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NDT Advance Access originally published online on August 8, 2006
Nephrology Dialysis Transplantation 2006 21(11):3196-3201; doi:10.1093/ndt/gfl359
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Polymorphonuclear leucocyte priming in long intermittent nocturnal haemodialysis patients—is melatonin a player?

Ronit Geron1, Revital Shurtz-Swirski2, Shifra Sela2,3, Yevgeny Gurevitch1, Tatiana Tanasijtchouk1, Zila Shenn Orr4, Galina Shkolnik1, Olga Tanhilevski1 and Batya Kristal1,3

1Nephrology and Hypertension Department, 2Eliachar Research Laboratory, Western Galilee Hospital, Nahariya, 3Bruce Rappaport Faculty of Medicine, Technion and 4Endocrinology Lab, Rambam Hospital, Haifa, Israel

Correspondence and offprint request to: Ronit Geron, MD, Department of Nephrology and Hypertension, Western Galilee Hospital, Nahariya 22100, Israel. Email: ronit.geron{at}naharia.health.gov.il



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
Background. The relationships between sleep quality, melatonin circadian rhythm and polymorphonuclear leucocyte (PMNL) priming during the night of dialysis treatment compared with a night without dialysis were studied in a group of nocturnal haemodialysis (HD) patients.

Methods. Twenty-eight long intermittent nocturnal HD patients were included. Sleep quality was assessed by a questionnaire and wrist actigraphy. Plasma melatonin levels were assayed every 2 h, from 9 p.m. to 5 a.m. PMNL priming was assessed by the rate of superoxide release from separated PMNLs at 9 p.m. and 5 a.m., on a night of dialysis and a night with sleepover in the dialysis unit without being dialysed.

Results. Melatonin levels increased similarly during a night with and without dialysis, reaching peak level at 5 a.m. Most (73%) of the patients had severe sleep disturbances. A significant negative correlation was found between the sleep quality score, the rate of superoxide release from separated PMNLs and melatonin levels. While during a night without dialysis a significant reduction of the rate of superoxide release was found at 5 a.m. (compared with 9 p.m.), no significant reduction was observed when the patients were dialysed. Patients with flat melatonin curves, with <10 pg/ml, showed a faster rate of superoxide release than those with higher levels.

Conclusions. The nocturnal HD process does not affect plasma melatonin levels or rhythms, suggesting that melatonin is not dialysed. Higher endogenous melatonin levels are associated with better sleep and lower PMNL priming. The lower PMNL priming in patients with higher plasma melatonin levels suggests that melatonin overrides the oxidative burden induced by the dialysis process.

Keywords: long intermittent nocturnal hemodialysis; melatonin; oxidative stress; PMNL priming



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgement
 References
 
Sleep disorders are frequent among haemodialysis (HD) patients; up to 86% are affected [1, 2]. These include delayed sleep onset, frequent awakening during the night, early arousal, restless leg syndrome and sleep apnoea [1, 2]. The factors involved in these disturbances are many, and include systemic diseases, metabolic, endocrine and mental disorders, drugs and impaired circadian rhythm [3]. Sleep disturbance leads to daytime sleepiness, decreased cognitive and mental functions and impaired quality of life.

The hormone melatonin, produced at night in the pineal gland, is a regulator of circadian rhythms and sleep. Melatonin secretion exhibits a circadian rhythm with a nocturnal surge normally between 1–3 a.m. [4]. Beyond its known role in regulation of sleep and circadian rhythms, melatonin was found to be a potent antioxidant. Both in vivo and in vitro studies have shown that melatonin reduces oxidative stress (OS) in several ways [4, 5]. Melatonin is a potent scavenger of both the peroxyl and hydroxyl radical [4,5]. Besides these direct antioxidative activities, melatonin has indirect effects, such as stimulation of some important antioxidative enzymes, i.e. glutathione peroxidase, glutathione reductase and superoxide dismutase (SOD) [6].

