Kidney phosphate homeostasis

Schiavi SC, Kumar R The phosphatonin pathway new insights in phosphate homeostasis. Kidney Int 65 1-14,2004. 

Figure 1 Phosphorus homeostasis and balance. The intestine, kidneys, and bone are organs Involved in phosphate homeostasis. Fluxes of phosphate ions between blood and these organs are shown. Note the high fluxes in and out of bone each day. To convert phosphorus values from g to mmol, multiply by 32.29 from mg/dl to mmol/l, multiply by 0.3229. Steps enhanced by parathyroid hormone. (Adapted with permission from Anderson JJB, Sell ML, Garner SC, and Calvo MS (2001) Phosphorus. In Bowman BA and Russell R (eds.) Present Knowledge in Nutrition, 8th edn, p. 282. Washington, DC International Life Sciences Institute Press.)...

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. 

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 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. 

Calcium and phosphate enter the body from the intestine. The average American diet provides 600-1000 mg of calcium per day, of which approximately 100-250 mg is absorbed. This figure represents net absorption, because both absorption (principally in the duodenum and upper jejunum) and secretion (principally in the ileum) occur. The amount of phosphorus in the American diet is about the same as that of calcium. However, the efficiency of absorption (principally in the jejunum) is greater, ranging from 70% to 90%, depending on intake. In the steady state, renal excretion of calcium and phosphate balances intestinal absorption. In general, over 98% of filtered calcium and 85% of filtered phosphate is reabsorbed by the kidney. The movement of calcium and phosphate across the intestinal and renal epithelia is closely regulated. Intrinsic disease of the intestine (eg, nontropical sprue) or kidney (eg, chronic renal failure) disrupts bone mineral homeostasis. 

Q7 Calcium is present in both intracellular fluid (ICF) and ECF, but the concentration in the ECF is twice as high as that in the ICF. Calcium is found in both ionized and bound forms, and Ca2+ homeostasis is mainly controlled by parathyroid hormone, which increases absorption of calcium in the intestine and reabsorption in the nephron. Calcitonin also affects ECF calcium concentration by promoting renal excretion when there is an excess of calcium in the body. The normal kidney filters and reabsorbs most of the filtered calcium however, in renal disease this is reduced and blood calcium decreases. Calcium and phosphate imbalance can occur in patients with renal failure, leading to osteomalacia (defective mineralization of bone). Osteomalacia is mainly due to reduced production of 1,25-dihydroxycholecalciferol, an active form of vitamin D metabolized in the kidney. Deficiency of 1,25-dihydroxycholecalciferol reduces the absorption of calcium salts by the intestine. 

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. 

Dietary phosphate intake is usually 1.2 to 1.4 g (39 to 45 mmoi)/day, nearly twice the recommended intake, of which approximately 60% to 70% is absorbed, principally in the jejunum. As with calcium, both passive and active transport systems exist 1,25(OH)2D is the prmcipal regulator of the active transport of phosphate. PTH-stimulated synthesis of 1,25(0H)2D thus offsets the phosphaturic effect of PTH. The prevailing serum phosphate concentration also modulates renal 25(0H)D-la-hydroxylase. Phosphate depletion or hypophosphatemia stimulates formation of l,25(OH)2D by the kidneys. In general, at pharmacological concentrations, calcitonin has the opposite effect of PTH. It is unclear, however, if calcitonm has any physiological role in mineral homeostasis in adult humans. 

Digestion of dietary substances and tissue metabolism also results in the production of nonvolatile acids. These acids are derived primarily from the sulfur-containing amino acids cysteine and methionine, as well as from ingested sulfur. In addition, phosphates are generated from the metabolism of proteins and phospholipids. Neutral substances such as glucose may also be incompletely metabolized to intermediates, such as lactic and pyruvic acid, and fatty acids may be incompletely metabolized to acetoacetic acid and / -hydroxybutyric acid. These dietary and metabolic fixed acids are excreted, primarily by the kidney, to maintain acid-base homeostasis. On average, daily fixed acid excretion is approximately 0.8 mEq/kg per day. ... 

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. 

A number of hormones interact to regulate the and phosphate concentrations. The most important are PTH and 1,25-dihydroxyvitamin D (l,25-(OH)2D caldtriol), which regulate mineral homeostasis by effects on the kidney, intestine, and bone (Figure 61-3). 

Since phosphate is also involved in calcium homeostasis via its effects on the renal 25-OHD-la-hydroxylase (and not involving PTH), an imbalance of calcium and phosphate in the diet, or impairment of absorption, can lead to derangement of the control mechanism. It is of interest in relation to food safety evaluation that, in rats, calcium deposition in the kidney (nephrocalcinosis) has been observed in a number of studies on modified starches and microbial biomass . In the latter case, rats fed Candida utilis biomass rich in phosphorus and low in calcium developed nephrocalcinosis, but when the Ca/P ratio was adjusted to unity, renal changes were minimal. There is a clear lesson to be learned here if dietary imbalance per se can cause, or increase the severity of, pathological lesions, particular caution has to be exercised in the design and interpretation of toxicity tests where the test material is included in the diet at high concentrations. 

The kidneys are two fist-sized organs whose primary function is to generate urine for excretion of water and metabolic waste products. The kidneys not only remove accumulated nitrogen products (urea, creatinine, uric acid, and others) but also maintain homeostasis of water and electrolytes (sodium, potassium, chloride, calcium, phosphate, magnesium) and regulate acid-base balance. In addition, human kidneys perform a few endocrine and metabolic functions, such as production of the hormone erythropoietin (a hormone that stimulates blood cell production) and conversion of vitamin D to its active form. Because of the tremendous overcapacity of normal kidney function, a person can live with only a fraction of normal kidney capacity, and the 0.1% of the population who are bom with a single kidney often are not even aware of the missing kidney. 

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