Control of parathyroid function in patients with a short history of hemodialysis

Secondary hyperparathyroidism (SHPT) is one of the serious complications in patients with chronic kidney disease. Parathyroid glands secrete parathyroid hormone (PTH), stimulated partly by hyperphosphatemia and hypocalcemia complicating chronic kidney disease (CKD). Use of a calcium-based phosphate binder might be sufficient to reduce serum PTH levels in mild SHPT, while the recent K/DOQI clinical guidelines recommended vitamin D therapy for dialysis patients with serum level of intact parathyroid hormone of 300 pg/mL or more. We conducted a 6-month prospective controlled trial of 50 patients initiating hemodialysis therapy who were randomized to receive oral calcium carbonate alone or the drug plus oral vitamin D sterol, calcitriol or alfacalcidol. The primary end point was the proportion of randomized patients who had a mean PTH level of 300 pg/mL or less at the end of this study. The secondary end point included the percent change in the values for corrected calcium, phosphorus, the calcium-phosphorus product, and PTH. Eighty percent of patients receiving calcium carbonate without vitamin D sterols (20 of 25) reached the primary end point-a mean PTH level of 300 pg/mL or less after the period-as compared with 84% of those receiving calcium carbonate and vitamin D sterol (21 of 25) (Mantel-Haenszel odds ratio 0.76, 95% confidence interval: 0.18-3.25, P = 0.71). The other effects of the two regimens on the secondary end points were not significantly different after 6 months. In SHPT of dialysis patients initiating hemodialysis, oral calcium carbonate use alone was not inferior to additional vitamin D sterol use with calcium carbonate in reducing serum PTH levels. Our result indicated that, if serum calcium and phosphorus levels are controlled primarily regardless of used agents, it will be followed by reduction of serum PTH level in these patients.     

The role of the vitamin D receptor in regulating vitamin D metabolism: a study of vitamin D-dependent rickets, type II

In vitro studies and animal experiments suggest that the production of 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] and 24,25-(OH)(2)D is reciprocally controlled by 1,25-(OH)(2)D. To investigate the role of the vitamin D receptor (VDR) in controlling vitamin D metabolism in humans, we studied 10 patients with vitamin D-dependent rickets type II due to a defective VDR. After a period of high dose calcium therapy, 7 of the patients had normal serum calcium, phosphorus, alkaline phosphatase, and plasma PTH levels (PTH-N), and 3 showed increased serum alkaline phosphatase and plasma PTH (PTH-H). Serum calcium, phosphorus, alkaline phosphatase, PTH, vitamin D metabolites, urinary calcium/creatinine, and renal phosphate threshold concentration were compared with unaffected family members that comprised the control group. Vitamin D metabolites were measured before and after an oral load of 50,000 U/m(2) cholecalciferol. Compared with the control group, 1,25-(OH)(2)D levels were significantly higher and 24,25-(OH)(2)D levels were lower in the PTH-N group and even more so in the PTH-H group. 1alpha-Hydroxylase (1-OHase) and 24-OHase activities were estimated by the product/substrate ratio. In the PTH-N group, 1-OHase activity was higher and 24-OHase activity was lower than in controls. In the PTH-H group, 1-OHase activity was even higher, probably due to an additive effect of PTH. Thus, 1,25-(OH)(2)D-liganded VDR is a major control mechanism for vitamin D metabolism, and PTH exerts an additive effect. Assessment of the influence of 1,25-(OH)(2)D shows reciprocal control of enzyme activity in man, suppressing 1-OHase and stimulating 24-OHase activity.     

Regulatory mechanisms of circulating fibroblast growth factor 23 in parathyroid diseases