HD patients are exposed to OS, partially due to a primed state of their polymorphonuclear leucocytes (PMNLs), which is aggravated by the haemodialysis process itself [7–11]. As primed PMNLs from HD patients release superoxide more readily, they can further exacerbate the OS in these patients [10, 11] especially in absent or reduced antioxidant levels, common in these patients [7–9].

Studies reporting melatonin levels and circadian rhythms in patients with chronic kidney disease (CKD) show conflicting results [12–14]: increased [12], unchanged [13] or decreased [14] melatonin levels in HD patients compared with healthy subjects. Furthermore, the relevance of these findings to the patient's well-being was not explored. The aim of the present study was to evaluate the melatonin circadian rhythm in long intermittent nocturnal HD (LIND) patients in relation to PMNL priming and sleep disorders, as well as to evaluate the effect of nocturnal dialysis sessions on the above parameters.



   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgement
 References
 
Patients
Group I
Twenty-eight CKD patients undergoing LIND [4 women and 24 men, aged 54.5 ± 12.6 (SD) years], with mean duration of dialysis treatment of 45.2 months (range 6–132 months), were included in the study. The comorbid diseases in the 28 patients were diabetes mellitus (n = 11), hypertension (n = 9), polycystic kidney (n = 7), chronic glomerulonephritis (n = 3) and nephrolithiasis (n = 1). All the patients underwent nocturnal HD for 6 h (between 11 p.m. and 5 a.m.) thrice weekly, which was carried out with low-flux polysulphone membranes (F8-HPF, Fresenius Medical Care, Bad Homburg, Germany) using bicarbonate dialysate with an average single-pool Kt/V of 1.2 ± 0.2. The water for dialysis met the standards of the Association for the Advancement of Medical Instrumentation (AAMI). In all these patients the relation of melatonin levels, PMNL priming and sleep assessment was performed as described subsequently.

Group II
In order to compare the effect of the nocturnal dialysis session on various parameters, seven of the above patients were assessed twice, once during a night while receiving HD treatment and once during a night of sleepover in the dialysis unit without being dialysed.

The intensity of light (lux) in the patient's treatment area was measured using a light meter and was kept at 40–60 lx.

Patients were enrolled in this study after giving informed consent for blood sampling approved by the institutional committee in accordance with the Helsinki Declaration. Patients with evidence of acute or chronic infection, malignancy, on HD for <3 months or those who had received a blood transfusion within 3 months before blood sampling, were excluded.

Sleep disorder assessment in Group II patients
Mini sleep questionnaire (MSQ)
The MSQ comprised 10 questions with seven-point severity rating scales for primary identification of sleep disturbances. A total score above 30 indicates a severe sleep disturbance [15]. The MSQ was completed once for each patient during the study.

Actigraph
Actigraphy is an established method that records wrist movements and automatically discriminates rest–activity patterns interpreted in terms of sleep and wake episodes [16]. Sleep quality was objectively assessed by wrist actigraphy for 7 consecutive days and nights.

Blood samples for melatonin, PMNL separation and priming measurements
Blood samples for plasma melatonin levels were drawn every 2 h during a night with HD and on a night without dialysis, between 9 p.m. and 5 a.m. Blood samples for assessing PMNL priming were obtained at 9 p.m. and 5 a.m. on the same nights. On a night without dialysis the blood samples were taken from the intravenous line, which was inserted at 9 p.m., the beginning of the night.

Blood was drawn into heparinized tubes (50 U/ml) from the afferent line. PMNLs were isolated using a ‘semi-separation’ protocol that yielded a great amount of PMNL. This quantity was needed because PMNLs become very fragile after the dialysis session and they are used to compare PMNLs when needed before and after HD. With this procedure, we started from buffy coat obtained after letting the blood stand for 20 min at room temperature. The erythrocytes were lysed in 50 ml of lysing buffer (NH4Cl, 0.8%; NaHCO3, 0.08%; ethylene diaminetetraacetate, 0.037%), for 10 min at room temperature. The cells were then centrifuged and washed twice in Hank's balanced salt solution HBSS for 5 min at 300g at room temperature [17].

