Sarcopenia is a condition of multifaceted etiology arising in many elderly people. In patients with chronic kidney, the loss of muscle mass is much more intensive and the first signs of sarcopenia are observed in younger patients than it is expected. It is associated with the whole-body protein-energy deficiency called protein-energy wasting (PEW). It seems to be one of the major factors limiting patient's autonomy as well as decreasing the quality of life. If it cannot be treated with the simple methods requiring some knowledge and devotion, we will fail to save patients who die due to cardiovascular disease and infection, despite proper conduction of renal replacement therapy. Many factors influencing the risk of sarcopenia development have been evaluated in number of studies. Many studies also were conducted to assess the efficacy of different therapeutic strategies (diet, physical activity, hormones). Nevertheless, there is still no consensus on treatment the patients with PEW. Therefore, in the paper we present the reasons and pathophysiology of sarcopenia as an important element of protein energy wasting (PEW) in elderly patients suffering from chronic kidney disease. We also analyze possible options for treatment according to up-to-date knowledge.
The development of dialysis and the increasing availability of this renal replacement therapy method is the reason elderly patients have become a growing population in dialysis centers. The average age of hemodialyzed patients in many countries exceeds 60 years. Sarcopenia is a condition arising in many elderly people mainly as a result of reduced physical activity, although a lot of data suggests a multifaceted etiology of the phenomenon. An adult without chronic kidney disease should expect a loss of muscle mass reaching 1% per year [
Patients with chronic kidney disease experience probably the same age-related processes. It is interesting, however, that in those patients the loss of muscle mass is much more intensive. Moreover, the first signs of sarcopenia in CKD patients are observed earlier compared to their peers. It is very well marked in patients with the end-stage renal disease (ESRD or CKD V according to K/DOQI guidelines), who are treated with various methods of renal replacement therapy. The most significant aberrations have been recorded in patients treated with hemodialysis.
The question is, what factors can influence such situation and whether sarcopenia developing in healthy people over 60 years old has the same pathogenic basis as the one developing in CKD patients.
Many authors have studied the phenomenon of muscle wasting. According to the International Society of Renal Nutrition and Metabolism (ISRNM), it is a significant element of the condition defined as protein-energy wasting (PEW). It describes the organism’s state of reduced protein and energy resources. It is assumed that 18–75% of patients with CKD suffers from PEW [
According to the ISRNM statement, there are 4 main criteria useful in PEW diagnosis: low body weight, reduced body fat and weight loss, reduced muscle mass judged on the basis of mid-arm circumference, dual X-ray absorptiometry, near-infrared interactance, bioelectrical impedance, or creatinine appearance, low protein/energy intake, biochemical indicators [
BMI is one of the methods to assess low body weight, although in patients with ESRD it might be inappropriate, because of fluid imbalance [
Unintentional weight loss of at least 5% of body weight in 3 months or ≥10% in 6 months is another (independent of BMI) indicator of PEW. In patients with CKD, body fat mass less than 10% may also be pathognomonic for PEW [
Reduced muscle mass seems to be the most important element of PEW. Mid-arm circumference is a simple, but precise method of muscle loss assessment. Noori et al. proved it is correlated with the survival and quality of life in patients on hemodialysis [
Both low protein/energy intake and anorexia are associated with high cardiovascular risk. In fact, anorexia is a severe form of low protein/energy intake, very often connected with cachexia. In many cases, it is associated with high concentrations of proinflammatory factors and ESA resistance leading to low quality of life and increased mortality [
Serum albumin is the most important biochemical indicator of PEW in patients on maintenance dialysis. It should be controlled regularly, as serum albumin still remains the most readily available PEW indicator with very high sensitivity of predicting ESRD patient outcome. The difference in serum albumin as little as 20 mg/L may be crucial. Low serum albumin concentration is the strongest predictor of mortality in ESRD patients, even when compared to traditional cardiovascular risk factors (obesity, diabetes, smoking, hypertension, dyslipidemia) [
Low serum prealbumin concentration is another good PEW indicator in patients on maintenance dialysis. It was proved, that the concentration below 20 mg/dL or a fall in serum prealbumin over 6 months is an independent risk factor for death, even when the albumin level remains in normal range [
Transferrin serum level as well as serum cholesterol (<100 mg/dL) may also serve as protein energy wasting indicators [
The interest in the phenomenon of protein and energy loss seems to be obvious when we realize what important consequences result therefrom. First of all, it is one of the main predictors of mortality in patients with ESRD [