Fibroblast growth factor-23 (FGF-23) is a circulating factor regulating phosphate and vitamin D homeostasis. Phosphate intake and an administration of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) increase circulating FGF-23 levels, and elevated FGF-23 prevents hyperphosphatemia and vitamin D toxicity by hyperphosphaturia and suppression of circulating 1,25(OH)(2)D level, comprising a feedback loop to maintain phosphate and vitamin D homeostasis. Excess secretion of parathyroid hormone (PTH), another phosphaturic factor, elevates the serum calcium level in primary hyperparathyroidism. PTH also elevates circulating FGF-23 level, which cooperatively enhances the phosphaturia, resulting in hypophosphatemia. The circulating FGF-23 level increases as renal function declines in chronic kidney disease (CKD), and it exhibits significant and positive correlations with serum phosphate, calcium, and PTH in CKD patients on maintenance hemodialysis, suggesting that these parameters regulate circulating FGF-23 level. Tight associations between circulating FGF-23 and calcium levels were observed both in patients with primary hyperparathyroidism and in CKD patients on maintenance hemodialysis, suggesting the role of serum calcium on FGF-23 regulatory mechanisms. FGF-23 may have a physiological role in preventing tissue damage such as ectopic calcifications, partly via suppressing the serum calcium x phosphate product by accelerating urinary phosphate excretion and suppressing vitamin D activation.     

Serum vitamin D metabolites and their binding protein in patients with liver cirrhosis

Serum parameters of calcium metabolism were measured in 32 consecutive patients with biopsy-proven cirrhosis due to either hepatitis (n = 13), alcohol abuse (n = 11), Wilson's disease (n = 3), or primary or secondary biliary cirrhosis (n = 5). All measurements were normal in the small group of patients with Wilson's disease. The serum concentrations of albumin, vitamin D-binding protein, total calcium, phosphorus, and 1,25-dihydroxyvitamin D3 (1,25-(OH2)D3) were decreased in the other patients with cirrhosis, but their mean serum concentrations of ionized calcium, 25-hydroxyvitamin D3 (25-OHD3) and free 1,25-(OH2)D3 index were normal. A slight but significant increase in the serum PTH measured using a carboxyl-terminal antiserum was found. A significant correlation was found between the serum concentration of either albumin or vitamin D-binding protein and the serum concentrations of total calcium, 25-OHD3, 1,25-(OH2)D3, and PTH but not with ionized calcium or free 1,25-(OH2)D3 index. The observed abnormalities of calcium metabolism in unselected patients with cirrhosis were mainly due to decreased protein synthesis. Only the patients with severe cirrhosis had decreased concentrations of 25-OHD3 but they were nevertheless able to maintain a normal ionized serum calcium and free 1,25-(OH2)D3 level, possibly by means of compensatory hyperparathyroidism.     

New therapeutic strategies in secondary hyperparathyroidism on dialysis (II): vitamin D analogues and calcium-mimetics

Secondary hyperparathyroidism (SHP) is a frequent complication of dialysis patients. In this second article we will analyze the new vitamin D analogs, capable of decreasing parathyroid hormone (PTH) levels with a lower effect on intestinal calcium and phosphorus absorption. Among other advantages described in the experimental setting, paricalcitol shows a survival benefit in dialysis patients as compared to calcitriol, at least in retrospective studies, and thus it became our first-line vitamin D derivative. Calcimimetics are unique since they decrease PTH levels without increasing serum calcium and phosphorus. Actually, calcium and phosphorus decrease in a significant number of patients. These drugs will soon be authorized in Spain, and we describe the better achievement of K/DOQI guidelines as well as other beneficial effects observed in the experimental animal with them. Finally, we mention the potential benefit of mild metabolic acidosis, the use of bisphosphonates, the role of bone morphogenetic protein BMP-7, and the use of teriparatide. The future treatment of SHP will probably require the independent management of calcium, phosphorus, vitamin D and PTH. Thus, low-dose combined treatments with selective drugs may prove more effective than sequential therapies.     

High-turnover-Osteodystrophie

In chronic kidney disease hyperphosphatemia, vitamin D deficiency and rising fibroblast growth factor (FGF) 23 levels lead to increased parathyroid hormone (PTH) levels. Progressive hyperparathyroidism which has been present for long periods of time leads to an increase in bone turnover (high turnover osteodystrophy, HTO) which in turn leads to demineralization of the skeleton, bone fractures and calcification of soft tissue and blood vessels. A decrease in PTH and treatment of HTO can be achieved by administration of vitamin D and/or cinacalcet as well as optimized phosphate control and balanced calcium metabolism. In HTO therapy, target levels of phosphate, calcium and PTH should be considered and bone metabolism should be maintained at a slightly elevated level in order to prevent low turnover osteodystrophy.     

