Review

Uremic Sarcopenia and Its Possible Nutritional Approach

Annalisa Noce 1,*, Giulia Marrone 1,2,*, Eleonora Ottaviani 1, Cristina Guerriero 1, Francesca Di Daniele 1,2,
Anna Pietroboni Zaitseva 1 and Nicola Di Daniele 1

1 UOC of Internal Medicine-Center of Hypertension and Nephrology Unit, Department of Systems Medicine,
University of Rome Tor Vergata, via Montpellier 1, 00133 Rome, Italy; [email protected] (E.O.);
[email protected] (C.G.); [email protected] (F.D.D.);
[email protected] (A.P.Z.); [email protected] (N.D.D.)
2 PhD School of Applied Medical, Surgical Sciences, University of Rome Tor Vergata, Via Montpellier 1,

00133 Rome, Italy

* Correspondence: [email protected] (A.N.); [email protected] (G.M.);
Tel.: +39-06-2090-2194 (A.N.); Tel.: +39-06-2090-2191 (G.M.)

Abstract: Uremic sarcopenia is a frequent condition present in chronic kidney disease (CKD) pa-
tients and is characterized by reduced muscle mass, muscle strength and physical performance.
Uremic sarcopenia is related to an increased risk of hospitalization and all-causes mortality. This
pathological condition is caused not only by advanced age but also by others factors typical of CKD
patients such as metabolic acidosis, hemodialysis therapy, low-grade inflammatory status and in-
adequate protein-energy intake. Currently, treatments available to ameliorate uremic sarcopenia
include nutritional therapy (oral nutritional supplement, inter/intradialytic parenteral nutrition, en-
teral nutrition, high protein and fiber diet and percutaneous endoscopic gastrectomy) and a person-
alized program of physical activity. The aim of this review is to analyze the possible benefits induced
by nutritional therapy alone or in combination with a personalized program of physical activity, on
onset and/or progression of uremic sarcopenia.
Citation: Noce, A.; Marrone, G.;
Ottaviani, E.; Guerriero, C.; Keywords: uremic sarcopenia; physical activity; hemodialysis; nutritional supplementation;
Di Daniele, F.; intra-dialytic parenteral nutrition; ω-3 polyunsaturated fatty acids
Pietroboni Zaitseva, A.; Di Daniele,
N. Uremic Sarcopenia and Its
Possible Nutritional Approach.
Nutrients 2021, 13, 147.
1. Introduction
https://doi.org/10.3390/nu13010147
“Sarcopenia” is a term derived from the Greek “sarx”—meat and “penia”—loss, and
Received: 10 November 2020 it was first coined in 1988 by Irwin Rosenberg to describe the modifications that occur in
Accepted: 30 December 2020 the muscles during aging [1]. Progressive and generalized loss of muscle strength and
Published: 4 January 2021 muscle mass (MM) is also a frequent complication in patients with chronic kidney disease
(CKD), especially in end-stage renal disease (ESRD) [2–4]. The mechanisms involved are
Publisher’s Note: MDPI stays neu- many and not yet fully clarified, but it is certain that they all converge towards a final
tral with regard to jurisdictional process of increasing protein degradation and reducing protein synthesis, leading to a
claims in published maps and insti- negative nitrogen balance [5]. Muscle is one of the most represented tissues in the human
tutional affiliations. body. Skeletal muscles are the predominant component, while other types such as cardiac
and smooth musculature are less represented. Skeletal muscle is mainly composed of pro-
teins and it represents the “best indicator” of overall protein shift [6]. The reduction of
muscle strength and mass, especially skeletal, is associated with a worsening quality of
Copyright: © 2021 by the authors.
life (Qol), an increased vulnerability to adverse events such as falls, loss of personal au-
Licensee MDPI, Basel, Switzerland.
tonomy and ultimately increased hospitalization and mortality [7].
This article is an open access article
In 1931 the British neurologist Critchley Macdonald was the first, in the scientific
distributed under the terms and con-
literature, to correlate aging with the tendency to loss of skeletal MM [7]. Since then, sev-
ditions of the Creative Commons At-
tribution (CC BY) license (http://cre-
eral studies have been carried out to deepen the qualitative and quantitative changes that
ativecommons.org/licenses/by/4.0/).
occur physiologically in the MM and fat mass with aging [8].

Nutrients 2021, 13, 147. https://doi.org/10.3390/nu13010147 www.mdpi.com/journal/nutrients

Nutrients 2021, 13, 147 2 of 29

Quantitative changes consist in the reduction of MM and volume, while the qualita-
tive ones consist in the reduction of muscle strength and in physical performance. Among
qualitative changes of uremic muscle should include alterations of muscle mitochondrial
morphology, their protein pathways, and decreased mitochondrial respiratory function
[9,10]. Moreover, the uremic condition predisposes to a capillary rarefaction altering phys-
iological muscle function [11]. It has also been observed that aging, in addition to the loss
of muscle strength and mass, is associated with increase in fat mass, especially localized
in the abdominal area [12]. Many studies conducted on changes in musculature, during
lifespan, are transversal. The data obtained overall indicate an estimated reduction in MM
by about 1–2% per year after 50 years and muscle strength declines by 1.5% between ages
50–60, with a tendency to a further reduction of up to 3% per year, thus achieving a total
loss of MM and muscle strength of about 40% from 30 to 70 years of age [8]. Longitudinal
studies in geriatric populations confirmed the results of these cross-sectional studies, as
discussed below. A study by Delmonico et al. [12], conducted on 1678 subjects (heteroge-
neous for age, sex and ethnicity), showed that from 70 years of age there is an annual
reduction of the muscular area of 4.9 ± 7.4% in men and 3.2 ± 7.9% in women. Similar
results were obtained by Cameron et al. [13] in a population of seventy, in which lean
mass was measured with magnetic resonance imaging (MRI) and dual-energy X-ray ab-
sorptiometry (DXA). The loss of MM was approximately 5% in five years of follow-up
regardless of basal MM values. The phenomenon of aging is characterized by a primary
reduction in muscle strength and subsequently occurs a reduction in MM. This could be
due to the progressive infiltration of adipose tissue into the muscle [14] and the develop-
ment of muscle fibrosis [15], processes that reduce muscle performance but do not result
in a reduction of muscle volume.
Since 2010 sarcopenia has gained more interest in the scientific community, thanks
to the publication of the first consensus on the subject published by the European Working
Group for Sarcopenia for Older People (EWGSOP) [16]. The criteria to be considered are
three: 1—reduced MM, 2—reduced muscle strength, 3—reduced physical performance.
According to the EWGSOP, the presence of criterion 1, associated with criterion 2 or 3, is
required for the diagnosis of sarcopenia. Over the years, consensus has developed by dif-
ferent societies that agree in defining sarcopenia as a syndrome characterized by the pro-
gressive and generalized loss of MM and strength, associated with the high risk of adverse
events such as physical disability, reduced Qol and death. The first consensus was revised
in 2019 and the main parameter considered for the diagnosis of sarcopenia is no longer
MM but muscle strength [16–20]. The EWGSOP1 [16] divided sarcopenia into primary,
when this condition is related to age in the absence of other obvious causes, and second-
ary, when it is determined by other pathological conditions and not necessarily by ad-
vanced age. Secondary sarcopenia can occur in conditions of reduced physical activity
(lodging, sedentary life, zero-gravity conditions), in diseases (CKD, inflammatory dis-
eases, endocrine and malignant diseases) and under conditions of reduced intake of nu-
tritional factors (reduced intake of nutrients, malabsorptive conditions, gastrointestinal
diseases, use of anorexic drugs) [21,22]. The main difference between primary and sec-
ondary sarcopenia is that in the former the loss of MM occurs consistently and generally
continues from the fourth to fifth decade, while in secondary sarcopenia the loss of MM
is not only related to advancing age, but also to the development of pathological processes
of protein degradation that are more aggressive than those that occur physiologically with
aging [23]. The EWGSOP2 defined the concept of acute and chronic sarcopenia, consider-
ing the first as an acute condition present for less than six months, while the second is
considered a chronic condition present for more than six months. Acute sarcopenia is of-
ten linked to an acute disease; on the contrary chronic sarcopenia is correlated with a
chronic and progressive disease that induces an increased risk of mortality [20]. Experi-
mental data showed that muscle tissue should be investigated through the execution of
biopsies which permits the detection of distinct variations between primary and second-
ary sarcopenia [24]. In fact, primary sarcopenia is generally characterized by atrophy of
Nutrients 2021, 13, 147 3 of 29

both type I and type II fibers, while secondary sarcopenia, especially that associated with
CKD, causes a specific reduction of type II fibers. In any case, these data need to be con-
firmed by further research. Secondary sarcopenia is often associated with two other well-
known pathological conditions: protein-energy wasting (PEW) (present in between 18%
and 75% of chronic hemodialysis (HD) patients [25,26] and cachexia. PEW is a condition
of malnutrition characterized by a reduced and inadequate protein and energy intake. It
is a multifactorial condition whose diagnosis is complex and involves the integration of
laboratory and anthropometric parameters. The International Society of Renal Nutrition
and Metabolism (ISRNM) has defined a set of criteria necessary for the diagnosis of PEW
[27]. These criteria are body mass index (BMI) < 23 kg/m2; unintentional body weight loss
of about 5% in 3 months or 10% in 6 months; reduction of arm circumference > 10% com-
pared to the 50° percentile of the reference population; MM reduction of about 5% in 3
months or 10% in 6 months; albuminemia < 3.8 g/dL; total cholesterol < 2.59 mmol/L; un-
intentional protein intake < 0.8 g/kg per day in HD patients; unintentional energy intake <
25 kcal/kg per day. Cachexia is a condition of metabolic imbalance characterized by the
loss of MM with or without loss of adipose tissue [28,29]. The Society of Sarcopenia, Ca-
chexia and Wasting Disorders (SCWD) [28] has proposed a series of criteria necessary for
the definition and diagnosis of cachexia: albuminemia < 3.2. g/dL; hemoglobin < 12 g/dL;
increment of inflammatory markers or C-reactive Protein (CRP) > 5 mg/L, interleukin (IL)-
6 > 0.4 pg/mL; BMI < 20 kg/m2; unintentional loss of 5% of body weight in 12 months;
appendicular skeletal muscle index, measured with DXA, <7.25 kg/m2 in men and <5.45
kg/m2 in women; reduced arm circumference; “fatigue” understood as physical and/or
mental fatigue resulting from the effort or inability to continue an exercise with the same
intensity, resulting in a worsening of performance; reduced appetite; unintentional reduc-
tion of energy intake < 20 kcal/kg per day; 70% reduction in usual daily energy intake [28].
Sarcopenia should be considered not only as a geriatric disease, but a multidiscipli-
nary condition. Since the first consensus on sarcopenia, published in 2010 by the EWGSOP
[16], numerous studies have been performed to investigate the possible correlations of
sarcopenia with CKD, especially with ESRD [30–32]. It has been shown that secondary
uremic sarcopenia is determined by a more severe protein degradation process with re-
spect to primary sarcopenia [33]. In primary sarcopenia, it is essential to restore a proper
motor activity and an adequate Qol, thereby reducing the mortality rate. In secondary
sarcopenia, where “muscle wasting” and PEW are prominent, the main goal is to reverse
the process that causes sarcopenia or to restore optimal nutritional status. The latter allows
patients to respond more effectively to therapeutic treatment. Further therapeutic objec-
tives are to restore appropriate mobility and Qol and to reduce mortality and hospitaliza-
tion rates. In 2019, EWGSOP2 [20] continues to define sarcopenia as a concomitant pres-
ence of altered quantity and quality of MM but, differently from the previous consensus,
EWGSOP2 proposed the use of reduced muscle strength as a key criterion to identify
“probable-sarcopenia”. The diagnosis of sarcopenia is confirmed by the presence of low
muscle strength and low muscle quantity or quality. The stage of severe sarcopenia is
reached when the patient presents a reduction in MM (quality and quantity), muscle
strength and physical performance simultaneously. According to EWGSOP2, therefore,
reduced MM is no longer the key element in the diagnosis of sarcopenia, but reduced
muscle strength. This change is justified by the fact that reduced muscle strength is better
than reduced MM in predicting adverse outcomes in sarcopenic patients [34]. Leong et al.
[34], in fact, measured the prehensile force of the hand of 142,861 subjects whose age was
between 35–70 years. After a follow-up of 4 years, the authors observed that the degree of
prehensile strength of the hand was inversely related to all causes of mortality, cardiovas-
cular (CV) and otherwise, and to the onset of acute myocadiac infarction and stroke. This
study confirmed that the simple dynamometer measurement of the prehensile force of the
hand would provide information about the patient’s prognosis, since it would relate to all
causes of mortality. Thanks to the simple use of the portable manual dynamometer, mus-
cle strength is therefore easily detectable, not only in hospital facilities, but also in other
Nutrients 2021, 13, 147 4 of 29

care centers. Another method for assessing muscle strength characterized by easy execu-
tion is the chair stand test as defined by the EWGSOP2. The chair stand test evaluates the
muscle strength of the quadriceps group and its proper execution requires both strength
and endurance from the patient. This test is adjuvant in the early diagnosis of sarcopenia
[20].
In this review we discuss the uremic sarcopenia condition and the possible therapeu-
tic strategies currently available, with particular interest in nutritional therapy. The re-
search was conducted on Medline (Pubmed) including studies published until April 2020.
The terms used for the research were: “uremic sarcopenia”, “nutritional therapy”,
“chronic kidney-disease”, “CKD”, “dialysis” and “hemodialysis”.

2. Sarcopenia in Chronic Kidney Disease

Loss of MM is common in CKD, especially in ESRD patients in hemodialytic treat-
ment [2–4,31]. In this population, the consequences of MM loss are not only related to
reduced physical ability, as happens in the elderly population. Many studies in fact have
associated the loss of MM in CKD to the reduction of Qol, to the manifestation of PEW, to
fractures, to CV complications, to loss of graft and to postoperative complications in kid-
ney transplant [35,36]. These conditions together lead to an increased risk of hospitaliza-
tion and mortality in the nephropathic patient with sarcopenia [25,37,38]. For this reason,
sarcopenia can be considered a negative prognostic factor in CKD patients and only an
adequate knowledge of this pathology and the mechanisms involved in its genesis can
allow a valid and effective treatment of the same [39]. The possible etiological factors in-
volved in MM loss in CKD patients are various, as reported in Figure 1.

Figure 1. Possible causes of uremic sarcopenia. AA, amino acids.

