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REVIEW
Journal of Cachexia, Sarcopenia and Muscle 2021; 12: 1380–1392
Published online 21 October 2021 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/jcsm.12839

Effects of hormonal changes on sarcopenia in chronic

kidney disease: where are we now and what can we
do?

Ozkan Gungor1, Sena Ulu2, Nuri Baris Hasbal3 , Stefan D. Anker4* & Kamyar Kalantar-Zadeh5
1
Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey; 2Department of Internal
Medicine and Nephrology, Faculty of Medicine, Bahcesehir University, Istanbul, Turkey; 3Clinic of Nephrology, Basaksehir Cam and Sakura City Hospital, Istanbul, Turkey;
4
Department of Cardiology (CVK), Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin,
Charité Universitätsmedizin Berlin, Berlin, Germany; 5Division of Nephrology, Hypertension and Kidney Transplantation, University of California Irvine School of Medicine,
Orange, CA, USA

Abstract
Sarcopenia or muscle wasting is a progressive and generalized skeletal muscle disorder involving the accelerated loss of
muscle mass and function, often associated with muscle weakness (dynapenia) and frailty. Whereas primary sarcopenia
is related to ageing, secondary sarcopenia happens independent of age in the context of chronic disease states such as
chronic kidney disease (CKD). Sarcopenia has become a major focus of research and public policy debate due to its
impact on patient’s health-related quality of life, health-care expenditure, morbidity, and mortality. The development
of sarcopenia in patients with CKD is multifactorial and it may occur independently of weight loss or cachexia including
under obese sarcopenia. Hormonal imbalances can facilitate the development of sarcopenia in the general population
and is a common finding in CKD. Hormones that may influence the development of sarcopenia are testosterone, growth
hormone, insulin, thyroid hormones, and vitamin D. Although the relationship between free testosterone level that is
low in uraemic patients and sarcopenia in CKD is not well-defined, functional improvement may be seen. Unlike
testosterone, it is known that vitamin D is associated with muscle strength, muscle size, and physical performance in
patients with CKD. Outcomes after vitamin D replacement therapy are still controversial. The half-life of growth
hormone (GH) is prolonged in patients with CKD. Besides, IGF-1 levels are normal in patients with Stage 4 CKD—a
minimal reduction is seen in the end-stage renal disease. Unresponsiveness or resistance of IGF-1 and changes in the
GH/IGF-1 axis are the main causes of sarcopenia in CKD. Low serum T3 level is frequent in CKD, but the net effect
on sarcopenia is not well-studied. CKD patients develop insulin resistance (IR) from the earliest period even before
GFR decline begins. IR reduces glucose utilization as an energy source by hepatic gluconeogenesis, decreasing muscle
glucose uptake, impairing intracellular glucose metabolism. This cascade results in muscle protein breakdown. IR and
sarcopenia might also be a new pathway for targeting. Ghrelin, oestrogen, cortisol, and dehydroepiandrosterone may
be other players in the setting of sarcopenia. In this review, we mainly examine the effects of hormonal changes on the
occurrence of sarcopenia in patients with CKD via the available data.
Keywords Sarcopenia; Chronic kidney disease; Hormones; Cachexia; COVID-19

Received: 12 May 2021; Revised: 2 September 2021; Accepted: 19 September 2021

*Correspondence to: Stefan D. Anker, Department of Cardiology (CVK); and Berlin Institute of Health Center for Regenerative Therapies (BCRT); German Centre for
Cardiovascular Research (DZHK) partner site Berlin; Charité Universitätsmedizin Berlin, Berlin, Germany. Email: [email protected]

© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,
provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
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Hormonal effects on sarcopenia in chronic kidney disease 1381

