| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
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Clinical Dialysis |






,

* School of Exercise and Sport Science and 
Faculty of Medicine, University of Sydney,
Department of Medicine, University of New South Wales, Departments of
Nutrition and Dietetics and ¶ Renal Medicine, St. George Hospital, and Departments of || Nutrition and Dietetics and ** Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia;
Institute of Food, Nutrition & Human Health, Massey University, Wellington, New Zealand; and 
Hebrew SeniorLife and Jean Mayer USDA Human Nutrition Center on Aging at Tufts University, Boston, Massachusetts
Address correspondence to: Dr. Bobby Cheema, Institute of Food, Nutrition and Human Health, Te Kura Hangarua o Kai-oranga-a-tangata, Massey University, Wellington Campus, Private Bag 756, Wellington, New Zealand. Phone: +64-4-801-2794, ext. 6801; Fax: +64-4-801-4994; E-mail: b.cheema{at}massey.ac.nz
Received for publication December 7, 2006. Accepted for publication February 20, 2007.
| Abstract |
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| Introduction |
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High-intensity progressive resistance training (PRT) has been prescribed successfully to enhance skeletal muscle and related physiologic and psychologic attributes in frail elders and those with chronic catabolic illnesses, including nursing facility residents and cardiac patients (7). The prevalence of muscle wasting in ESRD suggests that PRT is indicated and may be of significant benefit in this patient population as well (810). In fact, recent evidence suggests that moderate to vigorous physical activity confers a survival advantage in this cohort, although limitations exist in pursuing such activities (11).
The rationale for prescribing PRT to patients with ESRD in an attempt to counteract muscle wasting is extremely strong (8,9). However, barriers to regular exercise participation in this cohort are many, including, most notably, the sedentariness that is incurred by attending 12 to 18 h of dialysis treatment per week. Behaviors that dominate dialysis treatment time include sleeping and watching television, and few clinical units worldwide have promoted an active approach toward this patient "down time" despite much evidence for the health and clinical benefits of intradialytic cycling (9,12).
To date, only one trial has investigated the efficacy of prescribing PRT during routine hemodialysis treatment. Johansen et al. (13) reported that patients with ESRD can improve quadriceps muscle area secondary to 12 wk of moderate intensity, lower body PRT with either placebo or nandrolone decanoate injections.
The purpose of this study was to determine whether an isolated, full-body, high-intensity PRT regimen administered during routine hemodialysis treatment could safely induce favorable shifts in skeletal muscle quantity and quality in patients who receive maintenance hemodialysis treatment for the medical management of ESRD. We hypothesized that our novel intervention (14) would increase skeletal muscle cross-sectional area (CSA) and reduce intramuscular lipid infiltration while inducing additional health-related adaptations, including improved exercise capacity, psychologic health, inflammatory markers, nutritional status, and quality of life in our exercising patients.
| Materials and Methods |
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18 yr of age, (2) on hemodialysis for >3 mo, (3) without acute or chronic medical conditions that would preclude PRT or collection of outcome measures, (4) independent ambulation with or without an assistive device for
50 m, (5) adequately dialyzed (Kt/V
1.2) and stable during dialysis, (6) cognition and English language sufficient to understand research procedures and provide written informed consent, and (7) willingness to be randomly assigned and to undergo study protocols.
Study Design
The South Eastern Sydney Area Health Service and the University of Sydney Human Research Ethics Committees approved all procedures, and written informed consent was obtained from all participants (Australian Clinical Trials Registry 12605000101684). Patients were randomly assigned via computer-generated randomly permuted blocks stratified by gender in blocks of four to PRT + usual care (PRT), or usual care control. Patients were not stratified by diabetic status. Randomization assignments were generated by an investigator who was not involved in testing or training and delivered to patients in opaque sealed envelopes on the completion of all baseline testing.
PRT Intervention
Patients who were randomly assigned to PRT exercised under the direct supervision of an exercise physiologist during routine hemodialysis treatment three times per week for 12 wk as described previously (14). All PRT exercises were performed in a seated or supine position in a standard hemodialysis chair (LA-Z-BOY Pty Ltd, Moorebank, Australia). The limb that contained the forearm arteriovenous or Gortex fistula was exercised immediately before each dialysis session. A temporary vas catheter access precluded upper body training only.
During each PRT session, two sets of eight repetitions of 10 exercises that targeted major muscle groups of the upper and lower extremities were performed at a rating of perceived exertion of 15 to 17 of 20 ("hard" to "very hard"). Upper body exercises that were performed using free-weight dumbbells (Australian Barbell Co., Mordialloc, Australia) included the shoulder press, side shoulder raise, triceps extension, biceps curl, and external shoulder rotation. Lower body exercises, performed unilaterally using weighted ankle cuffs (Australian Barbell Co.), included seated knee extension, supine hip flexion, supine hip abduction, and supine straight-legged raise. Seated hamstring curls were also performed, using Thera-Band tubing (Akron, OH) attached to a fixed position on the weight trolley. Abdominal musculature was targeted with bilateral leg raises in a supine position or bilateral leg lifts in a seated position, depending on patient preference and level of ability.
