Fibroblast Growth Factor 23 Trajectories in Children and Association with CKD Progression: The CKD in Children Study

In a large longitudinal study of predialysis CKD, plasma fibroblast growth factor 23 was stable in most of the children when modeled as linear trajectories over time Children with rapidly rising fibroblast growth factor 23 trajectories exhibited lower eGFR, higher serum phosphorus, proteinuria, and anemia compared with those with stable levels Longitudinal fibroblast growth factor 23 monitoring provides a powerful, independent predictor of kidney disease progression in children with CKD.

In children and adults, plasma fibroblast growth factor 23 (FGF23) concentrations increase early in CKD and associate with disease progression and adverse cardiovascular outcomes. However, longitudinal changes in FGF23 in children with progressive CKD are not well characterized.

We measured c -terminal FGF23 biannually and eGFR in 543 children with CKD stages 2-4 enrolled in the CKD in children study. All participants had 2-3 FGF23 measurements. We used a linear mixed model to estimate the average percent change in FGF23 and eGFR over time for the overall cohort and latent group-based trajectory modeling to identify populations with distinct patterns of change in FGF23 concentration, eGFR, and phosphorus z -score. We used Cox proportional hazards model to examine the risk of progression to kidney failure according to FGF23 trajectory group.

At study enrollment, the median age was 12 years and eGFR 52 ml/min per 1.73 m 2 . In univariate models with repeated measures, FGF23 increased by a mean of 3.7% annually, and eGFR decreased by 3.8% annually over a median observation period of 4 years. We identified three distinct FGF23 trajectories: stable in 64% of participants (FGF23 slope 0% per year); slowly rising in 30% (slope 6% per year) and rapidly rising in 6% (slope 39% per year). Membership in the faster-rising trajectory groups was associated with lower eGFR, higher serum phosphorus, greater proteinuria, and anemia. With subsequent median 4.9 years of follow-up, the risk of kidney failure was 1.7-fold higher (95% confidence interval, 1.09 to 2.67) in the slowly rising and 8-fold higher (95% confidence interval, 2.41 to 23.56) in the rapidly rising FGF23 trajectory group compared with the stable trajectory group, in fully adjusted analyses. Phosphorus z -score trajectories did not associate with progression to kidney failure in adjusted models.

By characterizing longitudinal changes in FGF23 in children with CKD, we find that FGF23 was stable in most children. Membership in the faster-rising FGF23 trajectory groups associates with increased risk of progression to kidney failure. Future studies are needed to investigate whether FGF23 is a modifiable cause or a consequence of CKD progression in children with CKD.