ABSTRACT

Kidney transplantation is the treatment of choice for patients with end-stage renal disease. Next to the risk of allograft failure, major obstacles to disease-free survival after kidney transplantation include a higher incidence of cancer, infection, and cardiovascular events. Risk factors for adverse clinical outcomes include pre-existent comorbidities, the introduction of an immunodeficient status, and (lack of) lifestyle changes after transplantation. Indeed, physical inactivity and poor physical fitness are important targets to address to improve clinical outcomes after kidney transplantation. This review summarizes the current evidence on exercise training after kidney transplantation, derived from randomized controlled trials. As much as possible, results are discussed from the perspective of the Standardized Outcomes in Nephrology-Transplantation core outcomes, which were recently described as critically important outcome domains for trials in kidney transplant recipients.

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KIDNEY TRANSPLANTATION: A SPECIFIC ENTITY

Solid organ transplantation (SOT) has emerged from an experimental approach in the 20th century to now being an established treatment option for patients with end-stage organ dysfunction. Over the past decades, the field of SOT has seen considerable advances in surgical techniques and pharmacotherapy [1]. The remaining obstacles to long-term disease-free survival after SOT include allograft rejection, malignancy, infection, and a tremendously high cardiovascular (CV) risk [2–4]. Risk factors for adverse outcomes, some of them modifiable, include pre-existing conditions, the introduction of an immunodeficient status, and (lack of) lifestyle changes after transplantation. This holds for all SOT recipients, but kidney transplant recipients (KTRs) have some specific features in the light of which existing literature on SOT should be carefully interpreted.

First, about half of all incident patients with the end-stage renal disease worldwide are >65 years of age [5, 6]. This results in a higher proportion of ‘older’ KTRs compared with other SOT recipients. In the Eurotransplant countries, about one in four kidney transplantations is performed in a recipient >65 years of age which is rather uncommon for heart, lung, and pancreas transplantations. Next, advancements in dialysis techniques allow for a variable, sometimes very long, waiting time on dialysis. However, this is counterproductive, as the waiting time on dialysis negatively impacts post-transplant survival [7]. The majority of deceased-donor KTRs required a waiting time of 2– 4 years, compared with 0–5 months for liver, heart, and lung transplant recipients. This chronic disease burden has a great impact on the progression of comorbid conditions and quality of life and translates to poor physical function, a summary measure of health, and an independent predictor of mortality post-transplantation [8]. Apart from age and comorbidities, another specific challenge for KTRs is organ function after transplantation. Many KTRs have an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 1 year after transplantation, placing them in chronic kidney disease (CKD) Stage 3 or worse [9]. As such, the pre-transplant uraemic state may continue to exist, but at a decreased severity. However, KTRs are different from CKD patients without transplantation as they require immunosuppressive therapy daily. Common side effects of immunosuppressive regimens comprise hypertension, hyperlipidemia, diabetes mellitus, nephrotoxicity, and anemia. In the long run, this immunosuppressed state places the patients at a higher risk of cancer, CV disease, and infection [10].

PHYSICAL INACTIVITY AND POOR PHYSICAL FITNESS AS MODIFIABLE RISK FACTORS FOR ADVERSE CLINICAL OUTCOMES

An overview of relevant terminology is given in Table 1. Low physical activity and poor physical fitness are integral features of SOT, with a debilitating impact on quality of life [11]. In KTRs, low physical activity is associated with higher CV and all-cause mortality [12, 13]. Pre-transplantation physical activity levels predict all-cause mortality in KTRs [14] and greater physical activity in de novo KTRs is associated with improved graft function in the initial year post-transplant [15]. Although KTRs modestly improve their physical activity status compared with patients with advanced CKD, relatively few patients meet the minimum recommendations [16, 17]. The World Health Organization (WHO) recommends ≥ 150 min of moderate-intensity, ≥75 min of vigorous-intensity, or an equivalent combination of moderate- and vigorous-intensity aerobic physical activity every week [18]. Physical activity levels in KTRs are lower than in similar-aged patients with rheumatoid arthritis and osteoarthritis [13]. Different factors contribute to low physical activity levels in KTRs, both at the environmental and individual levels, such as fear of harming the graft [16, 19]. Multiple comorbidities and immunosuppressive drugs (corticosteroids in particular) impaired physical fitness are also at play [16, 20].

In line with physical activity, physical fitness does not fully normalize after transplantation [21, 22]. This adds to the vicious circle of inactivity. Many KTRs are considered sarcopenic (low muscle strength, muscle mass, and physical function/performance) [23, 24] and frail [25], which may or may not be in combination with obesity. After transplantation, an increase in cardiorespiratory fitness is seen, but peak oxygen uptake (VO2peak) remains lower than that in age-matched healthy controls [21, 26]. VO2peak is a potentially stronger predictor of mortality than smoking, hypertension, hypercholesterolemia, and type 2 diabetes [27]. In healthy adults, each 1 metabolic equivalent of task (MET; 3.5 mL/kg/min) improvement in VO2peak is associated with a 15% reduction in CV events and a 13% reduction in all-cause mortality [28].

