cholecalciferol and Uremia

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.

Topics: Animals; Biomarkers; Calcitriol; Calcium; Calcium Channel Agonists; Cholecalciferol; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Hypocalcemia; Parathyroid Hormone; Uremia

The biologically active form of vitamin D3, 1,25-dihydroxycholecalciferol is produced by the kidney. The biosynthesis of 1,25-dihydroxycholecalciferol from 25-hydroxycholecalciferol is apparently controlled and important factors in this control are dietary calcium and phosphorus, and parathyroid hormone secretion. The direct effects of vitamin D and its metabolites on renal function are uncertain. Patients with chronic renal failure have defective synthesis of 1,25-dihydroxycholecalciferol. Uremic patients treated with small doses of 1,25-dihydroxycholecalciferol or 1 alpha-hydroxycholecalciferol show increased intestinal calcium absorption and bone healing.

Topics: Animals; Bone and Bones; Calcium; Cholecalciferol; Humans; Intestines; Kidney; Kidney Failure, Chronic; Parathyroid Hormone; Phosphorus; Rats; Uremia; Vitamin D

Topics: Animals; Calcium; Cholecalciferol; Chronic Kidney Disease-Mineral and Bone Disorder; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Kidney; Kidney Failure, Chronic; Liver; Parathyroid Hormone; Rats; Uremia; Vitamin D

Topics: Bone and Bones; Bone Diseases; Calcium; Cholecalciferol; Dihydrotachysterol; Homeostasis; Intestinal Absorption; Kidney; Kidney Failure, Chronic; Uremia; Vitamin D

Topics: Animals; Biological Transport; Bone Development; Bone Diseases; Calcification, Physiologic; Calcium; Cholecalciferol; Fanconi Syndrome; Humans; Hypoparathyroidism; Intestinal Absorption; Kidney; Liver; Rats; Rickets; Uremia; Vitamin D; Vitamin D Deficiency

End-stage renal disease results in B cell lymphopenia and low levels of vitamin D. Since the link between vitamin D deficiency and B lymphocytes dysfunction are not clear in patients with end-stage renal disease, we suggest that vitamin D adequacy and factors related to the homeostasis of these cells should be investigated. B lymphocytes homeostasis is a process mainly regulated signals of grown and death as interleukin (IL)-7, B cell-activating factor (BAFF)/BAFF-receptor and CD95 expression.. As vitamin D serum levels were reduced in patients with end stage renal disease and it is associated with human B homeostasis, we evaluated the effect of cholecalciferol supplementation on dialysis.. Randomized, double blind clinical trial in dialysis patients with 25OH Vitamin D deficiency for a period of 12 weeks.. In a pilot study, we investigated the effect of cholecalciferol supplementation (100,000 UI once per week or placebo. In vitro, peripheral blood mononuclear cells isolated by Ficoll-Hypaque centrifugation from 12 healthy volunteers were incubated with healthy or uremic serum in the presence or absence of 25 (OH)DC with 5% CO.. There was an increase in the serum 25(OH)D level in the cholecalciferol group. No differences were found in BAFF and IL7 levels and CD95 and BAFF-R expression in B lymphocytes from patients on dialysis after cholecalciferol supplementation. Uremic serum induced an increase in the IL-7, BAFF, BAFF-R and CD95 expression compared with the control. However, we observed no effect of incubation of 25(OH)D3 and 1,25(OH)2D3 on the expression of IL-7, BAFF, BAFF-R and CD95 when incubated in the presence of normal or uremic serum.. Our results suggest that vitamin D is not involved in mechanisms of regulation of differentiation and survival in B lymphocytes. In conclusion, further studies are needed to explore the effects of vitamin D on B lymphocytes to better evaluate the possible impact of vitamin D on humoral response in the CKD population.

Topics: Adult; Aged; B-Cell Activating Factor; B-Lymphocytes; Cholecalciferol; Dietary Supplements; Double-Blind Method; fas Receptor; Female; Humans; Interleukin-7; Kidney Failure, Chronic; Lymphopenia; Male; Middle Aged; Pilot Projects; Renal Dialysis; Uremia; Vitamin D; Vitamin D Deficiency; Vitamins

