Iron Supplementation: What's New?
Authors: Macdougall Iain C. 
Published: April 2021

Abstract
Supplemental orally-administered iron has been available for centuries, but parenteral administration of iron as a therapeutic agent dates from the 1930s. The original agents were iron salts, and their administration to man was associated with severe and unacceptable side-effects even with doses of 4-8 mg. The modern-day practice of IV iron supplementation was transformed in the 1940s with the introduction of iron incorporated into a carbohydrate shell, to allow slow release in the circulation and rapid binding to plasma transferrin. The older iron-carbohydrate complexes included iron dextran, iron sucrose, and iron gluconate, with different iron release kinetics. Iron dextran had significant toxicity with possible anaphylactic reactions. Other iron preparations can also induce hypersensitivity reactions, although recent evidence suggests that these are not immunoglobulin-mediated, but may be due to free iron in circulation or mediated via complement, the so-called CARPA reactions (complement activation-related pseudo-allergy). Newer oral iron preparations include ferric citrate which is much more tolerable than ferrous sulphate, while newer IV iron compounds include ferric carboxymaltose, iron isomaltoside 1000 , and ferumoxytol. Iron supplementation has traditionally been used to ameliorate iron deficiency anaemia, and in the early 1990s, IV iron was found to be mandatory in dialysis patients to support erythropoiesis under stimulation with recombinant human erythropoietin. Recent data also suggest that IV iron may have benefits in chronic heart failure, independent of any effect on haemoglobin or red cell production, possibly by enhancing cardiac myocyte mitochondrial function. Although most RCTs suggest better efficacy with IV iron versus oral iron, there are some concerns regarding the safety of parenteral iron, not only in relation to hypersensitivity reactions, but also exacerbation of oxidative stress or infections. Several ongoing RCTs are seeking to provide further evidence in this regard, e.g. the PIVOTAL trial. Newer strategies for replenishing iron stores include HIF prolyl hydroxylase inhibitors (HIF PHIs), antagonists of the hepcidin pathway, or dialysate iron administration as ferric pyrophosphate citrate. HIF PHIs (such as roxadustat and vadaddustat) have been shown to reduce hepcidin, probably indirectly via stimulation of erythropoiesis, as well as by stimulating a number of iron-regulatory genes, and allowing greater amounts of iron to be absorbed orally. Many molecules designed to interfere with hepcidin activity are in varying stages of clinical development, including monoclonal antibodies against hepcidin or its signalling pathway, spiegelmers, anticalins, and antisense oligonucleotides. Administering ferric pyrophosphate citrate (Triferric™) across dialysis has recently become clinical reality in the US, although this is not available in Europe. Thus, strategies to supplement iron have developed considerably over the last two decades, with several novel approaches transitioning from bench to bedside.

Disclosures
Macdougall: Astellas: Honoraria, Research Funding; GlaxoSmithKline: Consultancy; Akebia: Consultancy; Vifor Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacosmos: Honoraria; AMAG: Consultancy, Honoraria, Research Funding; FibroGen: Consultancy, Speakers Bureau.