Sarcopenia, sarcopenic obesity, and frailty in individuals with chronic kidney disease: a comprehensive review
Article information
Abstract
Population aging is a global challenge that increases the burden of chronic kidney disease (CKD) and geriatric syndromes such as sarcopenia, sarcopenic obesity, and frailty. These conditions affect almost half of older CKD individuals and are associated with poor outcomes, including CKD progression, cardiometabolic complications, increased health and social care costs, and mortality. They can be both the cause and consequent of CKD and lead to a vicious downward spiral if not addressed early. Frailty is a multidimensional syndrome characterized by reduced physiological reserve and increased vulnerability to stressors. Sarcopenia refers to the progressive and generalized loss of skeletal muscle mass, strength, and/or physical performance with aging. Sarcopenic obesity denotes the combination of sarcopenia and obesity that synergistically leads to poor outcomes. They share common pathogenic mechanisms, such as multimorbidity, inflammation, oxidative stress, uremic milieu, insulin resistance, endocrine disturbances, CKD complications, and psychosocial factors that may limit access to proper nutrition and resources. Management requires a multidisciplinary and patient-centered approach, taking into consideration their baseline physical function and endurance, CKD stage, nutrition status, comorbidities, symptoms, treatment goals, cost, and accessibility. Interventions include exercise, nutrition, comorbidity optimization, geriatric assessment, sensory training, and kidney-oriented care. This review summarizes the current knowledge on the diagnosis and treatment of sarcopenia, sarcopenic obesity, and frailty in individuals with CKD, followed by up-to-date summaries of how best to manage affected individuals.
Introduction
With population aging and increasing life expectancy, the burden of chronic kidney disease (CKD) increases globally. In 2017, 697.5 million CKD cases were reported worldwide with an estimated prevalence of 9.1% [1]. It was the 12th leading cause of death in 2017 and is projected to be the 5th leading cause of death by 2050 [2]. CKD accelerates biological aging. In addition, older adults with CKD face challenges from anorexia of aging, multiple comorbidities, polypharmacy, reduced functional and cognitive reserve, and geriatric syndromes such as sarcopenia, sarcopenic obesity (SO), and frailty [3].
Frailty is a multidimensional syndrome characterized by reduced physiological reserve and increased vulnerability to stressors, leading to multiple complications. Sarcopenia denotes the progressive and generalized loss of skeletal muscle mass and strength or physical performance with aging [4]. It is a multisystem condition as muscle accounts for 40% of total body weight (BW), considered as the largest endocrine organ in the body and secretes various myokines such as irisin which impacts cardiometabolic outcomes [5]. Muscle strength loss may supersede muscle mass loss especially in CKD individuals, due to changes in muscle quality or atrophy of muscle fibers, compromising muscle function [6]. Myosteatosis (fat infiltration within muscle), a source of pro-inflammatory cytokines and negative cardiometabolic outcomes, can impact muscle composition and elasticity, and interfere with muscle contraction even before the onset of loss of muscle mass [6]. SO is the combination of sarcopenia and obesity, which has a synergistic effect on adverse outcomes. Individuals with SO often have multiple cardiometabolic diseases, insulin resistance, and ongoing chronic inflammation which leads to a downward spiral and increased risk of mortality [7]. Sarcopenia, SO, and frailty are common and interrelated conditions in older adults with CKD, affecting up to 50% of this population. They accelerate progression to end-stage kidney disease (ESKD), increase cardiometabolic complications such as insulin resistance and poor diabetes control, increase healthcare utilization (e.g., length of stay and readmission), and increase health and social care cost, and mortality [7–10]. Current diagnostic criteria for sarcopenia, SO, and frailty are based on anthropometric measurements, performance tests, and questionnaires, which have limitations in accuracy, feasibility, and applicability to different settings and populations [9]. Pharmacological interventions for these conditions in individuals with CKD are still limited and under active investigation.
Despite their high prevalence and clinical impact, there is a lack of awareness, recognition, and management of these conditions in clinical practice. In this review, we summarize current evidence on the complex interplay of CKD and these aging-related syndromes, and to facilitate the development of comprehensive strategies to improve the health and well-being of older adults with CKD.