Usual Care Control Group
Patients who were randomly assigned to the control group were provided usual care but no instructions to exercise or access to equipment.
Outcome Measures
All outcomes measures were collected at baseline and 12 wk after randomization.
Primary Outcomes
Computerized tomography (CT) of the nondominant mid-thigh was performed on a nondialysis day using a General Electric High Speed CTi Scanner (model CEE0459; Milwaukee, WI) to determine thigh muscle CSA and attenuation (i.e., intramuscular lipid infiltration [15]). Muscle CSA provided an index of muscle quantity, whereas muscle attenuation provided an index of muscle quality. Lower measures of muscle attenuation indicate less intramuscular lipid and thus better muscle quality. CT scans also provided areas of subcutaneous and total fat of the mid-thigh. All CT scans were collected and analyzed blindly as previously reported (16). Coefficient of variability of triplicate analysis of area and attenuation measures in this cohort is 0.005%.
Secondary Outcomes and Clinical Covariates
Peak force (kg) of the knee extensors, hip abductors, and triceps was measured bilaterally in triplicate with the best score recorded, using an isometric digital dynamometer (Chatillon CSD 200 Dynamometer; AMETEK, Paoli, PA; coefficient of variability 9.4%). These individual strength measures were summed to create a total strength measure.
The 6-min walk (17) was used as an index of exercise capacity. The coefficient of variability of this test is reported to be 5 to 10% in older or clinical cohorts (18).
A blinded dietitian collected all nutritional and anthropometric measures after dialysis, including body weight, height, waist, and mid-arm and mid-calf circumferences, using standard protocols. Limb circumference measures were collected on the right side of the body, as per standard protocol. The Mini-Nutritional Assessment was used because it is an objective, well-validated instrument to evaluate nutritional status in clinical and older cohorts and comprises medical history, reported dietary intake, and anthropometric measures (19). Dietary intake during the previous month was evaluated at baseline and week 12 using an Australian Food Frequency Questionnaire (20), analyzed using FoodWorks software (Version 3; Xyris Software, Highgate Hill, Queensland, Australia).
All blood samples were drawn before dialysis, before the midweek dialysis session, at least 48 h after the previous exercise bout. Urea kinetics evaluation included the collection of blood urea after midweek and before end-of-week dialysis sessions. Samples that potentially were affected by acute illness or trauma were discarded and repeated. C-reactive protein (CRP) was evaluated as an index of catabolism and systemic inflammation using a high-sensitivity assay, as were albumin, creatinine, and complete blood count (coefficient of variability 1.5 to 4.8%).
The Medical Outcomes Trust Short Form-36 (SF-36) (21) survey was used to measure health-related quality of life. The Geriatric Depression Scale (22) was used to evaluate depressive symptoms. The Physical Activity Scale for the Elderly (23) was used as a valid instrument to evaluate occupational, leisure, and daily habitual activity level apart from the study exercise prescription.
Compliance and Adverse Events
Compliance to training was defined as the number of training sessions attempted divided by the number offered multiplied by 100%. Change of health status, including acute illnesses, falls, changes in medication usage, dialysis-related complaints (e.g., headaches, hypotension, cramping), and visits to health care professionals were documented via weekly interview using a structured questionnaire developed a priori, open-ended questions, and weekly review of clinical notes. PRT-related adverse events were defined as any injury or exacerbation of underlying disease that potentially was attributable to the PRT regimen.
Statistical Analyses
Sample size estimates were calculated by hypothesized differences between the PRT and control groups in thigh muscle CSA on CT scan. On the basis of previous studies (16), the control group was estimated to have no change, whereas the PRT group was hypothesized to have a +3.5% change in CSA with an SD of ±4.5% after 12 wk. Using a two-tailed test of significance and setting the
at 0.05 and
at 0.20, a total of 44 patients were estimated to be required; this was inflated to 50 in anticipation of dropout/less-than-complete adherence to the protocol.