It has been reported that vitamin D regulates the immune system. However, whether vitamin D repletion modulates inflammatory responses in lymphocytes from dialysis patients is unclear. In the clinical trial, thirty-two (32) dialysis patients with 25 vitamin D ≤ 20ng/mL were randomized to receive either supplementation of cholecalciferol 100,000 UI/week/3 months (16 patients) or placebo (16 patients). In the in vitro study, B and T lymphocytes from 12 healthy volunteers (HV) were incubated with or without uremic serum in the presence or absence of 25 or 1,25 vitamin D. We evaluated the intracellular expression of IL-6, IFN-γ TLR7, TLR9, VDR, CYP27b1 and CYP24a1 by flow cytometry. We observed a reduction in the expression of TLR7, TLR9, INF-γ and CYP24a1 and an increase in VDR and CYP27b1 expression in patients which were supplemented with cholecalciferol, whereas no differences were found in the placebo group. Uremic serum increased the intracellular expression of IL-6, IFN-γ, TLR7, TLR9, VDR, CYP27b1 and CYP24a1. Treatment with 25 or 1,25 vitamin D decreased IL-6 and TLR9. CYP24a1 silencing plus treatment with 25 and/or 1,25 vitamin D had an additional reduction effect on IL-6, IFN-γ, TLR7 and TLR9 expression. This is the first study showing that cholecalciferol repletion has an anti-inflammatory effect and improves vitamin D intracellular regulatory enzymes on lymphocytes from dialysis patients.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Case-Control Studies; Cholecalciferol; Cytokines; Double-Blind Method; Humans; Inflammation; Inflammation Mediators; Pilot Projects; Placebos; Receptors, Calcitriol; Toll-Like Receptors; Uremia; Vitamin D; Vitamin D3 24-Hydroxylase

The results of recent studies suggest that uremic patients with large parathyroid hyperplasia are often resistant to active vitamin D3 therapy. Percutaneous ethanol injection has become an interesting option in such cases, although there are only a few publications on that subject. In this work we would like to present our experience with this method. 20 patients with serum iPTH > 400 pg/ml and 1-4 hyperplastic parathyroids (mean volume 1.07) underwent 56 percutaneous ethanol injection sessions under ultrasonographic guidance. In 9 patients a marked (> 75%), long-term (12-24 months) decrease in serum iPTH was achieved; lesser (> 50%) reduction in parathyroid activity persisted for 36-42 months in 5 out of 9 patients observed in this period. In almost every patient a significant reduction of alphacalcidol dose was possible. Our data confirm that percutaneous ethanol injection therapy is a useful and safe adjunct in severe uremic hyperparathyroidism treatment strategy which allows to restore the responsiveness to active vitamin D3 metabolites.

Topics: Adult; Aged; Cholecalciferol; Drug Resistance; Ethanol; Female; Humans; Hyperparathyroidism; Hyperplasia; Injections, Subcutaneous; Male; Middle Aged; Parathyroid Glands; Parathyroid Hormone; Ultrasonography; Uremia

End-stage renal disease is strongly associated with progressive cardiovascular calcification (CVC) and there is currently no therapy targeted to treat CVC. SNF472 is an experimental formulation under development for treatment of soft tissue calcification. We have investigated the pharmacokinetics of SNF472 administration in rats and its inhibitory effects on CVC. SNF472 was studied in three rat models: (1) prevention of vitamin D3-induced CVC with an intravenous SNF472 bolus of 1 mg/kg SNF472, (2) inhibition of progression of vitamin D3-induced CVC with a subcutaneous SNF472 bolus of 10 or 60 mg/kg SNF472, starting after calcification induction, (3) CVC in adenine-induced uremic rats treated with 50 mg/kg SNF472 via i.v. 4h -infusion. Uremic rats presented lower plasma levels of SNF472 than control animals after i.v. infusion. CVC in non-uremic rats was inhibited by 60-70% after treatment with SNF472 and progression of cardiac calcification completely blocked. Development of CVC in uremic rats was inhibited by up to 80% following i.v. infusion of SNF472. SNF472 inhibits the development and progression of CVC in uremic and non-uremic rats in the same range of SNF472 plasma levels but using in each case the required dose to obtain those levels. These results collectively support the development of SNF472 as a novel therapeutic option for treatment of CVC in humans.

Topics: Animals; Calcinosis; Cardiovascular Diseases; Cholecalciferol; Disease Models, Animal; Disease Progression; Humans; Inositol; Kidney Failure, Chronic; Rats; Renal Insufficiency, Chronic; Uremia

Calcidiol insufficiency is highly prevalent in chronic kidney disease (CKD), but the reasons for this are incompletely understood. CKD associates with a decrease in liver cytochrome P450 (CYP450) enzymes, and specific CYP450 isoforms mediate vitamin D(3) C-25-hydroxylation, which forms calcidiol. Abnormal levels of parathyroid hormone (PTH), which also modulates liver CYP450, could also contribute to the decrease in liver CYP450 associated with CKD. Here, we evaluated the effects of PTH and uremia on liver CYP450 isoforms involved in calcidiol synthesis in rats. Uremic rats had 52% lower concentrations of serum calcidiol than control rats (P < 0.002). Compared with controls, uremic rats produced 71% less calcidiol and 48% less calcitriol after the administration of vitamin D(3) or 1alpha-hydroxyvitamin D(3), respectively, suggesting impaired C-25-hydroxylation of vitamin D(3). Furthermore, uremia associated with a reduction of liver CYP2C11, 2J3, 3A2, and 27A1. Parathyroidectomy prevented the uremia-associated decreases in calcidiol and liver CYP450 isoforms. In conclusion, these data suggest that uremia decreases calcidiol synthesis secondary to a PTH-mediated reduction in liver CYP450 isoforms.