Frailty in chronic kidney disease
Frailty, originally a term describing weakness and emaciation, entered the field of medicine as a geriatric syndrome in the late 20th century. The concept of frailty was initially equated with institutionalization and failure to thrive. It later became entangled with disability and comorbidity, which were then separated into distinct entities with close correlations. Frailty now stands out as an overarching syndrome that accounts for the tendency to develop adverse outcomes when exposed to stressors. The first attempt at operationalizing frailty emerged more than two decades ago with the introduction of the frail phenotype (or physical frailty) and the frail index. In recent years, questionnaire-based screening for frailty, such as the FRAIL (fatigue, resistance, ambulation, illnesses, and loss of weight) scale, has gained increased traction due to its ease and simplicity of administration [11]. These frameworks have successfully transformed diagnostic approaches, aiming to elucidate the intricate relationship between biological aging and clinical manifestations. In the past decade, frailty research has made tremendous strides in both quality and quantity, and clinicians have also paid more attention to screening for frailty in practice.
Prevalence
The prevalence of frailty in community-dwelling middle-aged to older adults, reaches 13%, according to a systematic review, with an incidence between 6% and 10% within 3 years [12]. In those with CKD, the prevalence of frailty is significantly higher; a meta-analysis incorporating 22,788 CKD patients reported the prevalence of prefrailty (the precursor stage of frailty) and frailty to be 43.9% and 41.9%, respectively [13]. Evidence further suggests that frailty contributes to a myriad of adverse consequences in older adults, especially those with CKD. A meta-analysis incorporating 31 studies involving community-dwelling older adults reported that frailty significantly increased the risk of mortality, hospitalization, and incident disability by 1.8, 1.2, and 1.6-fold, respectively [14]. A similar degree of frailty-associated negative outcomes has been observed among individuals with CKD [13]. Moreover, there are more clinical features and phenotypes that are influenced by frailty and warrant specific attention (Fig. 1). Based on the experiences of COhort of GEriatric Nephrology in National Taiwan University Hospital, we demonstrated that frailty in individuals with CKD, or frail renal phenotype (FRP), increased the risk of healthcare utilization and intensive care requirement [10]. We also showed that the presence of FRP increased organ complications and dysfunction in the renal population, including bone loss, cognitive impairment, urolithiasis, and urinary tract infection [15]. FRP may accelerate the speed of renal function decline in non-dialysis CKD individuals, suggesting that frailty assessment can assist in ESKD risk estimation [16]. FRP can compromise morbidity management by reducing medication adherence. Finally, if CKD individuals are afflicted by FRP, their treatment plans are likely to be altered, since their dialysis accesses are more frequently crippled and the efficacy of morphine administration during conservative kidney care would be altered [17].
Risk factors, subtyping, and outcome associations of frail renal phenotype, using a fishbone diagram.
The upper part indicates contributors to frailty in this population, whereas the lower part delineates different frailty subtypes. The right part summarizes the outcome influence of frail renal phenotype.
CKD, chronic kidney disease; ESKD, end-stage kidney disease; MIA, malnutrition-inflammation-anemia.
Pathophysiology and risk factors
A plethora of risk factors for frailty exist in individuals with CKD (Fig. 1). Traditional frailty risk factors in older adults comprise demographic and social features (advanced age, female, unmarried), social lifestyle factors (smoking), and comorbidity profiles (hypertension, diabetes mellitus, osteoarthritis, and mental illnesses) [18]. Besides these, the CKD-specific milieu serves as an important yet under-recognized layer of risk factors for frailty in individuals with CKD. A prior review summarized the pivotal influences of uremic toxins on frailty development [19], and these connections likely account for the observed rising frailty risk following higher CKD stages. Additional risk factors specific to CKD further include cognitive dysfunction, malnutrition-inflammation-anemia syndrome, dialysis prescriptions (if reaching end-stage), and how we manage comorbidities in these individuals (Fig. 1). CKD is characterized by a chronic inflammation state, rising oxidative stress, resultant protein-energy wasting (PEW), and renal anemia, all of which are established biologic predisposing factors for frailty development. Body homeostasis is heavily deranged by kidney dysfunction, and potentially worsened by renal replacement therapy. Dialysis procedures lead to excessive nutrient removal and low-grade endotoxemia, whereas dialysis-related complications are partly responsible for fatigue and exhaustion post-treatment.
