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PubMed2002

Update on vitamin D and its newer analogues: actions and rationale for treatment in chronic renal failure.

Vitamin D is an important hormone for mineral homeostasis and the proper formation and maintenance of bone. In addition, vitamin D has broader functions in the body that expand its traditionally known role in mineral balance. In chronic renal failure, calcitriol deficiency contributes to the development and progression of secondary hyperparathyroidism, bone disorders, and altered mineral metabolism. Recent revelations of the broader role of vitamin D also suggest calcitriol deficiency may contribute to decreased cardiac and immune function in chronic renal failure patients. Research on vitamin D has led to a more complete understanding of the actions of vitamin D at the transcriptional level and with respect to the clinical use of vitamin D and its analogs to control parathyroid hormone overactivity and to replace the other D hormone-dependent actions in patients with renal failure. Limitations of vitamin D and its metabolites include hypercalcemia, hyperphosphatemia and suppression of bone turnover with the risk of adynamic bone disease. Vitamin D analogs may offer greater selectivity and potentially greater safety as compared to calcitriol because of their altered relative potency on calcium and phosphorus metabolism. This review focuses on the current understanding of the biological actions of vitamin D and its analogs and the rationale for treating patients with chronic renal failure.

Humans↗

PubMed2003

Autoregulation in the parathyroid glands by PTH/PTHrP receptor ligands in normal and uremic rats.

BACKGROUND: The secretion of parathyroid hormone (PTH) from the parathyroid glands might be regulated by autocrine/paracrine factors. We have previously shown that N-terminal parathyroid hormone-related protein (PTHrP) enhanced the secretory PTH response to low calcium in vivo and in vitro in rat parathyroid glands. N-terminal PTHrP fragments are equipotent to N-terminal PTH as ligands for the PTH/PTHrP receptor that is demonstrated in parathyroid tissue. This supports the possibility that the parathyroid cells respond to PTH/PTHrP receptor ligands and as such are target for an autoregulatory action of PTH and PTHrP. Our aim was to search for the PTH/PTHrP receptor in rat parathyroid glands and to examine the effects of PTHrP 1-40 on PTH secretion in in vivo models of secondary hyperparathyroidism (HPT) in uremic rats. METHODS: PTH secretion was examined during ethyleneglycol tetraacetic acid (EGTA)-induced hypocalcemia both with and without PTHrP. Five groups, each of six normal rats, received a bolus of increasing doses of 0.1, 1.0, 10, and 100 microg of PTHrP 1-40, or vehicle only. Chronic renal failure (CRF) was induced by 5/6 nephrectomy. One group of 12 CRF rats received a standard diet, while another CRF group of 18 rats received a high phosphorus diet to induce more severe HPT. After 8 weeks of uremia, the rats were infused with EGTA and PTHrP 1-40 or vehicle. The presence of the PTH/PTHrP receptor in the rat parathyroid glands was examined by reverse transcription-polymerase chain reaction (RT-PCR) technique. PTH was measured by a rat PTH assay that does not cross-react with PTHrP. RESULTS: In a dose-related manner, PTHrP enhanced the PTH response to hypocalcemia in normal rats. A similar rate of decrease of plasma Ca++ was induced by EGTA in all experimental groups. In CRF rats, plasma creatinine (0.99 +/- 0.10 mmol/L vs. 0.33 +/- 0.01 mmol/L, P < 0.001) and plasma PTH (226 +/- 32 pg/mL vs. 69 +/- 16 pg/mL, P < 0.001) levels were significantly increased. The CRF rats on high phosphorus diet had significant hypocalcemia (Ca++, 1.04 +/- 0.02 mmol/L vs. 1.28 +/- 0.03 mmol/L, P < 0.001), hyperphosphatemia (3.48 +/- 0.3 mmol/L vs. 2.25 +/- 0.1 mmol/L, P < 0.001) and severe secondary HPT, PTH (984 +/- 52 pg/mL vs. 226 +/- 32 pg/mL, P < 0.001) compared to CRF rats on a standard phosphorus diet. The maximal PTH response to hypocalcemia was enhanced in CRF rats (maximum PTH 382 +/- 58 pg/mL vs. 196 +/- 29 pg/mL in normal rats, P < 0.01) and further enhanced by PTHrP 1-40 to 826 +/- 184 pg/mL (P < 0.01). The secretory capacity of the parathyroid glands in response to low Ca++ was severely diminished in uremia. In CRF rats given a high phosphorus diet, the basal PTH levels were at the upper part of the calcium/PTH curve, and the induction of more marked hypocalcemia did not stimulate PTH secretion further (maximum PTH 1475 +/- 208 pg/mL vs. basal 1097 +/- 69 pg/mL, NS). PTHrP, however, further enhanced the maximal PTH levels significantly (maximum PTH 3142 +/- 296 pg/mL, P < 0.01). The presence of the PTH/PTHrP receptor in the rat parathyroid glands was confirmed by RT-PCR technique. CONCLUSION: PTHrP enhanced significantly, in a dose-related manner, the low Ca++-stimulated PTH secretion in normal rats. The PTH/PTHrP receptor is present in rat parathyroid glands. The impaired secretory capacity of the parathyroid glands in uremic rats is significantly enhanced by PTHrP. An autocrine/paracrine role in the parathyroid glands of the PTH/PTHrP receptor targeting peptides, PTHrP and PTH, is suggested. Thus, it is hypothesized that PTH during hypocalcemia might have a positive auto-feedback regulatory role on its own secretion.