Introduction Category

Sarcopenia is the combination of the Greek words sarcos As stated earlier, sarcopenia is considered ‘primary
(meat) and penia (loss). This term was first used in 1989 by sarcopenia’ when it is age-related and when no other specific
Irwin H. Rosenberg. Rosenberg defined sarcopenia as a causes are evident. It is called ‘secondary sarcopenia’ when
reduction in muscle mass occurring in association with sarcopenia occurs resulting from one or more causal factors.7
ageing.1 Hence, the ageing related sarcopenia can be referred Sarcopenia categories are presented in Table 2.
to ‘primary sarcopenia’ as opposed to the age independent
‘secondary sarcopenia’ in the context of chronic disease
states. The European Working Group on Sarcopenia in Older Risk factors
People (EWGSOP) has reported that sarcopenia is a syndrome
characterized by the general and progressive loss of skeletal There are many risk factors that facilitate the development of
muscle mass and strength and resulting risks such as physical sarcopenia.8,9 We can examine them as grouped under the
disability, low quality of life, and death.2 An increasing following categories:
number of studies have classified sarcopenia as an indepen-
dent disease coded as M62.84 in the International Classifica- 1 Structural: Genetic predisposition, gender, and low birth
tion of Diseases-10 system (ICD-10) in 2016.3 In 2018, the weight
definition of sarcopenia was revised by EWGSOP and the 2 Effect of ageing: Reduction in the muscle cell count, hor-
main parameters of the disease were determined as muscle monal dysregulation, and neuromuscular system changes
strength and muscle mass (Table 1, Part a).4 That consensus 3 Lifestyle: Diet, smoking and alcohol use, and physical
positioned the physical performance as a variable that indi- inactivity
cates the severity of the disease. Terminology related to 4 Chronic health problems: Diabetes mellitus, chronic kidney
sarcopenia is summarized in Table 1, Part b. disease, liver disease. Other chronic disease states such as
The incidence of sarcopenia is increased in patients with liver disease, rheumatoid arthritis, neurologic disorders,
chronic kidney disease and its aetiology is multifactorial. Hor- and cancer cachexia.
monal imbalance is one of them. In this review, first, general
information about sarcopenia will be given, and then the ef-
fects of hormones on the development of sarcopenia in pa- Pathophysiology
tients with chronic kidney disease will be explained.
Although the mechanism of the development of sarcopenia is
unclear, some theories have been suggested besides ageing.
Epidemiology There are reductions in the levels of anabolic hormones [tes-
tosterone, oestrogen, growth hormone, insulin-like growth
The incidence of sarcopenia increases with age. Muscle mass factor-1 (IGF-1)].10,11 The apoptotic activity of myofibrils in-
starts to diminish linearly at the beginning of the fourth de- crease and oxidative stress is invoked by the accumulation
cade of life. Such losses of muscle mass account for 8% mus- of pro-inflammatory cytokines [tumour necrosis factor-alpha
cle quantity loss per each decade of life until the age of 70.5 (TNF-α)], interleukin (IL- 6), and free radicals.12 Low levels
After 70 years of age, muscle loss per decade increases to of circulating angiotensin-II are associated with muscle weak-
15%, and total loss reaches 50% in the 8th decade.5 In a ness, decreased IGF-1 levels, and insulin resistance leading to
study, the incidence of sarcopenia ranged from 5% to 13% be- sarcopenia.13 There are also changes in the mitochondrial
tween the ages of 60 and 70.6 That study reported that the functions of muscle cells, and the number of α-motor neu-
sarcopenia incidence ranged from 11% to 50% at the age of rons decrease and sarcopenia is also associated with chronic
80 and older.6 inflammation.14

Table 1 (a) Sarcopenia diagnostic criteria [European Working Group on Sarcopenia in Older People (EWGSOP), 2018] and (b) terminology related to
sarcopenia

a: Sarcopenia diagnostic criteria (EWGSOP, 2018)

Probable sarcopenia is identified when Criterion 1 was detected. (1) Low muscle strength
Additional documentation of Criterion 2 confirms the diagnosis. (2) Low muscle mass or quality
Sarcopenia is considered severe when Criteria 1, 2, and 3 are all met. (3) Low physical performance
b: Terminology related to sarcopenia
Dynapenia Muscle weakness without loss of muscle mass.
Sarcopenic obesity Having abdominal adiposity but also sarcopenia.
Severe sarcopenia Criteria 1, 2, and 3 in Table 1, Part a are all met.

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1382 O. Gungor et al.

Table 2 Classification of sarcopenia.

