Interleukin-18 A Predictive Marker of Major Adverse Cardiovascular Events in Hemodialysis Patients

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1 CLINICAL STUDY Interleukin-18 A Predictive Marker of Major Adverse Cardiovascular Events in Hemodialysis Patients Shiying Wang, 1,* MD, Fang Chen, 1,* MD, Suxia Yang, 1 MD and Jun Shi, 1 MD Summary A prospective observational study was conducted to evaluate the predictive value of interleukin-18 (IL-18) for major adverse cardiovascular events (MACEs) in hemodialysis patients. A total of 85 participants (45 hemodialysis patients and 40 healthy volunteers) with a mean age of 56.3 years were enrolled in this study. Demographic and clinical data were collected. MACE was used as the primary endpoint. Results showed that the hemodialysis patients had higher levels of IL-18 ( versus pg/ml, P < 0.01) and a high rate of MACE (15.6% versus 2.5%, P < 0.01) compared with healthy controls. Multiple linear regression analysis showed that the serum creatinine and left ventricular ejection fraction were significantly effective factors influencing IL-18 (P < 0.01). Receiver-operating characteristic curve analysis showed that IL-18 levels were better predictors for MACE. The area under the curve of IL-18 was 0.81 ( ) (P = 0.004). IL-18 levels provided 87.5% sensitivity and 26% specificity with a threshold value of pg/ml. Our findings indicated that hemodialysis patients with high levels of IL-18 had a high incidence rate of MACE. IL-18 is a good predictive marker of MACE in hemodialysis patients. (Int Heart J Advance Publication) Key words: Predictive value C hronic kidney disease (CKD) is a worldwide health problem and has over 10-fold increased risk of cardiovascular disease mortality compared with age-matched general population. 1) Although hemodialysis is an effective replacement therapy for improving the prognosis of end-stage renal disease (ESRD) patients, a high rate of major adverse cardiovascular events (MACEs) still occurs in hemodialysis patients. 2) Therefore, identifying an early and effective marker to predict MACE in hemodialysis patients will be valuable for early intervention and decreased cardiovascular mortality. IL-18 is a cytokine that belongs to the IL-1 superfamily that can induce immunological response and inflammatory reactions. 3,4) Previous findings show that inflammatory disorder exists in hemodialysis patients and that serum levels of IL-18 were increased in chronic renal failure and continuous ambulatory peritoneal dialysis patients. 5) Recently, Formanowicz, et al. 6) demonstrated that IL-18 predicted cardiovascular mortality in CKD patients. However, it is not known whether IL-18 is a good indicator for predicting MACE in hemodialysis patients. We performed a prospective observational study. The primary endpoint is MACE during the one-year follow-up period. The levels of IL-18 and the survival rate of non- MACE among the participants were compared. We aim to investigate the predictive value of IL-18 for MACE in hemodialysis patients and to explore the influencing factors of IL-18. Methods Study population: Between January 2014 and December 2016, a total of 85 participants at Huaihe Hospital of Henan University were initially enrolled in this study. Forty participants were healthy volunteers, and 45 participants were hemodialysis patients. The healthy controls were sex and age matched with hemodialysis patients. The hemodialysis patients underwent regular dialysis for at least six months. Exclusion criteria were age < 18 years and those suffering from acute cardiovascular and cerebrovascular ischemia diseases, severe infection, severe hepatic failure, or malignant tumor. All participants were followed up for one year. The study endpoint was MACE. The primary MACE outcome included cardiovascular death, myocardial infarction, stroke or heart failure, severe and life threatening cardiac rhythm (ventricular tachycardia and ventricular fibrillation), and all-cause mortality. 7) The study was conducted in accordance with the ethical standards of the Henan University Ethics Committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants included in the study. Data collection: Demographic and clinical data were collected: age, gender, body mass index, systolic blood pres- From the 1 Department of Nephrology, Huaihe Hospital of Henan University, Henan, China. * These authors contributed equally to this study Address for correspondence: Jun Shi, MD, Department of Nephrology, Huaihe Hospital of Henan University, Ximen Street No. 115, Henan , China. shidocjun@sohu.com Received for publication March 18, Revised and accepted August 8, Released in advance online on J-STAGE July 18, doi: /ihj All rights reserved by the International Heart Journal Association. 1

