vitamin-d-2 and Calcinosis

Recent evidence suggests that the traditional syndromes known as renal osteodystrophy, secondary hyperparathyroidism, and vitamin D deficiency are related to mortality in persons with moderate to advanced chronic kidney disease (CKD). The so-called 'kidney bone disease', also known as 'mineral and bone disorders', is defined to include bone disorders, mineral disarrays, and vascular calcification. We have identified 14 common and clinically relevant conditions of contemporary nature that are related to the kidney bone disease, including calcitriol (active vitamin D) deficiency, 25(OH)-vitamin D deficiency, biochemical hyperparathyroidism, relatively low parathyroid hormone (PTH) level, increased serum alkaline phosphatase (hyperphosphatasemia), elevated fibroblast growth factor (FGF)-23, high turnover bone disease, adynamic bone disease, uremic osteoporosis, vascular calcification, hyper- and hypophosphatemia, and hyper- and hypocalcemia. We present a critical review of these 14 conditions with emphasis on patient survival and other pertinent clinical outcomes. We also review unresolved controversies surrounding the management of these conditions by administration of nutritional vitamin D (ergocalciferol and cholecalciferol), vitamin D receptor activators (calcitriol, alphacalcidiol, doxercalciferol), D-mimetics (paricalcitol, maxacalcitol), calcimimetics (cinacalcet), recombinant PTH (teriparatide), and receptor activator of nuclear factor-kappaB ligand modulators (denosumab); compare mortality predictability of PTH and alkaline phosphatase; and examine potential risks of bone disorders and mineral disarrays in CKD patients.

Topics: Alkaline Phosphatase; Calcinosis; Calcitriol; Chronic Kidney Disease-Mineral and Bone Disorder; Ergocalciferols; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Hyperphosphatemia; Hypocalcemia; Hypophosphatemia; Kidney Failure, Chronic; Minerals; Osteoporosis; Parathyroid Hormone; Receptors, Calcitriol; Vitamin D; Vitamin D Deficiency

The articles providing answers to the questions on vascular calcification of most interest from a clinical point of view were selected. 1. How is it measured?: Studies showing the clinical utility of different tools to quantify it were analyzed. 2. What does it measure?: Both in dialysis patients and the general population, vascular calcification and arterial stiffness are prognostic factors for morbidity and mortality. Other markers such as fetuin-A are associated with mortality in patients on hemodialysis but not in patients in early stages of chronic kidney disease. 3. What causes it?: In two selected studies, it was demonstrated again that low bone turnover and diabetes cause cardiovascular disease and vascular calcification, respectively. 4. How is it treated?: There is still no clinical evidence of regression of vascular calcification. However, a prospective study in new hemodialysis patients showed that sevelamer compared to calcium compounds slows the progression of vascular calcification and confers greater survival. A study comparing both compounds in chronic hemodialysis patients showed that sevelamer only had a benefit on survival in patients older than 65 years. It remains to be demonstrated whether the good experimental results of paricalcitol and cinacalcet are confirmed in prospective clinical studies.

Topics: Aged; Animals; Atherosclerosis; Calcinosis; Chronic Disease; Cinacalcet; Coronary Artery Disease; Diabetes Complications; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Kidney Diseases; Mice; Mice, Knockout; Multicenter Studies as Topic; Naphthalenes; Polyamines; Randomized Controlled Trials as Topic; Renal Artery; Sevelamer; Tomography, Spiral Computed; Tomography, X-Ray Computed; Vascular Diseases

Chronic kidney disease (CKD) patients encounter an increased risk of cardiovascular disease and mortality compared with healthy individuals, most likely due to the presence of severe atherosclerosis and accelerated vascular calcification. Vascular calcification is an active, regulated process resulting from an imbalance between losses in inhibitory factors and gains in inducing factors present in cells and the blood circulation. However, exactly which inhibitory and inducing factors are involved remains unknown. The vitamin D receptor (VDR) is a nuclear receptor present in over 30 different tissues. Several VDR activators (VDRAs), including paricalcitol and calcitriol, are currently available for the treatment of secondary hyperparathyroidism in patients with CKD. Recent clinical observations demonstrate that VDRA therapy provides survival benefits for CKD patients in the order of paricalcitol > calcitriol > no VDRA therapy, independent of serum parathyroid hormone, phosphorus and calcium levels. The survival benefit of VDRAs seems contradictory to the perception that VDRAs, due to their potential impact of increasing serum phosphorus and calcium, may cause calcification in vessels. A review of the current literature shows that inconsistent data exist regarding the role of VDRAs in vascular calcification. A possible explanation is that the VDR may be involved in regulating several different pathways as an endocrine, paracrine and/or autocrine factor, and different VDRAs may have differential effects on the endocrine versus the paracrine/autocrine aspect.

Topics: Animals; Calcinosis; Calcitriol; Ergocalciferols; Humans; Kidney Failure, Chronic; Receptors, Calcitriol; Vitamin D

Controlling the development of vascular calcification in chronic kidney disease is essential, because it is associated with increased cardiovascular pathology. However, the precise mechanism of vascular calcification has not been completely elucidated. In the literature, the involvement of passive calcium and phosphate deposition as well as an active process stimulating the transformation of vascular smooth muscle cells into an osteoblastic phenotype is suggested. New promising insights into the etiology could lead to better treatment strategies, as Mizobuchi et al. now report.

Topics: Animals; Bone Density Conservation Agents; Calcinosis; Ergocalciferols; Humans; Renal Insufficiency, Chronic

Vitamin D, a fat-soluble vitamin, can be associated with significant morbidity when prescribed in large doses. We describe a hypoparathyroid patient with vitamin D intoxication who developed painful periarticular calcinosis, nephrocalcinosis with hypertension and chronic renal failure in addition to band keratopathy and hearing loss. He was treated with combination therapy including prednisone, phosphate-binding antacid, phenytoin and disodium etidronate. After 20 months of follow-up there was a significant reduction of periarticular calcinosis, but no improvement in renal function, band keratopathy or hearing loss and possible calcification of the ossicles. The clinicopathologic features of metastatic calcification and the various treatment modalities are reviewed.

Topics: Adult; Aluminum Hydroxide; Calcinosis; Ergocalciferols; Etidronic Acid; Humans; Joint Diseases; Male; Nephrocalcinosis; Phenytoin; Prednisone

Topics: Bone Diseases; Calcinosis; Chronic Kidney Disease-Mineral and Bone Disorder; Diet Therapy; Ergocalciferols; Fibrous Dysplasia of Bone; Fractures, Spontaneous; Humans; Hyperparathyroidism, Secondary; Hypocalcemia; Kidney Transplantation; Metabolic Diseases; Osteomalacia; Osteosclerosis; Parathyroid Glands; Phosphates; Renal Dialysis; Tendon Injuries; Vitamin D

The risk of cardiovascular disease is tremendously high in dialysis patients. Dialysis patients treated with vitamin D analogs show decreased cardiovascular morbidity and mortality compared with untreated patients. We examined the influence of two common vitamin D analogs, alfacalcidol and paricalcitol, on important cardiovascular biomarkers in hemodialysis patients. Anti-inflammatory effects and the influence on regulators of vascular calcification as well as markers of heart failure were examined.. In 57 chronic hemodialysis patients enrolled in a randomized crossover trial comparing paricalcitol and alfacalcidol, we examined the changes in osteoprotegerin, fetuin-A, NT-proBNP, hs-Crp, IL-6 and TNF-α, during 16 weeks of treatment.. NT-proBNP and osteoprotegerin increased comparably in the paricalcitol and alfacalcidol-treated groups. Fetuin-A increased significantly in the alfacalcidol-treated group compared with the paricalcitol-treated group (difference 32.84 μmol/l (95% C.I.; range 0.21-67.47)) during the first treatment period. No difference was found between the groups during the second treatment period, and IL-6, TNF-α and hs-Crp were unchanged in both treatment groups.. Paricalcitol and alfacalcidol modulate regulators of vascular calcification. Alfacalcidol may increase the level of the calcification inhibitor fetuin-A. We did not find any anti-inflammatory effect or difference in changes of NT-proBNP.. ClinicalTrials.gov NCT00469599 May 3 2007.

Topics: Aged; Aged, 80 and over; Biomarkers; Calcinosis; Cross-Over Studies; Ergocalciferols; Female; Humans; Hydroxycholecalciferols; Inflammation Mediators; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Renal Dialysis; Vitamin D

Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease. The management of SHPT commonly involves vitamin D, either calcitriol or newer analogs (paricalcitol or doxercalciferol), along with dietary phosphorus restriction and phosphate binding agents. Published reports have suggested that treatment with paricalcitol in hemodialyzed (HD) patients offers a morbidity or mortality advantage in comparison with treatment with calcitriol. We have recently reported that switching from calcitriol to paricalcitol resulted in a lower serum calcium and calcium-phosphorus product (Ca x P product), as well as lower parathyroid hormone (PTH) and alkaline phosphatase during 6 months of serial treatment. We converted all HD patients in our large urban dialysis center from calcitriol to paricalcitol using a 1:3 conversion ratio, on the basis of published data. Comparisons of individual patient mean biochemical values, as well as episodes of hypercalcemia and elevated Ca x P product, were made after adjusting for equivalent doses. In addition, we recorded the number of missed doses during two years of therapy. No patient in this study had received a calcimimetic before or during the study period. Fifty-nine patients were treated with calcitriol for at least 12 months and then completed 12 months of paricalcitol. Conversion from calcitriol to paricalcitol resulted in lower serum calcium (P=0.0003), lower serum phosphorus (P=0.027), lower Ca x P product (P=0.003), reduced PTH (P=0.001) and reduced serum alkaline phosphatase (P=0.0005). Most dramatically, there was a highly significant difference in the number of missed doses (P<0.0001) during the treatments. This 2-year single-center study, comparing long-term calcitriol with paricalcitol treatment in the same HD patients, extends our previous findings, offers new information regarding single episodes of potentially adverse biochemical effects related to vitamin D therapy, and provides several clues that may explain the outcome advantages suggested by previously published retrospective analyses of large dialysis provider-pooled databases.

