NDT Advance Access originally published online on November 3, 2006
Nephrology Dialysis Transplantation 2007 22(3):973-975; doi:10.1093/ndt/gfl650
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Vitamin E and selenium co-supplementation attenuates oxidative stress in haemodialysis patients receiving intra-dialysis iron infusion
Email: ardalanm{at}tbzmed.ac.irSir,
Parenteral iron administration is a common practice in the era of advanced haemodialysis (HD). A major concern is that the oversaturation of transferrin and subsequent propagation of redox-active iron occurs with the recommended doses of parenteral iron (1–4 mg/kg) [1]. Redox-active iron is a potent pro-oxidant that triggers free-radical chain reaction by the formation of hydroxyl radicals (Fenton reaction) [1–3]. Intravenous iron also increases neutrophil respiratory burst and thus the generation of oxygen radicals [4]. Lipid peroxidation, protein oxidation and DNA damage are the main consequences of this oxidative stress (OxS) [2]. It has been suggested that high cumulative doses of iron may contribute to increased morbidity and mortality among end-stage renal disease (ESRD) patients, through increasing OxS which favours atherosclerosis and is an independent risk factor for cardiovascular mortality [5,6]. Vitamin E and selenium are effective body antioxidants that prevent free-radical formation and halt the damaging free-radical chain reaction once it begins [7–10]. The aim of this study was to assess the efficacy of vitamin E and selenium supplementation on reducing the OxS in HD patients receiving intra-dialysis iron infusion.
Nineteen ESRD patients (mean age, 43 ± 12 years; 11 male and 8 female) on chronic HD were enrolled to this prospective and interventional study. All patients had been undergoing HD twice weekly, while receiving an iron infusion (100 mg iron/5 ml as ferric hydroxide sucrose complex in 10 min via the venous line of the dialysis circuit) 10 min after the beginning of a HD session. Supplements were prepared as capsules, each containing 400 IU vitamin E and 600 µg sodium selenide. All patients received one dose of the aforementioned supplement, 6 h in advance of a scheduled HD session. The same patients were used as the control if they had not consumed the supplement before the HD session. The study was approved by the local research council and ethics committee and informed consent was obtained from patients ahead of the study.
The venous blood samples were drawn immediately before (
10 min after the beginning of HD) and 45–50 min after iron infusion; they were then separated to serum and stored in a refrigerator until biochemical analysis. The serum concentration of malondialdehyde (MDA), an intermediate product of lipid peroxidation [11] was used as a marker of OxS. Briefly, MDA was reacted with thiobarbituric acid by incubating for 1 h at 95–100°C. Fluorescence intensity was then measured in the n-butanol phase using a fluorescence spectrophotometry with excitation and emission at 525 and 547 nm, respectively. The statistical analyses were performed by paired t-test using SPSS version 11.0. A P-value less than 0.05 was considered to indicate statistical significance.
We found that the mean serum MDA level was 3.75 ± 1.36 µg/dl before intravenous iron injection, and increased to 4.53 ± 1.93 µg/dl after administration (P < 0.05). However, with prophylactic administration of vitamin E and selenium, the serum MDA level did not change significantly (3.47 ± 1.8 vs 3.76 ± 2.27 µg/dl before and after intravenous iron administration, P > 0.05).
The results of this study show that iron infusion increases serum MDA level and thus intra-dialysis OxS by 21% in haemodialysis patients and that vitamin E and selenium co-supplementation can offset this effect. We did not include a non-iron control group. However, as the blood samples were collected after the beginning of HD session (immediately before the iron infusion) and 45 min thereafter, the increased OxS reflects mostly the effect of an infused iron. Furthermore, in the study of Roob et al. [1], the serum MDA level remained constant during the course of a dialysis where iron was not infused. In the same study, the MDA showed a marked and rapid increase by 30 min of iron infusion [1].
Selenium functions primarily in the form of the selenoproteins. At least 30 selenoproteins have been identified, including glutathione peroxidase, selenoprotein P, thioredoxin reductase, selenoprotein W, iodothyronine deiodinase and selenophosphate synthetase [9]. Glutathione peroxidase, selenoprotein P and thioredoxin reductase are the major components of the body antioxidant system [9]. Vitamin E and glutathione peroxidase function at two different locations within the cell; glutathione peroxidase in the cytosol and vitamin E within the lipid membranes [7,8,10]. Although no synergy has been detected between vitamin E and selenium in experimental studies, these two agents may have reciprocal sparing effects on each other's requirements [7]. Vitamin E-mediated protection of lipid membranes may spare the requirement for glutathione peroxidase by reducing free radicals at the cell membrane, thereby preventing the leakage of free radicals into the cytosol.
HD patients have a high OxS that is correlated with the total time on dialysis [12]. Although vitamin E status is generally not impaired among HD patients, its oral administration at a high dose of 1200 IU 6 h before haemodialysis has already been shown to attenuate intra-dialysis OxS. HD patients often have reduced blood selenium and glutathione peroxidase concentrations [13]. However, selenium supplementation has failed to increase plasma antioxidant activity in these patients [11,13]. This is largely because the kidneys that are the major sources of plasma glutathione peroxidase have already lost their function in HD patients [11]. In a previous study, it has been postulated that selenium supplementation increases red blood cell glutathione peroxidase activity but not that of plasma [11].
Intravenous ferrotherapy is also associated with increased risk of bacterial infection in HD patients [14]. It has been shown that parenteral iron markedly increases plasma and renal monocyte chemoattractant protein-1 and may induce inflammation [15]. Immuomodulatory properties of vitamin E and selenium may further add to its efficacy in dialysis patients. Finally, a single oral dose of vitamin E (400 IU) and selenium (600 µg), taken 6 h before a dialysis session, can markedly reduce intra-dialysis OxS in HD patients receiving iron infusion.
1Department of Nephrology
Dialysis and Renal
Transplantation
Tabriz, Iran
2Department of Cell Biology
University of Alabama at Birmingham
and Children's Hospital Birmingham
Alabama, USA
3Faculty of Medicine
Tabriz University of Medical
Sciences (TUMS)
Tabriz, Iran
Acknowledgments
The authors are grateful to Dr Bahlol Habibi, Dr N. Rashtchi Zadeh, Dr Amir Qorbani Hagjoo and Dr Mahsar Rashtchi from TUMS for their assistance in the pharmaceutical preparation and biochemical analysis.
Conflict of interest statement. None declared.
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