Physical Exercise in Kidney Renal Recipients: Where Have We Come?

Chronic noncommunicable diseases, including chronic kidney disease, are of increasing importance in the healthcare context of industrialized countries [1]; a sedentary lifestyle is identified as one of the main risk factors for the development of cardiovascular disease (CVD) and cancer [2]. Kidney transplantation constitutes the most effective therapeutic option for patients with end-stage renal disease in terms of survival rate and quality of life (QoL) perception. Kidney transplant recipients (KTRs) have an incidence of developing CVD 5–10 times higher than the general population [3, 4]; immunosuppressive therapy also contributes to the multiple risk factors (overweight, diabetes, arterial hypertension, metabolic syndrome, subclinical inflammation, sarcopenia). Immediately after transplantation, KTRs have reduced exercise capacity, and a partial improvement is shown during the first year post-renal transplant, but levels remain considerably lower than those of the population of the same age and sex [5].

The percentage of active patients is low, although it differs widely between different studies [6‒8]. Some of these studies are open to selection bias; patients in poor health conditions or with severe comorbidities are less likely to engage in physical activity, with potential overestimation of the level of physical inactivity. Furthermore, there are logistical and psychological barriers to carrying out physical activity [9] which lead to a vicious circle of reduction in physical activity and physical deconditioning. The pathophysiological assumptions on the effectiveness of physical exercise on multiple cardiovascular risk factors are well documented in the general population [10], and there are no scientific data to suggest that this does not also apply to people with renal transplantation. The active lifestyle is becoming increasingly important in various nephrological healthcare settings [11‒14]; combating a sedentary lifestyle and increasing physical activity levels represents an important aspect of healthcare activity to counteract many of the CVD risk factors in KTR [15], often underestimated and underused [16].

Scientific data published on solid organ transplant patients confirm the importance of physical activity even if transplant patients present less statistical power than what has been demonstrated in the general population [17].

The number of cases examined is small, the observation time is limited, the interventions are difficult to superimpose in terms of time, intensity, method of exercise administration, and there is often a heterogeneity of the endpoints examined, often intermediate outcomes for major cardiovascular events [18]. Scientific reviews suggest that the benefits of engaging in regular physical activity still outweigh the potential risks; there is a safety of “use” [19‒21] if there are no specific contraindications to exercise and if physical activity is based on functional capabilities with progressive adjustments over time.

In patients with solid organ transplantation, the improvements related to the physical exercise reported in the literature reach more consolidated evidence in relation to physiological aspects as aerobic capacity, muscle strength, arterial stiffness [17, 22‒24]. In the general population, these improvements are correlated with life expectancy and cardiovascular outcomes. Specifically, there is an improvement in cardiorespiratory fitness (expressed as VO₂ peak) and exercise capacity as well as maximum heart rate [25, 26] after structured aerobic or strength exercise programs administered separately or combined. Similarly, regular physical activity programs are also suggested to patients awaiting transplantation [27]. A recent study evaluated oxygen uptake (VO₂ peak) kinetics as indicator of muscular oxidative metabolism showing a slower VO₂ kinetics in KTR compared to healthy controls. VO₂ peak seems to improve during the first year after transplantation, but the reduced aerobic exercise capacity of KTRs is strongly correlated with slower VO₂ kinetics [28]. Significant increases in muscle strength and muscle performances linked to the improvement of muscle mass and metabolic functioning are also reported. Reduced muscle mass and strength are common conditions in patients with advanced chronic renal failure, and muscle atrophy is a serious clinical problem due to duration of conservative pharmacological treatment pre-dialysis and dialysis therapy [29]. Furthermore, immunosuppressive therapy as cyclosporine reduces muscles oxidative activity and capillarity, contributing to the reduction of exercise tolerance [9]. The long-term systematic combination of immunosuppressive drug and glucocorticoid therapy may also induce muscle atrophy and bone loss [30]. KTRs may improve the exercise performance following combined endurance and strength training programs, thus counteracting the side effects of the pharmacological therapies and reducing muscles atrophy and weakness [31].

