Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Secondary hyperparathyroidism (SHPT) remains an inevitable consequence of untreated chronic uremia. It is the result of a combination of phosphate (P) retention, failure of calcitriol synthesis, and hypocalcemia. Therapies used to correct these abnormalities, namely active vitamin D replacement, calcium (Ca) supplementation, and phosphate (P) restriction, have moderate efficacy but are prone to unacceptable side-effects. However, there have been new developments in the control of P, vitamin D replacement and modulation of the Ca sensing receptor (CaSR) using calcimimetics. Sevelamer, and in the near future lanthanum, are offering a reasonable level of P control without the toxicities inherent with either aluminum- or Ca-based phosphate binders, and other phosphate binders are in development. 'Non calcemic' vitamin D metabolites include 22-oxacalcitriol, paricalcitol, and doxercalciferol. In various experimental models 22-oxacalcitriol, in particular, exhibits impressive suppression of parathyroid hormone (PTH) with minimal calcemia, although it has been less impressive when compared with calcitriol in controlled studies in hemodialysis (HD) patients. The advantages of these agents over conventional treatment with calcitriol or alfacalcidol remain uncertain. Cinacalcet, a calcimimetic agent that up-regulates the sensitivity of the CaSR in parathyroid and other cells, is a new type of therapy for SHPT that simultaneously reduces the concentrations of PTH, Ca, and P in HD patients, enabling a significant number to achieve K/DOQI or other national guidelines. The extent to which this new therapy will improve clinical outcomes remains uncertain. In conclusion, with the advent of new therapies the emphasis in the management of SHPT has evolved to incorporate reduction of Ca loading, control of PTH within specific target ranges, and avoidance of hypercalcemia, hyperphosphatemia and elevation of the calcium phosphorus product.
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PMID:Management of secondary hyperparathyroidism. 1610 40

In June 2003, sevelamer hydrochloride became widely available in Japan and was expected to control hyperphosphatemia in hemodialysis patients without inducing hypercalcemia. To evaluate the impact of sevelamer therapy on mineral metabolism, we recruited 954 hemodialysis patients from 21 renal units just before the general release of sevelamer in Japan. The serum calcium, phosphate, and parathyroid hormone levels determined on enrollment were compared with those later measured in June 2004. Sevelamer was prescribed for 169 of the 859 patients for whom data were available in 2004. The mean calcium level, phosphate level, and calcium x phosphate product were all significantly reduced during the 12-month study period, but the intact parathyroid hormone (iPTH) level did not change. As a result, the percentage of patients who achieved a calcium x phosphate product of <55 mg(2)/dL(2) was significantly increased, but there were no changes in that of patients who achieved the target ranges for phosphate (3.5-5.5 mg/dL) or iPTH (150-300 pg/mL). Among sevelamer-treated patients, iPTH significantly increased, and this change was more marked in the patients with an initial iPTH level <150 pg/mL. Sevelamer was useful for reducing the serum calcium level and calcium x phosphate product, but hyperphosphatemia and hyperparathyroidism were not improved in our study population at 12 months after the release of sevelamer. A decrease in the calcium load might result in the exacerbation of hyperparathyroidism. However, among patients with relative hypoparathyroidism, sevelamer therapy may be beneficial for the prevention of adynamic bone disease.
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PMID:Influence of sevelamer on mineral metabolism and hyperparathyroidism in Japanese hemodialysis patients. 1749 3

