Exercise as an Adjunct Therapy In Chronic Kidney Disease

Abstract

Physical activity levels are low in patients with chronic kidney disease (CKD). Evidence indicates that a sedentary lifestyle contributes to increased morbidity and mortality risk; thus, increasing physical activity is an undeniable aspect of a healthy lifestyle. Despite the myriad of health benefits associated with exercise, as well as clinical guidelines in its favor, exercise is still not prescribed as part of routine care in the CKD patient population. This article briefly discusses the benefits of regular exercise implemented across all stages of CKD on independent predictors of survival such as cardiorespiratory fitness, cardiovascular health and protein-energy wasting. Health care providers of the multidisciplinary nephrology team play a pivotal role in the encouragement and implementation of increasing physical activity levels. In order to increase physical activity counseling and enhance healthcare providers’ confidence in prescribing exercise for CKD patients, general recommendations for physical activity in these patients are provided.

Introduction

With irrefutable evidence supporting poor physical activity status as a risk factor for numerous chronic diseases, it is well established that physical inactivity is a leading cause of non-communicable diseases and mortality in our society today (1). Cardiorespiratory fitness is impaired in the early stages of CKD ranging from 50 – 80% of normative values in Stages 1–4 (2). Physical function has also been reported as reduced in these earlier stages (3) with declines in self reported function becoming apparent around Stage 3 (4). Both cardiorespiratory fitness and physical function continue to decline with the progression of kidney failure (5). When patients reach Stage 5 CKD and commence some form of renal replacement therapy, such as hemodialysis (HD) for example, physical activity levels are approximately 25% of those recorded in age matched sedentary healthy individuals (6), with one third of these patients being unable to carry out activities of daily living unassisted (7). These patients report very low exercise tolerance with a typical VO_2peak of 17 – 20 mL/kg/min as compared with values ranging from 30–35mL/kg/min observed in healthy aged matched sedentary individuals (8, 9). With oxygen consumption levels of approximately 13 mL/kg/min required to perform activities of daily living, patients would have to work at 65–76% of their maximum capacity just to carry out everyday activities, clearly having an impact on their functional ability and quality of life.

The mechanisms responsible for the diminished physical capacity in this patient population are not fully elucidated. While factors such as anemia (4) and inflammation (10) may play a role, the impaired physical function observed with declining renal function appears to be independent of age, anemia and comorbidity (5). Central factors such as cardiac output and blood oxygen carrying capacity are the primary determinants of cardiorespiratory fitness in healthy individuals. However, in CKD patients, despite complete correction of anemia, fitness levels still remain 38% below age matched healthy controls as well as below population normative values (11). As these patients often report lower limb fatigue as the reason for exercise intolerance, the limitations are thought to be at the peripheral rather than the central level (12). In support of this viewpoint, Odden at al., (5) reported that the relationship between kidney function and physical function was mediated through muscle strength in mild to moderate CKD. In the HD population, muscle strength has been shown to be a better predictor of maximum cardiorespiratory fitness as compared to blood oxygen carrying capacity (13). This evidence suggests that altered skeletal muscle function explains the exercise and functional intolerance in this cohort. These reductions in physical capacity are noteworthy as not only do they contribute to a reduced quality of life (14) but they also increase the risk of mortality across all stages of CKD (15).

As a result of the relationship between physical activity, morbidity and mortality, regular exercise is an undeniable aspect of a healthy lifestyle and there has been a movement towards implementing exercise for the prevention and management of a wide range of chronic diseases. Over three decades of research has revealed a myriad of health benefits of increased physical activity and regular exercise for CKD patients (16). Despite the fact that the National Kidney Foundation KDOQI Clinical Practice Guidelines for Cardiovascular Disease in Dialysis Patients state that patients should be counseled and encouraged to increase their level of physical activity (17), exercise is still not prescribed as part of routine care in this patient population and rehabilitation programs remain undeveloped in comparison to those implemented in other disease states such as cardiac and pulmonary populations. The benefits of exercise training for CKD patients have been reviewed extensively elsewhere (16). This article aims to highlight the main benefits of exercise training pertaining to physical capacity and performance, cardiovascular risk factors and protein-energy wasting in both mild to moderate CKD and HD patients.

Cardiorespiratory Fitness and Physical Performance

Significant increases in cardiorespiratory fitness ranging from 13–17% have been observed following both aerobic and combined aerobic and resistance training in both mild to moderate CKD and HD patients (16). In addition, significant increases in muscular strength have been reported throughout all stages of CKD following aerobic exercise, but more so following resistance exercise training (16). These increases in aerobic capacity and muscular strength have been observed following as little as three months of exercise training carried out at least 3 times per week (16).

