The Effect of Nutrition and Exercise on Body Composition, Exercise Capacity, and Physical Functioning in Advanced CKD Patients

Patients with stages 4 and 5 chronic kidney disease (CKD), and particularly chronic dialysis patients, commonly are found to have substantially reduced daily physical activity in comparison to age- and sex-matched normal adults. This reduction in physical activity is associated with a major decrease in physical exercise capacity and physical performance. The CKD patients are often physically deconditioned, and protein energy wasting (PEW) and frailty are commonly present. These disorders are of major concern because physical dysfunction, muscle atrophy, and reduced muscle strength are associated with poor quality of life and increased morbidity and mortality in CKD and chronic dialysis patients. Many randomized controlled clinical trials indicate that when CKD and chronic dialysis are provided nutritional supplements or undergo exercise training their skeletal muscle mass and exercise capacity often increase. It is not known whether the rise in skeletal muscle mass and exercise capacity associated with nutritional support or exercise training will reduce morbidity or mortality rates. A limitation of these clinical trials is that the sample sizes of the different treatment groups were small. The aim of this review is to discuss the effects of nutrition and exercise on body composition, exercise capacity, and physical functioning in advanced CKD patients.


Introduction
Patients with advanced chronic kidney disease (CKD), and especially those undergoing chronic dialysis, display decreased physical activity [1]. Reduced activity is considered to have many causes including superimposed physical illness, psychological stress [2,3], protein energy wasting (PEW), frailty [4], and inflammation [5]. Reduced physical activity and impaired physical functioning may affect the quality of life, morbidity, and mortality in this population [6,7]. Evidence shows that rehabilitation interventions to increase exercise capacity in CKD patients may reduce the risk of morbidity and mortality [8]. Many studies have been conducted regarding the effect of exercise training or nutritional supplementation on physical functioning, physical activity, and nutritional indices [9][10][11][12][13]. In general, these studies show that nutritional supplements or exercise training may enhance nutritional intake and improve muscle mass and exercise capacity in advanced CKD patients. The aim of this review is to describe the effects of nutrition and exercise on body composition, exercise capacity, and physical functioning in advanced CKD Patients. Significant changes within each group: Rx1: ↑ dietary intake of energy, protein, fat, fiber, and magnesium, ↑ mid-arm circumference, ↑ body weight, ↑ BMI, ↑ pre-albumin and albumin; ↓ MIS; no change in muscle mass, handgrip strength, percentage body fat, and triceps skinfold thickness Rx2: ↑ dietary intake of energy, protein, fat, fiber, and magnesium, ↑ mid-arm circumference, ↑ handgrip strength, ↑ body weight, ↑ BMI; ↓ MIS; no change in muscle mass, percentage body fat, triceps skinfold thickness, and pre-albumin and albumin Control: no change in any markers Two Rx groups vs. control: ↑ dietary intake of energy, protein, fat, fiber, and magnesium, ↑ albumin; ↓ MIS; no change in muscle mass, mid-arm circumference, handgrip strength, body weight, BMI, percentage body fat, triceps skinfold thickness, and pre-albumin 2 Sahathevan  fiber composition or size, muscle power (leg extension), muscle strength (knee extension), physical performance (chair stand test), body weight, and BMI Two Rx groups vs. control: ↑ energy intake, ↑ muscle power (leg extension), ↑ muscle strength (knee extension), ↑ physical performance (chair stand test), ↑ body weight, ↑ BMI; ↓ type 2x muscle fiber number ↑ Increase; ↓ Decrease. Rx: Treatment group; HD: hemodialysis; ONS: oral nutrition supplementation; IDPN: intradialytic parenteral nutrition; MIS: malnutrition inflammation score; BMI: body mass index; PEW: protein energy wasting syndrome; CSA: cross sectional area; hs-CRP: high sensitive c-reactive protein; IL-6: Interleukin-6; 6MWT: six-minute walk test; TUG: timed up-and-go; STS: sit-to-stand; mtDNA copy no.: mitochondrial DNA copy number; mitochondrial PGC-1 alpha: mitochondrial peroxisome proliferator-activated receptor gamma coactivator-1 alpha; VO 2 peak : peak oxygen consumption; HIV: human immunodeficiency virus; IL-1beta: Interleukin-1 beta; PD: peritoneal dialysis.

