Phosphate plays a critical role in the body as a constituent of bone and as a urinary buffer for H+. Because the kidneys regulate the blood phosphate concentration, the renal mechanisms deserve special attention. (Overall phosphate homeostasis and its hormonal regulation are discussed in Chapter 9.)
Phosphate is localized primarily in bone matrix (85%), and the remainder of the body phosphate is divided between ICF (15%) and ECF (<0.5%). In ICF, phosphate is a component of nucleotides (DNA and RNA), high-energy molecules (e.g., ATP), and metabolic intermediates. In ECF, phosphate is present in its inorganic form and serves as a buffer for H+. About 10% of the phosphate in plasma is protein bound.
The renal handling of phosphate is illustrated in Figure 6-33. Phosphate that is not bound to plasma proteins (90%) is filtered across glomerular capillaries. Subsequently, about 70% of the filtered load is reabsorbed in the proximal convoluted tubule, and 15% of the filtered load is reabsorbed in the proximal straight tubule. At the cellular level, phosphate reabsorption is accomplished by an Na+-phosphate cotransporter in the luminal membrane of the proximal tubule cells (see Fig. 6-20). Similar to the reabsorption of glucose, phosphate reabsorption is saturable and exhibits a Tm. When the Tm is reached, any phosphate that is not reabsorbed will be excreted. Whether phosphate is reabsorbed in later segments of the nephron (e.g., distal tubule) is debatable, but it seems to depend on the level of dietary phosphate and parathyroid hormone. When compared with other substances (e.g., Na+, Cl−, HCO3−, glucose), phosphate excretion of 15% of the filtered load is a high percentage. The comparatively high level of phosphate excretion is physiologically important because unreabsorbed phosphate serves as a urinary buffer for H+ (called titratable acid; see Chapter 7).
Figure 6–33 Phosphate handling in the nephron. Arrows show location of phosphate reabsorption; numbers are percentages of the filtered load reabsorbed or excreted. PTH, Parathyroid hormone.
Parathyroid hormone (PTH) regulates the reabsorption of phosphate in the proximal tubule by inhibiting Na+-phosphate cotransport, thereby decreasing the Tm for phosphate reabsorption. When PTH inhibits phosphate reabsorption, it causes phosphaturia, or increased phosphate excretion. In the context of this action, it is significant that little or no phosphate reabsorption occurs beyond the proximal tubule. PTH inhibits phosphate reabsorption in the proximal tubule, and the unreabsorbed phosphate then is excreted because segments beyond the proximal tubule have little or no reabsorptive capacity for phosphate.
At the cellular level, the mechanism of action of PTH involves binding of hormone to a basolateral receptor in the proximal tubule cells, which is coupled to adenylyl cyclase via a Gs protein. When activated, adenylyl cyclase catalyzes the conversion of ATP to cyclic adenosine monophosphate (cAMP), the second messenger. cAMP then activates a series of protein kinases, which phosphorylate components of the luminal membrane. The final step in this sequence is inhibition of Na+-phosphate cotransport. As an aside, the luminal membrane of proximal tubule cells has a transporter for cAMP, so cAMP moves into the lumen and is excreted. Increased urinary cAMP and phosphaturia are the hallmarks of PTH action.
A defect in the receptor, Gs protein, or adenylyl cyclase complex causes an inherited disorder called pseudohypoparathyroidism. In this disorder, renal cells are resistant to the action of PTH. Although circulating PTH levels are elevated, PTH cannot produce its usual phosphaturic effect, and both urinary phosphate and cyclic AMP are decreased.
Like phosphate, most of the body’s calcium (Ca2+) is contained in bone (99%). The remaining 1% is present in ICF (mostly in bound form) and in ECF. The total Ca2+ concentration in plasma is 5 mEq/L or 10 mg/dL. Of the total plasma Ca2+, 40% is bound to plasma proteins, 10% is bound to other anions such as phosphate and citrate, and 50% is in the free, ionized form. The plasma Ca2+ concentration is regulated by PTH, involving a complex interaction of bone, the gastrointestinal tract, and the kidneys. Like phosphate, the renal mechanisms are an integral part of overall Ca2+ homeostasis, as discussed in Chapter 9.
The renal handling of Ca2+ is illustrated in Figure 6-34. The pattern of Ca2+ reabsorption along the nephron is quite similar to the pattern for Na+ reabsorption (see Fig. 6-19). Like Na+, over 99% of the filtered Ca2+ is reabsorbed, leaving less than 1% to be excreted. Ca2+ reabsorption is tightly coupled to Na+ reabsorption in the proximal tubule and loop of Henle, and only in the distal tubule is the reabsorption of the two ions dissociated.
Figure 6–34 Ca2+ handling in the nephron. Arrows show location of Ca2+ reabsorption; numbers are percentages of the filtered load reabsorbed or excreted. PTH, Parathyroid hormone.
