Journal of Nephrology

https://doi.org/10.1007/s40620-020-00840-y

REVIEW

Sarcopenia in chronic kidney disease: what have we learned so far?

Alice Sabatino1   · Lilian Cuppari2   · Peter Stenvinkel3   · Bengt Lindholm3   · Carla Maria Avesani3,4 

Received: 2 April 2020 / Accepted: 12 August 2020

© The Author(s) 2020

Abstract
The term sarcopenia was first introduced in 1988 by Irwin Rosenberg to define a condition of muscle loss that occurs in the
elderly. Since then, a broader definition comprising not only loss of muscle mass, but also loss of muscle strength and low
physical performance due to ageing or other conditions, was developed and published in consensus papers from geriatric
societies. Sarcopenia was proposed to be diagnosed based on operational criteria using two components of muscle abnormali-
ties, low muscle mass and low muscle function. This brought awareness of an important nutritional derangement with adverse
outcomes for the overall health. In parallel, many studies in patients with chronic kidney disease (CKD) have shown that
sarcopenia is a prevalent condition, mainly among patients with end stage kidney disease (ESKD) on hemodialysis (HD). In
CKD, sarcopenia is not necessarily age-related as it occurs as a result of the accelerated protein catabolism from the disease
and from the dialysis procedure per se combined with low energy and protein intakes. Observational studies showed that
sarcopenia and especially low muscle strength is associated with worse clinical outcomes, including worse quality of life
(QoL) and higher hospitalization and mortality rates. This review aims to discuss the differences in conceptual definition of
sarcopenia in the elderly and in CKD, as well as to describe etiology of sarcopenia, prevalence, outcome, and interventions
that attempted to reverse the loss of muscle mass, strength and mobility in CKD and ESKD patients.

Keywords  Sarcopenia · Chronic kidney disease · End stage kidney disease · Skeletal muscle mass · Muscle strength ·
Physical performance

Introduction (PEW) that for long has been mostly attributed to malnutri-
tion [5]. In addition to PEW/malnutrition, the terms sarco-
Loss of muscle mass is a prevalent complication in patients penia and cachexia denote nutritional derangements that are
with chronic kidney disease (CKD) and especially in those related to the loss of muscle mass (wasting) that often is pre-
with end stage kidney disease (ESKD) [1–3]. The causes are sent in CKD. These conditions share common criteria and
diverse and ultimately converge to increased protein degra- clinical outcome (Fig. 1) but have distinct definitions. Pure
dation and reduced protein synthesis, resulting in a state of malnutrition is the loss of body weight, muscle mass and
negative protein balance [4]. This condition eventually leads body fat due to insufficient energy and nutrient intake, while
to a nutritional disturbance known as protein energy wasting PEW has similar criteria, but with low-grade inflammation
as an additional etiological condition [5]. Sarcopenia, on the
other hand, is understood as the concomitant loss of muscle
* Carla Maria Avesani mass and muscle strength that occurs with aging. Cachexia
[email protected] is a syndrome that is present in diseases with chronic inflam-
1
Division of Nephrology, Department of Medicine
mation and increased breakdown of muscle proteins, such
and Surgery, University of Parma, Parma, Italy as in cancer, and is characterized by severe muscle loss that
2
Division of Nephrology, Federal University of São Paulo
may or may not be accompanied by loss of body fat [6].
and Oswaldo Ramos Foundation, São Paulo, Brazil These nutritional abnormalities may occur concomitantly
3
Division of Renal Medicine and Baxter Novum, Department
depending on the severity of the nutritional impairment. As
of Clinical Science, Technology and Intervention, Karolinska for example, a patient with malnutrition/PEW may also pre-
Institute, Stockholm, Sweden sent sarcopenia, but not necessarily cachexia; while a patient
4
Nutrition Institute, Rio de Janeiro State University, with cachexia may have malnutrition and sarcopenia.
Rio de Janeiro, Brazil

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 Journal of Nephrology

Fig. 1  Criteria and clinical

outcome of malnutrition/protein
energy wasting (PEW), sarcope-
nia, caquexia and muscle wast- Malnutrition / PEW
Body fat↓
ing in chronic kidney disease

Energy & Weight loss

protein Inflammation
intake↓ Muscle
wasting
Sarcopenia Cachexia
Low body fat
↓Muscle strength Inflammation
may coexist
↓ Muscle function ↑Protein catabolism

Common Etiological Factors Common Outcome

- Inflammation - Low quality of life
- Increased protein catabolism - Increased falls/fractures
- Insufficient energy and nutrient intake - Increased hospitalization rate
- Aging - Increased mortality
- Comorbidities
- Decreased appetite
- Sedentarism
- Nutrient losses into the dialysate
- Resistance to anabolic hormones

The interest in sarcopenia increased in 2010, with the also part of the muscle compartment. The loss of muscle
publication of the sarcopenia consensuses from different mass, especially of skeletal muscle mass, is directly asso-
societies focusing mainly on the geriatric population [6–10]. ciated with diminished strength and indirectly associated
Since then, the subject of sarcopenia got the attention of with worse quality of life (QoL), increased vulnerability to
other medical specialties as a condition also present in clini- undesirable outcomes such as falls, loss of independency
cal settings, independent of ageing. Since the publication of and, ultimately, higher hospitalization rates and mortality
the first Sarcopenia Consensus from the European Working [11]. To the best of our knowledge, Macdonald Critchley
Group for Sarcopenia for Older People (EWGSOP) [6], a in 1931, a neurologist in London, was the first in modern
considerable amount of studies including CKD and ESKD scientific literature to connect the loss of skeletal muscle
patients on dialysis and kidney transplant recipients has been to ageing when observing that the musculature tends to
published. Now is time to analyze the strengths, flaws and decrease in the elderly [12]. Since then, many observations
applicability of the sarcopenia concept and its relevance for were reported regarding the changes in the musculature and
renal care management. This review aims to go through the body fat that occurs with ageing [13]. These changes refer
conceptual definition of sarcopenia, its etiology, prevalence, mainly to an interrelated loss in muscle quantity (mass and
association with clinical outcomes, and how it is affected volume), decrease in muscle strength and muscle quality,
by interventions aiming at improving muscle mass, muscle and increase in body fat [14]. Most studies assessing changes
strength and mobility in CKD and ESKD patients. in muscularity over life are cross-sectional and the results
indicate an estimated decrease in muscle mass of about 1 to
2% per year after the age of 50 years, which tends to further
Sarcopenia: definition, etiology, operational increase after 70 years of age accounting for a total accumu-
criteria and methods of assessment lated loss of about 40% between the age of 20 and 70 years
[13]. Longitudinal studies including elderly subjects confirm
The muscle tissue is one of the main organs in the body. these cross-sectional findings. In septuagenarian individu-
The skeletal muscle is the largest component, but other als, Delmonico et al. [14] demonstrated an annual decrease
types, including smooth muscle and cardiac muscle are in muscle area of − 4.9 ± 7.4% in men and of − 3.4 ± 7.9%