Animals↗

PubMed2003

Sevelamer hydrochloride prevents ectopic calcification and renal osteodystrophy in chronic renal failure rats.

BACKGROUND: Hyperphosphatemia is associated with severe complications, including ectopic calcification of soft tissues, secondary hyperparathyroidism, and renal osteodystrophy (ROD). Sevelamer hydrochloride is a nonabsorbed calcium- and metal-free phosphate binder that lowers serum phosphorus levels in hemodialysis patients. This study examined the efficacy of sevelamer in preventing ectopic calcification of soft tissues and ROD in adenine-induced renal failure rats. METHODS: Male, 12-week-old Wistar-Jcl rats were freely fed an adenine diet (0.75 g adenine in 100 g normal diet) for four weeks. After three weeks of the adenine diet, when serum phosphorus levels had significantly increased, the rats were freely fed a normal diet that contained 1% or 2% of sevelamer for another five weeks. Time course changes of serum levels of phosphorus, calcium, and parathyroid hormone (PTH) were measured. At the end of the study, calcium and phosphorus levels in the heart and aorta were measured, and the calcification of kidney, heart, aorta, and stomach were histopathologically examined. The severity of ROD was evaluated by a histopathologic and morphometric analysis of the femurs. RESULTS: Compared with the adenine controls (N = 10), the sevelamer-treated (1%, N = 6; and 2%, N = 10) groups of adenine-induced renal failure rats had reduced serum phosphorus, serum calcium x phosphorus product, and serum PTH levels. Moreover, in the treatment groups, sevelamer suppressed calcification of the aorta media, and also the osteoid volume, fibrosis volume, and porosity ratio of femurs. CONCLUSION: These results suggest that sevelamer treatment might contribute to the suppression of ectopic calcification and ROD.

Animals↗

PubMed2002

The calcimimetic agents: perspectives for treatment.

Recognition of the role of the extracellular calcium sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The biology of the low affinity, G-protein-coupled CaR and the effects of its activation in various tissues are reviewed. Physiological roles include regulation of parathyroid hormone (PTH) secretion by small changes in ionized calcium (Ca++), and control of urinary calcium excretion with small changes in blood Ca++. The CaR also affects the renal handling of sodium, magnesium, and water. Mutations affecting the CaR that make it either less or more sensitive to Ca++ cause various clinical disorders. Disorders, such as primary and secondary hyperparathyroidism, may exhibit acquired abnormalities of the CaR. Calcimimetic drugs, which amplify the sensitivity of the CaR to Ca++, can suppress PTH levels with a resultant fall in blood Ca++. Experiences with R-568 in patients with secondary and primary hyperparathyroidism and parathyroid carcinoma are summarized. In humans with hyperparathyroidism, these agents produce a dose-dependent fall in PTH and blood Ca++, with larger doses causing more sustained effects. The second generation calcimimetic, AMG 073, with a better pharmacokinetic profile appears to be an effective and safe treatment for secondary hyperparathyroidism, producing suppression of PTH levels with a simultaneous reduction in serum phosphorus levels and the calcium X phosphorus product. The advantage of controlling PTH secretion without the complications related to hypercalcemia, hyperphosphatemia, and increased calcium X phosphorus product is very promising. Treatment trials have been relatively short-term except for one patient treated with R-568 for more than 600 days for parathyroid carcinoma; nonetheless the drug had no major side effects and appeared to be safe. Further long-term controlled studies are underway to further confirm the effectiveness and safety of these compounds.

