Chronic kidney disease (CKD) is abnormalities of kidney structure or function that are present for more than three months, and is implicated in cardiovascular, metabolic, and endocrine complication, as well as premature mortality (1). More than 10% of the general population is affected by CKD, which accounted for an estimated 843.6 million patients worldwide in 2017 (2). CKD is classified based on cause, glomerular filtration rate (GFR), and albuminuria category (1). End-stage renal disease (ESRD) is a terminal illness with a GFR of less than 15 ml/min that requires a renal replacement therapy (RRT), including regular course of dialysis or kidney transplantation (3). The global prevalence of CKD stage 5, with GFR of less than 15 ml/min, is estimated at 0.1% of the global population, which is approximately 7.9 million people (4). Among them, 3.3 million people are in an ESRD state, and require RRT (5). In South Korea, the proportion of RRT is 84% with hemodialysis (HD), 4% with peritoneal dialysis (PD), and 12% with kidney transplant (KT), and the total number of RRT increased annually by 7.0% (6). In ESRD patients undergoing hemodialysis, sarcopenia prevalence was 28.5%, which varied in the range 25.9-35.6%, and sarcopenia was related to 80% increased mortality risk (7). Given the escalating prevalence of ESRD patients and the significant clinical impact of sarcopenia, investigations into the underlying mechanisms and treatment strategies for muscle wasting in these patients are ongoing.
Patients with ESRD experience muscle wasting that overwhelms the normal aging process. Age-related muscle loss begins at around age 30, with approximately 3-8% muscle mass decrease per decade, and the loss is even higher after age 60 (8). At age 75, muscle strength is lost at a rate of 3-4% per year in men, and 2.5-3% per year in women (9). As a result, elderly individuals lose 12% of their muscle mass in their 60s, and 30% in their 80s (10). In a study of 286 HD patients with a mean age of 65.8 ± 13.0 years, the annual change of psoas muscle mass index was −9.5% (11).
Muscle wasting in ESRD patients is attributed to a variety of factors that collectively contribute to the progressive loss of muscle mass in this population. Metabolic acidosis and impaired insulin/IGF-1 signaling pathways disrupt the regulation of muscle protein synthesis and degradation, leading to muscle atrophy (12). Chronic inflammation, dysregulated appetite regulation, and altered microRNA expression patterns also contribute to muscle wasting in ESRD (13). Further, dialysis itself involves a filtration process that results in the significant loss of amino acids (14). Muscle wasting by the multiple factors described above has significant impact on physical function. Moreover, sarcopenia was associated with higher cardiovascular events (OR = 3.80) (15). Both muscle wasting and the deterioration of physical function in ESRD patients receiving HD are associated with increased mortality (11, 16). Patients with low hand-grip strength (HGS) had an almost twofold higher risk of all-cause mortality (HR = 1.99), compared to those with high HGS. Additionally, individuals with slow gait speed had a greater risk of all-cause mortality (HR = 2.45), in comparison to those with fast gait speed (16). In brief, various pathological factors and the protein loss during dialysis significantly accelerate muscle wasting in patients with ESRD, which has a detrimental effect on physical function and mortality.
Numerous trials have been conducted to prevent and address muscle wasting in patients with ESRD. These trials could be categorized as nutritional intervention, pharmacological therapy, exercise, and physical modalities intervention (12). Typical nutritional interventions include the supplementation of amino acids, proteins, vitamin D, and probiotics. On the pharmacological front, strategies involve myostatin inhibitors, interleukin-1 blockade, ghrelin and leptin regulation, and the utilization of miRNAs. Physical activities, like aerobic and resistance exercises, are key strategies to combat muscle wasting. The final facet of intervention, physical modalities, comprises methodologies such as neuromuscular electrical stimulation, extracorporeal shockwave therapy, and photobiomodulation.
