Disturbances Of Calcium Metabolism Research Articles

Dynamic changes in calcium and phosphate plasma concentrations in the patients on peritoneal dialysis

The disturbances of active forms of vitamin D synthesis and disturbances in calcium and posphate metabolism develop early in chronic renal failure, when creatinine clearance is about 30 ml/min. Chronic hemodialysis and peritoneal dialysis only partially correct the biochemical enviroment of patients on chronic renal replacement therapy because of end-stage renal disease. These dialysis modalities can't signifficantly affect the endocrine disturbances of chronic renal failure and they have minimal modulatory effect. The management of disturbed calcium (Ca) and phosphate (P) metabolism and the maintainance of Ca x P product below 4.4 mmol/l thanks to the use of dialysate solutions with the appropriate calcium concentration and the careful dosage of phosphate binders, calcium and active vitamin D metabolits, are extremely important for the prevention of renal osteodystrophy, secondary hyperparathyroidism as well as low-bone turnover disease. The aim of the study was to analyze the plasma levels of calcium, phosphate, albumin, alkaline phosphatase and parathormon (PTH) in 58 patients who were treated with continuous ambulatory peritoneal dialysis (CAPD) from March to August 2003. The use of phosphate binders and the substitution with active vitamin D metabolits were also analyzed. We examined 58 patients, 30 males and 28 female, mean-age 52 years (range, 26-78 years), affected by end-stage renal disease of the different leading cause. The average time on peritoneal dialysis program was 20 months (2-66 months). Most of the patients were treated by CAPD, while only few of them performed authomatic, cyclic or intermitent peritoneal dialysis. Most of the patients used a dialysate with 1.75 mmol/l calcium concentration. The study showed that our patients on chronic CAPD program during several months had normal calcemia, phosphatemia and the level of alkaline phosphatase, and that they had Ca x P product in the recommended range. PTH serum level ranged from 16 to 490 pg/l in our patients. The study showed that a balanced diet and a correct dosage of phosphate binders, as well as a careful substitution with active vitamin D metabolits render a good control of calcium and phosphate serum balance, as well as an effective prevention of renal osteodystrophy development in the patients on chronic peritoneal dialysis treatment.

Disturbed calcium metabolism in a patient with bipolar disorder and impaired renal function

Disturbed calcium metabolism in a patient with bipolar disorder and impaired renal function

Intracellular changes in astrocytes and NG 108-15 neuroblastoma X glioma cells induced by advanced glycation end products.

The extracellular effects caused by advanced glycation end products (AGEs) themselves formed by the Maillard-reaction from proteins and sugars, are well known. Less is known about the effects of AGEs on cellular function. Cellular dysfunctions accumulate with increasing age and can be found as a pathogenetic principle of different diseases where AGEs are involved. The causal mechanisms of these cellular dysfunctions are not fully understood. AGEs effects were examined in cell culture using video microscopy, immunohistochemistry, flow cytometry and biochemical methods in neural (NG 108-15) and glial (primary culture of astrocytes) cells. AGEs can bind to the cell surface of neural and glial cells. AGEs induce an altered distribution of vesicles and a statistically significant reduction in the velocity of microvesicles. The proteins dynamin 2 and clathrin, which are an important part of the transport apparatus, show changes in intracellular distribution similar to that of microvesicles. The immunoreactivity of dynamin 2 in AGE-treated cells is increased after AGE-incubation. After incubation durations of 2 h, 6 h and 12 h we found an increase (maximum +34.6%) of the relative fluorescence intensities of dynamin 2 in the AGE-BSA treated cells in comparison to the control cells (BSA). Using flow cytometry we found a minimal increase (14.4%) in clathrin immunoreactivity after 2 h incubation with 500 nM AGE-BSA. The non-quantitative western blot showed no difference of the electrophoretic behaviour of both dynamin 2 and clathrin in AGE-BSA-incubated cells (2 h, 500 nM) and in control cells (2 h, 500 nM BSA-incubation). The incubation with AGE-BSA up to a concentration of 500 nM in culture was not followed by apoptotic or necrotic cell death. We could show defined effects on the cells induced by incubation with AGEs. One of the effects is a significant reduction of the velocity of microvesicles, the reason for this is unclear. It could be due to disturbed calcium metabolism or caused by microtubuli-changes. The aggregation of intracellular microvesicles could be the result of an altered binding-behaviour of the vesicles or the destruction of the transport apparatus. The proteins dynamin 2 and clathrin, which are involved in transport apparatus, show changes in intracellular distribution indicating a breakdown of the normal cellular distribution system. The current results may contribute to the understanding of the pathologic processes in the cell in Mb. Alzheimer and other neurodegenerative diseases, where AGEs-accumulation can be found in tissues.

