Post on 26-Apr-2022
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Les toxines urémiques
Philippe Rieu Service de Néphrologie, CHU Reims
FRE CNRS 3481
Uremic toxicity: Definition
The uremic syndrome a clinical condition developing during the progression of renal failure
Uremic toxicity: Definition
The uremic syndrome a clinical condition developing during the progression of renal failure
Encéphalopathie péricardite
neuropathie ostéodystrophie
athérome accéléré cardiopathie
thrombopathie immuno-dépression
etc....
The uremic syndrome a clinical condition developing during the progression of renal failure
Uremic toxins
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Uremic toxin: Definition
The high concentration of the compound should be related to a specific uremic dysfonction and/or symptom that decrease or disappear when the concentration is reduced
The total body and plasma level of the compound should be higher in uremic than in non uremic subjects
1.
2.
JASN p1258-70, 2012
Uremic toxins: Classification
1. Inorganic molecules: H2O, ions
2. Free water-soluble low-molecular weight solutes (< 500 D)
3. Middle molecules (500 – 60000 D)
4. Protein-bound solutes
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Free water-soluble low-molecular weight uremic solutes (N=45)
Vanholder et al.KI, 2003, 63:1934 EUTox (European Uremic Toxin Work Group )
Free water-soluble low-molecular weight uremic solutes (N=45)
Vanholder et al.KI, 2003, 63:1934 EUTox
Uremic toxin: Definition
The high concentration of the compound should be related to a specific uremic dysfonction and/or symptom that decrease or disappear when the concentration is reduced
The total body and plasma level of the compound should be higher in uremic than in non uremic subjects
1.
2.
Uremic toxins: Definition
Only a few solutes conform more or less with this strict definition: – H2O? – Phosphate? – Potassium? – ß2-microglobulin? – ……?
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Uremic toxins: Classification
1. Inorganic molecules: H2O, ions
2. Free water-soluble low-molecular weight solutes (< 500 D)
3. Middle molecules (500 – 60000 D)
4. Protein-bound solutes
H2O
Na+
K+
PO42-
Intracellular hyperhydration
Extracellular hyperhydration
Cardiac arrhythmias
Hyperparathyroidism Vascular calcifications
Inorganic molecules
H2O
Na+
K+
PO42-
Intracellular hyperhydration
Extracellular hyperhydration
Cardiac arrhythmias
Hyperparathyroidism Vascular calcifications
Inorganic molecules
Conventional Hemodialysis
Phosphate Mass Removal Rate
mmol/h
Time (hours)
2
4
6
8
10
1 2 3 4 5
2
1
1,5
2,5
0,5
Phosphoremia mmol/L
Phosphate removal during HD
Man et al. ASAIO 1991, 37:463 9 15 20 24 mmol
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Phosphate Mass Removal Rate
mmol/h
Time (hours)
2
4
6
8
10
1 2 3 4 5
2
1
1,5
2,5
0,5
Phosphoremia mmol/L
Inaccesibility of phosphate during HD
Man et al. ASAIO 1991, 37:463 9 15 20 24 mmol
Serum P
93 mg
Intracellular P
63 g
2.5
3.5
4.5
5.5
6.5
7.5
Pre Dialyse T0 T30 T60 T90 T120
time
Phosphate mg/dL
30
45
60
75
90
105
15
BUN
mg/dL
Pre Dialyse T0 T30 T60 T90 T120
time
Postdialytic Rebound of Serum Phosphorus
Minutolo et al. 2002 JASN 13: 1046
Phosphate Mass Removal Rate
mmol/h
Time (hours)
2
4
6
8
10
1 2 3 4 5
2
1
1,5
2,5
0,5
Phosphoremia mmol/L
Phosphate removal during HD
Man et al. ASAIO 1991, 37:463
9 15 20 24 mmol
Phosphate Mass Removal Rate
mmol/h
Time (hours)
2
4
6
8
10
1 2 3 4 5
2
1
1,5
2,5
0,5
Phosphoremia mmol/L
Short daily dialysis
Man et al. ASAIO 1991, 37:463
9 15 20 24 mmol 2 hours daily dialysis Conventional hemodialysis
15 x 6 = 90 mmol/week 24 x 3 = 72 mmol/week
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Uremic toxins: Classification
1. Inorganic molecules: H2O, ions
2. Free water-soluble low-molecular weight solutes (< 500 D)
3. Middle molecules (500 – 60000 D)
4. Protein-bound solutes
Free water-soluble low-molecular weight uremic solutes (N=45)
Vanholder et al.KI, 2003, 63:1934 EUTox work group
Guanidines Neurotoxicity Inhibition NO - synthesis (?)