Calcium-Binding Proteins↗

PubMed2002

Pathogenesis of refractory secondary hyperparathyroidism.

Calcitriol is currently used to reduce parathyroid hormone (PTH) levels in uremic patients. However, a significant number of patients fail to respond to calcitriol therapy. The data suggest that a poor response to calcitriol can be anticipated in patients with severe hyperparathyroidism (with a high basal PTH levels) and uncontrolled serum phosphate. The abnormal parathyroid response to calcitriol in uremic patients with severe parathyroid hyperplasia may be attributed, to a large extent, to the development of nodular hyperplasia as a result of clonal transformation from a diffuse polyclonal hyperplasia. The factors involved in the development of polyclonal parathyroid hyperplasia, at earlier stages of secondary hyperparathyroidism, appear to be the same factors that stimulate PTH secretion and synthesis: hypocalcemia, hyperphosphatemia and low serum calcitriol levels. Studies performed in vitro using parathyroid tissue from uremic patients who required parathyroidectomy demonstrate that in nodular hyperplasia there is an abnormal response to calcium and calcitriol, which suggests that there are factors intrinsic to the hyperplastic cell (such as decrease in calcium sensor receptors and vitamin D receptors) responsible for an abnormal regulation of parathyroid function. Accumulation of phosphate is a key factor in the pathogenesis of secondary hyperparathyroidism and a poor response to calcitriol treatment is associated with the failure to control the serum phosphorus. High phosphate stimulates PTH secretion as demonstrated by in vivo and in vitro studies. In addition, animal studies strongly suggest that phosphate increases parathyroid cell proliferation. There are growth-related genes potentially involved in uremic hyperparathyroidism; however, changes in the expression of these genes may be the consequence rather than the cause of parathyroid hyperplasia.

Humans↗

PubMed2003

A multicenter study on the effects of lanthanum carbonate (Fosrenol) and calcium carbonate on renal bone disease in dialysis patients.

BACKGROUND: Lanthanum carbonate (LC) (Fosrenol) is a novel new treatment for hyperphosphatemia. In this phase III, open-label study, we compared the effects of LC and calcium carbonate (CC) on the evolution of renal osteodystrophy (ROD) in dialysis patients. METHODS: Ninety-eight patients were randomized to LC (N = 49) or CC (N = 49). Bone biopsies were taken at baseline and after one year of treatment. Acceptable paired biopsies were available for static and dynamic histomorphometry studies in 33 LC and 30 CC patients. Blood samples were taken at regular intervals for biochemical analysis and adverse events were monitored. RESULTS: LC was well tolerated and serum phosphate levels were well controlled in both treatment groups. The incidence of hypercalcemia was lower in the LC group (6% vs. 49% for CC). At baseline, subtypes of ROD were similarly distributed in both groups, with mixed ROD being most common. At one-year follow-up in the LC group, 5 of 7 patients with baseline low bone turnover (either adynamic bone or osteomalacia), and 4 of 5 patients with baseline hyperparathyroidism, had evolved toward a normalization of their bone turnover. Only one lanthanum-treated patient evolved toward adynamic bone compared with 6 patients in the CC group. In the LC group, the number of patients having either adynamic bone, osteomalacia, or hyperpara decreased overall from 12 (36%) at baseline to 6 (18%), while in the calcium group, the number of patients with these types of ROD increased from 13 (43%) to 16 (53%). CONCLUSION: LC is a poorly absorbed, well-tolerated, and efficient phosphate binder. LC-treated dialysis patients show almost no evolution toward low bone turnover over one year (unlike CC-treated patients), nor do they experience any aluminum-like effects on bone.

