Rationale
Physical activity levels are low in haemodialysis patients [
79]. Data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) has reported that 43.9% (
n = 9176) of haemodialysis patients perform no physical activity or exercise [
80]. Unsurprisingly, low levels of physical activity are associated with poor health-related quality of life (HRQoL), symptoms of depression [
80], and increased mortality rate in this population [
80‐
82]. The factors that relate to these low levels of physical activity are unclear; however reductions in lean body mass [
83], aging [
84] and the numerous comorbidities [
85] present in this population are all believed to play a role. Moreover, the haemodialysis treatment itself exacerbates these low levels, with physical activity levels reported to be lower on dialysis compared to non-dialysis days [
86]. However, mortality risk has been shown to be lower in haemodialysis patients who are more physically active compared to those who are sedentary [
80,
81,
87], indicating a benefit of even small modifications in physical activity in this highly sedentary population. Unfortunately, there is no RCT data on the effect of increasing physical activity levels and the association with mortality in the haemodialysis population. Although, as recommended by the most recent Kidney Disease Improving Global Outcomes (KDIGO) guidelines [
88] and the UK Chief Medical Officers’ Guideline [
89] increasing physical activity levels should be encouraged (aiming for at least 30 min of moderate intensity activity, 5 times per week). It is also important to highlight that even small increases in physical activity levels is likely to provide some benefit.
Data from one of the largest RCTs in the area (
n = 296) showed that increasing physical activity levels outside of haemodialysis treatment through a 6-month personalised walking exercise programme improves physical function as measured by the 6-min walk test performance (an improvement of 39 m was reported in the exercise group) and HRQoL [
90]. The participants with the highest adherence had the largest improvement in performance, and no serious adverse events or safety flags were reported [
90]. This indicates that on the limited current evidence increasing levels of physical activity outside of haemodialysis is safe. In data from this trial [
90], limited to participants who completed the trial, there was a significant reduction in hospitalisation in the exercise compared to the control group. The walking exercise programme was supervised by a rehabilitation team, and participant self-reported compliance was 83%. A further trial reported no significant effect on the 6-min walking test following 6-months of unsupervised home-based walking [
91]. However, there was a greater increase in 6-min walk test performance in the home-based walking group (49 m) compared to usual care (where there was also a small improvement of 21 m), with the magnitude of the improvement being greater than minimal clinically important difference for this outcome [
92]. Furthermore, there was analysable data for only 15 participants in both groups with the authors acknowledging that they were ultimately underpowered for their primary outcomes [
91]. Finally, a non-randomised, non-controlled study of a 12 week combination of supervised class and home based exercise resulted in improvements in measured physical function (including the incremental shuttle walk test, the timed up and go test and the sit-to-stand 60) and self -reported physical activity [
93]. Taken together, to date there is limited high quality RCT data on the efficacy of increasing physical activity levels outside of haemodialysis on outcomes.
Individuals receiving haemodialysis are highly sedentary (low physical activity levels) particularly on days when they receive their haemodialysis treatment. There are benefits and disadvantages to both programmes of intradialytic exercise or exercise/physical activity taking place outside of haemodialysis treatment (interdialytic). However, it is currently not clear whether one is superior to the other with regards to benefits for clinical and patient reported outcomes (including mortality cardiovascular, physical function and health-related quality of life) [
94]. However, increasing and maintaining exercise behaviour in the sedentary haemodialysis population is challenging, therefore to initially encourage an increase in levels of exercise and physical activity in general, supervised intradialytic exercise (alongside other lifestyle and behaviour change advice) may be preferable (i.e. supported environment, no extra burden on time, exercising with peers). This has been highlighted by its inclusion in the latest Renal Association Clinical Practice Guideline on Haemodialysis [
95]. Future trials may wish to directly compare the clinical, cost benefits and acceptability to participants of intradialytic and programmes of exercise taking place outside of haemodialysis directly.
