Introduction: Data on the role of irisin in vascular calcification in patients with end-stage renal diseases on regular dialysis are inconsistent, and the underlying mechanisms are not clearly defined. The present study was designed to explore the association of serum irisin with vascular stiffness and with the impact of well-established risk factors. Methods: The clinical study enrolled 52 hemodialysis (HD) and 15 continuous ambulatory peritoneal dialysis (PD) patients with an age of >18 years receiving dialysis therapy for >3 months. Patients who had major pathologies affecting carbohydrate, lipid, and bone metabolism and those who had acute cardiovascular events were excluded. Thirty-seven healthy subjects matched for age and sex served as controls. Routine biochemical parameters were measured in fasting serum samples by standard methods. Serum irisin was determined using the commercial ELISA kit (BioVendor Laboratory Medicine Inc., Brno, Czech Republic). Arterial stiffness parameters – carotid-femoral pulse wave velocity (cf PWV) and augmentation index (Aix) – were measured using applanation tonometry (SphygmoCor System; AtCor Medical, Sydney, Australia). Body composition was assessed by segmental bioelectric impedance (InBody 2.0; Biospace Co. Ltd., Seoul, Korea). Results: It was demonstrated that serum irisin levels were markedly depressed (p < 0.05), while the cf PWV significantly increased (p < 0.05) in HD/PD patients as compared to controls. Serum irisin proved to be independent of serum insulin, glucose, and HOMA-IR. However, it was inversely related to HbA1c (β = −0.544, p = 0.035), iPTH (β = −0.260, p = 0.035), and alkaline phosphatase (r = −0.325, p = 0.007). Furthermore, significant negative relationships were found of irisin to serum triglyceride and indices of body fat mass. Retrospective analysis at a follow-up period of 40 months revealed a direct relationship of irisin to all-cause mortality (p = 0.039). Conclusions: Our study demonstrated that serum irisin levels are reduced in uremic patients on regular HD/PD but failed to establish significant associations of irisin deficiency with vascular stiffness. However, the significant negative relationship of irisin to HbA1c, iPTH, and alkaline phosphatase suggests that it improves insulin sensitivity, inhibits bone resorption, mitigates bone-vascular interaction, and protects vascular function.

Irisin is a recently discovered myokine, an exercise-induced peptide hormone that consists of 212 amino acids. It is cleaved from its transmembrane protein precursor, fibronectin type III domain-containing protein 5, and secreted into circulation [1, 2]. The major source of irisin is the skeletal muscle, but the white adipose tissue, pancreas, cardiac muscle, and liver have also been identified as secretory tissues [3]. It functions to promote the browning of white adipose tissue and thus to enhance energy expenditure, as well as to improve insulin sensitivity in insulin-resistant states including obesity, diabetes mellitus type 2, metabolic syndrome, and polycystic ovary syndrome [4-8]. Furthermore, convincing pieces of evidence have been provided for the critical role of irisin in protecting the functional integrity of the vascular endothelium, in preventing vascular calcification, and also reducing cardiovascular mortality in clinical conditions when insulin resistance prevails [9-15]. Irisin has also been claimed to increase bone mass and mineral density of cortical tissue in disease-associated osteopenia [16]. It is achieved by promoting the expression of osteoblastic genes and by decreasing the expression of osteoblastic inhibitory genes and by reducing osteoclasts [17, 18].

The multiple functions of irisin have been widely studied in patients with end-stage renal diseases (ESRD). Although there have been some inconsistencies in the results, it appears to be well established that in ESRD patients, plasma irisin level is depressed [19-22], and it is related to insulin resistance and plasma lipid profile, as well as to estimated body composition. Importantly, irisin deficiency has been shown to contribute to the development of endothelial dysfunction, vascular calcification, and pathologic bone metabolism [23].

