Medical Physiology, 3rd Edition


The metabolism of inorganic phosphate (Pi) depends on bone, the gastrointestinal tract, and the kidneys (see p. 1054). About half of total plasma phosphate (Table 36-4) is in an ionized form, and the rest is either complexed to small solutes (~40%) or bound to protein (10% to 15%). The plasma concentration of total Pi varies rather widely, between 0.8 and 1.5 mM (2.5 to 4.5 mg/dL of elemental phosphorus). Thus, the filterable phosphate (i.e., both the ionized and complexed) varies between ~0.7 and 1.3 mM. At a normal blood pH of 7.4, 80% of the ionized plasma phosphate is image and the rest is image. Assuming that the total plasma phosphate concentration is 4.2 mg/dL, that only the free and complexed phosphate is filterable, and that the GFR is 180 L/day, each day the kidneys filter ~7000 mg of phosphate. Because this amount is more than an order of magnitude greater than the total extracellular pool of phosphate (see pp. 1054–1056), it is clear that the kidney must reabsorb most of the phosphate filtered in the glomerulus.

TABLE 36-4

Components of Total Plasma Phosphate





Ionized image and image




Diffusible phosphate complexes




Nondiffusible (protein-bound) phosphate




Total phosphate




The proximal tubule reabsorbs phosphate via apical Na/phosphate cotransporters

The proximal tubule reabsorbs 80% to 95% of the filtered phosphate (Fig. 36-14A). More distal nephron segments reabsorb a negligible fraction of the filtered phosphate. Thus, the kidneys excrete 5% to 20% of the filtered load of phosphate in the urine under normal conditions.


FIGURE 36-14 Phosphate handling by the kidney. In A, the numbered yellow boxes indicate the fraction of the filtered load that various nephron segments reabsorb. The green boxes indicate the fraction of the filtered load that remains in the lumen at various sites. The values in the boxes are approximations. In B, the top path illustrates reabsorption of divalent phosphate (image), and the bottom path illustrates the reabsorption of monovalent phosphate (image). PCT, proximal convoluted tubule; PST, proximal straight tubule.

The proximal tubule reabsorbs most of the filtered phosphate by the transcellular route (see Fig. 36-14B). Phosphate ions enter the cell across the apical membrane by secondary active transport, energized by the apical electrochemical Na+ gradient. At least three separate Na/phosphate cotransporters contribute: NaPi-IIa (SLC34A1; see Table 5-4), NaPi-IIc (SLC34A3) and PiT-2 (SLC20A2).

NaPi-IIa translocates three Na+ ions and one divalent phosphate ion (image). Thus, the process is electrogenic (net positive charge into the cell). imageN36-11 In contrast, NaPi-IIc is electroneutral, with a stoichiometry of two Na+ ions per one image. Because image rather than image is the preferred substrate of NaPi-IIc, low luminal pH inhibits phosphate reabsorption by shifting the phosphate equilibrium toward image. Of the three transporters, NaPi-IIc is most important in humans, based on the phosphate wasting and hypophosphatemia that occurs in patients with NaPi-IIc mutations. Finally, PiT-2 is electrogenic, with a stoichiometry of 2 Na+ ions per monovalent phosphate (image).


The Type II Na/Phosphate Cotransporter NaPi-IIa

Contributed by Jürg Biber

As noted in the text, the apical Na/phosphate cotransporter NaPi-IIa (SLC34A1; see Table 5-4) translocates three Na+ ions and one divalent phosphate ion (image), and thus the process is electrogenic. As pH along the lumen of the proximal tubule falls, the relative concentration of image falls as well, so that one might expect that the uptake of inorganic phosphate by NaPi-IIa would become less effective. On the other hand, the affinity of NaPi-IIa for image is so high (Ki ≅ 50 µM) that the effect should not be severe.

The passive exit of phosphate across the basolateral membrane occurs by mechanisms that are still unknown (see Fig. 36-14B).

Phosphate excretion in the urine already occurs at physiological plasma concentrations

Phosphate handling by the kidney shares some of the properties of renal glucose handling, including threshold, saturation with Tm kinetics, and splay (Fig. 36-15). However, important differences exist. First, some phosphate excretion (green curve) occurs even at normal levels of plasma [phosphate]. Thus, a small increment in the plasma [phosphate] results in significant acceleration of phosphate excretion (i.e., to higher values along the green curve), whereas plasma [glucose] must double before glucose excretion even commences. Second, the kidney reaches the Tm for phosphate (red curve) at the high end of normal plasma [phosphate] values, whereas the kidney reaches the Tm for glucose at levels that are far higher than physiological plasma [glucose] levels. Third, the renal phosphate Tm is sensitive to a variety of stimuli, including hormones and acid-base balance, whereas the glucose Tm is insensitive to regulators of glucose metabolism, such as insulin. Accordingly, the kidney plays an important role in the regulation of plasma [phosphate] but does not normally modulate plasma [glucose].


