The Effect of Resistance Exercise to Augment Long-term Benefits of Intradialytic Oral Nutritional Supplementation in Chronic Hemodialysis Patients
Article Outline
Background
Resistance exercise combined with intradialytic oral nutrition (IDON) supplementation improves net protein balance in the acute setting in chronic hemodialysis patients. We hypothesized that combination of long-term resistance exercise and IDON would improve markers of muscle mass and strength further compared with IDON alone.
Methods
Thirty-two participants (21 male; mean age, 43 ± 13 years) on chronic hemodialysis were randomly assigned to IDON plus resistance exercise (NS + EX), or IDON (NS) alone for 6 months. IDON consisted of a lactose-free formula consisting of protein, carbohydrate, and fat. Three sets of 12 repetitions of leg-press were completed before each dialysis session in the NS + EX arm. Primary outcome measurement was lean body mass. Muscle strength and other nutritional parameters were measured as secondary outcomes.
Results
Of 32 participants, 22 completed the 6-month intervention. There were no statistically significant differences between the study interventions with respect to changes in lean body mass and body weight, when comparing NS + EX to NS. There were also no statistically significant differences in any of the secondary outcomes measured in the study. Body weight (80.3 ± 16.6 kg, 81.1 ± 17.5 kg, and 80.9 ± 18.2 kg at baseline, month 3, and month 6, respectively; P = .02) and 1-repetition maximum (468 ± 148 lb, 535 ± 144 lb, and 552 ± 142 lb, respectively; P = .001) increased statistically significantly during the study for all patients combined.
Conclusion
This study did not show further benefits of additional resistance exercise on long-term somatic protein accretion above and beyond nutritional supplementation alone. When both treatments groups were combined, body weight and muscle strength improved during the study.
PROTEIN ENERGY WASTING in advanced chronic kidney disease is highly prevalent and represents an important target for improving hospitalization events and death risk in this patient population.1, 2, 3, 4, 5 Previous studies showed that intradialytic nutritional supplementation, administered parenterally or orally, prevent hemodialysis (HD)-associated protein catabolism and result in a protein anabolic response, at least in the acute setting.6, 7, 8, 9 A recent randomized clinical trial further extended the beneficial effects of nutritional supplementation to a longer-term in chronic hemodialysis (CHD) patients with apparent protein energy wasting.10
A potential strategy to augment the anabolic effects of nutritional supplementation is concomitant exposure to resistance exercise around the time of administration of nutritional supplementation. Short-term studies in healthy subjects and CHD patients showed that postexercise net muscle protein accretion is increased with oral nutrition supplement when compared with exercise or oral supplement alone.11, 12, 13 Furthermore, recent long-term studies indicated a limited beneficial effect of long-term exercise alone on muscle protein accretion in CHD patients.14, 15, 16, 17 There are no studies that examined the long-term effects of resistance exercise combined with intradialytic oral nutritional supplementation (IDON) on muscle protein accretion in CHD patients. In this study, we hypothesized that the combination of resistance exercise with IDON would lead to a higher accretion in lean body mass (LBM) when compared with IDON alone in CHD patients. To test this hypothesis, we performed a randomized clinical trial in 32 CHD patients over a 6-month period.
Materials and Methods
Study Participants
Participants were recruited from the Vanderbilt University Medical Center outpatient dialysis unit. Inclusion criteria included patients who were 18 years of age or older, had been on CHD for more than 3 months, and were delivered an adequate dose of dialysis (double pool Kt/V ≥ 1.2) on a thrice-weekly HD program using a biocompatible HD membrane (Optiflux®, Fresenius USA, Lexington, MA). Patients with active inflammatory or infectious disease, pregnancy, hospitalization within 1 month before the study, and those not capable of exercise because of cardiovascular disease or osteoarthritis were excluded from the study. The Institutional Review Board of Vanderbilt University approved the study protocol, and written informed consent was obtained from all study participants.
