Giannaki, Christoforos D.*†; Stefanidis, Ioannis*‡; Karatzaferi, Christina‡§; Liakos, Nikos∥; Roka, Violeta*; Ntente, Ioanna§; Sakkas, Giorgos K.*‡
The uremic syndrome is a consequence of a failing kidney function that leads to the accumulation of body fluids and byproducts which in turn induce systemic damages in a concentration-dependent manner.1 Hemodialysis (HD) is a substitute to transplantation therapy that occurs three times a week for approximately 4 hours per session and lasts until the patient receives an allograph or for a patient's whole life. Optimal HD dose and dialysis frequency is very important to patients' health and survival and for these reasons various indices of adequacy have been incorporated into the current clinical practice to monitor dialysis efficiency.1
An HD treatment is characterized as “adequate” when the patients are fully rehabilitated from uremia symptoms, have good nutritional status, sufficient production of red blood cells, maintain normal blood pressure, and the development of neuropathy is prevented.2 The most popular HD adequacy index is the Kt/Vurea, which represents the urea clearance at t time of HD treatment per unit of urea distribution volume. A good Kt/V is translated into better solute removal and this has been associated with less organ toxicity since in the medium long term the vital organs are generally exposed into less toxicity reducing thus the severity of systemic damage.3 HD efficiency can be improved by manipulating HD procedure in ways such as increasing the duration or frequency of HD session, increasing the HD solution flow rate, and by using high-flux HD techniques.
Survival in patients treated with HD is influenced by the dialysis dose and unfortunately the statistics are disappointing for such a “lifesaving therapy.”4 The results of the HEMO study show that the minimum recommended dialysis dose is also the best possible attainable and therefore interest is now turning to alternative approaches modifying the HD session to improve patients treatment and survival.5
Intradialytic exercise also influence HD efficiency when it is implemented either chronically6,7 or acutely.8 A single bout of 60-minute intradialytic exercise at submaximal level improved HD efficiency by 14%, corresponding approximately to a 20-minute extra HD time.8 For the past three decades, intradialytic exercise programs have been applied in many HD units worldwide to improve the patient's general health and quality of life. Benefits from an exercise training program include improvements in muscle size and composition, functional capacity and cardiorespiratory fitness, blood pressure, cardiac dysfunction, and improving mental health.9–13 Such improvements have been also observed after daily HD (six sessions/week) or nocturnal HD (for a review, see Ref. 1); however, such treatment options require specific and complex organization including training centers for patients, in-house nursing assistance, and 24/7 technical assistance and support.14
So far, there are no available treatment options that can be applied within an HD protocol without modifying the duration or the frequency of HD. Even though such approaches could be very effective in terms of HD adequacy, they alter patients' life schedule; reduce quality of life leading inevitably to a very low adherence. Although brief intermediate exercise during HD can improve dialysis efficiency by 14%,8 it has not yet been examined whether a single bout of continued low-intensity intradialytic exercise could possibly lead to further improvements in HD efficiency markers. The current study aims to examine whether a low-intensity intradialytic continued aerobic exercise bout lasting for approximately 3 hours could further improve HD efficiency markers.
Thirty-six stable HD patients were screened for the current study; however, only 10 patients (45.7 ± 10.9 years, 2 females) fulfilled the inclusion criteria and agreed to participate to the study. All patients gave written informed consent for study participation after full explanation of the procedure. The study was approved by the Human Research and Ethics Committee at the University of Thessaly.
The entry criteria for the study were receipt of chronic HD for 6 months or more with adequate HD delivery (Kt/V >1.0), stable clinical condition, and arm arteriovenous fistula. Patients should have scored on the subjective physical health component scale in the Short Form-36 (SF-36) health survey quality of life questionnaire a score ≥75 points, which was considered as the cut-off point for “high-conditioning” HD patients.
