Pediatric Nephrology

https://doi.org/10.1007/s00467-020-04732-y

REVIEW

Pathophysiology and consequences of arterial stiffness in children

with chronic kidney disease
Karolis Azukaitis 1 & Augustina Jankauskiene 1 & Franz Schaefer 2 & Rukshana Shroff 3

Received: 6 July 2020 / Revised: 16 July 2020 / Accepted: 28 July 2020

# IPNA 2020

Abstract
Changes in arterial structure and function are seen early in the course of chronic kidney disease (CKD) and have been causally
associated with cardiovascular (CV) morbidity. Numerous potential injuries encompassing both traditional and uremia-specific CV
risk factors can induce structural arterial changes and accelerate arterial stiffening. When the buffering capacity of the normally elastic
arteries is reduced, damage to vulnerable microcirculatory beds can occur. Moreover, the resultant increase to cardiac afterload
contributes to the development of left ventricular hypertrophy and cardiac dysfunction. Adult studies have linked arterial stiffness with
increased risk of mortality, CV events, cognitive decline, and CKD progression. Pulse wave velocity (PWV) is currently the gold
standard of arterial stiffness assessment but its measurement in children is challenging due to technical difficulties and physiologic
aspects related to growth and poor standardization between algorithms for calculating PWV. Nevertheless, studies in pediatric CKD
have reported increased arterial stiffness in children with advanced CKD, on dialysis, and after kidney transplantation. Development
of arterial stiffness in children with CKD is closely related to mineral-bone disease and hypertension, but other factors may also play a
significant role. The clinical relevance of accelerated arterial stiffness in childhood on cardiovascular outcomes in adult life remains
unclear, and prospective studies are needed. In this review we discuss mechanisms leading to arterial stiffness in CKD and its clinical
implications, along with issues surrounding the technical aspects of arterial stiffness assessment in children.

Keywords Arterial stiffness . Children . Pediatric . Chronic kidney disease . Pulse wave velocity . Cardiovascular disease

Introduction reduced life-expectancy on dialysis and after kidney transplan-

tation, respectively [3]. Based on the significantly increased risk
Cardiovascular disease (CVD) remains the leading cause of of premature CVD development, children with CKD 5 are
death in children with stage 5 chronic kidney disease (CKD classified as the highest pediatric CVD risk group [4].
5) [1]. The burden of CVD is particularly evident in young Although overt CVD is rare in childhood, subclinical chang-
adults with CKD who have a nearly fivefold increased risk of es in the arterial tree are evident even in young children with
ischemic heart disease (IHD) [2] and up to 55 and 20 years CKD, and their prevalence increases with advancing CKD [5].
Arterial stiffness resulting from structural alterations associated
Electronic supplementary material The online version of this article with CKD represents an important independent axis of CKD-
(https://doi.org/10.1007/s00467-020-04732-y) contains supplementary associated CV morbidity. In this review we discuss the patho-
material, which is available to authorized users.
physiology and clinical relevance of CKD-associated
arteriopathy and arterial stiffness, along with the technical as-
* Karolis Azukaitis
karolis.azukaitis@santa.lt pects of its measurement in the pediatric population.

1
Clinic of Pediatrics, Institute of Clinical Medicine, Faculty of
Medicine, Vilnius University, Santariskiu 4, Arterial structure and function in healthy
08406 Vilnius, Lithuania children
2
Division of Pediatric Nephrology, Center for Pediatrics and
Adolescent Medicine, Heidelberg University, Heidelberg, Germany Arteries can be classified into large elastic arteries (aorta and
3
Great Ormond Street Hospital for Children NHS Foundation Trust, its major branches) and smaller muscular (distributing) arter-
University College London, Institute of Child Health, London, UK ies found distal to aorta (e.g., radial and femoral arteries). All
 Pediatr Nephrol