2 2 Wang, ET AL IntHeartJ Advance Publication Table I. Demographic and Clinical Characteristics of Healthy Controls and Hemodialysis Patients Control (n = 40) HD (n = 45) Age (years) 53.5 ± ± Sex ratio (Male/Female) 22/18 28/ Mean period of HD (years) MACE (n) 1 7 < 0.01 Cause of MACE (n) Sudden death 1 - CVD 1 - Heart failure 2 - Stroke 1 - MI 3 - BMI (kg/m 2 ) 25.6 ± ± SBP (mmhg) ± ± 1.9 < 0.01 DBP (mmhg) 78.7 ± ± 1.25 < 0.01 Glucose (mmol/l) 4.8 ± ± Creatinine (umol/l) 82.4 ± ± < 0.01 TC (mmol/l) 4.2 ± ± Triglycerides (mmol/l) 1.2 ± ± LDL-c (mmol/l) 2.4 ± ± IL-18 (pg/ml) ± ± < 0.01 hs-crp (mg/l) 0.85 ± ± 3.2 < 0.01 LA (mm) 32 (30-35) 38 (33-42) < 0.01 LVDd (mm) 46 (42-49) 51 (46-60) LVPWd (mm) 9 (8-10) 11 (9-13) LVEF (mm) 55 ± 6 46 ± 10 < 0.01 Continuous data were expressed as means ± standard error (SEM) when in normal distribution, or median [interquartile range (IQR) ] in skewed distribution and were compared using t-test or Mann-Whitney U test according to data distribution. A P value < 0.05 (two-tailed test) was considered significant. BMI indicates body mass index; CVD, cardiovascular death; DBP, diastolic blood pressure; HD, hemodialysis; hs-cpr, high-sensitivity C-reactive protein; IL-18, interleukin-18; LA, left atrium; LDL-c, low-density lipoprotein cholesterol; LVDd, left ventricular diastolic dimension; LVEF, left ventricular ejection; LVPWd, left ventricular posterior wall depth; MI, myocardial infarction; SBP, systolic blood pressure; and TC, total cholesterol. sure (SBP), diastolic blood pressure (DBP), heart rate, duration of dialysis, and medical history. Venous blood samples were drawn after overnight fasting. Serum samples were obtained after suitable centrifugation and stored at -80 C. Laboratory data were measured from blood samples, including glucose, creatinine, total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-c), and high-sensitivity C- reactive protein (hs-crp) (Siemens Healthcare Diagnostics Inc., Marburg, Germany). Serum IL-18 was measured by using commercial sandwich enzyme-linked immunoassay kits (MBL Co., Ltd., Nagoya, Japan) with detection threshold of 7.8 pg/ ml. All participants underwent 2D Doppler (Vivid 3, GE VingMed Ultrasound; Haifa, Israel) echocardiography examination. Echocardiographic parameters, including left ventricular ejection fraction (LVEF), left atrium (LA), left ventricular diastolic dimension (LVDd), and left ventricular posterior wall depth (LVPWd), were measured. Statistical analysis: Continuous data were expressed as means standard error when in normal distribution or median (interquartile range) in skewed distribution and P were compared using t-test or Mann-Whitney U test according to data distribution. Statistical analyses were performed using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). Non-MACE survival related to IL-18 levels was analyzed in a Kaplan-Meier model. Receiver-operating characteristic (ROC) curve analysis was used to quantify the assessing value of IL-18 for MACE. Multiple linear regression analysis was calculated for the correlation of variables with IL-18 levels. A P value < 0.05 (two-tailed test) was considered significant. Results Demographic and clinical characteristics of enrolled participants at baseline: A total of 85 participants with a mean age of 56.3 years were enrolled in this study. The admission causes of the 45 hemodialysis patients were chronic glomerulonephritis (n = 15), diabetic nephropathy (n = 10), hypertensive nephropathy (n = 12), polycystic kidney disease (n = 5 patients), and other etiologies (n = 3). Hemodialysis patients were maintained on their regular prescription, three times per week for 4-5 hours per session. The blood flow ranged from 250 to 300 ml/minute, with a dialysate flow rate of ml/minute. The mean duration of hemodialysis was 2.5 years in hemodialysis patients. The baseline demographic and clinical characteristics of the participants are shown in Table I. The hemodialysis patients had significant higher levels of IL-18 than healthy controls ( versus pg/ml, P < 0.01). Furthermore, SBP, DBP, creatinine, and hs-crp were significantly higher and LVEF was significantly lower in hemodialysis patients (P < 0.01) than in healthy controls. However, no significant difference was found in