Major causes include metabolic acidosis, dialysis therapy, and typical low-grade
chronic inflammatory status [40,41]. These elements together result in an increase in pro-
tein degradation and in a reduction in protein synthesis, producing a negative nitrogen
balance (Figure 2) [42,43]. CKD, in addition to the development of metabolic acidosis, is
associated with the onset of insulin resistance (IR) and vitamin D deficiency, and these
factors can also act as promoters of protein catabolism and of reduced protein synthesis
[44–47]. It has been observed that metabolic acidosis acts as a powerful stimulator of pro-
tein catabolism thanks to the solicitation of two systems responsible for intracellular pro-
tein degradation: caspase 3 and the ubiquitin proteasome system (UPS) [48]. In particular,
Nutrients 2021, 13, 147 5 of 29

it has been shown that caspase 3 is responsible for the cleavage of actomyosin of myofi-
brils generating actin fragments from 14 kDa. Workeneh et al. [49] performed muscle bi-
opsy on 28 patients in chronic hemodialysis treatment. The authors noted that patients
with malnourished and reduced physical activity had high levels of actin from 14 kDa to
muscle biopsy.
Metabolic acidosis seems to be related to increased IR and to the enhancement of
insulin-like growth factor-1 (IGF1) [50]. IGF1 is an important regulator of muscle turnover.
In fact, through the suppression of the PI3K pathway, it determines the increased activa-
tion of the ubiquitin ligases enzyme (E3s), that activates the UPS protein degradation sys-
tem [51,52]. CKD, particularly in the presence of metabolic acidosis, is associated with
resistance to the action of growth hormone (GH), the anabolic hormone responsible for
the turnover of skeletal muscle cells. This condition, present in CKD patients, alters the
balance between anabolism and catabolism of the MM [53].
Vitamin D deficiency in experimental studies has been shown to be involved in re-
duced insulin secretion by beta pancreatic cells, participating in the IR process [54,55].
Vitamin D deficiency also appears to decrease protein synthesis, reducing muscle expres-
sion of vitamin D receptors and changing intracellular calcium flow, leading to an altered
functionality of muscle cells [46]. The renal dysfunction is associated with many hormonal
alterations including the increase of cortisol and the reduction of testosterone [56,57]. Cor-
tisol in vitro studies has been shown to possess the ability to activate the UPS system and
to suppress the PI3K pathway, leading to an increase in protein degradation at the mus-
cular level, thus participating in the development of sarcopenia [58].
The action of testosterone is related to skeletal muscle tropism. In CKD patients and,
in particular, in HD patients, there is a reduction of this sexual hormone with a reduction
in MM and strength. In fact, the reduction of testosterone induces an increased expression
of myostatin (protein that inhibits muscle growth), and an alteration of IGF-1 mediated
signaling [59].
HD treatment is a determining factor in the altered degradation/protein synthesis
ratio. During the HD session, a substantial loss of proteins and amino acids is observed,
with a reduction in the availability of nutrients for the synthesis of muscle proteins. It has
been calculated that, during a single dialytic session, up to 5–8 g of free amino acids can
be lost [60]. It has also been shown that, during and at the end of dialysis treatment, there
is increased protein degradation [61]. In addition to the loss of protein during dialysis
session, there is also a tendency of HD patients to a reduced spontaneously energy and
protein intake, above all in the day of HD treatment [62], determining a state of energy
and protein imbalance. In fact, CKD patients presented a reduced sense of appetite related
to multiple factors such as sedentary life, high level of uremic toxins [63,64], the chronic
inflammatory state, and hormonal disorders. Among these can be mentioned the reduc-
tion of ghrelin and various neuropeptides (neuropeptide Y) and the increase in leptin lev-
els [65]. The chronic inflammatory condition present in HD patients, due to increased pro-
tein catabolism, is related to various factors, first of all, the pro-inflammatory response of
the organism induced by the dialyzer, despite the use of membranes with high biocom-
patibility. Tumor necrosis factor (TNF)-α appears to be the cytokine most responsible for
activating protein catabolism processes and for increasing the anabolic processes, as it re-
sults in increased action of caspase-3 and suppression of insulin action [66].
Chronic HD patients usually show high levels of other pro-inflammatory cytokines
such as Interleukin (IL)-6 often associated with an increase in serum CRP. IL-6 in associa-
tion with TNF-α reduces the suppression of cytokine signaling (SOCS)-3 proteins by de-
termining the intracellular activation of UPS and caspase-3 [67].
IL-6 also accelerates muscle degradation by stimulating the expression of the signal
transducer and transcriptional activator-3 (Stat3) responsible for the altered expression of
myostatin. IL-6 would result in muscle loss [68].
In recent years, the development of a systemic and chronic inflammatory state has
also been attributed to gut microbiota alterations [69]. It has been observed that in CKD
Nutrients 2021, 13, 147 6 of 29

patients gut dysbiosis occurs due to the production of toxins harmful to the integrity and
functionality of cells of the enteric tract. Among these, p-cresol sulfate and indoxyl sulfate
induce an inflammatory cascade, which in turn induce a low-grade systemic inflamma-
tion. The alteration of the gut microbiota, therefore, participates in the development of the
chronic inflammatory state typical of CKD. Dysbiosis is produced mainly as a result of
exposure of the intestinal mucosa to a uremic environment and reduced fiber intake due
to dietary restrictions typical of HD patients (reduction of potassium-rich foods but also
of fibers such as fruit, vegetables and whole grains) [70]. CKD patients often reduce phys-
ical activity that causes not only increased CV mortality but also a progressive reduction
in MM. This MM reduction is described as “atrophy from disuse” and is related to an
increased risk of developing sarcopenia. For this reason, physical activity is one of the
main therapeutic strategies for sarcopenia, and its intensity in duration and frequency
depends on the severity of the CKD and the clinical conditions of the patient [71]. In HD
patients, an activation of caspase 3 that induces an increased muscle proteolysis has been
observed. This factor in association with intracellular apoptosis can contributes to MM
loss in CKD patients [49,72]. CKD patients are often elderly, and age is a prominent factor
in the development of sarcopenia. In CKD patients, therefore, the risk of developing sar-
copenia is greater when compared to individuals of the same age in the general popula-
tion. CKD was also defined as a “premature aging” model [73,74] and, for this reason,
nephropathic patients often experience a reduction in MM at an earlier age than the gen-
eral population, thereby increasing the risk of disability and mortality.
The development of sarcopenia in CKD patients leads to reduced Qol and autonomy,
but especially an increased risk of complications and mortality. It is clear that the use of
appropriate methods for its diagnosis and the setting up of an effective therapy to restore
an increase in MM are necessary to prevent and treat this condition, and to improve its
prognosis quoad vitam.

2.1. The Diagnosis of Sarcopenia

The methods available for the evaluation of the three main parameters useful for the
diagnosis of sarcopenia (muscle strength, MM and physical performance) are several and
include simple and cheap or more accurate but expensive methods. The consensus of the
EWGSOP describes the different diagnostic methods available for the evaluation of the
three principal parameters. The first EWGSOP1 consensus [16] focused on the condition
of sarcopenia and quantitative alterations of MM. The second, revised in 2019,
(EWGSOP2) [20], updated the criteria of sarcopenia diagnosis based on the reduction in
muscle strength. With regard to the evaluation of MM, several diagnostic methods can be
used such as computed tomography (CT), MRI, DXA, or bioimpedance analysis (BIA).
Currently, CT and MRI are considered the gold standard methods. Both methods allow
not only the evaluation of quantity but also of muscle quality. Their limitation is that not
all clinical centers have such methods available and their use exposes the patient to radi-
ation. A valid alternative at low cost could be DXA, that allows the evaluation of fat mass,
lean mass and bone mineral density [75]. Unfortunately, even this method is not present
in all centers and in CKD patients does not allow a distinction between MM and extracel-
lular fluid, thus limiting its use in this population [76]. BIA is a tool with simple use and
low cost for the estimation of lean and fat mass. It is therefore a valid alternative to DXA
for the evaluation of body composition, although in CKD patients the inflammatory state
and the excess of extracellular fluid could alter the results [77].
For the study of muscle strength, “functional” tests are used: grip force, the flexion
and extension of the muscles of the thigh, and forced expiratory flow. The test most com-
monly used in clinical practice is that of handgrip strength (HGS). HGS is related to lower
limb muscle strength and is considered a predictor of reduced overall MM [78]. The meth-
ods to be used in clinical practice, recommended by the EWGSOP for the evaluation of
physical performance, are the usual gait speed, the timed get-up-and-go test and the short
physical performance battery (SPPB) [16,79]. The gait speed test evaluates the time taken
Nutrients 2021, 13, 147 7 of 29

to walk 4 m, while the timed get-up-and-go test measures the time taken to get out of a
chair, walk three meters, turn around and return to the chair to sit again. The SPPB as-
sesses the functionality of the lower limbs and includes a test battery divided into three
different sections. The first section allows the evaluation of the equilibrium through three
tests: the maintenance of the joined foot position for 10 s, the maintenance of the semi-
tandem position for 10 s (big toe of the foot placed laterally to the heel of the counter-
lateral foot) and the maintenance of the tandem position for 10 s (toe of the foot placed
behind the heel of the foot against the side). The second section includes the usual gait
speed test. The third section investigates the ability to perform, five consecutive times, the
sit-to-stand test, or the ability to stand up and sit down from a chair without the help of
the upper limbs.
Pereira et al. [30] conducted one of the few studies aimed at defining criteria for the
diagnosis of sarcopenia, in CKD patients in particular, in conservative therapy. According
to the authors, the diagnosis of sarcopenia in nephropathic patients is defined by the pres-
ence of: a reduced muscular function evaluated by HGS (HGS 30% percentile of the refer-
ence population adjusted for sex and age); reduced MM assessed by three different meth-
ods, namely arm circumference (mid arm muscle Circumference—MAMC), 90% of the
reference value, loss of MM estimated by Subject Global Assessment (SGA), and finally a
reduced skeletal MM index (<10.76 kg/m2 in men; <6.76 kg/m2 in women) estimated by
BIA.

2.2. Possible Therapeutic Strategies for Uremic Sarcopenia

There are many current treatments available to implement MM and improve physical
performance in patients with uremic sarcopenia. In this review, the role of nutritional
therapy will be deepened, whose role has been object of study and experimentation, es-
pecially in recent years, providing decidedly promising results in the treatment of this
pathological condition. Finally, the other main therapeutic options available according to
the scientific literature will be dealt with, with a final reference to possible future thera-
peutic strategies.

3. Nutritional Therapy
Dietary interventions necessary to preserve MM and provide an adequate energy
and protein load are essential for the health of HD patients and their nutritional status,
especially when the processes of MM reduction are already established [80]. For CKD
(stages III–V) patients, a protein intake of 0.6–0.8 g/kg body weight (b.w.)/day and an en-
ergy intake of 30–35 kcal/kg b.w./day is recommended. Despite the risk of a negative ni-
trogen balance, a low protein diet (LPD) is indicated for CKD, because it is related to a
better metabolic status and a better control of the signs and symptoms of CKD, if com-
pared to a diet with high protein intake [81,82]. The risk of protein restriction consists in
the possibility of establishing a state of malnutrition, complicated by the reduction of MM,
and therefore by sarcopenia. For this reason, it has been proposed to combine the LPD
with the use of energy supplements with controlled fats and carbohydrates content
[83,84]. In this regard, a study by Wu et al. [84] was conducted on 109 CKD patients (stage
III-IV), divided into a control group (54 patients) and an experimental group (55 patients).
For a duration of 24 weeks, all participants were prescribed a diet with a controlled protein
intake (CPI), comprising between 0.6–0.8 g/kg b.w./day and an energy intake of 30–35
kcal/kg b.w./day, associated with dietary counseling. Only the experimental group was
required also to consume an energy supplement of 200 kcal/day (40 g of maltodextrin
together with 5 g of oil creamer). The authors noted that the patients in the experimental
group, thanks to the energy supplementation, had a greater adherence to the prescribed
nutritional therapy and, therefore, better values for the renal function indices. Urinary
protein excretion values were significantly lower respect to the control group, as well as
creatinine and azotemia values, while glomerular filtration rate (GFR) values were higher.
This study suggested that CKD patients in conservative therapy can successfully benefit
Nutrients 2021, 13, 147 8 of 29

from a diet with a CPI. At the same time, a controlled energy supplementation would
ameliorate, on the one hand, the adherence to the same diet with CPI, and on the other
would improve the nutritional status of the CKD patient.
The LPD, with or without energy supplementation, can be used successfully espe-
cially in younger CKD patients. In fact, the protective effects of the LPD on the progression
of CKD were less evident in the geriatric population. An example of this is the study of
Levine et al. [85] that examined the epidemiological data from NHANES III—National
Health and Nutrition Examination Survey [86]. NHANES III is a cross-sectional study
conducted to assess the health and nutritional status of a representative sample of the US
population for ethnicity, education and comorbidity (6381 subjects aged over 50 years).
From the observation of such data, the authors have evidenced that the mortality rate
among the individuals with LPD was different, depending on the age of the subjects ana-
lyzed. In particular, individuals between the 50–65 years who followed a high-protein diet
(HPD) had a significant increase in mortality for all causes up to a value of 74% compared
to individuals of the same age but who followed a LPD. These results were opposed if the
subject of the study were individuals over 66 years of age. This group, on the contrary,
presented a 60% reduction in mortality rate for all causes if it consumed a LPD, while the
reduction was only 28% if it consumed a diet rich in protein. This study shows that in the
geriatric population higher protein intake is related to a better prognosis due to a reduced
risk of mortality. The reduced protein intake in CKD patients must always take into ac-
count the possible risks of malnutrition associated with this dietary restriction, therefore
the LPD must be prescribed by a multidisciplinary team that includes a nephrologist, a
nutritionist expert in renal diseases and a psychologist, the latter necessary to allow the
acceptance of chronic pathology and increase adherence to the prescribed dietary-nutri-
tional treatment. It has been observed that malnutrition in CKD patients is associated with
a faster progression of kidney disease, and thus a worsening of the prognosis with an
increase in the mortality rate [87]. The recommendations for protein intake in ESRD pa-
tients reflect the need to ensure an adequate nutritional intake to prevent the development
of comorbidities such as sarcopenia, PEW and cachexia. The recommendations of the cur-
rent guidelines and consensus published so far is to take at least 1.1–1.2 g/kg b.w./day of
protein for ESRD patients under HD treatment [81,88–90]. In HD subjects, a higher protein
intake is therefore recommended compared to the one advised to the general population
(0.8/kg b.w./day), especially considering the loss of amino acids and proteins that occurs
during HD treatment. Moreover, in HD patients an intake of 35 kcal/kg b.w./day is rec-
ommended, taking into consideration also the age, the physical activity carried out by the
patient and the hypercatabolic state induced by dialysis [81,88–90].
In ESRD, uremic intoxication and the need to slow the progression of nephropathy
are no longer the focal point of nutritional therapy, as they are treated by adequate HD
therapy. The prevention and management of MM reduction thus becomes the focal point
of nutritional therapy that is focused on maintaining an equal or positive nitrogen balance,
so as to ensure better outcomes in patients in HD treatment. Sabatino et al. [91] have pro-
posed an interesting algorithm that indicates the intervention times on the nutritional sta-
tus, the types of intervention, and the protein-energy intake targets to be achieved in
chronic HD patients. The need to further implement the protein intake in HD patients is
due to the presence in this category of an increased protein catabolism and reduced syn-
thesis that induces the development of pathological conditions such as sarcopenia. In ad-
dition, as emerged from a study of Cupisti et al. [92], often up to 50% of HD patients as-
sume less than 1 g/kg b.w./day protein and experience a reduced energy intake, aggravat-
ing their negative nitrogen balance condition.
Nutrients 2021, 13, 147 9 of 29

Figure 2. Clinical management of hemodialysis (HD) patients to counteract the onset and the progression of uremic sar-
copenia [91]. Abbreviations: b.w., Body weight; DEI, Diet energy intake; DPI, Diet protein intake; EN, Enteral nutritional;
GI, Gastrointestinal; IDPN, Intra-parenteral nutrition dialysis; MIS, Malnutrition inflammation score; MM, Muscle mass;
PEG, Percutaneous endoscopic gastrectomy; SGA, Subject global assessment; TPN, Total parenteral nutrition.

