Physiological benefits of exercise in pre‐dialysis chronic kidney disease

Chronic kidney disease (CKD) has many heterogeneous causes, but is always associated with increased morbidity and mortality. Estimated glomerular filtration rate (eGFR) is an independent predictor of death, cardiovascular events and frequency of hospitalization,1 and the prognosis for patients with CKD is poor regardless of cause. CKD is also associated with a wide variety of metabolic conditions including type 2 diabetes, cardiovascular disease (CVD) and obesity.2 Furthermore, groups of patients with CKD ranging from end‐stage renal disease (ESRD)3 to pre‐dialysis patients,4 display poor physical functioning and reduced exercise capacity, which is directly associated with all‐cause mortality.5 These impairments have numerous causes, including inactivity,6 anaemia,7 inflammation,8 muscle wasting and reduced muscle function.9, 10 These factors in turn, further reduce exercise capacity, culminating in a downward spiral of physical inactivity and de‐conditioning associated with significantly increased cardiovascular risk.11

Exercise is accepted as an important intervention in preventing, ameliorating and rehabilitating other chronic diseases. The role of exercise in kidney disease is less well defined,12 and provision of exercise advice and rehabilitation programs for CKD patients in the UK is well behind that of cardiology and respiratory services. Whilst uptake and incorporation of exercise into standard treatment of CKD is slow, current clinical guidelines for the treatment and management of both non‐dialysis13 and dialysis dependent14 CKD recommend performing 30 min of moderate intensity exercise compatible with cardiovascular health on most if not all days of the week for the prevention of CVD.

There is growing evidence documenting the benefits of regular exercise in CKD on both patient and organ centred outcomes, as highlighted in a Cochrane review15 on exercise training in adults with CKD, which concluded exercising regularly for >30 min/session for three sessions/week will improve physical fitness, cardiovascular dimensions and health related quality of life. Following on from this, a recent position statement published by Exercise and Sports Science Australia (ESSA)16 offers exercise prescription recommendations for both dialysis and non‐dialysis patients consisting of >30 min aerobic exercise at >60% maximum capacity to improve cardio‐respiratory fitness, with the addition of resistance exercise being performed twice weekly on non‐consecutive days.

Despite this there still remains little guidance on the optimal modalities of exercise and how these should be implemented. The majority of evidence provided for the integration of exercise in the treatment of CKD has come from trials conducted in patients undergoing dialysis with numerous systematic reviews demonstrating its safety with no exercise related deaths being reported in over 28 400 patient‐hours and its efficacy at improving both physiological and patient related outcomes.17, 18 On the other hand, little research has been conducted amongst the pre‐dialysis population. The sheer number of patients with earlier stage CKD, the potential for earlier co‐morbidity modulation and the fact that sedentary patients at the initiation of dialysis have a 62% greater risk of mortality compared to patients who are active19 make exercise interventions particularly attractive for this group of patients. Therefore, this article aims to summarize what is currently known about exercise in pre‐dialysis patients with CKD, discuss the physiological effects and highlight the need for further research in order to optimize exercise prescription for this patient group.

Literature Search

For this narrative review, PubMed, Medline and Google Scholar were searched for studies investigating the effect of exercise training in pre‐dialysis CKD patients. Search terms ‘exercise’, ‘exercise training’, ‘aerobic exercise’, ‘resistance exercise’, ‘strength exercise’, ‘pre‐dialysis’, ‘chronic kidney disease’ and ‘renal disease’ were used to identify studies, and those that implemented an exercise intervention in pre‐dialysis CKD patients were included and can be found in Table 1.

Progression of Renal Disease

One of the main aims in the treatment of CKD is slowing disease progression. Exercise has the ability to impact positively on many of the upstream factors associated with the progression of kidney disease.39 Indeed, higher levels of leisure‐time physical activity are associated with slower declines in kidney function in elderly adults40 and patients with established CKD,28 however, evidence as to whether exercise training interventions impacts on renal function remains equivocal.

