Modification de la réponsethérapeutique à visée

cardiovasculaire chez l’insuffisant rénal chronique du fait

de l’inflammation

Dr Gérard LondonCentre hospitalier F.H. Manhes

Service de Néphrologie-HémodialyseFleury-Mérogis

Arteriosclerosis versus atherosclerosis (atheromatosis)

• Arteriosclerosis (sclerosis=hardening)• Generalized involvement of arterial tree, principally the elastic

arteries, associated with aging

• Intimal and medial thickening with enlargement and increased length of arteries

• thinning, fragmentation, disorganization of elastin fibers , increased in collagen and calcium content

• alteration of dampening function - increased stiffness

• Atherosclerosis (atheros=gruel)• Inflammatory response to oxidized LDLand others

• Limited and patchy distribution starting in the intima with presence of plaques

• Evolution from foam cells - fatty streak- preatheroma-atheroma-fibroatheroma

• alteration of conduit function- stenosis and occlusions

Arteriosclerosisvs

Atherosclerosisin CRF

altered tensile stress(hypertension)

age

homocysteine

antiatherogenicfactors

AGE

AOPP Lp(a)

gender

altered shear stress(change in blood flow)

local growthfactors / inhibitors

Ca, P, Vit D, PTH

lipoprotein changes

Prevalence of discrete plaques on common carotid artery in control subjects and ESRD

patients

Controls ESRD

Age (years) 48.5 ± 16 51 ± 16 NS

Plaques (%) 17.8% 56.3% < 0.01

Type of plaques

• Calcified 23.1% 91.5% <0.01

• Soft/mixed 77% 9% <0.01

London et al Sem Dial 1999

Common carotid artery (CCA) geometry in controls and ESRD patients on hemodialysis

CCA diameter (mm) 5.75 + 0.82 6.45 + 0.88 ***

CCA intima-media thickness (µm) 713 + 96 797 + 110 ***

CCA wall-to-lumen ratio 0.25 + 0.03 0.25 + 0.03

*** p < 0.001

Controls HD

London et al Kidney Int 1996

Functional characteristics of arterial system in control subjects and ESRD patients

Controls ESRD

Common carotid arterydistensibility (kPa-1.10-3) 19.3 ± 7.1 15.8 ± 8.8**

Common carotid artery elasticmodulus (kPa.103)+ 0.50 ± 0.22 0.74 ± 0.46***

Aortic pulse wave velocity (cm/s) 1020 ± 180 1115 ± 309**

Radial artery elastic modulus(kPa.103) 3.3 ± 2.4 5.53 ± 4*

Brachial pulse wave velocity (cm/s) 1117 ± 170 1167 ± 170*

Mean ± SD; *p<0.05; **p<0.01; ***p<0.001 / + (controls n=20; ESRD n=20) London et al OUP 2001

Arterial structural and functional parameters according to the calcification score (0 to 4) in hemodialysis patients

Parameter 0 1 2 3 4 ANOVA

CCA diameter (mm) 6 ± 0.82 6.3 ± 0.89 6.3 ± 0.70 6.67 ± 0.97 6.73 ± 0.80 0.001

CCA IMT (m) 700 ± 95 784 ± 156 800 ± 102 849 ± 80 830 ± 81 0.001

Aortic root (mm) 26.4 ± 4 26.3 ± 4 27.8 ± 3.9 27.5 ± 4.1 29.7 ± 4.5 0.01

Aortic bifurc. (mm) 16 ± 2.4 16.7 ± 4.4 16.7 ± 1.5 17.8 ± 3.3 18.1 ± 2.6 0.01

CCA Einc (kPa.10-3)0.47 ± 0.24 0.61 ± 0.310.62 ± 0.48 0.76 ± 0.37 1.01 ± 0.60 0.001

Aortic PWV (cm/s) 940 ± 180 946 ± 141 1040 ± 268 1270 ± 384 1302 ± 317 0.001

Guérin et al. NDT 2000

Values are means ± SD.

