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American Journal of
a
Department of Biomedical Sciences and Surgical Specialties, Section of Sport Sciences, University of Ferrara, b Department
of Rehabilitation Medicine, Hospital University of Ferrara, c Vascular Diseases Center, University of Ferrara, Ferrara,
d
Nephrology Dialysis Unit, Civil Hospital Imola, Imola, e CNR-IFC, Clinical Epidemiology and Physiopathology of Renal
Diseases and Hypertension of Reggio Calabria, Reggio Calabria, f Nephrology Dialysis Unit, Hospital University of Ferrara,
Ferrara, g Nephrology and Renal Transplantation Division, Ospedali Riuniti, Reggio Calabria, Italy
Key Words subjects. Results: rmVO2 was twice higher (p < 0.001) in
Dialysis · End-stage renal disease · Exercise · Muscle ESRDs patients (0.083 ± 0.034 ml/100 g/min) than in healthy
metabolism · Noninvasive · Near-infrared spectroscopy · subjects (0.041 ± 0.020 ml/100 g/min) indicating substantial
Biomarker · Oxygen consumption · Mobility · Physical skeletal muscle dysfunction in ESRD. rmVO2 correlated with
functioning resting heart rate (r = 0.34, p = 0.009) but was independent
of age, dialysis vintage, biochemical, vascular and nutrition
parameters. After the 6-month exercise program, rmVO2 re-
Abstract duced to 0.064 ± 0.024 ml/100 g/min (–23%, p < 0.001) in the
Background: Skeletal muscle dysfunction and poor exercise exercise group indicating that skeletal muscle dysfunction is
tolerance are hallmarks of end-stage renal disease (ESRD). largely reversible but remained identical in the control group
Noninvasively measured (near-infrared spectroscopy, NIRS) (0.082 ± 0.032 to 0.082 ± 0.031 ml/100 g/min). Conclusion:
resting muscle oxygen consumption (rmVO2) is a biomarker Deconditioning has a major role in ESRD myopathy. rmVO2
of muscle dysfunction, which can be applied to study the is a marker of physical deconditioning and has the potential
severity and the reversibility of ESRD myopathy. We tested for monitoring re-conditioning programs based on physical
the hypothesis that deconditioning is a relevant factor in exercise in the ESRD population. © 2015 S. Karger AG, Basel
ESRD myopathy. Methods: The whole dialysis population
(n = 59) of two of the eight centers participating into the
EXCITE study (ClinicalTrials.gov NCT01255969), a random-
ized trial evaluating the effect of a home-based exercise pro- Introduction
gram on the functional capacity of these patients was stud-
ied. Thirty-one patients were in the active arm (exercise Skeletal muscle dysfunction and poor exercise toler-
group) and 28 in the control arm (no intervention). Norma- ance are established determinants of a sedentary lifestyle
tive data for rmVO2 were obtained from a group of 19 healthy and physical deconditioning in end-stage renal disease
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DOI: 10.1159/000431339
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6 p.m.), according to the dialysis schedule. These measurements Statistical Analysis
were performed at baseline and after 6 months. Skinfold thickness The comparison between groups was performed by unpaired
was measured in triplicate according to the international stan- Student’s t-test and the Fisher’s exact test, as appropriate. Spear-
dards [17] at the calf at the level of the largest circumference by man rank correlation was applied to evaluate the relationship
using the Holtain-Tanner/Whitehouse plicometer (Holtain Ltd., between rmVO2 values and putative functional correlates (age,
UK). dialysis vintage, resting heart rate, biochemical parameters), as
well as the vascular or functional capacity measurements. Be-
NIRS-Based Measurements tween groups, differences were tested by the unpaired Student’s
NIRS measurement to determine the rmVO2 was made at the t-test or Mann-Whitney U test, as appropriate. The proportion
level of skinfold measurement, along the medial gastrocnemius of patients with abnormal rmVO2 values among patients with
muscle as detailed elsewhere [5]. The distance between the NIRS high and low compliance to the exercise program was compared
sensor and malleolus medialis was measured and recorded for each by the χ2 test. A one-way analysis of variance was used to com-
patient to maintain the correct positioning at 6 months follow-up pare the mean rmVO2 values in the presence of different comor-
evaluation. The interoptode distance was set at 40 mm, allowing a bidities. Significance was set at a p value ≤0.05. Statistics were
maximum light penetration depth of approximately 25 mm. The performed using MedCalc 14.8.1 (MedCalc Software, Mariaker-
NIRS sensors were connected to a continuous wave system (Oxy- ke, Belgium).
