1. Cardiovascular Disease In CKD: Is It for Children
Gérard M. London
Hopital Manhes
Fleury-Mérogis
France

2. Cardiovascular Disease Mortality General Population vs ESRD Dialysis Patients
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
Annual CVD Mortality (%)
This graph shows that the incidence of death due to cardiovascular disease is dramatically higher in ESRD dialysis patients compared to the general population. Data are stratified in both groups by age, race, and gender.1
Death due to cardiovascular disease is defined by arrhythmias, cardiomyopathy, cardiac arrest, myocardial infarction, atherosclerotic heart disease, and pulmonary edema.
1. Foley RN, et al. Am J Kidney Dis. 1998;32:S112-S119.
Dialysis Female
Dialysis Black
Dialysis White
Age (years)
GP: General Population.
Foley RN, et al. Am J Kidney Dis. 1998;32:S112-S119.

3. Distribution (%) of causes of death for all dialysis patients by age (1994–96)
20–44 years Rate: 95 deaths/103 patient years
45–64 years Rate: 173 deaths/103 patient years 21 7 12 6 53 22 11 16 6 45 21 10 19 6 44
Cardiac arrest
Acute MI
Other cardiac
Cerebrovascular
Non-cardiac
+65 years Rate: 341 deaths/103 patient years
USRDS. AJKD, 1998

4. The causes of Cardiovascular Diseases in CKD
Arteriosclerosis Atherosclerosis
Systolic BP; Diastolic BP
(Decreased coronary perfusion)
Adaptive LVH
Ischemic Heart Disease
(Decreased coronary reserve)
Volume*
Overload
Maladaptive LVH
Systolic/diastolic dysfunction
Cerebrovascular and
Peripheral artery disease
Cardiac Failure
Sudden Death
*Hgb; AVF; Na+

5. Approximate prevalence of CVD by target population
Coronary artery
disease(%)
Left ventricular
hypertrophy (%)
General population
5–12 20
Chronic renal failure
N/a
25–50
Hemodialysis (HD) 40 75
Peritoneal dialysis (PD) 40 75
Renal transplant recipients 15 50
Foley et al. AJKD, 1998

6. Baseline prevalence of LVH by degree of renal function
% patients
* p<0.001; Ccr <25 vs all others 50 * 40 30 20 10
Cr clearance (ml/min)
>50
35-49
25-34
<25
Levin et al. AJKD, 1999

7. Impact of LVH on survival rates
100 80 60
<125 g/m2 40
n=91
>125 g/m2 20 1 2 3 4 5
Time (years)
Silberberg et al. J Kidney Int, 1989

8. Correlation in ESRD patients between the stroke work index and LVMI
410
r = 0.62
p <
LVMI (g/m2) 50 20
170
Stroke work index (g.m/m2)
London et al. Seminar Dial 1999

9. LV volume-pressure relationship during cardiac cycle
Area under the
curve represents
the stroke work
Ventricular pressure
Ventricular volume

10. Fibrosis normal abnormal
Stimuli to myocardial remodelig and their impact on stiffness and function
overload GH
Load+
RAAS
Local
factors
Infammation
ischemia
stimuli
pressure
volume T4
RAAS
Fibrosis
remodeling
Myocyte hypertrophy
Function and
stiffness
normal
abnormal
Adapted from Weber et al Blood Press 1991

11. Determinants of LV mass in ESRD patients
Dependent variable: LV mass (g)
Independent variables
t value p RMS error
Stroke volume (ml/beat) 7.52 <
Age (years) 5.18 <
Body height (cm) 4.52 <
Mean aortic systolic 4.51 < pressure (mmHg)
Gender (1 M; 2 F)
r2=0.65; p<0.0001

12. Hemodynamic factors of LV hypertrophy
Volume overload
Pressure overload
A-V fistula
Na+/H20 retention
Chronic anemia
increased stroke volume
increased heart rate
Hypertension
Arteriosclerosis
Aortic stenosis

