ferric-carboxymaltose and Inflammation

Fibroblast growth factor 23 (FGF23) was initially characterized as an important regulator of phosphate and calcium homeostasis. New research advances demonstrate that FGF23 is also linked to iron economy, inflammation and erythropoiesis. These advances have been fuelled, in part, by the serendipitous development of two distinct FGF23 assays that can substitute for invasive bone biopsies to infer the activity of the three main steps of FGF23 regulation in bone: transcription, post-translational modification and peptide cleavage. This 'liquid bone biopsy for FGF23 dynamics' enables large-scale longitudinal studies of FGF23 regulation that would otherwise be impossible in humans. The balance between FGF23 production, post-translational modification and cleavage is maintained or perturbed in different hereditary monogenic conditions and in acquired conditions that mimic these genetic disorders, including iron deficiency, inflammation, treatment with ferric carboxymaltose and chronic kidney disease. Looking ahead, a deeper understanding of the relationships between FGF23 regulation, iron homeostasis and erythropoiesis can be leveraged to devise novel therapeutic targets for treatment of anaemia and states of FGF23 excess, including chronic kidney disease.

Topics: Anemia, Iron-Deficiency; Bone and Bones; Calcium; Erythropoiesis; Familial Hypophosphatemic Rickets; Ferric Compounds; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hypophosphatemia; Inflammation; Iron; Maltose; Phosphates; Protein Processing, Post-Translational; Renal Insufficiency, Chronic; RNA, Messenger; Transcription, Genetic

Intravenous iron supplementation is an effective therapy in iron deficiency anemia (IDA), but controversial in anemia of inflammation (AI). Unbound iron can be used by bacteria and viruses for their replication and enhance the inflammatory response. Nowadays available high molecular weight iron complexes for intravenous iron substitution, such as ferric carboxymaltose, might be useful in AI, as these pharmaceuticals deliver low doses of free iron over a prolonged period of time. We tested the effects of intravenous iron carboxymaltose in murine AI: Wild-type mice were exposed to the heat-killed Brucella abortus (BA) model and treated with or without high molecular weight intravenous iron. 4h after BA injection followed by 2h after intravenous iron treatment, inflammatory cytokines were upregulated by BA, but not enhanced by iron treatment. In long term experiments, mice were fed a regular or an iron deficient diet and then treated with intravenous iron or saline 14 days after BA injection. Iron treatment in mice with BA-induced AI was effective 24h after iron administration. In contrast, mice with IDA (on iron deficiency diet) prior to BA-IA required 7d to recover from AI. In these experiments, inflammatory markers were not further induced in iron-treated compared to vehicle-treated BA-injected mice. These results demonstrate that intravenous iron supplementation effectively treated the murine BA-induced AI without further enhancement of the inflammatory response. Studies in humans have to reveal treatment options for AI in patients.

Topics: Administration, Intravenous; Anemia; Animals; Biomarkers; Brucella abortus; Cytokines; Diet; Ferric Compounds; Hepcidins; Inflammation; Iron; Maltose; Mice; Reticulocytes; RNA, Messenger

Treatment with parenteral iron causes oxidative stress, inflammation and endothelial dysfunction. Ferric carboxymaltose (FCM) is a new preparation of non-dextran iron which, due to its pharmacokinetics and stability, may induce less toxicity than other iron molecules. The aim of this study was to analyse the effect of FCM on inflammation and adhesion molecules in chronic kidney disease (CKD).. Forty-seven patients with predialysis CKD and iron-deficiency anaemia received a single dose of FCM (15 mg/kg, maximum dose 1 gram). At baseline and after 60 minutes (acute effect) and after 3 weeks and 3 months (sub-acute effect), we determined inflammatory markers: C-reactive protein (CRP), interleukin-6 (IL-6) and endothelial dysfunction: intercellular adhesion molecule (ICAM) and vascular adhesion molecule (VCAM).. Treatment with FCM was associated with a significant increase in haemoglobin levels: 10 (0.7) vs. 11.4 (1.3)g/dl, p<.0001. CRP, IL-6, ICAM and VCAM levels did not correlate with baseline haemoglobin or ferritin levels and there was no relationship between changes in these markers and those of haemoglobin after administration of FCM. No significant, acute or sub-acute changes occurred in any of the inflammatory or endothelial markers studied. Statin therapy was associated with lower VCAM concentrations.. Treatment with high doses of FCM in patients with predialysis CKD has no proinflammatory effect and does not alter levels of adhesion molecules ICAM and VCAM in this population.

