Regulation Of Calcium And Phosphate Homeostasis
Ca++ and inorganic phosphate (Pi)* are multivalent ions that subserve many complex and vital functions.
Ca++ is an important cofactor in many enzymatic reactions, it is a key second messenger in numerous signaling pathways, it plays an important role in the excitability of nerve and muscle, signal transduction, blood clotting, and muscle contraction, and it is a critical component of the extracellular matrix, cartilage, teeth, and bone.
Pi, like Ca++, is a key component of bone. Pi is important for metabolic processes, including the formation of adenosine triphosphate, and it is an important component of nucleotides, nucleosides, and phospholipids. Phosphorylation of proteins is an important mechanism of cellular signaling, and Pi is an important buffer in cells, plasma, and urine.
In adults, the kidneys play important roles in regulating total body Ca++ and Pi by excreting the amount of Ca++ and Pi that is absorbed by the intestinal tract (normal bone remodeling results in no net addition of Ca++ and Pi to the bone or Ca++ and Pi release from the bone).
If the plasma concentrations of Ca++ and Pi decline substantially, intestinal absorption, bone resorption (i.e., the loss of Ca++ and Pi from bone), and renal tubular reabsorption increase and return plasma concentrations of Ca++ and Pi to normal levels.
During growth and pregnancy, intestinal absorption exceeds urinary excretion, and these ions accumulate in newly formed fetal tissue and bone.
In contrast, bone disease (For example osteoporosis) or a decline in lean body mass increases urinary Ca++ and Pi loss without a change in intestinal absorption. These conditions produce a net loss of Ca++ and Pi from the body.
Finally, during chronic renal failure, Pi accumulates in the body because absorption by the intestinal tract exceeds excretion in the urine.
This situation can lead to the accumulation of Pi in the body and changes in bone. The kidneys, in conjunction with the intestinal tract and bone, play a major role in maintaining plasma Ca++ and Pi levels and Ca++ and Pi balance.
Accordingly, this chapter discusses Ca++ and Pi handling by the kidneys, emphasizing the hormones and factors that regulate urinary excretion.
Calcium
Cellular processes in which Ca++ plays an important role include bone formation, cell division and growth, blood coagulation, hormone-response coupling, and electrical stimulus-response coupling (muscle contraction and neurotransmitter release).
A total of 99% of Ca++ is stored in bone and teeth, approximately 1% is found in the intracellular fluid (ICF), and 0.1% is located in the extracellular fluid (ECF). The total Ca++ concentration ([Ca++]) in plasma is 10 mg/dL (2.5 mmol/L, or 5 mEq/L), and its concentration is normally maintained within very narrow limits.
Approximately 50% of the Ca++ in plasma is ionized, 40% is bound to plasma proteins (mainly albumin), and 10% is complexed to several anions, including Pi, bicarbonate (HCO3–), citrate, and SO4=. The pH of plasma influences this distribution.
Acidemia increases the percentage of ionized Ca++ at the expense of Ca++ bound to proteins, whereas alkalemia decreases the percentage of ionized Ca++, again by altering the Ca++ bound to proteins.
Persons with alkalemia are susceptible to tetany (tonic muscular spasms), whereas persons with acidemia are less susceptible to tetany, even when total plasma Ca++ levels are reduced.
The increase in [H+] in patients with metabolic acidosis causes more H+ to bind to plasma proteins, Pi, HCO3–, citrate, and SO4=, thereby displacing Ca++. This displacement increases the plasma concentration of ionized Ca++.
In alkalemia, the [H+] of plasma decreases. Some H+ ions dissociate from plasma proteins, Pi, HCO3–, citrate, and SO4= in exchange for Ca++, thereby decreasing the plasma concentration of ionized Ca++. In addition, the plasma albumin concentration also affects ionized plasma [Ca++].
Hypoalbuminemia increases the ionized [Ca++], whereas hyperalbuminemia decreases ionized plasma [Ca++]. The total measured plasma [Ca++] does not reflect the total ionized [Ca++], which is the physiologically relevant measure of plasma [Ca++].
A low ionized plasma [Ca++] (hypocalcemia) increases the excitability of nerve and muscle cells and can lead to hypocalcemic tetany.