arteries have a similar triple-layered structure (tunica intima, stiffness in the pediatric population is usually viewed as path-
media, and adventitia) but with a pronounced variation in the ological, healthy children demonstrate a gradual progressive
intrinsic composition of the arterial wall. Muscular arteries are increase in arterial stiffness with growth. This physiologic
smaller in diameter, and their medial layer is predominantly stiffening is accompanied by increasing arterial size and total
composed of vascular smooth muscle cell (VSMC) fibers. In arterial buffering capacity [14]. When measured by PWV,
contrast, the medial layer of large elastic arteries is mainly arterial stiffness is static in pre-school children and starts to
composed of multiple concentric layers of elastin fibers [6]. rise gradually thereafter [12, 15–18]. The timepoint of PWV
In healthy children, growth is associated with a gradual in- increase approximates the convergence of BP and PWV tra-
crease in the arterial wall diameter and total wall thickness. jectories, suggesting that at a certain age the elasticity of the
The latter increases predominantly due to the increase of arterial wall is unable to further compensate for the increasing
intima-media layer and is directly related to increasing blood pulsatile stress to the arterial wall [16]. In adolescence, a di-
pressure (BP), age, and body dimensions and is gender- vergence of arterial stiffness increase becomes apparent in
specific with higher arterial dimensions in boys [7]. girls and boys, with higher stiffness in the latter [12, 15–17,
The arterial system serves two principal functions: a con- 19]. Finally, increasing height and body dimensions have a
duit to deliver blood ejected by the left ventricle (LV) to the direct and independent effect on arterial stiffness [14, 17].
peripheral tissues and as vascular buffers that provide a “cush-
ioning and dampening” function. Large elastic arteries behave
similar to Windkessel’s; these are elastic reservoirs, compara- Risk factors for arterial pathology in children
ble with hydraulic pumps used by firefighters. The aorta and with CKD
other central arteries store half of the stroke volume and accu-
mulate approximately 10% of the energy generated by the LV Children with CKD are exposed to a wide spectrum of
during systole. The stored energy is required for effective potential vascular injuries that can be broadly categorized
arterial recoil during diastole which pushes out of the stored into the ‘traditional’ (Framingham) CV risk factors and
blood and thus ensures an uninterrupted blood flow reaching those that are CKD-specific (Fig. 1). The importance of
the microvasculature. The attenuation of the pulsatile nature of individual traditional CV risk factors has been demon-
the blood flow generated by LV contraction also prevents strated in numerous studies showing premature vascular
damage that pressure oscillations could cause in the microcir- aging in children with diabetes, hypertension, obesity, and
culation [8]. dyslipidemia [20–23]. More importantly, cohort studies
Elastic properties of the large arteries are essential to ensure such as the Bogalusa Heart Study [24] or the Young
the buffering function of the arterial tree. Arteries are non- Finns Study [25] have shown the impact of childhood
Hookean materials meaning they exhibit non-linear elasticity exposure to traditional CV risk factors on adult CV
that depends on the BP [9]. Arterial elasticity is mainly deter- health. These landmark studies have linked development
mined by elastin fibers; however, at higher pressures, elastic- of premature atherosclerosis in adult life with childhood
ity is lower and is predominantly maintained by collagen fi- blood pressure, dyslipidemia, obesity, and smoking [24,
bers [8]. If arterial elasticity is reduced (e.g., due to elastin 25] as well as cognitive dysfunction [26] and CKD in
fragmentation and loss), the arterial tree becomes stiffer. In young adulthood [27]. It is hoped that results of ongoing
physical terms, stiffness can be explained as resistance of an collaborative initiatives, such as the International
elastic object to strain (relative change in length) imposed by Childhood Cardiovascular Cohort (i3C), will further de-
stress (force applied over an area) [10]. Increased arterial stiff- scribe the effects of childhood risk exposure on CV
ness results in reduced arterial compliance and distensibility events in adulthood [28].
(change in arterial volume for a given change in pressure) and Besides the traditional CV risk factors, uremia has a pro-
increased pulse wave velocity (PWV). The latter relationship found effect on vascular health. As discussed further in this
is explained by the Moens-Korteweg equation article, several studies in children with CKD have shown that
pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
(PWV ¼ Eh=2rρ ), according to which PWV is directly uremic CV risk factors, such as mineral-bone disease (CKD-
related to arterial elasticity (E) and wall thickness (h) and MBD), hypertension and volume overload, inflammation, and
inversely to vessel radius (r) and blood density (ρ) [8]. oxidative stress, induce significant alterations in vascular
Elastin has a very long half-life (up to 40 years), and its structure and function. The prevalence and extent to which
synthesis is most active during the perinatal period, declines individual traditional or CKD-specific factors contribute to
thereafter, and becomes virtually negligible once adult dimen- CVD development, however, depends on many different as-
sions are reached. [11]. This is reflected in children with in- pects such as primary kidney disease or degree of kidney
trauterine growth restriction who have stiffer arteries com- function [29], but their interplay in the causal pathway of
pared to age-matched controls [12, 13]. Although arterial vascular damage in the pediatric CKD population is not al-
ways clear.
Pediatr Nephrol