Primary sarcopenia
Age-related sarcopenia No factors are evident other than advanced age
Secondary sarcopenia
Bed ridden status, sedentary lifestyle, and neurologic or other disorders
Activity-related sarcopenia that limit physical activity such as morbid obesity or orthopaedic disorders/deformity
Chronic disease states including advanced organ failure (heart, lungs,
Disease-related sarcopenia liver, kidneys, and brain), inflammatory diseases, malignancies, and endocrine diseases
Inadequate diet for the intake of calories and protein malabsorption,
Nutritional sarcopenia starvation, anorexia nervosa, diseases, or medicine-induced anorexia

Although the biological mechanism of sarcopenia is not define sarcopenia,4 the feasibility of using such criteria in CKD
fully understood, it is thought that the number of satellite patients has not yet been clarified yet.23 The type of test used
cells involved in muscle regeneration decreases with ageing to detect sarcopenia may influence the diagnosis of
and this may contribute to the development of sarcopenia.15 sarcopenia in CKD patients.24 For example, the
Levels of IGF-1 and androgen—which are effective in the reg- hypervolaemia seen in CKD patients may act on the bioelec-
ulation of skeletal muscle development—decrease with trical impedance analysis; but the measurement of the lean
ageing.16 mass by dual-energy X-ray absorptiometry is not
influenced.25
There are various studies in the literature examining the
Diagnosis prevalence of sarcopenia and factors involved in sarcopenia
in CKD patients and in patients undergoing dialysis. Souza
Many consensus reports have been developed for the diag- et al. conducted a study on 100 patients and found that the
nosis of sarcopenia to date. A recent one is the EWGSOP frequency of sarcopenia was 11.9% according to the EWGSOP
criteria that were updated in 2018 (Table 1). Computed to- criteria and 28.7% according to the Foundation for the Na-
mography, magnetic resonance imaging, ultrasonographic im- tional Institutes of Health criteria. The frequency of
aging, or dual-energy X-ray absorptiometry can be used to sarcopenia increases as the CKD stage advances.26 Pereira
measure muscle mass.17,18 A hand-grip strength test is usu- et al. found that the frequency of sarcopenia was between
ally performed to measure muscle strength. The walking 5.9% and 9.8% in 287 non-dialysis CKD patients.27 The fre-
speed test, the get up and go test, and the short physical per- quency of sarcopenia is a little bit higher in dialysis patients.
formance battery can measure physical performance. In a study by Kim et al. with 95 haemodialysis patients, an in-
EWGSOP2 developed an algorithm to identify individuals with cidence of sarcopenia was found 37% in men and 29.3% in
sarcopenia to be used in both clinical practice and clinical re- women.28
search (Figure 1).4 The underlying mechanisms of sarcopenia in the context of
CKD revolve around the loss of muscle mass. This is a
‘chicken-or-the-egg’ conundrum because it is unknown
Significance whether reduced physical activity causes muscle loss or
whether muscle loss causes reduced activity. Regardless of
Sarcopenia has negative consequences including frailty, de- the initiating factor, the loss of muscle mass in CKD may be
creased health-related quality of life, impaired immune sys- attributed to a negative balance of protein homeostasis that
tem, impaired respiratory functions, and higher likelihood of leads to increased catabolism and decreased synthesis of
fall.19,20 It may sometimes even lead to death.21 muscle.22,26,28
Chronic kidney disease may facilitate impairments of mus-
cle regeneration process (by decreased production of myo-
The relationship between chronic kidney disease genic regulatory factors and reduced cellular activation).
and sarcopenia The permanent imbalance between protein breakdown and
synthesis in muscles results in muscle loss.22 Blood levels of
Chronic kidney disease (CKD) is often called a model of ‘accel- myostatin (negative regulator of skeletal muscle mass) in-
erated ageing’; therefore, it is likely that the loss of lean crease in patients with CKD.29 The binding of myostatin to
mass, reduced skeletal muscle strength, and low physical per- activin-A type-IIB receptors stimulates the expression of
formance (all components of sarcopenia) are in the same di- atrogens such as atrogin-1 and muscle-ring factor 1—both
rection as patient-centred outcomes of ageing such as of these are members of the muscle-specific ubiquitin ligase
mobility limitations, disability, and mortality as in the general family.29,30 Impaired mitochondrial function also contributes
population.22 Although some criteria have been developed to to decreased muscular endurance.31

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Hormonal effects on sarcopenia in chronic kidney disease 1383

Figure 1 Sarcopenia: EWGSOP2 algorithm for case-finding, diagnosis, and quantifying severity in practice. DXA, dual-energy X-ray absorptiometry; BIA,
bioelectrical impedance analysis; CT, computed tomography; MRI, magnetic resonance imaging.

