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 α-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, α-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 α-klotho levels.

Keywords: Cholecalciferol; Cholesterol, LDL; Double-Blind Method; Epidemiologic Studies; FGF23; Fasting; Fibroblast Growth Factors; Hypophosphatemia, Familial; KLOTHO; Phosphates; Phosphorus; Random Allocation; Renal Insufficiency, Chronic; chronic kidney disease; creatinine; fibroblast; fibroblast growth factor 23; glomerular filtration rate; mineral metabolism; phosphate binders; randomized controlled trials; sevelamer.

Figure 1.

Study design.

Figure 2.

Study flow chart. ITT, intention to treat; PP, per protocol.

Figure 3.

No significant difference between the treatment groups for serum C-terminal fibroblast growth factor 23 (FGF23) level or in related variables. Except where noted otherwise, the band within each box marks the median, the ends of the boxes mark the first and third quartiles, and the whiskers mark the range. Change in (A) serum C-terminal fibroblast growth factor 23 level, (B) serum phosphorus (mean change; error bars indicate SD), (C) serum intact FGF23 levels, (D) serum α-klotho level and phosphorus level, (E) phosphaturia-to-creatinuria ratio level, (F) serum parathyroid hormone (PTH) level, and (G) serum 1,25 dihydroxyvitamin D.

Figure 3.

No significant difference between the treatment groups for serum C-terminal fibroblast growth factor 23 (FGF23) level or in related variables. Except where noted otherwise, the band within each box marks the median, the ends of the boxes mark the first and third quartiles, and the whiskers mark the range. Change in (A) serum C-terminal fibroblast growth factor 23 level, (B) serum phosphorus (mean change; error bars indicate SD), (C) serum intact FGF23 levels, (D) serum α-klotho level and phosphorus level, (E) phosphaturia-to-creatinuria ratio level, (F) serum parathyroid hormone (PTH) level, and (G) serum 1,25 dihydroxyvitamin D.

Figure 4.

Total and LDL cholesterol decreased more for the sevelamer group. Change in (A) serum total cholesterol level and (B) serum LDL cholesterol.