Frailty subtypes
The elucidation of frailty pathogenesis paves the way toward frailty subtyping, ranging from physical and cognitive frailty to psychosocial frailty. These subtypes each require the combination of frailty with other elements of outcome-modifying factors. In individuals with CKD, the importance of these frailty subtypes can become more far-reaching, as they tend to be more severe due to influences posed by CKD-related complications and the etiologies are more complex (Fig. 1). For example, the prevalence of cognitive frailty is approximately one-third of that of frailty in CKD individuals. Other emerging subtypes, such as oral frailty and vascular frailty [20], are rarely addressed in the renal population, which is an important research void to fill. Interestingly, frailty per se can lead to cognitive dysfunction [15], whose presence heralds the occurrence of cognitive frailty and aggravated outcomes. Comorbidities can also increase the probability of developing frailty, subclinical vascular injuries, and oral integrity impairment at the same time, constituting a vicious cycle for the simultaneous emergence of multiple frailty subtypes.
Assessment and diagnosis
The identification of frailty depends on the utilization of frailty assessment tools, regardless of physical documentation or self-report-based ones. Available instruments may include the clinical frailty scale (CFS), physical frailty phenotype, FRAIL scale, Study of Osteoporosis scale, and the deficit accumulation index [11]. In individuals with CKD, physical frailty phenotype is the most common tool used, followed by CFS and FRAIL scale. However, concerns exist regarding frailty assessment in this population, such as the failure to report the context and interpretation of assessment. The coherence between frailty risk stratification and intended outcome based on different instruments in CKD individuals is another concern unresolved. There is an emerging interest in using biomarkers to identify those with frailty, such as protein-based and microRNA (miRNA) [21]. However, relevant studies in this population remain preliminary, and their results need more validation.
Sarcopenia in chronic kidney disease
The term sarcopenia was first coined by Dr. Irvin Rosenberg in 1989 and initially defined as age-related muscle mass loss [22]. Since then, the definition has further evolved from loss of muscle mass and function to loss of muscle mass and muscle strength or physical performance [4]. There are multiple consensus guidelines from across the globe such as the 2018 Asian Workgroup for Sarcopenia, and the European Working Group on Sarcopenia in Older People 2 [4,23]. In most of the consensus guidelines, low muscle strength or poor physical performance in the absence of low muscle quantity is classified as possible sarcopenia. Low muscle quantity or quality is required to confirm the diagnosis of sarcopenia (Fig. 2). Sarcopenia is a progressive condition, but it is not just a disease of aging. It can be caused by chronic diseases that affect muscle mass and function (e.g., CKD, cancer, or chronic heart failure). There are commonly shared risk factors such as sedentary lifestyle, and mitochondrial dysfunction but certain risk factors may be more prevalent in different conditions such as anemia, uremia, inflammation, PEW, and acidosis in CKD. Sarcopenia can be both the cause and consequence of CKD [8]. There are a few differences between sarcopenia due to aging compared with sarcopenia due to CKD. While anabolic resistance and reduced muscle protein synthesis dominate in aging, increased protein degradation dominates in CKD-related sarcopenia [24]. With aging, there is a reduction in size and number of type II fibers whereas for sarcopenia in CKD, both type 1 and type 2 muscle fibers are affected.
CKD complications, comorbidities, and age-related factors causing sarcopenia, frailty, and cachexia.
CKD, chronic kidney disease; PTH, parathyroid hormone; RAAS, renin-angiotensin-aldosterone system.
Prevalence
Prevalence of sarcopenia in CKD is double that of general population. A recent systematic review reported a pooled prevalence of 21%. It varies between 4% and 63% depending on the disease stage or dialysis, population studied, and criteria used to diagnose in different continents [9,25]. Sarcopenia has been classified as a disease since 2016 and has its own International Classification of Diseases, 10th Revision (ICD-10) code [4].
