Abstract
Background: Chronic kidney disease (CKD) affects 11–13% of the world population. The main risk factors for CKD include diabetes, hypertension, and obesity. Metabolic syndrome (MS) is associated with the onset of CKD in the nondiabetic population. Obesity and MS are also risk factors for a worse progression of established CKD. Therapeutic exercise is an effective option to treat and manage obesity, MS, and diabetes in the general population. However, the evidence on the effect of exercise on patients with CKD, obesity, and MS is scarce. Summary: We evaluated available evidence on the effect of therapeutic exercise in patients with CKD, excluding dialysis, particularly in improving the metabolic risk factors and main renal outcomes: renal function loss and albuminuria/proteinuria. This review includes prospective studies and clinical trials. A total of 44 studies were analysed in 1,700 subjects with renal disease (2–5), including patients with renal transplantation. Most studies did not prove a major effect of exercise on albuminuria/proteinuria, glomerular filtration rate (GFR), obesity, or MS. These results are intriguing and deserve attention. The exploratory nature of most studies, including a low number of cases and short follow-up, might explain the lack of efficacy of exercise in our analysis. Specific aspects like the type of exercise, frequency, intensity, duration, accommodation during follow-up, individualization, safety, and adherence are crucial to the success of therapeutic exercise. The beneficial role of exercise in patients with CKD remains to be determined. Key Messages: Key messages of this review are as follows. (1) The effect of therapeutic exercise on renal and metabolic outcomes in patients with CKD remains to be determined. (2) According to the evidence selected, therapeutic exercise seems to be safe to treat patients with CKD. (3) Most studies are exploratory by nature, with results that need further investigation. (4) Therapeutic exercise is a complex procedure that must be specifically designed to treat patients with CKD.
Introduction
Chronic kidney disease (CKD) is defined by reduced glomerular filtration rate (GFR): <60 mL/min/1.73 m2 and markers of organ damage: renal ultrasound, proteinuria, altered albuminuria during the last 3 months [1]. CKD has become a public health problem; its prevalence is approximately 11–13% worldwide with trends that have been increasing during the last decades [2].
The main risk factors for CKD include diabetes, hypertension, and obesity [3‒5]. The incidence for CKD increases with the increment in body mass index [5]. In the same line, metabolic syndrome (MS), a cluster of dyslipidemia, hypertension, overweight-obesity, hyperglycemia, and insulin resistance, is associated with CKD in the nondiabetic population [6]. Moreover, the higher the components of MS present in a patient, the higher the risk for CKD. Finally, obesity and MS are not only risk factors for CKD but also portend a worse prognosis of established CKD [7]. Renal function loss can be faster, histological damage more severe, and proteinuria higher in obese patients with CKD [7]. Taken together, this information indicates that the pathogenesis of CKD is, in part, associated with factors potentially reversible, i.e., obesity, hypertension, dyslipidemia, and hyperglycemia. This offers a clear opportunity to improve CKD treatment and prevention in clinical practice.
Therapeutic exercise is an effective option to treat and manage major metabolic diseases. In fact, exercise can prevent the progression of prediabetes to diabetes by inducing weight reduction and improving insulin sensitivity [8‒10]. In patients with diabetes, exercise improves glycaemic control. Not surprisingly, therapeutic exercise proved to reduce cardiovascular events in patients at risk. The diseases in which exercise has a therapeutic role are associated to CKD [11]. However, the impact of exercise in reducing the renal disease or limiting the progression of established CKD is unknown. In this review, we evaluate the available evidence on the effect of exercise in patients with CKD (excluding dialysis), particularly in reducing metabolic risk factors and major renal outcomes: renal function loss and albuminuria/proteinuria. This review did not evaluate the improvement on physical capacities related to exercise.
Methodology
A search was carried out in the following databases: Pubmed, Science Direct, Sport Discus, and Web of Science (WOS) about the available evidence on the different exercise interventions in patients with established chronic kidney disease and MS with data on major renal outcomes. The inclusion or exclusion criteria for articles were established based on the following characteristics:
Inclusion criteria include full-text studies available in English, those that use exercise training as main intervention, patients >18 years old, patients with CKD of diverse origins, evaluation of the effect of exercise on renal outcomes (albuminuria/proteinuria; GFR decline), and evaluation of the effect of exercise on MS traits. Exclusion criteria include meta-analysis, narrative reviews, and studies with exercise that do not include the analysis of major renal outcomes and exercise training in dialysis patients.
We proceeded to search for the different studies with the following keywords in multiple combinations in the databases mentioned above: “renal function,” “estimated glomerular filtration rate,” “proteinuria,” “renal disease,” “renal transplantation,” “chronic kidney disease,” “metabolic syndrome,” “overweight,” “obesity,” “physical activity,” “exercise training,” “therapeutic exercise,” “resistance training,” “aerobic training,” and “strength training.” The process of selection is summarized in Figure 1.
Chronic Kidney Disease
Randomized Clinical Trials
Twenty-three clinical trials (shown in Table 1a), including a total of 733 patients, compared the effect of therapeutic exercise versus standard clinical care in patients with CKD 2–4 [12‒34]. The main outcomes included changes in GFR (22–95%), proteinuria (14–60%), body mass index (BMI; 16–70%), blood pressure (BP; 13–55%), and dyslipidemia (13–55%). Most of the studies enrolled a small number of cases, i.e., 20–40 overweight/obesity patients. Three studies specifically evaluated patients with diabetes. Half of the studies had a short follow-up (3–6 months), and the other half had a longer duration (6–12 months).