All available data were included regardless of patient compliance to the intervention in an intention-to-treat analysis performed using StatView statistical software package (Version 5.0; SAS Institute, Cary, NC). Data from patients who were unavailable for follow-up assessments at week 12 were carried forward from baseline values. All data were inspected visually and statistically for normality. Normally distributed data were described using mean ± SD and non-normally distributed data using median and ranges. Non-normally distributed continuous variables were log-transformed before entry into linear models or analyzed by Mann-Whitney U test. Variables with non-normal distributions were reported as median and range values with 95% confidence intervals (CI) expressed as a difference between medians. Between-group differences over time were expressed as PRT minus control group adjusted mean differences and 95% CI, as well as relative effect size (ES), calculated as change in treatment group minus change in control group divided by pooled SD, corrected for sample size (Hedge's bias corrected ES) (24). Group effect was analyzed by analysis of covariance (ANCOVA) using change scores (final minus baseline) as the dependent variables and baseline value of the dependent variable in the model as a covariate. Additional covariates for the ANCOVA models were identified by comparison of group means and CI at baseline for clinically meaningful differences in characteristics that were identified a priori as potential confounders (age and hemodialysis vintage), because these factors might confound the change in the dependent variable as a result of their potential to influence anabolic adaptations to PRT. P < 0.05 and/or 95% CI not inclusive of 0 was considered indicative of statistical significance. Clinical significance was evaluated via consideration of the magnitude of differences that were observed between groups relative to known clinically meaningful differences as well as the relative ES calculated.
| Results |
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Adverse Events
No statistically significant differences were observed between the PRT group and controls for the number of dialysis-related complaints, including headaches (PRT 0 [0 to 2]; control 0 [0 to 3]; 95% CI 0 to 0), hypotension (PRT 1 [0 to 7]; control 0 [0 to 6]; 95% CI 2 to 1), cramping (PRT 0 [0 to 8]; control 0 [0 to 6]; 95% CI 0 to 0), and fistula cannulation difficulties (PRT 0 [0 to 2]; control 0 [0 to 3]; 95% CI 0 to 0). No fistula infections or angina was reported in either group during the trial. The incidence of falls was low and did not differ significantly between groups (PRT 0 [0 to 1]; control 0 [0 to 2]; CI not computed because of rarity of events). No differences were observed between groups in acute illness (PRT 2.45 ± 1.64; control 1.83 ± 1.93; 95% CI 1.65 to 0.41) or number of visits to health care professionals (PRT 3.80 ± 1.40; control 4.83 ± 2.63; 95% CI 0.19 to 2.25) during the trial. No case of cannula dislodgement was observed during exercise in any patient during the course of the trial. One adverse event was documented: An elderly woman in the PRT group (73.3 yr, 3.8 yr on HD) sustained partial tearing of a right rotator cuff muscle (supraspinatus) in week 6 of training (25). The injury was managed conservatively, and the patient continued with lower body training for the remainder of the trial and underwent final assessment (25).
Sensitivity Analyses
Secondary sensitivity analyses were performed using all available data regardless of compliance without imputation of missing data from the five patients who did not undergo final assessment. The outcomes of these analyses did not differ with the intention-to-treat primary analysis with respect to statistically significant findings (data not shown).
| Discussion |
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Accrual of intramuscular lipid (i.e., muscle attenuation) has been associated with aging, frailty, mobility impairment, muscle weakness, insulin resistance, visceral obesity, and type 2 diabetes (15,26). Exercise-induced improvements in muscle attenuation in older and clinical cohorts result in enhanced insulin sensitivity (27,28). Therefore, our finding that intradialytic PRT can enhance muscle attenuation may be of clinical importance given that diabetes has become the leading cause of ESRD (29).
The reduction of intramuscular lipid is potentially initiated via PRT-induced muscle damage, which, through the activation of the immune system, satellite cells (30), and growth factors, degrades necrotic muscle fibers and promotes the synthesis of muscle fibers of higher integrity (31). In this process, the intramuscular lipid is potentially used as a substrate and oxidized, perhaps in place of muscle glycogen (27,32,33). Several studies have noted an improvement of muscle attenuation with exercise relative to sedentary controls in other cohorts (27,28,34), and our findings demonstrate for the first time that this beneficial adaptation occurs in ESRD as well.
Our training regimen did not significantly increase muscle CSA. However, the 95% CI varied from a 1.9-cm2 reduction relative to control to a 6.1-cm2 increase for PRT. The upper bound, favoring PRT, represents a clinically important difference with an ES of 0.30 (Table 2). As such, this finding should be viewed as indeterminate, rather than negative, because our study was powered for a larger ES (0.77) estimated from previous literature. It is also possible that a significant change in muscle CSA may have been detected by investigating muscle biopsies, which are highly sensitive to change. For example, in our previous randomized, controlled trial that compared 12 wk of PRT with sham exercise in 26 patients with chronic renal insufficiency (35), significant type I (P = 0.03) and type II (P = 0.04) muscle fiber hypertrophy (24 and 22%, respectively), detected via muscle biopsies, was demonstrated despite a nonsignificant change in mid-thigh muscle CSA as evaluated via CT (P = 0.11).
