Calcium renal reabsorption

Parathyroid hormone, a polypeptide of 83 amino acid residues, mol wt 9500, is produced by the parathyroid glands. Release of PTH is activated by a decrease of blood Ca " to below normal levels. PTH increases blood Ca " concentration by increasing resorption of bone, renal reabsorption of calcium, and absorption of calcium from the intestine. A cAMP mechanism is also involved in the action of PTH. Parathyroid hormone induces formation of 1-hydroxylase in the kidney, requited in formation of the active metabolite of vitamin D (see Vitamins, vitamin d). 

Hydroxy vitamin D pools ia the blood and is transported on DBF to the kidney, where further hydroxylation takes place at C-1 or C-24 ia response to calcium levels. l-Hydroxylation occurs primarily ia the kidney mitochondria and is cataly2ed by a mixed-function monooxygenase with a specific cytochrome P-450 (52,179,180). 1 a- and 24-Hydroxylation of 25-hydroxycholecalciferol has also been shown to take place ia the placenta of pregnant mammals and ia bone cells, as well as ia the epidermis. Low phosphate levels also stimulate 1,25-dihydtoxycholecalciferol production, which ia turn stimulates intestinal calcium as well as phosphoms absorption. It also mobilizes these minerals from bone and decreases their kidney excretion. Together with PTH, calcitriol also stimulates renal reabsorption of the calcium and phosphoms by the proximal tubules (51,141,181—183). 

Vitamin D hormone is derived from vitamin D (cholecalciferol). Vitamin D can also be produced in the body it is formed in the skin from dehydrocholesterol during irradiation with UV light. When there is lack of solar radiation, dietary intake becomes essential, cod liver oil being a rich source. Metaboli-cally active vitamin D hormone results from two successive hydroxylations in the liver at position 25 ( calcifediol) and in the kidney at position 1 ( calci-triol = vit. D hormone). 1-Hydroxylation depends on the level of calcium homeostasis and is stimulated by parathormone and a fall in plasma levels of Ca or phosphate. Vit D hormone promotes enteral absorption and renal reabsorption of Ca and phosphate. As a result of the increased Ca + and phosphate concentration in blood, there is an increased tendency for these ions to be deposited in bone in the form of hydroxyapatite crystals. In vit D deficiency, bone mineralization is inadequate (rickets, osteomalacia). Therapeutic Liillmann, Color Atlas of Pharmacology... 

In 53 patients studied prospectively at 1, 6, 12, and 24 months, lithium increased serum PTH concentrations (apparent by 6 months) and increased renal reabsorption of calcium in the absence of a significant change in serum calcium (660). A prospective study of 101 lithium maintenance patients and 82 healthy controls showed higher serum calcium concentrations during lithium treatment than at baseline or in the controls, and higher calcium serum concentrations in those lithium patients over 60 years of age (633). 

However, calcitriol is well established as the most potent agent with respect to stimulation of intestinal calcium and phosphate transport and bone resorption. Calcitriol appears to act on the intestine both by induction of new protein synthesis (eg, calcium-binding protein) and by modulation of calcium flux across the brush border and basolateral membranes by a means that does not require new protein synthesis. The molecular action of calcitriol on bone has received less attention. However, like PTH, calcitriol can induce RANK ligand in osteoblasts and proteins such as osteocalcin, which may regulate the mineralization process. The metabolites 25(OH)D and 24,25(OH)2D are far less potent stimulators of intestinal calcium and phosphate transport or bone resorption. However, 25(OH)D appears to be more potent than l,25(OH)2D in stimulating renal reabsorption of calcium and phosphate and may be the major metabolite regulating calcium flux and contractility in muscle. Specific receptors for l,25(OH)2D exist in target tissues. However, the role and even the existence of receptors for 25(OH)D and 24,25(OH)2D remain controversial. 

It is now well established that l,25-(OH)2D3 is the active hormonal form of vitamin D3 [32], The production of l,25-(OH)2D3 in the kidney is regulated by dietary calcium and phosphate and also by changes in serum calcium and parathyroid hormone, which clearly highlight the hormonal nature of this compound. Functionally, the three classical actions of l,25-(OH)2D3 are to stimulate intestinal calcium and independently phosphate absorption, the mobilization of calcium from bone, and increase renal reabsorption of calcium. The focus of this review will be to explore the most recent concepts of vitamin D in regard to its metabolism and physiology, and with respect to the medicinal applications of vitamin D3 metabolites and analogues. 

