0.05

Sirich et al, NDT, 27:1574-1579; 2012


HOMOCYSTEINE LOWERING AND INCREASE

OF ADMA BREAKDOWN

Koyama et al, AJKD, (55: 1069-1078; 2010)

Effects of oral folate supplementation alone (folate group) and coadministration of intravenous ethylcobalamin and oral folate

(methylcobalamin group) on the concentrations of (A) plasma homocysteine (Hcy) and (B) serum asymmetric

dimethylarginine (ADMA) in each patient on maintenance hemodialysis therapy. Also shown for baseline and end point, are

group mean ± standard deviation. (A) Dashed lines indicate the upper limit of the normal reference range for homocysteine

(15 µmol/L).


PAI-1 AS AN INDICATOR OF OXIDATIVE

STRESS IN RENAL TUBULAR CELLS

Motojima et al, KI, 63: 1671-1680; 2003

Effects of uremic toxins on the expression of immunoreactive plasminogen activator inhibitor-1 (PAI-1) antigen in human renal

proximal tubular cells (HK-2). HK-2 were seeded in 24-well tissue culture plates at a cell density of 2 104 cells/well. The cells were

incubated with indicated amount of uremic toxins for 24 hours. The amount of immunoreactive PAI-1 antigen in medium was

determined by the PAI-1 enzyme-linked immunosorbent assay (ELISA). Values are mean SD (N = 4). (A) Effect of indoxyl sulfate.

(B) Effect of indoleacetic acid. *P < 0.05 vs. nontreated control.


ROLE OF ORGANIC ANION TRANSPORTER IN THE

TRANSPORT OF INDOXYL SULFATE IN THE KIDNEY

Deguchi et al, KI, 61: 1760-1768; 2002

Time-course of [3H]indoxyl sulfate uptake by X. laevis oocytes injected with water or rOAT3 cRNA. The

uptake of 2 mol/L [3H]indoxyl sulfate in water-injected oocytes () and rOAT3-expressing oocytes () were

measured during a 120-minute incubation. Each bar represents the mean SEM (N = 10 to 12).


EFFECT OF INDOXYLSULFATE ON CELL VIABILITY

Enomoto et al, JASN, 13: 1711-1720; 2002


ADSORPTION BETA2-MICROGLOBULIN

Abe et al, KI, 64: 1522-1528; 2003


ENHANCE METABOLIC DEGRADATION


EFFECT OF DDAH OVEREXPRESSION ON CARDIAC

ALLOGRAFT FUNCTION

Tanaka M. et al, Circulation, 112: 1549-1556; 2005

DDAH: dimethylarginine

dimethylaminohydrolase


COMPARTMENTALISATION GUANIDINES

Eloot et al, KI, 67: 1566-1575; 2005


Reference

3*8_150

3*8_200

6*2_300

6*8_200 3*4_350

Urea 645 ± 180 682 ± 172 760 ± 200 733 ± 175* 1137 ± 307* 668 ± 173

GSA 0.175 ± 0.071 0.186 ± 0.065 0.206 ± 0.072* 0.202 ± 0.072* 0.298 ± 0.104* 0.176 ± 0.063

CREA 18 ± 5 21 ± 6* 24 ± 7* 21 ± 6* 36 ± 10* 20 ± 6*

MG 0.079 ± 0.042 0.091 ± 0.049* 0.111 ± 0.061* 0.089 ± 0.049* 0.179 ± 0.097* 0.093± 0.049*

EFFECT OF FREQUENCY AND LENGTH ON GUANIDINO

REMOVAL

Eloot S et al, NDT, 24: 2225-2232; 2009

* P<0.05, compared to reference dialysis


OSTEOCALCIN AND MYOGLOBIN

Maduell et al, AJKD, 40: 582-589; 2002

removal of suspected toxins: a pathway for …table 5 reduction ratios (rrs) at the end of the 4-...

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