glucose, TC, triglycerides, LDL-c, LA, LVDd, and LVPWd (P > 0.05). Predictive value of IL-18 for MACE in hemodialysis patients: During the one-year follow-up period, one participant (2.5%) in the control group suffered sudden death, whereas seven participants (15.6%) in the hemodialysis group had MACE. In particular, the seven participants with MACE in the hemodialysis group suffered cardiovascular death (n = 1), myocardial infarction (n = 3), heart failure (n = 2), and stroke (n = 1) (Table I). Kaplan-Meier survival curve analysis was performed to analyze the predictive value of IL-18 for MACE in hemodialysis patients, as shown in Figure 1. The hemodialysis patients with higher levels of IL-18 had a significantly lower non- MACE survival rate (P = 0.011). ROC curve analysis was further used to analyze whether IL-18 levels could be better predictors for MACE than other factors. The area under the curve of IL-18 was 0.81 ( ) (P = 0.004). IL-18 levels provided 87.5% sensitivity and 26% specificity with a threshold value of pg/ml (Figure 2). Multivariate correlation analysis of IL-18 levels: As shown in Table II, multiple linear regressions were performed to assess the relationships between serum IL-18 levels and other factors. In hemodialysis patients, serum IL-18 levels were significantly correlated with hs-crp, creatinine, SBP, DBP, and LVEF (P < 0.05). However, no significant relationship was found in glucose, TC, LDL-c, triglycerides, and echocardiographic parameters LA,

3 IntHeartJ Advance Publication IL-18 and MACE 3 Figure 1. Kaplan-Meier survival curves according to interleukin-18 (IL-18) levels. We grouped hemodialysis patients on the basis of median IL-18 levels (197 pg/ml): patients with IL-18 levels more than and less than 197 pg/ml were placed in the high IL-18 group and low IL-18 group, respectively. The comparison of the non-major adverse cardiovascular events (non-maces) survival rate between groups showed a significant difference (P = 0.011). Table II. Multivariate Correlation Analysis of IL-18. Figure 2. Receiver-operating characteristic (ROC) curve for interleukin-18 (IL-18) in assessing major adverse cardiovascular events (MACEs). For each screening test, sensitivity is plotted against 100% specificity. LVDd, and LVPWd (P > 0.05). Discussion In this observational study, we demonstrated that the serum levels of IL-18 were elevated and that IL-18 was a good predictive marker of MACE in hemodialysis patients. Serum creatinine and LVEF are the effective factors that influence IL-18 levels in hemodialysis patients. Cardiovascular disease mortality is the leading cause of death in hemodialysis patients. A series of risk factors has been found to be related with MACE for hemodialysis patients, such as LDL-c, hypertension, diabetes, vascular Variable IL-18 r P Glucose (mmol/l) hs-crp (mg/l) 0.43 < 0.01 Creatinine (umol/l) 0.35 < 0.01 TC (mmol/l) Triglycerides (mmol/l) LDL-c (mmol/l) SBP (mmhg) DBP (mmhg) LA (mm) LVDd (mm) LVPWd (mm) LVEF (mm) 0.36 < 0.01 r denotes multiple linear regression. A P value < 0.05 was considered significant. DBP indicates diastolic blood pressure; hs-crp, highsensitivity C-reactive protein; IL-18, interleukin-18; LA, left atrium; LDL-c, low-density lipoprotein cholesterol; LVDd, left ventricular diastolic dimension; LVEF, left ventricular ejection; LVPWd, left ventricular posterior wall depth; SBP, systolic blood pressure; and TC, total cholesterol. calcification, malnutrition, and neutrophil-to-lymphocyte ratio. 8-10) All these risk factors can induce the elevation of a number of serum inflammatory cytokines in hemodialysis patients, such as C-reactive protein, IL-6, and IL ) IL-18 is also an important inflammatory cytokine that can be elevated in ESRD patients. Yong, et al. 12) showed that IL-18 was elevated in CKD stage 5 compared with that in CKD stages 3-4 and healthy controls. In their study, they found that only glomerular filtration rate was an inde-