In pre‐dialysis patients, 12 weeks water‐based exercise22 resulted in a small but non‐significant improvement in eGFR and decrease in proteinuria. It remains unclear how more traditional aerobic and resistance forms of exercise impact on renal function, with some studies reporting no beneficial effects on eGFR.20, 30, 38 However, a recent study by Baria et al.41 noted a significant improvement in eGFR following 12 weeks of centre‐based aerobic training in overweight male patients with stages 3 and 4 CKD. The improvements in eGFR occurred with a significant decrease in visceral fat and mean blood pressure, both of which (obesity and hypertension) may be risk factors for the development and progression of CKD.39 Similarly, Toyama and colleagues42 reported significant improvements in renal function and lipid metabolism following 12 weeks of daily home based walking and one supervised cycling session per week. The improvement in eGFR was significantly associated with the concomitant increase HDL cholesterol and changes in triglycerides, which have been reported to accelerate CKD progression,43 possibly through increased renal tissue injury by increasing oxidative stress and inflammation.25, 44 Castaneda et al.45 also reported significant improvements in systemic inflammation and eGFR with a concomitant increase in serum pre‐albumin following 12 weeks of resistance exercise. High inflammatory burden is a predictor of low serum albumin46 and is associated with proteinuria47 in CKD patients. Therefore the exercise‐induced reduction in inflammation (discussed below) might be associated with improvements in improved eGFR by reducing proteinuria. Whilst it remains inconclusive as to whether exercise impacts upon progression of disease, the lack of consensus is mainly due to the lack of large scale, long‐term randomized controlled trials with disease progression as the primary outcome. Whilst these trials will be challenging, the primary aim of treatment in early CKD is preventing or slowing disease progression, therefore such trials are well indicated and long overdue.

Exercise Capacity and Physical Function in CKD

Exercise capacity is an important factor in maintaining physical function and is significantly reduced in pre‐dialysis patients, with levels reported to be 50–80% of healthy individuals48 and shown to decrease with disease progression.49 Peak oxygen consumption (VO_2peak), a measure of exercise capacity is an independent predictor of mortality in ESRD patients,31 demonstrating the importance of interventions capable of improving exercise capacity in CKD.

Aerobic exercise in pre‐dialysis patients has been shown to significantly increase VO_2peak,20, 21, 34, 50 exercise tolerance22, 30, 38, 51and anaerobic threshold.42 Increases in exercise capacity have also been reported with improvements in physical functioning and quality of life (QOL). An uncontrolled interventional study of 10 CKD patients21 reported significant improvements in various functional outcome measures and VO_2peak following 12 weeks of aerobic exercise, performed three times per week at ventilatory threshold. Furthermore, improvements in exercise tolerance, QOL and uraemic symptom scores were reported following 6 months of walking,51 whilst clinically meaningful improvements in overall QOL and physical domain were reported with a significant increase in VO_2peak following 12 months of mixed aerobic exercise.50

One of the main causes for reduced exercise capacity in CKD is muscle weakness.23 Increases in muscular strength have been reported following 4 months of aerobic walking and cycling with an increased VO_2peak.20 Similarly, 12 weeks of resistance exercise, performed 3 times weekly significantly improved muscle strength, which corresponded to significant increases in walking capacity and functional mobility.52 A combination of resistance and aerobic training was seen to improve functional performance above that of resistance training alone, in a group of haemodialysis patients.33 Furthermore, it has been suggested that a combination of resistance and cardiovascular exercise, performed three times per week at high intensity for 30–90 min for a period of 4–6 months is required to improve aerobic capacity as effectively as possible.15 Headley et al.37 noted significant increases in VO_2peak and time to exhaustion, following a 48 week exercise intervention in which optional resistance exercises were offered to subjects at weeks 24–48. Similarly, significant improvements in exercise capacity and functional ability were reported in CKD stage 3–4 patients taking part in a renal rehabilitation exercise intervention consisting of aerobic, resistance and balance training.53 These data suggest that all forms of exercise are effective at improving exercise and functional capacities in pre‐dialysis CKD patients, but more research is required to identify the optimal training methods.

Cardiovascular Risk

It is well established that patients with CKD are at greatly increased risk of developing cardiovascular disease (CVD),54, 55 and are, in fact, more likely to develop CVD than progress to dialysis.56 The reasons behind this are multi‐factorial, including high prevalence of traditional risk factors (hypertension, hyperlipidaemia and diabetes) as well as factors related to kidney disease itself (endothelial dysfunction, oxidative stress, inflammation and abnormal lipid patterns).2, 55 Physical inactivity is itself an important modifiable risk factor for the development of CVD29, 57 and in other populations exercise has shown to ameliorate several of the possible mediators, although this is not well established in CKD.

Headley et al.58 studied the acute effects of aerobic exercise on blood pressure in pre‐dialysis CKD patients. Forty minutes of moderate walking exercise at 50–60% VO_2peak reduced blood pressure for up to 60 min following exercise. However, evidence of exercise interventions reducing hypertension is inconclusive. Boyce et al.20 trialled the effects of 4 months aerobic exercise on cardiorespiratory fitness (CRF) and blood pressure (BP) in pre‐dialysis patients with hypertension. Exercise consisted of supervised walking and cycling performed three times weekly at a target intensity of 70% heart rate reserve for up to 60 min. In addition to improvements in CRF, significant reductions in systolic and diastolic BP were noted following exercise, returning back to baseline values following 2 months of detraining.

