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E Slatopolsky

Publications and source records attributed to E Slatopolsky.

At least 37 records · Page 2Linked to original sources
PubMed1999

The role of phosphorus in the development of secondary hyperparathyroidism and parathyroid cell proliferation in chronic renal failure.

Hyperplasia of the parathyroid glands and high levels of parathyroid hormone (PTH) are among the most consistent findings in patients with chronic renal failure. In early renal failure, alterations in vitamin D metabolism play a key role in the development of secondary hyperparathyroidism. Low levels of calcitriol and decreased expression of the vitamin D responsive element may allow greater synthesis and secretion of PTH. Phosphorus independent of serum calcium and calcitriol increases PTH synthesis and secretion by a post-transcriptional mechanism. Studies in vivo in uremic rats demonstrated that an increase in dietary phosphorus induces parathyroid gland hyperplasia. If the rats are then fed a low-phosphorus diet, the levels of serum PTH return to normal; however, the size of the parathyroid glands remains enlarged. No apoptosis was observed in the glands. To further characterize the effects of phosphorus on PTH synthesis and secretion, intact rat parathyroid glands were metabolically labeled during a 4-hour incubation in methionine-free medium containing 1.25 mM Ca2+, [35S]methionine, and either 2.8 mM or 0.2 mM phosphorus. Total PTH secretion, as measured in the medium, was increased more than 6-fold in glands incubated in high-phosphorus medium compared with glands incubated in the low-phosphorus medium. Thus, in the past 20 years, numerous investigators have provided strong evidence for the action of phosphorus on PTH secretion. Unfortunately, the absence of a parathyroid cell line is slowing the progress in understanding the molecular mechanism(s) involved in phosphorus regulation of PTH.

Animals↗
PubMed1999

Vitamin D.

The vitamin D endocrine systems plays a critical role in calcium and phosphate homeostasis. The active form of vitamin D, 1, 25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], binds with high affinity to a specific cellular receptor that acts as a ligand-activated transcription factor. The activated vitamin D receptor (VDR) dimerizes with another nuclear receptor, the retinoid X receptor (RXR), and the heterodimer binds to specific DNA motifs (vitamin D response elements, VDREs) in the promoter region of target genes. This heterodimer recruits nuclear coactivators and components of the transcriptional preinitiation complex to alter the rate of gene transcription. 1,25(OH)(2)D(3) also binds to a cell-surface receptor that mediates the activation of second messenger pathways, some of which may modulate the activity of the VDR. Recent studies with VDR-ablated mice confirm that the most critical role of 1, 25(OH)(2)D(3) is the activation of genes that control intestinal calcium transport. However, 1,25(OH)(2)D(3) can control the expression of many genes involved in a plethora of biological actions. Many of these nonclassic responses have suggested a number of therapeutic applications for 1,25(OH)(2)D(3) and its analogs.

Animals↗
PubMed1999

Differential effects of 1,25-dihydroxy-vitamin D3 and 19-nor-1,25-dihydroxy-vitamin D2 on calcium and phosphorus resorption in bone.

