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Randomized Clinical Trial of Sevelamer Carbonate on Serum Klotho and Fibroblast Growth Factor 23 in CKD.

ABSTRACT: BACKGROUND AND OBJECTIVES:Epidemiologic studies suggest that higher serum phosphaturic hormone fibroblast growth factor 23 levels are associated with increase morbidity and mortality. The aim of the FGF23 Reduction Efficacy of a New Phosphate Binder in CKD Trial was to evaluate the effect of sevelamer carbonate on serum C-terminal fibroblast growth factor 23 levels in normophosphatemic patients with CKD stage 3b/4. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Patients with CKD, eGFR between 45 and 15 ml/min per 1.73 m2, fasting serum phosphate concentration >3.1 mg/dl, and serum C-terminal fibroblast growth factor 23 >80 relative units/ml were included in our double-blind, placebo-controlled, randomized multicenter study. All patients received 100,000 IU cholecalciferol at time of randomization. Participants received either placebo or sevelamer carbonate 4.8 g daily during a 12-week period. Biologic parameters, including serum C-terminal fibroblast growth factor 23, intact fibroblast growth factor 23, and ?-klotho, were evaluated at baseline and 12 weeks after inclusion. RESULTS:Of 96 screened patients, 78 (mean±SD age: 63±13 years old; 70% men; mean eGFR: 27±9 ml/min per 1.73 m2) met the inclusion criteria. At baseline, mean eGFR was 27±9 ml/min per 1.73 m2, mean serum phosphate level was 3.8±0.5 mg/dl, and median (interquartile range) serum C-terminal fibroblast growth factor 23 level was 157 (120-241) relative units/ml. After 12 weeks of treatment, urinary phosphate-to-creatinine ratio fell significantly in the sevelamer group. The sevelamer and placebo groups did not differ significantly in terms of median change in serum C-terminal fibroblast growth factor 23 levels: the median (interquartile range) change was 38 (-13-114) relative units/ml in the placebo group and 37 (-1-101) relative units/ml in the sevelamer group (P=0.77). There was no significant difference in serum intact fibroblast growth factor 23, ?-klotho, or phosphate levels changes between the two groups. Serum total and LDL cholesterol levels fell significantly in the sevelamer group. CONCLUSIONS:In our double-blind, placebo-controlled, randomized study performed in normophosphatemic patients with CKD, a 12-week course of sevelamer carbonate significantly reduced phosphaturia without changing serum phosphorus but did not significantly modify serum C-terminal fibroblast growth factor 23 and intact fibroblast growth factor 23 or ?-klotho levels.

SUBMITTER: Liabeuf S

PROVIDER: S-EPMC5718266 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Randomized Clinical Trial of Sevelamer Carbonate on Serum Klotho and Fibroblast Growth Factor 23 in CKD.

Liabeuf Sophie S Ryckelynck Jean-Philippe JP El Esper Najeh N Ureña Pablo P Combe Christian C Dussol Bertrand B Fouque Denis D Vanhille Philippe P Frimat Luc L Thervet Eric E Mentaverri Romuald R Prié Dominique D Choukroun Gabriel G

Clinical journal of the American Society of Nephrology : CJASN 20171026 12

<h4>Background and objectives</h4>Epidemiologic studies suggest that higher serum phosphaturic hormone fibroblast growth factor 23 levels are associated with increase morbidity and mortality. The aim of the FGF23 Reduction Efficacy of a New Phosphate Binder in CKD Trial was to evaluate the effect of sevelamer carbonate on serum C-terminal fibroblast growth factor 23 levels in normophosphatemic patients with CKD stage 3b/4.<h4>Design, setting, participants, & measurements</h4>Patients with CKD, e ...[more]

