550

ARTICLE
Beneficial effects of an intradialytic cycling training program
in patients with end-stage kidney disease
Carole Groussard, Myriam Rouchon-Isnard, Céline Coutard, Fanny Romain, Ludivine Malardé,
Sophie Lemoine-Morel, Brice Martin, Bruno Pereira, and Nathalie Boisseau

Abstract: In chronic kidney disease (CKD), oxidative stress (OS) plays a central role in the development of cardiovascular
diseases. This pilot program aimed to determine whether an intradialytic aerobic cycling training protocol, by increasing
physical fitness, could reduce OS and improve other CKD-related disorders such as altered body composition and lipid profile.
Eighteen hemodialysis patients were randomly assigned to either an intradialytic training (cycling: 30 min, 55%–60% peak
power, 3 days/week) group (EX; n = 8) or a control group (CON; n = 10) for 3 months. Body composition (from dual-energy X-ray
absorptiometry), physical fitness (peak oxygen uptake and the 6-minute walk test (6MWT)), lipid profile (triglycerides (TG), total
cholesterol, high-density lipoprotein, and low-density lipoprotein (LDL)), and pro/antioxidant status (15-F2␣-isoprostanes (F2-IsoP)
and oxidized LDL in plasma; superoxide dismutase, glutathione peroxidase, and reduced/oxidized glutathione in erythrocytes)
were determined at baseline and 3 months later. The intradialytic training protocol did not modify body composition but had
significant effects on physical fitness, lipid profile, and pro/antioxidant status. Indeed, at 3 months: (i) performance on the 6MWT
was increased in EX (+23.4%, p < 0.001) but did not change in CON, (ii) plasma TG were reduced in EX (–23%, p < 0.03) but were not
modified in CON, and (iii) plasma F2-IsoP concentrations were lower in EX than in CON (–35.7%, p = 0.02). In conclusion, our
results show that 30 min of intradialytic training, 3 times per week for 3 months, are enough to exert beneficial effects on the
most sensitive and reliable marker of lipid peroxidation (IsoP) while improving CKD-associated disorders (lipid profile and
physical fitness). Intradialytic aerobic cycling training represents a useful and easy strategy to reduce CKD-associated disorders.
These results need to be confirmed with a larger randomized study.

Key words: chronic kidney disease, exercise training, oxidative stress, physical fitness, lipid profile, isoprostanes.

Résumé : Chez les patients souffrant d’insuffisance rénale chronique terminale (« CKD »), le stress oxydatif (« OS ») joue un rôle central
dans le développement des maladies cardiovasculaires. Cette étude pilote se propose de tester l’hypothèse selon laquelle un protocole
d’entraînement aérobie intradialytique sur bicyclette ergométrique, en améliorant la condition physique permet de diminuer le OS
et les désordres associés à la pathologie (composition corporelle et profil lipidique). 18 patients hémodialysés ont été répartis aléa-
toirement dans deux groupes : un groupe entraîné (« EX »; n = 8) pendant la dialyse (bicyclette ergométrique : 30 min, 55–60 % de la
puissance pic, 3 jours/semaine) ou dans un groupe de contrôle (« CON »; n = 10), et ce, pendant 3 mois. Nous avons mesuré au début de
l’intervention et 3 mois plus tard, la composition corporelle (absorptiométrie à rayons X en double énergie), la condition physique
(consommation maximale d’oxygène et test de marche de 6 min (« 6MWT »)), le profil lipidique (triglycéride (« TG »), cholestérol total,
lipoprotéine de haute densité, lipoprotéine de faible densité (« LDL »)) et le statut pro/antioxydant (dans le plasma :15-F2-isoprostanes
(« F2-IsoP ») et LDL oxydées; dans les érythrocytes : l’activité de la superoxyde dismutase et de la glutathion peroxydase, le rapport
glutathion réduit/glutathion oxydé). Le protocole d’entraînement intradialytique ne modifie pas la composition corporelle, mais
améliore la condition physique, le profil lipidique et le statut pro/antioxydant. En effet, après 3 mois, nous observons : (i) une
amélioration de la performance au 6MWT dans le groupe EX (+23,4 %, p < 0,001), sans amélioration dans le groupe CON, (ii) une
diminution des TG plasmatiques dans le groupe EX (–23 %, p < 0,03), sans amélioration dans le groupe CON et (iii) une plus faible
concentration des F2-IsoP plasmatiques dans le groupe EX comparé au groupe CON (–35,7 %, p = 0,02) après 3 mois. Pour conclure, nos
résultats démontrent que 30 min d’entraînement intradialytique, 3 fois par semaine pendant 3 mois suffisent à exercer des effets
bénéfiques notamment sur le marqueur le plus sensible et fiable de la peroxydation lipidique (IsoP) tout en luttant contre certains
désordres associés à la pathologie (amélioration du profil lipidique et de la condition physique). De plus, notre étude illustre la
faisabilité d’un programme de pédalage pendant les séances de dialyse et souligne que l’activité physique devrait faire partie inté-
grante de la prise en charge du patient hémodialysé. Ces résultats doivent être confirmés par d’autres études randomisées à grande
échelle. [Traduit par la Rédaction]

Mots-clés : néphropathie chronique, entraînement physique, stress oxydatif, condition physique, profil lipidique, isoprostanes.