Topics: Aged; Calcinosis; Calcitriol; Calcium; Cross-Over Studies; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Retrospective Studies

Topics: Arterioles; Breast Diseases; Calcinosis; Ergocalciferols; Female; Humans; Kidney Failure, Chronic; Middle Aged; Skin Ulcer; Thiosulfates; Uremia

Topics: Basal Ganglia Diseases; Calcinosis; Calcium; Epilepsy, Tonic-Clonic; Ergocalciferols; Humans; Male; Middle Aged; Neurodegenerative Diseases; Seizures; Syndrome; Tomography, X-Ray Computed; Treatment Outcome

Observational data associate lower levels of serum vitamin D with coronary artery calcification, cardiovascular events and mortality. However, there is little interventional evidence demonstrating that moderate vitamin D deficiency plays a causative role in cardiovascular disease. This study examined the cardiovascular effects of dietary vitamin D deficiency and of vitamin D receptor agonist (paricalcitol) administration in apolipoprotein E knockout mice.. Mice were fed atherogenic diets with normal vitamin D content (1.5 IU/kg) or without vitamin D. Paricalcitol, or matched vehicle, was administered 3× weekly by intraperitoneal injection. Following 20 weeks of these interventions cardiovascular phenotype was characterized by histological assessment of aortic sinus atheroma, soluble markers, blood pressure and echocardiography. To place the cardiovascular assessments in the context of intervention effects on bone, structural changes at the tibia were assessed by microtomography.. Vitamin D deficient diet induced significant reductions in plasma vitamin D (p<0.001), trabecular bone volume (p<0.01) and bone mineral density (p<0.005). These changes were accompanied by an increase in calcification density (number of calcifications per mm(2)) of von Kossa-stained aortic sinus atheroma (461 versus 200, p<0.01). Paricalcitol administration suppressed parathyroid hormone (p<0.001), elevated plasma calcium phosphate product (p<0.005) and induced an increase in calcification density (472 versus 200, p<0.005) similar to that seen with vitamin D deficiency. Atheroma burden, blood pressure, metabolic profile and measures of left ventricular hypertrophy were unaffected by the interventions.. Vitamin D deficiency, as well as excess, increases atherosclerotic calcification. This phenotype is induced before other measures of cardiovascular pathology associated clinically with vitamin D deficiency. Thus, maintenance of an optimal range of vitamin D signalling may be important for prevention of atherosclerotic calcification.

Topics: Animals; Apolipoproteins E; Calcinosis; Diet; Ergocalciferols; Hypertrophy, Left Ventricular; Male; Mice; Mice, Knockout; Plaque, Atherosclerotic; Sinus of Valsalva; Vitamin D; Vitamin D Deficiency

Cardiovascular diseases are more prevalent in patients with chronic kidney disease than in the general population and they are considered the leading cause of death in patients with end-stage renal disease. The discovery that vitamin D3 plays a considerable role in cardiovascular protection has led, in recent years, to an increase in the administration of therapies based on the use of this molecule; nevertheless, several studies warned that an excess of vitamin D3 may increase the risk of hypercalcemia and vascular calcifications. In this study we evaluated the effects of vitamin D3, and of its selective analog paricalcitol, on immature cardiomyocytes. Results show that vitamin D3 induces cAMP-mediated cell proliferation and significant intracellular calcification. Paricalcitol, however, induces cell differentiation, morphological modifications in cell shape and size, and no intracellular calcification. Furthermore, vitamin D3 and paricalcitol differently affect cardiomyoblasts responses to acetylcholine treatment. In conclusion, our results demonstrate that the effects of vitamin D3 and paricalcitol on cardiomyoblasts are different and, if these in vitro observations could be extrapolated in vivo, they suggest that paricalcitol has the potential for cardiovascular protection without the risk of inducing intracellular calcification.

Topics: Acetylcholine; Animals; Calcinosis; Cardiovascular Diseases; Cell Line; Cell Proliferation; Cell Survival; Cholecalciferol; Ergocalciferols; Myocytes, Cardiac; Rats; Renal Insufficiency, Chronic

Cardiovascular diseases are the most important cause of death in patients with impaired kidney function. Left ventricular hypertrophy (LVH), cardiac interstitial fibrosis and cardiovascular calcifications are characteristic of chronic renal insufficiency (CRI). Periostin is a fibrogenesis- and calcification-related matricellular protein re-expressed in adult tissues undergoing remodelling in response to pathological stimuli. The role of periostin in CRI-induced LVH is unknown.. Rats were 5/6-nephrectomized (NX), and after 15 weeks of disease progression high-calcium, high-phosphate or paricalcitol treatment was given for 12 weeks. Cardiac tissue and blood samples were taken to study periostin gene expression and to determine factors contributing to its reactivation, respectively. Left ventricular (LV) periostin expression was also examined in response to angiotensin II or arginine(8)-vasopressin (AVP)-induced pressure overload and in spontaneously hypertensive rats.. CRI resulted in a 6.5-fold increase in LV periostin messenger RNA (mRNA) levels. Positive extracellular immunostaining for periostin was detected in areas of infiltrated inflammatory cells and fibrotic lesions. There was a significant correlation between LV periostin mRNA levels and plasma biomarkers of impaired kidney function, LVH, fibrogenesis-related proteins osteopontin and osteoactivin, and anti-calcific matrix Gla protein. Moreover, LV periostin gene expression in CRI correlated positively with systolic blood pressure (BP) and was activated rapidly in response to angiotensin II or AVP infusions.. Periostin is involved in fibrotic cardiac remodelling in CRI. The re-expression of periostin is localized to the fibrotic and inflammatory lesions and is most likely the consequence of elevated BP.

Topics: Animals; Biomarkers; Blotting, Western; Bone Density Conservation Agents; Calcinosis; Cell Adhesion Molecules; Disease Models, Animal; Ergocalciferols; Fibrosis; Gene Expression; Heart Ventricles; Hypertension; Immunoenzyme Techniques; Kidney Function Tests; Myocardial Infarction; Nephrectomy; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Renal Insufficiency; RNA, Messenger

Vitamin D sterols may modulate vascular response to inflammation and vascular calcification (VC).. Rat aortic rings (RARs) and human vascular smooth muscle cells (HVSMCs) were treated in vitro with phosphate (P), tumour necrosis factor alpha (TNF-α), calcitriol (CTR) and paricalcitol (PCT). Rats having undergone subtotal nephrectomy (Nx) (n = 66) on a high-phosphorus diet were treated with Escherichia coli lipopolysacharide (LPS) (40-400 μg/kg/day) or LPS plus CTR (80 ng/kg/48 h) or LPS plus PCT (240 ng/kg/48 h) for 14 days.. In vitro, the addition of TNF-α to the medium increased the mineral content of RAR and HVSMC. Treatment with both vitamin D analogues decreased bone morphogenetic protein 2 but did not modify Runx-2. Calcification was prevented only by PCT. In vivo, treatment with LPS increased plasma levels of TNF-α, monocyte chemotactic protein-1 and interleukin-1alfa and induced calcification. The concomitant administration of LPS with either CTR or PCT led to a significant decrease in cytokine plasma levels and the decrease was more accentuated after treatment with PCT than with CTR. Rats treated with CTR showed an elevation in aortic Ca and marked Von Kossa staining; however, rats treated with PCT did not increase aortic Ca and did not show Von Kossa staining.. Treatment with PCT resulted in more marked anti-inflammatory effect than treatment with CTR and, as opposed to CTR, PCT prevented VC.

