Lower serum irisin levels are associated with the increasing mortality of cardiovascular and cerebrovascular diseases in hemodialysis patients

Introduction

Irisin is a recently discovered myokine/adipokine composed of 112 amino acid and a product of fibronectin type III domain 5 (FNDC5) cleavage (1). It could drive brown-fat-like conversion of white fat and increase energy expenditure. Studies have proved that irisin was involved in many metabolic diseases such as obesity, type 2 diabetes, nonalcoholic fatty liver disease and polycystic ovary syndrome (PCOS) (2). Additionally, lower irisin levels were also associated with cardiovascular disease (CVD) (3-5) and cerebrovascular disease (6,7), especially with their adverse outcomes in general population. Patients with chronic kidney disease (CKD) have a higher prevalence of cardiovascular and cerebrovascular diseases (CCVD) (8). CVD is the leading cause of deaths in patients with end-stage renal disease (ESRD) (9). Besides, the stroke risk in patients with CKD was also proved to have a graded and independent association with estimated glomerular filtration rate (eGFR) (10,11). Recently, accumulating evidences have shown that decreasing irisin serum concentrations in parallel with the increasing CKD stage can predict kidney function (12). Furthermore, He and Wen et al. also reported that the circulating irisin levels were significantly decreased in CKD and hemodialysis (HD) patients (13,14). The reason why patients with CKD or undergoing renal replacement therapy have lower irisin levels could be attributed to persistent protein energy wasting (PEW) in CKD which is caused by metabolic acidosis, inflammation, increased angiotensin II level, abnormal appetite regulation (15,16) and results in striking loses of muscle proteins and skeletal muscle wasting and atrophy (17). Taken together, we hypothesized that decreased irisin levels may increase the risk of CCVD mortality in HD patients. In this research, we performed a retrospective cohort study with Chinese HD patients. We aimed at investigating the association of serum irisin with CCVD mortality. We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/apm-21-406).

Methods

Subjects

This retrospective cohort study was to investigate the relationship between irisin and CCVD mortality in HD patients. Participants were excluded if: (I) their age is under 18; (II) they had initiated HD for less than 3 months. Inclusive criteria were as follow: (I) age over 18; (II) initiated HD time over three months; (III) agree to participate this study.

From January to May 2014, 170 patients had received HD in our hospital, 152 of them were consecutively enrolled according to inclusive and exclusive criteria and were followed by the end of December 2019. The patients enrolled who had a history of cardiovascular/cerebrovascular diseases were all at stable state. Besides, we compared the irisin levels of patients with and without a history of cardiovascular/cerebrovascular diseases, the result didn’t show any statistical significance (data not shown). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of our hospital (No. [2019]130), and individual consent for this retrospective analysis was waived.

Data collection

Demographic and clinical data including age, sex, HD vintage were collected. All the laboratory data such as hemoglobin, serum creatinine, urea nitrogen, uric acid, glucose, phosphorus, calcium, albumin, intact parathyroid hormone (iPTH), lipid profile, ultra-sensitive C reactive protein (usCRP), etc. were collected at baseline. Fractional urea clearance (Kt/V urea) was calculated by Daugirdas formula.

Measurement of serum irisin

Blood samples were collected after fasting for at least 8 hours before HD using vacuum tubes without anticoagulant. Then they were centrifuged and the serum was separated and stored at −80 °C until analysis. Serum irisin was measured using enzyme linked immunosorbent assay (ELISA) kits (Phoenix Pharmaceuticals, USA). Inter- and intra-assay coefficients of variation were less than 15% and less than 10%, respectively.

End point event definition

All-cause deaths were defined as the deaths of CCVD, cancer or malignant tumor, infectious diseases or other causes (liver necrosis, malnutrition), CCVD deaths were defined as deaths of coronary heart disease, congestive cardiac failure, cardiac sudden death, cerebro infarction or cerebro hemorrhage.

Statistical analysis

Results were expressed as proportions for categorical variables, means ± standard deviation (SD) for continuous variables with normal distributions, and medians (range) for continuous variables with non-normal distributions. The Student’s t-test was employed to compare differences between the two groups for normally distributed data, while the Mann-Whitney U test was used for non-normal data. Categorical data were compared using the Chi-square test. Kaplan-Meier methods were used to estimate cumulative mortality of CCVD. The differences between the survival curves were compared by log-rank test. We selected variables that were statistically significant (P<0.05) in the comparisons of baseline irisin and other parameters between HD patients CCVD/all-cause death and survival HD patients as covariates for the multivariable analysis (Cox regression analysis) of all-cause mortality or CCVD mortality. Additionally, we confirmed that the covariates we included didn’t have multicollinearity. SPSS version 23.0 was used for statistical analysis, all analyses were two-tailed, and a P value <0.05 was defined as the threshold of statistical significance.