process that develops and is exacerbated by dysregulated min-

eral metabolism, systemic inflammation, and oxidative stress
[33, 34]. The calcification process involves the release of min-
eralizing lipid vesicles by vascular smooth muscle cells
(VSMC) that contain abnormally reduced quantities of miner-
alization inhibitors (e.g., fetuin A, osteoprotegerin) [32, 35].
In addition, hyperphosphatemia induces apoptosis of VSMC
and leads to deposition of mineralizing apoptotic bodies in
arterial walls [32, 34].
Another distinct characteristic of arterial alterations in
CKD is the osteoblastic transformation of VSMC induced
by high serum phosphate levels [32] with an upregulation of
bone-forming proteins such as alkaline phosphatase and the
development of osteoblasts within the vessel wall [34].
Although phosphate is deemed to be the predominant vascular
toxin in CKD, other components of CKD-MBD, such as de-
ficiency of klotho and vitamin D, increased circulating fibro-
blast growth factor 23 (FGF23), and secondary hyperparathy-
roidism also plays a role in the calcification process [36]. In
addition, iatrogenic factors, in particular the use of calcium-
based phosphate binders and vitamin D analogs, may also
contribute to the pro-calcific state [33].
Apart from the microstructural changes observed in arterial
biopsies from children in CKD, clinically detectable arterial
pathology has been reported even in young children.
Fig. 1 Risk factors, mechanisms and consequences of arterial stiffness Measurement of the carotid intima-media thickness (cIMT)
Abbreviations: cIMT carotid intima-media thickness, CKD chronic kid- by high-resolution ultrasound of the carotid artery is a well-
ney disease, CVD cardiovascular disease, LV left ventricle, LVH left ven- established marker of atherosclerotic burden. Increased cIMT
tricle hypertrophy, MBD mineral-bone disease, VSMC vascular smooth has been observed in children with mild-to-severe CKD, on
muscle cells
dialysis, and after kidney transplantation [5, 37–39]. In early
CKD, dyslipidemia has been associated with increased cIMT
Mechanisms of arterial structural alterations [37], whereas in CKD stages 4–5 [5], and most markedly in
in CKD patients on dialysis [39], CKD-specific risk factors are caus-
ally associated with vascular changes. Direct evidence of cal-
CKD is associated with significant structural changes in the cification, predominantly of the coronary arteries, has been
arterial wall characterized by abnormal vascular remodeling shown on computed tomography in a smaller proportion of
and progressive arterial calcifications. The typical phenotype children with CKD 5 and on dialysis [39, 40].
of uremic arteriopathy consists of arterial wall hypertrophy, Although dysregulated mineral homeostasis and CKD-
reduced elastin content and arterial calcifications [30]. MBD-related factors likely play a central role in arterial struc-
Vascular calcifications are considered to be the hallmark of tural alterations observed in CKD, other factors, such as hy-
CKD-associated arterial disease and may occur in either inti- pertension, oxidative stress, chronic inflammation and aging
mal or medial layers of the arterial wall. Intimal calcifications may also contribute to vascular damage. Arterial
are typically observed in older patients when classical athero- hypertension—a widely prevalent complication of CKD—
sclerotic plaques become evident [31]. In contrast, progressive increases pulsatile wall stress in major arteries and contributes
calcification of the tunica media of large arteries, a distinct to progressive elastin fragmentation [41]. Activated inflam-
form of CKD-associated vasculopathy termed Monckeberg matory cells in uremia produce cytokines that stimulate oste-
sclerosis, develops even in childhood [31, 32]. oblastic transformation of VSMC and release matrix metallo-
Medial calcification is seen even in young patients, and proteinases, cathepsins, and other proteolytic enzymes that
arteries from children with pre-dialysis or dialysis-dependent induce elastin degradation and promote calcification [34].
CKD reveal increased calcium load and hydroxyapatite depo- Recently, accelerated vascular senescence, oxidative DNA
sition within the arterial wall [32]. In vitro studies examining damage, and inflammation, collectively termed
arterial biopsies from patients with CKD have revealed that “inflammaging,” has been shown in children with CKD 5
arterial calcification is a complex, active, and highly regulated and was closely correlated with vascular pathology [42].
 Pediatr Nephrol