Exercise training in patients with chronic kidney disease: (a) randomized clinical trials and (b) non-randomized studies
| (a) Randomized clinical trial | ||||||
|---|---|---|---|---|---|---|
| Author | N (E/C) | Patients | Exercise – adherence | Time | Outcomes | |
| metabolic/renal | improvements | |||||
| Clyne et al. [31] 1991 | 19; 10/9 | CKD 4 | Supervised calisthenics; 45 min, 3/w – AR | 3 m | HbA1c, HT, eGFR | ---- |
| Heiwe et al. [25] 2001 | 25; 16/9 | CKD 2–4 | Strength (60% 1-RM) training 3/w – AR | 3 m | BMI, measured renal function, proteinuria | ---- |
| Castaneda et al. [24] 2001 | 26; 14/12 | CKD 2–4 | Strength (80% RM); 45 min, 3/w – AR | 3 m | BMI, dyslipidemia eGFR, proteinuria | ---- |
| Pechter et al. [23] 2003 | 26; 17/9 | CKD 3–4 | Aerobic (swimming); 30 min, 2/w – NAR | 3 m | BMI, HT, dyslipidemia, proteinuria, eGFR | HT: 147 to 139 and 87 to 84 (p < 0.05)Proteinuria (g): 0.7±0.2–0.4±0.2, p < 0.05 |
| Heiwe et al. [33] 2005 | 18; 12/6 | CKD 2–4 | Strength; 45 min, 3/w – NAR | 3 m | Measured renal function, proteinuria | ---- |
| Leehey et al. [34] 2009 | 11; 7/4 | CKD 2–4 | Supervised for 6 w + home based 18 w aerobic ex. 30–40 min, 3/w – AR | 2–6 m | BMI, HT, dyslipidemia, HbA1c eGFR, proteinuria | ---- |
| Toyama et al. [30] 2010 | 19; 10/9 | CVD | Aerobic; 30 min, 3/w – NAR | 3 m | Dyslipidemia, HT, BMI, eGFR | |
| CKD 2–4 | GFR (mL/min) from 47±14 to 55±17; p = 0.021 | |||||
| Chen et al. [12] 2010 | 94; 45/49 | CKD 2–4 | Aerobic; 30 min, 3–5/w – NAR | 3 m | Dyslipidemia, glucose | TC (mg/dL): 198±44 to 161±37; p < 0.001 |
| Balakrishnan et al. [26] 2010 | 23; 13/10 | CKD 3–4 | Resistance; 45 min, 3/w – AR | 3 m | BMI, albuminuria, eGFR | ---- |
| Gregory et al. [28] 2011 | 21; 10/11 | CKD 2–4 | Aerobic + resistance + nutrition counselling; 55 min, 3/w – AR | 12 m | BMI and eGFR | ---- |
| Mustata et al. [29] 2011 | 20; 10/10 | T2DM (50%) | 2 aerobic session + 1 home based; 20–60 min, 2–3/w – AR | 12 m | BMI, dyslipidemia, and eGFR | ---- |
| CKD 3–4 | ||||||
| Headley et al. [27] 2012 | 21; 10/11 | T2DM | Aerobic: 3/w x 24 w + resistance: 2/w x 24 w – NAR | 12 m | Dyslipidemia, HT, BMI, eGFR, proteinuria | ---- |
| CKD 2–4 | ||||||
| Kosmadakis et al. [18] 2012 | 32; 18/14 | CKD 4 | Aerobic, 30 min, 5/w – NAR | 6 m | BMI, HT, dyslipidemia, eGFR | BMI (kg/m2): 27.3±1.2 to 26.9±1; p < 0.05 |
| Baria et al. [22] 2014 | 27; 18/9 | CKD 3–4 | Aerobic; 30 min, 3/w – AR | 3 m | HT; BMI, eGFR, proteinuria | ---- |
| Headley et al. [15] 2014 | 46; 25/21 | CKD 3 | Aerobic; 45 min, 3/w – NAR | 4 m | BMI, TC, HT eGFR, proteinuria | ---- |
| Aoike et al. [20] 2014 | 29; 14/15 | CKD 3–4 | Incremental aerobic home-based; 30 min, 3/w – AR | 3 m | HT; BMI; HbA1c, eGFR, proteinuria | HT (mm Hg): 133 to 119 and 83 to 76; p < 0.05 |
| Greenwood et al. [32] 2015 | 18; 8/10 | CKD 3–4 | Aerobic + resistance; 45 min, 3/w – AR | 6–12 m | Dyslipidemia, HT, BMI, eGFR | BMI (kg/m2): 27.5±3.5 to 25±3.5; p = 0.01 |
| Van Craenenbroeck et al. [16] 2015 | 40; 19/21 | CKD 3–4 | Aerobic; 30 min, 5/w, 10 min 4/d – NAR | 3 m | Dyslipidemia, HT, BMI, eGFR | ---- |
| Howden et al. [13] 2015 | 72; 36/36 | CKD 3–4 | Aerobic + resistance; 5/w, 30 min/d – NAR | 6–12 m | Dyslipidemia, HT, BMI, HbA1c, glucose, eGFR, proteinuria | BMI (kg/m2): 32.5±7 to 32±7; p < 0.05 |
| Leehey et al. [19] 2016 | 32; 14/18 | T2DM | Aerobic and resistance; 45 min, 3/w/3m + 40 w home-based – NAR | 3–12 m | Dyslipidemia, HT, BMI eGFR, proteinuria | ---- |