Adult↗

PubMed2003

New vitamin D analogs.

BACKGROUND: 1,25-(OH)2D3 (calcitriol) controls parathyroid gland growth and suppresses the synthesis and secretion of parathyroid hormone. Because of this, 1,25-(OH)2D3 has been used successfully for the treatment of secondary hyperparathyroidism, which almost always accompanies renal failure. However, the potent effect of 1,25-(OH)2D3 on intestinal calcium and phosphorus absorption and bone mineral mobilization often leads to the development of hypercalcemia and hyperphosphatemia precluding 1,25-(OH)2D3 therapy. METHODS: This has led to the development of vitamin D analogs that retain the suppressive action on PTH and parathyroid gland growth, but that have less calcemic and phosphatemic activity. Currently, two analogs, 19-nor-1,25-(OH)2D2 and 1,alpha(OH)D2, are being used for the treatment of secondary hyperparathyroidism in the United States, and two are being used in Japan, 22-oxa-calcitriol and 1,25-(OH)2-26,27F6 D3. RESULTS: All four analogs suppressed PTH, but had less calcemic and phosphatemic activity than 1,25-(OH)2D3. In rats, 19-nor-1,25-(OH)2D2 has been shown to be less calcemic and phosphatemic compared to 1,alpha(OH)D2. CONCLUSION: Therapeutic doses of 19-nor-1,25-(OH)2D2 could produce a lower Ca x P product compared to 1,alpha(OH)D2, which could be an important consideration in patient treatment. Further studies are necessary to define these differences and to understand the mechanisms behind the differential actions of vitamin D analogs.

Humans↗

PubMed2003

Calcimimetic agents: review and perspectives.

BACKGROUND: Recognition of the role of the extracellular calcium-sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The activation of this receptor by small changes in the extracellular ionized calcium (ec(Ca2+)) regulates PTH, calcitonin secretion, urinary calcium excretion, and, ultimately, bone turnover. METHODS: The cloning of the CaR and the discovery of mutations that make the receptor less or more sensitive to calcium have allowed a better understanding of several hereditary disorders characterized by either hyperparathyroidism or hypoparathyroidism. The CaR, able to amplify the sensitivity of the CaR to Ca++ and suppress PTH levels with a resulting decrease in blood Ca++, became an ideal target for the development of compounds, the calcimimetics. Experience with the calcimimetic R-568 in patients with primary and secondary hyperparathyroidism and parathyroid carcinoma are summarized. RESULTS: The first clinical studies with the first-generation calcimimetic agents have demonstrated their efficacy in lowering plasma intact PTH concentration in uremic patients with secondary hyperparathyroidism. However, the low bioavailability of these first calcimimetics predicts a difficult clinical utilization. The second-generation calcimimetic, AMG 073, having a better pharmacokinetic profile, appears to be effective and safe for the treatment of secondary hyperparathyroidism, suppressing PTH levels while simultaneously reducing serum phosphorus levels and the calcium x phosphorus product. CONCLUSION: The advantage of controlling PTH secretion without the complications related to hypercalcemia, hyperphosphatemia, and increased calcium x phosphorus product is very promising.

Aniline Compounds↗

PubMed2003

Parathyroidectomy: whom and when?

