Introduction: This study aimed to investigate the prospective role of serum irisin – a novel adipo-myokine – in all-cause mortality and cardiovascular (CV) mortality in patients on peritoneal dialysis (PD). Methods: A prospectively observational study was conducted with 154 PD patients. Baseline clinical data were collected from the medical records. Serum irisin concentrations were determined using enzyme-linked immunosorbent assay. Patients were divided into the high irisin group (serum irisin ≥113.5 ng/mL) and the low irisin group (serum irisin <113.5 ng/mL) based on the median value of serum irisin. A body composition monitor was used to monitor body composition. Cox regression analysis was utilized to find the independent risk factors of all-cause and CV mortality in PD patients. Results: The median serum irisin concentration was 113.5 ng/mL (interquartile range, 106.2–119.8 ng/mL). Patients in the high irisin group had significantly higher muscle mass and carbon dioxide combining power (CO2CP) than those in the low irisin group (p < 0.05). Serum irisin was positively correlated with pulse pressure, CO2CP, and muscle mass, while negatively correlated with body fat percentage (p < 0.05). During a median of follow-up for 60.0 months, there were 55 all-cause deaths and 26 CV deaths. Patients in the high irisin group demonstrated a higher CV survival rate than those in the low irisin group (p = 0.016). Multivariate Cox regression analysis showed that high irisin level (hazard ratio [HR], 0.341; 95% confidence interval [CI], 0.135–0.858; p = 0.022), age, and diabetic mellitus were independently associated with CV mortality in PD patients. However, serum irisin level failed to demonstrate a statistically significant relationship with all-cause mortality. Conclusion: Low serum irisin levels at baseline were independently predictive of CV mortality but not all-cause mortality in PD patients. Therefore, serum irisin could be a potential target for monitoring CV outcomes in PD patients.

Cardiovascular disease (CVD) is prevalent and remains the leading cause of death in patients with end-stage renal disease (ESRD) [1]. Peritoneal dialysis (PD) provides relatively stable cardiovascular (CV) state, better volume regulation, reduced blood pressure, fewer electrolyte disturbances, and reduced cardiac workload [2] during the renal replacement therapy and thus could be the optimal choice for patients with ESRD and CVD. However, CVD often aggravates continuously with a prolonged duration of dialysis and correlates with high death risk. Recently, muscle and muscle-derived myokines have been supposed to be closely associated with the progression and unfavorable outcomes of CVD, leading to novel alternative monitoring indicators and therapeutic targets for patients with ESRD and CVD.

Irisin, a newly discovered adipo-myokine, is derived from fibronectin III domain protein5 in response to exercise via upregulated expression of peroxisome proliferator activated receptor-γ coactivator-1 α [3]. Irisin could increase energy expenditure and improve insulin sensitivity under metabolic disorder conditions, such as diabetes mellitus and metabolic syndrome [4]. Emerging evidence demonstrated that irisin is deeply involved in the CV metabolism. In basic studies, irisin treatment could protect against endothelial dysfunction [5] and promote angiogenesis [6]. In our previous study, circulating irisin concentration was negatively associated with abdominal aorta calcification in PD patients [7]. Low serum irisin levels were predictive of poor functional outcomes in patients with ischemic stroke [8, 9]. Dong et al. [10] found that low serum irisin levels were associated with increased CV mortality in patients undergoing hemodialysis. However, the significance of serum irisin level in the clinical outcomes of PD patients had never been studied. Taken together, we hypothesized that low serum irisin levels may be associated with poor prognosis in PD patients. Therefore, a prospective cohort study was conducted to investigate the prognostic value of serum irisin on all-cause and CV mortality in Chinese PD patients.

Study Population

Patients undergoing PD were recruited from the PD Center of Peking University Third Hospital from May 1, 2018 to July 31, 2018 for this prospective study. The patients had an age of >18 years and had received PD therapy for >3 months. The exclusion criteria were as follows: (1) CV instability within 3 months, such as acute coronary syndrome, percutaneous coronary intervention therapy, acute heart failure, and acute stroke; (2) active infections such as sepsis, peritonitis, and pneumonia; (3) significant mental illness or dementia; and (4) patients who refused to participate in the study.

The participants were prospectively followed up until death or to the end of the study (Jun 30, 2023). All-cause and CV death were both recorded as the primary endpoint events. CV death includes deaths caused by malignant arrhythmia, myocardial infarction, heart failure, sudden cardiac death, and stroke. Censored events included transferal to hemodialysis, loss to follow-up, and renal transplantation. No intentional interventions were conducted by the investigators. The study has been approved by the Ethics Committee of Peking University Third Hospital.

Clinical Data Collection

At baseline, demographic data (age, gender, and body mass index), primary causes of ESRD, duration of dialysis, CVD spectrum, and CVD risk factors (blood pressure, diabetes mellitus) were collected. A definite CVD was defined as coronary artery disease, congestive heart failure, and ischemic stroke. Medication data (statin, renin angiotensin system inhibitor, β receptor blocker, calcium carbonate, and non-calcium-phosphorus binding agent) were also recorded. Serum biochemical data were obtained from the routine clinic medical records, including hemoglobin, high-sensitivity C-reactive protein (hs-CRP), albumin, creatinine, corrected calcium, phosphorus, carbon dioxide combining power (CO2CP), total cholesterol (TCHO), triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, intact parathyroid hormone, and alkaline phosphatase. Kt/V urea, including total Kt/V urea and residual kidney Kt/V urea, was calculated by the Daugirdas formula.

Measurements of Serum Irisin Concentrations

At admission, blood samples of the enrolled patients were collected in serum collecting tubes. Plasma was extracted after centrifugation and stored at −80°C for measuring the serum irisin concentrations. Enzyme-linked immunosorbent assay kits (Phoenix Pharmaceuticals, Burlingame, CA, USA) were used according to the manufacturer’s instructions. The detection limit was 0.1 ng/mL. The intra- and interassay variations were <4.5 and 8%, respectively, which suggested that the test method was reliable.

