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NDT Advance Access published online on September 4, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn486
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


IL-18 is involved in vascular injury in end-stage renal disease patients

Tomasz Porazko1, Jakub Kuzniar1, Mariusz Kusztal1, Tomasz J. Kuzniar2, Waclaw Weyde1, Magdalena Kuriata-Kordek1 and Marian Klinger1

1 Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland 2 Sleep Disorders Center, Mayo Clinic, Rochester, MN 55905, USA

Correspondence and offprint requests to: Tomasz Porazko, Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, ul. Traugutta 57/59, 50-417 Wroclaw, Poland. Tel: +48-717332504; Fax: +48-717332509; E-mail: porazko{at}gazeta.pl



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. The role of interleukin (IL)-6 and IL-18 in induction of the inflammatory reaction underlying arteriosclerosis, and protective effect of an anti-inflammatory cytokine IL-10 in this process, have been confirmed by experimental and clinical observations. A systemic inflammatory reaction marker, C-reactive protein (CRP), is known to be associated with the induction of IL-6 and IL-18 release. The chronic inflammatory state associated with renal insufficiency contributes to acceleration of arteriosclerosis, reflected by decreased elasticity which can be measured with aortal pulse wave velocity (PWV). It is well known that chronic kidney disease (CKD) is associated with the chronic inflammatory process, as evidenced by increase in CRP and IL-6 level. It also results in a drop of fetuin-A concentration which is the calcification inhibitor negatively regulated by inflammation. Part of the derangements associated with the progressive renal failure is also the rise of activated monocyte pool, which among others produces IL-18. The aim of the present study was to evaluate, through measurements of CRP, fetuin-A and aortal pulse wave velocity (aoPWV), whether IL-6 and IL-18 affect the arterial wall of CKD patients as a part of general inflammatory process or locally, through their effect on the arterial lesion development.

Materials and methods. The study was performed in a group of 102 patients with stage V CKD (73 treated with haemodialysis and 29 treated with continuous ambulatory peritoneal dialysis) (CKD5 group) and in 30 healthy controls. We measured serum high-sensitivity C-reactive protein (hs-CRP), fetuin-A, IL-6, IL-18, IL-10 (ELISA) and others (haemoglobin level, white blood cell count, serum calcium, phosphate, calcium–phosphate product, albumin, fibrinogen, cholesterol, high-density lipoprotein (HDL), triglycerides and parathormone). ECG-gated carotid and femoral artery waveforms were recorded and analysed.

Results. Serum levels of hs-CRP, IL-6, IL-10 and IL-18 were higher and fetuin-A levels were lower in the CKD5 group than in controls [6.4 (0.6–22.3) mg/dl versus 2.5 (0.5–5.2) mg/dl; 8.29 pg/ml (0.96–74.48)] versus 2.78 (7.91–0.77) pg/ml; 6.5 (3.7–29.7) pg/ml versus 4.1 (3.8–7.2) pg/ml; 254.4 (468.8–47.5) pg/ml versus 89.3 (91.3–27.5) pg/ml]. The aoPWV was higher in the CKD5 group patients than in the control group (9.4 ± 1.75 m/s versus 7.76 ± 1.67 m/s; P < 0.05, respectively). Serum fetuin-A level was negatively associated with hs-CRP and IL-6 but not with IL-18 or IL-10. The aoPWV positively correlated with hs-CRP (r = 0.246; P < 0.05), IL-6 and IL-18 (r = 0.220; P < 0.05) and negatively correlated with fetuin-A (r = –0.204; P < 0.05). No relationship between IL-10 and aoPWV was found. In a multiple regression analysis model respecting inflammatory markers the influence of hs-CRP, IL-18 and fetuin-A on aoPWV remained significant.

Conclusions. The novel observations in the present study are the data indicating that the distinctive contribution of IL-18, but not IL-6, to the arteriosclerosis occurrence in CKD patients, is independent from CRP, fetuin A or other factors involved in the general inflammatory process.

