Uremic myopathy and deconditioning in patients with chronic kidney disease (including those on dialysis)

INTRODUCTION — Patients with advanced chronic kidney disease (CKD), particularly those on dialysis, often have significant muscle weakness and lack of endurance. This often results in a sedentary lifestyle that causes progressive deconditioning and increases morbidity and mortality among patients on dialysis. Exercise may reverse or mitigate effects of deconditioning and improve survival.

This topic reviews the pathophysiology of uremic myopathy and its effect on sedentary lifestyle among patients with CKD, including those on dialysis. The beneficial effects of exercise are discussed and recommendations provided for patients with nondialysis CKD and those on dialysis.

The effects of a sedentary lifestyle and the effects of exercise in the general adult population are discussed elsewhere:

●(See "The benefits and risks of aerobic exercise".)

●(See "Physical activity and exercise in older adults".)

●(See "Obesity in adults: Role of physical activity and exercise".)

EPIDEMIOLOGY — Uremic myopathy is considered common in patients with advanced CKD, particularly those on dialysis given the obvious decline in physical function observed [1,2]. However, the prevalence of a specific pathophysiological process directly attributable to uremia is not well defined, since the symptoms are minor and slowly evolving coupled with the lack of specific diagnostic criteria [3]. In one study including 330 patients on dialysis, sarcopenia (defined as decreased muscle mass with decreased function/mobility) was present in 20 percent, decreased muscle mass alone was present in 24 percent, and decreased muscle strength was present in 15 percent [4].

PATHOPHYSIOLOGY — Factors that cause sarcopenia or atrophy and weakness among patients with CKD include uremia-induced inflammation and accumulation of reactive oxygen species resulting in mitochondrial uncoupling and deficient muscle repair mechanisms [5-7]. Deconditioning not specific to CKD also plays an important role in progressive muscle impairment as do comorbid illnesses such as diabetes mellitus, poor nutrition, and peripheral vascular disease. Erythropoietin, vitamin D, and androgen deficiencies all likely contribute to muscle weakness.

●Mitochondrial uncoupling – Studies have suggested that there is a decrease in mitochondrial efficiency in CKD that is characterized by a decline in adenosine triphosphate (ATP) production per unit of oxygen consumption (ie, mitochondrial uncoupling) [8,9]. Mitochondrial uncoupling may occur prior to the functional decline in exercise tolerance and endurance [10]. The initial cause of mitochondrial uncoupling is not known but may be related to increased oxidative stress as the glomerular filtration rate (GFR) declines [11].

●Deconditioning – Deconditioning is a major contributor to the progressive myopathy among patients with CKD. Deconditioning is a loss of muscle mass (sarcopenia), strength, and power that occurs as a result of inactivity [12]. The role of deconditioning in uremic myopathy was demonstrated in a study that used resting muscle oxygen consumption (rmVO2) as a marker of myopathy [13]. The rmVO2 was twice as high in patients with end-stage kidney disease (ESKD) compared with healthy controls.

Patients with CKD are extremely vulnerable to deconditioning. Patients with CKD tend to be less active than sedentary healthy controls [14-16]. The reasons for the decreased activity level are not completely understood, but early muscle fatigue (possibly caused by mitochondrial uncoupling), orthostatic hypotension, anemia, and multiple comorbidities and hospitalizations may play a role.

Deconditioning is reversible. In the study cited above, six months of exercise caused a decrease in the rmVO2 of patients with ESKD; 39 percent achieved a normal rmVO2 [13].

Multiple studies have shown that exercise improves the muscular functioning and physical performance of patients with CKD [17-19].

●Erythropoietin deficiency – Erythropoietin deficiency may contribute to myopathy, but it is not clear whether this is because the resulting anemia causes a decrease in oxygen delivery to muscle and/or contributes to inactivity and deconditioning or whether erythropoietin has direct effects on muscle.

The correction of anemia with erythropoietin improves endurance and strength in patients with CKD [20]. In an early study, the correction of anemia with erythropoietin to a target hemoglobin of 11 g/dL in 11 previously transfusion-dependent patients on dialysis resulted in a 10 to 30 percent increase in arm and leg muscle strength in three months, although this improvement still left the patients significantly less strong than healthy controls [21].