A recent RCT in 130 participants receiving prevalent haemodialysis has indicated that a six-month programme of 30 min moderate intensity (at an RPE of 12–14) intradialytic cycling was able to reduce left ventricular mass (between group reduction of − 11.1 g,
P < 0.001 for between group change) and improve other measures of cardiovascular health compared to a usual care control group [
96]. This is in agreement with the results of two smaller studies showing the benefits of single intradialytic cycling sessions on cardiovascular health [
97,
98]. The six-month programme in the aforementioned RCT [
19] was delivered and supervised by trained members of the research team and reported exercise programme adherence levels to be > 70% [
96]. Furthermore, a cost analysis of this trial showed that the six-month programme of intradialytic cycling was cost-effective (which appeared to be driven by a reduction in hospitalisations) [
99] - this analysis included the costs associated with implementing the intervention (equipment and staff). This may be important as a recent international survey of nephrologists reported that the leading barrier to implementation of exercise programmes at haemodialysis units was funding [
100]. The benefits of aerobic intradialytic cycling have been supported by a recent systematic review and meta-analysis indicating that solely intradialytic cycling results in a significant improvement of 87.84 m in six-minute walk test performance and a non-significant improvement of 1.19 mL/kg/min in V̇O
2peak [
101]. Further systematic reviews have confirmed this by showing that aerobic based intradialytic interventions [
102,
103], and exercise interventions comprised of aerobic, resistance or combinations of these exercise modalities [
102‐
106] results in improvements in the six-minute walk test and V̇O
2peak. Improvements in V̇O
2peak in this population may be of particular significance as it has been shown that values below 17.5 mL/min/kg are associated with increased mortality [
107]. However, currently there is no RCT data to indicate that intradialytic exercise can reduce the risk of mortality in the haemodialysis population.
There are a number of recent systematic reviews [
101,
104,
105,
108,
109] assessing the efficacy of exercise interventions (predominantly those involving aerobic exercise, resistance exercise or a combination) on HRQoL in the haemodialysis population. When assessing HRQoL some systematic review data [
104,
108,
109] but not all [
101], have reported improvements in the physical component score of the short form-36 following programmes of exercise. The inclusion of a range of heterogenous interventions (e.g., intra and inter dialytic, aerobic and resistance programmes (or combinations)), and methods of assessing HRQoL in the systematic review data makes providing firm guidelines for this outcome (and others) difficult. Results from the recent PEDAL trial, which investigated the effect of a 6-month programme of intradialytic exercise on Kidney Disease Quality of Life Short Form Physical Composite Score (PCS) in 335 randomised participants demonstrated that aerobic-only intra-dialytic cycling did not statistically improve HRQoL in a deconditioned population receiving haemodialysis therapy [
110]. Moreover, the recent Cycle-HD trial [
96] (which was not powered for HRQoL) also reported that a 6-month programme of aerobic intradialytic cycling did not statistically improve the EQ-5D-5L score, or both the physical and mental component scores of the SF-12. Resultantly, we have not provided a recommendation for HRQoL in this guideline.
Intradialytic cycling exercise delivered by means of cycle ergometer is the most prevalent modality of exercise delivered (usually performed three times a week) as part of clinical care [
111] and is the most common intervention in trials of exercise in this population [
112]. There may be benefit of adding an additional resistance training component to a programme of intradialytic exercise to improve muscle strength [
113]. This may be important as there is a reported association between increased muscle mass and improved survival in the haemodialysis population [
114,
115]. Promising results from a small, randomised pilot study have indicated that a 12-week programme of resistance training resulted in an increase in thigh muscle volume of 193 (63 to 324) cm
3 mean difference (95% CI) [
116]. Although in general the evidence for resistance training only is less clear and depending on the outcome measure it does not always provide additional benefit compared to aerobic training alone [
103,
105,
117]. A consideration that must be made when adding a resistance training component is that it may require more supervision than aerobic training alone, and for this reason providing it in clinical care may be more challenging than intradialytic cycling alone.
Interventional trials have consistently demonstrated that physical activity or exercise is effective in reducing blood pressure [
118]. The relationship between blood pressure and outcome in dialysis patients is “U”-shaped [
119], that is high blood pressure associates with mortality, whilst low blood pressure is even more strongly associated with adverse outcomes [
120]. Therefore, effects of exercise on blood pressure in the haemodialysis population should be interpreted with this in mind. Systematic review data on the effect of exercise on blood pressure in the haemodialysis population is mixed. Some systematic reviews and meta-analyses have shown that intradialytic exercise training may reduce blood pressure [
103,
104,
109], whilst others have reported either no effect [
105,
121] of exercise training or a very small non-significant reduction [
121]. A recent randomised controlled trial of 130 participants reported a non-significant reduction of 4.9 mmHg in interdialytic systolic blood pressure in the exercise group (there was also a reduction in the control group) following a 6-month programme of intradialytic exercise [
96]. However, there was no change in blood pressure following a 6-month personalised home-based walking programme in 104 participants randomised to the exercise group in a previous RCT [
90]. This supports an earlier interventional trial showing no effect of either intradialytic or home-based aerobic exercise interventions on blood pressure [
91]. The current evidence base for the exercise or physical activity inducing favourable changes in blood pressure in the haemodialysis population is weak.