Assessment of Body Composition

Based on the principle of bioelectrical impedance, a Body Composition Monitor (Fresenius Medical Care AG&CO., KGaA D-61346 Bad Homburg, Germany) was used for measuring the body composition parameters, including muscle mass (kg), body fat mass (kg), and body fat percentage (%) of the enrolled patients. All the body composition tests were carried out by well-trained physicians.

Statistical Analysis

The SPSS software package version 22.0 (IBM, Armonk, NY, USA) was used for statistical analyses. Data were shown as mean ± standard deviation for normally distributed variables, or median and percentile (p25, p75) for nonnormally distributed variables. Categorical variables were expressed as count (percentage).

Patients were divided into two groups according to the serum irisin levels. Comparisons between the two groups were conducted using the independent sample t test for normally distributed variables, Mann-Whitney U test for nonnormally distributed variables, and χ2 test for categorical variables. To analyze the linear correlation between serum irisin and other parameters, Pearson analysis was used for normally distributed variables and Spearman analysis for nonnormally distributed variables and categorical variables. Univariate and multivariate Cox regression analyses with hazard ratios (HRs) and 95% confidence intervals (CIs) were performed to examine the associations between the clinical factors and patients’ survival. Clinical outcomes among different serum irisin groups were compared using the Kaplan-Meier method and log-rank test. A p value of <0.05 was considered to be statistically significant.

Baseline Characteristics of the Study Population

The enrolment flowchart for this study is shown in Figure 1. The study included 165 patients who met the inclusion criteria. Among these, 11 patients were excluded, 5 of them due to CV instability within 3 months previously, 3 of them due to suffering from active infection, and the rest due to unwillingness to participate. Thus, a total of 154 patients were enrolled in the study. No patients were lost during the follow-up period. The median follow-up length was 60.0 (46.3–60.0) months.

Fig. 1.

Flowchart of patients’ enrollment and their outcomes. CV, cardiovascular; PD, peritoneal dialysis.

Fig. 1.

Flowchart of patients’ enrollment and their outcomes. CV, cardiovascular; PD, peritoneal dialysis.

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Baseline characteristics of the study participants are presented in Table 1. Of the 154 patients, 75 (48.7%) were male and the mean age was 58.1 ± 13.2 years. The median duration of dialysis was 51.5 (21.8–88.0) months. The primary causes of ESRD were chronic glomerulonephritis (36.4%), diabetic kidney disease (26.0%), hypertensive nephropathy (12.3%), chronic interstitial nephritis (10.4%), other diseases (5.2%), and uncertain (9.7%). 70 (45.5%) patients had CVD at baseline, which consisted of coronary artery disease (10.4%), congestive heart failure (24.7%), and ischemic stroke (12.3%).

Table 1.