Received 4 November 2014. Accepted 17 December 2014.

C. Groussard, L. Malardé, S. Lemoine-Morel, and B. Martin. Laboratory “Movement, Sport and Health Sciences” (M2S), Rennes 2 University–ENS
Cachan, Avenue Robert Schuman, Campus de Ker Lann, F-35170 Bruz, France.
M. Rouchon-Isnard, C. Coutard, and F. Romain. AURA Auvergne, 8 rue du Colombier, F-63400 Chamalières, France.
B. Pereira. University Hospital Center (CHU) of Clermont-Ferrand, Biostatistics Unit, DRCI, F-63000 Clermont-Ferrand, France.
N. Boisseau. Laboratoire des Adaptations Métaboliques à l'Exercice en conditions Physiologiques et Pathologiques (AME2P), Université Blaise Pascal,
Campus Universitaire des Cézeaux, Bât. Biologie B, 5 impasse Amélie Murat, TSA 60026, CS 60026, 63178 Aubière Cedex, France.
Corresponding author: Nathalie Boisseau (e-mail: nathalie.boisseau@univ-bpclermont.fr).

Appl. Physiol. Nutr. Metab. 40: 550–556 (2015) dx.doi.org/10.1139/apnm-2014-0357 Published at www.nrcresearchpress.com/apnm on 8 May 2015.
Groussard et al.
Introduction
Chronic kidney disease (CKD) is a serious public health problem
worldwide that substantially reduces quality of life and signifi-
cantly affects patients’ short-term and long-term survival (Tonelli
et al. 2006). This pathology is characterized by a progressive loss of
renal function; in end-stage kidney disease (ESKD), the patient
requires dialysis or kidney transplantation to survive.
Patients with CKD (especially those with ESKD) are at high risk
of cardiovascular diseases (CVD), which are the leading cause of
mortality (Baigent et al. 2000). Although the prevalence of tradi-
tional cardiovascular risk factors (such as hypertension, diabetes,
and low high-density lipoproteins (HDL)) is elevated in these pa-
tients, the extent and severity of associated cardiovascular mor-
bidity and mortality remain disproportionate to traditional risk
factor profiles. Consequently, nontraditional risk factors such as
increased oxidative stress (OS) and increased inflammation are
postulated to be important contributors to cardiovascular compli-
cations (Himmelfarb 2004).
Patients with CKD suffer from a variety of comorbid diseases in
addition to cardiovascular disorders; this creates a vicious cycle
that gradually leads to inactivity (Painter 2005), which in turn
reduces physical function and increases mortality (O’Hare et al.
2003).
Few strategies are available to reduce the progression of CKD and
its associated disorders. In a range of disease conditions (obesity,
diabetes, etc.), exercise training is well known to have beneficial
effects on health (Hawley and Holloszy 2009; Bird and Hawley 2012).
Moreover, physical training may also prevent physical decondi-
tioning by increasing aerobic fitness (Storer et al. 2005) and may
reduce OS (Gomez-Cabrera et al. 2008). While the benefits of phys-
ical training in patients with CKD have been extensively studied
by evaluating physical fitness using objective laboratory tests
(i.e., cardiorespiratory fitness through peak oxygen uptake (V̇O2peak))
and (or) physical performance tests (i.e., the 6-minute walk test
(6MWT)) (Painter 2005; Segura-Orti and Johansen 2010; Heiwe and
Jacobson 2014), less is known about the effects of aerobic exercise
training on OS in this population. To our knowledge, only 2 stud-
ies have evaluated the potential benefits of aerobic physical train-
ing on OS in patients with CKD (Pechter et al. 2003; Wilund et al.