Topics: Animals; Calcifediol; Cells, Cultured; Cholecalciferol; Cholestanetriol 26-Monooxygenase; Hydroxylation; Liver; Male; Parathyroid Hormone; Parathyroidectomy; Rats; Rats, Sprague-Dawley; Uremia

Since our original demonstration of the metabolism of 1alpha,25(OH)2D3 into 1alpha,25(OH)2-3-epi-D3 in human keratinocytes, there have been several reports indicating that epimerization of the 3 hydroxyl group of vitamin D compounds is a common metabolic process. Recent studies reported the metabolism of 25OHD3 and 24(R),25(OH)2D3 into their respective C-3 epimers, indicating that the presence of 1alpha hydroxyl group is not necessary for the 3-epimerization of vitamin D compounds. To determine whether the presence of a 25 hydroxyl group is required for 3-epimerization of vitamin D compounds, we investigated the metabolism of 1alphaOHD3, a non-25 hydroxylated vitamin D compound, in rat osteosarcoma cells (ROS 17/2.8). We noted metabolism of 1alphaOHD3 into a less polar metabolite which was unequivocally identified as 1alphaOH-3-epi-D3 using the techniques of HPLC, GC/MS, and 1H-NMR analysis. We also identified 1alphaOH-3-epi-D3 as a circulating metabolite in rats treated with pharmacological concentrations of 1alphaOHD3. Thus, these results indicated that the presence of a 25 hydroxyl group is not required for 3-epimerization of vitamin D compounds. Furthermore, the results from the same studies also provided evidence to indicate that 1alphaOH-3-epi-D3, like 1alphaOHD3, is hydroxylated at C-25. We then evaluated the biological activities of 1alphaOH-3-epi-D3. Treatment of normal rats every other day for 7 days with 2.5 nmol/kg of 1alphaOH-3-epi-D3 did not raise serum calcium, while the same dose of 1alphaOHD3 increased serum calcium by 3.39 +/- 0.52 mg/dl. Interestingly, in the same rats which received 1alphaOH-3-epi-D3 we also noted a reduction in circulating PTH levels by 65 +/- 7%. This ability of 1alphaOH-3-epi-D3 to suppress PTH levels in normal rats without altering serum calcium was further tested in rats with reduced renal function. The results indicated that the ED50 of 1alphaOH-3-epi-D3 for suppression of PTH was only slightly higher than that of 1alpha,25(OH)2D3, but that the threshold dose of the development of hypercalcemia (total serum Ca > 10.5 mg/dl) was nearly 80 times higher. These findings indicate that 1alphaOH-3-epi-D3 is a highly selective vitamin D analog with tremendous potential for treatment of secondary hyperparathyroidism in chronic renal failure patients.

Topics: Animals; Calcium; Cell Line, Tumor; Cholecalciferol; Female; Humans; Male; Molecular Structure; Osteosarcoma; Parathyroid Hormone; Rats; Rats, Sprague-Dawley; Uremia

In chronic renal failure leptin levels are elevated and BMD decreased, however, so far data about correlations between leptin and BMD in dialyzed patients are scarce. It has been suggested that leptin is a predictor of BMD in postmenopausal women. We examined the relationships between leptinemia, BMD and bone metabolism in HD and CAPD patients. We also assessed whether leptin is significant and independent predictor of BMD in dialyzed patients.. BMD was measured using dual energy X-ray absorptiometry (DEXA) at lumbar spine and femoral neck in 25 HD and 23 CAPD patients. Markers of bone turnover and leptin were studied using commercially available kits.. In femoral neck BMD was significantly higher in CAPD patients, without significant differences in BMD in lumbar spine. There was a negative correlation between BMD at the femoral neck and time on hemodialysis (r= -0.45, p < 0.05). In CAPD patients BMD at the lumbar spine correlated negatively with vitamin D3 (r= -0.54, p < 0.05), osteocalcin (r= 0.54, p < 0 .05), and positively with BMI (r= 0.63, p < 0.01). BMD at the femoral neck correlated positively with BMI (r= 0.59, p < 0.01), and negatively with osteocalcin (r= -0.63, p < 0.05) and time on CAPD (r= -0.52, p < 0.05). Leptin correlate only with cholesterol (r= 0.25, p < 0.05), TSH (r= 0.35, p < 0.01), ss(2) microglobulin (r= 0.32, p < 0.001) and BMD at the femoral neck (r= -0.23, p < 0.05)in all dialyzed (HD and CAPD) patients.. BMD depends on time of renal replacement therapy. Biochemical markers of bone metabolism poorly correlate with BMD and leptin in dialyzed patients. Leptin is not a predictor of BMD in dialyzed patients.