| CKD 2–4 | ||||||
| Miele et al. [14] 2017 | 46; 25/21 | CKD 3 | Aerobic; 15–55 min, 3/w – NAR | 4 m | Dyslipidemia, HT, BMI eGFR | ---- |
| Gomes et al. [17] 2017 | 39; 24/15 | CKD 3–4 | Aerobic; 30 min, 3–5/w + 10 min every 4 w – NAR | 8 m | BMI, eGFR, proteinuria | ---- |
| Hiraki et al. [21] 2017 | 28; 14/14 | CKD 3–4 | Aerobic; 30 min, 5/w – AR | 12 m | eGFR, proteinuria | ---- |
| (a) Randomized clinical trial | ||||||
|---|---|---|---|---|---|---|
| Author | N (E/C) | Patients | Exercise – adherence | Time | Outcomes | |
| metabolic/renal | improvements | |||||
| Clyne et al. [31] 1991 | 19; 10/9 | CKD 4 | Supervised calisthenics; 45 min, 3/w – AR | 3 m | HbA1c, HT, eGFR | ---- |
| Heiwe et al. [25] 2001 | 25; 16/9 | CKD 2–4 | Strength (60% 1-RM) training 3/w – AR | 3 m | BMI, measured renal function, proteinuria | ---- |
| Castaneda et al. [24] 2001 | 26; 14/12 | CKD 2–4 | Strength (80% RM); 45 min, 3/w – AR | 3 m | BMI, dyslipidemia eGFR, proteinuria | ---- |
| Pechter et al. [23] 2003 | 26; 17/9 | CKD 3–4 | Aerobic (swimming); 30 min, 2/w – NAR | 3 m | BMI, HT, dyslipidemia, proteinuria, eGFR | HT: 147 to 139 and 87 to 84 (p < 0.05)Proteinuria (g): 0.7±0.2–0.4±0.2, p < 0.05 |
| Heiwe et al. [33] 2005 | 18; 12/6 | CKD 2–4 | Strength; 45 min, 3/w – NAR | 3 m | Measured renal function, proteinuria | ---- |
| Leehey et al. [34] 2009 | 11; 7/4 | CKD 2–4 | Supervised for 6 w + home based 18 w aerobic ex. 30–40 min, 3/w – AR | 2–6 m | BMI, HT, dyslipidemia, HbA1c eGFR, proteinuria | ---- |
| Toyama et al. [30] 2010 | 19; 10/9 | CVD | Aerobic; 30 min, 3/w – NAR | 3 m | Dyslipidemia, HT, BMI, eGFR | |
| CKD 2–4 | GFR (mL/min) from 47±14 to 55±17; p = 0.021 | |||||
| Chen et al. [12] 2010 | 94; 45/49 | CKD 2–4 | Aerobic; 30 min, 3–5/w – NAR | 3 m | Dyslipidemia, glucose | TC (mg/dL): 198±44 to 161±37; p < 0.001 |
| Balakrishnan et al. [26] 2010 | 23; 13/10 | CKD 3–4 | Resistance; 45 min, 3/w – AR | 3 m | BMI, albuminuria, eGFR | ---- |
| Gregory et al. [28] 2011 | 21; 10/11 | CKD 2–4 | Aerobic + resistance + nutrition counselling; 55 min, 3/w – AR | 12 m | BMI and eGFR | ---- |
| Mustata et al. [29] 2011 | 20; 10/10 | T2DM (50%) | 2 aerobic session + 1 home based; 20–60 min, 2–3/w – AR | 12 m | BMI, dyslipidemia, and eGFR | ---- |
| CKD 3–4 | ||||||
| Headley et al. [27] 2012 | 21; 10/11 | T2DM | Aerobic: 3/w x 24 w + resistance: 2/w x 24 w – NAR | 12 m | Dyslipidemia, HT, BMI, eGFR, proteinuria | ---- |
| CKD 2–4 | ||||||
| Kosmadakis et al. [18] 2012 | 32; 18/14 | CKD 4 | Aerobic, 30 min, 5/w – NAR | 6 m | BMI, HT, dyslipidemia, eGFR | BMI (kg/m2): 27.3±1.2 to 26.9±1; p < 0.05 |
| Baria et al. [22] 2014 | 27; 18/9 | CKD 3–4 | Aerobic; 30 min, 3/w – AR | 3 m | HT; BMI, eGFR, proteinuria | ---- |
| Headley et al. [15] 2014 | 46; 25/21 | CKD 3 | Aerobic; 45 min, 3/w – NAR | 4 m | BMI, TC, HT eGFR, proteinuria | ---- |
| Aoike et al. [20] 2014 | 29; 14/15 | CKD 3–4 | Incremental aerobic home-based; 30 min, 3/w – AR | 3 m | HT; BMI; HbA1c, eGFR, proteinuria | HT (mm Hg): 133 to 119 and 83 to 76; p < 0.05 |
| Greenwood et al. [32] 2015 | 18; 8/10 | CKD 3–4 | Aerobic + resistance; 45 min, 3/w – AR | 6–12 m | Dyslipidemia, HT, BMI, eGFR | BMI (kg/m2): 27.5±3.5 to 25±3.5; p = 0.01 |
| Van Craenenbroeck et al. [16] 2015 | 40; 19/21 | CKD 3–4 | Aerobic; 30 min, 5/w, 10 min 4/d – NAR | 3 m | Dyslipidemia, HT, BMI, eGFR | ---- |