The present study was designed to further explore the cardiometabolic effects of irisin in ESRD patients receiving regular peritoneal dialysis (PD) or hemodialysis (HD). Specifically, (a) the impact of irisin on traditional markers of uremia, insulin resistance, and lipid profile was determined. (b) The association of serum irisin levels with vascular status of the patients as assessed by arterial stiffness was studied. (c) Bioimpedance analysis of body composition including bone mineral density was also performed, and the results were evaluated as a function of serum irisin. (d) The cross-sectional design allowed us to analyze retrospectively the effects of irisin on all-cause mortality during the follow-up period of 40 months.

Subjects

This cross-sectional clinical study enrolled 52 HD and 15 continuous ambulatory PD patients in the FMC Dialysis Center, Pécs, in November 2018. The patients had an age of >18 years and received dialysis treatment for >3 months. The exclusion criteria were as follows: diabetes mellitus, autoimmune or active inflammatory diseases, primary endocrinopathies, acute cardiovascular events, pathologies affecting the central nervous or musculoskeletal systems, malignancies, and advanced liver diseases. HD was performed as hemodiafiltration by using Fresenius 5008 equipment with the Helixone/Fresenius polysulfone high-flux dialyzer membrane, 3 times weekly in 240-min long sessions. Continuous ambulatory PD patients had 2-L fluid exchanges 4 times per day. Thirty-seven healthy individuals matched for age and sex served as controls.

The study complied with principles laid down by the Declaration of Helsinki and was approved by the Local Ethics Committee at the University of Pécs. Written informed consent was provided by all participants.

Laboratory Measurements

Routine biochemical parameters were measured by standard methods. Fasting blood samples were collected in vacuum tubes without anticoagulants. Following centrifugation, serum was separated and stored at −80°C until analysis. Serum irisin concentrations were determined using commercial ELISA kits manufactured by BioVendor Laboratory Medicine Inc., Brno, Czech Republic. The intra- and interassay coefficients of variation were <5 and 15%, respectively. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated according to the following formula: fasting serum insulin (mU/L) × fasting serum glucose (mmol/L)/22.5. Insulin resistance was assessed by the model of HOMA-IR (FPI × FPG/22.5) and the β-cell function by the model of HOMA-β (20 × FPI/FPG − 3.5) where FPI = fasting plasma insulin (mU/L) and FPG = fasting plasma glucose (mmol/L) concentrations [24].

Blood Pressure and Pulse Wave Velocity

Blood pressure was measured using calibrated automated devices with appropriate cuff sizes. The results presented here are predialysis values. Pulse pressure and mean arterial pressure were calculated.

Carotid-femoral pulse wave velocity (cf PWV) and augmentation index (Aix) were measured using applanation tonometry (SphygmoCor System; AtCor Medical, Sydney, Australia). Measurements were performed before HD session in the supine position after at least 10-min rest in a quiet, temperature-controlled room. Pulse wave recording was performed consecutively at 2 superficial artery sites (carotid-femoral segment). The cf PWV was calculated.

Body Composition

Body composition measurements were performed only in patients receiving HD or PD treatment by segmental bioelectric impedance using 8 tactile electrodes according to the manufacturer’s instruction (InBody 2.0; Biospace Co. Ltd., Seoul, Korea). The measured parameters were fat tissue mass (kg and %) lean body, mass (kg), muscle mass (kg), and bone mineral content (%).

Statistical Analysis

Statistical analyses were performed using SPSS 21.0 software (SPSS, Inc., Chicago, IL, USA). Normality of data distribution was tested by the Kolmogorov-Smirnov test. Nonnormally distributed parameters were transformed logarithmically. Comparison of clinical and laboratory parameters was made by Student’s t test and ANOVA as appropriate. Data were expressed as mean ± SD in case of normal distribution. Correlations between continuous variables were assessed by linear regression using Pearson’s test. Values of p < 0.05 were considered statistically significant. The force of irisin for predicting all-cause mortality within the follow-up period was determined using receiver operating characteristic (ROC) curve analysis.

