FGF23 and Phosphate-Cardiovascular Toxins in CKD

Abstract

Elevated levels of fibroblast growth factor 23 (FGF23) and phosphate are highly associated with increased cardiovascular disease and mortality in patients suffering from chronic kidney disease (CKD). As the kidney function declines, serum phosphate levels rise and subsequently induce the secretion of the phosphaturic hormone FGF23. In early stages of CKD, FGF23 prevents the increase of serum phosphate levels and thereby attenuates phosphate-induced vascular calcification, whereas in end-stage kidney disease, FGF23 fails to maintain phosphate homeostasis. Both hyperphosphatemia and elevated FGF23 levels promote the development of hypertension, vascular calcification, and left ventricular hypertrophy by distinct mechanisms. Therefore, FGF23 and phosphate are considered promising therapeutic targets to improve the cardiovascular outcome in CKD patients. Previous therapeutic strategies are based on dietary and pharmacological reduction of serum phosphate, and consequently FGF23 levels. However, clinical trials proving the effects on the cardiovascular outcome are lacking. Recent publications provide evidence for new promising therapeutic interventions, such as magnesium supplementation and direct targeting of phosphate and FGF receptors to prevent toxicity of FGF23 and hyperphosphatemia in CKD patients.

Keywords: FGF23; cardiovascular disease; chronic kidney disease; hypertension; left ventricular hypertrophy; phosphate; vascular calcification.

Figure 1

Cardiovascular pathomechanisms of elevated FGF23 and hyperphosphatemia in chronic kidney disease (CKD). The phosphate excretion attenuates with declining kidney function. Resulting FGF23 elevation counteracts the phosphate retention by downregulating NaPi-2a/c in the kidney, but also directly promotes LVH via FGFR4–calcineruin–NFAT signaling. FGF23 induces hypertension by activation of the RAAS and NCC expression. Hyperphosphatemia stimulates the osteochondrogenic differentiation and release of Ca/P loaded vesicles in VSMCs via Pit-1, and thereby induces VC. Phosphate-induced vascular calcification (VC) together with activation of the RAAS and SNA contribute to the development of hypertension. eGFR, estimated glomerulus filtration rate; NaPi-2a/c, type IIa/c sodium-dependent phosphate transporter; FGFR4, fibroblast growth factor receptor 4; NFAT, nuclear factor of activated T-cells; RAAS, renin-angiotensin-aldosterone system; NCC, Na⁺Cl⁻ co-transporter; SNA, sympathetic nerve system; VC, vascular calcification.

Figure 2

Clinical and experimental therapeutic strategies to target phosphate homeostasis in CKD. Dietary phosphate restriction and inhibition of the intestinal phosphate absorption by phosphate binders and NAM are common phosphate-lowering treatments in CKD patients. Experimental studies investigate the direct targeting of the intestinal phosphate absorption and renal reabsorption by NaPi-2b or NaPi-2a inhibitors. NaPi-2a/b, type IIa/b sodium-dependent phosphate transporter; NAM, nicotinamide.

Figure 3

Potential treatments to target FGF23 levels and cardiovascular disease in CKD. Administration of the FGF23 Ab or DMP1 reduces FGF23 levels, but also leads to more severe VC and increased mortality. Thus, application of FGF23-reducing therapies is only conceivable together with a phosphate-lowering therapy or magnesium supplements that decrease phosphate-induced VC. The FGFR4 inhibitor specifically blocks the FGF23-mediated development of LVH. FGF23 Ab, fibroblast growth factor 23 antibody; DMP1, dentin matrix protein 1; FGFR4, fibroblast growth factor receptor 4; Mg, magnesium; LVH, left ventricular hypertrophy.