Calcium renal tubular reabsorption

Physiological actions of PTH include regulation of bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption... 

Teriparatide is a parathyroid hormone, which regulates bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium reabsorption. It is indicated in the treatment of postmenopausal women with osteoporosis who are at high risk for fracture (e.g., history of osteoporotic fracture) and to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk of fracture (e.g., history of osteoporotic fracture). 

Tables 63-6.5 list some of the causes that affect plasma calcium, magnesium, and phosphate. Increased plasma calcium concentration may occur when the xeno-biotic specifically targets calcium metabolism, behaves similarly to vitamin D, and causes hyperparathyroidism or renal disease. Lead and cadmium enter bone and inhibit bone growth, increase calcium release from bone, and inhibit renal tubular reabsorption of calcium salts lead inhibits the renal bioactivation of 25-hydroxy-cholecaliciferol (Sauk and Somerman 1991). In longer-term studies, increased plasma calcium may be associated with tumor burden. Because roughly half of circulating calcium is bound to plasma albumin, hypercalcemia can also arise from dehydration. Hypoparathyroidism, pancreatitis, and renal disease can reduce plasma calcium. Acidosis increases plasma-ionized calcium concentrations, whereas alkalosis causes a decrease due to the effects of pH in the ECF or on protein binding.

Calcitonin acts on receptors in bone osteoclasts with a resulting reduction of bone resorption, and it also acts on the renal tubular reabsorption of phosphate. The phosphaturic effects are accompanied by diuresis and increased excretion of other electrolytes. Calcitonin and parathyroid hormone act as a dual negative feedback mechanism in controlling calcium in intra- and extracellular fluids. The range of calcitonin assays suitable for laboratory animals is limited, but the hormone can be measured by two-site radioimmunometric assays (Moukhtar et al. 2005). 

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. ... 

Calcium ion activity in blood is strictly regulated by a hormonal feedback mechanism. When the activity tends to decrease, the parathyroids secrete parathyroid hormone (PTH), which stimulates renal tubular reabsorption of Ca , K , and Na and decreases the reabsorption of phosphate. The net effect is a decreased excretion of Ca , Na" ", and K and an increased excretion of phosphate. PTH stimulates the hydroxylase activity in the kidney, and there is a negative feedback system which means that an increased amount of 1,25(OH)2D3 inhibits this hydroxylation procedure. Other hormones such as prolactin, estrogen, and growth hormone also stimulate hydroxylase activity, as does as a low serum phosphate concentration [6]. 

Ciclosporin increases the survival of allografts in man. However, it causes renal vasoconstriction and increases proximal tubular reabsorption, leading in some cases to hjrperten-sion (20). The concomitant use of calcium channel blockers can prevent most of these adverse effects of ciclosporin. However, some calcium channel blockers (verapamil, dUtia-zem, nicardipine) can increase plasma concentrations of ciclosporin up to three-fold through inhibition of cjhochrome P450. Eight different studies have been performed on the combination of amlodipine and ciclosporin given for 1-6 months to kidney transplant recipients, and the results have been reviewed (21). In three studies, in a total of 41 patients, amlodipine increased ciclosporin concentrations, while in the others, a total of 85 patients, there was no evidence of an interaction. 

After persistent hypercalciuria, osteopenia can develop, causing metabolic bone disease, pathological fractures, and immobilization. Hypercalciuria can also lead to nephrolithiasis and nephrocalcinosis, factors that can impair renal function. Intravenous chlorothiazide has been successfully used for its hypocalciuric effect, with remarkable effect over a period of 6 months in a 13-year-old child who had received parenteral nutrition for 6 years. Calcium excretion and tubular reabsorption of phosphate returned to normal (48). What is not clear from this study is whether the drug actually has a positive long-term beneficial effect on metabolic bone disease. 

Renal magnesium wasting is the main mechanism responsible for the hypomagnesemia associated with cisplatin (172), and it can be associated with enhanced tubular reabsorption of calcium and consequent hypocalciuria (173). This dissociation in the renal handling of calcium and magnesium is similar to what is found in Bartter s syndrome. The site of the renal tubular defect in these conditions is not known, but there is evidence that active renal tubular transport systems are disrupted. 

The amount of calcium excreted into the urine reflects intestinal absorption, skeletal resorption, and renal tubular filtration and reabsorption. Under fasting conditions, the intestinal and renal components are relatively fixed, and calcium excretion (miUigrams per 100 mL of GF) in the fasting state is used to assess the skeletal component. A value exceeding 0.16 mg/lOO mL (>0.04 mmol/L) of GF usually implies an increase in osteoclastic bone resorption. This test is useftil in assessing renal stone disease and high-turnover osteoporosis. 

As intestinal absorption of calcium increases, urinary calcium excretion also increases. When the latter exceeds 300 mg/d, formation of calcium phosphate or calcium oxalate stones (urolithiasis) may occur. Hypercalciuria may result from decreased reabsorption of calcium due to a renal tubular defect or from increased intestinal absorption of calcium. Hypercalciuria may be due to an intrinsic defect in the intestinal mucosa or secondary to increased synthesis of 1,25-(OH)2D in the kidney. Disordered regulation of 1,25-(0H)2D synthesis is relatively common in idiopathic hypercalciuria. Treatment usually includes reduction in dietary calcium. Increased vitamin D intake, hyperparathyroidism, and other disorders can also cause hypercalciuria and urolithiasis. 