Topics: Adult; Biomarkers; Bone and Bones; Bone Density; Cholecalciferol; Female; Humans; Leptin; Male; Middle Aged; Osteocalcin; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Uremia

Topics: Cholecalciferol; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Uremia

To study possible correction of bone disorders (osteopenia, Ca/P-imbalance, bone pain, limited volume of indolent movements) which are still a serious complication associated with renal diseases and pathogenic therapy (steroids).. The bone disorders were treated in 10 uremic hemodialyzed patients (8 men, 2 women; group 1) with vitamin D3 (calcitriol made in Russia) + rhEPO (recormon; Boehringer Mannheim), in 15 patients (15 women, 0 men) with lupus-nephritis (group 2) with vitamin D3 (n = 5, group 2a) or miscalcic (Sandoz) (n = 10, group 2b), in 2 patients (2 men, 0 women) with glomerulonephritis (group 3) with vitamin D3 + miacalcic. Additionally all the patients received Ca salts. In groups 2 and 3 renal function was normal. The duration of the treatment was 3-6 months.. In all the groups we obtained an analgetic effect (attenuation of bone pain and more indolent movements), improvement of life quality, diminished need in analgetics, elevation of serum Ca level (p > 0.05).. Treatment of renal patients with bone affection with vitamin D3 and miacalcic has an analgetic effect, improves life quality.

Topics: Adult; Analgesics; Bone Diseases; Calcitonin; Calcium; Cholecalciferol; Drug Therapy, Combination; Erythropoietin; Female; Glomerulonephritis; Humans; Lupus Nephritis; Male; Middle Aged; Quality of Life; Recombinant Proteins; Renal Dialysis; Treatment Outcome; Uremia

During the course of chronic renal failure (CRF) in man, renal osteodystrophy (osteitis fibrosa and/or osteomalacia) gradually develops. The present study aimed to establish a similar type of CRF leading to renal osteodystrophy in rats. During progressive CRF development over 225 days after 5/6 nephrectomy, the following serum variables were measured: creatinine, immunoreactive parathyroid hormone (iPTH), 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), a25-hydroxyvitamin D3, (25(OH)D3), alkaline phosphatase, albumin, phosphate, urea nitrogen, total calcium, and other blood electrolytes. Subsequent to sacrifice, mechanical properties of the rat femur, bone histomorphometry (osteoid and eroded surfaces) and bone contents of calcium, phosphate and hydroxyproline were also examined. Serum creatinine in rats with CRF gradually escalated by some 70%, while circulating 1,25(OH)2D3 was reduced beneath detection level. Total plasma calcium and phosphate concentrations were, however, almost unchanged indicating that PTH-induced bone remodeling due to moderate hyperparathyroidism sustained calcium homeostasis. Alkaline phosphatase levels were reduced by some 50%, which reflects chronically impeded bone formation. Bone histomorphometry assessment revealed substantial elevation of resorption with moderate accompanying fibrosis in about 70% of afflicted animals. Bone calcium, phosphate and hydroxypyrroline contents remained unaltered. However, hydroxyproline/calcium ratio was marginally reduced. These results, together with altered mechanical bending stress characteristics and diminished diaphysis cross section area, confirm development of mixed bone lesions in the uremic animals. Our results are compatible with the early development of CRF in man. The established rat model is therefore useful in elucidating the precipitation and early treatment of renal osteodystrophy in humans.

Topics: Alkaline Phosphatase; Animals; Biomarkers; Bone and Bones; Calcium; Cholecalciferol; Chronic Kidney Disease-Mineral and Bone Disorder; Disease Models, Animal; Female; Hydroxyproline; Hyperparathyroidism, Secondary; Nephrectomy; Parathyroid Hormone; Rats; Rats, Wistar; Second Messenger Systems; Stress, Mechanical; Uremia

We studied 54 patients in replacement dialytic therapy divided into two groups: Group 1, 26 patients with normal parathyroid hormone (PTH) (10-80 pg/ml): and Group 2, 28 patients with elevated PTH (80-400 pg/ml). Total T lymphocytes, CD4, CD8, and CD4/CD8 ratio were evaluated. We found a reduction of total T lymphocytes in both groups compared with controls. A decrease of CD4 and CD4/CD8 ratio with a rise of CD8 occurred in Group 2 but not in Group 1. In Group 2, PTH presented a linear correlation with CD8 and a reverse correlation with total T cells. CD4, and CD4/CD8 ratio. PTH might act on T-cellular immunity with an immunosuppressive effect from the earlier phases of hyperparathyroidism.