The limited systematic review and meta-analysis data to date show that exercise training had no effect on circulating total cholesterol [
103,
104], supported by RCT data showing no effect of a 6-month home based walking programme on circulating cholesterol or triglyceride [
90]. To date there is no strong data that exercise or physical activity interventions may lower circulating lipids. Moreover, it is not clear whether small changes in lipid profiles would result in meaningful changes in outcomes given the role of lipids in the pathogenesis of cardiovascular disease in this population. It has been suggested that exercise training during dialysis (intradialytic exercise) may improve dialysis efficiency (Kt/V
urea) through increases in skeletal muscle blood flow which may reduce the rebound of solutes [
122]. Although this has yet to be consistently shown in RCTs. Some systematic reviews and meta-analyses have shown an improvement in Kt/V
urea with intradialytic exercise [
103,
104] whilst a recent systematic review found no effect in seven out of 13 included studies, which suggested little to no effect on dialysis clearance [
123]. There is limited data on the effect of exercise on medication. An observational study has shown that a 6-month intradialytic exercise programme resulted in a reduction in antihypertensive medication and weekly dose of erythropoietin [
124]. Furthermore, a recent cost-effective analysis of an RCT showed a reduction in mean cost of medication after a 6-month intradialytic exercise programme [
99]. Currently, there is limited evidence to provide recommendations for the effect of exercise on medication.
Evidence for the safety of exercise
Systematic review data has reported no significant serious adverse events due to exercise training, citing this as evidence of safety [
109,
125,
126]. However, a previous systematic review [
101] has highlighted inconsistencies in adverse event reporting in trials of exercise in the haemodialysis population. There have been safety concerns that exercise during dialysis may exacerbate the detrimental effect of the haemodialysis process. However, a recent RCT has reported that intradialytic cycling did not increase the number of arrhythmias during and following haemodialysis treatment [
96]. In addition, the six-month programme of intradialytic cycling which was employed in this RCT was associated with favourable cardiovascular remodelling [
96], which also suggests no detrimental effects. A primary concern for performing intradialytic exercise is the precipitation of intradialytic hypotension; this is of concern as episodes of intradialytic hypotension are associated with poor outcomes and increased mortality [
127], with intradialytic hypotension being present in around 10% of total sessions [
128]. Data from a small, randomised controlled crossover trial of 15 participants [
129] demonstrated that despite blood pressure increases during intradialytic cycling there is a resultant period of asymptomatic hypotension in the period following exercise. Reassuringly, this was not associated with changes in humoral markers of cardiac disease or systemic inflammation (including hsTroponin I, IL-6 or TNF-α) [
129]. The reduction in blood pressure observed following exercise in this trial [
129] likely reflects a normal physiological response to exercise. Traditionally, it has been believed that exercise should be avoided in the second half (the last 2 h) of the haemodialysis treatment, particularly in individuals who are having a large amount of fluid removed [
130]. However, in a recent multi-centre randomised crossover trial which included 84 participants, there was no significant difference between rate of intradialytic hypotension per 100 haemodialysis hours when exercise was performed in the first half compared to the last half of treatment [
131]. This supports data from another smaller mechanistic crossover study [
132], which showed that intradialytic cycling did not exacerbate instability during haemodialysis treatment when conducted in the first or third hour of treatment, independent of participant hydration status [
132]. The current evidence base indicates that intradialytic exercise is safe and is not associated with increased cardiovascular risk. A large RCT involving intradialytic exercise and hard outcomes (i.e., mortality) may be needed to provide conclusive answers regarding the safety of intradialytic exercise.
In summary, it is recommended that intradialytic exercise be performed three times a week, for at least 30 min. It is important to note that performance of intradialytic exercise three times per week (as performed in all the intradialytic exercise trials) is still not sufficient to meet the recommended levels (a 150 min of moderate intensity activity a week (or 75 min of vigorous activity)) of physical activity in recommendation 2 of this guideline. Therefore, intradialytic exercise will require supplementing with exercise or physical activity activities performed outside of the haemodialysis setting (interdialytic) to meet recommended UK Government guidelines.