The role of 25-hydroxyvitamin D in normal and disturbed calcium metabolism.

The role of 25-hydroxyvitamin D in normal and disturbed calcium metabolism.

Inhibiting a Pump Within a Pump

Heart failure affects nearly 5 million people in the United States. Most inherited forms of heart failure have been linked to defects in cardiac contractile proteins. Schmitt et al. show that heart failure can be initiated by disturbances of calcium metabolism in heart muscle cells. Humans with an inherited form of congestive heart failure were found to have a mutation in phospholamban (PLN), a protein that inhibits the cardiac sarcoplasmic reticulum Ca 2+ -ATPase (SERCA2a). Subsequent experiments revealed that the mutant PLN causes constitutive inhibition of SERCA2a, leading to alterations in Ca 2+ kinetics. J. P. Schmitt, M. Kamisago, M. Asahi, G. H. Li, F. Ahmad, U. Mende, E. G. Kranias, D. H. MacLennan, J. G. Seidman, C. E. Seidman, Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science 299 , 1410-1413 (2003). [Abstract] [Full Text]

Calcium taste preference and sensitivity in humans: II. Hemodialysis patients

Calcium is an essential nutrient. However, in humans, despite widespread belief in a calcium appetite, it has hardly been studied experimentally. Here, we compared the avidity for calcium in 10 hemodialysis patients and 10 healthy controls to test whether disturbed calcium metabolism alters the preference for calcium. Hemodialysis patients did not differ from controls in their taste responses to CaCl 2 solution. However, they found high levels of CaCl 2 in cheese tastier. Our findings are indicative of a possible increased calcium appetite related to perturbed calcium metabolism in humans. The findings also suggest that for hemodialysis patients calcium added to foods might increase their palatability.

Bone and calcium metabolism in subclinical autoimmune hyperthyroidism and hypothyroidism.

Bone turnover is reported to increase in favour of resorption in overt hyperthyroidism and the rate of resorption is associated with the levels of thyroid hormones. Hypothyroidism, on the other hand, was shown to cause no disturbance of calcium kinetics and found to associate lower trabecular resorption surfaces and increased bone cortical thickness. Similar studies are very rare in subclinical thyroid disorders and consequently we aimed to examine calcium and bone metabolism in subclinical thyroid disorders. Thirteen patients with subclinical hyperthyroidism secondary to untreated Graves' disease, 20 patients with subclinical hypothyroidism and 10 healthy subjects participated in this survey. Briefly calcium, phosphorus, and creatinine (Cre), urinary deoxypyridinoline (U-DPD) and serum osteocalcin (OC) were measured as biochemical markers for calcium metabolism. Concerning serum Ca and phosphorus levels, there were no differences between three of the groups, but urinary Ca excretion was higher in subclinical hyperthyroid patients compared to control and hypothyroid subjects. Hypothyroid patients had similar U-DPD levels with control subjects (p = 0.218). Serum OC and U-DPD were higher in subclinical hyperthyroid compared to control subjects (p<0.001 and p<0.001 respectively). We demonstrated a higher bone turnover and greater calcium excretion in subclinical hyperthyroid patients. Additionally, we found that subclinical hypothyroidism is not associated with disturbed calcium metabolism. As persistent increase in bone turnover is responsible for accelerated bone loss, patients with Graves' disease may have increased risk for osteoporosis.

Association of calcium channel blockers and mortality in haemodialysis patients.

