uraemic vascular damage and calcification in children on ... · vasculopathy. conclusions •...

Uraemic vascular damage and calcification

in children on dialysis

Prevention vs damage limitation?

Rukshana Shroff

Great Ormond Street Hospital and Institute of Child Health, London,

United Kingdom

Prevention vs damage limitation?

Cardiovascular disease in children –does it happen?

Outline

• CVD in childhood CKD

– epidemiology

– when does it begin?

• What is the nature of the vascular damage?

- Risk factors

- Clinical studies

• Is there direct evidence of vascular damage and

calcification?

– Clinico – pathological correlations

The role of Ca and P in vascular injury

Mortality in childhood-onset CKD

Oh et al, Circulation, 2002

CVD is the most common cause of death in childhood CKD

US

- 38% deaths were from CVD Chavers et al, KI 2002

Dutch cohort studyDutch cohort study

- 24% deaths due to CVD / cerebrovascular disease

Groothoff et al, KI 2002

ANZDATA

- 57% deaths on HD and 43% on PD are due to

cardiac causes McDonald et al, NEJM 2004

There is an independent and graded association between GFR and CVD

Go et al, NEJM; 2004

Metabolic disturbances in early CKD

GFR 90

↑↑↑↑ FGF-23

↓↓↓↓ Vitamin D

Dialysis

↑↑↑↑ Ca x P

↓↓↓↓ Vitamin D

↑↑↑↑ PTH

Levin et al, KI; 2007

Atherosclerosis Arteriosclerosis

Arterial Medial Calcification in CKD

distance

Pulse Wave Velocity

Carotid

Adapted frm London et al, NDT 2002

VSMC damage and

calcification

↑Ca + ↑P

Time∆t (msec)

∆t

distancePWV =

Pressure

Carotid

Femoral

Risk factors for vascular injury

Risk factors in CKD

• Abnormal Ca & Phosphate

• Hyperpapathyroidism

• ? Vitamin D analogues

‘Traditional’ risk factors

• Hypertension

• Diabetes • ? Vitamin D analogues

• Chronic fluid overload

• Inflammation

• Oxidative stress

• Hyperhomocysteinemia

• Albuminuria

• Malnutrition

• Perturbation in physiological

inhibitors (fetuin-A, OPG)

• Abnormal FGF-23 levels

• Diabetes

• Hypercholesterolemia

• Dyslipidemia

• Insulin resistance

• Obesity

• Smoking

• Male gender

• Family history of CVD

Clinical studies in children –key papers

Patients with calcification were:

- older- older

- longer dialysis vintage

- Higher P & CaxP

- Higher Ca intake from binders

Goodman et al, NEJM, 2000

Authors / Journal

Number of dialysis pts

Vascular measures

Clinical / biochemical associations

Oh /

Circulation

2002

39 cIMT

CAC

- dialysis duration

- mean serum Ca x P

- PTH levels

Litwin /

JASN 2005

37 cIMT - dialysis duration

- mean serum Ca x P

- Mean calcitriol dose

Mitsnefes /

JASN 2005

16 cIMT

distensibility

- dialysis duration

- mean serum Ca x PJASN 2005 distensibility - mean serum Ca x P


- mean PTH levels

Shroff /

JASN 2007

85 cIMT

PWV

CAC

- dialysis duration

- mean serum Ca x P


- mean PTH levels

Civilibal /

Ped Nephrol

2007

37 cIMT

FMD

ECHO

- mean serum Ca x P

- total & LDL cholesterol

- mean calcitriol dose

PTH levels and vascular outcome

Calcium

Phosphorus

Low PTH levels High PTH levels

Calcium

Phosphorus

Ca + PO4 deposition in soft tissues

Ca + PO4 deposition in soft tissues

CKD 3 - 4 Dialysis

KDIGO unknown 2 - 9 times ULN

European guidelines

Normal range 2 – 3 times ULN

Is high PTH a risk factor for CVD?

Inclusion criteria

Children on dialysis who are:

• 5 – 18 years old

• Dialysis for ≥ 6 months

Exclusion criteria

• Underlying inflammatory

disease eg vasculitis

• Diabetes mellitus

• Uncontrolled hyperlipidaemia• Dialysis for ≥ 6 months

• CKD Stage IV for ≥3 years

• Uncontrolled hyperlipidaemia

• Uncontrolled hypertension

• Smokers

Shroff et al, JASN 2007

Based on mean time-integrated PTH levels –

Group I - PTH ≤ 2x ULN [n = 41]

Group II - PTH > 2x ULN [n = 44]

Matched for confounders

Increased cIMT is associated with high PTH levels

0.6

0.7

0.8

p < 0.0001

R2 = 0.65

0.38 ± 0.010.39 ± 0.01

0.58 ± 0.02

Inti

ma M

ed

ia T

hic

kn

ess

Controls PTH < 2xULN PTH > 2xULN0.2

0.3

0.4

0.5

n = 33 n = 41 n = 44

0.39 ± 0.01

Inti

ma M

ed

ia T

hic

kn

ess

(m

m)


