Solid organ transplantation is the treatment of choice for the majority of patients with end-stage organ failure, but it is not without complications. Weight gain, muscle weakness, reduced exercise tolerance, and decreased aerobic capacity are prevalent among solid organ transplant recipients because of prolonged bed rest, inactivity, immunosuppression use, and resultant muscle deconditioning (1–3). Metabolic syndrome, a complication of insulin resistance and a sedentary lifestyle, are also common after solid organ transplantation (4–6). A recent observational study reported a significant increase in the incidence of metabolic syndrome after liver transplantation, from 5.1% before transplantation to 50% after transplantation, with an associated increase in cardiovascular morbidity by at least threefold compared with those without metabolic syndrome (7). Cardiovascular disease is also a major cause of mortality and morbidity in other solid organ transplant recipients (8). The 5-year mortality from cardiovascular disease in cardiac and kidney transplant recipients are 30% and 15%, respectively (9, 10), with an overall mortality rate of at least 5- to 10-fold greater than the general population. With improvements in graft survival and infection deaths over the past two to three decades, death with a functioning graft, due to cardiovascular disease, is now a critical issue for solid organ transplant recipients.
Despite the magnitude and the severity of cardiovascular disease in the transplant population, there is a paucity of high-quality evidence regarding interventions for prevention and treatment. Solid organ transplant recipients have been systematically excluded from most trials of physical therapies (11). Exercise training consisting of a structured program of physical activity reduces cardiovascular risk factors in the nontransplantation setting (12). However, results of the few observational studies that have assessed the outcomes of exercise training in the transplant population are contradictory, which may be due to confounding from the effects of immunosuppression and other comorbidities or residual selection bias (13–15). Despite this apparent lack of evidence, most clinical practice guidelines recommend exercise training as standard care for solid organ transplant recipients (16). The aim of our study was to determine the health benefits and harms of supervised exercise training programs in solid organ transplant recipients.
Of the 506 records identified electronically, 102 were duplicates (see Fig. 1) and 350 were ineligible after abstract review. The remaining 54 articles were retrieved and reviewed in full text form, with 15 randomized controlled trials (RCTs) found to be eligible and thus included. We contacted authors of three included RCTs for further detailed information and received information from two trials.
Characteristics of Included Studies
The baseline characteristics of the studies are shown in Appendix 1 (see SDC, http://links.lww.com/TP/A757). A total of 643 patients from 15 RCTs (9 cardiac transplants [n=250 patients], 2 kidney transplants [n=164 patients], 3 lung transplants [n=110 patients], and 1 liver transplant [n=119 patients]) were included. Of the 15 included studies, only 14 trials provided extractable information for the meta-analyses. There were no found studies of pancreas, intestine, or combined solid organ transplant recipients such as heart/lung or kidney/pancreas.
Risk of Bias in Included Trials
Appendix 2 (see SDC, http://links.lww.com/TP/A757) shows the risk of bias assessment of all the included trials. Three of 15 (20%) trials were judged as high risk of bias. Allocation concealment was adequate in 6 of 15 (40%) trials and unclear in 9 (60%). None of the participants were blinded to the interventions in any of the studies. Investigators were blinded in only 3 (20%) trials. Methods of randomization were reported in only 4 (27%) studies. Publication bias was assessed using funnel plots, but there were insufficient studies to evaluate for such bias.
Clinical outcomes are summarized in Table 1. Major outcomes included exercise capacity such as maximal oxygen consumption (VO2 max); cardiopulmonary parameters such as resting heart rate and systolic and diastolic blood pressures; and serum cholesterol and bone mineral density (BMD). No studies were reported on cardiovascular-related events and cardiovascular or all-cause mortality. Given the limited number of studies that reported other specific outcomes such as quality of life (QoL) and body composition, the majority of findings for these outcomes were drawn from our systematic review instead of the meta-analysis. There was also statistically significant heterogeneity between the included studies. Studies were drawn predominantly from four different solid organ transplant populations. Not only were there differences between organ groups, there was also substantial variability in the types (aerobic, resistance, or both) of exercise training, the prescribed exercise intensity, duration of the exercise (4–84 weeks) intervention, and the time of intervention after surgery (immediately after discharge to >4 years after surgery).