Demographic and clinical characteristics of the study population

VariablesTotal (n = 154)Low irisin level (n = 77)High irisin level (n = 77)p value
Age, years 58.1±13.2 57.9±13.0 58.3±13.4 0.860 
Male, n (%) 75 (48.7) 41 (53.2) 34 (44.2) 0.259 
CVD, n (%) 70 (45.5) 40 (51.9) 30 (39.0) 0.106 
Coronary artery disease, n (%) 16 (10.4) 9 (11.7) 7 (9.1) 0.597 
Congestive heart failure, n (%) 38 (24.7) 23 (29.9) 15 (19.5) 0.135 
Ischemic stroke, n (%) 19 (12.3) 14 (18.2) 5 (6.5) 0.027 
Diabetic mellitus, n (%) 53 (34.4) 30 (39.0) 23 (29.9) 0.235 
Duration of dialysis, months 51.5 (21.8, 88.0) 42.0 (25.0, 79.0) 55.0 (16.5, 94.0) 0.297 
BMI, kg/m2 23.7±3.5 23.4±3.3 23.9±3.7 0.377 
Systolic BP, mm Hg 133.3±17.3 132.7±16.6 133.9±18.0 0.674 
Diastolic BP, mm Hg 79.0±12.7 78.8±12.7 79.3±12.8 0.799 
Pulse pressure, mm Hg 53.8±14.0 53.0±14.2 54.6±13.8 0.484 
Total Kt/V urea (per week) 1.82 (1.59, 2.01) 1.81 (1.55, 2.11) 1.82 (1.64, 2.01) 0.899 
Residual kidney Kt/V urea (per week) 0.00 (0.00, 0.35) 0.00 (0.00, 0.36) 0.00 (0.00, 0.36) 0.679 
Hemoglobin, g/L 116.4±16.3 116.9±14.5 115.9±18.6 0.721 
Hs-CRP, mg/L 3.25 (0.95, 10.02) 2.78 (0.71, 8.94) 4.47 (1.46, 12.87) 0.156 
Albumin, g/L 37.0±3.8 37.1±4.1 36.9±3.4 0.744 
Creatinine, μmol/L 944.1±235.5 952.1±251.4 936.2±219.9 0.677 
CO2CP, mmol/L 25.5±2.8 25.0±2.7 26.0±2.7 0.026 
Corrected calcium, mmol/L 2.53±0.24 2.51±0.22 2.55±0.25 0.285 
Phosphorus, mmol/L 1.62±0.41 1.63±0.36 1.62±0.46 0.887 
iPTH, pg/mL 148.7 (70.1, 299.5) 139.8 (70.2, 263.9) 157.4 (69.3, 331.0) 0.546 
ALP, U/L 71.0 (56.5, 90.0) 68.0 (55.5, 87.5) 76.5 (57.0, 96.8) 0.272 
TCHO, mmol/L 4.73±1.06 4.75±1.09 4.72±1.04 0.866 
TG, mmol/L 1.90 (1.35, 2.94) 1.97 (1.35, 2.81) 1.82 (1.30, 3.08) 0.717 
HDL-C, mmol/L 0.96 (0.82, 1.15) 0.95 (0.83, 1.15) 0.98 (0.82, 1.13) 0.737 
LDL-C, mmol/L 2.78±0.75 2.74±0.78 2.82±0.71 0.518 
Muscle mass, kg 35.5±9.2 33.5±8.8 37.6±9.3 0.007 
Body fat mass, kg 26.0±10.1 25.9±10.1 26.1±10.0 0.922 
Body fat percentage, % 40.5±12.9 41.5±13.0 39.3±12.8 0.308 
Medication status 
 Statin use, n (%) 80 (51.9) 44 (57.1) 36 (46.8) 0.197 
 RASI use, n (%) 104 (67.5) 48 (62.3) 56 (72.7) 0.169 
 β-Blocker use, n (%) 72 (46.8) 40 (51.9) 32 (41.6) 0.196 
 Calcium carbonate use, n (%) 93 (60.4) 43 (55.8) 50 (64.9) 0.249 
 Non-calcium-phosphorus binding agent use, n (%) 55 (35.7) 29 (37.7) 26 (33.8) 0.614 
VariablesTotal (n = 154)Low irisin level (n = 77)High irisin level (n = 77)p value
Age, years 58.1±13.2 57.9±13.0 58.3±13.4 0.860 
Male, n (%) 75 (48.7) 41 (53.2) 34 (44.2) 0.259 
CVD, n (%) 70 (45.5) 40 (51.9) 30 (39.0) 0.106 
Coronary artery disease, n (%) 16 (10.4) 9 (11.7) 7 (9.1) 0.597 
Congestive heart failure, n (%) 38 (24.7) 23 (29.9) 15 (19.5) 0.135 
Ischemic stroke, n (%) 19 (12.3) 14 (18.2) 5 (6.5) 0.027 
Diabetic mellitus, n (%) 53 (34.4) 30 (39.0) 23 (29.9) 0.235 
Duration of dialysis, months 51.5 (21.8, 88.0) 42.0 (25.0, 79.0) 55.0 (16.5, 94.0) 0.297 
BMI, kg/m2 23.7±3.5 23.4±3.3 23.9±3.7 0.377 
Systolic BP, mm Hg 133.3±17.3 132.7±16.6 133.9±18.0 0.674 
Diastolic BP, mm Hg 79.0±12.7 78.8±12.7 79.3±12.8 0.799 
Pulse pressure, mm Hg 53.8±14.0 53.0±14.2 54.6±13.8 0.484 
Total Kt/V urea (per week) 1.82 (1.59, 2.01) 1.81 (1.55, 2.11) 1.82 (1.64, 2.01) 0.899 
Residual kidney Kt/V urea (per week) 0.00 (0.00, 0.35) 0.00 (0.00, 0.36) 0.00 (0.00, 0.36) 0.679 
Hemoglobin, g/L 116.4±16.3 116.9±14.5 115.9±18.6 0.721 
Hs-CRP, mg/L 3.25 (0.95, 10.02) 2.78 (0.71, 8.94) 4.47 (1.46, 12.87) 0.156 
Albumin, g/L 37.0±3.8 37.1±4.1 36.9±3.4 0.744 
Creatinine, μmol/L 944.1±235.5 952.1±251.4 936.2±219.9 0.677 
CO2CP, mmol/L 25.5±2.8 25.0±2.7 26.0±2.7 0.026 
Corrected calcium, mmol/L 2.53±0.24 2.51±0.22 2.55±0.25 0.285 
Phosphorus, mmol/L 1.62±0.41 1.63±0.36 1.62±0.46 0.887 
iPTH, pg/mL 148.7 (70.1, 299.5) 139.8 (70.2, 263.9) 157.4 (69.3, 331.0) 0.546 
ALP, U/L 71.0 (56.5, 90.0) 68.0 (55.5, 87.5) 76.5 (57.0, 96.8) 0.272 
TCHO, mmol/L 4.73±1.06 4.75±1.09 4.72±1.04 0.866 
TG, mmol/L 1.90 (1.35, 2.94) 1.97 (1.35, 2.81) 1.82 (1.30, 3.08) 0.717 
HDL-C, mmol/L 0.96 (0.82, 1.15) 0.95 (0.83, 1.15) 0.98 (0.82, 1.13) 0.737 
LDL-C, mmol/L 2.78±0.75 2.74±0.78 2.82±0.71 0.518 
Muscle mass, kg 35.5±9.2 33.5±8.8 37.6±9.3 0.007 
Body fat mass, kg 26.0±10.1 25.9±10.1 26.1±10.0 0.922 
Body fat percentage, % 40.5±12.9 41.5±13.0 39.3±12.8 0.308 
Medication status 
 Statin use, n (%) 80 (51.9) 44 (57.1) 36 (46.8) 0.197 
 RASI use, n (%) 104 (67.5) 48 (62.3) 56 (72.7) 0.169 
 β-Blocker use, n (%) 72 (46.8) 40 (51.9) 32 (41.6) 0.196 
 Calcium carbonate use, n (%) 93 (60.4) 43 (55.8) 50 (64.9) 0.249 
 Non-calcium-phosphorus binding agent use, n (%) 55 (35.7) 29 (37.7) 26 (33.8) 0.614 

PD, peritoneal dialysis; CVD, cardiovascular disease; BP, blood pressure; Kt/V urea, fractional urea clearance; BMI, body mass index; ALP, alkaline phosphatase; iPTH, intact parathyroid hormone; TG, triglyceride; TCHO, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; hs-CRP, hypersensitive C-reactive protein.

