Advisory Committee Chair
Advisory Committee Members
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Chronic kidney disease (CKD) is a global health threat that increases risk of death, which is credible to both impaired renal function and a multitude of CKD- associated comorbidities such as systemic inflammation, anemia and skeletal muscle dys- function. A distinctive feature of CKD is the dysregulation of mineral metabolism, where excess serum levels of phosphate (hyperphosphatemia) and of fibroblast growth factor 23 (FGF23) are not only viewed as biomarkers for disease severity but also exert deleterious effects towards various CKD-associated pathologies. Elevated levels of FGF23 can lead to the activation of FGF receptor 4 (FGFR4) in cell types that lack the canonical FGF23 co-receptor, α-klotho, such as hepatocytes, thereby contributing to elevated serum levels of inflammatory cytokines. Unlike this non-canonical hepatic FGF23 effect, whether hy- perphosphatemia by itself or in the context of CKD have direct pathologic effects on hepatocytes, has not been investigated to date. In addition, the dysregulation of FGF23 and phosphate still lacks direct mechanistic evidence distinguishing their roles towards functional iron deficiency (FID) and skeletal muscle wasting. Utilizing mouse models with coinciding states of hyperphosphatemia, in the absence and presence of CKD, we document how non-canonical FGF23/FGFR4-mediated signaling versus excess extracellular phosphate contributes to these two specific comorbidities. We show that independently of amplified FGF23/FGFR4-mediated signaling in vivo, elevations in liver and serum phosphate levels transpire following a high dietary phosphate load or CKD and act as triggers toward these debilitating CKD-associated pa- thologies. Exclusively, high extracellular phosphate activates NFkB signaling in primary cultured hepatocytes to stimulate the production of pro-inflammatory cytokines and hep- cidin, thereby contributing to FID as well as widespread tissue injury, such as skeletal muscle wasting. Our study suggests that establishing novel therapeutics targeting these hyperphosphatemic actions or enhancing the awareness of phosphate-based additives in the food industry to reduce hyperphosphatemia, may ultimately improve the survival of patients with CKD.
Czaya, Brian Anthony, "Hyperphosphatemia Contributes To Functional Iron Deficiency And Skeletal Muscle Wasting" (2021). All ETDs from UAB. 768.