A second member of the parathyroid hormone family, parathyroid hormone-related protein (PTHrP), is quite similar to PTH in amino acid sequence and protein structure. Like PTH, it activates the parathyroid hormone receptor causing increased bone resorption and renal tubular calcium reabsorption. Increased serum concentrations of parathyroid hormone-related protein are the predominant cause of hypercalcemia in cancer patients with solid tumors. This observation led to its discovery and to the elucidation of its many cellular functions in normal tissues. In contrast to PTH, which is expressed only in parathyroid glands, PTHrP is detected in many tissues in fetuses and adults it is found in epithelia, mesenchymal tissues, endocrine glands, and the central nervous system. This protein is also the principal regulator of placental calcium transport to the fetus. 

The most common cause of hyperphosphatemia is a decrease in urinary phosphorus excretion secondary to decreased glomerular filtration rate. ° Retention of phosphorus decreases vitamin D synthesis and induces hypocalcemia, which leads to an increase in PTH. This physiologic response inhibits further tubular reabsorption of phosphorus to correct hyperphosphatemia and normalize serum calcium concentrations. Patients with excessive exogenous phosphorus administration or endogenous intracellular phosphorus release in the setting of acute renal failure may develop profound hyperphosphatemia. Severe hyperphosphatemia is commonly encountered in patients with chronic kidney disease, especially those with GFRs less than 15 mL/ min per 1.73 m (see Chap. 44). 

Renal calcium transport Because the vertebrate organism is in constant need for calcium from the environment in order to maintain skeletal integrity, the calcium that is cleared from the circulation by glomerular filtration must be efficiently reabsorbed during the course of its passage along the renal tubular epithelium (for a review, Bushinsky 1999). The bulk of filtered calcium ( 70%) is reabsorbed in the proximal tubule, mainly on the paracel-lular route, while 20% is reabsorbed in the loop of Henle, where transcellular calcium transport - which is probably under the influence of PTH - becomes increasingly important. Reabsorption of 8% of filtered calcium occurs in the distal convoluted tubule, and involves transcellular transport that is activated by PTH and l,25(OH)2D3 (Bronner 1989). 

Independently of PTH and l,25(OH)2D3, the extracellular calcium-sensing receptor (CaR) (Riccardi et al. 1995) controls renal calcium reabsorption, namely by inhibiting tubular reabsorption when the level of peri-... 

Hypercalcemia of malignancy is a common occurrence in solid tumors of the lung and breast as well as multiple myeloma and adult T-cell lymphoma/leukemia (26). The hypercalcemia associated with breast cancer is usually seen in late stages of the disease in patients with extensive bone metastases. In squamous cell carcinoma of the lung or kidney, however, hypercalcemia is not correlated with disease stage and is not necessarily associated with bone metastases. The hypercalcemia results from increased bone resorption, decreased bone formation and increased renal tubular calcium reabsorption. These findings suggest that some tumors may secrete humoral factors with PTH-like actions. 

All the hyperuricosuric patients in this investigation had a urate clearance of the same order as the controls. Only one hyperuricosuric patient had a clearance urate/clearance creatinine of 14.5%, thus exceeding the 95% tolerance limit in the controls. In this patient, however, 95% of the excretion was PZA suppressible. The PZA-suppressible fraction of urate excretion and the tubular reabsorption of filtered urate in hyperuricosuric stone formers did not differ from the controls. Thus it is concluded that the renal tubular handling of urate in hyperuricosuric calcium stone patients does not differ from that of healthy subjects. 

Strontium is excreted in urine and, to a lesser extent, in feces, milk, and sweat. In healthy adult subjects, total clearances of 9.4-11.7 mL/min [58,59] were demonstrated, while the renal clearance appeared to vary between 4.0 and 5.4 mL/min [58,59]. Studies based on the simultaneous administration of radioactive calcium and strontium revealed that the strontium/calcium ratio is higher in urine than in the glomerular filtrate, which suggests that the two elements are discriminated during tubular reabsorption in the kidney [72-74]. In the process of aging, the strontium/calcium ratio in urine decreases rapidly until about 25 weeks of age, followed by a much slower decrease [5]. 

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. 

A group of patients forming calcium oxalate stones are hyperuri-cosuric and it is thought that their excessive urate excretion contributes to calcium-stones formationl. The pathomechanisms invoked are dietary purine excess and endogenous uric acid overproduction, being defective tubular reabsorption of urate "unattractive because uricemia was found to be normal in patients with recurrent calcium nephrolithiasis (RCN) and hyperuricosuria. Current studies were undertaken to define the incidence, role of diet, abnormalities of the renal handling of urate, and associated metabolic disturban-c"es in patients with RCN and hyperuricosuria. 

A major regulator of Pi is PTH, whose role has been fairly well uncovered. PTH increases bone resorption of Pi (and calcium ions), it blocks renal tubular Pi reabsorption following glomerular filtration (whereas PTH favors calcium reabsorption), and it enhances intestinal Pi absorption (and calcium absorption) via the vitamin D hormone, l,25(OH)2 vitamin D. Other hormones have more modest effects on serum Pi concentration. 

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