Kidney calcium resorption

Three effiects of parathyroid hormone The presence of parathyroid hormone in the plasma is required for the maintenance of I-hydroxylase activity in the kidney. The increase in PTH levels induces an increase in the activity of the hydroxylase, resulting in an increase in the production of l,25-(OH)D3 and an increase in the plasma levels of l,25-[OH)Di. In addition, PTH works in tandem with 1,25-(OH)2Dj in stimulating the osteodasts to dissolve bones and in increasing the efficiency of calcium resorption by the kidneys. Both PTH and l,25-(OH)2D3 are required for these latter two effects, i H is not required for the effect of the vitamin on the intestines. 

CaJciiim sensor protein also occurs in the kidney Specificaliy, the calcium sensor occurs in the thick ascending loop, where the N-terminal half juts Out into the extracellular fluid (not into the lumen of the tubule, but in the space between tubules). When extracellular Ca ions increase in concentration, the thick ascending loop decreases its rale of calcium resorption (Chattopadhyay d (j/., 1996 Pearce and Thakkar, 1997 Pearce ef uf., 1996), The regulatory scenario in the kidney represents a mode of regulating the body s calcium balance that appears completely independent of vitamin D, The overall scenario is that, as extracellular Ca " increases, the parathyroid gland decreases its release of PTH, and the kidney reduces its reabsorption of calcium ions from the developing urine. 

Three effects of l,25-(OH)2Di l,25-Dihydrox)rvitamin D3, in increased concentrations, has three effects that act to restore plasma calcium to the normal value of about 1.5 mM (1) activation of the vitamin D-dependent calcium transport system of the enterocyte, (2) activation of the osteoclasts, and (3) enhancement of calcium resorption by the kidney. Osteoclasts are cells that reside on the outside and inside surfaces of bones. They dissolve the bone, releasing the constituent calcium and phosphate ions into the circulation. l,25-(OH)2D3 can induce an increase in the activity of the osteoclasts. 

Clinically, the animals do not show signs until 24-48 or more hours after ingestion of the bait. The affected animals are depressed, have reduced urine production, and the urine is of low specific gravity. Severely poisoned animals have hematemesis, azotemia, and cardiac arrhythmias. Animals with renal impairment are more susceptible to cholecalciferol poisoning than those with normal renal function. Cholecalciferol poisoning requires protracted treatment, which may require as long as 3 weeks in severe intoxications. Appropriate treatment consists of fluid therapy to assist the kidneys in removing the excess calcium, corticosteroids to minimize inflammation, and calcitonin to enhance calcium resorption into the bone. Pamidronate disodium is the new antidote for this poison. 

Intracellular calcitriol receptors are widespread in the body. They are found, for example, in the small intestine, the kidneys, the bones, and the parathyroid gland. Calcitriol binds to these receptors and induces at the DNA level the transcription of hormone-sensitive genes. It influences cell differentiation and proliferation, stimulates an increased uptake of calcium ions from the intestine through enhanced formation of calcium-binding proteins, and also controls the release of calcium from the bones. [91] Since the counter-ion of the calcium is mostly phosphate, calcitriol raises consequently the phosphate level in blood as well. While the release of calcium from the bones appears counterproductive, this effect is however over-compensated by the increased intestinal calcium resorption, resulting in an elevated serum concentration. 

Calcitonin is active in nephrectomized and parathy-roidectomized animals, indicating that the hormone does not act through the kidney or the parathyroid. Thyrocalcitonin causes hypocalcemia even in rats fed a low-calcium diet. Consequently, the hormone does riot seem to influence intestinal absorption of calcium. Calcitonin facilitates calcium retention in bone cultures. It is likely that the hormone acts by interfering with calcium resorption in bone, but the exact mechanism by which the interference takes place is not known. 

Vitamin D2 and D3 are hydroxylated first in the liver to the prohormone 25-hydroxycholecalciferol (calcidiol) and subsequently in the kidney to the vitamin D hormone la,25-dihy-droxycholecalciferol (calcitriol). Calcitriol acts as an inductor of proteins in various organs. It promotes calcium resorption in the intestine and... 

Factors controlling calcium homeostasis are calcitonin, parathyroid hormone(PTH), and a vitamin D metabolite. Calcitonin, a polypeptide of 32 amino acid residues, mol wt - SGOO, is synthesized by the thyroid gland. Release is stimulated by small increases in blood Ca " concentration. The sites of action of calcitonin are the bones and kidneys. Calcitonin increases bone calcification, thereby inhibiting resorption. In the kidney, it inhibits Ca " reabsorption and increases Ca " excretion in urine. Calcitonin operates via a cyclic adenosine monophosphate (cAMP) mechanism. 

