Nephrol Dial Transplant (2013) 28: 28342840

doi: 10.1093/ndt/gft288
Advance Access publication 8 August 2013

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
1

Christoforos D. Giannaki1,2,
Georgios M. Hadjigeorgiou2,3,
2,4

Christina Karatzaferi ,

Centre for Research and TechnologyHellas, Trikala, Greece,

Faculty of Medicine, Department of Neurology, University of

Thessaly, Larissa, Greece,

Maria D. Maridaki5,

Yiannis Koutedakis ,

Department of PE and Sport Science, University of Thessaly,

Trikala, Greece,

Paraskevi Founta ,

Nikolaos Tsianas6,

Greece,

Ioannis Stefanidis

2,7

2,4,7

Nephrology Clinic, General Hospital of Trikala, Trikala, Greece and

Faculty of Medicine, Department of Nephrology, University of

Thessaly, Larissa, Greece

and Giorgos K. Sakkas

Keywords: depression, exercise with no resistance, haemodialysis, sleep disorder, sleep quality

Correspondence and offprint requests to: Giorgos

K. Sakkas; E-mail: [email protected]

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 signicant decline was observed in the control
group (17% change, P = 0.124). Exercise training was also effective 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 signicant 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 signicantly better in the progressive 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.

A B S T R AC T
Background. Uraemic restless legs syndrome (RLS) affects a
signicant proportion of patients receiving haemodialysis
(HD) therapy. Exercise training has been shown to improve
RLS symptoms in uraemic RLS patients; however, the mechanism 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 ergometer. This is the rst randomized controlled exercise study
in uraemic RLS patients.
Methods. Twenty-four RLS HD patients were randomly assigned 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 intradialytic cycling for 45 min at 50 rpm. However, only in the
progressive exercise training group was resistance applied, at
6065% 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
The Author 2013. Published by Oxford University Press on
behalf of ERA-EDTA. All rights reserved.

Department of PE and Sport Science, University of Athens, Athens,

2834

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2,4

ORIGINAL ARTICLE

Department of Life & Health Sciences, University of Nicosia,

Nicosia, Cyprus,

Ethics Committee at the University of Thessaly and the two hospitals, 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 neuropathies 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 exercise 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].

INTRODUCTION

SUBJECTS AND METHODS

Haemodialysis procedure
The patients received the HD therapy (Fresenius 4008B,
Oberursel, Germany) three times per week with low-ux,
hollow-ber dialysers and bicarbonate buffer, with each
session lasting 4 h. All patients had a forearm arteriovenous
stula as a vascular access to receive the HD treatment. An enoxaparin dose of 4060 mg was administered intravenously
before the beginning of each HD session. EPO therapy was
given after the completion of the HD session in order to normalize haemoglobin levels within 1112 (g/dL).

Subjects
Twenty-four uraemic RLS patients were recruited from the
HD units of the University Hospital of Larisa and the General
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
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Therapeutic exercise training for uraemic RLS

ORIGINAL ARTICLE

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 randomization 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 hospital (Hospital 1, n = 12, Hospital 2, n = 12). The exercise training 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 6065% of the patients maximal exercise capacity
(in Watts), which was estimated during a previous HD session
using a maximal ergometer ramp test [11]. The exercise intensity 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 physiologist, 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 Inrmary test
(NSRI), the sit to stand 5 repetitions (STS5) and the sit to
stand 60 seconds (STS60) as previously described [2].

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Restless legs syndrome (RLS) prevalence in haemodialysis

(HD) patients reaches 30%, and it is signicantly 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 treatment 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 patients
quality of life, depression and sleep quality [24], 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
left-ventricle structure abnormalities [6]. Taken together, these
ndings indicate the need of not only investigating further the
impact of uraemic RLS but also devising alternative successful
treatmentsfree of the dopamine agonist-related side effects
[7]in this specic 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, signicant 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 promising, 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 conferred 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 observed 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 exerciseinduced systemic effects and rather than to an acute movement-induced RLS relief.

Subjective sleep quality, depression and daily sleepiness

status assessment
The patients subjective sleep quality levels were assessed by
using a weekly sleep diary [12]. The HD patients depression
score was evaluated by using the self-rating depression scale
developed by Zung [13]. Finally, the HD patients daily sleepiness status was assessed by using the Epworth sleepiness scale
(ESS) [14].

