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NDT Advance Access originally published online on January 29, 2007
Nephrology Dialysis Transplantation 2007 22(5):1407-1412; doi:10.1093/ndt/gfl789
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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

Effect of repeated intravenous iron administration in haemodialysis patients on serum 8-hydroxy-2'-deoxyguanosine levels

Yukio Maruyama1,3, Masaaki Nakayama2, Kazunobu Yoshimura1, Hirofumi Nakano1, Hiroyasu Yamamoto1, Keitaro Yokoyama1 and Bengt Lindholm3

1Division of Kidney and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan, 2Reseach Division of Dialysis and Chronic Kidney Disease, Tohoku University Graduate School of Medicine, Sendai, Japan and 3Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden

Correspondence and offprint requests to: Yukio Maruyama MD, Division of Kidney and Hypertension, The Jikei University School of Medicine, 3-19-18 Nishi-shinbashi, Minato-ku, Tokyo, 105-8471, Japan. Email: maruyama{at}td5.so-net.ne.jp



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. Iron supplementation is a mainstay for management of renal anaemia in patients receiving haemodialysis (HD). Although it is well known that a single intravenous iron (IVIR) administration transiently enhances oxidative stress in HD patients, the consequence of repeated IVIR administration is still unknown. This study aims to clarify the time course of changes in serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA oxidative injury, during a period of repeated IVIR administration in HD patients.

Methods. Twenty-seven patients (62 ± 14 years and 23 males) on long-term HD participated in this study. All patients had been on HD more than 6 months and none had received a blood transfusion or iron therapy in previous 6 months. The patients were divided into three groups according to the baseline haematocrit (Ht) and serum ferritin (FTN) levels as a marker of body iron stores: IVIR group (Ht < 30% and FTN < 100 ng/ml; n = 7); High FTN group (Ht ≥ 30% and FTN ≥ 100 ng/ml; n = 11); and low FTN group (Ht ≥ 30% and FTN < 100 ng/ml; n = 9). The IVIR group patients received 40 mg of ferric saccharate i.v. after each HD session until Ht increased by 5%. Serum 8-OHdG and other parameters were prospectively monitored for 10 weeks.

Results. At baseline, the serum ferritin level was independently associated with 8-OHdG in a multiple regression model (total adjusted R2 = 0.47, P < 0.01). All patients in the IVIR group achieved the target Ht level during the study. IVIR administration resulted in significant increases in 8-OHdG levels (0.22 ± 0.07–0.50 ± 0.16 ng/ml: baseline to 10 week) as compared with both the high FTN group (0.52 ± 0.20–0.58 ± 0.28 ng/ml) and the low FTN group (0.39 ± 0.11–0.36 ± 0.11 ng/ml) (ANOVA for repeated measures P < 0.01). Additionally, serum 8-OHdG and serum ferritin changed in the same manner.

Conclusions. Repeated IVIR administration for HD patients was associated with signs of increased oxidative DNA injury, as reflected by increased serum levels of 8-OHdG. As these changes were accompanied by increased serum ferritin levels, excess body iron stores might play an important role in oxidative stress.

Keywords: anaemia; haemodialysis; 8-hydroxy-2'-deoxyguanosine (8-OHdG); intravenous iron administration; oxidative stress



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
Anaemia is common in patients with end-stage renal disease (ESRD), and associated with excess mortality and morbidity in this population [1]. The mainstays of treatment are recombinant human erythropoietin (rHuEPO) and iron supplementation [2]. In order to support efficient erythropoiesis in the clinical settings, repeated intravenous iron (IVIR) administration has been recommended by the KDOQI Clinical Practice Guidelines and the Clinical Practice Recommendations for Anaemia in Chronic Kidney Disease [3]. It is known that IVIR administration may release nontransferrin-bound iron (NTBI), so-called free iron, due to oversaturation of transferrin caused by the abrupt elevation of serum iron [4]. Ferrous iron [Fe2+] reacts with hydrogen peroxide to form strong oxidant hydroxyl radicals (the Fenton reaction), which could enhance the oxidation process in patients. Several reports have demonstrated that a single administration of IVIR in haemodialysis (HD) patients transiently increases prooxidants and suppresses antioxidants, thereby increasing oxidative stress (OS) markers in vivo [5–8]. However, these reports estimated only the short-term effects of IVIR administration on OS, and the effect of repeated IVIR administration is still unknown. However, the change in the redox state of patients receiving repeated IVIR administration could be a matter of clinical concern, since enhanced OS could play a crucial role in the excess-mortality and morbidity of HD patients.