Tetany associated with hypocalcemia occurs because hypocalcemia causes the threshold potential to shift to more negative values (i.e., closer to the resting membrane voltage.
![Regulation Of Calcium And Phosphate Homeostasis Effect of pH on plasma concentration of Ca++ ([Ca++]).](https://bdsnotes.com/wp-content/uploads/2024/07/Regulation-Of-Calcium-And-Phosphate-Homeostasis-Effect-of-pH-on-plasma-concentration-of-Ca-Ca.png)
An elevated ionized plasma [Ca++] (hypercalcemia) may decrease neuromuscular excitability or produce cardiac arrhythmias, lethargy, disorientation, and even death. This effect of hypercalcemia occurs because an elevated plasma [Ca++] causes the threshold potential to shift to less negative values (i.e., further from the resting membrane voltage).
Plasma [Ca++] is regulated within a very narrow range primarily by parathyroid hormone (PTH), calcitriol (1,25-dihydroxy vitamin D), the active metabolite of vitamin D3, and plasma Ca++.
Within cells, Ca++ is sequestered in the endoplasmic reticulum and mitochondria, or it is bound to proteins. Thus the free intracellular [Ca++] is very low (~100 nmol).
The large concentration gradient for [Ca++] across cell membranes is maintained by a Ca++–adenosine triphosphatase (ATPase) pump (PMCa1b) in all cells and by a 3Na+-Ca++ exchanger (NCX1) in some cells.
Overview of Ca++ Homeostasis Ca++ homeostasis depends on two factors: (1) the total amount of Ca++ in the body and (2) the distribution of Ca++ between bone and the ECF.
The total body Ca++ level is determined by the relative amounts of Ca++ absorbed by the intestinal tract and excreted by the kidneys.
The intestinal tract absorbs Ca++ through an active, carrier-mediated transport mechanism that is stimulated by calcitriol, the active metabolite of vitamin D3 that is produced in the proximal tubule of the kidneys.
Net Ca++ absorption by the intestine is normally 200 mg/day (5 mmol/day), but it can increase to 600 mg/ day (15 mmol/day) when calcitriol levels rise. In adults, Ca++ excretion by the kidneys equals the amount absorbed by the gastrointestinal tract (200 mg/day), and it changes in parallel with intestinal absorption.
Thus in adults, Ca++ balance is maintained because the amount of Ca++ ingested in an average diet (1000 mg/day or 25 mmol/day) equals the amount lost in the feces (800 mg/day or 20 mmol/day), the amount that escapes absorption by the intestinal tract, plus the amount excreted in the urine (200 mg/day).
The second factor that controls Ca++ homeostasis is the distribution of Ca++ between bone and the ECF.
Two hormones (PTH and calcitriol) regulate the distribution of Ca++ between bone and the ECF and thereby, in concert with the kidneys, regulate the plasma [Ca++]. PTH is secreted by the parathyroid glands, and its secretion is stimulated by a decline in the plasma [Ca++] (i.e., hypocalcemia).
Plasma Ca++ is an agonist of the calcium-sensing receptor (CaSR), which is located in the plasma membrane of chief cells in parathyroid glands (see the discussion that follows).
Hypercalcemia activates the CaSR, which decreases PTH release, whereas hypocalcemia reduces CaSR activity, which in turn increases PTH release.
PTH increases the plasma [Ca++] by (1) stimulating bone resorption, (2) increasing Ca++ reabsorption by the distal tubule of the kidney, and (3) stimulating the production of calcitriol, which in turn increases Ca++ absorption by the intestinal tract and facilitates PTH-mediated bone resorption.
The production of calcitriol in the kidney is stimulated by hypocalcemia and hypophosphatemia. Calcitriol increases the plasma [Ca++] primarily by stimulating Ca++ absorption from the intestinal tract. It also facilitates the action of PTH on bone and enhances Ca++ reabsorption in the kidneys by increasing the expression of key Ca++ transport and binding proteins in the kidneys.
In addition, hypercalcemia activates the CaSR in the thick ascending limb of Henle’s loop, inhibiting Ca++ reabsorption in this segment, which results in an increase in urinary Ca++ excretion and thereby reduces plasma [Ca++].