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Journal of Nephrology

in women after > 5 years of follow up. A similar result was In the disease-related secondary sarcopenia, wasting and
found by Cameron et al. [15] also in septuagenarian recrea- cachexia are usually present, as is the case in CKD/ESKD,
tionally active men and women, in whom the decrease in where PEW diagnosed by subjective global assessment or
thigh lean mass assessed by magnetic resonance imaging the malnutrition-inflammation score is reported to occur in
(MRI) and whole body lean mass assessed by dual energy 11–54% of the patients [20]. Differentiating aging-related
x-ray absorptiometry (DXA) was approximately 5% during from chronic-illness induced sarcopenia is relevant to bring
5 years. These changes in muscularity have been termed awareness that this phenomenon should be screened in other
sarcopenia by Irwin Rosenberg in 1988, which comes from susceptible groups, such as in young adult CKD patients. In
Greek and means sarx = flesh and penia = loss [16]. Table 1 we describe the main differences between aging-
For many years, sarcopenia was mostly understood as loss related and CKD-related sarcopenia; the most important
of muscle mass that occurs with ageing; however, studies feature that differentiates between the two conditions is the
showed that not only the muscle quantity, but also muscle presence of protein degradation in CKD-related sarcope-
strength and physical performance decreases during life [17, nia, which may be absent in the aging-related sarcopenia.
18]. These new findings, conveyed in five sarcopenia consen- Because of these differences, the treatment goals when treat-
sus papers from different medical societies [6–10], resulted ing sarcopenia in elderly individuals may differ from those
in a common definition in which sarcopenia is a “syndrome in individuals with a disease-related condition. In the first
characterized by progressive and generalized loss of muscle group, the main aim is to restore mobility and QoL and not
mass and strength with a risk of adverse outcomes including primarily to diminish death rates. In disease-related sarco-
physical disability, poor QoL and death” [6]. The opera- penia, where muscle wasting and PEW are more prominent,
tional criteria proposed were similar among the consensus the main aim of reversing sarcopenia is to recover nutritional
reports: sarcopenia is diagnosed when low muscle mass (by status allowing individuals to better respond to the treatment
measurements of muscle quantity) and low muscle function of a determined disease; thus, in addition to reestablishing
(by measurements of muscle strength and/or physical per- mobility and QoL, the aim is to diminish the rate of hospi-
formance) occur concomitantly [6–10]. Out of the aforemen- talization and death.
tioned consensuses, the EWGSOP categorized sarcopenia as After almost 10 years following the publication of the
primary sarcopenia when the etiology is related to aging and first EWGSOP consensus, a revised consensus was released
as secondary sarcopenia when it results from other condi- in 2019 (EWGSOP 2) [10]. Although sarcopenia continued
tions that can be concomitant or not with aging and that can to be assessed by the concomitant presence of low muscle
occur early in the adult life [6]. Secondary sarcopenia can strength and muscle mass, the EWGSOP 2 proposed that
occur due to low physical activity conditions (bed rest, zero- low muscle strength should be used as the first measurement
gravity conditions, sedentary life style), diseases (advanced to screen for pre-sarcopenia, and low muscle mass and/or
organ failures disease, inflammatory disease, malignant or poor muscle quality should be used to confirm the sarcope-
endocrine diseases) and nutritional factors (insufficient food nia diagnosis. If low physical performance is also present,
intake, malabsorption conditions, gastrointestinal diseases, severe sarcopenia is diagnosed.
use of anorexic medications). The shift from low muscle mass to low muscle strength as
The main difference between primary and secondary the key characteristic for the diagnosis of sarcopenia in the
sarcopenia is that in the first, loss of muscle mass occurs EWGSOP 2 is justified by the fact that low muscle strength
continuously and in a similar fashion after the fourth dec- is better than low muscle mass in predicting worse outcome
ade of life, but in the latter, muscle loss is connected not in the elderly [21]. Moreover, low strength can be easily
only to ageing but also to conditions that increase protein screened in hospitals, other clinical settings, and commu-
degradation and therefore is more intense and occurs with nity health care, by grip strength using a portable handheld
greater magnitude than in the natural aging process [19]. dynamometer. Muscle mass, on the other hand, can be more

Table 1  Comparison between CKD-related sarcopenia Ageing-related sarcopenia

CKD -related sarcopenia and
ageing-related sarcopenia in Muscle protein degradation Increased No change
terms of underlying metabolic
Muscle protein synthesis Decreased Decreased
abnormalities and changes in
body fat and muscle fibers Resting energy expenditure Increased/unchanged Unchanged
Inflammation Increased Increased or unchanged
Insulin resistance Present Present
Body fat Unchanged, increased or decreased Normally increased
Muscle fiber change Atrophy in type I and II fibers Preferential loss of type II fibers

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 Journal of Nephrology

difficult to evaluate. Many methods enable the assessment of from cellular membranes [38]. Moreover, other factors such
muscle mass, but the method of choice is dependent mainly as hormonal derangements (testosterone, insulin growth
on the purpose of assessment (research or clinical practice) factor (IGF-1) and GH resistance), the substantial loss of
and one should be aware that differences related to the defi- amino acids during the HD procedure [43] and reduced
nition of the tissue assessed can modify the results observed. energy and protein intake which has shown to be even lower
For instance, fat free mass (FFM), lean body mass/lean soft on the dialysis day [44] can also lead to a state of nega-
tissue (LBM/LST), and skeletal muscle mass (SMM) are not tive energy and protein balance. The inflammatory condi-
equivalent although they are often used as interchangeable tions related to CKD include mainly the pro-inflammatory
surrogates. The FFM, as the name suggests, is the total body response induced by the bioincompatibility of the dialysis
mass except the body fat, and it includes the LBM and the membranes [4]. More recently, an important role has been
bone mineral tissue. The LBM in turn is composed by the attributed to the gastrointestinal tract in the development of
total body water, the SMM, and the fat free part of organs inflammation as a consequence of intestinal dysbiosis and
[22]. The available methods for the assessment of FFM and barrier disruption [45–47]. This can result from the uremic
its compartments are many, and each one has advantages and environment and the reduced fiber intake due to commonly
disadvantages. Different techniques measure different body advised dietary restrictions of food sources of potassium,
compartments and identifying the specific body compart- including fruits, vegetables, grains, nuts and whole cereals,
ment of interest must precede the choice of the method of which predisposes to an increase in protein fermentation and
assessment. Table 2 describes the methods for the assess- its metabolites (i.e. ammonium, thiols, phenols, indoles) that
ment of FFM and its components, as well as for muscle accumulates in ESKD patients due to reduced renal clear-
strength and physical function. ance [47]. In addition, the gut dysbiosis in uremia may lead
to increased exposure to endotoxins that induce inflamma-
tory cascades and systemic low-grade inflammation. Obesity
Sarcopenia and CKD in CKD patients can also act as a pro-inflammatory factor
due to adipocyte dysfunction, characterized by increased
Muscle loss is a frequent finding in CKD, especially for synthesis of cytokines and chemokines (adipokines) that
patients with more advanced stages of the disease including occurs independently of macrophage infiltration in the adi-
ESKD patients undergoing hemodialysis (HD) [1–3]. The pose tissue, which comes secondarily from adipocyte hyper-
consequences of muscle loss are not only related to physical trophy and hypoxia [48]. Finally, the low physical activity
disability as commonly observed in the elderly. In fact, many frequently found in HD patients [49] results in “muscle dis-
studies in the past decades have also linked muscle loss in use”, which is another important but underappreciated cause
CKD patients with worse QoL, depression, PEW, fracture of muscle loss and sarcopenia in this population.
risk, cardiovascular complications, graft failure and post- Altogether, the conditions that patients with CKD, espe-
operative complications in transplant recipients, as well as cially those on dialysis, are exposed to will result in negative
with increased hospitalization and mortality [23–30]. protein balance that can result in muscle loss, weakness (low
The etiologic factors of muscle derangements leading to muscle strength), low physical performance, disability and
muscle loss in CKD are diverse and can be related to several frailty [50] (Fig. 2). Since the CKD population is getting
conditions including the kidney disease itself, the dialysis older, ageing is a prominent cause of sarcopenia in ESKD;
procedure and the typical chronic low-grade inflammation however, it is likely that this group is more vulnerable to
present in CKD patients that together increase protein deg- muscle changes than their non-CKD counterparts, but also in
radation, decrease protein synthesis and lead to a negative comparison to the younger CKD population. This was dem-
protein balance [31, 32] (Fig. 2). The non-inflammatory onstrated by Çelik et al. [51] who noticed that HD patients
factors related to the loss of kidney function include the aged 65  years and older had lower FFM index, serum
development of metabolic acidosis, insulin resistance and creatinine and dry body weight than the younger patients
vitamin D deficiency that act as promotors of protein catab- (< 65 years) and by D’Alessandro et al. [52] who showed
olism and decreased protein synthesis [33–38]. Metabolic that sarcopenia was more prevalent in older (> 75 years) than
acidosis acts as a potent stimulator of protein catabolism in younger (65–74 years) seniors with CKD stage 3a and 4
by triggering two systems responsible for intracellular pro- (prevalence 55% vs 12.5%, respectively). Of note, the latter
tein degradation (caspase-3 and the ubiquitin–proteasome study showed that the three components of sarcopenia—
systems (UPS)) [39] and by promoting insulin and growth skeletal muscle index, handgrip strength (HGS) and per-
hormone (GH) resistance [40]. Vitamin D deficiency can formance tests (sit-to-stand-chair-test and 6-min-walk-test)
reduce pancreatic insulin secretion [41, 42], and diminish were significantly lower in the older senior CKD patients
the stimulus for protein synthesis by decreasing Vitamin D [52]. A study based on the EQUAL study (n = 1334) showed
receptors present in muscle and reducing the calcium influx that the risk of PEW in CKD patients with eGFR < 20 ml/

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 Table 2  Advantages and limitations of methods used for the assessment of fat free mass and its compartments, muscle strength, and physical performance in patients with CKD
Methods Method Assessed compartments Advantages Limitations