1,25-Dihydroxy-vitamin D3 [1,25-(OH)2D3] suppresses the secretion and synthesis of parathyroid hormone (PTH) and has been used in the treatment of secondary hyperparathyroidism. However, 1,25-(OH)2D3 can induce hypercalcemia, which often precludes its use. Therefore, an analog of 1,25-(OH)2D3 that would retain its therapeutic effects but produce minor effects on calcium and phosphorus metabolism could be an ideal tool for the treatment of secondary hyperparathyroidism. It has been shown that 19-nor-1,25-dihydroxy-vitamin D2 [19-nor-1,25-(OH)2D2], an analog of 1,25-(OH)2D3, can suppress PTH levels in uremic rats at doses that do not affect plasma ionized calcium levels. The experiments presented here, using parathyroidectomized rats fed diets deficient in either calcium (0.02%) or phosphorus (0.02%), were performed to compare the effects of 1,25-(OH)2D3 and 19-nor-1,25-(OH)2D2 on calcium and phosphorus resorption in bone. Parathyroidectomized rats received daily intraperitoneal injections of vehicle, 1,25-(OH)2D3 (100 ng), or 19-nor-1,25-(OH)2D2 (100 or 1000 ng) for 9 d. Plasma calcium and phosphorus levels were monitored during the study, and ionized calcium levels were determined at the end of the study. By 9 d, 1,25-(OH)2D3 (100 ng/d) increased total calcium levels to 12.4+/-0.26 mg/dl, compared with 6.32+/-0.25 mg/dl (P<0.001) in control animals. The same dose of 19-nor-1,25-(OH)2D2 (100 ng/d) was much less potent (9.45+/-0.28 mg/dl, P<0.001). Similar results were seen with ionized calcium levels [19-nor-1,25-(OH)2D2, 3.61+/-0.12 mg/dl; 1,25-(OH)2D3, 5.03+/-0.16 mg/dl; P<0.001]. Ionized calcium levels were also lower in rats receiving the higher dose (1000 ng) of 19-nor-1,25-(OH)2D2 (4.59+/-0.09 mg/dl, P<0.05). Similar results were seen in rats fed the phosphorus-deficient diet. 1,25-(OH)2D3 (100 ng) increased plasma phosphorus levels from 4.30+/-0.39 mg/dl in vehicle-treated rats to 7.43+/-0.26 mg/dl (P<0.001). The same dose of 19-nor-1,25-(OH)2D2 had no effect (5.19+/-0.32 mg/dl), whereas the high dose (1000 ng) increased plasma phosphorus levels (7.31+/-0.24 mg/dl) in a manner similar to that of 1,25-(OH)2D3 (100 ng). Therefore, 19-nor-1,25-(OH)2D2 is approximately 10 times less effective in mobilizing calcium and phosphorus from the skeleton, compared with 1,25-(OH)2D3. With its ability to suppress PTH at noncalcemic doses, 19-nor-1,25-(OH)2D2 is a potential therapeutic tool for the treatment of secondary hyperparathyroidism in chronic renal failure.

Animals↗
PubMed1999

A randomized trial of sevelamer hydrochloride (RenaGel) with and without supplemental calcium. Strategies for the control of hyperphosphatemia and hyperparathyroidism in hemodialysis patients.

OBJECTIVE: We have previously shown sevelamer hydrochloride (RenaGel) to be an effective and well-tolerated treatment for hyperphosphatemia in hemodialysis patients. PATIENTS AND METHODS: We performed a randomized clinical trial to compare the efficacy of RenaGel alone and RenaGel with calcium, using the serum phosphorus concentration and intact parathyroid hormone (PTH) as the principal outcomes of interest. Calcium (900 mg elemental) was provided as a once-nightly dose on an empty stomach. 71 patients were randomized and included in the intent-to-treat population; 55 completed the 16-week study period (2 weeks washout, 12 weeks treatment, 2 weeks washout). 49% of subjects were taking vitamin D metabolites. RESULTS: Serum phosphorus and PTH rose significantly when patients stopped their phosphate binders during both washout periods. RenaGel and RenaGel with calcium were equally effective at reducing serum phosphorus (mean change -2.4 mg/dL vs. -2.3 mg/dL). RenaGel with calcium was associated with a small increase in serum calcium (mean change 0.3 mg/dL vs. 0.0 mg/dL in RenaGel group, P = 0.09) that was not statistically significant. During the treatment phase, the reduction in PTH tended to be greater in the RenaGel with calcium group (median change -67.0 vs. -22.5 pg/mL in RenaGel group, P = 0.07). Non-users of vitamin D metabolites treated with RenaGel with calcium experienced a significant decrease in PTH (median change -114.5 vs. -22 pg/mL in RenaGel group, P = 0.006). Adverse events were seen with equal frequency in both groups, being generally mild in intensity, and rarely attributable to the drugs. CONCLUSION: We conclude that RenaGel and RenaGel with calcium are similarly effective in the treatment of ESRD-related hyperphosphatemia. Provision of supplemental calcium or metabolites of vitamin D with RenaGel may enhance control of hyperparathyroidism.