Hypocalcemia has the opposite effect. Importantly, the regulation of Ca++ excretion by the kidneys is one of the major ways that the body regulates plasma [Ca++].
Conditions that lower parathyroid hormone (PTH) levels (For example, hypoparathyroidism after parathyroidectomy for an adenoma) reduce plasma [Ca++], which can cause hypocalcemic tetany (intermittent muscular contractions). In severe cases, hypocalcemic tetany can cause death by asphyxiation.
Hypercalcemia also can cause lethal cardiac arrhythmias and decreased neuromuscular excitability.
Clinically, the most common causes of hypercalcemia are primary hyperparathyroidism and malignancy-associated hypercalcemia. Primary hyperparathyroidism results most often from the overproduction of PTH caused by a benign tumor of the parathyroid glands.
In contrast, malignancy-associated hypercalcemia, which occurs in 10% to 20% of all patients with cancer, is caused by the secretion of parathyroid hormone-related peptide, a PTH-like hormone secreted by carcinomas in various organs. Increased levels of PTH and parathyroid hormone-related peptides cause hypercalcemia and hypercalciuria.
Ca++ Transport Along the Nephron
Ca++ available for glomerular filtration consists of the ionized fraction and the amount complexed with anions. Thus about 60% of the Ca++ in the plasma is available for glomerular filtration. Normally, 99% of the filtered Ca++ is reabsorbed by the nephron.
The proximal tubule reabsorbs about 50% to 60% of the filtered Ca++. Another 15% is reabsorbed in the loop of Henle (mainly the cortical portion of the thick ascending limb), about 10% to 15% is reabsorbed by the distal tubule, and <1% is reabsorbed by the collecting duct.
About 1% (200 mg/ day) is excreted in the urine. This fraction is equal to the net amount absorbed daily by the intestinal tract. Ca++ reabsorption by the proximal tubule occurs primarily via the paracellular pathway.
This passive, paracellular reabsorption of Ca++ is driven by the lumen-positive transepithelial voltage across the second half of the proximal tubule and by a favorable concentration gradient of Ca++, both of which are established by transcellular sodium and water reabsorption in the first half of the proximal tubule. Ca++ reabsorption by the loop of Henle also occurs primarily via the paracellular pathway.
Like the proximal tubule, Ca++ and Na+ reabsorption in the thick ascending limb parallel each other.
These processes are parallel because of the significant component of Ca++ reabsorption that occurs via passive, paracellular reabsorption secondary to Na+ reabsorption that generates a lumen-positive transepithelial voltage.
Loop diuretics inhibit Na+ reabsorption by the thick ascending limb of the loop of Henle, and in so doing reduce the magnitude of the lumen-positive transepithelial voltage.
This action in turn inhibits the reabsorption of Ca++ via the paracellular pathway. Thus loop diuretics are used to increase renal Ca++ excretion in patients with hypercalcemia.
In the distal tubule, where the voltage in the tubule lumen is electrically negative to the blood, Ca++ reabsorption is entirely active because Ca++ is reabsorbed against its electrochemical gradient.
Thus Ca++ reabsorption by the distal tubule is exclusively transcellular. Calcium enters the cell across the apical membrane by a Ca++-permeable ion channel (TRPV5). Inside the cell, Ca++ binds to calbindin-D28k.
The calbindin-Ca++ complex carries Ca++ across the cell and delivers it to the basolateral membrane, where it is extruded from the cell primarily by the 3Na+/Ca++ antiporter (NCX1); however, the Ca++ ATPase (PMCA1b) also may contribute. Urinary Na+ and Ca++ excretion usually change in parallel.
However, the excretion of these ions does not always change in parallel because the reabsorption of Ca++ and Na+ by the distal tubule is independent and is differentially regulated.
For example, thiazide diuretics inhibit Na+ reabsorption by the distal tubule and stimulate Ca++ reabsorption by this segment. Accordingly, the net effects of thiazide diuretics are to increase urinary Na+ excretion and reduce urinary Ca++ excretion.
Accordingly, because thiazide diuretics reduce urinary Ca++ excretion, they often are given to reduce the urinary [Ca++] in persons who produce kidney stones that contain Ca++.
