Comparison of Calcium Acetate and Sevelamer on Vascular Function and Fibroblast Growth Factor 23 in CKD Patients: A Randomized Clinical Trial

Yılmaz, Mahmut İlker; Sönmez, Alper; Sağlam, Mutlu; Yaman, Halıl; Kılıç, Selim; Eyıleten, Tayfun; Çağlar, Kayser; Oğuz, Yusuf; Vural, Abdülgaffar; Yenicesu, Müjdat; Mallamaci, Francesca; Zoccali, Carmine

doi:10.1053/j.ajkd.2011.11.007

Cited by 124 publications

(105 citation statements)

References 29 publications

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“…Yilmaz et al 25 Despite what seems to represent similar efficacy in terms of intestinal phosphate binding, intestinal phosphate binders seem to exert disparate effects on serum concentrations of FGF23. 17,25 Treatment with phosphate binders resulted in significant progression of vascular calcification in coronary arteries and the abdominal aorta.…”

Section: Discussionmentioning

confidence: 99%

“…17,25 Treatment with phosphate binders resulted in significant progression of vascular calcification in coronary arteries and the abdominal aorta. Assessment of coronary artery calcification (CAC) progression using the square-root followup method in the work by Hokanson et al 26 has been shown to be the best method to predict mortality in a large cohort of asymptomatic patients.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Phosphate Binders in Moderate CKD

Block

Wheeler

Persky

et al. 2012

Journal of the American Society of Nephrology

481

383

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Some propose using phosphate binders in the CKD population given the association between higher levels of phosphorus and mortality, but their safety and efficacy in this population are not well understood. Here, we aimed to determine the effects of phosphate binders on parameters of mineral metabolism and vascular calcification among patients with moderate to advanced CKD. We randomly assigned 148 patients with estimated GFR=20-45 ml/min per 1.73 m 2 to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus from baseline to the average of months 3, 6, and 9. Serum phosphorus decreased from a baseline mean of 4.2 mg/dl in both active and placebo arms to 3.9 mg/dl with active therapy and 4.1 mg/dl with placebo (P=0.03). Phosphate binders, but not placebo, decreased mean 24-hour urine phosphorus by 22%. Median serum intact parathyroid hormone remained stable with active therapy and increased with placebo (P=0.002). Active therapy did not significantly affect plasma C-terminal fibroblast growth factor 23 levels. Active therapy did, however, significantly increase calcification of the coronary arteries and abdominal aorta (coronary: median increases of 18.1% versus 0.6%, P=0.05; abdominal aorta: median increases of 15.4% versus 3.4%, P=0.03). In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. The safety and efficacy of phosphate binders in CKD remain uncertain. CKD is a significant public health concern; roughly 13% of the US population has an estimated GFR (eGFR) below 60 ml/min per 1.73 m 2 or albuminuria. 1 The risks of death and cardiovascular disease in CKD are not fully explained by associated diabetes, hypertension, and other conventional risk factors. 2 With declining kidney function, serum phosphorus concentration increases but generally remains within the normal range until late in stage 4 or 5 CKD. A normal or near-normal serum phosphorus concentration is maintained at the expense of elevated levels of the phosphaturic hormones parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). 3,4 Serum concentrations of phosphorus and hormones responsible for its regulation have been implicated as putative cardiovascular risk factors. [5][6][7][8][9]

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of Phosphate Binders in Moderate CKD

Block

Wheeler

Persky

et al. 2012

Journal of the American Society of Nephrology

481

383

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“…The effect of phosphate binders on FGF-23 has been investigated in both patients with CKD and patients on maintenance dialysis (29)(30)(31)(32)(33)(34). Overall, these data suggest that the use of non-Ca-based binders seems to lower FGF-23 levels, whereas the use of Ca-containing binders either minimally affects or actually raises FGF-23 levels.…”

Section: Discussionmentioning

confidence: 99%

Effect of Cinacalcet and Vitamin D Analogs on Fibroblast Growth Factor-23 during the Treatment of Secondary Hyperparathyroidism