Calcium↗
PubMed1998

Effects of 19-nor-1,25(OH)2D2, a new analogue of calcitriol, on secondary hyperparathyroidism in uremic rats.

The active metabolite of vitamin D, calcitriol [1,25(OH)2D3] suppresses parathyroid hormone (PTH) gene transcription and PTH secretion. Although 1,25(OH)2D3 is effective in suppressing secondary hyperparathyroidism in uremic patients, the mandatory use of large amounts of calcium salts to control serum phosphorus may preclude in some patients the use of ideal therapeutic doses of 1,25(OH)2D3 because of hypercalcemia. We have studied a new analogue of calcitriol,19-nor-1,25(OH)2D2 that possesses low calcemic and phosphatemic activity. We have clearly demonstrated that this analogue of calcitriol can suppress secondary hyperparathyroidism without inducing hypercalcemia or hyperphosphatemia in uremic rats. In addition, this analogue of vitamin D supresses pre-pro PTH messenger RNA in a similar fashion to that of 1,25(OH)2D3. Contrary to the effect of 1,25(OH)2D3 that increases the intestinal vitamin D receptor, this analogue of vitamin D suppresses the intestinal vitamin D receptor. This finding may be critical for the lack of calcemic activity of 19-nor-1,25(OH)2D2 seen in these studies. One of the explanations for the lack of an increasing intestinal VDR is the fact that 19-nor-1,25(OH)2D2 decreases endogenous levels of 1,25(OH)2D3. In summary, we have shown that 19-nor-1,25(OH)2D2, a new analogue of calcitriol is effective in suppressing PTH in uremic rats with secondary hyperparathyroidism. In addition, there is a significant decrease in the VDR in the intestine, which may explain in part the less calcemic and hyperphosphatemic effect of this analogue.

Animals↗
PubMed1998

Suppression of parathyroid hormone secretion in hemodialysis patients by a novel vitamin D analogue: 19-nor-1,25-dihydroxyvitamin D2.

In this double-blind, placebo-controlled, randomized, multicenter study, 35 patients with end-stage renal disease undergoing maintenance hemodialysis were treated three times weekly for 4 weeks with either 19-nor-1,25-dihydroxyvitamin D2 (paricalcitol) intravenously at doses ranging from 0.04 to 0.24 microg/kg or placebo. Eligible patients with secondary hyperparathyroidism (HPT; intact parathyroid hormone [iPTH] level > 300 pg/mL) were initially withdrawn from any existing vitamin D therapy over a 4-week washout period and then randomized to treatment for 4 weeks with either paricalcitol or placebo. Overall, there was a clinically and statistically significant reduction in iPTH level for patients receiving paricalcitol compared with placebo (P = 0.006). The study end point for efficacy was at least a 30% reduction from maximum baseline in iPTH level for 75% of the patients receiving paricalcitol per dosing group. The study end point for efficacy was at least a 30% reduction from maximum baseline in iPTH for 75% of patients receiving paricalcitol per dosing group. Sixty-eight percent (15 of 22) of patients receiving paricalcitol attained this efficacy end point regardless of dosage received (0.04, 0.08, 0.16, and 0.24 microg/kg). Eighty-three percent (5 of 6) of the patients in each of the paricalcitol groups receiving 0.16- and 0.24-microg/kg dosages attained the efficacy end point. Only two patients receiving placebo attained the iPTH end point. There were no clinically relevant differences in serum calcium (Ca) or phosphorus (P) levels between the group treated with paricalcitol and that treated with placebo. Although there was a statistically significant difference between the change from baseline to final-visit Ca levels in the paricalcitol group and the placebo group (P < 0.001), the final-visit mean Ca level in the paricalcitol group was within the normal range (9.44 mg/dL). There was no statistically significant difference between groups for the change from baseline in P level (P = 0.625). Only one patient treated with paricalcitol developed hypercalcemia before or coincident with the iPTH end point. Three other patients receiving paricalcitol experienced elevated serum Ca levels subsequent to reaching the iPTH end point, with iPTH reductions of 83% to 98%. There were no significant differences between patients treated with paricalcitol and patients treated with placebo in adverse reactions. These results show that paricalcitol safely and effectively reduces iPTH levels in hemodialysis patients with secondary HPT.