Muscle structure improves with erythropoietin treatment. In one study, muscle biopsies performed before and after correction of anemia showed an improvement in the diameter of muscle fibers and a reduction in structural abnormalities after partial correction of anemia [22]. These changes would be expected to produce an increase in both muscle strength and performance and are most probably a consequence of an increase in muscle oxygen delivery. (See "Treatment of anemia in nondialysis chronic kidney disease" and "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease".)

That erythropoietin may have a direct effect on muscle (ie, that is unrelated to anemia) is suggested by the fact that the correction of anemia with transfusion in nonuremic patients (who would not be expected to have a decrease in endogenous erythropoietin levels) does not appear to improve muscle function [23].

●Androgen deficiency – Both male and female patients with CKD have decreased androgen production. (See "Causes of primary hypogonadism in males", section on 'Chronic kidney disease'.)

Androgen deficiency likely contributes to muscle impairment. Prior to the availability of recombinant erythropoietin, androgen therapy was used to treat anemia in some patients on hemodialysis [24,25], and, in one study, the androgen, nandrolone decanoate, was noted to increase muscle mass [25,26]. This agent was subsequently shown to improve body composition and muscle strength [27,28]. In one study, 79 patients were randomly assigned in a 2x2 factorial fashion to anabolic steroid administration and resistance exercise training [28]. Nandrolone administration increased lean body mass and quadriceps muscle size, while exercise increased muscle size alone.

●Vitamin D deficiency – Vitamin D deficiency has been associated with myopathies of various causes including statin-induced and vitamin D-dependent rickets [29-31]. In several reports, supplementation with appropriate doses of vitamin D improved muscle function [29-31]. (See "Etiology and treatment of calcipenic rickets in children" and "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Skeletal changes'.)

●Secondary hyperparathyroidism – Myopathy has been reported in patients with both primary [32-35] and secondary hyperparathyroidism [36,37]. The myopathy associated with primary hyperparathyroidism has been shown to be reversible with reduction in parathyroid hormone (PTH) suggesting causality [33,35]. However, it is difficult to distinguish effects of PTH from those of vitamin D deficiency and uremia in published reports of secondary hyperparathyroidism [36,37].

●Carnitine deficiency – Some studies demonstrated that L-carnitine supplementation improved muscle strength but not endurance [38,39]. However, when muscle metabolism and function were assessed by magnetic resonance or near-infrared spectroscopy, L-carnitine supplementation for 16 weeks in patients receiving maintenance hemodialysis showed no effect [40].

●Dialysis access – The hemodialysis access may have local effects on muscle function. A forearm access likely affects the function of both large and fine motor skills in the affected arm [41]. A hemodialysis access or peritoneal dialysis catheter may also decrease patient activity for fear of harming the access or catheter. Although restrictions are often placed upon patients with various access (eg, swimming and heavy lifting with peritoneal catheters; lifting with the vascular access arm, heavy perspiration, or swimming with a hemodialysis catheter; etc), these recommendations are largely based on anecdotal practices.

●Other factors – Other factors that may contribute in some patients include steroid myopathy, altered potassium metabolism, and malnutrition. These factors are generally recognized to be associated with decreased muscle function. (See "Glucocorticoid-induced myopathy".)

CLINICAL PRESENTATION AND DIAGNOSIS — Uremic myopathy is defined by a constellation of signs and symptoms including muscle weakness and wasting involving both proximal and distal muscles, decreased endurance and exercise capacity, and easy fatigability [3,42]. The severity increases as the glomerular filtration rate (GFR) declines [43]; the most severe cases have been described among patients on hemodialysis [3,44].

Except for weakness, the physical examination is normal. Electromyographic studies and muscle enzymes are also normal [3].

Atrophy may be observed by imaging [44,45]. In one study, magnetic resonance imaging (MRI) of the lower extremities showed less contractile tissue among patients on dialysis compared with controls, although the total cross-sectional area was comparable [44].

Muscle biopsies show characteristic structural, electrolyte, and enzymatic abnormalities [3,46-48]. In a small study in which muscle biopsies from eight patients with CKD were compared with healthy controls, light microscopy showed atrophy, particularly involving type 2 muscle fibers (ie, "fast twitch" or anaerobic) and evidence of degeneration and regeneration of muscle fibers [46]. Electron microscopy showed mitochondrial changes, loss of myofilaments, and the accumulation of intracellular glycogen. However, it is not clear how closely the structural muscle abnormalities correlate with functional impairment [1,2,49].