Furthermore, increased catabolic processes in CKD are ef- on 128 pre-dialysis CKD patients with a median of 2.8 years
fective in the development of sarcopenia. Chronic inflamma- follow up, decreased handgrip strength was independently
tion, uraemic toxins, malnutrition, hormonal imbalance associated with a composite outcome of progression to
(insulin resistance, vitamin D deficiency, and hypogonadism), end-stage kidney disease and mortality in men and women
oxidative stress, and increased ubiquitination are key players and across different stages of pre-dialysis CKD.35
in the catabolic process.22,32 The renin–angiotensin–aldoste-
rone system is up-regulated in CKD; this can impair muscle re-
generation and invoke ubiquitin proteasome system Sarcopenic obesity and chronic kidney disease
proteolytic pathways.33 We can group the factors involved
in the development of sarcopenia in CKD patients as follows There is a reverse epidemiology between obesity and CKD. Lu
(Figure 2). et al. found that U-shaped association is seen between body
Increased frequency of sarcopenia in CKD patients has mass index and clinical outcomes in patients with CKD, and
been shown to have negative consequences. Pereria et al. re- also worse outcomes were seen in patients with body mass
ported that sarcopenia in CKD was associated with mortality index under 25 kg/m2.36 ‘Obesity paradox’ or a better defini-
with an hazard ratio of 1.8 (95% CI: 0.78–4.17).27 In a study tion named ‘sarcopenic obesity’ have been discussing re-
on 385 patients with a mean estimated glomerular filtration cently. This phenomenon defines the patients who has
rate (eGFR) of 41 mL/min/1.73 m2, each 0.1 m/s decrement especially abdominal adiposity but also sarcopenia. In a study,
in gait speed was associated with a 26% higher risk for death sarcopenic obesity was found to be associated with an in-
and each 1-s longer ‘timed up and go’ test result was associ- creased risk of death in individuals without CKD, whereas
ated with an 8% higher risk for mortality.34 In another study such a relationship was not demonstrated in those with

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1384 O. Gungor et al.

Figure 2 Factors affecting the development of sarcopenia in patients with chronic kidney disease.

CKD.37 It is well defined in patients with end-stage renal dis- Testosterone

ease, Honda et al. demonstrated that sarcopenic obesity is
associated with more inflammatory situation and increased Testosterone and chronic kidney disease
mortality.38 There is a clear need for more clinical investiga- Regarding the patients with CKD or undergoing dialysis,
tions about sarcopenic obesity and CKD. hypogonadotropic hypogonadism with low testosterone
levels, suppression of the pituitary–testicular axis, high LH
levels and testicular calcification in secondary hyperparathy-
roidism due to CKD may be seen in the majority of the cases.
Effects of hormones on the development of It appears that uraemic metabolites occurring in advanced
sarcopenia stages of CKD affect the testicle more than the hypothalamic
or pituitary function. Previous trials have shown a negative
Hormones play an important role in the development of correlation between endogenous testosterone levels and
muscle mass and regulation of muscle strength including in CKD Stages 1–5. Recently, we showed that this deficiency is
patients with CKD.10,11 Hormones that influence the devel- very common (65% in male Turkish HD patients).39–41
opment of sarcopenia are testosterone, growth hormone
(GH), insulin, thyroid hormones, and vitamin D. In the next Testosterone and sarcopenia
part of the review, hormones essentially responsible for Testosterone is an important anabolic hormone required for
the development of sarcopenia in CKD patients will be de- muscle protein synthesis, muscle mass, and strength.42 Tes-
tailed with the light of the studies showing the effects of tosterone increases protein synthesis, reduces its breakdown,
such hormones on the development of sarcopenia in pa- and increases the size of Types I and II muscle fibres. It also
tients with and without CKD. helps to transport mesenchymal stem cells to satellite cells