Fat free ­massa

 Anthropometry MAMC SMM Simple Low sensibility
Calf circumference Can be used at the bedside Difficulties caused by edema
Journal of Nephrology

APMT Non-invasive Need for high skilled anthropometrics

Cheap
 Bioelectrical impedance BIA FFM Can be used at the bedside Not a direct measure of lean mass
BIS TBM Non-invasive Can be influenced by numerous
ECW Simple factors (hydration status, body
Cheap temperature, nutrition)
Provides information regarding Available equations that estimate
nutritional and hydration status SMM developed in community liv-
ing elderly people
Amputations and pacemakers pre-
clude its use
 Physical examination Visual signs of muscle depletion SMM estimation Simple It is not an objective measurement,
in specific sites (temple, clavicle, Requires no equipment and therefore, not precise
shoulder, scapula/ribs, quadriceps, Provides information regarding Not sensitive to small changes
knee, calf, interosseous) nutritional status Requires detailed training
Can be used at bed side
 Imaging techniques CT SMM Highly accurate for assessing cross- Uses ionized radiation (CT)
MRI sectional area and volume Non-applicable at bedside
CT allows assessment of muscle Very expensive
density which provides informa- Need for specialized staff
tion regarding muscle quality Variation between different machines
Not influenced by hydration status Implanted metal precludes its use
Allows whole body or regional (MRI)
evaluation
DXA LBM High precision Low dose of ionized radiation
 FFM: LBM + bone Total body and regional evaluation Non-applicable at bedside
 ALBM: LBM arms and legs Available in many hospitals Need for specialized staff
High fixed cost (low variable costs)
Do not differentiate extra-cellular
from intra-cellular water
Ultrasound SMM Can be used at the bedside Limited data on CKD patients
Non-invasive No available cutoffs
Simple
Cheap
Reliable and repeatable
Echogenicity allows assessment of
muscle quality
Assessment of cross-sectional area
and thickness

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Table 2  (continued)
Methods Method Assessed compartments Advantages Limitations
Muscle strength

13
 Grip ­strengthb Handgrip dynamometer Strength from upper limbs Simple May not represent strength in the
Portable lower limbs
Cheap May not be suitable for patients with
Can be easily acquired for use in arthritis
dialysis clinics, outpatient clinics
and hospitals
Does not require contribution from
the examiner
 Chair stand test Five chair rise tests Strength from lower and upper limbs Simple Requires patient’s collaboration
Does not require equipment
Can be easily performed in dialysis
clinics, outpatient clinics and
hospitals
Physical performance
 Gait speed Gait speed NA Easy to perform Requires a space with a flat corridor
Suitable for clinical practice and
research
Does not requires equipment
 Short physical performance battery Combination of three scores from NA Easy to perform Requires the patient’s collaboration
(SPPB) tests: balance, gait speed and chair Does not require equipment Requires a space with a flat corridor
­standc
 Timed-up-and-go test (TUG) NA Easy to perform Cutoff points are not extensively vali-
Does not require equipment dated as compared with gait speed
and SPPB
Requires a space with a flat corridor
 400-m walk or long-distance cor- TUG​ NA Easy to perform Requires a space with a flat corridor
ridor walk 400 m walk Does not require equipment

ALBM Appendicular lean body mass, APMT adductor police muscle thicknesses, BIA bioelectrical impedance analysis, BIS bioelectrical impedance spectroscopy, CKD chronic kidney disease,
CT computerized tomography, DXA dual energy x ray absorptiometry, ECW extracellular water, FFM fat free mass, LBM lean body mass, MAMC mid-arm muscle circumference, MRI magnetic
resonance imaging, TBW total body water, SMM skeletal muscle mass, NA non-applicable
a
 In order to minimize influence from fluid retention, special care is advised for dialysis patients when assessing fat free mass. For those on hemodialysis, it should be evaluated after the hemodi-
alysis session, and for patients on peritoneal dialysis after the drainage of the dialysis fluid from the peritoneal cavity [166–168]
b
 For patients on hemodialysis, assessment should be preferably performed before the dialysis session when handgrip strength was shown to be higher than after the dialysis session [169]
c
 Each test is scored in 0 to 4 and the maximum score is 12 [170]
Journal of Nephrology
Journal of Nephrology

- Gut dysbiosis
↓ Energy and
- Dialysis membrane biocompability
protein intake
Inflammaon - Obesity
- Ageing
Loss of amino acids and protein into
the dialysate in PD;
Loss of amino acids during HD session
Insulin
resistance
↓ Regenerave
smulus

Hormonal Metabolic
derangements acidosis
Testosterone, IGF-1,
insulin and GH
resistance
Vitamin D
deficiency
Sedentary
lifestyle

↑ Oxidave
stress
↓ Energy and
protein intake
mainly on the
Ageing
HD day
Negave protein balance
↓ Appete
Dietary restricons
Muscle loss = Weakness = Low physical Disability and
Muscle wasng) Low muscle strengh performance frailty

Fig. 2  Etiologic factors of muscle derangements leading to muscle loss in chronic kidney disease

min increases substantially with age and is commonly char- mass (DXA, BIA or anthropometry) and the different cutoffs
acterized by muscle wasting [53]. Hence, aging adds up as adopted—the prevalence of sarcopenia can be as low as 4%
a contributing factor to the etiology of sarcopenia in CKD. [55, 57] and as high as 63% [70]. These findings suggest that
for clinical practice as well as for scientific purposes, there is
not yet an agreement on which operational criteria to apply
Prevalence of sarcopenia in CKD: the role when diagnosing sarcopenia in CKD and dialysis patients.
of different operational criteria, methods, Also of relevance, is to contextualize the operational
and cutoffs definitions of sarcopenia in the general population. These
definitions were first developed to predict the risk of mobil-
For many years, muscle loss was considered part of the ity loss as well as declines in functional status in the geri-
malnutrition/PEW syndrome [5]. However, after the pub- atric population. However, accounting for the fact that 92%
lication of the sarcopenia consensuses [6–9], muscle loss of older adults have at least one chronic disease [71], the
due to chronic diseases, such as CKD, became a separate associated effect of ageing and chronic comorbidity must be
condition to be assessed in the clinical practice. In CKD, taken into account when defining sarcopenia. CKD has often
the first studies assessing the prevalence of sarcopenia are been called a model of “accelerated ageing” [72, 73]; there-
from 2013 and 2014 [54–58], and only in the last couple of fore, it is likely that the direction of associations between the
years the scientific literature in this area received many more components of sarcopenia (low muscle mass, strength and
contributions (Table 3). Up to now, the most used sarcopenia performance) and outcomes related to disability and mortal-
operational criteria was the EWGSOP 1, which was applied ity is the same as in the general population. Nevertheless, the
in 12 studies [52, 55, 57–66] (sarcopenia prevalence 4–49%), magnitude of these relationships is probably different and
while 4 studies defined sarcopenia only by low muscle mass, more pronounced in CKD because of the independent effects
not assessing muscle strength or performance [54, 67–69]. of the disease on muscle. In fact, in HD patients, muscle loss
An important finding in these studies is that sarcopenia, occurs at younger ages, and are more marked in comparison
understood as concomitant low muscle mass and low muscle to age-matched controls [74, 75]. Therefore, currently used
strength, is a feature of muscle changes in CKD. In addition, cutoffs to clinically identify sarcopenia in the general popu-
another consistent result is that—depending on CKD stage lation might not be appropriate for CKD including dialysis
and age, but mostly on the method used to assess muscle patients. The definition of what constitutes a low nutritional

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Table 3  Summary of studies on sarcopenia prevalence in non-dialyzed CKD, dialysis, and kidney transplanted patients, and methods and criteria used for establishing presence of sarcopenia
Author Population Sample size Age (years)* Muscle mass assess- Strength and/or Sarcopenia Preva- Operational crite- Observation
ment performance lence ria used

