New aspects of CKD-MBD pathogenesis

The hormone fibroblast growth factor (FGF) 23 is a central regulator of phosphate metabolism and mediates phosphaturic effects by binding to FGF receptors in the presence of the coreceptor alpha-Klotho in renal tubular cells. Alpha-Klotho exists as membrane-bound and soluble variants. A great number of cohort studies have shown an association between elevated FGF-23 plasma levels and adverse cardiovascular outcome in patients with chronic kidney disease (CKD). It is noteworthy that the relationship between FGF 23 and the occurrence of acute cardiac failure was more pronounced than the relationship between FGF 23 and atherosclerotic events. A possible pathophysiological explanation for this close relationship is the direct alpha-Klotho independent activation of FGF receptor 4 by FGF 23 in myocardial cells, which results in left ventricular hypertrophy. In contrast, other experimental studies have suggested a central role of alpha-Klotho deficiency in the pathogenesis of uremic cardiomyopathy; however, these experimental results could not be supported by findings from recent clinical trials, which did not show an association between soluble alpha-Klotho levels and cardiovascular events. Thus, the selective blockade of FGF 23 signaling through FGF receptor 4 could be a promising therapeutic option in the treatment of CKD mineral and bone disorders (MBD). © 2017, Springer Medizin Verlag Berlin.