13. Correlation between left ventricular mass and interdialytic
body weight changes in ESRD patients on hemodialysis
600
500
400
left ventricular mass (g)
300
200
100
R=0.29
p<0.01
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
interdialytic weight changes (kg)
London et al advanc.Nephrol 1991

14. Correlation between arteriovenous shunts flow
and left ventricular mass in ESRD patients
500
450
400
350
Left ventricular mass (g)
300
250
200
R=0.537
p<0.015
150
100
250
500
750
1000
1250
1500
1750
2000
Arterio-venous shunt flow (ml)
London et al advanc.Nephrol 1991

15. Correlation between hematocrit and
left ventricular mass index in ESRD patients
350
r=-0.331
p<0.001
300
250
200
LV mass index (g/m²)
150
100 50 15 20 25 30 35 40 45 50
Hematocrit (%)
London et al Kidney Int 1987

16. r r r h h h
r/h>0.45
r/h<0.45
r/h<0.45
Normalll
Eccentric LVH
Concentric LVH
Geometric characteristics of left ventricular hypertropy
r-radius
h-wall thickness
r/h- relative wall thickness

17. Echocardiographic measurements
Measurement ESRD Controls (n=210) (n=150)
LV end-diastolic diameter (mm) 54 ± 4 50 ± 3 **
Posterior wall thickness (mm) 11 ± ± 1.6 **
Interventricular septal thickness (mm) 12.5 ± ± 1.8 **
LV mass index (g/m2) 197 ± ± 30 **
** p < 0.001
London et al. Advances in Nephrol 1991; 20:

18. Incidence of Cardiovascular Disease in Pediatric Dialysis Patients
Herzog Ch Kidney Int
0-4
5-9
10-14
15-19

20. According the Stage of CKD in Pediatric Patients
Distribution of Left Ventricular Mass Index and Relative wall thickness
According the Stage of CKD in Pediatric Patients

21. Echocardiographic findings in pediatric patients with CKD and healthy controls

22. LVH regression after use of EPO in ESRD (hemodialysis)
Macdougall
Pascual
McMahon
Zehnder
Martinez
Wizemann
LVMI (g/m2)
Multifactorial origin (partial treatment)
Partial anemia correction (insufficient treatment)
Myocardial fibrosis (delayed treatment)
Only partial LV
regression due to:
250
200
150
Normal
100 50
6 month intervals

23. Correlation between left ventricular mass index and systolic BP
in ESRD patients on hemodialysis
400
350
R=0.385
p<0.001
300
250
Left ventricular mass index (g/m²)
200
150
100 50 80
100
120
140
160
180
200
220
240
Systolic BP (mm Hg)

24. Correlation between systolic BP and interventricular septal
thickness in ESRD patients on hemodialysis
1.80
1.48
interventricular septal thickness (cm)
1.15
0.83
R=0.522
p<0.001
0.50 80
100
120
140
160
180
200
220
240
Systolic BP (mm Hg)

25. 140 80 time Systolic pressure mm Hg Mean BP Diastolic pressure
Pulse pressure
Mean BP 80
Diastolic pressure
time
Mean BP: Cardiac output
peripheral resistance
Pulse pressure: ventricular ejection
arterial stiffness
wave reflection

26. 1-year Mortality predicted by SBP Experience at 782 US dialysis facilities
Ref
Klassen et al. JAMA 2002;287:

27. 1-year Mortality predicted by DBP
Experience at 782 US dialysis facilities
Adjusted for level of systolic blood pressure
n = 37,069
Hazard Ratio For Death
Klassen et al. JAMA 2002;287:

28. One Year Mortality for Patients on Hemodialysis
Adjusted for level of systolic blood pressure
n = 37,069
That question is addressed by adjusting for level of systolic blood pressure in the Cox proportional hazards model. When systolic pressure is adjusted for, there is a dramatic and consistent association between higher pulse pressure and greater risk of death.
To give this a clinical face, this relationship suggests that when considering a group of patients with a systolic blood pressure of 180, those with a diastolic pressure of 90 (and a pulse pressure of 90) have a death risk that is four to six times higher than those with a diastolic pressure of 120 (and a pulse pressure of 60).
CHANGED
Ref
Klassen et al. JAMA 2002;287:

29. Correlation between arterial pulse pressure, wave reflexion (Augmentation index)
aortic pulse wave velocity (stiffness) and stroke volume in ESRD patients (n=230)
160
160
R=0.47
p<0.0001
R=0.60
p<0.0001
132
132
104
104
Pulse Pressure (mm Hg)
Pulse Pressure (mm Hg) 76 76 48 48 20 20
-40
-15 10 35 60
500
1000
1500
2000
2500
Wave reflections (Augmentation Index %)
Aortic stiffness ( pulse wave velocity -cm/s)
160
R=0.16
p=0.025
132
104
Pulse Pressure (mm Hg) 76 48 20
Adapted from London et al KI 1996 20 55 90
125
160
Stroke volume (ml)

30. Arterial Stiffness (kPa 10-3)
Relationship between arterial stiffness (Einc - incremental modulus) and Aortic Pulse Wave Velocity (PWV)
25.0
R=0.745
p<
22.5
20.0
17.5
Aortic PWV (m/s)
15.0
12.5
10.0
7.5
5.0 .1 1 10
Arterial Stiffness (kPa 10-3)
London et al adapted from Kidney Int 1996

31. Diagrammatic representation of pressure-volume relationships
Einc=2
Einc=1
Pressure
dP/dV
Volume
Einc - incremental elastic modulus characteristic of the mechanical properties of biomaterials

32. Arterial function and blood pressure
Pure Conduit Function
Conduit and Cushioning Function
Blood pressure
Blood pressure
Mean pressure
Mean pressure
Systole Diastole
Systole Diastole

33. Blood pressure in end-stage renal disease
Controls
(n = 100)
47 ± 12
144 ± 21
88 ± 15
107 ± 17
56 ± 16
ESRD
(n = 100)
48 ± 14
151 ± 23*
83 ± 14*
107 ± 17
68 ± 18**
Age (yrs)
Systolic BP (mm Hg)
Diastolic BP (mm Hg)
Mean BP (mm Hg)
Pulse pressure(mmHg)
London et al Kidney Int 1989

34. Determinants of LV afterload in ESRD
Controls
(n = 100)
47 ± 12
60 ± 17
1 521 ± 458
914 ±185
12 ±4
ESRD
(n = 100)
48 ± 14
65 ± 24*
1 563 ± 426
1185 ± 245**
24 ±6**
Age (yrs)
Stroke volume (ml)
Peripheral résistances
(dynes sec cm -5)
Aortic PWV (cm/s)
Augmentation Index (%)
Common carotid artery elastic modulus (kPa.103)+
0.50 ± 0.22
0.74 ± 0.46***
Common carotid artery distensibility (kPa )
19.3 ± 7.1
15.8 ± 8.8**
London et al Kidney Int 1989

35. Correlation between aortic pulse wave velocity
and left ventricular mass index in HD patients
200
Left
ventricular
mass (g/m2)
150
r = 0.52
p < 0.001
100
500
1000
1500
2000
Aortic pulse wave velocity (cm/sec)
London et al Adv.Nephrol 1991

36. Echographic characteristics of common carotid artery
Measurement ESRD Controls
CCA end-diastolic diameter (mm) 54 ± 4 50 ± 3 **
CCA Intima media thickness (mm) 11 ± ± 1.6 **
CCA relative wall thickness (mm) 12.5 ± ± 1.8 **
LV mass index (g/m2) 197 ± ± 30 **
** p < 0.001
London et al. Advances in Nephrol 1991; 20:

37. Aortic Pulse wave velocity (m/s) Carotid wall thickness (mm)
1.1
20.0
r=0.561
P<0.0001
r=0.631
P<0.0001
1.0
17.5
0.9
15.0
Aortic Pulse wave velocity (m/s)
Carotid wall thickness (mm)
12.5
0.8
10.0
0.7
7.5
0.6
5.0
0.5 10 20 30 40 50 60 70 80 90 10 20 30 40 50 60 70 80 90
Age (years)
Age (years)
1.8
20.0
r=0.508
P<0.0001
r=0.564
P<0.0001
1.6
17.5
1.3
15.0
Aortic pulse wave velocity (cm/s)
12.5
1.1
Left ventricular wall thickness (cm)
10.0
0.9
7.5
0.6
5.0
0.4
0.5
0.6
0.7
0.7
0.8
0.9
1.0
1.0
1.1
0.5
0.6
0.7
0.7
0.8
0.9
1.0
1.0
1.1
Carotid wall thickness (mm)
Carotid wall thickness (mm)

38. Correlation between Age and Aortic Pulse Wave Velocity
in General population ( ) and ESRD patients ( ) 25
600
500
r=0.525
P< 20
400
r=0.625
p<
Characteristic impedance
(dynes.s.cm-5) 15
300
Aortic PWV (m/s)
200
r=0.340
P<0.01 10
100
r=0.719
p< 5 25 50 75
100 10 20 30 40 50 60 70 80 90
100
Age (years)
Age (years)

39. Aortic PWV Brachial PWV CV Survival CV Survival ²=72.8 P<0.00001
1.00
1.00
<9.7m/s
0.75
0.75
CV Survival
0.50
>9.7 m/s
CV Survival
0.50
0.25
²=72.8
P<
0.25
²=1.78
P=0.411
>12 m/s
0.00
0.00
0.0 50
100
150
200
250
0.0 50
100
150
200
250
Follow-up (months)
Follow-up (months)
Femoral PWV
1.00
0.75
CV Survival
0.50
1st tertile
0.25
²=2.34
P=0.310
2nd tertile
3rd tertile
0.00
0.0 50
100
150
200
250
Follow-up (months)
Pannier et al Hypertension 2005

40. Correlation Between CCr (C-G formula) and Aortic PWV30 r
= –0.30 P
<0.0001 25 20
Aortic PWV (m/s) 15 10 5 50
100
150
200
CCR (mL/min/m²)
Bortolotto et al KI 2001

42. Arterial and cardiac parameters in dialysis children
Covic A et al. NDT 2006;21:

43. Carotid IMTh and Compliance in Children with CKD
Mitsnefes MM et al JASN 2005;16:

45. Impact of renal transplantation on arterial and heart characteristics
De Lima JJG et al NDT 17;645,2002

46. Changes of mean blood pressure and aortic PWV
MBP (mmHg)
PWV (m/s)
MBP (mmHg)
PWV (m/s)
120 14
120 14 13 13 12 12
110
110 11 11 10 10
100 9
100 9
Inclusion
At target BP
End of follow up
Inclusion
At target BP
End of follow up
Survivors
Non Survivors
Guérin and al. circulation 2001 ; 103 :

47. Duration of follow-up (months)
All cause survival according to changes in aortic pulse wave velocity ( PWV) in response to BP decrease 1
0.75
Decreased PWV
Survival rate
0.50
0.25
Unchanged or
increased PWV
2 = 28.01
P< 35 70
105
140
Duration of follow-up (months)
Guérin et al. Circulation

48. 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)
Gender (0-M,1-F)
Systolic BP (mm Hg)
Heart rate (b/m)
CRP (mg/l)
Duration of HD (months)
Aortic calcification (0-no ; 1-yes)
Adjusted sequential r ; F ratio ; p<

49. Correlation between aortic calcification score and
aortic PWV in ESRD patients
20.0
17.5
15.0
Aortic PWV (ms)
12.5
10.0
7.5
r = 0.754
P <
5.0 4 8 12 16 20 24
Abdominal aortic calcification score
Pannier et al. Artery 2007

