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30  The Cardiovascular Status of Pediatric Dialysis Patients

hyperhomocysteinemia, or dysregulation of the
Ca–phosphate–PTH axis, are risk factors primarily
present in CKD patients. Furthermore, there are a
number of potential iatrogenic or treatment-related
risk factors such as exposure to a high Ca load from
dialysate, calcium-based phosphate binders, and
vitamin D therapy; advanced glycation end-products, metabolic acidosis, and warfarin therapy can
all contribute to the pro-calcific uremic milieu. The
key factors are described in detail below.
Dysregulations in the Ca–P–PTH axis (see
also Chap. 29) are central to the vascular damage
and calcification in CKD patients. Phosphate has
probably the best described spectrum of toxicity
of all molecules that circulate in excess in
CKD. Decreased renal P excretion plays a major
role in the onset of hyperparathyroidism.
Furthermore, plasma P levels are positively and
independently correlated with an increasing risk
of death from CVD [45]. Phosphate is filtered at
the glomerulus and reabsorbed in the proximal
tubules, with approximately 85% of the filtered
phosphate reabsorbed via the sodium-phosphate
co-transporter IIa located in the proximal tubular
brush border membranes. It would be expected,
therefore, that CKD would result in hyperphosphatemia. However, we now know that compensatory mechanisms in the form of increased
fibroblast growth factor-23 (FGF-23) levels act to
preserve a normal plasma P in early CKD [46].
FGF-23 is a hormone produced by the osteocyte,
and together with its obligate co-receptor, Klotho,

results in a negative phosphate balance, by
decreasing renal tubular phosphate reabsorption
and suppressing renal 1-α hydroxylase, thereby
reducing the synthesis of 1,25-dihydroxyvitamin
D (1,25(OH)2D) [46]. However, as CKD progresses, there is increasing FGF-23 resistance and
P retention occurs, stimulating PTH secretion.
Studies in adult patients have conclusively
identified that plasma phosphate is an independent predictor of mortality in CKD. This link was
first demonstrated in adult HD patients: as serum
phosphate levels increased above 5.6  mg/dL (=
1.8  mmol/L), the hazards ratio for mortality
increased by 6% for every 1  mg/dL (=
0.3  mmol/L) increase in serum phosphate [45].
Hyperphosphatemia has also been shown to be an

563

independent risk factor for death in the pre-­
dialysis population [47, 48]. Data from >26,000
adult dialysis patients have shown that in over
80% of patients, at least one biochemical variable
was uncontrolled. Pediatric studies have similarly shown that plasma phosphate adversely
affects cIMT, coronary calcification, and left ventricular mass, and these studies are discussed in
detail below. Several in vitro studies using vascular smooth muscle cell (VSMC) cultures and
intact human vessels have shown the direct causal
role of P in inducing and promoting vascular calcification [49, 50], and are discussed below.
CKD patients are thought to be in a net positive Ca balance as a result of iatrogenic Ca loading from Ca-based phosphate binders, vitamin D
therapy, dialysate Ca, and reduced or absent Ca
removal via the kidneys. In the above study by
Block et al., patients with high calcium levels and

PTH  >  300  pg/dl were consistently associated
with a higher risk of death or cardiac dysfunction
[51]. Current guidelines state that hypercalcemia
may be harmful in all GFR categories of CKD
and call for restriction in the use of calcium-containing phosphate binders [52]. Current K/DOQI
guidelines recommend a maximum elemental
calcium load of 2000 mg/day, including calciumcontaining medication (maximum 1500 mg/day)
and a maximum dialysate calcium concentration
of 1.25  mmol/L (to avoid intradialytic Ca loading) [53]. Ca balance studies during HD have
shown that the majority of HD patients are continually experiencing Ca overload. Also, the
amount of Ca removed during dialysis was independent of the exogenous Ca load from diet or
binders [54]. These transient increases in Ca that
inevitably occur in clinical practice may go unrecorded, but can impact on ectopic calcification,
particularly in the setting of high P conditions.
Clinical studies have reported that the extent of
arterial calcification was directly related to the
number of episodes of hypercalcemia during the
preceding 6  months [55] and in the “Treat-toGoal” study, the Ca-treated group had significantly more hypercalcemic episodes than the
sevelamer group [56].
Oxidative stress is a major contributor to
increased atherosclerosis and cardiovascular