One of the most abundant oxidative DNA products, 8-hydroxy-2'-deoxyguanosine (8-OHdG), is formed by hydroxylation that occurs at the C8 position of deoxyguanosine in DNA by ferrous iron [Fe2+] and reactive oxygen species (ROS) [9]. The 8-OHdG levels are increased in several ROS-mediated conditions, such as diabetes, cancer, radiation injury, smoking, normal aging [9] and kidney disease [10,11].

Thus, we conducted a prospective study of patients with renal anaemia to clarify the effects of repeated IVIR administration on serum 8-OHdG levels, and examined those changes with respect to their relationship to iron parameters.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
Twenty-seven chronic HD patients treated with HD for more than 6 months (23 males and 4 females with an average age of 62 ± 14 years; range, 34–77 years; duration of HD 6–251 months) were enrolled into the study from two institutions (Shin–Kashiwa Clinic, Chiba and Kashima Hospital Dialysis Center, Fukushima). Exclusion criteria were acute infection [C-reactive protein (CRP) ≥1.0 mg/dl], bleeding, liver dysfunction, history of blood transfusions or iron therapy (including oral iron in the 6 months prior to enrolment), and unwillingness to participate in this study. The cause of ESRD was chronic glomerulonephritis in 10 (37%), diabetic nephropathy in seven(26%), nephrosclerosis in seven (26%), and unknown in three patients (11%). The demographic data recorded at enrolment included age, gender, smoking status, underlying renal disease, history of cardiovascular disease (CVD) and prescribed medication. CVD was defined as a history of previous cerebrovascular disease, ischaemic heart disease, angina or peripheral vascular disease. Prescribed medications included angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB), and hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins). None of the patients took antioxidant agents such as vitamin C or E. Twenty-two patients were receiving rHuEPO at the start of the study. The patients had been receiving a standard bicarbonate HD session three times a week, 3–4 h/session, using polysulfone (PS) in nine patients, polymethylmethacrylate (PMMA) in seven patients, cellulose triacetate (CTA) in six patients, modified regenerated cellulose (MRC) in three patients, and ethylenevinylalcohol (EVAL) membrane in two patients. None had used vitamin E-bonded membranes.

IVIR administration protocol
The patients were divided into three groups according to the baseline haematocrit (Ht) and serum ferritin (FTN) levels: the IVIR group, Ht < 30% and FTN < 100 ng/ml (n = 7); the high FTN group, Ht ≥ 30% and FTN ≥ 100 ng/ml (n = 11); and the low FTN group, Ht ≥ 30% and FTN < 100 ng/ml (n = 9). All IVIR group patients had a transferrin saturation (TSAT) <25%. Only the IVIR group patients received 40 mg of ferric saccharate (Fesin; Mitsubishi Pharma, Osaka, Japan) i.v. after each HD session until Ht increased by 5%. When Ht levels increased by 5%, IVIR was stopped. We did not prescribe oral iron to any patients during the study period. Ht, iron profile parameters and serum 8-OHdG were monitored prospectively every other week for 10 weeks. Other conditions, including dialytic procedure, medication and dose of rHuEPO, remained unchanged through the whole study period. The Ethics Committee of the Jikei University Hospital approved this study protocol, and informed consent was obtained from all patients.

Blood sampling and laboratory analysis
Blood samples were drawn from the arterial line at the start of HD treatment after a 2-day interval from the last HD treatment. After sampling, whole blood was centrifuged at 3000 g for 10 min. The supernatant was transferred to a new tube and stored at –80°C until analysis. Determination of Ht, serum creatinine, plasma CRP, and iron profile parameters were performed by an automatic analyser at the clinical laboratory. Serum ferritin levels were measured by radioimmunoassay. Serum 8-OHdG was measured using a competitive ELISA kit (Japan Institute for the Control of Aging, Fukuroi, Shizuoka, Japan). The kit can measure 8-OHdG values ranging 0.125–10 ng/ml using a monoclonal specific antibody, N45.1 [12].