50. Cardiovascular Calcification Is Increased in Dialysis Patients
2500
Non-dialysis, No CAD (n=22)
Non-dialysis, CAD (n=80)
2000
Dialysis (n=49)
1500
Mean Coronary Artery Calcium Score*
1000
Key Point: The risk for coronary heart disease is dramatically increased in dialysis patients, and it increases with age.
Braun and colleagues assessed the value of electron beam computed tomography (EBT) for detection of coronary artery calcifications and calcification of heart valves of dialysis patients. They compared results from 49 chronic hemodialysis patients (28-74 years old) versus 102 nondialysis patients (32-73 years old) with documented or suspected coronary artery disease (CAD). They calculated a coronary artery calcium score and assessed calcification of mitral and aortic valves. The coronary artery calcium score was from 2.5- to 5-fold higher in the dialysis patients than in the nondialysis patients. Mitral valves were calcified in 59% of dialysis patients, whereas the aortic valve was calcified in 55%. Coronary artery calcium score also increased with age in dialysis patients, with mean scores in the 60- to 69-year-old group over 2-fold higher than those in the 40- to 49-year-old group. [Braun, 1996, 394A, 396A, 397A-C] In the general population, coronary artery calcium scores >400 by EBT are associated with very high cardiovascular risk. [Rumberger et al, 1999, 250A]
Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC. Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis. 1996;27:
Rumberger JA, Brundage BH, Rader DJ, Kondos G. Electron beam computed tomographic coronary calcium scanning: a review and guidelines for use in asymptomatic persons. Mayo Clin Proc. 1999;74:
500
Very high CV risk†
28-39
40-49
50-59
60-69
Age (years)
*Determined by EBT.
CAD = coronary artery disease.
†Rumberger JA et al. Mayo Clin Proc. 1999;74: Braun J et al. Am J Kidney Dis. 1996;27:

51. Coronary Artery Calcification in Young Dialysis Patients
10000
1000
100
Calcification Score* 10
Key Point: There is significant coronary artery calcification in young dialysis patients that progresses rapidly as they grow older.
In a study by Goodman and colleagues, 39 dialysis patients younger than 30 years underwent electron beam computed tomography (EBT) scans, which were compared with those of age- and sex-matched controls. Fourteen of 16 dialysis patients 20 to 30 years of age had positive EBT scans, with a mean score of Only 3 of 60 control patients had positive scans, with scores ranging from 1 to 77. In 10 patients with positive initial scans who underwent repeat EBT evaluation after an average of 20 months, the mean calcification score nearly doubled, demonstrating the rapidly progressive nature of cardiac calcification in the dialysis population. [Goodman, 2000, 1478A, 1479A, 1480A, 1481A, 1482A]
Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342: 1
0.1 5 10 15 20 25 30 35
Age (years)
N=39
Calcification scores nearly doubled in a majority of patients with positive initial scan when rescanned at 20 months
*Determined by EBT.
Goodman WG et al. N Engl J Med. 2000;342:

52. Blacher et al Hypertension 2001
Calcification score
Probality of all-cause survival according to calcification score. Comparison (log-rank test) between curves was highly significant ( Chi D =42.66 ; P<0.0001). 1
Calcification score : 0
0.75
Calcification score : 1
Calcification score : 2
Probality of survival
0.50
Calcification score : 3
0.25
Calcification score : 4 20 40 60 80
Duration of follow-up (months)
Blacher et al Hypertension 2001

53. Inductors (+) and inhibitors (-) of vascular calcifications
CBfa1
BMP2
Osteonectin
PO4 + +
Leptin
Dexamethasone
Osteocalcin + + + + +
ALP + +
PTH 7-84 +
Collagen I
Fibronectin +
TNF- + +
Oncostatin
LDLox + + +
Vit D3 Ca
Klotho-/- - - -
pyrophosphate -
Fetuin - - -
Osteopontin
MGP -
BMP7
Osteoprotegerin
Collagen IV -
PTHrP
PTH 1-34