Patients with end-stage renal disease show disturbances of calcium metabolism, including calcification of arterial walls. Such patients show increased mortality, in particular due to increased cardiovascular-associated deaths. The association of calcium channel blockers and mortality in patients undergoing haemodialysis was investigated. A total of 188 patients who were receiving haemodialysis as of July 1998 were followed up for 30 months. Baseline characteristics, including age, sex, laboratory and clinical data, medication and dialysis prescription, were obtained. As of December 2000, 51 of the patients (27%) had died. In the deceased group, age was significantly higher, body mass index was significantly lower, and smoking was significantly more frequent compared with the survival group (each P <0.001). The percentage of patients taking calcium channel blockers was significantly higher in the survival group. Cox proportional hazard regression analysis showed that haemodialysis patients assigned calcium channel blocker therapy had a significantly lower risk of mortality [relative risk 0.33 (95% confidence interval 0.17-0.67); P <0.001]. Thus, in haemodialysis patients who were at high risk of cardiovascular events, administration of calcium channel blockers was associated with lower mortality.

Cloning and sequence analysis of the complementary DNA for feline preproparathyroid hormone.

To clone and sequence the cDNA for feline preproparathyroid hormone (preproPTH) and to compare that sequence with other known parathyroid hormone (PTH) sequences. Parathyroid glands from 1 healthy cat. A cDNA library was constructed in lambda phage from feline parathyroid gland mRNA and screened with a radiolabeled canine PTH probe. Positive clones were sequenced, and nucleic acid and deduced amino acid sequences were analyzed and compared with known preproPTH and PTH sequences. Screening of approximately 2 X 10(5) recombinant plaques revealed 3 that hybridized with the canine PTH probe; 2 clones comprised the complete sequence for feline preproPTH. Feline preproPTH cDNA consisted of a 63-base pair (bp) 5'-untranslated region (UTR), a 348-bp coding region, and a 326-bp 3'-UTR. The coding region encoded a 115-amino acid peptide. Mature feline PTH consisted of 84 amino acids. Amino acid sequence analysis revealed that feline PTH was > 83% identical to canine, bovine, swine, equine, human, and macaque PTH and 69, 71, and 44% identical to mouse, rat, and chicken PTH, respectively. Within the region responsible for hormonal activity (amino acids 1 to 34), feline PTH was > 79% identical to other mammalian PTH sequences and 64% identical to the chicken sequence. The amino acid sequence of PTH is conserved among mammalian species. Knowledge of the cDNA sequence for feline PTH may be useful to investigate disturbances of calcium metabolism and alterations in PTH expression in cats.

Vitamin D Metabolism, Rickets, and Osteomalacia

Rickets in the growing child or adolescent and osteomalacia in the adult develop in a variety of clinical situations and have in common an absence or delay in the mineralization of growth cartilage and in newly formed bone collagen. Classically, deficiency of vitamin D, which is essential for the absorption of dietary calcium, has been the major cause. However, rickets is also seen as a result of hereditary defects in critical vitamin D signaling molecules. Disturbances of phosphate metabolism can also lead to signs of rickets and osteomalacia, notably X-linked hypophosphatemic rickets, and oncogenic osteomalacia. Extrarenal synthesis of 1,25-dihydroxyvitamin D, such as that associated with granulomatous disease, can also lead to disturbances in calcium metabolism, with associated skeletal and nonskeletal changes.

Vitamin D Status, Parathyroid Hormone and Bone Mineral Density in Patients with Inflammatory Bowel Disease

Background: Although the pathogenesis of osteoporosis in inflammatory bowel disease (IBD) is not established, vitamin D deficiency and disturbances in calcium metabolism are thought to be of importance, especially in Crohn disease (CD). Vitamin D status is assessed and the relation between indices of calcium metabolism, including 25-hydroxyvitamin D and parathyroid hormone concentrations, and bone mineral density (BMD) in CD and ulcerative colitis (UC) are examined. Sixty patients with CD and 60 with UC were investigated. Each group comprised 24 men and 36 women. Methods: Vitamin D metabolites, parathyroid hormone and biochemical markers of bone metabolism were measured in blood and urine. Lumbar spine, femoral neck and total body BMD were measured by dual X-ray absorptiometry (DXA) and Z-scores were obtained by comparison with age- and sex-matched normal values. Results: Vitamin D deficiency (25-hydroxyvitamin D3 <30 nmol/l) was present in 27% of patients with CD and in 15% with UC. Furthermore, CD patients had a significantly lower mean concentration of 25-hydroxyvitamin D3 compared with UC patients. Vitamin D status was not related to BMD at any of the skeletal sites measured. Secondary hyperparathyroidism was found in 10 out of 27 patients with CD after small-bowel resections. No differences were found in serum osteocalcin and urine pyridinoline between patients with CD and those with UC. Conclusions: Hypovitaminosis D is common in CD patients. Patients with CD and small-bowel resections are at risk of developing secondary hyperparathyroidism and low BMD.