Several studies have been carried out to investigate the different strategies that en-
sure an adequate protein-energy intake in HD patients. Numerous studies have shown
that, in nephropathic patients, HPD causes an accumulation of toxic compounds (derived
from protein metabolism), while a LPD offers better outcomes in these patients [93]. In
particular, in CKD it is necessary to distinguish two categories of patient: the first (i) is
represented by patients undergoing conservative therapy and the second (ii) is repre-
sented by patients in renal replacement therapy. In the first category, an HPD, defined as
a diet with an intake greater than 1.2 g prot/kg/b.w. per day, is able to alter renal hemody-
namics, inducing the condition of hyperfiltration [94]. Renal hyperfiltration consists in the
increase in renal blood flow inducing an enhancement in intra-glomerular pressure that
causes a GFR increase and the elimination of protein-derived waste nitrogen products.
This cause an increase of renal parenchyma volume and body weight [94]. An HPD is also
associated with an increase in urinary excretion of albumin or protein, which induces con-
sequences both at the level of the kidney and at the level of other organs [95]. The presence
and degree of albuminuria, according to current guidelines, are related to the severity of
CKD and to CV mortality risk. Proteinuria induces apoptosis of renal tubular cells and
alters the regeneration of podocyte cells, inducing tubular atrophy that favors the pro-
gression of kidney damage [96]. A further effect induced by an HPD is that related to
metabolic acidosis. Protein metabolism is able to generate acids, derived from the metab-
olism of sulfide amino acids, and this phenomenon induces a decrease in bicarbonatemia
worsening the picture of metabolic acidosis typical of CKD. In the literature, the phenom-
enon that correlates acid retention with the decline of kidney function has been described,
inducing the chronic condition of metabolic acidosis [97]. This phenomenon alters protein
metabolism, increases muscle catabolism and loss of muscle mass, worsens residual kid-
ney function and, simultaneously, uremic symptoms [98]. Gaggl et al. [99] demonstrated
a positive correlation between metabolic acidosis and the assumption of sodium bicar-
bonate in IV-stage CKD patients. In fact, they demonstrated that sodium bicarbonate oral
supplementation was able to slow the decline of kidney function and improve nutritional
status, with two years follow-up. HPD is also related to high phosphorus intake, mainly
content in animal origin proteins and in food additives [100]. Its high blood levels help to
induce the alteration of calcium-phosphorus metabolism, a very frequent condition in
Nutrients 2021, 13, 147 10 of 29

CKD patients [92]. The increase in phosphoremia is directly related to high levels of par-
athyroid hormone and fibroblast growth factor (FGF)-23 [101], and induces an alteration
of the vasal walls. The latter increases the risk of CV disease [102]. Therefore, in this pa-
tient population, the administration of HPD would not be a valid therapeutic tool since it
would lead to a faster decline in kidney function. In the second category of patients, it is
necessary to consider the impact of dialysis treatment on protein metabolism in order to
determine the correct daily protein intake per kg of b.w. Current guidelines [103] for HD
patients recommend a high protein intake, as previously mentioned, because dialytic pro-
cedure stimulates protein catabolism with high the risk of MM loss. Therefore, in HD pa-
tients a high protein intake is necessary in order to avoid the establishment of PEW syn-
drome, induced by the loss of amino acids and proteins during the dialysis treatment. In
fact, it is possible to observe in ESRD patients the phenomenon of “obesity paradox”,
highlighted as a higher BMI reduces the risk of mortality [104].
The HPD seems to be inversely related to the onset of the fragility state [105]. Fragility
is defined as having at least three of the following five symptoms: weight loss, low phys-
ical activity, asthenia, slowing down, and fatigue. This condition is characterized by an
increased susceptibility to adverse health events, leading to an enhancement incidence of
hospitalization, falls and consequent fractures, disability, request for nursing assistance,
and death [106–108]. Therefore, a diet associated with physical exercise plays a key role
in the prevention and treatment of frailty [109]. All studies agree on the importance of
early and regular dietary counselling to ensure a better success of nutritional therapy, es-
pecially in terms of adherence to the same [91]. Nutritional counseling must provide cor-
rect dietary nutritional information, evaluate past eating habits and identify the presence
of any deficit in protein or energy intake. In addition, for patients with an energy intake
less than 30 kcal/kg/day or protein intake less than 1 g/kg/day, it is necessary to provide
information and tools to increase intake. Correct indication must be provided to avoid
foods with high content of phosphorus, potassium and sodium and to try to avoid unnec-
essary fasting periods, as may occur after dialysis or in periods of acuity or hospitaliza-
tion. It is therefore appropriate to reiterate the concept that a multidisciplinary team as-
sesses the risk of uremic sarcopenia and identifies the best protein intake for each patient
[92]. The therapeutic possibilities identified so far to provide a proper protein–energy in-
take in HD patients are manifold and include the use of oral nutritional supplements
(ONS), intra-parenteral nutrition dialysis (IDPN), enteral nutrition (EN) or total parenteral
nutrition (TPN). Other useful tools proposed are specific nutritional products such as fi-
bers and ω-3 (Table 1) [91].
Nutrients 2021, 13, 147 11 of 29

Table 1. Possible nutritional treatments of uremic sarcopenia in humans.

Nutritional
Author Year Study Population Nutritional Treatment Primary Outcome Primary End-Point
Approaches
Significant increases in serum
ONS assumed during each HD session, ONS assumed during HD im-
albumin and prealbumin lev-
Caglar K. et al. 85 malnourished CHD, containing 16.6 g of proteins, 22.7 g of li- proves some nutritional bi-
2002 els were detected.
[110] HD patients pids and 52.8 g of carbohydrates with en- omarkers in malnourished
In addition, there was a 14%
ergy content of 475 kcal. HD patients.
increase in SGA score.
Four different intradialytic ONS were ad-
5.227 HD patients with al- ministered: A reduction in mortality was
ONS treatment allows a sig-
Lacson Jr E. et al. bumin level ≤3.5 g/dL (a) 19 g proteins, 425 kcal for dose; found in patients treated with
2012 nificant increase in survival of
[111] vs. 5.227 patients (control (b) 15 g proteins, 60 kcal for dose; ONS compared to non-treated
HD patients.
group) (c) 14 g proteins, 210 kcal for dose; group.
(d) 20 g proteins, 210 kcal for dose.
ONS significant decreased
urine protein excretion there-
ONS has improved some
55 CKD patients One daily ONS containing 0.6 g of pro- fore, daily protein intake was
ONS

blood parameters and im-

(stage III-IV) teins, 8.2 g of lipids, 30.9 g of carbohy- lower in the ONS group. Sig-
Wu H.L. et al. [84] 2013 proved the adherence to the
vs. 54 patients (control drates and 1.9 g of fiber with energy con- nificant decrease of creatinine
nutritional therapy with less
group) tent of 200 kcal. and urea nitrogen levels; in
protein excretion.
addition, there was a signifi-
cant increase of eGFR.
Significant increases in serum
albumin levels were detected.
ONS containing 14 g of proteins, 19.2 g of
Furthermore, there was a sig-
lipids and 41.3 g of carbohydrates with en-
32 malnourished HD pa- nificant increase in the dry ONS treatment improves se-
ergy content of 400 kcal.
tients weight of the ONS patients rum albumin levels and al-
Sezer S. et al. [112] 2014 In addition, during HD sessions was
vs. 30 patients (control and a significative reduction lows a lower EPO dose re-
served a snack containing 14 g of proteins,
group) in the dry weight of the con- quirement in HD patients.
10 g of lipids and 55 g of carbohydrates
trol group.
with energy content of 300 kcal.
In addition, a reduction of
EPO dose requirement and
Nutrients 2021, 13, 147 12 of 29

MIS was detected in the

treated group.
3.374 HD patients with al- Two different ONS were used: ONS treatment allows a sig-
There was a 69% reduction in
Benner D. et al. bumin level ≤3.5 g/dL (a) 21.6 g of proteins and 475 kcal for nificant increase in survival in
2018 mortality and a 33% reduction
[113] vs. 3.374 patients (control dose; HD patients with albumin
in missed dialysis sessions.
group) (b) 16 g of proteins and 70 kcal for dose. level ≤3.5 g/dL.
Six different intradialytic ONS were used:
(a) 19 g proteins and 425 kcal for dose;
1420 HD patients (b) 15 g proteins and 60 kcal for dose; There was a decrease of re- ONS treatment reduces post-
Leonberg-Yoo
2019 vs. 4.059 patients (control (c) 14 g proteins and 210 kcal for dose; hospitalization within 30 days discharge hospital readmis-
A.K. et al. [114]
group) (d) 20 g proteins and 210 kcal for dose; of first discharge. sion rates.
(e) 16 g proteins and 90 kcal for dose;
(f) 16 g proteins and 160 kcal for dose.
IDPN treatment three times/week contain-
ing (one dose):
39 HD patients
 glucose (70%); Significant increases in serum IDPN used during HD ses-
Marsen T.A. et al. with PEW
2017  amino acids (15%); prealbumin levels were de- sion improves prealbumin
[115] vs. 44 patients (control
 lipids (20%) tected. levels.
group)
 vitamins;
 L-carnitine.
Significant increases in hemo- IDPN treatment allows an im-
globin and albumin levels provement of refractory ane-
IDPN

20 HD patients IDPN treatment three times/week. In addi- were detected. In addition, mia, as it permits an increase
Thabet A.F. et al.
2017 vs. 20 patients (control tion, patients received EPO, iron dextran, there was a significant in- in hemoglobin and prealbu-
[116]
group) folic acid and vitamin B 12. crease in BMI. min levels and also an in-
Significant reduction in MIS crease in body weight. It also
was detected. leads to a reduction in MIS.
Two dialysates were used during HD During the HD treatment
The use of dialysate enriched
treatment: with standard dialysate a re-
Deleaval P. et al. in BCAA allows the restora-
2020 6 HD patients  Standard dyalisate; duction in plasmatic valine
[60] tion of normal plasma BCAA
 Dialysate enriched in BCAA (valine, was found, while with dialy-
levels.
isoleucine, leucine). sate enriched in BCAA HD
Nutrients 2021, 13, 147 13 of 29

treatment there was an in-

crease in plasmatic valine, iso-
leucine and leucine.
ω-3 supplementation is a sig-
nificant independent predic-
tor for the increase of serum
27 HD patients Six capsules per day of ω-3 supplementa- prealbumin level after adjust- ω-3 supplementation in HD
Gharekhani A. et
2014 vs. 27 patients (control tion (180 mg eicosapentaenoic acid and 120 ing post-treatment nutritional patients permits a slight re-
al. [117]
group) mg docosahexaenoic acid in each capsule). markers. duction of inflammation.
ω-3 supplementation

Significant decrease in ferritin

levels and IL-10/IL-6 ratio was
detected.
Four groups for supplementation per day:
 1250 mg/day ω-3 PUFA containing
600 mg eicosapentaenoic acid and 300 mg Significant reduction in SGA,
ω-3 PUFA and vitamin E
90 HD patients docosahexaenoic acid; FPG, insulin levels and
Asemi Z. et al. combined supplementation
2016 vs. 30 patients (control  400 IU/day vitamin E; HOMA-IR were detected. In
[118] improve SGA and the meta-
group)  1250 mg ω-3 PUFA containing 600 addition, there was a signifi-
bolic profile in HD patients.
mg eicosapentaenoic acid and 300 mg do- cant enhancement in QUICKI.
cosahexaenoic acid + 400 IU vitamin E;
 placebo (control group).
1.105 CKD patients Two groups were divided into two sub- Significant decrease in CRP The high dietary fiber con-
Fiber

Krishnamurthy (stage IIIa-IV) groups according to fiber dietary intake: was detected in CKD patients sumption is associated with a
2012
V.M.R. et al. [119] vs. 13.438 subjects (control  Low total fiber (<14.5 g/day); with high total fiber dietary minor inflammation risk and
group)  High total fiber (≥14.6 g/day). consumption. mortality in CKD patients.
Abbreviations: BCAA, Branched-chain amino acid; BIA, Bioelectrical impedance analysis; BMI, Body mass index; CHD, Coronary heart disease; CKD, Chronic kidney disease; CRP, C-
reactive protein; e-GFR, Estimated glomerular filtration rate; EPO, Erythropoietin; FPG, Fasting plasma glucose; HD, Hemodialysis; HOMA-IR, Homeostasis model of assessment of
insulin resistance; IDPN, Intra-dialytic parenteral nutrition; IL, Interleukin; MIS, Malnutrition inflammation score; MPS, Muscle protein synthesis; ONS, Oral nutritional supplements;
PUFA, Polyunsaturated fatty acids; QUICKI, Quantitative insulin sensitivity check index; SGA, Subjective global assessment.
Nutrients 2021, 13, 147 14 of 29

3.1. Oral Nutritional Supplements

As mentioned in Figure 2, ONS are the first step to be taken when a reduction of the
protein-energy intake by the patient is highlighted. Generally, a standard ONS ensures
the achievement of nutritional targets, as it provides up to 10 kcal/kg b.w./day and 0.3–0.4
g/kg b.w./day of protein, if consumed twice a day. It is essential that the ONS provides a
high energy intake (1.8–2 kcal/mL), so as to reduce the risk of overload of liquids, a dan-
gerous event for HD patients. In addition, the ONS are generally formulated to present a
pleasant taste and good palatability for the patient in order to ensure assumption [91].
HD patients are often elderly and have issues related to appetite reduction or swal-
lowing, therefore the use of ONS with high protein and energy content in the form of
small-volume snacks has clear advantages in terms of spontaneous assumption of the nu-
tritional supplement [120,121].
Consumption of ONS may be intra-dialytic or inter-dialytic. Intra-dialytic admin-
istration is usually preferred because it is associated with greater compliance of the pa-
tient, not interfering with the intake of the conventional meal at home [91].The main func-
tion of ONS is to provide a protein load to counteract the protein catabolism associated
with HD treatment [60]. According to various studies, ONS have demonstrated their ef-
fectiveness not only in the improvement of nutritional status but also in inflammatory
indices, in physical performance and in prognosis and lower risk of mortality [110–
114,122].
Lacson et al. [111] conducted an observational study lasting one year on a large sam-
ple of HD patients, characterized by an albuminemia of 3.5 g/dL. These patients were di-
vided into a control group and an experimental group, to which an ONS was administered
three times a week during HD treatment. Each group included 5227 patients, respectively.
The authors highlighted that those who assumed ONS treatment had a protein intake in-
crease, an enhancement of albuminemia (an important biomarker of nutritional status),
but primarily a higher survival rate than the control group.
Similar data emerged from the Sezer et al. study [112], conducted on 62 chronic HD
patients divided into a control group and an experimental group to which an intra-dialytic
ONS was administered. The authors, in a follow-up period of six months, showed in the
experimental group a progressive increase in albuminemia values and in body weight
that instead was reduced in the control group. An interesting aspect emerged from this
study is that the patients in the experimental group, thanks to the achievement of a better
nutritional status, presented a reduced need for therapy with recombinant human eryth-
ropoietin (EPO). The ONS thus demonstrate to have multiple beneficial effects, specifi-
cally including the ability to allow a reduction of EPO therapy, a fundamental tool for the
anemia treatment in the CKD patient.
Caglar et al. [110] conducted a study of 85 HD patients who were given an ONS dur-
ing the HD session for a period of six months. The authors observed a significant and
progressive increase of albumin and prealbumin and a SGA improvement in the group
that assumed ONS. The SGA [123] is a diagnostic tool that through a series of specific
questions about the clinical conditions and the patient’s history allows a detailed assess-
ment of nutritional status. Based on the results obtained, SGA divides patients into three
categories: A—well-fed, B—moderately malnourished, C—severely malnourished. In
conclusion, the study of Caglar et al. [110] has shown that the use of ONS is associated
with an improvement in nutritional status, detected through laboratory parameters but
also through an evaluation of the clinical state, detected with SGA. HD patients are hos-
pitalized on average twice a year, and up to 35% of these are re-hospitalized within 30
days of the first discharge [122]. Some studies have demonstrated that the use of ONS is
able to reduce the hospitalization rate in HD patients. In this regard, Benner et al. [113]
conducted a study on a large sample of HD patients with hypoalbuminemia (albu-
minemia < 3.5 g/dL) divided into an experimental group (n = 3374) who assumed an ONS
Nutrients 2021, 13, 147 15 of 29

vs. control group (n = 3374). The study highlighted that the use of ONS, during HD treat-
ment, induced a mortality reduction of up to 69% and a significant increase in protein
intake. Another interesting fact emerged from the study, in that ONS caused an increase
in body weight but especially a reduction of up to 33% of the number of dialysis sessions
considered “lost” or not performed. Hospitalization results in a failure to conduct the di-
alysis session at the reference center. According to the authors, a better nutritional status
would therefore be related to an improvement of outcomes and therefore a reduced risk
of hospitalization.
Leonberg-Yoo et al. [114] conducted a study of 5479 patients in chronic HD who were
hospitalized (for any reason) during the 12 months before the start of the study and with
hypoalbuminemia at the time of discharge (albuminemia < 3.5 g/dL). The experimental
group receiving ONS consisted of 1420 patients, and 4059 patients received no ONS (con-
trol group). The study showed that the control group presented a risk of re-hospitalization
within 30 days of the first discharge, significantly higher than the experimental group.
The association between the use of ONS and the reduction of the hospitalization rate is an
important factor for the HD patient. The latter, in fact, is often elderly and suffering from
multiple comorbidities, and is therefore considered a “fragile” individual. The use of ONS
is a possible tool to reduce the hospitalization rate, decreasing intra-hospital complica-
tions and consequently the risk of mortality in HD patients.
Some studies have demonstrated that ONS assumption not only induced a nutri-
tional benefit but also a better prognosis with a reduced risk of hospitalization and mor-
tality [113,124].

