Abstract

INTRODUCTION

Exercise training is generally recommended to people even if they have comorbidities in order to improve their physical and psychological health. According to the data from the United States Renal Data System 2015, overall prevalence of chronic kidney disease in the general population was approximately 14% and the great proportionate increase in the incidence of treated end-stage renal disease (ESRD) in the Republic of Korea (120%) over the period between 2000/2001 and 2012/2013 were reported [1].

The importance of exercise for the maintenance hemodialysis (MHD) patients is emphasized in some guidelines. The National Kidney Foundation, using the Kidney Disease Outcome Quality Initiative guidelines on the management of cardiovascular disease in patients on MHD (2005), advises nephrologists to counsel and regularly encourage patients on MHD to increase levels of physical activity despite of numerous barriers [2]. European guidelines on nutrition in hemodialysis (HD) patients also evidently recommend regular physical exercise [3].

MHD patients are profoundly deconditioned, often vulnerable and older with muscle wasting and altered nutritional status. Dialysis leads to distinct metabolic changes such as hypovolemia, electrolyte imbalance, and systemic inflammation [4]. As a result, the exercise capacity in ESRD is about 50% to 60% of that seen in normal subjects [5].

Exercise training has a myriad of potential benefits that can ameliorate a sustained decline in functional status. In ESRD patients, chronic regular exercise showed improved aerobic capacity, muscle strength, and cardiovascular function [6]. Moreover, exercise revealed strong positive correlations with dialysis efficacy, high-sensitivity C-reactive protein, blood pressure, arterial stiffness, health-related quality of life (QOL), and depression [6,7]. However, there might be several exercise related adverse effects which include fatigue, hypotensive episodes, musculoskeletal complications, and rare cardiovascular complications [7].

Toxic substances, also called uremic toxins, in the blood result in malaise, paraesthesia, mental impairment, peripheral circulatory disturbance, and muscle dysfunction [8]. While patients exercise during dialysis, those toxins move through the dialyzer with a large flux from the tissue to the vascular compartment. It results in increased muscle blood flow and opened capillary surface area [9]. Besides, the intradialytic exercise showed not only a better adoption and adherence but also a lower drop-out and greater compliance [7].

Commonly, exercises are divided into aerobic and anaerobic types. Aerobic exercise is usually prescribed to enhance endurance by using large muscle groups (e.g., cycle ergometers). On the other hand, anaerobic exercise is proven to increase muscle size and strength (e.g., elastic bands, dumbbells) [10]. Therefore, combined aerobic and anaerobic exercise should produce greater effects than each exercise method alone.

We hypothesized that there might be numerous positive improvements after the completion of 6-month intradialytic, combined aerobic and anaerobic exercise. Overall evaluation was thoroughly carried out to measure physical, psychological, and laboratory effects. In addition, we included patients who had episodes of intradialytic hypotension (IDH) unless they were unable to perform exercise. We planned to examine the effect of exercise on IDH that was previously impossible due to exclusion of IDH patients.

METHODS

RESULTS

Baseline clinical characteristics of 22 eligible HD participants are described in Table 1. Patients ranged in age from 30 to 73 years with their average age of 57.0 ± 12.4 years. The mean hemodialysis vintage was 45.0 ± 45.9 months. Diabetic nephropathy was the leading cause of ESRD (n = 9).

Table 1.

Baseline characteristics of the participants (n = 22)

Variable	Value
Sex, male:female	9:13
Age, yr	57.0 ± 12.4
Weight, kg	57.6 ± 11.77
Body mass index, kg/m2	24.1 ± 4.02
Duration of dialysis, mon	45.0 ± 45.9
Smoking history
Comorbidity	7
Diabetes	12
Hypertension	20
Congestive heart failure	4
Ischemic heart disease	6
Etc.	5
Aetiology of ESRD
Diabetes	9
Hypertension	6
Glomerular disease	2
Other causes	5
Hemoglobin, g/dL	10.0 ± 1.3
Urea, mg/dL	61.6 ± 17.6
Creatinine, mg/dL	9.0 ± 2.4
Potassium, mEq/L	4.8 ± 0.8
Sodium, mEq/L	139.2 ± 2.4
Calcium, mg/dL	8.3 ± 0.4
Phosphorus, mg/dL	4.6 ± 1.8
Albumin, g/dL	3.9 ± 0.4

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Values are presented as mean ± SD.