Johansen et al. (13) reported that 12 wk of moderate-intensity, lower body intradialytic PRT combined with either placebo or anabolic steroid injections was sufficient to induce statistically significant muscle hypertrophy of the quadriceps muscle group, as evaluated via magnetic resonance imaging. However, the investigators evaluated changes within the quadriceps muscle group only, which would have been specifically targeted by the knee extension exercises used (13). By contrast, we measured combined muscle groups of the mid-thigh, despite that the hip extensors, hamstrings, and adductors were not adequately targeted by the exercises that could be performed in a dialysis chair. Therefore, we may have underreported adaptations specific to the quadriceps muscle.
Additional health-related benefits that were experienced by our PRT group occurred despite no significant change between groups in dietary protein and total energy intake or recreational and daily physical activity (Table 3), suggesting that these adaptations occurred secondary to PRT, rather than other lifestyle changes. The changes in body composition that were experienced by our PRT group all were favorable, including increased weight, BMI, and mid-arm and mid-thigh circumference, without an increase in central adiposity or mid-thigh, subcutaneous, or intramuscular lipid (Table 2). Such changes have been associated with survival benefit in this cohort. For example, higher BMI is associated with lower all-cause mortality in patients with ESRD (36,37), particularly when these patients have normal to high muscle mass (36). Johansen et al. (13) reported an increase in whole-body fat mass as a result of intradialytic PRT; however, they did not report on dietary intake in this trial, and this outcome requires confirmation, because it is an unexpected outcome of anabolic interventions such as PRT.
Our finding that PRT lowered CRP levels relative to those in control subjects by a clinically significant amount with a large ES of 0.85 is important given the proinflammatory state that is characteristic of patients with ESRD and the morbidity and the excess mortality that are associated with elevation of CRP in this (38) and other cohorts. The mechanism for the reduction in CRP with resistance training is not established. However, PRT, without diet or weight loss, has been shown to reduce visceral fat in other studies, and a subsequent reduction in inflammatory adipokines (including IL-6 and TNF-
) or increase in adiponectin related to visceral fat changes may, in turn, reduce hepatic CRP production (39). Future studies with direct measurements of visceral fat and assessments of other inflammatory cytokines are needed to understand this clinically relevant adaptation more fully.
The improvements of quality-of-life domains, including Physical Function and Vitality, suggest the potential importance of intradialytic PRT as a therapeutic intervention for enhancing physical and psychologic health status in this cohort. Similarly, Painter et al. (40) showed that 16 wk of home-based exercise combined with intradialytic cycling improved these same domains of quality of life. Johansen et al. (13) also observed an improvement of Physical Function in their trial of intradialytic PRT.
Limitations of our study include the lack of a sham exercise control activity because of the single geographic site used, and the unblinded assessment of secondary outcomes of physical performance measures (6-min walk and strength) measures and non-nutritional questionnaire data (quality of life and Physical Activity Scale for the Elderly).
| Conclusion |
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| Disclosures |
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| Acknowledgments |
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We sincerely thank all of the participants for dedication to this research project. This investigation was enhanced through the valuable contributions of Dr. Rob Herbert, Dr. Masashi Shibata, Tanya Newton, Scott Cuthbert, Robert Russell, Michael Russo, Andrea Pantoja, Andrew Kilday, Gary Osborne, Alicia Morris, Kylie Simpson, Belinda Stewart, Samantha Tang, Keith Westbury and SEALS Pathology, Tracy Blow and the nursing staff of the St. George Public Hospital Hemodialysis Unit, and Kay Cook and the staff of the Radiology Department at Royal Prince Alfred Hospital.
Partial findings of this research have been published in abstract form (J Am Geriatr Soc 53: S13S14, 2005; and J Aging Phys Act 12: 260, 2004).
This study was completed in partial fulfillment of the degree of Doctor of Philosophy by B.C. at the School of Sport and Exercise Science, University of Sydney, Australia.
B.C.'s current affiliation is Institute of Food, Nutrition and Human Health, Massey University, Wellington Campus, Wellington, New Zealand. The current affiliation for H.A., B.S., B.L., and M.F.S. is the School of Sport and Exercise Science, University of Sydney (Cumberland Campus), Australia; A.O.'s current affiliation is Department of Medicine, University of New South Wales, and St. George Hospital, Kogarah, New South Wales, Australia; M.C. and G.P.'s current affiliation is Department of Nutrition and Dietetics, St. George Hospital, Kogarah, New South Wales, Australia; A.P.'s current affiliation is Department of Nutrition & Dietetics, Prince Alfred Hospital, Camperdown, New South Wales, Australia; J.K.'s current affiliation is Department of Renal Medicine, St. George Hospital, Kogarah, New South Wales, Australia; A.G.'s current affiliation is Department of Renal Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
| Footnotes |
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| References |
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