3.2. Amino Acids Supplementation

A further nutritional strategy useful in countering the onset of, and improving, ure-
mic sarcopenia is the administration of keto-analogues (KAs). The latter are essential
amino acid nitrogen-free analogs [125]. According to previous studies, a LPD in combina-
tion with essential amino acids and KAs is useful in maintaining good nutritional status
in patients with advanced nephropathy [126]. In fact, in order to prevent inadequate in-
take of amino acids, it is mandatory to supply the optimal amount of these nutrients. The
mechanisms responsible for muscle alteration are represented by an increased OS and by
mitochondrial dysfunction associated with an up-regulation of p66SHC and Forkhead
box O3A (FoxO3A). A study in CKD mouse models conducted by Wang et al. showed
that KAs supplementation is able to improve muscle atrophy and reduce OS and mito-
chondrial damage [127].
A subsequent study conducted by Zhang et al. [128] in CKD mouse models evaluated
the effects of KAs supplementation on autophagy and inflammation of skeletal muscle.
The authors concluded that the LPD diet supplemented with KAs improves autophagy
but does not appear to have any effect on the inflammatory state.
A study conducted on CKD rats evaluated the effect of KAs on the mechanisms of
prevention of muscle atrophy [129]. The authors divided the study population into 3 sub-
groups fed for 24 weeks with the following dietary treatments: 1—normal-protein diet-
group, 2—LPD group and 3—LPD + KAs group. The results obtained showed that KAs
improve protein synthesis and inhibit ubiquitin-proteasome mechanisms. They also re-
duce DNA fragmentation in muscle cells, confirming their action as a supportive thera-
peutic strategy to counteract muscle atrophy.
A further protocol of KAs supplementation is that obtained by combining amino ac-
ids with the KAs [130]. In a study conducted by Barsotti et al., the authors demonstrated
that a LPD supplemented with KAs and amino acids allowed a slowing of the progression
of renal disease and reduced CV risk. This finding was explained by the fact that the sup-
plemented LPD carried a low amount of phosphorus which in turn induced a negative
balance so as to determine a decrease in serum phosphorus [131].
Nutrients 2021, 13, 147 16 of 29

A subsequent study by Zemchenkov et al. of 96 CKD patients with stage 3b-5 con-
firmed that an LPD supplemented with essential amino acids and KAs induced a slow-
down in the progression of CKD, particularly in female elderly patients and in those with
low levels of plasma phosphorus [132].

3.3. Intra-Dialytic Parenteral Nutrition

IDPN consists of the administration of an amino acids, glucose and lipids mixture
through the venous line of the dialysis circuit during each session of HD. The IDPN pre-
sents a shortening of the administration time depending on the frequency and duration
of the dialysis session. A safe and effective IDPN for a patient with an average weight of
75 kg should consist of no more than 1 L of infusion fluid (to avoid water overload) and a
maximum of 1000 kcal and 50 g of amino acids [133]. The choice to administer IDPN de-
pends on the difference between the value of the protein-energy intake to be reached and
the protein intake energy taken by the patient. The maximum nutrient intake that can be
obtained with IDPN is about 3000 kcal and 150 g of amino acids, that is 5 kcal/kg b.w./day
and 0.25 g/kg b.w./day of amino acids in a patient of about 70 kg. Since IDPN can guaran-
tee up to a maximum of 25% of the ideal nutritional intake, it may only be administered
if the patient has a spontaneous protein intake of 0.8–0.9 g/kg b.w./day and an energy
intake of 20 kcal/kg/day [89,133].
IDPN cannot be considered as a long-term treatment. After the achievement of the
predetermined targets that usually takes place within 3–6 months from the start of the
IDPN, its suspension and continuation of nutritional treatment with the ONS is required
[89,133]. Intra-dialytic ONS could therefore be useful to ensure an adequate protein and
energy intake in HD patients, compensating for the loss of amino acids that occurs during
HD treatment and counteracting the catabolic effect of HD itself [60,61].
The criteria that allow stopping of therapy with IDPN and implementation of the
switch to ONS are: albuminemia values stable > 3.8 g/dL for more than three months;
improvement of the SGA score up to stage A (well nourished) or B (moderation malnour-
ished); positive clinical examination for effective nutritional improvement; increased pro-
tein intake > 1 g/kg b.w./day and energy > 30 kcal/kg b.w./day [133].
The studies conducted so far concerning the effectiveness of IDPN in HD patients are
encouraging. Marsen et al. [115] conducted a prospective multicenter randomized study
of 107 malnourished patients in chronic HD (SGA stage B—moderate malnutrition or
stage C—severe malnutrition) divided into a control group and an experimental group,
to which IDPN was administered three times a week for 16 weeks. The observation period
continued for 12 weeks after the end of nutritional therapy. The authors noted that the
administration of IDPN was associated with a significant increase in pre-albumin, which
was stable in the weeks following the discontinuation of the IDPN. This was even more
evident in patients with moderate malnutrition (SGA stage B). IDPN would therefore be
responsible for the improvement of pre-albumin values, whose reduction is a known neg-
ative prognostic marker for CKD patients [134]. The study highlights the importance of
early intervention to prevent or treat malnutrition. Despite that IDPN is a more invasive
nutritional intervention than ONS, it still has less effectiveness in conditions of serious
malnutrition that must be carefully avoided by using early nutritional counselling. The
improvement of pre-albumin thanks to IDPN was in fact more evident in patients with
moderate malnutrition (SGA stage B) than those with severe malnutrition (SGA stage C).
Thabet et al. [116] have shown that the IDPN, as already described for the ONS, im-
proves the nutritional status of the patient, improves anemia status and therefore reduces
the necessary dose of EPO therapy. The authors conducted a study on 40 HD patients with
refractory anemia and malnutrition. The participants were divided into a control group
and an experimental group under IDPN for a period of six months. The data obtained at
the time of enrollment, after three and six months, showed a progressive and significant
increase in albumin, BMI and especially hemoglobin. Moreover, the values of the malnu-
trition inflammation score (MIS) were reduced. The MIS [135] is a questionnaire used for
Nutrients 2021, 13, 147 17 of 29

the assessment of nutritional status that includes a part on the patient’s self-completed
history about dietary intake and possible interdialytic symptoms, and a part compiled by
the medical-nursing staff that reports on the physical examination, the value of BMI, al-
bumin and transferrin. Transferrin is an indicator of depletion of protein deposits and
therefore of nutritional status [136].

3.4. Enteral and Total Parenteral Nutrition

In patients with severe malnutrition and a spontaneous energy intake of less than 20
kcal/day, ONS and IDPN are generally unable to guarantee an adequate nutritional status.
Under such conditions, as well as in the presence of impaired swallowing capacity, daily
nutritional support is required. The therapeutic possibilities are EN and TPN. Generally,
if possible, it is preferable to use EN than TPN [89]. According to the guidelines of ESPEN
(European Society for Clinical Nutrition and Metabolism) [137], EN must be taken into
account in severely malnourished patients with a BMI < 20 kg/m2, a reduction in body
weight > 10% in the last 6 months, albumin values < 3.5 g/dL and pre-albumin values <
300 mg/L. Frequently, these patients also have other comorbidities (such as central or pe-
ripheral neurological diseases) that do not allow the administration of ONS or the achieve-
ment of an adequate nutritional status via this administration. EN can be administered
via nasogastric or naso-jejunal in case of gastroparesis and non-responsibility to pro-ki-
netic agents, or through percutaneous endoscopic gastrostomy (PEG) [90]. EN is also less
expensive compared to TPN, and at the same time presents a lower risk of infectious or
metabolic complications.
The enteral administration of nutrients has a trophic action towards the gastrointes-
tinal mucosa, improving its integrity, damaged by the uremic toxins. Parenteral admin-
istration, in addition to requiring good vascular access which is not always available, can
have an irritating effect on the vascular district itself [90]. Although the use of EN is pref-
erable, the choice of administering TPN is mandatory in the case of severe gastrointestinal
dysfunction such as intestinal ischemia, gastro-intestinal obstruction or peritonitis [89].
TPN is the last possible choice in the event of failure of adequate nutritional intake
through ONS, EN and IDPN.

4. Other Special Types of Nutritional Supplements

4.1. Ω-3 PUFAs
Ω-3 polyunsaturated fatty acids (PUFAs) are known for their multiple protective ef-
fects against CV and inflammatory diseases [138]. Smith et al. [139] conducted a study on
16 elderly patients without a noteworthy pathology subdividing them into two subgroups
(group 1 and group 2). For 8 weeks, group 1 was given maize oil at the dose of 4 g/day,
while Group 2 was given ω-3 at the dose of 4 g/day, of which a share was represented
respectively by 1.86 g of eicosapentaenoic acid (EPA) and by 1.50 g of docosahexaenoic
acid (DHA). Authors noted that only in group 2 individuals who were given ω-3 was there
an increase in the rate of muscle protein synthesis (MPS). The MPS monitors the dosage
of phenylalanine and leucine, considered the main regulators of protein synthesis. An in-
crease of the level of these two amino acids is therefore related to an enhancement in mus-
cle protein synthesis and therefore of MPS. The results of the study also showed an in-
crease in muscle expression of mammalian target of rapamycin (mTOR) and ribosomal
protein S6 kinase beta-1 (p70S6K), two protein kinases involved in intracellular signaling,
responsible at the muscular level for the activation of anabolic protein processes. Such
data show that, in older patients, ω-3 PUFAs would stimulate muscle protein synthesis
by countering catabolic events and sarcopenia. Studies of the role of ω-3 PUFAs in the
prevention of sarcopenia in CKD patients are still few. Azemi et al. [118] conducted a
study of 120 HD patients randomly divided into 4 subgroups (group 1, 2, 3, 4), for a total
duration of 12 months. Only vitamin E was administered to group 1, only ω-3 PUFAs to
Nutrients 2021, 13, 147 18 of 29

group 2, ω-3 PUFAs and vitamin E together to group 3, and placebo to group 4. The ad-
ministration of ω-3 PUFAs in groups 2 and 3 showed benefits in reducing the SGA score.
Ω-3 PUFAs also reduced glucose plasma fasting, serum insulin levels, homeostasis model
of assessment (HOMA)-IR, and improved the quantitative insulin sensitivity check index
(QUICKI). The administration of ω-3 would allow an improvement in nutritional status
by preventing the development of diseases such as sarcopenia, and at the same time
would improve the glycol-metabolic status of the patient, reducing the status of IR. The
latter is particularly important considering that diabetes is a common in CKD patients and
is the cause of a further worsening of their prognosis [140].
Gharekhani et al. [117] conducted a study of 25 chronic HD patients divided into two
groups, a control group and an experimental group, to which ω-3 PUFAs were adminis-
tered daily for four months. The authors pointed out that, following the administration of
ω-3 PUFAs, there was an increase in pre-albumin values and a reduction in ferritin, IL-10
and IL-6 (known inflammation indices). This study demonstrated the ability of ω-3 PUFAs
to improve both the nutritional status of the patient and the systemic inflammatory state
notoriously increased in CKD patients. Dessì et al. [141] conducted a study of 99 HD pa-
tients (experimental group) and 160 healthy subjects who did not take any ONS or drugs
(control group). It was observed that chronic HD patients had a reduced intake of protein,
carbohydrates and lipids and therefore a reduced total energy intake, confirming the in-
creased risk of malnutrition present in this category of patients. Furthermore, in the ex-
perimental group, a reduction of PUFAs was observed at both plasma and erythrocytic
membrane levels. Erythrocytes are used as model cells for assessing membrane fatty acid
composition and phospholipid intake through diet. In particular, an increase in the ω-6/ω-
3 ratio was observed, mainly due to the reduction of ω-3. The reduction of PUFAs and
especially ω-3 was associated with an increased risk of CV events and mortality, already
notoriously high in HD patients. The reduction in plasma and erythrocyte PUFA concen-
tration appears to be due not only to reduced dietary intake, but also to the loss of such
elements in dialysis during HD treatment [142,143]. This study confirms the importance
of ensuring a nutritional diet that provides an adequate amount of the different nutrients,
including ω-3. Such intervention would lead to an improvement in the prognosis of HD
reducing the risk of malnutrition and especially of CV events and mortality [144].

4.2. Fiber
The use of fiber as a nutritional supplement has shown benefits in reducing toxins
related to uremic proteins produced by the gut microbiota such as indoxyl sulfate and p-
cresol. The plasma reduction of these toxins according to various studies would lead to
an improvement in the prognosis of CKD patients reducing their mortality. Dysbiosis, in
fact, through the production of uremic toxins, participates in the establishment of the sys-
temic inflammatory status typical of CKD patients, responsible for catabolic protein pro-
cesses at the muscular level that will lead to the development of sarcopenia [70]. Fiber
ingestion is associated not only with the reduction of uremic toxins but also with the re-
duction of creatinine and azotemia values [145]. Krishnamurthy et al. [119] analyzed the
data from the NAHNES III study [86] including 14,543 patients. The authors noted that in
CKD patients (5.8% of the population analyzed) with a fiber intake of 10 g/day, the prob-
ability of detecting an increase in CRP changed from 11% to 38%. The mortality rate was
also inversely related to the quantity of fiber intake. The ingestion of fibers would seem
correlated to a reduction in the degree of chronic inflammation present in the CKD patient
and a reduction of mortality. According to data from the NHANES III [145], it would ap-
pear that CKD patients take low amounts of fiber i.e., on average 15.4 g/day. The recom-
mended intake of fiber in nephropathic patients is 25–30 g/day, as in the normal popula-
tion. The reduced intake can be explained by dietary restrictions imposed due to potas-
sium content, which is widely present in vegetables. For this reason, in CKD patients care-
ful nutritional counselling should be performed to allow appropriate management of the
dietary-nutritional plan.
Nutrients 2021, 13, 147 19 of 29

5. Other Therapeutic Approaches to Uremic Sarcopenia

Physical exercise was the most commonly studied and validated therapy for the
treatment of both primary and secondary sarcopenia [39]. The performance of both aero-
bic and anaerobic physical exercises has been shown to reduce the degree of sarcopenia
thanks to the progressive increase of MM and muscle strength. Physical exercise also al-
lows an improvement in sarcopenia as it also leads to a reduction of IR and anorexia,
processes involved in the reduction of MM [146]. In view of the generally sedentary life
of HD patients, the beginning of a physical exercise program adapted to the age and
comorbidity of the individual has demonstrated beneficial effects on both MM and
strength and is recommended in all patients at risk for the development of sarcopenia. A
further possible approach for the treatment and prevention of sarcopenia is to intervene
in the processes involved in the alteration of the balance between catabolism and protein
anabolism, the cause of sarcopenia.
Poor physical activity is one of the most frequent disabling problems in ESRD pa-
tients, confirmed by the fact that several studies have highlighted the benefits derived
from physical exercise in hemodialysis patients [16,20,31]. These data were confirmed by
a multi-center randomized clinical trial, “Exercise introduction to enhance performance
in dialysis” [147] with six months follow-up which evaluated the effect of a simple walk-
based exercise program, conducted at home, supervised by the staff of the dialysis center,
on the functional status of hemodialysis patients. Specifically, 296 HD patients were di-
vided into two subgroups, of which the first one represented the control group and per-
formed normal physical activity, while the second group was instructed in the walking-
based physical activity protocol. After six months of intervention, it appeared that the
group subjected to walking exercise had an improvement in physical performance as-
sessed by the six minutes walking test and the five times sit-to-stand test. In addition,
physical activity also positively impacted on the cognitive function and on the quality of
social interactions of patients. These parameters were monitored by the Kidney Disease
Quality of Life Short Form questionnaire.
A recent study has highlighted how medium or high intensity intra-dialytic re-
sistance exercise is a useful therapeutic tool in HD patients [148]. In fact, after 12 weeks of
this exercise program, repeated three times a week, dialysis efficiency improved. Further-
more, physical exercise also seemed to have a positive impact on inflammatory parame-
ters, improving the chronic inflammatory status of uremic patients.
A subsequent study compared high-intensity and moderate-intensity resistance ex-
ercise repeated for 12 weeks in a group of hemodialysis patients, demonstrating that high-
intensity intradialytic exercise compared to the other form of exercise induced an en-
hancement in lower limb muscle mass and quality of life [149], while other parameters
such as functional capacity, appendicular muscle mass and sarcopenia ameliorated re-
gardless of the intensity of physical exercise.
The positive impact of physical activity was observed not only in HD patients but
also in CKD patients under conservative therapy. Secondary analysis from the ExTra CKD
study showed that supervised physical exercise in CKD patients under conservative ther-
apy is able to significantly improve the volume of the quadriceps femoris [150]. Further-
more, studies conducted on CKD non-dialysis patients demonstrated that aerobic exer-
cise, intermittent exercise, and resistance training are able to enhance VO2 peak [151–153].
The combination of nutritional therapy with physical exercise could represent a fur-
ther useful tool to counteract the onset and progression of sarcopenia. In fact, as previ-
ously demonstrated by several studies, the two therapeutic approaches could be more
effective in combination than the single treatment [154]. In fact, in conservative therapy
for patients with CKD, the combination of LPD with endurance exercise counteracts the
loss of muscle mass [155]. This study highlighted that endurance training carried out dur-
ing LPD reduces protein catabolism, with an improvement in body composition. This is
supported by the fact that a direct correlation was observed in patients undergoing this
training program between the increase in type I and II muscle fibers, that of muscle
Nutrients 2021, 13, 147 20 of 29

strength, and serum albumin levels. This is also associated with a reduction in the inflam-
matory state. A study conducted on HD patients demonstrated that intra-dialytic paren-
teral nutrition, associated with physical exercise, was able to increase the absorption of
essential amino acids following the dialysis session, compared to a group of HD patients
treated with intra-dialytic parenteral nutrition alone. In particular, these authors observed
an increase in the uptake of amino acids in the forearm [156].
In order to avoid a state of metabolic acidosis, it is desirable to maintain bicarbonate
values above 22mmol/L through a suitable HD treatment or administration of sodium
bicarbonate. According to a study by Boirie et al., a concentration of 16 mmol/L bicar-
bonates would result in double protein muscle loss compared to values > 22 mmol/L [157].
IR is an important risk factor for the development of sarcopenia, and can be counteracted
primarily through constant exercise, especially if aerobic [158]. Among the drugs used for
diabetes mellitus (DM), thiazolidinediones have gained particular interest as they have
demonstrated the ability to activate the PI3K pathway, generally suppressed in sarcopenia
by the UPS system; further studies are required to validate the efficacy of thiazolidinedi-
ones in increasing MM in sarcopenic patients [159].
Hormonal therapy with nandrolone, due to reduced testosterone concentration in
CKD patients, unfortunately has limited use due to possible side effects such as erectile
dysfunction, gynecomastia and increased CV risk [160]. Among future therapeutic per-
spectives that are being studied with murine samples, we mention the use of microRNA
and sirtuins (SIRTs). MicroRNAs, by binding specific regions of the 3′ end, named un-
translated regions (UTRs), of the mRNA, block its translation and thus limit the expression
of certain gene regions. The use of microRNAs could reduce the expression of mRNA
areas involved in muscle protein degradation or reduced myogenesis [161,162]. The func-
tional integrity of the mitochondria is fundamental for the metabolism of the whole cell
and its alteration is associated with the loss of muscle tissue [163]. It has been observed
that in HD patients there is a reduction of peroxisome gamma proliferator coactivator 1α
(PGC-1α), a protein responsible for the expression of genes involved in the regulation of
mitochondrial activity. A reduction of PGC-1α would cause impaired mitochondrial func-
tion [164]. SIRTs are enzymes responsible for the stimulation of mitochondrial biosynthe-
sis, and their use in the expression of murine has been associated with slow aging and loss
of MM [165].

