24-25-dihydroxyvitamin-d-3 and Uremia

Topics: 24,25-Dihydroxyvitamin D 3; Acidosis; Calcitriol; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Dihydroxycholecalciferols; Humans; Intestinal Absorption; Kidney Failure, Chronic; Phosphorus; Uremia; Vitamin D

1. Peak 47Ca absorption and 7 day 47Ca retention were measured by a whole-body radioactivity counting technique in 10 haemodialysis patients before and after treatment with 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] and 24,25-dihydroxycholecalciferol [24,25-(OH)2D3]. 2. Before treatment all patients had low peak 47Ca absorption and 7 day 47Ca retention. 3. After treatment with 1,25-(OH)2D3 (0 . 25-l microgram/day for 4-12 months) peak 47Ca absorption and 7 day 47Ca retention returned to normal. 4. After treatment with 24,25-(OH)2D3 (2 microgram/day for 4-12 months) peak 47Ca absorption and 7 day 47Ca retention remained at pretreatment levels. 5. It is concluded that physiological doses of 24,25-(OH)2D3 have no effect on calcium absorption or retention in uraemic man.

Topics: 24,25-Dihydroxyvitamin D 3; Calcitriol; Calcium; Dihydroxycholecalciferols; Female; Humans; Hydroxycholecalciferols; Intestinal Absorption; Male; Renal Dialysis; Uremia

We have previously established an uremic rat model which is suitable for investigating the effect of various treatment modalities on the progression of renal osteodystrophy [1]. Four months subsequent to 5/6 nephrectomy, animals were treated three times a week for 3 months with either vehicle, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], 1,25(OH)2D3 + 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], 1,25(OH)2D3 + calcitonin (CT), or 1,25(OH)2D3 + 24,25(OH)2D3 + CT. At termination of the study, clinical chemistry, chemical composition, and mechanical properties of femurs, calvarial parathyroid hormone (PTH)-elicited adenylate cyclase (AC), and phospholipase C (PL-C) activities, femoral cross-sectional area, and bone histomorphometry were analyzed. The main findings were that 1,25(OH)2D3 +/- 24,25(OH)2D3 treatment enhanced elasticity as well as time to fracture at the femoral metaphysis. CT potentiated the increase in elasticity obtained by 1,25(OH)2D3 +/- 24,25(OH)2D3 treatment. Only 24,25(OH)2D3 administration rectified the supernormal PTH-stimulated uremic bone AC, and only 1,25(OH)2D3 medication normalized the diminished CT-elicited AC. The obliterated uremic bone PTH-sensitive PL-C was fully normalized by all drug regimens. Femoral shaft inner zone diameter was enhanced by uremia, however, all drug treatments normalized it. Ditto effect was registered with either drug treatment on the subnormal outer and inner zone widths. Histomorphometrical analyses showed that 1,25(OH)2D3 administration reduced both eroded and osteoid surfaces. Most prominently, adjuvant 24,25(OH)2D3 or CT administration potentiated the beneficial effect of 1,25(OH)2D3 on fibrosis and osteomalacia. We assert that vitamin D3 treatment markedly reverses the development of renal osteodystrophy, and CT potentiates the effect of vitamin D3.

Topics: 24,25-Dihydroxyvitamin D 3; Adenylyl Cyclases; Animals; Bone and Bones; Bone Density; Calcitonin; Calcitriol; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Creatinine; Disease Models, Animal; Drug Administration Schedule; Female; Femur; Rats; Rats, Wistar; Type C Phospholipases; Uremia

Previously we demonstrated that bone resorption in uremic patients appears to be related to increased serum parathyroid hormone (PTH) and to osseous PTH-stimulated adenylate cyclase (AC), the latter being inversely correlated to serum 24,25-dihydroxyvitamin D3 [24,25(OH)2D3]. In this study, we continue to examine the possible modulatory role of vitamin D3 analogs on the progression of the uremic condition. Four groups of predialytic uremic patients received oral administrations of CaCO3 (control), 1,25-dihydroxy-vitamin D3 [1,25(OH)2D3] (0.25-0.50 microgram/day), 24,25(OH)2D3 (15 micrograms/day) or a combination of the two vitamin D3 analogs for 6 months. In the treatment groups receiving single or combined therapy, respectively, the low pretrial serum levels of 1,25(OH)2D3 were raised (p < 0.05) within upper normal range, while the serum levels of 24,25(OH)2D3 were increased (p < 0.05) to twice the average physiological level. Neither regimens alone resulted in significant changes in serum levels of calcium of PTH. 1,25(OH)2D3 moderately hampered bone formation by reducing serum alkaline phosphatase (ALP) by some 15%. 24,25(OH)2D3 significantly decreased (p < 0.01) bone PTH-AC up to 98% after 2 and 6 months. However, no correlation was found between serum 24,25(OH)2D3 and the bone turnover parameters serum ALP, serum osteocalcin and urine hydroxyproline/creatinine ratio. These parameters were all positively correlated (p < 0.05) to serum PTH, indicating an on-going bone turnover. These biochemical events strongly indicate that 24,25(OH)2D3 may retard the PTH-dependent progression in bone demineralization occurring in uremic patients. This effect is apparently not reduced by concomitant 1,25(OH)2D3 administration.