In this review, we present a comprehensive analysis of muscle wasting in ESRD, encompassing various aspects from assessment techniques to therapeutic interventions. Initially, we explore the methods of assessing muscle mass and function in humans, which serves as a foundation to understand the clinical manifestations of muscle mass and function in ESRD patients. We subsequently probe the intricate molecular mechanisms responsible for muscle wasting in ESRD, thereby forging a connection between theoretical constructs and practical patient experiences. We conclude with a discussion on current and emerging strategies aimed at mitigating muscle wasting in ESRD, including dietary adjustments, exercise routines, and novel therapeutic approaches. Finally, this review provides insightful perspectives on muscle wasting in ESRD patients.
The idea of sarcopenia, which refers to the reduction in skeletal muscle mass associated with aging, was initially introduced in 1989 by Irwin Rosenberg (17). The concept of sarcopenia has evolved to assess not just muscle mass, but to also include muscle strength and physical performance from the 2010 sarcopenia criteria by the European Working Group on Sarcopenia in Older People (EWGSOP) (18). Currently, sarcopenia is defined as a progressive and generalized skeletal muscle disorder that involves the accelerated loss of muscle mass and function (19). The latest guideline from the Korean Working Group on Sarcopenia (KWGS) has classified sarcopenia into three domains: severe sarcopenia, sarcopenia, and functional sarcopenia.
Severe sarcopenia is defined as a state of decreased muscle mass in the presence of both weak muscle strength and decreased physical performance.
Sarcopenia refers to decreased muscle mass combined with either low muscle strength or poor physical performance.
Functional sarcopenia is classified as a state of weak muscle strength and low physical performance, without a loss of muscle mass.
Muscle mass can be estimated by appendicular skeletal muscle mass measurement using dual-energy X-ray absorptiometry (DEXA) and bioimpedance analysis (BIA). Using the skeletal muscle index (SMI), which is calculated by dividing the ASM by the square of the height, the KWGS criteria discriminate decreased muscle mass; according to the DEXA method, < 7.0 kg/m2 in male and < 5.4 kg/m2 in female; and in the BIA method, < 7.0 kg/m2 in male and < 5.7 kg/m2 in female. In terms of muscle strength, KWGS recommends hand-grip strength as a surrogate index for measuring muscle strength, due to its accessibility; low muscle strength is < 28 kg in male, and < 18 kg in female.
Physical performance is assessed by the Short Physical Performance Battery (SPPB), which includes gait speed, static balance, and five-time chair stand test. To measure gait speed, participants are requested to walk a distance of either 3 or 4 meters at their normal pace. Gait speed of less than 1.0 m/s is regarded as low performance. The balance examination involves a series of stances: side-by-side, semi-tandem, and tandem, where the participant is required to maintain each stance for at least 10 seconds. The chair stand test prompts individuals to rise from a seated position in a chair five times, without the assistance of their arms. For the five-time sit-to-stand test, a low performance is indicated by taking more than 10 seconds to end in a standing position, and more than 11 seconds to end in a sitting position. Every component is rated from 0 to 4, allowing for a maximum achievable score of 12 points. A SPPB score of 9 or less is considered low performance (20).
There are some limitations in the assessment of sarcopenia in ESRD patients using current guidelines or consensuses for the geriatric population. First, unlike the general population, ESRD patients undergoing dialysis exhibit fluctuations in fluid status that depend on their dialysis schedule. Although DEXA is regarded as a reference method for assessing body composition, excess extracellular water (ECW) with overhydration is added to lean body mass (LBM), leading to the overestimation of muscle mass. The problem of overestimation also applies to classic two-compartment models of single- and multi-frequency BIA (SF- and MF-BIA), which divide the body into two compartments of fat mass and fat-free mass (FFM), as excessive extracellular water (ECW) is included in the FFM measurement (21). To address this issue, three-compartment bioelectrical impedance spectroscopy (3C-BIS) has been established. This model can distinguish overhydration from lean tissue mass and adipose tissue mass (22). However, current guidelines or consensuses do not specify cut-off values for 3C-BIS; instead, they recommend using SF-BIA. At this point, according to the KDOQI guidelines, it is recommended to measure BIA at least 30 minutes after the completion of dialysis, to allow the redistribution of body fluid (23). Second, the prevalence of sarcopenia might be underestimated when muscle mass is adjusted using the square of the height, particularly in overweight and obese patients. To reduce this underestimation, it would be better to adjust muscle mass using the body surface area (24). Third, the cutoffs of current guidelines or consensuses are derived from two standard deviations below the mean reference value from the normative population (healthy young adult). Using several cutoffs from guidelines and consensuses, the prevalence of sarcopenia shows a wide range of from 4 to 64% (25). To reproducibly identify patients with sarcopenia, a guideline for ESRD patients on dialysis is required. Fourth, comorbidities affecting physical performance including neuropathy, metabolic acidosis, and chronic inflammation, should be considered in the diagnosis of sarcopenia. Fifth, given the high prevalence of sarcopenia among dialysis patients, it is essential to stratify sarcopenia for more personalized treatment approaches.