Physical Inactivity and Physical Function in CKD Patients
People with advanced chronic kidney disease (CKD) tend to be more physically inactive, have a sedentary lifestyle [1,39], and display impaired physical exercise capacity [40,41] and physical performance [40,42]. The degree of inactivity and impaired performance is heavily dependent on the severity of CKD [1,[43][44][45]. In general, people with CKD stages 1, 2, and often 3a (Glomerular Filtration Rate (GFR) < 60 to ≥45 mL/min/1.73 m 2 ) who do not have much proteinuria and who do not have other symptomatic, debilitating comorbidities (e.g., no heart or lung failure, active cancer, vasculitis, obesity, vascular insufficiency, or uncontrolled hypertension) may have an exercise capacity which is normal or, if the person chronically exercises, above normal [46,47]. By contrast people with CKD stage 3b, and particularly CKD stages 4 and 5 and chronic dialysis patients, which we will refer to in this paper as advanced CKD, commonly lead more physically inactive lives [43,[46][47][48][49]. In general, the more severely reduced the glomerular filtration rate (GFR), the more physically inactive [1,43,50] and the more severely impaired the exercise capacity of many CKD patients [37,46]. These matters are considered to be of major clinical importance because physical dysfunction, muscle atrophy, and reduced muscle strength are all associated with poor quality of life and increased morbidity and mortality in CKD and ESRD patients [4,6,[51][52][53][54][55].
First, to define some terms: Physical activity (PA) is defined as any bodily movement that is produced by the contraction of skeletal muscle and that increases energy expenditure above basal levels [53]. Physical functioning (PF) is the ability to perform the normal activities of daily living and is generally assessed by simple tests of physical activity [7]. It characterizes an essential component of health status and depends on the sensory and motor skills necessary for usual daily activities [56]. PF may be assessed by the usual gait speed test, the handgrip strength, the timed up-and-go test, and the 6-min walk test [55]. Physical performance (PP) is one's ability to carry out specific physical tasks that might be necessary in the course of normal daily living (e.g., walking and stair-climbing) and is generally assessed by the ability to perform these activities [56]. Exercise capacity is the maximum level of oxygen consumption achieved during maximum exercise [56]. Exercise capacity is often expressed as metabolic equivalents (METs) which is defined as the multiple of a person's basal oxygen consumption at rest. Individuals consume a basal amount of oxygen in the performance of their resting metabolism. This basal oxygen consumption is generally measured in the morning after an overnight fast (i.e., in the post-absorptive state) while lying comfortably in bed. This level of oxygen consumption is referred to as one metabolic equivalent or one MET. One MET equals the resting metabolic rate of a person. One MET will vary somewhat from person to person, and is approximately 3.5 mL O 2 /kg/min [56].
Another measure of exercise capacity is called maximal oxygen consumption (VO 2max ) which is the highest oxygen consumption observed during graded exercise to physical exhaustion. Peak oxygen consumption (V o2peak ) refers to a person's peak oxygen consumption that is attained during a specific maximal exercise test and is more commonly used than VO 2max [56].
Advanced CKD patients are clearly less physically active than matched normal people [1,47,57]. Although the World Health Organization recommends that adults exercise each week for at least 150 min of moderate intensity PA or 75 min of vigorous intensity PA or some combination therein, it is clear that the great majority of advanced CKD patients do not exercise at anywhere near this level [1,47,57,58]. The National Health and Nutrition Examination Survey (NHANES) III indicated that 28% of subjects with CKD (defined as eGFR < 60 mL/min/1.73 m 2 , stages 3-5), reported being physically inactive compared to 13.5% of the non-CKD population age range, sex, and race [59]. Using more objective methods of measuring physical activity, such as with accelerometers, Beddhu et al. found that patients with CKD (mean eGFR, 48.5 ± SD12.9 mL/min/1.73 m 2 ) were sedentary more than two-thirds of the waking day compared to one-half of the waking day in individuals without CKD [60]. Stack et al. reported that 75% of new onset dialysis patients showed severe limitations in their ability to conduct vigorous activities, and 42% of these patients described severe limitations in moderate activities (e.g., moving a table or vacuuming) [61].