Topics: Adult; Aged; CD4-CD8 Ratio; Cholecalciferol; Female; Humans; Male; Middle Aged; Parathyroid Hormone; Renal Dialysis; T-Lymphocytes; Uremia

The initial step in cholecalciferol (vitamin D3) metabolism is the photo-conversion of 7-dehydrocholesterol to previtamin D3. This reaction occurs in the epidermis and requires ultraviolet light. We measured the circulating concentration of vitamin D (ergocalciferol and cholecalciferol), 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in 14 normal white, 9 normal black subjects, and in 9 white and 17 black hemodialysis patients. The mean plasma vitamin D in normal white subjects was greater than in normal black subjects, 4.01 +/- 1.02 ng/ml versus 0.96 +/- 0.30 ng/ml, respectively (P less than 0.05). Plasma 25-hydroxyvitamin D in normal blacks was also less than in normal whites, 17.7 +/- 1.5 ng/ml versus 31.3 +/- 3.0 ng/ml, respectively (P less than 0.01). In uremic white subjects, plasma vitamin D, 6.7 +/- 2.6 ng/ml, was similar to normal white subjects. However, vitamin D was not detectable in 12 of 17 uremic black subjects and was depressed in the remainder of the group. Following exposure to a single minimal erythema dose of ultraviolet-B irradiation, the maximal increase in plasma vitamin D was depressed in white dialysis patients as compared to healthy white subjects, 6.3 +/- 1.9 ng/ml versus 21.3 +/- 2.8 ng/ml, respectively (P less than 0.02). 7-Dehydrocholesterol content was similar in epidermis from site-matched skin of fresh cadavers and white hemodialysis patients, 131 +/- 23 ng/mg versus 124 +/- 14 ng/mg skin, respectively. It is concluded that chronic hemodialysis patients exhibit defective photoproduction of cholecalciferol, despite normal epidermal content of substrate, 7-dehydrocholesterol.

Topics: Adult; Cholecalciferol; Dehydrocholesterols; Epidermis; Ergocalciferols; Humans; Male; Renal Dialysis; Ultraviolet Rays; Uremia

Changes in vitamin D metabolism and their effect on calcium and bone metabolism in uremia have been extensively studied. However, the possible effect of uremia on intestinal absorption of vitamin D has not been investigated. We determined the rate of intestinal absorption of vitamin D3 in uremic and normal rats using a well-defined in vivo perfusion technique under identical experimental conditions. The rate of jejunal absorption of vitamin D3 in uremic animals (5.09 +/- 1.87 pmol/100 cm/h) was significantly less (p less than 0.001) than that found in the control animals (11.5 +/- 1.6 pmol/100 cm/h). While the underlying mechanism(s) of the observed reduction in vitamin D absorption in uremia is not known, its recognition adds another dimension to the previously recognized abnormalities of vitamin D metabolism in uremia.

Topics: Animals; Blood Urea Nitrogen; Bone and Bones; Calcium; Cholecalciferol; Creatinine; Intestinal Absorption; Jejunum; Male; Phosphates; Rats; Rats, Inbred Strains; Uremia

Topics: Adult; Calcium; Cholecalciferol; Chronic Kidney Disease-Mineral and Bone Disorder; Dietary Proteins; Energy Intake; Female; Humans; Male; Middle Aged; Renal Dialysis; Uremia

The objectives of this study were to evaluate the effects of vitamin D(3) (D(3)) and 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) on uremic bone disease independent of their action on the intestine. The histomorphology of tibial metaphyses in uremic (5/6 nephrectomized [5/6 Nx]) rats fed a low-calcium-low-phosphorus (LCLP) diet was compared with sham-operated (SO) rats fed an LCLP diet and 5/6 Nx rats fed an LCLP diet and given 15,000 IU D(3) or 5 units (135 ng) 1,25-(OH)(2)D(3) daily for 7 days. A marked osteomalacia characterized by an increased percentage of active and inactive trabecular osteoid surface and thickened growth plates developed in proximal tibial metaphyses in 5/6 Nx rats given the placebo, compared with SO rats. These bone changes were associated with relative hypophosphatemia, hypophosphaturia, and hypercalciuria in 5/6 Nx rats. In 5/6 Nx rats treated with D(3) or 1,25-(OH)(2)D(3) the growth plates had undergone mineralization and vascular invasion and were markedly reduced in thickness. Other parameters of osteomalacia in trabecular bone were not different from 5/6 Nx rats given the placebo. There was a significant decrease in osteoclasts per millimeter of trabecular surface perimeter in D(3)- and 1,25-(OH)(2)D(3)-treated rats. These bone changes were associated with hypercalcemia, hyperphosphatemia, and hyperphosphaturia, compared with 5/6 Nx rats given the placebo. It was concluded that in uremic rats fed the LCLP diet, shortterm treatment with either pharmacologic levels of D(3) or 1,25-(OH)(2)D(3) corrected only lesions in the growth plate. Osteoid seams were not reduced in treated rats, although the serum calcium-phosphorus product was elevated. The 5/6 Nx rat fed the LCLP diet appears to be a useful model for the rapid induction of uremic osteomalacia in adult animals.

