This thesis focused on the question whether it is beneficial to modify FGF23 levels, in order to improve patient outcome. In chapter 1 an introduction to the thesis is given. The chapter provides a broader perspective on the possible clinical usefulness of FGF23 in the near future. Several aspects concerning the clinical use of FGF23 measurement are discussed. Up to date there are no prospective intervention studies in humans aiming to reduce FGF23 concentrations and testing whether cardiovascular morbidity and mortality is improved by this approach.Ahead of such a trial we studied in chapter 2.1 the natural course of FGF23 levels on clinical outcome. We explored to what extend the spontaneous change of FGF23 levels over time outperforms a single measurements as indicator of future cardiovascular events and mortality. However, we did not found that multiple FGF23 measurements are more strongly associated with outcome than a single measurement. . This study did confirm earlier studies by demonstrating that a single FGF23 measurement is an important risk factor for cardiovascular disease, as FGF23 was significantly associated with a composite of cardiovascular events, all-cause mortality and the initiation of renal replacement. In chapter 2.2 a meta-analysis of FGF23 and its associations with different outcomes and in the different populations is described In chapter 3 we investigated if the association of FGF23 with risk might be partially the result of this FGF23 resistance instead of FGF23 perse. In this study of a cohort of patients with CKD stage 3-4 the association of FGF23 with outcome was not influenced by the fractional excretion of phosphate, suggesting that resistance to FGF23 does not contribute to the adverse outcome related to elevated FGF23 levels. In chpater 4 we investigated an intervention assumed to lower FGF23 and its effect on pulse wave velocity (PWV). PWV, a well-established marker for arterial stiffness, was chosen as a surrogate endpoint for CVD since arterial stiffness is strongly associated with cardiovascular events and all-cause mortality.. The hypothesis of this study was that a sevelamer–induced reduction of FGF23 would lead to improved vascular function as assessed by PWV. Unexpectedly however no significant improvement of PWV after treatment with sevelamer was found. Interestingly, in a subgroup of patients with no or limited vascular calcification at baseline, the use of sevelamer actually was associated with a decline in PWV. Notably, no significant reduction of FGF23 was found, despite an effective reduction of phosphate absorption due to the use of sevelamer. A finding also present in the subgroup of patients with low baseline calcification, suggesting that the effect of sevelamer on PWV was not mediated by FGF23. In chapter 5 the effect of lowering FGF23 by hemodiafiltration (HDF) on outcome was studied, Previous studies have shown that convective transport can effectively lower FGF23. In this study very high levels of FGF23 were observed and over time strongly diverging FGF23 concentrations were seen as was expected. However, this reduction of FGF23 in 6 months’ time was not accompanied by a decreased risk for all-cause mortality. On the other way, increasing FGF23 concentrations were associated with an increased risk for all-cause mortality. This study therefore argues against the rationale to actively lower FGF23 in patients on hemodialysis of hemodiafiltration, in order to improve all-cause mortality risk. Only patients with increasing FGF23 were at higher risk, suggesting that increasing FGF23 merely identifies patients with a certain phenotype with a higher-risk for mortality.
|Qualification||Doctor of Philosophy|
|Award date||7 Sep 2021|
|Place of Publication||s.l.|
|Publication status||Published - 8 Sep 2021|