Pathophysiology and potential treatment of uremic sarcopenia

Shao-Yu Yang; Jia-Huang Chen; Chih-Kang Chiang; Kuan-Yu Hung

doi:10.23876/j.krcp.24.176

Kidney Res Clin Pract > Epub ahead of print

Yang, Chen, Chiang, and Hung: Pathophysiology and potential treatment of uremic sarcopenia

Review Article

Kidney Research and Clinical Practice 2025;j.krcp.24.176.

Published online: February 21, 2025

DOI: https://doi.org/10.23876/j.krcp.24.176

Pathophysiology and potential treatment of uremic sarcopenia

Shao-Yu Yang¹

, Jia-Huang Chen²

, Chih-Kang Chiang^1,^2,³

, Kuan-Yu Hung¹

¹Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

²Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan

³Division of Blood Purification, Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei, Taiwan

Correspondence: Chih-Kang Chiang Graduate Institute of Toxicology, College of Medicine, National Taiwan University, No.1 Jen Ai Road Section 1, Taipei 100, Taiwan. E-mail: ckchiang@ntu.edu.tw

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial and No Derivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted non-commercial use, distribution of the material without any modifications, and reproduction in any medium, provided the original works properly cited.

Abstract

Sarcopenia, commonly found in the elderly and characterized by the loss of skeletal muscle mass, decreased muscle strength, and reduced physical performance, draws attention because it often leads to frailty, an increased risk of falls and fractures, and higher morbidity and mortality. Patients with chronic kidney disease (CKD) usually suffer from malnutrition, physical inactivity, inflammation, metabolic acidosis, insulin resistance, and other hormonal changes, which are all aggravating factors of sarcopenia. Therefore, the prevention, early detection, and adequate management for sarcopenia in patients with CKD help to improve their quality of life, prevent various complications and disabilities, as well as to reduce the risk of major morbidities and death. We reviewed the diagnosis and prevalence of sarcopenia in CKD and discussed the risk factors, etiology, pathophysiology, clinical impacts, and present treatment strategies for sarcopenia in CKD. The applications of exercises along with nutritional interventions, correction of metabolic acidosis caused by CKD, anabolic hormones, appetite stimulants, and other agents in uremic sarcopenia were discussed. Early detection and adequate management help to improve muscle strength and mass and enhance physical performance, therefore improving the quality of life and reducing mortality in CKD patients with sarcopenia.

Keywords: Chronic kidney disease, Dialysis, Exercise, Nutrition therapy, Sarcopenia

Introduction

Sarcopenia is characterized by the loss of skeletal muscle mass, the decrease of muscle strength and physical performance, which was defined by different diagnostic tools and criteria by several working groups originally developed in older people. Handgrip strength or chair stand test for evaluating muscle strength, appendicular lean mass measured by dual X-ray absorptiometry or bio-impedance analysis for evaluating muscle mass, and gait speed or other physical activity assessments for evaluating physical performance, are usually used for the diagnosis of sarcopenia [1–5]. The etiology of sarcopenia is usually multifactorial and can include physical inactivity, chronic diseases, nutritional deficiencies, inflammation, insulin resistance, etc. However, in patients with chronic kidney disease (CKD), the direct application of the above diagnostic criteria may not be feasible because the adequate cutoff points in these patients remain unknown. In addition, the etiology and pathophysiology of sarcopenia in CKD may be more complicated, not only due to aging but also due to multiple CKD-related complications. Metabolic acidosis, inflammation, reduced appetite with protein-energy wasting, defective insulin signaling, and increased angiotensin II levels are commonly found in CKD and may activate catabolic pathways that cause protein and muscle wasting [6]. Further, the adverse effects of sarcopenia in patients with CKD usually result in worse outcomes because the coexistence of comorbidities and CKD-related complications such as anemia and mineral-bone disorders make these patients more vulnerable to falls and fractures. The strategies of prevention and treatment for sarcopenia in CKD are also challenging due to multiple CKD-related complications, such as oral nutritional interventions that may be hindered by complicated dietary restrictions and poor appetite.

This review will discuss the diagnosis, prevalence, risk factors, etiology, pathophysiology, and clinical impacts of sarcopenia in CKD, focusing on the effects of CKD complications on sarcopenia. We will also review the therapeutic interventions for prevention and treatment of sarcopenia in CKD, mainly based on available evidence of the studies in patients with CKD and sarcopenia simultaneously.

