Longitudinal FGF23 Trajectories and Mortality in Patients with CKD

Abstract

Elevated fibroblast growth factor 23 (FGF23) levels, measured at a single time, are strongly associated with increased risk of mortality in patients with CKD. There are minimal data on serial FGF23 measurements in CKD. In a prospective case-cohort study of the Chronic Renal Insufficiency Cohort, we measured FGF23 at two to five annual time points (mean 4.0±1.2) in a randomly selected subcohort of 1135 participants, of whom 203 died, and all remaining 390 participants who died through mid-2013. Higher FGF23 was independently associated with increased risk of death in multivariable-adjusted analyses of time-varying FGF23 (hazard ratio per 1-SD increase in ln-transformed FGF23, 1.84; 95% CI, 1.67 to 2.03). Median FGF23 was stable over 5 years of follow-up, but its gradually right-skewed distribution suggested a subpopulation with markedly elevated FGF23. Trajectory analysis revealed three distinct trajectories: stable FGF23 in the majority of participants (slope of lnFGF23 per year =0.03, 95% CI, 0.02 to 0.04, n=724) and smaller subpopulations with slowly (slope=0.14, 95% CI, 0.12 to 0.16, n=486) or rapidly (slope=0.46, 95% CI, 0.38 to 0.54, n=99) rising levels. Compared with stable FGF23, participants with slowly rising FGF23 trajectories were at 4.49-fold higher risk of death (95% CI, 3.17 to 6.35) and individuals with rapidly rising FGF23 trajectories were at 15.23-fold higher risk of death (95% CI, 8.24 to 28.14) in fully adjusted analyses. Trajectory analyses that used four or three annual FGF23 measurements yielded qualitatively similar results. In conclusion, FGF23 levels are stable over time in the majority of patients with CKD, but serial measurements identify subpopulations with rising levels and exceptionally high risk of death.

Keywords: CKD; FGF23; mortality risk.

Graphical abstract

Figure 1.

Sampling strategy for the case-cohort study population. The randomly selected subcohort included 1135 CRIC Study participants, of whom 203 died during the longitudinal follow-up period and 932 survived. All 390 remaining deaths from outside the subcohort were also sampled, providing a total study population of 1525 participants represented by the blue-shaded boxes.

Figure 2.

Longitudinal FGF23 levels are stable in the majority of the CRIC Study case-cohort participants, but there is a small subset of severely elevated outliers. Insets show the right tails of the distributions beginning at 375 reference units (RU) per 1 ml. For clarity, values >3000 RU/ml are not shown (five observations at baseline, 11 observations at year 1, 13 observations at year 2, nine observations at year 3, and 13 observations at year 4 post-baseline).

Figure 3.

Trajectory modeling identified three distinct FGF23 trajectory groups. (A) The primary analysis derived FGF23 trajectory groups using the maximum of five time points, set the onset of survival time (time 0) at the fifth time point (year 4 visit after baseline), and adjusted for concurrent covariates. (B and C) Secondary analyses repeated the weighted Cox modeling strategy after deriving FGF23 trajectory groups using four and three time points and adjusted for covariates ascertained at the analysis-specific time 0, which corresponded to the timing of the last possible FGF23 test for that specific analysis. (D) A sensitivity analysis introduced a 1-year lag, starting survival time at the year 5 visit after baseline, with adjustment for concurrent covariates. (E) Primary FGF23 trajectory analysis. Observed medians and interquartile ranges of FGF23 across the five time points (solid lines) and predicted FGF23 trajectories (dashed lines) with 95% CIs (shaded areas). The predicted FGF23 values approximate the observed values. The posterior predicted probabilities for each individual of being a member of a given trajectory group ranged from 0.91 to 0.96 across the trajectory groups. RU, reference unit.

Figure 4.

Comparison of risks of mortality according to trajectories of FGF23, eGFR, systolic BP (SBP), and phosphate demonstrates specificity of the association between FGF23 trajectories and risk of mortality. Fully adjusted hazard ratios comparing the higher-risk with the lowest-risk trajectory groups for each exposure are shown. Trajectory groups were derived using the maximum of five time points, and the onset of survival time (time 0) in the Cox models was set at the fifth time point (year 4 visit after baseline). R, reference.