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NDT Advance Access originally published online on September 22, 2007
Nephrology Dialysis Transplantation 2007 22(12):3606-3609; doi:10.1093/ndt/gfm231
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org


Higher plasma interleukin-18 levels associated with poor quality of sleep in peritoneal dialysis patients

Ju-Yeh Yang1, Jenq-Wen Huang2, Chih-Kang Chiang2, Chun-Chun Pan3, Kwan-Dun Wu2, Tun-Jun Tsai2 and Wan-Yu Chen2

1Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, 2Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, and 3Department of Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan

Correspondence and offprint requests to: Tun-Jun Tsai, MD, PhD, No. 7, Chung-Shan South Road, Taipei 100, Taiwan. Email: tjtsai{at}ntuh.gov.tw



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. Sleep disorders are prevalent in patients with end-stage renal disease. Increasing evidence suggests that cytokines are involved in the regulation of sleep and wakefulness. The purpose of this study was to examine the relationship between quality of sleep and plasma interleukin-18 levels in peritoneal dialysis patients.

Methods. Plasma interleukin-18 levels were determined by the enzyme-linked immunosorbent assay (ELISA) methodology in 57 peritoneal dialysis patients. Quality of sleep was measured using the Pittsburgh Sleep Quality Index. Demographic and routine laboratory data were recorded.

Results. In our cohort, the poor sleepers had higher plasma interleukin-18 levels (559.16 ± 261.22 pg/ml vs 397.49 ± 191.81 pg/ml, P = 0.01). The plasma interleukin-18 level was positively correlated with the Pittsburgh Sleep Quality Index score (r = 0.286, P = 0.031), that is, there was a positive association between higher plasma interleukin-18 levels and poorer quality of sleep.

Conclusion. This study demonstrates that interleukin-18 may be involved in sleep disorders in end-stage renal disease patients. Higher plasma interleukin-18 levels are associated with poorer quality of sleep in peritoneal dialysis patients. Whether a cause-and-effect relationship exists between interleukin-18 and quality of sleep deserves further study.

Keywords: cytokine; sleep; peritoneal dialysis; interleukin-18



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
Sleep disorders are common in patients with end-stage renal disease (ESRD) who are undergoing either haemodialysis (HD) or peritoneal dialysis (PD). Sleep disorders are associated with significant medical, psychological, and social disturbances in dialysis patients [1–4]. Numerous clinical parameters may account for the high prevalence of sleep disturbance in these patients [1,2].

The interactions between blood and the dialyser during HD or between the peritoneum and dialysate during PD have been postulated to activate mononuclear cells, and as a result, to produce inflammatory cytokines [3]. These cytokines are believed to play significant roles in dialysis-associated morbidity and mortality [4]. Furthermore, excessive cytokines may alter sleep patterns in chronically dialyzed patients, which may account for sleep disorders in these patients [4].

Increasing evidence suggests that cytokines are involved in the regulation of sleep and wakefulness. Among these cytokines, interleukin-1 (IL-1) and tumour necrosis factor (TNF) have been studied the most and data derived from electrophysiological, biochemical and molecular genetic studies support their roles in the regulation of sleep-wake behaviour [5]. HD patients with sleep complaints have significantly higher pre-dialysis IL-1 beta levels than those without sleep complaints and healthy controls [6].

Interleukin-18 (IL-18), a new member of the IL-1 cytokine superfamily, is recognized as an important regulator of immune responses [7]. It is expressed at sites of chronic inflammation, autoimmune diseases, cancers and in the context of numerous infectious diseases [7]. Several studies have shown that an elevated serum IL-18 concentration is associated with poor clinical outcome in severe inflammatory and septic conditions [8]. Markedly elevated IL-18 levels have been observed in ESRD patients [9] and have been reported to predict outcomes in HD patients [10]. There are many similarities between IL-18 and IL-1. The purpose of this study was to examine the relationship between quality of sleep and plasma IL-18 levels in PD patients.



   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Subjects
During the study period, 57 patients with ESRD who were undergoing PD were recruited. These patients were receiving either continuous ambulatory PD (CAPD) with a twin-bag system (Ultrabag®, Baxter, Singapore) or continuous cyclic PD with a cycler (CCPD) (HomeChoice®, Baxter, IL, USA) as renal replacement therapy for more than 3 months. All subjects were aged over 18 years and did not have malignancy, autoimmune disease, acquired immunodeficiency syndrome, active infection or obvious inflammation. Patients who received steroids, immunosuppressants or immunomodulators were excluded. The study was approved by the Ethics Committee of National Taiwan University Hospital. Informed consent was obtained from all participating subjects.

