Klotho and endocrine fibroblast growth factors: markers of chronic kidney disease progression and cardiovascular complications?

Three members of the fibroblast growth factor (FGF) family, FGF19, FGF21 and FGF23, are different from the other members in two major aspects. First, they are actually not growth factors but endocrine factors that regulate various metabolic processes. Second, their physiological receptors are not FGF receptors (FGFRs) but binary complexes of FGFRs and Klotho proteins. FGF23 and FGF21 have emerged as biomarkers that start increasing in early-stage chronic kidney disease (CKD). FGF23 is a bone-derived phosphaturic hormone that binds to the alpha Klotho-FGFR complex expressed in renal tubules to increase phosphate excretion per nephron. The FGF23 increase is deemed necessary to compensate for the decrease in the nephron number during CKD progression and to maintain the phosphate balance. However, the increase in phosphate excretion per nephron induces renal tubular damage and accelerates nephron loss. CKD progression is also associated with an increase in calciprotein particles (CPPs) in the blood. CPPs are calcium-phosphate nanoparticles with the ability to induce endothelial damage and inflammatory responses. The fact that serum CPP levels are correlated with vascular calcification/stiffness and mortality in CKD patients suggests that CPPs may serve as a 'pathogen' of cardiovascular complications. Like FGF23, FGF21 starts increasing in early-stage CKD. FGF21 is a liver-derived hormone that binds to the beta Klotho-FGFR complex expressed in the central nervous system to induce stress responses, including activation of the sympathetic nervous system and the hypothalamus-pituitary-adrenal axis. Thus FGF21 and FGF23 are not merely biomarkers for CKD progression but potential pathogenic agents that accelerate CKD progression and aggravate cardiovascular complications.