6. Conclusions
Sarcopenia is defined by the reduction of MM, associated with the loss of muscle
strength and the reduction of physical performance. It is a frequent condition in CKD pa-
tients, especially if undergoing HD treatment. The development of sarcopenia in nephro-
pathic patients is not associated solely with their generally advanced age. Uremic sarco-
penia is mainly related to the comorbidities typical of uremia: metabolic acidosis, low-
grade chronic inflammatory state, vitamin D deficiency, IR, hormonal alterations (in par-
ticular testosterone, IGF-1 and cortisol) and gut dysbiosis. These processes contribute to
the development of an increased protein catabolism and of a reduced protein synthesis,
resulting in a reduction of the muscle protein pool that induces a loss of MM and strength.
The same hemodialytic treatment, fundamental for the patient’s survival in ESRD, causes
the loss of amino acids and proteins. During and after the HD session, an increase in the
processes of protein catabolism was also observed. The development of sarcopenia causes
a worsening of the prognosis of CKD patients, leading not only to a worsening of Qol and
of personal autonomy, but also to an increased risk of complications and mortality.
For this reason, sarcopenia should be suspected and diagnosed as soon as possible in
patients considered at risk. There are many tools available to investigate the presence of
this disease, the choice of which is often dictated by the clinician and by diagnostic equip-
ment availability. In reference to these latter, the most commonly used are DXA, BIA or
HGS. Sarcopenia treatment is essential to improve the prognosis and survival of CKD
Nutrients 2021, 13, 147 21 of 29

patients. Physical exercise has been studied in several studies [154,166,167] and has pro-
vided encouraging results, but CKD patients cannot always perform it optimally, espe-
cially if they are very old and suffering from multiple comorbidities. Nutritional therapy
could be a valid and effective solution in ensuring a correct protein and energy intake,
which contrasts with the increased protein catabolism and the reduced protein synthesis.
The possible types of nutritional therapy administration are multiple and include
ONS, EN, TPN and IDPN. The assumption of supplements such as fiber or ω-3 PUFAs
could also be useful in counteracting the onset and progression of sarcopenia. Studies
conducted so far on different types of nutritional therapies [114,115,123,133] have pro-
vided positive results, so their use, associated with careful nutritional counselling, should
be encouraged in CKD patients.
Currently, it is believed that the combination of targeted and personalized physical
exercise for the patient with personalized dietary-nutritional therapy [168] to ensure an
adequate protein, fiber and energy intake represents the ideal approach to treat uremic
sarcopenia.

Author Contributions: Conceptualization, A.N.; writing—original draft preparation, G.M., E.O.,

C.G., F.D.D. and A.P.Z.; writing—review and editing, A.N. and N.D.D. All authors have read and
agreed to the published version of the manuscript.
Funding: This review article received no external funding.
Conflicts of Interest: The authors declare no conflict of interests.

Abbreviations
BIA Bioimpedance analysis
BMI Body mass index
b.w. Body weight
CKD Chronic kidney disease
CPI Controlled protein intake
CRP C-reactive protein
CT Computed tomography
CV Cardiovascular
DHA Docosahexaenoic acid
DM Diabetes mellitus
DXA Dual-energy X-ray absorptiometry
E3s Ubiquitin ligases enzyme
EN Enteral nutrition
EPA Eicosapentaenoic acid
EPO Erythropoietin
ESPEN European society for clinical nutrition and metabolism
ESRD End-stage renal disease
EWGSOP European working group for sarcopenia for older people
FGF-23 Fibroblast growth factor-23
FoxO3A Forkhead box O3A
GH Growth hormone
GFR Glomerular filtration rate
HD Hemodialysis
HGS Handgrip strength
HOMA Homeostasis model of assessment
HPD High-protein diet
IDPN Intra-parenteral nutrition dialysis
IGF1 Insulin-like growth factor-1
IL Interleukin
IR Insulin resistance
ISRNM International society of renal nutrition and metabolism
KAs Ketoanalogues
Nutrients 2021, 13, 147 22 of 29

LPD Low protein diet

MAMC Mid arm muscle circumference
MIS Malnutrition inflammation score
MM Muscle mass
MPS Muscle protein synthesis
MRI Magnetic resonance imaging
mTOR Mammalian target of rapamycin
NHANES National health and nutrition examination survey
ONS Oral nutritional supplements
p70S6K Ribosomal protein S6 kinase beta-1
PEG Percutaneous endoscopic gastroctomy
PEW Protein-energy wasting
PGC-1α Peroxisome gamma proliferator coactivator-1α
PI3K Protein kinase B
PUFAs Polyunsatured fatty acids
Qol Quality of life
QUICKI Improved quantitative insulin sensitivity check index
SCWD Society on sarcopenia, cachexia and wasting disorders
SGA Subject global assessment
SIRTs Sirtuins
SOCS-3 Suppressor of cytokine signaling-3
SPPB Short physical performance battery
Stat3 Signal transducer and transcriptional activator 3
TNF-α Tumor necrosis factor-α
TPN Total parenteral nutrition
UPS Ubiquitin proteasome system
UTRs Untranslated regions

References
1. Rosenberg, I.H. Sarcopenia: Origins and clinical relevance. J. Nutr. 1997, 127, 990S–991S, doi:10.1093/jn/127.5.990S.
2. Giglio, J.; Kamimura, M.A.; Lamarca, F.; Rodrigues, J.; Santin, F.; Avesani, C.M. Association of Sarcopenia with Nutritional
Parameters, Quality of Life, Hospitalization, and Mortality Rates of Elderly Patients on Hemodialysis. J. Ren. Nutr. 2018, 28,
197–207, doi:10.1053/j.jrn.2017.12.003.
3. Sabatino, A.; Regolisti, G.; Delsante, M.; Di Motta, T.; Cantarelli, C.; Pioli, S.; Grassi, G.; Batini, V.; Gregorini, M.; Fiaccadori, E.
Noninvasive evaluation of muscle mass by ultrasonography of quadriceps femoris muscle in End-Stage Renal Disease patients
on hemodialysis. Clin. Nutr. 2019, 38, 1232–1239, doi:10.1016/j.clnu.2018.05.004.
4. Foley, R.N.; Wang, C.; Ishani, A.; Collins, A.J.; Murray, A.M. Kidney function and sarcopenia in the United States general pop-
ulation: NHANES III. Am. J. Nephrol. 2007, 27, 279–286, doi:10.1159/000101827.
5. Stenvinkel, P.; Carrero, J.J.; von Walden, F.; Ikizler, T.A.; Nader, G.A. Muscle wasting in end-stage renal disease promulgates
premature death: Established, emerging and potential novel treatment strategies. Nephrol. Dial. Transplant. 2016, 31, 1070–1077,
doi:10.1093/ndt/gfv122.
6. Mitch, W.E.; Goldberg, A.L. Mechanisms of muscle wasting. The role of the ubiquitin-proteasome pathway. N. Engl. J. Med.
1996, 335, 1897–1905, doi:10.1056/NEJM199612193352507.
7. Doherty, T.J. Invited review: Aging and sarcopenia. J. Appl. Physiol. 2003, 95, 1717–1727, doi:10.1152/japplphysiol.00347.2003.
8. Von Haehling, S.; Morley, J.E.; Anker, S.D. An overview of sarcopenia: Facts and numbers on prevalence and clinical impact. J.
Cachexia Sarcopenia Muscle 2010, 1, 129–133, doi:10.1007/s13539-010-0014-2.
9. Thome, T.; Salyers, Z.R.; Kumar, R.A.; Hahn, D.; Berru, F.N.; Ferreira, L.F.; Scali, S.T.; Ryan, T.E. Uremic metabolites impair
skeletal muscle mitochondrial energetics through disruption of the electron transport system and matrix dehydrogenase activ-
ity. Am. J. Physiol. Cell Physiol. 2019, 317, C701–C713, doi:10.1152/ajpcell.00098.2019.
10. Yazdi, P.G.; Moradi, H.; Yang, J.Y.; Wang, P.H.; Vaziri, N.D. Skeletal muscle mitochondrial depletion and dysfunction in chronic
kidney disease. Int. J. Clin. Exp. Med. 2013, 6, 532–539.
11. Afsar, B.; Afsar, R.E.; Dagel, T.; Kaya, E.; Erus, S.; Ortiz, A.; Covic, A.; Kanbay, M. Capillary rarefaction from the kidney point
of view. Clin. Kidney J. 2018, 11, 295–301, doi:10.1093/ckj/sfx133.
12. Delmonico, M.J.; Harris, T.B.; Visser, M.; Park, S.W.; Conroy, M.B.; Velasquez-Mieyer, P.; Boudreau, R.; Manini, T.M.; Nevitt,
M.; Newman, A.B.; et al. Longitudinal study of muscle strength, quality, and adipose tissue infiltration. Am. J. Clin. Nutr. 2009,
90, 1579–1585, doi:10.3945/ajcn.2009.28047.
13. Cameron, J.; McPhee, J.S.; Jones, D.A.; Degens, H. Five-year longitudinal changes in thigh muscle mass of septuagenarian men
and women assessed with DXA and MRI. Aging Clin. Exp. Res. 2020, 32, 617–624, doi:10.1007/s40520-019-01248-w.
Nutrients 2021, 13, 147 23 of 29

14. Zoico, E.; Rossi, A.; Di Francesco, V.; Sepe, A.; Olioso, D.; Pizzini, F.; Fantin, F.; Bosello, O.; Cominacini, L.; Harris, T.B.; et al.
Adipose tissue infiltration in skeletal muscle of healthy elderly men: Relationships with body composition, insulin resistance,
and inflammation at the systemic and tissue level. J. Gerontol. A Biol. Sci. Med. Sci. 2010, 65, 295–299, doi:10.1093/gerona/glp155.
15. Sakkas, G.K.; Kent-Braun, J.A.; Doyle, J.W.; Shubert, T.; Gordon, P.; Johansen, K.L. Effect of diabetes mellitus on muscle size
and strength in patients receiving dialysis therapy. Am. J. Kidney Dis. 2006, 47, 862–869, doi:10.1053/j.ajkd.2006.01.013.
16. Cruz-Jentoft, A.J.; Baeyens, J.P.; Bauer, J.M.; Boirie, Y.; Cederholm, T.; Landi, F.; Martin, F.C.; Michel, J.P.; Rolland, Y.; Schneider,
S.M.; et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia
in Older People. Age Ageing 2010, 39, 412–423, doi:10.1093/ageing/afq034.
17. Muscaritoli, M.; Anker, S.D.; Argiles, J.; Aversa, Z.; Bauer, J.M.; Biolo, G.; Boirie, Y.; Bosaeus, I.; Cederholm, T.; Costelli, P.; et al.
Consensus definition of sarcopenia, cachexia and pre-cachexia: Joint document elaborated by Special Interest Groups (SIG)
“cachexia-anorexia in chronic wasting diseases” and “nutrition in geriatrics”. Clin. Nutr. 2010, 29, 154–159,
doi:10.1016/j.clnu.2009.12.004.
18. Fielding, R.A.; Vellas, B.; Evans, W.J.; Bhasin, S.; Morley, J.E.; Newman, A.B.; Abellan van Kan, G.; Andrieu, S.; Bauer, J.; Breuille,
D.; et al. Sarcopenia: An undiagnosed condition in older adults. Current consensus definition: Prevalence, etiology, and conse-
quences. International working group on sarcopenia. J. Am. Med. Dir. Assoc. 2011, 12, 249–256, doi:10.1016/j.jamda.2011.01.003.
19. Studenski, S.A.; Peters, K.W.; Alley, D.E.; Cawthon, P.M.; McLean, R.R.; Harris, T.B.; Ferrucci, L.; Guralnik, J.M.; Fragala, M.S.;
Kenny, A.M.; et al. The FNIH sarcopenia project: Rationale, study description, conference recommendations, and final esti-
mates. J. Gerontol. A Biol. Sci. Med. Sci. 2014, 69, 547–558, doi:10.1093/gerona/glu010.
20. Cruz-Jentoft, A.J.; Bahat, G.; Bauer, J.; Boirie, Y.; Bruyere, O.; Cederholm, T.; Cooper, C.; Landi, F.; Rolland, Y.; Sayer, A.A.; et
al. Sarcopenia: Revised European consensus on definition and diagnosis. Age Ageing 2019, 48, 16–31, doi:10.1093/ageing/afy169.
21. Beaudart, C.; McCloskey, E.; Bruyere, O.; Cesari, M.; Rolland, Y.; Rizzoli, R.; Araujo de Carvalho, I.; Amuthavalli Thiyagarajan,
J.; Bautmans, I.; Bertiere, M.C.; et al. Sarcopenia in daily practice: Assessment and management. BMC Geriatr. 2016, 16, 170,
doi:10.1186/s12877-016-0349-4.
22. Andreoli, A.; Lauro, S.; Di Daniele, N.; Sorge, R.; Celi, M.; Volpe, S.L. Effect of a moderately hypoenergetic Mediterranean diet
and exercise program on body cell mass and cardiovascular risk factors in obese women. Eur. J. Clin. Nutr. 2008, 62, 892–897,
doi:10.1038/sj.ejcn.1602800.
23. Molfino, A.; Chiappini, M.G.; Laviano, A.; Ammann, T.; Bollea, M.R.; Alegiani, F.; Rossi Fanelli, F.; Muscaritoli, M. Effect of
intensive nutritional counseling and support on clinical outcomes of hemodialysis patients. Nutrition 2012, 28, 1012–1015,
doi:10.1016/j.nut.2012.01.008.
24. Fahal, I.H.; Bell, G.M.; Bone, J.M.; Edwards, R.H. Physiological abnormalities of skeletal muscle in dialysis patients. Nephrol.
Dial. Transplant. 1997, 12, 119–127, doi:10.1093/ndt/12.1.119.
25. Domanski, M.; Ciechanowski, K. Sarcopenia: A major challenge in elderly patients with end-stage renal disease. J. Aging Res.
2012, 2012, 754739, doi:10.1155/2012/754739.
26. Carrero, J.J.; Chmielewski, M.; Axelsson, J.; Snaedal, S.; Heimburger, O.; Barany, P.; Suliman, M.E.; Lindholm, B.; Stenvinkel,
P.; Qureshi, A.R. Muscle atrophy, inflammation and clinical outcome in incident and prevalent dialysis patients. Clin. Nutr.
2008, 27, 557–564, doi:10.1016/j.clnu.2008.04.007.
27. Carrero, J.J.; Stenvinkel, P.; Cuppari, L.; Ikizler, T.A.; Kalantar-Zadeh, K.; Kaysen, G.; Mitch, W.E.; Price, S.R.; Wanner, C.; Wang,
A.Y.; et al. Etiology of the protein-energy wasting syndrome in chronic kidney disease: A consensus statement from the Inter-
national Society of Renal Nutrition and Metabolism (ISRNM). J. Ren. Nutr. 2013, 23, 77–90, doi:10.1053/j.jrn.2013.01.001.
28. Bauer, J.; Morley, J.E.; Schols, A.; Ferrucci, L.; Cruz-Jentoft, A.J.; Dent, E.; Baracos, V.E.; Crawford, J.A.; Doehner, W.;
Heymsfield, S.B.; et al. Sarcopenia: A Time for Action. An SCWD Position Paper. J. Cachexia Sarcopenia Muscle 2019, 10, 956–961,
doi:10.1002/jcsm.12483.
29. Dev, R. Measuring cachexia-diagnostic criteria. Ann. Palliat. Med. 2019, 8, 24–32, doi:10.21037/apm.2018.08.07.
30. Pereira, R.A.; Cordeiro, A.C.; Avesani, C.M.; Carrero, J.J.; Lindholm, B.; Amparo, F.C.; Amodeo, C.; Cuppari, L.; Kamimura,
M.A. Sarcopenia in chronic kidney disease on conservative therapy: Prevalence and association with mortality. Nephrol. Dial.
Transplant. 2015, 30, 1718–1725, doi:10.1093/ndt/gfv133.
31. Moorthi, R.N.; Avin, K.G. Clinical relevance of sarcopenia in chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 2017, 26,
219–228, doi:10.1097/MNH.0000000000000318.
32. Sabatino, A.; Cuppari, L.; Stenvinkel, P.; Lindholm, B.; Avesani, C.M. Sarcopenia in chronic kidney disease: What have we
learned so far? J. Nephrol. 2020, doi:10.1007/s40620-020-00840-y.
33. Ortiz, A.; Sanchez-Nino, M.D. Sarcopenia in CKD: A roadmap from basic pathogenetic mechanisms to clinical trials. Clin. Kidney
J. 2019, 12, 110–112, doi:10.1093/ckj/sfz001.
34. Leong, D.P.; Teo, K.K.; Rangarajan, S.; Lopez-Jaramillo, P.; Avezum, A., Jr.; Orlandini, A.; Seron, P.; Ahmed, S.H.; Rosengren,
A.; Kelishadi, R.; et al. Prognostic value of grip strength: Findings from the Prospective Urban Rural Epidemiology (PURE)
study. Lancet 2015, 386, 266–273, doi:10.1016/S0140-6736(14)62000-6.
35. Noce, A.; Marrone, G.; Di Lauro, M.; Urciuoli, S.; Pietroboni Zaitseva, A.; Wilson Jones, G.; Di Daniele, N.; Romani, A. Cardio-
vascular Protection of Nephropathic Male Patients by Oral Food Supplements. Cardiovasc. Ther. 2020, 2020, 1807941,
doi:10.1155/2020/1807941.
Nutrients 2021, 13, 147 24 of 29