Many authors have evaluated the degradation of skeletal muscle protein in their studies trying to link the observed phenomena with the metabolic state of the organism. During hemodialysis, we observe enhanced proteolysis in muscle. It should be noted that about 10 g of amino acids are irreversibly lost to the dialysate during hemodialysis [
An unrecognized steering mechanism causes the products of muscle protein breakdown which are released to the blood and transported to the liver, where they serve probably as substrates for acute phase proteins synthesis [
Not only the protein loss and not just reduction of muscle mass affect the patients’ functioning, however. Another negative phenomenon is the change of the quality of the muscular compartment. In patients with ESRD, we observe both the accumulation of fat in the striated muscle cells (intramuscular lipid) and in the form of intermuscular adipose tissue (IMAT), subfascially [
In the study with 49 hemodialyzed patients, Cheema et al. demonstrated that such disturbed muscle structure is more common in older people, with hypoalbuminaemia and high levels of proinflammatory cytokines. IMAT was associated particularly with high BMI and larger waist circumference. The researchers pointed out that this influenced the functioning of patients with statistically significant reduction of physical fitness, which was confirmed by objective methods (reduced gait velocity, decreased 6-minute walking distance, peak isometric strength) [
Global dialysis development brought us the possibility of observation made in many patients with ESRD, including of course, the anatomical and functional assessment of the muscular system. Many reports have described the mechanisms of muscle tissue destruction.
The current state of knowledge indicates that the factors predisposing patients with chronic kidney disease to the development of sarcopenia in fact can be divided into two groups (Figure associated with the kidney disease (nutritional deficiencies, development of acidosis, vitamin D deficiency and calcium-phosphate disorders, insulin resistance, diabetes as a cause of chronic kidney disease, sometimes proteinuria), associated with the developing inflammatory process, particularly characteristic for hemodialysis patients, but also observed in patients not enrolled in the chronic dialysis [
Causes of sarcopenia in chronic kidney disease patients.
Nutritional deficiencies seem to be the most important reason of muscle loss in ESRD patients. Besides socioeconomical causes (very significant in many countries) leading to malnutrition, there are some other bases for inadequate protein/energy intake. Altered taste, gastroesophageal reflux, and impaired gastric emptying (particularly in patients with diabetic gastroparesis) are the most common. The phenomenon is potentiated by depression development, quite frequent in patients with chronic diseases. It leads not only to low protein/energy intake, but also may promote proinflammatory status. Bellisle et al. and Hung et al. found the association between depression and high IL-6 serum concentration, which was correlated with low serum albumin level [
In patients with ESRD, inadequate nutrition is also a consequence of leptin and ghrelin perturbation. In a healthy human, kidney is the place of the two hormones degradation. With decreasing GFR, the metabolism of ghrelin and leptin becomes insufficient. Increased concentration of proinflammatory cytokines also contributes to leptin accumulation [
The data concerning leptin influence on PEW remain conflicting, although some experimental data bring some hope for future treatment. Cheung et al. in their study proved that leptin signaling through hypothalamic melanocortin-4 receptor blockade leads to cachexia amelioration in mice. The authors pointed, that it could be only one of many pathways, as some indicators of excessive muscle degradation remained high during the study [
The role of ghrelin in ESRD-PEW development remains uncertain. There are two major forms of circulating ghrelin: acylated ghrelin and des-acyl ghrelin. The latter is responsible for negative energy balance and that form is probably associated with low protein/energy intake [
Metabolic acidosis inevitably accompanying chronic kidney disease, especially in its advanced stages (when it comes to glomerular filtration rate reduction below 25 mL/min/1.73 m2), is one of the most common reasons of PEW [
Insulin resistance has appeared as one of the most important metabolic challenges in patients with CKD [
Insulin resistance is observed also in nondiabetic and nonobese patients on maintenance dialysis. It is associated with increased muscle protein breakdown mainly mediated by ubiquitin-proteasome pathway (described below) [
The more effective treatment of secondary hyperparathyroidism in chronic kidney disease is probably the reason the calcium-phosphate metabolism disturbances are not the main problem in the development of sarcopenia. There is still a phenomenon of muscle weakness (mainly proximal muscle groups) in patients with uncontrolled hyperparathyroidism. Moreover, some authors treat myopathy as an indication for parathyroidectomy [
Vitamin D deficiency associated with renal failure also contributes to the development of myopathy, mainly through increasing insulin resistance [
In some patients, proteinuria in the course of primary kidney disease may lead to significant protein losses. It may be an important reason in patients with earlier stages of chronic kidney disease. During hemodialysis, with decreasing residual diuresis, this way of protein loss becomes less important.