564

R. Shroff and M. M. Mitsnefes

morbidity and mortality in CKD.  Malnutrition homocysteine through diet or drugs may be parand hypoalbuminemia reduce the antioxidant alleled by a reduction in cardiovascular risk. It is
defense and increase vulnerability to oxidant presumed that homocysteine exerts a direct toxic
injury. Retained uremic solutes, such as the effect on the vessel wall, and one small study in

advanced glycation end-products (AGE) that are children has shown that folic acid supplementasubstrates of oxidized dialysate components, tion may improve endothelial function with an
homocysteine, cysteine, and ß2-microglobulin, increased resistance of LDL to oxidation [70].
further contribute to the pro-atherogenic milieu However, several randomized controlled studies
in uremia. Although dialysis treatment reduces in adults have failed to show a beneficial effect of
the concentration of oxidized substrates, amelio- folic acid supplementation, and very high doses
rating the oxidant–antioxidant balance, dialysis-­ of folic acid have recently been linked with an
associated factors such as vascular catheters, increased risk of malignancies [71].
dialysis membranes, and exposure to dialysate or
Anemia (see also Chap. 27) is a major uremia-­
oxidants in HD water, can also induce further related cardiovascular risk factor that is highly
pro-atherogenic insults [57].
prevalent in children and adolescents with
ESRD can be considered a low-grade inflam- advanced CKD. Unlike the other major uremia-­
matory state. Oxidative and carbonyl stress may related risk factors, it appears relatively early in
stimulate cells and the endothelium to release the course of CKD. Despite the introduction and
IL-6 and other pro-inflammatory cytokines that wide use of recombinant erythropoeisis stimulatare directly linked with the initiation and progres- ing agents (ESAs), anemia remains common.
sion of atherosclerosis in HD and PD patients Data from the CKiD cohort have demonstrated
[58–60]. The inflammatory state is often associ- that below a measured GFR of 43  mL/
ated with malnutrition, and the combination is min/1.73 m2, the hemoglobin decreased by 0.3 g/
directly linked with a high risk of atherosclerosis dL for every 5  mL/min/1.73  m2 decrement in
[61], often known as the malnutrition-­GFR [72]. Data from the NAPRTCS registry supinflammation-­
atherosclerosis (MIA) complex. port the finding that anemia is common in pediatThe presence of MIA in a CKD patient is associ- ric CKD patients (increasing from 18.5% in stage
ated with a significantly higher mortality rate 2 CKD to 68% in stage 5 pre-dialysis patients);
[62]. The physiological calcification inhibitor, furthermore, patients with anemia were 55%
fetuin-A, is a negative acute phase reactant and more likely to be hospitalized than those with a
its production is downregulated in an inflamma- normal hemoglobin level [73]. Anemia remains a
tory milieu [63]; fetuin-A may be the missing significant risk for both morbidity and mortality
link between inflammation and atherosclerosis [74, 75]. Data from IPPN demonstrated that 25%
[64]. Recent studies have shown that vitamin D of patients had hemoglobin levels below target,
has a cardioprotective effect, and one of its sev- and low hemoglobin levels were associated with

eral beneficial effects on the heart and vascula- low urine output, low serum albumin, high parature may be mediated by its anti-inflammatory thyroid hormone, high ferritin, and the use of bioeffects [65, 66].
incompatible PD fluid [76]. In this study, anemia
Hyperhomocysteinemia is a significant risk and high ESA dose requirements (likely secondfactor for atherosclerosis [67, 68] and has been ary to ESA resistance due to inflammation) indeassociated with increased carotid artery intima-­ pendently predict mortality. Until recently,
medial thickness (cIMT) and LVH in children posttransplant anemia has also been under-­
[60, 69]. Folic acid and B vitamins, required for appreciated. However, with introduction of more
remethylation of homocysteine to methionine, potent immunosuppression therapy, recently
are the most important dietary determinants of reported anemia prevalence rates have ranged
homocysteine, and daily supplementation typi- from 61% to 86% [75, 77].
cally lowers plasma homocysteine levels, but it is
Dialysis vintage (the time on dialysis) has
unclear whether the decreased plasma levels of been implicated as a predictor of coronary artery