Topics: Aged; Anemia, Iron-Deficiency; Cell Adhesion Molecules; Female; Ferric Compounds; Humans; Inflammation; Kidney Failure, Chronic; Male; Maltose; Prospective Studies

Anemia is common in critically ill patients, due to inflammation and blood loss. Anemia can be associated with iron deficiency and low serum hepcidin levels. However, iron administration in this setting remains controversial because of its potential toxicity, including oxidative stress induction and sepsis facilitation. The objective of this work was to determine the efficacy and toxicity of iron administration using a mouse model mimicking critical care anemia as well as a model of acute septicemia.. Prospective, randomized, open label controlled animal study.. University-based research laboratory.. C57BL/6 and OF1 mice.. Intraperitoneal injection of zymosan inducing generalized inflammation in C57BL/6 mice, followed in our full model by repeated phlebotomies. A dose equivalent to 15 mg/kg of ferric carboxymaltose was injected intravenously on day 5. To assess the toxicity of iron in a septicemia model, OF1 mice were simultaneously injected with iron and different Escherichia coli strains.. To investigate the effect of iron on oxidative stress, we measured reactive oxygen species production in the blood using luminol-amplified chemiluminescence and superoxide dismutase 2 messenger RNA levels in the liver. These markers of oxidative stress were increased after iron administration in control mice but not in zymosan-treated mice. Liver catalase messenger RNA levels decreased in iron-treated control mice. Iron administration was not associated with increased mortality in the septicemia model or in the generalized inflammation model. Iron increased hemoglobin levels in mice fed with a low iron diet and subjected to phlebotomies and zymosan 2 wks after treatment administration.. Adverse effects of intravenous iron supplementation by ferric carboxymaltose seem to be minimal in our animal models. Furthermore, iron appears to be effective in correcting anemia, despite inflammation. Studies of efficacy and safety of iron in critically ill patients are warranted.

Topics: Anemia; Animals; Antimicrobial Cationic Peptides; Catalase; Diet; Disease Models, Animal; Ferric Compounds; Hematinics; Hemoglobins; Hepcidins; Inflammation; Injections, Intravenous; Iron; Liver; Luminescence; Maltose; Mice; Mice, Inbred C57BL; Phlebotomy; Random Allocation; Reactive Oxygen Species; RNA, Messenger; Sepsis; Spleen; Superoxide Dismutase; Trace Elements; Zymosan

Intravenous (i.v.) iron is associated with a risk of oxidative stress. The effects of ferumoxytol, a recently approved i.v. iron preparation, were compared with those of ferric carboxymaltose, low molecular weight iron dextran and iron sucrose in the liver, kidneys and heart of normal rats. In contrast to iron sucrose and ferric carboxymaltose, low molecular weight iron dextran and ferumoxytol caused renal and hepatic damage as demonstrated by proteinuria and increased liver enzyme levels. Higher levels of oxidative stress in these tissues were also indicated, by significantly higher levels of malondialdehyde, significantly increased antioxidant enzyme activities, and a significant reduction in the reduced to oxidized glutathione ratio. Inflammatory markers were also significantly higher with ferumoxytol and low molecular weight iron dextran rats than iron sucrose and ferric carboxymaltose. Polarographic analysis suggested that ferumoxytol contains a component with a more positive reduction potential, which may facilitate iron-catalyzed formation of reactive oxygen species and thus be responsible for the observed effects. Only low molecular weight iron dextran induced oxidative stress and inflammation in the heart.

Topics: Animals; Antioxidants; Blood Pressure; Creatinine; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferrosoferric Oxide; Glucaric Acid; Heart; Hematinics; Immunohistochemistry; Inflammation; Injections, Intravenous; Iron-Dextran Complex; Kidney; Lipid Peroxidation; Liver; Magnetite Nanoparticles; Male; Maltose; Molecular Weight; Oxidative Stress; Proteinuria; Rats; Rats, Sprague-Dawley