NDT Advance Access published August 8, 2013
Nephrol Dial Transplant (2013) 0: 1–7
doi: 10.1093/ndt/gft288
Original Article
A single-blind randomized controlled trial to evaluate the effect
of 6 months of progressive aerobic exercise training in patients
with uraemic restless legs syndrome
Christoforos D. Giannaki1,2,
Georgios M. Hadjigeorgiou2,3,
2,4
Christina Karatzaferi ,
Maria D. Maridaki5,
2,4
Yiannis Koutedakis ,
Paraskevi Founta6,
Nikolaos Tsianas6,
2,7
Ioannis Stefanidis
2,4,7
and Giorgos K. Sakkas
Correspondence and offprint requests to: Giorgos
K. Sakkas; E-mail: gsakkas@med.uth.gr
A B S T R AC T
Background. Uraemic restless legs syndrome (RLS) affects a
significant proportion of patients receiving haemodialysis
(HD) therapy. Exercise training has been shown to improve
RLS symptoms in uraemic RLS patients; however, the mechan-
ism of exercise-induced changes in RLS severity is still
unknown. The aim of the current randomized controlled
exercise trial was to investigate whether the reduction of RLS
severity, often seen after training, is due to expected systemic
exercise adaptations or it is mainly due to the relief that leg
movements confer during exercise training on a cycle erg-
ometer. This is the first randomized controlled exercise study
in uraemic RLS patients.
Methods. Twenty-four RLS HD patients were randomly as-
signed to two groups: the progressive exercise training group
(n = 12) and the control exercise with no resistance group
(n = 12). The exercise session in both groups included intra-
dialytic cycling for 45 min at 50 rpm. However, only in the
progressive exercise training group was resistance applied, at
1
© The Author 2013. Published by Oxford University Press on
behalf of ERA-EDTA. All rights reserved.
1
Department of Life & Health Sciences, University of Nicosia,
Nicosia, Cyprus,
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2
Centre for Research and Technology—Hellas, Trikala, Greece,
3
Faculty of Medicine, Department of Neurology, University of
Thessaly, Larissa, Greece,
4
Department of PE and Sport Science, University of Thessaly,
Trikala, Greece,
5
Department of PE and Sport Science, University of Athens, Athens,
Greece,
6
Nephrology Clinic, General Hospital of Trikala, Trikala, Greece and
7
Faculty of Medicine, Department of Nephrology, University of
Thessaly, Larissa, Greece
Keywords: depression, exercise with no resistance, haemodia-
lysis, sleep disorder, sleep quality
60–65% of maximum exercise capacity, which was reassessed
every 4 weeks to account for the patients’ improvement.
The severity of RLS symptoms was evaluated using the
IRLSSG severity scale, functional capacity by a battery of tests,
while sleep quality, depression levels and daily sleepiness
status were assessed via validated questionnaires, before and
after the intervention period.
Results. All patients completed the exercise programme with
no adverse effects. RLS symptom severity declined by 58%
(P = 0.003) in the progressive exercise training group, while a
no statistically significant decline was observed in the control
group (17% change, P = 0.124). Exercise training was also ef-
fective in terms of improving functional capacity (P = 0.04),
sleep quality (P = 0.038) and depression score (P = 0.000) in
HD patients, while no significant changes were observed in the
control group. After 6 months of the intervention, RLS severity
(P = 0.017), depression score (P = 0.002) and daily sleepiness
status (P = 0.05) appeared to be significantly better in the pro-
gressive exercise group compared with the control group.
Conclusion. A 6-month intradialytic progressive exercise
training programme appears to be a safe and effective
 approach in reducing RLS symptom severity in HD patients.
It seems that exercise-induced adaptations to the whole body
are mostly responsible for the reduction in RLS severity score,
since the exercise with no applied resistance protocol failed to
improve the RLS severity status of the patients.
Clinical Trial Registry number. NCT00942253.
INTRODUCTION
Restless legs syndrome (RLS) prevalence in haemodialysis
(HD) patients reaches ∼30%, and it is significantly higher than
in the general population [1]. Despite the high prevalence and
great impact of the syndrome in the HD population, limited
data are available regarding any non-pharmacological treat-
ment options to reduce symptom severity.