Topics: 24,25-Dihydroxyvitamin D 3; Alkaline Phosphatase; Bone and Bones; Calcitriol; Calcium; Humans; Hydroxyproline; Osteocalcin; Parathyroid Hormone; Phosphates; Uremia

The administration of aluminum (Al) to uremic rats leads to Al accumulation in different brain regions with subsequent alteration of brain gangliosides. Addition of 24R,25-dihydroxyvitamin D3[24R,25-(OH)2D3] did not influence the brain Al content determined by plasma argon emission spectrometry, but prevented the decrease in brain gangliosides. By using electron microscopy and laser microprobe mass analysis, it was demonstrated that in rats given 24R,25-(OH)2D3 together with Al, the metal was mainly kept within perivascular astrocytes of the blood-brain barrier. On the contrary, in rats given Al only, the metal was evenly distributed throughout the brain areas causing extensive demyelination, chromatolysis of nerve cells in some brain regions (hippocampus) and brain edema. Our results could find application in the prevention of Al-induced encephalopathy in patients on hemodialysis.

Topics: 24,25-Dihydroxyvitamin D 3; Aluminum; Animals; Astrocytes; Blood-Brain Barrier; Brain; Gangliosides; Microscopy, Electron; Nephrectomy; Organ Specificity; Rats; Reference Values; Sialic Acids; Uremia

The rate of aluminium accumulation in bone may be related to the presence of vitamin D metabolites. The present study investigated the effect of 1,25(OH)2D3 (24 pmol/d s.c.) and 24R,25(OH)2D3 (480 pmol/day), combined or alone, on the deposition of aluminium (119 mumol/kg per day) in bone of uraemic rats during concomitant parenteral administration of aluminium for 9 weeks. Bone histomorphometry of trabecular bone revealed a severe low-turnover osteodystrophy in aluminium-treated uraemic rats, as evidenced by a decrease in osteoblastic osteoid surfaces and mineral apposition rates. 1,25(OH)2D3 as well as 24R,25(OH)2D3 decreased stainable bone aluminium and the aluminium content of trabecular bone and, in parallel, the number of osteoblasts and osteoclasts increased. Additional treatment with one or both vitamin D metabolites 14 days prior to the aluminium load further improved these results. Despite these effects, dynamic histomorphometric parameters remained suppressed and osteoidosis persisted. Serum PTH concentrations were significantly elevated in aluminium-loaded uraemic rats treated with 24R,25(OH)2D3 alone compared to controls. In conclusion, administration of 1,25(OH)2D3 or 24R,25(OH)2D3 reduces the accumulation of aluminium in trabecular bone in uraemic rats and prevents some of its excess toxicity. The mechanism of action may be different for either vitamin D metabolite; however, combined treatment does not result in further reduction of the accumulation rate of aluminium in bone in this model.

Topics: 24,25-Dihydroxyvitamin D 3; Aluminum; Animals; Bone and Bones; Calcitriol; Chronic Kidney Disease-Mineral and Bone Disorder; Male; Premedication; Rats; Rats, Inbred Strains; Uremia

The bone adenylyl cyclase (AC) complex of iliac crest biopsies of normals, uremic patients and subjects with primary hyperparathyroidism (PrHPT) have been investigated. Bone resorption (RS) in uremic patients appears to be related partly to increased serum parathyroid hormone (s-PTH) levels and to netto PTH-stimulated AC (net PTH-AC) and partly to the uremic condition (as estimated by s-Creatinine) per se. Serum PTH is able to completely desensitize the PTH dependent bone AC in normals in vivo, but only partially in uremic patients. In patients with PrHPT, the bone AC appears to be inert to homologous desensitization. Positive aluminum staining is associated with blunted CT-responsive and low basal AC. In the combined group of normals and uremic patients, net PTH-AC is (as predicted from human in vitro data and the rat model) inversely related to serum 24,25-diOH-D3. Net PTH-AC, when corrected for s-24,25-diOH-D3 levels, correlated well with RS. The described action of 24,25-diOH-D3 presents a clearly defined rationale for the use of 24,25-diOH-D3 concurrently with 1,25-diOH-D3 to treat renal osteodystrophy: By administering 1,25-diOH-D3, s-Ca2+ and s-PTH will normalize and consequently net PTH-AC diminish. 24,25-diOH-D3 is then believed to further reduce net PTH-AC and RS. A concomitant alleviation of the uremic condition would eventually ensure the fastest possible restoration of bone structure and function.