| Howden et al. [13] 2015 | 72; 36/36 | CKD 3–4 | Aerobic + resistance; 5/w, 30 min/d – NAR | 6–12 m | Dyslipidemia, HT, BMI, HbA1c, glucose, eGFR, proteinuria | BMI (kg/m2): 32.5±7 to 32±7; p < 0.05 |
| Leehey et al. [19] 2016 | 32; 14/18 | T2DM | Aerobic and resistance; 45 min, 3/w/3m + 40 w home-based – NAR | 3–12 m | Dyslipidemia, HT, BMI eGFR, proteinuria | ---- |
| CKD 2–4 | ||||||
| Miele et al. [14] 2017 | 46; 25/21 | CKD 3 | Aerobic; 15–55 min, 3/w – NAR | 4 m | Dyslipidemia, HT, BMI eGFR | ---- |
| Gomes et al. [17] 2017 | 39; 24/15 | CKD 3–4 | Aerobic; 30 min, 3–5/w + 10 min every 4 w – NAR | 8 m | BMI, eGFR, proteinuria | ---- |
| Hiraki et al. [21] 2017 | 28; 14/14 | CKD 3–4 | Aerobic; 30 min, 5/w – AR | 12 m | eGFR, proteinuria | ---- |
| (b) Non-randomized studies | ||||||
|---|---|---|---|---|---|---|
| Author | N | Patients | Exercise – Adherence | Time | Outcomes | |
| metabolic/renal | improvements | |||||
| Eidemark et al. [35] 1997 | 25 | CKD 2–4 | Aerobic; 60 min, 7/w – NAR | 18–20 m | HT, dyslipidemia, eGFR | ---- |
| Boyce et al. [36] 1997 | 16 | T2DM (50%) | Supervised aerobic exercise; 45 min, 3/w – AR | 4 m | BMI, HT, dyslipidemia, glucose, eGFR | ---- |
| CKD 2–4 | ||||||
| Venkataraman et al. [37] 2005 | 115 | CKD 2–4 | Aerobic exercise, 29 sessions – NAR | 3 m | BMI, HT, dyslipidemia | ---- |
| Aoike et al. [38] 2012 | 10 | CKD 2–4 | Supervised aerobic exercise; 30–45 min, 3/w – AR | 3 m | BMI, HT, glucose, HbA1c, eGFR, proteinuria | HT (mm Hg): 126 to 112 and 80 to 73 (p = 0.002 and p = 0.02) |
| Nylen et al. [39] 2015 | 128 | T2DM CKD1-3 | Supervised aerobic + resistance; 60 min, 3/w – AR | 3 m | BMI, HT, HbA1c, albuminuria, eGFR | ---- |
| Hamada et al. [40] 2015 | 47 | T2DM CKD 1–5 | Aerobic + resistance; 1–2/w, 90–120 min - NAR | 6 m | BMI, HT, dyslipidemia, proteinuria, eGFR | HT (mm Hg): 134 to 128 and 78 to 70 (p < 0.01 and p < 0.001) |
| (b) Non-randomized studies | ||||||
|---|---|---|---|---|---|---|
| Author | N | Patients | Exercise – Adherence | Time | Outcomes | |
| metabolic/renal | improvements | |||||
| Eidemark et al. [35] 1997 | 25 | CKD 2–4 | Aerobic; 60 min, 7/w – NAR | 18–20 m | HT, dyslipidemia, eGFR | ---- |
| Boyce et al. [36] 1997 | 16 | T2DM (50%) | Supervised aerobic exercise; 45 min, 3/w – AR | 4 m | BMI, HT, dyslipidemia, glucose, eGFR | ---- |
| CKD 2–4 | ||||||
| Venkataraman et al. [37] 2005 | 115 | CKD 2–4 | Aerobic exercise, 29 sessions – NAR | 3 m | BMI, HT, dyslipidemia | ---- |
| Aoike et al. [38] 2012 | 10 | CKD 2–4 | Supervised aerobic exercise; 30–45 min, 3/w – AR | 3 m | BMI, HT, glucose, HbA1c, eGFR, proteinuria | HT (mm Hg): 126 to 112 and 80 to 73 (p = 0.002 and p = 0.02) |
| Nylen et al. [39] 2015 | 128 | T2DM CKD1-3 | Supervised aerobic + resistance; 60 min, 3/w – AR | 3 m | BMI, HT, HbA1c, albuminuria, eGFR | ---- |
| Hamada et al. [40] 2015 | 47 | T2DM CKD 1–5 | Aerobic + resistance; 1–2/w, 90–120 min - NAR | 6 m | BMI, HT, dyslipidemia, proteinuria, eGFR | HT (mm Hg): 134 to 128 and 78 to 70 (p < 0.01 and p < 0.001) |
AR, adherence report; BMI, body mass index; C, control group; CKD, chronic kidney disease; CVD, cardiovascular disease; D, day; E, exercise group; eGFR, estimated glomerular filtration rate; HbA1c, glycated haemoglobin; HT, hypertension; M, month; NAR, no adherence report; TC, total cholesterol; T2DM, type 2 diabetes mellitus; W, week.