30  The Cardiovascular Status of Pediatric Dialysis Patients

calcification in children and young adults
(Table 30.2). Coronary calcification can be seen
as early as the first decade of life in children on
dialysis. Dialysis vintage was associated with the
presence of calcifications, even in patients who
had undergone transplantation (dialysis vintage
was calculated as cumulative time on dialysis)
[78].This suggests that calcification develops in a
time-dependent manner on dialysis, and suggests
that there is little or no regression associated with
a functioning transplant. A recent review article
has suggested that there is a strong, albeit insignificant linear association between dialysis vintage and coronary artery calcification (CAC)
score across all published studies of CAC in
young patients with childhood-onset ESRD, suggesting an exponential effect of dialysis vintage
on the development of CAC [79].

Surrogate Measures
of Cardiovascular Risk in CKD
Patients
Unlike studies in adult CKD patients where
“hard” end points such as death or cardiovascular
events are used, pediatric studies must rely on
surrogate measures of cardiovascular damage.
These include cardiac and vascular measures of
structure and function, and biomarkers from
blood and urine. Echocardiography is a gold
standard to assess for the presence of LVH or systolic and diastolic dysfunction. Measures of
structural changes in the vessels include the
cIMT (measured by high-resolution ultrasound
scan of the common carotid arteries) and direct
evidence of CAC on multi-slice CT scan.
Functional changes in the vasculature can be
determined by the pulse wave velocity (PWV)
that determines stiffness or loss of compliance in
the vessel and distensibility of the common
carotid artery measured by ultrasound (Fig. 30.2).
Although cIMT, PWV, and CAC have been
extensively used in many studies of vascular outcome, there is recent evidence to show that they
are not sensitive markers of early vascular damage and must be interpreted with caution [76]. In
addition, numerous biomarkers of vascular dam-

565

age and future cardiovascular events have been
described and some validated against “hard end-­

points.” In our current state of knowledge, these
can best serve as corroborative evidence of vascular injury or predictors of future cardiovascular
events, but cannot replace the established vascular measures described above. Some of the better
defined biomarkers are vitamin D levels
(25-hydroxyvitamin D and 1,25-­dihydroxyvitamin
D) [80–82] and FGF-23 [83], the physiological
calcification inhibitors (fetuin-A, matrix Gla-­
protein, and osteoprotegerin) [84], endothelial
microparticles, and cardiac troponin levels [85].

Left Ventricular Structure
and Function
As in adults, a number of studies have shown that
LVH develops relatively early in the course of
CKD in children, and becomes more common as
renal function declines. Although some small retrospective studies demonstrate regression of
LVH with better blood pressure and volume control while on dialysis, others have demonstrated
worsening of LVH. Left ventricular hypertrophy
is also commonly seen after renal transplantation
in children. Considering all of the available data,
approximately one third of children with CKD
stages 2–4 [23, 86, 87] and up to 50–80% of pediatric dialysis patients have LVH [24]. The prevalence of LVH has remained stable and quite high
over last two decades. Data from the Turkish registry of children on maintenance dialysis collected from 2008 to 2013 showed the prevalence
of LVH to be 59% [88]. Data from IPPN demonstrated the overall LVH prevalence to be 48%. In
the IPPN prospective analysis, the incidence of
LVH developing de novo in patients with normal
baseline LV mass was 29%, and the incidence of
regression from LVH to normal LV mass was
40% per year [89]. Beyond childhood, in the follow-­
up of 140 adults who developed ESRD

before the age of 14 years, the Dutch Late Effects
of Renal Insufficiency in Children (LERIC) study
has also demonstrated that LVH is common (47%
of male and 39% of female patients), as is diastolic dysfunction (13%) [3].


Eifinger
et al., NDT,
2000 [105]
Oh et al.,
Circulation,
2002

2.

Groothoff
et al., JASN,
2002 [106]

Litwin et al.,
JASN, 2005

Mitsnefes
et al., JASN,
2005

4.

5.

6.

3.

Goodman
et al., NEJM,
2000

Author,
journal, year

1.

No.