Topics: 24,25-Dihydroxyvitamin D 3; Adenylyl Cyclases; Adult; Biopsy; Bone and Bones; Clinical Enzyme Tests; Dihydroxycholecalciferols; Female; Humans; Ilium; Isoproterenol; Kinetics; Male; Middle Aged; Parathyroid Hormone; Prognosis; Reference Values; Uremia

Rats were subjected to a two-stage subtotal nephrectomy or sham operation, and treated with aluminum (Al) or both aluminum and vitamin D3 metabolites for 5 weeks with a cumulative dose of 13.6 mg aluminum. Animals were injected with 3H-thymidine and 3H-proline. The following analyses were performed: quantitative histology of tibial metaphyses and cytomorphometric electron microscopy of osteoclasts, quantitative (ICP-spectroscopy) and qualitative determination (histochemical staining) of aluminum within organs, and serum biochemistry (Ca, P, Mg, vitamin D3 metabolites, alkaline phosphatase, urea). The following new facts of the aluminum-related bone disease became evident: (a) Application of aluminum to growing uremic rats induced rickets, whose major epiphyseal growth plate changes were 1 alpha,25(OH)2D3-dependent. Addition of 1 alpha,25(OH)2D3 prevented the formation of rachitic metaphysis, but failed to prevent osteoid accumulation on epiphyseal and metaphyseal trabecular surfaces. Moreover, calcitriol produced hyperosteoidosis and osteosclerosis in the same rats. Aluminum did not alter the function of osteoblasts, while osteoclasts seemed inactivated. (b) The development of rickets was associated with suppressed serum levels of 1,25(OH)2D3, reduced phosphorus level and the high content of aluminum in the bone, kidney, and liver. The addition of 24R,25(OH)2D3 markedly exaggerated the reduction of serum levels of calcitriol. We suggested that aluminum induces rickets in growing uremic rats, which consists of two components: vitamin D refractory osteomalacia and 1 alpha,25(OH)2D3-dependent epiphyseal growth plate changes.

Topics: 24,25-Dihydroxyvitamin D 3; Aluminum; Animals; Bone and Bones; Bone Development; Calcitriol; Dihydroxycholecalciferols; Male; Rats; Rats, Inbred Strains; Rickets; Thymidine; Tissue Distribution; Uremia

Uraemic rats maintained on either a high or a low phosphate diet for 12 weeks were allocated to one of the following oral vitamin D treatment groups and received: 1,25-dihydroxycholecalciferol [1, 25-(OH)2D3], 24,25-dihydroxycholecalciferol [24,25-(OH)2D3], both 1,25-(OH)2D3 and 24,25-(OH)2D3, or no vitamin D supplements. Mean serum creatinine concentrations were elevated to a similar extent in all groups. Mean serum concentrations of calcium, phosphate and alkaline phosphatase were not significantly different from normal in any of the groups. In the group receiving the high phosphate diet and no vitamin D supplements, calcified bone area measured by quantitative computerized histomorphometry was significantly lower than in the group receiving the low phosphate diet and no vitamin D supplements (0.01 greater than P greater than 0.001), and in the groups receiving high phosphate diet and either 1,25-(OH)2D3 (0.01 greater than P greater than 0.001) or 24,25-(OH)2D3 (0.01 greater than P greater than 0.001). We conclude that uraemic rats maintained on a high phosphate diet for 12 weeks develop skeletal demineralization, this process does not occur in rats on a low phosphate diet, and a decrease in calcified bone area may be prevented by treatment with either 1,25-(OH)2D3 or 24,25-(OH)2D3.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Bone Diseases, Metabolic; Calcinosis; Calcitriol; Chronic Kidney Disease-Mineral and Bone Disorder; Creatinine; Dihydroxycholecalciferols; Male; Nephrectomy; Phosphates; Rats; Rats, Inbred Strains; Uremia

