Kidney calcium homeostasis

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. 

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. 

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. 

The kidney is an endocrine organ. The classification of calcitriol (vitamin D3) as a vitamin is erroneous because the active molecule is synthesized in vivo by a process which usually provides an adequate amount to ensure correct calcium homeostasis. The final step in the biosynthesis of calcitriol (also known as 1,25 cholecalciferol or 1,25... 

The GP made a provisional diagnosis of osteomalacia and prescribed vitamin D supplements. Vitamin D measurements are not performed routinely, but the assumption is that a low result would have been obtained on the blood sample. Most of the vitamin D necessary to maintain normal calcium homeostasis is derived from endogenous synthesis by reactions in the skin (which require UV radiation from sunlight), liver and kidney. The cultural habits of Mrs Al-Ameri required her to dress in a burqah and niqab whenever she left the home, meaning that very little of her skin was exposed to daylight. 

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... 

Vitamin Dj, through its active metabolite, 1,25-(0H)2D3, also plays an important role in maintaining calcium homeostasis by enhancing intestinal calcium absorption, PTH-induced mobilization of calcium from bone, and calcium reabsorption in the kidney. 

Vitamin D is the collective term for a group of compounds formed by the action of ultraviolet irradiation on sterols. Cholecalciferol (vitamin D3) and calciferol (vitamin D2) are formed by irradiation of the provitamins 7-dehydrocholesterol and ergosterol, respectively. The conversion to vitamin D3 occurs in the skin. The liver is the principal storage site for vitamin D, and it is here that the vitamin is hydroxylated to form 25-hydroxyvitamin D. Additional hydroxylation to form 1,25-dihydroxyvita-min D occurs in the kidney in response to the need for calcium and phosphate. A discussion of the role of vitamin D in calcium homeostasis is provided in Chapter 66. 

CaR expression is greatest in the parathyroid glands, calcitonin-secreting C-cells of the thyroid gland, and kidney, but the CaR is also found in the two other key organs that participate in calcium homeostasis gut and bone (Brown and MacLeod, 2001). This review will focus on the structure and function of the CaR, its role in normal physiology and in various disorders of Ca -sensing, and the development of CaR-based therapeutics. 

The kidney plays several critical roles in calcium homeostasis. The CaR is widely expressed along essentially the whole nephron. The cellular localization and putative function(s) of the CaR in the kidney seem to depend upon the region of the nephron in which the receptor resides (Ward and Riccardi, 2002). The CaR s... 

The physiological role of vitamin D is to maintain calcium homeostasis. Phosphate metabolism is also affected. Vitamin D accomplishes its role by enhancing the absorption of calcium and phosphate from tte small intestines, promoting their mobilization from bone, and decreasing their excretion by the kidney. Also involved are parathyroid hormone and edeitonin. 

Cholecalciferol is a rodenticide that has been introduced relatively recently and that has been reported to be frequently involved in poisonings of dogs. The compound alters calcium homeostasis by promoting calcium absorption from the gut and also by mobilizing calcium from bone for tissue deposition. Consequently, poisoned animals have increased levels of blood calcium. The calcium is then subsequently deposited in soft tissues like the kidneys, digestive tract mucosa, lungs, heart, liver, and muscle. Mineralization of soft tissues interferes with normal function of these organs. 

Under normal conditions each of the two million nephrons of the kidney work in an organized approach to filter, reabsorb, and excrete various solutes and water. The kidney is a primary regulator of sodium and water as well as acid-base homeostasis. The kidney also produces hormones necessary for red blood cell synthesis and calcium homeostasis. Impairment of normal kidney function is often referred to as renal insufficiency. Based on the time course of development, renal insufficiency has historically been divided into two broad categories. Acute renal failure (ARF) refers to the rapid loss of renal function over days to weeks. Chronic kidney disease (CKD)", also called chronic renal insufficiency (CRI) by some, is defined as a progressive loss of function occurring over several months to years, and is characterized by the gradual replacement of normal kidney architecture with interstitial fibrosis. Progressive kidney disease or nephropathy is... 

Calcium and phosphorus balance is mediated through the complex interplay of hormones and their effects on bone, the Gi tract, kidney, and parathyroid gland. What begins as relatively minor imbalances in phosphorus and calcium homeostasis leads to secondary hyperparathyroidism (sHPT) in the short term and ultimately renal osteodystrophy (ROD) if these metabolic abnormalities are not corrected. 

The kidney plays a critical role in calcium homeostasis. PTH acts directly on the kidney to suppress calcium ion excretion in the urine by maximizing tubular calcium reabsorption. It increases phosphate ion excretion in the kidney (phosphaturic effect) to prevent excessive accumulation of this anion released during bone demineralization. 

Osteomalacia is caused by deficiency of vitamin D. Vitamin D regulates calcium homeostasis in the body by facilitating absorption of calcium from the intestine and, together with PTH, by enhancing calcium mobilization from bone and by reducing excretion of calcium by the kidney. Deficiency of vitamin D leads to inadequate absorption of calcium. Low levels of calcium stimulate the release of PTH, which in turn causes release of calcium from bone and failure to mineralize newly formed bone. 

Calcium homeostasis is modulated by hormones (Fig. 2). Parathyroid hormone (PTH) is the most important calcium regulator. It is a hormone of 84 amino acids, and is secreted from the parathyroid glands in response to a low unbound plasma calcium. PTH causes bone resorption and promotes calcium reabsorption in the renal tubules, preventing loss in the urine. 1,25-dihydroxycholecalciferol (1.23 DHCC) maintains intestinal calcium absorption. This sterol hormone is formed from vitamin D (cholecalciferol). following hydroxylation in the liver (at carbon-25) and kidney (at carbon-1). However.hydroxylation in the kidney is PTH dependent.andsoeven (he absorption of calcium from the gut relies (albeit indirectly) on PTH. 

Kurokawa, K. 1994. The kidney and calcium homeostasis. Kidney International 45 (Suppl. 44) S97-105. 

Arnaud (7) has developed a butterfly model that provides a diagrammatic view of the complex interrelationships among the three hormones (parathyroid, calcitonin, and vitamin D) that control calcium homeostasis (serum concentrations of ionic calcium) and their target organs (bone, kidney, and intestine) (Fig. 35.1). The right side (B loops) of the butterfly model describes the processes that increase the serum calcium concentration in response to hypocalcemia the left side (A loops) depicts the events that occur in response to hypercalcemia. 

The active form of vitamin D3, la,25-dihydroxy-vitamin D3, is an important regulator of calcium metabolism and elicits most of its biological effects by binding to a high-affmity receptor in target tissues. In the formation of la,25-dihydroxyvitamin D3, vitamin D3 is hydroxylated in two sequential steps. An initial 25-hydroxylation in the liver is followed by an la-hydroxylation in the kidney (De-Luca and ScHNOES 1983). The 25-hydroxyvitamin D3 la-hydroxylase (la-hydroxylase) is the key enzyme in the determination of the level of la,25-dihydroxyvitamin D3 and plays a vital role in calcium homeostasis. It is present in the inner mitochondrial membrane of renal proximal tubular cells (Kawashima et al. 1981, Paulson and DeLuca 1985). While under physiological conditions, the kidney is the only site of la,25-dihydroxyvitamin D3 (DeLuca 1988), in sarcoidosis or lymphoma, la-hydroxylase may be expressed at other sites (Armbrecht et al. 1992). 

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