Abstract Decreased heart rate variability is an indepen-
dent risk factor for cardiac mortality in hemodialysis
patients. Our aim was to determine whether it is already
present in uremic children and young adults on hemodi-
alysis and following renal transplantation. Twenty-two
hemodialysis patients [age 17.2 years (median, quartiles
13.0–22.6)], 22 transplant patients [18.4 years (14.4–
21.2)], and 29 healthy controls [16.4 years (15.7–21.1)]
were examined. Heart rate and its high (HF) and low
(LF) frequency variability were measured in the supine
position for 10 min. High and low frequency variability
was significantly reduced, whereas heart rate and LF/HF
ratio was significantly elevated in both patient groups
compared with controls. There was a clear-cut difference
between the dialyzed and the transplanted groups based
on the HF variability, with the lowest values in the dialy-
sis group (P<0.01). LF and LF/HF data did not allow us
to distinguish between the patient groups. In conclusion,
heart rate variability in the HF range is a sensitive tool
for detecting cardiovascular autonomic dysfunction that
is already present in children and adolescents with im-
paired kidney function.
Keywords Heart rate · Kidney failure · Sympathetic
nervous system · Vagus nerve
Introduction
Cardiovascular disease is the leading cause of mortality
in adult hemodialysis (HD) patients, accounting for
about 44% of the overall mortality. Between 15 and
30 years of age, the incidence of cardiovascular death is
about two orders of magnitude higher in HD patients
compared with the general population [1, 2, 3]. A num-
ber of possible mechanisms have been proposed to ex-
plain the excess of cardiovascular mortality, including
hypertension, anemia, inflammation, and increased arte-
rial stiffness due to disturbed calcium, phosphate, homo-
cysteine, and lipid metabolism [4, 5, 6, 7, 8, 9]. Recently,
the role of cardiovascular autonomic dysfunction has
been emphasized as an independent risk factor for sud-
den cardiac death in uremia [3, 10]. Traditionally, cardio-
vascular autonomic dysfunction has been assessed by
simple, bedside tests (the so-called Ewing tests) [11].
Using this technique we have demonstrated the presence
of autonomic dysfunction with a dominant parasympa-
thetic involvement in dialyzed children, and its almost
complete resolution following kidney transplantation
[12].
In the past decade, the non-invasive, computerized
evaluation of the variability of heart rate has been proven
to be a potent, sensitive, and reproducible tool for the di-
agnosis of autonomic dysfunction in a number of patho-
logical conditions, including diabetic neuropathy, myo-
cardial infarction, and chronic renal failure [13]. Heart
rate variability (HRV) is the physiological arrhythmia in-
duced by autonomic impulses to the sinus node. Depend-
ing on the frequency range of HRV, it reflects the activity
of the sympathetic and the parasympathetic nervous
system [14]. HRV in the high-frequency range (HFV
0.15–0.4 Hz) is induced mainly by respiration, and medi-
ated by the vagal nerve. Low-frequency variability (LFV
0.15–0.04 Hz) is mediated by both sympathetic and para-
sympathetic impulses [14, 15, 16]. The present study
aimed to assess the autonomic dysfunction of uremic and
transplant (NTX) children and young adults using the
method of HRV.
K. Tory · Z. Süveges · E. Horváth · É. Bokor · P. Sallay
A. Szabó · T. Tulassay · G. S. Reusz
1st Department of Pediatrics, Semmelweis University,
Budapest, Hungary
K. Berta
1st Department of Internal Medicine,
Semmelweis University, Budapest, Hungary
G. S. Reusz (✉)
1st Department of Pediatrics,
Bókay u. 53., 1083 Budapest, Hungary
e-mail: reusz@gyer1.sote.hu
Tel.: +36-1-3343186/2611, Fax: +36-1-3138212
Pediatr Nephrol (2003) 18:1167–1171
DOI 10.1007/s00467-003-1280-4
O R I G I N A L A RT I C L E
Kálmán Tory · Zsuzsanna Süveges
Erzsébet Horváth · Éva Bokor · Péter Sallay
Klára Berta · Attila Szabó · Tivadar Tulassay
György S. Reusz
Autonomic dysfunction in uremia assessed by heart rate variability
Received: 9 April 2003 / Revised: 3 July 2003 / Accepted: 14 July 2003 / Published online: 17 September 2003
© IPNA 2003

Patients and methods
Seventy-three children and young adults participated in the study.
These included 22 HD patients [age 17.2 years (median, quartiles
13.0–22.6)], 22 NTX patients [18.4 years (14.4–21.2)], and 29
healthy controls [16.4 years (15.7–21.1)]. The average time spent
on dialysis was similar in the HD and NTX (considered before
transplantation) groups [HD 12 months (median, range 1–62),
NTX 14 months (9–23)]. NTX patients were transplanted
60 months (mean, range 9–123 months) prior to the study. Pa-
tients’ heart rate and HRV data were compared with those of 29
age-matched healthy volunteers. Glomerular filtration rate (GFR)
was evaluated using the Schwartz equation, with k=49 for girls
and k=62 for boys [17]. Relevant patient characteristics are shown
in Table 1.