Mustata et al.50 reported a significant reduction in arterial stiffness, as estimated by augmentation index, following 3 months mixed supervised and home based exercise, performed at 40–60% VO_2peak for up to 60 min, despite no significant effect on blood pressure. Furthermore, Kosmadakis et al.51 investigated the benefits of walking exercise in patients with CKD stages 4–5 not on dialysis. Exercise sessions included a minimum of 30 min walking performed 5 times per week at a rate of perceived exertion (RPE) of 12–14. Blood pressure remained unchanged in exercising subjects, but a significant reduction in the number of antihypertensives required to maintain good blood pressure control was reported, along with stable values for stroke volume (SV), heart rate (HR) and cardiac output (Q). The usual‐activity control group however, had an increase in antihypertensive prescriptions, and reductions in SV, HR and Q. Similarly, improvements in resting and ambulatory HR were reported following 48 weeks of mixed aerobic and resistance exercise.37 The authors also observed that 1 minute post exercise HR recovery worsened over time in control subjects, but was preserved within the exercise group.37 These data suggest that exercise appears to have a beneficial effect on autonomic nervous function which has been implicated in the development of CVD in this population.59

Chronic Inflammation

CKD is associated with a state of chronic inflammation, as evidenced by elevated levels of pro‐inflammatory cytokines (tumour necrosis factor alpha (TNF‐α), interleukin(IL)‐1 and IL‐6) and acute phase proteins (C‐reactive protein (CRP)), which in addition to being well‐known risk factors for the development of CVD also appear to mediate many of the processes involved in muscle wasting commonly seen in patients with CKD. Inflammation in CKD and the impact of exercise has recently been reviewed extensively elsewhere,60 so only a brief review will be given here.

In healthy individuals and other chronic disease cohorts, exercise has been shown to have an anti‐inflammatory effect,36, 61 however there has been little research into the effects of exercise on inflammation in CKD populations. Our group has shown that 6 months of regular walking (30 min/day, 5 times/week) exerted anti‐inflammatory effects, as indicated by reductions in the plasma IL‐6 to IL‐10 and in the activation of inflammatory cells.26 Castaneda and colleagues62reported significant reductions in serum CRP and IL‐6 following 12 weeks of supervised progressive resistance training, performed three times per week, in pre‐dialysis patients receiving a low protein diet. Other studies however, have reported no change in IL‐6 and CRP levels following aerobic38 and combined aerobic and resistance exercise.37 Despite being a longer duration, the aforementioned study by Headley et al.37 of 48 weeks aerobic and resistance training did not significantly alter levels of IL‐6 or CRP. The release of IL‐6 as a myokine during exercise triggers an anti‐inflammatory cascade that is proportional to the intensity, duration and amount of muscle mass used.63 This may explain the lack of effect seen and suggest that exercise intensity was insufficient. There is need for further research in this area to identify exercise interventions with potential to reduce chronic inflammation in CKD.

Muscle Mass and Function

Skeletal muscle wasting is prevalent in patients with CKD and is associated with increased morbidity and mortality.24 The cause of which is multifactorial and complicated. Vastus lateralis muscle biopsies from pre‐dialysis CKD patients have shown histopathological abnormalities64 and atrophy of type IIa and IIx fibres,35 suggesting that the wasting process begins early in the disease.

In the study by Kosmadakis et al.51 patients performing 6 months walking exercise were randomized to receive exercise plus additional bicarbonate or exercise only, in order determine the effect of exercise and acidosis on skeletal muscle. Walking exercise lead to a depletion of free intramuscular amino acids, which was prevented by administering additional bicarbonate.65 Exercise plus additional bicarbonate also resulted in decreased mRNA expression of ubiquitin E3 ligases, indicating reduced catabolism; however no increase in lean body mass was seen.65 This suggests that aerobic exercise alone is insufficient to induce hypertrophy, which is important in this population.

In comparison, resistance exercise strongly upregulates protein synthesis resulting in increases in muscle fibre cross sectional area (MF‐CSA). Heiwe and colleagues64 investigated the effect of 12 weeks of resistance exercise on muscle histopathology, fibre type proportion and CSA compared to healthy controls. Having previously reported increases in strength and physical function in the same cohort,52 they reported no effect of the training intervention on histopathological abnormalities noted at baseline, or MF‐CSA and type proportion within or between groups. Increases in muscular strength without corresponding hypertrophy could be indicative of neuromuscular adaptations.66 Although not yet investigated in pre‐dialysis CKD, improvements in muscular strength together with increased rate of force development and neuromuscular function27 have recently been reported following high‐load resistance training in haemodialysis patients.