Persistence of parathyroid hypersecretion after vitamin D treatment in Asian vegetarians

An investigation into plasma calcium concentrations and the biochemical factors which regulate it in vegetarian Asian subjects without clinical or radiological features of osteomalacia revealed the presence of low serum 25-hydroxyvitamin D concentrations and elevated PTH concentrations, even in the presence of calcium levels in the normal range (up to 2.35 mmol/liter). These elevated PTH concentrations, though not as high as those in osteomalacic patients with hypocalcemia, often persisted despite treatment with vitamin D, normalization of 25-hydroxyvitamin D, and an increase in calcium concentrations. In one patient the PTH concentration remained high even when the plasma calcium concentration became supranormal. Therefore, secondary hyperparathyroidism is commonly associated with vegetarianism, and may play an important role in maintaining calcium concentrations within the normal range. Persistent elevation of PTH despite normalization of 25-hydroxyvitamin D also points to autonomous PTH hypersecretion, which may result in osteolysis in the long term, and raises the question of the need for vitamin D supplementation in vegetarians with low dietary intake of vitamin D.     

On the mechanism of secondary hyperparathyroidism in moderate renal insufficiency

The effect of prolonged (60 days) dietary phosphate restriction on divalent ion metabolism was studied in four patients with moderate renal insufficiency in an effort to delineate the mechanisms of secondary hyperparathyroidism in renal failure. The patients had low normal serum phosphorous and normal vitamin D metabolite levels but had evidence of disturbances in target organs for vitamin D, including impaired intestinal absorption of calcium, reduced calcemic response to PTH, low serum ionized calcium levels, and, consequently, elevated PTH levels. After dietary phosphate restriction, there was marked improvement or normalization of intestinal absorption of calcium, calcemic response to PTH, and ionized calcium and PTH levels. There was also a significant rise (44%) in serum 1,25-dihydroxyvitamin D levels. The data suggest that intracellular phosphorous retention, which may develop as renal insufficiency ensues, may interfere with the action and production of 1,25-dihydroxyvitamin D. This leads to defective intestinal calcium absorption and reduced calcemic responses to PTH. As a result, hypocalcemia develops, causing secondary hyperparathyroidism. Our data assign a critical role for a disturbance(s) in vitamin D metabolism in genesis of the hyperparathyroidism of renal failure.     

Vitamin D therapy in predialysis renal failure

Vitamin D therapy is indicated in predialysis renal failure patients with secondary hyperparathyroidism caused by vitamin D deficiency. Vitamin D therapy brings about suppression of PTH and ameliorates oseitis fibrosa. To prevent aggravation of renal function, starting with small dose (0.25 microg/day) of calcitriol or alfacalcidol and dose adjustment of vitamin D with careful monitoring of serum calcium, phosphorus and PTH are recommended.     

60万单位维生素D3单次口服治疗维生素D缺乏

目的寻找治疗维生素D缺乏有效且依从性良好的治疗方案,为寻找治疗维生素D缺乏症的理想治疗方案提供依据。方法采用前瞻性干预方法,给予62例维生素D缺乏症患者单次口服60万单位负荷剂量维生素D3,观察用药第4、30、60和90天血钙、磷、尿钙和血清25OHD和甲状旁腺素（PTH）水平。结果患者血清25OHD水平基线值为（8.9±2.9）ng/m L,用药第4天为（58.9±11.1）ng/m L,第90天为（30.3±9.6）ng/m L,差异均有统计学意义（均P〈0.001）;PTH基线值水平为（66.6±30.2）pg/m L,用药第4天降至（32.7±21.6）pg/m L,第90天为（38.8±18.3）pg/m L,差异均有统计学意义（均P〈0.001）;用药后不同时点血钙与和血磷均较基线水平升高,但在正常值范围内;尿钙水平在用药第4天显著升高,但高尿钙患者未见明显增多。所有受试者均未出现泌尿系结石。结论单次口服60万单位负荷剂量维生素D3,可快速纠正维生素D缺乏,维持血清25OHD理想水平并持续3个月,该治疗方案可有效逆转继发性甲状旁腺功能亢进,且未增加发生高钙血症和高尿钙的危险。     

Perinatal vitamin D metabolism. IV. Maternal and cord serum 24,25-dihydroxyvitamin D concentrations.