2010), and both assessed plasma lipid peroxidation by the most
widely used method, thiobarbituric acid reactive substances, which
is known to lack sensitivity and specificity (Janero 1990).
Therefore, the aim of the present study was to evaluate the impact
of an intradialytic aerobic exercise training program (cycling) on OS
markers, including the most reliable lipid peroxidation marker,
15-F2␣-isoprostanes (F2-IsoP) (Roberts and Morrow 2000). Physical
fitness and other variables that are commonly altered in patients
with CKD (lipid profile and body composition) were also evalu-
ated. We hypothesized that intradialytic aerobic exercise training
would improve pro/antioxidant status and lipid profile.
Materials and methods
Subjects
Twenty patients with ESKD (stage 5; 5 females, 15 males) in
maintenance hemodialysis were recruited from 2 autodialysis
centers through the dialysis association AURA Auvergne. All pa-
tients were treated by conventional hemodialysis 3 times a week.
‘Health and medical history questionnaires were used to deter-
mine patients’ eligibility for the study. The inclusion criteria were
as follows: (i) age = 20–85 years, (ii) dialysis for at least 2 years,
(iii) consent of the patient’s cardiologist, (iv) no orthopedic prob-
lems that prevented cycling during dialysis, and (v) no participa-
tion in another study. None of the patients had been exercising
regularly before starting the study. Eligible subjects were randomly
divided into 2 groups. Ten patients participated in the intradialytic
exercise training study (EX group). A comparison group, designated
as non-exercising patients (CON group), consisted of 10 individuals
551
who received no intradialytic exercise training but participated in
assessments for all measures before and after the 3-month study
period. It was not possible to blind participants or researchers to
group assignment.
Written informed consent was obtained from all participants
prior to the beginning of the experiment. This pilot program con-
formed to the principles of the Declaration of Helsinki and was
approved by the local Ethics Committee: CPP Sud est VI, VI-AU818,
Clermont-Ferrand, France.
Experimental protocol
Clinical testing and measurements
At baseline (T0) and 3 months later (T3, at the end of the exercise
training program), all patients underwent clinical examination
(anthropometric and body composition measurements), a physical
fitness evaluation (V̇O2peak, 6MWT), and laboratory data collection
as described below.
During the clinical examination, height, weight, and body mass
index (BMI = weight (kg)/[height (m)]2) were determined for each
subject. Dual-energy X-ray absorptiometry was used to assess body
composition, including total and lower-limb fat-free mass (FFM)
and fat mass (FM) (QDR-4500A, Hologic Inc., Waltham, Mass., USA).
Physical fitness was assessed using cardiopulmonary exercise
testing (V̇O2peak and the 6MWT). For measurements of V̇O2peak,
each participant completed a maximal incremental cardiopul-
monary exercise test on an electrically braked cycle ergometer
(Cardiosoft, Marquette Hellige, Munzinger, Germany) with 12-lead
electrocardiography (Asept Inmed, Quint Fonsegrives, France).
Oxygen consumption was measured by a breath-by-breath gas
analyzer (CareFusion, Masterscreen CPX, Houten, The Netherlands),
and the power output (watts) was also recorded. Subjects began with
a warm-up at 10 to 50 W, depending on age, sex, and physical capac-
ity. The power output was then increased at a rate of 10 W/min until
exhaustion. The test was performed until volitional exhaustion or
until the subject exhibited any of the criteria for the termination of
an exercise test as recommended by the American College of Sports
Medicine. The duration of the test was between 12 and 15 min.
The 6MWT was used as an index of aerobic capacity and was
performed without any assistance in a quiet hospital corridor
(25 m long) as described in detail by Fitts et al. (Fitts and Guthrie
1995).
Exercise training intervention
After group assignment and baseline testing, subjects in the
EX group underwent a 3-month intradialytic aerobic exercise train-
ing program consisting of cycling 3 days/week on specialized cycle
ergometers (OxyCycle II, Kinou Medical) adapted on the subject’s
dialysis chair. Cycling was performed in a seated position during
the first 2 h of dialysis. During the first exercise session, subjects
cycled for 15 min at a tolerable pace. The duration was then grad-
ually increased by 5 min during the first week and then by 10 min
during the second week to reach 30 min after 2 weeks of training.