Cardiovascular mortality is the leading cause of death in the uremic patient. Hyperphosphatemia is considered an independent risk factor associated with cardiovascular morbidity and mortality in dialysis patients. As phosphate control is not efficient with diet or dialysis, phosphate binders are commonly prescribed in patients with chronic renal failure. Aluminum salts, the first phosphate binders, even if effective, have several side effects due to their deposition in CNS, bone and hematopoietic cells. Calcium-containing phosphate binders, used in the last 15 years, increase total body calcium load and may exacerbate metastatic calcification, thus, increasing the risk of cardiovascular mortality. Recently two new compounds non-aluminum and non-calcium phosphate binders, sevelamer hydrochloride and lanthanum carbonate, have been introduced. Sevelamer, besides the effect on phosphate, has been associated with reduction of coronary and aortic calcification and with other pleiotropic effects especially on lipid metabolism. Lanthanum carbonate has similar phosphate control to calcium-based binders with less incidence of hypercalcemia but long-term clinical studies are needed for testing long-term exposure. Recently the authors found in dialysis patients, that salivary phosphorus correlated with serum phosphorus. Therefore, they supposed that the use of salivary phosphate binders could reduce its absorption and represent a chance for reducing the serum phosphate concentration in uremic patients.
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PMID:Emerging drugs for hyperphosphatemia. 1787 64

We conducted a prospective study in hemodialysis patients to assess the safety and efficacy of sevelamer, a non-absorbable phosphate binding polymer free of calcium and aluminum, in lowering serum phosphorus, serum intact parathyroid hormone, and serum lipids. Phosphate binders were discontinued during a two-week washout period. We considered the patients with serum phosphorus levels more than 1.8 mmol/l during the washout period eligible for treatment. Sevelamer was administered to 29 hemodialysis patients for eight weeks. Sevelamer reduced the mean serum phosphorus levels to 1.8 mmol/l by the end of the eight-week treatment period (p < 0.0001). Two weeks after the completion of the sevelamer study the mean serum phosphorus levels increased to 2.09 mmol/l (p < 0.02). Mean serum calcium levels did not significantly change during sevelamer trial. Mean serum intact parathyroid hormone declined from 501 pg/ml at the start of the study to 425 pg/l at the end of the eight week treatment period (p = 0.05). In addition, sevelamer reduced the mean serum total cholesterol levels from 5.22 mmol/l to 4.26 mmol/l (p < 0.0001), and the mean serum low density lipoprotein cholesterol from 3.56 mmol/l to 2.79 mmol/l (p < 0.0001) at the end of the study. However, the mean serum levels of high density lipoprotein and triglycerides did not change during the study period. We conclude that sevelamer can control serum phosphorus and reduce the level of intact parathyroid hormone and cholesterol without inducing hypercalcemia or other side effects.
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PMID:Effect of sevelamer on mineral and lipid abnormalities in hemodialysis patients. 1831 Aug 64

In chronic kidney disease patients, bone and mineral abnormalities have a major impact on morbidity and mortality. Hyperphosphatemia has been associated with increased mortality and with the development of cardiovascular calcification, an independent predictor of mortality. Vascular calcifications have been associated with low bone turnover, low bone volume and lower activation frequency. In dialysis patients, the treatment of hyperphospathemia with calcium based compounds, when compared with sevelamer, is associated with more frequent episodes of hypercalcemia, suppression of intact parathyroid hormone and with progression of coronary calcifications. In the presence of adynamic bone disease, calcium load has a significantly higher impact on aortic calcifications and stiffening. A randomized, prospective, open label study, evaluated patients with bone biopsies at the beginning and after 1 year treatment period with sevelamer hydrochloride or calcium carbonate. Sevelamer treatment resulted in no statistically significant changes in bone turnover or mineralization compared with calcium carbonate, but bone formation rate increased and trabecular architecture improved only with sevelamer. In incident dialysis patients, treatment with sevelamer has been associated with better survival, while in prevalent patients a clear benefit could only be demonstrated in older patients and in patients treated for more than 2 years.In conclusion, the treatment of hyperphosphatemia with sevelamer hydrochloride, a non-calcium and non-metal containing phosphate binder, is associated with a beneficial effect on vascular calcification progression, bone disease and most likely with a survival benefit in some hemodialysis patients populations.
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PMID:Treatment of hyperphosphatemia with sevelamer hydrochloride in dialysis patients: effects on vascular calcification, bone and a close look into the survival data. 1903 24

