Fibroblast Growth Factor 23 Trajectories in Chronic Hemodialysis Patients: Lessons from the HEMO Study

Abstract

Background: Long-term patterns of fibroblast growth factor 23 (FGF23) are poorly characterized among dialysis patients. Objectives: To identify different FGF23 trajectories and determine clinical factors that predict distinct FGF23 trajectories and whether FGF23 trajectories differ in regard to their associations with all-cause mortality among prevalent hemodialysis patients. Methods: The HEMO study was a randomized multicenter study evaluating the effects of high-dose vs. standard-dose and high-flux vs. low-flux hemodialysis on mortality. We measured intact FGF23 levels in stored serum samples at baseline and annually among 919 HEMO participants and identified FGF23 trajectories using group-based modeling. Logistic regression determined predictors of trajectories. Cox regression models evaluated the association between trajectory and all-cause mortality. Results: We identified 5 distinct FGF23 trajectory groups during the initial 24 months: low stable, low increasing, elevated increasing, elevated decreasing, and elevated stable. In multivariable models, diabetes, high dose dialysis, no venous catheter, low serum calcium, phosphorus, and interleukin-6, no vitamin D analog use, and greater residual kidney function were associated with the low stable trajectory group compared to the elevated stable group. High flux dialysis, no venous catheter, and low serum phosphorus and 25-hydroxyvitamin D were associated with the elevated decreasing trajectory group compared to the elevated stable group. After full adjustment, the low stable trajectory group was associated with reduced mortality (hazard ratio [HR] 0.61; 95% CI ­0.41–0.91) compared to the elevated stable trajectory group. Conclusions: We identified 5 distinct FGF23 trajectories over 24 months among HEMO study participants including a decreasing trajectory. The low stable FGF23 trajectory was associated with a reduced HR of all-cause mortality.

Fibroblast Growth Factor 23 and Mortality Among Prevalent Hemodialysis Patients in the Japan Dialysis Outcomes and Practice Patterns Study

“…[33][34][35][36] Of note, a recent ancillary study of the Chronic Renal Insufficiency Cohort (CRIC) study 44 demonstrated that individuals with rapidly rising FGF23 trajectories were at >15-fold higher risk of death than those with stable FGF23 levels. A similar pattern of association was reported from the HEMO study, 45 but the effect size was far smaller than that of the CRIC study. In aggregate, it appears that an association between elevated FGF23 and mortality could exist in prevalent hemodialysis patients, but to a lesser extent compared with the predialysis and incident hemodialysis populations.…”

Elevated Fibroblast Growth Factor 23 Levels Are Associated With Greater Diastolic Dysfunction in ESRD

“…Median iFGF23 was elevated at 1135 (interquartile range: 361, 3195) pg/ml, which is comparable to values observed in end-stage kidney disease cohorts 5 . The strongest association was between higher levels of iFGF23 and grades of diastolic dysfunction (r s = 0.75; P < 0.001), followed by serum phosphate and iFGF23 (r s = 0.51; P < 0.001).…”

Fibroblast growth factor 23: are we ready to use it in clinical practice?

“…Both studies found, in different populations, that increasing FGF23 is disadvantageous. However, the study by Jovanovich in over 900 dialysis patients showed that, although over 24 month stable low FGF23 concentration was associated with a favourable outcome compared to stable high FGF23 concentrations, the group with high FGF23 in which FGF23 further increased over time, had no further increased risk for all-cause mortality [59]. More importantly, this study also showed that in patient with high baseline, and subsequently decreasing FGF23 concentrations had no improved risk for mortality.…”

“…Future studies should evaluate whether multiple measurements of FGF23 may be advantageous compared to a single measurement for individual patients risk assessment in those with CKD, as it was shown that especially increasing FGF23 concentrations over time are associated with increased mortality [58,59].…”