Study Design
This was a 6-month prospective, randomized, open label, parallel arm clinical trial (clinicaltrials.gov, number NCT00179218). After obtaining written informed consent, subjects underwent 2 comprehensive baseline assessments, which included testing for body composition, muscle strength, and nutrition status. Body composition was measured by Dual Energy X-ray Absorptiometry (DEXA), Bioelectrical impedance, and anthropometric measures, as previously described.18, 19 One-Repetition Maximum (1-RM) testing using a pneumatic leg press was done to measure muscle strength. Subjective global assessment (SGA) based on history and physical examination according to the 7-scale method was also recorded.20 Dietary protein and energy intake, normalized by the body weight from DEXA (dietary protein intake and dietary energy intake), were collected by a trained registered dietitian for two 24-hour diet recalls (1 from a HD day and 1 from a non-HD day) and analyzed using the Nutrition Data System for Research software version 5.0 (University of Minnesota, Minneapolis, MN). A fasting blood sample was obtained to examine serum concentrations of total protein, albumin, prealbumin, C-reactive protein, and creatinine. All measurements were done at a specialized chemistry laboratory (RenaLab, Richland, MS). Serum albumin, prealbumin, and C-reactive protein were analyzed using bromocresol green technique, an antigen-antibody complex assay, and nephelometric analysis, respectively.
The baseline assessments were done 4 weeks apart, during which subjects were asked to keep all physical activity and energy intake similar to their normal schedule. After the second baseline assessments were completed, subjects were randomly assigned to either nutrition supplementation alone (NS) or nutrition supplementation plus resistance exercise (NS + EX) using a computer-generated randomization schema. All subjects were exposed to body composition, muscle strength, and nutritional assessment at month 3 and 6 during the study.
Nutritional Supplementation
All study participants were provided nutritional supplementation during the study at each dialysis treatment, 3 days per week for 6 months. The supplement used was Nepro®, a lactose-free formula that is specially designed for CHD patients (Abbott Laboratories, Indianapolis, IN). Each can contained 240 mL and 480 kcal (66.8 kcal from protein, 211.2 kcal from carbohydrates, and 204.3 kcal from fat). Study subjects were prescribed 2 cans to be consumed during their routine dialysis sessions. Some participants who were not able to tolerate the full amount of the NS initially were allowed to consume 1 can during dialysis with the other can taken at home on the same day until full tolerance was achieved. At the end of the study, the compliance with the supplement dose was similar at 76% and 87% for NS + EX and NS groups, respectively. Weekly visits were completed by study personnel with each subject to evaluate tolerance and compliance to the supplement, and to restock additional supplement.
Resistance Exercise
Subjects randomized to receive exercise (NS + EX) performed the prescribed resistance exercise, under supervision of study personnel, within 30 minutes before each dialysis session and ingestion of at least 1 can of Nepro®. A pneumatic leg press machine (Keiser®, Fresno, CA) was used, mainly focused at exercising the quadriceps, hamstring, and gluteus muscles. Subjects sat on the leg press machine with their feet placed on a platform, their legs at a 90° angle, and were instructed to push the platform forward, leaving their knees slightly bent. For the first month, exercise was set at approximately 70% of the subject's 1-RM established at the baseline control visits. An initial leg press weight approximately equal to the participant's body weight was used. Additional weight (∼25 to 50 lb) was added at each repetition until the participant could no longer push the platform. After the 1-RM was determined, 70% of this weight was used for participants in the NS + EX arm performing 3 sets of 12 repetitions before each dialysis session. At the month 3 and 6 assessments, 1-RM was repeated in all subjects to evaluate progress and determine a new 1-RM for those in the NS + EX arm.
