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