Comparison of Characteristics between Patients with Different Serum Irisin Levels

The median serum irisin concentration was 113.5 ng/mL (interquartile range, 106.2–119.8 ng/mL). Patients were divided into the low irisin group (serum irisin concentration <113.5 ng/mL) and the high irisin group (serum irisin concentration ≥113.5 ng/mL). The demographic and clinical characteristics of two groups are detailed in Table 1. Patients in the high irisin group had significantly higher serum CO2CP and muscle mass than those in the low irisin group (p < 0.05).

The proportion of patients who experienced ischemic stroke at baseline was higher in the high irisin group than in the low irisin group. There were no significant differences in medication, age, gender, diabetic mellitus proportion, duration of dialysis, body mass index, blood pressure, Kt/V urea, hemoglobin, albumin, hs-CRP, lipid profile, body fat mass, body fat percentage, and other laboratory parameters between the two groups (Table 1).

Correlation Analysis of Serum Irisin with Other Parameters

As shown in Table 2, serum irisin was positively correlated with CO2CP (Pearson r = 0.201, p = 0.013), pulse pressure (Pearson r = 0.189, p = 0.020), and muscle mass (Pearson r = 0.280, p = 0.001). However, serum irisin was negatively correlated with body fat percentage (Pearson r = −0.186, p = 0.026).

Table 2.

Correlation between serum irisin and other clinical parameters

VariablesCorrelation efficientp value
Age, years 0.081* 0.316 
Gender (male = 1, female = 2) 0.036a 0.662 
CVD (no = 0, yes = 1) −0.068a 0.404 
Diabetic mellitus (no = 0, yes = 1) −0.027a 0.738 
Duration of dialysis, months 0.045a 0.581 
BMI, kg/m2 0.091* 0.262 
Systolic BP, mm Hg 0.110* 0.177 
Diastolic BP, mm Hg −0.048* 0.556 
Pulse pressure, mm Hg 0.189* 0.020 
Total Kt/V urea (per week) −0.062a 0.442 
Residual kidney Kt/V urea (per week) −0.053a 0.517 
Hemoglobin, g/L −0.070* 0.390 
Hs-CRP, mg/L 0.106a 0.191 
Albumin, g/L −0.088* 0.277 
Creatinine, μmol/L 0.010* 0.901 
CO2CP, mmol/L 0.201* 0.013 
Corrected calcium, mmol/L −0.034* 0.675 
Phosphorus, mmol/L −0.026* 0.751 
iPTH, pg/mL 0.027a 0.738 
ALP, U/L 0.091a 0.265 
TCHO, mmol/L 0.004* 0.959 
TG, mmol/L 0.027a 0.743 
HDL-C, mmol/L −0.057a 0.484 
LDL-C, mmol/L −0.003* 0.971 
Muscle mass, kg 0.280* 0.001 
Body fat mass, kg −0.040* 0.639 
Body fat percentage, % −0.186* 0.026 
VariablesCorrelation efficientp value
Age, years 0.081* 0.316 
Gender (male = 1, female = 2) 0.036a 0.662 
CVD (no = 0, yes = 1) −0.068a 0.404 
Diabetic mellitus (no = 0, yes = 1) −0.027a 0.738 
Duration of dialysis, months 0.045a 0.581 
BMI, kg/m2 0.091* 0.262 
Systolic BP, mm Hg 0.110* 0.177 
Diastolic BP, mm Hg −0.048* 0.556 
Pulse pressure, mm Hg 0.189* 0.020 
Total Kt/V urea (per week) −0.062a 0.442 
Residual kidney Kt/V urea (per week) −0.053a 0.517 
Hemoglobin, g/L −0.070* 0.390 
Hs-CRP, mg/L 0.106a 0.191 
Albumin, g/L −0.088* 0.277 
Creatinine, μmol/L 0.010* 0.901 
CO2CP, mmol/L 0.201* 0.013 
Corrected calcium, mmol/L −0.034* 0.675 
Phosphorus, mmol/L −0.026* 0.751 
iPTH, pg/mL 0.027a 0.738 
ALP, U/L 0.091a 0.265 
TCHO, mmol/L 0.004* 0.959 
TG, mmol/L 0.027a 0.743 
HDL-C, mmol/L −0.057a 0.484 
LDL-C, mmol/L −0.003* 0.971 
Muscle mass, kg 0.280* 0.001 
Body fat mass, kg −0.040* 0.639 
Body fat percentage, % −0.186* 0.026 

CVD, cardiovascular disease; BMI, body mass index; BP, blood pressure; Kt/V urea, fractional urea clearance; hs-CRP, hypersensitive C-reactive protein; CO2CP, carbon dioxide combining power; iPTH, intact parathyroid hormone; ALP, alkaline phosphatase; TCHO, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

*Pearson’s r for normally distributed variables.

aSpearman’s rho for nonnormally distributed variables and categorical variables.

Association between Serum Irisin and All-Cause Mortality in PD Patients

Patients were followed until June 30, 2023. During the follow-up period, 13 (8.4%) patients switched to hemodialysis. 55 (35.7%) patients died, with CV cause accounting for 26 (16.9%) death. The other causes of death were infection, multiple organ failure, cancer, and gastrointestinal bleeding (Table 3).

Table 3.