Given their relationship with adverse clinical outcomes, physical inactivity, and physical fitness represent important targets for intervention in KTRs [26, 29–32]. In the general population, the pleiotropic health benefits of physical activity and exercise include attenuation of CV and cancer risk, as well as beneficial effects on metabolic, muscular, bone, digestive, reproductive, and mental health [33–37]. Regular exercise at moderate intensity is also associated with lower infection rates, but excessive strenuous exercise may induce immune dysfunction [38].

The current review critically revises the available evidence on the effects of exercise training programs in KTRs from randomized controlled trials (RCTs). The search strategy is given in Table 2. Interventions addressing solely physical activity are beyond the scope of this review, but physical activity and exercise training interventions are a continuum with a sustainable active lifestyle as the ultimate goal.

EFFECTS OF EXERCISE TRAINING: EVIDENCE FROM RCTS

Outcomes of interest

Seventeen RCTs (Table is provided in supplementary file) report on a wide variety of different outcomes and exercise interventions. Consensus-based identification of critically important outcome domains for trials in KTRs was recently established by the Standardized Outcomes in Nephrology-Transplantation (SONG-Tx) initiative [44]. A large sample of patients, family members, and healthcare professionals acknowledged graft health, CV disease, cancer, infection, life participation, and mortality as core outcomes critically important for all stakeholder groups. Although a thorough selection process generated an initial list of 35 outcome domains to be graded on their importance, some outcome domains relevant to the field of physical rehabilitation may have been left out. From the perspective of the rehabilitation field, physical fitness, and physical functioning are considered important outcomes. Both are closely related to mortality, CV disease, and life participation after kidney transplantation [12, 13, 26, 29–32, 45]. Next, in the evaluation of an exercise intervention, reporting exercise-induced injuries or any other adverse events is mandatory. Figure 1 gives a schematic overview of the effects of exercise training in KTRs.

Long-term (>12 months) effects of exercise training

The SONG-Tx outcomes are typically long-term outcomes, and none of them is addressed in the available studies. Only five records from four studies reported follow-up data at ~ 12 months after the start of the intervention [46–50]. Importantly, in three of four studies, the intervention rather than the follow-up itself was long-term. In the study by Painter et al. [46, 50], 167 KTRs were recruited within 1 month after transplantation to investigate the effects of 11 months of home-based aerobic exercise training versus usual care. The study was powered to detect changes in VO2peak, which significantly improved in the intervention compared with the control group. Other outcomes comprised muscle strength (improved) [46], body composition (no change) [46], quality of life (improved) [46], and CV risk factors (no change) [50]. Exercise training did not affect mortality (n =1 death in each group). Two patients allocated to usual care versus none of the patients in the training group dropped out due to graft rejection. One patient in usual care dropped out due to CV concerns, but no other CV events were reported. No significant effect of exercise training was seen on graft function as assessed with creatinine levels.

Another 12-month training study by Korabiewska et al. [47] recruited 67 recipients immediately after transplantation to investigate the effects of an exercise regimen composed of resistance, walking, breathing, coordination, and relaxation exercises. In addition to many methodological flaws, this study did not report on mortality, CV events, or any other adverse events that may have occurred. Although this study did not include clear statistical reports on graft function, reported data did not suggest any effect of exercise training on creatinine levels.

A pilot study by Tzvetanov et al. [48] in 17 de novo obese KTRs investigated the effects of 12 months of individually supervised, low-impact, low-repetition resistance training in conjunction with cognitive behavior therapy and nutritional advice. eGFR in the exercise group tended to improve compared with usual care, although without significant group differences in serum creatinine. No deaths occurred throughout the study period. Interestingly, a significantly higher employment rate was observed in the intervention group.

O’Connor et al. [49] studied the long-term effects of 3 months of aerobic training versus resistance training versus usual care on arterial stiffness at 9 months follow-up (12 months after training initiation) in 60 de novo recipients. Exercise training, and resistance training, in particular, appeared to induce a long-term beneficial effect on arterial stiffness. There were no deaths across the sample. A CV event occurred in both the aerobic and resistance training groups, but not in the usual care group. One myocardial infarction was deemed unrelated to the exercise intervention and occurred in a participant in the resistance training group who was non-compliant with all medications. The other CV event occurred in a participant in the aerobic training group who was non-compliant with the exercise intervention and was investigated for a pre-existing cardiac issue. There were 11 unplanned hospitalizations across the sample: 7 in usual care, 3 in the aerobic training group, and 1 in the resistance training group. Six episodes of graft rejection occurred: 3 in usual care, 1 in the aerobic training group, and 2 in the resistance training group. Graft function at 12 months post-transplant was not reported.

Short-term (<12 months) effects of exercise training

Health-related physical fitness and physical function. Aerobic exercise with [51–54] or without [46, 55] resistance training effectively improves cardiorespiratory fitness in both de novo and stable KTRs. Although not a consistent finding [56], some data suggest resistance training on its own improves cardiorespiratory fitness in de novo [55] and stable [52] recipients. However, these training effects were reported to be less sustainable compared with those elicited by aerobic exercise [49]. Recent data in a small group of 12 KTRs suggest discarding whole-body vibration training as an efficient strategy to improve cardiorespiratory fitness [58].