The fact that chronic kidney disease is a state of permanent inflammatory process has been known for many years [
Permanent inflammation promotes oxidative stress, and thus the formation of oxygen free radicals. That is another factor exacerbating inflammatory response by affecting NF
Chronic inflammation promotes reduced muscle mass by inhibiting insulin signaling and increasing energy expenditure, which cannot be covered by appropriate energy intake in ESRD patients. Increase energy expenditure in terms of inadequate energy intake is a characteristic feature of PEW. Besides activation of proinflammatory processes, also increased activity of mitochondrial anion transporters-uncoupling proteins (UCP) may lead to increased resting metabolic rate. UCP-1 and UCP-3 seem to be key regulators of energy expenditure in humans [
Three main systems are involved in the degradation of muscle proteins: the cytosolic calcium dependent calpain system, the lysosomal proteases (cathepsin system), and ubiquitin-proteasome system (UPS) [
Ubiquitin is a member of the heat shock protein family. It is activated by the ubiquitin-activating enzyme (E1), which is followed by its transfer to an ubiquitin-conjugating enzyme (E2). E2 transfers the activated ubiquitin moieties to the protein substrate that is bound specifically to a unique ubiquitin ligase E3. Successive conjugation of ubiquitin moieties to one another generates a polyubiquitin chain (containing 5 ubiquitin moieties) that serves as the binding signal for the 26S proteasome degrading the target substrates to peptides [
Ubiquitin-proteasome system. U: ubiquitin, AU: activated ubiquitin, E1: ubiquitin-activating enzyme, E2: ubiquitin-conjugating enzyme, E3: ubiquitin ligase.
Impaired insulin/IGF-I signaling is another pathway leading to muscle degradation. The lack of IGF-I receptor stimulation is most commonly caused by metabolic acidosis, elevated angiotensin II, and chronic inflammation. Inhibiting of Act phosphorylation leads to Caspase-3 activation and thus to severe proteolysis. The reduction of a forkhead transcription factor (FOXO) phosphorylation is another effect of impaired IGF-I receptor stimulation. In such conditions, FOXO is transited to the cell nucleus and stimulates the synthesis atrogin-1/muscle atrophy f-box (MAFbx) and Muscle ring finger 1 protein (MuRF1). They belong to a group of UPS E3 enzymes that recognize specific muscle proteins, leading to their degradation [
Myostatin is another protein having its negative impact on the development of sarcopenia in patients with chronic kidney disease. Its role is to block the expression of MyoD that enhances myogenesis. Sun et al. have demonstrated increased expression of myostatin in the muscle of rats with end-stage renal disease. They also indicate at the imbalance between myostatin and IGF-I as one of the mechanisms responsible for muscle atrophy in chronic kidney disease [
Based on the above-cited advances in understanding the mechanisms causing sarcopenia, several studies were designed to propose some treatment and improve patients’ survival and their quality of life.