In sixty patients aged 75-95 who have undergone dialysis for an average of three years, the prevalence of sarcopenia was found to be 37-40%, with severe sarcopenia ranging 18-37% using the EWGSOP2 diagnostic algorithm (25). Over a two-year follow-up period, half of them were deceased, and the baseline ASM, gait speed, timed-up and go test (TUG), and SPPB score were significantly different between survivors and those who died. A retrospective study compared body composition of patients for 10 years by their dialysis vintage of 1, 10, and 20 years. Muscle mass, as measured by BIA, did not change in the groups with 1 and 10 years of dialysis vintage, whereas the group with 20 years of dialysis vintage lost a significant amount of muscle mass over 10 years. In the study, muscle mass change rate was increased by dialysis vintage: −0.054, −0.079, and −0.160 kg/year in the dialysis vintage 1, 10, and 20 year group, respectively (26). Another 12 month longitudinal study of enrolled 46 ESRD patients on PD or HD showed that LBM change was prominent in the normal weight group, compared to the overweight and obese group: −0.57, −0.11, and 0.95 kg/year in the normal weight, overweight, and obese group, respectively (27). In an observational study involving fifteen individuals starting dialysis, none gained muscle cross-sectional area (MCSA) in the first year, with the average MCSA change of −4.4% (28).
Cross-sectional studies have revealed correlations between physical function and certain variables. Specifically, patient age and the dialysis vintage are negatively correlated with physical function, while serum creatinine levels exhibit a positive correlation with physical function (29, 30). In addition, the presence of diabetes mellitus (DM) and undergoing HD rather than PD were associated with poorer physical function (29). In a multicenter randomized controlled trial (RCT) that assessed physical functioning with a questionnaire and followed up the physical functioning for 2 years, only 15.3% of patients maintained a good physical function after 2 years. From the study, increasing age and low albumin were factors related to decline and low physical functioning (31). Furthermore, initiation of dialysis is associated with a substantial and sustained decline in functional status (32). Longitudinal studies have shown that the decline in muscle strength occurs more rapidly than the loss of muscle mass, suggesting that factors other than muscle mass contribute to the loss of muscle strength (33, 34). Moreover, physical performance and muscle strength, rather than muscle mass, are predictors of all-cause mortality in ESRD patients (11, 35). However, there is a lack of longitudinal studies. Further studies are required to evaluate changes in physical function over time with dialysis, and whether the initiation point of hemodialysis has any impact on subsequent physical function.
Understanding the molecular mechanisms underlying muscle wasting in ESRD is crucial for developing targeted therapeutic strategies. This section provides a comprehensive overview of the molecular mechanisms involved in muscle wasting in ESRD (Fig. 1).
The ubiquitin-proteasome system (UPS) plays a critical role in the breakdown of muscle proteins (36). In ESRD patients, the UPS is activated, leading to accelerated protein degradation (37). Muscle-specific E3 ubiquitin ligases, such as atrogin-1 (MAFbx) and muscle-specific ring finger-1 (MuRF-1), are upregulated in ESRD, promoting the ubiquitination and subsequent degradation of muscle proteins (38, 39). The autophagy-lysosome pathway (ALP) and the caspase-dependent pathway, particularly caspase-3, also contribute to muscle wasting in ESRD by facilitating the breakdown of muscle proteins (40).
