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Management of Hypertension
in Pediatric Dialysis Patients

31

Elke Wühl and Joseph T. Flynn

Abbreviations

Introduction

ABPM
ambulatory
blood
pressure
monitoring
ACEi angiotensin converting enzyme
inhibitor
BP
blood pressure
CAKUT congenital anomalies of kidney and
urinary tract
ESRD

end-stage renal disease
HDhemodialysis
LVH
left ventricular hypertrophy
NO
nitric oxide
PD
peritoneal dialysis
PTH
parathyroid hormone
PWV
pulse wave velocity
RAAS
renin-angiotensin-aldosterone-­system

Patients on maintenance dialysis therapy have an
excessively increased all-cause and cardiovascular morbidity and mortality compared with the
general population. Adolescents and young
adults may already have symptomatic cardiovascular disease, including ischemic heart disease
and stroke, and at least every second child on
dialysis presents with early signs of cardiovascular end-organ damage such as left ventricular
hypertrophy (LVH) or alterations of vascular
morphology and function. One of the main risk
factors for the high cardiovascular morbidity and
mortality is arterial hypertension. The percentage
of hypertensive patients on maintenance dialysis
is up to 80%, and while hypertension in mild-to-­
moderate chronic kidney disease (CKD) is
mainly caused by underlying renal parenchymal
disease, in dialysis patients the most important

factor influencing blood pressure (BP) is fluid
and salt overload.
The aim of this chapter is to review the prevalence and etiology of hypertension and associated cardiovascular morbidity and mortality in
children on dialysis, as well as treatment strategies and targets.

E. Wühl
Center for Pediatrics and Adolescent Medicine,
University Hospital Heidelberg, Division of Pediatric
Nephrology, Heidelberg, Germany
e-mail:
J. T. Flynn (*)
University of Washington School of Medicine,
Division of Nephrology, Seattle Children’s Hospital,
Seattle, WA, USA
e-mail:

© Springer Nature Switzerland AG 2021
B. A. Warady et al. (eds.), Pediatric Dialysis, />
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590

Prevalence of Hypertension
in Pediatric Dialysis Patients
Hypertension is highly prevalent in the pediatric
dialysis population. Almost 4 out of 5 children
and adolescents requiring dialysis are hypertensive or have been prescribed antihypertensive
medication.
In a survey of the European ERA/EDTA registry, comprising more than 1300 pediatric dialysis

patients from 15 European countries, the prevalence of hypertension was 69.7% in hemodialysis
(HD) and 68.2% in peritoneal dialysis (PD)
patients. Forty-five percent of HD and 35% of PD
patients had uncontrolled hypertension [72].
Similar findings have been seen in data from the
North American Pediatric Renal Trials and
Collaborative Studies (NAPRTCS) registry. In an
analysis including almost 3500 children, 67.9%
of patients were found to be hypertensive
6  months after initiation of dialysis [49]. In
another study in long-term HD patients, hypertension was present in 79% of patients. Sixty-two
percent of patients were on antihypertensive
medication; however, hypertension was uncontrolled in 74% of treated patients. [22].
It should be noted that these epidemiologic
data were derived from casual/office BP measurements with single BP recordings per patient
reported to the registries. Hypertension was commonly defined as either systolic or diastolic BP
above the 95th percentile for sex, age and height.
For the interpretation of these data, consideration
of the time of BP measurement is important. Pre-­
dialysis measurements are usually higher compared with post-dialysis measurements, resulting
in a higher probability to be classified as hypertensive when only pre-dialysis measurements are
available. In HD patients, the median (or mean)
interdialytic BP measured by ambulatory BP
monitoring (ABPM) is usually lower compared
with casual pre-dialysis measurements, resulting
in a lower number of patients being classified as
hypertensive by ABPM [51]. When the ABPM
measurement duration has been extended from
the conventional 24  h to 44  h, covering a complete midweek interdialytic period, a higher percentage of patients were diagnosed with

E. Wühl and J. T. Flynn

hypertension and all BP indexes and loads were
significantly higher on interdialytic day 2 compared to day 1 [51]. Volume fluctuations and fluid
overload are probably the most important factors
responsible for the poor diagnostic value of preand post-dialytic BP measurements to predict
hypertension in the interdialytic period [3, 125].
It should also be noted that ABPM may identify patients with nocturnal or masked hypertension [21] and patients with reversed nocturnal
dipping or altered circadian and ultradian BP
rhythms. Unfortunately, data on hypertension
prevalence according to interdialytic ABPM are
scarce [21, 77].