Outcomes among groups according to serum irisin levels

Cause of deathTotal (n = 154)Low irisin group (n = 77)High irisin group (n = 77)p value
CV death, n (%) 26 (16.9) 19 (24.7) 7 (9.1) 0.010 
Infection, n (%) 13 (8.4) 8 (10.4) 5 (6.5) 0.385 
Multiple organ failure, n (%) 10 (6.5) 4 (5.2) 6 (7.8) 0.744 
Malignant tumor, n (%) 4 (2.6) 1 (1.3) 3 (3.9) 0.603 
Gastrointestinal bleeding, n (%) 2 (1.3) 1 (1.3) 1 (1.3) 1.000 
All-cause death, n (%) 55 (35.7) 33 (42.9) 22 (28.6) 0.064 
Cause of deathTotal (n = 154)Low irisin group (n = 77)High irisin group (n = 77)p value
CV death, n (%) 26 (16.9) 19 (24.7) 7 (9.1) 0.010 
Infection, n (%) 13 (8.4) 8 (10.4) 5 (6.5) 0.385 
Multiple organ failure, n (%) 10 (6.5) 4 (5.2) 6 (7.8) 0.744 
Malignant tumor, n (%) 4 (2.6) 1 (1.3) 3 (3.9) 0.603 
Gastrointestinal bleeding, n (%) 2 (1.3) 1 (1.3) 1 (1.3) 1.000 
All-cause death, n (%) 55 (35.7) 33 (42.9) 22 (28.6) 0.064 

CV, cardiovascular.

The Kaplan-Meier method was utilized to analyze the prognosis of patients in the low irisin group and the high irisin group. The results of the survival analysis are presented in Figure 2, which showed that there was no significant difference in the overall survival rate between the low irisin group and the high irisin group (p = 0.109). At the end of study, the survival rate of the high irisin group was higher than that of the low irisin group (71.4 vs. 57.1%, p = 0.064), but the difference did not reach statistical significance.

Fig. 2.

Kaplan-Meier survival curves for all-cause mortality comparing PD patients with different levels of serum irisin. PD, peritoneal dialysis.

Fig. 2.

Kaplan-Meier survival curves for all-cause mortality comparing PD patients with different levels of serum irisin. PD, peritoneal dialysis.

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On univariate Cox regression, age, duration of dialysis, CVD, diastolic blood pressure, total Kt/V urea, residual kidney Kt/V urea, albumin, hs-CRP, and muscle mass were significantly correlated with all-cause mortality in PD patients (p < 0.05). High serum TCHO was also associated with a higher risk of all-cause death (p < 0.1). Serum irisin level was not shown to have a significant relationship with all-cause mortality in the univariate analysis (HR, 0.647; 95% CI, 0.377−1.109; p = 0.113). Serum irisin level and factors with the p value <0.1 in the univariate analysis were then put in the multivariate Cox regression analysis. Finally, age, duration of dialysis, and total Kt/V urea remained the independent predictors for all-cause mortality after adjusting for CVD, diastolic blood pressure, residual Kt/V urea, albumin, hs-CRP, TCHO, serum irisin level, and muscle mass (p < 0.05) (Table 4).

Table 4.

Univariate and multivariate Cox regression models of predicting all-cause death in PD patients

VariableUnivariate analysisMultivariate analysis*
HR (95% CI)p valueHR (95% CI)p value
Age (per 1-year increase) 1.075 (1.050–1.103) <0.001 1.070 (1.043–1.098) <0.001 
Female gender 0.972 (0.573–1.650) 0.917   
Duration of dialysis (per 1-month increase) 1.009 (1.003–1.016) 0.005 1.009 (1.001–1.017) 0.020 
CVD 2.121 (1.236–3.640) 0.006 1.285 (0.728–2.267) 0.388 
Diabetic mellitus 1.259 (0.731–2.170) 0.406   
Systolic BP (per 1-mm Hg increase) 0.989 (0.973–1.005) 0.182   
Diastolic BP (per 1-mm Hg increase) 0.962 (0.942–0.983) <0.001 0.998 (0.971–1.025) 0.876 
Pulse pressure (per 1-mm Hg increase) 1.011 (0.992–1.030) 0.242   
Total Kt/V urea (per 1 increase) 0.331 (0.141–0.775) 0.011 0.278 (0.103–0.746) 0.011 
Residual kidney Kt/V urea (per 1 increase) 0.284 (0.100–0.810) 0.019 1.752 (0.379–8.106) 0.473 
BMI (per 1-kg/m2 increase) 0.975 (0.906–1.049) 0.499   
Hemoglobin (per 1-g/L increase) 1.005 (0.989–1.022) 0.508   
Albumin (per 1-g/L increase) 0.897 (0.842–0.955) 0.001 0.982 (0.901–1.071) 0.684 
ALP (per 1-U/L increase) 1.003 (0.999–1.006) 0.156   
iPTH (per 1-pg/mL increase) 1.002 (0.999–1.003) 0.388   
Corrected calcium (per 1-mmol/L increase) 1.554 (0.497–4.861) 0.449   
Phosphorus (per 1-mmol/L increase) 0.648 (0.337–1.243) 0.192   
TG (per 1-mmol/L increase) 1.004 (0.876–1.151) 0.950   
TCHO (per 1-mmol/L increase) 1.243 (0.968–1.596) 0.088 1.305 (0.993–1.715) 0.056 
LDL-C (per 1-mmol/L increase) 1.283 (0.904–1.819) 0.163   
HDL-C (per 1-mmol/L increase) 1.075 (0.397–2.910) 0.887   
Hs-CRP (per 1-mg/L increase) 1.017 (1.004–1.029) 0.008 1.005 (0.990–1.020) 0.524 
Muscle mass (per 1-kg increase) 0.967 (0.938–0.997) 0.031 0.993 (0.955–1.033) 0.726 
Body fat mass (per 1-kg increase) 0.999 (0.973–1.026) 0.953   
Body fat percentage (per 1-% increase) 1.009 (0.988–1.030) 0.407   
High irisin level 0.647 (0.377–1.109) 0.113 0.552 (0.302–1.010) 0.054 
VariableUnivariate analysisMultivariate analysis*
HR (95% CI)p valueHR (95% CI)p value
Age (per 1-year increase) 1.075 (1.050–1.103) <0.001 1.070 (1.043–1.098) <0.001 
Female gender 0.972 (0.573–1.650) 0.917   
Duration of dialysis (per 1-month increase) 1.009 (1.003–1.016) 0.005 1.009 (1.001–1.017) 0.020 
CVD 2.121 (1.236–3.640) 0.006 1.285 (0.728–2.267) 0.388 
Diabetic mellitus 1.259 (0.731–2.170) 0.406   
Systolic BP (per 1-mm Hg increase) 0.989 (0.973–1.005) 0.182   
Diastolic BP (per 1-mm Hg increase) 0.962 (0.942–0.983) <0.001 0.998 (0.971–1.025) 0.876 
Pulse pressure (per 1-mm Hg increase) 1.011 (0.992–1.030) 0.242   
Total Kt/V urea (per 1 increase) 0.331 (0.141–0.775) 0.011 0.278 (0.103–0.746) 0.011 
Residual kidney Kt/V urea (per 1 increase) 0.284 (0.100–0.810) 0.019 1.752 (0.379–8.106) 0.473 
BMI (per 1-kg/m2 increase) 0.975 (0.906–1.049) 0.499   
Hemoglobin (per 1-g/L increase) 1.005 (0.989–1.022) 0.508   
Albumin (per 1-g/L increase) 0.897 (0.842–0.955) 0.001 0.982 (0.901–1.071) 0.684 
ALP (per 1-U/L increase) 1.003 (0.999–1.006) 0.156   
iPTH (per 1-pg/mL increase) 1.002 (0.999–1.003) 0.388   
Corrected calcium (per 1-mmol/L increase) 1.554 (0.497–4.861) 0.449   
Phosphorus (per 1-mmol/L increase) 0.648 (0.337–1.243) 0.192   
TG (per 1-mmol/L increase) 1.004 (0.876–1.151) 0.950   
TCHO (per 1-mmol/L increase) 1.243 (0.968–1.596) 0.088 1.305 (0.993–1.715) 0.056 
LDL-C (per 1-mmol/L increase) 1.283 (0.904–1.819) 0.163   
HDL-C (per 1-mmol/L increase) 1.075 (0.397–2.910) 0.887   
Hs-CRP (per 1-mg/L increase) 1.017 (1.004–1.029) 0.008 1.005 (0.990–1.020) 0.524 
Muscle mass (per 1-kg increase) 0.967 (0.938–0.997) 0.031 0.993 (0.955–1.033) 0.726 
Body fat mass (per 1-kg increase) 0.999 (0.973–1.026) 0.953   
Body fat percentage (per 1-% increase) 1.009 (0.988–1.030) 0.407   
High irisin level 0.647 (0.377–1.109) 0.113 0.552 (0.302–1.010) 0.054 