Uraemic RLS has attracted increasing attention during the
last decade since published evidence revealed that this form of
secondary RLS could induce further reductions in the patient’s
quality of life, depression and sleep quality [2–4], whereas the
symptom severity was associated with an increased risk of death
[4,5]. In addition, recent studies from our group shed light on a
possible association between uraemic RLS and muscle atrophy
[2] and a contribution from periodic limb movements in sleep
(a common characteristic of RLS patients) to the presence of
ORIGINAL ARTICLE
left-ventricle structure abnormalities [6]. Taken together, these
findings indicate the need of not only investigating further the
impact of uraemic RLS but also devising alternative successful
treatments—free of the dopamine agonist-related side effects
[7]—in this specific patient population, in order to confer
symptom relief and improve morbidity and mortality rates.
Previous data have shown that a 14-week intradialytic exercise
training programme reduced RLS symptom severity by 42%
compared with a non-exercising control group. In that study, sig-
nificant improvements were also observed in quality of life levels,
sleep quality and depression score of exercising HD patients [8].
Even though the outcomes of the above study were very promis-
ing, a randomized controlled study of longer duration was
needed in order to gain a clearer view of the effects of exercise
training on uraemic RLS symptoms, as there may be a possibility
that the acute relief to the discomfort induced by RLS, as con-
ferred by leg movements, could be the dominant effect.
The current study was designed to answer the question
whether the improvement in the severity of RLS symptoms ob-
served after exercise training may be due to systemic training
effects or due to the relief conferred by legs movement during
an exercise session.
We hypothesized that the changes in RLS severity score
seen in HD patients with RLS are probably due to the exercise-
induced systemic effects and rather than to an acute move-
ment-induced RLS relief.
SUBJECTS AND METHODS
Subjects
Twenty-four uraemic RLS patients were recruited from the
HD units of the University Hospital of Larisa and the General
2
C. D. Giannaki et al.
Hospital of Trikala, both located in the region of Thessaly in
central Greece. RLS diagnosis was based on the criteria set by the
International RLS Study Group (IRLSSG) [9], while the severity
of the symptoms was assessed using the IRLSSG severity rating
scale [10]. The study adhered to the Declaration of Helsinki and
ethical approval was obtained by the Human Research and
Ethics Committee at the University of Thessaly and the two hos-
pitals, while all patients gave their written informed consent.
The inclusion criteria were dialysis for at least ≥3 months
with adequate dialysis delivery (Kt/V) and with stable clinical
condition. The exclusion criteria included diagnosed neuropa-
thies or reasons for being in a catabolic state within 3 months
prior to the start of the study or being unable to exercise. None
of the recruited patients were engaged in any systematic exer-
cise training programme, and none of them has been treated
with any medication for RLS prior to the study. A neurologist
skilled in RLS (GMH) examined the patients in order to assess
any potential augmentation phenomena during the study
period, using the standard criteria [9].
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Aerobic exercise training
The patients were randomized in a 1:1 fashion to either
progressive exercise training or a no-resistance exercise
(control) group. The randomization procedure was completed
using customized randomization software. After the ran-
domization procedure, patients were asked to change their HD
day or shift (morning or afternoon session) in order to match
with the intervention arm in which they were randomized.
Patients were randomized separately based on the host hospi-
tal (Hospital 1, n = 12, Hospital 2, n = 12). The exercise train-
ing intervention programme included aerobic exercise
(cycling) for 45 min during the HD session three times per
week for a 6-month period. Cycling in the progressive exercise
training group was performed in a recumbent cycle ergometer
(Model 881 Monark Rehab Trainer, Varberg, Sweden) at an
intensity of 60–65% of the patient’s maximal exercise capacity
(in Watts), which was estimated during a previous HD session
using a maximal ergometer ramp test [11]. The exercise inten-
sity was readjusted every 4 weeks to account for the patients’
improvement. The no-resistance programme also involved
cycling during the dialysis session for 45 min, three times per
week, for a 6-month period on the same ergometer, but
without the application of resistance. The patients of both
groups exercised under the supervision of an exercise physiol-
ogist, during different dialysis days in order to sustain the
single-blind design. In order to avoid any potential acute
effects of exercise on the examined variables (RLS severity), all
assessments performed 48 h after the last exercise session.
