Skip Navigation


NDT Advance Access originally published online on June 8, 2006
Nephrology Dialysis Transplantation 2006 21(10):2834-2840; doi:10.1093/ndt/gfl263
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
21/10/2834    most recent
gfl263v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (2)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Guz, G.
Right arrow Articles by Dhondt, A. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Guz, G.
Right arrow Articles by Dhondt, A. W.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Impact of iron sucrose therapy on leucocyte surface molecules and reactive oxygen species in haemodialysis patients

Galip Guz, Griet L. Glorieux, Rita De Smet, Marie-Anne F. Waterloos, Raymond C. Vanholder and Annemieke W. Dhondt

Department of Nephrology, Ghent University Hospital, Ghent, Belgium

Correspondence and offprint requests to: Galip Guz, MD, Yale University School of Medicine Departments Nephrology/Immunobiology, The Anlyan Center S510, 300-Cedar Street, New Haven 06520, CT, USA. Email: galip_guz{at}hotmail.com



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. It has been suggested that iron increases oxidative stress and that an excess of iron contributes to cardiovascular disease and infections in haemodialysis patients. In the present study, the effects of parenterally administered iron on leucocyte surface molecule expression and the production of reactive oxygen species (ROS) were evaluated.

Methods. Ten chronic haemodialysis (HD) patients without iron overload were studied. To each patient, four different regimens were applied: placebo; iron sucrose, either 30 or 100 mg, administered via the outflow dialyser line; and 100 mg of iron sucrose infused via the inflow dialyser line. Blood was sampled at different time points: before, during and after infusion and immediately before the next dialysis session. Levels of CD11b and CD45 expression on granulocytes and of CD11b, CD14 and CD36 on monocytes were determined using flow cytometric analysis. The generation of ROS was quantified using chemiluminescence with and without ex vivo stimulation by phorbol myristate acetate (PMA).

Results. No significant differences among the four different treatment regimes were found, neither in chemilumescence activity nor in the expression of CD11b and CD45 on granulocytes, and of CD11b, CD14 and CD36 on monocytes.

Conclusions. Our results suggest that parenteral infusion of iron sucrose during haemodialysis in patients who have no signs of iron overload has no significant effect on the expression of leucocyte surface molecules and does not increase production of ROS.

Keywords: CD11b; CD14; CD36; CD45; iron sucrose; reactive oxygen species



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Most haemodialysis (HD) patients treated with recombinant human erythropoietin receive concurrent iron therapy. Although both oral and parenteral iron supplementation have been used in patients with stage V renal disease, the parenteral route has been found to be more effective. Polynuclear ferric hydroxide–carbohydrate complexes, such as iron dextran, iron sucrose and iron gluconate, have been used widely; nonetheless, lately, iron sucrose was considered to be one of the safest agents [1]. Iron overload and intravenous (IV) infusion of iron have been incriminated in the increased susceptibility for infection [2–5] and the accelerated rate of atherosclerosis [6,7], which are current complications in dialysis patients.

Leucocytes play a key role in the defence against infection and are important mediators in the progression of atherosclerosis. Their function relies at least in part on the expression of surface molecules such as CD11b, CD14, CD36 and CD45, and on the generation of mediators such as the reactive oxygen species (ROS). CD11b is mainly found on the surfaces of monocytes and granulocytes; CD14 is predominantly expressed on monocytes and macrophages. The surface molecule, CD36, belonging to the class B family of scavenger receptors, is expressed on monocytes, platelets, endothelial cells and on some lines of human tumour cells, but not on lymphocytes or granulocytes. Another leucocyte surface molecule, CD45, is abundantly found on granulocytes, lymphocytes, monocytes, eosinophils and basophils. These leucocyte surface molecules have many roles in inflammatory, chemotactic and immunological responses such as leucocyte and endothelial cell interactions, cell recognition, phagocytosis and atherogenesis [8–11]. Therefore, in the present study, all these surface molecules were studied, in order to cover a variety of points of action.