The major clinical and laboratory characteristics of HD/PD patients and those of healthy control subjects are summarized in Table 1. It is shown that hemoglobin, serum iron, total protein, albumin, and HDL-cholesterine levels are significantly lower, whereas serum levels of creatinine, phosphate, and the calcium-phosphate product are significantly higher in uremic patients as compared with healthy individuals. It is to be stressed that no significant differences can be detected between the 2 groups in serum insulin and glucose levels and in the HOMA-IR and HOMA-β values. However, HbA1c and serum irisin levels were markedly depressed in uremic patients irrespective of HD or PD therapy. With respect to the cardiovascular function systolic blood pressure, mean arterial pressure and cf PWV were significantly higher in HD/PD patients than those in healthy controls. Analysis of body composition revealed no significant differences in fat-free mass, muscle mass, and bone mineral content between HD/PD patients and control subjects. Conversely, fat mass expressed either in percent of body weight or in its absolute amount (kg) decreased significantly in HD/PD patients as compared with healthy controls (p < 0.05) supporting the contention that the fat tissue may serve as an important source of irisin in patients with uremia. There were no discernible differences in body composition between the HD and PD groups.

Table 1.

The major clinical and laboratory characteristics of patients receiving regular HD/PD and healthy control subjects

The major clinical and laboratory characteristics of patients receiving regular HD/PD and healthy control subjects
The major clinical and laboratory characteristics of patients receiving regular HD/PD and healthy control subjects

In an attempt to reveal the involvement of irisin in the development of vascular stiffness, irisin levels were analyzed as a function of markers of vascular stiffness (cf PWV and Aix) and that of various risk factors. Analyses were done separately in the HD and PD groups and also in a single group where all patients were considered together (HD + PD). Significant inverse relationships were found between irisin and alkaline phosphatase in each group (r = −0.30, p < 0.03, for HD; r = −0.60, p < 0.018, for PD; and r = −0.32, p < 0.007, for HD + PD patients). iPTH was also inversely related to irisin when all patients (HD + PD) were considered (r = −0.257, p < 0.036). In the HD group, irisin positively correlated with prealbumin levels and dialysis vintage (r = 0.28, p < 0.043, and r = 0.35, p < 0.01, respectively). Patients of the PD group had significant negative relationships of irisin to HbA1c (r = −0.703, p < 0.003), triglyceride levels (r = −0.529, p < 0.043), fat tissue index (r = −0.662, p < 0.01), and body fat content expressed either in kg (r = −0.767, p < 0.001) or in percent body weight (r = −0.546, p < 0.035). Importantly, irisin had also negative impact on HbA1c in the HD + PD group (Table 2).

Table 2.

Correlation analysis of serum irisin with clinical and laboratory parameters in ESRD patients on regular HD and PD

Correlation analysis of serum irisin with clinical and laboratory parameters in ESRD patients on regular HD and PD
Correlation analysis of serum irisin with clinical and laboratory parameters in ESRD patients on regular HD and PD

In search for independent predictors of irisin, the multiple linear regression model was established. After adjustments for potential confounders, serum iPTH (β = −0.260, t = −2.153, p < 0.035) in the HD + PD group and HbA1c (β = −0.544, t = −2.340, p < 0.036) in the PD group proved to be independent predictors of cf PWV (Table 3).

Table 3.

Multiple linear regression analysis of independent predictor of irisin in ESRD patients on regular HD and PD (panel A) and on PD (panel B)

Multiple linear regression analysis of independent predictor of irisin in ESRD patients on regular HD and PD (panel A) and on PD (panel B)
Multiple linear regression analysis of independent predictor of irisin in ESRD patients on regular HD and PD (panel A) and on PD (panel B)

Based on ROC analysis, the cutoff value for irisin was determined at 4.0 ng/mL with a sensitivity of 93.3% and a specificity of 44.2% for predicting all-cause mortality within the study period. The area under the ROC curve proved to be 0.676 (p = 0.039; 95% CI: 0.540–0.811). The survival of our patients having an irisin level of <4 ng/mL was significantly better (p = 0.018) than those having an irisin level of ≥4 ng/mL (Fig. 1).

Fig. 1.

Cumulative survival of dialysis patients having serum irisin levels of <4 or ≥4 ng/mL.

Fig. 1.

Cumulative survival of dialysis patients having serum irisin levels of <4 or ≥4 ng/mL.