Statistical analysis
Data are presented as mean ± SD or median and range when appropriate. A P-value of <0.05 was considered to be statistically significant. For comparisons between two groups, Student's t-test or the Wilcoxon rank sum test was used as appropriate. Differences between three groups were analysed by one-way analysis of variance (ANOVA) or the non-parametric Kruskal–Wallis test as appropriate. Differences were considered statistically significant when the F-value was <0.05. Then, the Tukey–Kramer test was used to determine which group caused the difference. Nominal variables were tested using the chi-square test. The Spearman correlation coefficient ({rho}) was used to determine the relationships between clinical parameters. A multiple regression model was used to assess the independent contributing factors of 8-OHdG. For this model, the duration of HD was log-transformed (ln HD duration) to reduce skewness of distribution. A within-group comparison among values at baseline (day 0), day 14, day 28, day 42, day 56 and day 70 was analysed by ANOVA for repeated measures. Additionally, Dunnett's test was used to compare with baseline. Statistical analyses were performed using JMP, version 5.1.1 for Windows (SAS Institute Inc., Cary, NC, USA).



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Acknowledgements
 References
 
The demographic, clinical, and laboratory characteristics of the three groups are listed in Table 1. There were no significant differences in gender, age, prevalence of diabetes and CVD, smoking habit, administration of ACEI/ARB and statin, serum creatinine and CRP among the three groups. On the other hand, the patients in IVIR group had a shorter duration of HD (P < 0.01), lower haematocrit (P < 0.01), lower serum iron (P < 0.01), higher unbound iron-binding capacity (UIBC) (P < 0.01), lower TSAT (P = 0.01) and lower serum 8-OHdG levels (P < 0.01). Although the dose of rHuEPO tended to be higher among patients of the IVIR group, this did not reach statistical significance (P = 0.10).


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  		Table 1. Baseline clinical characteristics

 
The results of the Spearman correlation tests are summarized in Table 2. Serum 8-OHdG level had positive associations with HD duration ({rho} = 0.64, P < 0.01), haematocrit ({rho} = 0.62, P < 0.01), and serum ferritin ({rho} = 0.55, P < 0.01). Additionally, there was a negative correlation between serum 8-OHdG and UIBC ({rho} = –0.52, P < 0.01). Serum 8-OHdG was not significantly different between two groups according to gender (0.39 ± 0.20 ng/ml vs 0.45 ± 0.13 ng/ml for male and female; P = 0.43), prevalence of diabetes (0.44 ± 0.29 ng/ml vs 0.38 ± 0.14 ng/ml for diabetes and non-diabetes group; P = 0.70), smoking habit (0.39 ± 0.13 ng/ml vs 0.41 ± 0.23 ng/ml for smoker and non-smoker; P = 0.88), administration of ACEI/ARB (0.42 ± 0.20 ng/ml vs 0.36 ± 0.15 ng/ml for administration and non-administration group; P = 0.72) and administration of statin (0.46 ± 0.07 ng/ml vs 0.39 ± 0.19 ng/ml for administration and non-administration group; P = 0.35). On the other hand, the patients with a history of CVD had significantly higher serum 8-OHdG as compared with those without a history of CVD (0.53 ± 0.22 ng/ml vs 0.33 ± 0.13 ng/ml; P < 0.01). Table 3 shows a multiple regression model (n = 27) including prevalence of CVD, age, haematocrit, UIBC, serum ferritin and ln HD duration. Only serum ferritin (P = 0.03) was independently associated with serum 8-OHdG (total adjusted R2 = 0.47, P < 0.01).


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  		Table 2. Spearman correlation coefficient ({rho}) between parameters

 

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  		Table 3. Multiple regression model for predictors of serum 8-OHdG