A statistically significant improvement in VO2 max (6 trials, 175 patients, standardized mean difference [SMD], +0.77; 95% confidence interval [CI], 0.10–1.45; P=0.03; I2=77%) was observed among cardiac but not in kidney or liver transplant recipients who engaged in aerobic exercise training compared with standard care (Fig. 2). Overall, there was an increase in VO2 max among all transplant recipients (10 trials, 485 patients; SMD, +0.47; 95% CI, 0.10–0.84; P=0.01; I2=72%; Fig. 2).
Compared with no supervised training, lung recipients who engaged in 3 months of supervised exercise training postoperatively experienced an increase of 15% and 16% in the predicted VO2 max and the maximum power output (Wmax), respectively. There was also a significant increase in the predicted quadriceps strength of 16% compared with controls after a follow-up time of 9 to 12 months (17). However, no significant differences in the overall maximum oxygen capacity were observed when data from the two trials in lung transplant recipients were pooled (2 trials, 48 patients; SMD, +0.09; 95% CI, −0.80 to 0.98; P=0.84; I2=78%).
Findings from our meta-analyses also showed no significant increase in the overall peak minute ventilation (2 trials, 61 patients; mean difference [MD], +7.51 L/min; 95% CI, 7.63–22.53; P=0.33; I2=93%) or the Wmax (3 trials, 104 patients; MD, +1.44 W; 95% CI, 0.47–3.36; P=0.14; I2=92%) among cardiac transplant recipients.
There was a consistent reduction in percentage body fat associated with exercise training compared with standard carein cardiac (1 trial, 32 patients; MD, −3.40%; 95% CI, −6.66 to −0.14; P=0.04) and liver (1 trial, 119 patients; MD, −5.40%; 95% CI, −8.03 to −2.77; P<0.001) transplant recipients. The overall effect size for the reduction across both organ groups was significant (MD, −4.61%; 95% CI, −6.66 to −2.57; P<0.001; I2=0%). In addition, we found a significant increase in the lumbar BMD (g/cm2) among cardiac transplant recipients who underwent 6 months of resistance training (1 trial, 16 patients) compared with standard care. After the intervention period, patients who exercised had restored lumbar BMD to within 1% of their preoperative level, whereas the control group continued to lose lumbar BMD (−6.9%) (18). However, no significant improvements in BMD were observed in liver and lung transplant recipients who received exercise training compared with standard care (Table 1). BMD was not an included outcome in any of the trials performed in the kidney transplant populations.
A single study reported a significant increase in the serum total protein (MD, +0.99 g/dL; 95% CI, 0.78–1.20; P<0.001) and total albumin (MD, +0.90 g/dL; 95% CI, 0.64–1.16; P<0.001) between the exercise and the standard-care arms in kidney transplant recipients. Compared with standard care, there were no statistical differences in fasting serum glucose, serum cholesterol, high- or low-density lipoprotein, triglycerides levels, body mass index (BMI), lean body mass, or waist-to-hip ratio between the exercise and the standard-care groups in kidney, heart, and liver transplant recipients (19–21). A recent study conducted in the lung transplant population showed a trend of lower incidence of diabetes (6% vs. 25%; P=0.11) and fasting mean serum glucose (90 vs. 107 mg/dL; P=0.13) in the exercise group compared with the control arm. However, the effects were not statistically significant (17). In addition, no significant differences in BMI, serum cholesterol, and triglycerides were observed between the exercise and the control arms 1 year after lung transplantation (17). These studies were limited by the small number of participants and were likely underpowered to detect any significant differences between the two arms.