Close modal

The present study demonstrated that serum irisin levels were markedly depressed while cf PWV, a marker of vascular stiffness, was elevated in PD/HD patients when compared to healthy controls. Serum irisin appeared to be independent of serum insulin, glucose, HOMA-IR, and HOMA-β, the measures of actual insulin sensitivity. However, it was inversely related to HbA1c providing indirect evidence that over a period of about 3 months, irisin improved insulin resistance. Moreover, our study revealed significant negative relationship of irisin to iPTH and alkaline phosphatase suggesting that it inhibits bone resorption, mitigates bone-vascular interaction, and protects endothelial/vascular function.

Clinical and experimental studies have shown that insulin plays an important role in the control of endothelial function [25, 26]. It operates in 2 opposite ways. On the one hand, it is vasoprotective, stimulates endothelial NO generation by activating the phosphoinosi-tide 3-kinase (PI3-K)-AKT pathway that induces the expression and activation of eNOS. On the other hand, it activates the mitogen-activated protein kinase (MAPK)-dependent signaling pathway that regulates the secretion of vasoconstrictor endothelin-1 (ET-1). Under physiological conditions, these opposing endothelial effects of insulin are in balance. However, in pathologies associated with insulin resistance, insulin signaling is directed toward the MAPK-ET-1 pathway, whereas the PI3-K-NO pathway is markedly reduced. This imbalance may lead to endothelial dysfunction characteristic for insulin-resistant states and may progress to remodeling of the vascular wall and atherosclerotic lesions [27, 28].

Oxidative and inflammatory stress may contribute to the predominance of the MAPK-ET-1 over PI3-K-Akt-NO pathway. It is of particularly relevant to patients receiving renal replacement therapy who encounter high levels of reactive oxygen species and pro-inflammatory molecules [29].

Irisin improves insulin resistance and directly protects the functional integrity of the endothelium via the AMPK-Akt-eNOS-NO pathway [11]. The impact of irisin on fasting glucose levels is a matter of debate. Although some authors have described no association between the 2 variables in diabetic patients [30], others have found positive (healthy women, obesity, metabolic syndrome, polycystic ovary syndrome, and PD patients) [4, 6, 7, 31-33] or even inverse associations (PD and HD patients) [33, 34], respectively. The positive correlation of irisin with fasting blood glucose is regarded as indicative of an adaptive increase of irisin to overcome insulin resistance prevalent in various pathologies [8]. The reduction of HbA1c with increasing irisin levels appears to challenge this adaptive irisin reaction. However, it can also be interpreted as indicating that this mechanism functions effectively, and irisin may control the HbA1c-related integrated blood glucose in metabolic syndrome [6] and in nondiabetic ESRD patients receiving renal replacement therapy as it was shown in the present study.

In addition to improving insulin resistance, irisin promotes the number and function of endothelial progenitor cells via the PI3-K/Akt/eNOS pathway [9]; therefore, the significant reduction in irisin levels in HD and PD patients certainly contributes to endothelial dysfunction, the early stage of uremic vasculopathy. Endothelial dysfunction may progress to vascular stiffness and calcification by stimulating myofibroblast proliferation and differentiation with enhanced synthesis of collagen and other extracellular matrix proteins and by triggering and amplifying inflammatory responses [35]. Vascular calcification is an active cell-mediated process that includes (a) transformation of vascular smooth muscle cells (VSMCs) to osteoblast/chondrocyte-like cells, (b) increased uptake of calcium and phosphate by the VSMCs, (c) apoptotic cell death, (d) release of VSMC-derived vesicles, and (e) deficiency of circulating or local calcification inhibitors [36]. Vascular stiffness is a clinical marker of arteriosclerotic lesion and an independent predictor of fatal and nonfatal cardiovascular events in the general population and in patients with hypertension, diabetes mellitus, and ESRD [37]. Recent studies indicate that impaired bone metabolism and the dysfunction of the bone-vascular axis may also have an important role in the development of vascular calcification [38]. Namely, bone loss and low bone mineral density is associated with increased vascular calcification and with increased cardiovascular events [39, 40]. The involvement of irisin in the control of bone metabolism and vascular health has also been established. In support of this notion, serum irisin levels were inversely associated with prevalence and progression of coronary artery calcification [15], carotid intima-media thickness [41], and abdominal aortic calcification in patients on regular PD and HD [21, 22].