In the present study, the possible effects of IV infusions of iron sucrose on leucocyte expression of CD11b, CD14, CD36 and CD45, and on the production of ROS were investigated in chronic HD patients without iron overload.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
Ten chronic HD patients (two females and eight males; mean age, 65.1 ± 8.9 years; mean dialysis duration 73.7 ± 64.4 months) participated in the study. Their baseline mean ferritin level was 104 ± 60 ng/ml, and mean transferrin saturation level 17.8 ± 3.8%. The causes of renal failure were renovascular disease (n = 3), immunoglobulin A (IgA) nephropathy (n = 2), diabetes mellitus (n = 2), chronic glomerulonephritis (n = 1), analgesic nephropathy (n = 1) and combined diabetes/renovascular disease (n = 1). No vitamin C or E, antibiotics, corticosteroids or non-steroidal anti-inflammatory agents were administered, and none of the patients had infectious or inflammatory conditions during the investigation period or in the month preceding the study. Likewise, no parenteral nutrition or mannitol was administered to any patient during this time frame.

Before and during the investigation, all patients were dialysed three times weekly for at least 4 h. Bicarbonate dialysate (formula 4002, Bieffe Medital, Grosotto, Italy or B 714, Sterima NV, Kortrijk, Belgium) and single-use low-flux polysulfone membranes (F8, 1.8 m2, Fresenius Bad Homburg, Germany) were used. All patients were taking epoetin beta (Recormon®, Roche, Hertfordshire, UK) at doses that maintained a stable haematocrit between 33 and 36%. None of the patients had received blood transfusions in the month prior to the study.

Study protocol
The investigation was conducted over four consecutive weeks. Each individual was subjected randomly to three different regimes of IV iron sucrose (Venofer® Vifor France SA, Levellois-Perret, France) administration and one placebo treatment. Every patient had one experimental session on the same day of each week, and the different regimens were applied in random order. The four forms of therapy were as follows: 100 ml of saline infused via the outflow (venous) dialyser blood line (placebo—treatment A); 30 mg iron sucrose dissolved in 100 ml of saline and infused via the outflow dialyser line (treatment B); 100 mg iron sucrose dissolved in 100 ml of saline and infused via the outflow dialyser line (treatment C) and 100 mg iron sucrose dissolved in 100 ml of saline and infused via the inflow dialyser line, upstream of the artificial kidney (treatment D). All placebo and iron sucrose infusions were started 60 min after the beginning of the session, and were administered over a period of 30 min. In the typical clinical setting, IV iron is usually administered during the last 30 min of the session. There were two reasons why we used a different time frame for the present study: (i) to allow evaluation of effects on leucocytes in a period at least 150 min after iron administration; this could be done by blood sampling after dialysis, without the need to recur to post-dialysis blood collections and (ii) to minimize the effect of potential membrane bioincompatibility on leucocyte activity, as this effect is most pronounced during the first 30 min of the session.

For each experimental treatment, blood samples were collected from the inflow dialyser blood line at six different time points: before the start of the session (t0i); after 60 min of dialysis (t1i); after 90 min (t2i); after 120 min (t3i); after 240 min (t4i) and before the start of the next session (t5i). We also collected blood from the outflow dialyser blood line 90 min after the start of the session (t2o). In each case, the sample at 60 min (t1i) was drawn just before the start of iron (or placebo) infusion. The samples at 90 min (t2i and t2o) were drawn just prior to the completion of iron (or placebo) infusion. Figure 1 illustrates the study design, including the sites of blood sampling at different time points and the two sites of infusion.


Figure 1
View larger version (9K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1. An illustration of the study design showing the sites of blood sampling at different time points, and the two sites of infusion (i, inflow; o, outflow).

 
Haematology
Each patient's haematocrit, leucocyte count, serum iron level, total iron-binding capacity, transferrin saturation level and serum ferritin level were measured before and at the end of the study, utilizing routine laboratory methods.