Topics: Animals; Blood Urea Nitrogen; Calcitriol; Calcium; Cholecalciferol; Dihydroxycholecalciferols; Hydroxycholecalciferols; Male; Osteomalacia; Phosphorus; Rats; Tibia; Time Factors; Uremia

Topics: Acute Disease; Animals; Blood Urea Nitrogen; Calcium; Cholecalciferol; Dihydroxycholecalciferols; Disease Models, Animal; Hydroxycholecalciferols; Intestinal Mucosa; Male; Phosphorus; Rats; Uremia; Vitamin D; Vitamin D Deficiency

Chronic renal disease in man and animals is associated with disturbances in calcium homeostasis which are resistant to vitamin D-therapy. Partially nephrectomized and intact rats were used to evaluate the effect of uremia on the response of bone to vitamin D. Serum calcium, serum phosphorus and blood urea nitrogen levels were higher in uremic rats than in intact rats, both given vitamin D. Metaphyseal bone in uremic rats was resistant to vitamin D-induced bone resorption; osteoblasts and osteocytes appeared less active ultrastructurally and osteoclass were infrequent. Calcitonin synthesis and release evaluated electron microscopically was greater in uremic rats. It is suggested that the altered response of bone to vitamin D in uremic rats was due in part to elevated serum phosphorus and increased calcitonin release. The present model does not refute experimental and clinical data that metabolism of vitamin D is altered in renal disease. It does, however, emphasize that in chronic renal failure other parameters (phosphorus levels, calcitonin release, uremia) are operating which may influence end organ response to pharmacologic doses of vitamin D. The partially nephrectomized rat may be a useful model for evaluating end-organ resistance to vitamin D in uremia.

Topics: Animals; Blood Urea Nitrogen; Bone and Bones; Calcitonin; Calcium; Cholecalciferol; Disease Models, Animal; Kidney Failure, Chronic; Male; Parathyroid Glands; Phosphates; Rats; Uremia; Vitamin D Deficiency

Importance sequelae of uremia are hormonal changes in calcium homeostasis combined with chronic calcium imbalance causing structural alteration and functional insufficiency of bone. Morphological findings of the so called renal osteodystrophy are osteomalacia, osteitis fibrosa and osteoporosis. Osteitis fibrosa and abnormal skeletal metabolism (changes of collagen turnover, insufficient maturation of stable bone crystals) impair the mechanical qualities of bone. Probably the uremia per se influences the collagen metabolism; additional factors such as secondary hyperparathyroidism and deficiency of vitamin D3 are discussed.

Topics: Animals; Bone and Bones; Bone Resorption; Calcification, Physiologic; Calcium Phosphates; Cholecalciferol; Chronic Kidney Disease-Mineral and Bone Disorder; Collagen; Humans; Hydroxyapatites; Parathyroid Hormone; Protein Conformation; Uremia

Epiphyseal slipping in uraemia differs strikingly from juvenile epiphyseal slipping with respect to pathology and therapy. Based on our own experience with the treatment of 8 uraemic children with epiphyseal slipping, an effort was made to establish the respective indications for conservative and surgical treatment. Mechanical stabilization of slipped epiphyses was achieved within a few weeks without any surgery and usually without parathyreoidectomy by vitamin D3 alone. The initial dose was 10,000 to 30,000 I.U./day, the total curative dose 1.8 to 5.6 millions I.U. Prolonged immobilization was unnecessary. Rising urinary calcium excretion was a valuable indicator of vitamin D intoxication even in advanced renal failure. In one case, pronounced metaphyseal deformations (distal femur, distal tibia) required surgical correction before the ability to walk normally was restored. - The following therapeutical approach is recommended: metabolic bone disease must be cured by vitamin D therapy with or without parathyreoidectomy. Osteotomy to correct metaphyseal deformities or coxa vara epiphysaria never should be performed before metabolic bone disease is healed.