The measurements of the rate of superoxide release are based on a SOD inhibitable reduction of 80 µM cytochrome C (Sigma, St Louis, MO, USA) to its ferrous form [18] with a slight modification [11]. The rate of superoxide release was monitored from 106 separated PMNLs after stimulation with 0.32 x 10–7 M phorbol 12-myristate 13-acetate (PMA; Sigma, St Louis, MO, USA), at 22°C for 50 min and expressed as nmol/106 cells/10 min.

Melatonin measurements
Plasma melatonin concentrations were analysed by a direct double-antibody radioimmunoassay (RIA), according to the kit instructions (Buhlman Melatonin RIA kit). Melatonin was extracted from plasma on reversed phase column (C-18) (Buhlmann Laboratories AG, Schonenbuch, Switzerland) and then RIA was performed. The analytical sensitivity of the method is 0.3 pg/ml.

Statistical analysis
Data were expressed as mean ± SEM. Differences in mean values at different time points were tested by two-way analysis of variance (ANOVA) and by the Bonferroni multiple comparison test, using Prism version 3.0 statistical software (GraphPad software, San Diego, CA, USA). The correlation between plasma melatonin levels, sleep quality assesment and PMNL priming was performed by linear regression analysis using Spearman and Pearson correlation coefficients. P < 0.05 was considered significant.



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgement
 References
 
Sleep disorders assessment
The average score of the questionnaire (MSQ) was 35.6 ± 11.6, with 73% of the patients scoring >30, representing severe sleep disturbance. Irregular sleep–wake patterns, as demonstrated by the actigraph were found in 50% of the patients, at least once during the 7 nights of sleep assessment. No differences could be found between nights with dialysis treatment compared with nights without, regarding the number of arousals, suggesting that the dialysis process itself did not change the frequency of arousals.

Melatonin levels
Plasma melatonin levels demonstrated a robust diurnal variation, with peak levels being delayed towards the morning hours, rising during the night from the lowest level at 9 p.m. (8.7 ± 4.1 pg/ml) and reaching a plateau at 5 a.m. (30.7 ± 8.2 pg/ml) as shown in Figure 1. No significant difference could be seen in the melatonin levels between nights with and without dialysis treatment (Figure 1), suggesting that the HD process per se has no effect on melatonin levels.


Figure 1
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  		Fig. 1. Plasma melatonin levels measured by RIA from nocturnal HD patients, drawn once during a night with dialysis (n = 7) and once without dialysis (n = 7). Melatonin was measured at 2 h intervals between 9 p.m. and 5 a.m. Data are mean ± SEM. *P = 0.04; plasma melatonin levels compared with its levels at 9 p.m.

 
Melatonin levels and sleep disorders in nocturnal HD patients
A negative and statistically significant correlation was found between plasma melatonin levels and sleep quality score (according to MSQ) in nocturnal HD patients; R = –0.68, P = 0.029. Thus, lower melatonin levels were associated with more severe sleep disturbances.

PMNL priming
PMNL priming, as expressed by the rate of superoxide release measured either at 9 p.m. or 5 a.m, from isolated phorbol 12-Myristate 13-Acetate (PMA)-stimulated PMNLs, correlated negatively to melatonin levels at 5 a.m. [R = –0.48, P = 0.007 (Figure 2A) and R = –0.43, P = 0.02 (Figure 2B), respectively]. The higher the melatonin levels, the slower rates of superoxide release (and thus lesser priming) were found at both time points. No significant correlation was observed with melatonin levels at 1, 3 and 5 a.m.


