MO546THE SHORT-TERM EFFECT OF HIGH DOSE THIRD GENERATION INTRAVENOUS IRON ON PATIENTS IN PATIENTS WITH CKD AND IRON DEFICIENCY ON OXIDATIVE STRESS, INFLAMMATION, ENDOTHELIUM AND MYOCARDIAL STRESS
Authors: Kassianides Xenophon , Hazara Adil , Kalra Philip A , Macdougall Iain , Bhandari Sunil 
Published: May 2021

Abstract

Background and Aims
Intravenous (IV) iron administration in patients with chronic kidney disease (CKD) may lead to both pro-oxidant and pro-inflammatory effects and thus secondarily compromise, potentially causing adverse cardiovascular outcomes. In-vitro and in-vivo studies suggest that these effects correlate with the amount of labile free iron circulating following infusion of iron. Third generation IV irons (e.g. ferric derisomaltose (FDI)) have been developed with more compact iron-carbohydrate cores, enabling higher doses to be delivered in a single sitting with lower labile iron generation.
The Iron & Heart study was a multicentre randomized placebo-controlled trial set out to examine the effect of high dose third generation iron (FDI) on the functional capacity of patients with CKD and iron deficiency. A pre-specified secondary mechanistic endpoint was the effect of FDI on markers of oxidative stress, inflammation, endothelial function and cardiac stress.

Method
This was a multicentre double blinded randomized placebo-controlled trial in three tertiary renal centres in the United Kingdom. Patients with CKD stages 3b-5 (non-dialysis) and iron deficiency without anaemia (serum ferritin &lt;100 micrograms/L and/or transferrin saturation &lt;20%) were enrolled. The participants were randomized 1:1 to receive either 1000 mg of FDI or placebo and followed up at 1- and 3-month intervals. Biomarkers of inflammation (CRP, IL6, IL8 and IL10), oxidative stress (thiobarbituric acid reactive substances and F2-isoprostane) and cardiac stress (NT-proBNP) were analysed. Endothelial function was investigated through biomarkers (E-selectin and P-selectin) and pulse wave velocity measurements. Statistical analysis using repeated measure ANOVA with baseline, 1 month and 3-month data was performed with statistical significance inferred at p&lt;0.05.

Results
A total of 54 patients were randomized to receive FDI (n=26) or placebo (n=28). The two groups were comparable for baseline characteristics. Both pro and anti-inflammatory cytokines (IL2, IL6 and IL10) were not affected by FDI at any study point, nor there was any statistical difference was exhibited in CRP (FDI vs. placebo: 1-month: 4.2 (2.7) vs. 6.9 mg/L (18.3), p=0.6; 3-months: 7.5 (6.8) vs. 10.3 mg/L (23.0); p=0.46). Markers of oxidative stress were not significantly altered following FDI treatment or in comparison to placebo. A non-significant trend for a decrease in F2-isoprostane measurements was noted during the first month following FDI infusion compared to placebo (-77% vs. -66%; p=0.83). FDI caused a greater reduction in NT-proBNP compared to placebo (FDI: baseline: 422 (881.9) ng/l; 1-month: 242.5 (209.1) ng/l; placebo: baseline: 485.2 (1268.1) ng/l; 1-month: 436.4 (1383.4) ng/l), but this was not statistically significant (p=0.37). Pulse wave velocity was not affected in either group while measurements of P-selectin remained unaltered. There was a statistically significant increase in E-selectin at both follow-up points following infusion with FDI compared with placebo (1-month: p=0.03; 3 months: p&lt;0.001).

Conclusion
High dose third generation iron treatment of CKD patients with iron deficiency did not lead to either a pro-oxidant or a pro-inflammatory signal. The decrease in markers of oxidative stress following administration of FDI may represent the anti-oxidant effects following alleviation of iron deficiency. Although there was no increase in inflammatory markers there was an increase in E-selectin which might impact vascular function, as upregulation of selectins can be a sign of inflammation or atherosclerosis but the unaffected pulse wave velocity and the reduction in NT pro-BNP are reassuring. Overall, the data confirm that high dose FDI therapy is mechanistically safe. Further larger studies are needed to confirm these findings and the longer term impact on cardiac and vascular function of high dose FDI administration.