The diagnosis and prevalence of sarcopenia in chronic kidney disease

Sarcopenia is considered according to the consensus definition of the European Working Group on Sarcopenia in Older People (EWGSOP2 2018) [4], the Asian Working Group for Sarcopenia (AWGS 2019 Consensus Update) [5], the Foundation for the National Institutes of Health Sarcopenia Project (FNIH) [3], and the International Working Group on Sarcopenia (IWGS) [2]. However, the above consensus definition for sarcopenia was defined as “age-related loss of muscle mass, plus low muscle strength, and/or low physical performance,” and the recommended cutoff points for various criteria were validated by evidence from older persons. The direct application of these diagnostic criteria in patients with CKD may be questionable because patients with CKD consist of younger patients, and complications of CKD make these patients more vulnerable to sarcopenia. However, until a specific definition for “sarcopenia in CKD” becomes available, research and clinical practice for sarcopenia in CKD will still depend on the above diagnostic criteria.

The operational definition of sarcopenia, updated by EWGSOP2 consensus in 2018, recommends the following: 1) identifying “probable sarcopenia” by low muscle strength (measured by grip strength and chair stand test) (Table 1), 2) confirming the diagnosis of “sarcopenia” by low muscle quantity or quality (estimated by appendicular skeletal muscle mass [ASMM], or further adjusted for height squared, etc.), and 3) considering “severe sarcopenia” by low physical performance (assessed by gait speed, the Short Physical Performance Battery, the Timed-up-and-go [TUG] test, and the 400-m walk test, etc.) [4]. On the other hand, AWGS consensus in 2019 suggests the following: 1) identifying “possible sarcopenia” by either low muscle strength or low physical performance only, 2) confirming the diagnosis of “sarcopenia” by low ASMM and low muscle strength, and 3) diagnosing “severe sarcopenia” by additional concomitant low physical performance [5]. In addition to the different definitions of diagnosis proposed by these two working groups, different cutoff points of the various assessments to evaluate muscle mass, strength, and physical performance are also noted (Table 1).

According to a systematic review and meta-analysis enrolling 42,041 CKD patients from 140 studies across 25 countries, the global prevalence of sarcopenia in CKD was 24.5% (95% confidence interval [95% CI], 20.9–28.3) and did not differ among CKD stages (p = 0.33). Low muscle strength was found in 43.4% (95% CI, 35.0–51.9), low muscle mass in 29.1% (95% CI, 23.9–34.5), and low physical performance in 38.6% (95% CI, 30.9–46.6) for overall patients with CKD. Prevalence was only higher in patients on dialysis (50.0%; 95% CI, 41.7–57.4) compared to non-dialysis (19.6%; 95% CI, 12.8–27.3; p < 0.01) for low muscle strength. Patients on dialysis were more prone to low muscle strength and severe sarcopenia [7]. In a cross-sectional analysis in a cohort of 260 patients with non–dialysis-dependent CKD in Japan, the prevalence of sarcopenia, using criteria of AWGS 2014 [8], increased with CKD stage: 17% and 20% in stage 3A and 3B, 29% in stage 4, and increased to 39% in stage 5 [9], suggesting the progression of CKD may worsen sarcopenia. Another study in Sweden showed that among patients with CKD stages 3–5, the loss of lean body mass, especially appendicular skeletal muscle, was significantly related to glomerular filtration rate (GFR) decline [10], providing evidence that the severity of sarcopenia increased as residual renal function deteriorated.

The risk factors, etiology, and pathophysiology of sarcopenia in chronic kidney disease

As shown in Fig. 1, the coexistence of aging, CKD, and other comorbidities is very common. In patients without CKD, aging itself may directly result in sarcopenia, whereas aging-related cognitive dysfunction or depression may cause physical inactivity, malnutrition, and following sarcopenia. Along with aging, common comorbidities such as diabetes mellitus, cardiovascular diseases, infections, and chronic inflammatory diseases, that are not caused by CKD, are frequently found in patients with CKD. These comorbidities may also contribute to physical inactivity, malnutrition, and inflammation, which may exist before CKD develops, but may be aggravated by the progression of CKD.

In patients with CKD, the uremic complications develop and increase in severity as the residual renal function deteriorates. Along with the uremic toxins accumulate, metabolic acidosis and other uremic complications worsen as CKD progresses toward end-stage kidney disease (ESKD). The worsening uremic complications, along with hormonal changes, including insulin-resistance–related decreased insulin-like growth factor-1 (IGF-1) signaling, decreased sex hormones and vitamin D, with increased levels of angiotensin II and myostatin (a regulator enhancing muscle protein proteolysis and muscle atrophy, and inhibiting growth of skeletal muscles), accelerate the muscle protein degradation, that is the major pathophysiology of uremic sarcopenia. Besides, the decreased muscle protein synthesis caused by malnutrition and insulin resistance, and the decreased muscle regeneration caused by increased uremic toxins and myostatin, both contribute to uremic sarcopenia.