Phosphate buffer in alkali eye burns as an inducer of experimental corneal calcification

Corneal calcification is a common problem in severe inflammation, chronic glaucoma, renal disorders and other diseases with disturbed calcium and phosphorus metabolism. The pathogenesis of corneal calcifications in ocular diseases is not yet completely understood. We present a model of an induced corneal calcification by local treatment. In a double-masked experiment 16 rabbits underwent eye burn of one cornea followed by immediate rinsing (160 ml) with isotonic phosphate buffer ( n=8) or saline solution ( n=8) three time a day for 16 days. Tissues were excised, shock frozen and cut into 10 μm slices, freeze dried and coated with evaporated carbon. In the phosphate buffer group an early onset of corneal opacification occurred resulting in completely white corneas after 16 days, combined with corneoscleral ulceration. The other group showed similar corneal erosion and a little corneal ulceration, but no opacifications. The opacifications of the phosphate buffer group could be identified as calcifications by direct measurements of calcium and phosphate (by energy dispersive X-ray analysis on corneal samples). In conclusion, inappropriate application of phosphate leads to uncontrolled calcifications of the cornea after severe burns to the eye. This reflects clinically observed calcifications after eye burns and possibly the adverse side effects of phosphate buffered eye drops being applied in ophthalmology.

Correlation between 25-hydroxyvitamin D3 1α-hydroxylase gene expression in alveolar macrophages and the activity of sarcoidosis

PURPOSE: To demonstrate expression of the 25-hydroxyvitamin D3 1α-hydroxylase (1α-hydroxylase) gene in human alveolar macrophages and measure the correlations among the 1α-hydroxylase mRNA level, the activity of sarcoidosis, and calcium metabolism. SUBJECTS AND METHODS: We examined 7 patients with sarcoidosis and 6 control patients with other pulmonary disorders who underwent bronchoalveolar lavage. Levels of 1α-hydroxylase mRNA were measured by semiquantitative polymerase chain reaction amplification. We measured serum levels of calcium, ionized calcium, parathyroid hormone, calcitriol (1,25-dihydroxyvitamin D3), and 25-hydroxyvitamin D3 to evaluate calcium metabolism. To estimate the activity of sarcoidosis, we measured the cell count, the CD4/CD8 ratio in bronchoalveolar lavage cells, and the serum angiotensin-converting enzyme (ACE) activity. RESULTS: Expression of 1α-hydroxylase was demonstrated in purified human alveolar macrophages. The 1α-hydroxylase mRNA levels in bronchoalveolar lavage cells were fivefold higher in sarcoidosis patients than in control patients (10.8 ± 3.6 vs. 2.2 ± 1.4, P <0.003). Among all patients studied, there were significant correlations between the 1α-hydroxylase mRNA level in bronchoalveolar lavage samples and the percentage of alveolar lymphocytes ( r = 0.83, P <0.005), the CD4/CD8 ratio ( r = 0.77, P <0.02), serum ACE level ( r = 0.58, P <0.05), serum ionized calcium level ( r = 0.58, P <0.05), and the calcitriol/25-hydroxyvitamin D3 ratio ( r = 0.57, P <0.05). In the sarcoidosis patients, a significant correlation was also observed between 1α-hydroxylase mRNA and the percentage of alveolar lymphocytes ( r = 0.82, P <0.05). CONCLUSION: There is a correlation between 1α-hydroxylase gene expression in alveolar macrophages with the activity of sarcoidosis and its associated disturbances in calcium metabolism.