Experimental evidence has been provided for the bone-related vasculoprotection by irisin. Notably, the metabolic actions of irisin on the skeleton have been documented by showing that recombinant irisin administration increases cortical bone mass, tissue mineral density, periosteal circumference, and strength. These actions were accounted for by osteoblast formation and proliferation with concomitant reduction in the number of osteoblasts. The authors have also explored the basic underlying molecular mechanisms, upregulation of pro-osteoblastic genes and transcription factors and diminished osteoblast inhibitors [17].

Surprisingly, in the present study, we could not detect association between vascular stiffness and markers of bone metabolism, but consistent with the observations by He et al. [22], the inverse relationship of irisin to serum levels of alkaline phosphatase and iPTH could be established suggesting that irisin simultaneously inhibits bone resorption and protects against vascular calcification. The inverse relationship between irisin and PTH has been recently confirmed by Palermo et al. [42]. These authors have demonstrated that PTH treatment markedly reduced the mRNA expression for irisin in cultured myotube cells, and conversely, irisin treatment downregulated PTH mRNA expression in osteoblasts. Furthermore, significantly lower serum irisin concentrations have been detected in postmenopausal women with primary hyperparathyroidism than in the age/BMI-matched control subjects who did not experience impaired calcium/phosphate metabolism.

In this regard, it is of worth noting that in a previous study, we have demonstrated that in HD patients, the bone-specific protein osteocalcin, as a dependent variable, was negatively associated with cf PWV, a measure of vascular stiffness. Such association was not found in case of osteopontin and osteoprotegerin when adjustments were made for relevant confounders [43].

Interestingly, the present study showed that the higher baseline serum irisin concentrations were paradoxically associated with higher mortality raising the possibility that the elevation of serum irisin levels is an adaptive reaction to the progression of uremic state to mitigate further worsening of the patients’ condition. These observations are consistent with those of Chiang et al. [44] who have reported inverse association of serum irisin with mortality in uremic patients on HD claiming that it might be due to inflammation indicated/mediated by increased levels of interleukin 6.

Our study has certain limitations: the patient number is relatively small, and the population is not homogenous regarding the primary kidney disease. On the other hand, the basic design of our study is cross-sectional.

In conclusion, our study confirmed previous observations that serum irisin levels are reduced in uremic patients on regular HD/PD. Furthermore, we failed to establish significant association of irisin with vascular stiffness; however, by demonstrating its independent negative impact on iPTH, alkaline phosphatase, and HbA1c, we provided indirect evidence for its vasculoprotective role. It is most likely achieved by inhibiting bone resorption and improving insulin sensitivity.

We thank Professor Tamás Kőszegi and his colleagues for performing ELISA measurements. We would also like to thank Dr. Szilárd Kun for his help in the statistical evaluations and Gábor Borbély for his help in performing bioimpedance parameter measurements.

The study complied with principles laid down by the Declaration of Helsinki and was approved by the Local Ethics Committee at the University of Pécs (Regional Ethics Committee of the Clinical Center, University of Pécs, 27/2017). Written informed consent was provided by all participants.

The authors do not have any conflicts of interest to declare.

The current research was funded by the Doctoral School of Health Sciences, University of Pécs.

B. Csiky designed the protocol, managed the clinical study, and prepared the manuscript with E. Sulyok. V. Emmert contacted the patients, obtained their informed consent, and performed the applanation tonometry. B. Sági collected all the data needed for the study and performed the statistical evaluation. I. Wittmann revised the manuscript.

