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      Hypophosphataemia, fibroblast growth factor 23 and third-generation intravenous iron compounds: a narrative review

      review-article
      , BSc (Hons), MBBS, MRCP(UK) , , MBChB, MRCP, FRCP, PhD, M Clin Edu, FHEA
      Drugs in Context
      BioExcel Publishing Ltd
      ferric carboxymaltose, ferric derisomaltose, ferumoxytol, fibroblast growth factor 23, hypophosphataemia, intravenous iron, iron-deficiency anaemia, safety

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          Abstract

          Third-generation intravenous (i.v.) iron preparations are safe and efficacious and are increasingly used in the treatment of iron-deficiency anaemia. Hypophosphataemia is emerging as an established side-effect following the administration of certain compounds. Symptoms of hypophosphataemia can be masked by their similarity to those of iron-deficiency anaemia and both acute and chronic hypophosphataemia can be detrimental. Hypophosphataemia appears to be linked to imbalances in the metabolism of the phosphatonin fibroblast growth factor 23. In this narrative review, we discuss the possible pathophysiology behind this phenomenon, the studies comparing third-generation i.v. iron compounds, and the potential implications of the changes in fibroblast growth factor 23 and hypophosphataemia. We also present an algorithm of how to approach such patients requiring i.v. iron in anticipation of hypophosphataemia and how the impact related to it can be minimized.

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          Most cited references127

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          2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.

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            Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease.

            A high level of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) is associated with mortality in patients with end-stage renal disease, but little is known about its relationship with adverse outcomes in the much larger population of patients with earlier stages of chronic kidney disease. To evaluate FGF-23 as a risk factor for adverse outcomes in patients with chronic kidney disease. A prospective study of 3879 participants with chronic kidney disease stages 2 through 4 who enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008. All-cause mortality and end-stage renal disease. At study enrollment, the mean (SD) estimated glomerular filtration rate (GFR) was 42.8 (13.5) mL/min/1.73 m(2), and the median FGF-23 level was 145.5 RU/mL (interquartile range [IQR], 96-239 reference unit [RU]/mL). During a median follow-up of 3.5 years (IQR, 2.5-4.4 years), 266 participants died (20.3/1000 person-years) and 410 reached end-stage renal disease (33.0/1000 person-years). In adjusted analyses, higher levels of FGF-23 were independently associated with a greater risk of death (hazard ratio [HR], per SD of natural log-transformed FGF-23, 1.5; 95% confidence interval [CI], 1.3-1.7). Mortality risk increased by quartile of FGF-23: the HR was 1.3 (95% CI, 0.8-2.2) for the second quartile, 2.0 (95% CI, 1.2-3.3) for the third quartile, and 3.0 (95% CI, 1.8-5.1) for the fourth quartile. Elevated fibroblast growth factor 23 was independently associated with significantly higher risk of end-stage renal disease among participants with an estimated GFR between 30 and 44 mL/min/1.73 m(2) (HR, 1.3 per SD of FGF-23 natural log-transformed FGF-23; 95% CI, 1.04-1.6) and 45 mL/min/1.73 m(2) or higher (HR, 1.7; 95% CI, 1.1-2.4), but not less than 30 mL/min/1.73 m(2). Elevated FGF-23 is an independent risk factor for end-stage renal disease in patients with relatively preserved kidney function and for mortality across the spectrum of chronic kidney disease.
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              FGF23 induces left ventricular hypertrophy.

              Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
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                Author and article information

                Journal
                Drugs Context
                Drugs Context
                DIC
                Drugs in Context
                BioExcel Publishing Ltd
                1745-1981
                1740-4398
                2021
                19 January 2021
                : 10
                : 2020-11-3
                Affiliations
                Department of Academic Renal Research, Hull University Teaching Hospitals NHS Trust, 2nd Floor Alderson House, Hull Royal Infirmary, Anlaby Road, Kingston upon Hull, UK
                Author notes
                Correspondence: Xenophon Kassianides, Department of Academic Renal Research, Hull University Teaching Hospitals NHS Trust, 2nd Floor Alderson House, Hull Royal Infirmary, Anlaby Road, Kingston upon Hull, HU3 2JZ, UK. xenophon.kassianides@ 123456hey.nhs.uk
                Article
                dic-2020-11-3
                10.7573/dic.2020-11-3
                7819638
                33519940
                6fbea5ed-510a-4105-baf4-a34a7901e298
                Copyright © 2021 Kassianides X, Bhandari S

                Published by Drugs in Context under Creative Commons License Deed CC BY NC ND 4.0, which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

                History
                : 10 November 2020
                : 08 December 2020
                Categories
                Review

                ferric carboxymaltose,ferric derisomaltose,ferumoxytol,fibroblast growth factor 23,hypophosphataemia,intravenous iron,iron-deficiency anaemia,safety

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