The regulation of plasma phosphate levels involves various hormones and factors. Parathyroid hormone (PTH) plays a crucial role in controlling phosphate excretion. It inhibits phosphate reabsorption in the proximal tubule, leading to increased phosphate excretion. Additionally, PTH stimulates the removal of Na+/Pi transporters from the brush border membrane of the proximal tubule, further reducing phosphate reabsorption. Fibroblast growth factor 23 (FGF-23) is another important hormone involved in phosphate regulation. Elevated plasma phosphate levels increase FGF-23, which inhibits both phosphate reabsorption and calcitriol production by the proximal tubule, resulting in decreased intestinal phosphate reabsorption.

Dietary phosphate intake also affects phosphate excretion independently of PTH levels. Increased phosphate loading leads to increased excretion, while phosphate depletion reduces excretion. The transport rate and number of Na+/Pi symporters in the apical membrane of the proximal tubule are modulated by changes in dietary phosphate intake.

Expansion of the extracellular fluid volume (ECFV) enhances phosphate excretion through multiple mechanisms. Firstly, it increases glomerular filtration rate (GFR), thereby increasing the filtered load of phosphate. Secondly, it reduces Na+/Pi coupled reabsorption, which in turn decreases ECFV. Finally, it decreases plasma calcium levels, resulting in increased PTH secretion and inhibition of phosphate reabsorption in the proximal tubule. Acid-base balance also influences phosphate excretion. Chronic acidosis increases phosphate excretion, while chronic alkalosis decreases it. These effects are mediated by changes in the expression of Na+/Pi symporters in the apical membrane. Systemic acidosis stimulates glucocorticoid secretion, which inhibits phosphate reabsorption in the proximal tubule. Additionally, growth hormone decreases phosphate excretion.

Klotho, a protein highly expressed in the early distal tubule of the kidney, plays a crucial role in phosphate regulation. Klotho acts as a coreceptor for FGF-23 and promotes phosphate excretion by the kidneys while reducing levels of 1,25-dihydroxyvitamin D3. It also has other functions, including modulation of ion transport, inhibition of renin-angiotensin signaling, and regulation of FGF-23's effect on PTH production. Experimental data suggest that Klotho may serve as a biomarker for chronic kidney disease (CKD) and that Klotho deficiency may contribute to the development of CKD. Furthermore, Klotho therapy shows promise in slowing the progression of CKD.
PTH Decrease FGF-23 Decrease Phosphate loading Decrease Phosphate depletion Increase Metabolic acidosis: chronic Decrease Metabolic alkalosis: chronic Increase ECFV expansion Decrease Growth hormone Increase Glucocorticoids Decrease • Fig. 36.20 Overview of the major hormones regulating plasma [Pi]. FGF-23, fibroblast growth factor 23; PTH, parathyroid hormone. Dashed lines indicate negative feedback. (From Koeppen BM, Stanton BA. Renal Physiology. 5th ed. Philadelphia: Elsevier; 2013.) plasma [Ca++] and therefore increases plasma PTH, which increases Pi excretion by the kidneys. PTH, the most important hormone that controls Pi excretion, inhibits Pi reabsorption by the proximal tubule and thereby increases Pi excretion. PTH reduces Pi reabsorption by stimulating endocytic removal of Na+/Pi transporters from the brush border membrane of the proximal tubule. Increased plasma Pi also increases FGF-23, which inhibits Pi reabsorption and calcitriol production by the proximal tubule. Elevated plasma Pi also suppresses calcitriol production, which results in a decrease in intestinal Pi reabsorption. Dietary Pi intake also regulates Pi excretion by mechanisms unrelated to changes in PTH levels. Pi loading increases excretion, whereas Pi depletion decreases it. Changes in dietary Pi intake modulate Pi transport by altering the transport rate of each Na+/Pi symporter and the number of symporters in the apical membrane of the proximal tubule.
ECFV also affects Pi excretion. Expansion of the ECF enhances Pi excretion by: (1) increasing GFR and thus the filtered load of Pi; (2) decreasing Na/Pi coupled reabsorption, which reduces ECFV, and (3) reducing plasma [Ca++], thereby increasing PTH, which inhibits Pi reabsorption in the proximal tubule. Acid-base balance also influences Pi excretion; chronic acidosis increases Pi excretion, and chronic alkalosis decreases it. These effects of acid-base balance, like the effect of PTH, are mediated by changes of expression of the Na /Pi symporters in the apical membrane. Systemic acidosis increases glucocorticoid secretion, and glucocorticoids increase excretion of Pi by inhibiting Pi reabsorption by the proximal tubule. This inhibition, together with the direct effect of acidosis on Pi reabsorption by the proximal tubule, enables the distal tubule and collecting duct to secrete more H+ as titratable acid and to generate more HCO3 − because Pi is an important urinary buffer. Growth hormone decreases Pi excretion.
Klotho, which was identified in 1997, is highly expressed in the early distal tubule of the kidney. Klotho knockout mice have a phenotype that resembles chronic kidney disease (CKD), including soft tissue calcification, hyperphosphatemia, and elevated plasma FGF-32. Klotho exists as both a membrane-bound and a soluble protein. The membrane-bound form is a coreceptor for FGF-23, thus Klotho promotes Pi excretion by the kidneys and reduces serum levels of 1,25-dihydroxyvitamin D3. Soluble circulating Klotho has a number of additional functions, including modulating ion transport and Wnt signal transduction, inhibiting reninangiotensin signaling, and modulating FGF-23 regulation of PTH production. A considerable body of experimental data suggests that Klotho may be a biomarker for CKD, and that Klotho deficiency may contribute to development of CKD. Moreover, experimental data also suggest that Klotho therapy may slow the progression of CKD.