Insulin-like growth factor-1 (IGF-1) and its downstream Akt pathway are major regulators of protein synthesis in skeletal muscle (41). However, insulin resistance, a common feature in ESRD, disrupts the IGF-1/Akt signaling cascade, leading to decreased protein synthesis (42, 43). Insulin resistance both inhibits protein synthesis, and activates proteolytic pathways, exacerbating muscle wasting in ESRD (44). The balance between protein synthesis and degradation is disrupted, resulting in net muscle loss.
Chronic inflammation, oxidative stress, and mitochondrial dysfunction are interconnected factors that contribute to muscle wasting in ESRD. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), are elevated in ESRD, and promote muscle protein degradation while inhibiting anabolic signaling pathways (12, 45). Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defense mechanisms, leads to the oxidation of biomolecules, and contributes to muscle wasting (46). Mitochondrial dysfunction, often observed in ESRD, further exacerbates muscle wasting. Impaired mitochondrial function results in reduced energy production, increased ROS generation, and the activation of signaling pathways involved in muscle protein breakdown (47).
Acidosis stimulates protein degradation and inhibits protein synthesis, exacerbating muscle atrophy (48). Vitamin D deficiency, prevalent in ESRD patients, also affects skeletal muscle metabolism. Vitamin D plays a role in muscle cell differentiation, proliferation, and protein metabolism. Its deficiency can impair myogenesis, and contribute to muscle wasting (49).
Hormonal imbalances are commonly observed in ESRD patients, and contribute to muscle wasting. Glucocorticoids, growth hormone, testosterone, and estrogen are important regulators of muscle protein metabolism (41). Imbalances in these hormones can inhibit protein synthesis, promote protein degradation, and disrupt the anabolic signaling pathways involved in muscle maintenance and growth (50-53).
In physiological condition, protein turnover rate is approximately 5.7 g/kg of body weight per day. During a single HD session, up to 12 g of amino acids are lost into the dialysate, leading to a significant decline in plasma amino acids concentrations (54). High-flux polysulfone (HF-PS) membranes resulted in significantly more amino acid losses into the dialysate, compared to low-flux polymethylmethacrylate (LF-PMMA) membranes (55). In the case of PD, patients lose an average 5 g per 24 h of continuous ambulatory peritoneal dialysis (14). The dialysis process itself results in protein loss. In addition, HD leads to the increased activation of proteolytic pathways, decreased physical activity, and dietary protein deprivation, all of which contribute to muscle wasting.
Uremic toxins, which accumulate in ESRD, have been implicated in the molecular mechanisms of muscle wasting. Uremic toxins contribute to oxidative stress, inflammation, and mitochondrial dysfunction, all of which play a role in the development of muscle atrophy (56, 57). Indoxyl sulfate and methylglyoxal are examples of uremic toxins that have been shown to induce muscle atrophy by increasing oxidative stress and promoting the activation of proteolytic systems (58, 59). These toxins can also disrupt mitochondrial function, leading to reduced energy production and increased ROS generation, which further contribute to muscle wasting.
The gut microbiota has a significant impact on health maintenance, including nutrient metabolism and immune regulation (60). In ESRD, dysbiosis of the gut microbiota can disrupt gut barrier function, increase intestinal permeability, and promote systemic inflammation. The dysregulated gut microbiota also contributes to insulin resistance, and further promotes muscle atrophy (61, 62). Additionally, dysbiosis-related changes in the production of bacterial fermentation products and uremic solutes may worsen oxidative stress and inflammation, thereby exacerbating muscle wasting (57).
A kind of short non-coding RNA molecule, microRNA, has emerged as an important regulator of muscle homeostasis, and has been implicated in the molecular mechanisms of muscle wasting in ESRD (63). Altered expression levels of miRNAs, such as miR-26a, miR-29, miR-23a, miR-27a, miR-206, and miR-486, have been observed in ESRD-associated muscle atrophy (12). These miRNAs can affect various signaling pathways involved in muscle protein metabolism, including those regulating protein degradation, myogenesis, and muscle regeneration. Understanding the role of miRNAs in ESRD-induced muscle wasting could potentially lead to the development of therapeutic interventions targeting these molecules.