13
CKD Stage 2–5 not on dialysis
 Pereira, NDT CKD 3–5 287 59.9 (10.5) MAMC: < 90% Strength: HGS MAMC: 9.8% EWGSOP 1 Only SMMI by BIA
2015 [57] 53% > 60 years reference value (< 30th percentile SGA: 9.4% predicted mortality
SGA—physical for sex and age) SMMI -BIA: 5.9%
exam for low
muscle mass
BIA: SMMI
(< 6.76 kg/
m2 for women
and < 10.76 kg/m2
for men)
 De Souza, Plos CKD 2–5 100 73.6 (9.22) DXA: Strength: HGS FNIH: 28.7% EWGSOP 1 and
One 2017 [65]  ASMI (< 7.26 kg/ (EWGSOP EWGSOP 1: FNIH
m2 for men 1: < 30 kg for 11.9%
and < 5.5 kg/m2 for men and < 20 kg
women) for women;
 ASM/BMI FNIH: < 26 kg for
(< 0.789 for men men and < 16 kg
and < 0.512 for for women)
women) Performance: Gait
speed (< 0.8 m/s)
 Ishikawa, Plos CKD 3–5 260 76 (69–80) DXA: Strength: HGS 25% AWGS Low mass + low
One 2018 [171]  ASMI (< 7.0 kg/ (< 26 kg in males strength and/or
m2 in males and performance
and < 5.4 kg/m2 in  < 18 kg in females)
females) Performance: Gait
speed (< 0.8 m/s)
 Hanatani, IJC In-hospital CKD 265 72.3 (9.8) Calf circumference Strength: HGS 62.6% Scoring Sarcope-
2018 [70] (according to sex (according to nia (sarcopenia
and age) score chart) score ≥ 105 in
men and ≥ 120 in
women) by Ishii
2014 [172]
 D’Alessandro, CKD 3b-4 80 (40 ≥ 75 years, 73.7 (7.2) BIA: Strength: HGS Older: 55% EWGSOP 1 Only included male
Nutrients 2018 40 > 60 Older: 79.8 (3.3)  SMMI (< 10.75 kg/ (< 30 kg) Younger: 12% patients > 60 years
[52] and < 75 years) Younger: 67.5 (4.3) m2)
 Vettoretti, Nutri- CKD 3b-5 113 80 (6) Anthropometry: Strength: HGS 24% EWGSOP 2 Only included
ents 2019 [173] MAMC reduc- (< 26 kg patients ≥ 65 years
tion > 10% of ref men, < 17 kg
population women)
Performance: Gait
speed (severity)
(< 0.8 m/s)
Journal of Nephrology
 Table 3  (continued)
Author Population Sample size Age (years)* Muscle mass assess- Strength and/or Sarcopenia Preva- Operational crite- Observation
ment performance lence ria used

 Fernandes, Nutri- CKD 3b-4 73 62.9 (1.1) DXA: Strength: HGS 12.3% EWGSOP 1 Sarcopenia defined
tion 2019 [64]  ASMI (< 7.26 kg/ (< 30 kg as low mass + low
Journal of Nephrology

m2 in men men, < 20 kg strength and/or

and < 5.5 kg/m2 in women) performance
women) Performance: Gait
speed (< 1 m/s)
 Sharma, CJASN CKS 2–4 5192 (CKD 2: CKD 2: 54.6 (0.4) DXA: NA CKD 2: < 15% EWGSOP 1 for Did not assess
2014 [54] 4086, CKD 3a: CKD 3a: 71 (0.6)  ASMI (< 7.26 kg/ CKD 3a: > 20% low muscle mass strength or perfor-
775, CKD 3b: CKD 3b: 74.5 (1) m2 in men CKD 3b: > 20% mance
254, CKD 4: 77) CKD 4: 73.2 (1.4) and < 5.45 kg/m2 CKD 4: 34.1%
in women)
 Androga, KIRep CKD 2–4 1101 70–77 DXA: NA 22% (12.5% only EWGSOP 1 for Did not assess
2017 [67]  ASMI (< 7.26 kg/ sarcopenia and low muscle mass strength or perfor-
m2 in men 9.7% obesity mance
and < 5.45 kg/m2 sarcopenia)
in women)
 Zou, NDT 2017 CKD 3–5 148 66 (19–87) NA Strength: HGS 14% EWGSOP 1 Did not assess mus-
[66] (< 30 kg cle mass
men, < 20 kg
women)
 Harada, AJC CKD 266 71 (62–78) CT scan: PSOAS NA 41.3% No consensus Assessed only
2017 [68] area—PSOAS used to identify muscle mass. Cut-
index (< 7.17 sarcopenia offs defined based
­cm2/m2 for man on the study area
and < 5.13 ­cm2/m2 under the ROC
for women) curve results
Renal replacement therapy (hemodialysis, peritoneal dialysis and kidney transplantation)
 Kim, CN 2013 HD 95 63.9 (10) BIS: Strength: HGS 37% in men EWGSOP 1
[56] LTI (2 standard (< 30 kg 29.3% women
deviations (SD) men, < 20 kg
or more below the women)
normal gender-
specific means for
young persons)

13


Table 3  (continued)
Author Population Sample size Age (years)* Muscle mass assess- Strength and/or Sarcopenia Preva- Operational crite- Observation
ment performance lence ria used

13
 Lamarca, JNHA HD 102 (n = 49 for 70.7 (7) DXA: Strength: HGS From 3.9 to 63.3% EWGSOP 1 and Cutoffs:
2014 [55] DXA + HGS) ASMI (< 8.12 kg/m2 (< 10th percentile depending on International ALMI and
for men; < 6.08 kg/ of young indi- the method used working group in LBMI: < 20th
m2 for viduals according to assess muscle sarcopenia percentile of young
women; < 6.95 kg/ to gender) mass individuals; < 2 SD
m2 for below means of
men; < 5.16 kg/m2 young individuals
for women)
BIA:
LBMI (< 18.1 kg/m2
for men; < 14.6 kg/
m2; < 15.9 kg/m2
for men; < 12.8 kg/
m2 for women)
SKF:
LBMI (same as
LBMI by BIA)
MAMC (< 90%
standard values)
Calf circumference
(< 31 cm)
 Isoyama, CJASN HD 330 53 (13) DXA Strength: HGS 20% EWGSOP 1 ASMI cutoff: two
2014 [58]  ASMI (< 7.3 kg/ (< 30 kg SDs below the sex-
m2 in men men, < 20 kg specific mean from
and < 5.5 kg/m2 in women) a young reference
women) population
 Kittiskulnam, HD 645 56.7 (14.5) BIS: Strength: HGS Using SMMI: FNIH (for muscle Reference popula-
JCSM 2016  SMM and SMMI (< 26 kg for men 3.9% strength and tions and cutoff
[174] and SMM/BMI and < 16 kg for Using SMM/BMI: performance) points of BIS-
(2SD or more women) 14% derived whole-
below sex specific Performance: gait body muscle mass
means of healthy speed (< 0.8 m/s) were obtained
young adults from the National
(18–49 years) Health and Nutri-
tion Examination
Survey (NHANES)
2003–2004
Journal of Nephrology
 Table 3  (continued)
Author Population Sample size Age (years)* Muscle mass assess- Strength and/or Sarcopenia Preva- Operational crite- Observation
ment performance lence ria used

 Slee, JRN 2019 HD 87 65.9 (13) BIA: Strength: HGS Females EWGSOP 1 and Janssen equation for
[59]  SMI (< 10.76 kg/ (< 30 kg for men EWGSOP: FNIH SMM and Sergi
Journal of Nephrology

m2 for men and < 20 kg for SMMI – 13% equation for ASM

and < 6.76 kg/m2 women; < 26 kg ASMI – 17% calculation
for women) for men FNIH: 8%
 ASMI (< 7.26 kg/ and < 16 kg for Males
m2 for men women; catego- EWGSOP:
and < 5.45 kg/m2 rized by BMI and SMMI – 56%
for women) sex based on the ASMI – 30%
Anthropometry: Fried criteria FNIH:
 MAMC (< 23.8 cm [175]) SMMI – 40%
for men ASMI – 22%
and < 18.4 cm for
women)
 Giglio, JRN 2019 HD 170 70.6 (7.2) Baumgartner equa- Strength: HGS 36.5% EWGSOP 1 Sarcopenia defined
[30] tion for ASM (pre- (< 30 kg for men as low mass + low
viously validated and < 20 kg for strength
in 47 patients), women)
ASMI calculated
(< 7.26 kg/m2 for
men and < 5.45 kg/
m2 for women)
 Kamijo, PDI PD 119 66.8 (13.2) BIS Strength: HGS 11% AWGS For diagnosis
2018 [176] SMI (< 7 kg/m2 in (< 26 men, < 18 strength or perfor-
men, < 5.7 kg/m2 women) mance were con-
in women) Performance: gait sidered together
speed (< 0.8 m/s) with muscle mass