Mutations in the tight junction protein claudin-16
(CLDN16) alter the diffusive movement of Ca++ across tight junctions in the thick ascending limb of Henle’s loop.
Familial hypomagnesemic hypercalciuria, an autosomal recessive disorder, is caused by mutations in claudin-16 (previously termed paracellin 1 [PCLN1]), a protein that is a component of the tight junctions in thick ascending limb cells.
This disorder is characterized by enhanced excretion of Ca++ and Mg++ because of a decrease in the passive reabsorption of these ions across the paracellular pathway in the thick ascending limb.
The mutation in the claudin-16 gene reduces the permeability of the paracellular pathway to Ca++ and Mg++, thereby reducing the passive, paracellular reabsorption of both ions. These persons have high levels of Ca++ in their urine, which leads to stone formation (nephrolithiasis).
Regulation of Urinary Ca++ Excretion
Several hormones and factors influence urinary Ca++ excretion Of these hormones and factors, PTH exerts the most powerful control on renal Ca++ excretion, and it is the primary hormone/factor responsible for maintaining Ca++ homeostasis.
Overall, this hormone stimulates Ca++ reabsorption by the kidneys (i.e., reduces Ca++ excretion).
Although PTH inhibits the reabsorption of NaCl and fluid, and therefore Ca++ reabsorption by the proximal tubule, PTH stimulates Ca++ reabsorption by the thick ascending limb of the loop of Henle and the distal tubule.
Thus the net effect of PTH is to enhance renal Ca++ reabsorption. Changes in the plasma [Ca++] also regulate urinary Ca++ excretion, with hypercalcemia increasing excretion and hypocalcemia decreasing excretion.
Hypercalcemia increases urinary Ca++ excretion by
- Reducing proximal tubule Ca++ reabsorption (reduced paracellular reabsorption due to increased interstitial fluid [Ca++);
- Inhibiting Ca++ reabsorption by the thick ascending limb of the loop of Henle via activation of the CaSR located in the basolateral membrane of these cells (NaCl reabsorption is decreased, thereby reducing the magnitude of the lumen-positive transepithelial voltage); and
- Suppressing Ca++ reabsorption by the distal tubule by reducing PTH levels.
As a result, urinary Ca++ excretion increases. Hypocalcemia has the opposite effect on urinary Ca++ excretion, primarily by increasing Ca++ reabsorption by the proximal tubule and thick ascending limb.
Calcitriol enhances Ca++ reabsorption by the distal tubule, but it is less effective than PTH. Several factors disturb Ca++ excretion. An increase in the plasma [Pi] (example caused by a dramatic increase in the dietary intake of Pi or by reduced kidney function) elevates PTH levels both directly and by decreasing the ionized plasma [Ca++], and thereby decreases Ca++ excretion.
A decline in the plasma [Pi] (example caused by dietary Pi depletion) has the opposite effect.
(With normal kidney function, changes in dietary Pi intake over a sevenfold range do not affect plasma [Pi].) Changes in the ECF volume alter Ca++ excretion mainly by affecting sodium chloride (NaCl) and fluid reabsorption in the proximal tubule. Volume contraction increases NaCl and water reabsorption by the proximal tubule and thereby enhances Ca++ reabsorption.
Accordingly, urinary Ca++ excretion declines. Volume expansion has the opposite effect. Acidemia increases Ca++ excretion, whereas alkalemia decreases excretion. The regulation of Ca++ reabsorption by pH occurs primarily in the distal tubule. Alkalosis stimulates the apical membrane Ca++ channel (TRPV5), thereby increasing Ca++ reabsorption.
By contrast, acidosis inhibits the same channel, thereby reducing Ca++ reabsorption. Finally, as previously noted, loop diuretics inhibit Ca++ reabsorption by the thick ascending limb (TAL), and thiazide diuretics stimulate Ca++ reabsorption by the distal tubule.
Calcium-Sensing Receptor
The CaSR is a receptor expressed in the plasma membrane of cells involved in regulating Ca++ homeostasis. The CaSR senses small changes in extracellular [Ca++]. Ca++ binds to CaSR receptors in PTH-secreting cells of the parathyroid gland and calcitriol-producing cells of the proximal tubule.