Flow cytometric analysis
The levels of expression of CD11b and CD45 on granulocytes and of CD11b, CD14 and CD36 on monocytes were evaluated by direct immunofluorescence staining, using a flow cytometer (FACScanTM, Becton-Dickinson Immunocytometry Systems, San Jose, CA, USA). The following monoclonal antibodies (BD Bioscience, San Jose, CA, USA) were used: (i) phycoerythrin (PE)-conjugated anti-CD11b (LeuTM-15); (ii) fluorescein isothiocyanate (FITC)-conjugated anti-CD36 and (iii) a mixture of FITC-conjugated anti-CD45 (anti-HLe-1) and PE-conjugated anti-CD14 (LeuTM-M3) (SimultestTM LeucoGATETM). For testing, 20 µl of monoclonal antibody was placed in a Falcon polystyrene test tube (Becton Dickinson Labware, Lincoln Park, New Jersey, USA) and 100 µl of whole blood was added. Each blood sample was incubated with the respective monoclonal antibodies for 20 min at 4°C. About 2 ml of 10 x diluted FACS® Lysing Solution (Becton-Dickinson) was then added to each tube, and this mix was incubated for 8 min. After washing the cells twice, the cell pellet was re-suspended in Hanks’ balanced salt solution (HBSS) (GIBCO BRL Life Technologies, Paisley, UK) and immediately analysed on a FACScanTM. CaliBRITETM beads and AutoCOMPTM Software were used to set photomultiplier tube voltages, adjust fluorescence compensation and check detector sensitivity. The mean channel of fluorescence intensity was calculated. Saturating concentrations of monoclonal antibodies were used. Non-specific labelling was excluded by SimultestTM Control FITC-conjugated IgG1/PE-conjugated IgG2a and FITC-conjugated IgM-{kappa} (BD Bioscience). Monocytes and granulocytes were gated selectively for analysis by low-forward-angle light scatter (FSC) and right-angled light scatter (SCC).

Chemiluminescence analysis
The generation of ROS in each sample was assessed on the basis of chemiluminescence production. For each sample, 50 µl of whole blood was placed in a polystyrene inserting tube, and 500 µl (56 µM) of luminol solution and either 100 µl of HBSS or 100 ml (20 µM) 1 phorbol 12-myristate 13-acetate (PMA; Sigma, St Louis, MO, USA) were added. Each test tube was then immediately processed in a luminescence analyser (Lumicon, Hamilton, Switzerland). The photon counting value, which is indicated arbitrarily in relative light units, was registered with the counting interval set at 30 s and a total cycling time of 30 min. Chemiluminescence production was recorded as integrated chemiluminescence emission in counts per 30 min. The ratio of the integral of counts over the total cycling time to total leucocyte count in each sample was used as an index of chemiluminescence activity. In addition to chemiluminescence in the basal state and in the phorbol myristate acetate (PMA)-stimulated state, delta chemiluminescence production was calculated as chemiluminescence production after PMA-stimulation minus chemiluminescence production without stimulation.

Data analysis and statistics
Data are expressed as mean ± SD, and were analysed using the software programme are SPSS 12.0 for windows. A potential effect of iron therapy was assessed by the general linear model (GLM) for repeated measures, to be followed by the Bonferroni post-test in case of significance. P-values below 0.05 were considered significant.



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
The laboratory results of pre-dialysis haematocrit, leucocyte counts and parameters related to iron stores, before and after the study, are presented in Table 1. Analysis revealed no significant differences between the findings at baseline and those at the end of the study.


View this table:
[in this window]
[in a new window]

  		Table 1. Haematocrit, leucocyte counts and parameters of iron-metabolism before and after the study (n = 10)

 
Expression of surface molecules on granulocytes
The levels of expression of CD11b and CD45 on granulocytes are illustrated in Figure 2.


Figure 2
View larger version (28K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2. Expression of CD45 (a) and CD11b (b) on granulocytes. Schedule A: placebo (open bars), B: 30 mg iron sucrose via the outflow dialyser blood line (vertically hatched bars), C: 100 mg iron sucrose via the outflow dialyser blood line (diagonally hatched bars) and D: 100 mg iron sucrose via the inflow dialyser blood line (closed bars).

 
CD11b: The iron treatment regimen had no significant effect on the expression of CD11b on granulocytes during dialysis. In each regimen, the level of expression at t2o was higher than the levels at the other time points.

CD45: The iron treatment regimen had no significant effect on the expression of CD45 on granulocytes during dialysis. In all the treatment regimens, the level of expression was slightly higher at t2o than at the other time points.

Expression of surface molecules on monocytes
The levels of expression of CD11b, CD14 and CD36 on monocytes during the four treatment regimes are shown in Table 2.


View this table:
[in this window]
[in a new window]

  		Table 2. The levels of CD11b, CD14 and CD36 expression on monocytes associated with the four treatment regimes

 
CD11b: The iron treatment regimen had no significant effect on the expression of CD11b on monocytes during dialysis. Again, in each regime, the expression at t2o was higher than the levels at the other time points.

CD14: The administration of iron also had no significant effect on the expression of CD14 during dialysis. The level of CD14 expression on monocytes did not change significantly throughout the observational period for any of the four regimes tested.