Exercise Intervention. Aerobic training was the prescription of choice in most studies, and the others added resistance or strength training. Aerobic exercise included brisk walking and cycling varying from 30 to 60 min based on VO2max (40–80%). Frequency, intensity, and time were generally fixed. Only 4 studies gradually increased the intervention. Resistance training included free-weight strength exercises of 10–15 reps divided into 2–3 sets using large muscle groups based on maximum repetition (RM).
Adherence to Exercise. Supervised sessions on site were used in 11 studies (∼50%), adherence was self-reported in 7 studies (30%), and 5 (20%) studies did not report any adherence evaluation.
Effects of Exercise on Metabolic Outcomes. In general, no major changes in body weight, lipid levels, and BP were observed. Three studies found significance in BMI (p < 0.05) [13, 18, 32], 2 in BP (p < 0.05) [20, 23], and 1 in total cholesterol (p < 0.001) [12]. Finally, no major changes in HbA1c were observed in the studies including diabetic patients.
Effects of Exercise in Renal Outcomes. No study found a significant reduction in urinary protein excretion except the study by Pechter et al. (0.7 (g) ± 0.2–0.4 ± 0.2, p < 0.05) [23]. Most of the studies did not find major changes in estimated GFR during follow-up with the exception of one: 47 (mL/min) ± 14–55 ± 17; p = 0.021 [30].
Prospective Non-Randomized Studies
General Description. A total of six studies (shown in Table 1b), including 341 patients with CKD stages 2–4, evaluated the impact of exercise in CKD [35‒40]. Most studies had an exploratory design with a limited number of patients, i.e., 20–40, except for 2 that enrolled >100 patients. In general, the studies included overweight or obese patients with low physical activity or sedentarism and 3 of them added patients with diabetes.
Exercise Intervention. Aerobic exercise alone was the intervention of choice in 4 of the studies, whereas the combination of aerobic and resistance training was chosen in the other two. Aerobic exercise consisted mainly of brisk walking. Time and frequency were fixed, i.e., 30 min per day and 3 times per week. No study gradually increased the intervention. Resistance training consisted of free-weight strength exercise of 10–15 reps in 1–3 sets using large muscle groups. In general, the frequency was twice per week. Most studies evaluated exercise capacity by VO2max. The intensity was based on VO2max and varied from 50 to 80% with a received perceived exertion (RPE) from 12 to 15. The follow-up of the studies was short: 3–6 months, and only one study lasted 20 months [35].
Adherence. Objective measures of adherence to exercise were reported in half of the studies. These include supervised sessions either by a health care professional and the use of an activity tracker [35‒40]. In the other half, self-reported adherence was used [35, 37, 40].
Effects of Exercise in Metabolic Outcomes. Most studies evaluated changes in BP (6–100%), weight (5–85%), dyslipidemia (4–65%), and glucose (3–50%). Twelve studies analysed changes in BMI, and no significant results were found. The effect of exercise on BP (mm Hg) was significant in 2 studies carried out by Hamada et al. [40]: systolic blood pressure (SBP) from 134 ± 19 to 128 ± 17 and diastolic blood pressure (DBP) from 78 ± 20 to 70 ± 21 (p < 0.01 and p < 0.001); and Aoike et al. [38]: SBP from 126 ± 8 to 112 ± 9 and DBP from 80 ± 5 to 73 ± 7 (p = 0.002 and p = 0.02). Finally, in the three studies that included diabetic patients, only one observed a significant reduction in HbA1c (%) of around 1% [39].
Effects of Exercise in Renal Outcomes. Changes in albuminuria or proteinuria were evaluated in 3 of 6 studies (50%) and those in GFR in 5 of 6 (85%). No study found major changes in proteinuria and renal function during follow-up. Moreover, Boyce et al. [36] showed that exercise intervention could not prevent eGFR decline over time (from 25.3 ± 12 to 21.8 ± 13.2 mL/min; p < 0.001).
Renal Transplantation
Randomized Clinical Trials
A total of eight clinical trials (shown in Table 2) including 431 patients compared the effect of therapeutic exercise versus standard clinical care [41‒48] in BMI (7–90%), BP (5–65%), lipid profile (4–50%), glucose (2–25%), and renal function (3–40%). Most of the studies had a small number of cases, i.e., 20–45 patients, and only 2 included around 100 patients [41, 42]. Most clinical trials had a short duration, that is, 1–4 months, while 2 studies had a follow-up of 12 months. Finally, 2 studies specifically evaluated patients with posttransplant diabetes mellitus (PTDM) [43, 47].