Controversy exists as to whether 24,25(OH)2D3 has a direct inhibitory effect on parathyroid hormone (PTH) secretion. Therefore, the present investigation examined the effect of long-term administration of 24,25(OH)2D3 on immunoassayable PTH levels (iPTH) and bone histology in dogs with chronic renal failure. Chronic renal failure was produced in 16 dogs, half of which served as controls whereas the other half received 2.5 micrograms/day of 24,25(OH)2D3, orally. Serum iPTH, serum total, ionized calcium, serum phosphorus, and creatinine were followed at weekly or biweekly intervals in both groups. Also, creatinine clearances, serum levels of 25(OH)D3, 24,25(OH)2D3, and 1,25(OD)2D3 and the intestinal absorption of calcium were measured. After 1 year of chronic renal failure the dogs were sacrificed and rib biopsy specimens were obtained for histological examination and measurement of mineral content. Serum iPTH increased equally in the two dog groups with no effect at any time of 24,25(OH)2D3 treatment, despite a significant increase in the serum levels of 24,25(OH)2D3 and a concomitant decrease of the 1,25(OH)2D3 levels. There was no difference in the levels of serum calcium or in the calcium content of bone. Furthermore, after 8 months of uremia three control dogs were switched to the group treated with 24,25(OH)2D3 and followed for another 7 months. No suppressive effect of administering 24,25(OH)2D3 on the iPTH levels could be demonstrated in these three dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Bone and Bones; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Creatinine; Dihydroxycholecalciferols; Dogs; Female; Intestinal Absorption; Kidney Function Tests; Magnesium; Osteoclasts; Parathyroid Hormone; Uremia

The role of 24,25(OH)2D3 on parathyroid gland function remains controversial. The present studies were performed in vitro using (a) dispersed normal bovine parathyroid cells (bPTC) and (b) dispersed canine PTC (cPTC) prepared from glands of normal dogs, dogs with chronic renal failure (CRF), and dogs with CRF treated with 24,25(OH)2D3, 2.5 micrograms orally every day for more than 6 months. Bovine parathyroid cells were incubated for up to 180 min at 0.5, 1.0, and 3.0 mM external calcium in the presence or absence of 24,25(OH)2D3 (100 or 1000 nM). Similar experiments were conducted with cells incubated for 24 h in the presence of either the ethanol vehicle or 24,25(OH)2D3 (1000 nM). Parathyroid hormone secretion, measured in the supernatant by both C-terminal and N-terminal assays, did not show any differences between control and experimental groups at any time interval. Canine parathyroid cells obtained from uremic animals showed an average threefold increase in the total amount of PTH secreted, on a per cell basis over 180 min at 0.5 mM Ca2+, when compared with normal controls. However, there was no significant difference in PTH secretion at any level of calcium concentration between the cells obtained from parathyroid glands of CRF dogs and 24,25(OH)2D3-treated CRF dogs. Acute exposure to 24,25(OH)2D3 (1000 nM) in vitro of the cells obtained from the glands of CRF dogs also had no effect on PTH secretion. We conclude that 24,25(OH)2D3 has no direct effect on PTH secretion from dispersed parathyroid cells of either normal or uremic animals.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Cattle; Cells, Cultured; Dihydroxycholecalciferols; Dogs; Hyperplasia; Parathyroid Glands; Parathyroid Hormone; Uremia

The release of cyclic AMP from bone in response to stimulation with PTH 1-34 was examined in 20 dogs with long-term chronic renal failure (CRF) produced by unilateral nephrectomy and contralateral partial renal artery ligation. After 9 to 15 months of uremia, the tibiae were removed and perfused in vitro. Seven dogs with CRF served as controls, 7 dogs with CRF were treated with 24,25(OH)2D3 - 2.5 micrograms per day, and 6 CRF dogs underwent thyroparathyroidectomy (TPTX) 42 h before they were sacrificed. The release of cyclic AMP from bone in response to PTH 1-34 in the CRF dogs was severely reduced compared to the response observed in 7 dogs with normal renal function (net accumulation of cyclic AMP release 86 +/- 8.5 versus 426 +/- 59.0 pmol/30 min). Long-term treatment of uremic dogs with 24,25(OH)2D3 had no effect on the release of cyclic AMP by bone. However, the release of cyclic AMP was restored to normal levels in the CRF dogs that underwent thyroparathyroidectomy. All CRF dogs had secondary hyperparathyroidism and the fact that TPTX returned the cyclic AMP response to normal values suggests that desensitization to PTH of the adenylate cyclase system of bone exists in chronic uremia.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Bone and Bones; Calcitriol; Chronic Disease; Cyclic AMP; Dihydroxycholecalciferols; Dogs; Female; Humans; Kidney Failure, Chronic; Parathyroid Hormone; Peptide Fragments; Rats; Teriparatide; Uremia

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Bone and Bones; Bone Resorption; Calcifediol; Calcitriol; Chronic Kidney Disease-Mineral and Bone Disorder; Dihydroxycholecalciferols; Female; Humans; Hydroxycholecalciferols; Male; Middle Aged; Nephrectomy; Renal Dialysis; Uremia