Iron deficiency anemia is a global condition co-existing with other medical comorbidities including chronic kidney disease (CKD), heart failure, inflammatory bowel disease, and malignancy [1,2]. It is associated with prognostic and financial implications and reduced quality of life [3,4].

Despite the broad availability of oral iron, issues remain with compliance and side effects [4]. Consequently, intravenous (IV) iron replacement has gained popularity and is incorporated in current clinical guidelines [5,6]. Several IV iron preparations are available including second-generation (e.g., iron sucrose [IS], low molecular weight iron dextran [ID]), and third-generation (e.g., ferric derisomaltose [FDI]) products.

Concerns exist regarding the risks of oxidative stress with parenteral iron administration [7–9]. Previous evidence suggests that the degree of oxidative stress caused by iron supplementation is relative to the labile plasma iron (LPI) released [10,11]. LPI can be involved in redox cycling and has a major role in the initiation and propagation of lipid peroxidation [12]. Works by Zager et al. [8,13,14] have indicated both a dose-related and a preparation-dependent association between iron and toxicity, especially with second-generation IV iron products (IVIPs). The amount of LPI released is related to the structural stability of the iron-carbohydrate complex; third-generation IV irons represent more tightly bound compounds than second-generation products [15]. This may explain why less stable IVIPs (e.g., IS) are linked to endothelial and renal dysfunction and inflammation [16-18].

This explorative study was designed to primarily assess the effect of different IV iron compounds and dosages on oxidative stress and inflammation in patients with non-dialysis-dependent CKD and absolute or functional iron deficiency.

Additionally, the effects of these IV iron treatments on hematinic profile and hemoglobin concentration, arterial stiffness, endothelial function, quality of life, and safety outcomes were investigated. We hypothesized that treatment with IV irons would primarily lead to variable effects on biomarkers of inflammation and oxidative stress and secondarily may result in differences in efficacy markers.

Forty patients, with a mean age of 58.8 ± 2.2 years, were recruited and randomized from a total of 49 patients who attended screening. Twenty-three patients (57.5%) were male.

One participant commenced hemodialysis before the last visit, but follow-up was completed as per protocol; the patient was included in the analysis. One patient became pregnant within 1 month of receiving 1,000 mg FDI, while another individual randomized to the 1,000 mg FDI group required a second IV iron infusion during the study due to severe symptomatic anemia. The latter two participants were excluded from the 3-month analysis. The flow of participants is summarized in Fig. 1.

In this IRON-CKD study, we examined whether administration of IVIPs with different structural stability and risk of labile iron release would have differential impacts on biomarkers of oxidative stress and inflammation and on measures of efficacy, endothelial function, and safety in iron-deficient individuals with CKD. We also compared different doses of FDI, a commonly used third-generation IVIP with low risk of labile release, to identify any dosage-related differences.

Previously, it was assumed that a short-lived increase in oxidative stress was pathogenic. In this study, markers of oxidative stress returned to baseline within 1 week irrespective of iron preparation and dose. Here, despite a trend for increase in TBARS with high-dose FDI and IS, this did not reach statistical significance at any point. LPI rose in a dose-dependent manner, with a statistically significant rise noted with the high-dose FDI. Indeed, results from cellular studies with IVIP have commented on iron-induced increases in cellular stress that are possibly dose- and tissue-dependent; however, no duration of effect was evaluated [22]. The dose-dependent rise displayed here was short-lived and did not translate into systemic adverse effects nor a statistically significant increase in oxidative stress and inflammatory markers. The unchanged LPI from baseline with 200 mg FDI potentially reflects the controlled iron delivery to iron-binding proteins with FDI. This results from the tight binding of iron in the carbohydrate matrix of FDI, which translates into a highly stable compound when compared to second-generation iron preparations such as IS [23]. Garbowski et al. [24] recently commented on two iron release modes; early (direct delivery of iron to transferrin in blood) and late (indirect release of iron from macrophages), with differences between IV irons dependent on their pharmacokinetic properties. They also concluded that FDI had a lower NTBI level compared to IS [24], similar to the findings in the current IRON-CKD study showing lower levels of NTBI with FDI vs. IS and ID at equivalent doses. The lack of impact on oxidative stress by FDI could explain the recent findings of the FERWON-NEPHRO trial where high-dose FDI (1,000 mg), when compared to IS (5 × 200 mg over 2 weeks), resulted in an improved incidence of cardiovascular events [25].

This can be inferred further through the transient rise in CRP with IS, a compound with weaker iron binding. The brief rise in IL-10 (an anti-inflammatory cytokine) caused by IS could represent part of a regulatory process in response to IL-12 (a pro-inflammatory cytokine) [26]. The lack of significant effect on inflammatory markers with third-generation IV iron, even at a high dose (FDI of 1,000 mg), may indicate that no LPI toxicity occurs with such compounds.

