Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.789206
Title: Hepcidin regulation in chronic kidney disease
Author: Rumjon, Adam Ryad
ISNI:       0000 0004 8500 1220
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Abstract:
Iron homeostasis in man is tightly regulated by a 25-amino-acide peptide hormone (hepcidin) that is produced in the liver in response to inflammatory stimuli and iron loading. Its main role is thought to be part of the innate immune system, restricting iron delivery to infectious microorganisms, and as a consequence, reducing iron availability for erythropoiesis in the host. The anaemia associated with chronic kidney disease (CKD) is known to be in part due to relative erythropoietin deficiency, and we also now know that excess hepcidin is one of the reasons that dietary iron is less well absorbed in these patients, necessitating the administration of intravenous iron. We know that haemodialysis patients in particular have elevated hepcidin levels, although the precise mechanisms remain unclear. Characterisation of hepcidin levels in a number of CKD cohorts, including non-dialysis and dialysis-CKD patients, confirm that patients receiving haemodialysis have the highest levels, and that a considerable degree of day-to-day variability exists that is not completely explained by the regular administration of intravenous iron. An approach designed to measure hepcidin production using 'HAMP' gene expression levels in circulating peripheral blood mononuclear cells found that patients with the highest circulating hepcidin levels had the lowest degree of 'HAMP' expression, suggesting the presence of a negative feedback mechanism. Although bacterial sepsis is an extremely powerful driver of hepcidin production, haemodialysis patients do not appear to be able to mount an increased hepcidin response under such conditions, raising the possibility that their hepcidin burden is maximised. It is therefore possible that the role of inflammation in this context may not be as significant as the role of reduced hepcidin clearance, or the role of iron loading. In contrast, inflammation is probably a major driver of hepcidin induction in those who develop an acute kidney as a result of ANCA-associated vasculitis or a crescentic glomerulonephritis. Hepcidin expression was suppressed following the use of dexamethasone in a cellular hepatocyte model, and this was partly IL-6 dependent. In a pilot study examining the aforementioned patient groups, hepcidin levels were elevated at presentation and were markedly reduced following treatment with intravenous methylprednisolone. The glucocorticoid-induced suppression of hepcidin in both in vitro and in vivo settings suggests this as a pathway for the improvement in anaemia seen in inflammatory conditions following steroid therapy.
Supervisor: Sharp, Paul Anthony Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.789206  DOI: Not available
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