We found no consistent improvements in the resting heart rate (4 trials, 120 patients; MD, 1.12 beats per minute; 95% CI, −1.29 to 3.53; P=0.36), systolic blood pressure (4 trials, 109 patients; MD, −4.06 mm Hg; 95% CI, −18.82 to 10.71; P=0.59), and diastolic blood pressure (4 trials, 109 patients; MD, −1.62 mm Hg; 95% CI, −7.97 to 7.72; P=0.62) among cardiac transplant recipients who received exercise training compared with standard care. Similar to the cardiac transplant patients, exercise training in kidney transplant patients showed no significant reduction in the systolic blood pressure (1 trial, 96 patients; MD, −1.20 mm Hg; 95% CI, −9.36 to 6.96; P=0.77) and diastolic blood pressure (1 trial, 96 patients; MD, −1.20 mm Hg; 95% CI, −5.85 to 3.45; P=0.61) compared with standard care. A single-center trial conducted in lung transplant recipients reported significantly lower values for the average 24-hr ambulatory diastolic (−9.00 mm Hg [−15.14 to −2.86]) and systolic (−16.00 mm Hg [−24.67 to −7.33]; P=0.01) blood pressure in the exercise compared with the control group (17). There were insufficient studies to evaluate exercise-induced changes in the cardiopulmonary parameters among liver transplant recipients (Table 1).
Quality of Life
Six (40%) of 15 studies (3 cardiac, 2 lung, and 1 liver) assessed the QoL outcomes in solid organ transplant recipients. One trial showed significant improvement by 0.61 points on the physical domain of the World Health Organisation Questionnaire on Quality of Life among cardiac transplant recipients who received exercise training compared with standard care (22). Using the Hospital Anxiety and Depression Scales, there was significant reduction in patient-reported anxiety and depression. Using the Short Form-36 (SF-36) questionnaire, improvements in general health, bodily pain, and mental health were evident among those who underwent exercise training compared with those who did not engage in the exercise intervention (23).
Among those with lung transplants, no significant improvement in any of the QoL domains of the three QoL tools: SF-36, the German Quality of Life Profile for Chronic Diseases, and St George’s Respiratory Questionnaire were observed between exercise training and standard care (24). More recently, the study by Langer et al. (17) comparing supervised exercise training and no training in lung transplant recipients also showed no significant improvements in the levels of anxiety and depression as reported on the Hospital Anxiety and Depression Scales at 3 months and 1 year after the treatment period. On the contrary, significant changes in the self-perceived health status were observed in two of the physical component subscales (physical functioning and role functioning physical) of the SF-36 at 1 year among those who received the exercise training compared to those who received no training (17).
Adverse events, costs, compliance, graft function, cardiovascular, and all-cause mortality were not reported. Other outcomes including blood lipid profile and percent hemoglobin A1c are summarized in Table 1.
Investigation for Sources of Heterogeneity
Figures 3 shows the VO2 max among cardiac transplant recipients who received exercise training compared with no exercise training stratified by the duration of exercise intervention, the time of commencing exercise training after transplantation, the risk of bias of the included studies, and whether the patients received supervised or unsupervised training after transplantation.
Duration of Exercise Intervention
We found that the duration of intervention was an effect modifier for functional capacity in cardiac transplant recipients (P for heterogeneity=0.01). Specifically, cardiac transplant recipients who engaged in a longer period of exercise training (12–24 weeks) experienced a significant improvement in VO2 max (MD, +4.06 mL/min/kg; 95% CI, 3.02–5.09; P<0.001; I2=0%) and Wmax (MD, 26.8 W; 95% CI, 22.57–31.31; P<0.001; I2=0%), whereas those who exercised for a lesser duration (≤8 weeks) had no significant improvement in their VO2 max (MD, 1.15 mL/min/kg; 95% CI, −1.47 to 3.78; P=0.39; I2=48%) and Wmax (MD, −7.70 W; 95% CI, −20.9 to 5.53; P=0.25; I2=0%).