CD36: As with CD11b and CD14, the iron schedule did not significantly influence the CD36 expression during dialysis. There were no significant changes in CD36 expression on monocytes throughout the time periods analysed for any of the four regimes tested.

Chemiluminescence
The chemiluminescence results are shown in Table 3. The schedule of iron administration did not influence the levels of chemiluminescence (basal, PMA-stimulated and delta values) during the session. The levels of chemiluminescence (basal, PMA-stimulated and delta values) did not change significantly throughout the time periods analysed with any of the four treatment regimes.


View this table:
[in this window]
[in a new window]

  		Table 3. Basal, PMA-stimulated and delta chemiluminscence results at each of the time points for each of the four treatment regimes

 


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
The objective of this study was to assess whether IV iron sucrose, administered at different doses and by different routes during HD, affects the expression of surface molecules on leucocytes and ROS production. The main finding is that the application of iron at the doses used in this study and in the type of patient evaluated in this study does not cause a major change, neither in baseline activity nor in stimulated response, as measured by the expression of leucocyte surface molecules and chemiluminescence.

The most critical concerns regarding iron therapy in HD patients are (i) the increased risk of infection and (ii) the potential to accelerate atherosclerosis, both of which seem related either to acute effects of iron administration or iron overload. The increased infection risk appears to be related to the effects of iron on microbial growth and on host immunity. Under normal conditions, the human body has nearly all of its iron in an inactive form, bound to transferrin and lactoferrin, in order to decrease the access of microorganisms to iron. Microorganisms use free iron in the bloodstream to enhance their growth. In the presence of inflammation and fever, iron binding to lactoferrin increases and this complex is taken up by macrophages to sequester the iron in the reticuloendothelial system [12,13]. This event decreases free iron in the bloodstream and, hence, inhibits bacterial growth. IV iron administration might exceed transferrin-binding capacity in some HD patients, and the unbound circulating iron may increase bacterial growth [14–18]. It has been reported that IV iron administration increases infection risk and bacteraemia episodes in dialysis patients [2–5,19]. Moreover, frequent administration of IV iron over a 6 month period was demonstrated to increase the risk of hospitalization and death [20]. Nevertheless, the relationship between IV iron therapy and infection is not consistent [21,22]. Similarly, no significant differences were identified in hospitalization and infection rates between HD patients receiving more vs less intense IV iron therapy [23].

The known effect of iron on host immunity is related both to the innate and adaptive immune systems. With respect to the innate immune system, a high dose (300 mg) of IV iron sucrose decreases leucocyte function and the ability of phagocytes to kill Escherichia coli in peritoneal dialysis patients [3]. In addition, fundamental neutrophil functions are impaired during IV 10 mg of iron saccharate infusion in HD patients with functional iron deficiency (high ferritin and low transferrin saturation) [4]. IV 62.5 mg of iron gluconate increases neutrophil respiratory burst activity assessed by chemiluminescence in HD patients [24]. On the other hand, one of the parenteral iron preparations, iron dextran, attenuated neutrophil function in HD patients without iron overload [25]. With respect to the adaptive immune system, IV 100 mg iron saccharate every week causes a decrease in the level of tumour necrosis factor-{alpha} (TNF-{alpha}), a pro-inflammatory cytokine, but an increase in a T-helper cell type 2 derived cytokine, interleukin-4 (IL-4), which has anti-inflammatory effects [26].

Several studies in haemodialysis patients have demonstrated that the IV administration of iron is associated with oxidative stress, as measured by: lipid peroxidation [27]; chemiluminescence [24]; superoxide dismutase activity [27]; carbonyl stress [28]; advanced oxidation protein products [6]; oxidation of serum albumin [29]; malondialdehyde (MDA) formation [27]; red blood cell glutathione and catalase activity [30]; DNA damage [31], as well as with parameters of atherosclerosis, such as elevated troponin concentration [32] and increased carotid artery intima–media thickness [6,7]. However, glutathione levels and glutathione peroxidase activity did not change with 100 mg of iron saccharate infusion [27]. In addition, the degree of protein oxidation, assessed by advanced oxidation protein products, during IV 100 mg iron saccharate therapy was found to be related to the degree of inflammation, but not to transferrin saturation or ferritin levels [33]. On the other hand, IV iron sucrose (20–100 mg) did not cause any detrimental effects on the plasma MDA levels or erythrocyte deformability [34]. In contrast to 125 mg iron gluconate, 62.5 mg iron gluconate did not induce carbonyl stress [28]. Additionally, 100 mg iron saccharate did not oversaturate transferrin, and peroxide concentrations were not found to be affected by IV iron therapy [16]. Furthermore, 100 mg iron saccharate every week slightly decreased endogenous peroxide and oxidative stress [26]. Recently, it has been claimed that low iron levels were related to elevated hospitalization and mortality rates in HD patients, and IV iron up to 400 mg/month is associated with improved survival [35].