Exercise training in renal transplant patients: (a) randomized clinical trials and (b) non-randomized studies
| (a) Randomized clinical trials | |||||
|---|---|---|---|---|---|
| Author | N (E/C) | Exercise – Adherence | Time | Outcomes | |
| metabolic/renal | improvements | ||||
| Painter et al. [41] 2002 | 97; 54/43 | Aerobic; 30 min, 4 d/w – AR | 12 m | Body composition, BMI | ---- |
| Painter et al. [42] 2003 | 96; 51/45 | Aerobic; 30–45 min, 3 d/w – NAR | 12 m | Dyslipidemia, HT, BMI | ---- |
| Juskowa et al. [43] 2006 | 69; 32/37 | Aerobic; 30 min, 7 d/w – AR | 1 m w | Dyslipidemia, HT, BMI, glucose, albuminuria | TC (mmol/L): 5.5 to 7; p = 0.001. Glucose (mg/dL): 102 to 83; p = 0.01 |
| Tzvetanov et al. [48] 2014 | 17; 9/8 | Aerobic; 30 min + nutrition guidance, 3 d/w – AR | 3 m | BMI, eGFR | eGFR: 47.5 to 55.5±18.6; p = 0.06 |
| Pooranfar et al. [45] 2014 | 44; 29/15 | Aerobic; 60–90 min, 3 d/w – AR | 2.5 m | Dyslipidemia, BMI | TG, TC, and LDL; p < 0.05 |
| Greenwood et al. [44] 2015 | 46; 26/20 | Aerobic or resistance; 30–60 min, 3 d/w – AR | 3 m | BMI, HT, eGFR | ---- |
| Karelis et al. [47] 2016 | 20; 10/10 | Aerobic; 45–60 min; 3 d/w – NAR | 4 m | Dyslipidemia, HT, BMI, OGTT, body composition | ---- |
| O´Connor et al. [46] 2016 | 42; 22/20 | Aerobic or resistance; 30–60 min, 3 d/w – NAR | 3 m | HT, BMI, eGFR | ---- |
| (a) Randomized clinical trials | |||||
|---|---|---|---|---|---|
| Author | N (E/C) | Exercise – Adherence | Time | Outcomes | |
| metabolic/renal | improvements | ||||
| Painter et al. [41] 2002 | 97; 54/43 | Aerobic; 30 min, 4 d/w – AR | 12 m | Body composition, BMI | ---- |
| Painter et al. [42] 2003 | 96; 51/45 | Aerobic; 30–45 min, 3 d/w – NAR | 12 m | Dyslipidemia, HT, BMI | ---- |
| Juskowa et al. [43] 2006 | 69; 32/37 | Aerobic; 30 min, 7 d/w – AR | 1 m w | Dyslipidemia, HT, BMI, glucose, albuminuria | TC (mmol/L): 5.5 to 7; p = 0.001. Glucose (mg/dL): 102 to 83; p = 0.01 |
| Tzvetanov et al. [48] 2014 | 17; 9/8 | Aerobic; 30 min + nutrition guidance, 3 d/w – AR | 3 m | BMI, eGFR | eGFR: 47.5 to 55.5±18.6; p = 0.06 |
| Pooranfar et al. [45] 2014 | 44; 29/15 | Aerobic; 60–90 min, 3 d/w – AR | 2.5 m | Dyslipidemia, BMI | TG, TC, and LDL; p < 0.05 |
| Greenwood et al. [44] 2015 | 46; 26/20 | Aerobic or resistance; 30–60 min, 3 d/w – AR | 3 m | BMI, HT, eGFR | ---- |
| Karelis et al. [47] 2016 | 20; 10/10 | Aerobic; 45–60 min; 3 d/w – NAR | 4 m | Dyslipidemia, HT, BMI, OGTT, body composition | ---- |
| O´Connor et al. [46] 2016 | 42; 22/20 | Aerobic or resistance; 30–60 min, 3 d/w – NAR | 3 m | HT, BMI, eGFR | ---- |
| (b) Non-randomized studies | |||||
|---|---|---|---|---|---|
| Violan et al. [49] 2002 | 12 | Aerobic; 50 min, 3 d/w – NAR | 6 m | HT, body composition | ---- |
| Sharif et al. [50] 2008 | PTDM | Aerobic; 30 min, 4 d/w – NAR | 6–12 m | OGTT, dyslipidemia, BMI, eGFR | ---- |
| 115 | |||||
| Romano et al. [51] 2010 | 8 | Interval aerobic training; 40 min, 3d/w – AR | 2.5 m | BMI, eGFR | ---- |
| Roi et al. [52] 2014 | 26 | Personalized aerobic training; 3 d/w – AR | 12 m | BMI, proteinuria, eGFR | BMI (kg/m2): 24.2±3.5 to 23.9±3.9; p < 0.05 |
| Wang et al. [53] 2014 | 9 | Video gaming; 30 min, 3 d/w – NAR | 2 m | BMI, HT | ---- |
| Galanti et al. [54] 2016 | 14 | Aerobic; 30–45 min, 3 d/w – AR | 6 m | BMI, HT | ---- |
| Morales et al. [55] 2023 | 27 | Incremental aerobic training; 30–60 min+strength, 5 d/w – AR | 12 m | OGTT, dyslipidemia, BMI, HT, insulin sensitivity, HbA1c, eGFR | OGTT (0–120′ mg/dL): 102.13±11 to 86.75±6.9–154.44±30 to 113.0±23.1; p = 0.006 and 0.002, respectively. TG (mg/dL): 153.9±61.1 to 95.7±26.6; p = 0.016. Insulin sensitivity (Matsuda): 4.3 [2.8–6.7] to 6.5 [6–12]; p = 0.001 |
| (b) Non-randomized studies | |||||
|---|---|---|---|---|---|
| Violan et al. [49] 2002 | 12 | Aerobic; 50 min, 3 d/w – NAR | 6 m | HT, body composition | ---- |
| Sharif et al. [50] 2008 | PTDM | Aerobic; 30 min, 4 d/w – NAR | 6–12 m | OGTT, dyslipidemia, BMI, eGFR | ---- |
| 115 | |||||
| Romano et al. [51] 2010 | 8 | Interval aerobic training; 40 min, 3d/w – AR | 2.5 m | BMI, eGFR | ---- |
| Roi et al. [52] 2014 | 26 | Personalized aerobic training; 3 d/w – AR | 12 m | BMI, proteinuria, eGFR | BMI (kg/m2): 24.2±3.5 to 23.9±3.9; p < 0.05 |
| Wang et al. [53] 2014 | 9 | Video gaming; 30 min, 3 d/w – NAR | 2 m | BMI, HT | ---- |
| Galanti et al. [54] 2016 | 14 | Aerobic; 30–45 min, 3 d/w – AR | 6 m | BMI, HT | ---- |
