Introduction

Parts of this report are reproduced or adapted with permission from Greenwood et al.1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.

Scientific background

Haemodialysis (HD) is a major treatment option for patients with end-stage kidney failure. Over 27,000 patients receive dialysis for chronic kidney disease (CKD) in the UK and 80% of these are treated with HD.2 Improved dialysis techniques and management of co-existing disease have made HD more tolerable, and many new patients can anticipate a longer life expectancy,3 although not always with a good quality of life (QoL).

Both physical inactivity and impaired physical function are strongly associated with increased morbidity, mortality and reduced QoL in patients on HD.3,4 Reduced QoL is also independently associated with mortality in patients on HD. Reports indicate that Short Form questionnaire-36 items (SF-36) physical component summary (PCS) scores of < 25 arbitrary units (AU) were associated with a 93% increased risk of death and a 56% increased risk of hospitalisation in HD patients, and a 10-point decrease in PCS score translated into a 25% increased risk of death within 2 years.5 Conversely, a 1-point increase in PCS score was associated with a 3.5% improvement in the odds of death.6 Interventions designed to increase physical function and reduce sedentary behaviour in patients on HD may mitigate cardiovascular disease risk, improve physical functioning, improve fitness for potential future kidney transplantation, lower levels of fatigue and, in turn, improve QoL. A non-randomised controlled trial (RCT) by Painter et al.7 reported an average 4-point increase in PCS score in the intervention group (in-centre intradialytic cycling or individualised home exercise programme) and an average 6-point decrease in PCS score in the non-intervention group. A study by DeOreo8 reported that for every increase in PCS score of 5 AU there is an ≈ 10% increase in the probability of survival.

Evidence from several systematic reviews9–22 indicates that a range of exercise training interventions show potential to improve exercise capacity and physical function in patients with dialysis-dependent CKD. The greatest effects were reported after 6 months of exercise and were associated with both supervised exercise and higher intensities of exercise. However, most of the studies reviewed were small trials, many of which were not methodologically robust, and non-intradialytic interventions were occasionally included in the evidence synthesis.16 Relatively few of the reviewed studies on intradialytic exercise training were appropriately powered to detect QoL outcomes, and none included a cost-effectiveness analysis. Moreover, adverse events (AEs) in the published literature were recorded in only a minority of studies17 or were poorly reported.16 A recent systematic review22 on intradialytic exercise training suggests that aerobic and resistance exercise programmes, delivered alone, can improve aerobic capacity, but that a combination of both can improve a greater range of outcomes, including exercise capacity, depression and some elements of QoL. By contrast, a recent systematic review by Young et al.18 indicated that there was insufficient evidence demonstrating whether or not cycling exercise during HD improves patient outcomes. The recommendations emerging from these systematic reviews indicated the need for (1) high-quality, adequately powered RCTs of intradialytic exercise and (2) routine collection and reporting of AE data associated with participation in these trials. The generation of this information may help to more fully identify recommendations for an exercise delivery pathway for HD patients and, ultimately, its clinical implementation.21

The PEDAL (PrEscription of intraDialytic exercise to improve quAlity of Life in patients with chronic kidney disease) trial was designed in response to a National Institute for Health Research (NIHR)-commissioned call to evaluate the clinical benefit and cost-effectiveness of exercise during HD (intradialytic exercise) in patients with end-stage kidney disease. At the time of planning and developing the PEDAL trial (2012) there was extremely limited evidence on the effectiveness of intradialytic cycling on patient-centred outcomes such as QoL indices. In CKD stages 2–5, overall QoL was improved with exercise training.9 Improved scores in the self-reported physical function subscales of the questionnaires appeared to be the main drivers for the overall improvement.9 Other elements of QoL, such as vitality, social function and general health, did not show a systematic change.9 Short-term (2–6 months), structured and supervised moderate-intensity aerobic training programmes (mainly cycling) have been reported to induce a systematic and large improvement in cardiorespiratory fitness (VO_2 peak) of 17–50%, with an overall mean difference between treatment and control groups of 5.22 ml/kg/minute. Such improvements exceed the clinically important criterion of 1 metabolic equivalent (MET) (3.5 ml/kg/minute). Thus, we utilised the evidence base promoting intradialytic cycling for improved cardiorespiratory fitness to investigate whether or not the physiological benefits derived from cycling could extend to perceived enhanced QoL. Furthermore, as inconsistent improvements have been noted for objectively measured functional capacity indices (walking speed/distance, sit-to-stand 60 performance) from previous intradialytic cycling studies, we chose to evaluate key secondary outcome measures of objective physical function.

The rationale for intradialytic exercise is both intuitively and pragmatically appealing because the environment of unit-based HD provides a platform for longer-term sustainable implementation of exercise rehabilitation programmes and, thus, could promote exercise-enhancing behaviours in HD patients. The current requirement for HD patients to attend 4-hour HD sessions three times per week provides a practical opportunity to deliver a structured and supervised rehabilitation programme with an enhanced potential for participation, associated with a substantially reduced patient burden in terms of time, effort and travel cost.

Objectives

Primary objective

The primary objective of this trial was to determine, in comparison with usual care, whether or not usual care augmented by intradialytic exercise training for a period of 6 months improved Kidney Disease Quality of Life Short Form, version 1.3 (KDQoL-SF), PCS score in stage 5 CKD patients receiving maintenance HD.

Secondary objectives

The secondary objectives were to determine, in comparison to usual care, whether or not usual care augmented by intradialytic exercise training improved:

• physical function and physical activity outcomes
  • peak aerobic capacity
  • physical fitness indicators
  • gait speed
  • lower-limb strength.
• clinical measures
  • resting blood pressure
  • haemoglobin, serum phosphate and parathyroid hormone levels
  • arterial stiffness [pulse wave velocity (PWV)].
• anthropometric measures
  • body mass index (BMI)
  • waist and hip circumference.
• patient-reported outcomes
  • QoL and symptom burden assessments [EuroQol-5 Dimensions, five level version (EQ-5D-5L)]
  • habitual physical activity levels (International Physical Activity Questionnaire)
  • Duke Activity Status Index
  • falls confidence (Tinetti Falls Efficacy Scale).

Economic analysis of cost-effectiveness

• Quality-adjusted life-years (QALYs) derived from the EQ-5D-5L.
• Resource use associated with physiotherapy assistant time.
• Resource use associated with delivery of exercise programme.
• Equipment costs.
• Hospital admissions and medication use recorded (with consent) from the patient’s clinical records.

Qualitative study

• A nested, qualitative study investigating the experience and acceptability of the intervention for both participants and members of the renal care team.

Harms

• Serious adverse events (SAEs).