Keywords: chronic kidney disease; ESRD; IL-18; pulse wave velocity; vascular injury



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Decreased elasticity of the aorta and main conducting arteries measured with pulse wave velocity (PWV) is an independent risk factor of cardiovascular morbidity and mortality among patients with chronic renal disease. It is strictly associated with decline of the glomerular filtration rate (GFR) [1,2]. Increased arterial stiffness in this population is caused by accelerated arteriosclerosis, atherosclerosis and vascular calcification [3,4]. Chronic inflammatory state, commonly observed in renal insufficiency, contributes to acceleration of atherosclerosis [5]. It has been widely reported that serum concentration of inflammatory marker C-reactive protein (CRP) and interleukin (IL)-6 is significantly associated with high cardiovascular morbidity and mortality rate among patients treated with haemodialysis and peritoneal dialysis [6,7,8]. The association of CRP and induction of IL-18 release has been documented in some studies [9,10]. Numerous reports indicate that patients with chronic kidney disease (CKD) have elevated serum levels of IL-18 [11], likely related to a greater percentage of active circulating monocytes, the main cellular source of this cytokine [12,13,14]. A variety of microbial products can stimulate cytokine production by these cells [13]. IL-18, through the induction of Th1 cells [13] to secretion of INF-{gamma}, plays a pivotal role in inflammation-related vascular injury [15], intimal atherosclerotic plaque formation [16] and its instability [17]. Clinical observations revealed associations between higher serum concentrations of IL-18 and the carotid intima-media thickness (IMT) [10] and also with poor outcome of subjects with coronary artery disease [18,9]. Elevated serum level of IL-18 is also a predictor of the higher hospitalization rate among patients with CKD on haemo- and peritoneal dialysis [19,20].

Induction of acute phase reaction is accompanied by the release of regulatory cytokine—IL-10 from immunocompetent cells with some delay after the release of pro-inflammatory cytokines [11,21]. IL-10 seems to have protective, anti-inflammatory and anti-atherogenic properties [21]. The magnitude of IL-10 response is related to the presence of certain alleles of specific genes [22], which has also been described in patients with CKD [23,24]. Chronic inflammatory state as observed in the CKD population is associated with vascular calcification, especially medial calcification [25,23]. This increased propensity of patients with CKD to vascular calcification was recently explained by the decreased serum concentration of fetuin-A [26], a circulating inhibitor of calcium phosphate precipitation [27] and a negative acute phase reactant [21].

Data from clinical observation of patients with CKD show that low levels of fetuin-A were accompanied by inflammation, malnutrition and highly advanced vascular calcification measured with electron-beam computed tomography. Low fetuin-A levels were also a strong predictor of high morbidity and poor outcome [26]. Deposits of fetuin-A were detected in the calcified arterial wall, which suggest its role in the process of vascular degeneration [27].

Based on these observations, we analysed the possible influence of the markers of inflammatory state—CRP, IL-6, IL-18, anti-inflammatory IL-10, calcification inhibitor fetuin-A and other biochemical risk factors (cholesterol, triglycerides, fibrinogen and albumin) on arterial wall stiffness as measured with aortal pulse wave velocity (aoPWV) in patients with stage V CKD.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
The study was approved by Bioethics Committee, Wroclaw Medical University. Informed consent was obtained from all participants. All included patients fulfilled criteria and completed the study.

Characteristic of studied groups
One hundred and two patients with stage V CKD (CKD5 group) from the Department of Nephrology and Transplantation Medicine, Wroclaw Medical University Hospital were included in the study. There were 73 Caucasian patients (27 females, 45 males), aged 58.0 ± 12.8 (mean ± SD) years, haemodialyzed for 44.0 ± 32.4 months, with prescriptions of 4.5–5.5 h/session, 3–4 times per week to achieve Kt/V ≥1.2 (mean 1.35 ± 0.12). The level of residual renal function was 500 ± 100 ml/day. There were also 29 Caucasian patients (18 female, 11 males), aged 50.1 ± 14.9 years, treated with continuous ambulatory peritoneal dialysis (CAPD) for 27.6 ± 11.2 months, with standard prescriptions of 4 dwells per day to achieve total weekly Kt/V 1.81 ± 0.45 and total weekly CCr 59 ± 16 l /1.73 m2. The level of residual renal function was 700 ± 200 ml/day. There were no significant differences between HD and CAPD groups according to age, female/male ratio and percentage of diabetic patients (27% versus 20%; P = NS) and smokers (30% versus 21%; P = NS). Causes of CKD and subsequent treatment are listed in Tables 1 and 2, respectively. Subjects were excluded from the study if: 1) they spent less than 6 months on dialysis, 2) were less than 18 years old, 3) had a history and symptoms of cardiovascular disease and cardiovascular instability in the past (myocardial infarction, congestive heart failure, arrhythmia, heart rate <65/min, peripheral vascular disease, transient ischemic attacks or cerebrovascular accidents, 4) had a current or recent (<1 month) active infection, 5) had liver disease, 6) had a catheter or graft as vascular access (for HD group).


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  		Table 1 Causes of CKD in the studied group

 

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  		Table 2 Subsequent treatment in the studied group

 
The control group included 30 healthy volunteers (14 females, 16 males) aged 57.6 ± 9.8 years.