PMID: 29074818

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Project description:BackgroundFibroblast growth factor 23 (FGF23) is a phosphaturic hormone that is secreted from bone and serum level increases as renal function declines. Higher levels of FGF23 are associated with increased mortality in hemodialysis-patients and in patients with chronic kidney disease (CKD) stage 2-4. The use of active vitamin D and phosphate binders as recommended in international guidelines, may affect the level of FGF23 and thereby clinical outcome. We investigated the effects of a phosphate binder and active vitamin D on the serum levels of intact FGF23 (iFGF23) and intact parathyroid hormone (iPTH) in patients with CKD stage 3b (glomerular filtration rate (GFR) 30-44 ml/min/1.73 m(2)).MethodsSeven women and 14 men were included, mean age 65.6 ± 12.2 years. They were randomized in a 1:1 ratio to receive one of two treatment sequences. Group-1 (the alphacalcidol-sevelamer carbonate group): alphacalcidol 0.25 μg once daily for two weeks followed by sevelamer carbonate 800 mg TID with meals for two weeks after a two-week washout period. Group-2 (the sevelamer carbonate-alphacalcidol group): vice versa. Nineteen patients completed the study. The 25-hydroxyvitamin D level at baseline was 97.6 ± 25.0 nmol/l.ResultsThere were no treatment effects on the iFGF23 and iPTH levels overall. In group-1 the iFGF23 level was higher after treatment with alphacalcidol compared with sevelamer carbonate (mean 105.8 ± 41.6 vs. 79.1 ± 36.5 pg/ml, p = 0.047 (CI: 0.4-52.9), and the iPTH level was lower (median: 26.5, range: 14.6-55.2 vs. median 36.1, range 13.4-106.9 pg/ml, p = 0.011). In group-2 the iFGF23 level increased non-significantly after treatment with sevelamer carbonate and throughout the washout period.ConclusionsIn this crossover trial with alphacalcidol and sevelamer carbonate in patients with CKD stage 3b, the levels of iFGF23 were not significantly different after the two treatments. However, in the group of patients initiating therapy with sevelamer carbonate the iFGF23 levels seemed to increase while this response was mitigated in the group of patients given alphacalcidol followed by sevelamer carbonate. This may have therapeutic implications on choice of first line therapy. The number of patients is small and this conclusion is in part based on subgroup analysis. It is therefore important that these results are confirmed in larger studies.Trial registrationTrial registration numberEuropean Clinical Trial Database (EudraCT) 2010-020415-36 and Clinical Trials.gov NCT01231438.

Project description:BackgroundHigh concentrations of both phosphate and fibroblast growth factor 23 (FGF23) observed in chronic kidney disease (CKD) are associated with an increased risk of cardiovascular morbidity and mortality. Pulse wave velocity (PWV) is a surrogate marker for cardiovascular events and all-cause mortality. It is not known whether a reduction of FGF23 or phosphate alters cardiovascular risk. Sevelamer has shown to have the ability to reduce both phosphate and FGF23 concentrations. Furthermore, reduction of PWV is reported with sevelamer use as well, but it is unclear if this is mediated by decline of phosphate or FGF23. We investigated if sevelamer induced a decline in PWV and if this was associated with a reduction in FGF23.MethodsIn all, 24 normophosphataemic CKD Stage 3 patients started treatment with a fixed dose of sevelamer-carbonate (Renvela®) 2.4 g twice daily, with their usual diet for 8 weeks in a single-arm study. PWV was measured and blood samples were obtained before, during and after washout of treatment with sevelamer. Vascular calcification was quantified using the Kauppila Index (KI). The primary outcome was the change of PWV from baseline to 8 weeks of treatment and the secondary endpoint was the difference of FGF23 following treatment with sevelamer. One of the linear mixed models was used to analyse the association between treatment and outcome. Mediation analysis was performed as a sensitivity analysis. The study was registered in the Dutch trial register (http://www.trialregister.nl: NTR2383).ResultsA total of 18 patients completed 8 weeks of treatment with sevelamer and were analysed. Overall, treatment with sevelamer did not induce a significant reduction of PWV (β = -0.36, P = 0.12). However, in patients with less vascular calcification (lower KI score), there was a statistically significant reduction of PWV, adjusted for mean arterial pressure, after treatment (β = 0.63, P = 0.02). Addition of FGF23 to the model did not alter this association. Mediation analysis yielded similar results. FGF23 did not decrease during treatment with sevelamer.ConclusionIn this short-term pilot study in normophosphataemic CKD patients, treatment with sevelamer did not improve PWV. In subgroup analysis, however, PWV improved in patients with no or limited abdominal aorta calcifications. This was not associated with a decline of FGF23.

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Randomized Clinical Trial of Sevelamer Carbonate on Serum Klotho and Fibroblast Growth Factor 23 in CKD.

Publications

Randomized Clinical Trial of Sevelamer Carbonate on Serum Klotho and Fibroblast Growth Factor 23 in CKD.

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