Before and after each session, respectively, subjects performed
a 5-min warm-up on the specialized cycle ergometer and a 5-min
cool-down. The workload was set at 55%–60% of the peak power
ouput achieved during the pretraining incremental exercise test.
Heart rate was monitored during each exercise training interven-
tion to control the intensity over time. All sessions were super-
vised by a professional team with expertise in physical activity.
Subjects were instructed to continue cycling for 30 min at a con-
stant pedal frequency of 50 r/min.
Nutritional assessment
Participants were asked to eat and drink normally and not to
consume any antioxidant supplements. They completed a 7-day
diet record 1 week before the beginning of the protocol (T0) and
1 week after the end of the 3-month exercise training period (T3).
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552 Appl. Physiol. Nutr. Metab. Vol. 40, 2015

Table 1. Patient characteristics at baseline (T0) and at 3 months (T3) in control (CON) and intradialytic
training (EX) groups.
CON (n = 10) EX (n = 8)
T0 T3 T0 T3
Age (y) 68.4±3.7 66.5±4.6
Sex 7 m, 2 f 5 m, 3 f
Anthropometric measurements
Weight (kg) 70.4±6.8 69.5±6.6 78.1±6.4 78.3±6.0
Height (cm) 161.8±3.0 161.8±3.0 162.9±4.3 162.9±4.4
BMI (kg/m2) 26.5±1.8 26.2±1.9 29.4±2.1 29.5±1.9
% Fat mass 27.2±2.7 27.3±2.8 32.2±3.1 32.4±3.2
Fat-free mass (kg) 49.4±3.5 48.7±3.4 51.8±4.7 52.2±4.9
Fat-free mass, lower limbs (kg) 14.9±1.3 14.8±1.4 16.3±1.8 16.3±1.9
Hemodialysis variables
S-creatinine (␮mol/L) 633.2±53.7 623.7±48.4 713.4±99.0 712.2±99.8
Albumin (g/L) 31.50±0.79 31.91±0.74 33.50±0.66 31.81±0.60
Transthyretin (g/L) 0.31±0.02 0.31±0.02 0.29±0.02 0.28±0.02
Hemoglobin (g/dL) 12.6±0.6 12.5±0.4 12.2±1.7 11.3±1.7
eKt/V 1.47±0.07 1.32±0.11 1.31±0.10 1.42±0.10
Time on dialysis (mo) 41.2±8.1 36.6±8.2
Dialysis prescription (h/wk) 11.9±0.1 12.2±0.7
Comorbidity (Charlson index) 5.7±1.5 6±1.7
Note: Values are means ± SE. BMI, body mass index; f, female; eKt/V, equilibrated Kt/V; h/wk, hours of dialysis per
week; m, male.

Kilocalorie, macronutrient, and antioxidant intakes were analyzed Table 2. Physical fitness and lipid profile at baseline (T0) and at
by the same technician using Nutrilog 2.5 software. 3 months (T3) in control (CON) and intradialytic training (EX) groups.
CON (n = 10) EX (n = 8)
Blood sample preparation and analysis
For each participant, blood samples (15 mL) were collected be- T0 T3 T0 T3
fore a dialysis session both at the beginning of the experiment Physical fitness
(before training) to establish the baseline (T0) and 3 months later V̇O2peak (L/min) 0.99±0.14 1.01±0.11 1.12±0.16 1.15±0.20
to determine the effect of the exercise training protocol (T3). V̇O2peak (mL/(min·kg)) 13.4±1.1 15.3±0.6 14.7±2.1 14.3±2.3
Peak power (W) 66.0±6.0 72.0±4.9 80.5±12.9 88.6±14.0
Biochemical parameters Peak power (W/kg) 0.97±0.05 1.11±0.06 1.06±0.17 0.99±0.19
Blood samples were collected in dry vacutainer tubes the week Lipid profile
before and 1 week after the end of the training program. The Total cholesterol (g/L) 1.53±0.09 1.63±0.09 1.71±0.15 1.61±0.13
following biochemical parameters were measured in the fasting HDL (g/L) 0.47±0.03 0.47±0.04 0.39±0.04 0.42±0.05
condition before dialysis: hemoglobin, albumin, transthyretin, LDL (g/L) 0.83±0.08 0.91±0.09 0.94±0.16 0.89±0.12
serum potassium, phosphate, calcium, alkaline phosphatase, TG (g/L) 1.20±0.13 1.09±0.13 1.90±0.43 1.46±0.33*
calcium–phosphorus product, and blood urea nitrogen. The fol- Note: Values are means ± SE. HDL, high-density lipoprotein-cholesterol; LDL,
lowing parameters were measured at the end of the dialysis ses- low-density lipoprotein-cholesterol; TG, triglycerides; V̇O2peak, oxygen uptake at
sion: urea to calculate the eKt/V, creatinine, calcium, phosphate, maximal load.