Activation of the receptor by an increase in plasma [Ca++] results in the inhibition of PTH secretion and the production of calcitriol by the proximal tubule. Moreover, the reduction in PTH secretion also contributes to decreased production of calcitriol because PTH is a potent stimulus of calcitriol synthesis.
By contrast, a decrease in plasma [Ca++] has the opposite effect on PTH and calcitriol secretion. The CaSR also maintains Ca++ homeostasis by directly regulating Ca++ excretion by the kidneys.
CaSRs in the thick ascending limb respond directly to changes in plasma [Ca++] and regulate Ca+ absorption. An increase in plasma [Ca++] activates CaSR in the TAL and inhibits Ca++ absorption, thereby stimulating urinary Ca++ excretion.
By contrast, a decrease in plasma [Ca++] leads to an increase in Ca++ absorption by the TAL and a corresponding decrease in urinary Ca++ excretion.
Thus the direct effect of plasma [Ca++] on CaSRs in the TAL acts in concert with changes in PTH, which regulates Ca++ reabsorption by the distal tubule to regulate urinary Ca++ excretion and thereby maintain Ca++ homeostasis.
Mutations in the gene coding for the calcium-sensing receptor (CaSR) cause disorders in Ca++ homeostasis. Familial hypocalciuric hypercalcemia is an autosomal dominant disease caused by an inactivating mutation of CaSR.
The hypercalcemia is caused by deranged Ca++-regulated parathyroid hormone (PTH) secretion; that is, the set point for Ca++-regulated PTH secretion is shifted such that PTH levels are elevated at any level of plasma [Ca++] and are not suppressed in the setting of hypercalcemia.
Hypocalciuria is caused by enhanced Ca++ reabsorption in the thick ascending limb and distal tubule as a result of elevated PTH levels and defective CaSR regulation of Ca++ transport in the kidneys. Autosomal dominant hypoparathyroidism is caused by an activating mutation in CaSR.
Activation of CaSRs causes deranged Ca++-regulated PTH secretion (i.e., the set point for Ca++-regulated PTH secretion is shifted such that PTH levels are decreased at any level of plasma [Ca++]). Hypercalciuria results and is caused by decreased PTH levels and defective CaSR-regulated Ca++ transport in the kidneys.
Phosphate
P i is an important component of many organic molecules, including deoxyribonucleic acid, ribonucleic acid, adenosine triphosphate, nucleotides, nucleosides, phospholipids, and intermediates of metabolic pathways.
Like Ca++, Pi is a major constituent of bone. Its concentration in plasma is an important determinant of bone formation and resorption. In addition, urinary Pi is an important buffer (titratable acid) involved in the maintenance of acid-base balance.
Eighty-fie percent of Pi is located in bone and teeth, approximately 14% is located in the ICF, and 1% is located in the ECF. The normal plasma [Pi] is 3 to 4 mg/dL (1-1.5 mmol/L). Pi in the plasma is ionized (45%), complexed (30%), and bound to protein (25%). Phosphate deficiency causes muscle weakness, rhabdomyolysis, and reduced bone mineralization, resulting in rickets (in children) and osteomalacia (in adults).
Overview of Pi Homeostasis
A general scheme of Pi homeostasis. The maintenance of Pi homeostasis depends on two factors:
The amount of Pi in the body and (2) the distribution of Pi between the ICF and ECF compartments. Total body Pi levels are determined by the relative amount of Pi absorbed by the intestinal tract versus the amount excreted by the kidneys.
Pi absorption by the intestinal tract occurs via active and passive mechanisms; Pi absorption increases as dietary Pi rises, and it is stimulated by calcitriol. Despite variations in P I intake between 800 and 1500 mg/day, in adults (i.e., the steady state), the kidneys maintain total body Pi balance constant by excreting an amount of Pi in the urine equal to the amount absorbed by the intestinal tract (normal bone remodeling results in no net addition of Pi to, or Pi release from, the bone).
By contrast, during growth, Pi is accumulated in the body. Renal Pi excretion is the primary mechanism by which the body regulates Pi balance and thereby Pi homeostasis. The second factor that maintains Pi homeostasis is the distribution of Pi among bone and the ICF and ECF compartments.