Adolescent↗
PubMed1997

Poly[allylamine hydrochloride] (RenaGel): a noncalcemic phosphate binder for the treatment of hyperphosphatemia in chronic renal failure.

Dietary phosphate restriction and the oral administration of calcium and aluminum salts have been the principal means of controlling hyperphosphatemia in individuals with end-stage renal disease over the past decade. Although relatively well-tolerated, a large fraction of patients treated with calcium develop hypercalcemia, particularly when administered concurrently with calcitriol, despite a lowering of the dialysate calcium concentration. We evaluated the efficacy of cross-linked poly[allylamine hydrochloride] (RenaGel; Geltex Pharmaceuticals, Waltham, MA), a nonabsorbable calcium- and aluminum-free phosphate binder, in a randomized, placebo-controlled, double-blind trial of 36 maintenance hemodialysis patients followed over an 8-week period. RenaGel was found to be as effective as calcium carbonate or acetate as a phosphate binder. The reduction in serum phosphorus was significantly greater after 2 weeks of treatment with RenaGel (6.6 +/- 2.1 mg/dL to 5.4 +/- 1.5 mg/dL) compared with placebo (7.0 +/- 2.1 mg/dL to 7.2 +/- 2.4 mg/dL; P = 0.037). There was no significant change in serum calcium concentration in either treatment group. The total serum cholesterol and low-density lipoprotein cholesterol fraction were significantly reduced in RenaGel-treated patients compared with placebo-treated patients (P = 0.013 and P = 0.003, respectively) without a concomitant reduction in high-density lipoprotein cholesterol (P = 0.93). There was no difference among recipients of RenaGel and placebo in terms of adverse events. RenaGel is a safe and effective alternative to oral calcium for the management of hyperphosphatemia in end-stage renal disease.

Adult↗
PubMed1997

A new analog of 1,25-(OH)2D3, 19-NOR-1,25-(OH)2D2, suppresses serum PTH and parathyroid gland growth in uremic rats without elevation of intestinal vitamin D receptor content.

