Roles of FGF23 in Mineral Metabolism and Cardiovascular Disease in CKD

by Dr Myles Wolf of the University of Miami
FGF-23 was first discovered as the use of hypophosphatemic disorders (both genetic and acquired). FGF-23 increases urinary phosphate excretion and inhibit production of vitamin D levels and stimulate vitamin D degradation –> severe hypophosphatemia. FGF-23 is secreted by both osteocytes and osteoblasts (AJP-Endocrinology Metab 2003 Vol 285). FGF-23 is a bone-derived hormone that regulates phosphate and vitamin D production.

FGF-23 requires klotho as a co-receptor to exert its function, in particular in the kidney. Every cell expresses FGF-23 receptors, but its selective function is mediated by the presence of klotho, which is found in select tissues, like the kidney. Phosphate intake, high levels of vitamin D and PTH all are stimuli for FGF-23 production. We now believe that an increase an FGF-23 is the earliest alteration of disorder of mineral metabolism (as high as at GFRs of > 60) (Wolf M. JASN 2010). If one neutralizes FGF-23 in a CKD patient, 1,25 vitamin D levels return to normal w/o any change in the GFR.

In Gutierrez NEJM 2008, the odds ratio of mortality increases with rising levels of FGF-23. Indeed this relationship holds true when we look at the crude data or adjusted data. This is in contrary to phosphate levels (Block JASN 2004) where mortality is increased with high phosphate levels but only after you make multivariate adjustments. From the CRIC study, there is concentration-dependent increase in mortality with rising levels of FGF-23 in early CKD patients (Isakova JAMA 2011).

FGF-23 is also a marker of increasing left ventricular mass index (LVMI) (Faul J Clin Invest 2011). In fact, there is some data to suggest that FGF-23 actually has a direct role in increasing LVMI, not just an association. This action is independent of the presence of klotho as the heart and cardiac myocytes do not express klotho. Thus, the idea that FGF-23 exerts effects only in the presence of klotho is falling out of favor.

The story for FGF-23, however, isn’t always negative. There is data to suggest that the presence of FGF-23 helps in mitigating vascular calcification. In a reanalysis of the CRIC data, at any level of coronary artery calcification (CAC levels > 0, > 100, > 400, or > 800), there is no association with levels of FGF-23 but significant association with phosphate levels (Scialla Kidney Int’l 2013).