Hyperparathyroidism (HPT) is common in patients on dialysis, and parathyroidectomy (PTx) is often required. We present a retrospective, descriptive analysis of data corresponding to 148 patients on dialysis undergoing PTx due to severe refractory HPT (PTH 1401 +/- 497 pg/mL, Ca 10.6 +/- 0.8 mg/dL, P 6.9 +/- 1.7 mg/dL). Demographic data were compared with those recorded in 309 patients on dialysis not subjected to PTx who were managed at the same hospital. In the PTx group, the factors age (49.3 +/- 14 years), male gender (48.6%), and diabetes (0.7%) were significantly lower than in the non-PTx group (61.5 +/- 14.9 years, male gender 59%, diabetes 19.4%), while time on dialysis was longer (8.6 +/- 5.8 vs. 5.5 +/- 5.4 years). In 129 of the study patients (87.4%), four or more glands were identified, and total PTx plus autotransplantation (AT) in the forearm was performed. In the remaining 19 patients, two to three glands were identified, and AT was not undertaken. Four of the 19 patients were successfully operated on again for persistent HPT, seven showed PTH levels <250 pg/mL, and eight maintained severe HPT. Perioperative complications included one death due to cardiac insufficiency, two repeat operations due to bleeding, and one patient with chronic hoarseness. Hospital stay was prolonged in 20% of patients due to a hungry bone syndrome. Among those patients with PTx and AT, HPT recurred in 21 patients (16.2%) at 3.1 +/- 2.3 years. In 13 of these patients, autograft was removed at 7.5 +/- 2.9 years. Serum calcium and phosphate levels improved after PTx, and these results were maintained for 5 years (9.6 +/- 0.8 and 4.2 +/- 1.2 mg/dL, respectively). In conclusion, PTx with AT is a safe option for the treatment of severe HPT that is accompanied by low morbidity and mortality and a good outcome. Medical treatment should not be prolonged at the expense of long repeated bouts of hypercalcemia and/or hyperphosphatemia with their irreversible consequences.

Aged↗

PubMedDate not supplied

Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment.

Calciphylaxis is a small vessel vasculopathy involving mural calcification with intimal proliferation, fibrosis, and thrombosis. This syndrome occurs predominantly in individuals with renal failure and results in ischemia and necrosis of skin, subcutaneous fat, visceral organs, and skeletal muscle. The syndrome causes significant morbidity in the form of infection, organ failure, and pain. Mortality rates are high. In individuals with renal failure, risk factors for the development of calciphylaxis include female sex, Caucasian race, obesity, and diabetes mellitus. Many cases occur within the first year of dialysis treatment. Several recent reports demonstrate that prolonged hyperphosphatemia and/or elevated calcium x phosphorus products are associated with the syndrome. Protein malnutrition increases the likelihood of calciphylaxis, as does warfarin use and hypercoagulable states, such as protein C and/or protein S deficiency. Recent advances in diagnostic tools and therapeutic strategies have helped in the management of patients with calciphylaxis.

Calciphylaxis↗

PubMed2003

Use of calcimimetics in uremic patients with secondary hyperparathyroidism: review.

Recognition of the role of the extracellular calcium sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The activation of this receptor by small changes in extracellular ionized calcium (ec(Ca2+)) regulates PTH, calcitonin secretion, urinary calcium excretion, and ultimately, bone turnover. The cloning of this CaR and the discovery of mutations making the receptor less or more sensitive to calcium allowed a better understanding of several hereditary disorders characterized either by hyperparathyroidism or hypoparathyroidism. This CaR became an ideal target for the development of compounds, the calcimimetics, able to amplify the sensitivity of the CaR to ec(Ca2+) suppressing PTH levels with a resultant fall in blood Ca2+. The first clinical studies with first-generation calcimimetic agents have demonstrated their efficacy lowering plasma intact PTH concentration in uremic patients with secondary hyperparathyroidism. However, the low bioavailability of these first calcimimetics predicts a difficult clinical utilization. The second-generation calcimimetic AMG-073, with a better pharmacokinetic profile, appears to be effective and safe for the treatment of secondary hyperparathyroidism, producing suppression of PTH levels with a simultaneous reduction in serum phosphorus levels and the calcium X phosphorus product. The advantage of controlling PTH secretion without the complications related to hypercalcemia, hyperphosphatemia, and increased calcium X phosphorus product is very promising.

Calcium↗

PubMed1981

Fetal growth and 1,25-dihydroxyvitamin D3 injections into thyroparathyroidectomized pregnant rats.