Yet despite significant increases in aerobic capacity following exercise training, values still fail to match those of the healthy age matched population, suggesting a unique mechanism limiting exercise in CKD (18). The mechanisms responsible for this blunted response to exercise training remain unclear, although autonomic dysfunction, endothelial dysfunction and an abnormal structural and metabolic muscle function, all of which are characteristic of CKD, have been suggested to play a role (15). Furthermore, despite significant increases in muscle strength following exercise training, these gains in strength surprisingly do not appear to translate into improved physical function. A recent meta-analysis of exercise training studies across all CKD stages reported that physical function, in terms of stair climbing capacity and ability to carry out activities of daily living, was not significantly increased following exercise training (16). Similarly in HD patients, physical function is also not increased despite gains in strength following resistance exercise (19). Further investigations into the mechanisms responsible for these blunted responses in aerobic and functional capacity in this patient population will assist in the development of clearer guidelines for the most effective exercise prescription. Regardless, the prescription of regular exercise in this patient population is important. Irrespective of the size of improvement in cardiorespiratory fitness and functional ability following exercise, the decline in these outcomes that are typically observed with remaining inactive are prevented with regular exercise, thus breaking the progressive downward spiral of inactivity, deconditioning and comorbidity (Figure 1).

Figure 1.

The deleterious cycle of a sedentary lifestyle and inactivity in chronic kidney disease.

Cardiovascular Disease Risk

Cardiovascular disease (CVD) remains a leading cause of hospitalization and mortality in patients across all stages of CKD in the US (20). The National Kidney Foundation KDOQI guidelines recommend moderate intensity aerobic exercise most days of the week for the prevention of CVD in dialysis patients (17); however, guidelines pertaining to the earlier stages of CKD remain to be developed and integrated into clinical practice. The lack of established guidelines pertaining to regular exercise for the prevention of CVD in these early stages of CKD is noteworthy as these individuals are more likely to die from CVD than progress to kidney failure (17).

With regards to traditional risk factors for CVD, the available evidence in the pre-dialysis and HD populations has shown exercise to significantly reduce systolic and diastolic blood pressure (16). Furthermore, exercise training in HD patients has been shown to reduce the use of antihypertensive medication use by 36% resulting in an annual cost saving per patient (21). Recommendations based on the available evidence suggest high intensity aerobic exercise combined with resistance training lasting at least seven to 12 months will lead to reductions in blood pressure (16).

Despite the significant reductions in serum cholesterol following exercise reported in the general population, exercise training does not appear to have any effect on blood lipids in both moderate CKD and HD patients (16). In fact, in some cases increases in total cholesterol have been observed following aerobic exercise training which appear to be driven by increases in low-density cholesterol (22). Chronic kidney disease patients, particularly HD patients, present with a ‘reverse epidemiology’, a phenomenon whereby traditional risk factors for CVD in the general population are considered as protective in CKD patients and factors such as reduced serum cholesterol and body mass index are associated with a greater risk of morbidity and mortality (23). KDOQI nutritional guidelines report total cholesterol levels below 200mg/dL are associated with an increased risk of mortality and recommend that patients presenting with low, low-normal or declining serum cholesterol be examined for nutritional deficiencies (24). In this respect, the attenuated blood lipid responses to exercise in this population may be reflective of an increased appetite and caloric intake following exercise typically seen in these patients (25) and thereby indicative of a beneficial change in nutritional status in a cohort where malnutrition is prevalent.

CKD patients also differ from the general population in that they present with a host of nontraditional risk factors for CVD with inflammation, oxidative stress and endothelial dysfunction being described as prominent factors explaining the burden of CVD in CKD (26). However, the effects of exercise on these outcomes in CKD remain relatively unexplored and the modality of exercise required to lower these risk factors has not yet been thoroughly elucidated. Reductions in markers of chronic inflammation, C-reactive protein and Interleukin-6, have previously been reported following aerobic exercise training in HD patients (27) and following resistance exercise training in both pre dialysis and HD patient populations (28, 29). Animal models of CKD have demonstrated beneficial effects of exercise training on oxidative stress (30) but studies in human subjects remain scant. The available evidence demonstrates that aerobic exercise training significantly reduces products of lipid peroxidation in patients with moderate CKD (31) and in HD patients (32).

