Intact FGF23 and α-Klotho during acute inflammation/sepsis in CKD patients

Abstract

Background: High FGF23 and low α-Klotho levels associate with systemic inflammation and reduced nitric oxide (NO) bioavailability, but the dynamics of this relationship in patients with CKD has not been investigated.

Methods: We sequentially measured serum intact FGF23 and carboxyl-terminal (iFGF23, cFGF23), the iFGF23/cFGF23 ratio, αKlotho, biomarkers of inflammation (hs-CRP, IL-6 and TNF-α) and sepsis (procalcitonin), nitrotyrosine (reflecting NO synthesis and oxidative stress), serum iron and ferritin and CKD-MBD biomarkers, PTH, 25(OH)VD, 1,25(OH)2 VD at peak of intercurrent sepsis and after complete resolution in a series of 17 patients with CKD.

Results: At peak infection, biomarkers of inflammation/sepsis, ferritin and nitrotyrosine were all very high (all P < 0·01) and declined towards the normal range thereafter (P < 0·01). iFGF23 was 191 ± 10 pg/ml (geometric mean, SD) and doubled to 371 ± 8 pg/ml (P = 0·003) after the resolution of infection, while cFGF23 did not change (246 ± 5 pg/mL vs. 248 ± 5 pg/mL, P = 0·50). As a consequence, the iFGF23/cFGF23 ratio, an indicator of the proteolytic cleavage of the FGF23 molecule, was 0·78 ± 3·87 at peak infection and increased to 1·49 ± 3·00 after resolution of infection (P < 0·001). In contrast, serum α-Klotho levels were upregulated at peak infection (peak infection: 526 ± 4 pg/ml, postinfection: 447 ± 4 pg/ml, P = 0·001). The eGFR, PTH and vitamin D did not change significantly throughout.

Conclusions: Acute inflammation/sepsis suppresses the active form of FGF23 and activates α-Klotho, the latter effect being likely attributable to enhance proteolysis of FGF23 molecule. iFGF23 downregulation and α-Klotho upregulation during acute sepsis may participate into the counter-regulatory response to severe inflammation in CKD patients with sepsis.

Keywords: Acute inflammation; Klotho; carboxy FGF23; chronic kidney disease; intact FGF23; sepsis.