PWV measurements
All measurements were performed on the haemodialyzed patients in the morning, on the day following their midweek dialysis. Patients rested in the supine position for 20 min in a quiet, temperature-controlled room and had their blood pressure measured with a mercury sphyngomanometer. PWV and carotid–femoral PWV (c–f PWV) were determined as previously described [31] by acquisition of pulse waves from the carotid and the femoral arteries using high-fidelity tonometer (Millar Instruments, INC Houston, TX, USA), referenced with the R waves on a simultaneously recorded ECG, by calculation of the difference in carotid to femoral path length (distance from sternal notch to femoral measurement point minus distance from sternal notch to carotid measurement point in direct line) divided by the difference in R wave to waveform foot times using SphygmoCor apparatus (AtCor Medical Pty. Ltd., Sydney, Australia) and customized software. In patients with CAPD, the measurements were performed during the exchange procedure, after draining out of the dialysate. All the measurements were performed by a single operator. Intraobserver coefficients of variation were estimated of 10 volunteers and 10 end-stage renal disease (ESRD) patients as previously described [32]; they were 4.4% and 4.9%, respectively. Intraobserver error was 5.5% in repeated, 4-h gated measurements in 10 HD patients.

Biochemical measurements
Blood samples were obtained after c–f PWV measurements. White blood cell count (WBC), haemoglobin, calcium, phosphorus, albumin, cholesterol, triglycerides, high-density lipoprotein-cholesterol (HDL), hs-CRP (latex enhanced immunoturbidimetric method with detection limit 0.07 mg/l; Roche Diagnostic, Mannheim, Germany), fibrinogen, serum IL-6, IL-10 (RnD Systems Minneapolis, MN, USA; with detection limit 0.7 pg/ml and 3.9 pg/ml, respectively) and IL-18 (MBL, Nagoya, Japan; with detection limit 12.5 pg/ml) were analysed [29]. Fetuin-A concentration was measured by indirect ELISA method as previously described [26]. Briefly, analysed sera were prediluted 1:10 000 in a 0.1 M solution of NaCO3 and NaHCO3, coated onto plates and incubated at temperature +4°C for minimum 16 h. Plates were then rinsed with 1% PBS buffer and filled with anti-human fetuin mouse monoclonal antibody (RnD Systems Minneapolis, MN, USA) and then incubated for 1 h at +22°C. Thereafter plates were rinsed three times with 1% PBS, and a polyclonal rabbit antibody (RnD Systems Minneapolis, MN, USA) labelled with peroxidase was added. The 2,2'-azino-di (3-ethyl-benzthiazoline-6-sulfonate) (ABTS, Roche, Germany) was used as a substrate. After 15-min incubation, the extinction at 405 nm was measured using Dynatec MR 5000 reader (Dynex Technologies, Denkendorf, Germany) and compared with the standard curve for human fetuin. Measurements were performed twice in two series. Inter- and intra-assay coefficients of variation were 8.6% and 10.2%, respectively. The limit of detection for fetuin-A was 0.03 g/l.

Statistical analysis
All values are expressed as means ± SD or median and range when not normally distributed, unless stated in the text. Comparisons between groups were made using the Student t-test for variables normally distributed and the Mann-Withney U-test for values not normally distributed. Spearman's and Pearson's correlation coefficient were used for bivariate correlation calculations. The multiple, standard, linear regression analysis model was used to study revealed correlations. All parameters that were significantly associated in linear manner with c–f PWV were introduced in the model. A P < 0.05 was considered statistically significant. All analyses were performed using the Statistica 5.1 software package (Statsoft Inc., OK, USA).



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Clinical data, inflammatory markers and arterial wall elasticity in studied groups
Characteristics of studied groups are listed in Table 3. There were no differences in age, male/female ratio and percentage of smokers between observed groups. Control subjects had significantly higher body mass index (BMI) than the CKD5 group.


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  		Table 3 Characteristic of the studied group and controls

 
The systolic, mean and pulse pressures were higher in the CKD5 group. Patients in CKD5 group had higher values of aoPWV than the controls. Serum concentrations of haemoglobin, albumin, HDL and calcium were lower in the CKD5 group whereas serum triglycerides, phosphorus and calcium–phosphorus product were significantly higher in control subjects. Values of total cholesterol did not differ statistically between analysed populations.