Table 1. Patient characteristics at baseline

divided into two groups according to the
assigned intervention
Control
group

12

12

Female/Male

3/9

4/8

Age (year)

59.2 11.8

58.0 10.7

BMI (kg/m )

27.7 3.6

26.5 4.4

Kt/V

1.1 0.0

1.2 0.0

Months in HD

24.0 15

30 26

Iron (g/dL)

55.0 37.0

72.2 17.9

Ferritin (ng/dL)

208.5 88.0

216.9 111.0

Hct

34.4 6.2

38.5 3.3

Hb (g/dL)

10.9 2.1

12.7 1.1

Albumin (g/dL)

4.1 0.2

4.4 0.4

BUN (mg/dL)

98 21

101 18

Phosphorus (mg/dL)

5.4 1.2

5.4 1.3

PTH (pg/mL)

312 212

298 289

Antihypertensive

8 (66%)

7 (58%)

Anticholesteraemic

6 (50%)

6 (50%)

Cardiac supportive

7 (58%)

8 (66%)

Peptic disease
therapy

2 (16%)

1 (8%)

Other

3 (25%)

5 (41%)

Diabetes prevalence

1 (8%)

1 (8%)

Cardiovascular disease
prevalence

2 (17%)

3 (25%)

Statistical analysis
The baseline values of each outcome measure were compared with the values obtained at 6 months by generalized
linear model (GLM) repeated measures. Categorical variables
were analysed using Chi-square analysis. Continuous variables
were analysed using an independent sample t-test. In the case
of outcome variables which changed in the same direction in
both the progressive exercise and control groups, betweengroup comparisons were also performed (comparing change values) to determine whether the change in one group
was signicantly greater than that of the other group. Spearmans rank correlation test was used to assess the relationships
between the examined variables. All statistical analyses were
performed using the SPSS version 18.0 (SPSS Inc. Chicago, Illinois). Data are presented as mean SD and the level of statistical signicance was set at P 0.05.

Medication

R E S U LT S

All data are expressed as mean SD. No statistical differences

were observed between the two groups. BMI, body mass index;
Kt/V, dialysis efciency; Hct, haematocrit; Hb, haemoglobin.

All of the patients successfully completed the 6-month intervention programme with no adverse effects and no augmentation phenomena to report. The patient characteristics at
baseline are presented in Table 1. No signicant differences in
the patients basic characteristics were found between the two
groups (P > 0.05). None of the basic characteristics were signicantly changed after the intervention period, except for the
Kt/V which signicantly 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 signicant 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 intervention in either of the groups.
Changes in IRLS severity score, sleep quality, daily sleepiness and depression score are presented in Table 2. At baseline, no signicant 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 signicant 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 contrast, no signicant changes were observed in the examined
variables in the control group (P > 0.05). Moreover, -change
values were different between the two groups in depression
and IRLS scores (P > 0.05). After the 6-month intervention
period, RLS severity (P = 0.017) (Figure 1), depression score
(P = 0.002) and daily sleepiness status (P = 0.05) appeared to
2836

C. D. Giannaki et al.

Exercise
group

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ORIGINAL ARTICLE

Biochemical assessment
The patients routine monthly laboratory results were recorded including iron, ferritin haematocrit, haemoglobin,
albumin and dialysis efciency parameters. A single-pool Kt/V
was calculated from pre- and post-dialysis BUN measurements
using the Daugirdas II equation [15] at baseline and at the end
of the 6-month intervention. The biochemical analysis was
performed at the clinical biochemistry laboratory of the University Hospital of Larissa under standard hospital procedures.

Variables

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

6-month post

7.2 4.3

10.7 3.5
P=0.038

9.4 3.1

Change

1.8 2.5

1.3 3.5

95% CI of
change

3.3 0.2

3.5 0.9

F I G U R E 1 : RLS severity scale score at baseline and after the 6-

ESS
Baseline

5.0 2.7

7.8 5.3

6-month post

5.0 1.8

6.9 3.3

change

0.1 2.7

0.9 5.0

95% CI of
change

1.8 1.6

4.0 2.2

Baseline
6-month post

45.1 6.5

44.7 12.7

P=0.000

34.2 7.0

change

10.9 6.0#

95% CI of
change

14.7 7.0

P=0.020

43.7 6.7

Variables

1.0 11.6
8.3 6.3

IRLS score
25.4 9.3

22.0 7.2

6-month post

10.7 8.5P=0.003

18.3 7.8

change

14.7 7.9#P=0.007

3.6 7.1

95% CI of
change

19.7 9.6

8.1 0.9

Control
group

92.0 17.3#P=0.019

62.0 15.9

NSRI (seconds)
Baseline

Baseline

Exercise group

P=0.047

60.0 14.1

6-month post

82.3 26.0

Change

9.6 14.1

1.9 5.5

19.2 0.1

7.1 3.1

95% CI of
change
STS-5 (repetitions)
Baseline

All data are expressed as mean SD. IRLS, International Restless

Legs Syndrome severity scale; signicantly different from the
respective baseline value. #Signicantly different than the control
group.