Two hormones, PTH and calcitriol, in concert with the kidneys, regulate plasma [Pi]. The release of Pi from bone is stimulated by the same hormones (i.e., PTH and calcitriol) that release Ca++ from this pool.
Thus the release of Pi is always accompanied by a release of Ca++. The kidneys also make an important contribution to maintaining plasma [Pi] within a narrow range (1-1.5 mmol/L). Pi excretion by the kidneys is regulated by PTH and calcitriol.
PTH increases Pi excretion, whereas calcitriol inhibits Pi excretion. Plasma [Pi] is determined by
- Intestinal absorption,
- Storage in bone, and
- Pi excretion by the kidneys. Maintenance of plasma [Pi] is essential for optimal Ca++-Pi complex formation required for bone mineralization without deposition of Ca++ Pi in vascular and other soft tissues.
A rise in the plasma [Pi] directly stimulates PTH synthesis and release and also decreases the ionized [Ca++], which stimulates PTH release by its interaction with CaSR. PTH enhances urinary Pi excretion by inhibiting proximal tubule Pi reabsorption.
Hyperphosphatemia also decreases calcitriol production by the proximal tubule, which leads to a reduction in Pi absorption by the intestine. Both the increase in PTH and the decrease in calcitriol reduce plasma [Pi].
Pi Transport Along the Nephro summarizes Pi transport by the various portions of the nephron. The proximal tubule reabsorbs 80% of the Pi filtered by the glomerulus, and the loop of Henle, the distal tubule, and the collecting duct reabsorb negligible amounts of Pi.
Therefore approximately 20% of the Pi fitered across the glomerular capillaries is excreted in the urine. P I reabsorption by the proximal tubule occurs by a transcellular route.
Pi uptake across the apical membrane of the proximal tubule occurs via two Na+-Pi symporters (IIa and IIc). Type IIa transports 3Na+ with one divalent Pi (HPO−4 2), and carries a positive charge into the cell.
Type IIc transports 2Na+ with one monovalent Pi (H2PO−4 ) and is electrically neutral. Pi exits across the basolateral membrane by a P i-inorganic anion antiporter that has not been characterized.
Regulation of Urinary Pi Excretion
Several hormones and factors regulate urinary Pi excretion. 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 the endocytic removal of Na+-Pi transporters from the brush border membrane of the proximal tubule. 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.
In patients with chronic renal failure, the kidneys cannot excrete inorganic phosphate (Pi). Because of continued P I absorption by the intestinal tract, Pi accumulates in the body, and the plasma [Pi] rises. The excess P I complexes with Ca++ and reduces the ionized plasma concentration of Ca++ ([Ca++]). Pi accumulation also decreases the production of calcitriol.
This response reduces Ca++ absorption by the intestine, an effect that further reduces the plasma [Ca++]. This reduction in plasma [Ca++] increases parathyroid hormone secretion and Ca++ release from bone. These actions result in renal osteodystrophy (i.e., increased bone resorption with replacement by fibrous tissue, which renders bone more susceptible to fracture).
Chronic hyperparathyroidism (i.e., elevated parathyroid hormone levels due to the decrease in plasma [Ca++]) during chronic renal failure can lead to metastatic calcifications in which Ca++ and Pi precipitate in arteries, soft tissues, and viscera. The deposition of Ca++ and Pi in the heart may cause myocardial failure.
The prevention and treatment of hyperparathyroidism and Pi retention include a low-Pi diet or the administration of a “phosphate binder” (i.e., an agent that forms insoluble Pi salts and thereby renders P I unavailable for absorption by the intestinal tract) in the diet. Supplemental Ca++ and calcitriol also are prescribed to increase plasma [Ca+].
ECF volume also affects Pi excretion. Expansion of the ECF enhances Pi excretion by (1) increasing glomerular filtration rate and thus the filtered load of Pi; (2) decreasing Na-Pi coupled reabsorption, which reduces the ECF volume; and (3) reducing the 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 in the expression of the Na-Pi symporters in the apical membrane. Systemic acidosis causes glucocorticoid secretion, and these glucocorticoids increase the 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− because Pi is an important urinary buffer. Growth hormone decreases Pi excretion.