Conversely, Castaneda et al.45 reported significant increases in type I and II MF‐CSA with corresponding increases in strength, following 12 weeks of resistance training consisting 3 sets of eight repetitions at 80% of 1‐repetition maximum (1RM). This was associated with reduced inflammatory markers (CRP and IL‐6) and an 18% increase in IGF‐1.62 Further analysis of biopsies67 revealed significant improvements in mitochondrial content measured by mitochondrial DNA (mtDNA), which showed significant associations with the increases in MF‐CSA and IGF‐1 previously reported. Furthermore, at baseline there was a significant negative association between IL‐6 and mtDNA, suggesting a causal relationship. Elevated levels of IL‐6 suppresses IGF‐1 signalling that lead to growth and repair, ultimately increasing proteolytic activity.32, 68 Gregory and colleagues69 reported no significant changes in the IGF‐1 system despite noting improvements in physical performance following a 48 week intervention of mixed aerobic and resistance training. This may reflect the lack of change in inflammatory markers reported in a corresponding publication,37 thus suggesting a possible causal link between inflammation, IGF‐1 signalling and hypertrophy in CKD patients.

Whilst increases in strength and function are important, increasing muscle mass is highly desirable due to its profound metabolic effects. A recent systematic review and meta‐analysis by Cheema and colleagues on the effects of progressive resistance training (PRT) in patients with CKD, concluded that PRT can induce skeletal muscle hypertrophy and improve muscular strength and health related‐QOL in men and women with CKD.70 However, only one randomized controlled trial out of the seven included in the analysis was conducted in pre‐dialysis CKD. This identifies the need for further research in order to identify the optimal training mode and intensities to elicit hypertrophy in this population, in addition to identifying mechanisms and possible pathways that lead to skeletal muscle growth in order to identify alternative therapies.

Screening of Patients and Safety of Exercise Interventions

The recent ESSA position statement suggests that exercise in CKD appears to be safe across all stages of disease with no deaths directly related to exercise training in over 30 000 patient‐hours.16 Although the majority of evidence again comes from studies in patients undergoing dialysis, its noteworthy that none of the above mentioned studies (Table 1) report any adverse events related to the exercise interventions implemented.

The American College of Sports Medicine71 and ESSA16 recommend a medical review and cardiopulmonary exercise stress test with concurrent 12‐lead ECG be carried out prior to commencing a vigorous exercise training programme (i.e. >60% VO_2max). Indeed, many of the studies reviewed in this paper conducted some form symptom‐limited exercise test with ECG analysis,21, 30, 37, 38, 45, 52 the majority of which report no findings. Clyne et al.30 reported 1 of the 10 participants in the exercise group had an abnormal resting ECG and showed increased ST depression (≥1 mm) during the exercise test, both of which occurred without chest pain. Similarly, Leehey and colleagues38 reported positive tests in 2 of the 19 patients that underwent exercise stress‐tests and were subsequently excluded from the study. Furthermore a study investigating physical functioning in pre‐dialysis CKD patients reported 8 out of 32 patients (25%) who performed a symptom‐limited exercise test exhibited abnormal responses to exercise, showing significant S‐T segment depression (n = 3), excessive hypertensive response to exercise (n = 2 had systolic BP >260 mmHg), a fall in systolic blood pressure with increased work >20 mmHg (n = 1) and significant ventricular ectopic activity (n = 2).72 Whilst available data suggests that around 25% of patients that are approached about exercise interventions are ineligible to take part due to numerous medical exclusion criteria,16 there are no reports of safety issues arising from exercise interventions15 therefore more research is needed to identify the appropriate management of any co‐morbidities that may exclude these patients participating in exercise and optimize the delivery of safe exercise interventions.

Conclusions and Recommendations

The lack of written guidelines and coordinated exercise provision means the incorporation of exercise in the treatment and management of CKD has been neglected, and falls far behind that of cardiac and pulmonary services. However, whilst there is still a lack of large scale, randomized controlled trials, particularly in pre‐dialysis CKD, the evidence for the implementation of exercise is promising. Trials conducted in the pre‐dialysis stages of CKD suggest that exercise can improve exercise capacity and multiple measures of physical function, which have been shown to decrease as disease progresses. Data also suggests that aerobic exercise in particular, confers protection against the decline in cardiac function and the development of cardiovascular disease through the improvement of both traditional and non‐traditional risk factors. Preliminary evidence also suggests that resistance training can increase strength, muscle mass and function. Interventions capable of improving muscle mass whilst providing protection against the development of cardiovascular disease are highly desirable, therefore, future research should focus on investigating the efficacy of combined aerobic and resistance exercise, to determine if when combined, both the cardio‐protective and the anabolic benefits can be gained.