Increased membraneous calcium concentrations in primary hypertension: a causal link to pathogenesis?

Disturbance in calcium metabolism has been suggested in the pathogenesis of hypertension, however, membrane calcium content in humans has not been studied in detail yet in primary hypertension. We compared plasma, intracellular and membrane calcium concentrations in erythrocytes of patients with essential hypertension and in healthy, normotensive control subjects to determine a possible alteration of membrane calcium in primary hypertension. Thirty-four never treated patients with essential hypertension were included and 34 healthy, age- and sex-matched volunteers served as controls. Atomic absorption spectroscopy was used for measurement of intracellular and membrane calcium content in erythrocytes and plasmalemmal preparations. Plasma and intracellular Ca(++) concentrations were not significantly different between hypertensives and controls (plasma: 2.59 +/- 0.18 vs2.50 +/- 0.16 mmol/l, intracellular: 1.89 +/- 0.20 mmol/l vs 1.97 +/- 0.24 mmol/l, NS resp., mean +/- s.e.m.). However, membrane calcium content was significantly higher in hypertensive patients compared to control subjects (2.38 +/- 0.28 micromol/g membraneous protein vs0.86 +/- 0.32 micromol/g membrane protein, P < 0.01). Membrane calcium content was correlated to mean arterial blood pressure (r = 0.59, P < 0.01). Membrane calcium content is significantly increased in patients with untreated primary hypertension and correlates to blood pressure levels. This data suggest, that an membrane mechanism may contribute to alterations in calcium metabolism and to the pathogenesis of primary hypertension.

Management of disturbed calcium metabolism in uraemic patients: 2. Indications for parathyroidectomy.

Management of disturbed calcium metabolism in uraemic patients: 2. Indications for parathyroidectomy.

Management of disturbed calcium metabolism in uraemic patients: 1. Use of vitamin D metabolites.

Chronic renal failure is characterized by diminished synthesis of, and resistance to, the active vitamin D metabolite 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3, calcitriol). Calcitriol results from the biotransformation of the precursor 25-hydroxy-vitamin D3 (25(OH)D3) to 1,25(OH)2D3. 25(OH)D3 is synthesized in the liver, and 1alpha-hydroxylase, the rate-limiting enzyme for its biotransformation into the most active metabolite, 1,25(OH)2D3, is located in the kidney. The regulation of 1alpha-hydroxylase in renal failure is not well known. Recent work indicates that, in contrast to previous opinion, 1alpha-hydroxylase is predominantly expressed not in the proximal tubule but in the distal tubule [1]. In vivo, the main stimulatory signal is presumably parathyroid hormone (PTH) and the main inhibitory signal hyperphosphataemia. Both signals are altered in renal failure. There is also evidence that the renal 1alpha-hydroxylase becomes substrate-dependent in patients with renal failure. This means that a higher concentration of the precursor 25(OH)2D3 will result in a higher rate of transformation into the active metabolite 1,25(OH)2D3 in renal patients. Calcitriol is not exclusively synthesized in the kidney, but may also be synthesized in extra-renal tissues, e.g. activated monocytes/macrophages [2], particularly in granuloma [3] as shown by anephric uraemic patients who develop hypercalcaemia and elevated calcitriol concentrations when sarcoidosis [4] or tuberculosis [5] supervenes. On the other hand, calcitriol is less effective in uraemia. This may be to some extent due to diminished expression of vitamin D receptors [6], particularly in parathyroid glands when they undergo nodular transformation [7], but there may also be resistance to calcitriol at the post-receptor level [8]. In a series of elegant experiments [9,10], calcitriol resistance has been related to disturbed genomic effects of active vitamin D because the interaction of the vitamin D receptor ligand complex with vitamin D-responsive elements (VDREs) upstream of vitamin D-regulated genes was disturbed by the action of low molecular weight substances in uraemia, which have not been completely characterized. The role of genetically determined polymorphisms of the vitamin D receptor in the genesis of disturbed calcium metabolism of renal failure is currently unclear.

Calcium metabolism in sarcoidosis and its clinical implications.

