**4. Exercise in Chronic Kidney Disease**

Haemodialytic CKD patients are considerably less physically active than their agematched counterparts [125,126]. Additionally, despite the diverse aetiologic factors of muscle wasting and decreased muscle quality observed in CKD patients, physical inactivity has been proposed as one of the major contributors [127–129]. In fact, a study performed on CKD patients showed similarly low levels of PA between two groups of CKD patients separated depending on disease severity [pre-dialytic (stage 3–4) vs. haemodialytic patients (stage 5)] [130].

Physical inactivity along with the disease itself leads to the patients experiencing skeletal muscle wasting, contributing to frailty, and limiting exercise tolerance [126]. Moreover, considering that CKD patients experience anaemia, hypertension, bone loss and take medications, it is understandable that these patients avoid exercise [131]. This result is unlucky since exercise is beneficial for cardiovascular health and helps with slowing down the progressive skeletal muscle mass loss [132]. Additionally, living a sedentary life and suffering from muscle mass loss negatively affect health [132]. For instance, a single resistance exercise session has been shown to be able to stimulate protein anabolism in haemodialytic patients [133], and 21 weeks of endurance exercise was found to improve protein metabolism markers (e.g., IGF-1 and myostatin). Although it may be demanding of dialysis patients to engage in moderate to vigorous exercise sessions, those who can often experience great benefits. Strategies such as regular resistance and aerobic exercise have shown promising effects in reducing the progression of sarcopenia [102,134–137]. In short, resistance training has shown to be effective in improving skeletal muscle strength and functional capacity and stimulating muscle hypertrophy (e.g., increase in type I, type IIa and type IIx muscle fibre cross sectional areas) [138–142], whereas aerobic training appears to significantly increase aerobic capacity and exercise duration, reduce intra- and interdialytic systolic and diastolic blood pressure, diminish arterial stiffness, increase dialysis efficiency, enhance exercise-induced capillarization in the muscle, improve quality of life (reducing anxiety symptoms), and even exert comparable effects with those of resistance training (i.e., muscle strength) due to poor initial physical state of patients [143–151].

Moreover, CKD is associated with a dysregulated myokine activity and a systemic increase in cytokines [152–154]. In response to exercise, skeletal muscle releases myokines (e.g., IL-15 and IL-6), which exert positive physiological effects on skeletal muscle and bone [155]. This crosstalk through the skeletal muscle secretome (e.g., IGF-1 and myostatin) positively influences bone health [155–157]. In CKD, intradialytic resistance training showed an elevation in osteoprotegerin, which acts by avoiding/protecting excessive bone resorption [158]; bone-specific alkaline phosphatase, another bone resorption inhibitor, showed elevation in resting concentrations after an 8-week intradialytic resistance exercise [159]. For more detailed information about skeletal muscle and bone crosstalk in CKD, see [160].

Connective tissue accumulation (e.g., ECM) has been observed in aged skeletal muscle [161]. A study with aged rats submitted to a resistance exercise protocol—3 times a week for 12 weeks—has shown that training mitigated the age-associated increase of connective tissue. These results can be extrapolated to CKD, since fibrosis is also present in this population [110].

In sum, although there is extensive evidence of the benefits of exercise in CKD, studies showing exercise-induced mechanistic ROS modulation are still lacking.
