Raised FGF23 Correlates to Increased Mortality in Critical Illness, Independent of Vitamin D

SIMPLE SUMMARY: Fibroblast Growth Factor 23 (FGF23) is a hormone which is known to control the levels of vitamin D, phosphate, and calcium in the body. There is evidence that high levels of FGF23 in patients with chronic kidney disease may increase the risk of death. The aim of this study is to see if patients who are extremely unwell (admitted to intensive care) with high levels of FGF23 are more likely to die than patients with lower levels. We investigated patients from two intensive care studies. We showed that patients who had higher FGF23 levels when they were admitted had a higher risk of death compared to patients with lower FGF23 levels. This applied to patients without chronic kidney disease as well as those with normal or low vitamin D levels. This may mean that FGF23 can affect the way our immune system works in a previously unexplored way. With more research, treating FGF23 levels might be a way to improve the survival of intensive care patients. ABSTRACT: Background: Fibroblast Growth Factor (FGF23) is an endocrine hormone classically associated with the homeostasis of vitamin D, phosphate, and calcium. Elevated serum FGF23 is a known independent risk factor for mortality in chronic kidney disease (CKD) patients. We aimed to determine if there was a similar relationship between FGF23 levels and mortality in critically ill patients. Methods: Plasma FGF23 levels were measured by ELISA in two separate cohorts of patients receiving vitamin D supplementation: critical illness patients (VITdAL-ICU trial, n = 475) and elective oesophagectomy patients (VINDALOO trial, n = 76). Mortality data were recorded at 30 and 180 days or at two years, respectively. FGF23 levels in a healthy control cohort were also measured (n = 27). Results: Elevated FGF23 (quartile 4 vs. quartiles 1–3) was associated with increased short-term (30 and 180 day) mortality in critical illness patients (p < 0.001) and long-term (two-year) mortality in oesophagectomy patients (p = 0.0149). Patients who died had significantly higher FGF23 levels than those who survived: In the critical illness cohort, those who died had 1194.6 pg/mL (range 0–14,000), while those who survived had 120.4 pg/mL (range = 15–14,000) (p = 0.0462). In the oesophagectomy cohort, those who died had 1304 pg/mL (range = 154–77,800), while those who survived had 644 pg/mL (range = 179–54,894) (p < 0.001). This was found to be independent of vitamin D or CKD status (critical illness p = 0.3507; oesophagectomy p = 0.3800). FGF23 levels in healthy controls were similar to those seen in oesophagectomy patients (p = 0.4802). Conclusions: Elevated baseline serum FGF23 is correlated with increased mortality in both the post-oesophagectomy cohort and the cohort of patients with critical illness requiring intensive care admission. This was independent of vitamin D status, supplementation, or CKD status, which suggests the presence of vitamin D-independent mechanisms of FGF23 action during the acute and convalescent stages of critical illness, warranting further investigation.