SCREENING — We screen most patients on hemodialysis, and selected patients with CKD not on hemodialysis whose symptoms appear out of proportion to their comorbid illness, for functional limitations. Screening for physical performance and self-reported functional limitation (defined by restrictions in basic activities such as ambulation and climbing stairs) may identify patients at risk for further functional decline, disability, and increased mortality [4,5].

The following screening questions have been proposed to assess functional and mobility limitations:

●Do you have difficulty walking a quarter of a mile (two to three city blocks) or climbing 10 steps?

●Have you changed the way you walk a quarter of a mile or how often you do this because of a physical condition?

In addition, physical performance may be objectively quantitated. There are multiple tests of physical function that are simple to administer and are commonly used in the non-CKD population, including the six-minute walk test, intermittent shuttle walk test, gait speed, and timed up and go test [50]. We use tests of gait speed or a timed up and go test. For measure of gait speed, the patient walks at their usual speed over 3 meters and is allowed to stop and rest as necessary. Walking speed <0.8 m/s has been associated with increased mortality in patients with CKD [51]. For the timed up and go test, the patient must stand from a fully seated position and walk 4 meters; time ≥4 seconds is associated with increased mortality in CKD.

Many transplant centers are now using objective measurements of physical function as screening criteria for suitability for kidney transplantation. As an example, our center sets 1000 feet in a six-minute walk as a minimum standard.

Other tests are being developed to assess for a variety of functional limitations in patients with kidney disease. As an example, a pilot study of patients with CKD identified smaller step length and slower gait speed as risk factors for falls [52].

PREVENTION — It is possible that myopathy cannot be prevented completely, particularly those aspects that are directly related to uremia (ie, oxidative injury and mitochondrial uncoupling). However, the prevention or treatment of deconditioning may delay or mitigate the progression of clinically significant muscle impairment [53]. Our approach for all patients includes an exercise regimen plus optimal treatment of vitamin D deficiency, anemia, and nutrition and is defined below.

Selected patients will have persistent and debilitating myopathy and atrophy despite these measures. Such patients may benefit from referral to a physical therapist or exercise physiologist as well as pharmacologic therapies. (See 'Treatment' below.)

Active lifestyle and exercise — We counsel all patients with CKD, including those on dialysis, to maintain an active lifestyle. Physical activity confers multiple benefits including prevention of progression of muscle impairment [53]. (See 'Benefits of exercise' below.)

Patients with CKD not on dialysis — Patients with CKD should follow recommendations for aerobic exercise, muscle strengthening, flexibility, and balance that exist for the general population (see "Physical activity and exercise in older adults", section on 'Overview of physical activity components'). A reasonable goal for patients with CKD is 150 minutes per week of moderate aerobic activity or 75 minutes per week of vigorous aerobic physical activity, with additional resistance training as appropriate [54].

Patients on dialysis — At our center, all patients undergoing dialysis are encouraged to participate in an exercise program after appropriate screening for medical limitations. The amount of exercise depends upon patient capability. For those who are capable, we advise patients to follow recommendations for the general public. A reasonable exercise dose would be walking a minimum of 4000 steps daily [55], and this approach has shown positive effects in a randomized trial, even with older patients [19,56]. (See "Physical activity and exercise in older adults", section on 'Overview of physical activity components'.)

However, patients on dialysis are frequently deconditioned and frail. Although functionally limited or frail individuals may never be able to meet minimum recommended activity levels, even modest activity and muscle strengthening can impact the progression of functional limitations [57,58]. While all elements of the physical activity recommendations should be incorporated into an activity plan, the adage "start low and go slow" should be kept in mind. It is acceptable to begin a baseline physical activity recommendation of walking for five minutes twice a day as a starting point. The key is to identify a set of activities the patient feels capable of doing, therefore incorporating the concept of self-efficacy into the physical activity recommendation [59]. Some dialysis centers, including ours, have offered basic stationary cycling at the dialysis center in the treatment chair during dialysis. Improvement occurs within 12 weeks of this simple program, although only approximately 20 percent of patients participate regularly [60]. Historically, some clinicians have been reluctant to permit exercise during the latter portions of the dialysis session due to a concern that physical activity near the end of dialysis might precipitate intradialytic hypotension. However, this concern is unfounded for most patients. In a crossover trial in which 98 patients on hemodialysis were randomly assigned to two sequential two-week intradialytic cycling regimens that occurred either during the first or second half of the dialysis session, the timing of intradialytic cycling had no appreciable effect on the rate or severity of intradialytic hypotension [61].