| Morales et al. [55] 2023 | 27 | Incremental aerobic training; 30–60 min+strength, 5 d/w – AR | 12 m | OGTT, dyslipidemia, BMI, HT, insulin sensitivity, HbA1c, eGFR | OGTT (0–120′ mg/dL): 102.13±11 to 86.75±6.9–154.44±30 to 113.0±23.1; p = 0.006 and 0.002, respectively. TG (mg/dL): 153.9±61.1 to 95.7±26.6; p = 0.016. Insulin sensitivity (Matsuda): 4.3 [2.8–6.7] to 6.5 [6–12]; p = 0.001 |
AR, adherence report; BMI, body mass index; C, control group; D, day; E, exercise group; eGFR, estimated glomerular filtration rate; HT, hypertension; LDL, low-density lipoprotein; M, months; NAR, no adherence report; PTDM, posttransplant diabetes mellitus; TC, total cholesterol; TG, triglycerides; W, week.
Exercise Intervention. Aerobic exercise (brisk walking, cycling) was the intervention of choice in all studies; 2 cases used a combination of aerobic and resistance training and one study added nutritional counselling. Time and frequency varied from 30 to 60 min per day and 3–5 times per week. Resistance training includes free-weight exercises of large muscle groups and lower and upper limbs. Most studies (75%) evaluated exercise capacity using VO2max, and the intensity of prescription was based on it, 40–80%.
Adherence to Exercise. It was evaluated only in five of the studies (5/8, 65%) by supervised sessions on site [41, 43‒45, 48]. In the others, no reported adherence was collected [42, 46, 47].
Effects of Exercise on Metabolic Outcomes. No significant changes were found in weight, body composition, BP, and glucose levels. Only two studies found a reduction in dyslipidemia with a significance of p < 0.05 [45] and p = 0.001 [43]. Finally, another study found a significant reduction in glucose levels (mg/dL): from 102 to 83; p = 0.01 [43].
Effects of Exercise on Renal Outcomes. Only one study evaluated the changes in proteinuria, and no significant results were found. Renal function was estimated in 3 studies, and one of them found remarkable results after the intervention: eGFR (mL/min/1.73 m2) from 55 ± 19 in the exercise group versus 39 ± 19 in the control group; p = 0.06) [48].
Non-Randomized Studies
A total of seven studies (shown in Table 2) including 184 patients evaluated the effect of exercise on renal and metabolic outcomes [49‒55]. Of relevance, 2 studies were specifically designed in patients with prediabetes or PTDM [50, 55]. Most studies included a small number of patients, i.e., 10–27 subjects, and only one included more than 100 cases. Follow-up was short for most of the studies: 2–6 months (4–60%), whereas the others (3–40%) ranged from 6 to 12 months.
Exercise Intervention. Aerobic exercise was the intervention selected in most studies (5∼85%), and one study used only active video gaming. Aerobic exercise was either brisk walking or jogging. Time and frequency were fixed, i.e., 30–60 min per day 3–5 times per week. Only 2 studies included a personalized exercise prescription based on health care decision progress [52, 55]. Exercise capacity was evaluated by VO2max in half of the studies, varying from 40 to 60%, and the intensity of prescription was based on RPE.
Adherence to Exercise. It was evaluated in 4 of the studies (4–60%) by supervised sessions on site [51, 52, 54, 55]. In the other studies, no objective measures were reported.
Effects of Exercise in Metabolic Outcomes. No study found changes in body composition and BP. One study made in patients with prediabetes found significant changes in dyslipidemia (p = 0.016) [55]. A study observed changes in BMI (kg/m2): 24.2 ± 3.5 to 23.9 ± 3.9; p < 0.05 [52]. Of relevance, one study showed an amelioration of hyperglycemia, reducing the 2-h postprandial glucose levels from 10.2 to 8.7 mmol/L (15% reduction) [50]. Finally, the study carried out in renal transplant patients with prediabetes found significant changes in insulin sensitivity (Matsuda index, p = 0.001) and oral glucose tolerance test (0–120) (p = 0.006 and 0.002) [55].
Effects of Exercise on Renal Outcomes. No study found changes in proteinuria or renal function.
Discussion
We evaluated the effect of exercise training on renal and metabolic outcomes in patients with renal disease. A total of 44 [12‒55] studies with 1,700 subjects including renal transplant patients were analysed. Most studies did not show a major effect of exercise on albuminuria/proteinuria, GFR, obesity, or MS. According to our analysis, the beneficial role of exercise in patients with CKD remains to be determined.