Collectively, muscle wasting in ESRD is a multifactorial process that involves various molecular mechanisms. Enhanced protein degradation through the activation of proteolytic pathways, including the UPS, ALP, and caspase-dependent pathways, along with impaired protein synthesis due to insulin resistance, are key contributors to muscle atrophy. Inflammation, oxidative stress, and mitochondrial dysfunction further exacerbate muscle wasting. Metabolic acidosis, vitamin D deficiency, hormonal imbalances, hemodialysis, uremic toxins, intestinal flora imbalance, and dysregulated miRNA expression are additional factors that contribute to muscle wasting in ESRD. Further research is needed to elucidate the precise interplay and relative contributions of these molecular mechanisms, paving the way for the development of targeted therapeutic strategies to mitigate muscle wasting and improve outcomes for individuals with ESRD.
Effective management of muscle wasting is crucial in preventing the progression of sarcopenia and reducing associated mortality (Fig. 2). In this section, we discuss interventions to prevent and treat muscle wasting in ESRD patients and their outcomes.
Guidelines on protein intake are divided based on whether patients are undergoing dialysis. This distinction aims to prevent the progression of CKD in patients not on dialysis, and to maintain muscle mass in those who are on dialysis. In patients with CKD stages 3-5, a low-protein diet of 0.55-0.60 g/kg of dietary protein per body weight per day (d), or a very low-protein diet providing 0.28-0.43 g/kg/d with additional keto acid/amino acid analog supplementation, is recommended (23).
Protein and amino acid supplementation are the mainstay of nutritional support strategies. Previous research supplied protein and amino acid via intradialytic parenteral or oral nutrition (64, 65). From these studies, supplying 45 g of amino acids parenterally or 57 g orally per HD session promotes positive protein balance in the whole body and skeletal muscles (64, 65). In a more long-term intervention, 27 g whey protein or 27 g soy protein intake before every HD session for 6 months lead to reduction in inflammation markers with improvement in gait speed and shuttle walk test (66). A meta-analysis concluded that while protein/amino acid supplementation resulted in no significant differences in muscle mass and strength, it did improve physical function, shuttle walking, and gait speed (67). Moreover, intradialytic oral nutrition of 15 g protein per HD session induced 29% of reduction in hazard of all-cause mortality during mean 14 months of follow-up period (68).
More targeted nutrition treatments based on muscle wasting mechanism were conducted. Injections of 1,000 mg L-carnitine, a naturally occurring amino acid derivative, after each HD session for 12 months prevented the reduction of muscle mass and HGS (69). Supplementation of daily 3,000 mg beta-hydroxy-beta-methylbutyrate (HMB), a metabolite of leucine, did not show any improvement in body composition, muscle strength, and physical function (70). Recently, our group reported that daily leucine supplementation of 6 g with resistance exercise improved physical performance, while those who had poor baseline physical performance benefitted from the intervention (71). Since a high-protein diet can induce metabolic acidosis and hyperphosphatemia, leucine, a type of purely ketogenic amino acid that induces less acid load, could be beneficial for patients with ESRD (72).
Despite extensive research into dietary supplementation for patients with ESRD, significant scientific uncertainties and challenges remain unresolved. Although guidelines advocate for a standardized protein intake for individuals undergoing dialysis, large studies are required to elucidate more sophisticated protein recommendations that incorporate variables such as the patient’s nutritional status, the presence of metabolic acidosis, dialysis vintage, and the dialysis adequacy of Kt/V.