Sprague

Wetmore

Gurevich³

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Cinacalcet and vitamin D are often combined to treat secondary hyperparathyroidism (SHPT) in patients on dialysis. Independent effects on fibroblast growth factor-23 (FGF-23) concentrations in patients on hemodialysis administered cinacalcet or vitamin D analogs as monotherapies during treatment of SHPT are evaluated.Design, setting, participants, & measurements A multicenter, randomized, open-label study to compare the efficacy of cinacalcet versus traditional vitamin D therapy for management of secondary hyperparathyroidism among subjects undergoing hemodialysis (PARADIGM) was a prospective, phase 4, multicenter, randomized, open-label study conducted globally. Participants (n=312) were randomized 1:1 to cinacalcet (n=155) or vitamin D analog (n=157) for 52 weeks. Levels of FGF-23 were measured at baseline and weeks 20 and 52. The absolute and percentage changes from baseline in plasma FGF-23, parathyroid hormone (PTH), calcium (Ca), phosphorus (P), and calcium-phosphorus product (Ca3P) were assessed. Correlations and logistic regression were used to explore relationships between changes in FGF-23 and changes in PTH, Ca, P, and Ca3P from baseline to week 52 by treatment arm.Results Median (quartiles 1, 3) decrease in FGF-23 concentrations was observed in the cinacalcet arm (240%; 263%, 16%) compared with median increase in the vitamin D analog arm (47%; 0%, 132%) at week 52 (P,0.001). Changes in FGF-23 in both arms were unrelated to changes in PTH (cinacalcet: r=0.17, P=0.11; vitamin D analog: r=20.04, P=0.70). Changes in FGF-23 in the vitamin D analog but not the cinacalcet arm were correlated with changes in Ca (cinacalcet: r=0.11, P=0.30; vitamin D analog: r=0.32, P,0.01) and P (cinacalcet: r=0.19, P=0.07; vitamin D analog: r=0.49, P,0.001). Changes in FGF-23 were correlated with changes in Ca3P in both arms (cinacalcet: r=0.26, P=0.01; vitamin D analog: r=0.57, P,0.001). Independent of treatment arm, participants with reductions in P or Ca3P were significantly more likely to show reductions in FGF-23.Conclusions During treatment of SHPT, cinacalcet use was associated with a decrease in FGF-23 concentrations, whereas vitamin D analogs were associated with an increase. The divergent effects of these treatments on FGF-23 seem to be independent of modification of PTH. It is possible that effects of cinacalcet and vitamin D analogs on FGF-23 may be mediated indirectly by other effects on bone and mineral metabolism.

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“…This may have led us to underestimate baseline phosphate intake and thus deliver dietary restriction of insufficient magnitude. Finally, we were not able to evaluate effects of other classes of phosphate binders that have been reported to have varying effects on FGF23 levels in CKD (9,11).…”

Section: Variablementioning

confidence: 99%

“…Blocking dietary phosphate absorption with phosphate binders may decrease FGF23 levels in patients with CKD (9)(10)(11), but the effects of reducing dietary phosphate intake have been less well studied and yielded inconsistent results (12)(13)(14). Additional limitations of the existing literature on FGF23 reduction in CKD include lack of information on the longerterm effectiveness of dietary interventions, sparse data on the efficacy of strategies based on outpatient dietary counseling that are feasible in usual clinical practice, and uncertainty about the effect of combining outpatient dietary counseling with phosphate binders.…”

Section: Introductionmentioning

confidence: 99%

Effects of Dietary Phosphate Restriction and Phosphate Binders on FGF23 Levels in CKD

Isakova

Barchi-Chung

Enfield

et al. 2013

Clinical Journal of the American Society of Nephrology

136

100

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SummaryBackground Elevated levels of fibroblast growth factor 23 (FGF23) are associated with increased risk of adverse outcomes in patients with CKD. Reducing dietary phosphate intake or absorption may decrease FGF23 levels, but data on the combined effects of dietary phosphate restriction and phosphate binders in CKD are limited.Design, setting, participants, & measurements In this 232 factorial, single-blinded, placebo-controlled, 3-month study, conducted between July 2009 and March 2012, 39 patients with CKD stages 3 or 4 and normal serum phosphate levels were randomly assigned to one of four groups: ad libitum diet plus lanthanum carbonate (LC) placebo (n=10), 900-mg phosphate diet plus LC placebo (n=10), ad libitum diet plus LC (n=11), or 900-mg phosphate diet plus LC (n=8). The dose of LC was 1000 mg three times daily with meals. Dietary restriction was accomplished with outpatient counseling. The primary end point was change in FGF23 levels from baseline.Results Compared with ad libitum diet, the 900-mg phosphate diet did not significantly reduce FGF23 levels (diet 3 time interaction, P=0.05). Compared with placebo, LC alone also did not significantly reduce FGF23 levels (LC 3 time interaction, P=0.21). However, the dual intervention significantly decreased FGF23 levels throughout the study period (diet 3 LC 3 time interaction, P=0.02), resulting in a 35% (95% confidence interval, 8%-62%) reduction by study end. ConclusionThe combination of LC plus counseling for a phosphate-restricted diet decreased FGF23 levels in patients with CKD stages 324 and normal serum phosphate levels.

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Comparison of Calcium Acetate and Sevelamer on Vascular Function and Fibroblast Growth Factor 23 in CKD Patients: A Randomized Clinical Trial

Cited by 124 publications

References 29 publications

Effects of Phosphate Binders in Moderate CKD

Effects of Phosphate Binders in Moderate CKD

Effect of Cinacalcet and Vitamin D Analogs on Fibroblast Growth Factor-23 during the Treatment of Secondary Hyperparathyroidism

Effects of Dietary Phosphate Restriction and Phosphate Binders on FGF23 Levels in CKD

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