Does FGF23 toxicity influence the outcome of chronic kidney disease?

Abstract

Maintenance of physiologic phosphate balance is important for essential cellular functions [1]. Dysregulation of the phosphate balance in the form of hypophosphataemia can lead to the development of myopathy, cardiac dysfunction, haematological abnormalities and bone mineralization defects [1]. In contrast, hyperphosphataemia can cause vascular and soft tissue calcification [2,3]. Studies have convincingly demonstrated that FGF23 is a master regulator of systemic phosphate homeostasis [4–9]. FGF23 is a 30 kDa protein that is proteolytically processed to generate smaller N-terminal (∼18 kDa) and Cterminal (∼12 kDa) fragments. The N-terminal fragment of FGF23 contains the FGF receptor-binding domain, while the C-terminal fragment is proposed to be necessary for interaction with Klotho (a type 1 membrane protein with homology to s-glucosidase), which is believed to be a cofactor in FGF23–FGF receptor interactions [10]. FGF23 is a circulating phosphaturic factor that controls systemic phosphate homeostasis by regulating renal inorganic phosphate reabsorption [5]. The expression of members of the sodium phosphate co-transporter family (Na/Pi-2a and Na/Pi-2c) that mediate phosphate uptake in proximal tubular epithelial cells can be suppressed by FGF23 [11]. By suppressing Na/Pi co-transporter activity, FGF23 can reduce renal phosphate reabsorption, thereby increasing urinary phosphate excretion. The in vivo phosphaturic effect of FGF23 is convincingly demonstrated in animal studies. For instance, transgenic mice overexpressing human or mouse FGF23/Fgf23 have severe urinary phosphate wasting due to the suppression of renal Na/Pi co-transporter activity [12–14]. Inactivation of Fgf23 function in mice resulted