Etiology of Hypertension
in Pediatric Dialysis Patients
The dominant factor contributing to hypertension
in dialysis patients is volume overload; other
contributing factors include activation of the
renin-angiotensin-aldosterone system and the
sympathetic nervous system, endothelial dysfunction, increased arterial stiffness, hyperparathyroidism, and exposure to BP elevating drugs.
Additionally, registry studies have identified
young age, being on HD, having glomerulopathies as the primary renal disease, and shorter
duration of renal replacement therapy as risk factors for dialysis-associated pediatric hypertension [22, 49, 72].
Volume overload plays a pivotal role in the
development of hypertension in dialysis patients.
Several studies in humans have demonstrated a
direct effect of extracellular volume on BP in HD
patients [4, 61, 133], and interdialytic weight
gain has been shown to correlate with higher systolic BP load in 44-h ABPM profiles on the second day of the BP recording [51]. As might be
expected, attainment of dry weight and normalization of sodium balance were able to normalize

BP without the need for antihypertensive medication [16].
In dialysis patients, extracellular volume, cardiac output, and BP are increased by impaired or
absent ability of the kidneys to excrete sodium
and water. These alterations are worsened by


31  Management of Hypertension in Pediatric Dialysis Patients

591

insufficient intradialytic removal of fluid and salt. controlled [71]. In addition, the significant
Therefore, in addition to an adequate dialysis decline in BP that occurs following bilateral
prescription, interdialytic fluid restriction and nephrectomy [138] points to volume-indepenlimited salt intake are therapeutic cornerstones dent mechanisms of hypertension in dialysis
for the attainment of dry weight as part of the patients.
management of hypertension in dialysis patients.
Children with end-stage renal disease showed
However, efforts to compensate for decreasing a 25-fold increase in angiotensin (1–7) compared
residual renal function and diuresis by increasing to control values. These marked changes in
intradialytic sodium and water removal are often plasma angiotensin (1–7) were associated with
insufficient, as seen in one recent study, in which the presence of hypertension and progression of
25% of dialysis-associated hypertension was felt kidney dysfunction [121], while angiotensin II
to be related to factors other than volume over- levels were similar and plasma renin activity was
load [32].
lower compared to hypertensive patients with
Loss of residual renal function is another risk non-ESRD CKD.  In dialysis patients, angiotenfactor for the development of hypertension. BP is sin II was only poorly suppressed by angiotensin
inversely correlated to residual renal function and converting enzyme inhibitor (ACEi) treatment.
hypertensive children on dialysis have less resid- The significance of the elevated angiotensin
ual urine output compared to normotensive chil- (1–7) levels is still not clear, but might be a condren [130].
sequence of the altered RAAS pathway in pediatFluid balance is inextricably linked to serum ric ESRD patients.
sodium concentration. However, the hypertensive

Dialysis patients also have higher sympathetic
effects of sodium are exerted by mechanisms nervous system (SNS) activity and vascular resisboth related and unrelated to extracellular vol- tance than healthy controls or ESRD patients
ume expansion; elevated sodium concentration after bilateral nephrectomies [26]. An early manimay also induce vasoconstriction by altering festation of abnormal activation of the SNS activendothelial cell responses and further contribute ity is the absence of the physiological nocturnal
to the development of hypertension [99].
BP dipping in 24  h ambulatory BP monitoring
It has been demonstrated that intradialytic salt [79].
exposure (i.e., the sodium content of the dialyEndothelial dysfunction, which participates in
sate) has a direct impact on BP. HD patients set to accelerated atherosclerosis, is a hallmark of
time-averaged dialysate sodium concentrations CKD.  Patients with ESRD display impaired
of 147  mEq/L were found to have higher 24-h endothelium-dependent vasodilatation, elevated
systolic BP levels compared to patients set to a soluble biomarkers of endothelial dysfunction,
sodium concentration of 138  mEq/L [124]. and increased oxidative stress. Several uremic
Additionally, a higher dialysate-to-plasma-­ toxins, mostly protein-bound, have been shown
sodium gradient may increase thirst and interdia- to have specific endothelial toxicity: e.g., asymlytic weight gain, impeding attainment and metric dimethylarginine (ADMA), homocystemaintenance of dry weight [115].
ine, and advanced glycosylation end-products
Contrary to the physiologically expected (AGEs). These toxins are insufficiently or not
suppression of the renin-angiotensin-aldoste- removed by dialysis, promote pro-oxidative and
rone system (RAAS) in a state of salt or fluid pro-inflammatory response, and inhibit endotheoverload, plasma renin activity was found to be lial repair, thereby inducing endothelial damage
significantly higher in a study comparing hyper- [64].
tensive to normotensive dialysis patients. The
The most important vasodilatory substance is
study results strongly suggested that the RAAS nitric oxide (NO). The disturbed balance between
is an important factor involved in the pathogen- decreased NO (mediator of vasodilatation) and
esis of hypertension in end-stage renal disease increased endothelin-1 (ET-1; mediator of vaso(ESRD), when sodium balance is adequately constriction) in dialysis patients results in endo-