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). 

Although it is being found that vitamin D metaboUtes play a role ia many different biological functions, metaboHsm primarily occurs to maintain the calcium homeostasis of the body. When calcium semm levels fall below the normal range, 1 a,25-dihydroxy-vitainin is made when calcium levels are at or above this level, 24,25-dihydroxycholecalciferol is made, and 1 a-hydroxylase activity is discontiaued. The calcium homeostasis mechanism iavolves a hypocalcemic stimulus, which iaduces the secretion of parathyroid hormone. This causes phosphate diuresis ia the kidney, which stimulates the 1 a-hydroxylase activity and causes the hydroxylation of 25-hydroxy-vitamin D to 1 a,25-dihydroxycholecalciferol. Parathyroid hormone and 1,25-dihydroxycholecalciferol act at the bone site cooperatively to stimulate calcium mobilization from the bone (see Hormones). Calcium blood levels are also iafluenced by the effects of the metaboUte on intestinal absorption and renal resorption. 

Three hormones regulate turnover of calcium in the body (22). 1,25-Dihydroxycholecalciferol is a steroid derivative made by the combined action of the skin, Hver, and kidneys, or furnished by dietary factors with vitamin D activity. The apparent action of this compound is to promote the transcription of genes for proteins that faciUtate transport of calcium and phosphate ions through the plasma membrane. Parathormone (PTH) is a polypeptide hormone secreted by the parathyroid gland, in response to a fall in extracellular Ca(Il). It acts on bones and kidneys in concert with 1,25-dihydroxycholecalciferol to stimulate resorption of bone and reabsorption of calcium from the glomerular filtrate. Calcitonin, the third hormone, is a polypeptide secreted by the thyroid gland in response to a rise in blood Ca(Il) concentration. Its production leads to an increase in bone deposition, increased loss of calcium and phosphate in the urine, and inhibition of the synthesis of 1,25-dihydroxycholecalciferol. 

PTH is the most important regulator of bone remodelling and calcium homeostasis. PTH is an 84-amino acid polypeptide and is secreted by the parathyroid glands in response to reductions in blood levels of ionised calcium. The primary physiological effect of PTH is to increase serum calcium. To this aim, PTH acts on the kidney to decrease urine calcium, increase mine phosphate, and increase the conversion of 25-OH-vitamin D to l,25-(OH)2-vitamin D. PTH acts on bone acutely to increase bone resorption and thus release skeletal calcium into the circulation. However, due to the coupling of bone resorption and bone formation, the longer-term effect of increased PTH secretion is to increase both bone resorption and bone formation. 

Parathyroid hormone stimulates bone resorption by increasing the number and activity of osteoclasts. This demineralization process in the bone releases calcium and phosphate into the blood. Although the action of PTH on the bone appears to increase blood phosphate, its action on the kidney, which increases phosphate excretion in the urine, more than compensates for this increase and the net effect is a decrease in serum phosphate. 

Calcium-phosphorus balance is mediated through a complex interplay of hormones and their effects on bone, GI tract, kidney, and parathyroid gland. As kidney disease progresses, renal activation of vitamin D is impaired, which reduces gut absorption of calcium. Low blood calcium concentration stimulates secretion of parathyroid hormone (PTH). As renal function declines, serum calcium balance can be maintained only at the expense of increased bone resorption, ultimately resulting in renal osteodystrophy (ROD) (Fig. 76-7). 

Calcium is the major mineral component of bone and normal repair and remodelling of bone is reliant on an adequate supply of this mineral. Calcium uptake in the gut, loss through the kidneys and turnover within the body are controlled by hormones, notably PTH and 1,25 dihydroxy cholecalciferol (1,25 DHCC or 1,25 dihydroxy vitamin D3 or calcitriol). Refer to Figure 8.12 for a summary of the involvement of PTH and vitamin D3 in controlling plasma calcium concentration. These two major hormones have complementary actions to raise plasma calcium concentration by promoting uptake in the gut, reabsorption in the nephron and bone resorption. Other hormones such as thyroxine, sex steroids and glucocorticoids (e.g. cortisol) influence the distribution of calcium. 

The polypeptide parathormone is released from the parathyroid glands when plasma Ca + level falls. It stimulates osteoclasts to increase bone resorption in the kidneys, it promotes calcium reabsorption, while phosphate excretion is enhanced. As blood phosphate concentration diminishes, the tendency of calcium to precipitate as bone mineral decreases. By stimulating the formation of vit D hormone, parathormone has an indirect effect on the enteral uptake of Ca + and phosphate. In parathormone deficiency, vitamin D can be used as a substitute that unlike parathormone, is effective orally. 