The incongruity of results from various studies might be due to a variety of factors, including: (i) the preparation of iron (dextran, sucrose or gluconate); (ii) iron dosage (from 10 up to 700 mg); (iii) iron infusion rate (bolus, 30 min or 4.5 h); (iv) the methods for determining infection risk and oxidative stress; (v) baseline iron indices such as transferrin saturation and ferritin levels; and (vi) the inflammation status of patients. Some results pertaining to iron toxicity come from in vitro experiments, in which the iron concentrations examined were much higher than those observed clinically in the serum of patients without iron overload [36,37].

Similar to the present study, the flow cytometric method and detection of ROS by chemiluminescence have generally been used to determine leucocyte functions in HD patients, and flow cytometric analysis has revealed the leucocyte surface molecule alterations associated with membrane bioincompability [24,38,39].

In our study, the expression of leucocyte surface molecules was highest in blood samples drawn from the outflow dialyser blood line (outlet HD membrane), demonstrating a high sensitivity to changes in the leucocyte surface molecules secondary to the HD membrane. Although the expression of leucocyte surface molecules was altered due to this membrane effect, these levels did not change from before to after iron sucrose infusion. In addition to low-dose iron administration, the low ferritin levels and transferrin saturation in our study population may be a reason that the expression of leucocyte surface molecules and chemiluminescence activity did not change significantly. It seems plausible that parenteral iron treatment during HD, in the setting of low transferrin saturation and serum ferritin levels, produces less chemiluminescence activity, because these patients have less free iron in circulation. Future studies need to compare patients with low, normal and high ferritin and transferrin saturation levels to confirm this hypothesis.

Our study has some limitations, including its small sample size. We also made no attempt to assess clinically relevant outcomes such as infection and death. The dose of iron sucrose infused, 30 and 100 mg, is certainly is lower than the one which others may use, and higher doses may have produced an observable effect on the expression of leucocyte surface molecule and ROS. Our findings indicate that parenteral administration of 30 or 100 mg iron sucrose during HD does not significantly change the expression of the leucocyte surface molecules CD11b, CD14, CD36 and CD45 in chronic HD patients without iron overload. Furthermore, these infusions do not appear to alter levels of ROS in this patient group. As the expression of these surface molecules and the generation of ROS are highly associated with leucocyte activation, the lack of effect of iron on these variables is an argument for a neutral effect of iron towards leucocyte activation. As the accelerated atherosclerosis and the propensity towards infection of haemodialysis patients are triggered by repetitive and inappropriate leucocyte activation, the results of this study do not point towards a causal effect of iron in these pathologies.