Topics: Animals; Aorta; Blood Pressure; Blotting, Western; Bone Density Conservation Agents; Calcinosis; Calcitriol; Calcium; Cells, Cultured; Cytokines; Ergocalciferols; Female; Humans; Inflammation; Lipopolysaccharides; Muscle, Smooth, Vascular; Nephrectomy; Phosphorus; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha; Uremia; Vascular Diseases

Despite an only minor reduction in the glomerular filtration rate, uninephrectomy (UNX) markedly accelerates the rate of growth of atherosclerotic plaques in ApoE-/- mice. It has been suggested that vitamin D receptor (VDR) activation exerts an antiproliferative effect on vascular smooth muscle cells, but the side effects may limit its use. To assess a potentially different spectrum of actions, we compared the effects of paricalcitol and calcitriol on remodeling and calcification of the aortic wall in sham-operated and UNX ApoE-/- mice on a diet with normal cholesterol content. Sham-operated and UNX mice were randomly allotted to treatment with solvent, calcitriol (0.03 μg/kg) or paricalcitol (0.1 μg/kg) 5 times/wk intraperitoneally for 10 wk. Semithin (0.6 μm) sections of the aorta were analyzed by 1) morphometry, 2) immunohistochemistry, and 3) Western blotting of key proteins involved in vascular calcification and growth. Compared with sham-operated animals (5.6 ± 0.24), the wall-to-lumen ratio (x100) of the aorta was significantly higher in solvent- and calcitriol-treated UNX animals (6.64 ± 0.27 and 7.17 ± 0.81, respectively, P < 0.05), but not in paricalcitol-treated UNX (6.1 5 ± 0.32). Similar differences were seen with respect to maximal plaque height. Expression of transforming growth factor (TGF)-β1 in aortic intima/plaque was also significantly higher in UNX solvent and UNX calcitriol compared with sham-operated and UNX paricalcitol animals. Treatment with both paricalcitol and calcitriol caused significant elevation of VDR expression in the aorta. While at the dose employed paricalcitol significantly reduced TGF-β expression in plaques, calcitriol in contrast caused significant vascular calcification and elevated expression of related proteins (BMP2, RANKL, and Runx2).

Topics: Animals; Aorta; Apolipoproteins E; Bone Density Conservation Agents; Bone Morphogenetic Protein 2; Calcinosis; Calcitriol; Cholesterol; Core Binding Factor Alpha 1 Subunit; Disease Models, Animal; Ergocalciferols; Kidney; Male; Mice; Mice, Knockout; Nephrectomy; Plaque, Atherosclerotic; RANK Ligand; Receptors, Calcitriol; Transforming Growth Factor beta1

Calcific uremic arteriolopathy, or calciphylaxis, is a serious and life-threatening complication of end-stage renal disease. Its pathogenesis is not yet fully elucidated and treatment is controversial. In the presence of severe hyperparathyroidism, parathyroidectomy should be considered. We report a case of a woman on maintenance hemodialysis therapy with calciphylaxis and parathyroid adenoma who refused to undergo parathyroidectomy. She was treated successfully with a combination of noncalcium phosphate binders, cinacalcet, and paricalcitol. Subcutaneous plaques disappeared, and the necrotic lesion was healed. Discontinuation of paricalcitol led to an increase in serum parathyroid hormone levels and reappearance of the patient's symptoms, whereas its reintroduction resulted in complete remission of the clinical picture. Paricalcitol, a less calcemic vitamin D analogue, is also a selective vitamin D receptor activator with a number of nonclassic actions (such as inhibition of inflammation and ossification-calcification) that could prove beneficial in cases of calciphylaxis.

Topics: Adenoma; Arterial Occlusive Diseases; Arterioles; Biopsy; Bone Density Conservation Agents; Calcinosis; Ergocalciferols; Female; Follow-Up Studies; Humans; Middle Aged; Parathyroid Neoplasms; Positron-Emission Tomography; Uremia

Vascular calcification is highly correlated with morbidity and mortality, and it is often associated with inflammation. Vitamin D may regulate vascular calcification and has been associated with cardiovascular survival benefits.. We developed a macrophage/smooth muscle cell (SMC) coculture system and examined the effects of vitamin D receptor activators (VDRA), calcitriol and paricalcitol, on SMC matrix calcification. We found that treatment of SMC alone with VDRA had little effect on phosphate-induced SMC calcification in vitro. However, coculture with macrophages promoted SMC calcification, and this was strikingly inhibited by VDRA treatment. Several VDRA-induced genes, including bone morphogenetic protein-2 (BMP2), tumor necrosis factor-alpha, and osteopontin, were identified as candidate paracrine factors for the protective effect of VDRA. Of these, osteopontin was further investigated and found to contribute significantly to the inhibitory actions of VDRA on calcification in macrophage/SMC cocultures.. The ability of VDRA to direct a switch in the paracrine phenotype of macrophages from procalcific to anticalcific may contribute to their observed cardiovascular survival benefits.

Topics: Animals; Bone Morphogenetic Protein 2; Calcinosis; Calcitriol; Calcium; Cells, Cultured; Coculture Techniques; Ergocalciferols; Gene Expression Regulation; Humans; Macrophages; Mice; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Osteopontin; Paracrine Communication; Phenotype; Receptors, Calcitriol; RNA Interference; RNA, Messenger; Time Factors; Tumor Necrosis Factor-alpha

Patients with poor metabolic control receiving conventional hemodialysis are at risk for developing severe secondary hyperparathyroidism. We postulated that daily hemodialysis may be effective at controlling parathyroid hormone (PTH) in the setting of severe secondary hyperparathyroidism by improving the control of hyperphosphatemia and allowing increased use of vitamin D analogs. We present 5 patients with severe secondary hyperparathyroidism (median iPTH=1783 pg/mL) who were treated with 3-hour daily hemodialysis (3 hours x 6 times a week). Daily hemodialysis, at 1 year, was associated with a 70.4% reduction in median PTH (1783 pg/mL [interquartile range: 1321-1983]-472 pg/mL [334, 704], P<0.001). Additionally, there was an increase in paricalcitol dose from 0 mcg/d to 10.8 (2.00, 11.7) mcg/d, a 39% reduction in calcium x phosphorus product (80.3 +/- 26.8-48.9 +/- 14.0, P<0.01), a 52% reduction in serum phosphorus (9.90 +/- 2.34-4.75 +/- 0.79 mg/dL, P<0.0001), and a 17.6% increase in serum calcium (8.18 +/- 2.04-9.62 +/- 0.93 mg/dL, P<0.01). Three-hour daily hemodialysis with the use of high-dose paricalcitol is associated with improved control of severe secondary hyperparathyroidism.

Topics: Adult; Appointments and Schedules; Biomarkers; Bone Density Conservation Agents; Calcinosis; Combined Modality Therapy; Dose-Response Relationship, Drug; Ergocalciferols; Female; Heart Valve Diseases; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Minerals; Phosphates; Renal Dialysis; Severity of Illness Index

Recent data have shown that aortic valve stenosis (AS) is an active and highly regulated process which shares similarities with atherosclerosis. However, AS cannot be considered as a purely atherosclerotic phenomenon, and a hypercholesterolemic rabbit model might not be fully representative of human AS pathophysiology.. Twenty-eight New Zealand White rabbits were assigned to three groups: group 1 (no dietary supplement for three months); group 2 (0.3% cholesterol-enriched-diet + 50,000 IU/day vitamin D2 for six months); and group 3 (1% cholesterol-enriched-diet + vitamin D2 for three months). The peak aortic gradient and permeability index (outflow tract/aortic velocity-time-integral) were assessed, as well as calcium staining within the aortic valve and ascending aorta.. AS hemodynamic severity was not different among the groups. The peak gradient was 4 +/- 2 mmHg at baseline, 4 +/- 2 mmHg at three months in controls, 4 +/- 1 mmHg at three months and 6 +/-3 mmHg at six months in group 2, and 4 +/- 1 mmHg at three months in group 3 (p = NS). The permeability index was 64 +/- 7 at baseline, 60 +/- 12 at three months in controls, 63 +/- 14 at three months and 58 +/- 12 at six months in group 2, and 60 +/- 5 at three months in group 3 (p = NS). The aortic valve of cholesterol-enriched-diet rabbits was thickened but not calcified, whereas the ascending aorta was both thickened and calcified.. When using a hypercholesterolemic rabbit model plus vitamin D2, no adverse hemodynamic effect or aortic valve calcification was observed, despite a high-level and prolonged cholesterol-regimen supplementation. These results raise questions with regard to the extrapolation of this animal model to humans.

Topics: Animals; Aorta; Aortic Valve Stenosis; Atherosclerosis; Blood Flow Velocity; Calcinosis; Capillary Permeability; Cholesterol, Dietary; Ergocalciferols; Male; Microscopy; Models, Animal; Rabbits; Vitamins

Vascular calcification is associated with an increase in cardiovascular mortality in stage 5 chronic kidney disease. To determine if vitamin D receptor activators (VDRAs) have differential effects in the pathogenesis of aortic calcification, we assessed the effects of paricalcitol and doxercalciferol in vivo using 5/6 nephrectomized (NX) rats. To quantify the functional consequences of vascular calcification, pulse wave velocity (PWV), an aortic compliance index, was measured.. NX rats were fed a diet containing 0.9% phosphorous and 0.6% calcium 4 weeks prior to and throughout the study. On Day 0, rats received vehicle or VDRA (0.083, 0.167 and 0.333 microg/kg, i.p.) three times per week for 6 weeks. At Day 0 and Weeks 2 and 6, blood was drawn and PWV was measured by Doppler ultrasound.. VDRAs (0.167 and 0.333 microg/kg) consistently lowered PTH at Weeks 2 and 6. All doses of paricalcitol increased serum calcium at Week 6 but not at Week 2, while the two higher doses of doxercalciferol increased serum calcium at both Weeks 2 and 6. Treatment with paricalcitol (0.333 microg/kg) increased serum phosphorus at Weeks 2 and 6; these changes were not different from those observed in 5/6 NX rats. All doses of doxercalciferol increased serum phosphorus at Week 6. Paricalcitol had no effect on Ca x P; however, the two highest doses of doxercalciferol increased Ca x P at Weeks 2 and 6 above that observed in the 5/6 NX vehicle-treated group. There were no differences in aortic calcium and phosphorus contents at the end of 6 weeks among SHAM-, 5/6 NX- and paricalcitol-treated rats. However, treatment with the two higher doses of doxercalciferol caused a significant elevation in aortic calcium and phosphorus contents. Measurements of PWV demonstrated differential effects of VDRAs on vascular compliance. Paricalcitol produced no effects on PWV, while the two highest doses of doxercalciferol increased PWV at Week 6.. In uraemic rats with established secondary hyperparathyroidism, we demonstrate differential effects of paricalcitol and doxercalciferol on aortic calcification and PWV, independent of serum Ca, P and Ca x P, suggesting different mechanisms of action between VDRAs.