sodium, and potassium. All variables were measured using an *Significant difference between T0 and T3, p < 0.05.
autoanalyzer (Olympus Inc.) at the Gen-Bio laboratory (Clermont-
Ferrand, France). blood was centrifuged (1500g, 10 min, 4 °C) and plasma was re-
moved. Then, the erythrocytes were washed according to the as-
Lipid profile say manufacturer’s recommendations. For the rest of the assays,
Blood samples were collected in lithium heparin vacutainer blood was immediately centrifuged at 1500g for 10 min at 4 °C to
tubes from subjects in a fasted state. Plasma total cholesterol, separate the plasma (Universal 320R, Hettich Zentrifugen, Germany).
HDL-cholesterol, and triglyceride (TG) concentrations were mea- For F2-IsoP, butylated hydroxytoluene (0.05%) was added to the
sured using a UniCel DxC system (Beckman Coulter) by a choles- plasma to prevent oxidation. The rest of the plasma was aliquoted
terol oxidase method (synchron CHOL) for total cholesterol, a direct (including 300 ␮L for oxidized LDL (oxLDL)) and stored at –80 °C.
homogeneous method (synchron HDLd) for HDL-cholesterol, and a SOD and GPx activities were determined using the Ransod and
lipase/glycerol kinase method (synchron TG GPO) for TG. The low- Ransel kits, respectively (Randox, Montpellier, France). The GSH/
density lipoprotein (LDL) subfraction was indirectly quantified GSSG ratio was determined using the GSH/GSSG-412 kit (Bioxytech,
using the Friedewald equation (Friedewald et al. 1972). Oxis International Inc., Portland, Ore., USA). oxLDL was determined
spectrophotometrically with a competitive enzyme-linked immu-
Pro/antioxidant status nosorbent assay (Immunodiagnostik). F2-IsoP was measured by
Blood samples were collected from non-fasted subjects. Blood liquid chromatography mass spectrometry as described previously
was drawn into EDTA vacutainer tubes and prepared for analysis (Youssef et al. 2009).
immediately after collection. For oxidized glutathione (GSSG)
measurement, 100 ␮L of whole blood was added to 10 ␮L of scav- Statistical analysis
enger, provided in the GSH/GSSG’ kit, and immediately stored at Data are presented as the mean ± standard error of the mean (SE).
–80 °C. For reduced glutathione (GSH) and glutathione peroxidase All statistical analyses were performed using Statistica 7.1 soft-
(GPx) measurements, 50 ␮L and 150 ␮L of whole blood, respectively, ware. The nonparametric Mann–Whitney test was used to com-
were collected and immediately stored at –80 °C. For measure- pare anthropometric data between the 2 groups. To study the
ment of superoxide dismutase (SOD) activity, 500 ␮L of whole influence of the intradialytic exercise program on the measured

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Groussard et al.
Fig. 1. The 6-minute walk test (6MWT) responses at T0 and T3 in control (CON) and intradialytic training (EX) groups.
parameters, 2-way analysis of variance (group, time, and group ×
time interaction) was conducted after checking the binomial
probability distribution and variance. Tukey’s post hoc test was
used when the interaction was significant. Differences were con-
sidered statistically significant at p < 0.05.
Results
Patient characteristics
Two patients of the EX group withdrew. The first one moved out
of the area and the second one underwent kidney transplantation.
Thus, 8 subjects were included in the EX group and 10 in the CON
group. Time on dialysis (months), dialysis prescription (hours per
week), and comorbidity (Charlson index) were not different be-
tween the 2 groups (Table 1). Similar eKt/V values were observed in
the CON and EX groups, indicating similar dialysis adequacy. The
nutritional status of the patients was not different between the
2 groups (creatinine, albumin, and transthyretin levels) (Table 1).
No significant differences were reported between the 2 groups for
age, body weight, height, BMI, % FM, total FFM, and FFM of the
lower limbs. The 3-month period did not affect any anthropomet-
ric parameters in the CON or EX group (Table 1).
