Fibroblast Growth Factor 23 Levels Associate with AKI and Death in Critical Illness

Abstract

Elevated plasma levels of the osteocyte-derived hormone fibroblast growth factor 23 (FGF23) have emerged as a powerful biomarker of cardiovascular disease and death in patients with CKD. Whether elevated urinary or plasma FGF23 levels are prospectively associated with AKI and death in critically ill patients is unknown. We therefore conducted a prospective cohort study of 350 critically ill patients admitted to intensive care units at an academic medical center to investigate whether higher urinary FGF23 levels associate with the composite end point of AKI or in-hospital mortality (AKI/death). We measured urinary FGF23 levels within 24 hours of admission to the intensive care unit. In a subcohort (n=131) we also measured plasma levels of FGF23, calcium, phosphate, parathyroid hormone, and vitamin D metabolites. Urinary and plasma FGF23 levels, but not other mineral metabolites, significantly associated with AKI/death. In multivariate analyses, patients in the highest compared with the lowest quartile of urinary FGF23 had a 3.9 greater odds (95% confidence interval, 1.6 to 9.5) of AKI/death. Higher urinary FGF23 levels also independently associated with greater hospital, 90-day, and 1-year mortality; longer length of stay; and several other important adverse outcomes. In conclusion, elevated FGF23 levels measured in the urine or plasma may be a promising novel biomarker of AKI, death, and other adverse outcomes in critically ill patients.

Keywords: acute renal failure; clinical nephrology; mortality risk; parathyroid hormone; vitamin D.

Copyright © 2017 by the American Society of Nephrology.

Figures

Figure 1.

Urine and plasma mineral metabolite correlations. (A) Spearman correlations with urine FGF23/Cr; (B) Spearman correlations with plasma FGF23; (C) Spearman correlations for all metabolites. *P<0.05; **P<0.01; ***P<0.001. PO4, phosphate.

Figure 2.

Highest urinary cFGF23/Cr quartile associates with increased risk of AKI/death. Model 1 is adjusted for age, sex, baseline eGFR, hypertension, and diabetes mellitus. Model 2 is further adjusted for ICU type (surgical versus medical), mechanical ventilation, and APACHE II score. This analysis was restricted to patients who did not have AKI on enrollment (n=243, events=105). *P<0.05.

Figure 3.

Western blot characterization of FGF23 in urine. (A) Western blot of FGF23 immunoprecipitated from human urine samples (n=4 without AKI and n=5 with AKI) using polyclonal antihuman FGF23 antibodies showing nondetectable intact (32 kD) FGF23 and variable concentrations of FGF23 fragments (28 and 12 kD). (B and C) The band intensity of each detected fragment was quantified as an indicator of its relative concentration. Horizontal bars indicate median levels.

Figure 4.

Higher urine and plasma cFGF23 levels associate with increased univariate risk of AKI/death. ORs are shown per 1 unit SD of log-transformed values for each biomarker. This analysis was restricted to patients who had both plasma and urine samples available and did not have AKI on enrollment (n=113, events=38).