It seems that the implementation of appropriate training in patients with chronic kidney disease both in predialysis period as well as during dialysis can reduce the risk of sarcopenia. This action also modulates the risk of cardiovascular diseases—the leading cause of death in patients with ESRD. Therefore, it is a strongly recommended strategy to implement in CKD patients both young and elderly. Storer et al. proved that endurance exercise might improve strength, power, and physical performance in haemodialysis patients [
Cheema et al. studied an impact of 12-week progressive resistance training (PRT) administered during hemodialysis on skeletal muscle quantity and quality. They showed that PRT is not sufficient in LBM improvement but proved a statistically significant improvement in muscle strength, attenuation, mid-arm, and mid-thigh circumference comparing to group treated in a usual way [
Johansen et al. in their study with anabolic steroid administration and resistance training proved there was an increase in quadriceps cross-sectional area. Unfortunately, they did not notice any increase in lean body mass in the group of patients, where exercise was the only therapeutical method. Nevertheless, their study showed some improvement in self-reported physical functioning [
According to our best knowledge in 29 clinical trials, the aerobic training improved patients’ physical condition (by increasing exercise capacity and exercise duration) [
In a number of studies, the beneficial effects of both aerobic and resistance training were proved. Deligiannis et al. showed that aerobic physical training leads to improved cardiac function measured by ejection fraction, cardiac output index, and systolic volume index [
Physical activity also seems to have an influence on arterial hypertension control both—during hemodialysis and in the interdialytic period [
In terms of metabolic changes caused by physical activity, decreased concentration of VLDL and triglycerides combined with improved level of HDL was proved by Goldberg et al. [
Parsons et al. and Oh-Park et al. proved that adequate physical activity may improve hemodialysis efficiency. The probable reason for such situation is increased muscle perfusion, which occurs during exercise. It leads to the transfer of uremic toxins concentrated in muscles to the circulation; therefore, they can be easily removed during hemodialysis. A so-called “post-dialysis rebound” (increased urea, creatinine, potassium after hemodialysis due to the slow transfer from poorly perfused regions, i.e., skeletal muscles) is diminished in physically active patients [
Some authors concentrated their efforts on proving a beneficial effect of exercise during hemodialysis on skeletal muscle fibers. A resistance training leads to reduction of atrophic fibers number, an increase in type I, type IIa, and type IIx muscle fibre cross-sectional areas. [
The great value of physical exercise for improved psychological adaptation also has been researched. Kouidi et al. showed that Beck’s Depression Index was decreased in patients physically active, which was confirmed in the Ouzouni et al. research [
As inadequate protein/energy intake and high energy expenditure are characteristic features of PEW, a proper nutrition seems to be a natural treatment option to choose in patients on maintenance dialysis. Up to date, the influence of nutritional therapy in ESRD patients was researched in 13 randomized trials. The results of the most important ones are presented in Table
Review of the most important randomized controlled trials concerning nutrition treatment in ESRD patients.
Author | Implemented treatment | Results | |
---|---|---|---|
Sundell et al. [ | Pro-Stat 64 administered during hemodialysis | 6 | (i) Increased essential, nonessential, and total plasma amino acids concentration. |
Allman et al. [ | Polycose-glucose polymer | 9 | (i) A mean increase in body fat of 1.8 kg and the lean body mass increased by 1.3 kg. |
Milano et al. [ | Glucose polymer | 27 | (i) Increase in body weight, body mass index, triceps skinfold, and brachial circumference at the end of the third month. |
Kuhlmann et al. [ | Dietary treatment—3 groups: A: 45 kcal/kg/d and 1.5 g protein/kg/d; B: 35 kcal/kg/d and 1.2 g protein/kg/d; C: spontaneous intake supplemented with 10% of mean protein and energy intake | 18 | (i) Weight gain ( |
Patel et al. [ | Dietary supplements | 17 | (i) Dietary supplements significantly increased both the nPCR and the total protein intake at 2 months and after 8 months. |
Hiroshige et al. [ | Oral branched-chain amino acids (BCAAs) supplementation (12 g/day) | 28 | (i) Anorexia and poor oral protein and caloric intakes improved. |
Leon et al. [ | Identification and intervention on nutritional barriers (depression, poor knowledge, poor appetite, help with shopping or cooking, low fluid intake, inadequate dialysis dose, depression, difficulty chewing, difficulty swallowing, gastrointestinal symptoms, and acidosis) | 180 | (i) Intervention patients had greater increases in albumin levels compared with control patients after 1 year. |
Fouque et al. [ | Renilon 7.5(R) daily for 3 months | 86 | (i) Increased DPI and DEI compared to control group. |
Caglar et al. [ | Oral nutritional supplement specifically formulated for CHD patients | 85 | (i) Significant increases in concentrations of serum albumin and serum prealbumin. |
The effect of appetite-stimulating agent, megestrol acetate, is still not enough documented in randomized controlled trials in large groups of the patients. In the studies designed by Boccanfuso and Burrowes on a small group of patients with ESRD, the risk of adverse events exceeded the benefits of megestrol use [
Some very promising data from studies with recombinant human Growth Hormone (rhGH) has been published so far. Pupim et al. observed its beneficial anabolic effect in hemodialysis patients in the short-term therapy [