Other factors, including endothelial dysfunction, renin- generated at points of impedance mismatch (e.g., arterial
angiotensin-aldosterone system activation, uremic toxins and branching or diameter narrowing). The sum of these reflected
advanced glycation-end products may also affect vascular waves creates a “net” reflected wave which returns to the prox-
morphology to varying extents [34]. imal aorta. The timing when this reflected wave meets the
forward-traveling waveform is critical and determined by
PWV and left ventricular ejection time (heart rate, HR) (Fig.
Arterial stiffness and functional consequences 2). At lower PWV and higher HR, the PW arrives in early
in CKD diastole and allows for increased coronary perfusion during
diastole. On the other hand, in case of a high PWV and low
Increased exposure to potential vascular injuries and afore- HR, the PW arrives in late systole, augmenting systolic BP (and
mentioned structural alterations may alter the function of large PP) in the aorta [6, 8]. This simplified mechanism, however,
arteries and accelerate arterial stiffening in CKD, leading to has been debated, and a pressure augmentation model that in-
several important clinical implications. Arterial stiffness is corporates aortic reservoir pressure and excess pressure related
strongly related to aortic pulse pressure (PP) and is one of to wave propagations and reflections has been proposed [43].
the major contributors to LV afterload (Fig. 2). According to Irrespective of the exact underlying mechanism, arterial
the traditional view, the arterial system was seen as a two- stiffness represents an important mechanism that may damage
element Windkessel where pressure-flow relationships are de- major target organs: the heart, brain, and kidneys (Fig. 1).
termined by arterial compliance and peripheral vascular resis- First, there is strong mechanistic evidence that increased arte-
tance. These arterial properties, along with the cardiac output rial stiffness contributes to increased LV afterload which can
were also considered to be the determinants of PP [43, 44]. result in LV remodeling and LV hypertrophy (LVH) [46]. In
Later, a three-element Windkessel model was proposed that addition to the impaired ventricular-vascular coupling, in-
additionally incorporates aortic characteristic impedance, creased arterial stiffness has also been linked to impaired cor-
which is mainly determined by local aortic stiffness and aortic onary perfusion and myocardial hypoperfusion [47, 48]. The
geometry [43, 45]. combined effect of these sequences can lead to diastolic and
In addition, arterial stiffness contributes to the shape and systolic LV dysfunction and development of clinically overt
magnitude of the aortic pressure waveform (PWf) by another heart failure (HF). These mechanistic notions are supported by
indirect mechanism. According to the classical paradigm, the a meta-analysis of over 17,000 adults that linked increased
aortic PWf is a net result of forward and backward traveling PWV to higher risk of IHD, stroke and CVD events indepen-
waves. LV ejection creates a forward PWf that propagates dis- dent of the conventional risk factors, such as smoking, diabe-
tally towards peripheral tissues and multiple reflected waves are tes, hypertension, or kidney function [49].

Fig. 2 Simplified schematic

representation of pulse wave
forms in healthy subjects and
patients with increased arterial
stiffness. Abbreviations: AC
arterial compliance, AIx
augmentation index, AP
augmented pressure, CO cardiac
output, PP pulse pressure, PPA
pulse pressure amplification, PR
peripheral resistance, PWV pulse
wave velocity, Zao characteristic
aortic impedance
Pediatr Nephrol