Functional capacity of the patients was assessed using a battery
of test including the North Staffordshire Royal Infirmary test
(NSRI), the sit to stand 5 repetitions (STS5) and the sit to
stand 60 seconds (STS60) as previously described [2].
Haemodialysis procedure
The patients received the HD therapy (Fresenius 4008B,
Oberursel, Germany) three times per week with low-flux,
hollow-fiber dialysers and bicarbonate buffer, with each
session lasting ∼4 h. All patients had a forearm arteriovenous
fistula as a vascular access to receive the HD treatment. An en-
oxaparin dose of 40–60 mg was administered intravenously Table 1. Patient characteristics at baseline
before the beginning of each HD session. EPO therapy was divided into two groups according to the
given after the completion of the HD session in order to nor- assigned intervention
malize haemoglobin levels within 11–12 (g/dL).
Variables Exercise Control
Subjective sleep quality, depression and daily sleepiness group group
status assessment n 12 12
The patient’s subjective sleep quality levels were assessed by Female/Male 3/9 4/8
using a weekly sleep diary [12]. The HD patient’s depression
score was evaluated by using the self-rating depression scale Age (year) 59.2 ± 11.8 58.0 ± 10.7
2
developed by Zung [13]. Finally, the HD patient’s daily sleepi- BMI (kg/m ) 27.7 ± 3.6 26.5 ± 4.4
ness status was assessed by using the Epworth sleepiness scale Kt/V 1.1 ± 0.0 1.2 ± 0.0
(ESS) [14].
Months in HD 24.0 ± 15 30 ± 26
Biochemical assessment Iron (μg/dL) 55.0 ± 37.0 72.2 ± 17.9
The patient’s routine monthly laboratory results were re- Ferritin (ng/dL) 208.5 ± 88.0 216.9 ± 111.0
corded including iron, ferritin haematocrit, haemoglobin,
Hct 34.4 ± 6.2 38.5 ± 3.3
albumin and dialysis efficiency parameters. A single-pool Kt/V

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was calculated from pre- and post-dialysis BUN measurements Hb (g/dL) 10.9 ± 2.1 12.7 ± 1.1
using the Daugirdas II equation [15] at baseline and at the end Albumin (g/dL) 4.1 ± 0.2 4.4 ± 0.4
of the 6-month intervention. The biochemical analysis was
performed at the clinical biochemistry laboratory of the Uni- BUN (mg/dL) 98 ± 21 101 ± 18
versity Hospital of Larissa under standard hospital procedures. Phosphorus (mg/dL) 5.4 ± 1.2 5.4 ± 1.3

ORIGINAL ARTICLE
PTH (pg/mL) 312 ± 212 298 ± 289
Statistical analysis
Medication
The baseline values of each outcome measure were com-
pared with the values obtained at 6 months by generalized Antihypertensive 8 (66%) 7 (58%)
linear model (GLM) repeated measures. Categorical variables Anticholesteraemic 6 (50%) 6 (50%)
were analysed using Chi-square analysis. Continuous variables
Cardiac supportive 7 (58%) 8 (66%)
were analysed using an independent sample t-test. In the case
of outcome variables which changed in the same direction in Peptic disease 2 (16%) 1 (8%)
both the progressive exercise and control groups, between- therapy
group comparisons were also performed (comparing Δ- Other 3 (25%) 5 (41%)
change values) to determine whether the change in one group
Diabetes prevalence 1 (8%) 1 (8%)
was significantly greater than that of the other group. Spear-
man’s rank correlation test was used to assess the relationships Cardiovascular disease 2 (17%) 3 (25%)
between the examined variables. All statistical analyses were prevalence
performed using the SPSS version 18.0 (SPSS Inc. Chicago, Il- All data are expressed as mean ± SD. No statistical differences
linois). Data are presented as mean ± SD and the level of stat- were observed between the two groups. BMI, body mass index;
istical significance was set at P ≤ 0.05. Kt/V, dialysis efficiency; Hct, haematocrit; Hb, haemoglobin.

