In this cross-sectional case series, we report for the first time that critically ill patients with AKI due to causes other than rhabdomyolysis have elevated FGF-23 levels compared with critically ill controls. Among patients with AKI, elevated FGF-23 levels were associated with an increased risk of death. As expected, AKI patients had, on average, higher concentrations of serum phosphorous compared with patients without AKI. In addition, a larger proportion of AKI patients had significant hyperparathyroidism compared with controls, although this result did not meet statistical significance. These results suggest that dysregulated mineral metabolism is common in AKI, analogous to CKD.
Interestingly, no correlation was observed between phosphorous and FGF-23 levels in this study. Few reports have analyzed this relationship in AKI patients, although in ESRD a patient's degree of elevation in FGF-23 is often correlated with severity of hyperphosphatemia [38, 44, 45]. In CKD, elevated FGF-23 levels are thought to be due to increased secretion by bone cells, rather than due to decreased renal clearance [46, 47]. Comparison of levels of intact versus degraded FGF-23 in patients on maintenance hemodialysis suggest that there is no increase in FGF-23 degradation products in these subjects and that decreased clearance of FGF-23 is therefore not the mechanism for increased FGF-23 levels . Therefore, as in CKD, elevated FGF-23 levels in AKI are likely not due to decreased clearance of FGF-23 and highlight the important paracrine role of the kidney, even in an acute illness (e.g., AKI).
Elevation of FGF-23 during AKI may have several implications. In ESRD patients undergoing hemodialysis, high FGF-23 concentrations are associated with early mortality, with an increased risk as high as 600% [37, 38]. Our study demonstrated an association between FGF-23 levels and death in subjects with AKI, although relatively small. If the association between elevated FGF-23 levels and death is confirmed in a larger study of patients with AKI, prevention or treatment of such processes could become a priority in AKI management. Treatment with phosphate binders and calcimimetics (Cinacalcet) has been shown to lower FGF-23 levels [49–51]. Treatments that are tailored more toward AKI-induced mineral dysregulation could be developed as further information is gathered about the exact role of FGF-23 in AKI. At present, there are no evidence-based guidelines about target goals for maintaining serum phosphorus levels. Treatments that improve the long-term outcomes of patients with AKI are needed, and dysregulated mineral metabolism, including FGF-23 levels, may represent a therapeutic target in AKI that is highly amenable to intervention.
There are several limitations in this study, including small sample size and relatively short follow-up time. Because FGF-23 levels were not measured repeatedly, duration of FGF-23 elevation also was unclear. Nevertheless, this is the first study to report an association between FGF-23 and non-rhabdomyolysis-related AKI, and that among patients with AKI, higher FGF-23 levels are associated with an increased risk of death. Larger and long-term studies should be conducted to clarify the impact of FGF-23 elevation among AKI patients.