Samples
Blood samples were obtained when patients were fasting in the morning and centrifuged immediately at room temperature at 3000 rpm and the supernatant was frozen at –80°C until measured. All the routine biochemical data were taken within 1 month of the time that sleep questionnaires were completed. IL-18 level was determined in plasma samples using commercially available enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturer's instructions (Biosource, Camarillo, CA, USA).

Questionnaires
Quality of sleep was measured using the Pittsburgh Sleep Quality Index (PSQI) [11]. This self-administered questionnaire assesses quality of sleep during the previous month and contains 19 self-rated questions which yield seven components: subjective sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbance, use of sleep medications and daytime dysfunction. Each component is scored from 0 to 3, which yields a global PSQI score between 0 and 21, with higher scores indicating lower quality of sleep. The Chinese Version of the PSQI has been used in Taiwan [12].

Statistical analysis
All values are presented as the mean ± SD unless otherwise specified. The parameters of interest were analysed with the unpaired t-test, chi-square test, and Pearson's correlation (r). All statistical calculations were performed with SPSS® 12.0 for Windows (SPSS Inc, Chicago Illinois). A p-value of less than 0.05 was considered statistically significant.



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
The average global PSQI was 8.18 ± 4.04 among PD patients. About 66.7% of the PD patients were classified as poor sleepers (defined as global PSQI ≥ 5). Demographic and biochemistry data are shown in Table 1. The poorer sleepers had higher plasma IL-18 levels (559.16 ± 261.22 pg/ml vs 397.49 ± 191.81 pg/ml, P = 0.01) (Figure 1). The Plasma IL-18 level was positively correlated with, the PSQI score (r = 0.286, P = 0.031) (Figure 2), that is, higher plasma IL-18 levels were associated with poorer quality of sleep.


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  		Table 1. Characteristics of patients according to median PSQI scores

 

Figure 1
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  		Fig. 1. Distribution (box plot representation) of plasma IL-18 according to sleep quality (PSQI {square} 8 vs PSQI {square} 8), expressed by medians (559.16 ± 261.22 pg/ml vs 397.49 ± 191.81pg/ml, P = 0.01). (Abbreviations: PSQI: Pittsburgh Sleep Quality Index; IL-18: interleukin 18).

 

Figure 2
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  		Fig. 2. Association between plasma IL-18 and PSQI scores in peritoneal dialysis patients. (r = 0.286, P = 0.031) (Abbreviations: IL-18: interleukin 18; PSQI: Pittsburgh Sleep Quality Index).

 
In a comparison of patients with high and low PSQI scores (PSQI {square} 8 and PSQI {square} 8), we found that poorer sleepers had higher levels of serum triglyceride (220.0 vs 135.4 mg/dl, P = 0.01), lower creatinine levels (10.1 vs 11.8 mg/dl, P = 0.09) and a higher body mass index (23.1 vs 21.2). However, there was no significant difference between these groups in gender, underlying diseases (diabetes, hypertension, myocardial infarction, congestive heart failure and peripheral arterial occlusive disease), dialysis duration, dialysis type (CAPD or APD), and the biochemical parameters of albumin, total cholesterol, iron profile, haematocrit, phosphate, uric acid and glucose (Table 1).



   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
In our study cohort, serum IL-18 levels correlated negatively with quality of sleep in PD patients. Although the correlation is rather weak in our work, the finding has never been reported before in ESRD patients.

The mechanism by which IL-18 correlates to quality of sleep regulation remains unclear. Some viewpoints may be illustrative. Studies of the central nervous system (CNS) suggested a role for IL-18 in modulating neuronal function. The IL-18 protein was detected in the medial habenula in rat CNS and IL-18 expression in the habenula was also demonstrated at mRNA levels by in situ hybridization [13]. In addition, acute or chronic restraint stress induced a strong elevation of IL-18 immunostaining in the habenula [13]. Interestingly, the habenula plays a role in the regulation of states of arousal [14].

In addition, serum levels of IL-18 were significantly higher in patients with obstructive sleep apnoea than in obese control subjects [15]. Increased levels of proinflammatory cytokines, obesity and nocturnal hypoxia may be involved in the elevated levels of IL-18 in patients with obstructive sleep apnoea. The fact that at least 60% of patients on chronic haemodialysis have sleep apnoea [16] may contribute indirectly to the association between serum IL-18 levels and sleep quality.