Supervised Versus Unsupervised Training
Supervised exercise training was undertaken in three studies (96 patients). There was significant improvement in the VO2 max among those who received supervised aerobic exercise training in cardiac transplant patients compared with standard care (MD, +4.6 mL/min/kg; 95% CI, 2.12–7.09; P<0.001; I2=0%) but not in those who engaged in home-based unsupervised regular exercise (MD, +2.17 mL/min/kg; 95% CI, −1.73 to 6.08; P=0.005; I2=83%).
Time after Transplantation
There was substantial variation in the length of time between the surgery and the commencement of the exercise program. We found that exercise training that commenced within 1 year after cardiac transplantation was associated with significant improvements in the overall VO2 max (MD, +3.91 mL/min/kg; 95% CI, 2.85–4.97; P<0.001; I2=0%) compared with standard care, whereas those who commenced the exercise program 12 months after surgery showed no significant improvement in functional capacity.
Risk of Bias
We found that studies of low and unclear risk of bias showed significant improvements in the overall VO2 max associated with exercise training compared with standard care: low risk of bias (1 trial; n=27; MD, +4.90 mL/min/kg [0.45–9.35]; P=0.03) and unclear risk of bias (4 trials; n=111; MD, +3.22 mL/min/kg [0.93–5.52]; I2=59%; P=0.006). However, this was not observed in the single study with high risk of methodologic bias.
Frequency, exercise intensity, and the types of exercise training did not affect outcomes in any of the included studies.
Our study findings suggest that regular exercise training is effective in improving exercise capacity compared with standard care in cardiac transplant recipients. Specifically, regimens that are of at least 12 weeks in duration, include supervision, and commence within 1 year after the transplant surgery appear to be the most effective. One recently conducted, randomized, controlled, trial suggests similar improvements in exercise capacity (increases in predicted VO2 max and Wmax) may be achieved through exercise training among lung transplant recipients (17). Despite favorable changes in the total body composition such as reduction in the overall body fat content among cardiac and liver transplant recipients, we identified no studies that were adequately powered to evaluate the longer-term patient important outcomes such as cardiovascular risk factors, cardiovascular, and all-cause mortality associated with structured exercise training in all solid organ transplant recipients.
Comparison With Other Studies
Reduction in exercise capacity is common after solid organ transplantation, particularly after cardiac transplantation. This reduction in exercise tolerance is in part due to the effects of immunosuppression, deconditioning due to prolonged hospital stay, graft dysfunction, and cardiac denervation (25). In cardiac transplant patients, exercise capacity is affected by denervation, which in turn reduces the overall responses to exercise compared with those in the general population. Introduction of a supervised exercise training program after cardiac transplantation, especially early after transplantation, has been consistently shown to improve the VO2 max up to 12 months after transplantation (26, 27). Our pooled analyses of these studies in the cardiac transplant population demonstrated, on average, a 10.2% increase in VO2 max among those who received structured exercise training and rehabilitation after the surgery compared with recipients who did not. However, similar benefits were not observed in other solid organ transplant recipients. The lack of observed benefits may be attributed to the differences in the types, duration, and the intensity of exercise prescriptions, because none of these trials performed in other solid organ transplant recipients included supervised aerobic training programs with durations greater than 8 weeks.
Wmax is highly correlated with the VO2 max and is also an important predictor for exercise endurance (28). All but one study performed in the cardiac transplant population reported a significant increase in Wmax (W) or physical workload among those who underwent structured exercise training. Contrary to findings from other studies, Wu et al. did not show any significant differences in functional or exercise capacity among those who received structured exercise training compared with standard care. In this study, inadequate randomization and the lack of allocation concealment have led to the imbalance of risk factors between the intervention and the control arms. Recipients in the control group (mean age, 51.6±12.8 years) were significantly younger than those who engaged in the exercise program (60.6±6.2; P<0.05), thus potentially confounding the overall effects of the intervention (22).