Patients on peritoneal dialysis have the same low physical performance measures as patients on hemodialysis [62]. For patients on peritoneal dialysis, a stretching and walking program is recommended at home, with observance of guidelines suggested to the general public [63]. Occasionally, patients will state that the presence of dialysis fluid limits their activity. For these patients, we drain the abdomen for one to two hours during their period of physical activity. Some patients may have concerns that exercise can lead to peritoneal dialysis catheter problems (eg, exit-site infections, leaks, pulling trauma) or the development of abdominal hernias that complicate the peritoneal dialysis regimen. However, none of these issues were observed in a systematic review that included 17 exercise or physical intervention studies of patients on peritoneal dialysis [64]. Further discussion of exercise among frail or functionally limited patients is elsewhere. (See "Physical activity and exercise in older adults", section on 'Functionally limited or frail'.)

Physical therapy has not been routinely incorporated into the care of patients with end-stage kidney disease (ESKD). Although one assumes a potential benefit, no large trial has examined the utility or benefit of routine referral to a physical therapist or exercise physiologist following the diagnosis of ESKD.

Benefits of exercise

Prevention of atrophy and myopathy — A number of studies have shown that exercise helps to preserve or improves muscle function and/or mass among patients with nondialysis and dialysis CKD, including those on a low-protein diet [17,18,65-76]. The best data are from two meta-analyses of randomized trials that showed improvements in muscle strength with exercise [17,18]. Regardless of type, intensity, or length of intervention, exercise improved muscle strength at all stages of CKD [17].

In a trial published after the meta-analyses, 296 patients on dialysis were randomly assigned to six months of a walking exercise program or usual physical activity [19]. At six months, patients in the exercise group experienced improvements in measured physical performance compared with baseline (as determined by six-minute walking test distance and five-times sit-to-stand test time), whereas those in the usual activity group did not. In addition, patients in the walking exercise group, compared with those in the usual physical activity group, had lower rates of hospitalization (35 versus 57 hospitalizations per 100 person-years, respectively) and improved cognitive and social interaction scores on the Kidney Disease Quality of Life Short Form (KDQOL-SF) questionnaire. A subsequent observational study of these trial participants found that those in the exercise group had a superior performance in the six-minute walking test, but not in the sit-to-stand test or in the KDQOL-SF score, compared with the control group up to 12 months after the end of the exercise intervention [77].

Slowing of decline in GFR — Multiple studies have suggested that exercise slows the decline in kidney function and reduces the risk of requiring dialysis [78-80]. The best data are from a randomized, controlled trial that compared the effects of a three-times-weekly exercise regimen (including both resistance and aerobic training) to usual care among 20 patients (17 men) who had a rate of decline in estimated glomerular filtration rate (eGFR) of 2.9 mL/min/1.73 m² per year for 12 months prior to intervention [78]. In the group undergoing exercise, the mean change in eGFR was -9.7±7.2 mL/min/1.73 m² during the year prior to intervention and -3.8±2.8 mL/min/1.73 m² per year in the year during which they performed exercise. At 12 months, compared with the control group, the mean rate of change in eGFR was lower in the exercise group, with a mean difference between groups of 7.8±3.0 mL/min/1.73 m² (95% CI, 1.1-13.5). There was no difference between groups in the absolute eGFRs at 12 months.

Longer-term data are limited to observational studies. A longitudinal cohort study compared physical activity, quantitated using the Four-Week Physical Activity History Questionnaire, with longitudinal measurement of eGFR at a median follow-up of 3.7 years [79]. Individuals who reported over 150 minutes of physical activity per week had a slower decline in eGFR compared with inactive individuals (-6.2 versus -9.6 percent per year, respectively). At a median follow-up of 3.7 years, each 60-minute increment in weekly activity was associated with a 0.5 percent slower decline in kidney function in adjusted analysis.

Cardiovascular benefit — The ill effects of sedentary lifestyle on cardiovascular disease and mortality are well accepted, and a benefit of exercise has been suggested by observational studies [81]. (See "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease", section on 'Benefits of exercise'.)

A few studies have examined the association between survival and exercise in patients on dialysis [80,82,83].