A second important consequence of abnormal arterial stiff- Several different parameters may be used to evaluate arte-
ening is the reduced “cushioning” capacity of the stiff arterial rial stiffness in children. In general, they can be categorized
tree which results in the transfer of pulsatile blood flow gen- into (i) elasticity parameters (distensibility, Young’s elastic
erated by intermittent LV contractions into the microvascula- modulus, β-stiffness index), (ii) PWV, and (iii) pulse wave
ture. Organs such as the brain and kidneys that are dependent analysis (PWA)-derived parameters (central BP, augmenta-
on continuous perfusion and have a widely spread low- tion index (AIx)). The mechanistic and technical details of
resistance microvascular network are particularly susceptible these approaches, along with their pros and cons, are outside
to damage caused by the exaggerated pulsatile pressure and the scope of this review and have been discussed elsewhere
flow [50]. Clinical studies in adults without kidney disease [56–58]. Of note, PWA-based parameters that are frequently
have reported the adverse effects of increased arterial stiffness used as markers of arterial stiffness are derived from other
on cognition and kidney function [51, 52]. hemodynamic measures and are not directly representative
of stiffness [57]. Overall, based on its clinical applicability,
strong physiological basis and associations with clinical out-
comes, carotid-femoral PWV (cfPWV) is currently recom-
Measuring arterial stiffness in children mended as the “gold standard” for arterial stiffness assessment
with CKD [59–62]. PWV is also recognized as a proxy of target organ
damage in adult and pediatric hypertension guidelines
Measuring early changes in the arterial system is important to [63–65].
quantify the presence and severity of subclinical arterial dis- Several types of devices for noninvasive assessment of
ease and to evaluate the remote risk of overt CVD develop- cfPWV are available. Noninvasive estimation of cfPWV typ-
ment. Measurements of structural changes are important to ically relies on the calculation of the time (transit time, TT)
understand the degree of premature atherosclerosis or arterial that a pulse waveform takes to travel a distance between two
calcifications but are not directly representative of arterial measurement points in the carotid and femoral arteries
stiffness; patients with CKD show moderate correlation be- (Fig. 3). This involves obtaining PWf in the respective arteries
tween cIMT and parameters of arterial stiffness, but these may by means of applanation tonometry, mechanotransducers, ul-
represent differential arterial response to various vascular in- trasound or oscillometry, and over-the-skin measurements of
juries [5, 53, 54]. While cIMT reflects the degree of premature the travel distance. The TT between the proximal and distal
atherosclerosis in children, arterial stiffness directly represents recording sites is then estimated by calculating the time delay
a functional risk factor of CKD arteriopathy and may have between the two systolic upstrokes (“foot-to-foot” method) of
superior predictive value [53, 55]. PWf (Fig. 3). Some devices, however, employ techniques that

Fig. 3 Examples of travel

distance and transit time
estimations for cfPWV
calculation. Abbreviations: Car
carotid artery, Fem femoral
artery, PWV pulse wave velocity,
SSN suprasternal notch, TT transit
time, T time, Umb umbilicus
 Pediatr Nephrol

involve single point measurements and statistical algorithms alternatives but may provide less reliable results due to the
(transfer functions) to estimate presumed PWV [58]. Among indirect nature of measurements. Device validation is an im-
the noninvasive techniques, magnetic resonance imaging portant aspect and according to the guidelines devices for use
(MRI) provides most accurate TT and distance measurements, in children should be validated in children [61, 78]. Several
but its use is limited in routine pediatric practice [57]. devices have undergone validation in the pediatric population
Common devices and techniques for PWV assessment are against the noninvasive gold standard (SphygmoCor)
summarized in Table 1. (Table 1) [67, 68, 71–73]. Of those, tonometric
Several factors must be considered when choosing the ap- (SphygmoCor and PulsePen) and oscillometric (Vicorder) de-
propriate device for cfPWV measurement in children. vices have gained most popularity in the pediatric CKD
Feasibility of measurements is an important consideration population.
and depends on the age and cognitive function of the child. The inherent differences between the devices for noninva-
Techniques involving tonometric readings or suprasystolic- sive cfPWV measurements preclude direct inter-device com-
inflated brachial cuffs are time-consuming and may be un- parisons of the results. This is partly due to technical differ-
comfortable for younger children leading to measurement fail- ences (e.g., devices using TT and distance measurements vs.
ure [71, 76]. Tonometric recordings also require trained oper- devices using transfer function) but also due to other aspects
ators and strict adherence to quality criteria that may not be of the cfPWV measurement procedure, including travel dis-
possible, making this technique observer-dependent and tance measurements. In adults, 80% of the direct measurement
fraught with bias, particularly in longitudinal follow-up stud- between the carotid and femoral measuring sites or subtraction
ies [77]. Oscillometric or other newer devices, such as Mobil- of the carotid-suprasternal notch (SSN) distance from SSN-
o-Graph or the pOpmetre [58], may be more attractive femoral distance have shown best anatomic and cfPWV

Table 1 Techniques and devices for cfPWV measurements and available data from pediatric studies