Oxalate Tissue deposition
Purines Resistance to vitamin D
Urea ?
Free water-soluble low-molecular weight uremic solutes
Free water-soluble low-molecular weight uremic solutes (N=45)
Vanholder et al.KI, 2003, 63:1934 EUTox work group
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Johnson et al, Mayo Clin. Proc., 47, 21-29, 1972.
Blo
od u
rea
(mg/
100
mL)
350
340
330
320
310
Seru
m (m
Osm
/Kg)
400 200
0
Dia
lysa
te u
rea
(mg/
100
ml)
5 10 15 20 30 40 50 60 70 80 90 100 Days
Plasma creatinine
(mg/100m
L)
286
596
Lethargy + + 0 0 0 0 0 0 + + + 0 0 0 + 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Headache 3+ 3+ 0 0 0 1+ 1+ 2+0 1+ 0 2+ 0 0 2+ 1+ 1+ 2+ 1+ 1+ 1+ 1+ 1+1+ 0 3+ 1+ 1+ 0 Emesis 0 0 0 0 1+ 0 2+ 1+1+1+ 0 2+ 0 0 2+1+ 2+ 2+ 2+ 2+ 2+ 0 0 0 0 2+ 2+ 1+ 0 Bleeding 0 2+ 2+ 2+ 0 1+ 1+ 1+1+1+ 2+ 2+ 1+ 0 0 1+ 1+ 1+ 1+ 0 0 0 0 0 0 0 1+ 0 0 0 Cramps 0 0 0 0 0 0 0 0 0 1+ 0 0 0 0 0 0 0 1+ 1+ 1+ 01+ 0 0 0 0 0 0 0 0 0 Tremor 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2+ 0 0 0
25 20 15 10 5 0
600
500
400
300
200
100
Plasma
Urea
Effect of Increasing
plasma urea
Carbamylation
Kraus, KI, 2001, 59: S102
C NH2
O
NH2 NH4+ NCO- +
Urea Cyanate
R-NH2 C O NH
+ R-N H
C NH2 O
Cyanic acide Carbamylated protein Protein
Carbamylation
• Blood proteins are carbamylated in vivo in kidney failure. • Carbamylation alters enzyme and hormone activity in vitro • Role of carbamylation in uremic toxicity ?
Kraus, KI, 2001, 59: S102
C NH2
O
NH2 NH4+ NCO- +
Urea Cyanate
R-NH2 C O NH
+ R-N H
C NH2 O
Cyanic acide Carbamylated protein Protein
Free water-soluble low-molecular weight uremic solutes (N=45)
Vanholder et al.KI, 2003, 63:1934
Conventional Hemodialysis
EUTox work group
8
HEMO-Study
Kt/Vsp = 1.32 ± 0.09 (1.16±0.08)
Kt/Vsp = 1.71 ± 0.11 (1.53±0.09)
Free water-soluble low-molecular weight uremic solutes
Eknoyan G et al, N eng J Med (2002); 347: 2010
Uremic toxins: Classification
1. Inorganic molecules: H2O, ions
2. Free water-soluble low-molecular weight solutes (< 500 D)
3. Middle molecules (500 – 60000 D)
4. Protein-bound solutes
Middle molecules (500 – 60000 D)
Vanholder et al.KI, 2003, 63:1934 EUTox work group
PTH
IL-1 IL-6
TNF-α Facteur D
Leptin
β2-microglobuline
Hyperparathyroïdie
Anorexie ? Amylose
Inflammation ?