We have previously reported that 19-nor-1,25-(OH)2D2, a new analog of 1,25-(OH)2D3, suppresses parathyroid hormone (PTH) secretion in uremic rats in the absence of hypercalcemia or hyperphosphatemia. In the current study, we examined the effect of 19-nor-1,25-(OH)2D2 on parathyroid gland growth and intestinal vitamin D receptor (VDR) content. After induction of uremia by 5/6 nephrectomy, rats were divided into five experimental groups and received intraperitoneal injections of vehicle, 1,25-(OH)2D3 (2 or 6 ng/rat), or 19-nor-1,25-(OH)2D2 (25 or 100 ng/rat) three times a week for 8 weeks. Twelve normal rats received vehicle and served as the normal control group. During the course of the study, rats were maintained on a 1.0% calcium and 0.8% phosphorus diet. The higher dose of 1,25-(OH)2D3, 6 ng, significantly decreased PTH from 52.7 +/- 10.2 pg/mL in the uremic control group to 25.7 +/- 6.7 pg/mL (P < 0.01). This dose of 1,25-(OH)2D3, however, increased serum levels of both ionized calcium (4.71 +/- 0.05 to 4.85 +/- 0.06 mg/dL; P < 0.05) and phosphorus (4.34 +/- 0.30 to 6.67 +/- 0.63 mg/dL; P < 0.01). Both doses of 19-nor-1,25-(OH)2D2 decreased serum PTH as effectively as 1,25-(OH)2D3 without changes in serum calcium or phosphorus. The 100-ng dose of 19-nor-1,25-(OH)2D2 decreased PTH to 20.7 +/- 3.1 pg/mL (P < 0.01) and suppressed parathyroid gland growth by more than 50%. Both doses of 19-nor-1,25-(OH)2D2 also decreased endogenous 1,25-(OH)2D3 levels compared with uremic control rats (25 ng:30.4 +/- 2.0, P < 0.05, and 100 ng:27.9 +/- 3.2, P < 0.01, v 48.4 +/- 6.6 pg/mL). The 6-ng dose of 1,25-(OH)2D3 elevated intestinal VDR content (138.5 +/- 20.0 fmol/mg protein) compared with animals receiving both doses of 19-nor-1,25-(OH)2D2 (25 ng:84.0 +/- 11.9, P < 0.05, and 100 ng:78.4 +/- 10.9, P < 0.01). This was probably attributable to the marked decrease in endogenous 1,25-(OH)2D3 levels caused by both doses of 19-nor-1,25-(OH)2D2 because intestinal VDR correlated directly with serum 1,25-(OH)2D3 (r = 0.963; P = 0.008). Thus, 19-nor-1,25-(OH)2D2 appears to exert a selective action on the parathyroid glands compared with the intestine. Its low calcemic and phosphatemic properties may result from the decreased endogenous 1,25-(OH)2D3 levels that lead to a reduction in intestinal VDR. This selectivity makes this analog ideal for the treatment of secondary hyperparathyroidism.

Animals↗
PubMed1997

gamma-Interferon-induced resistance to 1,25-(OH)2 D3 in human monocytes and macrophages: a mechanism for the hypercalcemia of various granulomatoses.

The hypercalcemia of various granulomatoses is caused by endogenous 1,25-dihydroxyvitamin D [1,25-(OH)2D3] overproduction by disease-activated macrophages. The inability of 1,25(OH)2D3 to suppress its synthesis in macrophages contrasts with the tight control of its production in macrophage precursors, peripheral blood monocytes (PBM). We examined whether 1,25(OH)2D3 resistance develops as PBM differentiate to macrophages or with macrophage activation. Normal human pulmonary alveolar macrophages (PAM) are less sensitive to 1,25(OH)2D3 than PBM, despite similar vitamin D receptor content; however, both PBM and PAM respond to exogenous 1,25-(OH)2D3 by inhibiting 1,25(OH)2D3 synthesis and inducing 1,25(OH)2D3 degradation through enhancement of 24-hydroxylase mRNA levels and activity. The human monocytic cell line THP-1 mimics PAM in 1,25(OH)2D3 synthesis and sensitivity to exogenous 1,25(OH)2D3. We utilized THP-1 cells to examine the response to 1,25(OH)2D3 with macrophage activation. Activation of THP-1 cells with gamma-interferon (gamma-IFN) enhances 1,25(OH)2D3 synthesis 30-fold, blocks 1,25-(OH)2D3 suppression of its synthesis, and reduces by 42.2% 1,25-(OH)2D3 induction of its degradation. The antagonistic effects of gamma-IFN are not merely restricted to enzymatic activities. In THP-1 cells and in normal PBM, gamma-IFN inhibits 1,25-(OH)2D3 induction of 24-hydroxylase mRNA levels without reducing mRNA stability, suggesting gamma-IFN inhibition of 1,25(OH)2D3 transactivating function. These results explain 1,25(OH)2D3 overproduction in granulomatoses and demonstrate potent inhibition by gamma-IFN of 1,25(OH)2D3 action in immune cells.

Cells, Cultured↗
PubMed1996

Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro.

