Analysis of oxidative stress, inflammation and endothelial function following intravenous iron in chronic kidney disease in the Iron and Heart Trial

Abstract

Iron deficiency commonly affects patients with chronic kidney disease and has an important burden in disease trajectory and quality of life; nonetheless current guidelines do not advocate treatment of iron-deficiency without anemia in this patient group. Concerns exist regarding the potential effects of intravenous iron on oxidative stress, inflammation, and endothelial function. As part of a multicenter double-blinded randomized controlled clinical trial, we examined the effects of a single dose of intravenous iron vs. placebo on biomarkers of oxidative stress, inflammation and endothelial function in non-anemic iron deficient patients (serum ferritin < 100 μg/L and/or transferrin saturation < 20%) with chronic kidney disease (stage 3b-5). Fifty-four individuals were randomized to receive ferric derisomaltose (n = 26) or placebo (n = 28). Ferric derisomaltose was associated with a non-significant decrease in mean F2-isoprostane and no effect on thiobarbituric acid reactive substances when compared to placebo throughout follow up. No effect on inflammatory markers was observed. A modest but statistically significant rise in E-selectin was noted in the intravenous iron group at 1 month and 3 month follow-up (p = 0.030 and p = 0.002 respectively). These results suggest ferric derisomaltose administration in non-dialysis dependent chronic kidney disease patients who are iron deficient does not induce prolonged oxidative stress or inflammation. Larger trials are required to quantify the benefit of intravenous iron administration in this patient group.

Functional iron deficiency anemia was associated with higher mortality in chronic kidney disease patients: the NHANES III follow-up study

“…The 2012 KDIGO Guidelines on anemia management in CKD suggest treating anemia with iron supplementation in adult CKD stage 3–5 patients when TSAT is <30% and ferritin is <500 ng/mL. Compared to oral iron, intravenous (IV) iron therapy was more effective in increasing Hb [ 23 ] despite their impact on inflammation [ 24 ] or the incidence of composite cardiovascular AEs [ 25 , 26 ] remains debatable. IV iron formulations such as ferric pyrophosphate citrate could even donate iron directly to transferrin and avoid iron sequestration in the reticuloendothelial macrophages [ 27 ], thus improving FID.…”

Iron homeostasis, recycling and vulnerability in the stressed kidney: A neglected dimension of iron‐deficient heart failure

“…It is therefore noteworthy that intravenous iron boluses have been predictably shown to produce short‐term increases in circulating indicators of lipid peroxidation (malondialdehyde and esterified F2‐isoprostanes), along with augmentation of markers of renal injury and inflammation, in proportion to the circulating levels of iron 109–123 . Inflammatory markers may persist even 3 months after dosing, 124 and thus, the long‐term renal safety of repeated dosing with intravenous iron has been questioned 125 …”

The clinical relevance of detectable plasma iron species in iron overload states and subsequent to intravenous iron‐carbohydrate administration

“…Recently, a large, prospective clinical trial conducted to compare low and high doses of iron sucrose over 4 years in hemodialysis patients did not show that adverse cardiovascular outcomes were worse with increasing iron exposure 72 . Additional published analyses of large dialysis patient datasets have shown modest associations with increased infections at higher doses of intravenous iron, however, this was not observed in a more recent prospective clinical trial in hemodialysis patients 73–75 . Notably, patients with advanced chronic kidney disease have profound background inflammation and oxidative stress attributable to their co‐morbidities 76 .…”

“…72 Additional published analyses of large dialysis patient datasets have shown modest associations with increased infections at higher doses of intravenous iron, however, this was not observed in a more recent prospective clinical trial in hemodialysis patients. [73][74][75] Notably, patients with advanced chronic kidney disease have profound background inflammation and oxidative stress attributable to their co-morbidities. 76 The commonly measured biomarkers (malondialdehyde, TBARS, etc.)…”