The more detailed pathophysiology of sarcopenia in CKD is shown in Fig. 2. After muscle injury or stimuli by growth factors, the usually quiescent satellite cells in the muscle begin to proliferate and differentiate into myoblasts and then myocytes. The myocytes fuse and further differentiate to form myofibrils to repair or enlarge muscles. Impaired insulin/IGF-1 signaling and elevated myostatin levels both inhibit the activation and proliferation of the satellite cells in the muscles, therefore retard the regeneration and growth of the muscle. Further, muscle protein degradation, the most dominant pathophysiology of sarcopenia in CKD, results from physical inactivity, malnutrition, metabolic acidosis, proinflammatory cytokines-induced activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and myostatin-induced Smads pathway and Forkhead box O (FoxO) signaling. These changes in CKD enhance muscle protein degradation through specific intracellular mechanisms, including enhancing the ubiquitin-proteosome (UPS) pathway [11], caspase 3, autophagic lysosomes, and atrogenin-1 [6,12–14]. On the other hand, muscle protein synthesis is reduced in patients with CKD by impaired insulin/IGF-1 signaling and decreased anabolic hormones through inhibiting Akt/mammalian target of rapamycin (mTOR) pathway.

In clinical practice, the etiology of sarcopenia in CKD is usually multifactorial and complicated. The coexistence of several above causes of sarcopenia in CKD is very common and should be evaluated carefully and managed simultaneously.

Clinical impact of sarcopenia in chronic kidney disease

In the elderly, sarcopenia is associated with an increased risk of recurrent falls [15], a lower quality of life [16], and an increased risk of death [17]. In patients with CKD, previous studies have revealed that sarcopenia, particularly the loss of muscle strength, is associated with increased mortality [18–20]. One study enrolling 8,767 patients with CKD showed that sarcopenic CKD individuals had a 10-year adjusted survival probability of 0.85 (95% CI, 0.82–0.88) compared with 0.89 (95% CI, 0.88–0.90) in those without sarcopenia, while sarcopenic CKD patients were twice as likely to develop ESKD than those without sarcopenia after adjusting for age, sex, ethnicity, and number of comorbidities [20]. In patients receiving hemodialysis (HD) and those with non–dialysis-dependent CKD, sarcopenia was shown to be a good predictor of mortality [21,22]. Besides, in patients receiving HD, sarcopenia was proved to be also a good predictor for cardiovascular events [21]. In a recently published study that included 323,801 participants with a median follow-up of 11.8 years, 20,146 participants died from all causes. Compared with participants with normal kidney function and without sarcopenia, those with both mild kidney dysfunction (estimated GFR [eGFR], 60.0–89.9 mL/min/1.73 m²) and sarcopenia (defined according to the criteria of EWGSOP2) had a higher risk of all-cause mortality (hazard ratio, 1.61; 95% CI, 1.52–1.71), with a significant overall additive interaction [23].

In contrast to the elderly, among pediatric patients (4–18 years old) with CKD, the prevalence of sarcopenia and its related traits, assessed by handgrip strength, 60-second sit-to-stand (STS-60) tests, and anthropometry through measurement of mid-upper arm circumference, was greater than 50% [24]. Because of such high prevalence, the assessment of sarcopenia in pediatric patients with CKD should be considered, while more evidence is needed to determine its prognostic value and clinical impacts.

Therapeutic interventions for sarcopenia in chronic kidney disease

Nutritional interventions

Dietary protein restriction can reduce the risk of CKD progression, therefore in patients with stage 3–5 non-dialytic CKD who are metabolically stable, the Kidney Disease Quality Initiative-National Kidney Foundation (KDOQI-NKF) clinical practice guideline for nutrition in CKD updated in 2020 [25] recommends protein restriction with or without keto acid analogs to reduce risk for ESKD/death. A protein intake of 0.6–0.8 g/kg/day for diabetic patients, or a low-protein diet providing 0.55–0.60 g/kg/day (or a very low-protein diet providing 0.28–0.43 g/kg/day with additional keto acid/amino acid analogs to meet the recommended protein requirements) for nondiabetic patients, along with an energy intake of 25–35 kcal/kg/day, based on age, sex, physical activity, body composition, weight goals, CKD stage, and concurrent illness or inflammation should be given to maintain normal nutritional status. However, in sarcopenic patients, a higher protein diet is usually recommended to diminish or even reverse sarcopenia. Because CKD progression and sarcopenia both increase morbidity and mortality, how much protein intake is adequate in CKD patients with sarcopenia, especially in the elderly, remains a challenging unsolved problem.