Exercise has beneficial effects on endothelial function [32] particularly on arterial stiffness. Exercise intervention induced a decrease of the pulse wave velocity, an improvement of the heart variability, and the arterial baroreflex sensitivity [23, 33]. Arterial stiffness constitutes a cardiovascular indicator and is predictive in patients on hemodialysis and in patients with chronic renal failure.

A large body of literature reports an improvement in patients’ self-perceptions recorded through specific questionnaires, including functional capabilities and QoL perception after personalized exercise programs [34]. Self-perception of patients’ QoL further improves in those patients who engage in sports activities [35].

In some studies, it is reported that regular physical activity in kidney transplant patients can favorably influence the functional performance of the transplanted organ [36]; however, the data are only partially supported by randomized controlled trials. A recent meta-analysis reported that physical exercise leads to an improvement in kidney functions [37]. An Italian retrospective study carried out on 6,055 transplant patients in 10-year follow-up highlighted a better trend of renal function over time in active transplant patients [38] compared to sedentary transplant patients. After applying the propensity score matching to reduce confounding factors, mixed-effect regression models corroborated such better long-term trend of graft function preservation in active KTRs. Despite that, the multiplicity of factors that contribute to the definition of renal function levels do not yet allow us to formulate conclusive considerations.

Improvements in the inflammatory condition have been reported after exercise programs on inflammatory markers such as C-reactive protein, TNF-α, TNFR-1, TNFR-2, fetuin-A values, or IL-6 in KTR [39, 40]; randomized controlled trials that confirm these data are currently lacking. Even more heterogeneous and non-definitive data are found in multiple observational studies on the relationship between physical activity and metabolic syndrome, dyslipidemia, glucose intolerance, blood pressure control, anemia; for more accurate analyses, longer observation periods are necessary. After transplantation, structured exercise alone is not sufficient to mitigate the increases in body mass often observed in posttransplant patients [41]; exercise must be associated with changes in dietary behavior with multi-professional management [42].

Consolidated data on physical activity and long-term outcomes such as the incidence of acute cardiovascular events and mortality are currently not available. In small cases, it has been found that a higher level of physical activity is associated with a reduction in mortality [43, 44] and that pretransplant physical activity levels were predictive of all-cause mortality (507 KTR, mortality of 16% active compared to 36% of those considered inactive). The most studied endpoints suggest a possible positive effect of physical activity on long-term events, but no conclusive considerations can be made which require studies with more prolonged follow-up.

The Italian experience began in 2008 with the “Transplant…and now sport” clinical study. Attention was first focused on verifying and confirming the safety of physical and sporting activity in patients with solid organ transplants [14, 19]. Through a regional program, a working model has been developed with a multidisciplinary and multi-professional network for the dissemination of supervised physical activity (transplant centers, sports medicine centers, fitness center) shown in Figure 1. The association of aerobic and resistance exercises continued for 12 months led to an improvement in aerobic capacity, muscle strength, perceived QoL and nutritional status [19]. For the sake of economic sustainability of the system, physical activity programs have also been developed in an unprotected, unsupervised environment [45] which constitute a possibility in various countries such as walking groups, outdoor gyms, wellness parks (shown in Fig. 1). In the sporting field, the possibility of sustaining even prolonged physical efforts without harmful effects has been found [46, 47]; engaging in sporting activities further improves the perception of QoL [35]. A further Italian experience has highlighted overlapping inflammatory indices (TNF-α, IL-6, IFN-γ adiponectin) between transplanted amateur cyclists and non-transplanted amateur cyclists, with significantly lower values than those found in sedentary transplant patients [40]. A retrospective data analysis of the Italian National Transplant Centre Information System associated a sedentary lifestyle with a worse functional performance of the organ transplanted in an observation period of 10 years [38]. Eventually, a multicenter study, “POST – Occupazione e Salute Post-Trapianto” project financed by the National Institute for Insurance on Accidents at Work (INAIL), was conducted with a view of creating a national network for the promotion and implementation of exercise programs for transplant patients through the use of wearable devices and a dedicated website. The project has led to the dissemination on YouTube of tutorial/video lessons of physical activity adapted for the transplanted population and awaiting transplantation. Furthermore, preliminary data showed that using a physical activity monitor can be a useful strategy to improving functional capacity and the QoL, thus possibly increasing motivation toward a more active lifestyle [48].