Serum levels of pro-inflammatory markers such as hs-CRP, IL-6, IL-18, fibrinogen, WBC and anti-inflammatory IL-10, were statistically higher in CKD5 group than in control group. Serum concentrations of fetuin-A were significantly lower in patients with CKD5 group than in age- and gender-comparable healthy subjects.

Determinants of arterial stiffness
The aoPWV positively correlated with age (r = 0.52; P < 0.05), BMI (r = 0.26; P < 0.05), pulse pressure (r = 0.43; P < 0.05), time on dialysis (r = 0.32; P < 0.05), WBC (r = 0.27; P < 0.05), hs-CRP (r = 0.25; P < 0.05) (Figure 1), IL-6 (r = 0.24; P < 0.05) and IL-18 levels (r = 0.22; P < 0.05) (Figure 2) (Table 4).


Figure 1
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  		Fig. 1 Linear association between variables aoPWV (m/s) and hs-CRP (mg/dl). r = 0.24; P < 0.05.

 

Figure 2
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  		Fig. 2 Linear association between variables aoPWV (m/s) and IL-18 (pg/dl). r = 0.22; P < 0.005.

 

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  		Table 4 Associations between demographic, biochemical, inflammatory markers, Fetuin-A and aortal pulse wave velocity (aoPWV) in patients with ESRD. Pearson's coefficients (r) of correlation are presented. All presented variables are significantly correlated with aoPWV (P < 0.05)

 
Arterial wall elasticity measured with aoPWV was negatively associated with DBP (r = –0.32; P < 0.05), serum albumin (r = –0.38; P < 0.05), HDL (r = –0.25; P < 0.05) and fetuin-A (r = –0.20; P < 0.05) (Figure 3). No relationship between IL-10 and aoPWV was found.


Figure 3
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  		Fig. 3 Linear association between variables aoPWV (m/s) and fetuin-A (g/dl). r = –0.20; P < 0.05.

 
In multiple, linear regression analysis age, DBP, hs-CRP, IL-18 and fetuin-A were found to be independent determinants of aoPWV (r2 = 0.54; P < 0.0002) (Table 5). No correlation was found with IL-6. There was no influence of aetiology of CKD, smoking habit and treatment on the aoPWV values.


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  		Table 5 Multiple, linear regression analysis of the aortic pulse wave velocity, treated as a dependent variable and age, diastolic blood pressure (DBP), C-reactive protein (CRP), IL-18 and fetuin-A concentrations (r2 = 0.54; P < 0.0002)

 
Associations of biochemical, inflammatory state markers and fetuin-A
Serum fetuin-A level was negatively associated with hs-CRP (r = –0.27; P < 0.05) and IL-6 (r = –0.32; P < 0.05), but positively with serum albumin (r = 0.4; P < 0.05) and with Ca x P product (r = 0.23; P < 0.05). No correlation was found with IL-18 or IL-10. Etiology of chronic kidney disease, smoking habit and treatment had no influence on serum concentrations of CRP, IL-6, IL-10, IL-18 or fetuin-A.

Arterial stiffness in control group
In the control group, aoPWV correlated positively with age (r = 0.5411; P < 0.05), BMI (r = 0.24; P < 0.05), SBP (r = 0.22; P < 0.05) and MBP (r = 0.30; P < 0.05). In linear, multiple regression analysis age, SBP and MBP were found to be independent predictors of arterial stiffness measured with aoPWV (r2 = 0.61; P < 0.00001).



   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
Independent association of elevated IL-18 and PWV that was detected in our study confirms the involvement of this cytokine in injury of the arterial wall, especially in stage V CKD patients. To our knowledge, this is the first report of IL-18 and fetuin-A as independent determinants of arterial wall stiffness in patients with chronic kidney disease.

IL-18 is a local, pro-inflammatory stimulant of atheromatous plaque formation in the arterial intima [16] and, via induction of INF-{gamma} secretion, plays a pivotal role in their instability [17]. Experimental data suggest that IL-18 stimulates proliferation of the vascular intima acting via a specific receptor on vascular smooth muscle cells [33]. IL-18 promotes collagen and lipid deposition by stimulating INF-{gamma} secretion [34]. IL-18 has previously been described to be strictly associated with inflammation localized within the arterial wall and the incidence of cardiovascular events [9,17]. It is well described that patients with CKD have higher serum concentrations of IL-18 than the general population [19,11,16] and that a decrease in GFR is associated with a rise in IL-18 [35], but is also dependent on other CKD-related factors [29].

Patients with CKD treated with haemodialysis and peritoneal dialysis, with higher concentrations of IL-18 had higher hospitalization rate, higher cardiovascular morbidity and mortality and lower overall survival than those with lower IL-18 levels [19,20].

