Non-transferrin bound iron,cytokine activation and intracellular reactive oxygen species generation in hemodialysis patients receiving intravenous iron dextran or iron sucrose |
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Authors: | Email author" target="_blank">Amy?Barton?PaiEmail author Todd?Conner Charles?R?McQuade Jonathan?Olp Paul?Hicks |
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Institution: | (1) Department of Pharmacy Practice, ANephRx-Albany Nephrology Pharmacy Group, Albany College of Pharmacy and Health Sciences, 106 New Scotland Avenue, Albany, NY 12208, USA;(2) VA Cooperative Studies Program, Albuquerque Veteran Affairs Medical Center, 1501 San Pedro NE, Albuquerque, NM 87108, USA;(3) College of Pharmacy, University of New Mexico, 2502 Marble NE, Albuquerque, NM 87106, USA |
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Abstract: | Intravenous (IV) iron supplementation is widely used to support erythropoeisis in hemodialysis patients. IV iron products
are associated with oxidative stress that has been measured principally by circulating biomarkers such as products of lipid
peroxidation. The pro-oxidant effects of IV iron are presumed to be due at least in part, by free or non-transferrin bound
iron (NTBI). However, the effects of IV iron on intracellular redox status and downstream effectors is not known. This prospective,
crossover study compared cytokine activation, reactive oxygen species generation and oxidative stress after single IV doses
of iron sucrose and iron dextran. This was a prospective, open-label, crossover study. Ten patients with end-stage renal disease
(ESRD) on hemodialysis and four age and sex-matched healthy were assigned to receive 100 mg of each IV iron product over 5 min
in random sequence with a 2 week washout between products. Subjects were fasted and fed a low iron diet in the General Clinical
Research Center at the University of New Mexico. Serum and plasma samples for IL-1, IL-6, TNF-α and IL-10 and NTBI were obtained
at baseline, 60 and 240 min after iron infusion. Peripheral blood mononuclear cells (PBMC) were isolated at the same time
points and stained with fluorescent probes to identify intracellular reactive oxygen species and mitochondrial membrane potential
(Δψm) by flow cytometry. Lipid peroxidation was assessed by plasma F2 isoprostane concentration. Mean ± SEM maximum serum NTBI values were significantly higher among patients receiving IS compared
to ID (2.59 ± 0.31 and 1.0 ± 0.36 μM, respectively, P = 0.005 IS vs. ID) Mean ± SEM NTBI area under the serum concentration–time curve (AUC) was 3-fold higher after IS versus
ID (202 ± 53 vs. 74 ± 23 μM*min/l, P = 0.04) in ESRD patients, indicating increased exposure to NTBI. IV iron administration was associated with increased pro-inflammatory
cytokines. Serum IL-6 concentrations increased most profoundly, with a 2.6 and 2.1 fold increase from baseline in ESRD patients
given IS and ID, respectively (P < 0.05 compared to baseline). In healthy controls, serum IL-6 was undetectable at baseline and after IV iron administration.
Most ESRD patients had increased intracellular ROS generation, however, there was no difference between ID and IS. Only one
healthy control had increased ROS generation post IV iron. All healthy controls experienced a loss of Δψm (100% with IS and
50% with ID). ESRD patients also had loss of Δψm with a nadir at 240 min. IS administration was associated with higher maximum
serum NTBI concentrations compared to ID, however, the both compounds produced similar ROS generation and cytokine activation
that was more pronounced among ESRD patients. The effect of IV iron-induced ROS production on pivotal signaling pathways needs
to be explored. |
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