Statistical Analysis
Data are presented as proportions for categorical variables and mean ± standard deviation for continuous variables. Patients' one time data were compared by using the chi-square test for categorical variables, and by using the Mann-Whitney U test for continuous variables. Body composition data, biochemistry, and other nutrition parameters including dietary records were compared between groups at baseline, month 3, and month 6 using Mann-Whitney U tests at each time point. Changes over time were also compared between groups using a general linear model analysis of variance, with bootstrap covariance accounting for correlation among repeated measures within a patient. The baseline value of the outcome variables was adjusted as a model covariate. The effect of treatment at each of the 2 time points was assessed only when the global test was rejected to avoid inflation of type I error. Residuals were assessed graphically for normality, and transformation on the dependent variable was done to correct non-normal residuals if needed. Sensitivity analysis was performed with adjustment of patients' age, gender, and body mass index (BMI) in the model. We further assessed the short-term treatment effect at month 3 of follow-up using similar models. In addition, change in outcome variables over time was also assessed, adjusting treatment effect. All analyses were performed with R-software version 2.7.2 (R Foundation for Statistical Computing, Vienna, Austria, www.r-project.org), and a 2-sided significance level of at least 0.05 was required to reject the null hypothesis.
The primary outcome of the study was total LBM (kg) measured by DEXA. A sample size of 36 patients provided at least 98% power to detect a difference of 2.5 kg of LBM (e.g., a first condition mean, m1, of 50 kg and a second condition mean, m2, of 52.5 kg), assuming a standard deviation of differences of 2.5, using an unpaired t-test approach with a 0.05 two-sided significance level. With a drop-out rate of approximately 30%, that is 22 patients completing the study, the same assumptions as described above would provide power of 90%.
Results
Baseline Characteristics
A total of 36 subjects were consented to participate in the study, 32 were randomized, and 22 completed the 6-month study: 12 in the NS group and 10 in the NS + EX group. A flow chart depicting subject allocation and drop-outs throughout the study period is shown in Figure 1. Baseline characteristics of the 32 randomized subjects are shown in Table 1. In general, the study cohort had a preponderance of males (66%), African Americans (72%), younger age (43 ± 13 years), and less than usual diabetics (19%). The mean BMI (28.4 ± 6.3 kg/m2) was consistent with the general CHD population in the United States. Mean serum albumin was indicative of a relatively well preserved nutritional status. No statistically significant differences were observed between groups in clinical or demographic parameters and biochemistry data.
Figure 1
Trial flow chart (NS, nutrition supplementation; NS + EX, nutrition supplementation plus resistance exercise).
Table 1. Baseline Patient Characteristics
| Total (n = 32) | NS + EX (n = 15) | NS (n = 17) | P | |
|---|---|---|---|---|
| Gender | .53 | |||
 Male | 21 (66) | 9 (60) | 12 (71) | |
| Female | 11 (34) | 6 (40) | 5 (29) | |
| Race | .74 | |||
| African American | 23 (72) | 10 (66) | 13 (76) | |
| Asian | 1 (3) | 1 (7) | 0 (0) | |
| Caucasian | 6 (19) | 3 (20) | 3 (18) | |
| Hispanic | 2 (6) | 1 (7) | 1 (6) | |
| Age (years) | 43.2 ± 13.1 | 46.5 ± 12.1 | 40.2 ± 13.5 | .17 |
| BMI (kg/m2) | 28.4 ± 6.3 | 27.5 ± 6.3 | 29.1 ± 6.4 | .45 |
| Etiology of ESRD | .78 | |||
| Diabetes | 6 (19) | 3 (20) | 3 (18) | |
| HTN | 19 (59) | 8 (53) | 11 (65) | |
| Other | 7 (22) | 4 (27) | 3 (18) | |
| Other variables | ||||
| Hemoglobin (g/dL) | 12.1 ± 1.5 | 12.0 ± 1.4 | 12.2 ± 1.7 | .66 |
| Albumin (mg/dL) | 41.2 ± 2.9 | 40.7 ± 2.8 | 41.8 ± 3.0 | .40 |
| Creatinine (mg/dL) | 10.1 ± 2.5 | 9.3 ± 2.5 | 10.9 ± 2.3 | .09 |
| CRP (mg/L) | 4.0 (1.9∼13.1) | 4.3 (1.9∼13.3) | 3.9 (1.0∼12.0) | .52 |
Compliance
The rate of achieving the consumption of expected cans for Nepro® was not significantly different between groups, 76% and 87%, respectively, in NS + EX and NS. All the subjects in the NS + EX group completed 3 sets of 12 repetitions in each exercise session except for 2 patients who missed 1 set in one session. The actual leg press weight achieved was 71%, 75%, and 82% of 1-RM at baseline, month 3 and month 6, respectively.