The scientific activity was integrated with an action on the institutions to recognize the primary role of physical activity in the population of transplanted patients or those awaiting a transplant; specific programs have been included in the Italian National Prevention Plan 2020–2025. In all phases of the national experiences, the involvement of patient associations was essential.

The guidelines issued by the International Society of Nephrology, starting from the “KDIGO Guidelines for clinical practice” of 2009 [49] and the KDOQI guidelines 2010 [50], have always suggested the promotion of adequate lifestyles for nephropathic patients, with generic indications that have expanded with research developments. Today, the importance of physical activity is emerging as a complementary therapy to both pharmacological and nutritional approaches. The National Institute for Management of Health and Care Excellence (NICE) guidance on kidney disease in adults encourages self-management, provides generic information on physical exercise, without any specific guidance, nor distinguishes between KTRs and other stages of chronic kidney disease [51]. The Japanese Society proposes guidelines for the implementation of physical activity and exercise as therapy for KTR [52]. Guidance from the Canadian Society of Transplantation indicates the need for regular exercise programs to be offered to both organ transplant patients and patients on the waiting list [53]. The importance of maintaining an adequate lifestyle, including physical activity, is reiterated by the European Society for Organ Transplantation which indicates some specific points for improvement in the management of patients in the pretransplant phase [54]. Due to the heterogeneity in the intervention of the different approaches, it is difficult to recommend or conclude which “exercise modality” constitutes the best strategy. Supervised exercise can maximize exercise results; the presence of a specialized kinesiologist or exercise physiologist allows to modulate and adapt the workload and intensity, improving patient compliance. The most reported experience is based on aerobic activities; positive results have also been reported with resistance exercises. The two types of exercise can be combined, with good results [31]. Different exercise methods such as high-intensity interval training are not conclusive in this patient population [55, 56].

For the sake of economic sustainability and a wide diffusion of “exercise therapy,” patients should be encouraged to carry out regular exercise even at home [57]. Regular physical activity programs should be set up already in the pretransplant phase [58].

Recent systematic research and a randomized meta-analysis of clinical trials investigating the effect of exercise interventions, supervised or unsupervised, on outcomes of patients with organ transplants or awaiting kidney transplants has recently resulted in more detailed recommendations which present different levels of scientific evidence [42]. KTRs should minimize the amount of time spent in sedentary behaviors and, when physically possible, should interrupt prolonged periods of inactivity with even light physical activity. For KTR, 150–300 min of moderate-intensity physical activity per week (or 75 min of vigorous-intensity physical activity) is recommended according to the UK Chief Medical Officers’ Physical Activity Guidelines [59]. In line with most studies, it is realistic to propose physical exercise at least 3 times per week for a duration of 3–6 months, trying to make exercise a regular lifelong habit. Structured exercises are recommended to improve cardiorespiratory capacity and to improve muscle strength and physical function, reducing perceived tiredness. To achieve health benefits, aerobic exercise should be performed preferably every day at an intensity >60% of theoretical maximum heart rate or VO₂ peak. The addition of strength training is important to improve muscle functions and should be performed at a >60% [42] of the estimate maximum load lifted for a single maximum repetition (1-RM), at least 2 times per week. Furthermore, 2020 WHO guidelines suggest, for patients with chronic disease, at least 3 days a week of varied multicomponent physical activity that emphasizes functional balance and strength training at moderate intensity to enhance functional capacity and prevent falls [2]. Exercise should be tailored to the individual’s comorbidities, goals, and functional abilities with the involvement of a kinesiologist trained to work with frail patient populations. Exercise volumes (loads), whether aerobic or strength, should be gradually increased through adjustments in frequency (how often is exercise done each week), intensity (how hard is the exercise), time (how long is the exercise duration), type (what is the mode of exercise), volume (what is the total amount of exercise), and progression (how is the program advanced) of physical exercise (FITT-VP) until the desired exercise goal is achieved (maintenance phase). Exercise programs should always start with a warm-up session (e.g., exercise for a minimum of 5 min, starting at half the prescribed training intensity) and conclude by cool-down activities (e.g., gradually decreasing intensity until exercise is stopped).