13


Table 3  (continued)
Author Population Sample size Age (years)* Muscle mass assess- Strength and/or Sarcopenia Preva- Operational crite- Observation
ment performance lence ria used

13
 Abro, EJCN 2018 PD 155 63 (14.9) BIA: Strength: HGS 11–15.5% depend- FNIH
[177]  ASM derived from (FNIH: < 26 kg ing on the EWGSOP
segmental BIA men, < 16 kg criteria AWGS
(FNIH: < 19.75 kg women; EWG-
in men, < 15.02 kg SOP: < 30 kg
in women) men, < 20 kg
 ASM/BMI women;
(FNIH: < 0.789 AWGS: < 26 kg
men, < 0.512 men, < 18 kg
women) women)
 ASMI (EWG-
SOP: < 7.23 kg/m2
in men, < 5.67 kg/
m2 in women;
AWGS: < 7 kg/m2
in men, < 5.7 kg/
m2 in women)
 Hung, NCP 2017 PD 325 56.7 (16.5) DXA: NA 2.2–31.3% for EWGSOP 1 Only muscle mass
[69]  ASM (< 2 SD from women and evaluation
young popula- 25.1–75.6% for
tion; < 19.75 kg in men depending
men and < 15 kg in on cutoff used
women)
ASMI (< 7.26/ < 7.2
5/ < 8.5/ < 6.95 kg/
m2 in men and < 
5.75/ < 5.67/ < 5.4
5/ < 5.16 kg/m2 in
women
ASM/BMI (< 0.789
men; < 0.512
women)
 Da Silva, EJCN PD 50 55.7 (16.2) ASMI (EWG- Strenght: EWGSOP 1: 4% EWGSOP 1 and
2019 [178] SOP: < 7.26 kg/m2 HGS (EWG- (ASMI + HGS); EWGSOP 2
in men, < 5.5 kg/ SOP: < 30 kg in 4% (ASMI + GS)
m2 in women; men, < 20 kg in EWGSOP 2: 4%
EWGSOP women; EWG-
2: < 7 kg/m2 in SOP 2: < 27 kg in
men and < 5.5 kg/ men, < 16 kg in
m2 in women) women)
Performance: Gait
speed (< 0.8 m/s)
Journal of Nephrology
 Table 3  (continued)
Author Population Sample size Age (years)* Muscle mass assess- Strength and/or Sarcopenia Preva- Operational crite- Observation
ment performance lence ria used

 Yanishi, TP 2016 KTR 51 46.2 (12.8) DXA: Strenght: HGS 11.8% AWGS
[179]  ASMI (< 7 kg/m2 in (< 27 kg in
Journal of Nephrology

men, < 5.4 kg/m2 men, < 18 kg in
in women) women)
Performance: Gait
speed (< 0.8 m/s)
Studies including non-dialysis CKD, dialysis and kidney transplanted patients
 Dierkes, BMC CKD 3–5 CKD: 112 CKD: 66 (51–76) BIA: Strength: HGS 35% (CKD: 37%, EWGSOP 1 ALM calculated
2018 [63] HD HD: 24 HD: 63 (50–76)  ASMI (≤ 8.87 kg/ (< 30 kg HD: 42%, KTR: using MacDonald
KTR KTR: 72 KTR: 60 (49–67) m2 in men men, < 20 kg 32%) equation [180]
and ≤ 6.42 kg/m2 women)
in women)
 Wilkinson, Neph- CKD 26 CKD 55.7 (14.4) DXA: Strength: HGS 26–35% depending EWGSOP 1 and
rology 2019 HD 11 HD CKD: 58.8 (17.8)  ASM (< 19.75 kg Performance: on the muscle FNIH
[181] KTR 35 KTR HD: 61.6 (7.7) in men SPPB (no infor- mass assessment
KTR: 51.6 (12.2) and < 15.02 kg in mation regarding method
women)  ASMI cut-offs)
(< 7.26 kg/m2 in
men and < 5.45 kg/
m2 in women)
 ASM/BMI (< 0.789
in men and < 0.512
in women)
 Lai, Nutrition CKD 3–5 77 (CKD: 26, 69.6 (9.85) BIA: Strength: HGS 49.4% EWGSOP 1 SMM calculated
2019 [62] Dialysis (HD + PD) Dialysis: 37,  SMMI (≤ 10.75 kg/ (< 30 kg in men using Janssen
KTR KTR: 14) m2 in men and < 20 kg in equation [18]
and ≤ 6.75 kg/m2 women)
in women)

ALM appendicular lean mass, ASM appendicular skeletal muscle, ASMI appendicular skeletal muscle index, AWGS Asian working group on sarcopenia, BIA bioelectric impedance analysis, BIS
bioelectric impedance spectroscopy, BMI body mass index, CKD chronic kidney disease, DXA dual energy X-ray absorptiometry, EWGSOP European working group on sarcopenia in older peo-
ple, FNIH Foundation for the National Institute of Health, HD hemodialysis, HGS handgrip strength, KTR kidney transplant recipients, MAMC mid-arm muscle circumference, SMMI skeletal
muscle mass index, SMM skeletal muscle mass.
*Values in parenthesis describes standard deviation

13
 Journal of Nephrology

marker of body composition is dependent on the normal approach to better recognize when an intervention should
distribution of a nutritional marker in a representative popu- be implemented as well as to monitor the possible impact in
lation. For example, in order to define the threshold for low ameliorating poor clinical outcomes.
SMM in CKD/ESKD patients, first it would be necessary to
search for the distribution of SMM in a representative popu-
lation of dialysis individuals to investigate the distribution Muscle mass, muscle strength or physical
of percentiles of SMM according to age and gender, before function: which one is more clinically
finally tracing those with threshold below, for example, the relevant for CKD?
10th or 5th percentile. In addition, it would also be important
to investigate whether SMM at these thresholds is associated Although the three main components of sarcopenia—low
with worse outcome. Such a study is difficult to perform muscle mass, low muscle strength and low physical perfor-
and, to the best of our knowledge, has not yet resulted in mance—are closely related, they do not necessarily have a
published work. Studies in CKD/ESKD patients to define causal relation. When sarcopenia was first conceptualized
appropriate cutoffs to screen for low muscle mass, strength by Rosenberg in 1988, the statement was that the reduction
and mobility are scarce. By using computed tomography in muscle mass affects ambulation, mobility and weakness,
(CT) to assess muscle mass at the level of the 3­ rd lumbar suggesting that loss of muscle mass would lead to low mus-
vertebra in 233 patients on CKD stages 3–5, Giglio et al. cle strength and mobility and that the opposite would also
demonstrated that among many surrogate methods tested to occur [16]. However, longitudinal studies following older
assess muscle mass (BIA, MAMC, anthropometry, Janssen individuals for 3–5 years showed that the loss of muscle
and Baumgartner equations, and physical examination of strength occurs more rapidly than the loss of muscle mass
muscle mass from subjective global assessment, SGA), the [14, 17]. Delmonico et al. [14] showed that among 1880
Baumgartner and Janssen equations (cutoffs for low muscle older individuals (aged 70–79 years), the annual decline in
mass for Baumgartner equation was below 21.4 kg for men leg muscle strength (~ 3%/year) was 3–5 times higher than
and below 14.8 kg for women and for Janssen was 29.3 kg the rate of loss in the leg lean mass (~ 1%/year); this pattern
for men and 18.2 kg for women) showed the best agree- of different decline rates occurred in the group that lost as
ment in terms of sensitivity, specificity and area under the well as in the group that maintained/gained body weight. Of
curve with muscle mass assessed by CT, using the value particular interest is the finding that the group that gained
below the 25th percentile to define low muscle mass (for body weight had a small increase in lean mass, although
men 139.1 cm2 and for women 97.5 cm2) [30]. In a subse- muscle strength decreased [14]. These findings suggest that
quent study with the same cohort, the use of muscle mass loss of muscle mass is not the only etiologic factor in the loss
assessed by CT at the 3rd lumbar vertebra with the cutoff of muscle strength and thus that other factors are involved.
value below the 25th percentile to define low muscle mass Manini and Clark [78] suggested that conditions related to
(< 138 cm2 for men and < 98 cm2 for women) was associated impairments in neural (central) activation combined with
with higher all-cause mortality [76]. For low muscle strength reductions in force-generating capacity of skeletal muscle
assessed by handgrip strength, when examining 265 dialysis are involved in the loss of muscle strength [78]. Examples of
patients (218 HD and 17 peritoneal dialysis (PD) patients) impaired neural (central) activation are decreased excitatory
followed for 13.4 ± 7.9 months to analyze mortality, it was voluntary stimulus from supraspinal centers and lower or
shown that the cutoff of handgrip strength best able to pre- suboptimal motor unit recruitment that cause lower muscle
dict mortality rate was 22.5 kg for men (61% sensitivity and strength. An example of damaged force-generated muscle
76% specificity) and 7 kg for women (83% sensitivity and capacity is that there are changes in actomyosin structure
37% specificity) [77]. However, since these cutoffs showed a and function with infiltration of adipocytes into muscle fib-
moderate sensitivity for men and a low specificity for women ers that can decrease muscle strength.
and that ideally, a cutoff to evaluate sarcopenia should screen Since CKD patients manifest a phenotype of accelerated
low values when it can still be reversed and not necessarily aging [79], one can expect that similar to changes observed in
when it associates with higher mortality rates, appropriate elderly, a decrease in muscle strength and function are associ-
cutoffs for CKD/ESKD patients are yet to be determined. ated, but not only as a result of muscle mass loss. In fact, in
Until we know better about cutoffs directed to CKD/ESKD, a study using an animal model of progressive CKD, it was
it may be prudent to assume that those proposed in the sarco- shown that compared to controls, muscle function of CKD
penia consensus can be used in CKD patients. However, it is rats decreased although muscle mass did not change. Instead,
important to acknowledge that cutoffs should be understood changes in muscle quality and increased muscle fiber atrophy
as a starting point to screen for patients at risk or who need was observed [80]. In dialysis patients, Fahal et al. [81] inves-
special medical nutritional attention; thus, continuous fol- tigated changes in muscle weakness by examining quadriceps
low up using the patient as his/her own control is the best muscle force and contractile properties, in addition to muscle