Figure 2
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  		Fig. 2. Correlation between plasma melatonin levels (measured by RIA) at 5 a.m. and the rate of superoxide release from PMNLs isolated at 9 p.m. (A) and 5 a.m. (B). The rate of superoxide release as measured by SOD-inhibitable reduction of cytochrome C, after PMA stimulation of 106 PMNLs in 22°C was expressed as nmol/106 cells/10 min.

 
A significant decrease in PMNL priming was observed during a night without dialysis, as judged by the decline in rates of superoxide release from PMNLs drawn at 5 a.m. compared with that at 9 p.m. During a night with dialysis this difference was abolished and the PMNL priming was similar at 5 a.m. and 9 p.m. (Figure 3).


Figure 3
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  		Fig. 3. Rate of superoxide release by PMA-stimulated PMNLs at 9 p.m. and 5 a.m. on a night with dialysis (right panel), compared with a night without dialysis (left panel). The rate of superoxide release as measured by SOD-inhibitable reduction of cytochrome C, after PMA stimulation of 106 PMNLs in 22°C was expressed as nmol/106 cells/10 min. Data are means ± SEM. *P = 0.04; the rate of superoxide release at 9 p.m. vs 5 a.m.

 
Patients with low melatonin levels (<10 pg/ml during all the night) and a flat melatonin rhythm showed a faster rate of superoxide release at 5 a.m. (range: 23.6–43 nmol/106 cells/10 min; black lines in Figure 4 panels A and B, respectively) than those with higher levels of plasma melatonin (range: 5–26.7 nmol/106 cells/10 min; gray lines in Figure 4 panels A and B, respectively) during a night with HD. However, during a night without dialysis the same trend of superoxide release was observed, lower at 5 a.m. compared with that at 9 p.m. in both melatonin groups (range: 6.3–24 nmol/106 cells/10 min; gray and black lines; Figure 4 panel C and D).


Figure 4
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  		Fig. 4. Individual plasma melatonin rhythms of HD patients, measured by direct RIA at 2 h intervals between 9 p.m.–5 a.m., were divided into two groups based on melatonin levels: Below 10 pg/ml (black lines) and above 10 pg/ml (gray lines): (A) HD patients during nocturnal dialysis; (C) During a night without dialysis treatment. The rates of superoxide release by PMA-stimulated PMNLs were measured in the two groups as in (A) and (C) based on melatonin levels: Below 10 pg/ml (black lines) and above 10 pg/ml (gray lines): (B) Before dialysis at 9 p.m. and after dialysis at 5 a.m.; (D) at 9 p.m. and at 5 a.m. during a night without dialysis.

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgement
 References
 
In nocturnal HD patients, besides the obvious observation of the significant correlation between the low levels of melatonin and sleep disorders, a new interesting correlation with PMNL priming is reported herein. To the best of our knowledge, this is the first report that analyses the relationships among sleep quality, plasma melatonin levels and circadian rhythms and PMNL priming in patients performing nocturnal HD, and the effect of a nocturnal dialysis session on the above parameters.

In all HD patients studied here, the peak nocturnal melatonin levels (at 5 a.m.) were lower (8–27 pg/ml) than the normally reported values for healthy people (50–100 pg/ml) [4, 12, 13, 19]. Our results are thus consistent with some of the previous studies [14] but contradict others that demonstrated high melatonin concentrations in CKD patients [12]. More than 70% of the studied patients had severe sleep disturbances with difficulties in falling asleep, high rate of early arousal and >50% had irregular sleep patterns as measured by actigraphy. The negative correlation between melatonin levels and sleep disturbances in the studied patients supports the current concepts on the role of melatonin in sleep regulation [4].