The United States Renal Data System Comprehensive Dialysis Study involving 1547 ambulatory patients new to dialysis indicated that physical activity levels were below the fifth percentile of healthy subjects matched by age and sex [62]. Physical performance tests related to activities of daily living that were conducted in 32 CKD patients (eGFR, 29.9 ± SD 17.0 mL/min/1.73 m 2 ) showed that the mean maximal gait speed, and sit-tostand performance tests, were lower, 85% and 79%, respectively, than normal sedentary reference values [63]. The findings of a Swedish study in 55 CKD individuals with a measured GFR ≤ 20 mL/min/1.73 m 2 revealed that mean peak values of handgrip strength were 78% and 84% of the values of normal age-matched males and females, respectively [64]. In this same study, for the patients with eGFR ≤ 12 mL/min/1.73 m 2 , for every 1 mL/min/1.73 m 2 further decrease in GFR, there was an increase in the proportion of patients who were not able to rise from a chair without the use of his/her arms [64]. Kim et al. found that in 72 hemodialysis (HD) patients, daily physical activity (assessed by an accelerometer over a 7 day period) and physical performance (measured by a 6-min walk test (6MWT), sit-to-stand test, and stair-climbing test) were about 60-70% of normal ageand sex-matched values [47].
The international DOPPS study (Dialysis Outcomes and Practice Patterns Study) reported that among 20,920 HD patients from 12 countries more than the half of the patients engaged in some type of exercise either less than 1 day per week or never [65]. Another study in 78 HD patients in Spain in which daily physical activity was measured for 6 consecutive days with a pedometer, indicated that 71% of HD patients were considered sedentary (<5000 steps/day) [66]. It might be argued that taking 4999 steps per day is not very sedentary. These patients actually took 3767 ± SD 3370 steps per day on non-HD days and 2274 ± SD 2048 steps per day on HD days [66]. In addition, 134 HD patients from five hemodialysis centers in France, Switzerland, Brazil, or Sweden were assessed by an armband activity monitor for 5 days for the number of steps they took each day [67]. These patients took an average of 5544 steps per day on non-HD days and 4620 steps per day on HD days [67].
Low physical functioning in advanced CKD patients is associated with reduced exercise capacity, especially at the time that they begin chronic dialysis therapy or after they are established on this treatment [37,46]. Reduced exercise capacity, lower peak oxygen consumption (VO 2 peak ), and impaired maximal oxygen consumption (VO 2max ) are very prevalent and often quite severe in CKD stages 3-5 and in chronic dialysis patients [40,41,46]. Moreover, in a national registry of nursing home residents whose functional status was monitored serially starting shortly after they commenced HD, a sharp and significant reduction in functional status of HD patients was observed by 12 months after the initiation of chronic dialysis [40]. As indicated above, one reason for such reduced physical function in advanced CKD patients may be that these individuals do not undertake much physical activity [47,68].
The degree of physical inactivity and deconditioning of peritoneal dialysis (PD) patients is similar to that of HD patients [1]. A few small studies in PD patients showed that VO 2 peak levels are similar to those of HD patients. Compared to the general population, PD patients also showed reduced physical function and lower physical activity levels [69]. Sixty-four automated peritoneal dialysis (APD) and continuous ambulatory peritoneal dialysis (CAPD) patients walked 4839 ± SD 3313 steps per day and were found to have sedentary behavior as defined by <5000 steps per day as measured by pedometers [66].