The steroid hormone calcitriol, which is formed in the kidneys (see p. 304), stimulates the resorption of both calcium and phosphate ions and thus increases the plasma level of both ions. 

Calcitriol is a derivative of vitamin D (see p. 364). On exposure to ultraviolet light, a precursor of the hormone can also arise in the skin. Calcitriol itself is synthesized in the kidneys (see p. 330). Calcitriol promotes the resorption of calcium in the intestine and increases the Ca "" level in the blood. 

Parathyroid hormone is a single-chain polypeptide of 84 amino acids which is produced in the parathyroid glands. It increases serum calcium and decreases serum phosphate. In bone it promotes resorption of calcium. It indirectly increases osteoclastic activity by promoting the action of osteoblasts. It has been shown that in low doses PTH may even increase bone formation without stimulating bone resorption. In the kidney PTH increases resorption of calcium and it increases excretion of phosphate. An other important activity in the kidney is the enhanced synthesis of 1,25-dihydroxyvitamin D. An increased serum calcium level inhibits PTH secretion and increased serum phosphate decreases free serum calcium and thus stimulates PTH secretion. 

Calcium is present in three forms e.g., as free calcium ion, bound to plasma protein albumin and in diffusable complexes. The endocrine system, through parathyroid hormone and calcitonin, helps in keeping the concentration of ionized plasma calcium in normal level. Decrease in plasma levels of ionized calcium leads to increased parathyroid hormone secretion. Parathyroid hormone tends to increase plasma calcium level by increasing bone resorption, increasing intestinal absorption and increasing reabsorption of calcium in kidney. Vitamin D acts by stimulating... 

The overall function of 1,25-diOH D3 is to maintain adequate plasma levels of calcium. It performs this function by 1) increasing uptake of calcium by the intestine, 2) minimizing loss of calcium by the kidney, and 3) stimulating resorption of bone when necessary (see Figure 28.23). 

Vitamin D is the most toxic of all vitamins. Like all fat-soluble vita mins, vitamin D can be stored in the body and is only slowly metab olized. High doses (100,000 IU for weeks or months) can cause loss of appetite, nausea, thirst, and stupor. Enhanced calcium absorption and bone resorption results in hypercalcemia, which can lead to deposition of calcium in many organs, particularly the arteries and kidneys. 

There can be increases in calcium and phosphorus loss because of effects on both the kidney and the bowel, with increased excretion and reduced resorption (131). Tetany, which has been seen in patients receiving high-dose longterm intravenous glucocorticoids, has been explained as being due to hypocalcemia, and there are also effects on bone. Tetany has also been reported in a patient with latent hyperparathyroidism after the administration of a glucocorticoid (122). 

The principal effects of calcitonin are to lower serum calcium and phosphate by actions on bone and kidney. Calcitonin inhibits osteoclastic bone resorption. Although bone formation is not impaired at first after calcitonin administration, with time both formation and resorption of bone are reduced. Thus, the early hope that calcitonin would prove useful in restoring bone mass has not been realized. In the kidney, calcitonin reduces both calcium and phosphate reabsorption as well as reabsorption of other ions, including sodium, potassium, and magnesium. Tissues other than bone... 

Parathyroid hormone (PTH) is an 84-amino acid peptide secreted by the parathyroid glands, and is the principal regulator of extracellular calcium levels [44, 45]. The effects of PTH on extracellular calcium are mediated directly or indirectly through effects on bone, kidney, and intestine. A decrease in extracellular calcium causes an increase in PTH secretion. As a consequence, the rise in PTH levels causes increased bone resorption and the release of calcium from bone, decreased calcium excretion by the kidney, and increased intestinal calcium absorption. The therapeutic application of PTH has centered on the bone effects as an anabolic treatment for osteoporosis. PTH increases the activity of both osteoblasts (which form bone) and osteoclasts (which mediate bone resorption). The desirable anabolic effects of PTH on osteoblasts appear to be highly dependent on dose schedule and the duration of daily exposure. 

Plicamycin [plick a MYE sin] (mithramycin) also exerts its cytotoxicity through restriction of DNA-directed RNA synthesis. Resistance is due to P-glycoprotein efflux. Plicamycin has a relative toxic specificity for osteoclasts preventing their resorption, and lowers plasma calcium concentration in hypercalcemic patients—especially those with bone tumors. Toxicities include hemorrhage as well as effects on the bone marrow, liver, and kidneys. 

---