Can features of phosphate toxicity appear in normophosphatemia?

Abstract

Phosphate is an indispensable nutrient for the formation of nucleic acids and the cell membrane. Adequate phosphate balance is a prerequisite for basic cellular functions ranging from energy metabolism to cell signaling. More than 85% of body phosphate is present in the bones and teeth. The remaining phosphate is distributed in various soft tissues, including skeletal muscle. A tiny amount, around 1% of total body phosphate, is distributed both in the extracellular fluids and within the cells. Impaired phosphate balance can affect the functionality of almost all human systems, including muscular, skeletal, and vascular systems, leading to an increase in morbidity and mortality of the involved patients. Currently, measuring serum phosphate level is the gold standard to estimate the overall phosphate status of the body. Despite the biological and clinical significance of maintaining delicate phosphate balance, serum levels do not always reflect the amount of phosphate uptake and its distribution. This article briefly discusses the potential that some of the early consequences of phosphate toxicity might not be evident from serum phosphate levels.

Fig. 1

Phosphate distribution in various compartments of the body. Please note that circulating serum phosphate measurement estimates only a tiny pool of total body phosphate

Fig. 2

Simplified diagram showing multi-organ interactions in regulation of phosphate homeostasis. Fibroblast growth receptor (FGF)23 produced in the bone cells can suppress renal NaPi-2a and NaPi-2c co-transporter activities to increase the urinary excretion of phosphate. Similarly, FGF23 can also suppress renal expression of 1α (OH)ase to reduce production of 1,25-dihydroxyvitamin D [1,25(OH)₂D], which can suppress intestinal NaPi-2b activities to reduce phosphate absorption, resulting in decreased serum phosphate levels [3]. Of relevance, parathyroid hormone (PTH) can induce the expression of the 1α(OH)ase, and thereby can increase the production of 1,25(OH)₂D, which in turn can inhibit PTH and 1α(OH)ase expression. Such transcriptional repression feedback maintains vitamin D homeostasis. The figure is adopted with modification from our earlier publication [29]