9

12

15

p = 0.03

5.8 ± 1.2

8.6 ± 2.3

5.6 ± 1.8

Pu

lse w

ave v

elo

cit

y (

m/s

ec)

Arterial stiffness is associated with high PTH levels

Controls PTH < 2xULN PTH > 2xULN0

3

6

9

n = 33 n = 41 n = 44

5.6 ± 1.8

Pu

lse w

ave v

elo

cit

y (

m/s

ec)


Vascular calcification is associated with high PTH levels

PTH <2 ULN

n = 41

PTH >2 ULN n = 44

p

Calcification present in 17/85 (20%) patients

n = 41 n = 44

Total 5 (12%) 12 (27%) <0.01

Calcification score

Median (range)

7.8

(0 – 98)

85.3

(0 – 2039)

0.001


Vitamin D as a predictor of cardiovascular damage?

Authors / Journal

Number of dialysis pts

Vascular measures

Clinical / biochemical associations

Oh /

Circulation

2002

39 cIMT

CAC

- dialysis duration

- mean serum Ca x P

- PTH levels

Litwin /

JASN 2005

37 cIMT - dialysis duration

- mean serum Ca x P


Mitsnefes /

JASN 2005

16 cIMT

distensibility

- dialysis duration

- mean serum Ca x PJASN 2005 distensibility - mean serum Ca x P


- mean PTH levels

Shroff /

JASN 2007

85 cIMT

PWV

CAC

- dialysis duration

- mean serum Ca x P


- mean PTH levels

Civilibal /

Ped Nephrol

2007

37 cIMT

FMD

ECHO

- mean serum Ca x P

- total & LDL cholesterol

- mean calcitriol dose

Bimodal effect of 1,25 dihydroxy D

0.5

0.6

0.7

0.8 p < 0.0001

Caro

tid

IM

T (

mm

)

100

1000

10000p = 0.0002

(lo

g a

xis

)Log c

alc

ific

ation s

core

0 50 100 150 200 2500.2

0.3

0.4

0.5

1,25 dihydroxy Vit D (pmol/L)

Caro

tid

IM

T (

mm

)


0 50 100 150 200 2500.1

1

10


(lo

g a

xis

)Log c

alc

ific

ation s

core

1

10

100 p < 0.0001r -0.53

hs

-CR

P (

mg

/L)

(lo

g a

xis

)The anti-inflammatory effect of Vit D influence calcification

50 100 150 200 2500.01

0.1


hs

-CR

P (

mg

/L)

(lo

g a

xis

)

1

10

100

1000

hs-CRP (mg/L) <10 >10 <10 >10 <10 >10p

1,25(OH)2D (pmol/L) low normal high

n = 8 14 18 10 5 6

Calc

ific

ati

on

sco

re(l

og

axis

)

A biphasic dose–response curve for vitamin D on vascular health

Vit D deficiency Vit D overdosing

Zittermann A; Curr Opin Lipidol; 2007

• Hyperparathyroidism

• Rickets

• Bone pain, fractures

• Vascular disease

• HT & LVH

• Increased mortality

• Adynamic bone

disease

• Hypercalcaemia

• Vascular

calcification

Is there direct evidence of vascular damage and

calcification in CKD vessels?

Shroff et al, Circulation, 2008

Shroff et al, JASN, 2010

Ex vivo changes in intact human arteries from children with CKD

Ca accumulation begins pre-dialysis

30

40

50p = 0.02

p = 0.0005

Ca load in the v

essel w

all

(µgm

/µL)

M

Ad

Normal Pre-dialysis Dialysis0

10

20

30

n = 6 n = 10 n = 24

Ca load in the v

essel w

all

(

The vessel Ca load correlates with the serum Ca x P product

40

50

p = 0.007

r2 = 0.41

Ca load in the v

essel (µ

g/µ

L)

30 40 50 60 70 800

10

20

30

Mean time-integrated Ca x P product (mg2/dL2)

n = 34

Ca load in the v

essel (

The vessel Ca load increases only with time on dialysis

40

50

p = 0.30

r2 = 0.03

(µg

/µL

)

40

50

p = 0.041

r2 = 0.29

ve

sse

l (µ

g/µ

L)

0 1 2 3 4 5 60

10

20

30

n = 34

Time in CKD IV-V before starting dialysis (yrs)

Ca

loa

d in

the

ve

sse

l

0 1 2 3 4 5 60

10

20

30

n = 24Time on dialysis (years)

Ca

loa

d in

the

ve

sse

l (

Ca load correlates with the carotid IMT in dialysis patients

30

40

50

ve

sse

l (µ

g/µ

L)

Pulse wave velocity

In 2 /31 patients

Coronary calcification

0.00

10

20

p = 0.01

r2 = 0.42

0.3 0.4 0.5 0.6 0.7

Pre-dialysis n = 9

Dialysis n = 22

Carotid Intima Media Thickness (mm)

Ca

lo

ad

in

the

ve

sse

l (

Coronary calcification on CT scan

In 2 /31 patients

Dialysis vessels have VSMC loss

75

100

125

150p < 0.001

nu

mb

er

of

VS

MC

s /

un

ita

rea

Normal Dialysis


n = 4 n = 8 n = 10

nu

mb

er

of

VS

MC

s /

un

it

Ad

MM

Ad

Dialysis vessels have maximum fetuin-A deposition

15

20

16.2 ± 5.6

8.5 ± 2.3

p = 0.03

% fetu

in-A

positi

ve a

reas /unit

are

a


5

10

n = 4 n = 4 n = 6

8.5 ± 2.3

1.2 ± 1.1

% fetu

in-A

positi

ve a

reas /unit

are

a

Pre-dialysis Dialysis

Circulating calcification inhibitors as biomarkers of cardiovascular damage?