The circadian rhythm of melatonin, although preserved in most of our patients is, however, delayed towards early morning hours. The appearance of the melatonin peak at 5 a.m. reflects a shift of the melatonin rhythm phase in nocturnal HD patients from that which is usual in healthy people, namely between 1–3 a.m. [13, 19]. The lack of major differences in melatonin rhythms and sleep patterns, as evaluated by actigraph, between nights with and without dialysis, suggests that the dialysis process itself does not affect sleep quality and nocturnal melatonin patterns in these patients. This is supported by the fact that melatonin is not dialysable, similar to previous findings reported by Vaziri et al. [13]. However, we did not compare the sleep quality (by MSQ) in a night with and without dialysis.

A statistically significant negative correlation was found between blood melatonin levels and the rate of superoxide release from PMNLs, indicating a new anti-priming aspect of melatonin activity in these patients, which may be in line with its previously described antioxidative properties [4–7]. Increased PMNL priming was reported in CKD patients and was found to be further aggravated by HD per se [8–11]. The decreased PMNL priming at 5 a.m. during a night without dialysis was abolished in a night with dialysis, probably due to the aggravation of PMNL priming caused by the nocturnal HD process. The decrease in PMNL priming during a night without dialysis is in line with our previous studies showing that the dialysis session per se aggravates PMNL priming [17]. Since the primed state of PMNL is lower in the morning of a night without dialysis, we can conclude that PMNLs also have diurnal variations in their priming.

A striking difference in the PMNL priming response to dialysis was seen between patients with low as compared with high endogenous melatonin levels: Patients with flat nocturnal melatonin rhythms and low maximal melatonin concentrations (<10 pg/ml) had an increased PMNL priming in the morning (5 a.m.) compared with the patients with the higher levels of melatonin and a surge of its levels. This finding suggests that endogenous melatonin may override the activating effects of the dialysis membrane on PMNLs, resulting in the attenuation of OS induced by this priming. This apparent attenuation by melatonin of PMNL priming may be mediated by melatonin receptors on PMNLs [20]. In this respect we should point out that the low melatonin levels found in some of the patients can be a result of the modification and degradation of the hormone due to PMNL priming. There is evidence that melatonin is oxidized by myeloperoxidase, an enzyme that is released from activated PMNLs [21, 22]. Since no differences in melatonin levels could be observed between nights with or without HD, despite the differences in the PMNL priming, the enhanced priming cannot be a result of the low levels of melatonin in these patients. Hence, it is more likely that other mechanisms affect the levels of blood melatonin in these patients.

The new findings on the correlation between diurnal variation of melatonin and PMNL priming open up new research opportunities for replacement therapy with melatonin in CKD patients. The subgroup of chronic HD patients with low melatonin levels may benefit both from improvement in their sleep quality concomitantly with a reduction in PMNLs-mediated OS by melatonin supplementation.



   Acknowledgement
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
References
 
This work was partially supported by grants donated by The Israel Society of Nephrology and Hypertension and by Teva Medical.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 