Dietary phosphorus (P) restriction is known to ameliorate secondary hyperparathyroidism in renal failure patients. In early renal failure, this effect may be mediated by an increase in 1,25-(OH)2D3, whereas in advanced renal failure, P restriction can act independent of changes in 1,25-(OH)2D3 and serum ionized calcium (ICa). In this study, we examined the effects of dietary P on serum PTH, PTH mRNA, and parathyroid gland (PTG) hyperplasia in uremic rats. Normal and uremic rats were maintained on a low (0.2%) or high (0.8%) P diet for 2 mo. PTG weight and serum PTH were similar in both groups of normal rats and in uremic rats fed the 0.2% P diet. In contrast, there were significant increases in serum PTH (130 +/- 25 vs. 35 +/- 3.5 pg/ml, P < 0.01), PTG weight (1.80 +/- 0.13 vs. 0.88 +/- 0.06 microg/gram of body weight, P < 0.01), and PTG DNA (1.63 +/- 0.24 vs. 0.94 +/- 0.07 microg DNA/gland, P < 0.01) in the uremic rats fed the 0.8% P diet as compared with uremic rats fed the 0.2% P diet. Serum ICa and 1,25-(OH)2D3 were not altered over this range of dietary P, suggesting a direct effect of P on PTG function. We tested this possibility in organ cultures of rat PTGs. While PTH secretion was acutely (30 min) regulated by medium calcium, the effects of medium P were not evident until 3 h. During a 6-h incubation, PTH accumulation was significantly greater in the 2.8 mM P medium than in the 0.2 mM P medium (1,706 +/- 215 vs. 1,033 +/- 209 pg/microg DNA, P < 0.02); the medium ICa was 1.25 mM in both conditions. Medium P did not alter PTH mRNA in this system, but cycloheximide (10 microg/ml) abolished the effect of P on PTH secretion. Thus, the effect of P is posttranscriptional, affecting PTH at a translational or posttranslational step. Collectively, these in vivo and in vitro results demonstrate a direct action of P on PTG function that is independent of ICa and 1,25-(OH)2D3.

Analysis of Variance↗
PubMed1996

Renal calcitriol synthesis and serum phosphorus in response to dietary phosphorus restriction and anabolic agents.

Calcitriol [1,25-(OH)2D3] synthesis by the renal 25-hydroxyvitamin D3-1alpha-hydroxylase (1alpha-hydroxylase) is induced in rats on a low phosphorus diet, but not in the hypophysectomized (HPX) or diabetic rat. However, the normal response is restored by the administration of growth hormone (GH) or insulin-like growth factor-I (IGF-I), or insulin, respectively. To further characterize this in vivo phenomenon, the acute effects of GH, IGF-I, and insulin were studied in the HPX rat. In the HPX rat the low phosphorus diet alone did not significantly alter serum phosphorus or 1alpha-hydroxylase activity, but treatment with GH resulted in a marked decrease in serum phosphorus that was associated with a fivefold induction of enzyme activity. Time course studies showed that by 6 hours after GH administration, hepatic IGF-I mRNA had increased 10-fold while renal IGF-I mRNA had increased by only 52%. Between 6 and 12 hours, serum phosphorus decreased dramatically and 1alpha-hydroxylase activity increased twofold. Treatment of phosphorus-restricted HPX rats with IGF-I resulted in a decrease in serum phosphorus by 2 hours that preceded a fourfold increase in enzyme activity between 6 and 10 hours. Treatment of phosphorus-restricted HPX rats with insulin produced similar results. This is the first demonstration of hypophosphatemia preceding induction of the 1alpha-hydroxylase after administration of IGF-I or insulin to the HPX rat on a low phosphorus diet. Although these growth factors may have a direct effect on the 1alpha-hydroxylase, these data suggest that the influence of GH, IGF-I, and insulin on transcellular phosphorus flux may have an independent effect on enzyme activity. Furthermore, the much greater induction of hepatic compared with renal IGF-I mRNA in response to GH suggests that systemic, rather than the local, IGF-I may be required for induction of the 1alpha-hydroxylase. This effect may be mediated by either the insulin or the IGF-I receptor.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1996

Phosphorus accelerates the development of parathyroid hyperplasia and secondary hyperparathyroidism in rats with renal failure.

