Abstract
In patients with chronic kidney disease (CKD), adverse outcomes such as systemic inflammation and anemia are contributing pathologies which increase the risks for cardiovascular mortality. Amongst these complications, abnormalities in mineral metabolism and the metabolic milieu are associated with chronic inflammation and iron dysregulation, and fibroblast growth factor 23 (FGF23) is a risk factor in this context. FGF23 is a bone-derived hormone that is essential for regulating vitamin D and phosphate homeostasis. In the early stages of CKD, serum FGF23 levels rise 1000-fold above normal values in an attempt to maintain normal phosphate levels. Despite this compensatory action, clinical CKD studies have demonstrated powerful and dose-dependent associations between FGF23 levels and higher risks for mortality. A prospective pathomechanism coupling elevated serum FGF23 levels with CKD-associated anemia and cardiovascular injury is its strong association with chronic inflammation. In this review, we will examine the current experimental and clinical evidence regarding the role of FGF23 in renal physiology as well as in the pathophysiology of CKD with an emphasis on chronic inflammation and anemia.
Highlights
Cardiovascular disease is the leading cause of mortality across all stages of chronic kidney disease (CKD), and common occurrences such as fibroblast growth factor 23 (FGF23) excess, chronic inflammation and iron deficiency have been shown as prominent risk factors [1,2,3,4]
This review focuses on the latest advances in understanding the complex role of FGF23 in inflammation and anemia, and how these multi-directional relationships present significant insights into the pathomechanisms of CKD
FRS2α, FGF receptor substrate 2α; MAPK, Ras/mitogen-activated protein kinase; Egr-1, early growth-responsive 1; PTH, parathyroid hormone; PLCγ; phospholipase Cγ; NFAT, nuclear factor of activated T-cells; PKA, protein kinase A; Rap1, Ras-proximate-1. Despite these notable pathological conditions, it is feasible for cells that are lacking αKlotho, but are FGF23 responsive, to express alternative co-receptor(s) for FGF23 binding such as cell adhesion proteins of the cadherin and immunoglobulin superfamilies, which might interact with FGFR4 [104,105,106,107,108,109]
Summary
Cardiovascular disease is the leading cause of mortality across all stages of chronic kidney disease (CKD), and common occurrences such as fibroblast growth factor 23 (FGF23) excess, chronic inflammation and iron deficiency have been shown as prominent risk factors [1,2,3,4]. This review focuses on the latest advances in understanding the complex role of FGF23 in inflammation and anemia, and how these multi-directional relationships present significant insights into the pathomechanisms of CKD
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