Sedentary lifestyle and being physically less active due to regular dialysis consuming several hours induces anabolic resistance (73). Therefore, the Renal Association recommended that patients on HD should aim for 150 min of moderate intensity activity a week (or vigorous activity) or a mixture of both, as a combination of interdialytic or intradialytic (74). A meta-analysis resulted in exercise, both in resistance and aerobic, improved objective measures of physical function of 6 min walking distance. Both intra- and inter-dialytic exercise improved 6 min walking distance, and the effect estimate was greater in intra- than in inter-dialytic exercise (75). In another meta-analysis, intradialytic exercise improved grip strength and sit-to-stand test, but not sit-to-stand test (76). In another study, intradialytic exercise had higher dialysis efficacy (Kt/V), compared to control group. In the study, VO2peak was significantly elevated when the trial duration was more than 6 months, but not in less than 6 months, and the VO2peak was higher in combination of aerobic and resistance training, compared to aerobic exercise alone (77). Resistance exercise training is considered the most potent exercise to maintain muscle mass and strength (78). In a meta-analysis, muscle volume and leg strength were significantly improved in the resistance exercise group, compared to control group. In terms of aerobic exercise, intradialytic cycling exercise improved 6 min walking distance, compared to control group (79). Combined resistance and aerobic exercise are the most effective intervention to improve physical function (80). Further research is needed to thoroughly examine the distinct effects of resistance and aerobic exercises on muscle mass, strength, and physical performance in hemodialysis patients. In addition, long-term outcomes and adherence to exercise regimens and the synergistic effects of nutrition and exercise should be investigated. Moreover, studies should also aim to unveil the underlying molecular and cellular mechanisms that mediate the beneficial effects of exercise on muscle health in these patients.
To maintain muscle mass and function, there have been several trials against muscle wasting in ESRD patients (summarized in Table 1):
Anabolic steroids: Nandrolone decanoate, which is a synthetic derivative of testosterone, has strong anabolic effects but weak androgenic effects. In phase II clinical trial, appendicular lean mass was dose-responsively increased by 6 month of nandrolone decanoate in CKD stage 5 patients without fluid overload (81). Despite the increase in appendicular lean mass, functional improvement was not statistically significant (82). In another study, oral anabolic steroid oxymetholone for 24 weeks increased fat-free mass, handgrip strength, muscle mRNA associated with IGF-1, but induced liver injury (83).
Myostatin inhibitors: In older weak fallers, myostatin neutralizing antibody LY2495655 for 24 weeks resulted in modest increase in appendicular LBM and decrease in fat mass. Moreover, among the performance-based measures, only 12-step stair climb time was improved (84). Phase I/II clinical trial evaluating anti-myostatin peptibody (a chimeric peptide-Fc fusion protein), PINTA 745, in ESRD patients found that 12 weeks of LBM using DEXA did not meet the primary endpoint, and the development was halted.
Interleukin-1 receptor antagonist: Four weeks of subcutaneous injection at each dialysis session of Anakinra, an interleukin-1 receptor antagonist, significantly reduced high-sensitivity C-reactive protein (hsCRP) by 53%, compared to 1% in the placebo group (85). In the study, LBM showed no appreciable change in either arm; 1.7% increase in the anakinra group and −0.1% in the placebo group.
Sodium bicarbonate: In pre-dialysis CKD stage 3-4 patients, oral sodium bicarbonate medication to achieve serum bicarbonate level of 25 mEq/L resulted in gain of total body muscle mass increase, compared to control group targeting serum bicarbonate level of 22 mEq/L. After four months of the study, myostatin was significantly decreased, but IGF-1 was not different between the two groups (86). In another study, 6 weeks of oral sodium bicarbonate supplementation improved sit-to-stand time (87).
Growth hormone: Recombinant human growth hormone (rhGH) administration in malnourished HD patients lead to increase in muscle protein synthesis and reduction in net protein catabolism (88). In an RCT, rhGH for 6 months increased LBM and reduced fat mass, particularly at the trunk, with serum IGF-1 significantly elevated (89). Additional benefit was found in a study adding rhGH to intradialytic parenteral nutrition and exercise protocol in whole-body net protein balance (90). Growth hormone-releasing hormone receptor agonist, AKL-0707, after 4 weeks of administration, showed improvement in nutritional state assessment with increased fat-free mass and decreased fat mass (91).