These results are intriguing and deserve special attention. Most studies include patients with conditions in which exercise has a proven therapeutic role: overweight/obesity and MS. However, in the studies evaluated in the review, the effect of exercise was mild, if any, in terms of weight reduction and changes in metabolic parameters. The causes of this finding are not clear. In patients with CKD, exercise is well demonstrated to improve physical parameters [56, 57]; however, CKD is a chronic syndrome that can induce resistance to the effects of exercise not related to physical performance and cardiorespiratory function. However, to the best of our knowledge, this hypothesis has not been tested so far.
Therapeutic exercise is a complex procedure, with many complementary aspects, all relevant to the efficacy of the treatment. These include (1) type of exercise, (2) frequency, (3) intensity and duration, (4) accommodation during follow-up, (5) efficacy of treatment, (6) safety, and (7) adherence/compliance [58]. Most studies prescribed aerobic training alone, while some combined it with resistance training. This is comparable to studies using therapeutic exercise to prevent diabetes or reduce weight in the general population [8‒10]. Thus, the prescription of exercise seemed appropriate in the studies evaluated.
A major aspect of exercise prescription is that it must be adapted to individual characteristics. Previous training history, muscle mass, age, gender, physical, or psychological barriers are the main factors to consider in the design of a training programme. Clearly, a tall subject, male of 45 years of age with good muscle mass composition and previous history of training needs a different baseline prescription than a short patient with lower muscle mass, particularly in the lower limbs. Applying a standard prescription in terms of intensity, frequency, mode, and duration may be sufficient to some subjects and insufficient to others. Also, the repetition of movements with the same intensity and frequency may induce muscle adaptation or accommodation. This phenomenon may diminish the expected effect of exercise in the medium and long term. Thus, exercise training must be regularly adapted (increase intensity or frequency) to achieve the goals of the specific treatment. Most of the studies applied the same prescription to all patients, which was not adapted or increased during follow-up. This issue may have played a role in the limited effectiveness of exercise in renal and metabolic outcomes.
Most studies have a short follow-up, that is, 3–6 months. The therapeutic role of exercise in MS and CKD is not clear. It may be plausible that exercise acts through the amelioration of risk factors like obesity, hyperglycemia, dyslipidemia, insulin resistance, and hypertension. However, the time needed to observe a positive impact of these metabolic changes in renal function and albuminuria is unknown. Possibly, short time studies may not be able to evaluate the effect of weight reduction and changes in MS traits on renal outcomes.
Therapeutic exercise is particularly dependent on patient adherence. Several limitations to physical activity have been described: low motivational status, self-efficacy, previous negative experiences with training, lack of coping skills, reduced access to physical activity facilities, low social skills, lack of cultural support, and time barriers [59]. In fact, noncompliance to exercise could be responsible for 40–60% of treatment failure. Thus, measures designed to improve compliance must be implemented simultaneously with training prescription to ensure the achievement of the goals expected by exercise. Only half of the studies indicated adherence measures, most of them non-objective and self-reported by the patient. This may also have played a role in the limited results of the studies. Few adverse events related to exercise have been reported, suggesting that moderate intensity regular exercise training may be safe in patients with CKD. This is in line with other studies in the general population or in patients with diabetes.
Finally, in line with our research, previous studies observed that in patients with CKD, the effect of therapeutic exercise in metabolic and renal outcomes traits is still to be determined. However, in some studies, BMI, BP, dyslipidemia, and renal function improved with therapeutic exercise [56, 57, 60, 61]. Specifically, in renal transplantation, some studies indicated that there is an association between physical activity and slower decline of GFR.
Conclusion
In patients with CKD, obesity, and MS, the evidence on the effect of exercise in both metabolic and renal outcomes is still to be determined. Most studies are exploratory in nature, with preliminary results that need further evaluation. Clearly, this limits the design of clinical trials in this field, in particular, to calculate the number of patients to treat to observe an effect of exercise. Simple exercise training – aerobic and resistance – appears to be safe in this population. More research in this important field is needed to determine the efficacy of this therapeutic approach in patients with renal disease.
Acknowledgments
The authors thank the Instituto de Salud Carlos III of the Spanish Ministry of Health for the PFIS Grant of Raúl Morales Febles (PFIS FI 17/00303) and the Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC) for the grants FIISC 20/49 and ENF 21/13. Particularly, to the ERA EDTA Working Group Diabesity CME meeting invitation “Treatment of diabetes, obesity, and assessment of end organ damage” in collaboration with DDA in Copenhagen in June 2021 in Nephron.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
The Instituto de Salud Carlos III of the Spanish Ministry of Health for the PFIS Grant of Raúl Morales Febles (PFIS FI 17/00303) and the Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC) for the grants FIISC 20/49 and ENF 21/13.
Author Contributions
Esteban Porrini and Raúl Morales Febles designed the study and wrote the review. Raúl Morales Febles, Esteban Porrini, Domingo Marrero Miranda, Coriolano Cruz Perera, Laura Díaz Martín, Ana Elena Rodríguez-Rodríguez, Amelia Remedios González Martín, and Daniel Javier Sánchez Báez interpreted and checked the data for the work, supervised the draft for important intellectual content, and approved the final version of the manuscript.