36. Bocedi, A.; Noce, A.; Rovella, V.; Marrone, G.; Cattani, G.; Iappelli, M.; De Paolis, P.; Iaria, G.; Sforza, D.; Gallu, M.; et al. Eryth-
rocyte glutathione transferase in kidney transplantation: A probe for kidney detoxification efficiency. Cell Death Dis. 2018, 9,
288, doi:10.1038/s41419-018-0289-3.
37. Ochi, M.; Kohara, K.; Tabara, Y.; Kido, T.; Uetani, E.; Ochi, N.; Igase, M.; Miki, T. Arterial stiffness is associated with low thigh
muscle mass in middle-aged to elderly men. Atherosclerosis 2010, 212, 327–332, doi:10.1016/j.atherosclerosis.2010.05.026.
38. Kato, A.; Ishida, J.; Endo, Y.; Takita, T.; Furuhashi, M.; Maruyama, Y.; Odamaki, M. Association of abdominal visceral adiposity
and thigh sarcopenia with changes of arteriosclerosis in haemodialysis patients. Nephrol. Dial. Transplant. 2011, 26, 1967–1976,
doi:10.1093/ndt/gfq652.
39. Noce, A.; Marrone, G.; Rovella, V.; Cusumano, A.; Di Daniele, N.; Casasco, M. Beneficial effects of physical activity on uremic
sarcopenia. Medicina Dello Sport 2018, doi:10.23736/S0025-7826.18.03389-6.
40. Noce, A.; Bocedi, A.; Campo, M.; Marrone, G.; Di Lauro, M.; Cattani, G.; Di Daniele, N.; Romani, A. A Pilot Study of a Natural
Food Supplement as New Possible Therapeutic Approach in Chronic Kidney Disease Patients. Pharmaceuticals 2020, 13, 148,
doi:10.3390/ph13070148.
41. Romani, A.; Bernini, R.; Noce, A.; Urciuoli, S.; Di Lauro, M.; Pietroboni-Zaitseva, A.; Marrone, G.; Di Daniele, N. Potential
Beneficial Effects of Extra Virgin Olive Oils Characterized by High Content in Minor Polar Compounds in Nephropathic Pa-
tients: A Pilot Study. Molecules 2020, 25, 4757, doi:10.3390/molecules25204757.
42. Honda, H.; Qureshi, A.R.; Axelsson, J.; Heimburger, O.; Suliman, M.E.; Barany, P.; Stenvinkel, P.; Lindholm, B. Obese sarcopenia
in patients with end-stage renal disease is associated with inflammation and increased mortality. Am. J. Clin. Nutr. 2007, 86,
633–638, doi:10.1093/ajcn/86.3.633.
43. Raj, D.S.; Sun, Y.; Tzamaloukas, A.H. Hypercatabolism in dialysis patients. Curr. Opin. Nephrol. Hypertens. 2008, 17, 589–594,
doi:10.1097/MNH.0b013e32830d5bfa.
44. Workeneh, B.T.; Mitch, W.E. Review of muscle wasting associated with chronic kidney disease. Am. J. Clin. Nutr. 2010, 91,
1128S–1132S, doi:10.3945/ajcn.2010.28608B.
45. Testelmans, D.; Crul, T.; Maes, K.; Agten, A.; Crombach, M.; Decramer, M.; Gayan-Ramirez, G. Atrophy and hypertrophy sig-
nalling in the diaphragm of patients with COPD. Eur. Respir. J. 2010, 35, 549–556, doi:10.1183/09031936.00091108.
46. Molina, P.; Carrero, J.J.; Bover, J.; Chauveau, P.; Mazzaferro, S.; Torres, P.U.; European Renal Nutrition (ERN); Chronic Kidney
Disease-Mineral; Bone Disorder (CKD-MBD) Working Groups of the European Renal Association-European Dialysis Trans-
plant Association (ERA-EDTA). Vitamin D, a modulator of musculoskeletal health in chronic kidney disease. J. Cachexia Sarco-
penia Muscle 2017, 8, 686–701, doi:10.1002/jcsm.12218.
47. Bosworth, C.; de Boer, I.H. Impaired vitamin D metabolism in CKD. Semin. Nephrol. 2013, 33, 158–168, doi:10.1016/j.semneph-
rol.2012.12.016.
48. Bailey, J.L.; Wang, X.; England, B.K.; Price, S.R.; Ding, X.; Mitch, W.E. The acidosis of chronic renal failure activates muscle
proteolysis in rats by augmenting transcription of genes encoding proteins of the ATP-dependent ubiquitin-proteasome path-
way. J. Clin. Investig. 1996, 97, 1447–1453, doi:10.1172/JCI118566.
49. Workeneh, B.T.; Rondon-Berrios, H.; Zhang, L.; Hu, Z.; Ayehu, G.; Ferrando, A.; Kopple, J.D.; Wang, H.; Storer, T.; Fournier,
M.; et al. Development of a diagnostic method for detecting increased muscle protein degradation in patients with catabolic
conditions. J. Am. Soc. Nephrol. 2006, 17, 3233–3239, doi:10.1681/ASN.2006020131.
50. Hu, Z.; Wang, H.; Lee, I.H.; Du, J.; Mitch, W.E. Endogenous glucocorticoids and impaired insulin signaling are both required
to stimulate muscle wasting under pathophysiological conditions in mice. J. Clin. Investig. 2009, 119, 3059–3069,
doi:10.1172/JCI38770.
51. Kerr, J.D.; Holden, R.M.; Morton, A.R.; Nolan, R.L.; Hopman, W.M.; Pruss, C.M.; Garland, J.S. Associations of epicardial fat
with coronary calcification, insulin resistance, inflammation, and fibroblast growth factor-23 in stage 3-5 chronic kidney disease.
BMC Nephrol. 2013, 14, 26, doi:10.1186/1471-2369-14-26.
52. Rolland, Y.; Czerwinski, S.; Abellan Van Kan, G.; Morley, J.E.; Cesari, M.; Onder, G.; Woo, J.; Baumgartner, R.; Pillard, F.; Boirie,
Y.; et al. Sarcopenia: Its assessment, etiology, pathogenesis, consequences and future perspectives. J. Nutr. Health Aging 2008,
12, 433–450, doi:10.1007/BF02982704.
53. Paschou, S.A.; Kanaka-Gantenbein, C.; Chrousos, G.P.; Vryonidou, A. Growth hormone axis in patients with chronic kidney
disease. Hormones 2019, 18, 71–73, doi:10.1007/s42000-018-0066-9.
54. Norman, A.W.; Frankel, J.B.; Heldt, A.M.; Grodsky, G.M. Vitamin D deficiency inhibits pancreatic secretion of insulin. Science
1980, 209, 823–825, doi:10.1126/science.6250216.
55. Wolf, M.; Shah, A.; Gutierrez, O.; Ankers, E.; Monroy, M.; Tamez, H.; Steele, D.; Chang, Y.; Camargo, C.A., Jr.; Tonelli, M.; et al.
Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 2007, 72, 1004–1013,
doi:10.1038/sj.ki.5002451.
56. Li, X.; Xiang, X.; Hu, J.; Goswami, R.; Yang, S.; Zhang, A.; Wang, Y.; Li, Q.; Bi, X. Association Between Serum Cortisol and
Chronic Kidney Disease in Patients with Essential Hypertension. Kidney Blood Press Res. 2016, 41, 384–391,
doi:10.1159/000443435.
57. Carrero, J.J.; Stenvinkel, P. The vulnerable man: Impact of testosterone deficiency on the uraemic phenotype. Nephrol. Dial.
Transpl. 2012, 27, 4030–4041, doi:10.1093/ndt/gfs383.
58. Raff, H.; Trivedi, H. Circadian rhythm of salivary cortisol, plasma cortisol, and plasma ACTH in end-stage renal disease. Endocr.
Connect. 2013, 2, 23–31, doi:10.1530/EC-12-0058.
Nutrients 2021, 13, 147 25 of 29

59. Sun, D.F.; Chen, Y.; Rabkin, R. Work-induced changes in skeletal muscle IGF-1 and myostatin gene expression in uremia. Kidney
Int. 2006, 70, 453–459, doi:10.1038/sj.ki.5001532.
60. Deleaval, P.; Luaire, B.; Laffay, P.; Jambut-Cadon, D.; Stauss-Grabo, M.; Canaud, B.; Chazot, C. Short-Term Effects of Branched-
Chain Amino Acids-Enriched Dialysis Fluid on Branched-Chain Amino Acids Plasma Level and Mass Balance: A Randomized
Cross-Over Study. J. Ren. Nutr. 2020, 30, 61–68, doi:10.1053/j.jrn.2019.03.079.
61. Mitch, W.E.; Price, S.R. Mechanisms activated by kidney disease and the loss of muscle mass. Am. J. Kidney Dis. 2001, 38, 1337–
1342, doi:10.1053/ajkd.2001.29249.
62. Martins, A.M.; Dias Rodrigues, J.C.; de Oliveira Santin, F.G.; Barbosa Brito Fdos, S.; Bello Moreira, A.S.; Lourenco, R.A.; Avesani,
C.M. Food intake assessment of elderly patients on hemodialysis. J. Ren. Nutr. 2015, 25, 321–326, doi:10.1053/j.jrn.2014.10.007.
63. Bocedi, A.; Noce, A.; Marrone, G.; Noce, G.; Cattani, G.; Gambardella, G.; Di Lauro, M.; Di Daniele, N.; Ricci, G. Glutathione
Transferase P1-1 an Enzyme Useful in Biomedicine and as Biomarker in Clinical Practice and in Environmental Pollution. Nu-
trients 2019, 11, 1741, doi:10.3390/nu11081741.
64. Noce, A.; Fabrini, R.; Dessi, M.; Bocedi, A.; Santini, S.; Rovella, V.; Pastore, A.; Tesauro, M.; Bernardini, S.; Di Daniele, N.; et al.
Erythrocyte glutathione transferase activity: A possible early biomarker for blood toxicity in uremic diabetic patients. Acta Di-
abetol. 2014, 51, 219–224, doi:10.1007/s00592-013-0497-3.
65. Carrero, J.J. Mechanisms of altered regulation of food intake in chronic kidney disease. J. Ren. Nutr. 2011, 21, 7–11,
doi:10.1053/j.jrn.2010.10.004.
66. Karalliedde, J.; Gnudi, L. Diabetes mellitus, a complex and heterogeneous disease, and the role of insulin resistance as a deter-
minant of diabetic kidney disease. Nephrol. Dial. Transplant. 2016, 31, 206–213, doi:10.1093/ndt/gfu405.
67. Zhang, L.; Du, J.; Hu, Z.; Han, G.; Delafontaine, P.; Garcia, G.; Mitch, W.E. IL-6 and serum amyloid A synergy mediates angio-
tensin II-induced muscle wasting. J. Am. Soc. Nephrol. 2009, 20, 604–612, doi:10.1681/ASN.2008060628.
68. Zhang, L.; Pan, J.; Dong, Y.; Tweardy, D.J.; Dong, Y.; Garibotto, G.; Mitch, W.E. Stat3 activation links a C/EBPdelta to myostatin
pathway to stimulate loss of muscle mass. Cell Metab. 2013, 18, 368–379, doi:10.1016/j.cmet.2013.07.012.
69. Ramezani, A.; Raj, D.S. The gut microbiome, kidney disease, and targeted interventions. J. Am. Soc. Nephrol. 2014, 25, 657–670,
doi:10.1681/ASN.2013080905.
70. Noce, A.; Marrone, G.; Di Daniele, F.; Ottaviani, E.; Wilson Jones, G.; Bernini, R.; Romani, A.; Rovella, V. Impact of Gut Micro-
biota Composition on Onset and Progression of Chronic Non-Communicable Diseases. Nutrients 2019, 11, 1073,
doi:10.3390/nu11051073.
71. Roshanravan, B.; Gamboa, J.; Wilund, K. Exercise and CKD: Skeletal Muscle Dysfunction and Practical Application of Exercise
to Prevent and Treat Physical Impairments in CKD. Am. J. Kidney Dis. 2017, 69, 837–852, doi:10.1053/j.ajkd.2017.01.051.
72. Cohen, S.; Nathan, J.A.; Goldberg, A.L. Muscle wasting in disease: Molecular mechanisms and promising therapies. Nat. Rev.
Drug Discov. 2015, 14, 58–74, doi:10.1038/nrd4467.
73. Stenvinkel, P.; Larsson, T.E. Chronic kidney disease: A clinical model of premature aging. Am. J. Kidney Dis. 2013, 62, 339–351,
doi:10.1053/j.ajkd.2012.11.051.
74. Kooman, J.P.; Kotanko, P.; Schols, A.M.; Shiels, P.G.; Stenvinkel, P. Chronic kidney disease and premature ageing. Nat. Rev.
Nephrol. 2014, 10, 732–742, doi:10.1038/nrneph.2014.185.
75. Choi, Y.J. Dual-Energy X-Ray Absorptiometry: Beyond Bone Mineral Density Determination. Endocrinol. Metab. (Seoul) 2016, 31,
25–30, doi:10.3803/EnM.2016.31.1.25.
76. Roubenoff, R.; Kehayias, J.J.; Dawson-Hughes, B.; Heymsfield, S.B. Use of dual-energy x-ray absorptiometry in body-composi-
tion studies: Not yet a “gold standard”. Am. J. Clin. Nutr. 1993, 58, 589–591, doi:10.1093/ajcn/58.5.589.
77. Chertow, G.M.; Lowrie, E.G.; Wilmore, D.W.; Gonzalez, J.; Lew, N.L.; Ling, J.; Leboff, M.S.; Gottlieb, M.N.; Huang, W.;
Zebrowski, B.; et al. Nutritional assessment with bioelectrical impedance analysis in maintenance hemodialysis patients. J. Am.
Soc. Nephrol. 1995, 6, 75–81.
78. Lauretani, F.; Russo, C.R.; Bandinelli, S.; Bartali, B.; Cavazzini, C.; Di Iorio, A.; Corsi, A.M.; Rantanen, T.; Guralnik, J.M.; Ferrucci,
L. Age-associated changes in skeletal muscles and their effect on mobility: An operational diagnosis of sarcopenia. J. Appl.
Physiol. (1985) 2003, 95, 1851–1860, doi:10.1152/japplphysiol.00246.2003.
79. Guralnik, J.M.; Simonsick, E.M.; Ferrucci, L.; Glynn, R.J.; Berkman, L.F.; Blazer, D.G.; Scherr, P.A.; Wallace, R.B. A short physical
performance battery assessing lower extremity function: Association with self-reported disability and prediction of mortality
and nursing home admission. J. Gerontol. 1994, 49, M85–94, doi:10.1093/geronj/49.2.m85.
80. Zha, Y.; Qian, Q. Protein Nutrition and Malnutrition in CKD and ESRD. Nutrients 2017, 9, 208, doi:10.3390/nu9030208.
81. Ikizler, T.A.; Cano, N.J.; Franch, H.; Fouque, D.; Himmelfarb, J.; Kalantar-Zadeh, K.; Kuhlmann, M.K.; Stenvinkel, P.; TerWee,
P.; Teta, D.; et al. Prevention and treatment of protein energy wasting in chronic kidney disease patients: A consensus statement
by the International Society of Renal Nutrition and Metabolism. Kidney Int. 2013, 84, 1096–1107, doi:10.1038/ki.2013.147.
82. Soeters, P.B. Editorial: Ketogenic diets: What is the benefit? Curr. Opin. Clin. Nutr. Metab. Care 2019, 22, 311–313,
doi:10.1097/MCO.0000000000000571.
83. Kovesdy, C.P.; Kopple, J.D.; Kalantar-Zadeh, K. Management of protein-energy wasting in non-dialysis-dependent chronic kid-
ney disease: Reconciling low protein intake with nutritional therapy. Am. J. Clin. Nutr. 2013, 97, 1163–1177,
doi:10.3945/ajcn.112.036418.
Nutrients 2021, 13, 147 26 of 29

