Targeting FGF23 and phosphorus in CKD, do not forget calcium

Sir, Isakova et al. [1] examined the impact of dietary phosphorus restriction and phosphorus binder (lanthanum carbonate) on fibroblast growth factor 23 (FGF23) serum levels in patients with chronic kidney disease (CKD). While either intervention significantly reduced 24-h urinary phosphorus excretion and fractional urinary phosphorus excretion over the course of the 2-week study period, FGF23 levels were unaffected. These findings, contrasting with observations made in healthy individuals [2], are intriguing indeed. First, reducing intestinal phosphorus load short term doesnot affect FGF23 levels in patients with CKD. The authors speculate that the duration of the intervention was probably too short for a CKD population, in which FGF23 levels are chronically elevated. The reasons for this lag time remain speculative. One aspect that was not touched upon was the role of calcium as determinant of FGF23 production. In vitamin D receptor-null mice, dietary calcium supplementation significantly increased FGF23 messenger RNA abundance [3]. In a recent intervention trial in CKD patients, a 6-week treatment with calcium acetate failed to decrease FGF23 levels, as opposed to sevelamer [4]. These findings indicate that calcium may be part of another feedback loop in bone and mineral homeostasis involving FGF23. Indeed, serum calcium is independently associated with FGF23 in dialysis patients, transplant recipients and in patients with primary hyperparathyroidism [5]. It is well known that the dietary ratio of phosphorus to calcium is an important determinant of calcium bioavailability [6]. Both dietary phosphorus restriction and non-calcium-containing phosphate binders may substantially decrease this ratio and, in turn, enhance calcium bioavailability. We postulate that CKD patients not taking calcium supplements, being in tight or even negative calcium balance [7], are extremely sensitive to changes in intestinal calcium transport. In these patients, an increased calcium bioavailability as a result of a lower dietary phosphorus-to-calcium ratio may be translated in an increased intestinal calcium absorption, thus increased FGF23 production. This stimulation, at least temporally (i.e. until a new steady state is reached), offsets the inhibition of FGF23 production, mediated by the simultaneously decreased phosphorus burden. An altered calcium bioavailability and intestinal transport thus represents a plausible explanation for the observation of a delayed response of FGF23 to dietary interventions targeting phosphorus in CKD. We acknowledge, however, that this hypothesis needs validation. Second, the kidney appears to respond appropriately to reduced intestinal phosphorus load in the absence of changes in the phosphaturic hormones parathroid hormone (PTH) and FGF23. Changes in renal phosphorus load, which are not captured by the blood sampling protocol, and yet to be defined phosphaturic factors such as intestinal phosphatonin [8], may explain this dissociation. We agree that measures to restrict phosphorus loading (diet, phosphate binder therapy) should be considered at earlier stages of CKD than currently practiced. FGF23 might be an interesting biomarker to monitor and to guide interventions. Current evidence indicates that an altered calcium bioavailability and intestinal transport may affect the response of FGF23 to interventions targeting phosphorus in CKD. Conflict of interest statement. None declared.