A change in paradigm occurred lately whereby not hypocalcemia but hypercalcemia and positive calcium balance were considered negative factors. Namely, the use of calcium- based binders in combination with vitamin D analogues, has been shown to lead to an over-suppression of parathyroid hormone (PTH) and development of low-bone turnover adynamic bone disease (ABD). The changing prevalence of various types of bone diseases from a high to low-bone turnover goes in line with the presence of increased risk for vascular calcification (VC), morbidity and mortality in the dialysis population. The attenuation of the previous great expectations in calcium-based phosphate binders and vitamin D-analogues entailed a new treatment strategy to preserve bone and vascular health. Hence, a new evidence for treatment of ABD with various types of non calcium based binders and low calcium dialysate is presented. Sevelamer treatment has reduced calcium concentration and increased PTH levels, resulting in the improvement of markers of bone turnover, increased bone formation and improved trabecular architecture, providing a slower progression of VC. Data on lanthanum beneficial effect on ABD histology have been demonstrated in long-term clinical studies. Although there is a slow release of lanthanum from its bone deposits after discontinuation of the treatment and no association with aluminium- like bone toxicity, there is still an ongoing scientific debate about its long-term toxic potential. Finally, reducing the number of calcium based binders and low calcium dialysate (1.25 mmol/l) has been reported to have an impact on the evolution towards markers reflecting higher bone turnover. Then, adoption of the non calcium-based binders should be reserved to high risk patients with ABD and progression of vascular calcifications associated with increased morbidity and mortality.
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PMID:Strategies to manage low-bone turnover. 1966 99

Hyperphosphatemia is considered as an independent risk factor for surrogate clinical endpoints like vascular calcification (VC) and bone disease, or hard clinical outcomes like cardiovascular events. To date, various treatment options for phosphate removal or reduction are available. The great expectations put into calcium-based phosphate binders were mitigated because of their possible contribution to progressive VC, particularly in patients treated simultaneously with active vitamin D derivatives. Thus, a paradigm change occurred whereby the main clinical concern shifted from the avoidance of hypocalcemia to that of the consequences of inducting a positive calcium balance. Sevelamer-HCl treatment allowed a comparable control of hyperphosphatemia with a lower risk of hypercalcemia than calcium-based phosphate binders, and a slower progression of VC; however, convincing evidence of improved clinical outcomes in dialysis patients is lacking. Although data on the safety and efficacy of lanthanum carbonate in the treatment of hyperphosphatemia have been provided in long-term clinical studies, there is still an ongoing scientific debate about its possible long-term toxicity. Moreover, there are no data from randomized clinical trials demonstrating beneficial effects of La carbonate treatment on VC or cardiovascular outcomes. In the absence of convincing clinical trials testing the effects of non-metal-based phosphate binders on cardiovascular and global outcomes it appears reasonable to maintain bone health and mineral homeostasis by mainly relying on adaptations of standard therapies. Noncalcium, non-aluminum-based binders might be reserved for patients with major mineral metabolism abnormalities and a high risk of VC.
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PMID:Phosphate metabolism in chronic kidney disease: from pathophysiology to clinical management. 1970 81

Hyperphosphatemia with decline of kidney function has been associated with increased mortality and the development of cardiovascular calcification. Sevelamer hydrochloride was the first synthetic non-aluminum and calcium-free phosphate binder commercially available. Sevelamer is as effective as calcium-based binders in lowering phosphate, but without the tendency to promote hypercalcemia. There is some evidence that sevelamer hydrochloride can attenuate cardiovascular calcification compared with calcium-based phosphate binders. Furthermore, sevelamer has several additional pleiotropic effects that may extend its basic indication, some of which may help attenuate vascular calcification. These includes effects on lipid metabolism, and systemic inflammatory response.
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PMID:[Treatment of hyperphosphatemia with sevelamer hydrochloride in CKD patients: effects on vascular calcification and mortality]. 2103 91

