Acute Adaption to Oral or Intravenous Phosphate Requires Parathyroid Hormone

Abstract

Phosphate (Pi) homeostasis is regulated by renal, intestinal, and endocrine mechanisms through which Pi intake stimulates parathyroid hormone (PTH) and fibroblast growth factor-23 secretion, increasing phosphaturia. Mechanisms underlying the early adaptive phase and the role of the intestine, however, remain ill defined. We investigated mineral, endocrine, and renal responses during the first 4 hours after intravenous and intragastric Pi loading in rats. Intravenous Pi loading (0.5 mmol) caused a transient rise in plasma Pi levels and creatinine clearance and an increase in phosphaturia within 10 minutes. Plasma calcium levels fell and PTH levels increased within 10 minutes and remained low or high, respectively. Fibroblast growth factor-23, 1,25-(OH)2-vitamin D3, and insulin concentrations did not respond, but plasma dopamine levels increased by 4 hours. In comparison, gastric Pi loading elicited similar but delayed phosphaturia and endocrine responses but did not affect plasma mineral levels. Either intravenous or gastric loading led to decreased expression and activity of renal Pi transporters after 4 hours. In parathyroidectomized rats, however, only intravenous Pi loading caused phosphaturia, which was blunted and transient compared with that in intact rats. Intravenous but not gastric Pi loading in parathyroidectomized rats also led to higher creatinine clearance and lower plasma calcium levels but did not reduce the expression or activity of Pi transporters. This evidence suggests that an intravenous or intestinal Pi bolus causes rapid phosphaturia through mechanisms requiring PTH and downregulation of renal Pi transporters but does not support a role of the intestine in stimulating renal clearance of Pi. ABSTRACTPhosphate (Pi) homeostasis is regulated by renal, intestinal, and endocrine mechanisms through which Pi intake stimulates parathyroid hormone (PTH) and fibroblast growth factor-23 secretion, increasing phosphaturia. Mechanisms underlying the early adaptive phase and the role of the intestine, however, remain ill defined. We investigated mineral, endocrine, and renal responses during the first 4 hours after intravenous and intragastric Pi loading in rats. Intravenous Pi loading (0.5 mmol) caused a transient rise in plasma Pi levels and creatinine clearance and an increase in phosphaturia within 10 minutes. Plasma calcium levels fell and PTH levels increased within 10 minutes and remained low or high, respectively. Fibroblast growth factor-23, 1,25-(OH) 2 -vitamin D 3 , and insulin concentrations did not respond, but plasma dopamine levels increased by 4 hours. In comparison, gastric Pi loading elicited similar but delayed phosphaturia and endocrine responses but did not affect plasma mineral levels. Either intravenous or gastric loading led to decreased expression and activity of renal Pi transporters after 4 hours. In parathyroidectomized rats, however, only intravenous Pi loading caused phosphaturia, which was blunted and transient compared with that in intact rats. Intravenous but no...

Impaired Phosphate Tolerance Revealed With an Acute Oral Challenge

“…A recent study by Thomas and colleagues demonstrated that the acute phosphaturic response is dependent on PTH‐mediated downregulation of renal phosphate transporters . Our data indicate that the PTH response is dependent on the resting level of circulating PTH.…”

“…A recent study by Thomas and colleagues demonstrated that the acute phosphaturic response is dependent on PTHmediated downregulation of renal phosphate transporters. (6) Our data indicate that the PTH response is dependent on the resting level of circulating PTH. Specifically, it is the relative change after an oral phosphate load, rather than the absolute magnitude of the PTH change, that is positively correlated with the excretion of the circulating phosphate.…”

“…PTH is a major regulator of acute phosphate reabsorption, and its secretion into the circulation results in endocytosis and degradation of renal NPT2a transporters . A recent study demonstrated the marked attenuation of an acute phosphaturic response after an oral gavage of phosphate in parathyroidectomized rats, suggesting that PTH is critical to timely phosphate excretion . FGF‐23, another phosphaturic hormone, suppresses NPT2a transporter expression .…”

“…(5) A recent study demonstrated the marked attenuation of an acute phosphaturic response after an oral gavage of phosphate in parathyroidectomized rats, suggesting that PTH is critical to timely phosphate excretion. (6) FGF-23, another phosphaturic hormone, suppresses NPT2a transporter expression. (5) With declining kidney function, both hormones are recognized to play significant roles in the long-term homeostatic control of circulating phosphate by decreasing reabsorption.…”

Postprandial adjustments in renal phosphate excretion do not involve a gut‐derived phosphaturic factor

“…Our findings show that although the kidney responds to changes in intestinal phosphate load, the response appears to occur only following exposure to very high levels of ingested phosphate. Interestingly, a recent study by (Thomas et al 2016a) has shown that the phosphaturia caused by intravenous infusion of phosphate is associated with elevated plasma phosphate and PTH concentrations, but that while intragastric administration of the same phosphate load increases urinary phosphate excretion to the same extent as when given intravenously, it is related to elevated plasma PTH and not plasma phosphate concentrations, highlighting the key role for PTH in the phosphaturic response. In keeping with this suggestion is the finding that in humans, phosphaturia caused by an acute intestinal phosphate load is also associated with changes in plasma phosphate and PTH concentrations (Nishida et al 2006;Bevilacqua et al 2010;Scanni et al 2014).…”