Targeting FGF23 to Ameliorate Anemia in Chronic Kidney Disease.

The progression of chronic kidney disease (CKD) entails the development of complications, such as anemia and disturbances in mineral homeostasis, among others, and both of them have been shown to be closely related. In fact, high phosphorus (P) and excessive production of fibroblast growth factor 23 (FGF23) are hallmarks of the mineral alterations found in CKD, both of which have been associated with the development of anemia. The objective of this study was to evaluate whether the modulation of P load may impact the severity of CKD-related anemia as well as to separate the effects of FGF23 from those of P by the administration of an AntiFGF23 antibody while also investigating the involvement of hypoxia-inducible factor (HIF) signaling in these actions. To address this objective, we used a CKD model based on 5/6 nephrectomy (Nx). In a first experiment, CKD rats received diets with 0.2, 0.6, or 1.2% of P for 4 weeks. In a second study, Nx rats fed a 1.2% P diet were treated with an AntiFGF23 antibody for the same period. In an additional experiment, the effect of the exogenous administration of FGF23 and AntiFGF23 was evaluated. In all the experiments, we analyzed the hematological status, parameters of renal function and mineral metabolism, and HIF signaling. In CKD, the increase in P load was associated with an expected progressive elevation in FGF23 and an aggravation of anemia. In a situation of uremia with high P load, the neutralization of FGF23 restored hematological alterations while producing a significant inhibition in renal HIF1Alpha. In the absence of renal damage, the administration of recombinant FGF23 produced a decrease in serum iron and reticulocytes without changes in HIF signaling. In conclusion, progressive and concomitant increases in P and FGF23 produce an aggravation of anemia of renal origin. In this setting, the normalization of hematological parameters induced by FGF23 blockade is associated with the inhibition of renal HIF signaling. Thus, the implementation of FGF23-targeting therapies might constitute an additional strategy for the clinical management of CKD-related anemia.