removal of suspected toxins: a pathway for …table 5 reduction ratios (rrs) at the end of the 4-...
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© 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).
© 2008 Universitair Ziekenhuis Gent
HEMODIALYSIS
4 4 © 2008 Universitair Ziekenhuis Gent
HEMO-STUDY: PRIMARY AND SECONDARY OUTCOMES
Eknoyan et al, NEJM, 25: 2010-2019; 2002
5 5 © 2008 Universitair Ziekenhuis Gent
EVOLUTION OF 2-M OVER TIME
Locatelli et al, KI, 50: 1293-1302; 1996
6 6 © 2008 Universitair Ziekenhuis Gent
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
7 7 © 2008 Universitair Ziekenhuis Gent
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
8 8 © 2008 Universitair Ziekenhuis Gent
PERCENTAGE CHANGE IN TSR 8 HRS VS. 4 HRS
Eloot et al, KI, 73: 765-770; 2008
9 9 © 2008 Universitair Ziekenhuis Gent
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
10 10 © 2008 Universitair Ziekenhuis Gent
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
11 11 © 2008 Universitair Ziekenhuis Gent
PRE-DIALYSIS CONCENTRATION WITH DAILY
VS. ALTERNATE DAY DIALYSIS
Fagugli et al, AJKD, 40: 339-347; 2002
12 12 © 2008 Universitair Ziekenhuis Gent
PRE-DIALYSIS CONCENTRATION WITH DAILY
VS. ALTERNATE DAY DIALYSIS
Fagugli et al, AJKD, 40: 339-347; 2002
© 2008 Universitair Ziekenhuis Gent
PERITONEAL DIALYSIS
14 14 © 2008 Universitair Ziekenhuis Gent
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)
15 15 © 2008 Universitair Ziekenhuis Gent
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)
16 16 © 2008 Universitair Ziekenhuis Gent
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
© 2008 Universitair Ziekenhuis Gent
DECREASE INTESTINAL GENERATION
18 18 © 2008 Universitair Ziekenhuis Gent
tyrosine
p-cresol
p-cresylglucuronide
p-cresylsulfate
intestinal flora intestinal wall
liver
ROLE INTESTINE IN GENERATION
CRESOLS
19 19 © 2008 Universitair Ziekenhuis Gent
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
© 2008 Universitair Ziekenhuis Gent
REDUCE INTESTINAL ABSORPTION
21 21 © 2008 Universitair Ziekenhuis Gent
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
22 22 © 2008 Universitair Ziekenhuis Gent
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.
© 2008 Universitair Ziekenhuis Gent
PREVENTION OF PROGRESSION OF KIDNEY
DISEASE
24 24 © 2008 Universitair Ziekenhuis Gent
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)
25 25 © 2008 Universitair Ziekenhuis Gent
LACK OF CORRELATION BETWEEN
SOLUTE CONCENTRATION AND eGFR
Eloot et al, cJASN, 6:1266-1273; 2011
© 2008 Universitair Ziekenhuis Gent
EXTRACORPOREAL ADSORPTION
27 27 © 2008 Universitair Ziekenhuis Gent
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.