Finally, IL-18 levels of moderate-severe depression patients were significantly higher than those of healthy donors [17]. Depression is the most common psychological problem encountered in dialysis patients and the reported prevalence was at least one third to one half in dialysis patients compared with an estimated 16% prevalence in the general population [18]. There is a well-documented and complex association between depression and insomnia. Elevation of circulating IL-18 levels was also found in other psychiatric disorders including schizophrenia and panic disorder [19]. Thus, IL-18 may be classified as a general, psychological stress-associated marker.

In the preliminary results of our group with regard to cognitive-behaviour therapy for sleep disorder in peritoneal dialysis patients, plasma IL-18 levels declined significantly in association with PSQI scores after intervention (data not shown). This may further confirm the association of plasma IL-18 level and quality of sleep in peritoneal dialysis patients.

Kubota et al.[20] injected three doses of IL-18 (10, 100 and 500 ng) intracerebroventricularly into rabbits at the onset of the dark period. The two higher doses of IL-18 markedly increased non-rapid eye movement sleep (NREMS) and brain temperature. These effects were lost after heat inactivation of IL-18. This result seems to be in conflict with our results. However, this effect was mainly due to an increase in the number of NREMS episodes. The mean duration of NREMS episodes tended to be shorter. Moreover, REMS was inhibited after the administration of the highest dose of IL-18 (500 ng) during the light period. Whether increased IL-18 levels in dialysis patients stimulate NREMS and in which way increased NREMS impacts on quality of sleep are not sure. Furthermore, increased IL-18 levels in dialysis patients may be the consequence of sleep loss. Thus, the exact relationship between IL-18 and sleep quality remains unresolved.

In conclusion, we reported that serum IL-18 levels correlated negatively with quality of sleep in PD patients. This is the first study demonstrating that IL-18 is involved in sleep disorders in ESRD patients. However, the exact relationship between IL-18 and sleep disorder remains unresolved and whether increased IL-18 levels are the cause or the result of sleep disturbance needs further investigation.



   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
This study was supported by Mrs Hsiu-Chin Lee Lin Kidney Research Fund. We thank Miss Yuan-Ting Chuang for plasma IL-18 level determination.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Lui SL, Ng F, Lo WK. Factors associated with sleep disorders in Chinese patients on continuous ambulatory peritoneal dialysis. Perit Dial Int (2002) 22:677–682.[Abstract/Free Full Text]
  2. Stepanski E, Faber M, Zorick F, et al. Sleep disorders in patients on continuous ambulatory peritoneal dialysis. J Am Soc Nephrol (1995) 6:192–197.[Abstract]
  3. Memoli B. Cytokine production in haemodialysis. Blood Purif (1999) 17:149–158.[CrossRef][Web of Science][Medline]
  4. Pertosa G, Grandaliano G, Gesualdo L, et al. Clinical relevance of cytokine production in haemodialysis. Kidney Int Suppl (2000) 76:S104–111.[Medline]
  5. Opp MR. Cytokines and sleep. Sleep Med Rev (2005) 9:355–364.[CrossRef][Web of Science][Medline]
  6. Erten Y, Kokturk O, Yuksel A, et al. Relationship between sleep complaints and proinflammatory cytokines in haemodialysis patients. Nephrology (2005) 10:330–335.[CrossRef][Medline]
  7. Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol (2003) 73:213–224.[Abstract/Free Full Text]
  8. Tschoeke SK, Oberholzer A, Moldawer LL. Interleukin-18: a novel prognostic cytokine in bacteria-induced sepsis. Crit Care Med (2006) 34:1225–1233.[CrossRef][Web of Science][Medline]
  9. Gangemi S, Mallamace A, Minciullo PL, et al. Involvement of interleukin-18 in patients on maintenance haemodialysis. Am J Nephrol (2002) 22:417–421.[CrossRef][Web of Science][Medline]
  10. Chiang CK, Hsu SP, Pai MF, et al. Interleukin-18 is a strong predictor of hospitalization in haemodialysis patients. Nephrol Dial Transplant (2004) 19:2810–2815.[Abstract/Free Full Text]
  11. Smyth C. The Pittsburgh Sleep Quality Index (PSQI). J Gerontol Nurs (1999) 25:10–11.[Medline]
  12. Chen WC, Lim PS, Wu WC, et al. Sleep behaviour disorders in a large cohort of chinese (Taiwanese) patients maintained by long-term haemodialysis. Am J Kidney Dis (2006) 48:277–284.[CrossRef][Web of Science][Medline]
  13. Sugama S, Cho BP, Baker H, et al. Neurons of the superior nucleus of the medial habenula and ependymal cells express IL-18 in rat CNS. Brain Res (2002) 958:1–9.[CrossRef][Web of Science][Medline]
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Received for publication: 8. 1.07
Accepted in revised form: 26. 3.07


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