*Variables with p value <0.1 in the univariate Cox regression analysis were included in the multivariate analysis.

PD, peritoneal dialysis; CVD, cardiovascular disease; BP, blood pressure; Kt/V urea, fractional urea clearance; BMI, body mass index; ALP, alkaline phosphatase; iPTH, intact parathyroid hormone; TG, triglyceride; TCHO, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; hs-CRP, hypersensitive C-reactive protein.

Association between Serum Irisin and CV Mortality in PD Patients

Kaplan-Meier curves demonstrated that patients in the high irisin group had a significantly better CV survival compared to the patients in the low irisin group (log rank χ2 = 5.767, p = 0.016; Fig. 3). Univariate regression analysis showed that age, CVD, TCHO, and high irisin level (HR, 0.362; 95% CI, 0.152−0.861; p = 0.022) were significantly associated with CV mortality (p < 0.05). Diabetic mellitus, hs-CRP, and muscle mass were also associated with CV mortality in the present study (p < 0.1), which were also put in the multivariate Cox regression analysis. On multivariate Cox regression, age, diabetic mellitus, and high irisin level (HR, 0.341; 95% CI, 0.135−0.858; p = 0.022) were independently associated with CV mortality after adjusting for CVD, TCHO, hs-CRP, and muscle mass (Table 5).

Fig. 3.

Kaplan-Meier survival curves for CV mortality comparing PD patients with different levels of serum irisin. CV, cardiovascular; PD, peritoneal dialysis.

Fig. 3.

Kaplan-Meier survival curves for CV mortality comparing PD patients with different levels of serum irisin. CV, cardiovascular; PD, peritoneal dialysis.

Close modal
Table 5.

Univariate and multivariate Cox regression models of predicting cardiovascular death in PD patients