●In an analysis of observational data for 2507 patients from the USRDS Dialysis Morbidity and Mortality Study (Wave 2), decreased mortality was associated in patients who exercised two to three and four to five times per week [82]. However, for unclear reasons, daily exercise provided no survival benefit.

●In one study of 6363 patients from China, walking was associated with decreased mortality in patients with CKD not on dialysis [80]. Compared with those who reported not walking at all (frequency = 0), the adjusted hazard ratios (HRs) were 0.83, 0.72, 0.42, and 0.41 for patients who walked one to two, three to four, five to six, and seven or more times per week, respectively.

●In an analysis of data from the Dialysis Outcomes and Practice Patterns Study (DOPPS), in which 5763 participants were classified into increasing levels of physical activity, aerobic activity was associated with decreased mortality [83]. The adjusted HR for death for very active participants compared with never or rarely active participants was 0.60 (95% CI 0.47-0.77).

Aerobic activity was also associated with increased health-related quality of life and decreased depression in this study.

●In a small trial in which 74 patients on hemodialysis were randomly assigned to 60 minutes of intradialytic exercise thrice weekly for six months or to usual care, one-year survival was higher in the exercise group [84]. However, participants in the exercise group were younger and were less likely to have diabetes than participants in the control group.

Other benefits — Other benefits of exercise include improved aerobic capacity and cardiovascular function [17,85], a reduction in severity of restless leg syndrome and improvement in sleep quality [86], improved quality of life in general [85], and improved social interactions as assessed by the KDQOL-SF questionnaire [18,19].

Treatment of vitamin D deficiency — We measure 25-hydroxyvitamin D and treat vitamin D deficiency according to standards set for the general population. The restoration of vitamin D levels has been shown to reduce muscle weakness in case reports [29-31]. (See 'Pathophysiology' above.)

However, a randomized controlled trial did not show a beneficial effect of cholecalciferol on muscle strength and functional capacity among patients on hemodialysis [87]. Sixty individuals were randomly assigned to receive either oral cholecalciferol, 50,000 international units, or placebo weekly for eight weeks and then monthly for four months. At six months, there was no difference between groups in muscle strength, functional capacity, or health-related quality of life, despite higher values of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D.

We do not treat secondary hyperparathyroidism specifically to improve muscle weakness. The treatment of secondary hyperparathyroidism is discussed elsewhere:

●(See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)

●(See "Management of secondary hyperparathyroidism in adult patients on dialysis".)

●(See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Vitamin D replacement'.)

Treatment of anemia — We carefully monitor for the development of iron deficiency and anemia and treat to accepted thresholds for patients with CKD. (See "Treatment of anemia in nondialysis chronic kidney disease" and "Treatment of anemia in patients on dialysis".)

Erythropoiesis-stimulating agents (ESAs) are generally not given until the hemoglobin is <10 g/dL for patients with CKD not on dialysis. However, we are attentive to possible symptoms of anemia in younger patients who have CKD with few comorbidities, whose symptoms of anemia may occur at higher hemoglobin levels (particularly if the patient is trying to maintain the recommended active lifestyle). For such patients, we may initiate ESAs at hemoglobin levels of 10 g/dL or even higher after discussing potential risks and benefits with each patient. (See "Treatment of anemia in nondialysis chronic kidney disease", section on 'Indications and contraindications'.)

Dietary protein intake — Patients placed on a low-protein diet are particularly prone to loss of muscle mass. We generally recommend the same intake of high-quality protein for patients with CKD as is generally recommended for the general population (ie, 0.8 g/kg/day). If patients have a lower protein intake than this, they should be followed closely by a kidney dietitian to be certain that nutrition is adequate since malnutrition almost certainly contributes to muscle weakness. (See "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Protein intake'.)

TREATMENT — Despite the preventive therapies defined above, some patients will have persistent and debilitating weakness (generally identified by screening as defined above); such patients should be referred to a physical therapist or an exercise physiologist. Although there is no high-quality evidence to support their routine use, pharmacologic treatment options include testosterone and carnitine supplementation:

●In all male patients with persistent and debilitating weakness and no contraindication to androgen therapy, we evaluate for testosterone deficiency and, if present, we treat with testosterone replacement therapy for three months and reassess muscle strength. If the patient demonstrates an improvement in muscle strength, we continue testosterone therapy indefinitely. If the patient demonstrates no improvement in muscle strength, we discontinue testosterone therapy. Details on the diagnosis and treatment of testosterone deficiency are presented separately. (See "Clinical features and diagnosis of male hypogonadism" and "Testosterone treatment of male hypogonadism".)

