INTRODUCTION

Patients with chronic kidney disease (CKD) exhibit skeletal muscle wasting and reduced muscular strength, physical function, and cardiorespiratory fitness, resulting in elevated cardiovascular risk. These are important modifiable risk factors associated with increased morbidity and mortality, reduced quality of life, and increased risk of falls (19, 22, 24).

Although international guidelines have begun to highlight that patients with CKD should engage in exercise (14, 21), specific advice is not given, and there is a lack of evidence from randomized controlled trials to underpin the guidance offered. Resistance exercise can increase muscle size, function (27), and metabolism (26), whereas aerobic exercise (AE) confers cardiovascular benefits, such as aerobic capacity improvements and cardiac protection (16). Ideally, a combination of these exercise modalities would be used in one session to maximize benefits received, but the effect of combining these modes of exercise has not been fully studied in nondialysis CKD. This is particularly important because the effects of AE on skeletal muscle remain equivocal. Our previous research has shown that in the absence of additional acidosis correction, AE depletes intramuscular amino acid stores, including reductions in leucine (28), which has well-documented anabolic effects (6, 7, 23). This may have negative implications for protein synthesis rates and may compromise gains in muscle mass if the effect persists when exercise modalities are combined.

This study investigated whether 12 wk of combined aerobic and resistance exercise (CE) would confer greater adaptations in muscle mass and strength compared with AE alone in nondialysis CKD. It aimed to determine whether, when exercise modalities are combined, patients receive improved cardiorespiratory fitness and cardiac function together with increased muscle mass and strength. These data will help to inform exercise recommendations for patients with CKD and provide pilot data for future randomized controlled trials.

MATERIALS AND METHODS

RESULTS

Baseline Characteristics, Recruitment, Retention, and Adherence Rates

Patient characteristics can be found in Table 1, and the Consolidated Standards of Reporting Trials (CONSORT) diagram can be found in Fig. 1. Apart from a higher plasma albumin level in AE (P = 0.01), the two groups were well matched. There were 483 patients identified as eligible by medical staff and approached for recruitment, of which 429 patients declined and 54 patients consented. This 11% uptake is comparable to our earlier report (27). Thirteen patients were excluded during the 6-wk control period because of voluntary withdrawal, treatment for associated medical conditions, and positive changes on ECG during CPET. We saw high retention once exercise training had begun with 85% of AE and 90% of CE groups completing the training period and an average 88% attendance at training sessions in both groups.

Table 1. Baseline patient characteristics

	Aerobic Exercise Group	Combined Exercise Group	P
Number of patients	21	20
Number of men	9	9
Age, yr	63 (58–71)	63 (51–69)	0.36
Ethnicity
White	15	11
Indian/South Asian	4	9
Black Caribbean	2	0
BMI, kg/m2	29.6 (25.5–35.5)	29.5 (25.5–33.0)	0.47
eGFR, ml·min−1·1.73 m−2	24 (20–30)	27 (22–32)	0.92
Systolic blood pressure, mmHg	135 (122–145)	125 (120–132)	0.15
Diastolic blood pressure, mmHg	73 (68–81)	70 (72–78)	0.57
Hemoglobin, g/dl	119 (115–131)	112 (105.5–128.5)	0.06
Albumin, g/l	42 (41–44)	40.5 (38.5–42)	0.01
Serum total cholesterol, mmol/l	4.4 (3.7–4.8)	3.6 (3.5–3.9)	0.13
Serum total triglycerides, mmol/l	1.6 (1.2–2.2)	1.3 (1.0–2.1)	0.51
C-reactive protein, mg/l	29.5 (19.5–39.2)	6 (6–6)	0.34*
Leukocyte count, × 109/liter	7.8 (6.8–8.3)	7.3 (6.5–8.8)	0.54
Hemoglobin A1c, %	6.3 (5.6–7.5)	5.8 (5.5–5.9)	0.27
Comorbid conditions
Essential hypertension	10	12
Diabetes	7	2
IHD	1	2
Heart failure	0	1
Valvular disease	1	0
Stroke	0	0
PAD	0	1
Godin LTEQ	34.0 (20.1–47.9)	21.0 (7.7–34.3)	0.17

Values for categorical variables are numbers of patients, and values for continuous variables are medians (interquartile range). BMI, body mass index; eGFR, estimated glomerular filtration rate; IHD, ischemic heart disease; PAD, peripheral artery disease; Godin LTEQ, Godin Leisure Time Exercise Questionnaire.