Device Method Pathwaya Clinical Validation in Device-specific pediatric

usabilityb children reference values

SphygmoCor (Atcor Medical) Applanation tonometry A, B +++ Gold standard Yes [17, 66]
Single sensor Age: 6–20
ECG-gating required
PulsePen (DiaTecne) Applanation tonometry A +++ Yes [67] Yes [17]
Single sensor Age: 6–20 years
ECG-gating required
SphygmoCor Xcel (Atcor Medical) Carotid tonometry A + Yes [68] No
Femoral cuff, simultaneous
PulsePen ETT (DiaTecne) Applanation tonometry A – No No
Two sensors, simultaneous
Complior (Alam Medical) Piezoelectric mechanotransducers C +++ No Yes [69]
Two sensors, simultaneous Age: 5–17 years
Aortic (Exxer) Piezoelectric mechanotransducers D + No No
Two sensors, simultaneous
Arteriograph (TensioMed) Oscillometric E ++ No Yes [16, 70]
Single brachial cuff Age: 3–22 years
Mobil-o-Graph (IEM) Oscillometric – ++ No Yes [15]
Single brachial cuff Age: 8–22 years
Vicorder (Skidmore Medical) Oscillometric A, B, F ++ Yes [67, 71, 72] Yes [12, 19]
Two cuffs (carotid and Age: 5–19 years
femoral), simultaneous
pOpmetre (Axelife SAS) Two photodiode sensors Height-derived ++ Yes [73] No
(fingers and toes), simultaneous
Doppler ultrasound Doppler probes Height-derived ++ – Yes [74]
ECG gating might be required Age: 0–20 years
MRI MRI Direct estimation + – Yes [75]
Age: 2–28 years

cfPWV carotid-femoral pulse wave velocity, ECG electrocardiography, MRI magnetic resonance imaging
a) A: [Femoral-SSN] – [SSN-Carotid]; B: [Carotid-Femoral] × 0.8; C: [Carotid-Femoral]; D: [Carotid-Femoral] – [Carotid-SSN]; E: [SSN-Symphysis];
F: [SSN-Umbilicus] + [Umbilicus-Femoral] – [SSN-Carotid] (SSN = suprasternal notch)
b) According to the judgment of adult studies by Milan et al. [58]
Pediatr Nephrol

measurement accuracy [61]. A recent study in children has Importantly, arterial stiffness has been correlated with hard
indicated that the subtracted distance estimation is more reli- outcomes in adults with CKD. As in the general adult popu-
able when compared with 80% of the direct measurement lation, increased cfPWV was attributed to higher risk of eGFR
which overestimated the MRI-determined aortic pathway by decline in adults with CKD [85]. Similarly, increased cfPWV
up to 10% [79]. In children, the agreement of the oscillometric was related to cognitive impairment or development of de-
Vicorder device with SpygmoCor was strongly influenced by mentia [82, 86]. Studies of adults with advanced CKD and
pathway calculation for the Vicorder measurements (Fig. 3). on HD also revealed independent associations of PWV with
Subtracted distance and distance calculated via umbilicus, but development of fatal and non-fatal CV events, incident hospi-
not the direct pathway measurement, showed excellent agree- talized heart failure and all-cause mortality [55, 82, 85].
ment between the two devices in several validation studies Importantly, the predictive value of cfPWV appears to out-
[67, 71, 72]. weigh that of conventional blood pressure measurements [82].
All of these considerations must be taken into account The associations of increased cfPWV with adverse outcomes,
when choosing the reference values for cfPWV in children. including all-cause mortality and CV events, are not amelio-
Selected reference data has to be device-specific and sim- rated by kidney transplantation and associations with graft
ilar TT distance calculation (if required) should be dysfunction have also been reported [84].
employed. Comparison of available reference data showed
differences in the established reference values using differ-
ent devices, with a significant difference between measure- Clinical studies in children with CKD
ments obtained with the Arteriograph compared with other
devices [12, 15]. Moreover, height is an important and Data about cfPWV in the pediatric CKD population remains
independent determinant of cfPWV in children; therefore, relatively scarce and largely comes from small case-control
the choice of height or age-standardized reference values is studies (summarized in Supplementary Table 1). In contrast
important [12, 15, 17–19]. Age-specific reference values to the adult population, studies in children with CKD do not
can underestimate PWV in small-for-age children [12]. reveal direct associations between eGFR and cfPWV [5,
This may be of particular importance for accurate stiffness 87–90]. Available evidence suggests that in earlier CKD
assessment in the pediatric CKD population, wherein short stages, when uremia-related risk factors are less pronounced,
stature is prevalent [80, 81]. The availability of device- arterial elastic properties in children remain relatively un-
specific reference values for children is summarized in changed. Two large studies involving children with mild-to-
Table 1 [12, 16, 17, 19, 66, 69, 70, 74, 75]. moderate CKD reported similar cfPWV compared with
healthy children [87, 91]. In fact, the determinants of
cfPWV in children with early CKD stages were age, BP,
and black race [87]—the same as reported in healthy children
Arterial stiffness in CKD: Lessons from adult [12, 15–19]. Studies of children with more advanced CKD,
studies however, have reported increased cfPWV, especially in chil-
dren on dialysis [5, 92–97]. In a large cohort of European
Arterial stiffness has been extensively studied in adults with children with advanced CKD, increased cfPWV was reported
CKD, and landmark studies, such as the Chronic Renal in 20% of the study population [5]. Interestingly, increased
Insufficiency Cohort (CRIC) study, have clearly established cIMT was observed in over 40% of participants in this study
a link between advancing CKD and increasing arterial stiff- and showed only a moderate correlation with cfPWV, imply-
ness [82]. In over 2500 adults from the CRIC study, cfPWV ing that structural changes in the arteries precede the develop-
increased by 0.23 m/s per each 10 ml/min/1.73 m2 decrease in ment of vascular stiffness.
estimated glomerular filtration rate (eGFR) [82]. In CKD 5 In contrast to the findings in those with early kidney dys-
patients the dialysis modality has an important effect on arte- function, the determinants of cfPWV in children with ad-
rial stiffness, with accelerated stiffening on hemodialysis vanced CKD and on dialysis are in line with the findings of
(HD) as compared with peritoneal dialysis (PD). The differ- arterial biopsy studies. Several studies have reported strong
ences are mainly related to residual kidney function and associations of cfPWV with markers of CKD-MBD, includ-
higher volume overload in patients on HD who also dem- ing serum fetuin A or fetuin A/Ca × P ratio, parathyroid hor-
onstrate cyclical pre-/post-HD session variability in mone (PTH), bone alkaline phosphatase, and lower levels of
cfPWV [83]. The benefits of kidney transplantation on ar- vitamin D [5, 39, 94, 98, 99]. In addition, a dose-dependent
terial stiffness and cfPWV remain unclear and may be in- effect of treatment with active vitamin D on increased cfPWV
fluenced by the change in risk factor profile, but patients was observed in children on dialysis and after kidney trans-
with a kidney transplant have a higher cfPWV compared plantation [39, 81, 98]. Furthermore, the gut-derived uremic
with the healthy adult population [84]. toxin indoxyl sulfate, but not p-cresyl sulfate, was
 Pediatr Nephrol