R E S U LT S
All of the patients successfully completed the 6-month inter-
vention programme with no adverse effects and no augmenta-
tion phenomena to report. The patient characteristics at
baseline are presented in Table 1. No significant differences in
the patients’ basic characteristics were found between the two
groups (P > 0.05). None of the basic characteristics were sig-
nificantly changed after the intervention period, except for the
Kt/V which significantly improved in the progressive exercise
training group compared with its respective baseline value
(1.10 ± 0.0 baseline versus 1.25 ± 0.1 post exercise, P = 0.041).
In contrast, no significant differences were found in Kt/V for
the control group (1.2 ± 0.0 baseline versus 1.2 ± 0.4 post
exercise, P > 0.05). None of the biochemical indices measured
in the current study changed statistically after the 6 months in-
tervention in either of the groups.
Changes in IRLS severity score, sleep quality, daily sleepi-
ness and depression score are presented in Table 2. At base-
line, no significant differences were observed between the two
groups in sleep quality, daily sleepiness status, depression
score and IRLS score (P > 0.05). However, after the 6-month
intervention, statistically significant improvements were found
in sleep quality (P = 0.038), depression score (P = 0.000) and
IRLS score (P = 0.003) in the progressive exercise training
group compared with its respective baseline values. In con-
trast, no significant changes were observed in the examined

3
Therapeutic exercise training for uraemic RLS
 Table 2. Sleep quality, daytime sleepiness,
depression and RLS symptom severity data
divided into two groups according to the
assigned intervention
Variables Exercise group Control
group
Sleep Diary
Baseline 9.0 ± 5.1 10.7 ± 3.5
†P=0.038
6-month post 7.2 ± 4.3 9.4 ± 3.1
Δ Change −1.8 ± 2.5 −1.3 ± 3.5
F I G U R E 1 : RLS severity scale score at baseline and after the 6-
95% CI of Δ −3.3 ± −0.2 −3.5 ± 0.9 month intervention. At baseline the two groups did not differ. The
change progressive exercise training group improved significantly (P = 0.003),
ESS while no significant changes were observed in the control group
(P > 0.05). After the intervention period there was a significant differ-
Baseline 5.0 ± 2.7 7.8 ± 5.3 ence between the groups (P = 0.017). All data are mean ± SD. IRLS,
6-month post 5.0 ± 1.8 6.9 ± 3.3 International Restless Legs Syndrome severity rating scale; ns = non-

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significant differences.
Δ change −0.1 ± 2.7 −0.9 ± 5.0
95% CI of Δ −1.8 ± 1.6 −4.0 ± 2.2
change
Table 3. Functional capacity data divided into
Zung depression scale two groups according to the assigned
ORIGINAL ARTICLE

Baseline 45.1 ± 6.5 44.7 ± 12.7 intervention.

†P=0.000
6-month post 34.2 ± 7.0 43.7 ± 6.7
Variables Exercise group Control
Δ change −10.9 ± 6.0# P=0.020
−1.0 ± 11.6 group
95% CI of Δ −14.7 ± −7.0 −8.3 ± 6.3 NSRI (seconds)
change
Baseline 92.0 ± 17.3#P=0.019 62.0 ± 15.9
IRLS score †P=0.047
6-month post 82.3 ± 26.0 60.0 ± 14.1
Baseline 25.4 ± 9.3 22.0 ± 7.2
Δ Change −9.6 ± 14.1 −1.9 ± 5.5
6-month post 10.7 ± 8.5†P=0.003 18.3 ± 7.8
95% CI of Δ −19.2 ± −0.1 −7.1 ± 3.1
Δ change −14.7 ± 7.9#P=0.007 −3.6 ± 7.1 change
95% CI of Δ −19.7 ± −9.6 −8.1 ± 0.9 STS-5 (repetitions)
change
Baseline 10.7 ± 2.0 9.1 ± 0.7
All data are expressed as mean ± SD. IRLS, International Restless
Legs Syndrome severity scale; †significantly different from the
6-month post 8.5 ± 2.5†P=0.003 8.5 ± 1.5
respective baseline value. #Significantly different than the control Δ change −2.2 ± 1.9 #P=0.045
−0.6 ± 1.3
group.