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Hormonal effects on sarcopenia in chronic kidney disease 1385

and inhibits the pathway to adipocyte progenitor cells.40 A patients in the literature the effect of testosterone replace-
decrease in testosterone levels and anabolic effects with ment on sarcopenia has been investigated based on the very
age or in chronic diseases (along with inflammatory condi- high probability of this relationship. Functional improvement
tions) mayF lead to bone loss as well as a reduction in muscle and significant increase in lean body mass have been noted
mass and strength.40,43 with nandrolone in both male and female dialysis patients,
Myostatin is a hormone released from the muscle that but unfortunate side effects include erectile dysfunction, gy-
inhibits muscle growth. A decrease in testosterone causes necomastia, and increased CV risk.45,48
an increase in myostatin expression and impairment in A 24-week RCT studied the effects of oxymetholone, an
IGF-1 signal transduction.44 Accordingly, testosterone defi- anabolic steroid with a lower androgenic effect, on HD pa-
ciency is an important factor in the development of tients. A significant improvement was found in patients’
sarcopenia. With the use of testosterone, the grip strength and physical function. Selective androgen re-
pro-inflammatory processes that cause muscle atrophy can ceptor modulators [GTx-024 (enobosarm)] are anabolic for
be reduced by increasing protein synthesis and increasing muscle and have lower side effects and are promising in
muscle mass and strength.45 In rat studies, the effects of this regard. Although these drugs have not yet been tried
sarcopenia on cell metabolism were reversed with testos- in CKD or dialysis patients, several studies showed that they
terone supplementation.46 improve lean body mass and physical function in chronic
diseases. In another RCT reported by Johansen et al. in
Testosterone and sarcopenia in chronic kidney disease which 69 patients completed the study, nandrolone, an an-
Uraemic patients have significantly lower free abolic steroid, was shown to increase quadriceps muscle
testosterone.47,48 The CKD population is at high risk for mus- cross-sectional area and lean body mass.49 The available
cle atrophy and sarcopenia due to both the existing testoster- data suggest that they have positive effects on muscle
one deficiency and the resulting complications of CKD, and bone.50 But further studies are needed to evaluate
inflammation, and malnutrition (Figure 3). Although there the long-term effects of both androgens and anabolic ste-
are no randomized controlled trial (RCT) evaluating the rela- roids and their effectiveness, benefits, and risks in patients
tionship between testosterone levels and sarcopenia in CKD with CKD.

Figure 3 Chronic kidney disease (CKD), testosterone deficiency, and sarcopenia.

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1386 O. Gungor et al.

Vitamin D regeneration and muscle strength but also reduces falls and
prevents fractures.54 Studies on vitamin D in sarcopenia re-
Vitamin D and chronic kidney disease main contradictory.56,57
Vitamin D deficiency is observed from the early stages of
CKD.51 A reduction in kidney mass, dietary restrictions, nutri- Vitamin D and sarcopenia in chronic kidney disease
tional deficiencies, impaired skin synthesis of cholecalciferol, Chronic kidney disease population is at high risk for
diabetes mellitus, obesity, accumulation of uraemic toxins, sarcopenia, both due to malnutrition, inflammation, and var-
proteinuria, reduction of reabsorption due to megalin in the ious complications as well as vitamin D deficiency seen in
proximal tubule, and increased FGF23 levels play a role in this CKD (Figure 4). The relationship between low 25(OH) D
process.52 levels and lower muscle strength and mass, body imbalance
and falls, worse physical performance, and frailty in older in-
Vitamin D and sarcopenia dividuals or individuals with chronic diseases has been stud-
Vitamin D is one of the main molecules of muscle and bone ied many times. However, trials on the role of vitamin D on
physiology.53 Vitamin D regulates myokines and osteokines sarcopenia in the CKD population are rare.58,59 Gordon et al.
(vascular endothelial growth factor, insulin-like growth fac- showed that there is a positive relationship between 1.25
tor-1, follistatin, fibroblast growth factor, osteoglycine, (OH) 2D levels and muscle size and physical performance
sclerostin, and osteocalcin) in muscle and bone tissue. Vita- in CKD patients, and Zahed et al. found an association be-
min D also has favourable effects on increasing the diameter tween 25 (OH) D levels and lower extremity muscle strength
and number of type II muscle fibres and muscle cells, which in haemodialysis patients.60,61 Taskapan et al. reported that
are effective in neuromuscular performance.54 Sarcopenia, vitamin D supplementation significantly improved physical
muscle weakness, falls, and increased fracture frequency performance (as assessed by the ascent and climb time test,
have been shown to correlate to vitamin D deficiency.55 In the walking speed test, and the stair climbing test) in pa-
vitro studies have reported that vitamin D reduces myostatin tients with severe vitamin D deficiency [average 25 (OH)
in cultured muscle cells and increases muscle and bone mass. D < 7 ng/mL (17.5 nmol/L)] with CKD Stages 3–4 and peri-
Vitamin D replacement not only increases muscle toneal dialysis.62 Vitamin D supplementation seems