ESRD, end-stage renal disease.

Although all participants accomplished intradialytic exercise for 3 months, five patients dropped out from the 6-month work-up. The reasons of withdrawal included procedures such as transarterial chemoembolization (n = 1), transfers of dialysis units (n = 2), a death because of a brain haemorrhage (n = 1), and voluntary interruption (n = 1). None of these reasons was related to exercise. Over the course of exercise, some patients complained of somatic leg pain symptoms (especially knee), cramps, tiredness, weakness, and oedema of lower extremities.

Clinical parameters of dialysis and changes of laboratory results over 6 months

The changes in blood pressure before, during, and after exercise are shown in Fig. 1. As the exercise progressed, the decrease in blood pressure during exercise was gradually improved, especially in systolic blood pressure (Fig. 2). Six patients never had IDH events during data collection period. For the rest of 16 patients, the IDH episodes from baseline to month 6 was significantly reduced (p < 0.05). However, there were no significant effects in the rest of parameters including dry weight, systolic blood pressure, diastolic blood pressure, and Kt/V (Table 3). At the end of the study, no significant changes were observed in hematological and biochemical variables after repeated measure analysis (data not shown).

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Figure 1.

The pattern of blood pressure before, during and after exercise. (A) Intradialytic hypotension (+) group (n = 16) and (B) intradialytic hypotension (–) group (n = 6). Values are expressed as mean ± SD. SBP, systolic blood pressure; DBP, diastolic blood pressure.

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Figure 2.

The change of blood pressure during 6 months. (A) Systolic blood pressure and (B) diastolic blood pressure.

Table 3.

Dialysis related results at baseline and during follow-up

Variable	Month 0	Month 3	Month 6	p value
DW, kg	57.60 ± 11.77	57.92 ± 11.73	57.62 ± 11.52	0.960
SBP, mmHg	160.53 ± 14.33	162.11 ± 16.19	158.95 ± 11.97	0.578
DBP, mmHg	91.05 ± 7.37	93.16 ± 8.85	91.05 ± 7.37	1.000
kt/V	1.51 ± 0.33	1.65 ± 0.39	1.53 ± 0.29	0.823
IDH (patient)a	16	10	6
IDH (episode)	2.22 ± 2.83	1.66 ± 2.65	1.06 ± 1.92	0.019

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Values are presented as mean ± SD. Repeated measurement of analysis of variance. p < 0.05.

DW, dry weight; SBP, systolic blood pressure; DBP, diastolic blood pressure; IDH, intradialytic hypotension.

^aTotal numbers and not mean values of patients are represented.

Depression

In Table 4, BDI showed a lower score (8.73) at month 6 and a higher score (13.74) at month 0 with statistically significant improvement (p < 0.01).

Table 4.

BDI data for depression

Variable	Month 0	Month 3	Month 6	p value
BDI	13.4 ± 6.7	10.3 ± 4.2	8.7 ± 4.2	0.004
Clinical diagnosis				-
No depression	15	18	15
Mild depression	4	1	1
Moderate depression	3	1	0

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Values are presented as mean ± SD. For clinical diagnosis, total numbers and not mean values of patients are represented.

Repeated measurement of analysis of variance. p < 0.05.

BDI, Beck Depression Inventory.

