cardiovascular disease in ckd: is it for children
TRANSCRIPT
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Cardiovascular Disease In CKD: Is It for Children
Gérard M. LondonHopital ManhesFleury-Mérogis
France
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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
(%)
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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
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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)
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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
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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
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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
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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
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LV volume-pressure relationship during cardiac cycle
Ventricular volume
Ven
tric
ula
r p
ress
ure
Area under thecurve representsthe stroke work
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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
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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 0.3Body 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
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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
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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
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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
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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
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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
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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
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0-4 5-9 10-14 15-19
Incidence of Cardiovascular Disease in Pediatric Dialysis Patients
Herzog Ch Kidney Int
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Distribution of Left Ventricular Mass Index and Relative wall thickness According the Stage of CKD in Pediatric Patients
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Echocardiographic findings in pediatric patients with CKD and healthy controls
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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)
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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
icul
ar m
ass
ind
ex (
g/m
²)
R=0.385p<0.001
Correlation between left ventricular mass index and systolic BPin ESRD patients on hemodialysis
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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
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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
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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
eath
Predialysis SBP
Postdialysis SBPRef
Klassen et al. JAMA 2002;287:1548-1555
n = 37,069
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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
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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
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Wave reflections (Augmentation Index %)
20
48
76
104
132
160
500 1000 1500 2000 2500
Aortic stiffness ( pulse wave velocity -cm/s)
Pu
lse
Pre
ssu
re (
mm
Hg)
20
48
76
104
132
160
20 55 90 125 160Stroke volume (ml)
Pu
lse
Pre
ssu
re (
mm
Hg)
20
48
76
104
132
160
-40 -15 10 35 60
Pu
lse
Pre
ssu
re (
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
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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
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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
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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
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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 ± 15107 ± 1756 ± 16
ESRD(n = 100)
48 ± 14151 ± 23* 83 ± 14*107 ± 1768 ± 18**
London et al Kidney Int 1989
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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
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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
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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
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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
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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
impe
dan
ce
(dyn
es.s
.cm
-5)
r=0.525P<0.00001
r=0.340P<0.01
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0.00
0.25
0.50
0.75
1.00
0.0 50 100 150 200 250Follow-up (months)
CV
Sur
viva
l
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
Sur
viva
l
Aortic PWV Brachial PWV
Femoral PWV
χ²=72.8P<0.00001
χ²=1.78P=0.411
χ²=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
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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
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Covic A et al. NDT 2006;21:729-735
Arterial and cardiac parameters in dialysis children
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Mitsnefes MM et al JASN 2005;16:2796-2803.
Carotid IMTh and Compliance in Children with CKD
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De Lima JJG et al NDT 17;645,2002
Impact of renal transplantation on arterial and heart characteristics
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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
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All cause survival according to changes in aortic pulse wave velocity (∆ PWV) in response to BP decrease
∀ χ2 = 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
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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
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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
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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
cium
Sco
re*
Non-dialysis, No CAD (n=22)
Non-dialysis, CAD (n=80)
Dialysis (n=49)
Very high CV risk†
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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
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Calcification score• Probality of all-cause survival according to calcification score. Comparison
(log-rank test) between curves was highly significant ( Chi ∆ =42.66 ; 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
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PO4
CBfa1BMP2
ALP
Osteocalcin
Osteonectin
Leptin
Collagen IFibronectin
LDLox
TNF-T
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
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Pit1
Na Pi hyperphosphatemia
Pi Smooth musclegenes
matrix vesicles
Cbfa-1
Collagen-rich extracel. matrix
APalkaline
phosphatase
Calcium-binding proteins(osteocalcin, MGP, osteopontin,..)
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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
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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.
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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
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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
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Possible links between bone turnover Possible links between bone turnover and vascular calcification in CKDand vascular calcification in CKD
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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
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Aor
tic
puls
e w
ave
velo
city
(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)
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Tims PM et al. QJ Med 95:787,2002
MMP9 is inversely correlated to serum 25(OH)D3
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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