: To examine the clinical implications of disturbed calcium metabolism in sarcoidosis and how the pathophysiology affects management strategies. : The literature concerning calcium metabolism in sarcoidosis was reviewed. : Dysregulated calcium metabolism is a well-recognized complication of sarcoidosis, resulting in hypercalcaemia (prevalence 5-10%), hypercalcuria (40-62%) and reduced bone density (40-55%). Extrarenal synthesis of calcitriol [1,25(OH)(2)D(3)] is central to the pathogenesis of abnormal calcium homeostasis, but alterations in parathyroid hormone (PTH) activity and the expression of PTH-related peptide have also been demonstrated. The immunosuppressive properties of calcitriol suggest that the raised levels seen in sarcoidosis could represent an adaptive response to the undefined antigen that causes sarcoidosis. : The mechanisms of abnormal calcium metabolism in sarcoidosis need to be understood when treating hypercalcaemia, hypercalcuria and corticosteroid-induced osteoporosis. Studies are required to determine if the currently available therapies for osteoporosis are safe and effective in sarcoidosis.

Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure.

In human and experimental models of heart failure, sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) activity is decreased, resulting in abnormal calcium handling. The disturbances in calcium metabolism have been shown to contribute significantly to the contractile dysfunction observed in heart failure. We investigated whether increasing SERCA2a expression can improve ventricular function in an animal model of heart failure obtained by creating ascending aortic constriction in rats. After 19-23 wk of banding during the transition from compensated hypertrophy to heart failure (documented by >25% decrease in fractional shortening), rats were randomized to receive either an adenovirus carrying the SERCA2a gene (Ad.SERCA2a, n = 13) or beta-galactosidase (Ad.betagal, n = 14) by using a catheter-based technique. The failing hearts infected with Ad. betagal were characterized by a significant decrease in SERCA2a expression and a decrease in SERCA2a activity compared with nonfailing sham-operated rats (n = 11). In addition, these failing hearts had reduced left-ventricular systolic pressure, maximal rate of left-ventricular pressure rise and decline (+dP/dt, -dP/dt), and rate of isovolumic relaxation (tau). Overexpression of SERCA2a restored both SERCA2a expression and ATPase activity to nonfailing levels. Furthermore, rats infected with Ad.SERCA2a had significant improvement in left-ventricular systolic pressure, +dP/dt, -dP/dt, and rate of isovolumic relaxation (tau) normalizing them back to levels comparable to sham-operated rats. In this study, we show that in an animal model of heart failure where SERCA2a protein levels and activity are decreased and severe contractile dysfunction is present, overexpression of SERCA2a in vivo restores both systolic and diastolic function to normal levels.

TOXIC NEURONAL APOPTOSIS AND MODIFICATIONS OF TAU AND APP GENE AND PROTEIN EXPRESSIONS*

The causes and the mechanisms of neuronal death in Alzheimer's disease are not elucidated, although some new insights have been proposed over the past years, including free-radical toxicity, beta-amyloid toxicity, excitotoxicity, and disturbed cellular calcium metabolism. Some authors have also pointed out that apoptosis could play a role in neuronal degeneration, but it is still largely debated. Here, we review some recent data linking the induction of experimental neuronal apoptosis in vitro and the molecular pathology of the tau protein and amyloid precursor protein (APP). In cultures exposed to mild glutamate toxicity, tau mRNA expression, not beta-actin, is enhanced in stressed neurons. The Guam cycad toxin metabolite methylazoxymethanol also produces an increase of tau gene transcription that exacerbates changes induced by glutamate. In serum-deprived cultures or glutamate-exposed cultures, neurons committed to apoptosis have a reduced tau gene expression, whereas resistant neurons display a stable or even augmented tau mRNA expression accompanied by a persistent tau phosphorylation near serine 202. In the same conditions, stressed neurons produce membrane blebbings strongly immunopositive for APP and putative amyloidogenic fragments that are subsequently released in the extracellular space. Experimental apoptosis in neurons can recapitulate tau and APP modifications that could be associated with a selective vulnerability and a progression of cellular degeneration along the neuronal network.

Aging, dementia and calcium metabolism.

After a brief discussion of the theory of disturbed neuronal calcium metabolism an overview is given on the results of clinical studies with nimodipine in the treatment of vascular and Alzheimer's dementia.