Thyroparathyroidectomy (TPTX) in pregnant rats on day 12.5 of gestation was associated with a progressive reduction of dietary intake between days 18 and 21 of gestation. In control mothers with a similar dietary restriction, the fetal plasma calcium and phosphate levels were unchanged, and a slight decrease in fetal weight (approximately 0.8 g) was observed at term. Maternal hypocalcemia in TPTX animals induced chronic fetal hypocalcemia beginning at day 18.5 of gestation; fetal hyperphosphatemia was only statistically significant on the last day of gestation. Weight, blood glucose and liver glycogen stores, which were greatly decreased in fetuses from untreated TPTX mothers, increased after injection of 1,25-(OH)2D3 into TPTX mothers. A marked increase in fetal weight (+ 1.6-2.0 g) occurred at term with doses ranging from 0.05 to 0.25 micrograms/kg of body weight; higher doses (greater than or equal to 0.5 micrograms/kg) inhibited this improvement. Fetal blood glucose was normalized (approximately 45-50 mg/100 ml) when TPTX mothers received 0.05 to 0.5 micrograms/kg, but decreased with higher doses. The highest fetal liver glycogen store (80 mg/g) was achieved using 0.05 micrograms of 1,25-(OH)2D3/kg, this increment being progressively inhibited when larger doses were given. Subcutaneous calcifications were observed in the fetuses of some litters after treatment of the TPTX mothers with 1 microgram of 1,25-(OH)2D3/kg.

Animals↗

PubMed1998

Controlled trial of falecalcitriol versus alfacalcidol in suppression of parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism.

Active vitamin D3 is extensively used for the treatment of secondary hyperparathyroidism in hemodialysis patients. But it is often impossible to administer enough dose to suppress parathyroid hormone (PTH) level, because of hypercalcemia and hyperphosphatemia. New modalities with higher specificity for PTH suppression are desirable. We conducted a crossover comparative study of falecalcitriol, an active vitamin D3 analog, and alfacalcidol (1alpha[OH]D3). In this study, 25 hemodialysis patients with moderate to severe secondary hyperparathyroidism who had normal serum calcium levels were enrolled. They received daily oral doses of alfacalcidol during an 8-week observation period. Based on serum calcium levels and intact PTH, the subjects were allocated into two groups, and a comparative study was conducted using unmasked crossover design of two drugs x two periods. The dosage of both drugs was adjusted to maintain the initial serum calcium levels, and the relative change (%change) of serum biochemical parameters were compared. Comparison of two drugs in period 1 was taken as primary efficacy evaluation. Reproducibility of drug action was confirmed by comparing the effect of falecalcitriol between period 1 and 2. The percent change of PTH of falecalcitriol was lower than that of alfacalcidol: Those were, respectively, -7.89% and +30.42% for c-terminal PTH (P = 0.022), -4.39% and +38.88% for i-PTH (P = 0.077), and +3.68% and +30.52% for midregion PTH (P = 0.099). The similar changes were observed in the falecalcitriol group during period 2, confirming the reproducibility. Falecalcitriol was found to be superior to alfacalcidol in suppression of PTH levels in patients with moderate to severe secondary hyperparathyroidism when it is administered in equivalent doses that might maintain similar serum calcium levels.

Adult↗

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

Therapy of secondary hyperparathyroidism with 19-nor-1alpha,25-dihydroxyvitamin D2.

Secondary hyperparathyroidism contributes to significant morbidity in patients with chronic renal failure. The treatment of this disorder with vitamin D compounds, such as calcitriol, although effective at suppressing parathyroid hormone (PTH) secretion, may promote the development of hypercalcemia and hyperphosphatemia, thus increasing the risk for metastatic calcification. A new vitamin D analogue, 19-nor-1alpha,25-(OH)2D2 (paricalcitol; Zemplar, Abbott Laboratories, Inc, Chicago, IL) has recently been developed for the treatment of secondary hyperparathyroidism, and, in experimental animals, it was found to be less calcemic and phosphatemic than calcitriol. In double-blind clinical trials, paricalcitol effectively decreased the levels of PTH by 60%, yet the mean serum calcium values remained within the normal range. The few episodes of hypercalcemia that occurred in the paricalcitol-treated patients (8 of 400 determinations > or =11.0 mg/dL in 7 patients) were associated with marked decreases in PTH levels (87% +/- 2% less than baseline) and absolute values of PTH less than 100 pg/mL in four of the seven patients. PTH values less than 100 pg/mL, however, occurred in 15 patients, but were not invariably associated with frank hypercalcemia, although serum calcium levels increased to 10.63 +/- 0.3 mg/dL, slightly greater than the upper limits of normal. Additional studies to evaluate the conversion from calcitriol to paricalcitol therapy showed that a dose ratio of 1:4 (calcitriol:paricalcitol) could maintain control of high levels of PTH without significant alterations in serum calcium and phosphorus levels. These studies indicate that effective control of hyperparathyroidism can be achieved with paricalcitol therapy with minimal perturbation of serum calcium and phosphorus levels, and may have a therapeutic advantage over current treatment strategies.