Q9 The hypercalcaemia which occurs in hyperparathyroidism may be reduced by administration of a loop diuretic such as furosemide, which helps calcium excretion. Bisphosphonates, which prevent bone resorption and so reduce calcium release from bone, can be used to treat hypercalcaemia associated with malignancies. Calcitonin may also be useful in treating the hypercalcaemia associated with cancer, as it reduces calcium levels both by attenuating its renal reabsorption and by increasing calcium deposition in bone. 

Parathyroid Hormone Parathyroid hormone raises plasma calcium by direct effects on bone resorption and renal reabsorption of calcium, and indirectly by regulating the metabolism of vitamin D. It is a peptide and acts via cell surface G-protein receptors linked to adenylate cyclase. The parathyroid glands have G-protein cell surface calcium receptors linked to phospholipase G, and parathyroid hormone is secreted in response to hypocalcemia. Magnesium is required for secretion of the hormone, which may explain the development of hypocalcemia in premature infants who are magnesium deficient. 

Nephrocalcin in the kidneys has considerable homology with matrix Gla protein. It is probably involved in renal reabsorption of calcium, but also acts to solubilize calcium salts in the urine. It is found in calcium oxalate renal stones. 

As a consequence of the blockade of the Na, K, 2Cr-cotransporter, the diuresis produced by furosemide (frusemide) results in increased urinary excretion of sodium, potassium, chloride, calcium and magnesium ions. The losses of sodium, potassium and chloride are approximately 1750, 600 and 2150 mmol, respectively, after i.m. administration of furosemide (frusemide) at 1 mg/kg. Although these electrolyte losses are substantial, they are largely replaced (within the 24 h period following furosemide (frusemide) administration) by enhanced renal reabsorption as well increased ion absorption from the intestinal tract. In addition to this primary action, furosemide (frusemide) may have a lesser inhibitory effect on other chloride ion transporters and the drug can also inhibit carbonic anhydrase activity (Martinez-Maldonado Cordova 1990, Rose 1989,1991, Wilcox 1991). Finally, some of the renal and extrarenal effects of furosemide (frusemide) appear to be mediated through increased prostaglandin production. 

Features of lithium-induced hyperparathyroidism include a) a low urinary calcium excretion and the absence of nephrolithiasis b) normal urinary cyclic adenosine monophosphate excretion and c) normal plasma inorganic phosphate [30]. In lithium-induced hypercalcemia, a higher frequency of conduction defects has been noted [42]. Lithium also inhibits parathyroid hormone-mediated renal reabsorption of Ca and Mg and blunts parathyroid hormone-mediated phos-phaturia [43]. Lithium interferes with the formation of renal cyclic adenosine monophosphate, which is regulated by parathyroid hormone. Levels of minary cy-... 

Calcium salts are contraindicated in hypercalcemia, ventricular fibrillation, and in digitalized patients, who may be predisposed to arrhythmias. Inadvertent calcium overloading may be treated by IV infusion of sodium chloride, which competes with calcium for reabsorption in the distal renal tubercle, and by furosemide (see also Figure 17). 

Calcitriol promotes renal reabsorption of calcium, and promotes a receptor-mediated increase in intestinal absorption of calcium and phosphorus. 

The role of 1,25-(OH)20 in the kidney is even less well understood, although its localization in the distal renal tubule cells, specifically in the nuclei, is known. No clear role for l,25-(OH)2D2 in renal tubular reabsorption of phosphorus has been established, and this area remains controversial. There is evidence that 1,25-(OH),D, stimulates renal reabsorption of calcium in the distal tubule but little else is known concerning that mechanism. ... 

It may seem disturbing that 1,25-(OH)2D3 can be considered a hormone with two signals (low calcium and low phosphoms) and two functions (calcium mobilization and phosphate mobilization). It would appear that a specific correction of the signal would not be possible. However, the calcium signal causes parathyroid secretion thus parathyroid hormone accompanies 1,25-(OH)2D3 in this circumstance, permitting mobilization of bone calcium and renal reabsorption of calcium. The effect of 1, 2S-(0H)2D3 on serum phosphate is negated by the parathyroid hormone induced loss of phosphate in urine. The composite effect of the low calcium signal is to elevate serum calcium but not phosphate ... 

Since 1,25-(OH)2D3 production responds slowly to parathyroid hormone a more quickly-reacting system is needed to prevent low calcium tetany. Parathyroid hormone secretion and action is very rapid as is the lifetime of the hormone itself Thus parathyroid hormone can, with endogenous 1,25-(0H)2D3, stimulate the mobilization of calcium from bone and renal reabsorption of calcium but not intestinal absorption Nevertheless, plasma calcium rises but... 