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

1.
Bostrom
P
,
WU
J
,
Jedrychowski
MP
,
Korde
A
,
Ye
l
,
Lo
JC
,
A PGC1-alpha-dependent myokine that drives brown fat-like development of white fat and thermogenesis
.
Nature
.
2012
;
481
:
463
8
.
2.
Chen
N
,
Li
Q
,
Liu
J
,
Jia
S
.
Irisin, an exercise-induced myokine as a metabolic regulator: an updated narrative review
.
Diabetes Metab Res Rev
.
2016
;
32
:
51
9
. .
3.
Aydin
S
.
Three new players in energy regulation: preptin, adropin and irisin
.
Peptides
.
2014
;
56
:
94
110
. .
4.
Pardo
M
,
Crujeiras
AB
,
Amil
M
,
Aguera
Z
,
Jiménez-Murcia
S
,
Baños
R
,
Association of irisin with fat mass, resting energy expenditure, and daily activity in conditions of extreme body mass index
.
Int J Endocrinol
.
2014
;
2014
:
857270
. .
5.
Kurdiova
T
,
Balaz
M
,
Vician
M
,
Maderiva
D
,
Vlcek
M
,
Valkovic
L
,
Effects of obesity, diabetes and exercise on Endc 5 gene expression and irisin release in human skeletal muscle and adipose tissue: in vivo and in vitro studies
.
J Physiol
.
2014
;
592
:
1091
107
.
6.
Yan
B
,
Shi
X
,
Zhang
H
,
Pan
L
,
Ma
Z
,
Liu
S
,
Association of serum irisin with metabolic syndrome in obese Chinese adults
.
PLoS One
.
2014
;
9
(
4
):
e94235
. .
7.
Wang
W
,
Guo
Y
,
Zhang
X
,
Zheng
J
.
Abnormal irisin level in serum and endometrium is associated with metabolic dysfunction in polycystic ovary syndrome patients
.
Clin Endocrinol
.
2018
;
89
:
474
80
. .
8.
Munoz
IYM
,
Romero
ESC
,
Garcia
JJG
.
Irisin a novel metabolic biomarkers: knowledge and future directions
.
Int J Endocrinol
.
2018
;
78
:
6806
.
9.
Song
H
,
Wu
F
,
Zhang
Y
,
Zhang
Y
,
Wang
F
,
Jiang
M
,
Irisin promotes human umbilical vein endothelial cell proliferation through the ERK signaling pathway and partly suppresses high glucose-induced apoptosis
.
PLoS One
.
2014
;
9
(
10
):
e110273
. .
10.
Zhu
G
,
Wang
J
,
Song
M
,
Zhou
F
,
Fu
D
,
Ruan
G
,
Irisin increased the number and improved the function of endothelial progenitor cells in diabetes mellitus mice
.
J Cardiovasc Pharmacol
.
2016
;
68
:
67
73
. .
11.
Han
F
,
Zhang
S
,
Hou
N
,
Wang
D
,
Sun
X
.
Irisin improves endothelial function in obese mice through the AMPK-eNOS pathway
.
Am J Physiol Heart Circ Physiol
.
2015
;
309
:
H1501
8
. .
12.
Aronis
KN
,
Moreno
M
,
Polyzos
SA
,
Moreno-Navarrete
JM
,
Ricart
W
,
Delgado
E
,
Circulating irisin levels and coronary heart disease: association with future acute coronary syndrome and major adverse cardiovascular events
.
Int J Obes
.
2015
;
39
:
156
61
. .
13.
Fu
J
,
Han
Y
,
Wang
J
,
Liu
Y
,
Zeng
S
,
Zhou
,
Irisin lowers blood pressure by improvement of endothelial dysfunction via AMPK-Akt-eNOS-NO pathway in spontaneously hypertensive rat
.
J Am Heart Assoc
.
2016
;
5
:
e003433
.
14.
Shen
S
,
Gao
R
,
Bei
Y
,
Li
J
,
Zhang
H
,
Zhou
Y
,
Serum irisin predicts mortality risk in acute heart failure patients
.
Cell Physiol Biochem