VariableUnivariate analysisMultivariate analysis*
HR (95% CI)p valueHR (95% CI)p value
Age (per 1-year increase) 1.043 (1.009–1.077) 0.012 1.049 (1.014–1.086) 0.006 
Female gender 0.942 (0.437–2.031) 0.878   
Duration of dialysis (per 1-month increase) 1.007 (0.998–1.016) 0.109   
CVD 3.155 (1.371–7.262) 0.007 1.638 (0.673–3.988) 0.277 
Diabetic mellitus 2.022 (0.937–4.362) 0.073 2.421 (1.089–5.381) 0.030 
Systolic BP (per 1-mm Hg increase) 1.014 (0.990–1.038) 0.250   
Diastolic BP (per 1-mm Hg increase) 0.994 (0.962–1.026) 0.695   
Pulse pressure (per 1-mm Hg increase) 1.014 (0.987–1.042) 0.309   
Total Kt/V urea (per 1 increase) 0.896 (0.326–2.458) 0.831   
Residual kidney Kt/V urea (per 1 increase) 0.543 (0.152–1.941) 0.347   
BMI (per 1-kg/m2 increase) 0.990 (0.890–1.101) 0.851   
Hemoglobin (per 1-g/L increase) 0.993 (0.968–1.016) 0.647   
Albumin (per 1-g/L increase) 0.947 (0.859–1.044) 0.271   
ALP (per 1-U/L increase) 1.001 (0.997–1.006) 0.397   
iPTH (per 1-pg/mL increase) 1.000 (0.997–1.003) 0.862   
Corrected calcium (per 1-mmol/L increase) 0.477 (0.083–2.734) 0.406   
Phosphorus (per 1-mmol/L increase) 0.746 (0.293–1.901) 0.539   
TG (per 1-mmol/L increase) 1.079 (0.913–1.277) 0.372   
TCHO (per 1-mmol/L increase) 1.425 (1.001–2.028) 0.049 1.391 (0.987–1.960) 0.059 
LDL-C (per 1-mmol/L increase) 1.472 (0.900–2.408) 0.123   
HDL-C (per 1-mmol/L increase) 0.612 (0.125–3.001) 0.545   
Hs-CRP (per 1-mg/L increase) 1.019 (1.000–1.038) 0.052 1.010 (0.992–1.029) 0.273 
Muscle mass (per 1-kg increase) 0.959 (0.917–1.002) 0.064 0.975 (0.925–1.027) 0.342 
Body fat mass (per 1-kg increase) 0.996 (0.958–1.036) 0.845   
Body fat percentage (per 1-% increase) 1.012 (0.982–1.043) 0.453   
High irisin level 0.362 (0.152–0.861) 0.022 0.341 (0.135–0.858) 0.022 
VariableUnivariate analysisMultivariate analysis*
HR (95% CI)p valueHR (95% CI)p value
Age (per 1-year increase) 1.043 (1.009–1.077) 0.012 1.049 (1.014–1.086) 0.006 
Female gender 0.942 (0.437–2.031) 0.878   
Duration of dialysis (per 1-month increase) 1.007 (0.998–1.016) 0.109   
CVD 3.155 (1.371–7.262) 0.007 1.638 (0.673–3.988) 0.277 
Diabetic mellitus 2.022 (0.937–4.362) 0.073 2.421 (1.089–5.381) 0.030 
Systolic BP (per 1-mm Hg increase) 1.014 (0.990–1.038) 0.250   
Diastolic BP (per 1-mm Hg increase) 0.994 (0.962–1.026) 0.695   
Pulse pressure (per 1-mm Hg increase) 1.014 (0.987–1.042) 0.309   
Total Kt/V urea (per 1 increase) 0.896 (0.326–2.458) 0.831   
Residual kidney Kt/V urea (per 1 increase) 0.543 (0.152–1.941) 0.347   
BMI (per 1-kg/m2 increase) 0.990 (0.890–1.101) 0.851   
Hemoglobin (per 1-g/L increase) 0.993 (0.968–1.016) 0.647   
Albumin (per 1-g/L increase) 0.947 (0.859–1.044) 0.271   
ALP (per 1-U/L increase) 1.001 (0.997–1.006) 0.397   
iPTH (per 1-pg/mL increase) 1.000 (0.997–1.003) 0.862   
Corrected calcium (per 1-mmol/L increase) 0.477 (0.083–2.734) 0.406   
Phosphorus (per 1-mmol/L increase) 0.746 (0.293–1.901) 0.539   
TG (per 1-mmol/L increase) 1.079 (0.913–1.277) 0.372   
TCHO (per 1-mmol/L increase) 1.425 (1.001–2.028) 0.049 1.391 (0.987–1.960) 0.059 
LDL-C (per 1-mmol/L increase) 1.472 (0.900–2.408) 0.123   
HDL-C (per 1-mmol/L increase) 0.612 (0.125–3.001) 0.545   
Hs-CRP (per 1-mg/L increase) 1.019 (1.000–1.038) 0.052 1.010 (0.992–1.029) 0.273 
Muscle mass (per 1-kg increase) 0.959 (0.917–1.002) 0.064 0.975 (0.925–1.027) 0.342 
Body fat mass (per 1-kg increase) 0.996 (0.958–1.036) 0.845   
Body fat percentage (per 1-% increase) 1.012 (0.982–1.043) 0.453   
High irisin level 0.362 (0.152–0.861) 0.022 0.341 (0.135–0.858) 0.022 

PD, peritoneal dialysis; CVD, cardiovascular disease; BP, blood pressure; Kt/V urea, fractional urea clearance; BMI, body mass index; ALP, alkaline phosphatase; iPTH, intact parathyroid hormone; TG, triglyceride; TCHO, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; hs-CRP, hypersensitive C-reactive protein.

*Variables with a p value <0.1 in the univariate Cox regression analysis were included in the multivariate analysis.

This is the first study to show the prognostic value of serum irisin level on the outcomes of PD patients. Low serum irisin levels at baseline were associated with increased CV mortality in incident PD patients. However, serum irisin was not associated with all-cause mortality in PD patients.

As CVD is the main cause of death in patients with ESRD, patients with CVD are at the highest risk of death. The predictive value of circulating irisin level in patients with CVD was controversial in previous reports. Ozturk et al. [11] reported that serum irisin level was significantly lower in patients with acute ST-elevation myocardial infarction compared to the control subjects However, higher serum irisin concentration was found to be correlated with an increased risk of acute coronary syndrome and adverse CV events in patients with CVD [12, 13]. Increased serum irisin was associated with higher mortality in patients with acute heart failure [14]. There are some potential explanations for this. On the one hand, irisin has favorable metabolic effects such as improving insulin sensitivity. Elevated irisin may act as a compensatory mechanism for the CVD-related metabolic disorders. On the other hand, the dose-effect relationship is a possible explanation for the heterogeneity. In diabetic cardiomyopathy mice, low-dose irisin treatment alleviated cardiac fibrosis by inhibiting endothelial-to-mesenchymal transition, while high-dose irisin led to cardiac fibrosis by enhancing matrix metalloproteinases [15]. Our previous study showed that serum irisin concentrations of PD patients were significantly lower than those of healthy controls [16]. Hence, the relatively low serum irisin levels may exert a protective effect on the CV outcomes of incident PD patients.