4 4 Wang, ET AL IntHeartJ Advance Publication pendent predictor of IL-18. Chiang, et al. 13) demonstrated that hemodialysis patients with high levels of IL-18 had a higher probability of hospitalization event during the follow-up period. In another study, Formanowicz, et al. 6) found that serum IL-18 concentration was increased in various stages of CKD. IL-18 was found to be superior to well-known cardiovascular risk parameters, such as hs- CRP, carotid intima media thickness, glomerular filtration rate, albumins, ferritin, and N-terminal prohormone of brain natriuretic peptide, in the prognosis of cardiovascular mortality in CKD. In agreement with previous studies, we also found that serum IL-18 levels were significantly elevated in hemodialysis patients. More importantly, we demonstrated that IL-18 was a good predictor for MACE in hemodialysis patients. IL-18 levels provided 87.5% sensitivity and 26% specificity with a threshold value of pg/ml for MACE in hemodialysis patients. There are several reasons for the elevation of IL-18 in hemodialysis patients. First, IL-18 is a middle molecule and a protein-bond uremic toxin, and it is difficult to remove by currently available dialysis strategies. 14) Second, IL-18 can be secreted by mononuclear phagocytes, and these cells are activated in hemodialysis patients. 15,16) Third, we found that LVEF significantly influenced IL-18 levels in accordance with previous studies. Mallat, et al. 17) demonstrated that plasma IL-18 levels were significantly elevated in patients with heart failure. In fact, regardless of the reason for the elevation of IL-18, it at least implies that IL-18 is elevated in hemodialysis patients and is a good and useful indicator for predicting MACE. Previous studies have explored the possible reasons for the increase in MACE by IL-18. Atherosclerosis is a leading cause for MACE, and it was found that IL-18 was highly expressed in human atherosclerotic plaque and significantly associated with plaque instability. 18) By using an animal experiment, Whitman, et al. 19) demonstrated that IL-18 enhanced atherosclerosis in apolipoprotein E(-/-) mice via the release of interferon gamma. In our study, we found that IL-18 was significantly associated with the inflammatory marker hs-crp. Inducing inflammatory reactions by IL-18 may be another key mechanism for enhancing MACE in hemodialysis patients. Inflammation was found to increase the risk of MACE. 20,21) IL-18 has been demonstrated to play a crucial role in the inflammatory cascade by activating monocytes, macrophages, lymphocytes, and endothelial cells. 22) However, more studies are needed to explore the mechanisms for the enhancement of MACE by IL-18 in hemodialysis patients. Study limitations: There are some limitations in the current study. First, the number of patients is small, and the follow-up period is short. Furthermore, we did not conduct subgroup analysis with regard to the influence of diabetes and hypertension on IL-18 levels. Larger scale and long-term follow-up studies are required to verify the relationship between the common risk factor of MACE and IL-18. Second, other factors may also influence MACE, such as IL-12, 12,23) which we did not estimate in this study. Third, we did not compare IL-18 with other inflammatory cytokines in predicting MACE in hemodialysis. Conclusions We demonstrated that hemodialysis patients have high levels of IL-18 and a high rate of MACE. IL-18 is a good predictive marker of MACE in hemodialysis patients. Therefore, IL-18 can be used in clinic practice for the early detection and management of clinically silent cardiovascular diseases. Disclosures Conflicts of interest: The authors declare that they have no conflict of interest. References 1. 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5 IntHeartJ Advance Publication IL-18 and MACE 5 Schönbeck U. Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med 2002; 195: Mallat Z, Heymes C, Corbaz A, et al. Evidence for altered interleukin 18 (IL)-18 pathway in human heart failure. FASEB J 2004; 18: Mallat Z, Corbaz A, Scoazec A, et al. Expression of interleukin- 18 in human atherosclerotic plaques and relation to plaque instability. Circulation 2001; 104: Whitman SC, Ravisankar P, Daugherty A. Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma. Circ Res 2002; 90: E Wada H, Dohi T, Miyauchi K, et al. Independent and combined effects of serum albumin and C-reactive protein on long-term outcomes of patients undergoing percutaneous coronary intervention. Circ J 2017; 81: Minamisawa M, Motoki H, Izawa A, et al. Comparison of inflammatory biomarkers in outpatients with prior myocardial infarction. Int Heart J 2016; 57: Gao Y, Tong GX, Zhang XW, et al. Interleukin-18 levels on admission are associated with mid-term adverse clinical events in patients with ST-segment elevation acute myocardial infarction undergoing percutaneous coronary intervention. Int Heart J 2010; 51: Minamisawa M, Miura T, Motoki H, et al. Prognostic impact of diastolic wall strain in patients at risk for heart failure. Int Heart J 2017; 58:

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