DISCUSSION

Following a 6-month intradialytic exercise study, there have been several changes when compared to the baseline data. The equipment used for exercise was costeffective, space-saving, and feasible to administer. Additionally, cardiac decompensation was prevented by performing exercise within first half hours of hemodialysis [11,12]. No common dangerous adverse events caused by exercise including musculoskeletal injuries and serious cardiovascular complications such as ischemic heart disease and arrhythmia occurred. Only mild adverse symptoms and IDH were observed.

Especially, in dialysis population, not just diminished muscle mass and altered muscle quality but also decreased physical functioning can lead to falling accidents. Moreover, sedentary life style with low physical activity was associated with higher cardiovascular mortality [13]. These features were substantially related to increased morbidity and mortality risk [14,15]. Therefore, the improvement of physical function could be achieved by the exercise, which promotes increased blood flow to peripheral tissues and enhances perfusion of muscle cells [9].

In the present study, anaerobic exercise was used to induce muscle contractions and to increase muscle strength and the size of skeletal muscles [16]. In addition, the control of exercise intensity was carried out individually because a significant overload and progression of exercise is crucial for hypertrophic adaptation [17].

Based on our results, intradialytic exercise led to significant enhancement of back muscle power, elbow flexion test, sit-to-stand test, trunk flexibility test (forward and backward), vertical jump, and 6-minute walk test in terms of physical function. The results of measurements and tests reflected muscle strength, muscle endurance, lower extremity function, flexibility, balance, coordination, and cardiorespiratory endurance [5,18]. It is therefore tempting to speculate that the exercise was beneficial for improving functional capacity, muscle power, endurance, fatigability, and cardiorespiratory function in dialysis patients [5,6,19].

On the other hand, HGS and circumferences of arm and thigh reflecting muscle mass did not show any statistical improvement after exercise. Vogt et al. [20] reported that HGS cut off values that predict mortality were 22.5 kg for men and 7 kg for women. Those values were also associated with nutritional status and muscle function [21]. Although there was no statistically significant increase of HGS, the baseline value of 22.1 kg increased to 23.3 kg in 6 months. Moreover, the other study reported that muscle strength association with mortality was greater than muscle mass association in dialysis patients [22].

Most patients with loss of renal function eventually develop anaemia, dysfunction of bone metabolism, and immunologic compromise [11] as they maintain hemodialysis treatment. Consequently, many researches have been done on various biochemical indices looking advancements. The results were controversial. Some studies have shown no changes after intradialytic exercise in oxidative stress, inflammation, and calcium content [11,23]. On the contrary, other studies demonstrated post-exercise improvement in dialysis adequacy, Kt/V [9], blood pressure [11], anemia [24], inflammation [25], and phosphorus clearance [26]. However, our findings on laboratory, and dialysis related parameters did not show any enhancement after 6 months of exercise, except for IDH.

It is known that IDH in hemodialysis patient occurs through various and complex pathophysiology; sudden reduction of circulating volume owing to ultrafiltration, decreased extracellular osmolality associated with sodium removal, overproduction of nitric oxide, decreased catecholamine and rennin release, and cardiac underfilling and impaired cardiovascular compensatory mechanism [27]. Also, patients with ESRD on HD commonly have autonomic nervous system dysfunction by alteration of decreased baroreceptor sensitivity, or the parasympathetic or sympathetic pathways [28].

The blood pressure rises when ordinary people exercise with a bicycle ergometer. Therefore, it was used as a tool for predicting the risks of future hypertension in patients with pre-hypertension [29]. However, there were cases that had reduced blood pressure [30] or no blood pressure changes [31] after the exercise. Also, the blood pressure decreased [32] or did not alter [33] after anaerobic elastic band exercise.

According to Fotbolcu et al. [28], ESRD patients with IDH have inadequate sympathetic activity of the cardiovascular system and impaired left ventricular systolic function during treadmill exercise compared to patients without IDH. Although the increase in blood pressure was less, blood pressure of those IDH patients were increased after initiation of exercise compared to preexercise blood pressure.