84. Wu, H.L.; Sung, J.M.; Kao, M.D.; Wang, M.C.; Tseng, C.C.; Chen, S.T. Nonprotein calorie supplement improves adherence to
low-protein diet and exerts beneficial responses on renal function in chronic kidney disease. J. Ren. Nutr. 2013, 23, 271–276,
doi:10.1053/j.jrn.2012.09.003.
85. Levine, M.E.; Suarez, J.A.; Brandhorst, S.; Balasubramanian, P.; Cheng, C.W.; Madia, F.; Fontana, L.; Mirisola, M.G.; Guevara-
Aguirre, J.; Wan, J.; et al. Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the
65 and younger but not older population. Cell Metab. 2014, 19, 407–417, doi:10.1016/j.cmet.2014.02.006.
86. Ahluwalia, N.; Dwyer, J.; Terry, A.; Moshfegh, A.; Johnson, C. Update on NHANES Dietary Data: Focus on Collection, Release,
Analytical Considerations, and Uses to Inform Public Policy. Adv. Nutr. 2016, 7, 121–134, doi:10.3945/an.115.009258.
87. Obi, Y.; Qader, H.; Kovesdy, C.P.; Kalantar-Zadeh, K. Latest consensus and update on protein-energy wasting in chronic kidney
disease. Curr. Opin. Clin. Nutr. Metab. Care 2015, 18, 254–262, doi:10.1097/MCO.0000000000000171.
88. Kalantar-Zadeh, K.; Cano, N.J.; Budde, K.; Chazot, C.; Kovesdy, C.P.; Mak, R.H.; Mehrotra, R.; Raj, D.S.; Sehgal, A.R.; Stenvinkel,
P.; et al. Diets and enteral supplements for improving outcomes in chronic kidney disease. Nat. Rev. Nephrol. 2011, 7, 369–384,
doi:10.1038/nrneph.2011.60.
89. Cano, N.J.; Aparicio, M.; Brunori, G.; Carrero, J.J.; Cianciaruso, B.; Fiaccadori, E.; Lindholm, B.; Teplan, V.; Fouque, D.; Guarnieri,
G.; et al. ESPEN Guidelines on Parenteral Nutrition: Adult renal failure. Clin. Nutr. 2009, 28, 401–414,
doi:10.1016/j.clnu.2009.05.016.
90. Cano, N.; Fiaccadori, E.; Tesinsky, P.; Toigo, G.; Druml, W.; Dgem; Kuhlmann, M.; Mann, H.; Horl, W.H.; Espen. ESPEN Guide-
lines on Enteral Nutrition: Adult renal failure. Clin. Nutr. 2006, 25, 295–310, doi:10.1016/j.clnu.2006.01.023.
91. Sabatino, A.; Regolisti, G.; Karupaiah, T.; Sahathevan, S.; Sadu Singh, B.K.; Khor, B.H.; Salhab, N.; Karavetian, M.; Cupisti, A.;
Fiaccadori, E. Protein-energy wasting and nutritional supplementation in patients with end-stage renal disease on hemodialy-
sis. Clin. Nutr. 2017, 36, 663–671, doi:10.1016/j.clnu.2016.06.007.
92. Cupisti, A.; Kalantar-Zadeh, K. Management of natural and added dietary phosphorus burden in kidney disease. Semin. Neph-
rol. 2013, 33, 180–190, doi:10.1016/j.semnephrol.2012.12.018.
93. Ko, G.J.; Obi, Y.; Tortorici, A.R.; Kalantar-Zadeh, K. Dietary protein intake and chronic kidney disease. Curr. Opin. Clin. Nutr.
Metab. Care 2017, 20, 77–85, doi:10.1097/MCO.0000000000000342.
94. Fouque, D.; Aparicio, M. Eleven reasons to control the protein intake of patients with chronic kidney disease. Nat. Clin. Pract.
Nephrol. 2007, 3, 383–392, doi:10.1038/ncpneph0524.
95. Kalantar-Zadeh, K.; Moore, L.W.; Tortorici, A.R.; Chou, J.A.; St-Jules, D.E.; Aoun, A.; Rojas-Bautista, V.; Tschida, A.K.; Rhee,
C.M.; Shah, A.A.; et al. North American experience with Low protein diet for Non-dialysis-dependent chronic kidney disease.
BMC Nephrol. 2016, 17, 90, doi:10.1186/s12882-016-0304-9.
96. Peired, A.; Angelotti, M.L.; Ronconi, E.; la Marca, G.; Mazzinghi, B.; Sisti, A.; Lombardi, D.; Giocaliere, E.; Della Bona, M.;
Villanelli, F.; et al. Proteinuria impairs podocyte regeneration by sequestering retinoic acid. J. Am. Soc. Nephrol. 2013, 24, 1756–
1768, doi:10.1681/ASN.2012090950.
97. Di Iorio, B.R.; Bellasi, A.; Raphael, K.L.; Santoro, D.; Aucella, F.; Garofano, L.; Ceccarelli, M.; Di Lullo, L.; Capolongo, G.; Di
Iorio, M.; et al. Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: The UBI
Study. J. Nephrol. 2019, 32, 989–1001, doi:10.1007/s40620-019-00656-5.
98. Goraya, N.; Simoni, J.; Jo, C.H.; Wesson, D.E. A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney
disease with fruits and vegetables or sodium bicarbonate. Clin. J. Am. Soc. Nephrol. 2013, 8, 371–381, doi:10.2215/CJN.02430312.
99. Gaggl, M.; Sliber, C.; Sunder-Plassmann, G. Effect of oral alkali supplementation on progression of chronic kidney disease. Curr.
Hypertens. Rev. 2014, 10, 112–120, doi:10.2174/1573402111666141231123314.
100. D'Alessandro, C.; Piccoli, G.B.; Cupisti, A. The “phosphorus pyramid”: A visual tool for dietary phosphate management in
dialysis and CKD patients. BMC Nephrol. 2015, 16, 9, doi:10.1186/1471-2369-16-9.
101. Scialla, J.J.; Appel, L.J.; Wolf, M.; Yang, W.; Zhang, X.; Sozio, S.M.; Miller, E.R., 3rd; Bazzano, L.A.; Cuevas, M.; Glenn, M.J.; et
al. Plant protein intake is associated with fibroblast growth factor 23 and serum bicarbonate levels in patients with chronic
kidney disease: The Chronic Renal Insufficiency Cohort study. J. Ren. Nutr. 2012, 22, 379–388, doi:10.1053/j.jrn.2012.01.026.
102. Foley, R.N. Phosphate levels and cardiovascular disease in the general population. Clin. J. Am. Soc. Nephrol. 2009, 4, 1136–1139,
doi:10.2215/CJN.01660309.
103. Ikizler, T.A.; Burrowes, J.D.; Byham-Gray, L.D.; Campbell, K.L.; Carrero, J.-J.; Chan, W.; Fouque, D.; Friedman, A.N.; Ghaddar,
S.; Goldstein-Fuchs, D.J.; et al. KDOQI Nutrition in CKD Guideline Work Group. KDOQI clinical practice guideline for nutrition
in CKD: 2020 update. Am. J. Kidney Dis. 2020, 76, doi:10.1053/j.ajkd.2020.05.006.
104. Rhee, C.M.; Ahmadi, S.F.; Kalantar-Zadeh, K. The dual roles of obesity in chronic kidney disease: A review of the current liter-
ature. Curr. Opin. Nephrol. Hypertens. 2016, 25, 208–216, doi:10.1097/MNH.0000000000000212.
105. Coelho-Junior, H.J.; Calvani, R.; Picca, A.; Goncalves, I.O.; Landi, F.; Bernabei, R.; Cesari, M.; Uchida, M.C.; Marzetti, E. Protein-
Related Dietary Parameters and Frailty Status in Older Community-Dwellers across Different Frailty Instruments. Nutrients
2020, 12, 508, doi:10.3390/nu12020508.
106. Clegg, A.; Young, J.; Iliffe, S.; Rikkert, M.O.; Rockwood, K. Frailty in elderly people. Lancet 2013, 381, 752–762, doi:10.1016/S0140-
6736(12)62167-9.
107. Morley, J.E.; Vellas, B.; van Kan, G.A.; Anker, S.D.; Bauer, J.M.; Bernabei, R.; Cesari, M.; Chumlea, W.C.; Doehner, W.; Evans, J.;
et al. Frailty consensus: A call to action. J. Am. Med. Dir. Assoc. 2013, 14, 392–397, doi:10.1016/j.jamda.2013.03.022.
Nutrients 2021, 13, 147 27 of 29

108. Scuteri, A.; Modestino, A.; Frattari, A.; Di Daniele, N.; Tesauro, M. Occurrence of hypotension in older participants. Which 24-
hour ABPM parameter better correlate with? J. Gerontol. A Biol. Sci. Med. Sci. 2012, 67, 804–810, doi:10.1093/gerona/glr232.
109. Artaza-Artabe, I.; Saez-Lopez, P.; Sanchez-Hernandez, N.; Fernandez-Gutierrez, N.; Malafarina, V. The relationship between
nutrition and frailty: Effects of protein intake, nutritional supplementation, vitamin D and exercise on muscle metabolism in
the elderly. A systematic review. Maturitas 2016, 93, 89–99, doi:10.1016/j.maturitas.2016.04.009.
110. Caglar, K.; Fedje, L.; Dimmitt, R.; Hakim, R.M.; Shyr, Y.; Ikizler, T.A. Therapeutic effects of oral nutritional supplementation
during hemodialysis. Kidney Int. 2002, 62, 1054–1059, doi:10.1046/j.1523-1755.2002.00530.x.
111. Lacson, E., Jr.; Wang, W.; Zebrowski, B.; Wingard, R.; Hakim, R.M. Outcomes associated with intradialytic oral nutritional
supplements in patients undergoing maintenance hemodialysis: A quality improvement report. Am. J. Kidney Dis. 2012, 60, 591–
600, doi:10.1053/j.ajkd.2012.04.019.
112. Sezer, S.; Bal, Z.; Tutal, E.; Uyar, M.E.; Acar, N.O. Long-term oral nutrition supplementation improves outcomes in malnour-
ished patients with chronic kidney disease on hemodialysis. JPEN J. Parenter Enteral Nutr. 2014, 38, 960–965,
doi:10.1177/0148607113517266.
113. Benner, D.; Brunelli, S.M.; Brosch, B.; Wheeler, J.; Nissenson, A.R. Effects of Oral Nutritional Supplements on Mortality, Missed
Dialysis Treatments, and Nutritional Markers in Hemodialysis Patients. J. Ren. Nutr. 2018, 28, 191–196,
doi:10.1053/j.jrn.2017.10.002.
114. Leonberg-Yoo, A.K.; Wang, W.; Weiner, D.E.; Lacson, E., Jr. Oral nutritional supplements and 30-day readmission rate in hy-
poalbuminemic maintenance hemodialysis patients. Hemodial. Int. 2019, 23, 93–100, doi:10.1111/hdi.12694.
115. Marsen, T.A.; Beer, J.; Mann, H.; German IDPN-Trial Group. Intradialytic parenteral nutrition in maintenance hemodialysis
patients suffering from protein-energy wasting. Results of a multicenter, open, prospective, randomized trial. Clin. Nutr. 2017,
36, 107–117, doi:10.1016/j.clnu.2015.11.016.
116. Thabet, A.F.; Moeen, S.M.; Labiqe, M.O.; Saleh, M.A. Could intradialytic nutrition improve refractory anaemia in patients un-
dergoing haemodialysis? J. Ren. Care 2017, 43, 183–191, doi:10.1111/jorc.12206.
117. Gharekhani, A.; Khatami, M.R.; Dashti-Khavidaki, S.; Razeghi, E.; Abdollahi, A.; Hashemi-Nazari, S.S.; Mansournia, M.A. Ef-
fects of oral supplementation with omega-3 fatty acids on nutritional state and inflammatory markers in maintenance hemodi-
alysis patients. J. Ren. Nutr. 2014, 24, 177–185, doi:10.1053/j.jrn.2014.01.014.
118. Asemi, Z.; Soleimani, A.; Bahmani, F.; Shakeri, H.; Mazroii, N.; Abedi, F.; Fallah, M.; Mohammadi, A.A.; Esmaillzadeh, A. Effect
of the omega-3 fatty acid plus vitamin E supplementation on subjective global assessment score, glucose metabolism, and lipid
concentrations in chronic hemodialysis patients. Mol. Nutr. Food Res. 2016, 60, 390–398, doi:10.1002/mnfr.201500584.
119. Krishnamurthy, V.M.; Wei, G.; Baird, B.C.; Murtaugh, M.; Chonchol, M.B.; Raphael, K.L.; Greene, T.; Beddhu, S. High dietary
fiber intake is associated with decreased inflammation and all-cause mortality in patients with chronic kidney disease. Kidney
Int. 2012, 81, 300–306, doi:10.1038/ki.2011.355.
120. Donini, L.M.; Savina, C.; Cannella, C. Eating habits and appetite control in the elderly: The anorexia of aging. Int. Psychogeriatr.
2003, 15, 73–87, doi:10.1017/s1041610203008779.
121. Ekramzadeh, M.; Mazloom, Z.; Jafari, P.; Ayatollahi, M.; Sagheb, M.M. Major barriers responsible for malnutrition in hemodi-
alysis patients: Challenges to optimal nutrition. Nephrourol. Mon. 2014, 6, e23158, doi:10.5812/numonthly.23158.
122. Chowdhury, R.; Peel, N.M.; Krosch, M.; Hubbard, R.E. Frailty and chronic kidney disease: A systematic review. Arch. Gerontol.
Geriatr. 2017, 68, 135–142, doi:10.1016/j.archger.2016.10.007.
123. Detsky, A.S.; McLaughlin, J.R.; Baker, J.P.; Johnston, N.; Whittaker, S.; Mendelson, R.A.; Jeejeebhoy, K.N. What is subjective
global assessment of nutritional status? JPEN J. Parenter Enteral Nutr. 1987, 11, 8–13, doi:10.1177/014860718701100108.
124. Liu, P.J.; Ma, F.; Wang, Q.Y.; He, S.L. The effects of oral nutritional supplements in patients with maintenance dialysis therapy:
A systematic review and meta-analysis of randomized clinical trials. PLoS ONE 2018, 13, e0203706, doi:10.1371/jour-
nal.pone.0203706.
125. Li, A.; Lee, H.Y.; Lin, Y.C. The Effect of Ketoanalogues on Chronic Kidney Disease Deterioration: A Meta-Analysis. Nutrients
2019, 11, 957, doi:10.3390/nu11050957.
126. Cupisti, A.; Bolasco, P. Keto-analogues and essential aminoacids and other supplements in the conservative management of
chronic kidney disease. Panminerva Med. 2017, 59, 149–156, doi:10.23736/S0031-0808.16.03288-2.
127. Wang, D.; Wei, L.; Yang, Y.; Liu, H. Dietary supplementation with ketoacids protects against CKD-induced oxidative damage
and mitochondrial dysfunction in skeletal muscle of 5/6 nephrectomised rats. Skelet. Muscle 2018, 8, 18, doi:10.1186/s13395-018-
0164-z.
128. Zhang, Y.Y.; Huang, J.; Yang, M.; Gu, L.J.; Ji, J.Y.; Wang, L.J.; Yuan, W.J. Effect of a low-protein diet supplemented with keto-
acids on autophagy and inflammation in 5/6 nephrectomized rats. Biosci. Rep. 2015, 35, doi:10.1042/BSR20150069.
129. Wang, D.T.; Lu, L.; Shi, Y.; Geng, Z.B.; Yin, Y.; Wang, M.; Wei, L.B. Supplementation of ketoacids contributes to the up-regula-
tion of the Wnt7a/Akt/p70S6K pathway and the down-regulation of apoptotic and ubiquitin-proteasome systems in the muscle
of 5/6 nephrectomised rats. Br. J. Nutr. 2014, 111, 1536–1548, doi:10.1017/S0007114513004091.
130. Walser, M.; Coulter, A.W.; Dighe, S.; Crantz, F.R. The effect of keto-analogues of essential amino acids in severe chronic uremia.
J. Clin. Investig. 1973, 52, 678–690, doi:10.1172/JCI107229.
131. Barsotti, G.; Guiducci, A.; Ciardella, F.; Giovannetti, S. Effects on renal function of a low-nitrogen diet supplemented with es-
sential amino acids and ketoanalogues and of hemodialysis and free protein supply in patients with chronic renal failure. Neph-
ron 1981, 27, 113–117, doi:10.1159/000182036.
Nutrients 2021, 13, 147 28 of 29