Wynne et al. and Ashby et al. assessed ghrelin subcutaneous injection in patients with ESRD, but the results proved only some improvement in short-term energy intake [
Cheung et al. demonstrated an important role of leptin in PEW development. They also proved that the blockade of melanocortin receptor 4 (MC4-R), by AgRP or NBI-12i, attenuated uremic cachexia in mice [
UPS is one of the central pathways that contribute to muscle breakdown. It seems that the current therapy proposals should be directed to modification of this system. Bortezomib—now used in cancer therapy proteasome inhibitor—can affect the UPS system by inhibiting NF
Hemodialysis patients are particularly vulnerable to the development of sarcopenia, mainly due to strong stimulation of the inflammatory response during hemodialysis. Attempts have been made, therefore, to shorten the exposure of blood to the dialysator membranes by reducing the time of hemodialysis, in exchange for increasing their frequency. Galland et al. observed a beneficial effect of such proceedings in 2 studies, with the increase in lean body mass, serum albumin, prealbumin, and cholesterol concentration during the 6- and 12-month followup [
An active form of vitamin D3 deficiency characterizes chronic kidney disease. Its supplementation may result in a reduction of insulin resistance and reduced activity of the UPS. Mak conducted a study with only intravenous use of vitamin D3. Intravenous 1,25(OH)2D3 therapy corrected glucose intolerance, insulin resistance, and hypoinsulinemia as well as hypertriglyceridemia in patients on HD, in the absence of PTH suppression [
In the studies using oral vitamin D3, the results are conflicting [
There is no doubt that the proper treatment of the metabolic acidosis accompanying chronic kidney disease may inhibit the development of sarcopenia [
In patients with CKD in predialysis period, oral supplementation of NaHCO3 was effective in increasing DPI/DEI as well as muscle mass (assessed by mid-arm circumference) and serum albumin concentration [
Sarcopenia is a common problem in patients with chronic kidney disease. In those patients, a number of clinical problems have its origins much earlier than in healthy peers. Sarcopenia also evolves much earlier than in the population without chronic kidney disease, and its development is much more rapid. It is associated with the whole-body protein-energy deficiency called protein-energy wasting (PEW).
Sarcopenia, as an important element of PEW, is the factor limiting patient’s autonomy as well as decreasing the quality of life. If it cannot be treated with the simple methods requiring some knowledge and devotion, we will fail to save patients who die due to cardiovascular disease and infection, despite proper conduction of renal replacement therapy.
Many factors influencing the risk of sarcopenia development have been evaluated in a number of studies. The fact is, however, that the arsenal for the prevention and treatment still remains relatively poor. Although we know a lot of hormonal and molecular mechanisms, in every day practice we can safely apply the method, which has been successfully used for many years in elderly people with or without kidney disease: a proper nutrition to ensure an adequate intake of calories and protein combined with skillfully matched and regular exercise may act both as prevention and treatment.
In our center, there is no specific program for patients on maintenance hemodialysis. We believe, that in terms of PEW, every patient should be treated individually depending on his physical possibilities and expected effects. Unfortunately, the national health system in many countries does not support such aspects of ESRD patients’ treatment. It seems, though, that a fresh glance is required, as hemodialysis itself is not enough for rescuing and improving patient’s life. There are some conditions, which are necessary for hemodialysis to become efficient and successful. Patient’s nutrition and good physical condition are the most important. Preventing and treatment of PEW is undisputedly a way to keep the patient in a good form.
Therefore, in our center we encourage the patients to some aerobic physical activity, which should be an element of every ESRD patient’s treatment. Progressive resistance training is possible for realization individually by the patient, as there is no appropriate equipment in the dialysis center.
Physical activity should be supported by a proper dietary protein intake. 1,5 g protein/kg/24 h should be a minimum in patients on maintenance dialysis. It is worth to consider even a higher dose of protein in patients on intensive exercise treatment. Simple methods like implementing more meat and eggs in the diet proved successful in the number of our patients, who started to lose their lean body weight. The very important feature of such a treatment is that it may be continued at home.
We have also got some experience with hormonal treatment. One could summarize our attitude, that we let the patients on hemodialysis do what is banned in competitive sports: we givethem erythropoiesis-stimulating agents (ESAs) and anabolic steroids [
Anabolic steroids proved to be efficient in some of our patients, especially in the group with ESA hypo-responsiveness and hemosyderosis. Although we find a growth hormone a valuable agent in PEW treatment, we have not used it in our centre yet.
Megestrol acetate proved to be efficient in people with decreased appetite—it is worth to notice, that we have not observed side effects described in the literature so far.
In our center, we have also implemented a program for patients with CKD in stage IV K/DOQI. In the number of them, oral supplementation of NaHCO3 was introduced, resulting in slower progression of the kidney disease into ESRD. We have also noticed that such treatment may lead to reduction of PEW symptoms in an early period after hemodialysis initiation.