Filtration. Ca2+ differs from Na+ at the filtration step. Any Ca2+ bound to plasma proteins (i.e., 40% of the total Ca2+) cannot be filtered across glomerular capillaries; therefore, only 60% is ultrafilterable.To calculate the filtered load of Ca2+, a correction is made for protein binding: If GFR is 180 L/day and total plasma Ca2+ is 5 mEq/L, then the filtered load of Ca2+ is 540 mEq/day (180 L/day × 5 mEq/L × 0.60).
Proximal tubule. Ca2+ parallels Na+ reabsorption in the proximal tubule in that 67% of the filtered load is reabsorbed (exactly the same percentage as Na+ reabsorption). In fact, Ca2+ reabsorption is tightly coupled to Na+reabsorption in the proximal tubule. For example, when Na+ reabsorption is inhibited by volume expansion, Ca2+ reabsorption is simultaneously inhibited; when Na+ reabsorption is stimulated by volume contraction, so is Ca2+reabsorption.
Thick ascending limb of the loop of Henle. As with Na+, 25% of the filtered load of Ca2+ is reabsorbed in the thick ascending limb of the loop of Henle. In this segment, Ca2+ reabsorption occurs along a paracellular route (between cells) and is tightly coupled to Na+ reabsorption. The mechanism of coupling in the thick ascending limb depends on the lumen-positive potential difference, which is generated by the Na+-K+-2Cl− cotransporter. This lumen-positive potential normally drives the reabsorption of divalent cations such as Ca2+, as positive charge repels positive charge. Coupling of Ca2+ and Na+reabsorption in the thick ascending limb has an important implication for diuretic action: Loop diuretics such as furosemide inhibit Ca2+ reabsorption to the same extent that they inhibit Na+ reabsorption. The mechanism is inhibition of Na+-K+-2Cl− cotransport and elimination of the lumen-positive potential, thereby eliminating the driving force for paracellular Ca2+ reabsorption. This action of loop diuretics underlies their usefulness in the treatment of hypercalcemia.
Distal tubule. The distal tubule reabsorbs about 8% of the filtered load of Ca2+. Although this is a quantitatively smaller amount than is reabsorbed in the earlier segments of the nephron, the distal tubule is the site of regulation of Ca2+ reabsorption. The following three points concerning regulation in the distal tubule are relevant: (1) The distal tubule is the only nephron segment in which Ca2+ reabsorption is notcoupled directly to Na+ reabsorption. In other words, Ca2+ reabsorption and Na+ reabsorption in the distal tubule are not necessarily parallel (as they are in the proximal tubule and the thick ascending limb). The uncoupling of Ca2+ and Na+ reabsorption in the distal tubule is illustrated by the action of thiazide diuretics (see point 3). (2) Not only is distal Ca2+ reabsorption uncoupled from Na+ reabsorption, but it has its own regulatory hormone, PTH. In the distal tubule, PTH increases Ca2+reabsorption via a basolateral receptor, activation of adenylyl cyclase, and generation of cAMP as the second messenger. This action of PTH on the distal tubule is called its hypocalciuric action. Thus, PTH has two effects on the nephron, both of which are mediated by cAMP: a phosphaturic action in the proximal tubule and a hypocalciuric action in the distal tubule. (3) Because of the uncoupling of distal Ca2+ and Na+ reabsorption, the effect of thiazide diuretics on Ca2+ reabsorption differs entirely from the effects of diuretics that act in the proximal tubule or thick ascending limb. Thiazide diuretics increase Ca2+ reabsorption, whereas the other classes of diuretics decrease it.
Recall that thiazide diuretics inhibit Na+ reabsorption in the early distal tubule by inhibiting Na+-Cl− cotransport, thereby increasing Na+ excretion. However, the effect on Ca2+ reabsorption is the exact opposite: Thiazide diuretics increase Ca2+ reabsorption, thereby decreasing Ca2+ excretion. This action of thiazides forms the basis for their usefulness in the treatment of idiopathic hypercalciuria (meaning increased urinary Ca2+ excretion of unknown etiology). Administration of thiazide diuretics increases Ca2+ reabsorption, decreases urinary Ca2+ excretion, and decreases the likelihood of Ca2+ stone formation.
In several respects, the pattern of magnesium (Mg2+) reabsorption differs from that of either Na+ or Ca2+. Overall reabsorption of Mg2+ by the nephron is 95%, leaving 5% for excretion, which is a higher percentage than for many other substances (Fig. 6-35). Twenty percent of plasma Mg2+ is bound to proteins, and 80% is filterable across glomerular capillaries. In the proximal tubule, 30% of the filtered load is reabsorbed, a small percentage when compared with Na+ and Ca2+ (67% for Na+ and Ca2+). In contrast to the other segments, the major site of Mg2+ reabsorption is the thick ascending limb, where 60% of the filtered load is reabsorbed. As with Ca2+, Mg2+ reabsorption in the thick ascending limb is driven by the lumen-positive potential difference. Here again, loop diuretics strongly inhibit Mg2+ reabsorption and increase Mg2+ excretion, which may lead to hypomagnesemia. In the distal tubule, a small percentage (5%) of Mg2+ is reabsorbed.
Figure 6–35 Mg2+ handling in the nephron. Arrows show location of Mg2+ reabsorption; numbers are percentages of the filtered load reabsorbed or excreted.