Protein-Energy Wasting

Protein energy wasting is evident in 20–25% of mild to moderate CKD patients and becomes more prominent as kidney disease progresses with up to 80% of HD patients showing evidence of muscle wasting (33). In mild to moderate CKD, a low protein diet is often prescribed to slow the progression of renal failure (34); however, this restriction contributes to a increase in protein energy wasting. In advanced renal failure the causes of protein energy wasting become multifactorial and include anorexia, uremia, inflammation, blood loss and the hemodialysis process itself. The catabolism of muscle protein in CKD poses a major problem as it is significantly associated with hospitalization and is an independent predictor of morbidity and mortality (35). Unsurprisingly, protein energy malnutrition is therefore a prominent focus in CKD clinical nutrition guidelines. KDOQI guidelines recommend assessing muscle mass and functional status to identify protein-energy nutritional status (24). Interventions aimed at increasing muscle mass would be expected to improve protein-energy nutritional status and exercise presents a potentially safe and cost effective option. Typically, resistance exercise, as opposed to aerobic exercise, is deemed the most effective modality of exercise for eliciting muscle hypertrophy and has therefore been investigated as an intervention for protein energy wasting in CKD.

Castaneda et al. (29) implemented high intensity resistance exercise to counteract the catabolic effects of a low protein diet in patients with moderate CKD. High intensity (80% of 1 repetition maximum) resistance exercise, 3 times a week over 12 weeks significantly increased total body potassium (a measure indicative of lean body mass), and muscle fiber cross sectional area and prevented a decline in body weight. The exercise prescribed included three sets of eight repetitions of five exercises targeting large upper and lower body muscle groups. In HD patients, similar resistance exercise prescriptions of both moderate intensity (60% of 1 repetition maximum) and high intensity (80% of 1 repetition maximum) implemented during hemodialysis have successfully increased muscle mass (19, 36).

Recommendations

Although optimal guidelines for exercise in the CKD population remain to be established, there is no need to delay the implementation of regular physical activity as part of routine care in patients who do not present with absolute contraindications to exercise. Design of exercise prescriptions utilizing either the American Heart Association guidelines for older adults (Table 2) or the American College of Sports Medicine guidelines (2, 37) for conditions such as hypertension, diabetes, metabolic or bone diseases as appropriate to the comorbidities of the individual patient is recommended. For sedentary individuals commencing exercise, pragmatic approaches such as lower intensity, unsupervised, home based exercise programs or exercising during hemodialyis are more realistic, obtainable and effective. A study carried out by Kosmadakis et al. (38) showed that low intensity regular walking for 30 minutes a day, 5 times per week had beneficial effects on exercise tolerance, weight loss, cardiovascular reactivity and blood pressure control in non dialysis dependent CKD patients. Furthermore, despite smaller physiological responses with low intensity exercise, the mental health benefits associated with this type of exercise justifies its implementation. It should be emphasized that with this type of intervention staff involvement and regular follow-ups such a phone calls or clinic visits for at least 6 months is encouraged to aid compliance. Specific to HD patients, carrying out exercise during hemodialysis is safe, effective and convenient option that ensures compliance and may have the additive benefit of reducing uncomfortable dialysis related symptoms such as restless legs and cramping.

Table 2.

General exercise recommendations for CKD.

Type	Frequency	Intensity	Duration
Aerobic Exercise Increase cardiorespiratory fitness and physical function; reduce cardiovascular risk	≥ 5 days per week	Moderate – Hard (RPE 12–15; noticeable increases in heart rate and breathing)	≥ 30 minutes
Resistance Exercises Increase muscle mass and muscle strength	2 – 3 days per week (non consecutive days)	Moderate – Hard (RPE 12–15; 60 – 80% 1repetition maximum)	8 – 10 exercises targeting upper and lower body large muscle groups 10 – 15 repetitions
Flexibility Exercises Maintain habitual physical activity; increase range of motion; reduce exercise related injury risk	≥ 2 days per week (perform on the same days as aerobic or resistance exercises)		10 minutes targeting major muscle and tendon groups Hold each static stretch for 10–30s Repeat each stretch 3 – 4 times
Balance Exercises Fall prevention	≥ 3 days per week

Adapted exercise recommendations based on American Heart Association and American College of Sports Medicine recommendations for physical activity in older adults (37). RPE, rating of perceived exertion.

Although the current evidence relies on scientific measures to prescribe and monitor the outcomes of exercise (such as VO₂peak), more simple measures such as Borg’s ‘Ratings of Perceived Exertion’ Scale (39), for example, may be used to monitor exercise training. Further, basic functional tests provided in the Senior Fitness Test Manual (40) and in the NIH Toolbox Motor Domain (www.nihtoolbox.org) could easily be implemented as outcomes of exercise interventions. Additional information and helpful resources pertaining to exercise in CKD for both health care professionals and patients is provided by The Renal Network 9 & 10 (http://www.therenalnetwork.org/services/exercise.php), the National Kidney Foundation (http://www.kidney.org/atoz/content/stayfit.cfm) and the British Renal Society (http://www.britishrenal.org/AboutUs/Time/Exercise.aspx).