Several studies have suggested that phosphorus (P) restriction, independent of serum levels of ionized calcium and 1,25-(OH)2D3, may prevent parathyroid hyperplasia and secondary hyperparathyroidism in patients and animals with chronic renal failure. A direct role of phosphorus in the pathogenesis of these abnormalities is, however, still controversial. Thus, studies were performed to examine the direct role of phosphorus on the development of these abnormalities. Female Sprague-Dawley rats underwent 5/6 nephrectomy or sham operation. The animals were then divided into two dietary groups (High-P: 0.8% P diet, Low-P: 0.2% P diet). Six to eight rats per group per time-point were killed at the following intervals: 0, 1, 2, and 4 days, and 1, 2, 3, and 4 weeks. Serum intact parathyroid hormone (PTH) levels in uremic rats fed the high-P diet increased 1 day after nephrectomy, and high levels persisted for the duration of the study. Parathyroid gland growth in uremic rats fed the high-P diet was apparent within 2 days of uremia and increased nearly twofold by 2 weeks. These abnormalities, however, did not develop in uremic rats fed the low-P diet. Serum P levels in uremic rats fed the high-P diet were significantly higher than those of uremic rats fed the low-P diet, but there was no significant difference in serum ionized calcium or 1,25-(OH)2D3 levels. These results demonstrate that phosphorus accelerates the development of parathyroid hyperplasia and secondary hyperparathyroidism in rats with renal failure, and that phosphorus restriction prevents these abnormalities independent of changes in serum ionized calcium and 1,25-(OH)2D3.

Animals↗
PubMed1996

Magnesium carbonate as a phosphorus binder: a prospective, controlled, crossover study.

The use of calcium carbonate (CaCO3) to bind phosphorus (P) in chronic hemodialysis patients has been a popular tactic in the past decade. Nonetheless, problems with hypercalcemia decrease its usefulness, particularly in patients treated with calcitriol. A P binder not containing calcium (Ca) would be of value in these circumstances. In short-term studies, we showed that magnesium carbonate (MgCO3) was well-tolerated and controlled P and Mg levels when given in conjunction with a dialysate Mg of 0.6 mg/dl. We, therefore, performed a prospective, randomized, crossover study to evaluate if the chronic use of MgCO3 would allow a reduction in the dose of CaCO3 and yet achieve acceptable levels of Ca, P, and Mg. We also assessed whether the lower dose of CaCO3 would facilitate the use of larger doses of calcitriol. The two phases were MgCO3 plus half the usual dose of CaCO3 and CaCO3 alone given in the usual dose. It was found that MgCO3 (dose, 465 +/- 52 mg/day elemental Mg) allowed a decrease in the amount of elemental Ca ingested from 2.9 +/- 0.4 to 1.2 +/- 0.2 g/day (P < 0.0001). The Ca, P, Mg levels were the same in the two phases. The maximum dose of i.v. calcitriol without causing hypercalcemia was 1.5 +/- 0.3 micrograms/treatment during the MgCO3 phase and 0.8 +/- micrograms/treatment during the Ca phase (P < 0.02). If these studies are confirmed, the use of MgCO3 and a dialysate Mg of 0.6 mg/dl may be considered in selected patients who develop hypercalcemia during treatment with i.v. calcitriol and CaCO3.

Adult↗
PubMed1996

1,25-dihydroxyvitamin D3 and 22-oxacalcitriol prevent the decrease in vitamin D receptor content in the parathyroid glands of uremic rats.