Figure 4 Chronic kidney disease (CKD), vitamin D deficiency, and sarcopenia.

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Hormonal effects on sarcopenia in chronic kidney disease 1387

beneficial for the treatment of sarcopenia in CKD and dialy- importantly, improved mortality-related factors.68 In an-
sis populations, but it requires larger RCTs both in CKD and other RCT involving 20 haemodialysis patients, a 6 month
dialysis patients. Studies investigating the relationship be- GH treatment decrease adipose tissue especially in the ab-
tween vitamin D levels and sarcopenia in patients with dominal region with an increase in lean body mass.69 The
CKD in Table 3. most important contribution of the study is that serum
IGF-1 level was decreased in the placebo group after
6 months of treatment while a significant increase was ob-
Growth hormone served in the treatment group. This study also proves that
there is a gradual decrease in IGF-1 level in CKD patients
Growth hormone and chronic kidney disease
despite renal replacement therapy. This treatment has en-
The kidneys play an important role in the elimination of GH.
couraging results, a low side effect profile, and has also
The half-life of GH is prolonged in patients with CKD. IGF-1
been used in other diseases such as growth hormone defi-
levels are normal in patients with Stage 4 CKD—a minimal
ciency but not yet been studied in ESRD. A randomized
reduction is seen in the end-stage renal disease.64 Factors
controlled trial named OPPORTUNITY™, published by Kopple
causing growth hormone resistance in patients with CKD
et al., which was terminated early due to slow patient re-
are shown in Figure 5.64 Some researchers argue that
cruitment, evaluated the effects of recombinant human
metabolic acidosis (common in most patients with CKD)
growth hormone (hGH) in stable haemodialysis patients.
deepens with increasing CKD stage and causes IGF-1 signal
Decreases in body weight, total bod fat, and C-reactive pro-
impairment.65
tein levels in the hGH group were demonstrated, while no
Growth hormone and sarcopenia difference was found in mortality, lean body mass, and se-
Sarcopenia is associated with decreased GH and IGF-1 levels. rum albumin level.70 In this context, studies including
Studies also suggest that the GH/IGF-1 axis increases muscle long-term data on the use of GH-based therapies for
mass but has no effect on muscle strength.66 sarcopenia in the CKD patient group are needed. We also
believe that its use with anti-inflammatory approaches
Growth hormone and sarcopenia in chronic kidney disease should be studied.
Growth hormone receptors are found in many tissues as well
as muscle. Metabolic acidosis, inflammation, reduced food in-
take, and uraemia are known to reduce the effectiveness of
GH. At the same time, unresponsiveness or resistance to Thyroid hormones
IGF-1 may occur in haemodialysis patients. Metabolic acido-
sis, hyperparathyroidism, inflammation, and signal transduc- Thyroid hormones and chronic kidney disease
tion are delayed after GH receptor activation. They can There is a very tight relationship between the thyroid and the
increase in IGF binding protein and its metabolites may ex- kidneys; their interactions with each other are uninterrupted
plain this phenomenon.67 and very important. Subclinical hypothyroidism and low T3
The GH/IGF-1 axis has an important place in the syndromes are more common in individuals with CKD than
aetiopathogenesis of sarcopenia in patients with CKD via in- in healthy individuals, via reduced Iodine clearance and
flammation. In a study of 139 hypoalbuminaemic chronic chronic inflammation.71 In a study of 510 CKD patients, hypo-
haemodialysis patients, human GH administration was rela- thyroidism and subclinical hypothyroidism were observed in
tively safe, increased lean body mass, and, most 10% and 14.9% of the cohort, respectively.72