.
2017
;
42
:
615
22
. .
15.
Hisamatsu
T
,
Miura
K
,
Arima
H
,
Fujiyoshia
A
,
Kadota
R
,
Kadowaki
S
,
Relationship of serum irisin levels to prevalence and progression of coronary artery calcification. A prospective, population-based study
.
Int J Cardiol
.
2018
;
267
:
177
82
.
16.
Palermo
A
,
Strollo
R
,
Maddaloni
E
,
Tuccinardi
D
,
D’Onofrio
L
,
Briganti
SI
,
Irisin is associated with osteoporotic fractures independently of bone mineral density, body composition or daily physical activity
.
Clin Endocrinol
.
2015
;
82
:
615
9
. .
17.
Colainanni
G
,
Cuscito
C
,
Mongelli
T
,
Pignatano
P
,
Buccoliero
C
,
Lin
P
,
The myokine irisin increases cortical bone mass
.
Proc Natl Acad Sci U S A
.
2015
;
112
:
12157
162
.
18.
Qiao
X
,
Yong Qiao
X
,
Nie
Y
,
Ma
Y
,
Xian Ma
Y
,
Chen
Y
,
Irisin promotes osteoblast proliferation and differentiation via activating the MAP kinase signaling pathways
.
Sci Rep
.
2016
;
6
(
1
):
18732
. .
19.
Wen
MS
,
Wang
CY
,
Lin
SL
,
Hung
KC
.
Decrease in irisin in patients with chronic kidney disease
.
PLoS One
.
2013
;
8
(
8
):
e64025
. .
20.
Morales
C
,
Leal
VO
,
Marinho
SM
,
Barroso
SG
,
Rocha
GS
,
Boaventura
GT
,
Resistance exercise training does not affect plasma irsisin levels of hemodialysis patients
.
Horm Metab Res
.
2013
;
45
:
900
4
.
21.
Lee
MJ
,
Lee
SA
,
Nam
BY
,
Park
S
,
Lee
SH
,
Ryu
HJ
,
Irisin, a novel myokine is an independent predictor for sarcopenia and carotid atherosclerosis in dialysis patients
.
Atherosclerosis
.
2015
;
242
:
476
82
. .
22.
He
L
,
He
WY
,
A
LT
,
Yang
WL
,
Zhang
AH
.
Lower serum irisin levels are associated with increased vascular calcification in hemodialysis patients
.
Kidney Blood Press Res
.
2018
;
43
(
1
):
287
95
. .
23.
Lu
J
,
Xiang
G
,
Liu
M
,
Mei
W
,
Xiang
L
,
Dong
J
.
Irisin protects against endothelial injury and ameliorates atherosclerosis in apolipoprotein E-null diabetic mice
.
Atherosclerosis
.
2015
;
243
:
438
48
. .
24.
Wallace
TM
,
Levy
JC
,
Matthews
DR
.
Use and abuse of HOMA modeling
.
Diabetes Care
.
2004
;
27
:
1487
95
. .
25.
DeFronzo
RA
,
Ferrannini
E
.
Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease
.
Diabetes Care
.
1991
;
14
:
173
94
. .
26.
Muniyappa
R
,
Montagnani
M
,
Koh
KK
,
Quon
MJ
.
Cardiovascular actions of insulin
.
Endocr Rev
.
2007
;
28
:
463
91
. .
27.
Muniyappa
R
,
Sowers
JR
.
Role of insulin resistance in endothelial dysfunction
.
Rev Endocr Metab Disord
.
2013
;
14
:
5
12
. .
28.
Janus
A
,
Szahidewicz-Krupska
E
,
Mazur
G
,
Doroszko
A
.
Insulin resistance and endothelial dysfunction constitute a common therapeutic target in cardiometabolic disorders
.
Mediators Inflamm
.
2016
;
2016
:
3634948
. .
29.
Sági
B
,
Peti
A
,
Lakatos
O
,
Gyimesi
T
,
Sulyok
E
,
Wittmann
I
,
Pro- and anti-inflammatory factors, vascular stiffness and outcomes in chronic hemodialysis patients
.
Physiol Int
.
2020
;
107
:
256
66
. .
30.
Timmons
JA
,