Body Composition
The body composition measurements during the study period are depicted in Table 2. The LBM at baseline was significantly higher in the NS group, which continued to be the case at month 3 and month 6 (48.1 ± 7.7 kg versus 54.3 ± 8.4 kg at baseline, 48.2 ± 7.8 kg versus 55.7 ± 9.1 kg at month 3, and 47.4 ± 7.1 kg versus 56.2 ± 9.9 kg at month 6 for NS + EX and NS; P = .03, .05, and .05 respectively). There was no difference when comparing changes over time between groups after adjusting for baseline LBM, age, gender, and BMI (P = .79 by 3 months, P = .65 by 6 months,; Fig. 2). Similar to whole-body LBM, leg LBM also showed no differences over time between groups (14.7 ± 2.2 kg versus 17.4 ± 3.2 kg at baseline, 15.1 ± 2.7 kg versus 18.2 ± 3.3 kg at month 3, and 14.6 ± 2.2 kg versus 18.2 ± 3.7 kg at month 6 for NS + EX and NS; P = .44 by 3 months, P = .33 by 6 months; Fig. 3). No statistically or numerically significant differences were observed between study groups during the study for whole-body LBM by % of body weight (Fig. 4) and leg LBM by % of body weight (Fig. 5). Although there were no differences between groups, there was a statistically significant increase over time in body weight for the whole cohort after adjusting for treatment effect (80.3 ± 16.6 kg at baseline, 81.1 ± 17.5 kg at month 3, and 80.9 ± 18.2 kg at month 6; P = .02; Fig. 6).
Table 2. Body Composition Measured by Anthropometrics, BIA and DEXA and Muscular Strength at the Follow-up Times Point During the Study Period
| Total | NS + EX | NS | |||||||
|---|---|---|---|---|---|---|---|---|---|
| 0 Month (n = 32) | 3 Month (n = 26) | 6 Month (n = 22) | 0 Month (n = 15) | 3 Month (n = 13) | 6 Month (n = 10) | 0 Month (n = 17) | 3 Month (n = 13) | 6 Month (n = 12) | |
| DEXA | |||||||||
| Weight (kg) | 80.3 ± 16.6 | 81.1 ± 17.5 | 80.9 ± 18.2 | 75.8 ± 15.1 | 74.9 ± 12.9 | 74.6 ± 12.7 | 84.2 ± 17.3 | 86.9 ± 19.6 | 86.2 ± 20.7 |
| FM (kg) | 26.3 ± 12.3 | 26.4 ± 12.1 | 26.3 ± 12.8 | 25.3 ± 12.1 | 24.2 ± 9.5 | 24.7 ± 10.5 | 27.2 ± 12.7 | 28.5 ± 14.2 | 27.6 ± 14.8 |
| FM (%) | 32.3 ± 10.8 | 32.2 ± 10.7 | 32.1 ± 10.6 | 32.9 ± 10.7 | 32.9 ± 8.2 | 33.5 ± 9.0 | 31.7 ± 11.1 | 31.6 ± 12.8 | 31.0 ± 12.0 |
| LBM (kg) | 51.4 ± 8.5 | 52.1 ± 9.2 | 52.2 ± 9.7 | 48.1 ± 7.7 | 48.2 ± 7.8 | 47.4 ± 7.1 | 54.3 ± 8.4∗ | 55.7 ± 9.1† | 56.2 ± 9.9‡ |
| LBM (%) | 65.1 ± 9.7 | 65.3 ± 9.3 | 65.6 ± 9.7 | 64.3 ± 9.4 | 64.8 ± 7.6 | 64.2 ± 8.4 | 65.8 ± 10.3 | 65.7 ± 11.0 | 66.8 ± 10.9 |
| Leg LBM (kg) | 16.1 ± 3.1 | 16.7 ± 3.4 | 16.6 ± 3.5 | 14.7 ± 2.2 | 15.1 ± 2.7 | 14.6 ± 2.2 | 17.4 ± 3.2∗ | 18.2 ± 3.3† | 18.2 ± 3.7‡ |
| Leg LBM (%) | 20.4 ± 3.8 | 20.9 ± 3.4 | 20.8 ± 3.6 | 19.7 ± 3.4 | 20.3 ± 2.9 | 19.9 ± 3.4 | 21.1 ± 4.0 | 21.4 ± 3.7 | 21.6 ± 3.8 |
| BMI (kg/m2) | 28.4 ± 6.3 | 28.2 ± 5.9 | 28.2 ± 5.8 | 27.5 ± 6.3 | 26.2 ± 4.0 | 26.8 ± 4.3 | 29.1 ± 6.4 | 30.0 ± 7.0 | 29.3 ± 6.8 |