Literature data suggest identifying inactive patients and monitoring physical activity levels through interviews or the use of specific questionnaires (e.g., PAVS, GPPAQ, IPAQ). The importance of identifying the psychological and logistical barriers that hinder physical activity and the need to provide individual stimuli to patients to encourage adherence to active lifestyle programs emerges [60]. To maintain adherence to exercise, strategies such as social support, setting realistic goals and results, exercise modulation are appropriate, and motivational counseling should be implemented. The use of devices for measuring daily physical activity can constitute a stimulus to greater patient compliance for the prescribed physical activity [48, 61]. The attitude and beliefs of healthcare personnel toward physical exercise could significantly contribute to combating physical inactivity and encouraging the initiation of regular physical activity. Awareness on the implementation of physical exercise is low among nephrologists, while a proactive approach by specialized teams can aid empowerment and motivation [62, 63].

In this context, it is highlighted the importance of creating a network of trained professionals, the organization of regular training programs related to the benefits of physical exercise and to stimulate the motivation to adhere to an active lifestyle for all healthcare personnel. A widespread training action for patients and family members is necessary; the availability of reference guides for performing regular physical activity at each transplant center constitutes a further opportunity to improve compliance.

Furthermore, sustainable strategies are needed over time and in different socioeconomic contexts such as free outdoor gyms or home-based self-managed activities to encourage and promote physical activity in people with solid organ transplantation. Interesting results have emerged on the effectiveness of multimedia programs for staff training, the dissemination of information, and specific methods of intervention for the administration of physical exercise for kidney transplant patients and those undergoing dialysis via digital healthcare platforms, demonstrating good adherence and significant improvement in QoL [64‒67].

More evidence is now available regarding the positive role of physical activity in patients with renal transplants; significant and unambiguous improvements have been demonstrated on cardiovascular capacity, muscle strength, arterial stiffness, and perceived QoL. Despite scientific evidence, regular physical activity prescription are largely underused. Specific indications are emerging regarding the FITT-VP of physical exercise to be proposed; 150–300 min of moderate-intensity aerobic activity per week, with at least 2 times per week of muscle-strengthening activities at moderate intensity and at least 3 days a week of multicomponent exercise. Educational and training activity on healthcare personnel, patients, and families, also through developing IT platforms, is essential for the regular diffusion of this non-pharmacological therapy. The creation of a multidisciplinary network and sustainable opportunities for physical activity favor and increase the possibilities for regular intervention, especially in the most fragile cases. Wearable devices and digital health intervention can improve patient compliance along with remote recording of daily physical activity data. Long-term studies are necessary to confirm the effectiveness of exercise on primary endpoints related to cardiovascular risk.

The authors thank Claudia Carella from the Italian National Transplant Center, Rome, Italy, for preliminary language revision. Finally, a thankful mention is made for the families of the organ donors.

Since this is a review of research, ethics approval was not required.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

All the authors contributed substantially to the study conception. Conceptualization, data curation, and analysis were performed by G.M. and V.T. The first draft of the manuscript was written by G.M. and V.T. Review and editing was performed by G.S., G.S.R., and A.N.C. Validations were performed by L.B. and M.C. All the authors commented on previous versions of the manuscript and read and approved the final manuscript.