Pilot study of dietary phosphorus restriction and phosphorus binders to target fibroblast growth factor 23 in patients with chronic kidney disease

Isakova, Tamara; Gutiérrez, Orlando M.; Smith, Kelsey; Epstein, Michael F.; Keating, Leigh; Jüppner, Harald; Wolf, Myles

doi:10.1093/ndt/gfq419

Cited by 154 publications

(132 citation statements)

References 25 publications

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“…This contrasts with findings from prior studies of dietary phosphate restriction or phosphate binder use in CKD, which reported significant reductions in urinary phosphate excretion commensurate with the intensity of the interventions (9,13,15). Possible explanations for this lack of an effect are insufficient dietary phosphate restriction, lower doses of LC than in prior reports (15,17), withinperson variability in 24-hour urinary collections, and waning adherence with the interventions in later weeks of the study.…”

Section: Variablecontrasting

confidence: 94%

“…This fixed dose was chosen because it reduced urinary phosphate excretion safely and effectively in CKD stages 324 (13,15). Matching placebo was prescribed at the same frequency.…”

Section: Randomization Interventions and Adherencementioning

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%

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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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Section: Variablecontrasting

confidence: 94%

“…This fixed dose was chosen because it reduced urinary phosphate excretion safely and effectively in CKD stages 324 (13,15). Matching placebo was prescribed at the same frequency.…”

Section: Randomization Interventions and Adherencementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…23 Whether our disparate findings with C-terminal and intact FGF23 reflect better precision with the intact assay or true differential effects on both molecules is unknown. A similarly discrepant result between the C-terminal and intact FGF23 assays was described in 66 subjects with normal kidney function, in whom dietary phosphate restriction reduced intact FGF23 but had no effect on C-terminal FGF2.…”

Section: Discussionmentioning

confidence: 93%

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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“…They showed that dietary P restriction and lanthanum carbonate reduced urinary P excretion without changes in serum P and FGF23 (25). In contrast, the group assigned to a higher dietary P and placebo had a significant increase in FGF23 levels (32 Our study is the first to evidence that a conspicuous protein restriction (0.3 g/kg body wt per day), with essential amino acids and ketoanalogues and without the administration of phosphate binders, is able to reduce FGF23 in CKD patients not yet on dialysis (stages 3 and 4) compared with a usual LpD (0.6 g/kg per day). Healthy subjects have a P intake of about 1200 mg (31,35); the diets used in our study contained 350-420 (VLpD) and 600-700 (LpD) mg/d of phosphorus, with a reduced P intake of 68% and 34%, respectively, compared with healthy subjects.…”

Section: Discussionmentioning

confidence: 99%

Acute Effects of Very-Low-Protein Diet on FGF23 Levels

Iorio¹,

Micco²,

Torraca³

et al. 2012

Clinical Journal of the American Society of Nephrology

104

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SummaryBackground and objectives High levels of fibroblast growth factor 23 are associated with mortality, CKD progression, and calcification in CKD patients. The aim of this pilot study is to assess whether a very-low-protein diet (0.3 g/kg per day) with a consequent low intake of phosphorus would reduce fibroblast growth factor 23 compared with a low-protein diet (0.6 g/kg per day) in CKD patients not yet on dialysis.Design, setting, participants, & measurements A prospective, randomized, controlled crossover study was performed in which 32 patients were randomized into two groups. Group A (16 patients) received a very-lowprotein diet (0.3 g/kg body wt per day) supplemented with ketoanalogues during the first week and a lowprotein diet during the second week, and group B (16 patients) received a low-protein diet during the first week and a very-low-protein diet during the second week. Fibroblast growth factor 23, seric, and urinary phosphate levels were measured at baseline and the end of each study period.Results After only 1 week of the very-low-protein diet, reductions in fibroblast growth factor 23 levels (33.5%), serum phosphate (12%), and urinary phosphate (34%) with the very-low-protein diet compared with the lowprotein diet were observed. Serum and urinary phosphate levels and protein intake were significant determinants of fibroblast growth factor 23 (95% confidence interval=1.04-1.19, 1.12-1.37, and 1.51-2.23, respectively).Conclusions A very-low-protein diet supplemented with ketoanalogues reduced fibroblast growth factor 23 levels in CKD patients not yet on dialysis.

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Pilot study of dietary phosphorus restriction and phosphorus binders to target fibroblast growth factor 23 in patients with chronic kidney disease

Cited by 154 publications

References 25 publications

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

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

Effects of Phosphate Binders in Moderate CKD

Acute Effects of Very-Low-Protein Diet on FGF23 Levels

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