FGF23: A Mature Renal and Cardiovascular Risk Factor?

Abstract

High FGF23 predicts renal function loss in chronic kidney disease (CKD) patients and graft failure in transplant patients. FGF23, parathyroid hormone and serum phosphate are all interrelated but among these CKD-MBD biomarkers only FGF23 is independently related with CKD progression. High FGF23 associates with endothelial dysfunction in CKD patients and in elderly individuals in the general population. Furthermore, independently of serum phosphate, high FGF23 associates with mortality and left ventricular hypertrophy in dialysis patients and with atherosclerosis in elderly individuals in the general population. FGF23 also predicts a high risk for death and cardiovascular events in predialysis CKD patients and in subjects with coronary artery disease. A recent trial in CKD patients showed that low phosphate intake associated with a phosphate binder produces a 35% decrease in plasma FGF23. Yet in this and in another trial testing several phosphate binders, FGF23 levels remained well beyond the upper limit of the normal range. Of note, in this latter study, calcification of the coronary arteries and abdominal aorta actually increased, rather than decreased, during treatment with these drugs in the face of evidence of negative phosphate balance and amelioration of hyperparathyroidism. Mechanistic studies are still needed before testing the hypothesis that FGF23 is implicated in a causal manner in cardiovascular and renal diseases. Given the modest effects of phosphate binders on serum FGF23 in CKD patients, pharmacologic interventions antagonizing the effects of this growth factor rather than phosphate-lowering interventions should be put in place to properly test this hypothesis in the clinical scenario in CKD.

Paricalcitol and Endothelial Function in Chronic Kidney Disease Trial

“…28 Of note, the increase in endothelium-dependent vasodilatation in our study occurred in the face of a doubling in plasma levels of FGF23, a biomarker that was associated to endothelial dysfunction in this population. 29 Observational studies in patients with CKD, like in the Chronic Renal Insufficiency Cohort (CRIC) study, 30 associated high FGF23 with adverse cardiovascular and renal outcomes. However, a recent meta-analysis 31 showed that in patients with CKD, paricalcitol is a safe drug with favorable effect on proteinuria.…”

Serum fibroblast growth factor-23 and incident hypertension

“…38 Although the current analyses adjusted for kidney function, FGF23 may be elevated prior to frank changes in the kidney. In addition, a positive association has been found between FGF23 and atherosclerosis, 39 though it is unclear whether it acts independently of phosphorus. 25,40 Finally, high circulating FGF23 has been associated with endothelial dysfunction and arterial wall stiffness, 41–43 and inflammation 44,45 - factors which may contribute to the increased peripheral resistance typical of essential hypertension.…”

Relation between Red Cell Distribution Width and Fibroblast Growth Factor 23 Cleaving in Patients with Chronic Kidney Disease and Heart Failure

“…Several novel risk factors have been implicated in the elevated cardiovascular risk in CKD. Prominent non-traditional risk factors include red cell related measures such as anemia, iron status and red cell distribution width (RDW) [4], and markers of mineral metabolism, especially fibroblast growth factor 23 (FGF23) [5]. Interestingly, recent studies suggest a mechanistic link between these two systems [6–8].…”