Fibroblast Growth Factor 23: a Bridge Between Bone Minerals and Renal Volume Handling

The work in this thesis addresses the interaction between the phosphate-regulating hormone Fibroblast Growth Factor 23 (FGF-23) as key player in bone-mineral homeostasis and renal volume handling, mainly in the context of the renin-angiotensin-aldosterone system (RAAS). First, we elaborate on the role of vitamin D in chronic kidney disease (CKD) and its potential to increase effectiveness of RAAS-blockade. Next, we review the role of (excessive) sodium intake and why patients with CKD are particularly susceptible to the effects of sodium. Consecutively, we found that high FGF-23 levels are associated with an impaired antiproteinuric response to RAAS-blockade combined with a low sodium diet in patients with CKD. High FGF-23 concentrations are strongly associated with a high risk of cardiovascular mortality in CKD and hemodialysis patients. We add to this that also in renal transplant recipients high FGF-23 concentrations are correlated with adverse cardiovascular events, independent of existing, established risk factors. Moreover, FGF-23 levels correlated with markers of high volume status as NT-proBNP and copeptin. FGF-23 levels are extremely high in end stage renal disease. We found that part of the variance in these levels can be explained by ultrafiltration volume: patients who need more fluid withdrawal in dialysis, have far higher FGF-23 levels. The aforementioned chapters strongly suggest a link between volume status and FGF-23. We tested whether volume interventions, i.e. infusion of 2L saline or a 6-week sodium restriction, could in turn affect FGF-23 levels, this seems not to be the case. Although sodium interventions do not change FGF-23 concentrations, interventions aimed at phosphate intake do. Therefore, we examined the relation between these two minerals. Sodium intake and phosphate intake, as assessed by 24h-excretion, are strongly and robustly correlated across different populations: in renal transplant recipients, but also in diabetes patients and healthy volunteers. We interpret these findings in line with the observation that food products rich in sodium are also rich in phosphate. For example, processed-foods are notorious for their high sodium content, but they also contain a lot of phosphate-based additives which is far less commonly known. Expanding on healthy components of a healthy diet, we next investigate potassium. Healthy food choices as fruits and vegetables are rich in potassium. Following the observation that potassium supplementation appears to increase serum phosphate level, we hypothesized that potassium may lower FGF-23 levels. We confirmed this in the KaNa trial, where participants received potassium supplements or placebo combined with a fully-controlled diet. Several of our findings advocate changes in dietary intake, however this is difficult to achieve. In the multicenter, randomized controlled trial SUBLIME we deployed an approach that combined E-health technology based on self-regulation (behavioral change) theory, group meetings and individual coaching and we discuss the first results and feedback from participants in this thesis. In conclusion, this thesis places FGF-23 firmly as a bridge between sodium-volume and bone-mineral (phosphate) homeostasis