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Cardiovascular Disease In CKD: Is It for Children
Gérard M. London
Hopital Manhes
Fleury-Mérogis
France
Cardiovascular Disease MortalityGeneral Population vs ESRD Dialysis
Patients
Foley RN, et al. Am J Kidney Dis. 1998;32:S112-S119.
GP: General Population.
0.001
0.01
0.1
1
10
100
25-34 35-44 45-54 55-64 66-74 75-84 >85
GP Male
GP Female
GP Black
GP White
Dialysis Male
Dialysis Female
Dialysis Black
Dialysis White
Age (years)
An
nu
al C
VD
Mo
rtal
ity
(%)
21
7
12
6
53
20–44 yearsRate: 95 deaths/103 patient years
45–64 yearsRate: 173 deaths/103 patient years
+65 yearsRate: 341 deaths/103 patient years
USRDS. AJKD, 1998
Distribution (%) of causes of death for all dialysis patients by age (1994–96)
22
11
166
45
21
10
196
44Cardiac arrest
Acute MI
Other cardiac
Cerebrovascular
Non-cardiac
The causes of Cardiovascular Diseases in CKD
Arteriosclerosis Atherosclerosis
Ischemic Heart Disease
Volume*Overload
Systolic BP; Diastolic BP
Adaptive LVH
Maladaptive LVHSystolic/diastolic dysfunction
Cardiac FailureSudden Death
Cerebrovascular andPeripheral artery
disease*Hgb; AVF; Na+
(Decreased coronary reserve)
(Decreased coronary perfusion)
Foley et al. AJKD, 1998
5015Renal transplant recipients
7540Peritoneal dialysis (PD)
7540Hemodialysis (HD)
25–50N/aChronic renal failure
205–12General population
Left ventricularhypertrophy (%)
Coronary artery disease(%)
Approximate prevalence of CVDby target population
0
10
20
30
40
50
>50 35-49 25-34 <25
* p<0.001; Ccr <25 vs all others*
Levin et al. AJKD, 1999
Baseline prevalence of LVH by degreeof renal function
Cr clearance(ml/min)
% patients
Silberberg et al. J Kidney Int, 1989
<125 g/m2
>125 g/m2n=91
Survival rate (%)
Time (years)
100
80
60
40
20
00 1 2 3 4 5
Impact of LVH on survival rates
Correlation in ESRD patients between the stroke work index
and LVMI
r = 0.62p < 0.0001
410
50
Stroke work index (g.m/m2)
LVM
I (
g/m
2)
20 170
London et al. Seminar Dial 1999
LV volume-pressure relationship during cardiac cycle
Ventricular volume
Ven
tric
ular
pre
ssur
e
Area under thecurve representsthe stroke work
FibrosisMyocyte hypertrophy
normal abnormal
overloadpressure volume
GHT4
Load+RAAS RAAS
Localfactors
Infammation ischemiastimuli
remodeling
Function andstiffness
Stimuli to myocardial remodelig and their impact on stiffness and function
Adapted from Weber et al Blood Press 1991
Determinants of LV mass in ESRD patients
Independent variables
t value p RMS error
Stroke volume (ml/beat) 7.52 <0.001 21.1Age (years) 5.18 <0.001 0.3
Body height (cm) 4.52 <0.001 7.8
Mean aortic systolic 4.51 <0.001 7.8pressure (mmHg)
Gender (1 M; 2 F) -2.0 0.045 1.3
Dependent variable: LV mass (g)
r2=0.65; p<0.0001
A-V fistula
Na+/H20 retention
Chronic anemia
– increased stroke volume
– increased heart rate
Hypertension
Arteriosclerosis
Aortic stenosis
Hemodynamic factors of LV hypertrophy
Volume overload Pressure overload
0
100
200
300
400
500
600
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5
interdialytic weight changes (kg)
left
ven
tric
ula
r m
ass
(g)
R=0.29p<0.01