  1. Walker S, Fine A, Kryger MH. (1995) Sleep complaints are common in dialysis unit. Am J Kidney Dis 26:751–756.[Web of Science][Medline]
  2. Hui DS, Wong TY, Ko FW, et al. (2000) Prevalence of sleep disturbance in Chinese patients with end stage disease renal failure on continuous ambulatory peritoneal dialysis. Am J Kidney Dis 36:783–788.[Web of Science][Medline]
  3. Chokroverty S. (2000) Epidemiology and causes of insomnia. Up To Date 8:1–6.
  4. Brzezinski A. (1997) Melatonin in humans. N Engl J Med 336:186–195.[Free Full Text]
  5. Reiter RJ, Tan DX, Manchester LC, Qi W. (2001) Biochemical reactivity of melatonin with reactive oxygen and nitrogen species. Cell Biochem Biophys 34:237–256.[CrossRef][Web of Science][Medline]
  6. Pablos MI, Agapito MT, Gutierrez R, et al. (1995) Melatonin stimulates the activity of the detoxifying enzyme glutathione peroxidase in several tissues of chicks. J Pineal Res 19:111–115.[Web of Science][Medline]
  7. Dasgupta A, Hussain S, Ahmad S. (1992) Increased lipid peroxidation on maintenance hemodialysis. Nephron 60:56–59.[Web of Science][Medline]
  8. Loughrey CM, Young IS, Lightbody JH, McMaster D, McNamee PT, Trimble ER. (1994) Oxidative stress in hemodialysis. Q J Med 16:339–346.
  9. Himmelfarb J, Lazarus JM, Hakim R. (1991) Reactive oxygen species production by monocytes and polymorphonuclear leucocytes during dialysis. Am J Kidney Dis 17:271–276.[Web of Science][Medline]
  10. Kristal B, Shurtz-Swirski R, Shasha SM, et al. (1999) Interaction between erythropoietin and peripheral polymorphonuclear leukocytes in hemodialysis patients. Nephron 81:406–413.[CrossRef][Web of Science][Medline]
  11. Sela S, Shurtz-Swirski R, Cohen-Mazor M, et al. (2005) The primed peripheral polymorphonuclear leukocyte – a culprit underlying chronic low-grade inflammation and systemic oxidative stress in chronic kidney disease. J Am Soc Nephrol 16:2431–2438.[Abstract/Free Full Text]
  12. Ludemann P, Zwernemann S, Lerchl A. (2001) Clearance of melatonin and sulfatoxymelatonin by hemodialysis in patients with end stage renal disease. J Pineal Res 31:222–227.[CrossRef][Web of Science][Medline]
  13. Vaziri ND, Oveisi F, Wierszbiezki M, Shaw V, Sporty LD. (1993) Serum Melatonin and 6-Sulfatoxymelatonin in end stage renal disease: Effect of hemodialysis. Artif Org 17:764–769.[Web of Science][Medline]
  14. Karasek M, Szuflet A, Chrzanowski W, Zylinska K, Swietoslawski J. (2002) Circadian serum melatonin profiles in patients suffering from chronic renal failure. Neuroendocrinol Lett 23:[Suppl 1], 97–102.[Medline]
  15. Zomer J, Peled R, Rubin A, Lavie P. (1984) Mini Sleep Questionnaire (MSQ) for screening large populations for EDS complaints. In Koella WP, Ruther E, Schulz H (Eds.). Sleep(Stuttgart, New York, Fisher-Verlag) pp. 467–470.
  16. Cole RJ, Kripke DF, Gruen W, Mullaney DJ, Gillin JC. (1992) Automatic sleep/wake identification from wrist activity. Sleep 15:461–469.[Web of Science][Medline]
  17. Sela S, Shurtz-Swirski R, Shapiro G, et al. (2001) Oxidative stress during hemodialysis: effect of heparin. Kidney Int 59:S159–S163.[CrossRef]
  18. Babior BM, Kipnes RS, Curnutte JJ. (1973) Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest 52:741–744.[Web of Science][Medline]
  19. Zeitzer JM, Daniels JE, Duffy JF, et al. (1999) Do plasma melatonin decline with age? Am J Med 107:432–436.[CrossRef][Web of Science][Medline]
  20. Lopez-Gonzalez MA, Calvo JR, Segura JJ, Guerrero JM. (1993) Characterization of melatonin binding sites in human peripheral blood neutrophils. Biotechnol Ther 4:253–262.[Medline]
  21. Silva SO, Ximenes VF, Catalani LH, Campa A. (2000) Myeloperoxidase-catalyzed oxidation of melatonin by activated neutrophils. Biochem Biophys Res Commun 279:657–662.[CrossRef][Web of Science][Medline]
  22. Allegra M, Furtmuller PG, Regelsberger G, et al. (2001) Mechanism of reaction of melatonin with human myeloperoxidase. Biochem Biophys Res Commun 282:380–386.[CrossRef][Web of Science][Medline]
Received for publication: 16. 3.06
Accepted in revised form: 23. 5.06


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