Fetal and maternal compartments differ in factors shown to regulate 24.25 dihydroxyvitamin D [24,25(OH)2D] metabolism [calcium, phosphorus, and parathyroid hormone (PTH)] such that one might predict that maternal serum 24,25(OH)2D levels are decreased and fetal 24,25(OH)2D concentrations are increased. To evaluate this, 25-hydroxyvitamin D (25OHD), 24,25(OH)2D, calcium, magnesium, calcitonin, and PTH were measured in 24 paired maternal and cord sera. The mean maternal serum 24,25(OH)2D concentration (2.9 +/- 0.26 ng/ml) was significantly lower than that of nonpregnant females (3.9 +/- 0.37 ng/ml). Mean serum PTH and calcitonin levels were, however, normal in maternal sera. The normal elevations of PRL, estrogen, and placental lactogen in serum of pregnant women could possibly decrease 24,25(OH)2D production, as seen in animal experimental systems. There was no correlation (R = -0.25) between 24,25(OH)2D levels in maternal and cord sera, as predicted; however, mean (+/-SE) fetal 24,25(OH)2D (2.5 +/- 0.26 ng/ml) was similar to the mean maternal concentration and significantly below the mean level in normal adults. The low fetal 24,25(OH)2D concentration may be due to 1) decreased 24-hydroxylase capacity of the fetus; 2) regulation by fetal factors other than calcium, phosphorus, and PTH; or 3) increased utilization of 24,25(OH)2D possibly for fetal bone mineralization.     

Effects of insulin on altered mineral and vitamin D metabolism in streptozotocin-induced diabetes

In order to ascertain whether or not abnormal mineral and vitamin D metabolism in diabetes can be reversed by insulin therapy, plasma calcium, ionized calcium, phosphorus, parathyroid hormone (PTH) and vitamin D metabolites were measured in control, streptozotocin (STZ) diabetic and insulin-treated diabetic rats. Blood glucose levels in diabetic rats treated with insulin decreased to normal. The low plasma calcium and ionized calcium levels in diabetic rats were found to be normal in insulin-treated diabetic rats. An elevated PTH level was observed in the diabetic group, but it was at normal levels in the insulin-treated diabetic group. Plasma 25-hydroxyvitamin D (25(OH)D) and 24,25-dihydroxyvitamin D (24,25(OH)2D) in the diabetic group were decreased compared to those in control rats, but these were also fully restored to control levels by insulin therapy. However, plasma 1,25-dihydroxyvitamin D (1,25(OH)2D) levels in the untreated diabetic group tended to be lower than in controls, and the values in insulin-treated rats were significantly decreased compared to the control group. The ratio of 1,25(OH)2D to 25(OH)D in diabetic rats was higher than in controls, but it was decreased after insulin therapy and was significantly lower than in the control group. It is suggested, therefore, that the negative calcium balance and decreased 25(OH)D and 24,25(OH)2D levels are derived from the metabolic derangement due to the insulin deficiency. Furthermore, insulin seems to suppress the conversion of 25(OH)D to 1,25(OH)2D in experimental diabetes in vivo.     

1,25-Dihydroxycholecalciferol deficiency: the probable cause of hypocalcemia and metabolic bone disease in pseudohypoparathyroidism.

Pseudohypoparathyroidism (PsH) is a genetic disease characterized by hypocalcemia, hyperphosphatemia, and metabolic unresponsiveness to parathyroid hormone (PTH). The administration of PTH elicits neither a significant rise in serum calcium (calcemic response) nor a decrease in the renal tubule reabsorption of phosphorus (phosphaturic response). The diminished phosphaturic response is due to an inability of PTH to generate cyclic AMP in renal tubule cells. We investigated the question of whether hypocalcemia and deficient calcemic response to PTH are due to a similar cyclic AMP defect in bone or to an acquired vitamin D deficiency. Four patients were studied. The active form of vitamin D (1,25-dihydroxycholecalciferol) was measured in 3 and was low. Treatment with vitamin D2 restored the serum calcium and the calcemic response to PTH to normal without changing the impaired renal response. Bone biopsy was performed in 2 patients and showed morphologic evidence of increased osteoclastic activity and osteomalacia. The data indicate that the hypocalcemia and bone disease in PsH are due to active vitamin D deficiency, possibly resulting from the genetic renal lesion.     