In the study, PD patients with CVD at baseline had relatively lower serum irisin than those without CVD (112.7 ± 9.7 vs. 113.8 ± 13.5 ng/mL, p = 0.575). Patients in the low irisin group had more ischemic strokes at baseline. All the discrepancies contributed to the higher CV mortality in the low irisin group. In addition, high serum irisin levels always represent a high muscle mass and well nutrition status [16]. The association between sarcopenia and the poor prognosis in PD patients [17] can partially explain the correlation between low serum irisin levels and increased mortality. Adipose tissue is another important source of circulating irisin in dialysis patients [18]. PD patients are characterized by obviously increased body fat mass and decreased muscle mass with prolonged time on dialysis [19], which is significantly different from that of hemodialysis patients. The source diversity of serum irisin may explain that serum irisin was independently associated with CV mortality of PD patients, while muscle mass was not in our current study. Moreover, recent studies demonstrated that irisin may actively play a CV-protective role through the following mechanisms: First, irisin could attenuate myocardial ischemia/reperfusion injury. In myocardial infarction mouse models, irisin treatment promoted angiogenesis, improved cardiac function, and reduced infarct size through activating the ERK signaling pathway [20]. Lu et al. found that irisin could ameliorate ischemia/reperfusion-induced cardiac dysfunction by activating mitochondrial ubiquitin ligase (MITOL), which inhibits hypoxia, reactive oxygen species generation, and apoptosis in cardiomyocytes [21, 22]. In recent studies, transplantation of cardiac progenitor cells, a specific regenerative cell source of the heart, was suggested to be a new approach for ischemic cardiac repair [23]. Animal studies showed that irisin treatment promoted cardiac progenitor cell-induced cardiac regeneration through increasing cardiac lineage commitment, enhancing neovascularization, and protecting against apoptosis [24]. Second, irisin may alleviate cardiac remodeling, which is a key pathophysiological process that leads to heart failure. Basic studies revealed that irisin inhibits cardiac remodeling in rats with pressure overload-induced cardiac hypertrophy by inhibiting oxidative stress [25] and increasing protective autophagy [26]. Third, irisin has been found to ameliorate atherosclerosis. In an apolipoprotein E-null diabetic mouse model, the systemic administration of irisin inhibits endothelial apoptosis, improves endothelial dysfunction, and decreases atherosclerotic plaque area [27]. Fourth, irisin may protect against vascular calcification. Vascular calcification was suggested to be an important contributor of CV mortality in patients with ESRD [28]. Advanced studies revealed that irisin treatment could alleviate vascular calcification by activating AMPK pathway, inhibiting mitochondria dysfunction, and suppressing the osteoblastic transformation of vascular smooth muscle cells [29]. The CV-protective functions of irisin make it a potential treating target to improve the CV outcomes of dialysis patients, which needs further study.

Severe infection is the second cause of death in our PD patients. Low serum irisin levels were correlated with higher infection-related mortality in this study. Wei et al. [30] reported that serum irisin was decreased in patients with sepsis. Moreover, recent research found that irisin could attenuate sepsis-associated organ injury. Wang et al. [31] found that irisin ameliorated inflammatory microenvironment in sepsis-associated encephalopathy by suppressing hippocampus ferroptosis via the Nrf2/GPX4 signaling pathway. Also, irisin treatment protected against sepsis-induced cardiac dysfunction by activating MITOL [32] and inhibiting pyroptosis, inflammation, and apoptosis [33]. The inhibition of inflammation and apoptosis by irisin also countered the sepsis-induced lung and liver dysfunctions [34, 35]. Since refractory PD-associated peritonitis is an important cause of technique failure in PD patients, more studies are needed to investigate the role of irisin in PD-associated peritonitis.

There were several limitations in the study. First, it was a single-center study and a center-specific effect was possible. Second, the study had a relatively small sample size and thus limited generalizability. Residual confounding factors could not be completely excluded. Third, the observational nature of the study precluded us to draw a causal conclusion between low serum irisin levels and the poor prognosis in PD patients. Fourth, a single time point measurement of serum irisin was performed, and the effects of time-varying irisin need further study.

This study suggested that low serum irisin levels were independently associated with CV mortality but not all-cause mortality in patients with ESRD on PD. Further large-scale studies are needed to explore the effective intervention to change serum irisin and its benefits to improve the CV outcomes of PD patients.

This study was approved by the Ethics Committee of Peking University Third Hospital (M2018043). The study procedure was conducted in accordance with the principles laid down by the Declaration of Helsinki. All the participants provided their written informed consent.

The authors have no conflicts of interest to declare.

This work was supported by the National Natural Science Foundation of China under Grant No. 81873619 and the Huizhi Talents Leading Cultivation Program of Xuanwu Hospital of Capital Medical University to Aihua Zhang, Key Clinical Program of Peking University Third Hospital under Grant No. BYSYZD2019039 to Sijia Zhou, and Key Clinical Program of Peking University Third Hospital under Grant No. BYSYZD2021036 to Qiong Bai.

Sijia Zhou and Aihua Zhang conceived the idea of this study. Wen Tang assisted in the data collection. Sijia Zhou wrote the final report. Xiaoxiao Wang, Qingfeng Han, and Qiong Bai assisted in the statistical analysis. Aihua Zhang and Qiong Bai reviewed the article and provided mentorship. All authors read and approved the final manuscript.

The data that support the findings of this study are not publicly available due to information that could compromise the privacy of research participants, but are available from Prof. Aihua Zhang, MD, PhD (corresponding author).

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