Nutritional assessment
Analysis of food records showed no significant difference in
nutritional intake between the 2 groups at T0. Moreover, statisti-
cal analysis of the food surveys showed no difference in food
habits or antioxidant consumption in either group between the
beginning and the end of the study (data not shown). Thus, inspec-
tion of the subjects’ diaries did not indicate any deviations from
the protocol that may have affected the results.
Physical fitness assessment
V̇O2peak and the 6MWT were not different at baseline between
the 2 groups (Table 2). Whereas no changes in relative or absolute
V̇O2peak or peak power were observed between T0 and T3 in either
group, the distance walked during the 6MWT test increased by
23.4% in the EX group (p < 0.001) but did not change in the CON
group (376 ± 20 and 406 ± 18 at T0 vs. 406 ± 29 and 500 ± 30 at T3
for CON and EX, respectively) (Fig. 1).
553
Lipid profile
The lipid profiles were not different between the CON and
EX groups at T0 (Table 2). The 3-month training program showed
beneficial effects on plasma TG levels in the EX group (–23% at
T3 compared with T0; 1.90 ± 0.43 vs. 1.46 ± 0.33 g/L; p < 0.03). No
change in plasma TG concentrations was observed in the CON group.
Other lipid profile markers (HDL, LDL, total cholesterol) were un-
changed throughout the intervention period.
Pro/antioxidant status
Markers of pro/antioxidant status are presented in Table 3 and
Fig. 2. No difference appeared at T0 between the 2 groups. After
the 3-month period, no change was observed in these markers
except for F2-IsoP (Fig. 2). Indeed, the EX group exhibited a signif-
icantly lower F2-IsoP value at T3 compared with the CON group
(p = 0.02).
Discussion
Our pilot program showed that an intradialytic aerobic cycling
program had beneficial effects on physical fitness and lipid profile
and prevented aggravation of OS in patients with ESKD. Further-
more, this study is the first to report a significant difference in
plasma F2-IsoP (the most sensitive and reliable marker of lipid
peroxidation) between trained and untrained patients at the end
of an intervention protocol.
Effects of exercise training on body composition and lipid
profile
The 3-month intradialytic aerobic training program did not in-
duce significant changes in the body composition of the ESKD
patients. Thus, the exercise training protocol failed to modify FM
in the EX group. The frequency (3 times/week) and duration of the
sessions (30 min) and the length of the protocol (3 months) were
probably insufficient to achieve the energy expenditure needed to
alter total fat mass. In parallel, food intakes did not change be-
tween T0 and T3 in either group (from a qualitative point of view
and in terms of total kilojoules consumed).
Muscle atrophy is regularly observed in patients with ESKD.
This loss of FFM contributes to the vicious cycle that induces
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554
Table 3. Pro/antioxidant status at baseline (T0) and at 3 months (T3) in control (CON) and intra-
dialytic training (EX) groups.
CON (n = 10)
T0
Oxidative stress markers
Ox-LDL (U/L) 38.6±4.6
GSH/GSSG 249±93
Antioxidant enzyme activity
GPx/g Hb 81.2±0.05
SOD/g Hb 1361.2±160.3
Note: Values are means ± SE. GPx, glutathione peroxidase activity; GSH/GSSG, ratio between reduced and
oxidized glutathione; Hb, hemoglobin; Ox-LDL, oxidized low-density lipoprotein; SOD, superoxide dismutase
activity.
Fig. 2. Plasma F2-IsoP at T0 and T3 in control (CON) and intradialytic training (EX) groups.
physical inactivity (Painter 2005) and favors morbidity and mor-
tality (O’Hare et al. 2003). In our study, the exercise training pro-
tocol did not modify FFM in the EX group. This result confirms
previous findings that resistance training (muscular strengthen-
ing) must be combined with aerobic training to induce muscle
hypertrophy (Kouidi et al. 1998).
Another ESKD-associated disorder is dyslipidemia. Hypertri-
glyceridemia is the most common blood lipid abnormality in pa-
tients with CKD and is considered a risk factor for CVD (Green
et al. 1983; Jeppesen et al. 1998). Fortunately, the training program
significantly reduced plasma TG (–23%), indicating an improve-
ment of the lipid profile. This result indicates that our training
program was a sufficient and successful lipid-lowering therapy.
Our results are consistent with the study of Goldberg et al. (1983),
in which a similar training protocol decreased plasma TG by 33%
and increased HDL by 16%. In our study, HDL increased by only 9%.