The rise in TSAT within hours in all groups demonstrates that current available iron preparations are efficacious, delivering iron rapidly and providing a source of circulating iron. SF achieved maximal rise after one week with 1,000 mg FDI, which provided the most significant and lasting elevation. This may reflect a greater iron repletion effect and highlights that a higher dose of IV iron is able to produce substantial and more effective iron repletion. It is important to underline that at maximal SF concentrations, achieved with high-dose FDI, there was no induced oxidative stress. These results reveal greater iron replenishment using high doses in a manner similar to the landmark PIVOTAL (Proactive IV Iron Therapy in Hemodialysis Patients) study [27]. The modest increase in hemoglobin is consistent with previous studies in non-anemic patients demonstrating little change [28].

IV iron did not aggravate arterial stiffness. This is consistent with other trials in patients receiving dialysis where no change in vascular reactivity was noted [29]. Here, treatment with IV iron resulted in a tendency for improvement in PWV and augmentation index.

Upregulation of selectins is associated with atherosclerosis and inflammation [30]. Evidence on the impact of iron on cell adhesion molecules such as E-selectin and P-selectin is scarce and conflicting [31,32]. In the current study, there were no significant changes in the expression of either E-selectin or P-selectin with any of the IVIPs or doses, suggesting that IV iron does not affect selectin-driven pathways.

This study has several limitations. It was open-label, which increases the risk of observer and participant bias. The study focused on non-smokers and may therefore not be representative of potential interactions of smoking (a powerful pro-oxidant factor) with IV iron treatment; however, it does not exclude any external effect of smoking. Moreover, the small number of participants in each of the four groups did not allow for stratification according to age and comorbidities, renal function, and medications, which are potentially important factors affecting oxidative stress. Additionally, as a pilot study it was not statistically powered for definitive conclusions; however, it can be used for hypothesis generation and for trend observation.

IRON-CKD provided a direct comparative assessment of the relative acute treatment effects of commonly used IV irons. The results indicate that, in the short term and following a single IV iron infusion, endothelial function and oxidative status are not affected. All studied preparations led to a rise in both stored and circulating iron, with more effective repletion with a higher dose. This translated into a small improvement in quality of life, in line with previous large cohort trials [4] underlining the impact of iron in non-anemic patients as witnessed in inflammatory bowel disease [33]. There were no infection-related hospital admissions with any of the preparations administered or with either low- or high-dose IV iron, which supports the good safety profile of high-dose iron and complements the findings in the PIVOTAL study where infection rates were identical irrespective of high- or low-dose IV iron treatment [34].

Additionally, this IRON-CKD study assessed the dose-dependent effects of FDI, supplementing evidence on its efficacy from studies in CKD patients comparing FDI with oral iron and second-generation IVIP [35,36]. As third-generation IV iron compounds share different pharmacodynamic properties from their predecessors [23], previous results on dose-associated toxicity cannot be necessarily extrapolated as indicated by this study.

Nuhu et al. [37] recently examined the mechanistic links between iron and CKD and concluded that the overall oxidation status in CKD is antioxidant. An interplay exists between iron homeostasis and oxidative stress in CKD that in turn impacts the effects of IV iron treatment [38]. It is believed that in CKD the system is primed with activation of both pro- and antioxidant pathways; iron deficiency may aggravate oxidative stress. It is, therefore, speculated that the resolution of iron deficiency with IV iron (despite a short transient increase in oxidative stress) provides an overall net antioxidant benefit due to mobilization of relevant enzymes [39].

The impact of multiple iron infusions and the long-term safety profile of IV iron require further research. Additional exploration of the impact of third-generation IVIP at comparative doses is needed, given their pharmacochemical differences and the potential impact on bone metabolism due to hypophosphatemia as reported with ferric carboxymaltose [40]. Such mechanistic evidence should be considered when incorporating IV iron therapy into other areas of medicine.

Although the patient sample size is too small to make any firm conclusions, this study provides evidence that currently available IV iron therapies are efficacious with a good safety profile. Additionally, this study revealed that high-dose FDI displays a trend of a greater treatment effect, resulting in higher SF and TSAT compared to a lower dose of FDI and to other IV iron preparations. This does not negatively affect oxidative stress, endothelial function, or inflammation. The successful IV iron repletion translates to improved quality of life and may positively affect arterial stiffness. Further larger studies are required to confirm the potential oxidative effects of IV iron and the impact of multiple doses in this patient group.