   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
G.G., MD studied in the renal division of University Hospital Ghent, Belgium with the help of a grant from The Scientific and Technical Research Council of Turkey. The authors wish to thank the dialysis staff at the HD Unit of University Hospital Ghent, and Stefan Claus and Antoine De Cubber, in particular, for their assistance.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Locatelli F and Aljama P, et al. (2004) European Best Practice Guidelines Working Group. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 19:1–47.[Free Full Text]
  2. Canziani MEF, Yumiya ST, Rangel EB, Manfredi SR, Neto MC, Draibe SA. (2001) Risk of bacterial infection in patients under intravenous iron therapy: dose vs length of treatment. Artif Organs 25:866–869.[CrossRef][Web of Science][Medline]
  3. Deichner R, Ziai F, Cohen G, Mullner M, Hoerl W. (2003) High-dose parenteral iron suucrose depresses neutrophil intracellular killing capacity. Kidney Int 64:728–736.[CrossRef][Web of Science][Medline]
  4. Patruta SI, Edlinger R, Sunder-Plassmann G, Hoerl WH. (1998) Neutrophil impairment associated with iron therapy in hemodialysis patients with functional iron deficiency. J Am Soc Nephrol 9:655–663.[Abstract]
  5. Tielemans CL, Lenclud CM, Wens R, Collart FE, Dratwa M. (1989) Critical role of iron overload in the increased susceptibility of haemodialysis patients to bacterial infections. Beneficial effects of desferrioxamine. Nephrol Dial Transplant 4:883–887.[Abstract/Free Full Text]
  6. Drueke T, Witko-Sarsat V, Massy Z, et al. (2002) Iron therapy, advanced oxidation protein products, and carotid artery intima-media thickness in end-stage renal disease. Circulation 106:2212–2217.[Abstract/Free Full Text]
  7. Reis KA, Guz G, Ozdemir H, et al. (2005) Intravenous iron therapy as a possible risk factor for atherosclerosis in end-stage renal disease. Int Heart J 46:255–264.[CrossRef][Web of Science][Medline]
  8. Febbraio M, Hajjar DP, Silverstein RL. (2001) CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J Clin Invest 108:785–791.[CrossRef][Web of Science][Medline]
  9. Harvath L, Balke JA, Christiansen NP, Russell AA, Skubitz KM. (1991) Selected antibodies to leukocyte common antigen (CD45) inhibit human neutrophil chemotaxis. J Immunol 146:949–957.[Abstract]
  10. Jutila MA, Rott L, Berg EL, Butcher EC. (1989) Function and regulation of the neutrophil MEL-14 antigen in vivo: comparison with LFA-1 and MAC-1. J Immunol 143:3318–3324.[Abstract]
  11. Springer TA. (1990) Adhesion receptors of the immune system. Nature 346:425–434.[CrossRef][Medline]
  12. Bullen JJ. (1981) The significance of iron in infection. Rev Infect Dis 3:1127–1138.[Web of Science][Medline]
  13. Ward CG, Hammond J, Bullen J. (1986) Effect of iron compounds on antibacterial function of human polymorphs. Infect Immun 15:723–730.
  14. Parkkinen J, von Bonsdorff L, Peltonen S, Gronhagen-Riska C, Rosenlof K. (2000) Catalytically active iron and bacterial growth in serum of haemodialysis patients after i.v. iron saccharate administration. Nephrol Dial Transplant 15:1827–1834.[Abstract/Free Full Text]
  15. Roob JM, Khoschsorur G, Tiran A, Winklhofer-Roob BM. (2000) Vitamin E attenuates oxidative stress induced by intravenous iron in patients on hemodialysis. J Am Soc Nephrol 11:539–549.[Abstract/Free Full Text]
  16. Scheiber-Mojdehkar B, Lutzky B, Schaufler R, Sturm B, Goldenberg H. (2004) Non-transferrin-bound iron in the serum of hemodialysis patients who receive ferric saccharate: no correlation to peroxide generation. J Am Soc Nephrol 15:1648–1655.[Abstract/Free Full Text]
  17. Sunder-Plassmann G and Hoerl WH. (1996) Safety of intravenous injection of iron saccharate in haemodialysis patients. Nephrol Dial Transplant 11:1797–1802.[Abstract/Free Full Text]
  18. Zanen AL, Adriaansen HJ, van Bommel EF, Posthuma R, de Jong GM Th. (1996) "Oversaturation" of transferrin after intravenous ferric gluconate (Ferrlecit®) in hemodialysis patients. Nephrol Dial Transplant 11:820–824.[Abstract/Free Full Text]
  19. Teehan GS, Bahdouch D, Ruthazer R, Balakrishnan VS, Snydman DR, Jaber BL. (2004) Iron storage indices: novel predictors of bacteremia in hemodialysis patients initiating intravenous iron therapy. CID 38:1090–1094.
  20. Feldman HI, Santanna J, Guo W, et al. (2002) Iron administration and clinical outcomes in hemodialysis patients. J Am Soc Nephrol 13:734–744.[Abstract/Free Full Text]