Results

Baseline characteristics of subjects

This study consisted of 152 HD patients. The mean of follow-up period was 52.58±20.64 (months). The primary renal diseases were composed of chronic glomerulonephritis (43 patients), diabetic kidney disease (DKD) (30 patients), hypertensive glomerulosclerosis (15 patients), other diseases such as chronic interstitial nephritis and systemic lupus erythematosus (27 patients) and renal diseases with unknown causes (37 patients). Of the 152 patients, 47 had a history of cardiovascular/cerebrovascular diseases and 105 didn’t. The baseline demographic and clinical characteristics are shown in Table 1. Besides, to confirm the baseline characteristics of patients with high and low levels of irisin didn’t have statistical significance which may influence the results, we stratified the patients by the median value of irisin concentrations (50.09 ng/mL) into two groups and compared their baseline characteristics. The result showed that there wasn’t any significant difference between the two groups (see Table 2).

Table 1 Baseline demographic and clinical characteristics in hemodialysis patients
Full table

Table 2 Comparison of baseline characteristics in patients stratified by high and low levels of serum irisin
Full table

Comparison of irisin and other parameters between HD patients of all-cause death and survival HD patients

Among all HD patients, 55 patients died and 97 HD patients survived. Compared with the survival group, the dead patients had older age, higher systolic pressure and significantly lower levels of serum creatinine, uric acid, phosphate, albumin, LDL-C, triglycerides and total cholesterol. However, the serum irisin levels in the two groups had no significant difference (see Table 3).

Table 3 Comparison of baseline irisin and other parameters in patients of all-cause death and survival HD patients
Full table

Comparison of baseline irisin and other parameters in HD patients died of CCVD and survival HD patients

Of the 152 HD patients, 18 patients died of CCVD and 97 HD patients survived. As shown in Table 4, compared to the survival patients, the HD patients died of CCVD had significantly lower levels of serum irisin [23.6 (2.2, 319.4) ng/mL vs. 45.7 (2.1, 367.8) ng/mL, P<0.05]. Additionally, there were more female patients in the patients died of CCVD, and they also had older age, lower hemoglobin, serum creatinine, phosphate and higher systolic pressure. Not surprisingly, patients who had a history of CCVD also presented higher risk of CCVD death. However, there was no significance in HD vintage, KT/V urea, serum urea, uric acid, calcium, albumin, glucose, lipids and iPTH in both groups.

Table 4 Comparison of baseline irisin and other parameters in HD patients died of CCVD and survival HD patients
Full table

Comparison of CCVD mortality with different levels of serum irisin by Kaplan-Meier survival analysis

The irisin levels revealed a nonnormal distribution and 50.09 ng/mL was the median. Therefore, the median value was selected as a cut-off. The Kaplan-Meier survival curves showed that the mortality in patients with irisin ≤50.9 ng/mL was significantly higher than that in the patients with irisin >50.09 ng/mL (P<0.05) (see Figure 1).

Figure 1 Comparison of CCVD mortalities with different irisin levels by Kaplan-Meier survival analysis. The Kaplan-Meier curve showed that during the follow-up time, the serum irisin levels higher than 50.9 ng/mL had a higher cumulatively survival rate of CCVD. CCVD, cardiovascular and cerebrovascular diseases.

Independent determinant factors for CCVD mortality by Cox regression analysis

From our statistical analysis, we found that irisin levels revealed a nonnormal distribution and 50.09 ng/mL was the median. Furthermore, we verified that the median value could predict CCVD mortality by Kaplan-Meier survival curves. Therefore, we used irisin >50.09 vs. ≤50.09 ng/mL as a dichotomous variable in the Cox models. Besides, we also selected variables that were statistically significant in Table 4 and employed Cox regression analysis to find determinant factors for CCVD mortality (P<0.05 included). Table 5 showed that irisin levels and CCVD history were independent risk factors of CCVD mortality.

Table 5 Cox regression analysis of determinant factors for CCVD mortality
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Independent determinant factors for all-cause mortality by Cox regression analysis

Variables that were statistically significant in Table 3 were selected for the Cox regression analysis to find the determinant factors of all-cause mortality (P<0.05 included). The variables included age, systolic pressure, serum creatinine, uric acid, phosphate, albumin, LDL-C, triglycerides, total cholesterol. As shown in Table 6, age, systolic pressure and serum creatinine were independent risk factors for all-cause mortality in HD patients.

Table 6 Cox regression analysis of the determinant factors for all-cause mortality in HD patients
Full table