Frailty, Protein Energy Wasting and Chronic Kidney Disease
Perhaps no discussion of exercise capacity and physical function in CKD patients would be complete without a discussion of frailty in CKD [4,70,71]. Previously, the concept of frailty was generally applied to older adults and could be defined as, "(older adults or aged) individuals who are lacking in general strength and are unusually susceptible to disease or to other infirmity" [72,73]. Now frailty is used to characterize people of all ages who are debilitated and who often have other illnesses (e.g., CKD) [74]. The diagnosis of frailty has elicited much interest because it is associated with adverse clinical outcomes, morbidity, and mortality [4,72,75] and because it is potentially treatable [4,73,74].
Many criteria have been developed for diagnosing frailty and measuring its severity. This is especially the case for people with specific clinical disorders or disease states [72,74,[76][77][78][79][80]. One set of criteria for diagnosing frailty in CKD patients, which was developed by Fried et al. and appears to be particularly useful, is the presence of at least three of the following five conditions: (1) unintentional weight loss, (2) self-reported exhaustion, (3) measured weakness, (4) low walking speed, and (5) low physical activity [63]. Using these criteria, frailty in CKD patients is associated with a substantially worse clinical prognosis [4,74,[81][82][83]. The above five individual elements involved in the diagnosis of frailty, as well as the diagnosis of frailty itself, increase in prevalence as the GFR decreases [83,84]. Moreover, frailty is more prevalent in chronic dialysis patients [70,74,85].
It is noteworthy that both frailty and protein energy wasting (PEW) are common in advanced CKD and are both characterized by unintentional weight loss, physical debility, and low physical activity [4,86]. PEW is often present in CKD patients who have frailty and impaired exercise capacity [4]. PEW is defined as the loss of somatic and circulating body protein and energy reserves [87]. The term PEW is used rather than protein energy malnutrition because some causes of PEW are unrelated to inadequate nutrient intake. There is no universally accepted criteria for diagnosis of PEW [86,88]. One commonly proposed diagnostic criteria for PEW is the presence of at least one measure from at least three of the following four categories of protein-energy status: decreased serum concentrations of certain compounds, primarily such proteins as albumin or pre-albumin (transthyretin), low or decreasing body mass, low or decreasing skeletal muscle mass, or unintentional decrease in dietary protein or energy intake [89].

Causes of Decreased Physical Activity in CKD Patients
The focus of this paper does not allow an extensive discussion of the causes or diagnosis of frailty or PEW in CKD patients. This subject has been extensively reviewed in other publications [4,[86][87][88][89]. It should be emphasized that many of the causes of frailty and PEW are similar or identical, and these two syndromes often occur together in CKD patients [4].

Nutrition and Exercise Training
Many studies have examined the effects of nutritional support on skeletal muscle [15] or total body protein [15,[106][107][108][109][110][111][112][113] synthesis in people with CKD. Most of these studies were conducted in patients undergoing HD rather than nondialyzed CKD patients or PD patients. Several reports indicate that nutritional supplements that provide protein or amino acids and energy may acutely increase skeletal muscle [15] or total body protein synthesis [15,[106][107][108][109][110][111][112][113] in CKD patients. Increased protein synthesis has also been noted in HD patients when they undergo HD while receiving nutrients intravenously [108,109] or orally [15,106,107,110] as compared to when they are fasted.
The long-term effects of nutritional support are more likely to be manifested by changes in body composition than by increased measured rates of protein synthesis or degradation. Table 1 summarizes clinical trials of the effects on body composition in CKD patients who received nutritional support. Patients in these trials were more likely to have advanced CKD and were almost always chronic dialysis patients. In some but not all studies, the patients had protein energy wasting. In some trials conducted in HD patients, supplements were given only during HD treatment, whereas in other trials HD patients were offered the supplements daily. Furthermore, cardiopulmonary (aerobic) or resistance exercise training was offered in addition to nutritional supplements in several trials. In one trial, calorie restriction and aerobic exercise training were offered to stage 3-4 CKD patients to reduce their body fat [16]. In most, but not all trials, patients were randomized to one or more treatment protocols or to control groups. The treatment protocols in these clinical trials were usually of only a few weeks' to several months' duration.