HRV measurements
Measurements were performed in a quiet room with a well regu-
lated temperature (23°C). HD patients were examined just before
HD treatment. Patients were supine during the whole examination.
After a 20-min supine resting period, electrocardiography was per-
formed for 10 min, at the end of which blood pressure was deter-
mined using a Cardiotens-01 combined Holter and oscillometric
blood pressure monitor (Meditech, Budapest, Hungary) [18]. Sub-
sequently, a blood sample was drawn for creatinine determination.
Heart rate was calculated as the average of all R waves during
HRV measurements. Electrocardiograms were digitally and visual-
ly processed (Medibase 1.35 software, Meditech). All patients and
subjects were in sinus rhythm. Complexes classified as noise or
ectopic were rejected (<1%). Power spectral density of HRV was
computed in 256-s segments with a 512-point fast Fourier trans-
form algorithm and Hanning windowing. High-frequency (HFV)
and low-frequency (LFV) spectral components were quantified by
measuring the area under the curve between 0.4 and 0.15 Hz and
0.15 and 0.04 Hz, respectively, and were expressed in absolute
values (sec2/Hz) [14, 16]. The ratio of LFV and HFV was comput-
ed (LF/HF). Blood pressure was expressed as height-dependent
standard deviation score [19].
Dialysis
Dialysis was carried out three times weekly for 4 h (median, range
3–5) on Gambro AK 10 systems using cuprophan membranes and
bicarbonate buffering.
Drugs
Fifteen patients in the HD group (68%) and 11 patients in the
NTX (50%) group received antihypertensive treatment. Antihy-
pertensive treatment consisted of an angiotensin converting en-
zyme (ACE) inhibitor [enalapril, 11 HD (50%) and 3 NTX (14%)
patients], a calcium channel blocker [slow-release nifedipine or
amlodipine, 11 HD (50%) and 9 NTX (41%) patients], and/or a
beta-blocker [metoprolol 7 HD (32%) and 5 NTX (23%) patients].
Only the number of patients taking ACE inhibitor differed signifi-
cantly between the two groups (P<0.05, Fisher’s exact test).
All antihypertensive medication was stopped at least 12 hours
prior to the examination. Beta-blockers were stopped for 24 h be-
fore the measurements. We did not intend to stop treatment for any
longer period for ethical reasons.
To study the bias due to the possible effect of antihypertensive
medication, patients without antihypertensive medication (7 HD
and 11 NTX patients) were re-evaluated separately.
Ethics
Written informed consent was obtained prior to entry into the
study. The study conformed to the Helsinki declaration and was
approved by the regional ethics committee (TUKEB25/2000).
Statistical analysis
GFR and heart rate data were normally distributed. HFV and LFV
were log-normally distributed. Age and LF/HF showed a non-
Gaussian distribution. Due to the heterogeneous variance of heart
rate and GFR data, they were compared using Kruskal-Vallis
ANOVA and Mann-Whitney U test evaluated according to Holm’s
method. Differences between lg HFV and lg LFV were assessed
by one-way ANOVA and Newman-Keuls post hoc test. Relation-
ships between HR, lg HFV, and lg LFV were evaluated using
Pearson correlation. Statistical analysis was performed using the
Statistica 5.0 software package.
Data with normal distribution are given as mean and 95% con-
fidence intervals, whereas those with non-Gaussian distribution
are given as median and quartiles (Table 1).
1168
Table 1 Clinical parameters
and heart rate variability data
of the hemodialyzed (HD),
transplant (NTX), and control
groups [HD hemodialysis,
NTX renal transplant patients,
MAP mean arterial pressure,
SDS standard deviation score,
HR heart rate, lg HFV loga-
rithm (base 10) of the high
frequency variability, lg LFV
logarithm (base 10) of the low
frequency variability, LF/HF
the LFV and HFV ratio]
HD NTX Control
n (F/M) 22 (11/11) 22 (10/12) 29 (15/14)
GFR (ml/min per 1.73 m2) 10.4 (9.5–11.2) 68 (58–78) 109 (101–117)
***, 3+ ***
MAP (SDS) 2.78 (0.74–5.56) 2.00 (0.90–2.56) −0.76 (−1.76 to −0.22)
*** ***
HR ( per min) 84 (78–90) 74 (69–79) 64 (61–68)
***, + **
lg HFV 2.43 (2.14–2.71) 2.82 (2.59–3.06) 3.22 (3.08–3.36)
***, 2+ **
lg LFV 2.70 (2.50–2.90) 2.89 (2.73–3.05) 3.18 (3.05–3.31)
*** *
LF/HF 1.78 (1.05–3.27) 1.54 (0.99–2.09) 0.73 {0.50–1.30)
** *
P values (compared with controls) are ***P<0.001, **P<0.01, *P<0.05. P values between HD and
NTX groups are 3+P<0.001, 2+P<0.01, +P<0.05.
MAP and LF/HF values are presented as median (quartiles)
GFR, HR, lg HFV, and lg LFV data are means (95% confidence intervals)