13
Journal of Nephrology

biopsy with quantification of the type of muscle fibers in HD Disease Quality Initiative—National Kidney Foundation
and PD patients and in healthy controls. The first finding is that (KDOQI-NKF) guidelines recommends a protein intake of
muscle strength in dialyzed patients was lower than in healthy 0.6 to 0.8 g/kg/day for patients with CKD on stages 3 to 5
controls, and dialyzed patients with malnutrition (assessed by with an energy intake of 30 kcal/kg/day. However, no spe-
SGA) were weaker than well-nourished patients. Secondly, the cific recommendation for elderly subjects with CKD was
most prominent difference between dialysis and controls was addressed [86]. For the elderly with CKD, a position paper
the slower relaxation in the muscle, which can compromise from the PROT-AGE Study Group, recommends a protein
muscle strength and contraction, regardless of muscle mass. intake of 0.8 g/kg/day for patients with GFR < 30 ml/min
Third, 78% of the dialysis patients presented some morpho- and > 0.8 g/kg/day if GFR is between 30 to 60 ml/min [87].
logic abnormality in the muscle biopsies, with atrophy in fiber As for elderly not with CKD, a recent guideline recom-
type I (slow-twitch) present in 45% of the patients and atrophy mended a minimum protein intake 1 g /kg/day with 30 kcal/
in fiber type II (fast-twitch) in 40% of the patients. Moreover, kg/day, but no specific recommendation for elderly with
fiber type II (fast-twitch) area was significantly smaller in the CKD was discussed [88]. These diverse protein recommen-
malnourished dialysis group as compared to the well-nour- dations can be explained by the outcome expected. In the
ished. These findings corroborate that muscle mass is not the elderly without CKD, a higher intake of protein—higher
only determinant of muscle strength, but other factors such than the intake of 0.8–1.0 g/kg/day recommended for healthy
muscle relaxation and fiber muscle atrophy can also explain a adults—is motivated by findings that protein intake lower
low muscle strength. In fact, in a subsequent cross-sectional than 1 g/kg/day is associated with loss of muscle mass in
study it was demonstrated that compared to age-and sex- non-CKD elderly, most likely due to the lower protein syn-
matched healthy individuals, HD patients had lower strength, thesis and higher protein degradation rates that are inher-
contractive muscle area and gait speed, although the total ent to aging [89]. In individuals with CKD not on dialysis,
muscle sectional area was similar to that of healthy matched the recommendation of controlling protein intake aims to
individuals [82]. These findings support the hypothesis that reduce the metabolic derangements from the gradual loss
similar to the elderly, muscle function worsens independently of renal function [86]. Therefore, the optimal protein intake
of the progressive loss of muscle mass. A decrease in muscle for elderly patients with CKD stages 3 to 5 not on dialysis is
quality caused by muscle fat infiltration seems to be a missing a controversial subject. The question is—how much protein
link. Although studies in this area are scarce, some studies in intake an elderly with CKD not on dialysis should eat to
CKD and HD patients showed that increased muscle fat infil- ensure muscle mass preservation and at the same time not
tration in the thigh was associated with lower muscle function further increase the derangements resulting from the loss of
assessed by muscle strength and physical performance tests renal function? So far, there are no clinical trials addressing
[83, 84]. However, longitudinal studies in CKD/ESKD are this question with conclusive endpoints, such as changes
warranted to further investigate the role of muscle fat infiltra- in muscle mass, muscle strength and physical performance.
tion mediating loss of muscle function. However, interventional studies in patients with CKD (stages
In addition, in longitudinal studies of patients with 3–5 not on dialysis) evaluating the use of controlled protein
ESKD, low muscle strength was a stronger predictor of intake (moderate to low protein diets—0.6 to 0.8 g/kg/day,
increased hospitalization and mortality rates than lower or very low protein diet—0.3 to 0.4 g/kg/day supplemented
muscle mass, reinforcing the idea that low muscle strength with amino acids or their nitrogen-free keto-analogues) and
is a more powerful determinant of worse outcome [3, 58, with adequate energy intake have shown positive findings in
85]. This does not mean, however, that muscle mass should elderly CKD patients in preserving good nutritional status
be of less importance when assessing nutritional status, but [90–93], postponing the beginning of dialysis therapy [90],
rather that measurements of muscle strength, that can be lowering all-cause mortality [91], good adherence to a mod-
easily assessed by HGS, should be incorporated as an impor- erate restriction in protein intake (0.8 g/kg/day) and increas-
tant component for the diagnosis of muscle derangements ing serum albumin [92] and better quality of life [93]. More
in CKD and ESKD. recently, not only the protein amount, but the adherence to
higher scores of plant-based diet in elderly men with CKD
stages 3–5 was associated with better insulin sensitivity and
Protein intake: how much is required lower inflammatory markers, supporting the concept that
to avoid muscle wasting in the elderly the source and type of protein also plays an important role
with CKD? and has the potential to offer benefits to elderly with CKD
[94]. Altogether, these findings are suggestive that control-
This question is particularly important for patients with ling the protein intake (0.6–0.8 g/kg/day) in elderly patients
CKD on stages 3 to 5 not on dialysis. The 2020 Updated with CKD 3–5 can be beneficial but only if an adequate
practice guideline for nutrition in CKD from the Kidney amount of energy is provided as this is needed to prevent