Early Intervention With Intravenous or Pulse Oral Vitamin D Therapy Is More Effective in the Treatment of Secondary Hyperparathyroidism

The K/DOQI clinical practice guidelines recommend vitamin D therapy should be started when the intact parathyroid hormone (iPTH) exceeds 300 pg/mL in patients with secondary hyperparathyroidism. To examine whether the effect of vitamin D therapy on mineral metabolism and parathyroid gland growth varies according to the stage of secondary hyperparathyroidism and iPTH level, 47 patients with secondary hyperparathyroidism received either intravenous or pulse oral vitamin D therapy. The patients were divided into two groups based on the iPTH level at the start of vitamin D therapy: the P_<300 group (N = 23) with iPTH <300 pg/mL; and the P^≥300 group (N = 24) with iPTH ≥300 pg/mL. We examined serial changes in several serum mineral parameters and parathyroid gland volume and the cumulative incidence of parathyroidectomy in the first two years. Serum calcium, phosphorus, calcium–phosphorus product, and iPTH levels of the P^≥300 group were significantly higher than those of the P_<300 group, and could not be maintained within the target ranges set by the K/DOQI guidelines. In contrast, the serum levels of phosphorus, calcium–phosphorus product, and iPTH were maintained within the target ranges and the parathyroid gland did not enlarge in the P_<300 group. The cumulative incidence of parathyroidectomy in the P^≥300 group was significantly higher than in the P_<300 group. Early intervention with intravenous or pulse oral vitamin D therapy at serum iPTH <300 pg/mL can control serum phosphorus, calcium–phosphorus product, and PTH levels to the target ranges and slow the progression of secondary hyperparathyroidism.     

Normal and abnormal regulation of 1,25-(OH)2D synthesis

1,25-Dihydroxyvitamin D (1,25-(OH)2D) plays a crucial role in the maintenance of blood calcium and phosphorus levels and in normal skeletal mineralization. The concentration of this metabolite in the blood is, by necessity, tightly regulated. The most important stimuli for renal 1,25-(OH)2D synthesis include parathyroid hormone (PTH), its second messenger cyclic adenosine monophosphate (cAMP) and phosphate deprivation. Hypocalcemia and calcitonin, initially thought to act via stimulation of PTH release, have now been shown to directly stimulate 1-hydroxylation. Estrogens also increase 1,25-(OH)2D production, probably by upregulating renal PTH receptors. Inhibitors of the renal 25-(OH)D 1 alpha-hydroxylase include 1,25-(OH)2D itself, hypercalcemia, and phosphate loading. The PTH-vitamin D axis as modulated by the serum ionized calcium level controls adaptation to alterations in dietary calcium and sodium intake and to changes in skeletal turnover based on the level of physical activity. Although normally the renal production of 1,25-(OH)2D is tightly regulated and changes little in response to vitamin D challenge, there are certain conditions in which 1,25-(OH)2D appears to be substrate-dependent. These include hypoparathyroidism, hyperparathyroidism, vitamin D deficiency, sarcoidosis and the anephric state, conditions in which PTH is not well-modulated by alterations in serum ionized calcium or in which extrarenal synthesis of 1,25-(OH)2D occurs. In several disorders, including absorptive hypercalciuria, pseudohypoparathyroidism, hypophosphatemic rickets, and tumoral calcinosis, the regulation of the renal 1 alpha-hydroxylase appears to be altered.     