Discussion

CCVD is a major cause of death in dialysis patients (18,19). The traditional risk factors of CCVD in dialysis patients include hypertension, smoking, hyperlipidemia, obesity, and diabetes mellitus, etc. In addition, non-traditional risk factors such as inflammation (20), malnutrition (21), endothelial dysfunction (22), oxidative stress (23), vacular calcification (24), vitamin D deficiency (25), and hyperhomocysteinemia (26) also contribute to the excess risk of CCVD in patients with CKD by triggering vascular injury and endothelial dysfunction. Recently, the levels of ferritin, hemoglobin and doses of iron or erythropoiesis-stimulating agents (ESAs) were also proved to be risk factors of CCVD in HD patients. Furthermore, uraemia-related factors such as abnormal calcium and phosphate metabolism, hyperparathyroidism and newly found Klotho protein all might increase the risk of CCVD among HD patients through affecting vascular calcification and endothelial dysfunction (27). In the present study, we firstly demonstrated that lower levels of irisin were associated with higher CCVD mortality in HD patients. The previous researchers clarified that not only myocardio infarction (4), but also coronary artery disease patients (3) had lower irisin levels than controls in general population. Another study reported that low serum irisin level was an independent predictor of coronary artery severity in patients with stable coronary artery disease (28). El-Lebedy et al. discovered that lower levels of irisin were associated with 1.6 times increased CVD risk in patients with type 2 diabetes mellitus (29). Hisamatsu et al. emphasized higher serum irisin levels were associated with less burden of coronary atherosclerosis, furthermore, in a healthy non-obese population, they consistently found inverse associations of serum irisin levels with the prevalence and progression of coronary artery calcification, regardless of the presence or absence of cardiometabolic risk factors (30). Furthermore, Lee et al. (31) demonstrated that serum irisin was significantly associated with carotid atherosclerosis in peritoneal dialysis patients. He et al. also found that irisin was associated with increased vascular calcification in HD patients (32). Additionally, Wu et al. announced that a low serum irisin level is a predictor of poor early functional outcome in ischemic stroke patients (6). Tu et al. also observed that decreased irisin concentration was associated with the poor functional outcome in ischemic stroke and with the increased mortality of stroke (7). However, our study associated irisin levels with CCVD in the specific group, HD patients, in which the CCVD mortality is relatively high. Moreover, according to the results from Cox regression, beside of CCVD history, the well-known risk factor for CCVD mortality in HD patients, low irisin level was proved to be a new independent risk factor which can predict CCVD mortality. Our findings have provided a new point of view to the clinical work.

Furthermore, we also studied the association of irisin with all-cause mortality in HD patients and the results didn’t show any association of them. But corresponded to the previous studies (33,34), we found that HD patients with older age or higher systolic pressure had higher risk of deaths and lower levels of serum creatinine which might represent the poor nutritional status also increased all-cause mortality in HD patients.

What might explain the association of lower irisin levels with CCVD mortality? Firstly, it might because of high blood pressure. Zhang et al. (35) found that irisin could regulate blood pressure and be involved in cardiovascular activities. This may be dependent or independent on vascular endothelial cells. Meanwhile, Zhang et al. (36) reported that circulating irisin had a negative relationship with blood pressure in patients with preeclampsia. Secondly, lower irisin levels may be associated with more severe endothelial dysfunction. Endothelial dysfunction is considered as the early step in the pathogenesis of atherosclerosis (37). Zhu et al. (38) verified that irisin alleviated endothelial dysfunction in type 2 diabetes partially via reducing oxidative/nitrative stresses through inhibiting signaling pathways implicating PKC-β/NADPH oxidase and NF-κB/iNOS, other researchers also demonstrated that irisin could maintain endothelial homeostasis by promoting angiogenesis (39). Thirdly, some researchers found that risin could exert anti-apoptotic effects on ischemic cardiomyocytes by protection of mitochondrial function (40). Moreover, researchers also emphasized that irisin could improve ischemia-induced neuronal injury through the Akt and ERK1/2 signaling pathways activation and contributes to the physical exercise neuroprotective effect against cerebral ischemia (41). Likewise, irisin was proved to have the function of diminishing oxygen-glucose deprivation-induced neuronal injury through inhibiting reactive oxygen species-NOD-like receptor pyrin 3 inflammatory signaling pathway (42).

There is still controversy regarding the relatively large variation in irisin concentrations among different ELISA assay kits. Kałużna et al. measured the levels of serum irisin in HD patients and the median value was 4.32 µg/mL (43). However, in another study related to irisin in patients with CKD stage 2-4, it was tested that the median values of serum irisin concentrations ranged from 13.00–21.41 ng/mL (44). The reasons of the large variation of serum irisin concentrations in different studies might be attributed to the unclarified changes of irisin level in the body in different physiological or pathological conditions. At present, there hasn’t been any evidence indicating any problem with the methodology used to measure irisin. More studies are needed to clarify the inconsistencies in circulating irisin concentrations and to find out the most accurate way to measure irisin concentrations and the standard range for serum irisin.

When interpreting results of this study, some limitations should be taken into account. The small sample size in our study may have prevented our results from reaching a more significant level. Besides, selection bias might occur for this retrospective study. Taken together, multi-center prospective studies are needed to further clarify the association of irisin with CCVD in HD patients.

Conclusions

Our results provided a clinical evidence of the association between lower levels of serum irisin and CCVD mortality in HD patients. Lower levels of serum irisin increased the mortality of CCVD in HD patients.

Acknowledgments

Thanks for all the patients who agreed to participate in our study. And we thank Dr. Dahl for editing the language of our paper.

Funding: The work was supported by Xuanwu Hospital Capital Medical University Hui Zhi Talent Leading Cultivation Plan to Aihua Zhang in the data collection and the decision to submit the article for publication.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/apm-21-406

Data Sharing Statement: Available at http://dx.doi.org/10.21037/apm-21-406

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/apm-21-406). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of our hospital (No. [2019]130) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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