Topics: Adolescent; Calcium; Child; Child, Preschool; Cholecalciferol; Epiphyses, Slipped; Female; Hip Joint; Humans; Joint Diseases; Male; Phosphates; Uremia; Vitamin D

Two patients with profound hypocalcaemia due to uraemia and hypoparathyroidism respectively presented with alterations of mental state as their dominant symptom. 1-Alpha-hydroxycholecalciferol (1-alpha-OHD3) was chosen as the principal therapy because of its potency and rapid action. In both patients the plasma calcium was restored towards normal and the symptoms relieved within a very short period. The cases illustrate the role of 1-alpha-OHD3 in severe hypocalcaemia due to two different causes and provide experience on which to base treatment regimes for future patients similarly afflicted.

Topics: Calcium; Cholecalciferol; Female; Humans; Hydroxycholecalciferols; Hypocalcemia; Hypoparathyroidism; Middle Aged; Psychotic Disorders; Uremia

Topics: Animals; Appetite Regulation; Cholecalciferol; Chronic Kidney Disease-Mineral and Bone Disorder; Financing, Government; Graft Rejection; Growth Disorders; Humans; Kidney Transplantation; Kidneys, Artificial; Rats; Research; Transplantation, Homologous; Uremia

Topics: Biopsy, Needle; Bone and Bones; Calcium, Dietary; Cholecalciferol; Chronic Kidney Disease-Mineral and Bone Disorder; Humans; Parathyroid Glands; Phosphates; Renal Dialysis; Uremia

Topics: Aerobiosis; Animals; Carbohydrate Metabolism; Carbon Dioxide; Cartilage; Cholecalciferol; Chronic Disease; Epiphyses; Glucose; Glycolysis; Lactates; Parathyroid Hormone; Pentosephosphates; Rats; Uremia

Topics: Animals; Calcium; Carbon Radioisotopes; Chickens; Cholecalciferol; Chromatography; Dihydroxycholecalciferols; Intestinal Absorption; Intestinal Mucosa; Kidney Failure, Chronic; Ligation; Tritium; Uremia; Ureter

Topics: Adult; Calcium; Calcium Radioisotopes; Cholecalciferol; Feces; Female; Humans; Intestinal Absorption; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Middle Aged; Phosphorus; Uremia

Topics: Adult; Biotransformation; Calcium; Calcium Radioisotopes; Cholecalciferol; Female; Humans; Intestinal Absorption; Kidney; Male; Middle Aged; Nephrectomy; Phosphates; Postoperative Complications; Renal Dialysis; Time Factors; Uremia

Topics: Animals; Bone Diseases; Calcium; Chemical Phenomena; Chemistry; Cholecalciferol; Dihydrotachysterol; Dihydroxycholecalciferols; Disease Models, Animal; Humans; Hydroxycholecalciferols; Isomerism; Kidney Failure, Chronic; Microradiography; Osteitis Fibrosa Cystica; Osteomalacia; Phosphates; Rats; Renal Dialysis; Uremia; Vitamin D

Topics: Adolescent; Affective Symptoms; Age Factors; Cardiovascular Diseases; Child; Child, Preschool; Cholecalciferol; Depression; Erythropoiesis; Family; Female; Glomerulonephritis; Growth Disorders; Humans; Infant; Kidney Transplantation; Male; Renal Dialysis; Seizures; Terminal Care; Transplantation, Homologous; Uremia

Topics: Calcium; Cholecalciferol; Homeostasis; Humans; Hydroxycholecalciferols; Intestinal Absorption; Kidney Failure, Chronic; Uremia

Topics: Animals; Biological Transport; Blood Urea Nitrogen; Bone Diseases; Calcium; Chickens; Cholecalciferol; Intestinal Absorption; Intestine, Small; Kidney; Kidney Failure, Chronic; Ligation; Male; Nephrectomy; Rats; Uremia; Ureter; Vitamin D

Topics: Carbon Isotopes; Cholecalciferol; Chromatography; Humans; Nephrectomy; Tritium; Uremia

Topics: Animals; Cholecalciferol; Female; Rats; Rats, Inbred Strains; Rickets; Tritium; Uremia

The development of a vitamin D-resistant state in the course of renal failure may be responsible for reduced intestinal absorption of calcium and an impaired response of skeletal tissue. Moreover, the kidney has been shown to carry out the conversion of 25-hydroxycholecalciferol (25-OH-CC) to a highly biologically active metabolite, 1,25-dihydroxycholecalciferol (1,25-diOH-CC). In the present studies, vitamin D-deficient rats, made acutely uremic by either bilateral nephrectomy or urethral ligation, received physiological doses of cholecalciferol (vitamin D(3)) (CC), 25-OH-CC or 1,25-diOH-CC; 24 hr later intestinal calcium transport, in vitro, and bone calcium mobilization, in vivo, were assessed. Whereas CC and 25-OH-CC stimulated calcium transport in sham-operated controls, they were without effect in the uremic animals. In contrast, administration of 1,25-diOH-CC stimulated calcium transport in both groups of uremic animals. Administration of 1,25-diOH-CC also stimulated calcium mobilization from bone in each group of animals. However, CC and 25-OH-CC were only effective in the sham controls and the uremic group produced by urethral ligation and had little or no effect in animals without kidneys. These results indicate that renal conversion of calciferol to a more biologically active form is necessary for the stimulation of intestinal calcium absorption and calcium mobilization from bone, and that 1,25-diOH-CC may bypass a possible defect in vitamin D metabolism in uremia. From these studies it is likely that uremia, per se, may also impair intestinal calcium transport.