Correlation between left ventricular mass and interdialyticbody weight changes in ESRD patients on hemodialysis
London et al advanc.Nephrol 1991
100
150
200
250
300
350
400
450
500
0 250 500 750 1000 1250 1500 1750 2000
Arterio-venous shunt flow (ml)
Lef
t ve
ntr
icu
lar
mas
s (g
)
Correlation between arteriovenous shunts flow and left ventricular mass in ESRD patients
R=0.537p<0.015
London et al advanc.Nephrol 1991
50
100
150
200
250
300
350
15 20 25 30 35 40 45 50
Hematocrit (%)
LV
mas
s in
dex
(g/
m²)
Correlation between hematocrit and left ventricular mass index in ESRD patients
r=-0.331p<0.001
London et al Kidney Int 1987
r
h
r/h<0.45
r
h
r/h<0.45
r
h
r/h>0.45
Normalll Eccentric LVH Concentric LVH
r-radius h-wall thickness r/h- relative wall thickness
Geometric characteristics of left ventricular hypertropy
Echocardiographic measurements
Measurement ESRD Controls (n=210) (n=150)
LV end-diastolic diameter (mm) 54 ± 4 50 ± 3 **
Posterior wall thickness (mm) 11 ± 1.8 8.5 ± 1.6**
Interventricular septal thickness (mm) 12.5 ± 2.0 9.6 ± 1.8**
LV mass index (g/m2) 197 ± 48 110 ± 30 **
London et al. Advances in Nephrol 1991; 20: 249-73** p < 0.001
0-4 5-9 10-14 15-19
Incidence of Cardiovascular Disease in Pediatric Dialysis Patients
Herzog Ch Kidney Int
Distribution of Left Ventricular Mass Index and Relative wall thickness According the Stage of CKD in Pediatric Patients
Echocardiographic findings in pediatric patients with CKD and healthy controls
LVH regression after use of EPO inESRD (hemodialysis)
Multifactorial origin(partial treatment)
Partial anemia correction(insufficient treatment)
Myocardial fibrosis(delayed treatment)
Only partial LVregression due to:
Macdougall
Pascual
McMahon
Zehnder
Martinez
Wizemann
Normal
50
100
150
200
250
6 month intervals
LVMI (g/m2)
50
100
150
200
250
300
350
400
80 100 120 140 160 180 200 220 240
Systolic BP (mm Hg)
Lef
t ve
ntr
icu
lar
mas
s in
dex
(g/
m²)
R=0.385p<0.001
Correlation between left ventricular mass index and systolic BPin ESRD patients on hemodialysis
0.50
0.83
1.15
1.48
1.80
80 100 120 140 160 180 200 220 240
Systolic BP (mm Hg)
inte
rven
tric
ula
r se
pta
l th
ick
nes
s (c
m)
R=0.522p<0.001
Correlation between systolic BP and interventricular septal thickness in ESRD patients on hemodialysis
80
140
Mean BP
Pulse pressure
Mean BP: Cardiac output peripheral resistance
mm
Hg
Pulse pressure: ventricular ejection arterial stiffness wave reflection
Systolic pressure
Diastolic pressuretime
1-year Mortality predicted by SBPExperience at 782 US dialysis facilities
0
0.5
1
1.5
2
2.5
< 115 115 -125
125 -135
135 -145
145 -155
155 -165
165 -175
> 175
Categories of SBP (mmHg)
Ha
zard
Ra
tio
fo
r D
ea
th
Predialysis SBP
Postdialysis SBPRef
Klassen et al. JAMA 2002;287:1548-1555
n = 37,069
1-year Mortality predicted by DBPExperience at 782 US dialysis facilities
0
1
2
3
4
5
6
30-40 40-50 50-60 60-70 70-80 80-90 90-100 100-110 > 110
DBP (mmHg)
Predialysis DBP
Postdialysis DBP
Klassen et al. JAMA 2002;287:1548-1555
Adjusted for level of systolic blood pressure
n = 37,069
Haz
ard
Rat
io F
or D
eath