Abbreviations used : CCA common carotid artery, IMT intima-media thickness; Einc-elastic incremental modulus, PWV pulse wave velocity

Multiple regression report for arterial calcifications score (0-4) in hemodialysis patients

Independent coefficient P value Sequential Partial r2

variable r2 (adj. for rest)

Age (years) 0.05 0.00000 0.3638 0.3517

Pulse pressure (mm Hg) 0.012 0.00287 0.4085 0.0766

Smoking (packs/year) 0.017 0.00105 0.4253 0.0918

Phosphoremia (mmol/l) 0.41 0.04598 0.4582 0.0351

CaCO3 (g of Ca/day) 0.23 0.01215 0.5303 0.0548

Duration of HD (months) 0.008 0.00000 0.6321 0.2855

Diabetes (0-no ; 1-yes) 1.28 0.00008 0.6803 0.1308

Adjusted r2 6603 ; F ratio 34.04 ; p< 0.00000Guerin et al NDT 2000

400

575

750

925

1100

15.0 40.0 65.0 90.0 115.0 140.0

CCA pulse pressure (mm Hg)

CC

A in

tim

a-m

edia

th

ick

nes

s (

m )

Correlation between common carotid artery (CCA)pulse pressure and CCA intima-media thickness in end-stage renal disease patients

R=0.563p<0.0001

London et al Kidney Int 1996

400

575

750

925

1100

-1.0 1.0 3.0 5.0

Correlation between serum CRP and Carotid Artery wall thickness in end-stage renal disease patients

Serum CRP (Ln mg/l)

Car

otid

wal

l th

ick

nes

s (m

m)

R=0.544p<0.0001

London GM Personal data

400

575

750

925

1100

15.0 35.0 55.0 75.0 95.0

Age (years)

CC

A in

tim

a-m

edia

th

ick

nes

s(m

)

Correlation between Age and Common carotid arteryintima-media thickness in ESRD patients

R=0.566p<0.0001

London et al Kidney Int 1996

400

575

750

925

1100

5 7 9 11

CCA diameter (mm)

CC

A in

tim

a-m

edia

th

ick

nes

s (

m )

Correlation between Common carotid artery (CCA)diameter and CCA intima-media thickness

R=0.736p<0.0001

London et al Kidney Int 1996

Correlation Between LV Outflow Velocity and CCA Diameter in ESRD Patients

London GM et al. Kidney Int 1996;50:600-608

9

4

Dia

met

er (

mm

)r = 0.50

P <0.0001

15 30 45LV outflow velocity integral (cm/beat)

CCA = common carotid artery

0

5

10

15

20

25

-1 0 1 2 3 4 5

Correlation between the CRP and aortic pulse wave velocity (PWV) measured at the end of follow-up

R=0.617p<0.001

Serum CRP (Ln mg/L)

Aor

tic

PW

V (

m/s

)

London et al submitted

Determinants of aortic pulse wave velocity in ESRD (multiple regression)

Independent bcoefficient P value Sequential Partial r2

variable r2 (adj. for rest)

Age (years) 6.1 0.00003 0.4115 0.1729

Gender (0-M,1-F) -67.4 0.06700 0.4444 0.0300

Systolic BP (mm Hg) 3.04 0.00000 0.5795 0.1884

Heart rate (b/m) 3.33 0.02136 0.5898 0.0420

CRP (mg/l) 5.15 0.01334 0.6186 0.0615

Duration of HD (months)-1.0 0.00023 0.6308 0.1254

Aortic calcification(0-no ; 1-yes) 193 0.00018 0.6869 0.1520

Adjusted sequential r2 0.6652 ; F ratio 31.65 ; p< 0.00000

Probality of all-cause survival according to calcification score.

Calcification score : 0Calcification score : 0

0.250.25

0.500.50

0.750.75

11

00

002020 4040 6060 8080

Calcification score : 1Calcification score : 1

Calcification score : 2Calcification score : 2

Calcification score : 3Calcification score : 3

Calcification score : 4Calcification score : 4

Duration of follow-up (months)Duration of follow-up (months)

Pro

bal

ity

of s

urv

ival

Pro

bal

ity

of s

urv

ival

Blacher et al Hypertension 2001

0.00

0.25

0.50

0.75

1.00

0 25 50 75 100

TIME (months)

SU

RV

IVO

RS

HIP

0

MAC

IAC

Probability of all-cause survival in ESRD patients according to absence of arterial calcifications (0),medial calcifications (MAC) and intimal calcifications (IAC)

P<0.0001

P<0.01

²=59.2; p<0.0001 London et al submitted

Probability of overall survival in hemodialysispatients according to aortic PWV

Duration of follow-up (months)