^*C-reactive protein values were only available for n = 4 in aerobic exercise group and n = 7 in combined exercise group.

Table 1. Baseline patient characteristics

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Muscular Strength

The total weight lifted in the CE group increased from 895 ± 408 to 1,510 ± 658 kg over the duration of the study (P = 0.001). This exceeds the 600-kg increase required to elicit a physiological adaptation from our power calculation. Changes in knee extensor strength measured by e-1RM are shown in Table 3 and Fig. 2. Mean increases of 9 kg (P = 0.001) and 22 kg (P < 0.001) were seen in the AE and CE groups, respectively. The gains achieved by patients performing CE were superior to those made by the patients in the AE group (+13 kg, P = 0.02; Table 3 and Fig. 2).

Table 3. Changes in muscle mass, strength, and cardiorespiratory fitness over 12-wk training period

Variable	Aerobic Exercise	Combined Exercise	Difference (95% CI)	P*
Weight lifted per session, kg
n	N/A	18	N/A
Baseline		895 ± 408
Postexercise		1,510 ± 658
Change		615 ± 486
P†		0.001
e-1RM, kg
n	17	16
Baseline	54 ± 27	45 ± 16
Postexercise	63 ± 26	67 ± 22	13 (5 to 21)	0.02
Change	9 (5 to 14)	22 (16 to 29)
P†	0.001	<0.001
Muscle volume, cm3
n	15	16
Baseline	939.0 ± 344.8	932.2 ± 269.9
Postexercise	979.5 ± 355.5	1,020.2 ± 329.0	47.5 (−5.7 to 100.7)	0.01
Change	40.5 (2.7 to 78.3)	88.0 (47.6 to 78.3)
P†	0.04	<0.001
RF ACSA, cm2
n	17	18
Baseline	8.6 ± 3.0	8.3 ± 2.7
Postexercise	9.0 ± 3.2	9.0 ± 2.7	0.4 (−0.1 to 0.9)	0.3
Change	0.4 (−0.1 to 0.9)	0.7 (0.4 to 1.1)
P†	0.1	<0.001
ISWT, m
n	18	17
Baseline	454 ± 194	380 ± 195
Postexercise	482 ± 190	417 ± 195	2 (−30 to 33)	0.8
Change	28 (6 to 50)	32 (9 to 56)
P†	0.02	0.01
V̇o2peak, l/min
n	15	17
Baseline	1.8 ± 0.6	1.5 ± 0.4
Postexercise	1.9 ± 0.5	1.6 ± 0.4
Change	0.1 (−0.2 to 0.04)	0.02 (−0.2 to 0.1)	−0.9 (−0.2 to 0.1)	0.6
P†	0.2	0.7
V̇o2peak, ml·kg−1·min−1
n	15	17
Baseline	21.4 ± 6.4	19.5 ± 4.7
Postexercise	22.5 ± 6.6	20.1 ± 5.0	−0.7 (−3.0 to 1.8)	0.7
Change	1.1 (−0.3 to 2.4)	0.6 (−1.2 to 2.5)
P†	0.1	0.4
Peak power, W
n	15	17
Baseline	129 ± 48	111 ± 32
Postexercise	138 ± 42	119 ± 37	−1 (−13 to 12)	0.3
Change	9 (−2 to 19)	8 (0.3 to 16)
P†	0.1	0.04
Maximum heart rate, beats/min
n	15	17
Baseline	142 ± 24	134 ± 19
Postexercise	143 ± 12	140 ± 29	17 (−23 to 57)	0.05
Change	1 (−12 to 9)	4 (−15 to 8)
P†	0.8	0.5

Values are means ± SD or means (confidence interval); n = number of patients. CI, confidence interval; e-1RM, estimated one-repetition maximum for knee extensor strength; ISWT, incremental shuttle walk test; N/A, not applicable; RF ACSA, rectus femoris anatomical cross-sectional area; V̇o_2peak, peak oxygen consumption.

^*P values compare changes in the intervention and control groups and were estimated using regression models.

^†P values test the within-group changes and were estimated using paired t-tests or Wilcoxon signed-rank test as appropriate.

Table 3. Changes in muscle mass, strength, and cardiorespiratory fitness over 12-wk training period

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Quadriceps Muscle Volume

A mean increase of 40.5 cm³ (5.1%, P = 0.04) was seen following AE compared with a mean increase of 88.0 cm³ (9.4%, P < 0.001) following CE. When accounting for differences in the presence of diabetes, hemoglobin level, age, sex, and baseline quadriceps volume, the magnitude of change was 47.5 cm³ (P = 0.01) greater in those performing CE (Table 3 and Fig. 3).