Table 3 Relationship between vitamin D levels and sarcopenia in patients with CKD

N included Patient Study

Author Year in analyses characteristics CKD stage design Conclusions
Hoffmann 2016 60 18–80 y Stage 1–4 RCT Serum 25(OH)D concentrations were inversely
63
MR et al. associated with total mass, weight, appendicular
skeletal mass, and sarcopenia occurred more
frequently in patients with 25(OH)D concentrations
≥100 nmol/L
Zahed 2014 135 50–70 y HD RCT There was a significant relation between 25-OHD
61
et al. level and muscle force
Gordon 2012 26 50–75 y Stage 3–4 RCT Gait speed, distance walked in 6 min and
60
et al. sit-to-stand time were associated with serum
1,25OH2D values
CKD, chronic kidney disease; m, months; N, number; RCT, randomized controlled trial; T, testosterone; wk, week; y, years.

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DOI: 10.1002/jcsm.12839
 1353921906009, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jcsm.12839 by Charité - Universitaetsmedizin, Wiley Online Library on [07/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1388 O. Gungor et al.

Figure 5 Factors associated with growth hormone resistance in patients with chronic kidney disease.

Thyroid hormones and sarcopenia hormones makes any changes on muscle loss or not with clin-
Skeletal muscle is one of the main targets of thyroid hor- ical studies over a large number of sarcopenic CKD patients.
mones. T3 is crucial for muscle growth, contraction–relaxa- Removing the pressure on the mechanism enables conver-
tion cycles, energy provision, glucose homeostasis, and sion from peripheral T4 to T3 and may also be beneficial for
muscle damage repair.73 T3 accelerates Myh1-2-4 gene ex- sarcopenia in this patient group. Therefore, the putative ef-
pression while decreasing Myh7 gene expression.74 Intracel- fects of anti-inflammatory drugs through thyroid hormone
lular T3 levels are very important for muscle building.75 modulation on causing sarcopenia are another important re-
Smooth muscle mitochondrial functions can also be regulated search topic.
by T3. There are many studies in the literature evaluating the
effects of thyroid hormones on skeletal muscle. Muscle sur-
face area is smaller in elderly patients with subclinical hypo- Insulin resistance
thyroidism compared to euthyroid age-matched controls.76
When this group of patients is rendered euthyroid with treat- Insulin resistance and chronic kidney disease
ment, there is an improvement in both muscle strength and Chronic kidney disease patients develop insulin resistance
muscle surface area.77 (IR) from the earliest period even before GFR decline begins.
Although the cause of IR in this patient group is not known,
lack of physical activity, chronic inflammation, oxidative
Thyroid hormones and sarcopenia in chronic kidney disease stress, vitamin D deficiency, metabolic acidosis, anaemia,
Unfortunately, there is no clinical study about the net effects and unknown uraemic toxins have been suggested.78 IR also
of thyroid hormones on sarcopenia in patients with CKD. Low contributes to the progression of CKD.79
T3 syndrome is very common in this patient population, and
the association of T3 with the development of sarcopenia is Insulin resistance and sarcopenia
amorous. It is beneficial for patients to determine levels of The relationship between IR and sarcopenia may be more
thyroid hormones and whether replacement of these descriptive in the name of sarcopenic obesity. Sarcopenic