| Waist/hip ratio | 0.93 ± 0.07 | 0.94 ± 0.06 | 0.94 ± 0.08 | 0.92 ± 0.05 | 0.92 ± 0.03 | 0.91 ± 0.06 | 0.95 ± 0.09 | 0.95 ± 0.07 | 0.96 ± 0.09 |
| FM% from BIA | 29.1 ± 13.6 | 28.2 ± 11.8 | 27.4 ± 10.7 | 30.1 ± 14.9 | 28.4 ± 12.5 | 29.4 ± 13.2 | 28.1 ± 12.7 | 27.9 ± 11.5 | 25.8 ± 8.3 |
| FM% from Anthropometry | 20.3 ± 9.2 | 19.1 ± 9.2 | 18.4 ± 7.9 | 21.2 ± 9.5 | 19.0 ± 9.2 | 19.9 ± 8.0 | 19.4 ± 8.7 | 19.1 ± 9.7 | 17.1 ± 8.0 |
| 1-RM (lb) | 468 ± 148 | 535 ± 144 | 552 ± 142 | 459 ± 117 | 536 ± 126 | 582 ± 147 | 475 ± 175 | 534 ± 165 | 527 ± 139 |
∗P < .05, compared to NS + EX group at baseline. |
†P < .05, compared to NS + EX group at 3rd month. |
‡P < .05, compared to NS + EX group at 6th month. |
Figure 2
Box and whisker plot (box represents the interquartile range, whiskers extend to the most extreme data point which is no more than 1.5 times the interquartile range from the box, and the line within the box represents the median) of the total lean body mass as measured by dual-energy X-ray absorptiometry (DEXA) at baseline, 3 month and 6 month of follow-up. P value comparing the 2 treatments over time was obtained from the general linear model with bootstrap covariance accounting for correlated measures within a subject.
Figure 3
Box and whisker plot (box represents the interquartile range, whiskers extend to the most extreme data point which is no more than 1.5 times the interquartile range from the box, and circles beyond the whiskers are extreme values, the line within the box represents the median) of the leg lean mass measured by DEXA at baseline, 3 month, and 6 month of follow-up. P value comparing the 2 treatments over time was obtained from the general linear model with bootstrap covariance accounting for correlated measures within a subject.
Figure 4
Box and whisker plot (box represents the interquartile range, whiskers extend to the most extreme data point which is no more than 1.5 times the interquartile range from the box, and circles beyond the whiskers are extreme values, the line within the box represents the median) of the lean body mass as percentage of body weight measured by DEXA at baseline, 3 month, and 6 month of follow-up. P value comparing the 2 treatments over time was obtained from the general linear model with bootstrap covariance accounting for correlated measures within a subject.
Figure 5
Box and whisker plot (box represents the interquartile range, whiskers extend to the most extreme data point which is no more than 1.5 times the interquartile range from the box, and circles beyond the whiskers are extreme values, the line within the box represents the median) of the leg lean mass as percentage of body weight measured by DEXA at baseline, 3 month, and 6 month of follow-up. P value comparing the 2 treatments over time was obtained from the general linear model with bootstrap covariance accounting for correlated measures within a subject.