However, as shown in Fig. 1 of our study, IDH (+) and IDH (–) groups displayed decreased blood pressure during exercise compared to the pre-exercise blood pressure. Those different outcomes may be attributed to the inclusion of patients with anti-hypertensive medications or cardiovascular diseases and the intradialytic exercise.

In Fig. 2, the degree of decrease in blood pressure after dialysis was alleviated when the exercise was performed during dialysis for several months. This suggests that intradialytic exercise was helpful for the improvement of the IDH.

IDH can result in the microcirculatory and microcardiac ischemia, which subsequently decreases cardiac output and increases mortality [34]. Thus, we can presume that IDH amelioration after exercise is useful in decreasing mortality and is associated with positive effects on blood pressure control. Further studies on the mechanism of alleviated IDH may be needed.

According to Carney et al. [35], hemodialysis patients have a similar degree of depression and anxiety compared to psychiatric patients. Besides, severe depression can lower patient’s mood and decrease his or her interest in all activities [36]. This symptom of depression might be relieved after exercise through increased levels of neurotransmitters such as serotonin and endorphins [19]. Additionally, it was demonstrated that most severely depressed patients had the greatest benefits [37].

In current study, the widely used scale of depression, BDI score, got better with a statistical significance after exercise training, taking into account that intradialytic exercise is advantageous for psychological health status after all.

Finally, SF36 health survey is a reliable and valid appraising tool of QOL, which is extensively used for hemodialysis patients [38]. There have been several studies using SF36 for the effect of intradialytic exercise on QOL. Some studies showed significantly higher score of physical component summary compared to the score of mental component summary [7,12]. Improvements in other domains have been also shown [11]. However, our findings about the QOL revealed a significant increase in the area of bodily pain score only.

Unlike improved physical function parameters after exercise prescription, the physical functioning score of SF36 survey did not show significant enhancement. It can be explained with a similar case which compared self-reported health-related QOL with the objective of exercise performance in patients with congenital heart disease [39]. Even though the subjects of study were different, there was severe overestimation of physical functioning in most patients when compared with actual exercise test results. Self-estimated physical functioning poorly predicted actual exercise capacity.

Also, because self-reported physical functioning score in the QOL survey assesses level of difficulty performing activities of daily living, instrumental activities of daily living, and more strenuous activities, the gap between objective physical function parameters and subjective physical functioning score in SF36 survey can exist [40].

This study has many limitations. First, because the study was carried out in one dialysis centre, a small number of participants were recruited. In addition, there was no contemporaneous control group. Second, the patients had to work out with limited resources in a fixed time. The arm with arterio-venous fistula was excluded from exercise, which might have had influence on our results. Third, patients with relatively high average activity levels were chosen for the study. It is hard to generalize the results to all dialysis patients because of the selection bias. For last, we did not take any consideration about maintaining same dialysis mode, medication, or other dialysis-related conditions. Moreover, five patients dropped out before the 6th month of the study which might have also have affected the study results. As per our literature review, this was the first study to evaluate the effect of intradialytic exercise on IDH; this is a major strength of the study. Furthermore, we could identify diverse influences of intradialytic exercise.

In summary, combined aerobic and anaerobic exercise training on dialysis days was found to have positive effects on physical health status. Besides, diminished IDH events and bodily pain after intradialytic exercise resulted in improved depression. This improvement is theoretically beneficial for morbidity and mortality reduction among hemodialysis patients. Therefore, the findings of the current study may provide an appropriate guidance for encouraging exercise by nephrologists. Because exercise method was adjusted for the typical outpatients who have a relatively good physical function, the novel exercise programs for less healthy patients will have to be researched continually. In addition, we recommend for that more clinical guidelines to be revised in order to encourage clinicians to actively implement intradialytic exercise programs.

KEY MESSAGE

Acknowledgments

Footnotes

REFERENCES