0

1

0 35 70 105 140

0.50

0.75

0.25

PWV < 9.4 m/s

9.4 < PWV < 12.0 m/s

PWV > 12.0 m/s

Blacher et al. Circulation. 1999

Pro

bab

ilit

y of

ove

rall

su

rviv

al

measured pressure wave

forward/incident pressure wave

reflected pressure wave

pulse wave velocity

Pressure wave analysis

Reflected Wave

SPTI DPTI SPTI DPTI

Superimposed simultaneous phasic recording of aortic (Ao) and left ventricular (LV) pressures and coronary

blood flow (CBF)

100

0

LVLV

AoAo

STTISTTI

DPTIDPTI

100

LA or LA or PAPAWedgeWedge

AoAo

sTTIsTTI

DPTIDPTI

BP

(m

mH

g)C

BF

(m

l/m

in)

(Buckeberg et al. Circ Res 1972)

0

200

100

Aortic pulse wave velocity (cm/sec)

Leftventricularmass (g/m2)

150

500 1000 1500 2000

r = 0.52p < 0.001

Correlation between morphologic and functional cardiovascular parameters in HD patients

London et al Adv Nephrol 1998

Approach to reduction of aortic stiffness with antihypertensive treatment

Control of overhydration

perindopril nitrendipine

Perindopril + atenolol Nitrendipine + atenolol

Perindopril-atenolol-nitrendipine Nitrendipine-atenolol-perindopril

BP>160/90

BP>160/90

BP>160/90

Guérin et al Circulation 2001

All cause survival according to changes in aortic pulse wave velocity ( PWV) in response to BP decrease

2 = 28.01

• P<0.00001

Guérin et al. Circulation. 2001.

Negative Negative PWV PWV

0.250.25

0.500.50

0.750.75

11

00

00 3535 7070 105105 140140

Positive Positive PWV PWV

Duration of follow-up (months)Duration of follow-up (months)

Su

rviv

al r

ate

Cox regression- cardiovascular mortality

VARIABLE RR (95% CI) P value

CVD (yes-1/no-0) 4.72 (1.91-11.6) 0.00077

LV massix (+10g) 1.11 (1.03-1.19) 0.00844

PWV (+=1/ neg= 0) 2.35 (1.23-4.51) 0.01004

ACE inhibitor (1yes/0 no) 0.18 (0.06-0.55) 0.00274

²=59.54 ; p<0.00001

Guerin et al Circulation 2001

Characteristics of Responders and Nonresponders

Parameters

Responders

(n = 72)

Nonresponders

(n = 81)

Baseline (1) Follow-up (2) Baseline (3) Follow-up (4)

Interdialytic weight

gain (kg)

2.56 ±0.74 2.55 ±0.70 2.42 ±0.62 2.45 ± 0.5

Serum albumin (g/L) 40.5 ±2.9 40.7 ±2.8 39.8 ±3.0 39.7 ± 3.2

CRP (mg/L) 5.1 ±3.0 5.3 ±2.7 11.9 ±12.0** 12.2 ± 12.1***

Body weight (kg) 63.1 ±14.0 63.6 ± 14 60.6 ±11.7 59.7 ± 11.9

1 vs 2; 3 vs 4: ***P <0.0011 vs 3: **P <0.01

London et al JASN 2001

LOGISTIC REGRESSION REPORT: VARIABLES RELATED TO AORTIC PULSE WAVE VELOCITY

(0-Responders;1-Nonresponders)

Variable

CRP(Ln mg/l)

ACEi (yes;no)

MBP (mm Hg)

Intercept

PTH (pg/ml)

Regressioncoefficient

Standard error

²; =0 Probability level

-0.069

0.053

-1.722

0.632

0.016

0.503

0.014

0.488

0.228

0.009

0.02

0.0001

0.0004

0.0055

0.0645

0.8905

14.89

12.43

7.68

3.42

R-squared 0.2927

ModelSummary

²=51.31 Probability 0.00001

Abbreviations - MBP-mean blood pressure; ACEi-Perindopril; CRP- C-reactive protein, PTH-parathormone

from Guérin et al. Circulation 2001

-8

-6

-4

-2

0

2

4

6

8

-1 0 1 2 3 4 5

Correlation between CRP and aortic pulse wave velocity(PWV) during the follow-up

r=0.431p<0.001

Serum CRP (Ln mg/L)

A

orti

c P

WV

(m

/s)

London et al submitted

-80

-35

15

60

-8 -3 3 8

Changes in aortic PWV (m/s)