Patients were not allowed to participate to the study if they had reasons for being in a catabolic state (including malignancies, HIV, opportunistic infections, infections that required intravenous antibiotics, etc.), within 3 months before enrollment. In addition, patients were excluded if they had any serious cardiovascular disease or even experienced a cardiac event or angina in the past, as well as if they had symptoms of uncontrolled hypertension or hypotension during the HD session.
The patients were studied under two different scenarios that took place during HD in the same mid-week day of two consecutive weeks. In particular, in the first scenario, the patient was required to act as usual during a typical HD session. In contrast, the second scenario required the patient to continuously cycle in the supine position for 3 hours during the HD session. The order of the scenarios was always the same (the no-exercise scenario applied first) to eliminate any exercise effect induced by the prolonged exercise regime, which could influence the following week's testing. In both scenarios, blood samples were collected before and after the initiation and the termination of the HD session to calculate the dialysis efficacy indices. The patients were asked to avoid any food and fluid intake during HD in both scenarios. In addition, the patients were recommended to maintain a stable fluid intake during the 2-week period of the study.
Rate of Perceived Exertion
To assess the patient's self-reported level of intensity during the exercise session, we used the scale of rating of perceived exertion (RPE) developed by Borg.15 Briefly, the Borg RPE scale is 15-point scale (ranges from 6 to 20), with 6 to denote “no exertion at all” and 20 to denote “maximal exertion.”
The patients underwent the HD therapy (Fresenius 4008B, Oberursel, Germany) with low-flux, hollow-fiber dialyzers and bicarbonate buffer. The HD session lasted 4 hours. An enoxaparin dose of 40–60 mg was administered intravenously before the beginning of each HD treatment session. Erythropoietin (EPO) therapy was given after the completion of HD session to normalize hemoglobin levels within 11–12 g/dl. The dialysate temperature was maintained at 36.5°C in both scenarios to keep a relatively constant body temperature. The dialysate temperature was assessed through a sensor in the blood line of the HD machine. The HD procedure was performed exactly the same way for both scenarios, while all HD sessions lasted precisely 4 hours.
HD Efficiency Indices
To calculate HD efficiency indices, blood samples were collected from the arterial needle exactly before the initialization of the HD session as well as from the arterial line after 20 seconds of slow blood flow (100 ml/min) according to the clinical practice guidelines for HD adequacy of the National Kidney Foundation.16
A single-pool Kt/V was calculated from pre- and post-HD blood urea nitrogen (BUN) measurements according to the Daugirdas second-generation formula17 as follows:
where R denotes the ratio of the post-HD to pre-HD BUN concentration, t indicates HD treatment time in hours, UF denotes the volume of fluid removed during the HD treatment in liters, and W indicates the post-HD body weight in kilograms.
Equation (Uncited)Image Tools
The reduction ratios of BUN and creatinine were calculated from pre- and post-HD BUN and creatinine concentrations, respectively:
Equation (Uncited)Image Tools
Equation (Uncited)Image Tools
The exercise regime required the patients to participate in an intradialytic exercise program on a bedside cycle ergometer (Model 881 Monark Rehab Trainer, Monark Exercise AB, Varberg, Sweden). Exercise session included supine cycling for a duration of 3 hours in an intensity of 40% of the patient's maximal exercise capacity. The appropriate level of exercise has been estimated through a modified version of Åstrand Bicycle Ergometer Test Protocol during a previous dialysis session,18 2 weeks before the start of the study with a calibrated ergometer. The exercise regime started 30 minutes after the initiation of the HD session and ended 30 minutes before the end of the HD session. The exercise regimes were performed under the continuous supervision of an exercise physiologist and a nephrologist, while blood pressure and heart rate levels were monitored automatically by the dialysis machine. Patients were allowed to watch TV or listen to music during the exercise session (and the same practices were adopted in both scenarios).