95% CI of Δ −3.5 ± −0.9 −1.6 ± 0.4
change
STS-60 (s)
variables in the control group (P > 0.05). Moreover, Δ-change
Baseline 24.7 ± 3.2 28.2 ± 1.9
values were different between the two groups in depression
†P=0.005
and IRLS scores (P > 0.05). After the 6-month intervention 6-month post 30.3 ± 6.8 30.0 ± 2.2
period, RLS severity (P = 0.017) (Figure 1), depression score Δ change 5.6 ± 4.7# P=0.052
1.7 ± 2.7
(P = 0.002) and daily sleepiness status (P = 0.05) appeared to
be significantly better in the progressive exercise group com- 95% CI of Δ 9.0 ± 2.1 4.2 ± −0.8
change
pared with the control group.
Moreover, the Δ-change values in sleep quality correlated All data are expressed as mean ± SD. STS-5, sit-to-stand test five-
significantly with the Δ-change values in Kt/V (r = 0,946, repetitions; STS-60, sit-to-stand test 60 s; NSRI, North
P = 0.000). Functional capacity was improved after the Staffordshire royal infirmary test.
6 months of the training regime however only in the Exercise
#
Significantly different than the control group. †Significantly
different from the respective baseline value.
group compared to the control (Table 3).

4
C. D. Giannaki et al.

DISCUSSION
This is the first randomized controlled exercise intervention
study investigating the effects of progressive exercise training
on RLS symptoms in HD patients with RLS. In the current
study, it was shown that a 6-month intradialytic progressive
aerobic exercise training regime was safe (no adverse effects
were reported), effective in reducing the severity of RLS symp-
toms and beneficial in improving sleep quality and depression
score. Such benefits were not observed in the control group.
Recently, exercise training was shown to be a safe and effec-
tive low-cost approach in reducing the RLS symptom severity
in HD patients [8]. Moreover, acute exercise appeared to be
very effective in reducing acute motor symptoms often seen
during HD session in the same type of patients [16].
Apart from the effect of exercise training on RLS symp-
toms, it is well known that this type of non-pharmacological
approach can also confer many beneficial physiological adap-
tations that impact on the patient’s quality of life and health
[17] adding significant clinical value to this approach. In
addition, the application of exercise training as a monotherapy
or in combination with the approved pharmacological treat-
ment can significantly limit augmentation and rebound
phenomena as well as a number of side effects because it
allows for a lower pharmaceutical dosage for the amelioration
of the RLS symptoms [7].
Our data show that intradialytic progressive exercise train-
ing effectively reduced uraemic RLS symptoms by almost 60%,
without adverse effects or augmentation phenomena. In line
with the reduction in RLS severity, both sleep quality and
depression score significantly improved with the exercise
training programme, further highlighting the beneficial effect
of exercise on these important health-related parameters. In-
terestingly, while there were no differences between the groups
at baseline, after the 6 months of intervention, RLS severity,
depression score and daily sleepiness status appeared to be sig-
nificantly better in the progressive exercise group compared
with the control group (Table 2).
Notably, this is the first study to show that some specific ex-
ercise-induced adaptations or responses must be responsible
for the improvements seen in the RLS severity score and not
just leg movement, which we know confers acute relief (as this
is the first study to employ an exercise training control group,
i.e. exercise with no resistance, and to thus also account for
any placebo effect previously unaccounted for in past exercise
versus non-exercise studies). What mechanism(s) by which
progressive exercise training may reduce RLS symptomatology
is still unclear, however, in a recent study in non-uraemic RLS
patients, an inverse relationship between β-endorphin release
after exercise training and the periodic limb movements index
was observed [18]. The amelioration of RLS symptoms
through an increase in the opioid levels such as β-endorphins
appears to be one of the strongest candidates as a mechanism,
since it is known that RLS is related to a defective opioid
system in the brain in this type of patients [19] while in pre-
vious studies, opioid treatment resulted in a successful im-
provement of RLS symptom severity [20]. In addition, a
5
possible pathway by which progressive exercise training could
affect RLS severity is the exercise-induced improvements in
HD efficiency. In the current study, a significant improvement
in Kt/V was found only in the progressive exercise group. We
should note that some studies associated inadequate dialysis
with RLS [21,22], while others do not support this hypothesis
[5,23]. Interestingly, the application of home short HD ses-
sions resulted in significant improvements in RLS symptom
severity score in a recent study by Jaber et al. [24]. In the HD
population, inadequate dialysis could induce sleep deprivation
and significantly reduce sleep quality [25]. In the past, we have
shown how aerobic exercise training improves sleep quality in
HD patients with RLS [8]. In the current study, the changes in
sleep quality after the exercise training in the progressive exer-
cise group correlated strongly with the respective changes in
Kt/V (r = 0.946, P = 0.000), thus indicating a possible associ-
ation of HD adequacy with sleep, possibly mediated by the
known favourable systemic effects of exercise.