Ample evidence also shows resistance training, with [47–49] or without [55, 57] aerobic training, improves muscle strength, irrespective of the time after transplantation. Eleven months [46], but not 3 months [55], of aerobic training were reported to improve muscle strength in de novo recipients. Resistance training in stable recipients improved lower body muscular endurance assessed by the 60-s sit-to-stand test (STS; physical function) test [57]. In de novo recipients, both aerobic and resistance training improved lower-body muscular endurance over time [55]. However, only patients engaged in 3 months of resistance training showed greater STS repetitions compared with usual care [55]. A brief study investigating early physiotherapy during a 7-day hospitalization period after transplantation found no effects on upper or lower body muscle strength [59].

Several RCTs evaluated physical function assessed with the 6-min walk test (6MWT) [54, 57, 59], 60-s STS [55, 57], and the 8-foot timed up and go (TUG) test [57]. The 6MWT correlates well with cardiorespiratory fitness, the 60-s STS can be considered an estimate of lower body muscular endurance and the 8-foot TUG test requires a combination of speed, agility, and dynamic postural stability. Compared with usual care, early physiotherapy after transplantation did not improve 6MWT results at hospital discharge (7 days post-transplant) [59]. However, 10– 12 weeks of resistance training, with or without aerobic training, improved 6MWT results in stable KTRs [54, 57]. Resistance and aerobic training on their own also improved 60-s STS results [55, 57]. Finally, resistance training was shown to improve the 8-foot TUG test [57].

Not a single study reported exercise benefits on isolated postural balance. Although often neglected, the clinical value of exercise training to reduce falls and related complications is not to be underestimated [60, 61].

Graft health. The evaluation of graft function was included in several studies, but never as a primary outcome [54, 55, 59, 62]. Two studies investigated the impact of a short-term (7 days– 5 weeks) exercise training program initiated immediately after transplantation; no effects on creatinine levels were observed [59, 62]. In the study by Juskowa et al. [62], no formal between-group comparison was reported. One small study reported a beneficial effect of a 12-week combined resistance and aerobic training program on renal function [54]. Indeed, creatinine levels decreased and eGFR increased significantly in the intervention group (n =7), whereas an increase in creatinine levels and worsening of eGFR was observed in the control group (n =5). Although the authors describe a post hoc power of 0.9 to detect significant changes in renal function, the unexplained decrease in renal function in the control group remains somewhat puzzling. In a well-designed RCT evaluating 12-week home-based aerobic (n =13) or resistance (n = 13) training in de novo recipients (~7 months after transplantation), no significant effects on creatinine levels or eGFR was observed in comparison with usual care (n =20) [55].

CV function. BP, ARTERIAL STIFFNESS, AND CARDIAC AUTONOMIC FUNCTION. BP was reported in eight studies (one aerobic training, two resistance training, four combined training, and one whole-body vibration), but none showed exercise training to modulate 24-h ambulatory BP [52] or BP at rest [48–51, 55, 56, 58]. Peak exercise diastolic but not systolic BP, however, decreased with 6 months of combined training compared with usual care [51]. one mode of delivery is superior to another and has not yet been formally investigated in KTRs. Home-based remotely mediated exercise programs may overcome patient-level barriers such as limited program availability, inconvenience of attending classes several times a week, transport problems, infection risks, and financial costs associated with facility-based rehabilitation programs [93– 95]. On the other hand, supervised center-based rehabilitation may be postulated to be associated with superior execution of intended exercise intensity, volume, and technique. Patients may feel safer and enjoy the social aspect of training in a group of peers. A hybrid form in which supervised center-based rehabilitation is progressively replaced by home-based training and subsequent physical activity well-embedded into daily life may allow a smooth transition to a sustainable physically fit and active status.

CONCLUSIONS

Well-designed large RCTs in KTRs addressing endpoints important for all stakeholders (SONG-Tx outcomes) are scarce. However, clinical evidence on the beneficial effects outweighs data on potential harm. Exercise training in KTRs is effective in improving quality of life, physical function, physical fitness (surrogate markers of adverse clinical outcomes), and some selected markers of CV disease, such as cardiac autonomic function and arterial stiffness. Whether this effectively leads to improved core outcomes needs to be addressed in future studies with long-term follow-up. Moreover, the stage has been set to test and formally establish from which type of exercise training and at what dose (intensity, frequency, and duration) patients derive the greatest benefits, using well-designed RCTs with sufficient power. Implementation science methods should be included early in the projects to speed up the translational process.

SUPPLEMENTARY DATA

Supplementary data are available at ckj online.

ACKNOWLEDGEMENTS 

The authors would like to thank Albert Herelixka for his technical assistance with the figure. S.D.S. is supported by the Transplantoux Foundation. 

CONFLICT OF INTEREST STATEMENT 

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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