Chronic Kidney Disease is associated with a high cardiovascular risk that is not explained by the traditional risk factors of diabetes and hypertension. This risk is amplified in people on hemodialysis, where mortality rates due to cardiovascular disease are 10-20 times greater than in the general population. Factors associated with decreased kidney function, and factors related to the hemodialysis treatment itself lead to remodeling in cardiac structure and function, driving increased rates of cardiac failure, sudden cardiac death, and increased mortality.
Although the mitigation of cardiac risk is seen as a top research priority, clinical trials, such as trials targeting atherosclerosis with statin therapy, have not shown to be beneficial in people on hemodialysis. Therefore, there is a need to investigate and implement innovative solutions that can improve cardiovascular health in this population and decrease the burden of high rates of cardiovascular morbidity and mortality. In the general population, physical activity is known to reduce the incidence of cardiovascular disease by 42-44%, reduce mortality, and hospital admissions. A growing body of literature suggests that physical activity during hemodialysis is a safe, low-cost option to improve heart health, however, there are several limitations to these data, and large, randomized controlled trials to improve the quality and consistency of evidence are needed.
CYCLE-HD was a multicenter cluster-randomized controlled trial. 131 individuals were recruited, with 101 completing the trial protocol. After completing a 1-month run-in period to ensure they were able to achieve the required exercise duration, individuals in the intervention group participated in a 6-month progressive cycling program 3 times weekly during dialysis, striving for 30 minutes continuous cycling at a rating of perceived exertion of 12-14, with adjusted resistance as necessary.
The main outcome was the change in left ventricular (LV) mass measured by cardiac MRI, and secondary outcomes included change in LV volumes, LV remodeling, aortic stiffness, myocardial fibrosis, ventricular arrhythmias, physical function and activity, and quality of life. There were clinically significant reductions in LV mass, along with the reduction in native T1 mapping, and aortic pulse wave velocity – each measure an important predictor of cardiovascular outcomes in hemodialysis. Although there were more serious adverse events in the intervention group, none of these events were linked to the exercise intervention.
An additional published paper from the CYCLE-HD study presenting the results from cost-effectiveness analyses from a health care service perspective showed a reduction in health care utilization costs favoring the intervention group (73% chance of the intervention being cost-effective at £20,000 and £30,000 per quality-adjusted life (QALY) year gained during a 6-month program). Interestingly, the cost savings appear largely due to a reduction in “renal admissions” (underdialysis, hemodialysis access issues, and volume overload) rather than cardiovascular admissions.
What implications do these findings have for clinical practice?
Taken together, the series of papers from this trial represents a seminal achievement in the field of exercise and ESKD, providing high-quality evidence supporting intradialytic exercise as a feasible, safe, and cost-effective intervention for improving surrogate cardiovascular outcomes.
Can these findings be generalized to all individuals receiving maintenance hemodialysis?
As the authors state themselves, this study was performed in a single clinical network in the United Kingdom, limiting the generalizability of results to other regions and populations. Several other aspects of the study limit the generalizability of findings. Participants in the trial were predominately male and younger than the overall hemodialysis population. In view of the run-in period, exercise group participants were also likely selected to be less frail and more adherent than all comers, as evidenced by a higher Short Physical Performance Battery (SPPB) score in the exercise group than that of the control group. How the run-in period affected participation in the exercise group is not really discussed in the paper.
Finally, there was no baseline measure of ultrafiltration (UF) rate reported between groups. The authors discuss exercise-induced reduction of cardiac stunning as a plausible mechanism for the impressive decrease in LV mass observed in the exercise group. High rates of intradialytic fluid removal and intradialytic hypotension have been associated with increased dialysis-related myocardial stunning. Baseline UF rate and change over time in the study groups is thus an important potential confounder of change in LV mass that was not accounted for in this study.
Is the implementation of intradialytic exercise programs feasible in busy dialysis clinics?
