In Focus FGF23 and vascular calci ﬁ cations: another piece of the puzzle?

At the time of its early discovery and characterization, fibroblast growth factor 23 (FGF23) was identified as a hormonal substance produced by bone cells (osteoblast/osteocytes)mainly devoted to controlling phosphorus balance by directly reducing phosphate reabsorption in the proximal renal tubule and indirectly decreasing phosphorus intestinal absorption, through a reduced bioavailability of the most active vitamin D metabolite (calcitriol) [1–3]. These characteristics formerly made this new hormone the object of interest mainly in the endocrinological field encompassing some acquired or genetically transmitted hypophosphatemic syndromes, such as tumor-induced (TIO), X-linked, autosomal dominant and recessive hypophosphatemic rickets/osteomalacia (XLHR/ADHR/ARHR) syndromes which have been demonstrated to be directly or indirectly linked to some disturbances associated with FGF23 and other strictly related phosphaturic substances (PHEX, DMP-1, MEPE). However, many subsequent experimental and observational studies reported on increased FGF23 concentrations from the very early stages of chronic kidney disease (CKD) and provided data suggesting that high FGF23 levels might represent an independent risk factor for both global and/or cardiovascular morbidity/mortality [4–6], not only in CKD patients but also in the general population [7]. However, the presence of many potential confounders and contradictions soon became evident, preventing a clear interpretation of the results of this bulk of published studies, with many questions still remaining unanswered. An important unanswered question concerns whether the increased circulating levels of FGF23 (the hormonal component) or some disturbance in its tissue expression and/or signaling (the autocrine/paracrine or ‘local’ component) can be implicated in the putative pathogenic link with cardiovascular morbidity. Anyway, for both these putative conditions a series of critical points arise. The increase of FGF23 levels in CKD probably represents a homeostatic response directed to maintain a neutral phosphorus balance, given the trend toward a reduced renal excretion, in spite of an almost unchanged intestinal phosphorus absorption in the course of CKD. It is worth underlining that the trend to phosphorus retention in CKD is secondary not only to the reduced glomerular filtration volume, but probably also to the tubular resistance to the phosphaturic action of FGF23, secondary to the progressive reduction of α-Klotho, which plays a basic role in increasing the affinity of FGF23 receptors. Since both phosphorus retention and α-Klotho reduction may independently play a pathogenic role in CV morbidity, it is not easy to understand how much of this putative pathogenic role should be ascribed to the FGF23 per se or to the above quoted primary conditions causative for the FGF23 increase [8]. In particular, the reduced tissue α-Klotho availability has recently gained much credit as a primary CV pathogenic factor [9, 10]. On the other hand, it cannot be excluded that extremely high FGF23 levels may cease to represent a compensatory phenomenon, displaying a direct pathogenic ‘off-target’ effect, possibly through a non-specific occupation of FGF receptors even in the absence of Klotho, given the exceedingly high concentrations occurring at the latest stages of CKD [6, 11, 12]. However, even if this is the case, uncertainties would still remain on what the FGF23 level threshold is above which the pathogenic role starts to be evident. In fact, looking at the results of the study by Faul et al. [6], the FGF23 levels associated with a pathogenic effect on cardiac mass in the experimental models were manifoldly higher than those found in the clinical observational section of the same study. Overall, when the effects of FGF23 have been blocked with monoclonal anti-FGF23 antibodies in an experimental animal model of CKD, even if hyperparathyroidism was better controlled, the net result was a net increase in animal mortality [13], these data cast some doubt on the putative direct pathogenic effect of FGF23. However, a basic limitation in making clear any message on the role of the circulating levels of FGF23 is represented by the lack of a widely accepted gold-standard method for dosing this hormone. In fact, circulating FGF23 is present as both intact-