Pioglitazone: Pioglitazone treatment in patients with type 2 diabetes mellitus (T2DM) showed that pioglitazone reduced intramyocellular fat, and it was correlated with increase in glucose disposal (92). Also, pioglitazone improved peak VO2 uptake and skeletal muscle energy metabolism by decreasing phosphocreatine loss during exercise in patients with metabolic syndrome (93). The reduction in mortality among patients with T2DM and ESRD due to pioglitazone is suggested to result from its insulin-sensitizing and appetite-stimulating effects, which in turn decrease protein energy wasting (94).
Vitamin D: Serum 25-hydroxyvitamin D concentration is well correlated with skeletal muscle mass and grip strength in both HD and PD patients (95, 96). In HD patients, treatment with active vitamin D, calcitriol or paricalcitol, elevated serum albumin, and increased thigh-muscle cross-section area, as well as muscle strength (97). Though the muscle size increased, none of the physical performance tests were improved. In another study, cholecalciferol 50,000 International Units (IU) orally once per week for 4-8 week in PD patients induced improvement in TUG test, gait speed, timed chair stand test, and stair climb test. In the study, balance tests and isometric strength tests were also improved by vitamin D supplementation (98).
Appetite stimulants: To support nutritional supplementation, appetite stimulants were applied to ESRD patients. Ghrelin, an orexigenic hormone that activates the appetitive center in the hypothalamus, in daily subcutaneous injection for 8 days, increased appetite with energy intake, without changing energy expenditure in ESRD patients on dialysis (99). In PD patients, a single injection of ghrelin was reported to increase appetite and energy intake (100). Oral ghrelin receptor agonist MK-0677 increased serum IGF-1 concentration (101). Another appetite stimulant, megestrol, was found to elevate the serum albumin of malnourished dialysis patients (102, 103).
Physical modalities, such as neuromuscular electrical stimulation (NMES), extracorporeal shockwave therapy (ESWT), and photobiomodulation (PBM), hold promise as interventions for addressing muscle wasting in ESRD patients. From a systematic review of eight RCTs with 8-20 week of intervention periods, NMES improved 6 minute walk distance, handgrip strength, and knee extensor strength (104). An RCT evaluating the effect of ESWT on muscle mass and function in HD patients revealed that ESWT once a week for 12 weeks improved leg lean mass and appendicular skeletal muscle mass index. In physical performance tests, timed up-and-go and sit-to-stand tests were significantly improved (105). PBM is a non-invasive, non-thermal therapeutic technique, employing non-ionizing light sources to trigger cellular biological reactions, potentially increasing ATP production, improving cellular metabolism, and stimulating tissue repair, with applications spanning pain management, wound healing, treatment of skin conditions, neurological disorders, and sports medicine (106). In an RCT evaluation of the effect of low-level laser therapy (LLLT) at quadriceps and gastrocnemius muscle in HD patients, the thrice-weekly intervention during HD session for 8 weeks improved functional capacity and lower limb muscle strength measured by 6 min walking distance and sit-to-stand test, respectively (107). In another study of PBM therapy at forearm flexors muscle in HD patients, handgrip strength was significantly improved (108).
Muscle wasting in patients with ESRD is a significant clinical concern, contributing to poor physical function and increased mortality risk. The prevalence of muscle wasting in ESRD is high, and it is associated with various pathological factors, such as metabolic acidosis, impaired insulin/IGF-1 signaling, chronic inflammation, dialysis-related protein loss, and hormonal imbalances. The molecular mechanisms involved in muscle wasting in ESRD are complex, and involve dysregulation of protein degradation and synthesis pathways, chronic inflammation, oxidative stress, mitochondrial dysfunction, metabolic acidosis, vitamin D deficiency, hormonal imbalances, uremic toxins, gut microbiota dysbiosis, and altered expression of microRNAs.
The recovery of muscle mass and strength post-transplantation in kidney recipients implicates the potential reversibility of muscle wasting with appropriate intervention in patients with ESRD. Studies on follow-up body composition in kidney recipients reported significant increase in muscle mass and strength (109, 110). While physical activity and the administration of low doses of corticosteroids seem to affect body composition, the specific mechanisms driving increases in muscle mass and strength following transplantation remain under-investigated (111). Further exploration in this area could provide critical insights for more effectively mitigating muscle wasting in patients.