28 28 © 2008 Universitair Ziekenhuis Gent
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
© 2008 Universitair Ziekenhuis Gent
BACK-UPS
30 30 © 2008 Universitair Ziekenhuis Gent
ALSO GUANIDINO COMPOUNDS ARE
AFFECTED
Toyohara et al, JASN; 20: 2546-2555; 2009
31 31 © 2008 Universitair Ziekenhuis Gent
LACK OF CORRELATION BETWEEN
SOLUTE CONCENTRATION AND eGFR
Eloot et al, cJASN, 6:1266-1273; 2011
32 32 © 2008 Universitair Ziekenhuis Gent
DIET: UNCOOKED VEGAN
Ling et al, J Nutr, 122: 924-930; 1992
33 33 © 2008 Universitair Ziekenhuis Gent
COMPARTMENTALISATION GUANIDINES
Eloot et al, AJKD, 50: 279; 2007
34 34 © 2008 Universitair Ziekenhuis Gent
LONG-TERM EVOLUTıON OF PRE-TREATMENT
CONCENTRATıON: 9 WEEKS POST-DıLUTıON HDF
Meert et al, Artif Organs, 34: 580-585; 2010
35 35 © 2008 Universitair Ziekenhuis Gent
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
36 36 © 2008 Universitair Ziekenhuis Gent
PREBIOTIC: OLIGOFRUCTOSE-ENRICHED
INULIN
Meijers et al, NDT, 25: 219-224; 2010
37 37 © 2008 Universitair Ziekenhuis Gent
ALSO GUANIDINO COMPOUNDS ARE
AFFECTED
Toyohara et al, JASN; 20: 2546-2555; 2009
38 38 © 2008 Universitair Ziekenhuis Gent Toyohara et al, JASN; 20: 2546-2555; 2009
ALSO GUANIDINO COMPOUNDS ARE
AFFECTED
39 39 © 2008 Universitair Ziekenhuis Gent
A SPECIES WITHOUT GLOMERULI Anglerfish FASEB J
Lowenstein, FASEB J, 25: 1781-1785; 2011
40 40 © 2008 Universitair Ziekenhuis Gent
LACK OF CORRELATION BETWEEN
SOLUTE CONCENTRATION AND eGFR
Eloot et al, cJASN, 6:1266-1273; 2011
41 41 © 2008 Universitair Ziekenhuis Gent
A SPECIES WITHOUT GLOMERULI Anglerfish FASEB J
Lowenstein, FASEB J, 25: 1781-1785; 2011
42 42 © 2008 Universitair Ziekenhuis Gent
ARTIFICIAL TUBULE
Sanechika, NDT, (2011)
doi: 10.1093/ndt/gfr066
© 2008 Universitair Ziekenhuis Gent
ARTIFICIAL TUBULE
44 44 © 2008 Universitair Ziekenhuis Gent
MAGNETIC BLOOD PURIFICATION
Herrmann et al, NDT (2011)
doi: 10.1093/ndt/gfq846
45 45 © 2008 Universitair Ziekenhuis Gent Meijers et al, Am J Transplant, 7: 2195-2199; 2007
46 46 © 2008 Universitair Ziekenhuis Gent
POST-DILUTION HEMODIAFILTRATION VS PRE-
DILUTION HEMOFILTRATION: REDUCTION RATIO (%)
Meert et al, NDT, 24: 562-570; 2008
47 47 © 2008 Universitair Ziekenhuis Gent
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
48 48 © 2008 Universitair Ziekenhuis Gent
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
49 49 © 2008 Universitair Ziekenhuis Gent
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).
50 50 © 2008 Universitair Ziekenhuis Gent
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.
51 51 © 2008 Universitair Ziekenhuis Gent
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).
52 52 © 2008 Universitair Ziekenhuis Gent
EFFECT OF INDOXYLSULFATE ON CELL VIABILITY
Enomoto et al, JASN, 13: 1711-1720; 2002
53 53 © 2008 Universitair Ziekenhuis Gent
ADSORPTION BETA2-MICROGLOBULIN
Abe et al, KI, 64: 1522-1528; 2003
© 2008 Universitair Ziekenhuis Gent
ENHANCE METABOLIC DEGRADATION
55 55 © 2008 Universitair Ziekenhuis Gent
EFFECT OF DDAH OVEREXPRESSION ON CARDIAC
ALLOGRAFT FUNCTION
Tanaka M. et al, Circulation, 112: 1549-1556; 2005
DDAH: dimethylarginine
dimethylaminohydrolase
56 56 © 2008 Universitair Ziekenhuis Gent
COMPARTMENTALISATION GUANIDINES
Eloot et al, KI, 67: 1566-1575; 2005
57 57 © 2008 Universitair Ziekenhuis Gent
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
58 58 © 2008 Universitair Ziekenhuis Gent
OSTEOCALCIN AND MYOGLOBIN
Maduell et al, AJKD, 40: 582-589; 2002