In male patients on hemodialysis who do not have testosterone deficiency or who do not respond to testosterone replacement therapy, a three- to six-month trial of intravenous (IV) L-carnitine supplementation (1000 mg at hemodialysis three times weekly) can be considered. However, the use of IV L-carnitine in patients on hemodialysis remains controversial [88,89]. The biochemical diagnosis of carnitine deficiency is difficult since nearly all patients on dialysis have abnormalities in serum carnitine levels, and no study has demonstrated a correlation between various blood carnitine measurements and muscle function.

●In female patients with persistent and debilitating weakness, we do not routinely evaluate for testosterone deficiency, since the role of androgen therapy in women is limited to the treatment of postmenopausal women with a diagnosis of female sexual interest/arousal disorder. In patients on hemodialysis, a three- to six-month trial of IV L-carnitine can be considered as discussed above for male patients. (See "Overview of androgen deficiency and therapy in females".)

●We do not give growth hormone. Although the anabolic effects of recombinant human growth hormone (rhGH) have been reported in many muscle-wasting conditions, including CKD [88], there are little data that show a sustained improvement in physical function and strength with rhGH administration. One placebo-controlled study of 20 patients reported increased handgrip strength and anabolic effects with subcutaneous rhGH at 66.7 mcg/kg thrice weekly following hemodialysis [89]. A phase III, international, multicenter trial of over 2000 patients on hemodialysis was terminated early due to slow recruitment but showed no improvement in grip strength or walking capacity in the 695 patients who received at least one dose of study medication [90].

PROGNOSIS — Decreased muscle strength is associated with increased mortality. This was best shown in an observational study including 330 patients on dialysis, 29 percent of whom died over a follow-up of five years [4]. Patients with decreased strength had increased mortality risk even if muscle mass was normal (hazard ratio [HR] 1.98, 95% CI 1.01-3.87). Decreased muscle mass in the absence of decreased strength did not increase mortality in this study. This suggests that a functional assessment may provide prognostic information beyond that provided by assessment of muscle mass. (See 'Screening' above.)

Decreased strength and endurance are important components of frailty, which is highly prevalent among older patients on dialysis [91,92]. Among patients on dialysis, frailty has been associated with increased mortality [92-98] and increased fractures [99,100], as well as decreased quality of life [101].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults" and "Society guideline links: Dialysis".)

SUMMARY AND RECOMMENDATIONS

●Overview – Patients with advanced chronic kidney disease (CKD), particularly those on dialysis, often have significant muscle weakness and lack of endurance. This often results in a sedentary lifestyle that causes progressive deconditioning and increases morbidity and mortality among patients on dialysis. Exercise may reverse or mitigate effects of deconditioning and improve survival. (See 'Introduction' above.)

●Pathophysiology – A decrease in striated muscle mitochondrial efficiency may occur in the early stage of CKD. Thereafter, progressive muscle impairment is caused by deconditioning. Erythropoietin, vitamin D, and androgen deficiencies all likely contribute to muscle weakness. (See 'Pathophysiology' above.)

●Screening – We screen all patients on hemodialysis and selected patients with CKD not on hemodialysis for functional limitations. Screening for physical performance and self-reported functional limitation may identify patients at risk for further functional decline, disability, and increased mortality. Screening questions may be used, or physical performance may be objectively quantitated using functional tests. (See 'Screening' above.)

●Prevention – The prevention or treatment of deconditioning may delay or mitigate the progression of clinically significant muscle impairment. Our approach for all patients includes an exercise regimen plus optimal treatment of vitamin D deficiency, anemia, and nutrition and is defined above. Exercise in particular has numerous benefits including potential preservation of kidney function in patients with CKD not on dialysis and possible cardiovascular and survival benefits. (See 'Prevention' above.)

●Treatment – Despite preventive therapies, some patients will have persistent and debilitating weakness. In addition to referring such patients to a physical therapist or an exercise physiologist, pharmacologic treatment options include testosterone and carnitine supplementation. However, there is no high-quality evidence to support their routine use. (See 'Treatment' above.)

●Prognosis – Decreased muscle strength is associated with increased mortality and contributes to increased falls, fracture risk, and frailty. (See 'Prognosis' above.)