The outcomes of these clinical trials were variable (Table 1). In a number of the studies, nutritional support with or without exercise was associated with a reduction in the number of patients who displayed evidence for malnutrition or inflammation. For example, the number of patients who displayed an abnormal malnutrition inflammation score (MIS) or who had evidence for PEW often decreased with nutritional support. Most of the studies indicated that nutritional support by itself or with some form of exercise training is often associated with an increase in muscle or fat mass or serum proteins, including serum albumin and pre-albumin (transthyretin). Sometimes serum proinflammatory cytokines decreased. However, usually there was no statistically significant difference between the patients who received nutritional support alone and those who underwent both nutritional support and some form of exercise training. Nutritional support with or without exercise training was not always associated with increased protein or fat mass. Table 2 summarizes the results of randomized controlled trials of exercise training without supplemental nutrition. Again, most of these studies were conducted in HD patients. With exercise training, muscle mass in the exercising extremities often increased, especially if the exercise involved resistance training rather than cardiopulmonary exercise. Fat mass sometimes decreased or rose. Exercise capacity and physical function often improved with exercise training, and the magnitude of improvement often was impressive. Serum pro-inflammatory cytokine levels sometimes decreased. Again, it is possible that a greater increase in muscle mass and exercise capacity, and more reduction in body fat might have been demonstrated if the sample sizes of the patients studied had been greater or if the number of weeks or months of exercise training had been extended.

Discussion
The results of the studies presented in this manuscript indicate that nutritional supplements, exercise training, and the combination of the two treatments were often associated with improvement in nutritional (protein-energy) status or physical function in advanced CKD patients and especially chronic dialysis patients. However, in a number of the trials the improvement, although often statistically significant compared to the baseline assessment of the patients, was not significantly different from the changes in the controls.
One reason for the discrepancy in the results of these trials could be related to the protein-energy status and comorbidity of the patients. It would seem likely that CKD patients who had PEW, especially if the PEW was due to malnutrition, would be more likely to respond to nutritional therapy. The small sample sizes in these studies may be another reason that there are not more significant differences in changes in body composition between the nutritional support and control groups. The baseline inflammatory status and comorbidity of the patient groups often were not well defined, which may have prevented a statistically significant response to nutritional support and/or exercise training from being observed. This is especially the case because the sample sizes of the studies were small. Moreover, the composition of the nutritional supplements offered to these patients might not have been optimal. Various clinical factors such as acidosis, the characteristics of the dialysis procedures, inflammation, diabetes, and other comorbidities may also have influenced the response to nutritional supplementation, exercise training, or the combination of the two treatments [86,114,115].
Protein energy wasting, frailty, and impaired exercise capacity are each associated with increased morbidity and mortality in CKD patients [4,55,68]. An open question that was not addressed by these clinical trials is whether treatment to improve these three disorders will reduce morbidity and mortality in CKD patients (Tables 1 and 2). Clinical trials with much larger sample sizes and much longer durations of treatments would be necessary to examine these questions. For logistical reasons, these types of trials will be harder to organize and fund.

Conclusions
Published data indicate that patients with stages 4 and 5 CKD, and particularly chronic dialysis patients, often have decreased exercise capacity and physical performance. Their daily physical activity is often substantially reduced in comparison to age-and sex-matched normal adults. Protein energy wasting and frailty are common in these patients. Many randomized controlled clinical trials indicate that when these individuals are treated with nutritional supplements, exercise training, or both procedures, their skeletal muscle mass and exercise capacity often increase. Further research is needed to determine whether exercise training and nutritional supplements or a combination of these two treatments will improve whole body protein or skeletal muscle mass, physical function, and exercise capacity. If muscle mass does increase with these treatments, it will become important to assess whether these treatments increase protein synthesis, reduce protein degradation, or do both. Ultimately, the value of nutrition supplementation and exercise training will be assessed by their effects, if any, on the quality of life, morbidity, and mortality rate of advanced CKD patients.