6-month post

be signicantly better in the progressive exercise group compared with the control group.
Moreover, the -change values in sleep quality correlated
signicantly with the -change values in Kt/V (r = 0,946,
P = 0.000). Functional capacity was improved after the
6 months of the training regime however only in the Exercise
group compared to the control (Table 3).

10.7 2.0

9.1 0.7

8.5 2.5P=0.003

8.5 1.5
0.6 1.3

change

2.2 1.9

95% CI of
change

3.5 0.9

1.6 0.4

24.7 3.2

28.2 1.9

#P=0.045

STS-60 (s)
Baseline
6-month post

30.3 6.8

P=0.005

change

5.6 4.7#

95% CI of
change

9.0 2.1

P=0.052

30.0 2.2
1.7 2.7
4.2 0.8

All data are expressed as mean SD. STS-5, sit-to-stand test verepetitions; STS-60, sit-to-stand test 60 s; NSRI, North
Staffordshire royal inrmary test.
#
Signicantly different than the control group. Signicantly
different from the respective baseline value.

DISCUSSION
This is the rst randomized controlled exercise intervention
study investigating the effects of progressive exercise training
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Therapeutic exercise training for uraemic RLS

ORIGINAL ARTICLE

Table 3. Functional capacity data divided into

two groups according to the assigned
intervention.

Zung depression scale

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month intervention. At baseline the two groups did not differ. The
progressive exercise training group improved signicantly (P = 0.003),
while no signicant changes were observed in the control group
(P > 0.05). After the intervention period there was a signicant difference between the groups (P = 0.017). All data are mean SD. IRLS,
International Restless Legs Syndrome severity rating scale; ns = nonsignicant differences.

ORIGINAL ARTICLE

current study, a signicant 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 sessions resulted in signicant 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 signicantly 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 exercise group correlated strongly with the
respective changes in Kt/V (r = 0.946, P = 0.000), thus indicating a possible association of HD adequacy with sleep,
possibly mediated by the known favourable systemic effects
of exercise.
The effect of dialysis efciency on the severity of RLS symptoms is still controversial [25,26]. Interestingly, in the current
study, the Kt/V index appeared to be signicantly increased
after the progressive exercise training intervention conrming
previous data in HD patients with unknown RLS status [27];
however, the changes in Kt/V correlated only with the
change in sleep quality and not with the change in IRLS
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 signicantly improved sleep quality even though the assessment was done by
a questionnaire (which is a less sensitive method than polysomnography). Changes in sleep quality could be a result of
improvement in depression score or vice versa [29]; however,
no signicant correlation between the depression score and
the sleep quality was observed in our study. It is possible that
exercise training could have inuenced these two parameters
in an independent way; however, further research is needed in
order to address this issue. On the other hand, exercise training 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 sleepiness, unless it is very severe, does not change after either exercise or medication treatment; however, more work is needed
on this issue to reach rm conclusions.
Limitations
Even though RLS is not a sleeping disorder, it would be
very helpful if we were able to perform an overnight polysomnographic study in order to objectively evaluate sleep quality
and quantity as well as an RLS-related movement disorder occurring during sleep called periodic limb movements in sleep.
In addition, the IRLS severity score was not assessed during
the 6-month period and, therefore, it is not possible to assess
the course of IRLS score change during the study time. A
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C. D. Giannaki et al.

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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
symptoms and benecial in improving sleep quality and
depression score. Such benets were not observed in the
control group.
Recently, exercise training was shown to be a safe and
effective 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 symptoms, it is well known that this type of non-pharmacological
approach can also confer many benecial physiological adaptations that impact on the patients quality of life and health
[17] adding signicant clinical value to this approach. In
addition, the application of exercise training as a monotherapy
or in combination with the approved pharmacological treatment can signicantly 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 training 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 signicantly improved with the exercise
training programme, further highlighting the benecial effect
of exercise on these important health-related parameters. Interestingly, 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 signicantly better in the progressive exercise group compared
with the control group (Table 2).
Notably, this is the rst study to show that some specic
exercise-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 rst 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 -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 -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 previous studies, opioid treatment
resulted in a successful improvement of RLS symptom
severity [20]. In addition, a possible pathway by which
progressive exercise training could affect RLS severity is the
exercise-induced improvements in HD efciency. In the

limited number of exercise sessions were characterized as incomplete, 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 nal outcomes.
Finally, we were not able to assess the levels of -endorphin
during the course of the study or during an exercise bout and
have to thus rely on available bibliography to surmise a possible mechanism.

CONCLUSIONS

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 University 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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Therapeutic exercise training for uraemic RLS

ORIGINAL ARTICLE

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Received for publication: 28.12.2012; Accepted in revised form: 17.5.2013

ORIGINAL ARTICLE

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