Topics: Animals; Aorta; Blood Flow Velocity; Calcinosis; Calcium; Ergocalciferols; Hyperparathyroidism, Secondary; Male; Nephrectomy; Parathyroid Hormone; Phosphorus; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Renal Insufficiency, Chronic; Uremia; Vascular Resistance

Topics: Calcinosis; Calcium; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Molecular Mimicry; Receptors, Calcitriol; Renal Dialysis

Vitamin D compounds are effective in managing elevated PTH levels in secondary hyperparathyroidism (SHPT) of renal failure. However, undesired increases in serum calcium and phosphorus associated with compounds such as calcitriol [1,25(OH)2D3] has prompted a search for compounds with improved safety profiles. 1alpha,24(S)(OH)2D2 (1,24(OH)2D2) is a vitamin D2 metabolite with low calcium-mo bilizing activity in vivo. We studied the efficacy of 1,24(OH)2D2 in mice lacking the CYP27B1 enzyme [25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-OHase)], a novel vitamin D deficiency model with SHPT.. 1alpha-OHase-deficient (-/-) mice and normal (+/-) heterozygous littermates re ceived 1,24(OH)2D2 (100, 300, 1000, and 3000 pg/g/day) or 1,25(OH)2D3 (30, 300, and 500 pg/g/day) for 5 weeks via daily sc injection. Control groups received vehicle.. Vehicle-treated 1alpha-OHase-deficient mice were hypocalcemic and had greatly elevated serum PTH. 1,24(OH)2D2 at doses above 300 pg/g/day normalized serum calcium, serum PTH, bone growth plate morphology, and other bone parameters. No hy percalcemia was observed at any dose of 1,24(OH)2D2 in normal or 1alpha-OHase-deficient animals. In contrast, 1,25(OH)2D3 at only 30 pg/g/day normalized calcemia, serum PTH, and bone parameters, but at higher doses completely suppressed PTH and caused hypercalcemia in both 1alpha-OHase-deficient and normal mice. Treatment with 500 pg/g/day of 1,25(OH)2D3 also induced osteomalacia in normal animals.. 1,25(OH)2D3 was maximally active at 10-fold lower doses than 1,24(OH)2D2, but induced hypercalcemia and osteomalacia at high doses. 1,24(OH)2D2 normalized serum calcium, serum PTH, and bone histomorphometry without hypercalcemia in 1alpha-OHase-deficient mice with SHPT.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Animals; Bone and Bones; Calcinosis; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Ergocalciferols; Femur; Hypercalcemia; Hyperparathyroidism, Secondary; Mice; Mice, Transgenic; Parathyroid Hormone; Vitamin D Deficiency

Vitamin D derivatives and calcimimetics are used to treat secondary hyperparathyroidism in patients with chronic renal failure. We investigated the effect of calcitriol, paricalcitol, and the calcimimetic AMG 641 on soft-tissue calcification in uremic rats with secondary hyperparathyroidism. Control and uremic rats were treated with vehicle, calcitriol, paricalcitol, AMG 641, or a combination of AMG 641 plus calcitriol or paricalcitol. Parathyroid hormone levels were reduced by all treatments but were better controlled by the combination of paricalcitol and AMG 641. The calcimimetic alone did not induce extraosseous calcification but co-administration of AMG 641 reduced soft-tissue calcification and aortic mineralization in both calcitriol- and paricalcitol-treated rats. Survival was significantly reduced in rats treated with calcitriol and this mortality was attenuated by co-treatment with AMG 641. Our study shows that extraskeletal calcification was present in animals treated with calcitriol and paricalcitol but not with AMG 641. When used in combination with paricalcitol, AMG 641 provided excellent control of secondary hyperparathyroidism and prevented mortality associated with the use of vitamin D derivatives without causing tissue calcification.

Topics: Animals; Aorta; Calcinosis; Calcitriol; Calcium; Calcium Channel Agonists; Ergocalciferols; Hyperparathyroidism, Secondary; Male; Phosphorus; Rats; Rats, Wistar; Uremia

An apparent conflict exists between observational studies that suggest that vitamin D receptor (VDR) activators provide a survival advantage for patients with ESRD and other studies that suggest that they cause vascular calcification. In an effort to explain this discrepancy, we studied the effects of the VDR activators calcitriol and paricalcitol on aortic calcification in a mouse model of chronic kidney disease (CKD)-stimulated atherosclerotic cardiovascular mineralization. At dosages sufficient to correct secondary hyperparathyroidism, calcitriol and paricalcitol were protective against aortic calcification, but higher dosages stimulated aortic calcification. At protective dosages, the VDR activators reduced osteoblastic gene expression in the aorta, which is normally increased in CKD, perhaps explaining this inhibition of aortic calcification. Interpreting the results obtained using this model, however, is complicated by the adynamic bone disorder; both calcitriol and paricalcitol stimulated osteoblast surfaces and rates of bone formation. Therefore, the skeletal actions of the VDR activators may have contributed to their protection against aortic calcification. We conclude that low, clinically relevant dosages of calcitriol and paricalcitol may protect against CKD-stimulated vascular calcification.

Topics: Animals; Aorta; Aortic Diseases; Bone Density Conservation Agents; Bone Diseases, Endocrine; Calcinosis; Calcitriol; Calcium; Dietary Fats; Ergocalciferols; Female; Femur; Gene Expression; Kidney Failure, Chronic; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoblasts; Phosphorus; Receptors, Calcitriol

We have previously proved that oxidized low-density lipoprotein (oxLDL), a proatherogenic lipoprotein, plays a pivotal role in the development of atherosclerotic calcification (AC). The present study was performed to investigate whether tanshinone II A (TS II A), an anti-oxidant which has been shown to inhibit in vitro oxidation of LDL, has the effects to inhibit AC in rat model and by which, if any, mechanisms.. Rat AC model was induced by excessive vitamin D(2) (VD) and high cholesterol diet (HCD), which was proven to be successful histopathologically and biochemically.. Administration of AC rats with TS II A (35, 70 mg/kg) dose-dependently attenuated the AC pathological changes, meanwhile reduced the vessel contents of lipid and calcium. However, TS II A had no effects on serum levels of lipids, calcium and 25-OH VD. Further studies revealed that TS II A decreased serum concentration of oxLDL, reduced the superoxide anion production and malondialdehyde (MDA) in vessel. In addition, TS II A increased vessel Cu/Zn SOD activity, upregulated vessel mRNA and protein expression of Cu/Zn SOD.. The results suggested that TS II A significantly attenuated the AC in rat model, which might be attributed to its inhibition of oxLDL production independent of the serum levels of lipids, calcium and 25-OH VD, and that increasing of Cu/Zn SOD activity as well as mRNA and protein expression by TS II A might protect LDL against oxidation induced by superoxide anion in vessel.

Topics: Abietanes; Animals; Antioxidants; Aorta, Thoracic; Atherosclerosis; Calcinosis; Calcium; Cholesterol; Cholesterol, Dietary; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Induction; Ergocalciferols; Lipoproteins, LDL; Male; Malondialdehyde; Oxidative Stress; Phenanthrenes; Rats; Rats, Sprague-Dawley; RNA, Messenger; Superoxide Dismutase; Superoxides; Time Factors

We tested the effects of calcitriol and its analog paricalcitol on VSMC calcification in vitro and in vivo. For that reason, cells and animals with five-sixths nephrectomy were treated with both compounds. Calcitriol, but not paricalcitol, increased VSMC calcification in vitro and in vivo independently of calcium and phosphate levels. This increase in calcification was parallel to an increase in the RANKL/OPG ratio.. Vascular calcification is a common finding in patients with endstage renal disease. Furthermore, those patients often present secondary hyperparathyroidism, partly because of a decrease of calcitriol synthesis on the kidney. Thus, one of the main therapeutic options is to treat those patients with calcitriol or analogs. However, this treatment presents unwanted side effects, such as increases in vascular calcification.. We tested the effect on vascular smooth muscle cell (VSMC) calcification of calcitriol and one of its analogs, paricalcitol, in vitro and in vivo in animals with endstage renal disease.. Calcitriol increased calcification of VSMCs cultured in calcification media. This effect was not present when cells were incubated with paricalcitol. Furthermore, only cells incubated with calcitriol showed an increased RANKL/osteoprotegerin (OPG) expression. Animals with renal failure treated with hypercalcemic doses of calcitriol and paricalcitol showed an increase in systolic blood pressure. However, diastolic blood pressure only raised significantly in those animals treated with paricalcitol. This effect led to a significant increase in pulse pressure in animals treated with calcitriol. The increase in pulse pressure was likely caused by the extensive calcification observed in arteries of animals treated with calcitriol. This increase in calcification was not seen in arteries of animals treated with paricalcitol, despite having similar levels of serum calcium and phosphorus as animals treated with calcitriol. Furthermore, the decreases in serum PTH levels were similar in both treatments.. We conclude that paricalcitol has a different effect than calcitriol in VSMC calcification and that this could explain part of the differences observed in the clinical settings.

