Phosphate Restriction Prevents Metabolic Acidosis and Curbs Rise in FGF23 and Mortality in Murine Folic Acid–Induced AKI

Abstract

Background In AKI, plasma FGF23 and Pi rise rapidly and are independently associated with disease severity and outcome. Methods The effects of normal (NP) and low (LP) dietary Pi were investigated in mice with FA-AKI after 3, 24, and 48 hours and 14 days. Results After 24 hours of AKI, the LP diet curbed the rise in plasma FGF23 and prevented that of parathyroid hormone and calcitriol as well as of osseous but not splenic or thymic Fgf23 mRNA expression. The absence of Pth prevented the rise in calcitriol and reduced the elevation of FGF23 in FA-AKI with the NP diet. Furthermore, the LP diet attenuated the rise in renal and plasma IL-6 and mitigated the decline in renal α-Klotho. After 48 hours, the LP diet further dampened renal IL-6 expression and resulted in lower urinary neutrophil gelatinase-associated lipocalin. In addition, the LP diet prevented the increased formation of CPPs. Fourteen days after AKI induction, the LP diet group maintained less elevated plasma FGF23 levels and had greater survival than the NP diet group. This was associated with prevention of metabolic acidosis, hypocalcemia, hyperkalemia, and cardiac electrical disturbances. Conclusions This study reveals Pi-sensitive FGF23 expression in the bone but not in the thymus or spleen in FA-AKI and demonstrates that Pi restriction mitigates CPP formation, inflammation, acidosis, and mortality in this model. These results suggest that dietary Pi restriction could have prophylactic potential in patients at risk for AKI.