Fibroblast growth factor 23 (FGF-23) regulates renal P I excretion and thereby contributes to the regulation of plasma [Pi].
FGF-23 is secreted by osteocytes and osteoblasts and inhibits Pi reabsorption and calcitriol production by the proximal tubule. Secretion of FGF-23 is stimulated by sustained hyperphosphatemia, PTH, and calcitriol.
Activating mutations in the FGF-23 gene cause hypophosphatemia, low plasma calcitriol, and rickets/osteomalacia, whereas inactivating mutations cause hyperphosphatemia, high serum calcitriol, and calcification of soft tissue.
In the absence of glucocorticoids (For example, in Addisodisease), inorganic phosphate (Pi) excretion is depressed, as is the ability of the kidneys to excrete titratable acid and to generate new bicarbonate (HCO−3 ).
Growth hormone also has an important effect on Pi homeostasis. Growth hormone increases the reabsorption of Pi by the proximal tubule. As a result, growing children are in positive Pi balance and have a higher plasma [Pi] than adults, and this elevated [Pi] is important for the formation of bone.
Phosphate homeostasis is altered by mutations in the fibroblast growth factor 23 (FGF-23) gene by mutations in PHEX, an endopeptidase, and by tumors that produce excess amounts of FGF-23. For example, in tumor-induced osteomalacia, excessive production of FGF-23 leads to hypophosphatemia, renal phosphate wasting, and a defect in bone mineralization.
This phenotype also is observed in patients with autosomal dominant hypophosphatemic rickets (caused by mutations in the FGF-23 gene that make FGF-23 resistant to proteolysis), autosomal recessive hypophosphatemic rickets (caused by elevated levels of FGF-23), and X-linked hypophosphatemic rickets (caused by inactivating mutations in PHEX). In contrast, an inactivating mutation in the FGF-23 gene causes hyperphosphatemia, hypophosphaturia, and calcification of soft tissues.
Integrative Review Of Parathyroid Hormone And Calcitriol On Ca++ And Pi Homeostasis
Hypocalcemia is the major stimulus of PTH secretion. PTH has numerous effects on Ca++ and Pi homeostasis. PTH stimulates bone resorption, increases urinary Pi excretion, decreases urinary Ca++ excretion, and stimulates the production of calcitriol, which stimulates Ca++ and Pi absorption by the intestine.
Because changes in Pi handling in bone, the intestines, and the kidneys tend to balance out, PTH increases the plasma [Ca++] while having little effect on the plasma [Pi]. Overall, a rise in the plasma PTH levels in response to hypocalcemia returns the plasma [Ca++] to the normal range.
A decline in plasma [Ca++] has the opposite effect. Calcitriol (the active form of vitamin D) also plays an important role in Ca++ and Pi homeostasis. The primary action of calcitriol is to stimulate Ca++ and Pi absorption by the intestine.
To a lesser degree, it acts with PTH to release Ca++ and Pi from the bone and decreases Ca++ excretion by the kidneys. The net effect of calcitriol is to increase the plasma [Ca++] and [Pi]. Thus the major stimuli of calcitriol production are hypocalcemia via PTH and hypophosphatemia (i.e., a low plasma [Pi]).
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The kidneys, in conjunction with the intestinal tract and bone, play a vital role in regulating the plasma [Ca++] and [Pi].
Plasma Ca++ is regulated by PTH and calcitriol. Calcitonin is not a major regulatory hormone in humans. Ca++ excretion by the kidneys is regulated by PTH, plasma [Ca++], and calcitriol, and is altered by changes in acid-base status, extracellular fluid volume, and plasma Pi.
Ca++ reabsorption by the thick ascending limb and distal tubule is regulated by PTH and calcitriol, both of which stimulate Ca++ reabsorption, and by plasma [Ca++].
The plasma [Pi] is regulated by PTH, FGF-23, and calcitriol. Pi excretion is regulated by PTH, FGF-23, dietary phosphate, and growth hormone, and it is altered by acid-base balance, ECFV expansion, and glucocorticoids.
Bone tumors secrete FGF-23, which enhances renal Pi excretion and thereby causes hypophosphatemia, hyperphosphatemia, and a defect in bone mineralization (i.e., osteomalacia).
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