Topics: Animals; Aorta; Blood Pressure; Bone Density Conservation Agents; Calcinosis; Calcitriol; Calcium; Cells, Cultured; Ergocalciferols; Gene Expression; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nephrectomy; Osteoprotegerin; Parathyroid Hormone; Phosphorus; RANK Ligand; Rats; Rats, Sprague-Dawley; Vascular Diseases; Vitamin D

Vascular calcification is associated with cardiovascular disease, the most common cause of death in chronic kidney disease (CKD). Patients with CKD are treated with vitamin D receptor activators (VDRAs); therefore, we determined if this treatment affects vascular calcification. Uremic rats were given vehicle, calcitriol, paricalcitol, or doxercalciferol three times a week for 1 month. Calcitriol significantly increased the serum calcium-phosphate product and aortic calcium content. Paricalcitol had no effect but the same dose of doxercalciferol significantly increased the calcium-phosphate product and the aortic calcium content, the latter being confirmed by von Kossa staining. To see if the increased aortic calcium was due to an increased serum calcium-phosphate product or to a differential effect of the two VDRAs, we lowered the dose of doxercalciferol and increased the dose of paricalcitol. A lower doxercalciferol did not increase the calcium-phosphate product but increased the aortic calcium content. A higher dose of paricalcitol still had no effect. Doxercalciferol treatment increased the mRNA and protein expression of the bone-related markers Runx2 and osteocalcin in the aorta, whereas paricalcitol did not. Hence, different VDRAs have different effects on vascular calcification in uremic rats. The effects are independent of the serum calcium-phosphate product suggesting independent mechanisms.

Topics: Animals; Aorta; Aortic Diseases; Bone Density Conservation Agents; Calcinosis; Calcitriol; Calcium; Ergocalciferols; Female; Parathyroid Hormone; Phosphates; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Uremia

Paricalcitol is a less hypercalcemic vitamin D analog that has been shown to suppress secondary hyperparathyroidism and to prevent the associated histomorphometric changes in bone. In this study, we show that paricalcitol also ameliorates the renal insufficiency-induced loss of bone mineral and the mechanical competence of bone.. Renal bone disease is a common consequence of chronic renal insufficiency and the associated secondary hyperparathyroidism (SH). Paricalcitol [19-nor-1,25(OH)(2)D(2)] has been shown to ameliorate SH and prevent renal failure-induced histomorphometric changes in bone with minimal calcemic and phosphatemic activity. However, information about its efficacy on restoration of bone structural strength is lacking. In this study, we explored the effects of paricalcitol treatment on bone structure and strength in a model of advanced renal disease.. Forty-five 8-week-old rats were randomly assigned to either surgical 5/6 nephrectomy (NTX) or Sham-operation. After a 15-week postoperative disease progression period, the NTX rats were further allocated to uremic control (NTX) and treatment (NTX + paricalcitol) groups, the latter of which received paricalcitol for the subsequent 12 weeks. After 27 weeks, the animals were killed, plasma samples were collected, and both femora were excised for comprehensive analysis of the femoral neck and midshaft (pQCT and biomechanical testing).. High mortality that exceeded 30% was observed in both NTX groups. NTX induced over a 13-fold increase in plasma PTH, whereas this increase was only 5-fold after paricalcitol treatment. At the femoral neck, NTX was associated with an 8.1% decrease (p < 0.05) in vBMD and a 16% decrease in breaking load (p < 0.05) compared with the Sham group, whereas paricalcitol treatment completely prevented these changes. At the femoral midshaft, the NTX resulted in a 6.6% decrease in cortical BMD (p < 0.01 versus Sham), and this change was also prevented by paricalcitol.. Paricalcitol administration prevented renal insufficiency-associated decreases in BMD in the femoral neck and the femoral midshaft and restored bone strength in the femoral neck. Therefore, paricalcitol can efficiently ameliorate renal insufficiency-induced loss of bone mineral and mechanical competence of bone.

Topics: Animals; Aorta; Biomechanical Phenomena; Bone Density; Bone Diseases; Calcinosis; Ergocalciferols; Kidney; Kidney Diseases; Rats; Tomography, X-Ray Computed

Administration of active vitamin D sterols to treat secondary hyperparathyroidism in patients with chronic kidney disease receiving dialysis has been associated with elevated serum calcium and phosphorus levels, which may lead to increased risk of vascular calcification. However, calcimimetics, by binding to the parathyroid gland calcium-sensing receptors, reduce serum parathyroid hormone, calcium, phosphorus, and the calcium-phosphorus product. Using cultured bovine aorta vascular smooth muscle cells (BASMCs), an in vitro model of vascular calcification, we compared calcification levels and gene expression profiles after exposure to the phosphate source ss-glycerolphosphate (BGP), the active vitamin D sterols calcitriol and paricalcitol, the calcimimetic R-568, or BGP with the active vitamin D sterols or R-568. Cells exposed to BGP (10 mM) alone or with calcitriol or paricalcitol showed dose-dependent BASMC calcification. No change in calcification was observed in cultures exposed to BGP with R-568, consistent with the observed lack of calcium-sensing receptor expression. Microarray analysis using total cellular RNA from cultures exposed to vehicle or BGP in the absence and presence of 10(-8) M calcitriol or paricalcitol for 7 days showed that cells exposed to BGP with calcitriol or BGP with paricalcitol had virtually identical gene expression profiles, which differed from those of cells treated with BGP or vehicle alone. Several osteoblast- and chondrocyte-associated genes were modulated by BGP and vitamin D exposure. In this study, exposure of BASMCs to phosphate and active vitamin D sterols induced calcification and changes in expression of genes associated with mineralized tissue.

Topics: Alkaline Phosphatase; Aniline Compounds; Animals; Aorta; Calcinosis; Calcitriol; Calcium; Cattle; Cells, Cultured; Drug Combinations; Ergocalciferols; Gene Expression; Glycerophosphates; Muscle, Smooth, Vascular; Oligonucleotide Array Sequence Analysis; Phenethylamines; Phosphorus; Propylamines; Receptors, Calcitriol; Receptors, Calcium-Sensing; Signal Transduction; Wnt Proteins

To determine the effectiveness of a vitamin D analog, 1alpha-hydroxyvitamin D(2) (1alpha-OH-D(2)), in inhibiting retinoblastoma in a transgenic retinoblastoma model (LHbeta-Tag mouse) and to evaluate its toxicity.. Experimental study using an animal (LHbeta-Tag transgenic mouse) randomized (controlled) trial.. Two hundred seventeen LHbeta-Tag transgene-positive 8- to 10-week-old mice total; 179 drug-treated animals, 38 control animals.. Mice were fed a vitamin D- and calcium-restricted diet and were randomized to treatment groups receiving control (vehicle), or 0.1, 0.3, 0.5, or 1.0 micro g/day of 1alpha-OH-D(2) via oral gavage 5 times weekly for 5 weeks. Body weight was measured at the start of treatment and twice weekly during treatment. Animals were euthanized on the last day of treatment. The eyes were enucleated, processed histologically, and serially sectioned. Representative sections from the superior, middle, and inferior regions of each globe were examined microscopically and tumor areas were measured using Optimas software. Serum was collected for serum calcium levels. Kidneys were removed for histologic processing and were analyzed microscopically for kidney calcification.. Mean tumor area was measured to determine drug effectiveness. Toxicity was assessed by survival, weight loss over the treatment period, serum calcium, and kidney calcification.. The mean tumor size in each 1alpha-OH-D(2) group was smaller than controls (all P values < 0.02): control, 90,248 micro m(2); 0.1 micro g, 31,545 micro m(2); 0.3 micro g, 16,750 micro m(2); 0.5 micro g, 30,245 micro m(2); and 1.0 micro g, 16,049 micro m(2). No dose-dependent response curve was evident. The survival percentage for each group was as follows: control, 97%; 0.1 micro g, 91%; 0.3 micro g, 88%; 0.5 micro g, 70%; and 1.0 micro g, 63%. Mortality was higher in the 0.5- micro g and 1.0- micro g doses (P values < 0.01) compared with other treatment groups and with the control group. Serum calcium levels were significant in all treatment groups compared with controls (all P values < 0.0001).. In the LHbeta-Tag mouse, 1alpha-OH-D(2) inhibits retinoblastoma with no significant increase in mortality in lower doses (0.1-0.3 micro g). 1alpha-OH-D(2) has approval by the Food and Drug Administration as an investigative drug for cancer treatment, and has shown efficacy with low toxicity in adult cancer trials. 1alpha-OH-D(2) meets the criteria for human clinical trials.