Decreased content of the 1,25-dihydroxyvitamin D3 receptor (VDR) in parathyroid glands from patients and animals with chronic renal failure has been implicated in the pathogenesis of secondary hyperparathyroidism. In these studies, we examined the regulation of VDR by 1,25-dihydroxyvitamin D3 (1,25-D3) and 22-oxacalcitriol (OCT) in parathyroid glands of uremic rats. After eight weeks of renal failure, VDR content in parathyroid glands of uremic rats was decreased (400 +/- 42 vs. 729 +/- 47 fmol/mg protein in normal control rats, P < 0.05) and strongly correlated with serum 1,25-D3 levels (r = 0.829, P = 0.0001). Treatment with either 1,25-D3 or OCT prevented the decrease in VDR. We conclude that low serum 1,25-D3 levels, at least in part, account for the decrease in VDR content in parathyroid glands of uremic rats and that treatment with 1,25-D3 or OCT prevents this decrease ameliorating the development of secondary hyperparathyroidism.

Animals↗
PubMed1996

Effect of 22-oxacalcitriol on hyperparathyroidism of dialysis patients: results of a preliminary study.

Intermittent high dose administration of calcitriol or alfacalcidol is effective in suppressing secondary hyperparathyroidism in chronic dialysis patients, however calcaemic action of these vitamin D derivatives is a major obstacle. 22-Oxacalcitriol (OCT) has been reported to have less calcaemic action than calcitriol, while preserving a comparable suppressive effect on parathyroid hormone (PTH) secretion. This preliminary study was conducted to examine the effects of OCT on secondary hyperparathyroidism in chronic dialysis patients. OCT was administrated intravenously immediately after every haemodialysis session three times a week for 12 weeks to three haemodialysis patients with secondary hyperparathyroidism. An initial dose of OCT of 5.5 micrograms/haemodialysis session was increased stepwise by 5.5 micrograms/haemodialysis up to 22 micrograms/haemodialysis according to the suppression of PTH and calcaemic action. OCT was discontinued for at least a week when serum calcium adjusted to albumin concentration measured just before haemodialysis exceeded 11.5 mg/dl. Marked reduction in plasma PTH, alkaline phosphatase and tartrate-resistant acid phosphatase was observed in all three patients. Although the dose of OCT was increased to 22 micrograms/haemodialysis in one patient, the final dose of OCT remained 5.5 micrograms/haemodialysis in the other two patients because of hypercalcaemia. It is concluded that OCT is highly effective in suppressing PTH in dialysis patients with secondary hyperparathyroidism. Hypercalcaemia may be a major factor which limits the use of OCT, though it may occur with higher doses of OCT than those of calcitriol usually given to suppress PTH hypersecretion.

Calcitriol↗
PubMed1996

Pathogenesis of secondary hyperparathyroidism.

Hyperplasia of the parathyroid glands and increased concentrations of immunoreactive parathyroid hormone are among the earlier alterations of mineral metabolism in patients with chronic renal failure. In the past five years several investigators have demonstrated that phosphorus retention plays a key role in the development of secondary hyperparathyroidism and chief cell hyperplasia of the parathyroid glands. Since phosphorus regulates the production of 1,25D3 by altering the enzyme 1-alpha-hydroxylase it is possible that the effect of phosphorus retention is mediated by a decrease in the synthesis of 1,25D3. This has been shown in patients with early renal insufficiency. However, in patients with advanced renal failure the reduced renal mass may limit the production of 1,25D3. It is clear now that phosphorus per se independent of the levels of ionized calcium and 1,25D3 can increase the synthesis and secretion of PTH in vivo and in vitro. The abnormalities in vitamin D metabolism are not only characterized by low levels 1,25D3 but by low number of vitamin D receptors. Thus, the parathyroid glands are resistant to the action of 1,25D3 and high pharmacological concentrations of 1,25D3 in blood are necessary to suppress the levels of parathyroid hormone in advanced renal failure. The development of monoclonal changes in glands obtained from patients with secondary hyperparathyroidism further complicates the treatment of secondary hyperparathyroidism in patients maintained on haemodialysis. Thus, correction of serum phosphorus is imperative for the success of 1,25D3 to control the levels of parathyroid hormone. Currently several laboratories are studying at the molecular level the mechanisms by which dietary phosphorus induces chief cell hyperplasia.

Calcitriol↗