Fibroblast Growth Factor 23 Predicts All-Cause Mortality in a Dose-Response Fashion in Pre-Dialysis Patients with Chronic Kidney Disease

Abstract

Background: Quantitative dose-response associations between fibroblast growth factor 23 (FGF23) and risks of mortality, cardiovascular disease (CVD), and renal events in chronic kidney disease (CKD) are not known. This study aimed to summarize and quantify the predictive effects of FGF23 among the pre-dialysis CKD stages 1-5 population. Methods: Data sources included PubMed, EMBASE, and Web of Science. Prospective cohort studies assessing the associations between FGF23 and all-cause mortality, CVD, and renal events in CKD patients were selected. Summary risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using the random-effects model. The composite higher or the highest level in FGF23 categories of each study was considered the high level. The reference level was regarded as the low level in the overall analysis. The restricted cubic spline model was used to estimate dose-response associations. Results: Fifteen prospective cohort studies centered around 15,355 subjects were analyzed. A high FGF23 level was associated with increased risks of all-cause mortality (RR 1.46, 95% CI 1.38-1.55, p < 0.001), CVD (RR 1.37, 95% CI 1.15-1.63, p < 0.001), and renal events (RR 1.31, 95% CI 1.07-1.59, p = 0.008), respectively. There was a positive, nonlinear, dose-response relationship between FGF23 and all-cause mortality. The reference level in dose-response analysis was defined as 51 RU/mL of c-terminal FGF23. We then calculated RRs for increments of 20 RU/mL, which was associated with increased risks of mortality (RR 1.04, 95% CI 1.00-1.07, p = 0.038), CVD (RR 1.02, p < 0.001), and renal events (RR 1.01, p < 0.001), respectively. Conclusions: There may be positive dose-response predictive effects of FGF23 on all-cause mortality, CVD, and renal events in patients with CKD.

Is Fibroblast Growth Factor 23 the New Biomarker for Cardiovascular Mortality in Chronic Kidney Disease Patients?

“…An ideal meta-analysis would also only include studies performed in children and young adults to eliminate the possibility of Framingham-type risk factor confounders. Nonetheless, this study by Xue et al [7] strengthens our knowledge of the emerging role of this important biomarker and highlights its importance in predicting CVD risk in patients with CKD.So, can we now recommend performing routine FGF23 testing? The answer is no.…”

“…In studies that just compared the lowest level or referent category of FGF23 with the higher categories ( ≥ 2 categories), the authors used the highest category as the high level. They elegantly illustrate the non-linear increase of the C-terminal FGF23 level in RU/mL and the relative risk for CVD mortality [7] . The dose-response relationship helps to strengthen this message.…”

“…This effect may be reversible with FGF23 receptor blockers. A comprehensive meta-analysis confirming the value of using FGF23 as a biomarker for CVD-associated mortality has been elusive.With that in mind, we were delighted to encounter such a meta-analysis by Xue et al [7] in this edition of the American Journal of Nephrology . Their rigorous analysis systematically evaluated 15 prospective cohort studies comprising a large sample size of 15,355 subjects with pre-dialysis CKD stages I-V. Their publication not only summarized the clear association between FGF23 and mortality, but also demonstrated the non-linear dose-dependent relationship between FGF23 and all-cause mortality [7] .…”

“…Their rigorous analysis systematically evaluated 15 prospective cohort studies comprising a large sample size of 15,355 subjects with pre-dialysis CKD stages I-V. Their publication not only summarized the clear association between FGF23 and mortality, but also demonstrated the non-linear dose-dependent relationship between FGF23 and all-cause mortality [7] . In their systematic meta-analysis, a high FGF23 level was associated with an increased risk of all-cause Individuals with chronic kidney disease (CKD) are at a high risk for cardiovascular vascular disease (CVD) mortality, and advances in this field form the final frontier of CKD research [1,2] .…”

“…FGF23 induces phosphaturia and lowers serum phosphorus by reducing the number of sodium-mortality (RR 1.46, 95%CI 1.38-1.55, p < 0.001) and CVD (RR 1.37, 95% CI 1.15-1.63, p < 0.001). In order to perform this analysis, the team had to compare the results from various c-terminal and intact FGF23 ELISAs by Kainos, Immutopics, and Kyowa Medex [7] . The interquartile ranges of the studies widely varied and used both arbitrary units (RU) and pg/mL.…”