In the elderly not with CKD, the European Society for Clinical Nutrition and Metabolism (ESPEN) guideline [26] recommends protein intake in older persons should be at least 1 g/kg/day with an energy intake of 30 kcal/kg/day, while protein intake <1 g/kg/day is associated with loss of muscle mass in non-CKD elderly [27]. The PROT-AGE study group recommends an average protein intake of at least 1.0–1.2 g/kg/day in older people (>65 years), and even 1.2–1.5 g/kg/day for the elderly with acute or chronic illness. However, in the elderly with CKD, the PROT-AGE study group recommends a protein intake of 0.8 g/kg/day for patients with GFR <30 mL/min/1.73 m² and >0.8 g/kg/day if GFR is 30–60 mL/min/1.73 m² [28].

Interventional studies in patients with CKD stages 3–5 not on dialysis using a moderate-to-low protein diet (0.6–0.8 g/kg/day) or very low-protein diet (0.3–0.4 g/kg/day) supplemented with essential amino acids or their keto-analogs, with simultaneous adequate energy intake, have shown that the lower dietary protein intake in metabolically stable CKD patients still could preserve good nutritional status [29,30]. Of note, controlling the protein intake in elderly patients with CKD 3–5 can be beneficial but only if accompanied by a sufficient energy intake to prevent impaired protein degradation and the risk of muscle wasting [31]. It requires particular attention that if signs of muscle wasting occur, the priority of the goals of dietary interventions should be to interrupt the loss of muscle mass and recover nutritional status. Therefore, a protein intake of 0.8–1 g/kg/day with an energy intake of 30 kcal/kg/day may be more sufficient to provide the nutritional needs to achieve these goals until the wasting state improves [32].

Besides, a cross-section study [33] showed that in 418 nondiabetic elderly men with stages 3–5 CKD, adherence to a plant-based diet was associated with higher insulin sensitivity and lower inflammation markers, suggesting plant-based diets may prevent metabolic complications of CKD, such as sarcopenia. Real-world evidence provided by a prospective observational study enrolling 148 patients with stage 4–5 CKD showed that keto-analog supplementation for 12 months prevented skeletal muscle mass loss [34]. However, further randomized controlled trials (RCTs) remain required to elucidate the effects of various nutritional interventions in different populations with CKD stage 3–5 not on dialysis.

For patients receiving dialysis, a previous cohort study indicated that low dietary protein intake is associated with a higher risk for mortality [35]. The KDOQI-NKF guideline recommends a dietary protein intake of 1.0–1.2 g/kg/day (or higher in diabetic patients) for patients receiving dialysis [25]. However, for patients receiving dialysis, if sarcopenia occurred already, the adequate nutritional intervention to improve the skeletal muscle protein homeostasis remains unknown.

An interventional study in patients receiving chronic HD with deranged nutritional status showed that both intradialytic parenteral nutrition (IDPN) and oral nutrition during HD attempting to match the nutritional content provided by IDPN improved skeletal muscle protein homeostasis assessed by protein turnover studies [36]. Oral nutritional supplement with branched-chain amino acid 12 g per day for 6 months improved lean body mass in elderly malnourished HD patients receiving chronic HD [37], and essential amino acid supplementation 3.6 g three times daily with meals for 3 months increased handgrip strength significantly in HD patients with hypoalbuminemia [38].

Exercise and combination of exercise and nutritional interventions

Evidence from studies on healthy elderly showed that exercise, especially resistance training, and physical activity improved muscle mass/strength and physical performance. In addition, doing resistance exercise while increasing protein intake may help the utilization of ingested amino acids for enhancing protein synthesis [39]. Further, protein supplementation increased muscle mass and strength gains during prolonged resistance-type exercise training [40].

In the non-dialysis CKD population, fewer studies exploring the effects of exercise on sarcopenia are available. An early RCT enrolling 26 older patients with moderate renal insufficiency achieved stabilization on a low-protein diet [41] showed that the addition of resistance training improved muscle strength and muscle mass. The RENEXC study compared balance and resistance exercise, both combined with endurance training, in 151 patients with CKD stages 3–5 for 4 months and reported a significant improvement in muscle strength and physical performance in both groups [42]. In addition, in a prespecified sub-analysis of the same study with a prolonged 12-month duration of the intervention, both exercise training seemed to be effective in preventing sarcopenia and maintaining muscle mass in non-dialysis CKD patients [43]. In the LIFE-P study [44], elderly CKD patients derived clinically meaningful benefits from physical activity intervention for 12 months. In non-dialysis patients with CKD stages 3b-5, the addition of resistance exercise to aerobic exercise for 12 weeks led to greater increases in muscle mass and strength in CKD patients than aerobic exercise alone [45]. An RCT in 40 overweight CKD patients showed that those doing home-based aerobic exercises had similar improvements in functional capacity tests (6-min walking test, 2-min step test, sit-to-stand, arm curl test, sit-and-reach test, and TUG) as those doing center-based exercises, with no changes seen in the control group (no exercise) [46]. A recent scoping review included 20 articles investigating the application of exercise therapy in patients with CKD-induced muscle atrophy and concluded that exercise intervention, primarily resistance training, can improve muscle strength, physical function, and quality of life in patients with CKD-induced muscle atrophy [47].