independently predictive of cfPWV increase over 12 months reported a significant decrease of cfPWV over time in patients
in children with CKD [100]. Whether this represents an effect on HD and HDF. In the 3H Study, HDF attenuated progres-
of altered gut microbiota remains unclear, but microbiota sion of cIMT when compared with HD, but the annualized
composition was not correlated with cfPWV in children with change of cfPWV did not differ between patients on conven-
mild CKD [89]. tional HD and HDF. The determinants of cfPWV in this large
BP appears to be the only factor independently and strong- multicenter cohort were interdialytic weight gain, BP, lower
ly associated with cfPWV in children across all CKD stages hemoglobin, and higher PTH [108].
[5, 87, 90, 96, 101, 102]. Higher PWV has been reported in A longitudinal study of 15 children who underwent kidney
patients with different ABPM profile abnormalities [90], and a transplantation after previous HD did not reveal a significant
recent study reported night-time and sustained hypertension to change in cfPWV within 6 months after the transplantation
be independent predictors of PWV in children with CKD. [109]. However, a study investigating the effects of pre-
Interestingly, lower PWV was observed in patients with a emptive KRT initiation in children with CKD 5 showed that
normal ABPM profile taking antihypertensive medications pre-emptive kidney transplantation was associated with a de-
compared with untreated patients [101]. Whether this is relat- crease of cfPWV compared with the initiation of dialysis
ed to the possible beneficial effect of frequently prescribed [110]. Irrespective of the dynamic changes, arterial stiffness
RAS inhibitors on arterial stiffness in pediatric CKD is in- appears to remain increased in the pediatric kidney transplant
triguing [41]. Studies in pediatric CKD did not demonstrate population [97, 98, 109] and may relate to a novel spectrum of
direct associations with body mass index (BMI) and increased risk factors. Studies in children, however, did not report a
arterial stiffness [5, 87]. However, recently both underweight significant effect of calcineurin inhibitors or obesity on arterial
and overweight children with CKD and on PD have been stiffness [109, 111]. Instead, cumulative calcitriol dose, dial-
reported to be at increased risk of higher PWV. In addition, ysis for more than 1 year, and impaired kidney function have
lower adipose tissue mass was independently associated with been linked to cfPWV augmentation [81, 98]. Of note, pa-
lower odds of increased PWV [93]. The U-shaped relationship tients with a decrease in cfPWV after kidney transplantation
of PWV with BMI may reflect the importance of the had better graft function [109].
malnutrition-inflammation-arteriopathy axis [103] and resem- Although available evidence suggests that arterial stiffness
ble the associations between cholesterol and mortality in is prevalent in children with advanced CKD, studies of its
adults with CKD [104]. functional consequences and long-term effects on CVD out-
Similar to BMI, direct independent associations of PWV comes in adult life are still lacking. PWV was not associated
with dyslipidemia were not identified in children with pre- with LVMI in a small study of children on HD but correlated
dialysis CKD [5, 87]. Instead, current evidence suggests that in children with autosomal dominant polycystic kidney dis-
the effects of traditional CV risk factors cannot be directly ease [107, 112]. In contrast, in the adult CKD population,
transferred to the pediatric CKD population and may be sig- increased PWV was associated with structural remodeling of
nificantly confounded by the uremic milieu. For instance, it the left ventricle and left atrium, myocardial fibrosis and LV
has been shown that qualitative changes in HDL, but not twist mechanics [113–115]. Whether other CKD-related risk
quantitative lipid abnormalities, may induce vascular injury factors of LV remodeling surpass the effect of arterial stiffness
and associate with arterial stiffness in pediatric CKD. Nitric in children requires further studies. One of the explanations
oxide (NO) release induced by high-density lipoprotein for these differences, however, could be age dependency of
(HDL) cholesterol, but not HDL levels, was significantly cor- the hemodynamic effects of PWV on LV afterload. In a study
related with cfPWV [105]. Two other studies also reported that included adults of different age, increased PWV in youn-
correlations between markers of the NO pathway and ger patients may be a consequence of increasing velocity of
cfPWV in children with pre-dialysis CKD [90, 106]. The re- myocardial shortening and may represent increased intraven-
lationship between endothelial dysfunction and cfPWV was tricular PWV [116].
further demonstrated by a study which showed an indepen-
dent association between cfPWV and circulating endothelial
microparticles [102]. Conclusions and implications for future
The effects of kidney replacement therapies (KRT) on ar- research
terial stiffness in the pediatric population have not been stud-
ied extensively. Increased cfPWV has been reported in chil- Increased arterial stiffness is an important risk factor that cor-
dren on PD, HD, and after kidney transplantation with the relates with arterial disease and has been linked to adverse
highest values in children on HD [80, 81, 92–95, 98, 102, cardiac, kidney, and cognitive outcomes in adult populations.
107]. Although patients on HD demonstrate highest arterial PWV is a validated and feasible technique that allows for
stiffness, a recent study investigating the effects of noninvasive evaluation of arterial stiffness in children but
hemodiafiltration (HDF) on heart and height (3H Study) careful considerations must be made in choosing the
Pediatr Nephrol

