uremic toxicity: definition les toxines urémiques - cuen

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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


Encéphalopathie péricardite

neuropathie ostéodystrophie

athérome accéléré cardiopathie

thrombopathie immuno-dépression

etc....


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 )


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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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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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


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


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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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



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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


Vanholder et al.KI, 2003, 63:1934

Conventional Hemodialysis

EUTox work group

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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






Middle molecules (500 – 60000 D)


PTH

IL-1 IL-6

TNF-α Facteur D

Leptin

β2-microglobuline

Hyperparathyroïdie

Anorexie ? Amylose

Inflammation ?


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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



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


LF-HD HF-HD



Convective HD

EUTox work group

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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






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Protein-bound solutes (N=25)


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


Leptin

Homocystein

p-cresol


Covalent binding

Non covalent binding


Leptin

Homocystein

p-cresol

16 000 D

108 D

10-50%

75 % 135 D

94 %

Protein bound fraction

MW

15


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)


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


Leptin

Homocystein

Phenol et indoles (p-cresol)


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

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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


NH

AGEs

RAGE

AGE receptors

Normal

NH

AGEs

NH

NH

AGEs


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

uremic toxicity: definition les toxines urémiques - cuen

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