592

thelial cell dysfunction with increased
vasoconstriction. NO release is reduced by CKD-­

induced elevation of ADMA, an endogenous
inhibitor of endothelial NO synthase. Increased
levels of ADMA have been found to be directly
associated with increased cardiovascular and all-­
cause mortality in the ESRD population [12].
Oxidative stress with increased reactive oxygen
species (ROS) can also interfere with NO synthesis and availability.
As a result, arterial stiffness, usually a problem of vascular aging and arteriosclerosis, is
accentuated in the presence of end-stage renal
disease and hypertension. The stiffened, non-­
compliant arteries transmit each ejected pulse
wave so quickly that the reflected pressure wave,
coming backwards from the peripheral circulation, coincides with the still ongoing systole. The
consequence is increased systolic BP and pulse
pressure resulting in LVH [80]. Higher pulse
wave velocity (PWV) due to increased vascular
stiffness is also present in pediatric ESRD. PWV
is elevated compared to age-, height-, and weight-­
matched controls [68]. However, the elevated
PWV in pediatric ESRD patients was not clearly
correlated with the BP level and was found to be
persistently elevated despite the use of pharmacological vasodilatation.
Another study in pediatric ESRD patients
showed that aortic distensibility, another measure
of arterial stiffness, was lower (i.e., higher arterial stiffness) in both HD and PD patients compared to healthy controls. Children on HD had
more severe impairment than PD patients [110].
Plasma levels of renalase, a protein released
by the kidneys and responsible for the degradation of catecholamines, are markedly decreased
in ESRD. Renalase deficiency and the resulting
increase of circulating catecholamine levels may

also contribute to hypertension and cardiovascular disease in ESRD [30, 137].
Secondary hyperparathyroidism, a complication of CKD, may be yet another contributor to
the high prevalence of hypertension. A retrospective study in adults with pre-dialysis CKD demonstrated that systolic and diastolic BP were
significantly increased in patients with elevated

E. Wühl and J. T. Flynn

parathyroid hormone (PTH) levels [108]. A possible mechanism might be increased platelet
cytosolic calcium in patients with elevated
PTH. Mean BP correlated highly with cytosolic
calcium and PTH.  In contrast, treatment with
vitamin D lowered cytosolic calcium, PTH, and
mean BP significantly.
Therapy with erythropoiesis stimulating
agents, i.e., erythropoietin, is also associated
with an increase of the BP level and development
of hypertension. The prevalence of BP increase
in adults on erythropoietin therapy is given as
high as 10–75%. In a study in 23 pediatric dialysis patients, hypertension developed or worsened
in 67% of CAPD patients and 36% of HD patients
after initiation of erythropoietin, while no differences were observed in plasma level of aldosterone or plasma renin activity [69].
Mechanisms involved in the development of
hypertension and cardiovascular end-organ damage in pediatric dialysis patients are summarized
in Fig. 31.1.
While most pediatric dialysis patients lack
the cardiovascular and metabolic comorbidities
that lead to hypertension in adults with ESRD,
underlying renal disease is another important
factor influencing the BP level in children with
ESRD.

In glomerulopathies, activation of the
RAAS, present from the earliest stages of glomerular disease through ESRD, may complicate BP control. Patients with glomerular
disease are also less likely to be normotensive
compared to patients with congenital anomalies
of the kidney and the urinary tract (CAKUT;
12% vs. 31%) [49] and to have an approximately two-fold higher risk of uncontrolled
hypertension [49, 72].
Patients with autosomal-recessive polycystic kidney disease may have very severe or
therapy refractory hypertension, necessitating
bilateral nephrectomy in some cases. In contrast, patients suffering from CAKUT are less
prone to renal hypertension, and attainment of
dry weight often succeeds in achieving BP
control without the need of additional antihypertensive medication.