New Aspects of the Kidney in the Regulation of Fibroblast Growth Factor 23 (FGF23) and Mineral Homeostasis

Abstract

The bone-derived hormone fibroblast growth factor 23 (FGF23) acts in concert with parathyroid hormone (PTH) and the active vitamin D metabolite calcitriol in the regulation of calcium (Ca) and phosphate (P) homeostasis. More factors are being identified to regulate FGF23 levels and the endocrine loops between the three hormones. The present review summarizes the complex regulation of FGF23 and the disturbed FGF23/Klotho system in chronic kidney disease (CKD). In addition to the reduced ability of the injured kidney to regulate plasma levels of FGF23, several CKD-related factors have been shown to stimulate FGF23 production. The high circulating FGF23 levels have detrimental effects on erythropoiesis, the cardio-vascular system and the immune system, all contributing to the disturbed system biology in CKD. Moreover, new factors secreted by the injured kidney and the uremic calcified vasculature play a role in the mineral and bone disorder in CKD and create a vicious pathological crosstalk.

Keywords: CKD-MBD; PTH; activin A; acute kidney failure; bone; calcitriol; calcium; chronic kidney failure; circadian rhythm; crosstalk; klotho; phosphate.

Figure 1

The key role of the kidney in regulating the plasma levels of fibroblast growth factor 23 (FGF23) (A) Disappearance curve of recombinant FGF23 (recFGF23) in normal rats. Rats were treated with the pan fibroblast growth factors (FGF) receptor tyrosine kinase (FGFR) inhibitor PD173074 to suppress FGF23 production in bone, resulting in negligible plasma levels of FGF23 prior to iv. administration of the recFGF23. The clearance of recFGF23 fitted a first order elimination and FGF23′s half-life (T½) was calculated as 4 min. (B) Measurement of intact FGF23 in the renal artery and vein demonstrates a high extraction ratio of 40%. (C) RecFGF23 was administered to bilateral nephrectomized (anephric) rats after suppression of endogenous FGF23 levels. The recFGF23 had a prolonged clearance and T½ was increased to 12 min in the anephric rats. (D) Measurement of intact FGF23 in the renal artery and vein in the kidney rudiment of the 5/6 nephrectomy model after 8 weeks of uremia. Similar FGF23 concentrations were found, illustrating that the injured kidney loses its ability to regulate plasma levels of FGF23. One of the key mechanisms behind the increase in plasma levels of FGF23 in kidney disease [12,19].

Figure 2

Circadian rhythm of FGF23 and mineral parameters. (A) Plasma levels of FGF23 show significant diurnal variation. Phase of fluctuation was complete reversed by feeding restricted to the inactive period (lower diagram). (B,C) Parathyroid hormone (PTH) and phosphate levels varied around the clock. Their acrophase and nadir were consistently shifted to the opposite value by the restricted feeding intervention. Data are fitted by cosinor regression and resulting p-values are shown, p < 0.05 is considered significant. Grey areas indicate dark period and white areas indicate light period. The figure has been published in Kidney International, Egstrand et al., 2020 [32].

Figure 3

The role of the kidney in setting the set point for calcium sensing. Rats underwent bilateral nephrectomy (NX) or sham surgery. Removal of the kidneys resulted in a significant drop in plasma Ca²⁺, illustrating a role of the kidney in the setting of Ca²⁺ set point. The calcium chelator EGTA was infused via the femoral vein and it lowered plasma Ca²⁺ in both groups, however, more pronounced in the bilateral nephrectomized rats. The concentration of plasma Ca²⁺ remained, at all time points, significantly lower in these rats during recovery from hypocalcemia (p  <  0.01). Data are presented as mean ± SEM. The figure has been published in BMC Nephrol, Nordholm et al., 2015 [96].

Figure 4

The loss of kidney function results not only in the complex disturbances in FGF23 and the mineral and bone homeostasis, but it also inflicts severe dysfunction of other organ systems. CKD: chronic kidney disease; CKD-MBD: CKD mineral and bone disorder.