Mechanism for the phosphaturia of NH4Cl: dependence on acidemia but not on diet PO4 or PTH

Abstract

The effects of metabolic acidosis on renal PO4 handling are controversial. Clearance experiments, therefore, were performed in fasted parathyroidectomized rats 1) to test the thesis that NH4Cl per se alters PO4 reabsorption, 2) to characterize the mechanisms responsible for these changes, and 3) to define the interaction of NH4Cl with parathyroid hormone (PTH) in PO4 deprivation. NH4Cl increased the clearance and fractional excretion of PO4 (FEPO4) without altering plasma PO4. Lactic acid and HCl, but not saline loading. NH4HCO3, or glutamine, produced similar effects. At steady-state phosphaturic effects of NH4Cl, neutralization of the acidemia by NaHCO3 abolished the increment. PTH (3.3 U.kg-1.h-1), superimposed on the maximal effective dose of NH4Cl (5.7 mmol.kg-1.h-1), further augmented FEPO4 (from 24.3 to 46.9%). The effects of NH4Cl (delta FEPO4 = 23 vs. 21%) and the synergism with PTH were not affected by PO4 deprivation. In both PO4 repletion and deprivation, NH4Cl increased basal and PTH-stimulated cAMP excretion, but the changes were poorly correlated with FEPO4. We conclude that NH4Cl inhibits PO4 reabsorption independent of PTH, extracellular fluid volume, natriuresis, NH4+ ion, plasma PO4, or the status of PO4 balance. The effects are mediated by mechanisms dependent on acidemia but are quite distinct from those of PTH. Our findings on cAMP are most compatible with the hypothesis that biochemical events beyond cAMP generation mediate both the phosphaturia of NH4Cl and its ability to restore PTH sensitivity in PO4 deprivation.

Acute metabolic acidosis enhances circulating parathyroid hormone, which contributes to the renal response against acidosis in the rat.

“…Also, acute metabolic acidosis after a 90-min infusion of either HC1 or ammonium chloride in acutely TPTX rats did not modify urinary phosphate excretion or phosphate absorption by the proximal convoluted tubule microperfused in vivo (35). However, in another study in chronically PTX rats, a 3-h infusion of ammonium chloride resulted in a significant increase in the urinary phosphate fractional excretion, which was attributed to acidemia-related undefined factors other than PTH (36).…”

Compensatory regulation of the sodium/phosphate cotransporters NaPi-IIc (SCL34A3) and Pit-2 (SLC20A2) during Pi deprivation and acidosis

“…Phosphaturia is a hallmark of metabolic acidosis, and it originates from either a low reabsorption rate of bonederived Pi protonation [8,10] or a reduction of Pi transporter expression in the brush-border membrane [1,15]. Previous works have reported a reduction of NaPi-IIa abundance in rat kidney BBMV [1], or conversely, they have reported increases in the expression of both NaPi-IIa and NaPi-IIc [15].…”

Regulation of phosphate transport in proximal tubules

“…Such a pH-dependence may have to be considered when assessing renal excretion of P i under conditions of an altered acid base status of the body [46,87]. In contrast, the predicted maximum transport velocity for Pit-1/2-mediated Na + /P i cotransport is quite constant within this pH range [93].…”