Figure 6
Box and whisker plot (box represents the interquartile range, whiskers extend to the most extreme data point which is no more than 1.5 times the interquartile range from the box, and circles beyond the whiskers are extreme values, the line within the box represents the median) of body weight measured by DEXA at baseline, 3 month, and 6 month of follow-up. P value showing the changes over time in the whole cohort adjusted for treatment effect was obtained from the general linear model with bootstrap covariance accounting for correlated measures within a subject.
Muscle Strength
There were no statistically significant differences between groups at baseline, month 3, or month 6 with respect to 1-RM (459 ± 117 lb versus 475 ± 175 lb at baseline, 536 ± 126 lb versus 534 ± 165 lb at month 3, and 582 ± 147 lb versus 527 ± 139 lb at month 6 for NS + EX and NS, respectively; Table 2, Fig. 7). Small differences in favor of NS + EX were observed in the changes of 1-RM over time between groups (P = .07 by month 3, P = .12 by month 6). When the overall time effect was evaluated for the whole cohort, there was a statistically significant increase over time in 1-RM after adjusting for treatment effect (468 ± 148 lb at baseline, 535 ± 144 lb at month 3, and 552 ± 142 lb at month 6; P = .001; Table 2, Fig. 7).
Figure 7
Box and whisker plot (box represents the interquartile range, whiskers extend to the most extreme data point which is no more than 1.5 times the interquartile range from the box, and circles beyond the whiskers are extreme values, the line within the box represents the median) of one-repetition maximum at baseline, 3 month, and 6 month of follow-up. P value showing the changes over time in the whole cohort adjusted for treatment effect was obtained from the general linear model with bootstrap covariance accounting for correlated measures within a subject.
Biochemical Parameters, SGA, and Dietary Recall
The biochemical, nutritional parameters, and SGA measurements during the study period are depicted in Table 3. Only glucose levels at baseline were significantly different between groups (P = .02). There were no statistically significant differences in study groups at baseline, month 3 or month 6 in other biochemical variables and SGA, nor were there any significant differences when comparing changes over time. Similarly, dietary protein intake and dietary energy intake were not different when comparing study groups at baseline, month 3 and month 6, as well as no significant changes over time were observed.
Table 3. Biochemistry and Nutrition Parameters at the Follow-up Time Points During the Study Period
| NS + EX | NS | |||||
|---|---|---|---|---|---|---|
| 0 Month (n = 15) | 3 Month (n = 13) | 6 Month (n = 10) | 0 Month (n = 17) | 3 Month (n = 13) | 6 Month (n = 12) | |
| SGA = 7 | 13 (87) | 11 (85) | 9 (90) | 14 (82) | 11 (85) | 10 (83) |
| CRP (mg/L) | 4.3 (1.9-13.3) | 3.7 (2.3-12.3) | 2.6 (1.3-8.3) | 3.9 (1.0-12.0) | 4.8 (1.9-11.7) | 6.9 (5.9-12.4) |
| Hemoglobin (g/dL) | 12.0 ± 1.4 | 12.6 ± 1.8 | 11.4 ± 1.9 | 12.2 ± 1.7 | 12.4 ± 1.1 | 12.2 ± 1.8 |
| Total protein (g/dL) | 7.3 ± 0.6 | 7.3 ± 0.7 | 7.3 ± 0.8 | 7.3 ± 0.4 | 7.4 ± 0.7 | 7.2 ± 0.5 |
| Albumin (mg/dL) | 40.7 ± 2.8 | 41.3 ± 3.5 | 41.5 ± 4.4 | 41.8 ± 3.0 | 42.9 ± 3.3 | 42.1 ± 2.2 |