0.25

0.50

0.75

1.00

1.25

1.50

1.75

0.41 ± 0.13

0.84 ± 0.3

Fe

tuin

-A le

ve

ls (

gm

/L)

Fetuin-A decreases with time on dialysis

p = 0.002

Healthy controls Dialysis patients0.00

p < 0.0001

n = 75 n = 61

0 1 2 3 4 5 6 7 8 90.00

0.25

0.50

0.75

1.00

1.25

1.50

1.75

p = 0.002

r2 = 0.32

Time on dialysis (years)

Fetu

in-A

levels

(gm

/L)

Fetuin levels influence vessel stiffness and calcification

p = 0.016

r2 = 0.19

6

8

10

12

Aort

ic P

WV

(m

/sec)

1.00

1.25

1.50

1.75 p = 0.0070.89 ± 0.4

0.64 ± 0.2

Fetu

in-A

levels

(gm

/L)

0.0

0.5

Fetuin-A levels (gm/L)

2

4

6

0.50 0.75 1.00 1.25 1.50 1.75

Aort

ic P

WV

(m

/sec)

Shroff et al, NDT, 2008

No calcifcation Calcification0.00

0.25

0.50

0.75

n = 46 n = 15

Fetu

in-A

levels

(gm

/L)

Mechanistic insights into the accelerated calcification in dialysis patients –role of Ca and P

Alk P

1mM P + 1.8mM Ca

2mM P + 1.8mM Ca

2mM P + 2.7mM Ca

ImmunoCa

Dialysis vessels have time - dependent Ca accumulation

750

Incubation in 2mM P + 2.7mM C a p = 0 .0007

1000

2000

Ca load in t

he v

ess

el w

all

( µg/ µ

L)

0

250

500

Day 14Day 7

Day 21

p = 0 .01

p = 0 .16

Norm al P re-dialy s is Dialy s is

n = 6 n = 10 n = 24

Ca load in t

he v

ess

el w

all

(

Ca is more potent at inducing calcification than P

500p < 0.0001

p = 0.02

1000

1500

2000

in the v

esselw

all

(µgm

/µL)

0

100

200

300

400

1mM PO4

+ 1.8mM Ca

2mM PO4 3mM PO4 2mM PO4

+ 1.8mM Ca + 1.8mM Ca + 2.7mM Ca

Pre-dialysis n =10

Dialysis n = 20

Normal n = 6

Ca

load

in the v

essel

Dialysis vessels have VSMC loss in high Ca + P media

�

�� p = 0.03

90

100

110

120

130

140

Num

ber

of V

SM

Cs

are

a o

f vessel)

Dialysis – high Ca + P

40

Pre-dialysis n = 8Dialysis n = 10

1mM PO4 2mM PO4 2mM PO4

+ 1.8mM Ca + 1.8mM Ca + 2.7mM Ca

�

Normal n = 4

40

50

60

70

80

90

Num

ber

of V

SM

Cs

(per

0.2

5m

2 a

rea o

f vessel)

300

400

p = 0.04

p = 0.12

g/µ

L)

Ca induced apoptosis may be a prerequisite to calcification

0

100

200

2mM P +ZVAD 2mM P +ZVAD

+ 1.8mM Ca + 2.7mM Ca

n = 5 in each group

Ca

loa

d (

µg

/

Clinico – pathological correlations

• Ca accumulation begins pre-dialysis

and is accelerated on dialysis

• Dialysis vessels have lost protective

mechanisms and appear to be ‘primed’

to calcify in high Ca and P conditions

• In the presence of a high P even a small

increase in Ca can significantly increase

calcification

Progression of vasculopathy

Conclusions

• Calcification begins early in CKD and

progresses inexorably on dialysis

• Transplantation can only partially reverse the

effects of dialysis on the vasculature

• Our currently available imaging techniques are

not sensitive enough to detect early vascular

calcification

Prevention is key- Prevent mineral dysregulation- Maintain normal vit D levels- Pre-emptive renal transplantation

Acknowledgements

Lesley Rees

Catherine ShanahanJohn Deanfield

Laboratory TechniciansRosamund McNair & Nichola Figg– Univ of Cambridge

Vascular TechniciansAnn Donald & Libby Ellins – Institute of Child Health

Collaborators- Jeremy Skepper – Univ of Cambridge- Leon Schurgers - Univ of Maastricht- Michael Schoppet & Lorenz Hofbauer

Univ of Dresden

uraemic vascular damage and calcification in children on ... · vasculopathy. conclusions •...

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