Topics: Animals; Calcinosis; Calcium; Disease Models, Animal; Dose-Response Relationship, Drug; Ergocalciferols; Kidney; Luteinizing Hormone, beta Subunit; Mice; Mice, Transgenic; Retinal Neoplasms; Retinoblastoma; Survival Rate; Transgenes

Identification of bone selective vitamin D analogues would provide an interesting substance class for the treatment of osteoporosis. The synthetic prodrug 1alpha-hydroxyvitamin D2 [1alpha(OH)D2] has been shown to combine equal bone-preserving activity with distinctly reduced calcemic effects relative to 1alpha-hydroxyvitamin D3 [1alpha(OH)D3] in 3-month-old ovariectomized (OVX) rats. Therefore, 1alpha(OH)D2 may be a bone-selective compound. The aim of this study was to compare the bone protective and the calcemic activities of chronically administered 1alpha(OH)D2 and 1alpha(OH)D3 in 6-month-old OVX rats over a broad dose range from ineffective to toxic doses. Ninety-six female 6-month-old Fischer-344 rats were used for this experiment. Eighty rats were bilaterally OVX, 8 rats were sham-operated (SHAM), and 8 rats were killed at the time of surgery as a baseline control. Groups of OVX rats received vehicle alone (n = 16) or daily doses in the diet of 0.025, 0.05, 0.1, and 0.2 microg of 1alpha(OH)D2 or 1alpha(OH)D3 per kg body weight (BW) per day (n = 8 each). After calcein double-labeling, all animals were killed 3 months post-OVX. Orally administered 1alpha(OH)D2 was significantly less toxic compared with 1alpha(OH)D3 in terms of BW gain and kidney calcium content. The effects of 1alpha(OH)D2 and 1alpha(OH)D3 on serum calcium and urinary calcium excretion were generally similar at all doses in this study. Both 1alpha(OH)D2 and 1alpha(OH)D3 prevented the estrogen deficiency-induced bone loss in OVX rats, and induced profound bone anabolic effects at high dosages. 1alpha(OH)D3 and 1alpha(OH)D2 also dose-dependently increased total bone mineral density (BMD), cortical area, and cortical thickness in the tibial diaphysis of OVX rats. Bone resorption as assessed by osteoclast numbers (Oc.Ns) in vertebral cancellous bone and urinary excretion of deoxypyridinoline (DPD) was dose-dependently suppressed by 1alpha(OH)D2 and 1alpha(OH)D3. These data show that although 1alpha(OH)D2 was slightly but significantly less toxic compared with 1alpha(OH)D3, it did not have increased skeletal effects at any dose. Taken together, our findings argue against selective metabolic activation of 1alpha(OH)D2 in bone.

Topics: Animals; Biotransformation; Bone and Bones; Bone Density; Calcinosis; Calcium; Creatinine; Ergocalciferols; Female; Hydroxycholecalciferols; Kidney Diseases; Lumbar Vertebrae; Organ Specificity; Osteocalcin; Osteoporosis; Ovariectomy; Phosphorus; Prodrugs; Rats; Rats, Inbred F344; Tibia; Urea; Weight Gain

Topics: Animal Feed; Animals; Calcinosis; Cardiomyopathies; Ergocalciferols; Female; Goat Diseases; Goats; Male; Plant Poisoning; Poaceae; Sheep

The role of the elastolytic system in pathogenesis of vascular diseases was investigated on adult and one-month old rabbits in experimental ergocalciferol-induced media calcinosis depending on age aspect. The obtained results indicate that elastase activity was increased in aortic homogenates of one-month old rabbits but not in adult animals. The level of alpha 1-proteinase inhibitor is reduced in one-month old rabbits, and decrease of the alpha 2-macroglobulin content in arterial walls occurs in adults. A higher level of antielastase proteins in both groups of animals in venous vessels is determined. After effect of ergocalciferol in the veins of one-month-old rabbits, differs from the adults, a significant increase of the inhibitor content is observed. The presented results confirm the importance of balance between elastase and it inhibitors in pathogenesis of arteriosclerosis.

Topics: Aging; Animals; Arteriosclerosis; Blood Vessels; Calcinosis; Disease Models, Animal; Ergocalciferols; Hydrolysis; Pancreatic Elastase; Rabbits; Statistics, Nonparametric; Substrate Specificity; Time Factors; Tunica Media

The effect of vitamin K2 on calcium (Ca) and inorganic phosphorus (P) levels in the aorta and kidney obtained from experimental calcinosis induced by vitamin D2(2.5 x 10(5) I.U./ kg b.w.) of male rats was investigated. A high dose of vitamin K2 (100 mg/kg b.w.) inhibited the increase in the aortic Ca and P or in the renal Ca and P induced by vitamin D2, and a low dose of vitamin K2 (10 mg/kg b.w.) showed the same tendency, but the degree of the efficacy was small. It may be suggested that a high dose of vitamin K2 suppressed experimental calcification of soft tissues induced by vitamin D2. Therefore, a pharmacological dose of vitamin K2 might have a usefulness for the prevention and treatment of arteriosclerosis with calcification.

Topics: Animals; Aorta; Calcinosis; Calcium; Ergocalciferols; Kidney; Male; Phosphorus; Rats; Rats, Sprague-Dawley; Vitamin K

Fahr's disease associates various degrees of neuropsychological impairment and calcium deposits in the basal ganglia. We report 3 cases. The first case was a 54-year-old man with hemichorea of one-year duration. Laboratory results demonstrated idiopathic hypoparathyroidism. In the second case, a 23-year-old man treated for epilepsia for 8 years was hospitalized for subintrant episodes and hemichorea. Dysmorphism and laboratory results led to the diagnosis of pseudo-hypothyroidism. The third case was a 62-year-old woman with generalized seizures of epilepsia and dementia of two-month duration. Physical examination revealed extra-pyramidal rigidity. Hyperparathyroidism due to an adenoma was confirmed histologically. In all three patients, correction of phosphocalcium levels led to clinical improvement, particularly with disappearance of the epileptic seizures and abnormal movements. Clinical expression of Fahr's syndrome varies greatly. Symptoms include psychiatric disorders, epileptic seizures, extra-pyramidal syndrome and various neurological conditions. Diagnosis requires CT brain scan which identifies calcium deposits in the basal ganglia. The main cause is hypoparathyroidism, whether primary or post-operative. Cases due to other causes of dysparathyroidism are rare. The pathophysiology of this condition remains unknown and results of treatment are often unsatisfactory. Since correcting the impaired calcium phosphorus metabolism often leads to considerable improvement, it is essential to systematically search for dysparathyroidism in patients presenting with neuropsychologic manifestations associated with calcifications of the basal ganglia.

Topics: Adult; Athetosis; Basal Ganglia Diseases; Calcinosis; Calcium; Chorea; Drug Therapy, Combination; Epilepsy, Tonic-Clonic; Ergocalciferols; Female; Humans; Hyperparathyroidism; Hypoparathyroidism; Male; Middle Aged; Syndrome; Tomography, X-Ray Computed

To clarify the anti-calcinosis actions of traditional Chinese medicine (Dai: Dai-saiko-to) and estradiol benzoate (E2), 7-week or retired (about 6-months-old) female rats were treated with Vit. D2 (1.75 x 10(5) I.U./kg b.w./day) for 4 days, and then were fed a basal diet containing Dai (at ten times the medical dose in humans) or were injected i.p. with E2 (at the medical dose in humans) for 6 weeks. The following results were obtained: 1) Dai did not improve Ca and P metabolism in experimental calcinosis of 7-week female rats; 2) in retired female rats, Dai decreased both P in the heart and the ratio of Ca to P in bone, similar to the treatment with E2. Dai, as well as E2, seemed to nomalize Ca and P metabolism disturbed by Vit. D2 treatment.

Topics: Animals; Calcinosis; Calcium; Drugs, Chinese Herbal; Ergocalciferols; Estradiol; Female; Myocardium; Phosphorus; Rats; Rats, Sprague-Dawley

Protective effects of benidipine hydrochloride (KW-3049) against arterial calcinosis and its possible mechanisms of action have been investigated. Arterial calcinosis was induced in rats by combined administration of vitamin D2 (1050000 IU/kg, s.c.) and nicotine (12.5 mg/kg, p.o., b.i.d.) for 6 successive days. Calcium antagonists, benidipine or nifedipine, were given orally twice a day during the same period. The aortic calcium content in vitamin D2 and nicotine-treated (control) rats increased to about 25 times that in normal rats, accompanying an increase of serum calcium level. Benidipine (10 mg/kg, p.o., b.i.d.) reduced the aortic calcium content to about 18% of control rats without reducing the serum calcium level. Although the presence of aortic endothelial cells was observed under light microscopy in control rats, their surfaces were degenerated under scanning electron microscopy. Benidipine exerted a protective effect against these degenerative changes. Acetylcholine-induced endothelial dependent relaxation was attenuated in control rats, compared with that in normal rats. Benidipine significantly improved this attenuation of the relaxation. These results suggest that the anticalcinotic effect of benidipine is accompanied by its protective effect on endothelial cells.