| Pre-albumin (mg/dL) | 40.0 ± 10.7 | 40.3 ± 11.7 | 41.7 ± 12.4 | 38.2 ± 9.5 | 42.5 ± 9.9 | 41.7 ± 7.2 |
| Creatinine (mg/dL) | 9.3 ± 2.5 | 10.3 ± 2.2 | 10.2 ± 2.5 | 10.9 ± 2.3 | 11.5 ± 2.1 | 11.7 ± 2.5 |
| Glucose (mg/dL) | 131.0 ± 72.9 | 111.7 ± 44.0 | 115.9 ± 47.1 | 105.6 ± 58.1∗ | 88.0 ± 10.8 | 91 ± 9.6 |
| Bicarbonate (mmol/L) | 26.1 ± 5.2 | 25.9 ± 6.0 | 27.6 ± 9.2 | 25.4 ± 6.9 | 24.4 ± 5.7 | 24.4 ± 7.9 |
| Cholesterol (mmol/L) | 163.8 ± 33.5 | 167.3 ± 46.2 | 168.5 ± 24.9 | 166.8 ± 50.4 | 174.8 ± 48.5 | 173.7 ± 42.6 |
| DPI (g/kg/day) | 0.8 ± 0.2 | 1.3 ± 0.5 | 1.0 ± 0.3 | 0.8 ± 0.3 | 1.0 ± 0.4 | 1.1 ± 0.4 |
| DEI (kcal/kg/day) | 23.8 ± 7.4 | 27.5 ± 6.4 | 26.5 ± 7.1 | 22.0 ± 8.5 | 26.5 ± 10.6 | 27.6 ± 11.9 |
∗P < .05, compared to NS + EX group at baseline. |
Discussion
This prospective, randomized, open-label clinical trial was undertaken to test the hypothesis that addition of resistance exercise would enhance the protein anabolic effects of IDON on body composition and visceral protein mass over a period of 6 months. Our rationale was based on encouraging data indicating that 1 bout of intradialytic parenteral or oral nutrition provides protein anabolic effects (measured by protein kinetic studies), and that resistance exercise augments these acute anabolic effects even further.13, 21 Despite increases in body weight and 1-RM test for the entire study population, we did not detect any discernible additional beneficial effect of resistance exercise over 3 or 6 months on body composition or markers of visceral protein concentrations compared with nutrition supplementation alone.
Despite the proven efficacy of resistance exercise as an anabolic intervention in otherwise healthy elderly and certain chronic disease states,22, 23 recent studies in CHD patients have not been encouraging in terms of long-term improvements in markers of muscle mass. Several recent studies reported a lack of significant effects with 12 to 24-weeks of resistance exercise on LBM.14, 15, 16, 17 An overlapping aspect of these studies is the lack of any attempt to increase nutritional intake in the study patients, especially around the time of exercise. Multiple studies demonstrated that resistance exercise combined with oral nutritional supplementation facilitates muscle uptake of amino acids and muscle protein accretion in healthy subjects, which is believed to be due to increased blood flow to the muscle as well as enhanced insulin signaling in the cellular level.24, 25, 26, 27 In accordance with these data, several short-term studies in CHD patients showed that net muscle protein accretion and albumin synthesis are increased with nutritional supplementation combined with exercise when compared to supplementation alone.13, 21, 28, 29 Of note, these beneficial effects of combined intervention were above and beyond of what nutritional supplementation provided alone. Accordingly, the principal aim of our study was to determine if resistance exercise can augment the long-term benefits of nutrition supplementation in HD patients.30, 31, 32, 33 Despite the encouraging results from short-term protein homeostasis studies, we were unable to show any additional long-term benefits of resistance exercise compared to nutritional supplementation alone.
