Effects of acute kidney injury and chronic hypoxemia on fibroblast growth factor 23 levels in pediatric cardiac surgery patients

Abstract

Background FGF23 levels are elevated in cardiopulmonary bypass (CPB)-associated acute kidney injury (AKI); however, it is unknown how much of the circulating FGF23 is intact and bioactive. Hypoxia may induce FGF23 production, yet its impact in humans is unknown. Pediatric cardiac surgery patients have both a high incidence of CPB-associated AKI and a high prevalence of chronic hypoxemia. Methods We assessed the effects of hypoxemia and CPB-associated AKI on C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels in 32 pediatric cardiac surgery patients with normal eGFR. Plasma cFGF23 and iFGF23 were measured pre-operatively and serially post-operatively. Results Despite normal renal and ventricular function, pre-operative cFGF23 levels were high and elevated out of proportion to iFGF23 levels. Pre-operative oxygen saturation measurements correlated inversely with FGF23 levels. Pre-operative cFGF23 and oxygen saturation both predicted post-operative AKI. Post-operatively, cFGF23 and iFGF23 increased by 2 hours post-reperfusion; iFGF23 then returned to baseline, but cFGF23 remained elevated through 24 hours post-reperfusion. Group status (AKI vs. non-AKI) modified the effect of time on changes in iFGF23 levels, but not cFGF23 levels. Conclusions Pre-operative cFGF23 may predict CPB-associated kidney dysfunction. Changes over time in cFGF23 and iFGF23 levels post-CPB differ. Chronic hypoxemia may affect FGF23 production in humans.

Fibroblast Growth Factor 23 and Klotho in AKI

“…Interestingly, the area under the receiver operating characteristic curve, a measure of the predictive performance of an exposure, was higher for plasma cFGF23 (0.78) at the end of cardiopulmonary bypass compared with several urinary injury biomarkers, including neutrophil gelatinase-associated lipocalin (0.61), kidney injury molecule-1 (0.65), and n-acetyl-b-(D)-glucosaminidase (0.60). 99 Early increase of circulating FGF23 in patients with AKI after cardiac surgery also has been reported by other investigators, including in infants 111 and in children 100 (Table 2).…”

“…Similar findings were reported by Hanudel et al in a cohort of 32 children undergoing cardiac surgery. 100 These data are consistent with marked increases in both the production and cleavage of FGF23 in AKI. Similar findings have been reported in mice exposed to acute inflammatory stimuli, and in animal and human studies of iron-deficiency anemia.…”

Fibroblast Growth Factor 23 Expression Is Increased in Multiple Organs in Mice With Folic Acid-Induced Acute Kidney Injury

“…Increase in cFGF23 levels is independent of changes in plasma PTH, phosphate and vitamin D metabolites ( Leaf et al, 2016 ). In pediatric and adult patients with AKI following cardiac surgery, there is a transient increase in plasma intact FGF23 (iFGF23) levels which subsequently normalize ( Hanudel et al, 2016 ; Leaf et al, 2016 ). Preoperative plasma cFGF23 levels in pediatric and adult patients undergoing cardiac surgery are associated with increased risk of AKI and post-operative mortality ( Speer et al, 2015 ; Hanudel et al, 2016 ).…”

“…In pediatric and adult patients with AKI following cardiac surgery, there is a transient increase in plasma intact FGF23 (iFGF23) levels which subsequently normalize ( Hanudel et al, 2016 ; Leaf et al, 2016 ). Preoperative plasma cFGF23 levels in pediatric and adult patients undergoing cardiac surgery are associated with increased risk of AKI and post-operative mortality ( Speer et al, 2015 ; Hanudel et al, 2016 ). Although, pre- and post-operative cFGF23 levels serve as prognostic tools to predict post-operative AKI severity and complications ( Speer et al, 2015 ; Leaf et al, 2016 ), the mechanisms by which FGF23 levels increase in AKI are poorly understood.…”

Potential targeted therapy and diagnosis based on novel insight into growth factors, receptors, and downstream effectors in acute kidney injury and acute kidney injury-chronic kidney disease progression

“…11,47,48 Clinical evidence confirmed that FGF-23 levels significantly increase in infants, children, adults, and older individuals suffering AKI. [49][50][51][52][53] FGF-23 is not only an early prognostic marker for cardiac surgeryassociated AKI and intensive care unit (ICU)-associated AKI but also serves as a prognostic marker for adverse outcomes in patients with established AKI. 11 Several studies have revealed the mechanisms underlying the upregulation of FGF-23 in AKI.…”