In a single-blind RCT [48] enrolling 23 HD patients, the thigh muscle volume and strength both increased in the patients who received progressive resistance exercise training thrice weekly for 12 weeks, compared with patients who received low-intensity lower body stretching activities as a control. In the EXCITE trial, a recent multicenter RCT [49] enrolling 296 patients receiving dialysis, a simple personalized walking exercise program at home for 6 months improved the physical performance assessed by a 6-minute walking test and the five times sit-to-stand test. An RCT enrolling 41 patients receiving maintenance HD with sarcopenia (AWGS criteria 2014) [50] showed that progressive intradialytic resistance exercise with high or moderate intensity for 12 weeks at three times per week on the basis of routine HD care can effectively improve physical activity status (grip strength, daily pace, and physical activity level), even if this simple exercise does not affect the muscle mass in maintenance HD patients with sarcopenia. A recent RCT involving 1,211 HD patients [51] showed that thrice-weekly supervised cycling and personalized resistance exercises during HD sessions for 12 months improved physical performance. This was assessed using an STS-60 test, which measures lower limb strength and endurance, as well as the TUG test and the 6-minute walk test. The study also revealed that supervised intradialytic exercise can be delivered safely, with similar adverse event rates and mortality between the exercise and usual care group (Table 2).

Correction of metabolic acidosis

Chronic metabolic acidosis, usually develops as GFR decreases, increases skeletal muscle protein degradation by the UPS pathway in CKD patients. Current KDOQI clinical practice guidelines for CKD [52] recommend pharmacological treatment with or without dietary interventions to prevent the development of acidosis. A recent meta-analysis including 1,995 patients in 12 interventional studies showed that correcting metabolic acidosis significantly improved muscle mass (assessed by mid-arm muscle circumference) and physical performance (assessed by sit-to-stand test) [53]. In a study enrolling 134 patients with advanced CKD (eGFR of 15–30 mL/min/1.73 m²) with metabolic acidosis, oral sodium bicarbonate administration for 2 years led to an increase in the mid-arm circumference, protein intake, and serum albumin levels [54]. An RCT including 200 new patients receiving continuous peritoneal dialysis (CAPD) showed that high alkali dialysate and oral sodium bicarbonate for 1 year resulted in an increase in body weight and mid-arm circumference and fewer hospitalizations in the first year of CAPD [55]. In addition, in a study with 46 stable HD patients, dialysate with a higher bicarbonate concentration (40 mmol/L) resulted in better control of acidosis, however, no differences in mid-arm circumference after 6 months [56].

Pharmacological interventions

Myostatin pathway inhibition

Myostatin, a member of the transforming growth factor superfamily, inhibits skeletal muscle growth and enhances muscle proteolysis and atrophy. Therefore, myostatin pathway inhibition may have roles in treating sarcopenia. In animal models and limited human studies, myostatin pathway inhibition has increased muscle size. Agents for myostatin pathway inhibition, such as monoclonal antibodies and soluble receptors, are being developed to treat obesity, sarcopenia, muscular dystrophy, and others. Though myostatin pathway inhibition revealed promising effects on increasing muscle mass in previous animal models, limited RCTs in humans are currently available. Bimagrumab, a monoclonal antibody directly against both activin type 2 receptor subtypes, prevents myostatin and activin from binding to their receptors, therefore inhibits myostatin pathway. In a phase 2 RCT enrolling 75 obese type 2 diabetic patients, bimagrumab for 48 weeks increased lean body mass and reduced fat mass in obese patients [57].

Vitamin D

In addition to regulating calcium homeostasis and bone metabolism, vitamin D also regulates skeletal muscle homeostasis, including muscle cell differentiation and proliferation [58]. An earlier study showed that vitamin D led to improvements in physical function and isometric strength in CKD stage 3–4 and peritoneal dialysis patients with initial vitamin D deficiency [59]. Another study also showed vitamin D supplementation in male HD patients improved muscle mass [60]. However, in an RCT including 68 HD patients with an initial 25(OH)D concentration <50 nmol/L, cholecalciferol 50,000 U/wk with the target of 25(OH)D concentration >80 nmol/L had no effect on muscle strength [61]. Besides, in an RCT enrolling 60 HD patients with a 25(OH)D concentration <60 nmol/L, oral cholecalciferol 50,000 U/wk for 8 weeks and then monthly for 4 months did not change muscle strength, functional capacity, and quality of life [62].