Baar
K
,
Davidsen
PK
,
Atherton
PJ
.
Is irisin a human exercise gene?
Nature
.
2012
;
488
:
E9
10
. .
31.
Huh
JY
,
Panagiotou
G
,
Mougios
V
,
Brinkoetter
M
,
Vamvini
MT
,
Schneider
BE
,
FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise
.
Metabolism
.
2012
;
61
:
1725
38
. .
32.
Fukushima
Y
,
Kurose
S
,
Shinno
H
,
Cao Thi Thu
H
,
Tamanoi
A
,
Tsutsumi
H
,
Relationships between serum irisin levels and metabolic parameters in Japanese patients with obesity
.
Obes Sci Pract
.
2016
;
2
:
203
9
. .
33.
Park
KH
,
Zaichenko
L
,
Brinkoetter
M
,
Thakkar
B
,
Sahin-Efe
A
,
Joung
KE
,
Circulating irisin in relation to insulin resistance and the metabolic syndrome
.
J Clin Endocrinol Metab
.
2013
;
98
:
4899
907
. .
34.
Tan
Z
,
Ye
Z
,
Zhang
J
,
Chen
Y
,
Cheng
C
,
Wang
C
,
Serum irisin levels correlated to peritoneal dialysis adequacy in nondiabetic peritoneal dialysis patients
.
PLoS One
.
2017
;
12
:
e0176137
.
35.
Li
PL
.
Cardiovascular pathology of inflammasomes: inflammatory mechanism and beyond
.
Antiox Redox Signal
.
2015
;
22
:
1079
83
.
36.
Jasins
S
,
Khera
R
,
Corrales-Medina
VF
,
Townsend
,
Chirions
JA
.
Inflammation and arterial stiffness in humans
.
Atherosclerosis
.
2014
;
237
:
381
90
.
37.
Vlachopoulos
C
,
Aznaouridis
K
,
Stefanadis
C
.
Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis
.
J Am Coll Cardiol
.
2010
;
55
:
1318
27
. .
38.
Evards
S
,
Delayane
P
,
Kamel
S
,
Cristol
JP
,
Cavalier
E
.
Vascular calcification: from pathophysiology to biomarkers
.
Clin Chim Acta
.
2015
;
438
:
401
14
.
39.
Shroff
RC
,
Shanahan
CM
.
Vascular calcification in patients with kidney disease: the vascular biology of calcification
.
Semin Dial
.
2007
;
20
:
103
9
.
40.
Vasalle
C
,
Mazzone
A
.
Bone loss and vascular calcification: a bi-directional interplay?
Vascul Pharmacol
.
2016
;
86
:
77
86
.
41.
Icli
A
,
Cure
E
,
Cure
MC
,
Uslu
AU
,
Balta
S
,
Arslan
S
,
Novel myokine: irisin may be an independent predictor for subclinic atherosclerosis in Behcet’s disease
.
J Invest Med
.
2016
;
64
:
875
81
.
42.
Palermo
A
,
Sanesi
L
,
Colaianni
G
,
Tabacco
G
,
Naciu
AM
,
Cesareo
R
,
A novel interplay between irisin and PTH: from basic studies to clinical evidence in hyperparathyroidism
.
J Clin Endocrinol Metab
.
2019
;
104
(
8
):
3088
96
. .
43.
Csiky
B
,
Sági
B
,
Peti
A
,
Lakatos
O
,
Prémusz
V
,
Sulyok
E
.
The impact of osteocalcin, osteoprotegerin and osteopontin on arterial stiffness in chronic renal failure patients on hemodialysis
.
Kidney Blood Press Res
.
2017
;
42
(
6
):
1312
21
. .
44.
Chiang
JM
,
Delgado
C
,
Kaysen
GA
,
Segal
MR
,
Chertow
GM
,
Johansen
KL
.
Correlates and consequences of high serum irisin concentration in patients on hemodialysis: a longitudinal analysis
.
J Ren Nutr
.
2020
;
28
:
S1051
2276
. .

Additional information

Botond Csiky and Balázs Sági contributed equally.

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