The Promise and Challenge of Aerobic Exercise in People Undergoing Long-Term Hemodialysis

• exercise
• hemodialysis

The literature chronicling exercise interventions among patients receiving KRT stretches back over 4 decades. Early exercise studies typically took the form of explorations of the physiology of exercise limitations in the dialysis population, and single-center studies testing whether exercise could improve physiologic parameters related to muscle function and cardiorespiratory fitness. In light of the encouraging findings from these studies, more investigations were performed, examining a wide variety of exercise modalities and a broad spectrum of outcomes. Exercise interventions vary in their modality, intensity, venue, frequency, and duration, among other things.

The most common types of exercise used have been aerobic and resistance training, and combinations of these two modalities. However, studies have also examined yoga, tai chi, and less vigorous exercise regimens (sometimes referred to as physical activity rather than exercise), such as walking programs, among other interventions. In terms of venue, the biggest distinguishing feature may be intradialytic versus extradialytic programs. Among interventions occurring outside of dialysis, some studies have taken place in gyms or exercise facilities, and others in participants’ homes. Intervention studies typically have prescribed or recommended activity ranging from twice weekly to daily over a duration of 8–52 weeks. Numerous systematic reviews and meta-analyses have suggested that exercise improves physical functioning and health-related quality of life among patients treated with dialysis (1). Some of these reviews have focused on specific exercise modalities (e.g., aerobic or resistance exercise training), specific venues (e.g., intradialytic exercise) (2), or specific outcomes (e.g., physical functioning) (1).

The systematic review and meta-analysis by Hargrove et al. (3) in this issue of CJASN is among the first to focus on the effects of aerobic exercise training on the symptoms patients experience, including restless legs, sleep disturbance, anxiety, depression, muscle cramping, and fatigue. The authors identified 15 randomized controlled trials (RCTs) that met their inclusion criteria of studying an aerobic exercise program of at least 8 weeks’ duration and having dialysis-related symptoms as a prespecified primary or secondary outcome. These studies enrolled 508 participants, of whom 283 were assigned to the exercise intervention. Two thirds of the included studies involved intradialytic exercise programs. The authors concluded that aerobic exercise improves symptoms of restless legs syndrome, muscle cramping, depressive symptoms, and fatigue, but effects on sleep disturbance and anxiety are less clear.

The review by Hargrove et al. is timely and important because dialysis patients’ immense symptom burden and the effect of symptoms on overall quality of life are receiving increasing recognition. The burden of symptoms among patients on dialysis is high relative to individuals without chronic disease and is similar to that of individuals with terminal cancer (4,5). High levels of symptom burden and severity are related to impaired health-related quality of life and depression (5). The international Standardized Outcomes in Nephrology initiative surveyed patients and caregivers to identify a ranked set of outcomes considered important and relevant to patients and their caregivers, with a view to informing patient-centered research in hemodialysis (6). The top-ranked outcome was fatigue. Shortly thereafter, in 2016, the Kidney Health Initiative (KHI), a public-private partnership between the American Society of Nephrology and the Food and Drug Administration, assembled an interdisciplinary workgroup to conduct a study to prioritize symptoms among patients on hemodialysis to target for therapeutic development and to convene a stakeholder meeting to identify opportunities for targeted therapeutic development for the prioritized symptoms (7). The top prioritized symptoms were insomnia, muscle cramps, and fatigue, and the top mood symptoms were anxiety, depression, and frustration (8). In the subsequent stakeholder meeting to consider therapeutic strategies to address insomnia, muscle cramps, and fatigue, exercise was identified as a possible therapeutic strategy for all three, and studies to test its efficacy were among the research goals identified by participants (7). In the context of these initiatives highlighting the importance of fatigue and other symptoms to patients on dialysis, the need for interventions specifically targeted to improve symptoms, and the possibility that exercise could be beneficial, the Hargrove review serves as a key first step toward examining the potential role of exercise in alleviating symptoms related to dialysis.

However, the results presented by Hargrove et al. serve only as the first step rather than a final determination of the benefits of exercise in alleviating symptoms among patients receiving hemodialysis. As encouraging as these results may seem at first glance, the authors also highlighted some discouraging issues (3). Despite combing 60 years of available literature for relevant studies and finding studies spanning almost 40 years, only 15 relevant studies were identified. The largest study included fewer than 100 participants. Included studies tested heterogeneous interventions and measured outcomes using different instruments. Participants were younger and healthier than the dialysis population as a whole. Although all of the included studies were RCTs, they were small and performed at single centers without blinding of participants to group assignment and, more importantly, likely without blinding of the study personnel conducting assessments (3). The risk of publication bias was high, as was the risk of false-positive findings related to bias in outcome assessment or to type I statistical error resulting from multiple hypothesis testing. For these reasons, some in the nephrology community have been skeptical about the quality of the evidence that exercise is beneficial (9) (despite considerably more evidence to support a benefit in terms of physical function [1]).

However, even if exercise improves physical functioning and symptoms among patients on dialysis, which seems highly likely, many questions remain: What is the best type of exercise? Are different exercise modalities best for different outcomes? What is the optimal intensity and duration of exercise? Is there a trade-off between efficacy and accessibility? In other words, might less-intense exercise be of greater net benefit if more patients can participate, even if it is less effective than more-intense exercise? These questions persist because of the wide variety of exercise interventions tested in RCTs and the rarity of head-to-head comparisons of different interventions. Thus, uncertainty about the form exercise programs should take, combined with a lack of infrastructure to support exercise interventions in dialysis facilities in the United States, has led to lack of adoption of exercise in the care of patients receiving dialysis (10). More concerning is that, despite the conclusion of the KHI workgroup that studies examining whether exercise can improve symptoms and quality of life among patients on dialysis should be prioritized at the highest level (7), there is no mechanism to support such studies. Indeed, few such studies are underway in the United States. ClinicalTrials.gov lists only 13 active studies of whole-body exercise interventions to address any outcome among patients on dialysis in the United States (11).

It is encouraging that the heavy symptom burden of patients on dialysis and its contribution to suboptimal quality of life are now considered high-priority targets of intervention. Furthermore, the review by Hargrove et al. (3) provides encouraging preliminary data to suggest aerobic exercise has the potential to alleviate many of the most bothersome symptoms. Support for large, multicenter studies to confirm the benefits of exercise and determine which exercise approaches are most beneficial and most accessible and acceptable to patients is urgently needed. It will also be crucial to focus on development of infrastructure for the delivery of effective exercise interventions.

• Copyright © 2021 by the American Society of Nephrology