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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?
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Cardiovascular disease in children –does it happen?
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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
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Mortality in childhood-onset CKD
Oh et al, Circulation, 2002
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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
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There is an independent and graded association between GFR and CVD
Go et al, NEJM; 2004
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Metabolic disturbances in early CKD
GFR 90
↑↑↑↑ FGF-23
↓↓↓↓ Vitamin D
Dialysis
↑↑↑↑ Ca x P
↓↓↓↓ Vitamin D
↑↑↑↑ PTH
Levin et al, KI; 2007
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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
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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
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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
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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 calcitriol dose
- mean PTH levels
Shroff /
JASN 2007
85 cIMT
PWV
CAC
- dialysis duration
- mean serum Ca x P
- Mean calcitriol dose
- mean PTH levels
Civilibal /
Ped Nephrol
2007
37 cIMT
FMD
ECHO
- mean serum Ca x P
- total & LDL cholesterol
- mean calcitriol dose
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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
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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
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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)
Shroff et al, JASN 2007
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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)
Shroff et al, JASN 2007
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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
Shroff et al, JASN 2007
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Vitamin D as a predictor of cardiovascular damage?
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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 calcitriol dose
- mean PTH levels
Shroff /
JASN 2007
85 cIMT
PWV
CAC
- dialysis duration
- mean serum Ca x P
- Mean calcitriol dose
- mean PTH levels
Civilibal /
Ped Nephrol
2007
37 cIMT
FMD
ECHO
- mean serum Ca x P
- total & LDL cholesterol
- mean calcitriol dose
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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
)
Shroff et al, JASN 2008
0 50 100 150 200 2500.1
1
10
1,25 dihydroxy Vit D (pmol/L)
(lo
g a
xis
)Log c
alc
ific
ation s
core
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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
1,25 dihydroxy Vit D (pmol/L)
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
)
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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
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Is there direct evidence of vascular damage and
calcification in CKD vessels?
Shroff et al, Circulation, 2008
Shroff et al, JASN, 2010
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Ex vivo changes in intact human arteries from children with CKD
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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
(
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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 (
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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 (
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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
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Dialysis vessels have VSMC loss
75
100
125
150p < 0.001
nu
mb
er
of
VS
MC
s /
un
ita
rea
Normal Dialysis
Normal Pre-dialysis Dialysis50
n = 4 n = 8 n = 10
nu
mb
er
of
VS
MC
s /
un
it
Ad
MM
Ad
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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
Normal Pre-dialysis Dialysis0
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
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Circulating calcification inhibitors as biomarkers of cardiovascular damage?
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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)
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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)
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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
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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
(
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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
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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)
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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
/
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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
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Progression of vasculopathy
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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
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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