In this review, we discussed several interventions to reduce muscle wasting, including nutritional interventions, exercise, pharmacological therapies, and physical modalities. Nutritional interventions aim to optimize protein and amino acid intake, while exercise, particularly resistance training, has shown promising effects on muscle mass, strength, and physical performance. Pharmacological therapies targeting myostatin, interleukin-1, growth hormone, and vitamin D have demonstrated mixed results. Additionally, physical modalities, such as neuromuscular electrical stimulation, extracorporeal shockwave therapy, and photobiomodulation, show potential in mitigating muscle wasting. However, there are still uncertainties and challenges in developing effective interventions, including the need for personalized approaches, long-term outcomes assessment, adherence to interventions, and understanding the underlying mechanisms. Further research is warranted to elucidate the interplay of molecular mechanisms, refine nutritional and exercise recommendations, and identify novel therapeutic targets to attenuate muscle wasting in ESRD patients. These efforts hold promise for improving outcomes and the quality of life in this population.
The authors have no conflicting interests.
Clinical trials of pharmacological treatment for muscle wasting in ESRD patients
|Mode of action||Drug||Clinicaltrials.gov identifier||Title||Status||Intervention||Phase and reference|
|Anabolic steroids||Nandrolone decanoate||NCT00250536||Anabolic Steroids and Exercise in Hemodialysis Patients||Completed||
|Anti- myostatin peptibody||PINTA 745||NCT01958970||Effects of PINTA 745 in End Stage Renal Disease (ESRD) Patients Who Require Hemodialysis and Have Protein Energy Wasting||Completed||
|Interleukin-1 receptor antagonist||Anakinra||NCT00420290||Inflammation, Proteolysis and IL-1 Beta Receptor Inhibition in Chronic Hemodialysis Patients||Completed||
|NCT02278562||Nutrition, Inflammation and Insulin Resistance in End Stage Renal Disease-Aim 2 (INSPIRED)||Completed||
|NCT03141983||Anti-Cytokine Therapy for Hemodialysis InflammatION (ACTION)||Completed||
|Systemic alkalizer||Sodium bicarbonate||NCT02692378||Effects of Oral Sodium Bicarbonate Supplementation in Haemodialysis Patients (BicHD) (BicHD)||Completed||
|Growth hormone||Recombinant human growth hormone (rhGH)||NCT00244075||Effects of Nutritional Supplementation on Protein and Energy Homeostasis in Malnourished Chronic Hemodialysis Patients||Completed||
|Growth hormone secretagogue, MK-0677||NCT00395291||Growth Hormone Secretagogue MK-0677 Effect on IGF-1 Levels in ESRD Patients||Completed||
|Phase 2 withdrawn due to drug supply failure|
|PPAR-γ agonist||Pioglitazone||NCT01301027||Effect of Adipokines in Hemodialysis Patients||Completed||
|NCT01253928||Pioglitazone, Body Composition,Insulin Sensitivity and Protein Metabolism in ESRD||Completed||
|Vitamin D||Cholecalciferol||NCT03710161||Effect of Vitamin D Supplementation on Balance in CKD||Terminated due to COVID pandemic||Vitamin D||2|
|Ergocalciferol||NCT05434377||A Study of Fixed Dose Versus Serum Level-Based Titration Regimen of Vitamin D Supplementation in Dialysis Patients||Not yet recruiting||Vitamin D supplementation||2|
|Appetite stimulants||Pentoxifylline||NCT00561093||Anit-Inflammatory and Anti-Oxidative Nutrition in Dialysis Patients (AIONID)||Completed||
|Omega-3 fatty acids||EPA:DHA (2:1 ratio)||NCT00655525||Omega-3 Fatty Acid Administration in Dialysis Patients||Completed||
|Antioxidant||N-acetylcysteine||NCT00440869||Effects of N-acetylcysteine on Muscle Fatigue in Hemodialysis (NAC)||Completed||