One Year Mortality for Patients on Hemodialysis
0
2
4
6
8
10
12
14
16
18
20
20-30 30-40 40-50 50-60 60-70 70-80 80-90 90-100
100-110
>110
Categories of Pulse Pressure (mmHg)
Ha
zard
Ra
tio
fo
r D
ea
th
Predialysis PP
Postdialysis PP
Adjusted for level of systolic blood pressure
Ref
Klassen et al. JAMA 2002;287:1548-1555
n = 37,069
Wave reflections (Augmentation Index %)
20
48
76
104
132
160
500 1000 1500 2000 2500
Aortic stiffness ( pulse wave velocity -cm/s)
Pul
se P
ress
ure
(mm
Hg)
20
48
76
104
132
160
20 55 90 125 160Stroke volume (ml)
Pul
se P
ress
ure
(mm
Hg)
20
48
76
104
132
160
-40 -15 10 35 60
Pul
se P
ress
ure
(mm
Hg)
R=0.47p<0.0001
R=0.60p<0.0001
R=0.16p=0.025
Correlation between arterial pulse pressure, wave reflexion (Augmentation index) aortic pulse wave velocity (stiffness) and stroke volume in ESRD patients (n=230)
Adapted from London et al KI 1996
5.0
7.5
10.0
12.5
15.0
17.5
20.0
22.5
25.0
.1 1 10
Arterial Stiffness (kPa 10-3)
Aor
tic
PW
V (
m/s
)
London et al adapted from Kidney Int 1996
Relationship between arterial stiffness (Einc - incremental modulus) and Aortic Pulse Wave Velocity (PWV)
R=0.745p<0.00001
Diagrammatic representation of pressure-volume relationships
Volume
Pre
ssu
re
dP/dV
Einc=1Einc=2
Einc - incremental elastic modulus characteristic of the mechanical properties of biomaterials
Arterial function and blood pressure
Pure Conduit Function Conduit and CushioningFunction
Blo
od
pres
sure
Systole Diastole
Meanpressure
Blo
od
pres
sure
Systole Diastole
Meanpressure
Blood pressure in end-stage renal disease
Age (yrs) Systolic BP (mm Hg) Diastolic BP (mm Hg) Mean BP (mm Hg) Pulse pressure(mmHg)
Controls(n = 100)
47 ± 12144 ± 2188 ± 15
107 ± 1756 ± 16
ESRD(n = 100)
48 ± 14151 ± 23* 83 ± 14*107 ± 1768 ± 18**
London et al Kidney Int 1989
Determinants of LV afterload in ESRD
Age (yrs) Stroke volume (ml) Peripheral résistances (dynes sec cm -5) Aortic PWV (cm/s) Augmentation Index (%)
Controls(n = 100)
47 ± 1260 ± 17
1 521 ± 458
914 ±18512 ±4
ESRD(n = 100)
48 ± 1465 ± 24*
1 563 ± 426
1185 ± 245**24 ±6**
London et al Kidney Int 1989
Common carotid artery distensibility (kPa-1.10-3)
19.3 ± 7.1 15.8 ± 8.8**
Common carotid artery elastic modulus (kPa.103)+
0.74 ± 0.46***0.50 ± 0.22
200
100
Aortic pulse wave velocity (cm/sec)
Leftventricularmass (g/m2)
150
500 1000 1500 2000
r = 0.52p < 0.001
Correlation between aortic pulse wave velocityand left ventricular mass index in HD patients
London et al Adv.Nephrol 1991
Echographic characteristics of common carotid artery
Measurement ESRD Controls
CCA end-diastolic diameter (mm) 54 ± 4 50 ± 3 **
CCA Intima media thickness (mm) 11 ± 1.8 8.5 ± 1.6**
CCA relative wall thickness (mm) 12.5 ± 2.0 9.6 ± 1.8**
LV mass index (g/m2) 197 ± 48 110 ± 30 **
London et al. Advances in Nephrol 1991; 20: 249-73** p < 0.001
5.0
7.5
10.0
12.5
15.0
17.5
20.0
10 20 30 40 50 60 70 80 90
Age (years)
Aor
tic
Pu
lse
wav
e ve
loci
ty (m
/s)
0.5
0.6
0.7
0.8
0.9
1.0
1.1
10 20 30 40 50 60 70 80 90
Age (years)
Car
otid
wal
l th
ick
nes
s (m
m)
5.0
7.5
10.0
12.5
15.0
17.5
20.0
0.5 0.6 0.7 0.7 0.8 0.9 1.0 1.0 1.1Carotid wall thickness (mm)