Assessment and diagnosis
One of the challenges in diagnosing and managing sarcopenia in CKD is the lack of validated anthropometry measurements, performance characteristics of cutoffs for muscle strength and physical function which are derived from general population, and biomarkers that can reliably reflect muscle mass, quality, and function. SARC-F (strength, assistance walking, rise from a chair, climb stairs and falls) questionnaire (score ≥4) (Supplementary Table 1, available online) albeit its low-moderate sensitivity and high specificity is recommended as a screening tool in various international and Asia Pacific sarcopenia guidelines [4,23]. In certain population groups (e.g., diabetes mellitus or peritoneal dialysis), the addition of calf circumference to SARC-F (SARC-CalF) may have a better performance in the diagnosis of sarcopenia [23]. Loss of muscle strength is a cardinal feature of sarcopenia, and measurement of handgrip strength is a necessity for all published guidelines. There is a lack of consensus if sit-to-stand is a measure of muscle strength or physical function. Nonetheless, in most Asian guideline recommendations, diagnosis of sarcopenia requires either low muscle strength or poor physical performance (which could serve as a surrogate for poor muscle quality) together with low muscle mass for the diagnosis of sarcopenia [23,26]. The 2023 Korean Working Group on Sarcopenia Guideline combined both case finding and assessment in one step to simplify the classification flow [26]. The guideline also recommends skipping screening and proceeding with sarcopenia evaluation in clinical conditions where sarcopenia is highly prevalent such as significant weakness or fatigue, weight loss, geriatric syndromes, chronic inflammatory conditions, neoplasm, polypharmacy, and recent hospitalization [26]. In research and clinical settings, muscle mass can be measured using bioelectrical impedance analysis, dual-energy X-ray absorptiometry (DEXA), computed tomography (CT), and magnetic resonance imaging (MRI). Myosteatosis is best evaluated using CT or MRI of different muscle groups such as rectus femoris or at the level of the third lumbar vertebra. Muscle biopsy is invasive but remains the gold standard.
Pathophysiology and risk factors
Malnutrition and PEW are the most significant and independent risk factors for sarcopenia. Food intake is expected to drop by 25% between 40 to 70 years old due to multiple interacting factors such as anorexia of aging, mobility and cognitive decline, polypharmacy, financial insecurity, and declining oral health [27]. Recommendation of low protein diet (LPD) or very low protein diet in the presence of CKD, associated metabolic acidosis, and inflammation plays a significant role in increased muscle degradation, poor muscle protein synthesis, anabolic resistance, and negative protein balance. Macro and micronutrient deficiencies in CKD individuals such as vitamin D have been shown to be associated with sarcopenia. Nutrition intervention needs to be targeted, and personalized based on optimal macro and micronutrient intake, individual goals, and priority. In addition, nutrition and exercise have to be administered at the right time to ensure maximal muscle protein synthesis [27].
Metabolic acidosis is a common complication of CKD. It can impair muscle protein synthesis, increase muscle protein breakdown, activate inflammatory and catabolic pathways, and reduce physical performance and quality of life. Moreover, metabolic acidosis can aggravate the complications of obesity, such as insulin resistance, dyslipidemia, and hypertension, with subsequent increase in the risk of cardiovascular disease and mortality. Metabolic acidosis is prevalent in one-third of individuals with CKD stage 5 [28]. While correcting metabolic acidosis may be a potential strategy to prevent or treat sarcopenia, there is limited evidence on the reversal of sarcopenia with correction of metabolic acidosis possibly due to its complex nature with multiple interacting factors where a personalized approach is necessary. In addition, prior studies used a cutoff of a serum bicarbonate concentration of <22 mmol/L, and the most recent Kidney Disease Improving Global Outcomes (KDIGO) 2024 guideline recommends corrections for serum bicarbonate <18 mmol/L for greater clinical impact [28,29].
Hyperphosphatemia is another common and serious complication of CKD. In addition to metabolic acidosis, it can also affect muscle and bone health mediated through secondary hyperparathyroidism and renal osteodystrophy, which can result in sarcopenia, bone loss, fractures, and disability [30]. Hyperphosphatemia can induce vascular calcification, endothelial dysfunction, and arterial stiffness, and increase the risk of cardiovascular disease and mortality [30]. Anemia and iron deficiency, also prevalent in CKD are recognized risk factors for sarcopenia [31]. Iron is important for both skeletal muscle and mitochondrial function, especially for energy metabolism [32]. Elevated ferritin in CKD may make a diagnosis of iron deficiency challenging in this group, and elevated serum ferritin may in fact be associated with negative outcomes due to ongoing inflammation [32]. Management of anemia has been associated with improvement in quality of life and reduction in morbidity and mortality, the benefit is significant in older individuals [31].