Although speculative, there may be several reasons why addition of resistance exercise failed to augment protein mass in our study. First, the subjects enrolled in our study were younger than the general dialysis population in the United States and in relatively good nutritional status. Therefore, interventions aimed at ameliorating muscle mass loss could not be detected as much as in the elderly or subjects with obvious muscle wasting.22, 23 The rationale for recruitment for such subjects in our study was the limited exercise capacity of the elderly, and lack of a gold standard for loss of muscle mass in CHD patients. While an older and more debilitated cohort would have been preferable, we were limited by our inclusion and exclusion criteria and the intervention administered in this study for recruitment of such subjects. This is a common limitation of published studies using this strategy including a very recent publication with results similar to ours.16, 34, 35 A second reason for lack of clear benefits can be attributed to the sensitivity and precision of DEXA to evaluate changes in muscle mass, as suggested by a study in which increases in quadriceps muscle area was observed by magnetic resonance imaging despite no changes in DEXA.14 Furthermore, Castaneda et al. showed that resistance exercise significantly increased type I and type II muscle fiber hypertrophy detected through muscle biopsies despite a nonsignificant change in mid-thigh muscle cross-sectional area (CSA) as evaluated by computed tomography scan.36 Finally, it is possible that the intensity and duration of exercise in our study was not adequate to induce a significant change in muscle homeostasis despite our best efforts to prescribe a progressive leg-press intervention. Of note, the intensity of exercise was progressively increased according to the month 3 and month 6 assessments, and the actual leg press weight achieved was beyond what was originally predicted. Moreover, although 1-RM increased in all subjects combined, there was a trend for a higher 1RM in the NS + EX group, suggesting an efficacy of exercise on muscle strength, albeit inadequate. Similar to our results, Flakoll et al. showed that specialized nutritional supplementation alone can improve leg muscle strength without resistance exercise.37 The overall improvement in the 1-RM during the study period suggests that the exercise regimen provided in this study either falls short of improving leg strength above and beyond of nutritional supplementation alone, or that the effect is too small to be detected by our assessment tools.
The results of this study have important implications. Despite no obvious additional benefit of resistance exercise, there was a statistically significant increase in body weight and muscle strength for the whole cohort over time, similar to the previous long-term studies regarding nutrition supplementation10, 38, 39, 40 or resistance exercise17 in CHD patients. Given the strong epidemiological data showing improved survival with increasing body weight in CHD patients, the interventions applied in this study are of obvious clinical benefit.41, 42, 43, 44 In contrast, if benefits of resistance exercise are to be tested further in CHD patients, either a more aggressive treatment regimen is necessary or outcome measures other than body composition should be considered.
This study has several strengths. To our knowledge, this is the first long-term trial which examines the potential additive effects of resistance exercise on IDON in CHD patients. The patients were closely monitored with good compliance and were thoroughly examined. In spite of the strengths of the present study, results should be interpreted in view of its limitations as well, including the relatively younger CHD population with good nutritional status and whether this might have limited the ability to detect clear benefits. In addition, in spite of the adequate power estimation, the relatively small sample size with 32% withdrawal of subjects during the study period prevented a robust comparison of differences in outcomes secondary to our interventions. Finally, we elected not to include a control group with no intervention, a decision based on ethical considerations since a plethora of studies indicate the beneficial effects of nutritional supplementation. Similarly, a group with resistance exercise alone was not included based on the studies indicating a lack of effect of exercise alone.14, 15, 16, 17
In conclusion, we showed that a 6-month nutrition supplementation regimen increases body weight and 1-RM, but the addition of resistance exercise to this regimen fails to show any extra long-term effects on muscle protein accretion as measured by DEXA. More precise and sensitive techniques such as computed tomography, magnetic resonance imaging, or muscle biopsy could provide more information on this aspect. At this point, the addition of resistance exercise to intradialytic nutrition supplementation, although practical, cannot be recommended until further studies confirm its benefits on muscle mass and muscle strength in CHD patients. Additional benefits of resistance exercise not explored in this study such as physical functioning, long-term protein turnover, and cardiovascular outcomes should also be explored in future studies.
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This study was supported in part by R01 DK45604, K24 DK62849 from the National Institute of Diabetes, Digestive and Kidney Diseases and Clinical Translational Science Award 1UL-1RR024975 from the National Center for Research Resources.
L.B.P. is currently an employee of Mitsubishi Tanabe Pharma Development America and declares no conflict of interest with regard to involvement with commercial entities that supply nutritional supplements.
PII: S1051-2276(10)00075-0
doi:10.1053/j.jrn.2010.03.004
© 2011 National Kidney Foundation, Inc. Published by Elsevier Inc All rights reserved.