Barriers

Reported barriers to exercise in this patient population include factors such as fatigue, lack of motivation and shortness of breath (41). The lack of physical activity counseling by healthcare providers may be an even more important factor. Health care providers of the multidisciplinary nephrology team report a lack of confidence in their ability to administer information regarding exercise (42). In addition, there appears to be a disparity in physician and patient opinions whereby a large proportion of physicians assume patients to be uninterested in physical activity when in fact patient surveys suggest that this is the case in only ~4% of patients (42). This problem needs to be addressed. Health care providers can play a pivotal role in the initiation and maintenance of exercise behavior, especially as patients place their trust in the advice of their providers.

Summary

Physical activity levels, cardiorespiratory fitness and physical function are reduced across all stages of CKD. Although the mechanisms responsible for the declines in functional capacity and ability are not yet fully elucidated, the limitations are thought to lie at the peripheral level in skeletal muscle. Regular aerobic exercise is beneficial for increasing cardiorespiratory fitness, muscle strength and cardiovascular health, while resistance exercise has proven beneficial for reversing protein energy wasting, maintaining muscle mass and increasing strength. Exercise implemented as an adjunct therapy across all stages of CKD can ameliorate independent risks of co-morbidity, hospitalization and mortality while enhancing quality of life. The multidisciplinary nephrology team is integral to the encouragement and implementation of increasing physical activity and regular exercise in CKD patients. Despite the need for specific evidence based guidelines derived from randomized controlled trials in this patient population, health care providers should not delay implementing regular physical activity as part of routine care in these patients as the potential benefits of exercise are substantial and can reduce the risks associated with remaining sedentary.

Table 1.

Glossary of physical activity terminology.

Aerobic Exercise Exercise that targets the cardiorespiratory system. Involves rhythmic activity of large muscle groups that can be continuously maintained. Examples include walking, jogging, cycling, rowing, swimming.

Balance Exercise: Balance exercises improve balance and help prevent falls. Examples include walking backwards, heel toe walking in a straight line or standing on one leg at a time.

Cardiorespiratory Fitness The ability of the circulatory and respiratory system to transport and deliver oxygen to the working skeletal muscle during sustained physical activity.

Exercise A subcategory of physical activity involving planned, structured and repetitive activities aimed at improving health and wellbeing.

Flexibility Exercise: Flexibility exercises help improve and maintain flexibly, range of movement, muscle stiffness and agility. These exercises can be static (e.g. bending over to touch your toes with out bending your knees) or dynamic (e.g. high knees or back kicks).

Physical Activity Any bodily movement produced by the skeletal muscles that results in energy expenditure.

Physical Function The ability to carry out activities requiring physical capability ranging from activities of daily living to more vigorous activities that require increased strength, mobility or endurance.

Rating of Perceived Exertion A validated subjective measure of physical activity intensity based on how difficult the individual perceives the activity to be. The scale ranges from ‘6’ (no exertion at all) to ‘20’ (maximal exertion).

Resistance Exercise Exercise that utilizes weight or resistance to induce skeletal muscle contractions. Resistance exercises can be carried out using free weights, weight machines, resistance bands, medicine balls or your own body weight.

Repetition Maximum Strength training terminology referring to the maximum amount of weight that can be lifted over a defined number of repetitions for a given exercise e.g. 1 Repetition Maximum is the maximum amount of weight that can only be lifted once.

VO2max The ‘gold standard’ measure of cardiorespiratory fitness. This value is the plateau of the maximum oxygen consumption during an incremental exercise test. Oxygen consumption does not increase beyond this value with an increase in effort or exercise intensity. This plateau may not always be reached before exhaustion. In this case, VO2peak is reported.

VO2peak This measure of cardiorespiratory fitness depicts the highest rate of oxygen consumption during an incremental exercise test till exhaustion.

Table 3.

Exercise Safety Considerations (43,44)

General CKD Considerations

Obtain physician consent before implementing an exercise intervention Consult the American College of Sports Medicine contraindications to exercise before prescribing exercise (45) Monitor blood glucose levels before during and after exercise in diabetic patients Ensure adequate warm up and cool down periods to prevent musculoskeletal injuries Be aware of medication related blunted heart rate and blood pressure responses to exercise

Specific Considerations for Hemodialysis Patients

For hemodynamic stability, avoid exercise in the first and last hour of hemodialysis if exercising during dialysis Monitor blood pressure during and after exercise and ensure an adequate cool down to prevent episodic hypotensive episodes if exercising during dialysis If exercising during dialysis be aware of intradialytic cramping With increased thirst during exercise be aware of fluid restrictions

Avoid exercise in the case of: Hyperkalemia Excess interdialytic weight gain Pulmonary congestion Peripheral edema