The Human Response to Acute Enteral and Parenteral Phosphate Loads

Abstract

The human response to acute phosphate (PO4) loading is poorly characterized, and it is unknown whether an intestinal phosphate sensor mechanism exists. Here, we characterized the human mineral and endocrine response to parenteral and duodenal acute phosphate loads. Healthy human participants underwent 36 hours of intravenous (IV; 1.15 [low dose] and 2.30 [high dose] mmol of PO4/kg per 24 hours) or duodenal (1.53 mmol of PO4/kg per 24 hours) neutral sodium PO4 loading. Control experiments used equimolar NaCl loads. Maximum PO4 urinary excretory responses occurred between 12 and 24 hours and were similar for low-dose IV and duodenal infusion. Hyperphosphatemic responses were also temporally and quantitatively similar for low-dose IV and duodenal PO4 infusion. Fractional renal PO4 clearance increased approximately 6-fold (high-dose IV group) and 4-fold (low-dose IV and duodenal groups), and significant reductions in plasma PO4 concentrations relative to peak values occurred by 36 hours, despite persistent PO4 loading. After cessation of loading, frank hypophosphatemia occurred. The earliest phosphaturic response occurred after plasma PO4 and parathyroid hormone concentrations increased. Plasma fibroblast growth factor-23 concentration increased after the onset of phosphaturia, followed by a decrease in plasma 1,25(OH)2D levels; a-Klotho levels did not change. Contrary to results in rodents, we found no evidence for intestinal-specific phosphaturic control mechanisms in humans. Complete urinary phosphate recovery in the IV loading groups provides evidence against any important extrarenal response to acute PO4 loads. Plasma phosphate (PO4) concentration is regulated within narrow limits and is the result of intestinal absorption, influx into and efflux from bone, renal excretion, and modest intestinal secretion. 1 Rapid changes in transcellular distribution are effected primarily by systemic acid-base equilibrium and hormones such as insulin and catecholamines. 2 1,25(OH) 2 D stimulates intestinal PO4 absorption, 4 while parathyroid hormone (PTH) and osteocytederived fibroblast growth factor-23 (FGF-23) are the best-characterized phosphaturic factors. Both inhibit proximal tubular sodium-dependent PO4 reabsorption (via Na/PO4 cotransport, NaPi2a and NaPi2c). 5,6 In addition, a-Klotho is a renal transmembrane and secreted protein that functions as an FGF-23 coreceptor and is phosphaturic independently of However, the relative roles of other phosphaturic agents, such as secreted frizzled related protein (sFRP-4), matrix extracellular phosphoglycoprotein, and FGF-8 are not yet defined in humans.1,25(OH) 2 D, PTH, and FGF-23 regulate PO4 metabolism within a complex system of positive and negative feedback mechanisms (for review, see Bergwitz and Jüppner 8 ). Increases in plasma PO4 concentration stimulate PTH secretion, while proximal tubule 1a-hydroxylase and, therefore,

Acute Adaption to Oral or Intravenous Phosphate Requires Parathyroid Hormone

“…However, there are conflicting data regarding the sequence of events triggered by high dietary Pi as well as the nature of the trigger itself. PTH may have a key role in the acute renal response, with other hormones coming into play only later on, 23,[32][33][34] but the presence of yet-unidentified intestinal factor(s) stimulating renal Pi excretion independent from PTH has been proposed. 22 Here, we administered a Pi load to rats both intravenously (to bypass the gastrointestinal tract) and intragastrically and compared the acute responses in intact and PTX animals.…”

“…Whether the response to Pi is independent from calcium has remained unclear, because Pi retains its ability to stimulate PTH secretion, even in the absence of a measurable fall in ionized or total calcium. [23][24][25]33,38 Along the same line, in vitro incubation of human parathyroid glands with escalating concentrations of Pi while keeping ionized calcium constant stimulated PTH secretion. 24,38 However, inhibitors of calcium-stimulated receptormediated PTH secretion (calcimimetics) have been shown to suppress Pi-induced PTH secretion in vivo, suggesting a role of the calcium-stimulated receptor, even in the absence of changes of ionized calcium levels.…”

“…The early response of PTH found in our animal model is consistent with experiments in humans and other rodent models. 23,32,33 PTH is critical for the early response to Pi, independent from the route of application. In PTX rats, massive and sustained hyperphosphatemia developed with a more pronounced fall in plasma total calcium than in intact rats.…”

“…Thus, in contrast to rodents, the human data are not consistent with the presence of an intestinal Pi sensor. 23 Local Pi sensing mechanisms in kidney and other organs may be involved in sensing changes in dietary Pi intake and may mediate or modulate some of the effects on renal Pi handling. Evidence for Pi sensing has been obtained from isolated parathyroid gland cells in vitro, 24,25 the opossum kidney-derived OK cell line, 26,27 bone, and vascular cells [28][29][30] The aim of this study was to investigate the endocrine, mineral, and renal responses to acute Pi loading in rats and test for evidence for a role of the intestine in determining the adaptive response by administering Pi either intravenously or intragastrically.…”

Mineral (Mal)Adaptation to Kidney Disease—Young Investigator Award Address

“…Interestingly, the latter does not appear to be mediated by intermediate changes in serum phosphate, which does not clearly regulate FGF-23 directly (32)(33)(34). Indeed, the mechanism of how dietary phosphate intake stimulates bone production of FGF-23 remains unknown.…”