Criteria of Potential Discontinuation of the Exercise Protocol
The exercise protocol would be terminated in the case of a patient complaining for muscle cramps, giving an hypotension episode, arrhythmias, chest pain, exhaustion or excessive fatigue, reporting a score in Borg scale >17, or if a repetitive disturbance (alarm) of the HD procedure occurred.
Subjective Physical Health Assessment
The patient's subjective quality of life outcomes were evaluated by using a SF-36 health survey version modified for patients receiving HD therapy.19 The patient's grade in the physical health component was considered as “physical functioning” score.20,21
Functional Capacity Assessment
The patient's functional capacity levels were evaluated using the North Staffordshire Royal Infirmary (NSRI) walk test and by a sit-to-stand test (STS-60), both used successfully for the assessment of functional capacity of HD patients.20 Briefly, the NSRI walk test consists of the time in seconds taken to complete a task of 50 m continuous walk, climbing up 22 stairs (total elevation 3.3 m), climbing down 22 stairs, and walking back 50 m to the starting point.22 The STS-60 test is considered as a surrogate index of muscular endurance and it assesses the number of sit-to-stand cycles achieved in 60 seconds.23
The changes in the examined variables between the exercise and the no-exercise scenario as well as the differences within the predialysis data between the two scenarios were evaluated using paired t tests. All analyses were carried out using the Statistical Package for the Social Sciences software (SPSS for Windows, version 13.0, Chicago, IL). Data are presented as mean ± SD, and the level for statistical significance was set at p ≤ 0.05. Based on post hoc power analysis, the 10 recruited subjects provided an 81.3% power to detect a standardized effect size of 1.01, with α = 0.05 and critical t = 2.26.
The patients' characteristics and functional capacity data are presented in Table 1. The statistical analysis of the examined variables did not show any significant differences between the “pre-hemodialysis” values for the two consecutive mid-week HD sessions (p > 0.05) (Table 2).
Kt/V, CRR, and URR were found to be significantly improved in the exercise session compared with the no-exercise session, p < 0.05 (Figures 1–3). In addition, the difference within the potassium levels before and after HD in the exercise session also appeared to be significantly increased (p = 0.046) (1.26 ± 0.16 exercise vs. 0.71 ± 0.22 no exercise) (Figure 4).
None of the patients complained for any special discomfort during the exercise regime. Assessed by the Borg RPE scale, no patient reported a score above 17, which would have indicated a “heavy effort.” In addition, none of the monitored parameters showed evidence for discontinuation of the exercise session according to the guidelines of the American College of Cardiology and the American Heart Association.24 Our participants were assessed as “high functioning patients” because they scored >75% in the SF-36 physical health dimension. Reinforcing the previous statement, the patients of the current study had also scored high values in both functional tests (STS60 and NSRI) compared with other studies using the same methodology.23
This is the first study to investigate whether a single bout of low-intensity prolonged intradialytic exercise could help improve HD efficiency markers. We found that an HD session in combination with low-intensity exercise was well tolerated by our high-functioning HD patients and resulted in a significant improvement in all examined indices of HD adequacy compared with the traditional no-exercise scenario.
According to the literature, only one study has so far attempted to investigate the potential effect of exercise on HD efficiency.8 In particular, Kong et al.8 using an acute intermediate exercise bout of approximately 60-minute duration observed significant improvements in Kt/V and URR as well as urea, creatinine, and potassium post-HD rebound. In the study by Kong et al., the Kt/V increased by 14% as a result of a single exercise bout and the authors estimated that this improvement was equivalent to extending the HD session by 20 minutes.
In the current study, we used a prolonged intradialytic exercise regime using “high-functioning” HD patients to assess whether an additional improvement would occur. Indeed, our data revealed that this type of exercise could evoke significant improvements in Kt/V, URR, and CRR by 20%, 11% and 26%, respectively, compared with the no-exercise scenario. It seems that a prolonged exercise regime could achieve better scores in HD adequacy than the conventional 45-minute intradialytic exercise regimes. However, it appears logical to question the applicability of such a prolong regime in such fragile population. It is very encouraging that in the current study, 10 of 36 patients were capable of participating in such a trial despite the fact that HD patients are known for their very low fitness and functional capacity levels.10 In addition, by using a simple questionnaire (SF36), it appears that patients can be screened for their functional status, and if they score above 75% in the “Physical Health” component, they would be more likely to be able to participate in such regime,21 whereas if they score lower, a possible reduction in the duration of exercise could be considered.