Ch

ange

s in

LV

mas

s (%

)

R=0.566p<0.001

Correlation between changes of aortic pulse wave velocity(PWV) and changes in left ventricular (LV) mass

London et al. JASN 2001London et al JASN 2001

-200

-150

-100

-50

0

50

100

150

-1 0 1 2 3 4 5

Relationship between Left ventricular (LV) mass index (g/m²)during the follow-up and the C-Reactive Protein (Ln CRP)

r=0.408 p<0.001

Serum CRP (Ln mg/L)

L

V m

ass

ind

ex (

g/m

²)

London et al submitted

LOGISTIC REGRESSION REPORT: VARIABLES RELATED TO LEFT VENTRICULAR MASS INDEX

(0-Responders;1-Nonresponders)

Variable

Hgb(g/dl)

ACEi (yes;no)

PWV (m/s)

Intercept

Regressioncoefficient

Standard error

²; =0 Probability level

1.038

0.370

-0.856

-0.454

0.318

0.010

0.416

01458

10.68

0.0001

0.0387

0.0018

0.0011

14.76

4.43

9.74

R-squared 02404

ModelSummary

²=46.84 Probability 0.00001

Abbreviations -PWV-pulse wave velocity; ACEi-perindopril;Hgb-hemoglobin,

from Guérin et al. Circulation 2001

0

0.5

1

1.5

2

2.5

3

3.5

Without ACEi With ACEi

Seru

m C

RP

(L

N m

g/l)

P=0.009

(11.811.1) (7.39.7)

Serum CRP levels in ESRD patients with treatment including or not ACE inhibitor (Perindopril)

London et al submitted

VARIABLES ASSOCIATED WITH CRP (LN mg/L) IN ESRD PATIENTS (Multivariate analysis)

Variable

Triglycerides (mMol/l)

DHP (0 no;1 yes)

ACEi (0 no;1 yes)

Age (years)

Gender (0 M;1-F)

P valueIncrementsequent r²

Cumulsequent r² Partial r

-0.0001

0.0027

0.0056

0.0401

0.0621

0.2447

0.0781

0.0609

0.0192

0.0170

-0.2795

0.2492

0.1853

-0.1695

0.5420

0.3228

0.3837

0.4029

0.4199R-squared 0.2927

ModelSummary

²=51.31 Probability 0.00001

Abbreviations - MBP-mean blood pressure; ACEi-Perindopril; CRP- C-reactive protein, PTH-parathormone

from Guérin et al. Circulation 2001

0.2447

CC

A w

all-

to-l

um

en r

atio

AOPP (µmol/l)

Correlation between advanced oxidation protein products (AOPP)and carotid artery (CCA) wall-to-lumen ratio in ESRD patients

0.14

0.18

0.22

0.26

50 100 150 200 250

r =0.56P <0.0001

Drüeke et.al Circulation 2002

0

2000

4000

6000

8000

10000

12000

14000

-1 0 1 2 3 4 5

Correlation between the CRP (Ln CRP) and the weekly dose of erythropoietin necessary to maintain hemoglobin level between 10-11 g/dl

R=0.500p<0.001

Dos

e of

EP

O (

un

its/

wee

k)

Serum CRP (Ln mg/l)

-1

0

1

2

3

4

5

0 20 40 60 80 100

Age (years)

CR

P (

Ln

mg/

L)

Correlation between age and CRP (Ln CRP) in ESRD patients

R=0.495p<0.001

0

350

700

1050

1400

0 1000 2000 3000 4000

r =0.60P <0.0001

Ser

um

Fer

riti

n (

pg/

ml)

Dose of elemental iron (mg/year)

Correlation between the dose of elemental ironand serum ferritin in ESRD patients

Drüeke et.al. Circulation 2002

Ferritin (pg/ml)

AO

PP

(µ

mol

/l)

Correlation between serum ferritin and advanced oxidation protein products (AOPP) in ESRD patients

50

100

150

200

250

0 350 700 1050 1400

r =0.42P <0.0001

Drüeke et. Circulation 2002

500

580

660

740

820

900

0.0 1750 3500

Correlation between yearly dose of elemental iron (mg) and carotid artery wall thickness

Dose of elemental Iron (mg/year)

Car

otid

wal

l th

ick

nes

s (m

g)

875 2625

r=0.368p=0.0153

Drüeke et al Circulation 2002