Vitamin D, parathyroid hormone, and acroosteolysis in systemic sclerosis

OBJECTIVE: .Sclerodactyly with acroosteolysis (AO) and calcinosis are prominent features of systemic sclerosis (SSc), but the pathogenesis of these findings is poorly understood. Vitamin D and parathyroid hormone (PTH) have a crucial role in bone metabolism and resorption and may affect AO and calcinosis. We assessed vitamin D and PTH in patients with SSc. METHODS: Medical records of 134 consecutive patients with SSc (American College of Rheumatology criteria) followed at the rheumatology department during the years 2003-2006 were reviewed for clinical assessment, laboratory evaluation [including 25(OH) vitamin D, calcium, phosphorus, alkaline phosphatase, PTH, creatinine, and albumin]; imaging data confirming AO and/or calcinosis. Patients followed routinely at least once a year were included (81 patients). Of these, 60 patients' medical records were found to have complete, relevant clinical, laboratory, and radiographic imaging. RESULTS: Thirteen patients had diffuse disease and 47 limited disease - 51 women and 9 men, 44 Jews and 16 Arabs; mean age 55 +/- 14 years; disease duration 8 +/- 6 years. AO with or without calcinosis was observed in 42 patients (70%). Vitamin D deficiency was found in 46% of patients (16 out of 44 Jewish patients, 10 out of 16 Arab patients). PTH was elevated in 21.7% of patients. Significant correlations were observed between acroosteolysis and PTH (p = 0.015), calcinosis (p = 0.009), and disease duration (p = 0.008), and between PTH and vitamin D levels (p = 0.01). All patients had normal serum concentrations of calcium, phosphorus, magnesium, and albumin, and liver and kidney functions. CONCLUSION: In this group of Mediterranean patients with SSc, the incidence of vitamin D deficiency and secondary hyperparathyroidism was surprisingly high. This finding correlated with the occurrence of AO and calcinosis. Low levels of vitamin D may reflect silent malabsorption and might be a risk factor for secondary hyperparathyroidism and bone resorption. Traditional dress habits and low exposure to sun may contribute to vitamin D deficiency in an Arab population but do not explain all the findings. The pathogenesis of these findings needs to be corroborated in other SSc populations.     

Vitamin D status and related parameters in a healthy population: the effects of age, sex, and season

The effects of age, sex, renal function, and seasonal variation on serum parameters within the vitamin D endocrine system were studied cross-sectionally in a healthy population of 167 men and 114 women, aged 20-94 yr. Serum 25-hydroxy- and 1,25-dihydroxyvitamin D [25OHD and 1,25-(OH)2D] did not decline with age in either sex. Nonlinear regression using a sine function showed a significant seasonal variation in 25OHD and 1,25-(OH)2D in both sexes (P less than 0.005). Serum intact PTH increased significantly by 35% over the age span in both sexes (P less than 0.005). In women, serum phosphorus and total and ionized calcium remained constant with age. In sharp contrast, males had a marked 25% fall in phosphorus across the age span (r = -0.564; P less than 0.0001) and a slight but significant 4% decline in total and ionized calcium. Creatinine clearance declined markedly with age, but was not related to 1,25-(OH)2D in either sex. Only in men was there a significant but modest inverse relationship between creatinine clearance and PTH (r = -0.212; P less than 0.05), which was multicollinear with age. We conclude that in healthy individuals 1) compromised vitamin D status or serum 1,25-(OH)2D levels are not a normal concomitant of aging; 2) declining glomerular filtration does not appear to be the principle cause of the age-related rise in PTH; and 3) there are marked male-female differences in phosphorus metabolism across the age span.     

维生素D缺乏与慢性阻塞性肺疾病

维生素D除了调节钙磷代谢外,近年来大量证据表明它还通过调节炎症因子、氧化应激,以及气道重塑等影响COPD的发展过程。此外,维生素D还能加强呼吸道上皮抗菌肽的表达而产生重要的先天免疫,能够减少病原体负荷和阻塞性肺疾病急性加重的频度。COPD患者的维生素D缺乏经常发生,而且与疾病严重程度相关,因此,严重的COPD患者应该补充维生素D。     

Serum calcium and vitamin D regulate 1,25-dihydroxyvitamin D3 receptor concentration in rat kidney in vivo.

The effects of vitamin D status, serum calcium, and serum phosphorus levels on 1,25-dihydroxyvitamin D receptor levels in kidney were investigated. Weanling rats were fed for 4 weeks on a diet with various levels of calcium and phosphorus with or without vitamin D. The 1,25-dihydroxyvitamin D3 receptor concentration in kidney was determined by an immunoradiometric assay. In the absence of vitamin D, total receptor concentration is increased 2-fold by an increase in serum calcium concentration. At normal serum calcium levels, the administration of vitamin D resulted in a 5-fold increase in receptor concentration. In hypocalcemic animals, however, vitamin D did not change receptor levels. Serum phosphorus levels could not be linked to any changes in 1,25-dihydroxyvitamin D3 receptor concentration. This study demonstrates that serum calcium levels and vitamin D regulate 1,25-dihydroxyvitamin D3 receptor concentration in vivo in kidney. On the other hand, vitamin D is unable to exert control of receptor levels in kidney under hypocalcemic conditions.