Sarcopenic obesity in chronic kidney disease
Definition of sarcopenic obesity
SO is a syndrome coined more than two decades ago, in which low muscle mass and function (i.e., sarcopenia) are combined with an increase in adiposity. Given the multitude of ways in which both sarcopenia and obesity (body mass index [BMI], waist circumference, total and visceral fat mass) can be defined, it is not surprising that currently no universally agreed-upon diagnostic criteria for SO exists [7]. The 2022 European Society for Clinical Nutrition and Metabolism and the European Association for the Study of Obesity consensus advocates for screening using BMI or waist circumference (together with screening for sarcopenia), with diagnosis confirmed through having low muscle strength, muscle mass and increased fat mass percentage (Fig. 3) [33]. The consensus also recommends a two-level staging based on the absence or presence of complications.
Case finding and diagnosis of possible sarcopenia, sarcopenia and severe sarcopenia.
CKD, chronic kidney disease; F, female; M, male.
*Body mass index may not be reliable in older individuals due to loss of height with aging.
Data from the article of Chen et al. (J Am Med Dir Assoc 2020;21:300–307) [23]. Data of obesity definition from the article of Donini et al. (Obes Facts 2022;15:321–335) [33].
Both sarcopenia and obesity are considered independent risk factors for poor health outcomes. Hypothetically, their combination (i.e., SO) should amplify the individual adverse effects. Indeed, SO is consistently associated with a higher risk of disability and functional impairment, falls, hospitalization, institutionalization, and mortality [33]. While the sarcopenia component has consistently been linked to poor outcomes in individuals with SO, obesity has not always amplified these associations. The seemingly counterintuitive observation of obesity not imparting a higher risk of adverse outcomes, or even being associated with better outcomes, has been termed the obesity paradox, which is prevalent in individuals with CKD and ESKD [34].
Prevalence of sarcopenic obesity
The global prevalence of SO exhibits wide variability due to differences in surveyed populations and in its definitions. A recent systematic review reported a combined prevalence of SO of 14% in nonhospitalized older adults, 33% in those with functional impairment, 35% in cognitive impairment, and 19% in ≥2 chronic diseases [35].
Assessing SO prevalence in CKD is challenging due to methodological issues and the impact of sarcopenia on CKD definition. Serum creatinine-based equations for CKD can underestimate severity due to reduced creatinine production from muscle loss. Serum cystatin C, a less muscle-dependent marker, is influenced by obesity and inflammation, making it an imperfect alternative [36]. Fluid retention in CKD may also obscure body mass loss, leading to inaccurate obesity or SO diagnosis when using BMI. A study using DEXA scans and both serum markers found a 9.7% SO prevalence in participants with reduced kidney function (estimated glomerular filtration rate, <60 mL/min/1.73 m2) [36]. Research on SO prevalence in ESKD remains limited.
Pathophysiology and risk factors
SO’s pathophysiology is rooted in a complex array of mechanisms, many of which are shared between sarcopenia and obesity. Aging-related mechanisms, physical inactivity, insulin resistance, oxidative stress, and nutritional imbalances are pivotal factors that serve as both causes and consequences within this dyad that drive a cycle of muscle loss and fat gain [37]. Individuals with CKD tend to be older and suffer from a high prevalence of comorbidities, chronic inflammation, oxidative stress, insulin resistance, vitamin D deficiency, and metabolic acidosis, which are exacerbated and amplified in a uremic milieu; as such, CKD can be considered a condition that puts individuals at high risk for the development of SO.
Considerations for the management of sarcopenic obesity
Conceptually, the treatment of SO should target the long-term increase in lean body mass with fat mass decrease. However, while sarcopenia has been consistently associated with adverse health outcomes, obesity may or may not amplify these outcomes (vide supra). Interventions can be beneficial if they target both conditions or sarcopenia alone. However, interventions targeting only obesity often result in both adiposity and muscle mass decrease (approximately 25% of weight loss) [38]. In individuals who regain weight following a weight loss intervention, most of the gain is in the form of adiposity as opposed to muscle mass, potentially worsening SO. Such weight loss interventions may be especially problematic in populations displaying a robust obesity paradox, such as individuals with CKD or ESKD in whom prevention of PEW should be prioritized and dietary interventions should ensure appropriate protein and energy intake [28].
Evidence for interventions targeting SO is limited, especially in CKD or ESKD populations. Careful extrapolation of interventions from non-sarcopenic obese individuals to SO individuals is needed as its effect on lean body mass may further exacerbate PEW. Despite scarce high-quality trials in CKD and ESKD individuals, applying proven anti-sarcopenic interventions individually should be considered.