Journal of Cachexia, Sarcopenia and Muscle 2021; 12: 1380–1392

DOI: 10.1002/jcsm.12839
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Hormonal effects on sarcopenia in chronic kidney disease 1389

obesity describes a process characterized by fat accumula- directly increases Myo D—one of the key factors involved in
tion in skeletal muscle as discussed earlier. Skeletal muscle human skeletal muscle cells.85 Oestrogen deficiencies are as-
is an important organ in the regulation of serum glucose. sociated with the development of sarcopenia, and women
Therefore, there is a complex interaction between insulin who received oestrogen replacement in the postmenopausal
resistance and sarcopenia.80 period have been shown to have more muscle strength than
those who do not. However, comprehensive studies on this
Insulin resistance and sarcopenia in chronic kidney disease topic are needed to reach a clear conclusion about the rela-
Simply, IR reduces glucose utilization as an energy tionship between oestrogen and sarcopenia in CKD
source. It also increases hepatic gluconeogenesis, decreases population.86
muscle glucose uptake, and leads to impaired intracellular
glucose metabolism via phosphatidylinositol 3 kinase and Cortisol
protein kinase B pathways.81 Deger et al. evaluated the an- A slight increase in cortisol levels can be seen with ageing and
abolic effects of insulin in 33 HD patients and 17 healthy in CKD leading to an increase in protein degradation. This sit-
subjects including the evaluation of muscle biopsy. They uation has been linked to muscle atrophy. However, there are
showed that HD patients responded less to no comprehensive clinical studies on the subject.87
hyperinsulinaemia and amino acid infusion; they also dem-
onstrated that HD patients had impaired insulin sensitivity Dehydroepiandrosterone
markers and tissue mitochondrial biogenesis.82 The same Dehydroepiandrosterone (DHEA) levels are associated with
group showed that the IR indicator HOMA is associated muscle mass and strength and decrease with age and in
with muscle protein degradation in non-diabetic CKD. Higher DHEA levels in this group improve muscle mass
haemodialysis patients. and reduce falls in the elderly population, but no study has
Uchiyama et al. found that IR and sarcopenia were more yet investigated the relationship between DHEA levels and
prominent in mice with CKD in an experimental animal sarcopenia in patients with CKD.88
model. Disruption of the insulin-related signalling, mito-
chondrial dysfunction in the skeletal muscles, and a reduc-
tion in intestinal tight junction proteins and adipocyte cell
size were all observed.83 The authors suggested that
Acknowledgements
uraemic dysbiosis may induce IR; therefore, IR and
The authors certify that they comply with the ethical guide-
sarcopenia might also be a new pathway for targeting. De-
lines for publishing in the Journal of Cachexia, Sarcopenia
spite all this validity of old and new information, a new
and Muscle.89
treatment agent for IR has not yet been found in the pa-
tient group with CKD.

Conflict of interest
Other hormones
S. D. A. reports receiving fees from Abbott, Bayer, Boehringer
Ghrelin Ingelheim, Cardiac Dimension, Cordio, Impulse Dynamics,
Ghrelin is a hormone produced in the stomach fundus. Novartis, Occlutech, Servier, and Vifor Pharma, and grant
Ghrelin and its analogues increase nutrient intake and release support from Abbott and Vifor Pharma. K. K. Z. has received
GH via cyclic CMP/nitric oxide pathways. Due to its effects on honoraria and/or support from Abbott, AbbVie, ACI Clinical
appetite and nutritional deficiency and GH secretion, defi- (Cara Therapeutics), Akebia, Alexion, Amgen, Ardelyx,
ciency of this hormone increases the risk of developing Astra-Zeneca, Aveo, BBraun, Chugai, Cytokinetics, Daiichi,
sarcopenia. Ghrelin levels decrease in CKD and this has been DaVita, Fresenius, Genentech, Haymarket Media, Hospira,
associated with malnutrition–inflammation–anaemia syn- Kabi, Keryx, Kissei, Novartis, Pfizer, Regulus, Relypsa,
drome and metabolic acidosis. In CKD-associated cachexia, Resverlogix, Sandoz, Sanofi, Shire, Vifor, UpToDate, and ZS
new therapeutic approaches such as ghrelin agonists and Pharma. Other authors have no competing interests to
melanocortin receptor antagonists are promising and are cur- declare.
rently at an experimental level awaiting confirmation by RCTs
in these patients.84

Oestrogen Funding
In older women, muscle mass and strength decrease associ-
ated with the loss of oestrogen after menopause. Oestradiol None.

Journal of Cachexia, Sarcopenia and Muscle 2021; 12: 1380–1392

DOI: 10.1002/jcsm.12839
 1353921906009, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jcsm.12839 by Charité - Universitaetsmedizin, Wiley Online Library on [07/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1390 O. Gungor et al.

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