13
 Journal of Nephrology

impaired protein degradation and the risk of muscle wasting predominantly improves cardio-respiratory endurance and
[95]. However, if poor adherence and signs of muscle wast- fitness, resistance training promotes muscle growth and
ing (indicating malnutrition/PEW, sarcopenia or cachexia) strength, and theoretically this may be considered to be the
occur, the priority of the dietary scheme should be to inter- preferred type of exercise to promote physical function in
rupt the loss of muscle mass and recover nutritional sta- this patient population. Furthermore, the timing of exer-
tus. In this case, an energy and protein recommendation cise is also of importance in the clinical setting. There are
of 30 kcal/kg/day and 0.8–1 g/kg/day, respectively, would reports suggesting that resistance training during the dialy-
likely cover for the nutritional needs and can be used as a sis session helps to improve compliance to prescribed exer-
starting point with subsequent monitoring. cise and could have a positive effect in counteracting the
increased catabolism caused by the HD session. An early
study from Kopple et al. [106] with 80 HD patients, showed
Can sarcopenia be reversed in CKD? that intradialytic exercise, resistance or endurance, induced
transcriptional changes in genes favoring muscle anabolism
Classically, nutritional interventions characterized by energy and improved LBM as assessed by anthropometric param-
and protein supplementation have been used to improve eters [106].
nutritional intake of malnourished or sarcopenic patients In a single-blind RCT in which 23 HD patients were ran-
[87, 89]. Evidences suggest that protein supplementation domized to progressive resistance exercise training (PRET)
alone may offer limited benefits to older adults in terms of or low-intensity lower body stretching activities [116],
improving muscle mass and strength [96–98] which may patients in the intervention group increased thigh muscle
be a reflection of the anabolic resistance present in older volume assessed by MRI, and strength assessed by isometric
individuals [99]. On the other hand, studies suggest that the dynamometer, while patients in the control group presented
best effect of protein supplementation on muscle protein muscle loss. However, in contrast to findings in the elderly
synthesis occurs when protein supplementation is given population, no effects on QoL and performance in physical
immediately after exercise [100, 101]. Despite some data function tests were detected. In a more recent multicenter
suggesting immediate additional anabolic benefits on com- RCT that tested the effects of a simple personalized walk-
bining oral nutritional supplementation and exercise training ing exercise program at home on functional status of HD
[102], the available randomized controlled trials (RCT) that patients [107], improvements of the six minutes walking test
investigated long-term effects of both interventions com- and the five times sit-to-stand test were described after six
bined, failed to demonstrate any additive benefits on func- months, together with improvements on self-reported QoL.
tion, strength and muscle mass [103, 104]. Reasons for the Regarding the non-dialysis CKD population, fewer stud-
lack of positive results may be related to the populations ies are available. The RENEXC study compared balance and
studied being younger than the general dialysis population resistance exercise, both combined with endurance training,
and had relatively adequate nutritional status; and secondly in 150 patients with CKD stages 3–5 for four months and
that the low volume and intensity of the exercise prescribed reported a significant improvement in muscle strength and
did not overcome the anabolic resistance that is character- physical performance in both groups [117]. In addition, in a
istic of ageing and of HD patients [105–107]. Of note, the pre-specified sub-analysis of the same study with prolonged
exercise load was not aligned with the recommended levels 12 months duration of the intervention, the effect of both inter-
by standard exercise guidelines [108]. ventions on sarcopenia status was assessed [118]; while no
Robust evidence in healthy elderly subjects demonstrate intervention was able to reverse sarcopenia the two groups
the benefits of exercise, particularly resistance training, and showed either stabilization (in the resistance exercise group)
physical activity, on muscle mass, strength and performance or improvement (in the balance group) in muscle mass. In
[109]. The synergistic effects of protein supplementation and
exercise to increase protein synthesis and stimulate muscle Table 4  Potential effects of exercise training (resistance/endurance)
growth have also been investigated in the elderly. Particu- on muscle parameters in CKD/ESKD patients summarized from
larly, resistance exercise in conjunction with increased pro- available evidence
tein intake may improve the utilization of ingested amino Resistance Aerobic
acids for de novo protein synthesis [110, 111]. Similar training training
results were found during prolonged protein supplementa-
Muscle mass ↑↑ –
tion combined with resistance exercise [112]. Results from
Muscle strength ↑↑ –
the renal population are summarized in Table 4.
Measures of functional fitness/capacity ↑ ↑↑
In the ESKD population, a number of studies have
Performance ↑ ↑
investigated various modalities of exercise in HD patients
Health-related quality of life – ↑
[113–115]. In comparison to aerobic exercise, that

13
Journal of Nephrology

the LIFE-P study, elderly subjects were randomized into two some potential pharmacological options that will be briefly
groups, physical activity (PA) and a successful aging health discussed.
education group (SA) for 12–18 months [119]. CKD patients
in the PA group had better physical performance results as
assessed by the short physical performance battery (SPPB) at Amino acids supplementation
12 months in comparison to patients enrolled in the SA group.
While in the ExTra CKD study [120], the addition of resist- CKD and ESKD are characterized by a status of abnor-
ance exercise to aerobic exercise conferred greater increases in mal amino acid (AA) metabolism, particularly involving
muscle mass and strength in CKD patients than aerobic exer- branched chain amino acids (BCAA) and keto acids (BCKA)
cise alone. Finally, in addition to the positive results of exercise [124]. As a consequence, low plasma and cellular levels of
in patients on HD reported by Manfredini et al. [107], a recent BCAA and BCKA are common [124, 125]. BCAAs, par-
RCT on exercise in overweight CKD patients by Aoike et al. ticularly leucine, are the most powerful AAs in the stimula-
[121] found that patients who were instructed to perform aero- tion of muscle anabolism and inhibition of catabolism [126].
bic exercises at home had similar improvements in functional Several studies have shown that leucine supplementation
capacity tests (6 min walking test, 2 min step test, sit to stand, improves muscle protein synthesis in older adults [127].
arm curl test, sit-and-reach test, and timed up-and-go), reflect- Therefore, BCAA supplements were proposed in CKD and
ing important improvements in cardiorespiratory fitness, as ESKD patients to improve muscle synthesis and AA plasma
well as improved QoL and quality of sleep when compared to levels. In addition, since protein restriction is a key factor in
patients that performed in-center exercises, while no changes the conservative management of CKD, essential AA (EAA)
in any of the parameters investigated were found in the control and keto-acid (KA) supplements including also BCAA and
group (no exercise). BCKA were proposed to maintain or improve nutritional
In summary, available data suggest a possible anabolic status while reducing protein intake as much as possible.
resistance in HD patients, probably due to catabolic factors The administration of EAA in malnourished HD
related to the kidney disease per se and disturbances affecting patients improved appetite, increased albumin and
HD patients (uremia, inflammation, acidosis, insulin resist- plasma AA concentrations, and enhanced muscle strength
ance etc.) [122], which might require a more intensive, com- [128–130]. In particular, BCAA supplementation was
prehensive, and tailored nutrition and exercise prescription to reported to stimulate appetite and to improve albumin
counteract the deleterious consequences of the uremic milieu. and anthropometric indices [128]. More recently, the use
Furthermore, presence of these catabolic factors highlights the of β-hydroxy-β-methylbutyrate (HMB), a metabolite of
notion that a one size-fit-all approach may not be equally ben- leucine that has been shown to attenuate muscle loss in
eficial for different patients. As discussed above, low muscle the elderly [131], has been studied in HD patients but
mass can be the cause of muscle weakness, which is strongly there was no apparent benefit of HMB on body composi-
associated with function and disability; however, muscle mass tion [132]. Considering the catabolic effects of HD ses-
alone may have no or little direct effect on function and dis- sion per se, during which substantial AA losses occur
ability [9]. Patients that are weak and have low muscle mass triggering muscle catabolism to maintain constant plasma
may benefit by interventions that address muscle hypertrophy, AA concentration [133, 134], Deleaval et al. [43], per-
such as high load resistance exercise, while weak patients with formed a pilot cross-over trial in which BCAA enriched
normal muscle mass may require other strategies. In addition, dialysis fluids were used to prevent BCAA losses and,
strength training in CKD was not shown to increase muscle consequently, protein catabolism. They found that the
mass, but could improve muscle strength in six out of eight intervention increased plasma concentration of valine,
tests and was capable to ameliorate self-rated physical health isoleucine and leucine, while in the standard dialysate
and physical function assessed by short-form 36 [123]. Future session the mass transfer of amino acids was negative
studies should characterize investigated populations in terms [43]. Regarding patients with CKD not yet on dialysis,
of presence of low muscle mass and strength alone or com- nutritional interventions are mainly characterized by a
bined, as this distinction may guide the appropriate tailoring reduction in protein intake in order to minimize uremic
of the intervention accordingly. toxicity, avoid malnutrition and delay progression of
the kidney disease [86]. In this clinical setting, BCKAs
are mainly used to fix amine groups and to regenerate
Pharmacological interventions BCAAs, with the advantage of being amino-free [135].
The supplementation of very low protein diets (VLPD,
Treatments for sarcopenia have focused mostly on pro- 0.3–0.4 g protein/kg/day) and LPD (0.6 g protein/kg/day)
moting exercise and improving nutritional intake. How- with EAA and keto acids is able to maintain a neutral
ever, recent scientific advances have brought attention to nitrogen balance and body composition [135, 136]. To