Middle molecules (500 – 60000 D)
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Middle molecules (500 – 60000 D)
Vanholder et al.KI, 2003, 63:1934 EUTox work group
β2-microglobuline
• Chaîne légère HLA classe I • 99 AA, 11 800 D • Exprimée par toute les cellules
nuclées de l ’organisme • Taux sérique = 1,5-3mg/L, • Taux x 10-60 en cas d ’IRC
Amylose β2-microglobuline
• Dépôts amyloïdes dans les tissus articulaires et périarticulaires : – Syndrome du canal carpien +++ – Ténosynovite des fléchisseurs de la main – Arthralgies chroniques (épaules, autres articulations) – Arthropathies destructrices, hémarthroses, fractures – Spondyloarthropathies destructrices (cervicale) avec
compression radiculaire ou médullaire. • Dépôts extra-osseux
– Cœur, tube digestif, vaisseaux, poumons... – Le plus souvent asymptomatique
Drüeke, KI, 1999, 56:S89 Floege, KI, 2001, 59:164
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van Ypersele, KI, 39, 1012-1019, 1991. Floege, KI, 2001, 59:164
Carpal tunnel syndrome and β2m amyloidosis
Niwa et al, KI, 50, 1303-1309, 1996 Lanes 2 : β2M-dimer
β2m amyloidosis β bulge
HLA β 2m
M β 2m
Trinh et al, PNAS, 2002, 99:9775
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HLA β 2m
M β 2m
Trinh et al, PNAS, 2002, 99:9775
Middle molecules (500 – 60000 D)
Vanholder et al.KI, 2003, 63:1934
HF- Hemodialysis
EUTox work group
Middle molecules removal in HF-HD versus LF-HD
Maduell F et al, Am J Kidney Dis 2002; 40: 582-589
81 69
4 0
-4
82 70
54 61
25
0
20
40
60
80
100
Urea 60d
Creat 113d
Osteoc 5.8kd
β2M 11.8kd
Myogl 16kd
LF-HD
HF-HD
Perc
enta
ge
of re
duct
ion
0
10
20
30
40
50
60
0 1 2 3 4 5 6 7 8 9 10
Koda Y et al, Kidney Int (1997) 52: 1096
Conventional (N=308)
High Flux (N=49)
[ß2M] (mg/l)
Years of haemodialysis
ß2-microglobulin concentrations over time, LF-HD vs HF-HD
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Actuarial occurrence of carpal tunnel syndrome
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Mantel-Cox, p=0.0118
100
80
60
40
20
J. Chanard BMJ 1989, 298: 867-868
Years of haemodialysis
%tage of patients without
carpal tunel syndrome LF-HD (Cuprophane)
HF-HD AN69
1,0
1,6 1,6 1,4
1,2
0,0 0,2 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8
<27.5 27.5-35 35-42.5 42.5-50 >50
Relative Risk of Death
Cheung AK et al, HEMO-Study, JASN (ePub Dec2005)
[ß2M], mg/l
β2 microglobuline and risk of death
MPO-Study Locatelli et al, JASN (2009); 20: 645
Middle molecules (500 – 60000 D)
LF-HD HF-HD
Middle molecules (500 – 60000 D)
Vanholder et al.KI, 2003, 63:1934
Convective HD
EUTox work group
13
Middle molecules removal in HDF versus LF-HD and HF-HD
Maduell F et al, Am J Kidney Dis 2002; 40: 582-589
HDF post 26.8l/s 81
69
4 0
-4
82 70
54 61
25
83 72
64 75
63
0
20
40
60
80
100
Urea 60d
Creat 113d
Osteoc 5.8kd
β2M 11.8kd
Myogl 16kd
LF-HD
HF-HD
HF-HDF Perc
enta
ge
of re
duct
ion
p<0,01 p<0,01 p<0,01
ß2-MICROGLOBULIN REMOVAL
Lornoy et al, NDT, 15 (Suppl 2), 49-54, 2000
HDF (mL/min) post dilution 0 20 40 60 80 100 120
60
80
100
120
140
160
180 PS 1,8M2, F80 QB= 300 ml/min QD = 600ml/min
Clairance ml/min
High-efficiency HDF reduces all-cause mortality compared vith conventional HD
Maduell, JASN, 02 2013
HDF 82%
HD 73%
30% risk reduction Log-rank p-value : 0.01
Uremic toxins: Classification
1. Inorganic molecules: H2O, ions
2. Free water-soluble low-molecular weight solutes (< 500 D)
3. Middle molecules (500 – 60000 D)
4. Protein-bound solutes
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Protein-bound solutes (N=25)
Vanholder et al.KI, 2003, 63:1934 EUTox work group
Protein-bound solutes
Leptin
Homocystein
p-cresol
AGE AOPP Carbamylated protein