Reduction in exercise capacity is a particular concern for heart and lung transplant recipients who exhibit exercise capacity in the range of 40% to 60% of normal postoperatively (17, 29, 30), which may impact on overall well-being and health-related QoL. Therefore, strategies to improve exercise capacity are considered as research and clinical priorities in thoracic organ recipients. Emerging data suggest that exercise training after transplantation improves exercise capacity, as assessed by 6-min walk distance, quadriceps force, total walking time, and self-assessed level of physical function, measured out to 1 year after transplantation (17).
Apart from exercise capacity, improvement in body composition such as reduction in the proportion of total body fat was also observed in cardiac and liver transplant recipients who engaged in exercise training and cardiac rehabilitation compared with those who did not. Similar findings have been reported in studies in the nontransplantation setting, whereby a combined supervised and unsupervised program of physical and exercise training program is effective in facilitating weight reduction, reducing total body fat and the incidence of type 2 diabetes mellitus in the general population. The observed benefits are predominately driven by the amelioration of peripheral insulin sensitivity, insulin-mediated transport of glucose to muscles, increased transport of lipids to the liver, slower heart rates, and improved autonomic system functioning associated with increased aerobic fitness (31).
Strengths and Limitations
Our review has a number of strengths and limitations. Strengths include a systematic search of medical databases, data extraction and analysis, and trial quality assessment by two independent reviewers based on a prespecified protocol. Our review is limited by the small number of studies that lack longer-term follow-up to assess the efficacy and effectiveness of patient relevant rather than surrogate outcomes such as cardiovascular and all-cause mortality associated with physical and exercise training in solid organ transplant recipients. In a practical sense, it is impossible to blind patients and clinicians/investigators to the intervention of exercise training given its complexity and physical nature. This lack of blinding of assessors, in particular, may incur risk of bias in the assessment of outcomes, particularly when the assessment required some form of subjectivity.
Systematic reviews are the preferred method for summarizing evidence because they use explicit and reproducible methods to limit bias. We acknowledge that the limited number of participants in the included studies may preclude accurate assessment of heterogeneity beyond chance in our stratified analyses. Ideally, meta-regression, an extension to the subgroup analyses that allows assessments of the study characteristics on the effect estimates to be examined simultaneously, should be done to assess the independent effects of each characteristic on the overall outcome. However, this was not feasible due to the inadequate number of studies. Our subgroup analyses, although limited by the small number of participants in each of the included trials, show that the heterogeneity was partly explained by the effects of duration of the exercise intervention, whether the program was supervised or unsupervised, the risk of bias of the included studies, and the length of time after the surgery and commencement of the exercise program. Similar to findings in other settings such as those without solid organ transplants, a prolonged and sustained program in cardiac transplant recipients is important to maintain physical and psychologic improvements achieved with increased aerobic fitness (32). However, no significant differences were observed between the different exercise intensities and the number of exercise sessions per week. Compared with home-based programs, supervised exercise training with emphasis on behavioral change such as education about goal setting, self-assessment, and self-reward skills may lead to lifestyle modification and consequent longer-term outcomes such as sustainable weight loss and improved blood pressure control (33, 34).
Another limitation of this review is that 1 of 15 studies (n=15 of 643 subjects) met the inclusion criteria but did not provide sufficient data to contribute to the meta-analysis. This represents a potential source of bias.
Implications for Clinical Practice and Research
Based on the current available evidence, a program of prolonged supervised exercise training after transplantation is effective in improving the short-term exercise capacity and body composition such as total body fat in cardiac transplant recipients. Despite the observed benefits of a structured exercise training program in preventing weight gain, reducing the incidence of type 2 diabetes, and improving cardiovascular risk among the high-risk nontransplanted population, the effectiveness of such interventions among transplant recipients has not been adequately addressed in the current literature. Longer-term, well-powered studies, with sufficient sample sizes and follow-up time analyzing the effects of exercise training in all solid transplant recipients, varied by intensities, modes, durations, and frequency on hard endpoints such as improvement in cardiovascular risk factors, including hypertension, diabetes, obesity and dyslipidemia, cardiovascular mortality, as well as graft survival, harms, and adverse effects of exercise training are warranted.