Management of sarcopenia, sarcopenic obesity, and frailty in individuals with chronic kidney disease
Managing frailty, sarcopenia, and SO requires a multidisciplinary approach and it is important to address other factors such as physical limitation, cognition, appropriate prescribing, psychosocial factors (e.g., availability of caregivers, cognition, depression, financial security, and access to medical care). The presence of frailty and limited life expectancy will influence the trajectory of CKD and treatment options. Table 1 summarizes the interventions, benefits, and barriers that may need to be addressed to improve the care of older individuals with frailty, sarcopenia and SO. Besides exercise, which is strongly recommended with sufficient evidence, most of the other interventions have at least fair evidence. However, only selected individuals with CKD may benefit from interventions such as comprehensive geriatric assessment such as those with geriatric syndromes and sensory training for those with documented decline.
Potential interventions benefits and barriers for frailty, sarcopenia, and sarcopenic obesity management
Retarding kidney function decline and comorbidities optimization
Effective CKD management requires a comprehensive and individualized approach. Addressing socio-economic factors is crucial for treatment adherence, preventing complications, and self-management. The primary goal is to slow disease progression and mitigate complication risk. Dialysis decisions should balance hyperphosphatemia management with the risk of frailty, symptoms, and malnutrition, prioritizing individualized care over age-based criteria. The 4M (Mobility, Mentation, Medication, Multimorbidity, what Matters Most) model is a useful approach in CKD management within the context of healthy aging [3,39].
Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists offer cardiovascular and renal benefits for individuals with CKD, with potential for weight and fat mass reduction, improved insulin sensitivity, and inflammation reduction [28]. They may be a promising intervention for sarcopenia, SO, and frailty in older adults with CKD. SGLT2 inhibitors in addition can increase the serum bicarbonate and correct metabolic acidosis, reduce the serum phosphate level, prevent hyperphosphatemia, and increase the serum parathyroid hormone level. GLP-1 receptor agonists modulate appetite and satiety and shown to increase lean body mass and muscle strength [40]. Furthermore, they increase serum calcium, increase bone formation, and prevent osteoporosis, all of which benefit muscle and bone health.
Exercise
Physical activity (PA) is any body movement supported by skeletal muscle during daily living that requires energy expenditure, whereas exercise is a subgroup of planned, structured, and repetitive activity involving different muscle groups to improve or maintain physical weakness. Exercise and PA reduce pro-inflammatory cytokines, improve mitophagy, restore appetite and cardiometabolic function, increase muscle mass, and reverse frailty. Exercise also improves constipation, cardiometabolic health, and improves endothelial function. Most studies on exercise in CKD or individuals on chronic dialysis are of short duration with variable exercise intensity and duration.
CKD or ESKD individuals experience significant fatigue and have lower endurance [41]. Besides fatigue, pre-dialysis and dialysis individuals also have a high prevalence of pain, breathlessness, depression, perceived burden of multimorbidity, and a lack of time and access to facilities [41]. Prescription of exercise to these CKD or ESKD individuals requires a patient-centered approach taking into consideration baseline physical function and endurance, CKD stage, nutrition status, comorbidities, symptoms, treatment goals, cost, and accessibility [39]. Such a prescription requires training and is ideally performed in a multidisciplinary team setting. Exercise prescriptions can include both aerobic components such as brisk walking, running, cycling, swimming, and resistance exercise using weights, BW, elastic bands, or machines at gym facilities [41].
The World Health Organization Guidelines on Physical Activity and Sedentary Behavior recommends that general and older adults with chronic diseases should do at least 150 to 300 minutes of moderate-intensity aerobic PA; or at least 75 to 150 minutes of vigorous-intensity aerobic PA; or an equivalent combination of moderate- and vigorous-intensity PA throughout the week. Based on the recommendations, duration and frequency can be personalized but the usual recommendations are 30 minutes 5 days a week. Suggested frequency and intensity of exercise for individuals with CKD, ESKD, and kidney transplant in described in Table 2.