The relatively high HDL level in the EX group before the beginning
of the study may explain this result. Changes in dietary intake can-
not explain this result, since no modifications of kilocalorie, ma-
cronutrient, and antioxidant intakes were observed during the
intervention (data not shown).
Effects of training on physical fitness
Physical fitness was evaluated by an objective laboratory test,
i.e., V̇O2peak, and by a field test that measures physical perfor-
mance of a standardized task, i.e., 6MWT. Although aerobic exer-
cise training had no effect on V̇O2peak, it improved the distance
Appl. Physiol. Nutr. Metab. Vol. 40, 2015
EX (n = 8)
T3 T0 T3
39.7±4.6 41.5±3.2 40.6±3.4
335±120 436±165 367±101
74.9±9.9 99.6±11.3 84.9±8.9
1490.31±184.4 1372.1±182.6 1425.6±115.8
walked (+23.4%). We can explain this apparent discrepancy as
follows. As evidenced in a recent meta-analysis, training-induced
changes in V̇O2peak are positively correlated with exercise training
duration. The most important changes have been observed in
patients who perform combined aerobic and strength training for
6 months or more on non-dialysis days (Smart and Steele 2011).
Moreover, even if the gold standard test used to evaluate func-
tional capacity is the determination of V̇O2max (Painter 2005), it is
unlikely that patients with ESKD will reach V̇O2max, because of
functional limitations including bone, joint, and/or muscle pain
and muscle fatigue. Consequently, the V̇O2peak test (which mea-
sures the highest oxygen uptake in a symptom-limited test) or
other indirect tests such as walk tests are preferred. Furthermore,
walk tests are more appropriate in the clinical setting to assess
physical fitness in subjects with low functional capacity, such as
patients with ESKD (American Thoracic Society 2002). The sig-
nificant increase in distance walked is of fundamental interest
because walking capacity is considered a better indicator than
physiological exercise capacity, as it assesses capability as well as
fitness and reflects the ability to perform activities that are similar
to those of everyday life, i.e., walking (Koufaki and Kouidi 2010).
The magnitude of improvement in the distance walked after the
training program is in the upper range of previously reported
increases of between 5% and 18% after aerobic training programs
(Parsons et al. 2006) and is considered to be clinically relevant
(Wise and Brown 2005). This result indicates that a 3-month int-
Published by NRC Research Press
Groussard et al.
radialytic aerobic cycling program improves physical fitness and
walking ability, leading to a better quality of life (Painter et al.
2000) and increased survival in these patients (Sietsema et al. 2004).
Effects of training on pro/antioxidant status
OS appears to play a central role in the development and pro-
gression of CVD and its complications. Many clinical studies have
demonstrated that patients with CKD are prone to chronic OS
(Martin and Goeddeke-Merickel 2005), owing to impaired pro/
antioxidant balance, but the exact causes are still debated. In
healthy or pathological subjects, training was demonstrated to be
a useful approach to decrease OS (Miyazaki et al. 2001; Rodriguez
et al. 2012). Indeed, the transient and low level of reactive oxygen
species (ROS) induced by acute exercise stimulates adaptive mech-
anisms such as increased antioxidant defense (Gomez-Cabrera
et al. 2008) and reduced ROS production (Venditti et al. 1999;
Coelho et al. 2010), which leads to decreased resting OS (Miyazaki
et al. 2001; Rodriguez et al. 2012). We found no significant differ-
ences in oxLDL, which is believed to be one of the major factors
involved in the pathogenesis of atherosclerosis. Moreover, even
though we failed to detect a significant decrease in F2-IsoP in the
EX group after the 3-month training program, there was a signif-
icant difference in plasma F2-IsoP concentration at T3 between EX
and CON subjects, indicating lower OS in the trained group. Be-
cause F2-IsoP is considered the most reliable biomarker of OS, and
since OS is thought to elevate CVD risk by increasing endothelial
dysfunction (Vogiatzi et al. 2009), we propose that intradialytic
training could reduce CVD risk. In humans, very few studies have
investigated the effects of exercise training on OS in patients with
CKD (Pechter et al. 2003; Wilund et al. 2010). Our study is the first
to measure plasma F2-IsoP in response to aerobic training. Since
training did not increase antioxidant enzyme activities, the signif-
icant difference in F2-IsoP at the end of the training period between
the EX and CON groups may be due to decreased ROS production.