appropriate techniques and reference data. Current evidence Biol 32:2516–2524. https://doi.org/10.1161/ATVBAHA.112.
252114
indicates accelerated arterial stiffening in children with CKD,
8. London GM, Pannier B (2010) Arterial functions: how to interpret
but the exact mechanisms and consequences remain to be the complex physiology. Nephrol Dial Transplant 25:3815–3823.
clarified. Prospective longitudinal studies with a particular https://doi.org/10.1093/ndt/gfq614
focus on the association with CV and kidney outcomes in 9. Chirinos JA (2012) Arterial stiffness: basic concepts and measure-
ment techniques. J Cardiovasc Transl Res 5:243–255. https://doi.
early CKD are needed to describe the natural course and
org/10.1007/s12265-012-9359-6
long-term effects of arterial stiffening in childhood. Finally, 10. Cavalcante JL, Lima JAC, Redheuil A, Al-Mallah MH (2011)
studies investigating interventions targeting major risk factors Aortic stiffness. J Am Coll Cardiol 57:1511–1522. https://doi.
of arterial stiffness—CKD-MBD, arterial hypertension, and org/10.1016/j.jacc.2010.12.017
11. Martyn C, Greenwald S (1997) Impaired synthesis of elastin in
inflammation—should consider including cfPWV as a surro-
walls of aorta and large conduit arteries during early development
gate marker of arterial health. as an initiating event in pathogenesis of systemic hypertension.
Lancet 350:953–955. https://doi.org/10.1016/S0140-6736(96)
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