There are many successful examples of thriving intradialytic cycling programs worldwide, including in low- and middle-income countries. In order to successfully implement programs, comprehensive strategies need to be considered for scaling and sustaining exercise programs. These might include employing dedicated exercise professionals in kidney health programs to support the day-to-day oversight of programs and supervision of individuals enrolled in the program, individualized exercise prescription and programming, and possibly incorporating virtual platforms to improve accessibility. Funding of exercise professionals to supervise intradialytic exercise programs has consistently been identified as a key barrier to the sustainability and success of such programs. However, successful rehabilitation programs in other chronic disease conditions (e.g. cardiovascular and pulmonary disease) have shown that it is possible to make exercise part of routine care.
But do patients actually want to exercise, and will clinicians prescribe exercise for individuals receiving HD?
Current KQOQI cardiovascular guidelines recommend routine counseling to increase physical activity, however, counseling by kidney health clinicians is low. Research by Delgado and Johansen identified a major discordance between patients’ actual attitudes towards exercise and what nephrologists thought patients felt – 35% of nephrologists surveyed reported that they thought people on dialysis would not be interested in exercise; however, , only 4% of patients actually said they were not interested. Although a significant proportion of nephrologists thought that most dialysis patients would not increase physical activity levels if advised to do so, the majority of the patients surveyed reported that they would increase activity if advised by their nephrologist to do so, highlighting the importance of the role that health professionals have in improving physical activity levels.
In a recent survey of nephrologists from Canada, Australia, and New Zealand, only 38% of respondents agreed that sufficient evidence exists to support regular exercise prescription in individuals with CKD and 35% expressed that they did not know whether there is evidence to support this. Considering that future research on the effect of exercise on cardiovascular outcomes was also identified as a priority by respondents to this survey, CYCLE-HD provides robust evidence for the benefit of intradialytic aerobic exercise for surrogate cardiovascular outcomes that may influence clinicians to promote the importance of exercise participation to their patients with CKD.
What is next?
The results of CYCLE-HD are impressive and exciting. Future research to investigate whether exercise performed outside of hemodialysis can achieve the same declines in LV mass and cost-benefit would be important to help with individualization and scalability of exercise programming in those who are not able or willing to participate in the intradialytic exercise. Obtaining an answer to whether the exercise-related change in this surrogate outcome leads to a decrease in cardiovascular events and mortality is extremely important for the funding of such exercise programs and will require a large multicenter randomized controlled trial.
In several research priority setting studies, exercise has been identified as a top research priority for people with CKD; patients think it is important to further investigate the role that lifestyle factors have in delaying the progression of CKD, as well as further understanding the effect of exercise on the health of people undergoing dialysis. Nephrologists have also identified the impact of exercise on clinical cardiovascular outcomes, CKD progression, and patient-reported outcomes, including quality of life, symptoms, and mental health as future research priorities. Current randomized clinical trials are working to contribute evidence investigating intradialytic exercise as a safe intervention that mitigates many of the effects brought on by dialysis, such as symptom burden, myocardial stunning, and myocardial remodeling and regional function, as well as cognitive decline.
To improve the evidence base for exercise in CKD, as well as move findings into practice, The Global Renal Exercise Network (GREX; https://grexercise.kch.illinois.edu/), is a multidisciplinary network of professionals striving to develop effective and feasible strategies to increase physical activity and exercise participation in order to optimize health outcomes in people with kidney disease. One of their current initiates, in collaboration with the Kidney Wellness Institute of Illinois, is to develop an exercise in CKD training program, with the goal of training exercise experts to develop and implement exercise programs for the CKD population.
Whilst implementing exercise programs during hemodialysis treatment is a convenient way to provide individuals with access to exercise equipment and exercise specialists, it is also important to provide individuals with resources that they can access outside of their dialysis treatments as well. There are currently several initiatives in the form of virtual platforms that are targeted to people living with kidney disease, including Kidney Beam - https://beamfeelgood.com/kidney-disease, a (currently free) resource providing people living with kidney disease from across the globe access to online live and on-demand exercise classes from qualified NHS kidney health professionals, along with health and well-being resources and community groups with other users.
Commentary written by
Clara Bohm MD, MPH, FRCPC
Associate Professor, University of Manitoba
Nephrologist, Manitoba Renal Program
and
Oksana Harasemiw, MSc
Seven Oaks Chronic Disease Innovation Centre,
Department of Internal Medicine, University of Manitoba
Winnipeg, Manitoba