Indeed, Coelho et al. (2010) observed a training-induced decrease
in OS markers that was explained not by upregulation of antiox-
idant enzyme activity but rather by decreased superoxide anion
production. This decrease could be due to upregulation of uncou-
pling mitochondrial proteins and/or to acceleration of electron
transport by an increase in the adenosine diphosphate supply
(Coelho et al. 2010). In our study, antioxidant enzyme activities
were not upregulated by training. In healthy and pathological
patients, upregulation of antioxidant enzyme activity and (or)
content is observed when training improves V̇O2max (Ohno et al.
1988; Ennezat et al. 2001; Miyazaki et al. 2001), which was not the
case in our study, probably because of the short duration of the
protocol (3 months) and of each session (30 min). The difference
between the results we obtained for SOD/GPx activities (no change
with training) and F2-IsoP (lower value at T3 for EX vs. CON) could
be explained by the tissue location (red blood cells for SOD/GPx
activities and plasma for F2-IsoP). Indeed, plasma is a crossroad for
F2-isoPs, which are produced in situ and subsequently removed
from the cell membrane (by a phospholipase A2) before ending up
in the plasma and the urine (Morrow et al. 1992).
Choice of training program
While the majority of studies have focused on interdialytic pre-
scription, the training program proposed in our study of ESKD
patients was an intradialytic one. We preferred an intradialytic
training program for several reasons. First, we expected better
compliance with an intradialytic protocol, which does not require
extra visits. Indeed, previous work has shown very low adher-
ence when exercise sessions are performed on non-dialysis days
(Konstantinidou et al. 2002). In our study, we lost only 2 trained
subjects: one moved out of the area and the second underwent
kidney transplantation. Moreover, intradialytic training allows
better patient’ monitoring and provides motivation in a struc-
tured environment. Second, the time spent at a hemodialysis ses-
555
sion is a period of forced inactivity, which contributes to further
degradation of physical function. An intradialytic training pro-
gram during this period reduces the side effects of inactivity and
provides the benefits of exercise. Third, increased blood flow in-
duced by exercise would increase the removal of solutes such as
toxins or urea (Parsons et al. 2006). The advantages of intradialytic
training have been discussed by Cheema et al. (2005), who recom-
mended its incorporation into routine dialysis care. In our study,
only one subject dropped out of the protocol for nonmedical rea-
sons. This high degree of participant approval was probably due to
the stimulation provided by aerobic exercise during dialysis, in-
terest in the activity, the social aspect (2 patients shared the same
exercise session), and the positive effects on health.
Conclusion
The main objectives of the therapeutic management of CKD
(including ESKD) are to slow disease progression (Ruggenenti et al.
2001) and prevent cardiovascular complications (Oberley et al.
2000; Zoccali et al. 2002). Our pilot program demonstrates that
an intradialytic aerobic cycling training program has beneficial
effects on physical fitness (by increasing the distance walked dur-
ing the 6MWT) and lipid profile (by lowering plasma TG) and
prevents increased basal OS (without aggravating F2-IsoP, which is
the most reliable and specific marker of lipid peroxidation). Intra-
dialytic aerobic cycling training represents a useful and easy strat-
egy against hypertriglyceridemia, loss of physical function, and
increased OS. These results are very encouraging, considering the
relatively low duration of our protocol (only 3 months). Thus, a
regular intradialytic aerobic cycling program that can be easily
transferred to any dialysis center needs to be developed. Of course,
these results must be confirmed in a larger randomized study.
Conflict of interest statement
The authors declare no conflict of interest.
Acknowledgements
This study was supported by the following partners: Amgen,
Baxter, Hemotech, Meditor, Roche, and ANCA (Association des
Néphrologues Centre Auvergne). We would like to thank all the
participants, the technicians and engineers (especially Luz Lefeuvre
of the M2S laboratory and Marine Perrot and Franck Enjolras from
the AME2P laboratory), and the medical staff of Durtol, especially
the cardiologist team of the cardiothoracic clinic, who contrib-
uted to the study (Dr Cuenin, Dr Moisa, and Dr D’Agrosa-Boiteux).
This study also received technical assistance from Dr Pincemail of
the Laboratory of the University Hospital of Liège (Belgium) for
oxLDL measurement and from Dr Forte of the Gen-Bio laboratory
(Clermont-Ferrand, France) for biochemical analysis of renal func-
tion. We also thank Professor Denis Fouque for his advice during
the publication period.
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