Intact FGF23 and ?-klotho during acute inflammation/sepsis in CKD patients

BACKGROUND: High FGF23 and low ?Klotho levels associate with systemic inflammation and reduced nitric oxide (NO) bio-availability but the dynamics of this relationship in CKD patients has not been investigated. METHODS: We sequentially measured serum intact FGF23 and carboxyl-terminal (iFGF23, cFGF23), the iFGF23/cFGF23 ratio, ?Klotho, biomarkers of inflammation (hs-CRP, IL-6 and TNF?), 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 inter-current sepsis and after complete resolution in a series of 17 CKD patients. RESULTS: At peak infection, biomarkers of inflammation/sepsis, ferritin and nitrotyrosine were all very high (all P<0.01) and declined toward 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 ?Klotho levels were upregulated at peak infection (peak infection: 526±4 pg/ml; post-infection: 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 ?Klotho, the latter effect being likely attributable to enhanced proteolysis of FGF23 molecule. iFGF23 down-regulation and ?Klotho up-regulation during acute sepsis may participate into the counter-regulatory response to severe inflammation in CKD patients with sepsis.