FIGURE 36-15 Phosphate titration curves. Tm is the transport maximum for reabsorption. The plasma phosphate concentration is the filterable phosphate (i.e., ionized plus complexed to small solutes). The dark vertical band is the approximate range of normal filterable values.

PTH inhibits apical Na/phosphate uptake, promoting phosphate excretion

Table 36-5 summarizes the major hormones and other factors that regulate phosphate transport by the proximal tubule.

TABLE 36-5

Factors that Modulate Phosphate Excretion






1,25-dihydroxyvitamin D

ECF volume expansion

ECF volume contraction



High dietary phosphate

Phosphate deprivation

High plasma [phosphate]







Thyroid hormone


Growth hormone



Phosphatonins (FGF23, sFRP4, MEPE)

Stanniocalcin-1 (STC1)







ECF, extracellular fluid; PTHrP, parathyroid hormone–related protein.

The most important hormonal regulator is PTH, which inhibits phosphate reabsorption (see p. 1062) and thus promotes phosphate excretion. PTH is a classic example of a rapid regulator that does not require protein synthesis. PTH binds to PTH 1 receptors (PTH1Rs), which appear to couple to two heterotrimeric G proteins (see p. 1061). The first (Gαs) activates adenylyl cyclase and, via cAMP, stimulates protein kinase A (PKA; see p. 57). The second (Gαq), particularly at low PTH levels, activates phospholipase C (PLC), and then protein kinase C (PKC; see pp. 60–61). Once activated, PKA and PKC promote endocytotic removal of NaPi from the apical membrane with targeting for degradation in lysosomes, which reduces phosphate reabsorption.

Another inhibitor of phosphate reabsorption is dopamine, which acts via D1 receptors and, like PTH, activates the cAMP/PKA pathway. High dietary phosphate intake decreases phosphate reabsorption, even without changes in PTH levels. Changes in plasma [phosphate], such as those that occur in phosphate depletion or loading, also modulate the surface expression of NaPi cotransporters. Both phosphate depletion and 1,25-dihydroxy-vitamin D (see pp. 1063–1065) upregulate the cotransporter. Glucocorticoid excess and metabolic acidosis downregulate the cotransporter; the latter effect is synergistic with the direct effects of H+ on the NaPi protein (see above). Because phosphate is the primary pH buffer in normal urine, factors that increase urinary [phosphate] (e.g., acidosis) increase the titratable acidity component of renal acid excretion (see p. 823).

Fibroblast growth factor 23 and other phosphatonins also inhibit apical Na/phosphate uptake, promoting phosphate excretion

Phosphatonins are the circulating factors that cause renal phosphate wasting in diseases such as oncogenic osteomalacia, autosomal dominant hypophosphatemic rickets, and X-linked hypophosphatemic rickets. In these diseases, phosphatonins—including fibroblast growth factor 23 (FGF23), secreted frizzled-related protein 4 (sFRP4), and matrix extracellular phosphoprotein (MEPE)—cause the kidneys to excrete more phosphate.

FGF23 has emerged as a particularly important phosphate-regulating hormone. In response to hyperphosphatemia, osteocytes release FGF23, which acts via the receptor tyrosine kinase FGFR1 (see p. 787) and the coreceptor KlothoimageN36-12 to reduce the expression of Na/phosphate cotransporters and thereby augment renal phosphate excretion. In addition, FGF23 decreases the renal production of 1,25-dihydroxyvitamin D and thus results in reduced phosphate absorption by the small intestine (see p. 1065).



Contributed by Emile L. Boulpaep, Walter F. Boron

The KL gene encodes two transcripts: a membrane protein with a single transmembrane segment (and related to β-glucosidase) and a secretory form. The transmembrane variant of Klotho associates with FGFR1 and acts as a coreceptor for FGF23. The secreted variant of Klotho, which is important in the resistance to aging (see p. 1247), is the result of ectodomain shedding.


Matsumura Y, Aizawa H, Shiraki-Iida T, et al. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun. 1998;242:626–630.