General metabolic significance. Vitamin D stimulates intestinal absorption of calcium and phosphate, renal reabsorption of these ions, deposition and mobilization of minerals in the hard tissue, controlling normal calcium and phosphate blood level by means of these processes. Molecular mechanism of the vitamin D effects most frequently conform to the effect of steroid hormones (induction of protein biosynthesis). 

Calcium homeostasis is maintained by hormonal regulation of the intestina absorption and renal reabsorption. During growth and lactation, body calcium requirements increase and the efficiency of calcium absorption can increase more than 60% compared with the adult steady-state conditions. With age and loss of estrogen stimulation this adaptive ability is blunted. 

Contrary to PTH, calcitonin has a lowering action on blood Ca activity. It is synthesized in the parafollicular cells (C cells) in the thyroid. An increased blood Ca activity leads to calcitonin secretion, and within a few minutes both calcium and phosphate concentrations in plasma are lowered. This effect is accomplished by an effect on the bone cells, where calcium is bound as hydroxyapatite. Besides this effect, calcitonin also decreases intestinal uptake and renal reabsorption. Calcitonin inhibits the osteoclasts ( bone eater cells ) and hence reduces the amount of calcium and phosphate released from bone to the extracellular fluid. The effect on the kidneys leads to an increased excretion of calcium, phosphate, sodium, chloride, and water. 

Calcium (Ca ) Parathyroid hormone Calcitonin Magnesium (helps in calcium metabolism and intestinal absorption) Intestinal absorption Renal reabsorption Renal excretion... 

Low phosphate levels, that is, levels less than 3.0 mg/dL (4.0 mg/dL in children) or 0.97 mmol/L (1.45 mmol/L in children), may result from poor absorption such as occurs with ingestion of antacids that bind to phosphate. Phosphate may be decreased with reduced renal reabsorption often secondary to high levels of parathyroid hormone (PTH), which causes a retention of calcium and loss of phosphate through the kidneys, or in high calcium levels and vitamin D deficiency. Low serum phosphate levels may be noted in alkalosis because phosphate is shifted into the cells to buffer the pH. 

If vitamin D has no effect on calcium absorption, it does affect calcium mobilization and thereby restores plasma concentrations of calcium. This finding explains why vitamin D deficiency was associated with hypocalcemia. The effect on the bone seems to require a synergetic action of vitamin D and parathormone. The 1,25-hydroxylated derivative seems to be the major active compound causing calcium release from the bone. The 25-hydroxyl derivative has, however, been shown to be active as well. Finally, vitamin D increases renal proximal tubular reabsorption of phosphate in normal and vitamin D deficient animals. Consequently phosphate excretion is decreased. Inasmuch as this effect occurs in parathyroidectomized animals, the effect of vitamin D or its metabolites must be direct. Again, the active metabolites are the 25 and 1,25-hydroxy derivatives. A calcium binding protein has been isolated from the kidney cortex, but its role in renal reabsorption is not known. 

Dietary calcium has a relatively small impact on urinary calcium (e.g., only 6-8% of an increase in dietary calcium intake will appear in the urine). The major food components that affect urinary calcium are protein, phosphorus, caffeine, and sodium. For each 50-g increment in dietary protein, approximately 1.5 mmol (60 mg) of additional calcium is lost in urine. The higher amounts of phosphorus consumed concurrently with a high-protein diet can blunt, but not eliminate, this phenomenon. Dietary phosphorus (as well as intravenously administered phosphorus) increases PTH synthesis and subsequently stimulates renal calcium reabsorption and reduces the urinary excretion of calcium. Caffeine causes a reduction in renal reabsorption of calcium and a subsequently increased loss of urinary calcium soon after it is consumed. It has been shown repeatedly in animals and humans that dietary sodium, in the form of salt (NaCl), increases urinary calcium excretion. On average, for every 100 mmol (2300 mg) of sodium excreted in urine, there is an approximately 0.6-1 mmol (24-40 mg) loss of calcium in free-living healthy populations of various ages. Because most of the urinary calcium is of bone origin, it is commonly hypothesized that those nutrients or food components that are hypercalciuretic are also detrimental to the skeleton. On the other hand, thiazide medications are hypocalciuric and, as such, may have modest positive effects on bone. 

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