16 000 D
108 D
150 AA
1 AA 135 D
1 AA to > 1000 AA 100 D to > 100 kD
Protein-bound solutes
Leptin
Homocystein
p-cresol
AGE AOPP Carbamylated protein
Covalent binding
Non covalent binding
Protein-bound solutes
Leptin
Homocystein
p-cresol
16 000 D
108 D
10-50%
75 % 135 D
94 %
Protein bound fraction
MW
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Protein-bound solutes
Leptin
Homocystein
p-cresol
16 000 D
108 D
10-50%
75 % 135 D
94 %
Protein bound fraction
MW
In Vitro: p-cresylsulfate CH
3
O
HOS --
O
O
Increases leukocyte free radical production (Schepers NDT 2007) synergistic effect of pCS and pCG (Meert NDT 2011) Induction of endothelial microparticle release (Meijers AJKD 2008) Induction of insulin resistance (Koppe JASN 2013) Renal tubular damage by inducing oxidative stress (Watanabe KI 2013)
Liabeuf et al, NDT, 25: 1183-1191; 2010
Free p-cresylsulfate predictor of overall mortality and CV death in CKD patients
Protein-bound solutes (N=25)
Vanholder et al.KI, 2003, 63:1934 EUTox work group
uf
Adsorption
Dialysate in
Dialysate out
Hemodiafiltration with reinfusion
(HFR)
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ultrafiltrate
Convection (through protein
leaking membrane)
Diffusion
Adsorption
Dialysate in
Dialysate out
Hemodiafiltration with endogenous reinfusion
Alb
Alb
Alb
resin
uf Convection
Diffusion
Adsorption
Dialysate in
Dialysate out
Hemodiafiltration with endogenous reinfusion
11.6 µM
2.5
[Hcy] t10
Splendiani, Artif Org2004 28: 592
Protein-bound solutes
Leptin
Homocystein
Phenol et indoles (p-cresol)
AGE AOPP Carbamylated protein
Covalent binding
Non covalent binding
Early Glycosylation Products
C
(CHOH)3
CH2OH
O
H NH2 NH+ C H
NH CH2
(CHOH)3
CH2OH
C O
Amadori Product Schiff Base Protein Glucose
+
CHOH
(CHOH)3
CH2OH
CHOH
Lys
17
Amadori Product
Advanced Glycation End-Products AGEs
O2 OXIDATION Dehydratation condensation fragmentation cyclisation ...
Schiff Base
Glucose + NH-Protein
Amadori Product
O2 Dehydratation condensation fragmentation cyclisation ...
Schiff Base
NH-Protein Glucose + O2
Arabinose Glyoxal
O2
NH-Protein
Carbonyl Stress
Advanced Glycation End-Products AGEs
Carboxymethyllysine Pyrraline Pentosidine Glyoxal-lysine-dimer Methyl-glyoxal-lysine-dimer
Lysylpyrropyrine Vesperlysine Dehydrofuroimidazole
Crossline Imidazolone Glucosepan Crosspy
Crossline Imidazolone Glucosepan Crosspy
NH
AGEs
NH
NH
AGEs
Protein cross linking
NH
AGEs
RAGE
AGE receptors
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Effects of AGEs on End-Organ Damage in ESRD patients
Mallipattu S et al. Seminars in Dialysis 2012;25:529
- Cardiovascular morbidity - Dysregulation of the immune system - Dialysis-related amyloidosis - Progression of chronic renal failure - Uremic Neuropathy - Peritoneal damage
NH
AGEs
NH
NH
AGEs
Protein cross linking
NH
AGEs
RAGE
AGE receptors
Normal
NH
AGEs
NH
NH
AGEs
Protein cross linking
NH
AGEs
RAGE
AGE receptors Mediators Gradient
Blood Flux Post-capillary veinules
Activated endothelial cells
Red blood cells
Collagen
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Mediators Gradient
Blood Flux Post-capillary veinules
Activated endothelial cells
Red blood cells
Effect of AGE-Collagen on
neutrophils migration ?
AGE-Collagen
Non stimulated FMLP-8
Native Collagen
AGE- Collagen
Migration Rate ( µm/min )
*
0 5
10 15 *
0 5
10 15
Non stimulated Stimulated FMLP-8
Migration
Touré et al. ASN 2003
En conclusion…
Toxine urémique
Défaut d’élimination rénale de la toxine
Modification du métabolisme
au cours de l’urémie
b2-microglobuline Homocystéine AGE
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Toxine urémique A Symptôme urémique A