Trials to date have shown that exercise training is effective in improving the exercise capacity of cardiac transplant recipients. However, data assessing the cardiovascular benefits of exercise training in other solid transplant recipients are sparse. Quality trial-based evidence of longer-term health benefits such as QoL, sustainable weight control, and graft and patient survival is needed to determine if resources should be directed to exercise programs after solid organ transplantation.
MATERIALS AND METHODS
We conducted a systematic review based on standard methods (35) and reporting in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement (35).
Data Sources and Searches
To identify RCTs of exercise training in solid organ transplant recipients, we searched MEDLINE (1948–June 2012), EMBASE (2010–2012), Transplant Library from the Centre for Evidence in Transplantation, and the Cochrane Library database (Central Register of Controlled Trials) using relevant text words and medical subject headings that included all spellings of exercise intervention, organ transplantation, physical activity, and physiotherapy (see Appendix 3, SDC, http://links.lww.com/TP/A757). The search was limited to RCTs, without age and language restriction. Reference lists from identified trials and review articles were manually scanned to identify any relevant studies. The clinicaltrials.gov Web site was also searched for randomized trials that were registered as complete but not yet published.
Two authors (M.D. and G.W.) independently reviewed titles, abstracts, and full text articles to determine study eligibility. We included RCTs if both reviewers agreed that an article described and compared the use of exercise training programs against standard care or compared two or more exercise training programs in all solid organ transplant recipients. We excluded trials comparing exercise to drug therapy or exercise and drug therapy to standard care. We included all solid organ transplant recipients (lung, liver, pancreas, heart, kidney, intestines, combined heart/lung, liver/kidney, heart/kidney, and kidney/pancreas) in the study. We excluded patients who received tissue and cell transplants such as skin, bone marrow, cornea, and islets.
Data Extraction and Quality Assessment
Published reports were obtained for each trial and information was extracted using standardized data extraction forms and imported into a spreadsheet. Studies reported in non-English language journals were translated before assessment. When more than one publication of a trial existed, only the article with the most complete data was included. Further information was requested from the corresponding authors when necessary. The methodologic quality of included studies was assessed independently by the two authors (M.D. and G.W.) using the Cochrane risk of bias tool (36). Any discrepancies were resolved by discussion with consensus agreement.
We collected data on a broad range of outcomes including cardiovascular parameters (resting and peak heart rate, systolic and diastolic blood pressures, heart rate, and blood lipid profile), exercise capacity (VO2 max, muscle strength, and Wmax [W]), body composition (serum albumin and protein, serum cholesterol, high and low lipoprotein, triglycerides levels, serum glucose levels, incidence of diabetes, weight circumferences, BMI, and waist-to-hip ratio), flexibility score (measured in centimeters), graft function (estimated glomerular filtration rate), QoL (SF-36 and Kidney Disease Quality of Life), adherence and dropout rates, adverse events, as well as cardiovascular and all-cause mortality.
Data Synthesis and Analysis
Results from individual trials were expressed as risk ratios with 95% CIs for dichotomous outcomes and continuous outcomes were expressed as MD or SMD if the same outcomes were measured in different ways. Data were combined using a random effects model. Heterogeneity was quantified using the chi-square test and I2 statistic (36) with preplanned subgroup analyses used to explore possible sources of heterogeneity, but because of insufficient data, this was not possible. Outcomes were stratified by transplanted organ (heart, kidney, lung and liver), duration and frequencies of exercise training, exercise supervision, and time commencing training after transplantation (from months to years; heart, kidney, lung, and liver). P≤0.05 was considered statistically significant. Where possible, publication bias was assessed using funnel plots (38). All analyses were conducted using Review Manager 5.
The authors thank Narelle Willis of the Cochrane Renal Group for help in coordinating this review and Gail Higgins of the Cochrane Renal Group for assistance in the development of search strategies.
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