Topics: Acetylcholine; Animals; Aorta; Arteries; Calcinosis; Calcium; Calcium Channel Blockers; Endothelium, Vascular; Ergocalciferols; Male; Microscopy, Electron, Scanning; Muscle Relaxation; Muscle, Smooth, Vascular; Nicotine; Nifedipine; Rats; Rats, Inbred Strains

Topics: Adult; Calcinosis; Cerebrovascular Disorders; Ergocalciferols; Female; Humans; Hypoparathyroidism; Skull; Syndrome; Tomography, X-Ray Computed

The present study was undertaken to examine changes in vascular ultrastructure of rats subjected to hypervitaminosis D with or without treatment with ethane-I-hydroxy-I, I-diphosphonate (EHDP). Five groups of rats were studied. Untreated rats were given 0.9% NaCl i.p. Sham-treated rats were given vehicle (corn oil). Treated rats were given ergocalciferol (75,000 IU i.p.) dissolved in vehicle with or without EHDP (5 mM/100 g body-weight i.p.). Rats which had been given ergocalciferol without EHDP developed hypercalcemia and demonstrated significant arterial calcinosis. A similar degree of calcinosis was not observed in rats given ergocalciferol with EHDP. EHDP appeared to inhibit arterial calcinosis; however, it did not affect plasma calcium levels. This suggests that EHDP might delay calcium influx into the cell and thereby prevent calcium overload. Our findings support the suggestion that EHDP therapy can be an effective treatment for the inhibition of dystrophic arterial calcinosis.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Calcinosis; Ergocalciferols; Etidronic Acid; Male; Microscopy, Electron; Rats; Rats, Inbred Strains

STUDY OBJECTIVE - The aim of the study was to develop an animal model to study the relationships between raised tissue calcium and vascular function. DESIGN - Ectopic calcification was developed in the animal model using chronic vitamin D2 intoxication, after which functional studies were performed in isolated superfused aortic rings. Results were compared with control preparations. EXPERIMENTAL ANIMALS - 160 female Sprague-Dawley rats weighing 200-225 g were randomly divided into experimental (vitamin D2 1 mg.d-1) and control (vehicle only) groups. MEASUREMENTS and RESULTS - Aortas from vitamin D treated animals had a higher calcium content than control aortas, without concomitant increases in cardiac calcium. Aortas with high calcium content were found to develop greater tension than control aortas when exposed to noradrenaline in the absence of extracellular calcium, but the tension maxima achieved in response to noradrenaline in calcium containing media or to high potassium depolarising solution were the same. The rate of development of contraction in response to noradrenaline was greater in aortas from the vitamin D treated animals than in controls. Isoprenaline and sodium nitroprusside produced less relaxation in the animal model aortas than in the controls. CONCLUSIONS - The results suggest that increased aortic calcium affects the response of the tissue to vasoactive agents. It appears that the additional vascular calcium may be stored in an agonist releasable pool, probably within the sarcoplasmic reticulum. The enlarged or newly developed pools appear to be refillable from the extracellular medium but not by intracellular reuptake of calcium, suggesting a bicompartmental model of intracellular calcium release and reuptake.

Topics: Animals; Aorta; Calcinosis; Calcium; Cardiomyopathies; Disease Models, Animal; Ergocalciferols; Female; Isoproterenol; Norepinephrine; Rats; Rats, Inbred Strains

Topics: Animals; Calcinosis; Calcium; Ergocalciferols; Ethionine; Female; Immunization; Peritoneal Diseases; Rats; Rats, Inbred Strains

In 1966, Verhoeff suggested that retinoblastomas might be sensitive to vitamin D because they sometimes undergo calcification and spontaneous regression. In recent years, the antineoplastic effect of vitamin D has been established in vitro and in vivo. This study presents evidence that vitamin D2 inhibits the growth of the human retinoblastoma cell line (Y-79) grown in athymic mice. In mice treated with ergocalciferol, the subcutaneous retinoblastomas were smaller and showed increased tumor necrosis and calcification. Unfortunately, the vitamin D caused significant toxic reactions. Further studies that reduce the toxicity of vitamin D will be needed before its use in children with retinoblastomas can be advocated. To our knowledge, this is the first demonstration of the activity of ergocalciferol against a tumor in vivo and it suggests that ergocalciferol or one of its derivatives may be an effective chemotherapeutic agent against retinoblastomas in humans.

Topics: Animals; Calcinosis; Calcium; Cell Line; Dose-Response Relationship, Drug; Ergocalciferols; Eye Neoplasms; Necrosis; Neoplasm Transplantation; Retinoblastoma; Skin Neoplasms; Vitamin D

An observational study was made of the localization of experimental calcification of blood vessels induced by hypervitaminosis D in 15 stock rabbits, in 10 rabbits with arteriovenous fistulae, and in 6 rabbits with experimental saccular aneurysms. An arteriotomy and a phlebotomy were performed on several animals from each group. The pulmonary trunk, aorta, common carotid arteries, and external jugular veins were dissected and stained with silver nitrate to demonstrate calcification macroscopically. The first major bifurcation from 37 renal arteries from these animals was examined by the serial section technique to localize calcification about the arterial forks histologically. There was evidence that early calcification was flow related with a predilection for sites where atrophic lesions occur. Proliferative lesions in which matrix vesicles are abundant exhibited no such predisposition. It was concluded that matrix vesicles do not appear to be susceptible to vitamin D calcification. The topography of the experimental calcification differed from that of diet-induced lipid deposition.

Topics: Animals; Aorta; Arteriovenous Shunt, Surgical; Calcinosis; Carotid Arteries; Ergocalciferols; Female; Hemodynamics; Intracranial Aneurysm; Jugular Veins; Male; Rabbits; Regional Blood Flow; Renal Artery; Vascular Diseases

Topics: Basal Ganglia Diseases; Calcinosis; Child; Ergocalciferols; Humans; Hypoparathyroidism; Male; Spasm; Tomography, X-Ray Computed

Glucocorticoids are often used to treat hypercalcemia due to vitamin D overdosage. We measured the effect of 1.5 mg/day of prednisolone on the amount of calcium deposited in the kidney of rats dosed with either 500 ng/d or 2000 ng/day of 1-alpha OHD2 or 1-alpha OHD3. The rats were given a diet containing 0.3% calcium and 0.5% phosphate. A second group of rats received 2000 ng/d of the vitamin D analogs and a diet which contained only 0.02% calcium. After 6 weeks, rats given the vitamin D analogs had two to six times more calcium in the kidney compared with the controls (0.096-0.276 mg vs. 0.240-1.064 mg). When a pharmacological dose of prednisolone was added to treatment, calcium in renal tissue increased to 0.305-3.083 mg. The urinary output of calcium seemed to be increased by prednisolone whereas the serum calcium was lowered. It appears that glucocorticoids given at the same time as vitamin D compounds increases the risk for nephrocalcinosis possibly due to increased amounts of calcium in the urine.

Topics: Animals; Calcinosis; Calcitriol; Calcium, Dietary; Disease Models, Animal; Ergocalciferols; Hypercalcemia; Kidney; Male; Prednisolone; Rats; Rats, Inbred Strains; Uremia

Topics: Animals; Bicarbonates; Calcinosis; Ergocalciferols; Female; Lung; Lung Diseases; Rats; Sodium Bicarbonate

Intraarticular calciphylaxis with cartilage and synovial calcification was produced in rabbits by oral administration of a single dose of dehydrotachysterol followed by an intraarticular injection of ferrous chloride. Synovial membrane apatite deposits were seen in the interstitium, on collagen fibers, and within cell vacuoles. In contrast, long-term administration of dehydrotachysterol alone induced only articular cartilage calcification. Such calcification was limited to the mid and deep zone of cartilage. Most calcium deposits were apatite-like crystals. Acute crystal-associated inflammation was not demonstrated in these specimens with crystals sequestered in synovial or cartilage tissue. Further studies on these models will examine the relation of apatite to joint disease.

Topics: Animals; Calcinosis; Cartilage, Articular; Disease Models, Animal; Ergocalciferols; Ferric Compounds; Hydroxyapatites; Microscopy, Electron; Rabbits; Synovial Membrane

Young boars supplemented orally with 800, 500,300 and 100 IU of vitamin D2/kg of feed and control boars not supplemented with vitamin D2 for four months developed mineralization in the left atrial endocardium, lamina muscularis mucosae of the fundic stomach and other sites. Since low levels of supplementation with vitamin D2 did not eliminate the lesions, the levels of vitamin D2 added appeared not to be involved in the pathogenesis. All boars had mild hypercalcemia throughout the experiment, and phosphorus levels in sera were lower in all animals receiving than in those not receiving calciferol. Mild morphological lesions of rickets developed in several boars not receiving supplemental vitamin D2 and in boars supplemented with 100 an 300 IU/kg of feed.

Topics: Administration, Oral; Animals; Calcinosis; Ergocalciferols; Male; Myocardium; Ribs; Rickets; Stomach; Swine; Swine Diseases

Widespread calcerous deposits developed in the aorta, heart and kidneys of rats fed for 4 days with purina chow and high doses of vitamin D2 (200,000 IU/kg body wt/day). Decomplementation of rats with highly purified cobra venom factor (CoF) prior to vitamin D2 feeding, almost completely prevented calcium deposition in the aorta and arteritis. The mortality rate in the CoF-treated vitamin D2-fed rats was much lower than in untreated rats. These findings suggest that the complement system may be recruited in the pathogenesis of vitamin D2-induced arteriosclerosis.

Topics: Animals; Arteriosclerosis; Calcinosis; Complement C3; Complement System Proteins; Dose-Response Relationship, Drug; Elapid Venoms; Ergocalciferols; Fluorescent Antibody Technique; Humans; Kidney; Myocardium; Rabbits; Rats; Sheep

Topics: Adult; Calcinosis; Deafness; Ergocalciferols; Female; Humans; Tympanic Membrane

Topics: Animals; Animals, Newborn; Aortic Diseases; Calcinosis; Calcium; Cholesterol; Dose-Response Relationship, Drug; Ergocalciferols; Female; Fetal Death; Hydroxycholecalciferols; Magnesium; Phosphorus; Pregnancy; Rabbits

Eight cases of vitamin-D poisoning are described. In six patients this therapy was unnecessary and in the remaining two patients inadequate supervision of the treatment resulted in overdosage. In five cases the history of vitamin-D therapy was either unknown or not appreciated by the referring clinician so that three surgical procedures of dubious value were performed on two patients. Large doses of vitamin D should only be used when strictly indicated and on the understanding that close biochemical and clinical supervision is necessary.