Topics: Animals; Biological Transport, Active; Bone and Bones; Calcium; Cholecalciferol; Hydroxycholecalciferols; Intestinal Absorption; Ligation; Male; Nephrectomy; Rats; Uremia; Vitamin D Deficiency

Topics: Calcium; Calcium Isotopes; Calcium, Dietary; Cholecalciferol; Feces; Humans; Hydroxycholecalciferols; Intestinal Absorption; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Phosphorus; Time Factors; Uremia; Vitamin D Deficiency

Topics: Cholecalciferol; Ergocalciferols; Humans; Hydroxycholecalciferols; Hydroxylation; Kidney; Liver; Uremia; Vitamin D

The appearance of a polar metabolite of 25-hydroxychotecalciferol has been studied in the intestinal mucosas of nephrectomized rats and rats which have been made uremic by ureter ligation. In confirmation of previous work by Fraser and Kodicek, it was found that nephrectomy prevents the appearance of this metabolite in the intestine. On the other hand, equivalent amounts of the metabolite were found in uremic rats and in sham-operated controls, showing that the production of this metabolite is independent of the uremic state of the animals. In addition, it was shown that the metabolite produced in vitro by kidney homogenates is identical to that found in vivo in the intestine.

Topics: Animals; Calcium; Chickens; Cholecalciferol; Chromatography; Intestinal Mucosa; Kidney; Nephrectomy; Rats; Tritium; Uremia; Vitamin D; Vitamin D Deficiency

Topics: Animals; Bone and Bones; Cholecalciferol; Intestinal Mucosa; Nephrectomy; Rats; Tritium; Uremia; Vitamin D

Topics: Animals; Biological Transport; Calcium; Carbon Isotopes; Cholecalciferol; Chromatography; Diet; Injections, Intravenous; Intestinal Mucosa; Kidney; Liver; Nephrectomy; Rats; Tritium; Uremia; Vitamin D; Vitamin D Deficiency

Topics: Animals; Bone and Bones; Cholecalciferol; Female; Intestinal Mucosa; Liver; Muscles; Nephrectomy; Rats; Tritium; Uremia; Vitamin D

Topics: Animals; Bone and Bones; Bone Diseases; Bone Resorption; Carbon Isotopes; Cholecalciferol; Collagen; Hydroxyproline; Kidney Failure, Chronic; Male; Parathyroid Hormone; Proline; Rats; Skin; Tibia; Uremia

Topics: Animals; Bone and Bones; Bone Development; Bone Diseases; Bone Resorption; Calcitonin; Calcium Isotopes; Cholecalciferol; Culture Techniques; Dactinomycin; Hydroxyproline; Kidney Failure, Chronic; Parathyroid Hormone; Phosphates; Rats; RNA; Uremia

Topics: Animals; Bone and Bones; Bone Diseases; Calcium; Cholecalciferol; Humans; Kidney; Kidney Failure, Chronic; Liver; Rats; Uremia; Vitamin D

Topics: Animals; Biological Transport, Active; Bone Diseases; Calcium; Cholecalciferol; Duodenum; Intestinal Absorption; Intestinal Mucosa; Kidney Failure, Chronic; Male; Protein Binding; Rats; Tritium; Uremia; Vitamin D

Topics: Adult; Calcium; Cholecalciferol; Humans; Intestinal Mucosa; Kidney Failure, Chronic; Liver; Tritium; Uremia

Topics: Bone Diseases; Cholecalciferol; Humans; Kidney Failure, Chronic; Uremia

When compared to that of normal animals, calcium-binding protein activity of duodenal mucosa obtained from uremic rats was decreased. There was no change in this activity after vitamin D(3), therapy. In contrast, prior treatment with 25-hydroxycholecalcijerol resulted in increased transport of calcium-45 and calcium-binding protein activity in the intestine.

Topics: Animals; Calcium; Cholecalciferol; Chronic Disease; Duodenum; Intestinal Absorption; Intestinal Mucosa; Male; Protein Binding; Rats; Stimulation, Chemical; Uremia