Disordered FGF23 and mineral metabolism in children with CKD

Abstract

Background and objectives: In children with CKD, information is limited regarding the prevalence and determinants of fibroblast growth factor 23 excess and 1,25-dihyroxyvitamin D deficiency across the spectrum of predialysis CKD. This study characterized circulating concentrations of fibroblast growth factor 23 and 1,25-dihyroxyvitamin D, and investigated their interrelationships and associations with GFR and secondary hyperparathyroidism in children with CKD who were enrolled in the Chronic Kidney Disease in Children observational cohort study.

Design, setting, participants, & measurements: Plasma fibroblast growth factor 23 concentrations and determinants of mineral metabolism were measured in 464 children ages 1-16 years with predialysis CKD. GFR was measured by plasma disappearance of iohexol in 70% of participants and estimated by the Chronic Kidney Disease in Children estimating equation using serum creatinine and cystatin C concentrations in the remainder of the participants. Participants were grouped according to CKD stage and by 10-ml/min categories of GFR.

Results: Median GFR for the cohort was 45 ml/min per 1.73 m(2) (interquartile range=33-57; range=15-109). Plasma fibroblast growth factor 23 concentration was above the normal range in 67% of participants (with higher levels observed among participants with lower GFR) before higher levels of serum parathyroid hormone and phosphorus were observed. Plasma fibroblast growth factor 23 levels were 34% higher in participants with glomerular disease than in participants with nonglomerular disease, despite similar GFR. Serum phosphorus levels, adjusted for age, were significantly lower at GFR of 60-69 ml/min per 1.73 m(2) than higher GFR, but thereafter they became higher in parallel with fibroblast growth factor 23 as GFR declined. Serum 1,25-dihyroxyvitamin D concentrations were lower in those participants with low GFR values, high fibroblast growth factor 23 levels, 25-hydroxyvitamin D deficiency, and proteinuria. Secondary hyperparathyroidism was present in 55% of participants with GFR<50 ml/min per 1.73 m(2).

Conclusion: In children with predialysis CKD, high plasma fibroblast growth factor 23 is the earliest detectable abnormality in mineral metabolism, and levels are highest in glomerular diseases.

Trial registration: ClinicalTrials.gov NCT00327860.

Figures

Figure 1.

Mineral and hormone values according to estimated GFR at 10-ml/min per 1.73 m2 intervals in children with CKD. Median concentrations of (A) serum corrected–calcium, phosphorus, and immunoreactive parathyroid hormone (iPTH) and (B) serum 25-hydroxyvitamin D (25OHD) (ng/ml), 1,25-dihyroxyvitamin D [1,25(OH)2D] (pg/ml), and plasma fibroblast growth factor 23 (FGF23). Higher levels of serum iPTH precede changes in serum calcium and phosphorus. Higher levels of plasma FGF23 precede changes in 25OHD and 1,25(OH)2D. *P<0.05 versus the reference GFR group of ≥70 ml/min per 1.73 m2 using Kruskal–Wallis ANOVA. The dotted lines indicate the upper limit of normal for PTH (65 pg/ml) and FGF23 (101 RU/ml). The number of participants in each GFR group is indicated below each figure. Additional data are provided in Supplemental Table 1.

Figure 2.

Mean phosphorus z scores and median plasma FGF23 concentrations according to estimated GFR at 10-ml/min per 1.73 m2 intervals in children with CKD. Phosphorus z score is expressed in SD units. *P<0.05 versus the reference GFR group of ≥70 ml/min per 1.73 m2 using Kruskal–Wallis ANOVA; **P<0.001 versus corresponding mean for age of a healthy control population (31).

Figure 3.

Prevalence of hyperphosphatemia, hyperparathyroidism, and increased plasma FGF23 according to GFR groups. Hyperphosphatemia is defined as phosphorus (Phos) z score>1.96 SD, hyperparathyroidism is defined as serum immunoreactive parathyroid hormone (iPTH) >65 pg/ml, and FGF23 excess is defined as plasma FGF23>101 RU/ml.