132. Zemchenkov, A.; Konakova, I.N. Efficacy of the Essential Amino Acids and Keto-Analogues on the CKD progression rate in
real practice in Russia -city nephrology registry data for outpatient clinic. BMC Nephrol. 2016, 17, 62, doi:10.1186/s12882-016-
0281-z.
133. Sabatino, A.; Regolisti, G.; Antonucci, E.; Cabassi, A.; Morabito, S.; Fiaccadori, E. Intradialytic parenteral nutrition in end-stage
renal disease: Practical aspects, indications and limits. J. Nephrol. 2014, 27, 377–383, doi:10.1007/s40620-014-0051-6.
134. Maraj, M.; Kusnierz-Cabala, B.; Dumnicka, P.; Gala-Bladzinska, A.; Gawlik, K.; Pawlica-Gosiewska, D.; Zabek-Adamska, A.;
Mazur-Laskowska, M.; Ceranowicz, P.; Kuzniewski, M. Malnutrition, Inflammation, Atherosclerosis Syndrome (MIA) and Diet
Recommendations among End-Stage Renal Disease Patients Treated with Maintenance Hemodialysis. Nutrients 2018, 10, 69,
doi:10.3390/nu10010069.
135. Aggarwal, H.K.; Jain, D.; Chauda, R.; Bhatia, S.; Sehgal, R. Assessment of Malnutrition Inflammation Score in Different Stages
of Chronic Kidney Disease. Pril (Makedon. Akad. Nauk. Umet. Odd. Med. Nauki) 2018, 39, 51–61, doi:10.2478/prilozi-2018-0042.
136. Raiten, D.J.; Namaste, S.; Brabin, B.; Combs, G., Jr.; L'Abbe, M.R.; Wasantwisut, E.; Darnton-Hill, I. Executive summary--Bi-
omarkers of Nutrition for Development: Building a Consensus. Am. J. Clin. Nutr. 2011, 94, 633S–650S,
doi:10.3945/ajcn.110.008227.
137. Cederholm, T.; Barazzoni, R.; Austin, P.; Ballmer, P.; Biolo, G.; Bischoff, S.C.; Compher, C.; Correia, I.; Higashiguchi, T.; Holst,
M.; et al. ESPEN guidelines on definitions and terminology of clinical nutrition. Clin. Nutr. 2017, 36, 49–64,
doi:10.1016/j.clnu.2016.09.004.
138. Noce, A.; Marrone, G.; Di Daniele, F.; Di Lauro, M.; Pietroboni Zaitseva, A.; Wilson Jones, G.; De Lorenzo, A.; Di Daniele, N.
Potential Cardiovascular and Metabolic Beneficial Effects of omega-3 PUFA in Male Obesity Secondary Hypogonadism Syn-
drome. Nutrients 2020, 12, 2519, doi:10.3390/nu12092519.
139. Smith, G.I.; Atherton, P.; Reeds, D.N.; Mohammed, B.S.; Rankin, D.; Rennie, M.J.; Mittendorfer, B. Dietary omega-3 fatty acid
supplementation increases the rate of muscle protein synthesis in older adults: A randomized controlled trial. Am. J. Clin. Nutr.
2011, 93, 402–412, doi:10.3945/ajcn.110.005611.
140. Cryer, M.J.; Horani, T.; DiPette, D.J. Diabetes and Hypertension: A Comparative Review of Current Guidelines. J. Clin. Hyper-
tens. (Greenwich) 2016, 18, 95–100, doi:10.1111/jch.12638.
141. Dessi, M.; Noce, A.; Bertucci, P.; Noce, G.; Rizza, S.; De Stefano, A.; Manca di Villahermosa, S.; Bernardini, S.; De Lorenzo, A.;
Di Daniele, N. Plasma and erythrocyte membrane phospholipids and fatty acids in Italian general population and hemodialysis
patients. Lipids Health Dis. 2014, 13, 54, doi:10.1186/1476-511X-13-54.
142. Koorts, A.M.; Viljoen, M.; Kruger, M.C. Red blood cell fatty acid profile of chronic renal failure patients receiving maintenance
haemodialysis treatment. Prostaglandins Leukot. Essent. Fatty Acids 2002, 67, 13–18, doi:10.1054/plef.2002.0375.
143. Dasgupta, A.; Kenny, M.A.; Ahmad, S. Abnormal fatty acid profile in chronic hemodialysis patients: Possible deficiency of
essential fatty acids. Clin. Physiol. Biochem. 1990, 8, 238–243.
144. Zambon, A.; Pirillo, A.; Zambon, S.; Norata, G.D.; Catapano, A.L. Omega n-3 Supplementation: Exploring the Cardiovascular
Benefits Beyond Lipoprotein Reduction. Curr. Atheroscler. Rep. 2020, 22, 74, doi:10.1007/s11883-020-00893-1.
145. Chiavaroli, L.; Mirrahimi, A.; Sievenpiper, J.L.; Jenkins, D.J.; Darling, P.B. Dietary fiber effects in chronic kidney disease: A
systematic review and meta-analysis of controlled feeding trials. Eur. J. Clin. Nutr. 2015, 69, 761–768, doi:10.1038/ejcn.2014.237.
146. Konstantinidou, E.; Koukouvou, G.; Kouidi, E.; Deligiannis, A.; Tourkantonis, A. Exercise training in patients with end-stage
renal disease on hemodialysis: Comparison of three rehabilitation programs. J. Rehabil. Med. 2002, 34, 40–45,
doi:10.1080/165019702317242695.
147. Manfredini, F.; Mallamaci, F.; D'Arrigo, G.; Baggetta, R.; Bolignano, D.; Torino, C.; Lamberti, N.; Bertoli, S.; Ciurlino, D.; Rocca-
Rey, L.; et al. Exercise in Patients on Dialysis: A Multicenter, Randomized Clinical Trial. J. Am. Soc. Nephrol. 2017, 28, 1259–1268,
doi:10.1681/ASN.2016030378.
148. Dong, Z.J.; Zhang, H.L.; Yin, L.X. Effects of intradialytic resistance exercise on systemic inflammation in maintenance hemodi-
alysis patients with sarcopenia: A randomized controlled trial. Int. Urol. Nephrol. 2019, 51, 1415–1424, doi:10.1007/s11255-019-
02200-7.
149. Lopes, L.C.C.; Mota, J.F.; Prestes, J.; Schincaglia, R.M.; Silva, D.M.; Queiroz, N.P.; Freitas, A.; Lira, F.S.; Peixoto, M. Intradialytic
Resistance Training Improves Functional Capacity and Lean Mass Gain in Individuals on Hemodialysis: A Randomized Pilot
Trial. Arch. Phys. Med. Rehabil. 2019, 100, 2151–2158, doi:10.1016/j.apmr.2019.06.006.
150. Gould, D.W.; Watson, E.L.; Wilkinson, T.J.; Wormleighton, J.; Xenophontos, S.; Viana, J.L.; Smith, A.C. Ultrasound assessment
of muscle mass in response to exercise training in chronic kidney disease: A comparison with MRI. J. Cachexia Sarcopenia Muscle
2019, 10, 748–755, doi:10.1002/jcsm.12429.
151. Nishi, H.; Takemura, K.; Higashihara, T.; Inagi, R. Uremic Sarcopenia: Clinical Evidence and Basic Experimental Approach.
Nutrients 2020, 12, 1814, doi:10.3390/nu12061814.
152. Howden, E.J.; Leano, R.; Petchey, W.; Coombes, J.S.; Isbel, N.M.; Marwick, T.H. Effects of exercise and lifestyle intervention on
cardiovascular function in CKD. Clin. J. Am. Soc. Nephrol. 2013, 8, 1494–1501, doi:10.2215/CJN.10141012.
153. Van Craenenbroeck, A.H.; Van Craenenbroeck, E.M.; Van Ackeren, K.; Vrints, C.J.; Conraads, V.M.; Verpooten, G.A.; Kouidi,
E.; Couttenye, M.M. Effect of Moderate Aerobic Exercise Training on Endothelial Function and Arterial Stiffness in CKD Stages
3-4: A Randomized Controlled Trial. Am. J. Kidney Dis. 2015, 66, 285–296, doi:10.1053/j.ajkd.2015.03.015.
154. Cupisti, A.; D’Alessandro, C.; Fumagalli, G.; Vigo, V.; Meola, M.; Cianchi, C.; Egidi, M.F. Nutrition and physical activity in CKD
patients. Kidney Blood Press Res. 2014, 39, 107–113, doi:10.1159/000355784.
Nutrients 2021, 13, 147 29 of 29

155. Castaneda, C.; Gordon, P.L.; Uhlin, K.L.; Levey, A.S.; Kehayias, J.J.; Dwyer, J.T.; Fielding, R.A.; Roubenoff, R.; Singh, M.F. Re-
sistance training to counteract the catabolism of a low-protein diet in patients with chronic renal insufficiency. A randomized,
controlled trial. Ann. Intern. Med. 2001, 135, 965–976, doi:10.7326/0003-4819-135-11-200112040-00008.
156. Pupim, L.B.; Flakoll, P.J.; Levenhagen, D.K.; Ikizler, T.A. Exercise augments the acute anabolic effects of intradialytic parenteral
nutrition in chronic hemodialysis patients. Am. J. Physiol. Endocrinol. Metab. 2004, 286, E589–597, doi:10.1152/ajpendo.00384.2003.
157. Boirie, Y.; Broyer, M.; Gagnadoux, M.F.; Niaudet, P.; Bresson, J.L. Alterations of protein metabolism by metabolic acidosis in
children with chronic renal failure. Kidney Int. 2000, 58, 236–241, doi:10.1046/j.1523-1755.2000.00158.x.
158. Venkatasamy, V.V.; Pericherla, S.; Manthuruthil, S.; Mishra, S.; Hanno, R. Effect of Physical activity on Insulin Resistance, In-
flammation and Oxidative Stress in Diabetes Mellitus. J. Clin. Diagn. Res. 2013, 7, 1764–1766, doi:10.7860/JCDR/2013/6518.3306.
159. Mullan, R.J.; Montori, V.M.; Shah, N.D.; Christianson, T.J.; Bryant, S.C.; Guyatt, G.H.; Perestelo-Perez, L.I.; Stroebel, R.J.; Yawn,
B.P.; Yapuncich, V.; et al. The diabetes mellitus medication choice decision aid: A randomized trial. Arch. Intern. Med. 2009, 169,
1560–1568, doi:10.1001/archinternmed.2009.293.
160. Macdonald, J.H.; Marcora, S.M.; Jibani, M.M.; Kumwenda, M.J.; Ahmed, W.; Lemmey, A.B. Nandrolone decanoate as anabolic
therapy in chronic kidney disease: A randomized phase II dose-finding study. Nephron. Clin. Pract. 2007, 106, c125–135,
doi:10.1159/000103000.
161. Wang, X.H.; Hu, Z.; Klein, J.D.; Zhang, L.; Fang, F.; Mitch, W.E. Decreased miR-29 suppresses myogenesis in CKD. J. Am. Soc.
Nephrol. 2011, 22, 2068–2076, doi:10.1681/ASN.2010121278.
162. Xu, J.; Li, R.; Workeneh, B.; Dong, Y.; Wang, X.; Hu, Z. Transcription factor FoxO1, the dominant mediator of muscle wasting
in chronic kidney disease, is inhibited by microRNA-486. Kidney Int. 2012, 82, 401–411, doi:10.1038/ki.2012.84.
163. Powers, S.K.; Wiggs, M.P.; Duarte, J.A.; Zergeroglu, A.M.; Demirel, H.A. Mitochondrial signaling contributes to disuse muscle
atrophy. Am. J. Physiol. Endocrinol. Metab. 2012, 303, E31–39, doi:10.1152/ajpendo.00609.2011.
164. Zaza, G.; Granata, S.; Masola, V.; Rugiu, C.; Fantin, F.; Gesualdo, L.; Schena, F.P.; Lupo, A. Downregulation of nuclear-encoded
genes of oxidative metabolism in dialyzed chronic kidney disease patients. PLoS ONE 2013, 8, e77847, doi:10.1371/jour-
nal.pone.0077847.
165. Mercken, E.M.; Mitchell, S.J.; Martin-Montalvo, A.; Minor, R.K.; Almeida, M.; Gomes, A.P.; Scheibye-Knudsen, M.; Palacios,
H.H.; Licata, J.J.; Zhang, Y.; et al. SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle
mass. Aging Cell 2014, 13, 787–796, doi:10.1111/acel.12220.
166. Naci, H.; Ioannidis, J.P. Comparative effectiveness of exercise and drug interventions on mortality outcomes: Metaepidemio-
logical study. BMJ 2013, 347, f5577, doi:10.1136/bmj.f5577.
167. Finch, C.F.; White, P.; Twomey, D.; Ullah, S. Implementing an exercise-training programme to prevent lower-limb injuries:
Considerations for the development of a randomised controlled trial intervention delivery plan. Br. J. Sports Med. 2011, 45, 791–
796, doi:10.1136/bjsm.2010.081406.
168. Di Renzo, L.; Gualtieri, P.; Romano, L.; Marrone, G.; Noce, A.; Pujia, A.; Perrone, M.A.; Aiello, V.; Colica, C.; De Lorenzo, A.
Role of Personalized Nutrition in Chronic-Degenerative Diseases. Nutrients 2019, 11, 1707, doi:10.3390/nu11081707.