Selective androgen receptor modulators

Selective androgen receptor modulators (SARMs) are ligands that bind to androgen receptor selectively in certain tissues in the body. Some SARMs have strong anabolic effects and weak androgenic effects, and are used to treat anemia, osteoporosis, and muscle wasting. In an RCT enrolling 29 HD patients, weekly intramuscular nandrolone decanoate for 6 months significantly increased lean body mass, improved functional capacity (walking and stair-climbing test) [63]. Another RCT involving 79 HD patients showed that nandrolone decanoate combined with intradialytic resistance training for 12 weeks increased the quadriceps muscle cross-sectional area in an additive manner, while patients who received nandrolone decanoate increased their lean body mass by 3.1 ± 2.2 kg (p < 0.0001) [64]. In an RCT enrolling 43 HD patients, oral anabolic steroid oxymetholone for 24 weeks showed an increase in fat-free mass, handgrip strength, and physical functioning scores as well as an increase in mRNA expression levels for several growth factors and a decrease in fat mass, but it also induced liver injury [65]. Notably, the increase in muscle mass caused by anabolic hormones may not be accompanied by a significant improvement in physical performance or muscle strength. Therefore, the long-term effectiveness, benefits, and risks of these agents in CKD patients with sarcopenia require further detailed studies.

Megestrol acetate

The appetite stimulant megestrol acetate (MA) was considered as a possible therapeutic approach for sarcopenia in CKD. However, a review of five small population-based retrospective studies in CKD patients revealed that MA increased body mass index, albumin levels, and reported protein and energy intake whereas potential adverse effects were noted, including venous thrombosis, liver injury, edema, impotence, hyperglycemia, diarrhea and gynecologic bleeding [66]. A systematic review for oral MA in dialysis patients revealed a significant increase in body weight, albumin levels, and appetite, although the nine enrolled studies were small with short duration (<24 weeks) and a high degree of bias. Adverse effects of MA were noted, including overhydration/excessive fluid gain, diarrhea, hyperglycemia, excessive weight gain, etc. The author concluded that oral MA should be used with significant caution, and only when other treatment options are unavailable [67].

Growth hormone

Growth hormone/IGF-1 axis increases muscle mass, and factors resulting in growth hormone resistance in patients with CKD include metabolic acidosis, inflammation, reduced food intake, and uremia [68]. In an RCT enrolling 20 elderly HD patients, recombinant human growth hormone (rhGH) for 6 months increased serum albumin, fat-free mass, and handgrip strength [69]. In another RCT enrolling 139 HD patients [70] rhGH treatment for 6 months increased lean body mass and improved health-related quality of life. However, a large multicenter RCT (OPPORTUNITY) investigating the long-term effects of rhGH in maintenance HD patients [71] was early terminated due to slow recruitment. In healthy elderly, the adverse effects of rhGH included soft tissue edema, arthralgia, carpal tunnel syndrome, gynecomastia, and dysglycemia [72].

Probiotics and oral adsorbents

The concept of kidney-gut-muscle axis suggests that dysbiosis and gut-derived uremic toxins, along with short-chain fatty acids, influence muscle mass, strength, and function through inflammation and insulin resistance. While probiotics improved muscle mass and function in rodents, evidence in humans remains unclear due to limited studies, population variability, and challenges in measuring muscle mass/strength and physical performance [73]. Another interventional approach for gut-derived uremic toxins, oral adsorbents, were also investigated for its possible benefit on sarcopenia. In an RCT (RECOVERY study) enrolling 150 patients with CKD, the 48-week treatment of AST-120, an oral adsorbent of indoxyl sulfate, had only modestly beneficial effects on gait speed change and quality of life and showed the potential to improve sarcopenia [74] (Table 3).

In conclusion, many pharmacological interventions have shown weak evidence and are only supported by poorly designed clinical trials. Therefore, pharmacological treatments are not recommended for sarcopenia, and there are currently no U.S. Food and Drug Administration-approved medications for the condition.

Future studies

The application of creatinine-based methods for estimating kidney function may be significantly biased by the presence of sarcopenia, therefore using cystatin C-based methods to estimate kidney function will be more feasible and will help to obtain more convincing evidence for investigating sarcopenia in CKD. Additionally, the current diagnostic criteria for sarcopenia should be further validated in the CKD population, and different cutoff values for various assessments may be required for diagnosing sarcopenia in patients with CKD. More detailed and rigorous research to understand the interactions of inflammation, anabolic resistance, exercise, and nutrition on muscle protein degradation and synthesis in patients with CKD will hopefully accelerate discoveries and treatments to ameliorate muscle wasting as well as the progression of CKD. Future studies should focus on validating diagnostic criteria for sarcopenia specifically in CKD populations and exploring the efficacy of combined nutritional and exercise interventions through large-scale RCTs.