44–
CKD 2–4
16 –
dialysis

55–
CKD 2–4
37 –
dialysis
34 –
transplant

cIMT correlated with
 Dialysis duration
 Mean serum Ca × PO4

 Ca intake from binders
 Mean calcitriol dose

cIMT correlated with
 Dialysis duration
 Mean serum Ca × PO4
 Ca intake from binders
 Mean calcitriol dose
Stiffness correlated with
 Mean serum Ca × PO4
 Mean PTH levels
IMT,
distensibility,
and stiffness of
carotid artery
and ECHO

Pre-dialysis
CKD –
7.1 ±  5.1 years
Dialysis –
2.2  ±  2.9 years
Transplant-2.8  ±
3.2 years
Pre-dialysis
CKD –?
Dialysis –
1.2  ±  1.3 years
(range
0.3–3.7 years)

Range
10–20 years

CAC and cIMT correlated with
 ESRD duration
 Dialysis duration
 Mean serum Ca × PO4
CAC correlated with
 PTH levels
 Hs-CRP
 Homocysteine levels
Hypertension main determinant of
abnormal arterial wall properties
No biochemical data available

Presence of CAC correlated with
 Age
 Dialysis duration
 Mean serum PO4 and Ca × PO4
 Ca intake from binders
None found

Clinical and biochemical
correlations

Carotid and
femoral IMT,
wall and lumen
cross-­sectional

areas

cIMT, stiffness
measures

RRT – 18 years
Dialysis – 4.5 years
Tx
(n =  101) –
13.5 years

29 (range
20.7–40.6) (young
adults with
childhood onset
ESRD)

130
29 dialysis

CAC +  cIMT

5.0 (range 0–22)

27.3 (range
19–39) (young
adults with
childhood onset
ESRD)

39

CAC

CAC

26.5 (range
14–39)

16

7 ± 6 (range
0.3–21)

Duration of dialysis Vascular
(years)
measures

RRT for
2.5–21 years

19 ±  7 (range
7–30)

Mean age (years)

39

No. of
patients

Increased cIMT in dialysis compared
with pre-dialysis patients
No change in vessel stiffness pre-dialysis,
but increased carotid artery stiffness
noted in the dialysis group, suggesting
that structural changes precede functional
abnormalities

CAC in 6/16 (37%) patients
All children asymptomatic despite high
CAC burden
50% of deaths are due to cardiovascular
or cerebrovascular causes
High prevalence of arteriopathy in young
adult survivors of CKD
Vascular damage correlates with Ca–PO4
load, hyperparathyroidism, and
microinflammation, but not “traditional”
risk factors
No increase in cIMT compared with
controls, but reduced distensibility and
increased vascular stiffness parameter in
all CKD groups
No difference in cIMT or arterial wall
stiffness between dialysis and transplant
groups
Increased cIMT in all CKD groups –
significantly greater in dialysis compared
with transplant patients. Suggest partial

reversibility post-Tx
Carotid lumen increased post-Tx –
possibly as a result of higher BP post-Tx

No CAC in any patients <20 years age,
but 14/16 patients >20 years had CAC
CAC doubled on follow-up scan at
20 months

Key message

Table 30.2  Vascular measures and their correlations in pediatric and young adult dialysis patients (in chronological order of publication date)

566
R. Shroff and M. M. Mitsnefes


Covic et al.,
NDT, 2006

Briese et al.,
NDT, 2006

Civilibal
et al., Ped
Nephrol,
2006

Shroff et al.,
JASN, 2007

Civilibal
et al., Ped
Nephrol,
2007

Poyrazoglu
et al., Ped
Nephrol,
2007 [111]

7.

8.

9.

10.

11.

12.

5–18 years

14.8  ±  3.8 years

18.0  ± 4.3 years

39

34

15.7 years (range
6.9–22.7 years)

53

85

23.6 years (young
adults who
developed ESRD
at ∼11 years age)

14.1  ±  2.6 years

40

14

4.6  ±  2.9 years

4.8  ± 2.6 years

Minimum
6 months; mean
2.2  ±  1.8 years

cIMT and

ECHO

cIMT,
endotheliumdependent
dilatation, and
ECHO

cIMT
PWV
CAC

CAC

cIMT correlated with
 Diastolic BP
 Higher mean serum Ca × PO4
 Higher total and LDL
cholesterol
 Higher homocysteine levels
 Higher mean calcitriol dose
cIMT correlated with
 Mean BP
 Left ventricular mass index
 Inversely with PTH (negative
correlation)
(No data available for phosphate
binder or calcitriol dosage)