mon MK III, Artinis Medical System, the Netherlands) composed
of two channels (two equivalent pulsed light sources, two ava-
lanche photodiode detectors, shielded from ambient light). The
system uses intensity-modulated light at a frequency of 1 Hz and Results
laser diodes at three wavelengths (905, 850, and 770 nm) corre-
sponding to the absorption wavelengths of oxyhemoglobin (O2Hb)
and deoxyhemoglobin (HHb) with an auto-sensing power supply Subjects
(approximately 40 W at 110–240 V). The light generated by the Among the 59 patients enrolled into this study, three
laser diodes and conducted to the tissue, is partly absorbed and in the exercise and two in the control arm failed to com-
partly scattered by the tissues and re-collected by the detector, pro- plete the training program and could not be included in
viding the measurement of the O2Hb and HHb concentrations
([O2Hb], [HHb]). NIRS measurement was made in a resting, su- the analysis. Thus, the final analysis was performed in 54
pine position. A blood pressure cuff was placed around the thigh patients, 28 patients randomized to the exercise arm and
and connected to a compressor with a manometer. Venous occlu- 26 to the control arm, respectively. Patients in the two
sion was induced by inflating the cuff to a pressure of 60 mm Hg arms of the study (table 1) were comparable for age, gen-
in 4 seconds. The pressure was maintained at a constant level for der, BMI, dialysis vintage, type of dialysis treatment (he-
30 seconds and then quickly released. The absolute value of rmVO2
was calculated by analyzing the rate of increase in [HHb] ensuing modialysis and peritoneal dialysis), blood pressure, co-
venous occlusion [18]. The concentration changes of HHb were morbidities, smoking habits as well as for serum creati-
converted from micromolar per second (μM/s) into milliliters of nine and the main biochemical parameters, including
O2 per 100 grams of tissue per minute (ml/100 g/min). rmVO2 dialysis dose (Kt/V). Furthermore, skinfold thickness,
values were measured in both legs and the mean value was consid- rmVO2 and vascular function indexes (TBI, ASI) were
ered for data analysis. The data collection and calculations were
performed using the Oxysoft 2.0.47 software (Artinis Medical Sys- similar in the two groups (table 1).
tem, the Netherlands).
NIRS-Based Measurement
Vascular Function Measurements The skinfold thicknesses at the calf were less than 16
The toe-brachial index (TBI) and the arterial stiffness index mm for all participants indicating no technical impedi-
(ASI) (calculated as the average value of the values collected from
the arms and legs) were measured by an automatic oscillometric ment for NIRS measurements. At baseline in the entire
4-channel device (AngE, Sonotechnik, Austria). study population, rmVO2 was higher in the dialysis pop-
ulation than in the healthy subjects (0.083 ± 0.034 ml/100
Functional Capacity Assessment g/min vs. 0.041 ± 0.020 ml/100 g/min, respectively; p <
Patients performed the 6-min walk test, validated for different 0.001) documenting an abnormally high necessity at rest
chronic populations including ESRD patients [19, 20]. They were
asked to walk back and forth in a corridor along a 22 m course (two to extract oxygen from the blood in dialysis patients. The
10 m straight sections connected by two 1 m curves) at their own mean rmVO2 values were similar for patients undergoing
pace, as quickly and safely as possible, aiming to cover the maximal hemodialysis (0.082 ± 0.028 ml/100 g/min) or peritoneal
distance in 6 min. The patients were allowed to rest in case of fa- dialysis (0.087 ± 0.048 ml/100 g/min) and were signifi-
tigue or pain and to continue when possible. The final distance cantly higher in males than in females (0.089 ± 0.035 vs.