Conclusion

In conclusion, the application of current diagnostic criteria, originally developed for the elderly, may require further validation in the CKD population. A better understanding of the risk factors and clinical impacts of sarcopenia in CKD will facilitate the early detection and management of this challenging clinical problem. Present strategies to prevent and manage sarcopenia include integrating nutritional and exercise interventions, along with correcting metabolic acidosis. The adequate application of vitamin D, MA, hormone therapies, probiotics, and oral adsorbents may provide additional benefits in treating sarcopenia in CKD.

Notes

Conflicts of interest

All authors have no conflicts of interest to declare.

Funding

This study was funded by grants from the Taiwan National Science and Technology Council (MOST 110-2314-B-002-130 and NSTC-111-2314-B-002-236-MY3) and grants from the National Taiwan University Hospital (NTUH-108-P02, NTUH-109-P09, NTUH-113-S0195).

Data sharing statement

The data presented in this study are available from the corresponding author upon reasonable request.

Authors’ contributions

Conceptualization: SYY, CKC

Supervision: CKC, KYH

Validation: JHC, CKC

Visualization: JHC, CKC, KYH

Writing–original draft: SYY

Writing–review & editing: JHC, CKC, KYH

All authors read and approved the final manuscript.

Figure 1.

Sarcopenia in CKD: risk factors, etiology, pathophysiology, and clinical impacts.

CKD, chronic kidney disease; ESKD, end-stage kidney disease; IGF-1, insulin-like growth factor-1.

Figure 2.

Simplified illustration of the molecular mechanisms of regulation of muscle satellite cells activation and proliferation, as well as muscle protein degradation and synthesis, in the pathophysiology of uremic sarcopenia.

CKD, chronic kidney disease; FoxO, Forkhead box O; IGF-1, insulin-like growth factor-1; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells.

Table 1.

Comparison of the definitions and cutoff points of sarcopenia suggested by Consensus EWGSOP2 2018 and AWGS 2019

EWGSOP2 2018	AWGS 2019
Possible sarcopenia	Possible sarcopenia
Low muscle strength	Low muscle strength
Handgrip strength (M: <27 kg, F: <16 kg)	Handgrip strength (M: <28 kg, F: <18 kg)
Chair stand test >15 sec for five rises	or
	Low physical performance
	5-time chair stand test ≥12 sec
Sarcopenia	Sarcopenia
Low muscle strength +	Low muscle strength + one of the following two criteria:
Low muscle quantity or quality	Low muscle mass
ASMM (M: <20 kg, F: <15 kg) or	ASMM measured by DEXA (M: <7.0 kg/m², F: <5.4 kg/m²) or by BIA (M: <7.0 kg/m², F: <5.7 kg/m²)
ASMM/Height² (M: <7.0 kg/m², F: <5.5 kg/m²) assessed by DEXA or BIA	or
or	Low physical performance
Lumbar muscle cross-sectional area by CT or	6-m walk <1.0 m/sec
MRI	or 5-time chair stand test ≥12 sec
	or SPPB ≤9 point
Severe sarcopenia	Severe sarcopenia
Low muscle strength +	Low muscle strength +
Low muscle quantity/quality +	Low muscle mass +
Low physical performance	Low physical performance
Gait speed ≤0.8 m/sec
SPPB ≤8 point
TUG ≥20 sec
400-m walk: non-completion or ≥6 min

ASMM, appendicular skeletal muscle mass; AWGS, Asian Working Group for Sarcopenia; BIA, bioelectrical impedance analysis; CT, computed tomography; DEXA, dual-energy X-ray absorptiometry; EWGSOP, European Working Group on Sarcopenia in Older People; F, female; M, male; MRI, magnetic resonance imaging; SPPB, Short Physical Performance Battery (with a maximal score 12 points, is a composite test that includes assessment of gait speed, a balance test, and a chair stand test); TUG, Timed-up-and-go test (in which individuals are asked to rise from a standard chair, walk to a marker 3 m away, turn around, walk back and sit down again).

Table 2.