54. Calcium-binding proteins (osteocalcin, MGP, osteopontin,..)Na Pi
hyperphosphatemia
Pit1 Pi
Smooth muscle
genes
Cbfa-1 AP
matrix vesicles
alkaline
phosphatase
Calcium-binding proteins
(osteocalcin, MGP, osteopontin,..)
Collagen-rich
extracel. matrix

55. CaCO3 (g Ca element/day) iPTH (pg/mL) Ca2+/totalCa(%)
Multiple correlation study for variables associated with abdominal aortic calcification score (n=200)
Variable
t - value
P-value
smoking (packs.year)
8.34
age (years)
6.93
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
Ca2+/totalCa(%)
–2.91
serum albumin (g/L)
–1.96
0.05
R2 = 0.757
Pannier B et al. Artery research 2007

56. Median Percentage Change in Coronary Scores at 52 Weeks35 30
25%* 25 20
Median Percentage Change 15 10 6% 5
Calcium
Sevelamer
*Within treatment P<0.0001; between treatment groups P=0.02.
Patients with a baseline score >30.

57. Hypercalcemia 10.5 mg/dL (2.63 mmol/L)25
Sevelamer
Calcium 20 15
Percentage of Patients 10 5 -2 3 6 9 12 16 20 24 28 32 36 40 44 48 52
Study Week

58. X X Calcium Balance in CKD 5 ECFCa 25mMol Calcium load Dialysate
Intake 20 mMol
Calcium load
Dialysate
ECFCa
25mMol
266 mMol
4 mMol X
270 mMol X
16 mmol
UCaV 4 mMol

59. Possible links between bone turnover and vascular calcification in CKD
What could be the possible link between bone turnover and vascular calcifications and uremic bone disease
We could speculate that the impairment of the calcium phosphorus metabolism observed in uremic patients could be the link between Bone and vessel diseases . Too high levels of PTH increase calcium and phosphorus release from bone while too low levels prevent bone from playing its buffering role.
want to conclude with just a few words about the assessment of PTH and our PTH targets and ask the question: “Does it really matter whether bone turnover is high or PTH is high or if it is too low?” And then ask: “What is too low?” Here you can see that if bone turnover is high and PTH is high in typical hyperparathyroidism, calcium and phosphorus can be mobilized from the skeleton. Perhaps that can facilitate its deposition into peripheral tissues and cause this calcification, like the vascular calcification I showed you On the other hand, if bone turnover is low and PTH levels are low and the bone is relatively inactive and not making matrix, then calcium and phosphorus that come into the body won’t be able to be deposited in the skeleton. If it can’t be deposited in bone, perhaps it gets deposited elsewhere. So in other words a PTH of too high is bad. A PTH of too low is bad.

60. Aortic pulse wave velocity (m/s)24 18
r = – 0.489
P < 0.01
r = – 0.655
P < 20 16 16 14
Aortic pulse wave velocity (m/s)
Aortic calcification score 12 12 8 10 4 8 6 3 6 9 12 15 18 21 24 27 3 6 9 12 15 18 21 24 27
Double tetracycline-labeled surfaces (%)
London GM et al JASN 2008

61. distensibility (kPa10-1.10-3)
Cross-sectional correlation between serum 25(OH)D
and aortic stiffness and brachial artery distensibility
r = – 0.535
P <
n = 52
r =
P <
n = 42 20 7 18 6 16 5 14
distensibility (kPa )
Brachial artery
Aortic pulse wave velocity (m/s) 4 12 3 10 2 8 6 1 4
0.40
0.60
0.80
1.00
(10 µg/L)
1.20
1.40
1.60
0.40
0.60
0.80
1.00
(10 µg/L)
1.20
1.40
1.60
Log10 25(OH)D(µg/L)
London GM et al (JASN 2007)

62. MMP9 is inversely correlated to serum 25(OH)D3
Tims PM et al. QJ Med 95:787,2002

63. Relationship between aortic PWV and serum MMP-9 levels
Yasmin, et al. Arterioscler Thromb Vasc Biol 2005;25:
Copyright ©2005 American Heart Association