covered (6MWD) by the patients was recorded. The resting heart
rate before this test was measured using a heart rate monitor (Polar 0.071 ± 0.026 ml/100 g/min, respectively; p = 0.04). In a
RS800CX, Polar Electro, Finland) with the patient in the standing categorical analysis, rmVO2 was higher than the upper
position. limit of the normal range in 41 patients (76%). No sig-
198.143.38.1 - 1/27/2016 3:17:47 AM
Discussion
nificant differences in the mean rmVO2 values were ob- In this study, rmVO2 was on average much higher in
served in patients with or without peripheral arterial dis- ESRD patients on chronic dialysis than in coeval healthy
ease (p = 0.42), diabetes (p = 0.26) or belonging to the subjects indicating substantial muscle function impair-
three different NYHA classes (p = 0.51). ment in this population. A home exercise program pro-
duced an improvement in physical performance and a
Functional Correlates of rmVO2 at Baseline clear reduction in rmVO2, which attained the normal
No significant relationship was found between rmVO2 range in a substantial proportion (39%) of patients.
and age, dialysis vintage, anthropometric and biochemi- These findings are compatible with the hypothesis that
cal measurements and vascular function (TBI, ASI) mea- the ESRD myopathy depends, to an important extent,
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DOI: 10.1159/000431339
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Table 2. NIRS, vascular and functional measurements in the two study arms
NIRS measurements
Mean rmVO2, ml/100 g/min 0.084±0.036 0.064±0.024* 0.082±0.032 0.082±0.031
Vascular measurements
TBI, arbitrary unit 0.87±0.16 0.85±0.26 0.82±0.21 0.82±0.15
ASI, m/s 8.87±4.46 7.67±2.15 7.05±1.57 8.70±3.61*
Functional measurements
Resting heart rate, bpm 74±9 73±9 74±8 73±9
6MWD, m 347±87 397±101* 333±118 331±115
0.12
rmVO2 (ml/100 g/min)
0.09
0.06
0.03
Fig. 1. Box and whisker plots of rmVO2 at
baseline and after 6 months in the two ex-
perimental groups. The upper and lower 0
dashed lines correspond to the 25th and
Baseline 6 months Baseline 6 months
75th percentiles of the values of the healthy
group.
on physical deconditioning. rmVO2 by NIRS has been that rmVO2 in resting condition was much higher in
sparsely measured in previous studies in ESRD patients ESRD patients than in coeval healthy subjects. Of note,
[12], but to our knowledge this parameter has never rmVO2 in these patients (0.083 ± 0.034 ml/100 g/min)
been applied to investigate the reversibility of ESRD my- was also higher than that we had previously observed –
opathy in these patients. In this study, we took the op- under the same experimental conditions and with the
portunity of a clinical trial testing the efficacy of a home- same NIRS device – in patients with peripheral artery
based physical exercise program for exploring the effect disease (0.069 ml/100 g/min) [5] and in those with mul-
of exercise on this fundamental parameter of muscle tiple sclerosis (0.059 ml/100 g/min) [6]. The increased
function. Along with our working hypothesis, we found muscle oxygen consumption in ESRD patients was un-
198.143.38.1 - 1/27/2016 3:17:47 AM
50
rmVO2. Indeed this parameter substantially decreased
0
in patients in the active arm of the trial and normalized
in about the 39% of patients. Furthermore, such an im-
provement paralleled the adherence to the exercise pro-
–50 gram being more marked in patients with a high compli-
ance to the same program. Improved oxygen utilization
–100 promoted by an increase in mitochondrial volume and
High Low Control in capillary density following exercise [29] likely ex-
plains the reduction in rmVO2 that we registered in
ESRD patients after physical training. Aerobic exercise
Fig. 2. Trends of rmVO2, vascular and functional changes for the training ameliorates endothelial function in dialysis pa-
exercise group, split according to adherence to prescribed sessions
(high adherence, n = 20; low adherence, n = 8), and control group. tients [30] and improved control of vascular tone might
contribute to the exercise-induced improvement in
rmVO2 that we had observed in these patients. In this
related to peripheral artery disease, diabetes or the func- study, neither the TBI nor the ASI showed significant
tional classification of heart insufficiency pointing to the changes in the exercise group, even though the second
disease burden of ESRD per se as the main factor under- parameter showed a favorable time trend. More sensi-
lying the muscle dysfunction in this condition. Overall, tive indicators of endothelial function and arterial stiff-
findings in this study set ESRD as a condition entailing ness and longer observations periods may be needed to
a risk for muscle function impairment similar or higher detect the hypothetic favorable effect of exercise on vas-
than that of other severe chronic disease like peripheral cular deconditioning in ESRD.
