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