Aor
tic
pu
lse
wav
e ve
loci
ty (c
m/s
)
0.4
0.6
0.9
1.1
1.3
1.6
1.8
0.5 0.6 0.7 0.7 0.8 0.9 1.0 1.0 1.1
Carotid wall thickness (mm)Lef
t ve
ntr
icu
lar
wal
l th
ick
nes
s (c
m)
r=0.631P<0.0001
r=0.561P<0.0001
r=0.564P<0.0001
r=0.508P<0.0001
Correlation between Age and Aortic Pulse Wave Velocityin General population ( ) and ESRD patients ( )
5
10
15
20
25
25 50 75 100
Age (years)
Aor
tic
PW
V (
m/s
)
r=0.625p<0.00001
r=0.719p<0.00001
0
100
200
300
400
500
600
10 20 30 40 50 60 70 80 90 100
Age (years)
Ch
arac
teri
stic
imp
edan
ce
(dyn
es.s
.cm
-5)
r=0.525P<0.00001
r=0.340P<0.01
0.00
0.25
0.50
0.75
1.00
0.0 50 100 150 200 250Follow-up (months)
CV
Su
rviv
al
0.00
0.25
0.50
0.75
1.00
0.0 50 100 150 200 250Follow-up (months)
CV
Su
rviv
al
0.00
0.25
0.50
0.75
1.00
0.0 50 100 150 200 250Follow-up (months)
CV
Su
rviv
al
Aortic PWV Brachial PWV
Femoral PWV
²=72.8P<0.00001
²=1.78P=0.411
²=2.34P=0.310
1st tertile
2nd tertile
3rd tertile
<9.7m/s
>9.7 m/s
>12 m/s
Pannier et al Hypertension 2005
Correlation Between CCr (C-G formula) and Aortic PWV
5
10
15
20
25
30
0 50 100 150 200
r = –0.30
P <0.0001
CCR (mL/min/m²)
Aor
tic
PW
V (
m/s
)
Bortolotto et al KI 2001
Covic A et al. NDT 2006;21:729-735
Arterial and cardiac parameters in dialysis children
Mitsnefes MM et al JASN 2005;16:2796-2803.
Carotid IMTh and Compliance in Children with CKD
De Lima JJG et al NDT 17;645,2002
Impact of renal transplantation on arterial and heart characteristics
Changes of mean blood pressure and aortic PWV
Guérin and al. circulation 2001 ; 103 : 987 - 92
9
10
11
12
13
14
Survivors
110
120
InclusionInclusion At targetAt targetBPBP
End ofEnd of follow upfollow up
MBPMBP(mmHg(mmHg))
PWVPWV(m/s)(m/s)
9
10
11
12
13
14
Non Survivors
100
110
120
InclusionInclusion At targetAt targetBPBP
End ofEnd of follow upfollow up
MBPMBP(mmHg(mmHg))
PWVPWV(m/s)(m/s)
100
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.
Decreased PWVDecreased PWV
0.250.25
0.500.50
0.750.75
11
00
00 3535 7070 105105 140140
Unchanged orUnchanged or
increased PWVincreased PWV
Duration of follow-up (months)Duration of follow-up (months)
Su
rviv
al r
ate
Variables associated with 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
5.0
7.5
10.0
12.5
15.0
17.5
20.0
0 4 8 12 16 20 24
Abdominal aortic calcification score
Aor
tic
PW
V (
ms)
r = 0.754P < 0.0001
Pannier et al. Artery 2007
Correlation between aortic calcification score and aortic PWV in ESRD patients
Cardiovascular Calcification Is Increased in Dialysis Patients
*Determined by EBT.CAD = coronary artery disease.†Rumberger JA et al. Mayo Clin Proc. 1999;74:243-252.Braun J et al. Am J Kidney Dis. 1996;27:394-401.
0
500
1000
1500
2000
2500
28-39 40-49 50-59 60-69
Age (years)
Mea
n C
oron
ary
Art
ery
Cal
ciu
m S
core
*
Non-dialysis, No CAD (n=22)
Non-dialysis, CAD (n=80)
Dialysis (n=49)
Very high CV risk†
51
Coronary Artery Calcification in Young Dialysis Patients
0.1
1
10
100
1000
10000
0 5 10 15 20 25 30 35Age (years)
Cal
cifi
cati
on
Sco
re*
N=39
*Determined by EBT.
Goodman WG et al. N Engl J Med. 2000;342:1478-1483.
