P0848PROSPECTIVE OPEN-LABEL EXPLORATIVE RANDOMISED SINGLE-CENTRE COMPARATIVE STUDY TO DETERMINE THE EFFECTS OF VARIOUS INTRAVENOUS IRON PREPARATIONS ON MARKERS OF OXIDATIVE STRESS AND KIDNEY INJURY IN CHRONIC KIDNEY DISEASE (IRON-CKD)
Authors: Kassianides Xenophon , Zeidan Ahmed , Sturmey Roger , Gordon Andrew , Bhandari Sunil 
Published: June 2020

Abstract

Background and Aims
Iron deficiency is commonly treated with intravenous (IV) iron where oral iron is insufficient or cannot be tolerated. While IV iron is considered efficient and effective, safety concerns exist regarding the potential effect of IV iron on oxidative stress, inflammation and endothelial function. Transferrin is unable to saturate all the iron administered. Consequently, evidence has suggested differential generation of “free” or catalytic labile iron, depending on iron preparation. Labile iron stimulates lipid oxidation and free radical generation which can lead to increased oxidative stress, inflammation and endothelial dysfunction. The comparative risk of IV iron preparations has not been previ-ously extensively assessed.
The possibility of IV iron leading to changes in oxidative stress, inflammation and endothelial function is assessed in this study. The potential interplay of IV iron changes with signaling pathways may lead to renal damage depending on the iron formulation used. This may lead to tubular and glomerular injury manifested as raised Neutrophil gelatinase-associated lipocalin (NGAL) levels in patients with chronic kidney disease (CKD).

Method
IRON-CKD is a prospective open-label explorative randomized, single-centre study assessing comparative safety and efficacy of three parenteral iron preparations. Patients with established CKD stages 3-5 and serum ferritin (SF) &lt; 200microg/L and/or transferrin saturation (TS) &lt;20% were recruited and randomized in a 1:1:1:1 ratio. The groups received a single infusion of 200mg Iron Dextran (Cosmofer ®), 200 mg Iron Sucrose (Venofer ®), and Iron Isomaltoside (Monofer ®) either as low (200mg) or high dose (1000mg). The patients were followed-up after IV iron at 2 hours and then at 1 day, 1 week, 1 month and 3 month intervals. Oxidative stress markers (Thiobarbituric acid reactive substances (TBARS)), inflammatory markers (Interleukin-1b, Interleukin-6, Interleukin-8, Interleukin-10) and surrogate markers of endothelial dysfunction (E-selectin, P-selectin) were measured. NGAL levels for establishment of potential acute kidney insult were measured. Free catalytic iron generation was also measured using the FeROS™ as-say. Data are presented as means and standard error of the mean (SEM). Statistical analysis was carried out using ANOVA. A p value of &lt;0.05 was statistically significant.

Results
Forty patients were recruited and randomised with 10 per group. The mean age was 58.8 (±2.2) years and 23 (58%) were male. Free labile iron and TBARS increased within 2 hours of infusion (1.4 ΔFU/min (±0.5) to 7.4 ΔFU/min (±2.4)) (1083.0 nM (± 117.1) to 1552.6 nM (±156.0)) respectively with complete recovery within one week. TBARS and free labile iron were more pronounced within one day in the group receiving high dose Monofer® (TBARS: pre-infusion: 846.0 nM (±108.9) to 1865.0 nM (±203.2); Free labile iron: pre infusion: 0.3 ΔFU/min (±0.2) to 19.6 ΔFU/min (±7.1)). These were statistically significant with p &lt; 0.001. These returned to pre-dosage levels and did not translate to any detriment in markers of inflammation or endothelial function (E-selectin or P-selectin). There was a non-statistically significant increase in Interleukin-10 (an anti-inflammatory cytokine) 2-hours post-infusion which was transient. Intravenous iron cumulatively and comparatively did not lead to a significant increase in NGAL (pre-infusion 570.5 ng/ml (±52.8); post-infusion 547.8 ng/ml (SEM: ±50.5); 3 months interval 534.8 ng/ml (±52.8)) at any given time point.

Conclusion
High dose of IV iron leads to a transient increased generation of free iron which disappears within one week. Iron therapy, at least in the short term, does not adversely affect markers of acute kidney injury, endothelial function, inflammation and oxidative stress status. This mechanistic data indicates that IV iron at both low and high doses is safe in patients with chronic kidney disease.