Suggested exercise protocols for CKD, ESKD and kidney transplant individuals
Nutrition
CKD exacerbates chronic inflammation and protein catabolism, leading to PEW characterized by high fat and low lean mass. Nutritional interventions in non-dialysis CKD individuals are under-researched, with existing studies primarily focused on the effects of protein restriction in metabolically stable individuals. Lower protein intake is associated with a significantly higher risk of frailty among older non-dialysis CKD individuals. The existing literature suggests that nutritional intervention without or with specific exercise prescription offers an option for improving exercise capacity and endurance in CKD individuals, but most studies are small and have flawed design with heterogeneous findings [42]. Current guidelines recommend a LPD of 0.6–0.8 g/kg BW and high energy intake (35 kcal/kg/day) [28]. The 2024 KDIGO Guideline dictates that in older, stable CKD patients, a higher protein intake of 1.0–1.2 g/kg BW with close monitoring may be prescribed to combat malnutrition and sarcopenia [28].
The effect of nutritional supplementation through providing high protein-energy intake (e.g., oral nutritional supplements or intradialytic parenteral nutrition [IDPN]) on muscle mass was examined in several small trials including patients receiving hemodialysis or peritoneal dialysis. Most, if not all, show an improvement in muscle mass after protein-energy supplementation [43,44]. A larger randomized trial comparing oral nutritional supplementation without and with IDPN in malnourished hemodialysis patients found no difference in nutritional or clinical outcomes between groups, but all participants receiving an increased protein intake had BMI increases [45]. Markers of muscle mass were not assessed. Trials of intraperitoneal amino acid supplementation showed no changes in anthropometric measures relative to those receiving dextrose-based dialysate [46]. Finally, ketoanalogue use may also offer an opportunity to decelerate frailty worsening in patients with non-dialysis CKD but may add to the pill burden [47].
Insufficient trial results make it difficult to conclude the efficacy of nutritional supplementation on muscle mass in patients with ESKD. There is currently insufficient information about the impact of different protein types (e.g., plant- vs. animal-protein) or dietary patterns (e.g., Mediterranean diet or plant-based diets) or timing of administration of protein on muscle mass or strength in patients with CKD or ESKD [28]. Vegetable proteins afford potential metabolic advantages, such as a decrease in absorbable phosphate content, the production and absorption of toxic middle molecules (p-cresyl sulfate, indoxyl sulfate, and trimethylamine oxide), a reduction in acid load and an increase in fiber content [48]. These effects can potentially contribute to nutritional improvement, including improvements in muscle mass and muscle strength.
Comprehensive geriatric assessment
Older adults present a heterogeneous group with a high prevalence of geriatric syndromes complicating CKD management [3]. Incorporating sarcopenia screening which may be as simple as measuring handgrip strength into routine care for CKD or ESKD patients, particularly in nephrology clinics and dialysis centers, is another key strategy that may help mitigate the negative outcome associated with sarcopenia [8]. There are many tools for frailty screening (Table 3) such as the Fried Frailty Phenotype Criteria, FRAIL scale, or the CFS which can be administered biannually, and those with a decline can be referred for comprehensive geriatric assessment and further evaluation [11]. While Fried Frailty Phenotype Criteria requires assessment of physical function and muscle strength, both the CFS and FRAIL are questionnaire-based and easily administered in dialysis centers and nephrology clinics. Components of comprehensive geriatric assessment are shown in Table 3. It can be completed by any trained nurse or doctor. Besides reviewing multimorbidity, a review of medications is necessary to reduce potentially inappropriate medications, those that affect appetite or cause dry mouth, which can contribute to malnutrition. Individualized interventions are essential, taking into account the time to benefit, baseline physical and cognitive functions, psychosocial background, personal goals, and overall life expectancy. Discussion on advanced care planning is necessary, especially for individuals with a declining trajectory.
Frailty screening tool and components of comprehensive geriatric assessment
Chronic kidney disease complication management
Anemia due to CKD has the potential to predispose individuals to geriatric syndromes such as falls, fatigue, sarcopenia, and cognitive dysfunction. Erythropoietin-stimulating agents can be initiated once other causes of anemia have been ruled out to maintain hemoglobin between 10 and 11 g/dL [28]. Osteoporosis and bone health are often overlooked in patients with CKD, and differentiating mineral bone disorder subtypes can be challenging. Secondary hyperparathyroidism, frailty, and sarcopenia can increase the risk of fragility fractures. Oral phosphate binders and sodium bicarbonate tablets may facilitate the optimization of hyperphosphatemia and metabolic acidosis. However, these efforts must be made to rationalize the pill burden, especially in individuals with PEW and/or cachexia.