Topics: Adolescent; Adult; Aged; Calcinosis; Diagnosis, Differential; Ergocalciferols; Female; Humans; Hypercalcemia; Hyperparathyroidism; Male; Middle Aged; Risk

Calcification of the aorta and the coronary vessels as well as metastatic calcification of the heart muscle in the rat was produced by daily oral administration of 300,000 i.u. vitamin D2/kg for 6 consecutive days. E.C.G. tracings showed different pathological conditions. The response of the cardiovascular system to certain arrhythmogenic substances, e.g. aconitine and CaCl2 was generally reduced in comparison to non-treated rats.

Topics: Aconitine; Aconitum; Animals; Arrhythmias, Cardiac; Arteriosclerosis; Calcinosis; Calcium Chloride; Electrocardiography; Ergocalciferols; Rats

Ergocalciferol (320,000 or 480,000 IU/kg) plus cholesterol (60 mg/kg) in olive oil solution was administered daily on 1, 2, or 4 consecutive days to pregnant rats from 9,10, 14, or 18 of gestation. The control animals received only olive oil. Disseminated lesions of metastic calcinosis were found in various tissues, in the coronary arteries and myocardium, in the media of the abnormal aorta, in the lung and pleura, in the gastoinstestinal tract, and in the kidney. This is in contrast to the atherosclerosis described in nonpregnant rats fed a similiar diet. A significant decline in maternal weight as well as a high rate of morbidity and mortality was observed. In mothers killed on day 22 of pregnancy, fetal and placental growths appeared significantly retarded suggesting a direct effect of the steroid or its more active metabolite, 1,25-dihydroxycholecalciferol, on the fetus or the trophoblastic tissue. Fetal bone lesionsassociated with a generalized retardation of ossification, placental edema, or calcification accompanied by a loss of the normal structure of the placenta and degenerative manifestation at this level were observed. Moreover, we noted a striking alteration of the fetal face in 33-39% of experimental fetuses, called by us carnival fetuses.

Topics: Abnormalities, Drug-Induced; Animals; Aorta, Abdominal; Bone Diseases, Developmental; Calcinosis; Cholesterol; Digestive System; Dose-Response Relationship, Drug; Ergocalciferols; Face; Female; Fetal Death; Fetal Diseases; Gestational Age; Intubation, Gastrointestinal; Placenta Diseases; Pregnancy; Pregnancy Complications; Rats

Topics: Animals; Asthenia; Calcinosis; Cholesterol; Emaciation; Ergocalciferols; Female; Fetal Diseases; Fetus; Placenta; Placenta Diseases; Pregnancy; Rats

Topics: Aged; Antineoplastic Agents; Bone Neoplasms; Calcinosis; Calcitonin; Cholecalciferol; Cyclophosphamide; Ergocalciferols; Fractures, Spontaneous; Humans; Hypercalcemia; Kidney Calculi; Lung Neoplasms; Male; Neoplasm Metastasis; Osteitis Deformans; Plicamycin; Podophyllin; Quinones; Sarcoma; Vitamin D

Topics: Anemia, Hypochromic; Animals; Calcinosis; Calcium; Carcinoma, Ehrlich Tumor; Chronic Disease; Deficiency Diseases; Ergocalciferols; Glucuronates; Humans; Iron; Iron Deficiencies; Mitosis; Osteoporosis; Rats; Sarcoma, Experimental

Topics: Animals; Calcinosis; Calciphylaxis; Disease Models, Animal; Ergocalciferols; Female; Histocytochemistry; Iron-Dextran Complex; Pancreas; Pancreatitis; Rats; Rats, Inbred Strains

Topics: Animals; Calcinosis; Chlorides; Ergocalciferols; Infertility, Male; Lanthanum; Male; Nitrates; Oxalates; Rats; Testis; Thorium; Time Factors; Trace Elements; Uranium; Yttrium

Topics: Acetates; Animals; Calcinosis; Cell Differentiation; Cortisone; Cytoplasm; Ergocalciferols; Female; Fetal Diseases; Placenta; Placenta Diseases; Pregnancy; Rats; Trophoblasts

Topics: Animals; Aorta; Calcinosis; Ergocalciferols; Hypertension; Pressoreceptors; Rabbits

Topics: Animals; Aorta; Calcinosis; Calciphylaxis; Chondroitin; Ergocalciferols; Glucuronates; Glycosaminoglycans; Iron; Rats

Topics: Animals; Calcinosis; Calciphylaxis; Calcium; Cornea; Edetic Acid; Ergocalciferols; Eye Diseases; Hypercalcemia; Phosphorus; Rabbits; Sulfonic Acids; Ultraviolet Rays; Uveitis; Vitamin D

Topics: Animals; Calcinosis; Ergocalciferols; Female; Myocarditis; Pregnancy; Pregnancy Complications; Rats; Reserpine

Topics: Analysis of Variance; Animals; Aorta; Blood Sedimentation; Body Weight; Calcinosis; Cholesterol; Chondroitin; Coronary Vessels; Ergocalciferols; Female; Flavonoids; Hematocrit; Necrosis; Nephrocalcinosis; Rats; Rutin

Topics: Acid Phosphatase; Alkaline Phosphatase; Animals; Calcinosis; Citrates; Ergocalciferols; Esterases; Histocytochemistry; Male; Microscopy, Electron; Periodontium; Rats; Sodium; Succinate Dehydrogenase; Time Factors

Topics: Animals; Calcinosis; Calcium; Ergocalciferols; Female; Hepatectomy; Injections, Subcutaneous; Intestines; Iron; Kidney; Liver; Male; Myocardium; Rats; Skin; Stomach

Topics: Animals; Aortic Diseases; Calcinosis; Ergocalciferols; Phosphates; Polymers; Rats; Staining and Labeling

Topics: Animals; Calcinosis; Calcium; Cholecalciferol; Dentin; Ergocalciferols; Male; Parathyroid Hormone; Rabbits; Rickets

Topics: Adrenal Glands; Animals; Aorta; Blood; Calcinosis; Calcium Isotopes; Ergocalciferols; Heart; Kidney; Liver; Lung; Male; Muscles; Rabbits; Skin; Spleen; Thyroid Gland; Tuberculosis, Cutaneous

Topics: Adolescent; Bone Neoplasms; Calcinosis; Calcium; Calcium Isotopes; Ergocalciferols; Feces; Geriatrics; Humans; Hyperparathyroidism; Hypoparathyroidism; Inositol; Intestinal Absorption; Malabsorption Syndromes; Neoplasm Metastasis; Neoplasms; Osteitis Deformans; Osteomalacia; Pancreatitis; Sarcoidosis; Tetany; Urine

Topics: Blood Vessels; Calcinosis; Cartilage; Cartilage, Articular; Epiphyses; Ergocalciferols; Osteogenesis; Pathology; Pharmacology; Pregnancy; Radiography; Rats; Research; Rickets; Vitamin D Deficiency

Topics: Adrenocorticotropic Hormone; Aging; Aluminum; Calcification, Physiologic; Calcinosis; Calciphylaxis; Cholecalciferol; Chromium; Dextrans; Dihydrotachysterol; Egg Yolk; Ergocalciferols; Iron-Dextran Complex; Methyltestosterone; Rats; Research; Skin; Toxicology; Vitamin E

Topics: Ascorbic Acid; Bone Diseases; Calcinosis; Diagnosis, Differential; Ergocalciferols; Fractures, Bone; Humans; Infant; Osteoporosis; Radiography; Rickets; Scurvy; Streptomycin; Vitamin A

Topics: Alloxan; Calcinosis; Cholecalciferol; Dihydrotachysterol; Ergocalciferols; Islands; Islets of Langerhans; Kidney Diseases; Kidney Tubules; Nephrocalcinosis; Pancreas; Pathology; Rats; Research

Topics: Calcification, Physiologic; Calcinosis; Ergocalciferols; Humans

Topics: Calcification, Physiologic; Calcinosis; Dinitrophenols; Ergocalciferols; Humans; Nitrophenols; Vitamin D; Vitamins

Topics: Animals; Calcification, Physiologic; Calcinosis; Ergocalciferols; Rats; Tooth; Vitamin D; Vitamins

Topics: Calcinosis; Drug-Related Side Effects and Adverse Reactions; Ergocalciferols; Nephrocalcinosis; Tetany; Vitamin D

Topics: Arthritis; Calcinosis; Ergocalciferols; Humans; Kidney; Renal Insufficiency

Topics: Arthritis; Calcification, Physiologic; Calcinosis; Ergocalciferols; Kidney; Vitamin D; Vitamins

Topics: Calcification, Physiologic; Calcinosis; Calcium; Ergocalciferols; Humans

Topics: Calcinosis; Drug-Related Side Effects and Adverse Reactions; Ergocalciferols; Humans; Vitamin D; Vitamins