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DISCUSSION

Despite a growing consensus that patients with CKD at all stages should engage in some form of regular exercise (8, 12, 13, 16, 32), no formal exercise guidelines exist. It is advised that patients perform both resistance and AE to gain benefits for muscle mass and strength as well as improvements in cardiorespiratory fitness and a reduction in cardiovascular risk (16, 27). For time and logistical reasons, combining both modes in the same session would be optimal. However, previous evidence from our group suggests that AE may reduce stores of essential amino acids, in particular leucine (28), which could have important implications for protein synthesis rates and hypertrophy. This report describes the effect of 12 wk of CE compared with AE alone on muscle size and strength and exercise capacity. These data will help to inform exercise recommendations for patients with CKD and provide pilot data for future randomized controlled trials.

Both AE and CE groups exhibited significant improvements in knee extensor strength measured by e-1RM of 9 and 22 kg, respectively. The gains (49% increase) seen in the CE group were significantly larger than those achieved by the AE group, but given the specificity of resistance training, this is unsurprising. Although this increase is similar to that reported by Castaneda et al. (4), who reported that 12 wk of resistance training resulted in a 47% increase in knee extensor strength measured by 1RM, it is larger than the 13% improvement in isokinetic knee extensor strength (at an angular velocity of 60°/s) previously reported in this population by our group (27). It is likely that the differences in assessment of strength account for the discrepancies in its improvement.

We have shown that 12 wk of CE resulted in a significant 9.4% increase in quadriceps volume, with smaller gains seen in the AE group. The gains achieved with CE are comparable to those previously reported (9.4%) following 8-wk resistance exercise using the same training and in the same population (27). It is important to highlight that 12 wk of aerobic exercise performed three times a week were sufficient to significantly improve muscular strength in this patient group. Despite not reaching statistical significance, patients in the AE group still achieved a 5% increase in quadriceps volume and a 3.5% increase in RF ACSA. Significant improvements in lean body mass of 2.3%, measured by dual-energy X-ray absorptiometry, have been reported previously following 12-wk treadmill AE (1). This demonstrates that in deconditioned patients, weight-bearing exercise alone can produce some improvement in muscle size and strength. Taken together, these data suggest that the addition of resistance exercise to AE confers greater increases in muscle mass and strength in CKD than AE alone. Therefore, combining both modes of exercise together, as in a rehabilitation class for example, still confers benefits for muscle mass, so long as the overload stimulus is sufficient.

Cardiorespiratory fitness is frequently reported to be lower in patients with CKD compared with healthy counterparts (12, 13), and the values reported here are much lower than predicted values (20). Although we saw no statistically significant improvements in V̇o_2peak in either group following 12 wk of exercise, with improvements of 5% after AE and 3% after CE, which remained after controlling for the presence of anemia, the changes are consistent with two large systematic reviews in which pooled mean aerobic capacity improved significantly following exercise training in nondialysis CKD (12, 13). Given the sample sizes (n = 847–928) of these meta-analyses, our study could be underpowered to detect such a change. Larger changes may have been seen with a longer intervention period. For example, Headley et al. saw a significant 8% improvement in V̇o_2peak following 48 wk of AE (11), whereas Greenwood et al. reported a 14% improvement in V̇o_2peak following 12 mo of supervised rehabilitation classes (9). We did, however, report an increase in the maximum power output achieved during the CPET in the CE group, which could not be attributed to the increase in either muscle size or muscle strength. Alongside modest improvements in cardiorespiratory fitness, we observed an improvement in walking ability in both groups as determined by greater distances covered in the ISWT.

Finally, BP, MAP, SV, and CO remained unchanged by either mode of exercise. TPR and TPRI were both seen to significantly increase following CE, which may reflect a worsening of endothelial dysfunction that was not seen with AE alone. Previously, we found that 6 mo of walking exercise in nondialysis CKD protects cardiovascular function (16). This effect of resistance exercise on hemodynamics warrants further investigation. Unfortunately, we were not able to reliably extract information about medication from patients’ medical notes. Information on prescription of antihypertensives would be critical in the full interpretation of the data on BP and TPR presented here. This means that we are unable to conclude whether there was any improvement in BP control as the dose of antihypertensives may have been reduced over the course of the study.

