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


Hamid, Ahmad Kamal; Pastor Arroyo, Eva Maria; Calvet, Charlotte; Hewitson, Timothy D; Muscalu, Maria Lavinia; Schnitzbauer, Udo; Smith, Edward R; Wagner, Carsten Alexander; Egli-Spichtig, Daniela (2024). Phosphate Restriction Prevents Metabolic Acidosis and Curbs Rise in FGF23 and Mortality in Murine Folic Acid–Induced AKI. Journal of the American Society of Nephrology (JASN), 35(3):261-280.

Abstract

Background: In AKI, plasma FGF23 and P$_{i}$ rise rapidly and are independently associated with disease severity and outcome.
Methods: The effects of normal (NP) and low (LP) dietary P$_{i}$ 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 P$_{i}$-sensitive FGF23 expression in the bone but not in the thymus or spleen in FA-AKI and demonstrates that P$_{i}$ restriction mitigates CPP formation, inflammation, acidosis, and mortality in this model. These results suggest that dietary P$_{i}$ restriction could have prophylactic potential in patients at risk for AKI.

Abstract

Background: In AKI, plasma FGF23 and P$_{i}$ rise rapidly and are independently associated with disease severity and outcome.
Methods: The effects of normal (NP) and low (LP) dietary P$_{i}$ 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 P$_{i}$-sensitive FGF23 expression in the bone but not in the thymus or spleen in FA-AKI and demonstrates that P$_{i}$ restriction mitigates CPP formation, inflammation, acidosis, and mortality in this model. These results suggest that dietary P$_{i}$ restriction could have prophylactic potential in patients at risk for AKI.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Nephrology, General Medicine
Language:English
Date:1 March 2024
Deposited On:08 Feb 2024 09:14
Last Modified:29 Jun 2024 03:42
Publisher:American Society of Nephrology
ISSN:1046-6673
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1681/asn.0000000000000291
PubMed ID:38189228
Project Information:
  • : FunderSwiss National Centre of Competence in Research Kidney Control of Homeostasis
  • : Grant ID
  • : Project Title
  • : FunderSwiss National Centre of Competence in Research Kidney Control of Homeostasis
  • : Grant ID
  • : Project Title
  • : FunderFP7
  • : Grant ID115523
  • : Project TitleCOMBACTE-NET - Combatting Bacterial Resistance in Europe
  • : FunderOlga Mayenfisch Stiftung
  • : Grant ID
  • : Project Title
  • : FunderGottfried und Julia Bangerter-Rhyner-Stiftung
  • : Grant ID
  • : Project Title
  • : FunderSylvia and Charles Viertel Charitable Foundation
  • : Grant ID
  • : Project Title
  • Content: Accepted Version
  • Language: English
  • Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)