The possible mechanism by which exercise could enhance the removal of urea and creatinine is not entirely clear. However, it is known that large amounts of urea and creatinine are taken up and stored in low-perfusion tissues such as skeletal muscles, skin, and bones.25 On the other hand, exercise induces vasodilatation and augments muscle blood flow, therefore enhancing the perfusion between muscle fibers and capillaries.26–28 The increased perfusion induced by the exercise lead to a rise in the exchange between the intercellular and intravascular compartments within the skeletal muscles. The increased blood flow that follows exercise activity mobilizes the intramuscular urea and creatinine and transfer them into the systemic circulation and from there and through the HD filter outside the patients' body. It might be also suggested that the vasoconstriction of the nonworking muscles might induce a stronger stimulus, superior or additive to the vasodilatative one, leading to a reduction of the perfused volume and thus a better/faster solute removal as a consequence.
A very impressive effect of this exercise protocol was observed in the removal of the potassium plasma levels. Even though it is known that exercise increases release of potassium from the working skeletal muscles into plasma,29 a reduction of 77.5% in potassium plasma concentrations was observed after the applied exercise regime. This is very important as one of the most common and silent conditions that could lead to a heart attack and/or arrhythmias in HD patients is hyperkalemia.30 Hyperkalemia is a condition of medical emergency, which requires immediate dialysis to reduce total body potassium levels not only in HD patients but also in other chronic and acute conditions. It is often encountered after excessive consumption of vegetables and fruits despite the specific nutritional guidelines applied to HD patients against consumption of “potassium-rich” products. The fact that prolonged exercise during dialysis appeared to be efficacious in terms of reducing potassium levels compared with the conventional HD could be a useful tool in patients who have difficulties in controlling blood potassium levels.
Even though the benefits derived from an exercise training program in HD patients are very well established, in fact, the majority of the nephrologists still hesitate to implement exercise as part of a routine HD care, while the patients remained inactive with poor exercise capacity and low quality of life.31,32 We strongly recommend that the HD patients should be encouraged and motivated to participate in supervised exercise training programs and as we saw in the current study, a 25% of the patients could tolerate such a long-lasting exercise regimes. Taking into account the fact that the median age of patients entering in HD appeared to be slightly decreased in the recent years,33 it would be even easier to recruit younger patients in such exercise programs.
In the current trial, we did not assess any postdialysis rebound phenomena of the examined substances. The lack of those measurements does not allow us to discuss in depth the possible effects of the prolonged exercise regime in postdialysis kinetics and the predicted Kt/V and leaves us presently unable to calculate the effects of the current exercise scenario on solute removal, expressed by dialysis time.
In conclusion, this is the first study to examine the effect of prolonged intradialytic exercise on HD adequacy. We found that preselected “high-functioning” HD patients could tolerate such type of exercise regime with no side effects, resulting in significant improvements in HD efficiency markers compared with a typical no-exercise HD session. Taking into account the fact that the study was realized using low-flux treatments, these findings have the added value of improving overall treatment efficiency and potassium removal. Further studies should examine whether there is an appropriate exercise approach for low-functioning patients. Hemodialysis patients should be encouraged and motivated to participate in intradialytic exercise programs not only for the well-known long-term benefits regarding the cardiovascular health but also for the acute benefits in the HD adequacy.
The authors thank the nursing staff at the hemodialysis unit of the University Hospital of Larissa and the General Hospital of Trikala for their cooperation. The authors also thank all hemodialysis patients for participating in this study.
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