Several studies have now been published describing the association of reduced physical function and muscle wasting with poor outcomes and an increased risk of mortality (3, 10, 15, 19, 22, 24). Therefore, any intervention that is able to impact upon either of these factors is likely to improve patient outcomes and reduce health care usage. However, as no health and socioeconomic analysis was performed here, this cannot be inferred. This would be an important assessment to make to encourage clinical adoption of such an intervention. Although we have observed improvements in many aspects of physical functioning, it is hard to infer how these changes may impact the overall long-term health of patients with CKD as there is little information in the literature regarding this. However, given recent evidence of the impact of poor physical function (24) and exercise capacity (19) and low muscular strength (19) and muscle mass (3, 10, 18) on outcomes in CKD patient groups, it is likely that any improvement would confer important benefits for patients. This should be an important focus of future work to help determine the appropriate dose of exercise to provide maximum long-term health benefits.

Disappointingly, we only recruited 11% of the patients who were approached; however, we did have high retention (CE 85%, AE 90%) and attendance rates (88% in both groups), suggesting that exercise training delivered in this way is acceptable for a small proportion of the population. Reasons for nonrecruitment were not formally collected, but patients frequently mentioned time commitments and frequent travel to the hospital as significant barriers to participation. The outcome measure protocol involved in this study, including muscle biopsies and MRI scans as well as a range of physiological measures, was fairly onerous and discouraged many patients. This is not a “real-life” effectiveness trial and therefore cannot indicate the feasibility of supervised exercise training delivered as part of a clinical service. However, supervised hospital-based training may not be a practical lifestyle choice for the majority of the renal population, and future research should focus on delivery of such interventions in the community where uptake may be enhanced or strategies to encourage self-directed exercise behavior (5).

Given the low adaptation rate of the intervention seen here, we should be cautious about the generalization of the results to the renal population as a whole. It is possible that we have recruited the fittest and healthiest patients here, and whether these results apply to a more elderly and frail population is unclear.

One of the main limitations of this study is the lack of a nonexercising control group, which was excluded to promote recruitment. However, we feel that this limitation is negotiated by the 6-wk control period; we observed no changes during this period, apart from e-1RM, which increased by 3 kg. However, this increase falls below the minimal detectable difference (6 kg) and may simply be due to inherent error/variation in this test (31). The lack of a resistance training-only group means that unfortunately, we are not able to draw any firm conclusions about the most suitable training programs for patients to undertake. This arm of the study was omitted as we have previously performed a randomized controlled trial of resistance exercise training in this population (27) and reported similar improvements in muscle mass and strength to those seen here. It was also excluded to ensure successful recruitment in a heavily researched patient population. The study design may also be limited by the difference in AE duration performed by the groups. In the two sessions including resistance exercise, only 20 min of AE were performed to ensure ~30 min of total exercise and to pragmatically match all sessions for duration. As such, it may be that the total of 4 h (i.e., 20 min less per wk times 12 wk) of reduced aerobic component performed by the CE group precluded greater improvements in aerobic-based parameters. As planned, our trial was adequately powered to elicit physiological hypertrophic responses in the muscle; however, it was not powered for other outcomes. The nonsignificant improvements observed should be investigated further.

In conclusion, the addition of resistance exercise to AE confers greater increases in muscle mass and strength in CKD than AE alone. This suggests that nondialysis patients with CKD should be encouraged to include resistance training in exercise programs to maximize the benefits. However, given the poor uptake of this hospital-based program, future studies need to effectively investigate incorporating resistance exercise into home- or community-based interventions for nondialysis CKD.

GRANTS

The research was supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The staff and running costs of this study were part-funded by the Stoneygate Trust. B. P. Vogt was funded by Coordination for the Improvement of Higher Education Personnel (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), an organization of the Brazilian federal government under the Ministry of Education. The funders had no role in study design, collection, analysis, or interpretation of data; writing the report; or decision to submit this manuscript for publication.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

E.L.W., J.L.V., and A.C.S. conceived and designed research; E.L.W., D.W.G., T.J.W., S.X., A.L.C., B.P.V., and J.L.V. performed experiments; E.L.W., D.W.G., and T.J.W. analyzed data; E.L.W., D.W.G., S.X., J.L.V., and A.C.S. interpreted results of experiments; E.L.W. and T.J.W. prepared figures; E.L.W. drafted manuscript; E.L.W., D.W.G., T.J.W., S.X., A.L.C., B.P.V., J.L.V., and A.C.S. edited and revised manuscript; E.L.W., D.W.G., T.J.W., S.X., A.L.C., B.P.V., J.L.V., and A.C.S. approved final version of manuscript.