Calcium↗

PubMed2001

Role of phosphorus in the pathogenesis of secondary hyperparathyroidism.

Secondary hyperparathyroidism (SH) and hyperplasia of the parathyroid glands (PTG) are universal complications in patients with CRF. In early renal failure, reduction in serum calcitriol and moderate decreases in ionized calcium contribute to greater synthesis and secretion of PTH. As renal disease progresses, a reduction in parathyroid expression of vitamin D receptor and calcium receptor renders the PTG more resistant to both calcitriol and calcium. High dietary phosphorus (P), independent of calcium and calcitriol, further enhances uremia-induced PTG hyperplasia and PTH synthesis and secretion, the latter by posttranscriptional mechanisms. Once SH develops, dietary P restriction can return the high serum PTH levels toward normal, however, parathyroid hyperplasia persists. Studies in our laboratory identified 2 of the mechanisms involved in the opposing effects of high and low dietary P content on PTG growth. Whereas high dietary P increases parathyroid expression of transforming growth factor alpha (TGFalpha), a growth promoter, P restriction induces the cyclin-dependent kinase inhibitor p21, an inducer of growth arrest. Both effects of P are specific for the PTG. No increase in either protein was observed in liver or intestine. TGFalpha induction of hyperplasia involves binding to the epidermal growth factor receptor and activation of mitogen activated protein (MAP) kinases cascades. p21 blocks progression through the cycle and cell division by inactivating cyclin/cyclin-dependent kinase complexes. Preventing hyperphosphatemia and elevated Ca x P product in renal failure not only ameliorates the progression of SH and bone disease but also the morbidity and mortality resulting from vascular calcification.

Animals↗

PubMed2001

Mönckeberg's medial sclerosis and inorganic phosphate in uremia.

Mönckeberg's medial sclerosis (MMS) is one of the characteristic calcified lesions of uremic artery disease and often exhibits osseous metaplasia. Although its pathogenic mechanism is largely unknown, MMS may contain two different pathologic processes: degenerative process leading to apoptosis or necrosis of medial smooth muscle cells and osteogenic process leading to formation of bone-like structures. It has long been known that calcification follows necrosis. Apoptotic/necrotic cells often release matrix vesicles or membranous cellular degradation products resulting from disintegration of the cells that frequently serve as the nidus of calcification. On the other hand, vascular cells may exhibit osteoblastic phenotype in vitro, and some of the markers for osteoblastic differentiation and noncollagenous proteins regulating mineralization have been demonstrated in calcified arterial lesions. As a possible etiologic factor inducing these two responses, hyperphosphatemia among various metabolic disturbances recognized in uremia may play an important role in the development of MMS in uremia.

Animals↗

PubMed2001

Acute renal failure secondary to spontaneous acute tumor lysis syndrome in myelofibrosis.

A 70-year-old man with myelofibrosis developed nonoliguric acute renal failure in association with acute uric acid nephropathy in the absence of chemotherapy or radiotherapy. The patient had an 18-month history of transfusion-dependent myelofibrosis and moderate chronic renal insufficiency. Admission laboratory findings were remarkable for severe hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia with acute deterioration of renal function, consistent with a diagnosis of acute uric acid nephropathy. Treatment, including hemodialysis and allopurinol administration, resulted in clinical improvement with normalization of serum uric acid concentrations and resolution of acute renal failure. With long-term allopurinol therapy, renal function has remained at his previous baseline, and there has been no transformation to acute leukemia. This case represents a rare instance of acute renal failure related to the occurrence of acute uric acid nephropathy associated with myelofibrosis and emphasizes the importance of early recognition and aggressive management, which can lead to recovery of renal function.

Acute Disease↗