Vascular calcification is a well-known complication of chronic kidney disease and one of the main predictors for increased cardiovascular morbidity and mortality in these patients. It may happen in 2 main types of intimal calcification, as a part of diffuse atherosclerosis, and medial calcification, which is generally focal in distribution, unrelated to atherosclerotic risk factors, and seen in younger hemodialysis patients. Pathogenesis may be genetic, mineral metabolism related, or nonmineral metabolism related. Increased calcium, phosphorus, and calcium- phosphorus product; decreased parathyroid hormone level; and overzealous use of active vitamin D supplements are the main mineral metabolism-related mechanisms of vascular calcification. Other mechanisms are formation of matrix vesicles and cellular apoptosis, with generation of hydroxyapatite crystals within vesicles and apoptotic bodies. The interplay of various activator proteins of vascular calcification such as bone morphogenetic proteins and receptor activator of nuclear factor-kappa B ligand, or inhibitor proteins like matrix Gla protein, bone morphogenetic protein-7, osteopontin, osteoprotegerin, fetuin-A, Smad6, and pyrophosphate are important in establishment of vascular calcification. Vascular calcification is related to all-cause and cardiovascular mortality both in general population and dialysis patients. Minimizing traditional risk factors of vascular calcification, prevention of hypercalcemia, and avoidance of high doses of calcium-based phosphate binders and vitamin D analogues are important measures for prevention or attenuation of progression of vascular calcification. Sevelamer and cinacalcet may prevent progression of vascular calcification. With the evolving knowledge of the pathogenesis of vascular calcification, we can look forward to emergence of novel therapies for this complication in the future.
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PMID:Vascular calcification in chronic kidney disease: mechanisms and clinical implications. 2187 4

In chronic kidney disease patients, bone and mineral abnormalities have a major impact on morbidity and mortality. Hyperphosphatemia has been associated with increased mortality and with the development of cardiovascular calcification, an independent predictor of mortality. Sevelamer, or more precisely 'sevelamer hydrochloride', is a weakly basic anion-exchange resin in the chloride form that was introduced in 1997 for the treatment of the hyperphosphataemia of patients with end-stage renal failure. Sevelamer sequesters phosphate within the gastrointestinal tract, so prevents its absorption and enhances its faecal excretion. Over the succeeding years, large numbers of patients have been treated with sevelamer, and it has fulfilled expectations in helping to control the hyperphosphataemia of end-stage renal failure. Additionally treatment with sevelamer was accompanied with lower incidence of hypercalcemia, decreased incidence of low PTH levels, a 15-31% decrease of LDL-cholesterol both in dialysis and predialysis patients, decreased C-reactive protein, amelioration of hyperuricemia and low fetuin A, decrease of uremic toxins, suggesting an overall anti-inflammatory effect. In incident dialysis patients, treatment with sevelamer has been associated with better survival, while in prevalent patients a clear benefit could only be demonstrated in older patients and in patients treated for more than 2 years. In dialysis patients, the treatment of hyperphospathemia with calcium based compounds, when compared with sevelamer, is associated with more frequent episodes of hypercalcemia, suppression of intact PTH and with progression of coronary calcifications. In the presence of adynamic bone disease, calcium load has a significantly higher impact on aortic calcifications and stiffening. Sevelamer treatment resulted in no statistically significant changes in bone turnover or mineralization compared with calcium carbonate, but bone formation rate increased and trabecular architecture improved only with sevelamer. In conclusion, the treatment of hyperphosphatemia with sevelamer hydrochloride, a noncalcium and non-metal containing phosphate binder, is associated with a beneficial effect on vascular calcification progression, bone disease and most likely with a survival benefit in some hemodialysis patients populations. Sevelamer carbonate is an improved, buffered form of sevelamer hydrochloride developed for the treatment of hyperphosphataemia in CKD patients. Sevelamer carbonate formulated as a powder for oral suspension presents a novel, patient- friendly alternative to tablet phosphate binders. Safety and efficacy of sevelamer carbonate powder compared with sevelamer hydrochloride tablets in CKD patients are equivalent, with Sevelamer carbonate having fewer side effects from gastrointestinal tract.
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PMID:Phosphate binders: Sevelamer in the prevention and treatment of hyperphosphataemia in chronic renal failure. 2189 54


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