The HIF-PHI BAY 85-3934 (Molidustat) Improves Anemia and Is Associated With Reduced Levels of Circulating FGF23 in a CKD Mouse Model

Fibroblast growth factor-23 (FGF23) plays a crucial role in chronic kidney disease (CKD), with elevated levels leading to disturbances in mineral metabolism and increased mortality risk. As kidney function declines, patients with CKD often develop anemia due to the reduced production of erythropoietin (EPO). Anemia is a significant stimulus for FGF23 secretion. To explore the effects of a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), currently in clinical trials to boost endogenous EPO and address anemia, we examined its impact on iron utilization and FGF23-related parameters in a CKD mouse model.

Mice were fed either a control diet containing casein or an adenine-based diet to induce CKD. The CKD mice exhibited significantly elevated levels of immunoreactive FGF23 (iFGF23), blood urea nitrogen (BUN), hyperphosphatemia, and anemia. Mice were subsequently treated with a patient-equivalent dose of BAY 85-3934 (BAY; Molidustat), which increased EPO levels and completely corrected abnormal complete blood counts (CBCs) in CKD mice. Vehicle-treated CKD mice showed a 120-fold increase in iFGF23, while BAY-treated CKD mice experienced a more than 60% reduction in circulating iFGF23. Additionally, BAY treatment led to decreased BUN levels, although it did not affect the expression of renal vitamin D metabolic enzymes.

Aligned with the increase in EPO, bone marrow levels of Erfe, transferrin receptor (Tfrc), and EpoR mRNAs were elevated in BAY-treated CKD mice. In vitro, hypoxic bone marrow cultures showed increased FGF23 levels with direct EPO treatment. Furthermore, liver expression of Bmp-6 and hepcidin was downregulated across all BAY-treated groups. Trabecular parameters and cortical porosity in the femur were not negatively affected by BAY administration.

In vitro studies with differentiated osteocyte-like cells subjected to an iron chelator to simulate iron depletion/hypoxia revealed increased FGF23 levels; however, repletion with holo-transferrin completely suppressed FGF23 and normalized Tfrc1 expression. Overall, these findings suggest that alleviating anemia with a HIF-PHI in CKD is associated with reduced BUN and lowered FGF23 levels, likely through the direct restoration of iron utilization, thus offering modifiable outcomes beyond just improving anemia in this patient population. © 2021 American Society for Bone and Mineral Research (ASBMR).