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assess the effect of supplemented VLPDs, Garibotto et al. Angiotensin II receptor blockers (ARB)
[136] performed a cross-over trial in which patients had
a period of supplemented VLPD and a period of classic Angiotensin II overexpression is known to intensify mus-
LPD. They observed that supplemented VLPD was not cle catabolism by inhibiting the mTOR pathway, but also
associated with changes in body weight and body com- to induce protein degradation through the activation of
position; however, in terms of muscle kinetics, supple- nuclear factor kappa B (NF-κB) and p38 mitogen-activated
mented VLPD was able to reduce the net muscle protein protein kinase by reactive oxygen species (ROS) accumula-
catabolism compared with the classic LPD. tion [149]. Cumulative evidence in animal studies reported
a protective effect of ARB on skeletal muscle by reduc-
ing muscle fibrosis and improving muscle function [150],
Blockage of the myostatin and ActRII pathway and a dose dependent enhancement in muscle healing and
regeneration [151, 152]. The only available study in humans
Myostatin is a negative regulator of muscle growth via the had a cross-sectional design and reported that ARB use in
ActRIIB receptor that is increased in inflamed CKD/ESKD chronic HD patients was protective, with an independent
patients [137], and is currently the most investigated tar- 75% decrease in the odds of having muscle weakness as
get for the development of new drugs intended to block assessed by handgrip, when compared to patients who did
muscle loss and stimulate muscle hypertrophy. The use of not use it [153]. Considering these positive results of ARBs
a recombinant fusion protein of modified human follista- that are common drugs patients with CKD/ESKD, further
tin (a natural myostatin inhibitor), showed an increase in longitudinal and interventional studies are needed to fully
muscle mass and strength in animal studies [138], but in clarify the role of ARB in the preservation of muscle mass
humans, no effect in muscle strength was observed [139]. and strength in ESKD.
The use of anti-myostatin peptibodies led to increased
muscle mass and body weight in animal studies [140], as AST‑120
well in humans [141–143]. However, effects on muscle
strength were absent or inconsistent, reinforcing the idea AST-120 is an adsorbent used to inhibit the intestinal
that strength is not directly related only to muscle mass, absorption of indole, p-cresol, and food derived advanced
but mainly to the neural system as previously described. glycation end-products [154]. It has been proposed to slow
The use of a receptor blockade of both ActRIIA and CKD progression as assessed by estimated creatinine clear-
ActRIIB in humans, resulted in increase in muscle mass ance in mild and moderate CKD [155] and to improve the
and reduced total fat mass [144], and improvement of uremic syndrome [156]. Uremic toxins, specially indoxyl
insulin sensitivity [145]. Effects in muscle strength and sulfate have been described as contributors to the chronic
function were only described in a proof-of-concept study inflammation present in ESKD, known to induce skeletal
with improvement of usual gait speed and 6-minute walk muscle loss [157]. Available evidence in animal and in vitro
distance [146]. In experimental uremia [147], the use of studies suggest that AST-120 has protective effects on mus-
anti-myostatin peptibody for four weeks reversed weight cle atrophy via the maintenance of mitochondrial function
loss and muscle wasting in mice by decreasing protein and reduction of the oxidative stress [158]. However, there
degradation, increasing protein synthesis and enhanc- are no clinical studies showing such effects.
ing IGF-signaling and satellite cell function. They also
reported a reduction in circulating inflammatory markers. Ghrelin
Dong et al. [148], showed that in rodents with CKD, the
inhibition of myostatin using a neutralizing peptibody Ghrelin, a peptide hormone derived from the gastrointesti-
improved muscle fibrosis. Both studies suggest anti-cata- nal tract that stimulates appetite, increases food intake and
bolic and anti-inflammatory effects of myostatin inhibitors promotes fat storage, has been reported to enhance oxygen
in experimental uremia. utilization in skeletal muscle [159]. In nephrectomized mice,
The results from different trials have shown that block- the use of acylated ghrelin increased muscle mass and mito-
age of myostatin and ActRII pathways had significant chondrial content of muscle [160]. Plasma ghrelin levels
effects on muscle hypertrophy; however, they failed to are elevated in patients with CKD/ESKD and correlate with
demonstrate any significant effect on muscle strength and fat mass [161]. In a placebo-controlled RCT in malnour-
physical function. As discussed above, muscle strength is ished PD patients administration of subcutaneous ghrelin
thought to be the most important parameter in the sarco- enhanced acute food intake [162]. However, the role if any
penia definition as it is strongly related to disability, hos- of ghrelin as a feasible adjunct pharmacologic therapy in
pitalization and mortality. No studies testing these novel patients with PEW/malnutrition, sarcopenia and cachexia
drugs on the CKD/ESKD population have been reported. remains unclear.

13
Journal of Nephrology

Ursolic acid protein catabolism have shown promising results in terms of

ameliorating CKD-related sarcopenia in experimental set-
Ursolic acid is a plant compound, found in apple peels, tings but are with some exceptions, such as supplementation
basil leaves, prunes and cranberries. In animal models it with amino acids or their keto acid analogues, not routinely
has shown beneficial effects in glucose and lipid metabo- used in clinical practice. Investigations with intervention
lism [163]. Recently, its effect on skeletal muscle has been with CKD-related sarcopenia are scarce and the research
investigated in animal models of starvation and denervation field is still in its infancy. Moreover, considering the major
[164]. In these models, ursolic acid reversed muscle atrophy negative impact on this complication on morbidity and mor-
by modulating the insulin/IGF-1 signaling. In CKD, a con- tality as well as quality of life in patients with CKD/ESKD,
dition with known insulin resistance and IGF-1 deficiency, further studies are warranted.
ursolic acid blocked CKD induced muscle atrophy by sup-
pressing myostatin expression, inflammatory responses asso- Acknowledgements  Baxter Novum is supported by a grant of Baxter
Healthcare to Karolinska Institutet.
ciated with NF-κB activations, and by stimulating protein
synthesis [165]. Author contributions  All authors contributed to this review/manu-
script. The conceptualization of the review was done by CMA. The
literature search and analysis were performed by CMA and AS. The
Future perspectives and conclusion first draft of the manuscript was written by CMA and AS. LC, PS, BL
critically revised the work. All authors read and approved the final
manuscript.
Undoubtedly, sarcopenia is an important nutritional distur-
bance present in CKD and ESKD that should be routinely Funding  This review was not funded. Open access funding provided
screened in clinical practice using one or more of the many by Karolinska Institute.
available methods (Table 2). CKD-related sarcopenia can
occur early in adult life and may develop rapidly as a con- Compliance with ethical standards 
sequence of the negative energy-protein balance coming
from insufficient food intake coupled with increased protein Conflict of interest  Bengt Lindholm is employed by Baxter Health-
care. Peter Stenvinkel received honoraria for serving at scientific advi-
catabolism in patients exposed to the uremic milieu and in sory boards at Baxter, Astra Zeneca, REATA, Astellas and FMC. Alice
HD-patients it may be further enhanced by catabolic effects Sabatino received honoraria from Fresenius Kabi for speaking at sym-
of the hemodialysis procedure. The prevalence of CKD- posia “International keto-analoghe symposium a Roma” in November
related sarcopenia is higher than that observed in ageing- 2019. Carla Maria Avesani and Lilian Cuppari have any conflict of
interest to declare.
related sarcopenia. It is notable that the prevalence of sar-
copenia is higher in HD patients than in non-dialyzed CKD Ethical approval  All work that included in this review involving human
or PD patients, and in kidney transplant recipients (Table 3). was conducted according to the principles expressed in the declara-
Reliable diagnostic methods using models with specific cut- tion of Helsinki and all subjects gave written informed consent upon
recruitment.
offs for muscle mass and strength that could be used for
operational screening for sarcopenia in CKD are however Informed consent  All work included in this review involving human
lacking and ought to be developed and tested for valida- had consent from the participants to be enrolled in the study.
tion. Criteria and methods for the diagnosis of sarcopenia
should consider the setting (research or clinical practice), the Open Access  This article is licensed under a Creative Commons Attri-
group assessed (CKD, HD, PD or kidney transplant recipi- bution 4.0 International License, which permits use, sharing, adapta-
ents) and periodicity of assessment. Interventions to reverse tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
sarcopenia usually include the use of oral energy and protein provide a link to the Creative Commons licence, and indicate if changes
supplementation combined with supervised physical resist- were made. The images or other third party material in this article are
ance exercise (Table 4). However, RCTs show controversial included in the article’s Creative Commons licence, unless indicated
results in reestablishing muscle mass and strength, and in otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons licence and your intended use is not
ameliorating physical performance, mobility and QoL. Dif- permitted by statutory regulation or exceeds the permitted use, you will
ferent study designs, length and type of intervention and pri- need to obtain permission directly from the copyright holder. To view a
mary outcomes make comparisons between studies difficult, copy of this licence, visit http://creat​iveco​mmons​.org/licen​ses/by/4.0/.
but, in general, positive findings in ameliorating one or more
components of sarcopenia (muscle mass, muscle strength or
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