  21. Brewster UC, Cocca SC, Reilly RF, Perazella MA. (2005) Effect of intravenous iron on hemodialysis catheter microbial colonization and blood-borne infection. Nephrology 10:124–128.[CrossRef][Medline]
  22. Hoen B, Paul-Dauphin A, Hestin D, Kessler M. (1998) Epibacdial: a multicenter prospective study of risk factors for bacteremia in chronic hemodialysis patients. J Am Soc Nephrol 9:869–876.[Abstract]
  23. Besarab A, Amin N, Ahsan M, et al. (2000) Optimization of epoetin therapy with the intravenous iron therapy in hemodialysis patients. J Am Soc Nephrol 11:530–538.[Abstract/Free Full Text]
  24. Hodkova M, Dusilova-Sulkova S, Skalicka A, Kalousova M, Zima T, Bartunkova J. (2005) Influence of parenteral iron therapy and oral vitamin E supplementation on neutrophil respiratory burst in chronic hemodialysis patients. Ren Fail 27:135–141.[Web of Science][Medline]
  25. Guo D, Jaber BL, Lee S, et al. (2002) Impact of iron dextran on polymorphonuclear cell function among hemodialysis patients. Clin Nephrol 58:134–142.[Web of Science][Medline]
  26. Weiss G, Meusburger E, Radacher G, Garimorth K, Neyer U, Mayer G. (2003) Effect of iron treatment on circulating cytokine levels in ESRD patients receiving recombinant human erythropoietin. Kidney Int 64:572–578.[CrossRef][Web of Science][Medline]
  27. Lim PS, Wei YH, Yu YL, Kho B. (1999) Enhanced oxidative stress in haemodialysis patients receiving intravenous iron therapy. Nephrol Dial Transplant 14:2680–2687.[Abstract/Free Full Text]
  28. 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]
  29. Anraku M, Kitamura K, Shinohara A, et al. (2004) Intravenous iron administration induces oxidation of serum albumin in hemodialysis patients. Kidney Int 66:841–848.[CrossRef][Web of Science][Medline]
  30. Herrera J, Nava M, Romero F, Rodriguez-Iturbe B. (2001) Melatonin prevents oxidative stress resulting from iron and erythropoietin administration. Am J Kidney Dis 37:750–757.[Web of Science][Medline]
  31. Muller C, Eisenbrand G, Gradinger M, et al. (2004) Effects of hemodialysis, dialyser type and iron infusion on oxidative stress in uremic patients. Free Radic Res 38:1093–1100.[CrossRef][Web of Science][Medline]
  32. Guz G, Sahinaslan A, Dhondt AWC, et al. (2004) Elevated cardiac troponin T in hemodialysis patients receiving more intravenous iron sucrose. Ren Fail 26:663–672.[CrossRef][Web of Science][Medline]
  33. Tovbin D, Mazor D, Vorobiov M, Chaimovitz C, Meyerstein N. (2002) Induction of protein oxidation by intravenous iron in hemodialysis patients: role of inflammation. Am J Kidney Dis 40:1005–1012.[CrossRef][Web of Science][Medline]
  34. Cavdar C, Temiz A, Yenicerioglu Y, et al. (2003) The effects of intravenous iron treatment on oxidant stress and erythrocyte deformability in hemodialysis patients. Scand J Urol Nephrol 37:77–82.[CrossRef][Web of Science][Medline]
  35. Kalantar-Zadeh K, Regidor DL, McAllister CJ, Michael B, Warnock DG. (2005) Time-dependent associations between indices of iron store and mortality in hemodialysis patients. J Am Soc Nephrol 16:3070–3080.[Abstract/Free Full Text]
  36. Hoepelman IM, Jaarsma EY, Verhoef J, Marx JJ. (1988) Polynuclear iron complexes impair the function of polymorphonuclear granulocytes. Br J Haematol 68:385–389.[Web of Science][Medline]
  37. Van Wyck DB. (2004) Labile iron: manifestations and clinical implications. J Am Soc Nephrol 15:S107–S111.[Free Full Text]
  38. Chen WT, Lin YF, Yu FC, Kao WY, Huang WH, Yan HC. (2003) Effect of ascorbic acid administration in hemodialysis patients on in vitro oxidative stress parameters: influence of serum ferritin levels. Am J Kidney Dis 42:158–166.[CrossRef][Web of Science][Medline]
  39. Tepel M, Echelmeyer M, Orie NN, Zidek W. (2000) Increased intracellular reactive oxygen species in patients with end-stage renal failure: effect of hemodialysis. Kidney Int 58:867–872.[CrossRef][Web of Science][Medline]
Received for publication: 9. 1.06
Accepted in revised form: 18. 4.06


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
21/10/2834    most recent
gfl263v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (2)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Guz, G.
Right arrow Articles by Dhondt, A. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Guz, G.
Right arrow Articles by Dhondt, A. W.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?