The effect of dialysis efficiency on the severity of RLS symp-
toms is still controversial [25,26]. Interestingly, in the current
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study, the Kt/V index appeared to be significantly increased
after the progressive exercise training intervention confirming
previous data in HD patients with unknown RLS status [27];
however, the Δ changes in Kt/V correlated only with the Δ
change in sleep quality and not with the Δ change in IRLS
ORIGINAL ARTICLE
severity score, continuing this discrepancy with Kt/V.
Studies have shown that sleep quality is diminished in
HD patients [28], while it seems that this phenomenon is
more intense in the patients with RLS [2,3]. The data of the
present study reveal that exercise training significantly im-
proved sleep quality even though the assessment was done by
a questionnaire (which is a less sensitive method than poly-
somnography). Changes in sleep quality could be a result of
improvement in depression score or vice versa [29]; however,
no significant correlation between the depression score and
the sleep quality was observed in our study. It is possible that
exercise training could have influenced these two parameters
in an independent way; however, further research is needed in
order to address this issue. On the other hand, exercise train-
ing failed to improve further the levels of daily sleepiness;
however, we should note that the mean values of both groups
regarding the ESS score were found to be above the cut-off
threshold of daily sleepiness (>10). This is also observed by the
classical pharmacological treatment used in RLS (dopamine
agonists) showing no improvements in daily sleepiness in
patients with idiopathic RLS [30]. It seems that daily sleepi-
ness, unless it is very severe, does not change after either exer-
cise or medication treatment; however, more work is needed
on this issue to reach firm conclusions.
Limitations
Even though RLS is not a sleeping disorder, it would be
very helpful if we were able to perform an overnight polysom-
nographic study in order to objectively evaluate sleep quality
and quantity as well as an RLS-related movement disorder oc-
curring during sleep called periodic limb movements in sleep.
In addition, the IRLS severity score was not assessed during
Therapeutic exercise training for uraemic RLS
 the 6-month period and, therefore, it is not possible to assess
the course of IRLS score change during the study time. A
limited number of exercise sessions were characterized as ‘in-
complete’, i.e. when the patients were unable to complete the
full 45 min cycling due to personal reasons. Unfortunately,
those events were not systematically recorded, thus we are
unable to comment on whether the level of compliance, which
we however gauge as very high, could affect the final outcomes.
Finally, we were not able to assess the levels of β-endorphin
during the course of the study or during an exercise bout and
have to thus rely on available bibliography to surmise a poss-
ible mechanism.
CONCLUSIONS
As this is the first study to employ a no-resistance exercise
control, and we observed an improvement in RLS symptoms se-
verity only with progressive exercise training, we conclude that
the exercise-induced amelioration of RLS symptoms is possibly
mostly due to chronic exercise-induced adaptations rather than
due to an acute relief conferred by leg movements per se. Six
months of intradialytic progressive exercise training appeared to
have a positive effect on uraemic RLS symptoms with parallel
changes in the patients’ sleep quality and depression. Further re-
ORIGINAL ARTICLE
search is needed in order to clarify the exact mechanism by
which systematic exercise training could affect the dopaminergic
system of the brain in the HD patients with RLS.
AC K N O W L E D G E M E N T S
We thank all HD patients who volunteered and participated in
this study as well as all the staff at the dialysis units of the Uni-
versity Hospital of Larissa, Greece and General Hospital of
Trikala, Greece for their expert advice and valuable help
during the course of the study.
C O N F L I C T O F I N T E R E S T S TAT E M E N T
None declared. The results presented in this paper have not
been published previously in whole or part, except in abstract
format.
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Received for publication: 28.12.2012; Accepted in revised form: 17.5.2013
Downloaded from http://ndt.oxfordjournals.org/ at Seton Hall on April 3, 2015
ORIGINAL ARTICLE
Therapeutic exercise training for uraemic RLS