Changes in fibroblast growth factor 23 levels in normophosphatemic patients with chronic kidney disease stage 3 treated with lanthanum carbonate: results of the PREFECT study, a phase 2a, double blind, randomized, placebo-controlled trial

Abstract

BackgroundHigh levels of circulating fibroblast growth factor 23 (FGF23) are associated with chronic kidney disease (CKD) progression and high mortality. In the Phosphate Reduction Evaluation of FGF23 in Early CKD Treatment (PREFECT) study, we assessed the effect of reducing intestinal phosphate absorption using lanthanum carbonate on FGF23 levels in normophosphatemic patients with CKD stage 3.MethodsThirty-five individuals were randomized to lanthanum carbonate 3000 mg/day (n = 23) or placebo (n = 12) for 12 weeks. Levels of intact FGF23 (iFGF23), C-terminal FGF23, serum and urinary phosphate and calcium, intact parathyroid hormone and 1,25-dihydroxyvitamin D were assessed.ResultsThe median age was 65 years in the lanthanum group and 73 years in the placebo group; 58.8% and 41.7% were men, respectively. No significant difference was seen in mean iFGF23 between groups at week 12. There was, however, a transient reduction from baseline in iFGF23 in the lanthanum group at week 1, from 70.5 pg/ml to 51.9 pg/ml, which was not seen in the placebo group; this between-group difference in percentage change from baseline was significant in post hoc analyses (p = 0.0102). Urinary phosphate decreased after 1 week of lanthanum treatment and remained low at week 12.ConclusionsReducing intestinal phosphate absorption with lanthanum carbonate did not lead to sustained reductions in iFGF23 in patients with CKD stage 3, although phosphaturia decreased. This suggests that factors other than phosphate burden may be responsible for driving increases in circulating FGF23 in patients with CKD.Trial registrationClinicalTrials.gov NCT01128179, 20 May 2010.

The future of phosphate binders: a perspective on novel therapeutics

“…Actually, the latter observation is true only if we consider globally the phosphate binders tested: indeed, in this study, sevelamer carbonate significantly reduced intact FGF23, but calcium acetate increased it, whereas patients receiving lanthanum carbonate did not show any difference compared with the placebo group. These results are confirmed by Ureña-Torres et al who reported no sustained decrease in intact FGF23 concentrations in normophosphatemic patients with stage 3 CKD treated with lanthanum carbonate [23]. Moreover, Nagano et al have previously demonstrated that sevelamer hydrochloride reduced serum phosphorus and subsequently FGF23 levels in rats with chronic renal failure [24].…”

Dietary Phosphorus Intake and the Kidney

“…However, the effect of phosphorus intake on FGF23 appears to be modest in human studies, with some studies unable to detect a significant effect (19, 32, 48, 78, 79, 94, 111, 161, 165). Recent human studies suggest that PTH rather than FGF23 explains the increased phosphaturia that occurs immediately after an acute phosphorus load (137).…”

Clinical rationale of sucroferric oxyhydroxide for controlling hyperphosphatemia in patients with chronic kidney disease

“…This link was demonstrated with a 42% mortality reduction in association with phosphate binder therapy in the well-known ArMORR study in incident dialysis patients (n = 8610) [8]. Recent studies aim toward measurement of alternate biomarkers, such as FGF-23 [47], and its relationship to hyperphosphatemia, as well as the use of phosphate binder therapy in the stage 3 and 4 CKD population [48][49][50]. Some of these studies have demonstrated that treatment with non-calcium-based phosphate binders, such as lanthanum carbonate, is associated with reductions of serum FGF-23 [48], and similar results have been observed with sucroferric oxyhydroxide [51].…”