Several lines of evidence indicate that elevated IL-18 levels translate into higher severity of arteriosclerosis. Observations made in a general population revealed that elevated IL-18 levels were associated with higher carotid IMT independent of classic risk factors and markers of systemic inflammatory response such as CRP and IL-6 [10].

In patients with CKD, high IL-18 levels may be related to uraemia-specific factors, such as accumulation of active monocytes—the primary cellular source of this cytokine [19,14].

IL-18 may also accelerate the arterial injury in CKD through the induction of lymphocyte differentiation towards Th-1 cells, the primary source of IFN-{gamma} [36,37]. Th1, but not Th2 cells, express receptor for IL-18 [38].

The relationship between IL-18 level and higher vascular stiffness detected in our study may also be related to the expression of IL-18 receptor on arterial smooth muscle cells [39] and on cells involved in bone turnover [30].

Positive relationship between IL-18 level and PWV has been recently reported in patients with lupus erythematosus and diabetes [40,41]. However, our study is the first report of the involvement of IL-18 in decreasing the arterial elastic proprieties in patients with CKD.

The serum concentration of IL-10 was significantly higher in CKD patients than in controls, confirming the observations of other authors [23,42]. Moreover, we found a positive correlation between serum levels of IL-18 and anti-inflammatory IL-10. This is an expected finding, as both IL-10 and IL-18 are released from the same type of cells involved in the local inflammatory process in the blood vessel wall [21,43]. On the other hand, there was no relationship between the IL-18 level and the markers of systemic inflammatory reaction, confirming the results of other studies on patients with stage V CKD on HD and PD [29,11].

Elevated PWV correlated positively with CRP, IL-6 and IL-18 and negatively with fetuin-A, which indicates the multifactorial pathomechanism of blood vessel injury in patients with CKD. We propose that both the decreased elasticity, as measured by PWV, and the increased IL-18 reflect the intensity of the same process of arterio- and atherosclerosis. This hypothesis is further supported by the data of Yamagami et al., who described a significant correlation of a intima-media thickness and IL-18 level in patients with coronary disease [10].

Arterial wall calcification is the second process contributing to the increased blood vessel wall stiffness, as measured by PWV, in patients with CKD [44,45]. Interrelationship between the processes contributing to blood vessel wall remodelling and stiffness, i.e. inflammation and vascular calcification, is well evidenced by number of reports, especially in patients with CKD [3,46], but its mechanism is only partially understood. Several cytokines and fetuin-A may be involved in this interrelationship [47].

The intensity of chronic local inflammation and low levels of serum fetuin-A on vascular and valvular wall calcifications in patients with CKD have been well described [26,47]. Furthermore, fetuin-A deposits have been observed in calcified plaques in the intimal layer of arterial wall [27]. Patients with CKD have low circulating levels of this inhibitor of calcification and a negative inflammatory reactant [28,27].

Hermans et al. [48] showed a linear, negative association between the serum fetuin-A and PWV, which was, however, insignificant in their multiple regression analysis. Compared to their patient sample, our patients were younger (58.0 ± 12.8 versus 63.0 ± 13.0 years), had higher CRP levels (median 6.4 mg/l; range 0.6–22.3 mg/l versus median 4.0 mg/l; range 0.4–66.4 mg/l) and less frequently had diabetes (21% versus 31%, respectively). The unexpected finding in the Hermans et al. study was the lack of the difference between fetuin concentrations in the patients and healthy control. In our investigation, similarly to the results obtained by Ketteler et al. fetuin levels in dialysis patients were significantly lower than those in healthy individuals. The slightly higher age of the patients studied by Hermans et al. and greater participation of diabetic patients (31% versus 21.5% in the present study) could be the reason that the relationship between fetuin-A and aortic PWV vanished in the multivariate analysis considering age and diabetes mellitus.

Several limitations of the study should be taken into account such as cross-sectional character, single point measurement of biochemical and inflammatory state markers, as well as arterial wall elasticity. The revealed, however significant and independent, could not predict morbidity and mortality.

In summary, our results confirm that patients with CKD may suffer from at least two independent processes that result in increased vascular stiffness. One is the systemic inflammatory response, here documented by the elevated CRP and decreased serum concentration of fetuin-A, the calcification inhibitor and the negative acute phase reactant. The other is the local inflammatory response, evidenced by an increased circulating IL-18 levels. These two processes combined with the higher tendency propensity towards vascular calcification may translate into higher morbidity and mortality observed in patients with CKD.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Received for publication: 12. 4.08
Accepted in revised form: 5. 8.08


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