artery disease or a neurologic disease like multiple scle- It was recommended that biomarkers of muscle func-
rosis. Along with higher rmVO2, physical inactivity and tion related to clinical status be tested and applied to de-
sedentarism induce vascular deconditioning, with re- velop biological models of recovery in severe, disabling
duced endothelium-dependent vasodilatation and in- diseases like stroke [31]. Findings in this study in ESRD
creased arterial stiffness and vasoconstriction [21, 22], patients and observations on other chronic conditions [5,
alterations which are almost universal in ESRD patients 6] concur in supporting rmVO2 as a biomarker of periph-
[23]. On the other hand, muscle deconditioning attrib- eral deconditioning in ESRD patients. In this study, we
utable to the burden of ESRD – including muscle wast- document that rmVO2 is not a mere surrogate of other
ing, anemia and other comorbidities – and the resulting risk factors or disease markers. Indeed this parameter was
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largely independent of age, dialysis vintage, hemoglobin observational studies and in large trials, like EXCITE.
concentration and biochemical values, vascular, func- rmVO2 is a marker of physical deconditioning and has
tional and nutrition factors and effectively captured not the potential for monitoring re-conditioning programs
only the severity of muscle dysfunction but also the im- based on physical exercise in the ESRD population. Fur-
provement in muscle performance brought about by a ther studies testing this biomarker in larger trials are still
physical rehabilitation intervention. Unlike circulating needed to confirm the usefulness of this technique in
biomarkers of deconditioning-reconditioning previously ESRD.
studied by us in dialysis patients [32, 33], rmVO2 seems
to be an easily and quickly measured biomarker giving an
insight into the heterogeneity of local muscle metabolism Acknowledgments
[4].
The main limitations of this study are inherent to the This work was supported by an Italian government grant from
NIRS technique [34]: the limited region of muscle evalu- the Health Minister (Ricerca Finalizzata).
ated, the technical variability of rmVO2 measurements
attributable to probe position and to the thickness of tis-
sues overlying muscles, which may affect the interpreta- Contributors
tion of muscle oxygen consumption by NIRS. However,
these potential shortcomings can be overcome by appro- Davide Bolignano, Filippo Aucella, Rossella Baggetta, Antonio
priate standardization, as we did in the present and in Barillà, Yuri Battaglia, Silvio Bertoli, Graziella Bonanno, Pietro Cas-
tellino, Daniele Ciurlino, Adamasco Cupisti, Graziella D’Arrigo,
previous studies in patients with chronic diseases [5, 6].
Luciano De Paola, Fabrizio Fabrizi, Pasquale Fatuzzo, Giorgio Fui-
The technicians collecting NIRS parameters were not ano, Luigi Lombardi, Gaetano Lucisano, Piergiorgio Messa, Renato
blinded to the group assignment of participants, although Rapanà, Francesco Rapisarda, Stefania Rastelli, Lisa Rocca-Rey,
this assessment is not operator dependent. As reported, Chiara Summaria.
adherence to the exercise program was estimated on the
basis of diaries and on the witness of the caregiver. These
methods have limitations as compared to accelerometers Disclosure Statement
and GPS-based instruments [35] but are deemed to be
reasonable estimates of physical activity in large-scale The authors declare that they have no conflict of interest.
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