 
In the IVIR group, all patients achieved target haematocrit levels, and the duration of IVIR administration was 44 ± 14 days (28–70 days). Figure 1 shows the time course of changes in haematocrit (A), UIBC (B), serum ferritin (C) and serum 8-OHdG (D), and all these parameters in the IVIR group patients changed significantly as compared with the high FTN group and the low FTN group (ANOVA for repeated measures, P < 0.01). IVIR resulted in significant increases from baseline in haematocrit (28.0 ± 4.0% vs 34.6 ± 4.2% at day 70; P < 0.01), serum ferritin (45 ± 20 ng/ml vs 131 ± 79 ng/ml; P < 0.01), and serum 8-OHdG (0.22 ± 0.07 ng/ml vs 0.50 ± 0.16 ng/ml; P < 0.01), and there was a significant decrease in UIBC (250 ± 41 µg/dl vs 169 ± 51 µg/dl; P < 0.01). Serum iron levels did not change significantly (data not shown). Interestingly, the increase in serum 8-OHdG was continuous and linear through the whole study period, even after the IVIR administration had ceased (Figure 1). Serum 8-OHdG and serum ferritin changed in the same manner. At baseline, patients in the IVIR group had significantly lower serum ferritin levels compared with patients in the high FTN group (45 ± 20 ng/ml vs 218 ± 85 ng/ml; P < 0.01). Thereafter, serum ferritin increased, and the difference between the two groups disappeared at day 42 (167 ± 65 ng/ml vs 210 ± 107 ng/ml; P = 0.28). On the contrary, the serum ferritin levels in the IVIR group patients were significantly higher than those in the low FTN group patients after day 42. Changes in serum 8-OHdG were similar, and the significant difference between the IVIR group and the high FTN group patients at baseline (0.22 ± 0.07 ng/ml vs 0.52 ± 0.20 ng/ml; P < 0.01) disappeared at day 28 (0.35 ± 0.07 ng/ml vs 0.49 ± 0.27 ng/ml; P = 0.22). Finally, compared with the low FTN group patients at day 70, IVIR group patients had a higher serum ferritin (131 ± 79, 179 ± 79, and 27 ± 20 for the IVIR, High FTN, and Low FTN group, respectively; P < 0.01) and higher serum 8-OHdG (0.50 ± 0.16, 0.58 ± 0.28, and 0.36 ± 0.11 for the IVIR, high FTN, and low FTN group, respectively; P < 0.05).


Figure 1
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  		Fig. 1. The time course of changes in haematocrit (A), UIBC (B), serum ferritin (C), and serum 8-OHdG (D) levels. * Significantly different from baseline (P < 0.01).

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Acknowledgements
 References
 
The present prospective study was designed to clarify the effects of repeated IVIR administration on an oxidative DNA marker, serum 8-OHdG. The IVIR group patients received IVIR for ~6 weeks, and were then observed for the remaining 4 weeks. Repeated IVIR administration resulted in significant increases in serum 8-OHdG, and this increment was continuous and linear through the whole period, even after the administration had ceased. Also the serum ferritin level increased following IVIR administration. On the contrary, neither serum 8-OHdG nor serum ferritin levels changed significantly among the patients who did not receive IVIR administration, i.e. patients included the high FTN group and low FTN group.

Several studies have reported that a single IVIR administration in HD patients transiently increases prooxidants such as advanced oxidation protein products (AOPP) [5], malondialdehyde (MDA) [6,7], and carbonylated fibrinogen [8], and suppresses anti-oxidants such as superoxide dismutase (SOD) [6] and glutathione peroxidase (GSHPx) [6,7]. However, these reports assessed the immediate effects of IVIR just after administration, and Herrera et al. [7] reported that the plasma MDA level had declined to near baseline 24 h after a single IVIR injection. We found that repeated IVIR administrations increased serum 8-OHdG levels, and the most interesting finding was that this increment was continuous even after the IVIR administration had ceased. This phenomenon cannot be fully explained by the release of free iron through the transient oversaturation of transferrin due to IVIR administration. Over the course of the study, similar changes were seen in serum 8-OHdG and serum ferritin levels. Furthermore, serum ferritin, which reflects the status of iron storage in the body, was independently associated with serum 8-OHdG. Although ferritin stores excess iron and maintains it chemically inert, it is possible that, as ferritin iron content increases, free iron may be more easily released and presumably more available for participation in redox reactions [13]. Taken together, the results of our study may well suggest that repeated IVIR administration increased OS by increasing body iron storage.

In this study, we used 8-OHdG as a marker of the oxidative alteration induced by IVIR. In regard to its relationship with iron-related parameters, 8-OHdG is well documented. Nakano et al. [14] measured urinary 8-OHdG excretion of 2507 Japanese healthy subjects, and found that 8-OHdG correlated with serum ferritin positively, and total iron-binding capacity (TIBC) negatively. Among HD patients, a number of smaller studies have reported that circulating 8-OHdG levels were positively correlated with serum ferritin, serum iron, and TSAT [15–17]. We also found that the serum 8-OHdG level was positively associated with haematocrit and serum ferritin, and negatively associated with UIBC. Especially, serum ferritin was an independent determinant of serum 8-OHdG in a multiple regression model. This appears to support the notion that increased body iron storage may lead to increased oxidative stress.

