Fibroblast Growth Factor 23 and Risk of CKD Progression in Children

Abstract

Background and objectives: Plasma fibroblast growth factor 23 (FGF23) concentrations increase early in the course of CKD in children. High FGF23 levels associate with progression of CKD in adults. Whether FGF23 predicts CKD progression in children is unknown.

Design, setting, participants, & measurements: We tested the hypothesis that high plasma FGF23 is an independent risk factor for CKD progression in 419 children, aged 1-16 years, enrolled in the Chronic Kidney Disease in Children (CKiD) cohort study. We measured plasma FGF23 concentrations at baseline and determined GFR annually using plasma disappearance of iohexol or the CKiD study estimating equation. We analyzed the association of baseline FGF23 with risk of progression to the composite end point, defined as start of dialysis or kidney transplantation or 50% decline from baseline GFR, adjusted for demographics, baseline GFR, proteinuria, other CKD-specific factors, and other mineral metabolites.

Results: At enrollment, median age was 11 years [interquartile range (IQR), 8-15], GFR was 44 ml/min per 1.73 m2 (IQR, 33-57), and FGF23 was 132 RU/ml (IQR, 88-200). During a median follow-up of 5.5 years (IQR, 3.5-6.6), 32.5% of children reached the progression end point. Higher FGF23 concentrations were independently associated with higher risk of the composite outcome (fully adjusted hazard ratio, 2.52 in the highest versus lowest FGF23 tertile; 95% confidence interval, 1.44 to 4.39, P=0.002; fully adjusted hazard ratio, 1.33 per doubling of FGF23; 95% confidence interval, 1.13 to 1.56, P=0.001). The time to progression was 40% shorter for participants in the highest compared with the lowest FGF23 tertile. In contrast, serum phosphorus, vitamin D metabolites, and parathyroid hormone did not consistently associate with progression in adjusted analyses.

Conclusions: High plasma FGF23 is an independent risk factor for CKD progression in children.

Keywords: CKiD; Confidence Intervals; Demography; Fibroblast Growth Factors; Follow-Up Studies; Minerals; Phosphorus; Renal Insufficiency, Chronic; Vitamin D; adult; child; chronic kidney disease; cohort studies; fibroblast growth factor 23; glomerular filtration rate; humans; iohexol; kidney; kidney transplantation; mineral metabolism; parathyroid hormone; progression of chronic renal failure; proteinuria; renal dialysis; risk factors.

Copyright © 2016 by the American Society of Nephrology.

Figures

Figure 1.

Higher tertiles of baseline plasma FGF23 concentration associate with higher cumulative incidence of progression to dialysis, transplant, or 50% decline in GFR from baseline. Log-rank test for trend, P<0.001. FGF23, fibroblast growth factor 23.

Figure 2.

Hazard ratio (and 95% confidence interval) for the composite end point of dialysis, transplant, or 50% decline in GFR from baseline, according to tertiles of baseline plasma FGF23 concentrations. Model 1: adjusted for gender, age, and race. Model 2: adjusted for covariates in model 1 plus GFR and Up/c. Model 3: adjusted for covariates in model 2 plus systolic BP z-score, glomerular diagnosis, angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers, active vitamin D, and phosphate binder use. Tertile 1 (FGF23<100 RU/ml) is the reference group (R) in all models. Bars represent 95% confidence intervals. Asterisks indicate P<0.02 relative to the reference group. FGF23, fibroblast growth factor 23; Up/c, urine protein-to-creatinine concentration.