Calcification scores nearly doubled in a majority of patients with positive initial scan when rescanned at 20 months
Calcification score• Probality of all-cause survival according to calcification score. Comparison
(log-rank test) between curves was highly significant ( Chi P<0.0001).
Calcification score : 0Calcification score : 0
0.250.25
0.500.50
0.750.75
11
00
00 2020 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
PO4
CBfa1BMP2
ALP
Osteocalcin
Osteonectin
Leptin
Collagen IFibronectin
LDLox
TNF-
Dexamethasone
Klotho-/-
PTH 7-84
+
++
+
++
+
+
+
+
+
+
+
+
Vit D3Ca
+Oncostatin
-
Osteoprotegerin
MGP Osteopontin
BMP7Collagen IV
Fetuin
PTHrP PTH 1-34
--
-
-
--
-
- pyrophosphate
+
Inductors (+) and inhibitors (-) of vascular calcifications
Pit1
Na Pi hyperphosphatemia
Pi Smooth musclegenes
matrix vesicles
Cbfa-1
Collagen-rich extracel. matrix
APalkaline
phosphatase
Calcium-binding proteins(osteocalcin, MGP, osteopontin,..)
Multiple correlation study for variables associated with abdominal aortic calcification score (n=200)
Variable t - value P-value
smoking (packs.year) 8.34 0.00001
age (years) 6.93 0.00001
hCRP (mg/L) 4.51 0.0001
serum phosphates (mMol/L) 3.33 0.001
CaCO3 (g Ca element/day) 3.18 0.01
iPTH (pg/mL) –3.74 0.001
Ca2+/totalCa(%) –2.91 0.01
serum albumin (g/L) –1.96 0.05
R2 = 0.757Pannier B et al. Artery research 2007
Median Percentage Change in Coronary Scores at 52 Weeks
0
5
10
15
20
25
30
35
Calcium Sevelamer
Med
ian
Per
cen
tag
e C
han
ge
25%*
6%
*Within treatment *Within treatment PP<0.0001; between treatment groups <0.0001; between treatment groups PP=0.02.=0.02.Patients with a baseline score >30.Patients with a baseline score >30.
Hypercalcemia 10.5 mg/dL (2.63 mmol/L)P
erce
nta
ge o
f P
atie
nts
Per
cen
tage
of
Pat
ien
ts
Study WeekStudy Week
-2-2 00 33 66 99 1212 1616 2020 2424 2828 3232 3636 4040 4444 4848 525200
55
1010
1515
2020
2525
Sevelamer Sevelamer Calcium Calcium
Calcium Balance in CKD 5
Intake 20 mMol
Calcium load
16 mmol
4 mMol ECFCa
25mMol
Dialysate
270 mMol
266 mMol
X
UCaV 4 mMol
X
Possible links between bone turnover Possible links between bone turnover and vascular calcification in CKDand vascular calcification in CKD
0
4
8
12
16
20
24
0 3 6 9 12 15 18 21 24 27
r = – 0.489P < 0.01
Double tetracycline-labeled surfaces (%)
Aor
tic
calc
ific
atio
n s
core
Aor
tic
pu
lse
wav
e ve
loci
ty (m
/s)
6
8
10
12
14
16
18
0 3 6 9 12 15 18 21 24 27
r = – 0.655P < 0.0001
London GM et al JASN 2008
Aor
tic
pu
lse
wav
e ve
loci
ty (
m/s
)
Log10 25(OH)D(µg/L)
Bra
chia
l art
ery
dis
ten
sib
ilit
y (k
Pa1
0-1.1
0-3)
4
6
8
10
12
14
16
18
20
0.40 0.60 0.80 1.00(10 µg/L)
1.20 1.40 1.60
r = – 0.535P < 0.0001
n = 52
0
1
2
3
4
5
6
7
0.40 0.60 0.80 1.00(10 µg/L)
1.20 1.40 1.60
r = 0.616P < 0.0001
n = 42
Cross-sectional correlation between serum 25(OH)Dand aortic stiffness and brachial artery distensibility
London GM et al (JASN 2007)
Tims PM et al. QJ Med 95:787,2002
MMP9 is inversely correlated to serum 25(OH)D3
Copyright ©2005 American Heart Association
Yasmin, et al. Arterioscler Thromb Vasc Biol 2005;25:372-378
Relationship between aortic PWV and serum MMP-9 levels