RCTs of nutritional and exercise interventions for sarcopenia in patients with CKD

Intervention	Patients	Main results related to sarcopenia
Branched-chain amino acid 12 g/day orally for 6 months [37]	RCT with crossover design enrolling 28 elderly malnourished HD patients	Increased lean body mass
Essential amino acid 3.6 g 3 times daily orally with meals for 3 months [38]	RCT enrolling 29 HD and 18 PD patients	Increased grip strength (statistically borderline significance) in HD patients
Resistance training 3 times/wk under the supervision of an exercise physiologist for 12 weeks [41]	RCT enrolling 26 older CKD patients who had achieved stabilization on a low-protein (0.6 g/kg/day) diet	Increased muscle mass and muscle strength
Exercise consisting of endurance in combination with either strength or balance exercise training, 150 min/wk for 4 months [42]	RCT including 151 non-dialysis dependent CKD patients	Improvements in muscle strength and physical performance in both groups
Exercise consisting of endurance in combination with either strength or balance exercise training, 150 min/wk for 12 months [43]	RCT including 151 non-dialysis dependent CKD patients	Unchanged prevalence of sarcopenia (EWGSOP2 2018) versus baseline
	RCT including 151 non-dialysis dependent CKD patients	Lean mass increased in balance group but unchanged in strength group
Combination of resistance and aerobic exercise versus aerobic exercise alone, 30 minutes for 3 times/wk for 12 weeks [45]	RCT enrolling 41 non-dialysis patients with CKD 3b–5	Increased muscle strength in both groups, greater in combination group
Home-based and center-based exercise versus control group without exercise for 24 weeks [46]	RCT enrolling 40 overweight non-dialysis CKD 3–4 patients	Improved functional capacity tests in both exercise groups
Progressive resistance exercise training during HD thrice weekly for 12 weeks [48]	RCT enrolling 23 HD patients and 9 healthy participants	Increased muscle mass and strength in HD patients
	RCT enrolling 23 HD patients and 9 healthy participants	No effects on lower body functional capacity in HD patients
Individualized, home-based, low-intensity personalized program of walking exercise for 6 months [49]	Multicenter RCT enrolling 296 patients receiving dialysis	Improvement in physical performance assessed by 6-minute walking test and 5 times sit-to-stand test
Progressive intradialytic resistance exercise with high or moderate intensity 3 times/wk for 12 weeks [50]	RCT enrolling 41 HD patients with sarcopenia (AWGS criteria 2014)	Improved physical activity status (grip strength, daily pace, and physical activity level)
		No effect on muscle mass
Thrice-weekly supervised cycling and personalized resistance exercise during HD for 12 months [51]	RCT enrolling 1,211 HD patients	Improved physical performance assessed by 60-second sit-to-stand test, timed up-to-go test, and 6-minute walk test

CKD, chronic kidney disease; EWGSOP, European Working Group on Sarcopenia in Older People; HD, hemodialysis; PD, peritoneal dialysis; RCT, randomized control trial.

Table 3.

RCTs of pharmacological interventions for sarcopenia, especially in patients with CKD

Medication	Patients	Main results related to sarcopenia
Activin type 2 receptor monoclonal antibody
Bimagrumab [57]	RCT enrolling 75 obese type 2 diabetic patients	Increased lean body mass
Bimagrumab [57]	RCT enrolling 75 obese type 2 diabetic patients	Decreased fat mass
Vitamin D
Cholecalciferol [61]	RCT enrolling 68 HD patients with initial 25(OH)D <50 nmol/L	No effect on muscle strength
Cholecalciferol [62]	RCT enrolling 60 HD patients with initial 25(OH)D <60 nmol/L	No effect on muscle strength and functional capacity
Selective androgen receptor modulators
Nandrolone decanoate [63]	RCT enrolling 29 HD patients	Increased lean body mass
		Increased function capacity (time to complete the walking and stair-climbing test)
		No effect on grip strength
Nandrolone decanoate [64]	RCT enrolling 79 HD patients	Increased lean body mass
Nandrolone decanoate [64]	RCT enrolling 79 HD patients	Increased quadriceps muscle cross-sectional area
Oxymetholone [65]	RCT enrolling 43 HD patients	Increased fat-free mass
		Increased handgrip strength
		Decreased fat mass
Growth hormone
Recombinant human growth hormone [69]	RCT enrolling 20 elderly HD patients	Increased fat-free mass
Recombinant human growth hormone [69]	RCT enrolling 20 elderly HD patients	Increased handgrip strength
Recombinant human growth hormone [70]	RCT enrolling 139 HD patients	Increased lean body mass
Other agents
AST-120 [74]	RCT enrolling 150 CKD patients	No significant difference in gait speed
AST-120 [74]	RCT enrolling 150 CKD patients	No effect on hand grip strength

CKD, chronic kidney disease; HD, hemodialysis; RCT, randomized control trial; 25(OH)D, 25-hydroxyvitamin D.

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