Sensory training
Studies have begun to elucidate the negative impact of sensory organ dysfunction on the risk of frailty in CKD patients. A prior study suggested that gustatory dysfunction independently correlated with frailty risk among patients with non-dialysis CKD, whereas better oral integrity signaled less frailty probability [49]. In older adults, olfactory impairment exhibits the strongest relationship with frailty compared to the other sensory organs. These findings support the notion that restoration of chemosensory function can be a potential approach for ameliorating CKD-associated frailty. Extrapolating from the experiences for therapies against olfactory loss associated with coronavirus disease-2019, researchers have established a clinical training program to improve olfactory function [50]. Other olfactory training programs for age-related decreasing olfaction also confer benefits for not only olfactory function but also cognitive status as well as depressive symptoms.
Emerging pharmacotherapeutics to prevent and treat sarcopenia
Many drugs have been developed to reverse sarcopenia. Potential agents exhibiting therapeutic potentials against muscle wasting in experimental models of CKD include activin type II receptor B antagonists and specific miRNAs (miR-23a and miR-27a precursors) whereas human trials although not limited to CKD patients have shown some benefits for Bimagrumab (Eli Lilly; fully human monoclonal antibody) and Sarconeos (Biophytis; MAS receptor activator) [36]. Other candidates have been trialed previously such as selective androgen receptor modulators, and myostatin inhibitors but few are found to provide clinical benefits and some even introduce untoward effects (e.g., telangiectasia and epistaxis with some myostatin inhibitors). Probiotics, prebiotics, and synbiotics supplementation have been shown to modulate inflammatory response in dialysis patients with some evidence of positive response on muscle health. Oral sodium bicarbonate may have an impact on muscle health possibly mediated through correction of metabolic acidosis.
A centralized training program for healthcare professionals can further enhance their skills in screening, diagnosing, and managing sarcopenia in CKD individuals. Culturally appropriate dietary interventions and guidelines can help individuals with CKD manage their nutritional needs, while accessible and practical exercise programs and rehabilitation can improve physical function and quality of life. Incorporating cultural relevance exercises or activities, such as tai chi or Korean dance, can enhance adherence making these interventions more effective and sustainable in the long term. These strategies collectively offer a comprehensive approach to overcoming the challenges and barriers to managing these conditions in CKD patients.
Future research
The future research agenda in sarcopenia, SO, and frailty in CKD patients is vast. Key areas include the validation of diagnostic criteria, optimization of interventions for CKD patients with sarcopenia, frailty, and multimorbidity, and understanding the impact of social determinants of health. The role of mitochondrial health, miRNAs, and biomarkers in managing CKD progression, especially with comorbid conditions like diabetes mellitus, is crucial. The cause of blunted exercise adaptations, the effect of LPD on exercise capacity, and the timing of specific macronutrient intake during combined exercise and diet for maximal anabolic effect are all areas that warrant further investigation. The role of increased calorie and/or carbohydrate intake before exercise in enhancing exercise training adaptations is another promising area of research. Lastly, rigorous trials are needed to evaluate the benefits and risks of pharmacological interventions, such as SGLT2 inhibitors and GLP-1 receptor agonists, for these conditions in older adults with CKD.
Conclusion
Sarcopenia, SO, and frailty are common and interrelated conditions in older adults with CKD, with significant implications for kidney disease progression, the choices of renal replacement therapy, and the overall prognosis. Validated biomarkers and evidence-based interventions for these conditions in this population are still lacking. There is a need for more research followed by policy redesign to develop effective strategies for improving the health and well-being of older adults with CKD. Promising biomarkers for these conditions in this population include serum and urine markers of muscle metabolism, inflammation, oxidative stress, hormonal regulation, nutritional status, and bone health. Interventions such as SGLT2 inhibitors and GLP-1 receptor agonists may emerge as useful candidates for these conditions. However, more studies are needed to identify the optimal combination and cutoff values of biomarkers and effective therapeutics for sarcopenia, SO, and frailty in older adults with CKD.
Supplementary Materials
Supplementary data are available at Kidney Research and Clinical Practice online (https://doi.org/10.23876/j.krcp.24.207).
Notes
Conflicts of interest
All authors have no conflicts of interest to declare.
Data sharing statement
This review does not generate new data to be shared.
Authors’ contributions
Conceptualization, Formal analysis, Methodology, Supervision: All authors
Writing–original draft: All authors
Writing–review & editing: All authors
All authors read and approved the final manuscript.