Patients with calcification were
 Older

 Longer dialysis duration
 Increased cIMT
 Higher mean serum Ca × PO4
 Increased Ca intake from
binders
 Increased mean calcitriol dose
Presence of CAC correlated with
 Longer dialysis duration
 Higher mean serum PO4 and
Ca × PO4
 Higher mean PTH levels
 Higher Ca intake from binders
 Higher mean calcitriol dose
cIMT and CAC correlated with
 Higher mean PTH levels
 Higher mean calcitriol dose
 Mean time-­averaged Ca x P

cIMT, ECHO,
and CAC

9-dialysis –
2.9  ±  3.5 years
31 – transplant
9.2  ±  4.3 years

39-dialysis – 4.9 ±
2.7 years
14 – transplant
3.4  ±  2.7 years

PWV correlated with
 Mean PO4 levels
 Mean serum Ca × PO4
Age was the only significant
predictor of aortic augmentation
index

cIMT, PWV,
and aortic
augmentation
index

1 month to 6 years
(all HD)

When mean PTH levels  >  twofold upper
limit of normal increased risk of vascular
damage and calcification as compared to
those with PTH levels  <  twofold upper
limit of normal
Increased cIMT, hs-CRP, and
homocysteine levels in patients compared
with controls, but no difference in
endothelium-dependent dilatation
between the groups
Endothelium-dependent dilatation
correlated with cIMT
Increased cIMT, left ventricular
hypertrophy, and higher left ventricular

mass index in the dialysis as compared to
control groups
Significant negative correlation between
cIMT and PTH

CAC was present in 8 of 53 (15%) – 6
currently on dialysis and 2 transplanted

PWV and aortic augmentation index
significantly higher in patients than
controls, and comparable with adult
values
No reversibility after a dialysis session,
suggesting that structural changes
underlie the loss of function
No difference in cIMT between dialysis
patients, transplant recipients, and
controls
10% had moderate to severe CAC, and
9% had mild CAC
cIMT was higher in patients with
calcification

30  The Cardiovascular Status of Pediatric Dialysis Patients
567


R. Shroff and M. M. Mitsnefes

568

a

b

c

Fig. 30.2  Surrogate measures of cardiovascular risk in pulse wave velocity. Inset shows carotid and femoral
CKD patients. (a) High-resolution ultrasound of the com- waveforms. (c) Multislice CT scan showing coronary
mon carotid artery to measure the carotid artery intima-­ artery calcification (inset)
media thickness (cIMT). (b) Tonometry to measure the

Diastolic dysfunction is thought to be the initial functional LV abnormality evident in children with CKD.  Historically, the most widely
used method of assessment of impaired LV relaxation has been the use of Doppler measurement
of the mitral inflow velocity (with E/A ratio <1.0
defined as abnormal relaxation). By this method,
a number of studies have demonstrated reduced
and/or frankly abnormal E/A ratios in patients
with CKD, and after renal transplantation [86,
90, 91]. Given that many patients with advanced
CKD are chronically hypervolemic, the E/A ratio
may not be the ideal means of assessing diastolic
function in this group. More recently, tissue
Doppler imaging (TDI) was introduced as a less
load-dependent and therefore more accurate
means of evaluating diastolic function in CKD. A
number of recent studies have documented the
presence of diastolic dysfunction by TDI [92–
94], thus confirming the findings of earlier studies. Overall, children on maintenance dialysis

(irrespective of modality) have worse diastolic
function than those with either CKD stages 2–4
or functioning renal transplants. In terms of functional consequences, diastolic dysfunction was
recently demonstrated to be independently associated with reduced maximal aerobic capacity
(VO2max) in patients with stages 2–4 CKD,
ESRD, and renal transplants [95]. There are no
longitudinal studies of whether abnormal diastolic function predicts the development of frank
systolic dysfunction and congestive heart failure
in this patient group, although that has been
clearly documented in adult survivors of myocardial infarction.
Normal systolic function has classically been
thought to be relatively well preserved in children with CKD. While that still appears to be true
in terms of overt systolic function abnormalities
as assessed by LV contractility or endocardial
shortening fraction (eSF), recent studies have
demonstrated that subclinical systolic dysfunc-