Higher than normal upper limits of serum ferritin (i.e. <500 ng/ml) have been proposed by KDOQI for managing renal anaemia [3]. The risk of a high ferritin level is supported by data indicating that the relative risk of death for a patient with a serum ferritin level >500 ng/ml was 2.7 in HD patients [18]. However, in the present study, IVIR was given cautiously to avoid values higher than this limit for serum ferritin, and none of the patients had a ferritin level >500 ng/ml. Nevertheless, a significant increase in serum 8-OHdG levels was found, and furthermore, a significant correlation was found between serum 8-OHdG and serum ferritin levels. The fact that oxidative stress was associated with a relatively low level of ferritin may lead us to consider whether changes in this marker's level had a negative impact on mortality and morbidity in HD patients. In the management of renal anaemia, sufficient iron supplementation can reduce rHuEPO usage, and thus reduce health care cost. However, in the present study, serum ferritin level in the low FTN group was similar to those in the general population, and serum 8-OHdG was also relatively low. These facts might raise the issue of developing modified criteria for iron replacement therapy.

There are several limitations of this study. First, the patient number is relatively small. Secondly, we did not measure NTBI, which plays an important role in oxidative damage by IVIR administration. Rooyakkers et al. [4] demonstrated that iron saccharate infusion induced the production of NTBI via the oversaturation of transferrin, which keeps the iron in a catabolically inactive form. Thirdly, we analysed neither antioxidant factors nor the repair system of DNA. Various enzymatic and non-enzymatic defence mechanisms such as SOD, catalase, ß-carotene and ascorbic acid could neutralize the oxidative reaction following IVIR administration. Additionally, the MutT protein hydrolyses 8-OHdGTP to 8-OHdGMP, and this potentially mutagenic substrate is eliminated from the deoxynucleotide pool in the nuclei [19]. Fourthly, we did not examine, and can therefore not exclude possible differences in oxidative stress between different iron preparations. Zager et al. [20] found that oxidative damage was seen with iron sucrose and iron gluconate, but not with iron dextran and iron oligosaccharide.

We conclude that repeated IVIR administration in HD patients resulted in an elevation of oxidative DNA injury, as reflected by increased serum 8-OHdG levels. These changes were accompanied by increased serum ferritin levels; thus, excess body iron stores may play an important role in oxidative stress. Further investigations are needed to confirm the clinical significance of this finding.



   Acknowledgements
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
References
 
We are grateful to Prof. Tatsuo Hosoya, Division of Kidney and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan, for his helpful encouragement and support of this study. Part of this study was supported by Foundation for renal anemia therapy. The authors thank to Dr Hirotomo Ochi (Japan Institute for the Control of Aging/JaICA) for provision of the 8-OHdG ELISA kits.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Langston RD, Presley R, Flanders WD, McClellan WM. (2003) Renal insufficiency and anemia are independent risk factors for death among patients with acute myocardial infarction. Kidney Int 64:1398–1405.[CrossRef][Web of Science][Medline]
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  8. Michelis R, Gery R, Sela S, et al. (2003) Carbonyl stress induced by intravenous iron during haemodialysis. Nephrol Dial Transplant 18:924–930.[Abstract/Free Full Text]
  9. Kasai H. (1997) Analysis of a form of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. Mutat Res 387:147–163.[CrossRef][Web of Science][Medline]
  10. Tarng DC, Huang TP, Wei YH, et al. (2000) 8-hydroxy-2'-deoxyguanosine of leukocyte DNA as a marker of oxidative stress in chronic hemodialysis patients. Am J Kidney Dis 36:934–944.[Web of Science][Medline]
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  15. Tarng DC, Huang TP, Liu TY, et al. (2000) Effect of vitamin E-bonded membrane on the 8-hydroxy 2'-deoxyguanosine level in leukocyte DNA of hemodialysis patients. Kidney Int 58:790–799.[CrossRef][Web of Science][Medline]
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Received for publication: 20. 5.06
Accepted in revised form: 5.12.06


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