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Targeting the hepcidin-ferroportin pathway in anaemia of chronic kidney disease.

ABSTRACT: AIMS:Erythropoiesis-stimulating agents used to treat anaemia in patients with chronic kidney disease (CKD) have been associated with cardiovascular adverse events. Hepcidin production, controlled by bone morphogenic protein 6 (BMP6), regulates iron homeostasis via interactions with the iron transporter, ferroportin. High hepcidin levels are thought to contribute to increased iron sequestration and subsequent anaemia in CKD patients. To investigate alternative therapies to erythropoiesis-stimulating agents for CKD patients, monoclonal antibodies, LY3113593 and LY2928057, targeting BMP6 and ferroportin respectively, were tested in CKD patients. METHODS:Preclinical in vitro/vivo data and clinical data in healthy subjects and CKD patients were used to illustrate the translation of pharmacological properties of LY3113593 and LY2928057, highlighting the novelty of targeting these nodes within the hepcidin-ferroportin pathway. RESULTS:LY2928057 bound ferroportin and blocked interactions with hepcidin, allowing iron efflux, leading to increased serum iron and transferrin saturation levels and increased hepcidin in monkeys and humans. In CKD patients, LY2928057 led to slower haemoglobin decline and reduction in ferritin (compared to placebo). Serum iron increase was (mean [90% confidence interval]) 1.98 [1.46-2.68] and 1.36 [1.22-1.51] fold-relative to baseline following LY2928057 600 mg and LY311593 150 mg respectively in CKD patients. LY3113593 specifically blocked BMP6 binding to its receptor and produced increases in iron and transferrin saturation and decreases in hepcidin preclinically and clinically. In CKD patients, LY3113593 produced an increase in haemoglobin and reduction in ferritin (compared to placebo). CONCLUSION:LY3113593 and LY2928057 pharmacological effects (serum iron and ferritin) were translated from preclinical-to-clinical development. Such interventions may lead to new CKD anaemia treatments.

SUBMITTER: Sheetz M

PROVIDER: S-EPMC6475730 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Targeting the hepcidin-ferroportin pathway in anaemia of chronic kidney disease.

Sheetz Matthew M Barrington Philip P Callies Sophie S Berg Paul H PH McColm Juliet J Marbury Thomas T Decker Brian B Dyas Gregory L GL Truhlar Stephanie M E SME Benschop Robert R Leung Donmienne D Berg Jolene J Witcher Derrick R DR

British journal of clinical pharmacology 20190304 5

<h4>Aims</h4>Erythropoiesis-stimulating agents used to treat anaemia in patients with chronic kidney disease (CKD) have been associated with cardiovascular adverse events. Hepcidin production, controlled by bone morphogenic protein 6 (BMP6), regulates iron homeostasis via interactions with the iron transporter, ferroportin. High hepcidin levels are thought to contribute to increased iron sequestration and subsequent anaemia in CKD patients. To investigate alternative therapies to erythropoiesis- ...[more]

PMID: 30677788

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Project description:Background Anaemia is a common presenting feature among patients with chronic kidney disease (CKD) and it is associated with poor clinical outcomes and quality of life. It is not clear if growth differentiation factor-15 (GDF-15) or hepcidin are useful as early markers of iron deficiency anaemia (IDA) among non-dialysis CKD patients. We therefore evaluated the diagnostic validity of GDF-15 and hepcidin as biomarkers of IDA among non-dialysis CKD patients in Johannesburg, South Africa. Method An analytic cross-sectional study was conducted among non-dialysis CKD patients (n?=?312) and apparently healthy controls (n?=?184) from June to December 2016 at an Academic Hospital, in Johannesburg, South Africa. An interviewer administered proforma was used to obtain the socio-biological and clinical characteristics of the participants. Serum levels of GDF-15 and hepcidin were determined. Predictive logistic regression models were built and post estimation receiver operator characteristics were determined to evaluate diagnostic validity of hepcidin and GDF-15 for absolute and functional iron deficiency anaemia. Results About half (50.6%) of the participants were female while the participants’ mean age was 49.7?±?15.8?years. The predictive value of diagnosing absolute IDA among CKD patients using GDF-15 was 74.02% (95% CI: 67.62–80.42%) while the predictive value of diagnosing functional IDA among CKD patients using hepcidin was 70.1% (95% CI: 62.79–77.49%).There was a weak negative correlation between hepcidin levels and GFR (r?=???0.19, p?=?0.04) in anaemic CKD patients, and between serum GDF-15 and haemoglobin (r?=???0.34, p?=?0.001). Serum ferritin (??=?0.00389, P-value<?0.001), was a predictor of log hepcidin. MCHC (??=???0.0220, P-value 0.005) and CKD stage (??=?0.4761, P-value <?0.001), race (??=?0.3429, P-value?=?0.018) were predictors of log GDF-15. Both GDF-15 (adj OR: 1.0003, 95%CI: 1.0001–1.0005, P?=?0.017) and hepcidin (adj OR: 1.003, 95%CI: 1.0004–1.0055, P?=?0.023) were associated with iron deficiency anaemia after multiple linear regression modelling. Conclusion Serum GDF-15 is a potential biomarker of absolute IDA, while hepcidin levels can predict functional IDA among CKD patients.

Dataset Information

Targeting the hepcidin-ferroportin pathway in anaemia of chronic kidney disease.

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Targeting the hepcidin-ferroportin pathway in anaemia of chronic kidney disease.

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